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ReferencesChapter 19, Part 3 August 30, 2023Biff Palmer’s Ted Talk-Why not? Biff Palmer at TEDxSMU 2013Anna mentioned this issue of lactic acidosis in a panic disorder: The Lactic Acid Response to Alkalosis in Panic Disorder | The Journal of Neuropsychiatry and Clinical NeurosciencesReminder of important clinical lesson: Lactate: panicking doctor or panicking patient? - PMCMelanie regaled the group with an excerpt (page 351) Cohen, J. J., Kassirer, J. P. (1982). Acid-base. United States: Little, Brown.Biff Palmer! Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023Melanie loves this study of chronic respiratory alkalosis on participants to traveled to the High ALpine research station on the Jungfraujoch in the Swiss Alps Chronic Respiratory Alkalosis — The Effect of Sustained Hyperventilation on Renal Regulation of Acid–Base Equilibrium | NEJM (and here’s a great picture: Services: Jungfraujoch Research Station - Climate and Environmental Physics (CEP)JC mentioned that there are cells in the carotid body which are called glomus cells Neurobiology of the carotid body.JC discussed respiratory alkalosis in cirrhosis and here’s a review he had melanie write that addresses this topic: Acid Base Disorders in Cirrhosis - Advances in Kidney Disease and Health and here are some reviews he likes: The hyperventilation of cirrhosis: progesterone and estradiol effects and Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunction and Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction ProteinsThe finding of respiratory alkalosis in pregnancy is not a new concept. Here’s a study from 1962: Acid-base balance of arterial blood during pregnancy, at delivery, and in the puerperium - American Journal of Obstetrics & GynecologyMelanie reminded us of the Charlie Brown sad face that occurs after bicarbonate infusion and delay in bicarbonate movement to the CSF! Spinal-Fluid pH and Neurologic Symptoms in Systemic Acidosis | NEJM (part 2 of chapter 11)Josh mentioned this report from Andrew Tarulli (a great neurologist previously at BIDMC who has moved to Overlook Hospital in NJ) Central Neurogenic Hyperventilation: A Case Report and Discussion of Pathophysiology | Allergy and Clinical Immunology | JAMA NeurologyHe also mentioned this important transporters that affect the pH. The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates mouse cerebrospinal fluid pHRefractory Central Neurogenic Hyperventilation: A Novel Approach Utilizing Mechanical Dead SpaceOutline: Chapter 21Respiratory AlkalosisIncreased pH, low pCO2, variable reduction in HCO3Differentiate from metabolic acidosis where pH is decreased(but pCO2 and HCO3 are likewise decreased)PATHOPHYSIOLOGYPrimary decrease in pCO2 when effective alveolar ventilation is increased beyond that needed to eliminate daily CO2 productionHow does the body respond to hypocapniaMass actionReduction in H+ induced by hypocapnia can be minimized by lowering HCO3One: rapid cell bufferingTwo: later decrease in net renal acid secretion → lower HCO3These two strategies explain the difference between acute and chronic respiratory alkalosisAcute Respiratory AlkalosisWithin 10 minutes, H ions move into extracellular fluidH+ combines with HCO3 → fall in plasma HCO3Converted to CO2 and H2OH+ comes from intracellular buffersProtein, phosphate, hemoglobinH+ may also come from alkalemia-induced increase in cellular lactic acid production (1)⁉️Enough H+ enters ECF to lower HCO3 by 2 mEq for each 10 mmHg decrease in pCO2 (Fig 20-3)Example: pCO2 falls to 20HCO3 falls by 4 → ~20 mEq/LpH ~7.63Not very efficient at protecting pHWithout compensation pH would be ~7.70Chronic Respiratory AlkalosisCompensatory ↓ renal H secretionBegins within 2 hoursNot complete for 2–3 daysDue to parallel rise in tubular cell pHManifested byHCO3 lossDecreased NH4 in urine4 mEq drop in HCO3 for each 10 mmHg decrease in pCO2Example: pCO2 20 → HCO3 16 → pH ~7.53ETIOLOGYRespiration governed by two sets of chemoreceptorsCentral (respiratory center in brainstem)Peripheral (carotid bodies at bifurcation, aortic bodies at arch)Central chemoreceptorsStimulated by ↑ pCO2 or metabolic acidosisPeripheral chemoreceptorsStimulated by hypoxia (and acidosis)Thus hyperventilation can be produced byHypoxemiaAnemiaReduction in arterial pHOther stimuliPainAnxietyMechanoreceptorsDirect stimulation of respiratory centerTable 21-1HypoxemiaRespiratory response occurs in stagesStage 1Peripheral chemoreceptor activationHyperventilation → respiratory alkalosisIncreased cerebral pH inhibits central respiratory centerLimits hyperventilationNo significant hyperventilation until pO2 < 50–60 mmHgIf lung disease prevents pCO2 reductionHypoxia stimulates ventilation at PaO2 < 70–80 mmHgStage 2⁉️Persistent hypoxemia → ↓ HCO3Lowers pH toward normalRemoves alkalosis inhibitionAllows greater ventilatory responsePulmonary DiseaseCommon in pneumonia, PE, interstitial fibrosisAlso pulmonary edema (though acidosis more common)Hyperventilation may be due to hypoxemiaOften not corrected by oxygenOther contributorsMechanoreceptors in airways, lungs, chest wallSignals via vagus nerveJuxtacapillary receptors (interstitium)Irritant receptors (epithelium)Activated by inflammation or inhaled irritants(asthma, pneumonia)These contribute to dyspnea even without hypoxiaDirect Stimulation of Medullary Respiratory CenterCortical input (psychogenic hyperventilation)Retained amines in hepatic failure (not prostaglandins⁉️)Bacterial toxins (gram-negative sepsis)SalicylatesProgesterone (pregnancy, luteal phase)Persistent acid CSF after rapid correction of metabolic acidosisNaHCO3 raises extracellular pHPeripheral chemoreceptors reduce ventilation → ↑ pCO2CO2 crosses BBB rapidly, HCO3 does notBrain senses ↑ pCO2 → ↓ CSF pHParadoxical prolongation of hyperventilationNeurologic disordersPontine tumors → local acidosis → ↓ CSF pH → ↑ ventilationHypocapnia in acute cerebral accidentsMechanical VentilationOverventilation can cause respiratory alkalosisCorrect byIncreasing dead space (no explanation given 🤷🏻‍♂️)Decreasing tidal volumeDecreasing respiratory rateSYMPTOMSDue to increased CNS and peripheral nerve excitabilityLightheadednessAltered consciousnessParesthesias (extremities, circumoral)CrampsCarpopedal spasmSyncopeCardiacSupraventricular and ventricular arrhythmiasMechanismsImpaired cerebral functionIncreased membrane excitability↓ cerebral blood flow35–40% reduction if pCO2 drops by 20 mmHgPsychogenic hyperventilation symptomsDyspneaHeadacheChest painSymptoms more prominent in acute disease (rapid pH change)Electrolytes↓ phosphate (as low as 0.5–1.5 mg/dL)Due to intracellular shiftIncreased glycolysis → ↑ phosphorylated compoundsDIAGNOSISTachypneaBut could be acidosis or alkalosisConsider sepsisCompensation equations can be ambiguousExample: 7.48 / 20 / XX / 16Could be chronic respiratory alkalosisOr acute respiratory alkalosis + metabolic acidosis 😖Case 21-15-year-old with AMS, playing with aspirinTREATMENTUsually not necessaryDo NOT giveRespiratory depressantsHClPaper bag rebreathing↑ inspired CO2Can correct acute respiratory alkalosisIf chronic → may leave patient with metabolic acidosisCan treat with NaHCO3“Give a mouse a cookie” 😉

ReferencesChapter 19, Part 3 August 30, 2023Joel and Roger mentioned the most common cause seems to be Sjögren’s syndrome for an acquired distal RTA. We mentioned this in an earlier episode and referenced this example of an absence of the H+ ATPase, presumably from autoantibodies to this transporter. Here’s a case report: Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosis Joel mentioned this paper in the New England Journal of Medicine in which there were patients who had hyperkalemia with a distal RTA: Hyperkalemic Distal Renal Tubular Acidosis Associated with Obstructive Uropathy | NEJM in this setting, some patients  Anna mentioned this article on “ampho-terrible:” It’s the holes!!!    Yano T, Itoh Y, Kawamura E, Maeda A, Egashira N, Nishida M, Kurose H, Oishi R. Amphotericin B-induced renal tubular cell injury is mediated by Na+ Influx through ion-permeable pores and subsequent activation of mitogen-activated protein kinases and elevation of intracellular Ca2+ concentration. Antimicrob Agents Chemother. 2009 Apr;53(4):1420-6Josh mentioned this study on furosemide’s effect on the TAL: Furosemide-induced urinary acidification is caused by pronounced H+ secretion in the thick ascending limb Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride - Kidney InternationalMelanie mentioned treatment of patients with cystinosis Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients | Clinical Kidney Journal | Oxford AcademicAmy shared her observations regarding base supplements including Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis - PubMed and Dosage of potassium citrate in the correction of urinary abnormalities in pediatric distal renal tubular acidosis patients - PubMedRoger mentioned that he has had good luck with Moonstone Nutrition drinks alkali citrates for kidney healthWe referred to David Goldfarb’s teaching on kidney stones in patients with acidification defects:  A Woman with Recurrent Calcium Phosphate Kidney Stones (we also referenced this in an earlier episode but this one is a fan favorite). Joel mentioned the concern of bone loss in distal RTA: Incomplete renal tubular acidosis in 'primary' osteoporosis and Abnormal distal renal tubular acidification in patients with low bone mass: prevalence and impact of alkali treatmentJC mentioned Ehlers-Danlos syndrome with renal tubular acidosis and medullary sponge kidneys. A report of a case and studies of renal acidification in other patients with the Ehlers-Danlos syndromeLety mentioned concerns of encrustation of stents in stone forming individuals Potassium Citrate as a Preventive Treatment for Double-J Stent Encrustation: A Randomized Clinical TrialJoel schooled us in toluene and the presentation which appears to be an RTA- https://journals.lww.com/JASN/Abstract/1991/02000/Glue_sniffing_and_distal_renal_tubular_acidosis_.3.aspxMelanie mentioned this work by Alan Yu’s lab on a mechanism of hypercalciuria Claudin-2 deficiency associates with hypercalciuria in mice and human kidney stone disease Furosemide/Fludrocortisone Test and Clinical Parameters to Diagnose Incomplete Distal Renal Tubular Acidosis in Kidney Stone Formers and an accompanying editorial by Goldfarb Refining Diagnostic Approaches in Nephrolithiasis: Incomplete Distal Renal Tubular AcidosisHere’s a nice piece on ifosfamide and phosphate from Josh New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2Here’s this crazy piece on excessive bicarbonate - Gas production after reaction of sodium bicarbonate and hydrochloric acidJosh points out that the pH can be important for inotropy:  An effect of pH upon epinephrine inotropic receptors in the turtle heartMel’s favorite from Halperin because of the pun: Renal tubular acidosis (RTA): recognize the ammonium defect and pHorget the urine pHAmy’s VOG on RTA and OsteoporosisKI Review on acidosis and bone health: Effects of acid on boneGuideline on congenital RTA: Distal renal tubular acidosis: ERKNet/ESPN clinical practice pointsAJKD article on acidosis and bone health: Serum Bicarbonate and Bone Mineral Density in US AdultsCitrate reversing CsA induced acidosis effects: Citrate reverses cyclosporin A-induced metabolic acidosis and bone resorption in ratsOutline: Chapter 19 Metabolic Acidosis part 3Renal Tubular AcidosisAcidosis from diminished net tubular acid secretionThree typesType 1 (Distal)Type 2 (Proximal)Type 4 (…)The acidosis of renal failure could be added to this groupBut NH4+ per nephron is normalThis is a problem of too few nephrons, not tubular acidosisNephrons able to maximally acidify the urineType 1 Distal RTADecrease in net H secretion in the collecting ductMinimal urine pH rises from 4.5 to 5.3HCO3 can fall below 10Three mechanismsDefect in H-ATPase found in cortex and medullaSjögren syndromeCan be genetic chloride bicarbonate exchangerThis pumps bicarbonate out basolateral membrane after it is generated in the splitting of water to form HDefect in cortical Na reabsorptionVoltage-dependent defectConcurrent K secretion defectFound in urinary obstruction and sickle cellVolume deficiency can decrease Na delivery to distal nephronDecreased amount of Na reabsorption can cause a reversible type 1 RTA of this typeIncreased membrane permeabilityAmphotericinpH of 5.0 is 250× plasmaTable 19-7Fractional excretion of bicarbonate in distal RTANormally negligible since bicarbonate can’t exist with pH down around 5In distal RTA it may be as high as 6.5; FEHCO3 is 3%If pH goes up over 7 this can rise to 5–10%Usually in infantsAs they age their urine pH falls a bitThis is called type 3Plasma KH-ATPase defects have low KPatients also have downregulation of H-K-ATPaseDownregulation of NaCl reabsorption in proximal tubuleDecreased filtered bicarbonate means less bicarbonate to absorb with Na, hence more Na excretion from proximal tubuleThis increases distal sodium delivery and increases aldosteroneVoltage defect also has decreased renal K clearance → hyperkalemiaDifferentiate from type 4 RTA by looking at urine pHLower in type 4Higher in voltage-dependent distal RTANephrocalcinosisHypercalciuria, hyperphosphatemia, nephrolithiasis, and nephrocalcinosis are frequentComes from bones buffering the acidosisKidney decreases reabsorption of these so they are lost in urineTwo other factorsLow urinary citrateHypokalemia drives thisAcidosis drives thisHigh urine pH (CaPhos stones)All corrected by correcting the metabolic acidosisIncomplete Type 1Defective urinary acidification but not acidemicIncreased proximal NH3 production lowers urinary HLow urinary citrateCan progress to complete type 1Etiology of Type 1Sjögren syndrome, rheumatoid arthritis19-8Clinical manifestationsStonesHypokalemiaGrowth defectsDiagnosisNAGMA and elevated urine pH5.3 in adults5.6 in childrenDifferentiate Type 1 vs Type 2Give bicarbonate drip1 mEq/kg/hrUrine pH remains high with Type 1Does not go up as it does with proximal Type 2Incomplete distal RTAGive acid load0.1 mmol/kgUrine pH remains >5.3 in classicFalls in normal patients (usually below 5)TreatmentTreat metabolic acidosisMinimize potassium lossReduce bone catabolismPrevent stonesAlkali requirementAdults: 1–2 mEq/kg/dayChildren: 4–14 mEq/kg/dayAlkaliSodium bicarbonateSodium citratePotassium citrate if hypokalemia persists despite correcting acidosisOr for calcium stone diseaseTreat hypokalemiaType 2 Proximal RTADecreased HCO3 reabsorption90% of bicarbonate reabsorption happens in proximal tubuleBicarbonate wasting starts normally at 26–28 mmol/L (Tm for bicarbonate)In RTA 2 the Tm falls to a lower level (maybe 17)Serum bicarbonate falls to 17 and stabilizesType 2 RTA is self-limitingTypically HCO3 around 14–20 Distal acidification intactCarbonic anhydrase inhibitor can block 80% of proximal HCO3 reabsorptionOnly 30% of filtered bicarbonate excreted due to distal H secretionTotal absence of proximal reabsorption results in HCO3 11–12Clinical difference in treatmentIn Type 2, giving bicarbonate and raising serum HCO3 above Tm → more wasted in urineFEHCO3 can reach 15% with normal serum HCO3Urine pH >7.5Below Tm, urine pH <5.3In Type 1, curve relating HCO3 excretion to plasma HCO3 similar to normal (with increased obligatory urine HCO3 due to higher urine pH)Defect in HCO3 reabsorptionCan be isolatedOr part of Fanconi syndromePathogenesis (three steps)Na-H exchange (apical membrane)Na-K-ATPase (basolateral membrane)Carbonic anhydraseIntracellularLuminalMultiple myeloma most common adult causeIfosfamideCan also cause phosphate wasting, NDI, and Type 1 RTAK balanceCommon but variableMild hypokalemia at baseline due to increased Na wasting → hyperaldosteronismWorse with bicarbonate therapyDistal delivery of nonreabsorbable anion increases obligate cation lossFigure 19-7Bone diseaseRickets (children), osteomalacia/osteopenia (adults)Up to 20%Phosphate wasting and vitamin D deficiency may contributeImpaired growthNo nephrocalcinosis or nephrolithiasisLower urine pHNonreabsorbable amino acids and organic anions bind calciumEtiology19-9Idiopathic and cystinosis (children)Carbonic anhydrase inhibitorsMultiple myelomaDiagnosisNAGMA and pH <5.3Look for Fanconi syndromeRaise serum HCO3 and watch urine pH riseFEHCO3 15–20%TreatmentCorrect acidosis to allow normal growthDifficult due to rapid urinary lossMay need 10–15 mEq/kg/dayHCO3 or citrateMore than 20 mEq HCO3 can cause stomach rupture from CO2 generationSmall dose thiazide to increase proximal Na reabsorption and HCO3 reabsorptionIdiopathic Type 2 may improve after yearsType 4 RTAAldosterone deficient or resistantNormally stimulates H secretion and K secretionLoss causes hyperkalemia and metabolic acidosisHyperkalemia antagonizes NH4 generationHigh K may outcompete NH4 on Na-K-2Cl in TALHLess ammonium recyclingLess NH3 available in collecting ductCorrecting hyperkalemia can correct acidosisMetabolic acidosis generally mildHCO3 >15Urine pH <5.3 (generally, not always)Mineralocorticoid can treat but causes hypertension and sodium retentionOften responds to loop diureticRhabdomyolysis can cause high anion gap metabolic acidosisSymptomsRespiratory compensation increases 4–8 fold → dyspneapH <7.0–7.1Fatal ventricular arrhythmiasReduced cardiac contractilityDecreased response to inotropesNeurologicalLethargy to comaMore related to CSF pH than plasmaLess neurologic symptoms than respiratory acidosisBBB more permeable to CO2 than HCO3Skeletal problemsDecreased growthKids/infants: anorexia, nausea, listlessnessTreatmentGeneral principlesCorrect with HCO3No alkali required for lactic or ketoacidosisGoal: pH >7.2Equations on page 629 need “log”Example: pH 7.1, pCO2 20, HCO3 6Raise HCO3 to 8 if pCO2 stays 20Raise to 10 if pCO2 risesParagraph “regardless…” highlights risks of bicarbonateBicarbonate deficitDeficit = HCO3 space × HCO3 deficit per literHCO3 space50% body weight (normal)60% (mild–moderate acidosis)70% (severe, HCO3 <8–10)Example: 70 kg, raise HCO3 6→10 using 0.7 space = 196 mEqRough guideline; does not account for ongoing acid productionEarly large bump in bicarbonateDrifts down as bicarbonate moves intracellularlyPlasma potassiumK depletion can cause metabolic acidosisMetabolic acidosis increases K“Normal” K may mask depletion (see DKA)Beware correcting acidosis in hypokalemiaHeart failureBicarbonate comes with sodium loadComment that bicarbonate moves into cellBut Na remains extracellularDialysis can be used

ReferencesChapter 19, Part 12Metabolic acidosis  June 14, 2023ReferencesChapter 19, Part 2Roger mentioned MELAS syndrome MELAS syndrome: Clinical manifestations, pathogenesis, and treatment optionsJosh mentioned this blog on lactate- Understanding lactate in sepsis & Using it to our advantageWe discussed the Warburg effect The Warburg Effect: How Does it Benefit Cancer Cells? - PMC and here’s a case from skeleton key- Skeleton Key Group Case #28: Mysterious Acidosis in Cancer - Renal Fellow NetworkOtto Warburg won the Nobel Prize in Physiology and Medicine in 1931 for describing how animal tumors produce large quantities of lactic acid (Wikipedia)Joel calls it the Lactate saline reflex, but the accepted term of art is Lacto-Bolo reflex The origins of the Lacto-Bolo reflex: the mythology of lactate in sepsisBuffer agents do not reverse intramyocardial acidosis during cardiac resuscitation.Josh mentioned this article the BICAR-ICU Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial - The LancetRoger shared 3 quotes to make the point that there has been little movement in our knowledge the past 40 years:Bicarbonate does not improve hemodynamics in critically ill patients who have lactic acidosis. A prospective, controlled clinical study from Cooper in the AnnalsLactic Acidosis and Bicarbonate Therapy | Annals of Internal Medicine from Robert HollanderLactic acidosis from Nick MadiasJosh mentioned the use of sodium bicarbonate for CKD Eubicarbonatemic Hydrogen Ion Retention and CKD Progression - Kidney Medicine  (Madias) Bicarbonate therapy for prevention of chronic kidney disease progression (from Wesson),  Sodium Bicarbonate Prescription and Extracellular Volume Increase: Real‐world Data Results from the AlcalUN StudyAmy’s VoG on metabolic acidosis/KDIGO guidelinesVery nice JASN review that describes the mechanisms of how metabolic acidosis leads to CKD progressionFirst description by THE Dr. Bright1930 Lancet description of benefit2009 RCT that the 2012 KDIGO guidelines sort of based their 2b recommendations off of2020 BiCARB Study2021 META AnalysisWe discussed methanol toxicity : Case Study: Methanol Poisoning from Adulterated Liquor | Food Safety, Acute methyl alcohol poisoning: a review based on experiences in an outbreak of 323 cases and josh poking at the osmolar gap: PulmCrit- Toxicology dogmalysis: the osmolal gap and shared these guidelines: METHANOL | extrip-workgroup and Roger loves this: Urine fluorescence using a Wood's lamp to detect the antifreeze additive sodium fluorescein: a qualitative adjunctive test in suspected ethylene glycol ingestionsFrom China to Panama, a Trail of Poisoned Medicine - The New York Times (diethylene glycol) . The Accidental Poison That Founded the Modern FDA - The AtlanticOutline: Chapter 19 Metabolic AcidosisEtiologies and DiagnosisLactic AcidosisPyruvate → lactate (LDH; NADH → NAD+)Normal production: 15–20 mmol/kg/dayMetabolized in liver/kidney → pyruvate → glucose or TCANormal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/LCauses:↑ production: hypoxia, redox imbalance, seizures, exercise↓ utilization: shock, hepatic hypoperfusionMalignancy, alcoholism, antiretroviralsD-lactic acidosisShort bowel/jejunal bypassGlucose → D-lactate (not metabolized by LDH)Symptoms: confusion, ataxia, slurred speechSpecial assay neededTx: bicarb, oral antibioticsTreatmentUnderlying causeBicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactateTarget pH > 7.1; prefer mixed venous pH/pCO2Ketoacidosis (Chapter 25 elaborates)FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)Requires:↑ lipolysis (↓ insulin)Hepatic preference for ketogenesisCauses:DKA (glucose > 400)Fasting ketosis (mild)Alcoholic ketoacidosisPoor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysisMixed acid-base (vomiting, hepatic failure, NAGMA)Congenital organic acidemias, salicylatesDiagnosis:AG, osmolar gap (acetone, glycerol)Ketones: nitroprusside only detects acetone/acetoacetateBHB can be 90% of total (false negative)Captopril → false positiveTreatment:Insulin +/- glucoseRenal Failure↓ excretion of daily acid loadGFR < 40–50 → ↓ ammonium/TA excretionBone buffering stabilizes HCO3 at 12–20 mEq/LSecondary hyperparathyroidism helps with phosphate bufferingAlkali therapy controversial in adultsIngestionsSalicylatesSymptoms at >40–50 mg/dLEarly: respiratory alkalosis → Later: metabolic acidosisTreatment: bicarb, dialysis (>80 mg/dL or coma)MethanolMetabolized to formic acid → retinal toxicityOsmolar gap elevatedTx: bicarb, ethanol/fomepizole, dialysisEthylene glycol→ glycolic/oxalic acid → renal failureSame treatment + thiamine/pyridoxineOtherToluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)GI Bicarbonate LossDiarrhea, bile/pancreatic drainage → loss of alkaline fluidsUreterosigmoidostomy → Cl-/HCO3- exchange in colonCholestyramine → Cl- for HCO3-

ReferencesPart 2, March 1, 2023The alkaline tide phenomenon in studies that measured both the alkaline tide and acid secretion, the bicarbonate accumulation increased in linear fashion with the acid secretion. Melanie thought this was first recognized in the 60’s but later found this manuscript from 1939 in JCI! ALKALINE TIDES - PMCMelanie mentioned this old study that explores the respiratory response of metabolic acidosis and finds it “incomplete” compared to expected. EVALUATION OF RESPIRATORY COMPENSATION IN METABOLIC ALKALOSIS and there’s another image in a review by Michael Emmett Figure 1. Metabolic Alkalosis: A Brief Pathophysiologic Review - PMC(here’s the image from JCI) The effect of changes in blood pH on the plasma total ammonia level - SurgeryThis is an interesting case that Melanie mentioned with the help of Stew Lecker Trust the Patient: An Unusual Case of Metabolic Alkalosis - PMCGot Calcium? Welcome to the Calcium-Alkali Syndrome : Journal of the American Society of Nephrology a favorite review of the “calcium alkali” syndrome- previously called milk alkali syndrome but now milk is not commonly part of the syndrome (as with Dr. Sippie). Lety mentioned this issue with a new contaminant of street drugs: Tranq Dope: Animal Sedative Mixed With Fentanyl Brings Fresh Horror to U.S. Drug ZonesHere are two references that illustrate how the urine pH changes over the course of the day. Circadian variation in urine pH and uric acid nephrolithiasis risk The diurnal variation in urine acidification differs between normal individuals and uric acid stone formers - PMCNotes for Melanie’s VOG on reference 47: Maladaptive renal response to secondary hypercapnia in chronic metabolic alkalosisFrom Biff Palmer Figure 4- Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023 - American Journal of Kidney DiseasesAnna’s VOG-  GI composition of cats or somethingOutline: Chapter 18Metabolic AlkalosisElevation of arterial pH, increased plasma HCO3, and compensatory hypoventilationHigh HCO3 may be compensatory for respiratory acidosisHCO3 > 40 indicates metabolic alkalosisPathophysiology: Two Key QuestionsHow do patients become alkalotic?Why do they remain alkalotic?Generation of Metabolic AlkalosisLoss of H+ ionsGI loss: vomiting, GI suction, antacidsRenal loss: diuretics, mineralocorticoid excess, hypercalcemia, post-hypercapniaAdministration of bicarbonateTranscellular shiftK+ loss → H+ shifts intracellularlyIntracellular acidosisRefeeding syndromeContraction alkalosisSame HCO3, smaller extracellular volume → increased [HCO3]Seen in CF (sweating), illustrated in Fig 18-1Common theme: hypochloremia is essential for maintenanceMaintenance of Metabolic AlkalosisKidneys normally excrete excess HCO3Example: Normal subjects excrete 1000 mEq NaHCO3/day with minor pH changeImpaired HCO3 excretion required for maintenanceTable 18-2Mechanisms of MaintenanceDecreased GFR (less important)Increased tubular reabsorptionProximal tubule (PT): reabsorbs 90% of filtered HCO3TALH and distal nephron manage the restContributing factors:Effective circulating volume depletionEnhances HCO3 reabsorptionAng II increases Na-H exchangeIncreased tubular [HCO3] enables more H+ secretionDistal nephron HCO3 reabsorptionStimulated by aldosterone (↑ H-ATPase, ↑ Na reabsorption)Negative luminal charge impedes H+ back-diffusionChloride depletionReduces NaK2Cl activity → ↑ renin → ↑ aldosteroneLuminal H-ATPase co-secretes Cl → low Cl increases H+ secretionCl-HCO3 exchanger needs Cl gradient → low Cl impairs HCO3 secretionKey conclusion: Cl depletion > volume depletion in perpetuating alkalosisAlbumin corrects volume but not alkalosisNon-N Cl salts correct alkalosis without fixing volumeHypokalemiaStimulates H+ secretion and HCO3 reabsorptionTranscellular shift (H/K exchange) → intracellular acidosisH-K ATPase reabsorbs K and secretes HSevere hypokalemia reduces Cl reabsorption → ↑ H+ secretionImportant with mineralocorticoid excessRespiratory CompensationHypoventilation: 0.7 mmHg PCO2 ↑ per 1 mEq/L HCO3 ↑PCO2 can exceed 60Rise in PCO2 increases acid excretion (limited effect on pH)EpidemiologyGI Hydrogen LossGastric juice: high HCl, low KClStomach H+ generation → blood HCO3Normally recombine in duodenumVomiting/antacids prevent recombination → alkalosisAntacids (e.g., MgOH)Mg binds fats, leaves HCO3 unbound → alkalosisRenal failure impairs excretionCation exchange resins (SPS, MgCO3) → same effectCongenital chloridorrheaHigh fecal Cl-, low pH → metabolic alkalosisPPI may help by reducing gastric Cl loadRenal Hydrogen LossMineralocorticoid excess & hypokalemiaAldosterone → H+ ATPase stimulation, Na+ reabsorption → negative lumen → ↑ H+ secretionDiuretics (loop/thiazide)Volume contractionSecondary hyperaldosteronismIncreased distal flow and H+ lossPosthypercapnic alkalosisChronic respiratory acidosis → ↑ HCO3Rapid correction (ventilation) → unopposed HCO3 → alkalosisGradual CO2 correction neededMaintenance: hypoxemia, Cl lossLow chloride intake (infants)Na+ reabsorption must exchange with H+/K+H+ co-secretion with Cl impaired if Cl is lowHigh dose carbenicillinHigh Na+ load without ClNonresorbable anion → hypokalemia, alkalosisHypercalcemia↑ Renal H+ secretion & HCO3 reabsorptionCan contribute to milk-alkali syndromeRarely causes acidosis via reduced proximal HCO3 reabsorptionIntracellular H+ ShiftHypokalemiaCommon cause and effect of metabolic alkalosisH+/K+ exchange → intracellular acidosis → ↑ H+ excretionRefeeding SyndromeRapid carb reintroduction → cellular shiftNo volume contraction or acid excretion increaseRetention of BicarbonateRequires impaired excretion to become significantOrganic anions (lactate, acetate, citrate, ketoacids)Metabolism → CO2 + H2O + HCO3Citrate in blood transfusion (16.8 mEq/500 mL)8 units → alkalosis riskCRRT + citrate anticoagulantSodium bicarbonate therapyRebound alkalosis possible with acid reversal (e.g., ketoacidosis)Extreme cases: pH up to 7.9, HCO3 up to 70Contraction AlkalosisNaCl and water loss without HCO3Seen in vomiting, diuretics, CF sweatMild losses neutralized by intracellular buffersSymptomsOften asymptomaticFrom volume depletion: dizziness, weakness, crampsFrom hypokalemia: polyuria, polydipsia, weaknessFrom alkalosis (rare): paresthesias, carpopedal spasm, lightheadednessMore common in respiratory alkalosis due to rapid pH shift across BBBPhysical exam not usually helpfulClues: signs of vomitingDiagnosisHistory is keyIf unclear, suspect:Surreptitious vomitingCFSecret diuretic useMineralocorticoid excessUse urine chlorideTable 18-3: urine Na is misleading in alkalosisTable 18-4: urine chemistry changes with complete HCO3 reabsorptionVomiting: low urine Na, K, Cl + acidic urineSufficient NaCl intake prevents this stageExceptions to low urine Cl:Severe hypokalemiaTubular defectsCKDDistinguishing from respiratory acidosisUse pH as guideCaution with typo (duplicate pCO2)A-a gradient might helpTreatmentCorrect K+ and Cl− deficiency → kidneys self-correctUpper GI losses: add H2 blockersSaline-responsive alkalosisTreat with NaClMechanisms:Reverse contraction componentReduce Na+ retention → promote NaHCO3 excretion↑ distal Cl delivery → enable HCO3 secretion via pendrinMonitor urine pH: from 5.5 → 7–8 with therapyGive K+ with Cl, not phosphate, acetate, or bicarbonateSaline-resistant alkalosisSeen in edematous states or K+ depletionEdema (CHF, cirrhosis): use acetazolamide, HCl, dialysisAcetazolamide: may ↑ CO2 via RBC carbonic anhydrase inhibitionMineralocorticoid excess: K+ + K-sparing diuretic (use caution)Severe hypokalemia:eNaC Na+ reabsorption must be countered by H+ if no K+Corrects rapidly with K+ replacementRestores saline responsivenessRenal failure: requires dialysis

ReferencesChapter 19, Part 1 Metabolic acidosis  June 14, 2023American Society of Nephrology | Medical Students - Kidney TREKS this is the program that Josh mentioned at Mount Desert Island! Effects of pH on Potassium: New Explanations for Old Observations - PMC here’s the review melanie from Peter Aronson that clarifies the fact that there are no H+-K+ antiporters outside the kidney but rather coupled transport-We discussed whether we like “Winter’s formula” Quantitative Displacement of Acid-Base Equilibrium in Metabolic Acidosis | Annals of Internal Medicine Dr. R. W. Winters was charged with larceny https://www.nytimes.com/1982/05/16/nyregion/ex-columbia-u-doctor-charged-with-larceny.htmlJCI - The Maladaptive Renal Response to Secondary Hypocapnia during Chronic HCl Acidosis in the Dog this was a classic experiment exploring the respiratory response to an infusion of HCl but the animals were maintained in a high pCO2 milieu (not generalizable to humans!)Here’s the thoughtful Pulmcrit post (by Josh Farkas)  that Josh mentioned regarding correction of anion gap for hypoalbuminemia: Mythbusting: Correcting the anion gap for albumin is not helpfulJC mentioned that the anion gap does change in cirrhosis when the albumin is very low but using the correction factor may not change the clinical findings Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunctionDiagnostic Importance of an Increased Serum Anion Gap | NEJM Melanie mentioned the work of Patricia Gabow on the anion gap. In this review, she refers to work that she had done to try to identify all the organic anions in the anion gap but it falls short. Also, check out this critical look at the delta/delta: The Δ Anion Gap/Δ Bicarbonate Ratio in Lactic Acidosis: Time for a New Baseline?Roger mentioned near drowning in the Dead Sea and the unusual electrolytes in that instance. Near-Drowning in the Dead Sea: A Retrospective Observational Analysis of 69 PatientsWe discussed this classic NEJM article by Daniel Batlle The Use of the Urinary Anion Gap in the Diagnosis of Hyperchloremic Metabolic AcidosisAmy mentioned this review from  Uribarri  and Oh in JASN on the urine anion gap: The Urine Anion Gap: Common MisconceptionsJoel has a great blog post on the urine osmolar gap. urine osmolar gap – Precious Bodily Fluids Anna’s VoG on the bicarb deficit:  Kurtz, I Acid-Base Case Studies, 2nd Edition. Trafford Publishing 2004.  And the Fernandez paper that derived a better equationReference for Josh’s VoG: Key enzyme in charge of ketone reabsorption of renal tubular SMCT1 may be a new target in diabetic kidney diseaseSevere anion gap acidosis associated with intravenous sodium thiosulfate administrationUnexpectedly severe metabolic acidosis associated with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathySodium Thiosulfate Induced Severe Anion Gap Metabolic AcidosisSodium Thiosulfate and the Anion Gap in Patients Treated by HemodialysisOutline: Chapter 19 Metabolic AcidosisOverviewLow arterial pHReduced HCO3Compensatory hyperventilation (↓ pCO2)Bicarb < 10 strongly suggests metabolic acidosis (renal compensation for respiratory alkalosis does not go that low)PathophysiologyH+ + HCO3- <=> H2CO3 <=> CO2 + H2OAcidosis results from H+ addition or HCO3 lossResponse to Acid LoadExtracellular bufferingExample: Add 12 mmol H+/L → HCO3 falls from 24 → 12 → pH drops to 7.1 (40 to 80 nmol/L)Intracellular and bone buffering55–60% buffered intracellularly and in bone12 mEq/L acid load only reduces serum HCO3 by ~5 mEq/LH+ into cells → K+ out (hyperkalemia)Notably in diarrhea or renal failureLess effect with organic acidosis (e.g., DKA, lactic acidosis)Respiratory compensationStimulates chemoreceptors → ↑ tidal volume (more than RR)Decreases pCO2, increases pHBegins within 1–2 hours; peaks at 12–24 hoursWinters formula alternative: for every 1 mEq ↓ HCO3, pCO2 ↓ by 1.2Chronic: respiratory compensation is blunted by renal adaptationRenal hydrogen excretion50–100 mEq/day acid generated from diet90% filtered HCO3 reabsorbed in PTAcid secreted:10–40 mEq via titratable acid (TA)30–60 mEq via NH3/NH4 (can ↑ to 250 mEq in acidosis)TA: phosphate (DKA → ketones act as TA)Max excretion up to 500 mEq/day in severe acidosisGeneration of Metabolic AcidosisMechanismsInability to excrete H+ (slow)Addition of H+ or loss of HCO3 (rapid)Anion Gap (AG)Normal: 5–11 (falling due to rising Cl-)Mostly due to negatively charged proteins (albumin)Adjust for albumin: AG ↓ 2.5 per 1 g/dL albumin ↓Revised: AG = unmeasured anions - unmeasured cations↑ AG = addition of unmeasured anions (e.g., lactate, ketones)Hyperchloremic acidosis: ↓ HCO3 replaced by ↑ Cl (normal AG)Delta–Delta AnalysisAdjust AG for albuminNormal ΔAG:ΔHCO3 = 1.6:1 (early 1:1)<1 → high + normal AG acidosisOther causes of AG variationHigh AG without acidosis: hemoconcentration, alkalosisLow AG: hypoalbuminemia, ↑ unmeasured cations (lithium, IgG, lab artifact)Urine Anion Gap (UAG)Normal = ~0; should be very negative (< -20) in acidosisType 1 & 4 RTA → UAG positive or near zeroInvalid in ketoacidosis or volume depletion (Na retention → ↓ distal acidification)Urine Osmolal GapEstimate NH4+ via osmolar gapRequires urine Na, K, glucose, ureaEtiologies and DiagnosisLactic AcidosisPyruvate → lactate (LDH; NADH → NAD+)Normal production: 15–20 mmol/kg/dayMetabolized in liver/kidney → pyruvate → glucose or TCANormal lactate: 0.5–1.5 mmol/L; acidosis if > 4–5 mmol/LCauses:↑ production: hypoxia, redox imbalance, seizures, exercise↓ utilization: shock, hepatic hypoperfusionMalignancy, alcoholism, antiretroviralsD-lactic acidosisShort bowel/jejunal bypassGlucose → D-lactate (not metabolized by LDH)Symptoms: confusion, ataxia, slurred speechSpecial assay neededTx: bicarb, oral antibioticsTreatmentUnderlying causeBicarb controversial: may worsen intracellular acidosis, overshoot alkalosis, ↑ lactateTarget pH > 7.1; prefer mixed venous pH/pCO2Ketoacidosis (Chapter 25 elaborates)FFA → TG, CO2, H2O, ketones (acetoacetate, BHB)Requires:↑ lipolysis (↓ insulin)Hepatic preference for ketogenesisCauses:DKA (glucose > 400)Fasting ketosis (mild)Alcoholic ketoacidosisPoor intake + EtOH → ↓ gluconeogenesis, ↑ lipolysisMixed acid-base (vomiting, hepatic failure, NAGMA)Congenital organic acidemias, salicylatesDiagnosis:AG, osmolar gap (acetone, glycerol)Ketones: nitroprusside only detects acetone/acetoacetateBHB can be 90% of total (false negative)Captopril → false positiveTreatment:Insulin +/- glucoseRenal Failure↓ excretion of daily acid loadGFR < 40–50 → ↓ ammonium/TA excretionBone buffering stabilizes HCO3 at 12–20 mEq/LSecondary hyperparathyroidism helps with phosphate bufferingAlkali therapy controversial in adultsIngestionsSalicylatesSymptoms at >40–50 mg/dLEarly: respiratory alkalosis → Later: metabolic acidosisTreatment: bicarb, dialysis (>80 mg/dL or coma)MethanolMetabolized to formic acid → retinal toxicityOsmolar gap elevatedTx: bicarb, ethanol/fomepizole, dialysisEthylene glycol→ glycolic/oxalic acid → renal failureSame treatment + thiamine/pyridoxineOtherToluene, sulfur, chlorine gas, hyperalimentation (arginine, lysine)GI Bicarbonate LossDiarrhea, bile/pancreatic drainage → loss of alkaline fluidsUreterosigmoidostomy → Cl-/HCO3- exchange in colonCholestyramine → Cl- for HCO3-Renal Tubular Acidosis (RTA)Type 1 (Distal)↓ H+ secretion in collecting duct → urine pH > 5.3Etiologies: Sjögren, RA, amphotericinFeatures: nephrocalcinosis, stones, hypokalemiaDiagnosis: NAGMA, persistent ↑ urine pHTreatment: alkali (1–2 mEq/kg/d adults; 4–14 kids), K+ if neededType 2 (Proximal)↓ HCO3 reabsorptionBicarb threshold reduced → self-limitedCauses: multiple myeloma, Fanconi, ifosfamideFeatures: rickets/osteomalacia, no stones, pH variableDiagnosis: NAGMA, pH < 5.3, high FE HCO3 when HCO3 loadedTreatment: alkali (10–15 mEq/kg/d), thiazidesType 4Aldo deficiency/resistance → hyperkalemia + mild acidosisK+ inhibits NH4 generationTx: correct K+, consider loop diureticsSymptomsHyperventilation (dyspnea)pH < 7.0–7.1 → arrhythmias, ↓ contractilityNeurologic: lethargy → coma (CSF pH driven)Skeletal growth issues in childrenTreatment PrinciplesNo alkali needed for keto/lactic acidosis unless pH < 7.2Bicarbonate DeficitDeficit = HCO3 space * (desired - actual HCO3)HCO3 space: 50–70% of body weightWatch for:K+ shifts: beware hypokalemia when correcting acidosisNa+ load in CHFDialysis if necessary

We are a bit slappy at the beginning of the episode since we had just recorded our conversation with the Glaucomfleckens. ReferencesChapter 18 Metabolic alkalosis! Part 1 February 23, 2023It is chloride depletion alkalosis, not contraction alkalosis classic review by Galla and Luke, the metabolic alkalosis mavens who review the role of chloride.On the mechanism by which chloride corrects metabolic alkalosis in man and this is the study when they induced a metabolic alkalosis and studied the effect of treating with KCl vs NaPhos and found the former (with chloride) reversed the alkalosis but not the sodium containing protocol. Some elegant reports on the increased proximal reabsorption of bicarbonate above normal stimulated by Ang II. Tubular transport responses to angiotensin | American Journal of Physiology-Renal PhysiologyCrosstalk between the renal sympathetic nerve and intrarenal angiotensin II modulates proximal tubular sodium reabsorption - Pontes - 2015 - Experimental Physiology - Wiley Online LibraryTHE RENAL REGULATION OF ACID-BASE BALANCE IN MAN. III. THE REABSORPTION AND EXCRETION OF BICARBONATE 1949  this is the correct figure for 11.14 and shows what happens when filtered bicarb exceeds normal threshold in normal human (men) and appears in the urine. Masterful review Symposium on acid-base homeostasis. The generation and maintenance of metabolic alkalosis by Seldin and Rector And a modern review from Michael Emmet! Metabolic Alkalosis - PMC (so many favorite reviews on this exciting topic!) and this one from Soleimani Metabolic Alkalosis Pathogenesis, Diagnosis, and Treatment: Core Curriculum 2022 both of these elaborate on pendrin’s role. The effect of prolonged administration of large doses of sodium bicarbonate in man  (Clin Sci. 1954 Aug;13(3):383-401)Kidney v Renal: KDIGO versus Don’tPlus: We got a little off topic and discussed the Kidney Failure Risk Equation: https://kidneyfailurerisk.com/Outline: Chapter 18Metabolic AlkalosisElevation of arterial pH, increased plasma HCO3, and compensatory hypoventilationHigh HCO3 may be compensatory for respiratory acidosisHCO3 > 40 indicates metabolic alkalosisPathophysiology: Two Key QuestionsHow do patients become alkalotic?Why do they remain alkalotic?Generation of Metabolic AlkalosisLoss of H+ ionsGI loss: vomiting, GI suction, antacidsRenal loss: diuretics, mineralocorticoid excess, hypercalcemia, post-hypercapniaAdministration of bicarbonateTranscellular shiftK+ loss → H+ shifts intracellularlyIntracellular acidosisRefeeding syndromeContraction alkalosisSame HCO3, smaller extracellular volume → increased [HCO3]Seen in CF (sweating), illustrated in Fig 18-1Common theme: hypochloremia is essential for maintenanceMaintenance of Metabolic AlkalosisKidneys normally excrete excess HCO3Example: Normal subjects excrete 1000 mEq NaHCO3/day with minor pH changeImpaired HCO3 excretion required for maintenanceTable 18-2Mechanisms of MaintenanceDecreased GFR (less important)Increased tubular reabsorptionProximal tubule (PT): reabsorbs 90% of filtered HCO3TALH and distal nephron manage the restContributing factors:Effective circulating volume depletionEnhances HCO3 reabsorptionAng II increases Na-H exchangeIncreased tubular [HCO3] enables more H+ secretionDistal nephron HCO3 reabsorptionStimulated by aldosterone (↑ H-ATPase, ↑ Na reabsorption)Negative luminal charge impedes H+ back-diffusionChloride depletionReduces NaK2Cl activity → ↑ renin → ↑ aldosteroneLuminal H-ATPase co-secretes Cl → low Cl increases H+ secretionCl-HCO3 exchanger needs Cl gradient → low Cl impairs HCO3 secretionKey conclusion: Cl depletion > volume depletion in perpetuating alkalosisAlbumin corrects volume but not alkalosisNon-N Cl salts correct alkalosis without fixing volumeHypokalemiaStimulates H+ secretion and HCO3 reabsorptionTranscellular shift (H/K exchange) → intracellular acidosisH-K ATPase reabsorbs K and secretes HSevere hypokalemia reduces Cl reabsorption → ↑ H+ secretionImportant with mineralocorticoid excessRespiratory CompensationHypoventilation: 0.7 mmHg PCO2 ↑ per 1 mEq/L HCO3 ↑PCO2 can exceed 60Rise in PCO2 increases acid excretion (limited effect on pH)EpidemiologyGI Hydrogen LossGastric juice: high HCl, low KClStomach H+ generation → blood HCO3Normally recombine in duodenumVomiting/antacids prevent recombination → alkalosisAntacids (e.g., MgOH)Mg binds fats, leaves HCO3 unbound → alkalosisRenal failure impairs excretionCation exchange resins (SPS, MgCO3) → same effectCongenital chloridorrheaHigh fecal Cl-, low pH → metabolic alkalosisPPI may help by reducing gastric Cl loadRenal Hydrogen LossMineralocorticoid excess & hypokalemiaAldosterone → H+ ATPase stimulation, Na+ reabsorption → negative lumen → ↑ H+ secretionDiuretics (loop/thiazide)Volume contractionSecondary hyperaldosteronismIncreased distal flow and H+ lossPosthypercapnic alkalosisChronic respiratory acidosis → ↑ HCO3Rapid correction (ventilation) → unopposed HCO3 → alkalosisGradual CO2 correction neededMaintenance: hypoxemia, Cl lossLow chloride intake (infants)Na+ reabsorption must exchange with H+/K+H+ co-secretion with Cl impaired if Cl is lowHigh dose carbenicillinHigh Na+ load without ClNonresorbable anion → hypokalemia, alkalosisHypercalcemia↑ Renal H+ secretion & HCO3 reabsorptionCan contribute to milk-alkali syndromeRarely causes acidosis via reduced proximal HCO3 reabsorptionIntracellular H+ ShiftHypokalemiaCommon cause and effect of metabolic alkalosisH+/K+ exchange → intracellular acidosis → ↑ H+ excretionRefeeding SyndromeRapid carb reintroduction → cellular shiftNo volume contraction or acid excretion increaseRetention of BicarbonateRequires impaired excretion to become significantOrganic anions (lactate, acetate, citrate, ketoacids)Metabolism → CO2 + H2O + HCO3Citrate in blood transfusion (16.8 mEq/500 mL)8 units → alkalosis riskCRRT + citrate anticoagulantSodium bicarbonate therapyRebound alkalosis possible with acid reversal (e.g., ketoacidosis)Extreme cases: pH up to 7.9, HCO3 up to 70Contraction AlkalosisNaCl and water loss without HCO3Seen in vomiting, diuretics, CF sweatMild losses neutralized by intracellular buffersSymptomsOften asymptomaticFrom volume depletion: dizziness, weakness, crampsFrom hypokalemia: polyuria, polydipsia, weaknessFrom alkalosis (rare): paresthesias, carpopedal spasm, lightheadednessMore common in respiratory alkalosis due to rapid pH shift across BBBPhysical exam not usually helpfulClues: signs of vomitingDiagnosisHistory is keyIf unclear, suspect:Surreptitious vomitingCFSecret diuretic useMineralocorticoid excessUse urine chlorideTable 18-3: urine Na is misleading in alkalosisTable 18-4: urine chemistry changes with complete HCO3 reabsorptionVomiting: low urine Na, K, Cl + acidic urineSufficient NaCl intake prevents this stageExceptions to low urine Cl:Severe hypokalemiaTubular defectsCKDDistinguishing from respiratory acidosisUse pH as guideCaution with typo (duplicate pCO2)A-a gradient might helpTreatmentCorrect K+ and Cl− deficiency → kidneys self-correctUpper GI losses: add H2 blockersSaline-responsive alkalosisTreat with NaClMechanisms:Reverse contraction componentReduce Na+ retention → promote NaHCO3 excretion↑ distal Cl delivery → enable HCO3 secretion via pendrinMonitor urine pH: from 5.5 → 7–8 with therapyGive K+ with Cl, not phosphate, acetate, or bicarbonateSaline-resistant alkalosisSeen in edematous states or K+ depletionEdema (CHF, cirrhosis): use acetazolamide, HCl, dialysisAcetazolamide: may ↑ CO2 via RBC carbonic anhydrase inhibitionMineralocorticoid excess: K+ + K-sparing diuretic (use caution)Severe hypokalemia:eNaC Na+ reabsorption must be countered by H+ if no K+Corrects rapidly with K+ replacementRestores saline responsivenessRenal failure: requires dialysis

ReferencesI said I used MDCalc but I was mistaken I use MedCalX which is nice but getting dated. We talked about this out of print book that we love: Cohen, J. J., Kassirer, J. P. (1982). Acid-base. United States: Little, Brown.Josh mentioned this article that looked at over 17,000 samples with simultaneous measured and calculated bicarbonate and found a very small difference. Comparison of Measured and Calculated Bicarbonate Values | Clinical Chemistry | Oxford AcademicBase deficit or excess- Diagnostic Use of Base Excess in Acid–Base Disorders | NEJM (check out the accompanying letter to the editor from Melanie challenging this article! Along with colleagues Lecker and Zeidel Diagnostic Use of Base Excess in Acid-Base Disorders )Melanie loves this paper which shows a nice correlation between arterial and venous pH but the rest of the comparisons are disappointing - Comparison of arterial and venous pH, bicarbonate, Pco2 and Po2 in initial emergency department assessment - PMCA nomogram for the interpretation of acid-base data is figure 17-1 in the book, this manuscript with the ! in the conclusion creates the acid-base map. We debated about whether we like Winter’s formula: Quantitative displacement of acid-base equilibrium in metabolic acidosis (melanie does b/c it used real patients). Amy’s Voice of God on Dietary Acid LoadReview of dietary acid load: https://pubmed.ncbi.nlm.nih.gov/23439373/, https://pubmed.ncbi.nlm.nih.gov/38282081/, https://pubmed.ncbi.nlm.nih.gov/33075387/Survey data from kidney stone formers regarding sources of dietary acid load: https://pubmed.ncbi.nlm.nih.gov/35752401/Urine profile for vegans and omnivories (urine pH and cations/anions): https://pubmed.ncbi.nlm.nih.gov/36364731/SWAP-MEAT pilot trial: https://pubmed.ncbi.nlm.nih.gov/39514692/ looked at urine profile on plant based meat diet (Beyond Meat) versus animal based meat dietNot all plant meat substitutes are the same in terms of net acid load: https://pubmed.ncbi.nlm.nih.gov/38504022/Frassetto paper showing that the dietary acid load effect is mostly from sodium chloride: https://pubmed.ncbi.nlm.nih.gov/17522265/Healthy eating is probably more important than plant based diet for CKD: https://pubmed.ncbi.nlm.nih.gov/37648119/, https://pubmed.ncbi.nlm.nih.gov/32268544/KDIGO 2024 guidelines: https://kdigo.org/guidelines/ckd-evaluation-and-management/Association (or lack thereof) of a pro-vegetarian diet and sarcopenia/protein energy wasting in CKD: https://pubmed.ncbi.nlm.nih.gov/39085942/Outline Chapter 17 Introduction to simple and mixed acid-base disordersIntroduction to Simple and Mixed Acid-Base DisordersDisturbances of acid-base homeostasis are common clinical problemsDiscussed in Chapters 18-21This chapter reviews:Basic principles of acid-base physiologyMechanisms of abnormalitiesEvaluation of simple and mixed acid-base disordersAcid-Base PhysiologyFree hydrogen is maintained at a very low concentration40 nanoEq/L1 millionth the concentration of Na, K, Cl, HCO3H+ is highly reactive and must be kept at low concentrationsCompatible H concentration: 16 to 160 nanoEq/LpH range: 7.8 to 6.8Buffers prevent excessive variation in H concentrationMost important buffer: HCO3Reaction: H+ + HCO3 <=> H2CO3 <=> H2O + CO2H2CO3 exists at low concentration compared to its productsHenderson-Hasselbalch Equation (HH Equation)Understanding acid-base can use both H+ concentration and pHMeasurement of pHMust be measured anaerobically to prevent CO2 lossMeasurement methods:pH: Electrode permeable to H+PCO2: CO2 electrodeHCO3: Calculated using HH EquationAlternative: Add strong acid, measure CO2 releasedPCO2 * 0.03 gives mEq of CO2Measured vs. Calculated HCO3pKa of 6.1 and PCO2 coefficient (0.03) varyMeasurement of CO2 prone to errorDebate remains unresolvedDifferences affect anion gap calculationsArterial vs. Venous Blood Gas (ABG vs. VBG)Venous pH is lower due to CO2 retentionVenous blood may be as accurate as arterial for pH if well perfusedPitfalls in pH MeasurementMust cool ABG quickly to prevent glycolysisAir bubbles affect gas readingsHeparin contamination lowers pHArterial pH may not reflect tissue pHReduced pulmonary blood flow skews resultsEnd tidal CO2 > 1.5% indicates adequate venous returnRegulation of Hydrogen ConcentrationHCO3/CO2 as the Principal BufferHigh HCO3 concentrationIndependent regulation of HCO3 (renal) and PCO2 (lungs)Renal Regulation of HCO3H secretion reabsorbs filtered bicarbonateLoss of HCO3 in urine equates to H retentionH combines with NH3 or HPO4, forming new HCO3Pulmonary Regulation of CO2CO2 is not an acid but forms H2CO3Lungs excrete 15,000 mmol of CO2 dailyKidneys excrete 50-100 mmol of H dailyH = 24 * (PCO2 / HCO3)pH compensation via respiratory and renal adjustmentsAcid-Base DisordersDefinitionsAcidemia: Decreased blood pHAlkalemia: Increased blood pHAcidosis: Process lowering pHAlkalosis: Process raising pHPrimary PCO2 abnormalities: Respiratory disordersPrimary HCO3 abnormalities: Metabolic disordersCompensation moves in the same direction as the primary disorderDiagnosis requires extracellular pH measurementMetabolic AcidosisLow HCO3 and low pHCauses:HCO3 loss (e.g., diarrhea)Buffering of non-carbonic acid (e.g., lactic acid, sulfuric acid in renal failure)Compensation: Increased ventilation lowers PCO2Renal excretion of acid restores pH over daysMetabolic AlkalosisHigh HCO3 and high pHCauses:HCO3 administrationH loss (e.g., vomiting, diuretics)Compensation: HypoventilationRenal HCO3 excretion corrects pH unless volume or chloride depletedRespiratory AcidosisDue to decreased alveolar ventilation, increasing PCO2Compensation: Increased renal H excretion raises HCO3Acute phase: Large pH drop, small HCO3 increaseChronic phase: Small pH drop, large HCO3 increaseRespiratory AlkalosisDue to hyperventilation, reducing CO2 and raising pHCompensation: Decreased renal H secretion, leading to bicarbonaturiaTime-dependent compensation (acute vs. chronic phases)Mixed Acid-Base DisordersMultiple primary disorders can coexistExample:Low arterial pH with:Low HCO3 → Metabolic acidosisHigh PCO2 → Respiratory acidosisCombination indicates mixed disorderExtent of renal and respiratory compensation clarifies diagnosisCompensation does not fully restore pHExample: pH 7.4, PCO2 60, HCO3 36 → Combined respiratory acidosis & metabolic alkalosisAcid-Base Map illustrates normal responses to disturbancesClinical Use of Hydrogen ConcentrationH+ vs. pH RelationshipH = 24 * (PCO2 / HCO3)Normal HCO3 cancels out 24, so H = 40 nMol/LpH to H conversion:Increase pH by 0.1 → Multiply H by 0.8Decrease pH by 0.1 → Multiply H by 1.25Example: Salicylate Toxicity7.32 / 30 / xx / 15Goal: Alkalinize urine to pH 7.45 (H+ = 35 nMol/L)Bicarb needs to reach 20 for compensationPotassium Balance in Acid-Base DisordersMetabolic AcidosisH+ buffered in cells, causing K+ to move extracellularlyK+ rises ~0.6 mEq/L per 0.1 pH dropLess predictable in lactic or ketoacidosisDKA-associated hyperkalemia due to insulin deficiencyHyperkalemia can induce mild metabolic acidosisRespiratory Acid-Base DisordersMinimal effect on potassium levels

ReferencesWe talked about winning the 2022 ASN innovation contest and here’s a link to our promo video https://www.dropbox.com/scl/fi/g4osnf0nradsfryyo51fi/ASN-Education-Contest-Channel-Your-Enthusiasm-Podcast.mp4?rlkey=pnso45x07nr3pane9y8cux8yg&e=1&dl=0We wondered about “permissive hypercreatinemia” and Josh referenced the DOSE trial: Relevance of Changes in Serum Creatinine During a Heart Failure Trial of Decongestive Strategies: Insights From the DOSE Trial - PMCPlus this editorial by Steve Coca: Ptolemy and Copernicus Revisited: The Complex Interplay between the Kidneys and Heart FailureWe refer to the Frank-Starling curve and reference an image from this paper by Jay Cohen: Blood pressure and cardiac performance - ScienceDirectWe felt that this chapter is dated with respect to heart failure. Check out this 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice GuidelinesUnderfilling versus overflow in hepatic ascites an editorial by Frank Epstein Effect of Head-Out Water Immersion on Hepatorenal Syndrome - American Journal of Kidney Diseases studies done by Schrier which Roger mentionedThe fading concept: https://www.tandfonline.com/doi/abs/10.3109/00365528309182102?journalCode=igas2Historical Aspects of Ascites and the Hepatorenal Syndrome - Wong - 2021 - Clinical Liver Disease - Wiley Online LibraryHere’s a great paper from Andrew Allegretti on HRS prognosis: Prognosis of Patients with Cirrhosis and AKI Who Initiate RRT - PubMedJoel mentions landmark paper in NEJM for treating SBP Effect of Intravenous Albumin on Renal Impairment and Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis | New England Journal of MedicineAlbumin infusion in patients undergoing large‐volume paracentesis: A meta‐analysis of randomized trials - Bernardi - 2012 - Hepatology - Wiley Online LibraryJoel wondered about the lore that minoxidil could lead to renal recovery: Minoxidil treatment of malignant hypertension. Recovery of renal functionRoger recalled an agent diazoxide: Hyperstat - Side Effects, Uses, Dosage, Overdose, Pregnancy, Alcohol | RxWikiHere’s an entertaining review on whether insulin leads to sodium retention: Invited Review: Sodium-retaining effect of insulin in diabetes - PMCInvasive monitoring for hemodynamicsFACTT: https://www.nejm.org/doi/full/10.1056/NEJMoa062200ESCAPE: https://pubmed.ncbi.nlm.nih.gov/16204662/PACMAN: https://pubmed.ncbi.nlm.nih.gov/16084255/EVEREST trial and use of tolvaptan in HFrEFEVEREST: https://pubmed.ncbi.nlm.nih.gov/17384437/Post-hoc analysis of hyponatremic patients of EVEREST: https://pubmed.ncbi.nlm.nih.gov/23743487/Outline Chapter 16 — Edematous States part 2Symptoms and diagnosisThree factors important in the mechanism of edemaThe pattern of distribution of edema which reflects those capillaries with altered hemodynamic forcesThe central venous pressurePresence or absence of pulmonary edemaPulmonary edemaShortness of breath and orthopneaTachypnic, diaphoretic, wet rales, gallops, murmursCheck a chest x-rayCardiac disease is most commonBut differential includes primary renal Na retention and ARDSWedge pressure will exceed 18-20 mmHg with heart or primary Na retention, but is relatively normal with ARDSUncomplicated cirrhosis does not cause pulmonary edemaIncreased capillary pressure in this disorder is only seen below the hepatic veinNormal or reduced blood volume in the cardiopulmonary circulationPeripheral edema and ascitesPeripheral edema is cosmetically undesireable but produces less serious symptomsSymptoms: swollen legs, difficulty walking, increased abdominal girth, shortness of breath due to pressure on the diaphragm.Pitting edema found in dependent areasAscites found in abdomenNephrotic syndrome low tissue pressure areas like eye orbitsHeart Failure (right sided) peripheral edema, abdominal wall, SOB is due to concomitant pulmonary disease. Right sided heart failure increases venous pressureCirrhosis develop cirrhosis and lower extremity edema, pressure above the hepatic vein is normal or low.Tense ascites can increase the pressure above the diaphragm but is relieved with a tapPortal pressure > 12 mmHg required for fluid retentionLove the case history 16-1Primary renal sodium retentionPulmonary and peripheral edemaJugular venous pressure is elevatedNephrotic SyndromePeriorbital and peripheral edema, rarely ascitesCVP normal to highIdiopathic edemaBehaves as volume depleted (especially with diuretics)Etiology and treatmentGeneral principles of treatmentWhen must edema be treatedWhat are the consequences of the removal of fluidHow rapidly should fluid be removedWhenPulmonary edema is the only form of generalized edema that is life threatening and demands immediate treatmentImportant for note: laryngeal edema and angioedema. Cerebral edemaWhat are the consequencesIf the edema fluid is compensatory (heart failure, cirrhosis, capillary leak syndromes) then removal of fluid with diuretics will diminish effective circulating volume.Despite this drop in effective circulating volume, most patients benefit from the appropriate use of diuretics.Cardiac output falls 20% with diuresis of pulmonary congestion but exercise tolerance increasesSays to be careful in diuresis leads to increases in CrHow rapidly should edema fluid be removedRemoving vascular fluid changes starling forces (reduced venous pressure) so fluid rapidly mobilized from interstitium. 2-3 liters per 24 hours can often be removed without difficultyAn exception is cirrhosis and ascites without peripheral edema. Mobilizing ascites is limited to 500-750 ml/dayHeart failureEdema is due to increase in venous pressure raising capillary hydrostatic pressureIschemic and hypertensive CM impairs left ventricular function causing pulmonary but little peripheral edemaIn acute pulmonary edema the LV disease results in increased LVEDP and increased left atrial pressure which transmit back to the pulmonary veinWhen wedge exceeds 18-20 (normal is 5-12) get pulmonary edemaCor pulmonale due to pure right heart failure prominent edema in the lower extremitiesCardiomyopathies tend to affect right and left ventricles leading to simultaneous onset of pulmonary and peripheral edema.Discusses forward hypothesis in which reduction in cardiac output triggers decreased tissue perfusion activation of SNS and RAAS.Catecholamines increase cardiac outputRAAS increase Sodium retentionEdema is absent and patients can be compensated at the expense of increased LVEDP see Figure 16-6Figure 16-6 A to B to C with compensationEventually the increased sodium retention and increased intracranial pressure are enough to cause edema.He then brings up multiple important points (in bullets none the less)Dual effects of fluid retention:Increased cardiac outputPotential harmful elevation in venous pressureBenefit is found with increase in LVEDP from 12 to 15, after that it seems mostly deleteriousVascular congestion (elevated LVEDP) and a low cardiac output do not have to occur together. See points B and C on 16-6.Frank-Starling relationship varies with exercise.Patients with moderate heart disease may be okay at rest but fail with mild exertion. This leads to more neurohormonal activation. This can worsen sodium retention and ischemia. Rest here can help augment diuretic effect. Doubling diuretic response. 40% increase in GFR.Mild to mod heart disease may have no edema with dietary Na restriction. Na intake will initially increase preload and improve cardiac output and allow the Na to be excreted but as the Frank Starling curves flatten then excess sodium cannot be excreted.Diastolic vs Systolic dysfunctionDecreased compliance in diastolic dysfunction can lead to flash pulmonary edemaMore common with hypertensionLook to the ejection fractionNeurohormonal adaptationInitial benefit long term adverse effectsNorepi, renin, ADH all are vasoconstrictorsThey raise cardiac outputRaise BP which is maladaptive in the long termTreatment of cardiogenic pulmonary edemaMorphineOxygenLoop diureticNTG/nitroprussideIf patient remains in pulmonary edema and has systolic dysfunction consider inotropic agentTreatment of chronic heart failureFeels datedMentions dig and loop diureticBut also ACEi/BB and AADeep diveLoop diureticsACEiCor PolminaleEdema here comes with increased CO2Associated with increased HCO3 which means increasedHCO3 reabsorption int he proximal tubule which leads to more sodium retentionHypoxemia can increase Na retentionCirrhosis and AscitesBoth lymphatic obstruction and increased capillary permeability contributeSinusoidal obstruction leads to increased hydraulic pressure in the sinusoids.Portal hypertension is necessary for ascites> 12 mmHgThe low albumin is often present but is not contributory to edemaSinusoids are freely permeable to albumin so no oncotic pressure from albumin hereMechanism of ascitesRenal sodium conservation is an early finding and some evidence for primary sodium retention but…Mostly underfill is thought to drive Na retentionSplanchnic vasodilation starts this ofNO drives thisEndotoxin absorption stimulates NoNormally endotoxin is detoxed in liver but portosystemic shunting allows endotoxin to escape the liver.Hepatorenal syndromeProgressive hemodynamically mediated fall in GFRInduced by intense renal vasocontstrictionWhere are the PGE and KininsFall in GFR is masked by decreased muscle mass and decreased BUN productionHyponatremia is a grave prognostic sign, as it is in heart failure, Indicates increased activation of vasopressinTreatmentLow Na intakeLow water intakeCare with diuretics, can only mobilize 300-500 ml of ascetic fluid a dayAvoid hypokalemiaStimulates NH3 productionTalks about the mechanism in proximal tubuleAlso discusses pKA of NH3->NH4 reaction and if the pH rises, this will shift the Eq to produce NH3Important aspect in NH3 is lipid soluble and NH is notSays that Spiro is diuretic of choiceStates it is more effective than furosemide in this conditionEffectiveness related to slower rate of drug excretionin urine (compromises furosemide but not spiro) competition with bile saltsRecommends 40 furosemide and 100 of spiroResistant ascitesOptionsparacentesisTIPSComplicated by higher mortalityPeritoneovenous shuntLargely abandoned,Primary renal sodium retentionCKD or AKI where low GFR linits excretion of Water and NaAcute GN or nephrotic syndromeBroken glom with intact tubules, mean the tubules see less Na so they think “underperfused” and then they increase renal retention of NADrugsDirect vasodilators like minoxidilRequire super high furosemide doses to counterOther antihypertensives either block sympathetic NS, Na retention directly or block RAAS explains why they don’t cause Na retentionNSAIDSFludrocortisonePregnancyNormal pregnancy is associated with retention of 900 to 1000 mEq of NaAnd! 6-8 liters of waterRefeeding edemaInsulin stimulate Na retention

ReferencesCapillary Hemodynamics  Insights into Salt Handling and Blood Pressure | NEJMAmy mentioned about the 3 phases of the interstitiumAre the precapillary sphincters and metarterioles universal components of the microcirculation? An historical review - PMCSafety factor?Renal Function during Recovery from Minimal Lesions Nephrotic Syndrome - Abstract - Nephron 1987, Vol. 47, No. 3 - Karger PublishersAre diuretics effective for idiopathic lymphedema? : Evidence-Based PracticeRapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema for fig 16-7Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart FailureAdditional notes from our chat (might be overlap with Amy’s notes belowNew insights into the pathophysiology of edema in nephrotic syndrome by Helbert RondonThe hyperlipidemia of the nephrotic syndrome. Relation to plasma albumin concentration, oncotic pressure, and viscosityPlasmin in Nephrotic Urine Activates the Epithelial Sodium ChannelLipoprotein metabolism in experimental nephrosisViscosity regulates apolipoprotein A-1 gene expression in experimental models of secondary hyperlipidemia and in cultured hepatocytesAmiloride in Nephrotic Syndrome | Clinical Research Trial Listing ( oedema | EdemaHypoalbuminemia and proteinuria contribute separately to reduced lipoprotein catabolism in the nephrotic syndromeOrigin of hypercholesterolemia in chronic experimental nephrotic syndromeExtrahepatic lipogenesis contributes to hyperlipidemia in the analbuminemic ratApolipoprotein gene expression in analbuminemic rats and in rats with Heymann nephritisAmy’s NotesJosh “Blessed are the days” https://link.springer.com/article/10.1007/s00467-013-2435-6Amy mentions mels’ article Capillary Hemodynamics  Insights into Salt Handling and Blood Pressure | NEJM, the 3 phases of the interstitiumJosh mentions a re: management of idiopathic edema (from up to date: https://www.uptodate.com/contents/idiopathic-edema)Amy stemmer sign: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635205/, https://pubmed.ncbi.nlm.nih.gov/31281100/Anna in chat talking about amiloride, ENaC re: edema: https://www.researchgate.net/publication/50989884_New_insights_into_the_pathophysiology_of_edema_in_nephrotic_syndromeOutline Chapter 16 — Edematous StatesEdema is a palpable swelling produced by expansion of the interstitial fluid volumeConditions associated with this Heart failure Cirrhosis Nephrotic syndromePathophysiology of edema formationTwo steps Alteration of capillary hemodynamics that favors movement of fluid out of the capillary Dietary sodium and water are retained by the kidneyEdema does not become clinically apparent until interstitial volume has increased 2.5 to 3 liters If this fluid came the plasma would have hemoconcentration and shock Instead as fluid moves from vascular space to interstitium you get decreased tissue perfusion leading to kidney Na and water retention Net result is expansion of total extracellular volume with maintenance of plasma volume at close to normal levels This means that the kidney is responding appropriately.Important because therapy with diuretics will break this response and may diminish tissue perfusion. There are other situations where primary abnormality is inappropriate renal fluid retention. Here both the plasma and interstitial volumes are expanded and there is no consequences from diuretic therapy. This is over filling. Seen in cirrhosis, primary renal disease. Certain drugs Capillary hemodynamics Exchange of fluids at teh capillary is determined by the hydraulic and oncotic pressures in each compartment This can be expressed by Starlings law Net filtration = LpS (delta hydraulic pressure - delta oncotic pressure) Lp is the unit permeability or porosity of the capillary wall. S is the surface area. Sigma is the reflection coefficient ranging from zero for completely permeable to 1 for for impermeable Difficult to measure these values in humans and animals 16-1 is a table of starling force values. No reflection coefficient though Figure 16-2 shows values in subcutaneous tissues. PCap 17.3 Oncotic pressure in cap is 28. Says mean net gradient is 0.3 mmHg favoring filtration out of the vascular space. This excess net is returned to the systemic circulation by lymphatics. In the liver the values are different. The hepatic sinusoids are highly permeable to protein so oncotic pressure is neutralized by zero reflection coefficient. SO hydraulic pressure favoring filtration is unopposed. Cap hydraulic pressure is lower since two thirds of hepatic blood flow is from low pressure portal vein. Still large pressure gradient favoring filtrationAlveolar capillaries are similar to the liver Low cap hydraulic pressure, more permeable to proteins so no transcapillary oncotic pressure. Edema formation requires alteration of one or more starling forces to favor net filtrationIncreased capillary hydraulic pressure would do it Increased interstitial oncotic pressure tooReduction in plasma oncotic pressureLymphatic obstruction too Increased capillary hydraulic pressureCapillary hydraulic pressure is insensitive to alteration in arterial pressure due to autoregulation in the pre-capillary sphincterConstricts in response to increases in arterial pressureNo sphincter at venous end, so changes in venous pressure are transmitted to capillary bed. Blood volume expanded increases pressure in enough system Heart failure Renal disease Venous obstruction Cirrhosis DVT Decreased plasma oncotic pressure Hypo albuminuria May be less common than previously suspected Increased capillary permeability Promotes edema directly and by permitting albumin to move into interstitium, decreasing the oncotic pressure gradient Burns both histamine and oxygen free radicals cause microvascular injury Therapy with IL-2 increases capillary permeability Episodic idiopathic capillary leak syndromes by IL-2 receptors on mononuclear cells or increased generations of kinins. Patients often with monoclonal gammopathy and during episodes have a massive leak of proteins and fluids, hematocrit rises 70-80%. Aminophylline and terbutaline may prevent. episodes ARDS Ischemia or sepsis induced release of cytokines such as IL-1, IL-8 or TNF may have role in creasing pulmonary capillary permeability DM also increases capillary permeability and may have a role in the edema which is primarily generated by other factors, heart failure or NS Lymphatic obstruction Most often with nodal enlargement due to malignancyCalled lymphedema Hypothyroidism marked increase in interstitial accumulation of albumin and other proteins. Low lymphatic flow in hypothyroidema, myxedema. Resistant to diuretics which will put patient at risk of hypovolemia. Safety factors Needs to be 15 mmHg increase in the gradient favoring filtration before edema is seen Three factors explain this protective response Increased lymphatic flow can remove excess filtrate Fluid entry into interstitium lowers the oncotic pressure by dilution and lymphatic mediated removal of proteins Increased fluid entry to interstitium increases interstitial hydraulic pressure Talks about hypoalbuminemia and edema This is a lot of underfill vs overfill theory. Nice bullet points at bottom of 487 how heterogeneity of etiology of edema with MCD. Talks about pulmonary edema and how high interstitial protein provides large safety factor, interstitial albumin has a long way to fall to prevent pulmonary edema. Mentions kwashiorkor and how it may not be low albumin that causes this. Renal sodium retention Can be due to primary renal disease causing sodium retention NS, GN More commonly is renal salt retention is an appropriate compensatory response to decreased effective circulating volume States that decreased effective circulating volume can become compensated and renin falls back to normal.Had interesting figure 16-5 “The Compensated State”Symptoms and diagnosisThree factors important in the mechanism of edemaThe pattern of distribution of edema which reflects those capillaries with altered hemodynamic forcesThe central venous pressurePresence or absence of pulmonary edemaPulmonary edemaShortness of breath and orthopneaTachypnic, diaphoretic, wet rales, gallops, murmurs Check a chest x-rayCardiac disease is most commonBut differential includes primary renal Na retention and ARDSWedge pressure will exceed 18-20 mmHg with heart or primary Na retention, but is relatively normal with ARDSUncomplicated cirrhosis does not cause pulmonary edemaIncreased capillary pressure in this disorder is only seen below the hepatic veinNormal or reduced blood volume in the cardiopulmonary circulationPeripheral edema and ascitesPeripheral edema is cosmetically undesireable but produces less serious symptomsSymptoms: swollen legs, difficulty walking, increased abdominal girth, shortness of breath due to pressure on the diaphragm.Pitting edema found in dependent areasAscites found in abdomenNephrotic syndrome low tissue pressure areas like eye orbitsHeart Failure (right sided) peripheral edema, abdominal wall, SOB is due to concomitant pulmonary disease. Right sided heart failure increases venous pressureCirrhosis develop cirrhosis and lower extremity edema, pressure above the hepatic vein is normal or low.Tense ascites can increase the pressure above the diaphragm but is relieved with a tapPortal pressure > 12 mmHg required for fluid retentionLove the case history 16-1Primary renal sodium retentionPulmonary and peripheral edemaJugular venous pressure is elevatedNephrotic SyndromePeriorbital and peripheral edema, rarely ascitesCVP normal to highIdiopathic edemaBehaves as volume depleted (especially with diuretics)Etiology and treatmentGeneral principles of treatmentWhen must edema be treatedWhat are the consequences of the removal of fluidHow rapidly should fluid be removedWhenPulmonary edema is the only form of generalized edema that is life threatening and demands immediate treatmentImportant for note: laryngeal edema and angioedema. Cerebral edemaWhat are the consequencesIf the edema fluid is compensatory (heart failure, cirrhosis, capillary leak syndromes) then removal of fluid with diuretics will diminish effective circulating volume. Despite this drop in effective circulating volume, most patients benefit from the appropriate use of diuretics.Cardiac output falls 20% with diuresis of pulmonary congestion but exercise tolerance increasesSays to be careful in diuresis leads to increases in CrHow rapidly should edema fluid be removedRemoving vascular fluid changes starling forces (reduced venous pressure) so fluid rapidly mobilized from interstitium. 2-3 liters per 24 hours can often be removed without difficultyAn exception is cirrhosis and ascites without peripheral edema. Mobilizing ascites is limited to 500-750 ml/dayHeart failureEdema is due to increase in venous pressure raising capillary hydrostatic pressureIschemic and hypertensive CM impairs left ventricular function causing pulmonary but little peripheral edemaIn acute pulmonary edema the LV disease results in increased LVEDP and increased left atrial pressure which transmit back to the pulmonary vein When wedge exceeds 18-20 (normal is 5-12) get pulmonary edema Cor pulmonale due to pure right heart failure prominent edema in the lower extremitiesCardiomyopathies tend to affect right and left ventricles leading to simultaneous onset of pulmonary and peripheral edema.Discusses forward hypothesis in which reduction in cardiac output triggers decreased tissue perfusion activation of SNS and RAAS.Catecholamines increase cardiac output RAAS increase Sodium retentionEdema is absent and patients can be compensated at the expense of increased LVEDP see Figure 16-6Figure 16-6 A to B to C with compensationEventually the increased sodium retention and increased intracranial pressure are enough to cause edema.He then brings up multiple important points (in bullets none the less)Dual effects of fluid retention:Increased cardiac outputPotential harmful elevation in venous pressureBenefit is found with increase in LVEDP from 12 to 15, after that it seems mostly deleterious Vascular congestion (elevated LVEDP) and a low cardiac output do not have to occur together. See points B and C on 16-6.Frank-Starling relationship varies with exercise.Patients with moderate heart disease may be okay at rest but fail with mild exertion. This leads to more neurohormonal activation. This can worsen sodium retention and ischemia. Rest here can help augment diuretic effect. Doubling diuretic response. 40% increase in GFR.Mild to mod heart disease may have no edema with dietary Na restriction. Na intake will initially increase preload and improve cardiac output and allow the Na to be excreted but as the Frank Starling curves flatten then excess sodium cannot be excreted. Diastolic vs Systolic dysfunctionDecreased compliance in diastolic dysfunction can lead to flash pulmonary edema More common with hypertensionLook to the ejection fractionNeurohormonal adaptation Initial benefit long term adverse effectsNorepi, renin, ADH all are vasoconstrictors They raise cardiac outputRaise BP which is maladaptive in the long termTreatment of cardiogenic pulmonary edemaMorphineOxygenLoop diureticNTG/nitroprussideIf patient remains in pulmonary edema and has systolic dysfunction consider inotropic agentTreatment of chronic heart failure Feels datedMentions dig and loop diureticBut also ACEi/BB and AADeep diveLoop diureticsACEiCor Polminale Edema here comes with increased CO2Associated with increased HCO3 which means increasedHCO3 reabsorption int he proximal tubule which leads to more sodium retentionHypoxemia can increase Na retentionCirrhosis and AscitesBoth lymphatic obstruction and increased capillary permeability contributeSinusoidal obstruction leads to increased hydraulic pressure in the sinusoids. Portal hypertension is necessary for ascites> 12 mmHgThe low albumin is often present but is not contributory to edemaSinusoids are freely permeable to albumin so no oncotic pressure from albumin hereMechanism of ascitesRenal sodium conservation is an early finding and some evidence for primary sodium retention but…Mostly underfill is thought to drive Na retentionSplanchnic vasodilation starts this ofNO drives thisEndotoxin absorption stimulates NoNormally endotoxin is detoxed in liver but portosystemic shunting allows endotoxin to escape the liver.Hepatorenal syndromeProgressive hemodynamically mediated fall in GFRInduced by intense renal vasocontstrictionWhere are the PGE and KininsFall in GFR is masked by decreased muscle mass and decreased BUN productionHyponatremia is a grave prognostic sign, as it is in heart failure, Indicates increased activation of vasopressinTreatmentLow Na intakeLow water intakeCare with diuretics, can only mobilize 300-500 ml of ascetic fluid a dayAvoid hypokalemia Stimulates NH3 productionTalks about the mechanism in proximal tubuleAlso discusses pKA of NH3->NH4 reaction and if the pH rises, this will shift the Eq to produce NH3Important aspect in NH3 is lipid soluble and NH is not Says that Spiro is diuretic of choiceStates it is more effective than furosemide in this conditionEffectiveness related to slower rate of drug excretionin urine (compromises furosemide but not spiro) competition with bile saltsRecommends 40 furosemide and 100 of spiroResistant ascitesOptionsparacentesisTIPSComplicated by higher mortality Peritoneovenous shunt Largely abandoned,Primary renal sodium retentionCKD or AKI where low GFR linits excretion of Water and NaAcute GN or nephrotic syndrome Broken glom with intact tubules, mean the tubules see less Na so they think “underperfused” and then they increase renal retention of NADrugsDirect vasodilators like minoxidilRequire super high furosemide doses to counterOther antihypertensives either block sympathetic NS, Na retention directly or block RAAS explains why they don’t cause Na retentionNSAIDSFludrocortisonePregnancyNormal pregnancy is associated with retention of 900 to 1000 mEq of NaAnd! 6-8 liters of waterRefeeding edemaInsulin stimulate Na retention

ReferencesProximal Tubule-Specific Deletion of the NHE3 (Na+/H+ Exchanger 3) in the Kidney Attenuates Ang II (Angiotensin II)-Induced Hypertension in Mice Melanie is in love with this paper that shows that sodium retention Bumetanide and furosemide in heart failure everyone agreed that we love this classic paper from Craig Brater on diuretics (and the source of figure 15-6). Lety referenced the Cr x 20 formula, a strategy to multiply the serum creatinine by 20 to estimate the initial furosemide dose. We agreed that this is more appropriate than the House of God formula of age + BUN = dose (which may be so much higher). Joel shared this excellent report Diuretic Optimization Strategies Evaluation (DOSE) trial: https://www.nejm.org/doi/full/10.1056/nejmoa1005419Amy shared how much she likes the two hour urine sodium (or random urine sodium) Rapid and Highly Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart Failure - PMCAnna shared  this paper which suggests that urinary sodium is more closely linked to outcome compared to urine volume  Natriuretic Response Is Highly Variable and Associated With 6-Month Survival: Insights From the ROSE-AHF Trial and the study showing Substantial Discrepancy Between Fluid and Weight Loss During Acute Decompensated Heart Failure Treatment Josh worried about obstructive sleep apnea and nocturia: Sleep disordered breathing and nocturnal polyuria: nocturia and enuresis.WAITING FOR JOSHJC mentioned this report from a group in the Netherlands regarding solute load and urine volume Determinants of Urine Volume in ADPKD Patients Using the Vasopressin V2 Receptor Antagonist TolvaptanWe also considered CLICK trail Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease | NEJM  (and here’s the Freely Filtered Podcast on this topic- a really great episode! Freely Filtered 040: Double CLICK for BP control in CKD stage 4 — NephJCRoger shared these articles on albumin and furosemide: Co-administration of albumin-furosemide in patients with the nephrotic syndrome and Albumin and Furosemide Combination for Management of Edema in Nephrotic Syndrome: A Review of Clinical Studies - PMC. This is an interesting study that showed that the serum and urine albumin does not predict of the response to loop diuretics.Serum and Urine Albumin and Response to Loop Diuretics in Heart Failure | American Society of Nephrology  JC”s abstract on use of loop diuretics in hepatorenal syndrome type 1 was ultimately published in the American Journal of the Medical Sciences: https://doi.org/10.1016/S0002-9629(23)00623-7Defining the role of albumin infusion in cirrhosis-associated hyponatremia this article explores the Gibbs-Donan Effect that Amy loves teaching us about. Distal Convoluted Tubule | American Society of Nephrology Figure 1 is a favorite (and a prerequisite to friendship with melanie)There is also a nice discussion of diuretic resistance in this year’s Nephmadness #NephMadness 2022: Cardiorenal Region – AJKD BlogJosh is excited about starting an SGLT2 inhibitor for acute heart failure and Anna mentions this article about how they may prevent AKI: ​​The SGLT2 Inhibitor Empagliflozin Might Be a New Approach for the Prevention of Acute Kidney InjuryJosh remembered this Tweetorial from Avi Cooper on the direct effect of furosemide: https://twitter.com/avrahamcoopermd/status/1292134482812604418?lang=enRoger reminded us about the practice of using bedrest for heart failure: Prolonged Bed Rest in the Treatment of the Dilated Heart and rotating tourniquets Effectiveness of Congesting Cuffs ("Rotating Tourniquets") in Patients with Left Heart Failure | Circulation and Rotating Tourniquets for Acute Cardiogenic Pulmonary Edema | JAMAAmy’s Voice of God: SGLT2i use in ADHFCCJM: https://www.ccjm.org/content/91/1/47EMPA AHF: https://pubmed.ncbi.nlm.nih.gov/38569758/Joel’s Voice of GodThe ADVOR Trial: https://www.nejm.org/doi/full/10.1056/NEJMoa2203094NephJC coverage: http://www.nephjc.com/news/advorFreely Filtered’s coverage: http://www.nephjc.com/freelyfiltered/52/advorOutline Chapter 15 — Clinical Use of DiureticsPart 2- beginning on page 460- Determinants of Diuretic responsiveness - 2 important determinants of diuretic response - Site of action - Presence of counterbalancing antinatriuretic forces - Ang2 - Aldo - Low systemic BP - Adds rate of drug excretion as # 2 and a half - Almost all diuretics are protein bound - So not well filtered - Enter tubule through organic anion and organic cation transporter - This can limit diuretic effectiveness - Natriuretic response plateaus at higher rates of diuretic excretion due to complete inhibition of the diuretic target - This plateau in normal people is 1 mg of bumetanide and 40 mg of furosemide given IV - Double this for oral furosemide, no adjustment needed for bumetanide - 15-6- Refractory edema - Start with a loop diuretic - Initial aim is to find the effective single dose - From the paragraph this is about threshold dosing - Double ineffective doses until good effect - Suggests maximum furosemide dose is 200 mg IV and 400 mg oral - Excess sodium intake - High sodium diet can work to prevent patients from achieving negative sodium balance. - Suggests diets after leaving the hospital maybe higher in sodium - Decreased or delayed intestinal absorption - Decreased intestinal perfusion, reduced intestinal motility and mucosal edema may contribute. - But why is this worse with furosemide than with bumetidine or torsemide? - Decreased drug entry into the tubular lumen - Thiazides don’t work below a GFR of 20 - CLICK - Renal failure - Increased organic anions compete for diuretic secretion - Bumetidine isn’t as dependent as furosemide on GFR - Use 1/20th rather than 1/40th the dose - Maximum of 8 to 10 mg - Furosemide has ototoxicirty at high doses, he advises against 2400 mg/day - There is a Na-K-2Cl carrier in the endolymph producing cells - Ethacrynic acid has the most ototoxicity - Only loop or thiazide that isn’t a sulfonamide derivative - Cirrhosis - Spiro is diuretic of choice - More effective than loops alone - Does not induce hypokalemia that can cause hepatic encephalopathy - Cirrhosis causes marked hyperaldo - Loop diuretics have to compete with bile salts for secretion in the proximal tubule - Spiro does not need to be secreted in the proximal tubule - Recommends to 100 to 40 spiro to furosemide ratio - And can double this to 200 and 80/day - and a maximum of of 400/160 - Hypoalbuminemia - <2 g/dL associated with decreased diuretic entry into the lumen - Protein binding keeps diuretics in the blood, reduces the volume of distribution - This maximizes the delivery to the kidney - In nephrotic syndrome tubular albumin can bind diuretic and prevent its activity - Co administration of albumin with diuretic has resulted in modest improvements in diuretic effectiveness in various studies - Intravenous infusion of loop diuretics - Infusions are greater than bolus - But if patient is not responding to blouses unlikely to respond to infusions since bolus provides a temporary spike in plasma level - Increased distal reabsorption - Increased distal sodium reabsorption decreases the effectiveness of proximal diuretics - Due to aldo and increased sodium delivery - Mentions that thiazides have a proximal effect (is that inhibition of carbonic anhydrase?) - 15-8 is very cool - Says all thiazides are created equal - Article from 1972 is why people use metolazone in advanced renal disease - When doing sequential nephron blocked be careful - Loss of lots of fluid - Loss of lots of potassium - Loss of 5 liters and 200 mEq of K a day is possible with sequential nephron blockade - Decreased loop sodium delivery - With heart failure and cirrhosis increased proximal resorption mediated by Ang II markedly reduces delivery of fluid to the diuretic sensitive sites. - Acetazolamide makes sense here - Supine or 10 degree head down can increase cardiac output possibly increased venous return - Can double Na excretion - Increase CrCl 40% - CAVH enters the chat!- Other uses of diuretics - Met alk, RTA, DI, hyponatremia due to SIADH, hypokalemia - Diuretics and prostaglandins - Loops and thiazides increase renal generation of prostaglandins - Can cause venous dilation may help with acute pulmonary edema - Can help without increased diuresis - NSAIDS counter the effect of loop diuretics - Is this natriuretic effect of PGE? Or due to renal ischemia due to unopposed Ang2 and norepi - They also raise BP and reduce cardiac output due to increased vascular resistance- Vasoconstrictor effect of loop diuretics - One hour after loop diuretics increase vasoconstriction and rise in systemic blood pressure - Increased Renin and norepinephrine, resolved 4 hours later - Seen in heart failure and cirrhosis - In cirrhosis decrease in RPF and GFR of 30-40% with furosemide

Outline Chapter 15 — Clinical Use of Diuretics- Among most commonly used drugs- Block NaCl reabsorption at different sites along the nephron- The ability to induce negative balance has made them useful in multiple diseases- Edematous states- Hypertension- Mechanism of action- Three major classes- Loop- NaK2Cl- Up to 25% of filtered sodium excreted- Thiazide- NCC- Up to 3-5% of filtered sodium excreted- Potassium sparing- ENaC- Up to 1-2% of filtered sodium excreted- Each segment has a unique sodium channel to allow tubular sodium to flow down a concentration gradient into the cell- Table 15-1 is interesting- Most of the sodium 55-655 is reabsorbed in the proximal tubule- Proximal diuretics would be highly effective if it wasn’t for the loop and other distal sites of Na absorption- Loop Diuretics- Furosemide- Bumetanide- Torsemide- Ethacrynic acid- NaK2Cl activated when all four sites are occupied- Loop diuretic fits into the chloride slot- In addition to blocking Na reabsorption results in parallel decrease in calcium resorption- Increase in stones and nephro albinos is especially premature infants which can increase calcium excretion 10-fold- Thiazide- Even though they are less potent than loops they are great for hypertension- “Not a problem in uncomplicated hypertension where marked fluid loss is neither necessary nor desirable”- Some chlorothiazide and metolazone also inhibit carbonic anhydrase in the proximal tubule- Increase Calcium absorption. Mentions that potassium sparing diuretics do this also- Potassium sparing diuretics- Amiloride- Spironolactone- Triamterene- Act at principal cells in the cortical collecting tubule,- Block aldosterone sensitive Na channels.- Discusses the difference between amiloride and triamterene and spiro- Mentions that trimethoprim can have a similar effect- Spiro is surprisingly effective in cirrhosis and ascites- Talks about amiloride helping in lithium toxicity- Partially reverse and prevent NDI from lithium- Trial Terence as nephrotoxin?- Causes crystaluria and casts- These crystals are pH independent- Faintly radio opaque- Acetazolamide- Blocks carbonic anhydrase- Causes both NaCl and NaHCO3 loss- Modest diuresis de to distal sodium reclamation- Mannitol- Nonreabsorbable polysaccharide- Acts mostly in proximal tubule and Loop of Henle- Causes water diuresis- Was used to prevent ATN- Can cause hyperosmolality directly and through the increased water loss- This hyperosmolality will be associated with osmotic movement of water from cells resulting in hyponatremia, like in hyperglycemia.- Docs must treat the hyperosmolality not the hyponatremia- Time course of Diuresis- Efficacy of a diuretic related to- Site of action- Dietary sodium action- 15-1 shows patient with good short diuretic response but other times of low urine Na resulting in no 24 hour net sodium excretion.- Low sodium diets work with diuretics to minimize degree of sodium retension while diuretic not working- Also minimizes potassium losses- Increase frequency- Increase dose- What causes compensatory anti-diuresis- Activation of RAAS and SNS- ANG II, aldo, norepi all promote Na reabsorption- But even when prazosin to block alpha sympathetic and capto[pril to block RAAS sodium retention occurs- Decrease in BP retains sodium with reverse pressure natriuresis- Even with effective diuresis there is reestablishment of a new steady state- Diuresis is countered by- Increases in tubular reabsorption at non-diuretic sensitive sites (neurohormonal mediated)- Flow mediated in creases in Tubular reabsorption distal to the diuretic from increased sodium delivery.- Hypertrophy- Increased Na-K-ATPase activity- Decreased tubular secretion of diuretic if renal perfusion is impaired- Getting to steady state requires- Diuretic dose and sodium intake be constant- Sodium balance is reestablished with 3 days of a fixed diuretic dose- K balance in 6-9 days- Figure 15-2- Which means that people on stable doses of diuretics don’t need regular labs, the abnormalities will emerge quickly.- Maximum diuresis happens with first dose- Figure 15-3- Fluid and Electrolyte complications- Volume depletion- “Effective circulating volume depletion also can develop in patients who remain edematous. Although fluid persists, there may be a sufficient reduction in intracranial filling pressures and cardiac output to produce a clinically important reduction in tissue perfusion.”- Azotemia- Decreased effective circulating volume with diuretic therapy also can diminish renal perfusion and secondarily the GFR.- Describes the traditional reason for increased BUN:Cr ratio- Then states that as much as a third of of the rise in BUN may reflect increased urea production; it is possible, for example, that reduced skeletal muscle perfusion leads to enhanced local proteolysis. This increases urea production.- Hypokalemia- Loop and thiazide increase urinary potassium losses- Often lead to hypokalemia- 50 mg of HCTZ drop K by 0.4 to 0.6 mEq/L with 15% falling below 3.5- He uses “associated” I think this is a place where we can use cause- 50 mg of chlorthalidone- K falls 0.8 to 0.9 mEq/L- Etiology- Increased distal delivery of Na and water- Increased aldo- From volume depletion- Underlying disease: cirrhosis and heart failure- Talk a lot about significance.- Info sounds dated- Increased risk of SCD in MRFIT trial- Association with increased ventricular arrhythmia with hypokalmia- Increased PVC and complex PVC by 27% with each drop in K of 0.5 mEq/L- Says that stress can induce epinephrine which can shift potassium inside cells leading to fatal arrhythmia especially if the patient begins at a low potassium concentration- Says v-fib two fold likely in MI patients with hypokalemia- Talks about crazy doses of HCTZ and Chlorthalidone 50+mg- Recommends 12.5 to 15 mg respectively- Metabolic alkalosis- Caused by loop and thiazide diuretics- Two factors cause this- Increased urinary H loss- Partly UE to secondary hyperaldo- Contraction of extracellular volume around remaining bicarb- Why not contraction hypernatremia, contraction hyperkalemia, etc?- Aldosterone contributes by stimulate ing H-ATPase- Stimulating Sodium reabsorption creating lumen negative charge that promotes Hydrogen secretion- Loop diuretics can also stimulate net H loss by increased Hsecretion in the cortical aspect of the thick limb- This segment has two luminal entry points for na, the traditional NaK2Cl and Na-H exchanger- Blocking NaK2Cl with loop diuretic stimulates the Na-H exchanger- Can use NaCl or acetazolamide to treat- Metabolic acidosis- K-sparing diuretics reduce both K and H secretion in the collecting tubule- Avoid if renal failure or on an ACEi- Good advice to avoid K supplement with the K sparing diuretic- Hyponatremia- Diuretics can cause volume depletion leading to enhanced secretion of ADH and to increased water intake- Almost always due to a thiazide- Loops destroy the concentrated medullary gradient making ADH less effective- Hyperdrive is- Increased urate reabsorption in the proximal tubule- Process mediated by parallel Na-H and urate OH exchangers see figure 3-13a- Urate reabsorption varies directly with proximal Na transport and in patients with diuretic-induced volume deficiency both Na and urate excretion are reduced.- May be related to Ang II- Do not need to treat the hyperuricemia in asymptomatic patients- Do not develop urate nephropathy because tubular urateis actually low- Hypomagnesemia- Generally mild- Loop diuretics since most reabsorbed in the loop- Thiazides don’t affect Mg (why with gitelmans?)- Hypokalemia may directly inhibit tubular cell mg uptake- Aldosterone increases Mg excretion, so K sparing diuretics decrease Mg secretion- Determinants of Diuretic responsiveness- 2 important determinants of diuretic response- Site of action- Presence of counterbalancing antinatriuretic forces- Ang2- Aldo- Low systemic BP- Adds rate of drug excretion as # 2 and a half- Almost all diuretics are protein bound- So not well filtered- Enter tubule through organic anion and organic cation transporter- This can limit diuretic effectiveness- Natriuretic response plateaus at higher rates of diuretic excretion due to complete inhibition of the diuretic target- This plateau in normal people is 1 mg of bumetanide and 40 mg of furosemide given IV- Double this for oral furosemide, no adjustment needed for bumetanide- 15-6- Refractory edema- Start with a loop diuretic- Initial aim is to find the effective single dose- From the paragraph this is about threshold dosing- Double ineffective doses until good effect- Suggests maximum furosemide dose is 200 mg IV and 400 mg oral- Excess sodium intake- High sodium diet can work to prevent patients from achieving negative sodium balance.- Suggests diets after leaving the hospital maybe higher in sodium- Decreased or delayed intestinal absorption- Decreased intestinal perfusion, reduced intestinal motility and mucosal edema may contribute.- But why is this worse with furosemide than with bumetidine or torsemide?- Decreased drug entry into the tubular lumen- Thiazides don’t work below a GFR of 20- CLICK- Renal failure- Increased organic anions compete for diuretic secretion- Bumetidine isn’t as dependent as furosemide on GFR- Use 1/20th rather than 1/40th the dose- Maximum of 8 to 10 mg- Furosemide has ototoxicirty at high doses, he advises against 2400 mg/day- There is a Na-K-2Cl carrier in the endolymph producing cells- Ethacrynic acid has the most ototoxicity- Only loop or thiazide that isn’t a sulfonamide derivative- Cirrhosis- Spiro is diuretic of choice- More effective than loops alone- Does not induce hypokalemia that can cause hepatic encephalopathy- Cirrhosis causes marked hyperaldo- Loop diuretics have to compete with bile salts for secretion in the proximal tubule- Spiro does not need to be secreted in the proximal tubule- Recommends to 100 to 40 spiro to furosemide ratio- And can double this to 200 and 80/day- and a maximum of of 400/160- Hypoalbuminemia- <2 g/dL associated with decreased diuretic entry into the lumen- Protein binding keeps diuretics in the blood, reduces the volume of distribution- This maximizes the delivery to the kidney- In nephrotic syndrome tubular albumin can bind diuretic and prevent its activity- Co administration of albumin with diuretic has resulted in modest improvements in diuretic effectiveness in various studies- Intravenous infusion of loop diuretics- Infusions are greater than bolus- But if patient is not responding to blouses unlikely to respond to infusions since bolus provides a temporary spike in plasma level- Increased distal reabsorption- Increased distal sodium reabsorption decreases the effectiveness of proximal diuretics- Due to aldo and increased sodium delivery- Mentions that thiazides have a proximal effect (is that inhibition of carbonic anhydrase?)- 15-8 is very cool- Says all thiazides are created equal- Article from 1972 is why people use metolazone in advanced renal disease- When doing sequential nephron blocked be careful- Loss of lots of fluid- Loss of lots of potassium- Loss of 5 liters and 200 mEq of K a day is possible with sequential nephron blockade- Decreased loop sodium delivery- With heart failure and cirrhosis increased proximal resorption mediated by Ang II markedly reduces delivery of fluid to the diuretic sensitive sites.- Acetazolamide makes sense here- Supine or 10 degree head down can increase cardiac output possibly increased venous return- Can double Na excretion- Increase CrCl 40%- CAVH enters the chat!- Other uses of diuretics- Met alk, RTA, DI, hyponatremia due to SIADH, hypokalemia- Diuretics and prostaglandins- Loops and thiazides increase renal generation of prostaglandins- Can cause venous dilation may help with acute pulmonary edema- Can help without increased diuresis- NSAIDS counter the effect of loop diuretics- Is this natriuretic effect of PGE? Or due to renal ischemia due to unopposed Ang2 and norepi- They also raise BP and reduce cardiac output due to increased vascular resistance- Vasoconstrictor effect of loop diuretics- One hour after loop diuretics increase vasoconstriction and rise in systemic blood pressure- Increased Renin and norepinephrine, resolved 4 hours later- Seen in heart failure and cirrhosis- In cirrhosis decrease in RPF and GFR of 30-40% with furosemideReferencesMelanie noted that thiazide diuretics were the Project MUSE - Releasing the Flood Waters: Diuril and the Reshaping of HypertensionFurosemide early review of furosemide effect in a range of different clinical conditions. Na+, K+, and BP homeostasis in man during furosemide: Effects of prazosin and captopril This article is quoted in Rose’s book-(Figure 2 is 5-1). The authors provide a figure with a balance study that shows how an initial “diuresis” is followed Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology - American Journal of Kidney Diseaseshttps://jasn.asnjournals.org/content/30/2/216  Thiazide induced hyponatremia, a detailed phenotypic and genotypic analysis (NephJC) https://www.sciencedirect.com/science/article/pii/B9780126356908500025Classic paper on diuretics in NEJM from Craig Brater: https://www.nejm.org/doi/full/10.1056/NEJM199808063390607Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders https://linkinghub.elsevier.com/retrieve/pii/S0085253820314046Nephrocalcinosis of 17% in preemies: https://pubmed.ncbi.nlm.nih.gov/35348900/Nephrocalcinosis with loop diuretics in neonates: https://pubmed.ncbi.nlm.nih.gov/38296790/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941622/We wondered whether the effect of hypercalemia on loop is complete –did we go too far saying that loop diuretics have no effect  Anna’s VOG on hypercalciuria and lasix, etc. NEJM Paper describing the dose of lasix needed for calciuria   Meta analysis of lasix used for calciuric effects .  David Ellison and Robert Schrier experiment showing NCC activation with chronic loops. NCC activation occurs with hypercalcemia as well via CASRThiazide Treatment in Primary Hyperparathyroidism—A New Indication for an Old Medication? | The Journal of Clinical Endocrinology & Metabolism | Oxford AcademicThiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades - PMCMajor Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) | Acute Coronary Syndromes | JAMAUromodulin upregulates TRPV5 by impairing caveolin-mediated endocytosis - University of IowaAcetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistanceRegulation of Potassium Homeostasis | American Society of Nephrology Biff Palmer’s review.Distal Convoluted Tubule - PMC  we did not discuss this paper by Subramanya and Ellison but it is a gemIt Is Chloride Depletion Alkalosis, Not Contraction Alkalosis | American Society of NephrologyThiazide Effects and Adverse Effects | HypertensionA comparison of the potassium and magnesium-sparing properties of amiloride and spironolactone in diuretic-treated normal subjects. - PMCSGLT2i case series for hypomag: SGLT2 Inhibitors for Treatment of Refractory Hypomagnesemia: A Case Report of 3 Patients - PMC Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomized controlled trialsAnti-EGFR monoclonal antibody-induced hypomagnesaemia - The Lancet Oncology

Outline Chapter 14 — Treatment- Treatment - Both oral and IV treatment can be used for volume replacement - The goal of therapy are to restore normovolemia - And to correct associated acid-base and electrolyte disorders - Oral Therapy - Usually can be accomplished with increased water and dietary sodium - May use salt tablets - Glucose often added to resuscitation fluids - Provides calories - Promotes intestinal Na reabsorption since there is coupled Na and Glucose similar to that seen in the proximal tubule - Rice based solutions provide more calories and amino acids which also promote sodium reabsorption - 80g/L of glucose with rice vs 20 g/L with glucose alone - IV therapy - Dextrose solutions - Physiologically equivalent to water - For correcting hypernatremia - For covering insensible losses - Watch for hyperglycemia - Footnote warns against giving sterile water - Saline solutions - Most hypovolemic patients have a water and a sodium deficit - Isotonic saline has a Na concentration of 154, similar to that of plasma see page 000 - Half-isotonic saline is equivalent to 550 ml of isotonic saline and 500 of free water. Is that a typo? - 3% is a liter of hypertonic saline and 359 extra mEq of Na - Dextrose in saline solutions - Give a small amount of calories, otherwise useless - Alkalinizing solutions - 7.5% NaHCO3 in 50 ml ampules 44 mEq of Na and 44 mEq of HCO3 - Treat metabolic acidosis or hyperkalemia - Why 44 mEq and not 50? - Do not give with calcium will form insoluble CaCO3 - Polyionic solutions - Ringers contains physiologic K and Ca - Lactated Ringers adds 28 mEq of lactate - Spreads myth of LR in lactic acidosis - Potassium chloride - Available as 2 mEq/mL - Do not give as a bolus as it can cause fatal hyperkalemia - Plasma volume expanders - Albumin, polygelastins, hetastarch are restricted to vascular space - 25% albumin can pull fluid into the vascular space - 25% albumin is an albumin concentration of 25 g/dL compare to physiologic 4 g/dL - Says it pulls in several times its own volume - 5% albumin is like giving plasma - Blood - Which fluid? - Look at osmolality, give hypotonic fluids to people with high osmolality - Must include all electrolytes - Example of adding 77 mEw of K to 0.45 NS and making it isotonic - DI can be replaced with dextrose solutions, pure water deficit - Case 14-3 - Diarrhea with metabolic acidosis - He chooses 0.25 NS with 44 mEq of NaCl and 44 NaHCO3 - Talks about blood and trauma - Some studies advocate delaying saline until penetrating trauma is corrected APR about to. Keep BP low to prevent bleeding. Worry about diluting coagulation factors - Only do this if the OR is quickly available - Volume deficit - Provides formula for water deficit and sodium deficit - Do not work for isotonic losses - Provides a table to adjust fluid loss based on changes in Hgb or HCTZ - Says difficult to estimate it from lab findings and calculations - Follow serial exams - Serial urine Na - Rate of replacement - Goal is not to give fluid but to induce a positive balance - Suggests 50-100 ml/hr over what is coming out of the body - Urine - Insensibles 30-50 - Diarrhea - Tubes - Hypovolemic shock - Due to bleeding - Sequesting in third space - Why shock? - Progressive volume depletion leads to - Increased sympathetic NS - Increased Ang 2 - Initially this maintains BP, cerebral and coronary circulation - But this can decrease splanchnic, renal and mucocutaneous perfusion - This leads to lactic acicosis - This can result in intracellular contents moving into circulation or translocation of gut bacteria - Early therapy to prevent irreversible shock - In dogs need to treat with in 2 hours - In humans may need more than 4 hours - Irreversible shock associated with pooling of blood in capillaries - Vasomotor paralysis - Hyperpolarization of vascular smooth muscle as depletion of ATP allows K to flowing out from K channels opening. Ca flows out too leading to vasodilation - Glyburide is an K-ATP channel inhibitor (?) caused increased vasoconstriction and BP - Pluggin of capillaries by neutrophils - Cerebral ischemia - Increased NO generation - Which Fluids? - Think of what is lost and replace that. - Bleeding think blood - Raise the hct but not above 35 - Acellular blood substitutes, looked bad at the time of this writing - Di aspirin cross linked hemoglobin had increased 2 and 28 day mortality vs saline - Colloids sound great but they fail in RCTs - SAFE - FEAST - Points out that saline replaces the interstitial losses why do we think those losses are unimportant - Pulmonary circulation issue - Pulmonary circulation is more leaky so oncotic pressure less effective there - Talks about the lungs be naturally protected from pulmonary edema - Rate of fluid - 1-2 liters in first hour - Suggests CVP or capillary wedge pressure during resuscitation - No refs in the rate of fluid administration section - Lactic acidosis - Points out that HCO can impair lactate utilization - Also states that arterial pH does not point out what is happening at the tissue level. Suggests mixed-venous sample.ReferencesWhy is Gonorrhea Called the Clap? - Nurx™Here’s the piece we celebrated from David Goldfarb: The Normal Saline Ceremony - PMCPotency of Oral Rehydration Solution in Inducing Fluid Absorption is Related to Glucose Concentration | Scientific Reports an interesting report on how Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in childrenHere’s a study in the Lancet that explored use the bicarbonate infusion in severe metabolic acidosis. https://www.sciencedirect.com/science/article/pii/S0140673618310808Joel briefly reviewed the issues with normal saline vs balanced solution and alluded to some of these reports: SMART  Balanced Crystalloids versus Saline in Critically Ill Adults | NEJM And  SALT-ED https://www.nejm.org/doi/10.1056/NEJMoa1711586We did not discuss this article on LR in cirrhotics but this study lower incidence of adverse outcomes and did not show higher lactate levels  Lactated Ringer's vs Saline Among Critically Ill Adults With Cirrhosis: A Secondary Analysis of the Isotonic Solutions and Major Adverse Renal Events TrialJoel mentioned a Cochrane review of albumin that showed increased mortality: Human albumin administration in a critically ill patients: systematic review of randomised controlled trialsThe SAFE Trial that exonerated albumin: A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit | NEJMIntravenous albumin infusion is an effective therapy for hyponatremia in patient with malignant ascites - PMCJC mentioned this study: Comparison of 5% human albumin and normal saline for fluid resuscitation in sepsis induced hypotension among patients with cirrhosis (FRISC study): a randomized controlled trial  and then this one: A randomized-controlled trial comparing 20% albumin to plasmalyte in patients with cirrhosis and sepsis- induced hypotension plus here is the CONFIRM Terlipressin plus Albumin for the Treatment of Type 1 Hepatorenal Syndrome | NEJM and ATTIRE A Randomized Trial of Albumin Infusions in Hospitalized Patients with Cirrhosis | NEJMAmy taught us that the military do use hetastarch in emergencies- up to 1 liter. Here’s a study that looked at its use. Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care | NEJMAnd here’s a cool resource: Fluid resuscitation in haemorrhagic shock in combat casualties | Disaster and Military Medicine | Full TextAnna reviewed European guidelines on volume resuscitation- Timing and volume of fluid administration for patients with bleeding - Kwan, I - 2014 | Cochrane LibraryThe Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) | Critical Care Medicine | JAMAStudies on the renin-angiotensin-aldosterone system in patients with cirrhosis and ascites: effect of saline and albumin infusionAnna’s VOG on SIRS being out the door

OutlineChapter 14- Hypovolemic States- Etiology - True volume depletion occurs when fluid is lost from from the extracellular fluid at a rate exceeding intake - Can come the GI tract - Lungs - Urine - Sequestration in the body in a “third space” that is not in equilibrium with the extracellular fluid. - When losses occur two responses ameliorate them - Our intake of Na and fluid is way above basal needs - This is not the case with anorexia or vomiting - The kidney responds by minimizing further urinary losses - This adaptive response is why diuretics do not cause progressive volume depletion - Initial volume loss stimulates RAAS, and possibly other compensatory mechanisms, resulting increased proximal and collecting tubule Na reabsorption. - This balances the diuretic effect resulting in a new steady state in 1-2weeks - New steady state means Na in = Na out - GI Losses - Stomach, pancreas, GB, and intestines secretes 3-6 liters a day. - Almost all is reabsorbed with only loss of 100-200 ml in stool a day - Volume depletion can result from surgical drainage or failure of reabsorption - Acid base disturbances with GI losses - Stomach losses cause metabolic alkalosis - Intestinal, pancreatic and biliary secretions are alkalotic so losing them causes metabolic acidosis - Fistulas, laxative abuse, diarrhea, ostomies, tube drainage - High content of potassium so associated with hypokalemia - [This is a mistake for stomach losses] - Bleeding from the GI tract can also cause volume depletion - No electrolyte disorders from this unless lactic acidosis - Renal losses - 130-180 liters filtered every day - 98-99% reabsorbed - Urine output of 1-2 liters - A small 1-2% decrease in reabsorption can lead to 2-4 liter increase in Na and Water excretion - 4 liters of urine output is the goal of therapeutic diuresis which means a reduction of fluid reabsorption of only 2% - Diuretics - Osmotic diuretics - Severe hyperglycemia can contribute to a fluid deficit of 8-10 Iiters - CKD with GFR < 25 are poor Na conservers - Obligate sodium losses of 10 to 40 mEq/day - Normal people can reduce obligate Na losses down to 5 mEq/day - Usually not a problem because most people eat way more than 10-40 mEq of Na a day. - Salt wasting nephropathies - Water losses of 2 liters a day - 100 mEq of Na a day - Tubular and interstitial diseases - Medullary cystic kidney - Mechanism - Increased urea can be an osmotic diuretic - Damage to tubular epithelium can make it aldo resistant - Inability to shut off natriuretic hormone (ANP?) - The decreased nephro number means they need to be able to decrease sodium reabsorption per nephron. This may not be able to be shut down acutely. - Experiment, salt wasters can stay in balance if sodium intake is slowly decreased. (Think weeks) - Talks about post obstruction diuresis - Says it is usually appropriate rather than inappropriate physiology. - Usually catch up solute and water clearance after releasing obstruction - Recommends 50-75/hr of half normal saline - Talks briefly about DI - Skin and respiratory losses - 700-1000 ml of water lost daily by evaporation, insensible losses (not sweat) - Can rise to 1-2 liters per hour in dry hot climate - 30-50 mEq/L Na - Thirst is primary compensation for this - Sweat sodium losses can result in hypovolemia - Burns and exudative skin losses changes the nature of fluid losses resulting in fluid losses more similar to plasma with a variable amount of protein - Bronchorrhea - Sequestration into a third space - Volume Deficiency produced by the loss of interstitial and intravascular fluid into a third space that is not in equilibrium with the extracellular fluid. - Hip fracture 1500-2000 into tissues adjacent to fxr - Intestinal obstruction, severe pancreatitis, crush injury, bleeding, peritonitis, obstruction of a major venous system - Difference between 3rd space and cirrhosis ascities - Rate of accumulation, if the rate is slow enough there is time for renal sodium and water compensation to maintain balance. - So cirrhotics get edema from salt retension and do not act as hypovolemia - Hemodynamic response to volume depletion - Initial volume deficit reduced venous return to heart - Detected by cardiopulmonary receptors in atria and pulmonary veins leading to sympathetic vasoconstriction in skin and skeletal muscle. - More marked depletion will result in decreased cardiac output and decrease in BP - This drop in BP is now detected by carotid and aortic arch baroreceptors resulting in splanchnic and renal circulation vasoconstriction - This maintains cardiac and cerebral circulation - Returns BP toward normal - Increase in BP due to increased venous return - Increased cardiac contractility and heart rate - Increased vascular resistance - Sympathetic tone - Renin leading to Ang2 - These can compensate for 500 ml of blood loss (10%) - Unless there is autonomic dysfunction - With 16-25% loss this will not compensate for BP when patient upright - Postural dizziness - Symptoms - Three sets of symptoms can occur in hypovolemic patients - Those related to the manner in which the fluid loss occurs - Vomiting - Diarrhea - Polyuria - Those due to volume depletion - Those due to the electrode and acid base disorders that can accompany volume depletion - The symptoms of volume depletion are primarily related to the decrease in tissue perfusion - Early symptoms - Lassitude - Fatiguability - Thirst - Muscle cramps - Postural dizziness - As it gets more severe - Abdominal pain - Chest pain - Lethargy - Confusion - Symptomatic hypovolemia is most common with isosmotic Na and water depletion - In contrast pure water loss, causes hypernatremia, which results in movement of water from the intracellular compartment to the extracellular compartment, so that 2/3s of volume loss comes from the intracellular compartment, which minimizes the decrease in perfusion - Electrolyte disorders and symptoms - Muscle weakness from hypokalemia - Polyuria/poly dips is from hyperglycemia and hypokalemia - Lethargy, confusion, Seizures, coma from hyponatremia, hypernatremia, hyperglycemia - Extreme salt craving is unique to adrenal insufficiency - Eating salt off hands ref 18 - Evaluation of the hypovolemic patient - Know that if the losses are insensible then the sodium should rise - Volume depletion refers to extracellular volume depletion of any cause, while dehydration refers to the presence of hypernatremia due to pure water loss. Such patients are also hypovolemic. - Physical exam is insensitive and nonspecific - Finding most sensitive and specific finding for bleeding is postural changes in blood pressure - I don’t find this very specific at all! - Recommends laboratory confirmation regardless of physical exam - Skin and mucous membranes - Should return too shape quickly - Elastic property is called Turgur - Not reliable is patients older than 55 to 60 - Dry axilla - Dry mucus membranes - Dark skin in Addison’s disease Frim increased ACTH - Arterial BP - As volume goes down so does arterial BP - Marked fluid loss leads to quiet korotkoff signs - Interpret BP in terms of the patients “normal BP” - Venous pressure - Best done by looking at the JVP - Right atrial and left atrial pressure - LV EDP is RAP + 5 mmHg - Be careful if valvular disease, right heart failure, cor pulmonare, - Figure 14-2 - Shock - 30% blood loss - Lab Data - Urine Na concentration - Should be less than 25 mmol/L, can go as low as 1 mmol/L - Metabolic alkalosis can throw this off - Look to the urine chloride - Figure 14-3 - Renal artery stenosis can throw this off - FENa - Mentions that it doesn’t work so well at high GFR - Urine osmolality - Indicates ADH - Volume depletion often associated with urine osm > 450 - Impaired by - Renal disease - Osmotic diuretic - Diuretics - DI - Mentions that severe volume depletion and hypokalemia impairs urea retension in renal medulla - Points out that isotonic urine does not rule out hypovolemia - Mentions specific gravity - BUN and Cr concentration - Normal ratio is 10:1 - Volume depletion this goes to 20:1 - Serum Na - Talks about diarrhea - Difference between secretory diarrhea which is isotonic and just causes hypovolemia - And osmotic which results in a lower electrolyte content and development of hypernatremia - Talks about hyperglycemia - Also can cause the sodium to rise from the low electrolyte content of the urine - But the pseudohyponatraemia can protect against this - Plasma potassium - Treatment - Both oral and IV treatment can be used for volume replacement - The goal of therapy are to restore normovolemia - And to correct associated acid-base and electrolyte disorders - Oral Therapy - Usually can be accomplished with increased water and dietary sodium - May use salt tablets - Glucose often added to resuscitation fluids - Provides calories - Promotes intestinal Na reabsorption since there is coupled Na and Glucose similar to that seen in the proximal tubule - Rice based solutions provide more calories and amino acids which also promote sodium reabsorption - 80g/L of glucose with rice vs 20 g/L with glucose alone - IV therapy - Dextrose solutions - Physiologically equivalent to water - For correcting hypernatremia - For covering insensible losses - Watch for hyperglycemia - Footnote warns against giving sterile water - Saline solutions - Most hypovolemic patients have a water and a sodium deficit - Isotonic saline has a Na concentration of 154, similar to that of plasma see page 000 - Half-isotonic saline is equivalent to 550 ml of isotonic saline and 500 of free water. Is that a typo? - 3% is a liter of hypertonic saline and 359 extra mEq of Na - Dextrose in saline solutions - Give a small amount of calories, otherwise useless - Alkalinizing solutions - 7.5% NaHCO3 in 50 ml ampules 44 mEq of Na and 44 mEq of HCO3 - Treat metabolic acidosis or hyperkalemia - Why 44 mEq and not 50? - Do not give with calcium will form insoluble CaCO3 - Polyionic solutions - Ringers contains physiologic K and Ca - Lactated Ringers adds 28 mEq of lactate - Spreads myth of LR in lactic acidosis - Potassium chloride - Available as 2 mEq/mL - Do not give as a bolus as it can cause fatal hyperkalemia - Plasma volume expanders - Albumin, polygelastins, hetastarch are restricted to vascular space - 25% albumin can pull fluid into the vascular space - 25% albumin is an albumin concentration of 25 g/dL compare to physiologic 4 g/dL - Says it pulls in several times its own volume - 5% albumin is like giving plasma - Blood - Which fluid? - Look at osmolality, give hypotonic fluids to people with high osmolality - Must include all electrolytes - Example of adding 77 mEw of K to 0.45 NS and making it isotonic - DI can be replaced with dextrose solutions, pure water deficit - Case 14-3 - Diarrhea with metabolic acidosis - He chooses 0.25 NS with 44 mEq of NaCl and 44 NaHCO3 - Talks about blood and trauma - Some studies advocate delaying saline until penetrating trauma is corrected APR about to. Keep BP low to prevent bleeding. Worry about diluting coagulation factors - Only do this if the OR is quickly available - Volume deficit - Provides formula for water deficit and sodium deficit - Do not work for isotonic losses - Provides a table to adjust fluid loss based on changes in Hgb or HCTZ - Says difficult to estimate it from lab findings and calculations - Follow serial exams - Serial urine Na - Rate of replacement - Goal is not to give fluid but to induce a positive balance - Suggests 50-100 ml/hr over what is coming out of the body - Urine - Insensibles 30-50 - Diarrhea - Tubes - Hypovolemic shock - Due to bleeding - Sequesting in third space - Why shock? - Progressive volume depletion leads to - Increased sympathetic NS - Increased Ang 2 - Initially this maintains BP, cerebral and coronary circulation - But this can decrease splanchnic, renal and mucocutaneous perfusion - This leads to lactic acicosis - This can result in intracellular contents moving into circulation or translocation of gut bacteria - Early therapy to prevent irreversible shock - In dogs need to treat with in 2 hours - In humans may need more than 4 hours - Irreversible shock associated with pooling of blood in capillaries - Vasomotor paralysis - Hyperpolarization of vascular smooth muscle as depletion of ATP allows K to flowing out from K channels opening. Ca flows out too leading to vasodilation - Glyburide is an K-ATP channel inhibitor (?) caused increased vasoconstriction and BP - Pluggin of capillaries by neutrophils - Cerebral ischemia - Increased NO generation - Which Fluids? - Think of what is lost and replace that. - Bleeding think blood - Raise the hct but not above 35 - Acellular blood substitutes, looked bad at the time of this writing - Di aspirin cross linked hemoglobin had increased 2 and 28 day mortality vs saline - Colloids sound great but they fail in RCTs - SAFE - FEAST - Points out that saline replaces the interstitial losses why do we think those losses are unimportant - Pulmonary circulation issue - Pulmonary circulation is more leaky so oncotic pressure less effective there - Talks about the lungs be naturally protected from pulmonary edema - Rate of fluid - 1-2 liters in first hour - Suggests CVP or capillary wedge pressure during resuscitation - No refs in the rate of fluid administration section - Lactic acidosis - Points out that HCO can impair lactate utilization - Also states that arterial pH does not point out what is happening at the tissue level. Suggests mixed-venous sample.ReferencesJCI - Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia and a nice review of this topic: Altered Prostaglandin Signaling as a Cause of Thiazide-Induced HyponatremiaThe electrolyte concentration of human gastric secretion. https://physoc.onlinelibrary.wiley.com/doi/10.1113/expphysiol.1960.sp001428A classic by Danovitch and Bricker: Reversibility of the “Salt-Losing” Tendency of Chronic Renal Failure | NEJMOsmotic Diuresis Due to Retained Urea after Release of Obstructive Uropathy | NEJMIs This Patient Hypovolemic? | Cardiology | JAMAAnd by the same author, a textbook: Steven McGee. 5th edition. Evidence-Based Physical Diagnosis Elsevier Philadelphia 2022. ISBN-13: 978-0323754835The clinical course and pathophysiological investigation of adolescent gestational diabetes insipidus: a case report | BMC Endocrine DisordersSensitivity and specificity of clinical signs for assessment of dehydration in endurance athletes | British Journal of Sports MedicineDiagnostic performance of serum blood urea nitrogen to creatinine ratio for distinguishing prerenal from intrinsic acute kidney injury in the emergency department | BMC NephrologyThe meaning of the blood urea nitrogen/creatinine ratio in acute kidney injury - PMCLanguage guiding therapy: the case for dehydration vs volume depletion https://www.acpjournals.org/doi/10.7326/0003-4819-127-9-199711010-00020?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmedValidation of a noninvasive monitor to continuously trend individual responses to hypovolemiaReferences for Anna’s voice of God on Third Spacing :  Shires Paper from 1964  (The ‘third space’ – fact or fiction? )References for melanie’s VOG:1. Appraising the Preclinical Evidence of the Role of the Renin-Angiotensin-Aldosterone System in Antenatal Programming of Maternal and Offspring Cardiovascular Health Across the Life Course: Moving the Field Forward: A Scientific Statement From the American Heart Association2. excellent review of RAAS in pregnancy: The enigma of continual plasma volume expansion in pregnancy: critical role of the renin-angiotensin-aldosterone systemhttps://journals-physiology-org.ezp-prod1.hul.harvard.edu/doi/full/10.1152/ajprenal.00129.20163. 10.1172/JCI107462- classic study in JCI of AngII responsiveness during pregnancy4. William’s Obstetrics 26th edition!5. Feto-maternal osmotic balance at term. A prospective observational study

ReferencesJC mentioned that the diagnostic accuracy of 24 hour urine collection increases with more collections! Metabolic evaluation of patients with recurrent idiopathic calcium nephrolithiasisWe didn't refer to a particular study on sodium intake and the 24 hour urine but this meta-analysis Comparison of 24‐hour urine and 24‐hour diet recall for estimating dietary sodium intake in populations: A systematic review and meta‐analysis - PMC 24‐hour diet recall underestimated population mean sodium intake.Anna looking up ace i and urinary sodium Effects of ACE inhibition on proximal tubule sodium transport | American Journal of Physiology-Renal PhysiologyThe original FENa paper by Espinel: The FeNa Test: Use in the Differential Diagnosis of Acute Renal Failure | JAMA | JAMA NetworkSchreir’s replication and expansion of Espinel’s data: Urinary diagnostic indices in acute renal failure: a prospective studyHere’s a report from our own JC on the Diagnostic Utility of Serial Microscopic Examination of the Urinary Sediment in Acute Kidney Injury | American Society of NephrologyJC shared his journey regarding FENa and refers to his recent paper Concomitant Identification of Muddy Brown Granular Casts and Low Fractional Excretion of Urinary Sodium in AKIAnd Melanie’s accompanying editorial Mind the Cast: FENa versus Microscopy in AKI : Kidney360 (with a great image from Samir Parikh)JC referenced this study from Schrier on FENa with a larger series: Urinary diagnostic indices in acute renal failure: a prospective study​​Nonoliguric Acute Renal Failure Associated with a Low Fractional Excretion of Sodium | Annals of Internal MedicineUrine sodium concentration to predict fluid responsiveness in oliguric ICU patients: a prospective multicenter observational study | Critical Care | Full TextA classic favorite: Acute renal success. The unexpected logic of oliguria in acute renal failure Marathon runners had granular casts in their urine without renal failure. Kidney Injury and Repair Biomarkers in Marathon RunnersCute piece from Rick Sterns on urine electrolytes! Managing electrolyte disorders: order a basic urine metabolic panelThe Urine Anion Gap: Common Misconceptions | American Society of NephrologyThe urine anion gap in context CJASNExcellent review from Halperin on urine chemistries (including some consideration of the TTKG): Use of Urine Electrolytes and Urine Osmolality in the Clinical Diagnosis of Fluid, Electrolytes, and Acid-Base Disorders - Kidney International ReportsRenal tubular acidosis (RTA): Recognize The Ammonium defect and pHorget the urine pH | SpringerLinkOutlineChapter 13- New part: Part 3, Physiologic approach to acid-base and electrolyte disorders - Do you remember the previous two parts? - Renal physiology - Regulation of water and electrolyte balance- Chapter 13: Meaning and application of urine chemistries - Measurement of urinary electrolyte concentrations, osmolality and pH helps diagnose some conditions - There are no fixed normal values - Kidney varies rate of excretion to match intake and endogenous production - Example: urine Na of 125/day can be normal if patient euvolemic on a normal diet, and wildly inappropriate in a patient who is volume depleted. - Urine chemistries are: - Useful - Simple - Widely available - Usually a random sample is adequate - 24-hour samples give additional context - Gives example of urinary potassium, with extra renal loss of K, urine K should be < 25, but if the patient has concurrent volume deficiency and urine output is only 500 mL, then urine K concentration can appropriately be as high as 40 mEq/L - Table 13-1 - Seems incomplete, see my notes on page 406 - What is Gravity ARF?- Sodium Excretion - Kidney varies Na to maintain effective circulating volume (I’d say volume homeostasis) - Urine Na affected by RAAS and ANP - Na concentration can be used to determine volume status - Urine Na < 20 is hypovolemia - Says it is especially helpful in determining the etiology of hyponatremia - Calls out SIADH and volume depletion - Used 40 mEq/L for SIADH - Also useful in AKI - Where differential is pre-renal vs ATN - In addition to urine Na (and FENa) look at urine osmolality - Again uses 40 mEq/l - Mentions FENa and urine osmolality - Urine Na can estimate dietary sodium intake - Suggests doing this during treatment of hypertension to assure dietary compliance - 24 hour urine Na is accurate with diuretics as long as the dose is stable and the drugs are chronic - Diuretics increase Na resorption in other segments of the tubule that are not affected by the diuretic - Points to increased AT2 induced proximal Na resorption and aldosterone induced DCT resoprtion - In HTN shoot for less than 100 mEq/Day - Urine Na useful in stones - Urine uric acid and urine Ca can cause stones and their handling is dependent on sodium - Low sodium diet can mask elevated excretion of these stone forming metabolites - 24-hour Na > 75 and should be enough sodium to avoid this pitfall - Pitfalls - Low urine sodium in bilateral renal artery stenosis or acute GN - High urine sodium with diuretics, aldo deficiency, advanced CKD - Altered water handling can also disrupt this - DI with 10 liters of urine and urine sodium excretion of 100 mEq is 10 mEq/L but in this case there is no volume deficiency - Opposite also important, a lot of water resorption can mask volume deficiency by jacking up the urine sodium - Advises you to use the FENa - THE FENA - < 1% dry - >2-3% ATN - It will fail with chronic effective volume depletion - Heart failure, cirrhosis, and burns - Suggests that tubular function will be preserved in those situations - Also with contrast, rhabdo, pigment nephropathy - Limitations - Dependent on the amount of Na filtered - Goes through the math of a normal person with GFR of 125/min and Na of 150 has filtered sodium of 27,000/day so if they eat 125-250 mEq their FENa will be <1% - Talks about diuretics - Can use FE lithium - Mainly reabsorbed in the proximal tubule - Not affected by loop diuretics - 20% in healthy controls - <15% in pre-renal disease - Can use FE Uric acid - Also not affected by loop diuretics - Below 12% is pre-renal - No FEUrea- Chloride excretion - Urine Cl and Na usually move in parallel - However as many as 30% of hypovolemic patients have more than a 15 mEq/L difference between urine Na and Cl - Due to Na excretion with another anion, HCO3 or carbenicillin or Cl with another cation, NH4+ - Discusses the metabolic alkalosis issue - Says the urine Na can be over 100 in volume depleted patients with metabolic alkalosis! - In metabolic acidosis (normal anion gap) - Urine Cl should rise to balance out the NH4 - RTA should also have urine pH > 5.3- Potassium excretion - Can go as low at 5-25/day - Low in extra renal losses - Or after the diuretics have worn off - More than 25/day indicates renal losses - Not so helpful in hyperkalemia since chronic hyperkalemia is always due to a defect renal potassium excretion - Expect always to have inappropriately low K with hyperkalemia due to - Renal failure - Hypoaldo- Urine osmolality - In hyponatremia it should < 100 - Hyponatremia here should be due to excessive water intake - In hypernatremia it should be > 600-800 - Urine osm < plasma osm in face of hypernatremia indicates renal water loss due to lack of or resistance to ADH - In ATN urine OSM < 400 - In pre-renal disease it could be over 500 - Specific but not sensitive due to people with CKD who are unable to concentrate urine- Specific gravity - Plasma is 8-10% igher than plasma so specific gravity is 1.008 to 1.010 - Every 30-35 mOsm/L raises urine Osm of 0.001 - so 1.010 is 300-350 mOsm/L H2O - Glucose raises urine specific gravity more than osmolality - Same with contrast - Carbenicillin- pH - Normally varies with systemic acid-base status - PH should fall before 5.3 (usually below 5.0) with systemic metabolic acidosis - Above 5.3 in adults and 5.6 in children indicate RTA - PH goal 6.0-6.5 - Separate individual RTAs through FR of HCO3 at various serum HCO3 levels - Also can monitor urine pH to look for success in treating metabolic alkalosis - Look for pH > 7 - In treatment of uric acid stone disease - Want to shift eq: H + urate – <=> uric acid to the left because urate is more soluble - PH goal 6.0-6.5

ReferencesWe considered the complexity of the machinery to excrete ammonium in the context of research on dietary protein and how high protein intake may increase glomerular pressure and contribute to progressive renal disease (many refer to this as the “Brenner hypothesis”). Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal diseaseA trial that studied low protein and progression of CKD The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease(and famously provided data for the MDRD eGFR equation A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study GroupWe wondered about dietary recommendations in CKD. of note, this is best done in the DKD guidelines from KDIGO Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.Joel mentioned this study on red meat and risk of ESKD. Red Meat Intake and Risk of ESRDWe referenced the notion of a plant-based diet. This is an excellent review by Deborah Clegg and Kathleen Hill Gallant.  Plant-Based Diets in CKD : Clinical Journal of the American Society of NephrologyHere’s the review that Josh mentioned on how the kidney appears to sense pH Molecular mechanisms of acid-base sensing by the kidneyRemarkably, Dr. Dale Dubin put a prize in his ECG book Free Car Prize Hidden in Textbook Read the fine print: Student wins T-birdA review of the role of the kidney in DKA: Diabetic ketoacidosis: Role of the kidney in the acid-base homeostasis re-evaluatedJosh mentioned the effects of infusing large amounts of bicarbonate The effect of prolonged administration of large doses of sodium bicarbonate in man and this study on the respiratory response to a bicarbonate infusion: The Acute Effects In Man Of A Rapid Intravenous Infusion Of Hypertonic Sodium Bicarbonate Solution. Ii. Changes In Respiration And Output Of Carbon DioxideThis is the study of acute respiratory alkalosis in dogs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC293311/?page=1And this is the study of medical students who went to the High Alpine Research Station on the Jungfraujoch in the Swiss Alps https://www.nejm.org/doi/full/10.1056/nejm199105163242003Self explanatory! A group favorite! It Is Chloride Depletion Alkalosis, Not Contraction AlkalosisEffects of chloride and extracellular fluid volume on bicarbonate reabsorption along the nephron in metabolic alkalosis in the rat. Reassessment of the classical hypothesis of the pathogenesis of metabolic alkalosisA review of pendrin’s role in volume homeostasis: The role of pendrin in blood pressure regulation | American Journal of Physiology-Renal PhysiologyInfusion of bicarbonate may lead to a decrease in respiratory stimulation but the shift of bicarbonate to the CSF may lag. Check out this review Neural Control of Breathing and CO2 Homeostasis and this classic paper Spinal-Fluid pH and Neurologic Symptoms in Systemic Acidosis.OutlineOutline: Chapter 11- Regulation of Acid-Base Balance- Introduction - Bicarb plus a proton in equilibrium with CO2 and water - Can be rearranged to HH - Importance of regulating pCO2 and HCO3 outside of this equation - Metabolism of carbs and fats results in the production of 15,000 mmol of CO2 per day - Metabolism of protein and other “substances” generates non-carbonic acids and bases - Mostly from sulfur containing methionine and cysteine - And cationic arginine and lysine - Hydrolysis of dietary phosphate that exists and H2PO4– - Source of base/alkali - Metabolism of an ionic amino acids - Glutamate and asparatate - Organic anions going through gluconeogenesis - Glutamate, Citrate and lactate - Net effect on a normal western diet 50-100 mEq of H+ per day - Homeostatic response to these acid-base loads has three stages: - Chemical buffering - Changes in ventilation - Changes in H+ excretion - Example of H2SO4 from oxidation of sulfur containing AA - Drop in bicarb will stimulate renal acid secretion - Nice table of normal cid-base values, arterial and venous- Great 6 bullet points of acid-base on page 328 - Kidneys must excrete 50-100 of non-carbonic acid daily - This occurs by H secretion, but mechanisms change by area of nephron - Not excreted as free H+ due to minimal urine pH being equivalent to 0.05 mmol/L - No H+ can be excreted until virtually all of th filtered bicarb is reabsorbed - Secreted H+ must bind buffers (phosphate, NH3, cr) - PH is main stimulus for H secretion, though K, aldo and volume can affect this.- Renal Hydrogen excretion - Critical to understand that loss of bicarb is like addition of hydrogen to the body - So all bicarb must be reabsorbed before dietary H load can be secreted - GFR of 125 and bicarb of 24 results in 4300 mEq of bicarb to be reabsorbed daily - Reabsorption of bicarb and secretion of H involve H secretion from tubular cells into the lumen. - Thee initial points need to be emphasized - Secreted H+ ion are generated from dissociation of H2O - Also creates OH ion - Which combine with CO2 to form HCO3 with the help of zinc containing intracellular carbonic anhydrase. - This is how the secretion of H+ which creates an OH ultimately produces HCO3 - Different mechanisms for proximal and distal acidification - NET ACID EXCRETION - Free H+ is negligible - So net H+ is TA + NH4 – HCO3 loss - Unusually equal to net H+ load, 50-100 mEq/day - Can bump up to 300 mEq/day if acid production is increased - Net acid excretion can go negative following a bicarb or citrate load - Proximal Acidification - Na-H antiporter (or exchanger) in luminal membrane - Basolateral membrane has a 3 HCO3 Na cotransporter - This is electrogenic with 3 anions going out and only one cation - The Na-H antiporter also works in the thick ascending limb of LOH - How about this, there is also a H-ATPase just like found in the intercalated cells in the proximal tubule and is responsible for about a third of H secretion - And similarly there is also. HCO3 Cl exchanger (pendrin-like) in the proximal tubule - Footnote says the Na- 3HCO3 cotransporter (which moves sodium against chemical gradient NS uses negative charge inside cell to power it) is important for sensing acid-base changes in the cell. - Distal acidification - Occurs in intercalated cells of of cortical and medullary collecting tubule - Three main characteristics - H secretion via active secretory pumps in the luminal membrane - Both H-ATPase and H-K ATPase - H- K ATPase is an exchange pump, k reabsorption - H-K exchange may be more important in hypokalemia rather than in acid-base balance - Whole paragraph on how a Na-H exchanger couldn’t work because the gradient that H has to be pumped up is too big. - H-ATPase work like vasopressin with premise H-ATPase sitting on endocarditis vesicles a=which are then inserted into the membrane. Alkalosis causes them to be recycled out of the membrane. - H secretory cells do not transport Na since they have few luminal Na channels, but are assisted by the lumen negative tubule from eNaC. - Minimizes back diffusion of H+ and promotes bicarb resorption - Bicarbonate leaves the cell through HCO3-Cl exchanger which uses the low intracellular Cl concentration to power this process. - Same molecule is found on RBC where it is called band 3 protein - Figure 11-5 is interesting - Bicarbonate resorption - 90% in the first 1-22 mm of the proximal tubule (how long is the proximal tubule?) - Lots of Na-H exchangers and I handed permeability to HCO3 (permeability where?) - Last 10% happens distally mostly TAL LOH via Na-H exchange - And the last little bit int he outer medullary collecting duct. - Carbonic anhydrase and disequilibrium pH - CA plays central role in HCO3 reabsorption - After H is secreted in the proximal tubule it combines with HCO# to form carbonic acid. CA then dehydrates it to CO2 and H2O. (Step 2) - Constantly moving carbonic acid to CO2 and H2O keeps hydrogen combining with HCO3 since the product is rapidly consumed. - This can be demonstrated by the minimal fall in luminal pH - That is important so there is not a luminal gradient for H to overcome in the Na-H exchanger (this is why we need a H-ATPase later) - CA inhibitors that are limited tot he extracellular compartment can impair HCO3 reabsorption by 80%. - CA is found in S1, S2 but not S3 segment. See consequence in figure 11-6. - The disequilibrium comes from areas where there is no CA, the HH formula falls down because one of the assumptions of that formula is that H2CO3 (carbonic acid) is a transient actor, but without CA it is not and can accumulate, so the pKa is not 6.1. - Bicarbonate secretion - Type B intercalated cells - H-ATPase polarity reversed - HCO3 Cl exchanger faces the apical rather than basolateral membrane- Titratable acidity - Weak acids are filtered at the glom and act as buffers in the urine. - HPO4 has PKA of 6.8 making it ideal - Creatinine (pKa 4.97) and uric acid (pKa 5.75) also contribute - Under normal cinditions TA buffers 10-40 mEa of H per day - Does an example of HPO4(2-):H2PO4 (1-) which exists 4:1 at pH of 7.4 (glomerular filtrate) - So for 50 mEq of Phos 40 is HPO4 and 10 is H2PO4 - When pH drops to 6.8 then the ratio is 1:1 so for 50 - So the 50 mEq is 25 and 25, so this buffered an additional 15 mEq of H while the free H+ concentration increased from 40 to 160 nanomol/L so over 99.99% of secreted H was buffered - When pH drops to 4.8 ratio is 1:100 so almost all 50 mEq of phos is H2PO4 and 39.5 mEq of H are buffered. - Acid loading decreases phosphate reabsorption so more is there to act as TA. - Decreases activity of Na-phosphate cotransporter - DKA provides a novel weak acid/buffer beta-hydroxybutyrate (pKa 4.8) which buffers significant amount of acid (50 mEq/d).- Ammonium Excretion - Ability to excrete H+ as ammonium ions adds an important amount of flexibility to renal acid-base regulation - NH3 and NH4 production and excretion can be varied according to physiologic need. - Starts with NH3 production in tubular cells - NH3, since it is neutral then diffuses into the tubule where it is acidified by the low pH to NH4+ - NH4+ is ionized and cannot cross back into the tubule cells(it is trapped in the tubular fluid) - This is important for it acting as an important buffer eve though the pKa is 9.0 - At pH of 6.0 the ratio of NH3 to NH4 is 1:1000 - As the neutral NH3 is converted to NH4 more NH3 from theintracellular compartment flows into the tubular fluid replacing the lost NH3. Rinse wash repeat. - This is an over simplification and that there are threemajor steps - NH4 is produced in early proximal tubular cells - Luminal NH4 is partially reabsorbed in the TAL and theNH3 is then recycled within the renal medulla - The medullary interstitial NH3 reaches highconcentrations that allow NH3 to diffuse into the tubular lumen in the medullary collecting tubule where it is trapped as NH4 by secreted H+ - NH4 production from Glutamine which converts to NH4 and glutamate - Glutamate is converted to alpha-ketoglutarate - Alpha ketoglutarate is converted to 2 HCO3 ions - HCO3 sent to systemic circulation by Na-3 HCO3 transporter - NH4 then secreted via Na-H exchanger into the lumen - NH4 is then reabsorbed by NaK2Cl transporter in TAL - NH4 substitutes for K - Once reabsorbed the higher intracellular pH causes NH4 to convert to NH3 and the H that is removed is secreted through Na-H exchanger to scavenge the last of the filtered bicarb. - NH3 diffuses out of the tubular cells into the interstitium - NH4 reabsorption in the TAL is suppressed by hyperkalemia and stimulated by chronic metabolic acidosis - NH4 recycling promotes acid clearance - The collecting tubule has a very low NH3 concentration - This promotes diffusion of NH3 into the collecting duct - NH3 that goes there is rapidly converted to NH4 allowing more NH3 to diffuse in. - Response to changes in pH - Increased ammonium excretion with two processes - Increased proximal NH4 production - This is delayed 24 hours to 2-3 days depending on which enzyme you look at - Decreased urine pH increases diffusion of ammonia into the MCD - Occurs with in hours of an acid load - Peak ammonium excretion takes 5-6 days! (Fig 11-10) - Glutamine is picked up from tubular fluid but with acidosis get Na dependent peritublar capillary glutamine scavenging too - Glutamine metabolism is pH dependent with increase with academia and decrease with alkalemia - NH4 excretion can go from 30-40 mEq/day to > 300 with severe metabolic acidosis (38 NaBicarb tabs) - Says each NH4 produces equimolar generation of HCO3 but I thought it was two bicarb for every alpha ketoglutarate?- The importance of urine pH - Though the total amount of hydrogren cleared by urine pH is insignificant, an acidic urine pH is essential for driving the reactions of TA and NH4 forward.- Regulation of renal hydrogen excretion - Net acid excretion vary inverse with extracellular pH - Academia triggers proximal and distal acidification - Proximally this: - Increased Na-H exchange - Increased luminal H-ATPase activity - Increased Na:3HCO3 cotransporter on the basolateral membrane - Increased NH4 production from glutamine - In the collecting tubules - Increased H-ATPase - Reduction of tubular pH promotes diffusion of NH3 which gets converted to NH4…ION TRAPPING - Extracellular pH affects net acid excretion through its affect on intracellular pH - This happens directly with respiratory disorders due to movement of CO2 through the lipid bilayer - In metabolic disorders a low extracellular bicarb with cause bicarb to diffuse out of the cell passively, this lowers intracellular pH - If you manipulate both low pCO2 and low Bicarb to keep pH stable there will be no change in the intracellular pH and there is no change in renal handling of acid. It is intracellular pH dependent - Metabolic acidosis - Ramps up net acid secretion - Starts within 24 hours and peaks after 5-6 days - Increase net secretion comes from NH4 - Phosphate is generally limited by diet - in DKA titratable acid can be ramped up - Metabolic alkalosis - Alkaline extracellular pH - Increased bicarb excretion - Decrease reabsorption - HCO3 secretion (pendrin) in cortical collecting tubule - Occurs in cortical intercalated cells able to insert H-ATPase in basolateral cells (rather than luminal membrane) - Normal subjects are able to secrete 1000 mmol/day of bicarb - Maintenance of metabolic alkalosis requires a defect which forces the renal resorption of bicarb - This can be chloride/volume deficiency - Hypokalemia - Hyperaldosteronism - Respiratory acidosis and alkalosis - PCO2 via its effect on intracellular pH is an important determinant of renal acid handling - Ratios he uses: - 3.5 per 10 for respiratory acidosis - 5 per 10 for respiratory alkalosis - Interesting paragraph contrasting the response to chronic metabolic acidosis vs chronic respiratory acidosis - Less urinary ammonium in respiratory acidosis - Major differences in proximal tubule cell pH - In metabolic acidosis there is decreased bicarb load so less to be reabsorbed proximally - In respiratory acidosis the increased serum bicarb increases the amount of bicarb that must be reabsorbed proximally - The increased activity of Na-H antiporter returns tubular cell pH to normal and prevents it from creating increased urinary ammonium - Mentions that weirdly more mRNA for H-Na antiporter in metabolic acidosis than in respiratory acidosis - Net hydrogen excretion varies with effective circulating volume - Starts with bicarb infusions - Normally Tm at 26 - But if you volume deplete the patient with diuretics first this increases to 35+ - Four factors explain this increased Tm for bicarb with volume deficiency - Reduced GFR - Activation of RAAS - Ang2 stim H-Na antiporter proximally - Ang2 also stimulates Na-3HCO3 cotransporter on basolateral membrane - Aldosterone stimulates H-ATPase in distal nephron - ALdo stimulates Cl HCO3 exchanger on basolateral membrane - Aldo stimulates eNaC producing tubular lumen negative charge to allow H secretion to occur and prevents back diffusion - Hypochloremia - Increases H secretion by both Na-dependent and Na-independent methods - If Na is 140 and Cl is 115, only 115 of Na can be reabsorbed as NaCl, the remainder must be reabsorbed with HCO3 or associated with secretion of K or H to maintained electro neutrality - This is enhanced with hypochloridemia - Concurrent hypokalemia - Changes in K lead to trans cellular shifts that affect inctracellular pH - Hypokalemia causes K out, H in and in the tubular cell the cell acts if there is systemic acidosis and increases H secretion (and bicarbonate resorption) - PTH - Decreases proximal HCO3 resorption - Primary HyperCard as cause of type 2 RTA - Does acidosis stim PTH or does PTH stim net acid excretion

The Channelers went where no nephrology podcasters have gone before, recording in front of a live audience at the National Kidney Foundation Clinical Meeting in Austin. We had all eight Channelers doing a live podcast.We did a Freely Filtered-inspired draft of the best diuretics.The draft order:Leticia Rolon Anna Gaddy Joel TopfRoger Rodby Josh Waitzman Amy Yau JC Velez And Melanie HoenigReferencesJC Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney DiseaseIntravenous conivaptan for the treatment of hyponatraemia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experienceRapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following TolvaptanTolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for HyponatremiaJosh Review on amiloride development https://pubmed.ncbi.nlm.nih.gov/7039345/Toad bladder: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1351665/Amiloride derivatives that inhibit flagella: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544414/Amiloride as taste sensor: https://www.science.org/doi/10.1126/science.6691151Batlle on diabetes Insipidus: https://www.nejm.org/doi/full/10.1056/NEJM198502143120705?query=recirc_curatedRelated_articleAmiloride + ddavp for DI https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518801/Amy Treatment of refractory congestive heart failure and normokalemic hypochloremic alkalosis with acetazolamide and spironolactone.Acetazolamide reversibly inhibits water conduction by aquaporin-4Inhibition of Human Aquaporin-1 Water Channel Activity by Carbonic Anhydrase InhibitorsAcetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes InsipidusAcetazolamide in Lithium-Induced Nephrogenic Diabetes InsipidusIn Vivo Antibacterial Activity of AcetazolamideRoger50th anniversary of aldosteroneJoelSotagliflozin in Patients with Diabetes and Recent Worsening Heart FailureThe SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trialEffects of Early Empagliflozin Initiation on Diuresis and Kidney Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF)Empagliflozin and Heart failure: Diuretic and Cardiorenal EffectsAnnaClinical Results of Treatment of Diabetes Insipidus with Drugs of the Chlorothiazide SeriesTreatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amilorideInfluence of renal nerves and sodium balance on the acute antidiuretic effect of bendroflumethiazide in rats with diabetes insipidusAntidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channelMajor Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs DiureticWalsh AC, Moyes A. Intractable Congestive Heart Failure Successfully Treated With Southey Tubes. Can Med Assoc J. 1964 Jun 13;90(24):1375-6.Godwin TF, Gunton RW. Clinical trial of a new diuretic, furosemide: comparison with hydrochlorothiazide and mercaptomerin. Can Med Assoc J. 1965 Dec 18;93(25):1296-300.Gerber JG. Role of prostaglandins in the hemodynamic and tubular effects of furosemide. Fed Proc. 1983 Apr;42(6):1707-10.Schlatter E, Salomonsson M, Persson AE, Greger R. Macula densa cells sense luminal NaCl concentration via furosemide sensitive Na+2Cl-K+ cotransport. Pflugers Arch. 1989 Jul;414(3):286-90. doi: 10.1007/BF00584628.

ReferencesWe considered the effect of a high protein diet and potential metabolic acidosis on kidney function. This review is of interest by Donald Wesson, a champion for addressing this issue and limiting animal protein: Mechanisms of Metabolic Acidosis-Induced Kidney Injury in Chronic Kidney DiseaseHostetter explored the effect of a high protein diet in the remnant kidney model with 1 ¾ nephrectomy. Rats with reduced dietary acid load (by bicarbonate supplementation) had less tubular damage. Chronic effects of dietary protein in the rat with intact and reduced renal massWesson explored treatment of metabolic acidosis in humans with stage 3 CKD in this study. Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rateIn addition to the effect of metabolic acidosis from a diet high in animal protein, this diet also leads to hyperfiltration. This was demonstrated in normal subjects;  ingesting a protein diet had a significantly higher creatinine clearance than a comparable group of normal subjects ingesting a vegetarian diet.   Renal functional reserve in humans: Effect of protein intake on glomerular filtration rate.This finding has been implicated in Brenner’s theory regarding hyperfiltration: The hyperfiltration theory: a paradigm shift in nephrologyOne of multiple publications from Dr. Nimrat Goraya whom Joel mentioned in the voice over: Dietary Protein as Kidney Protection: Quality or Quantity?We wondered about the time course in buffering a high protein meal (and its subsequent acid load on ventilation) and Amy found this report:Effect of Protein Intake on Ventilatory Drive | Anesthesiology | American Society of Anesthesiologists Roger mentioned that the need for acetate to balance the acid from amino acids in parenteral nutrition was identified in pediatrics perhaps because infants may have reduced ability to generate acid. Randomised controlled trial of acetate in preterm neonates receiving parenteral nutrition - PMCHe also recommended an excellent review on the complications of parenteral nutrition by Knochel https://www.kidney-international.org/action/showPdf?pii=S0085-2538%2815%2933384-6 which explained that when the infused amino acids disproportionately include cationic amino acids, metabolism led to H+ production. This is typically mitigated by preparing a solution that is balanced by acetate. Amy mentioned this study that explored the effect of protein intake on ventilation: Effect of Protein Intake on Ventilatory Drive | Anesthesiology | American Society of AnesthesiologistsAnna and Amy reminisced about a Skeleton Key Group Case from the renal fellow network Skeleton Key Group: Electrolyte Case #7JC wondered about isolated defects in the proximal tubule and an example is found here: Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalitiesAnna’s Voiceover re:  Gastric neobladder → metabolic alkalosis and yes, dysuria.  The physiology of gastrocystoplasty: once a stomach, always a stomach  but not as common as you might think Gastrocystoplasty: long-term complications in 22 patientsSjögren’s syndrome has been associated with acquired distal RTA and in some cases, an absence of the H+ ATPase, presumably from autoantibodies to this transporter. Here’s a case report: Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosisCan't get enough disequilibrium pH? Check this out- Spontaneous luminal disequilibrium pH in S3 proximal tubules. Role in ammonia and bicarbonate transport.Acetazolamide secretion was studied in this report Concentration-dependent tubular secretion of acetazolamide and its inhibition by salicylic acid in the isolated perfused rat kidney. | Drug Metabolism & DispositionIn this excellent review, David Goldfarb tackles the challenging case of a  A Woman with Recurrent Calcium Phosphate Kidney Stones (spoiler alert, many of these patients have incomplete distal RTA and this problem is hard to treat). Molecular mechanisms of renal ammonia transport excellent review from David Winer and Lee Hamm. OutlineOutline: Chapter 11- Regulation of Acid-Base Balance- Introduction - Bicarb plus a proton in equilibrium with CO2 and water - Can be rearranged to HH - Importance of regulating pCO2 and HCO3 outside of this equation - Metabolism of carbs and fats results in the production of 15,000 mmol of CO2 per day - Metabolism of protein and other “substances” generates non-carbonic acids and bases - Mostly from sulfur containing methionine and cysteine - And cationic arginine and lysine - Hydrolysis of dietary phosphate that exists and H2PO4– - Source of base/alkali - Metabolism of an ionic amino acids - Glutamate and asparatate - Organic anions going through gluconeogenesis - Glutamate, Citrate and lactate - Net effect on a normal western diet 50-100 mEq of H+ per day - Homeostatic response to these acid-base loads has three stages: - Chemical buffering - Changes in ventilation - Changes in H+ excretion - Example of H2SO4 from oxidation of sulfur containing AA - Drop in bicarb will stimulate renal acid secretion - Nice table of normal cid-base values, arterial and venous- Great 6 bullet points of acid-base on page 328 - Kidneys must excrete 50-100 of non-carbonic acid daily - This occurs by H secretion, but mechanisms change by area of nephron - Not excreted as free H+ due to minimal urine pH being equivalent to 0.05 mmol/L - No H+ can be excreted until virtually all of th filtered bicarb is reabsorbed - Secreted H+ must bind buffers (phosphate, NH3, cr) - PH is main stimulus for H secretion, though K, aldo and volume can affect this.- Renal Hydrogen excretion - Critical to understand that loss of bicarb is like addition of hydrogen to the body - So all bicarb must be reabsorbed before dietary H load can be secreted - GFR of 125 and bicarb of 24 results in 4300 mEq of bicarb to be reabsorbed daily - Reabsorption of bicarb and secretion of H involve H secretion from tubular cells into the lumen. - Thee initial points need to be emphasized - Secreted H+ ion are generated from dissociation of H2O - Also creates OH ion - Which combine with CO2 to form HCO3 with the help of zinc containing intracellular carbonic anhydrase. - This is how the secretion of H+ which creates an OH ultimately produces HCO3 - Different mechanisms for proximal and distal acidification - NET ACID EXCRETION - Free H+ is negligible - So net H+ is TA + NH4 – HCO3 loss - Unusually equal to net H+ load, 50-100 mEq/day - Can bump up to 300 mEq/day if acid production is increased - Net acid excretion can go negative following a bicarb or citrate load - Proximal Acidification - Na-H antiporter (or exchanger) in luminal membrane - Basolateral membrane has a 3 HCO3 Na cotransporter - This is electrogenic with 3 anions going out and only one cation - The Na-H antiporter also works in the thick ascending limb of LOH - How about this, there is also a H-ATPase just like found in the intercalated cells in the proximal tubule and is responsible for about a third of H secretion - And similarly there is also. HCO3 Cl exchanger (pendrin-like) in the proximal tubule - Footnote says the Na- 3HCO3 cotransporter (which moves sodium against chemical gradient NS uses negative charge inside cell to power it) is important for sensing acid-base changes in the cell. - Distal acidification - Occurs in intercalated cells of of cortical and medullary collecting tubule - Three main characteristics - H secretion via active secretory pumps in the luminal membrane - Both H-ATPase and H-K ATPase - H- K ATPase is an exchange pump, k reabsorption - H-K exchange may be more important in hypokalemia rather than in acid-base balance - Whole paragraph on how a Na-H exchanger couldn’t work because the gradient that H has to be pumped up is too big. - H-ATPase work like vasopressin with premise H-ATPase sitting on endocarditis vesicles a=which are then inserted into the membrane. Alkalosis causes them to be recycled out of the membrane. - H secretory cells do not transport Na since they have few luminal Na channels, but are assisted by the lumen negative tubule from eNaC. - Minimizes back diffusion of H+ and promotes bicarb resorption - Bicarbonate leaves the cell through HCO3-Cl exchanger which uses the low intracellular Cl concentration to power this process. - Same molecule is found on RBC where it is called band 3 protein - Figure 11-5 is interesting - Bicarbonate resorption - 90% in the first 1-22 mm of the proximal tubule (how long is the proximal tubule?) - Lots of Na-H exchangers and I handed permeability to HCO3 (permeability where?) - Last 10% happens distally mostly TAL LOH via Na-H exchange - And the last little bit int he outer medullary collecting duct. - Carbonic anhydrase and disequilibrium pH - CA plays central role in HCO3 reabsorption - After H is secreted in the proximal tubule it combines with HCO# to form carbonic acid. CA then dehydrates it to CO2 and H2O. (Step 2) - Constantly moving carbonic acid to CO2 and H2O keeps hydrogen combining with HCO3 since the product is rapidly consumed. - This can be demonstrated by the minimal fall in luminal pH - That is important so there is not a luminal gradient for H to overcome in the Na-H exchanger (this is why we need a H-ATPase later) - CA inhibitors that are limited tot he extracellular compartment can impair HCO3 reabsorption by 80%. - CA is found in S1, S2 but not S3 segment. See consequence in figure 11-6. - The disequilibrium comes from areas where there is no CA, the HH formula falls down because one of the assumptions of that formula is that H2CO3 (carbonic acid) is a transient actor, but without CA it is not and can accumulate, so the pKa is not 6.1. - Bicarbonate secretion - Type B intercalated cells - H-ATPase polarity reversed - HCO3 Cl exchanger faces the apical rather than basolateral membrane- Titratable acidity - Weak acids are filtered at the glom and act as buffers in the urine. - HPO4 has PKA of 6.8 making it ideal - Creatinine (pKa 4.97) and uric acid (pKa 5.75) also contribute - Under normal cinditions TA buffers 10-40 mEa of H per day - Does an example of HPO4(2-):H2PO4 (1-) which exists 4:1 at pH of 7.4 (glomerular filtrate) - So for 50 mEq of Phos 40 is HPO4 and 10 is H2PO4 - When pH drops to 6.8 then the ratio is 1:1 so for 50 - So the 50 mEq is 25 and 25, so this buffered an additional 15 mEq of H while the free H+ concentration increased from 40 to 160 nanomol/L so over 99.99% of secreted H was buffered - When pH drops to 4.8 ratio is 1:100 so almost all 50 mEq of phos is H2PO4 and 39.5 mEq of H are buffered. - Acid loading decreases phosphate reabsorption so more is there to act as TA. - Decreases activity of Na-phosphate cotransporter - DKA provides a novel weak acid/buffer beta-hydroxybutyrate (pKa 4.8) which buffers significant amount of acid (50 mEq/d).- Ammonium Excretion - Ability to excrete H+ as ammonium ions adds an important amount of flexibility to renal acid-base regulation - NH3 and NH4 production and excretion can be varied according to physiologic need. - Starts with NH3 production in tubular cells - NH3, since it is neutral then diffuses into the tubule where it is acidified by the low pH to NH4+ - NH4+ is ionized and cannot cross back into the tubule cells(it is trapped in the tubular fluid) - This is important for it acting as an important buffer eve though the pKa is 9.0 - At pH of 6.0 the ratio of NH3 to NH4 is 1:1000 - As the neutral NH3 is converted to NH4 more NH3 from theintracellular compartment flows into the tubular fluid replacing the lost NH3. Rinse wash repeat. - This is an over simplification and that there are threemajor steps - NH4 is produced in early proximal tubular cells - Luminal NH4 is partially reabsorbed in the TAL and theNH3 is then recycled within the renal medulla - The medullary interstitial NH3 reaches highconcentrations that allow NH3 to diffuse into the tubular lumen in the medullary collecting tubule where it is trapped as NH4 by secreted H+ - NH4 production from Glutamine which converts to NH4 and glutamate - Glutamate is converted to alpha-ketoglutarate - Alpha ketoglutarate is converted to 2 HCO3 ions - HCO3 sent to systemic circulation by Na-3 HCO3 transporter - NH4 then secreted via Na-H exchanger into the lumen - NH4 is then reabsorbed by NaK2Cl transporter in TAL - NH4 substitutes for K - Once reabsorbed the higher intracellular pH causes NH4 to convert to NH3 and the H that is removed is secreted through Na-H exchanger to scavenge the last of the filtered bicarb. - NH3 diffuses out of the tubular cells into the interstitium - NH4 reabsorption in the TAL is suppressed by hyperkalemia and stimulated by chronic metabolic acidosis - NH4 recycling promotes acid clearance - The collecting tubule has a very low NH3 concentration - This promotes diffusion of NH3 into the collecting duct - NH3 that goes there is rapidly converted to NH4 allowing more NH3 to diffuse in. - Response to changes in pH - Increased ammonium excretion with two processes - Increased proximal NH4 production - This is delayed 24 hours to 2-3 days depending on which enzyme you look at - Decreased urine pH increases diffusion of ammonia into the MCD - Occurs with in hours of an acid load - Peak ammonium excretion takes 5-6 days! (Fig 11-10) - Glutamine is picked up from tubular fluid but with acidosis get Na dependent peritublar capillary glutamine scavenging too - Glutamine metabolism is pH dependent with increase with academia and decrease with alkalemia - NH4 excretion can go from 30-40 mEq/day to > 300 with severe metabolic acidosis (38 NaBicarb tabs) - Says each NH4 produces equimolar generation of HCO3 but I thought it was two bicarb for every alpha ketoglutarate?- The importance of urine pH - Though the total amount of hydrogren cleared by urine pH is insignificant, an acidic urine pH is essential for driving the reactions of TA and NH4 forward.- Regulation of renal hydrogen excretion - Net acid excretion vary inverse with extracellular pH - Academia triggers proximal and distal acidification - Proximally this: - Increased Na-H exchange - Increased luminal H-ATPase activity - Increased Na:3HCO3 cotransporter on the basolateral membrane - Increased NH4 production from glutamine - In the collecting tubules - Increased H-ATPase - Reduction of tubular pH promotes diffusion of NH3 which gets converted to NH4…ION TRAPPING - Extracellular pH affects net acid excretion through its affect on intracellular pH - This happens directly with respiratory disorders due to movement of CO2 through the lipid bilayer - In metabolic disorders a low extracellular bicarb with cause bicarb to diffuse out of the cell passively, this lowers intracellular pH - If you manipulate both low pCO2 and low Bicarb to keep pH stable there will be no change in the intracellular pH and there is no change in renal handling of acid. It is intracellular pH dependent - Metabolic acidosis - Ramps up net acid secretion - Starts within 24 hours and peaks after 5-6 days - Increase net secretion comes from NH4 - Phosphate is generally limited by diet - in DKA titratable acid can be ramped up - Metabolic alkalosis - Alkaline extracellular pH - Increased bicarb excretion - Decrease reabsorption - HCO3 secretion (pendrin) in cortical collecting tubule - Occurs in cortical intercalated cells able to insert H-ATPase in basolateral cells (rather than luminal membrane) - Normal subjects are able to secrete 1000 mmol/day of bicarb - Maintenance of metabolic alkalosis requires a defect which forces the renal resorption of bicarb - This can be chloride/volume deficiency - Hypokalemia - Hyperaldosteronism - Respiratory acidosis and alkalosis - PCO2 via its effect on intracellular pH is an important determinant of renal acid handling - Ratios he uses: - 3.5 per 10 for respiratory acidosis - 5 per 10 for respiratory alkalosis - Interesting paragraph contrasting the response to chronic metabolic acidosis vs chronic respiratory acidosis - Less urinary ammonium in respiratory acidosis - Major differences in proximal tubule cell pH - In metabolic acidosis there is decreased bicarb load so less to be reabsorbed proximally - In respiratory acidosis the increased serum bicarb increases the amount of bicarb that must be reabsorbed proximally - The increased activity of Na-H antiporter returns tubular cell pH to normal and prevents it from creating increased urinary ammonium - Mentions that weirdly more mRNA for H-Na antiporter in metabolic acidosis than in respiratory acidosis - Net hydrogen excretion varies with effective circulating volume - Starts with bicarb infusions - Normally Tm at 26 - But if you volume deplete the patient with diuretics first this increases to 35+ - Four factors explain this increased Tm for bicarb with volume deficiency - Reduced GFR - Activation of RAAS - Ang2 stim H-Na antiporter proximally - Ang2 also stimulates Na-3HCO3 cotransporter on basolateral membrane - Aldosterone stimulates H-ATPase in distal nephron - ALdo stimulates Cl HCO3 exchanger on basolateral membrane - Aldo stimulates eNaC producing tubular lumen negative charge to allow H secretion to occur and prevents back diffusion - Hypochloremia - Increases H secretion by both Na-dependent and Na-independent methods - If Na is 140 and Cl is 115, only 115 of Na can be reabsorbed as NaCl, the remainder must be reabsorbed with HCO3 or associated with secretion of K or H to maintained electro neutrality - This is enhanced with hypochloridemia - Concurrent hypokalemia - Changes in K lead to trans cellular shifts that affect inctracellular pH - Hypokalemia causes K out, H in and in the tubular cell the cell acts if there is systemic acidosis and increases H secretion (and bicarbonate resorption) - PTH - Decreases proximal HCO3 resorption - Primary HyperCard as cause of type 2 RTA - Does acidosis stim PTH or does PTH stim net acid excretion

References for Chapter 10We did not mention many references in our discussion today but our listeners may enjoy some of the references below. Effects of pH on Potassium: New Explanations for Old Observations - PMC although the focus of this article is on potassium, this elegant review by Aronson and Giebisch reviews intracellular shifts as it relates to pH and K+.Josh swooned for Figure 10-1 is this right? Which figure was it? which shows the relationship between [H+] and pH. You can find this figure in the original reference from Halperin ML and others, Figure 1 here. Factors That Control the Effect of pH on Glycolysis in Leukocytes Here’s Leticia Rolon’s favorite Henderson-Hasselbalch calculator website: ​​Henderson-Hasselbalch Calculator | Buffer Solutions [hint! for this site, use the bicarbonate (or “total CO2”) for A- and PCO2 for the HA] There’s also a cooking tab for converting units! Fundamentals of Arterial Blood Gas Interpretation - PMC this review published posthumously from the late but beloved Jerry Yee and his group at Henry Ford Hospital, explores the details and underpinnings of our understandings of arterial blood gas interpretation (and this also addresses how our colleagues in clinical chemistry measure total CO2 - which JC referenced- but JC said “machine” and our colleagues prefer the word “instrument.”)Amy went deep on bicarbonate in respiratory acidosis. Here are her refs:Sodium bicarbonate therapy for acute respiratory acidosisSodium Bicarbonate in Respiratory AcidosisBicarbonate therapy in severe metabolic acidosisEffect of Intravenous Sodium Bicarbonate on Ventilation, Gas Exchange, and Acid-Base Balance in Patients with Chronic Pulmonary InsufficiencyBicarbonate Therapy in Severe Metabolic Acidosis | American Society of Nephrology this review article from Sabatini and Kurtzman addresses the issues regarding bicarbonate therapy including theoretical intracellular acidosis. Bicarbonate in DKA? Don’t do it: Bicarbonate in diabetic ketoacidosis - a systematic review Here’s a review  from Bushinsky and Krieger on the effect acidosis on bone https://www.sciencedirect.com/science/article/abs/pii/S0085253822002174Here is the primary resource that Anna used in here investigation of meat replacements Nutritional Composition of Novel Plant-Based Meat Alternatives and Traditional Animal-Based MeatsWe enjoyed this paper that Dr. Rose references from the Journal of Clinical Investigation 1955 in which investigators infused HCl into nephrectomized dogs and observed changes in extracellular ions. https://www.jci.org/articles/view/103073/pdWe wondered about the amino acids/protein in some available meat alternatives they are explored in this article in the journal Amino Acids: Protein content and amino acid composition of commercially available plant-based protein isolates - PMC and you may enjoy this exploration of the nutritional value of these foods: Full article: Examination of the nutritional composition of alternative beef burgers available in the United StatesOutlineChapter 10: Acid-Base Physiology - H concentration regulated tightly - Normal H+ is 40 nm/L - This one millionth the concentration of Na and K - It needs to be this dilute because H+ fucks shit up - Especially proteins - Cool foot note H+ actually exists as H3O+ - Under normal conditions the H+ concentration varies little from normal due to three steps - Chemical buffering by extracellular and intracellular bufffers - Control of partial pressure of CO2 by alterations of alveolar ventilation - Control of plasma bicarbonate by changes in renal H+ excretion - Acid and bases - Use definition by Bronsted - Acid can donate protons - Base can accept protons - There are two classes of acids** - Carbonic acid H2CO3 - Each day 15000 mmol of CO2 are generated - CO2 not acid but combines with water to form carbonic acid H2CO3 - CO2 cleared by the lungs - Noncarbonic acid - Formed from metabolism of protein. Sulfur containing AA generate H2SO4. Only 50-100 mEq of acid produced from these sources. - Cleared by the kidneys - Law of Mass Action - Velocity of reaction proportional to the product of the concentrations of the reactants - Goes through mass action formula for water - Concludes that water has H of 155 nanoM/L, more than the 40 in plasma - Says you can do the same mass experiment for every acid in the body - Can do it also for bases but he is not going to. - Acids and Bases can be strong or weak - Strong acids completely dissociate - Weak acids not so much - H2PO4 is only 80% dissociated - Weak acids are the principle buffers in the body - Then he goes through how H is measured in the blood and it becomes clear why pH is a logical way to measure. - Then there is a lot of math - HH equation - Derives it - Then uses it to look at phos. Very interesting application - Buffers - Goes tot he phosphate well again. Amazing math describing how powerful buffers can be - Big picture the closer the pKa is to the starting pH the better buffer, i.e. it can absorb lots of OH or H without appreciably changing pH - HCO3 CO2 system - H2CO3 to H + HCO3 has a PKA of 2.72 but then lots of Math and the bicarb buffer system has a pKa of 6.1 - But the real power of the bicarb buffer is that it is not a sealed system. The ability to ventilate and keep CO2 constant increases the buffering efficiency by 11 fold and the ability to lower the CO2 below normal increases 18 fold. - Isohydric principle - There is only one hydrogen ion concentration and since that is a critical part of the buffer equation, all buffer eq are linked and you can understand all of them by understanding one of them. So we just can look at bicarb and understand the totality of acid base. - Bicarb is the most important buffer because - High concentration in plasma - Ability for CO2 to ventilate - Other buffers include - Bone - Bone is more than just inorganic reaction - Live bone releases more calcium in response to an acid load than dead bone - More effect with metabolic acidosis than respiratory acidosis - Hgb - Phosphate - Protein

References for Chapter 9One of the few papers that Rose wrote as a single author explores electrolyte free water clearance. This seminal paper explores the issue in greater detail than the book. A New approach to disturbances in the plasma sodium concentrationWondering about the volume of sweat? Josh taught us that the volume of “transepidermal volume loss” is not affected by humidity https://www.jidonline.org/article/S0022-202X(15)48145-X/pdf but is greatly affected by temperature: Skin temperature and transepidermal water lossRegarding normal sweat physiology, there is a nice review (with figures!) titled Physiological mechanisms determining sweat composition which describes all the important cells and channels which make up sweat glands. And an important follow on paper titled Higher Bioelectric Potentials due to Decreased Chloride Absorption in the Sweat Glands of Patients with Cystic Fibrosis describing specifically the sweat characteristics of patients with cystic fibrosis.Melanie was enchanted by work from RA McCance who did early experiments to induce sodium deficiency using very low sodium diets and a homemade sauna-like tent. His musings are fascinating.  Lancet 1936 Experimental human salt deficiency MEDICAL PROBLEMS IN MINERAL METABOLISMAge-related decline in urine concentration may not be universal: Comparative study from the US and two small-scale societies from Jeff Sands (of urea transport fame!)In this initial report, after continually water loading 21 volunteers, the younger group (mean age 31) had a urine osmolality of 52 mOsm/kg compared to in the older group (mean age 84). Influence of age, renal disease, hypertension, diuretics, and calcium on the antidiuretic responses to suboptimal infusions of vasopressin. In a later report older subjects (mean age 72) vs younger controls (mean age 26) drank 20 ml/kg over 40 minutes. The younger group excreted more of the water in the first 2 hours and had a lower mean urine osmolality 86 vs 112 mOsm/kg compared to the older participants. Age-associated Alterations in Thirst and Arginine Vasopressin in Response to a Water or Sodium Load Howard Furst suggests the urine to plasma electrolyte ratio as a simpler strategy to consider the free water clearance: https://nephrology.edublogs.org/files/2014/03/Water-Restriction-in-Hyponatremia1-1eb8n40.pdf  or via pubmed: The urine/plasma electrolyte ratio: a predictive guide to water restrictionRapidity of Correction of Hyponatremia Due to Syndrome of Inappropriate Secretion of Antidiuretic Hormone Following TolvaptanInfoSnack picture of pre and post tolvaptan

References for chapter 8Robert Schrier proposed a unifying hypothesis to explain the sodium retention seen in edematous states like cirrhosis and heart failure, coining the term effective arterial blood volume (EABV). An open access review in JASN 2007 can be found here:  https://jasn.asnjournals.org/content/18/7/2028#ref-3  John P PetersASN Annual Award: https://www.asn-online.org/about/awards/award.aspx?awh_key=0ea83199-f86d-4506-9507-d7e4ce688cb4Short article discussing contributions of Dr. Peters by mentees Dr. Franklin Epstein and Dr. Donald Seldin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588700/ and https://pubmed.ncbi.nlm.nih.gov/12097739/Epstein FH et al. Studies of the antidiuresis of quiet standing: the importance of changes in plasma volume and glomerular filtration. JCI 1950. In this classic report, investigators studied their own sodium excretion supine, standing and with a variety of maneuvers (saline or albumin infusion)  and  showed that urinary sodium excretion is limited in the upright position compared to supine position. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC436228/pdf/jcinvest00414-0077.pdfAn interesting review of early concepts on hypertension feature notes on John J Hay and Paul Dudley White. The former was known to say, “The greatest danger to a man with high blood pressure lies in its discovery because then some fool is certain to try and reduce it!” and the latter has been quoted as saying that hypertension might be compensatory but apparently, these quotes are out of context. To find out what they really said, check out:  Elias MF and Goodell AL. Setting the record straight for two heroes in hypertension John J Hay and Paul Dudley White. J Clin Hypertens 2019 https://onlinelibrary.wiley.com/doi/epdf/10.1111/jch.13650 VA Cooperative Trial was an important study to establish the hypertension should, in fact, be treated The VA Cooperative Study and the Beginning of Routine Hypertension Screening, 1964-1980 This study was stopped after only 18 months because of an excess of deaths in the untreated group who had a mean diastolic BP of 115 mmHg. For a long time, only the diastolic BP was felt to be important until the Systolic Hypertension in Elderly Patients (“SHEP study”) clarified that treatment of isolated systolic hypertension is also importantPrevention of Stroke by Antihypertensive Drug Treatment in Older Persons With Isolated Systolic HypertensionWe continued to try to grapple with the work of Jens Titze on sodium which turns many of our assumptions about sodium upside down. His team studied astronauts on a long term high sodium diet and found an unexpected weekly (circaseptan) rhythm seemingly related inversely to aldosterone and directly with cortisol. His work also probes our notion of body sodium content. For a great first hand read, check out Dr TItze’s review in Kidney International 2014 which he aptly dubs, “Spooky Sodium Balence.” https://www.sciencedirect.com/science/article/pii/S0085253815562807Epstein M. The cardiovascular and renal effects of head-out of water Immersion in Man. Circulation Research 1976 Cardiovascular and renal effects of head-out water immersion in man: application of the model in the assessment of volume homeosSpace flight is an exaggeration of the water immersion experiments. Astronauts on either a low or normal sodium diet had a reset of natriuetic peptides. A Salty Tale: Study Examines Sodium Regulation in Space and Natriuretic Peptide Resetting in Astronauts | CirculationBaroreceptors feature mechanically activated ion channels called PIEZO1 and PIEZO2. Zeng W, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM. PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102061/We also relearned an unfortunate truth: lots of folks pee in pools. De Laat et al. Water Res. 2011.  Concentration levels of urea in swimming pool water and reactivity of chlorine with urea At the American College of Cardiology meeting in April, investigators shared the news that the combination of an ARB with new class of drugs called angiotensin receptor neprilysin inhibitor (ARNI) was not superior to ACE inhibitors at reduction of heart failure following acute MI. Here’s the press release for the PARADISE-MI trial. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial InfarctionA series of elegant experiments by Alicia McDonald’s team to characterize pressure natriuresis. In these studies, they induce hypertension by constriction of the superior mesenteric artery, the celiac artery and the infrarenal aorta (essentially increasing afterload without directly altering the blood flow to the kidney).  With this maneuver, the blood pressure of the experimental animal rises, urinary sodium excretion increases and then they demonstrate a shift in the Na-H ATPase from the apical membrane to intracellular vesicles in the proximal tubule and a shift in NCC from the luminal membrane to the intracellular vesicles in the distal tubules. Yang L et. al Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity. Am J Physiol Renal 2002 https://journals.physiology.org/doi/full/10.1152/ajprenal.00298.2001?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.orgLee DH Riquier ADM, Yang LE, Leong PK, Maunsbach and McDonough AA. Acute hypertension provokes acute trafficking of distal tubule NaCl (NCC) to subapical cytoplasmic vesicles. Am J Physiol Renal Physiol. 2009 Acute hypertension provokes acute trafficking of distal tubule Na-Cl cotransporter (NCC) to subapical cytoplasmic vesicles This review in KI reports is also worth a read McDonough AA. Maintaining Balance under pressure-hypertension and the proximal tubule. 2015 ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule

Chapter 7ReferencesSands JM, Blount MA and Klein JD. Regulation of Renal Urea Transport by Vasopressin. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116377/In this invited piece, Sands and colleagues explain that although urea is permeable across membranes, this is slow, thus urea transporters in the kidney, under control of vasopressin, are needed to facilitate transport and create the medullary gradient. Text book using 20% of extracellular compartment being in the intravascular compartment. https://courses.lumenlearning.com/ap2/chapter/body-fluids-and-fluid-compartments-no-content/ another one: https://med.libretexts.org/Bookshelves/Anatomy_and_Physiology/Book%3A_Anatomy_and_Physiology_(Boundless)/25%3A_Body_Fluids_and_Acid-Base_Balance/25.2%3A_Body_Fluids/25.2B%3A_Fluid_Compartments The chapter I wrote where I went through the math in figure 7-3. It was a major revelation to me: https://docs.google.com/document/d/17BM1xihvlztuQlU8GVNhEDoPLzr6GounHYZAtVUkLvw/edit?usp=sharing Association Between ICU-Acquired Hypernatremia and In-Hospital Mortality https://journals.lww.com/ccejournal/fulltext/2020/12000/association_between_icu_acquired_hypernatremia_and.26.aspx Rate of Correction of Hypernatremia and Health Outcomes in Critically Ill Patients https://pubmed.ncbi.nlm.nih.gov/30948456/ Edelman IS, Leibman J, O’Meara MP and Birkenfeld LW. Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. JCI 1958. This classic paper calculates the total body exchangeable sodium and potassium and establishes the relationship between these. Understanding this painstacking work helps understand the effect of supplementing potassium in the setting of hyponatremia. https://dm5migu4zj3pb.cloudfront.net/manuscripts/103000/103712/cache/103712.1-20201218131357-covered-e0fd13ba177f913fd3156f593ead4cfd.pdfEdelman is the Root of Almost All Good in Nephrology https://www.renalfellow.org/2014/11/20/edelman-is-root-of-almost-all-good-in/ Jens Titze and his team published a pair of articles that shocked those interested in salt and water in JCI in 2017. High Salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation https://www.jci.org/articles/view/88532Increased salt consumption induces body water conservation and decreases fluid intake https://www.jci.org/articles/view/88530in this exciting exploration of the basic assumptions that we hold true regarding salt and water (and staring Russian cosmonauts and an incredible controlled simulation of salt and water intake), Titze shows that high sodium intake does not simply drive water consumption (as we usually teach) but instead leads to a complex hormonal and metabolic response (even with diurnal variation!) and results in body water conservation and decreased water consumption. And accompanying editorial from Mark Zeidel: salt and water, not so simple. https://www.jci.org/articles/view/94004In addition, Titze and others have done interesting work on sodium deposition in tissues where it may also be a source for systemic inflammation.https://pubmed.ncbi.nlm.nih.gov/28154199/Jens Titze talking about salt, water, thirsting a TEDx talk. https://www.youtube.com/watch?v=jQQPBmnIuCY A discussion/debate of the overfill vs. underfill theory of edema in the nephrotic syndrome (hint- overfill theory triumphs) would be incomplete without a reference to congenital analbuminemia. This reference from Frontiers in Genetics explores the diagnosis, phenotype and molecular genetics and reveal that patients tend to have only mild edema but severe hyperlipidemia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478806/The finding that proteinuria can directly lead to sodium retention based on a study when puromycin aminoglycoside induced proteinuria of one kidney lead to sodium retention by that kidney which was localized to the distal nephron. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC436841/?page=9Plasmin may be the culprit at the level of the epithelial sodium channel based on Tom Kleyman’s work: https://jasn.asnjournals.org/content/20/2/233Amiloride may help! (stay tuned for amiloride in a future episode) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016639/An old favorite of JC’s from the Kidney International feature which debates the cause of edema in the nephrotic syndrome.https://www.sciencedirect.com/science/article/pii/S0085253815583075Under protest, we hobbled through a discussion of the Gibbs Donnan affect even encouraged by one of Amy’s fellows based on this article from QJM: https://academic.oup.com/qjmed/article/101/10/827/1520972 suggesting that our understanding of the role of hyponatremia in fractures might be all wrong- it could be related to hypoalbuminemia.

Chapter 6 part 2. ReferencesJosh touts the PARADIGM-HF Trial Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure | NEJM which found this combination was superior to an ARB alone Joel mentions an early atrial natriuretic peptide trial by Julie Lewis et al. Atrial natriuretic factor in oliguric acute renal failure - American Journal of Kidney Diseases and here’s a metanalysis that put this option to bed: Atrial Natriuretic Peptide for Management of Acute Kidney Injury: A Systematic Review and Meta-analysisSnack attack? Check out “Snack induced ANP” Snack-Induced Release of Atrial Natriuretic Factor | NEJMWant more natriuretic peptides than we discussed? Check out this review! Cardiac natriuretic peptides | Nature Reviews Cardiology or this fantastic review: Here’s an excellent review of ANP effect on the kidney: ANP-induced signaling cascade and its implications in renal pathophysiologyCerebral salt wasting and elevated brain natriuretic peptide levels after traumatic brain injury: 2 case reportsJoel mentions the study which probed CRIC cohort regarding NSAIDs. Association of Opioids and Nonsteroidal Anti-inflammatory Drugs With Outcomes in CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study - American Journal of Kidney Diseases and you may like the discussion on NephJC: ​​No Pain for the Kidneys from NSAIDs — NephJCThe KDIGO guidelines can be found here CKD-Mineral and Bone Disorder (CKD-MBD) – KDIGO Regulation and Effects of FGF23 in Chronic Kidney DiseaseElegant work on the calcium sensing receptor by Martin Pollak https://doi.org/10.1016/0092-8674(93)90617-YeClaudin 14, PTH, and calcium absorption in the loop of Henle: Parathyroid hormone controls paracellular Ca 2+transport in the thick ascending limb by regulating the tight-junction protein Claudin14Carboxymaltose induced hypophosphatemia by increasing FGF-23. Randomized trial of intravenous iron-induced hypophosphatemiaCurrent "corrected" calcium concept challenged. | The BMJThe Dialysis Encephalopathy Syndrome — Possible Aluminum Intoxication | NEJMNephMadness covered Aluminum binders in 2016.Roger mentioned the use of ferric citrate as a phosphate binder Ferric Citrate Controls Phosphorus and Delivers Iron in Patients on Dialysis | American Society of NephrologyJoel reminded us of the misadventures in efforts to normalize hemoglobin, first in hemodialysis patients The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin | NEJMLater, in patients with CKD, normalization was also not shown to be better: Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease | NEJM , Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia | NEJMA quick shout out for roxadustat and the Nephmadness Anemia region! Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis | NEJM, #NephMadness 2021: Anemia Region – AJKD BlogIn this review of vasopressin, you can find an excellent discussion of basic stimuli and vasopressin receptors: Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems | Physiological ReviewsX-Linked Nephrogenic diabetes insipidus is very rare and there was theory that all patients originated from the same family and traveled to the US on the Hopewell ship JCI - X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.  This report describes another family from the Netherlands with nephrogenic DI including the finding that the urine osmolarity never exceeds 200 mOsm/kg. Hereditary Nephrogenic Diabetes Insipidus - GeneReviews®  (and here’s a family with central diabetes insipidus  https://academic.oup.com/jcem/article/81/1/192/2649423?login=true )Although we have all learned that thiazides should be used with diabetes insipidus, to induce mild volume depletion, several case reports and animal data have found that acetazolamide might be the best diuretic for the job. Clinicians from Boston Medical Center tried it out in this report:    ​​Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus | NEJM based on exciting data in mice! https://jasn.asnjournals.org/content/27/7/2082.shortADH appears to have an effect on potassium excretion. This was investigated by Giebesch who found, with clearance and micropuncture studies in rats plus isolated perfused tubules, ADH increased potassium secretion  Influence of ADH on renal potassium handling: A micropuncture and microperfusion study   A corollary should be that inhibition of ADH would increase the risk of hyperkalemia but this was not observed in the SALT-1 and SALT-2 trials. 5% of patients developed hyperkalemia in both the tolvaptan group and the placebo group Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia | NEJMV1 vasopressin as a pressor Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature ReviewWe wondered/debated on our observation that hyponatremia is not reliably seen in patients receiving vasopressin in the ICU. In the VASST trial, Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock,  1 patient in each study arm of nearly 400 patients developed hyponatremia. Note that patients with hyponatremia (<130 mEq/L) were excluded from the study.Excellent review! Vasopressin and the Regulation of Aquaporin-2This report looks at the PET scan in individuals who are thirsty.  Neuroimaging of genesis and satiation of thirst and an interoceptor-driven theory of origins of primary consciousnessHere’s a little discussion of Dr. Grant Liddle. In addition to his eponymous syndrome, he coined the term “ectopic” and developed the dexamethasone suppression test. Grant Liddle (1921–1989) : The EndocrinologistThis is the sad case of licorice gluttony in NEJM which led to hypokalemia and a cardiac arrest. Case 30-2020: A 54-Year-Old Man with Sudden Cardiac ArrestIn this review of the principal and intercalated cells, check out Figure 8 which has an excellent figure of the aldosterone paradox. https://cjasn.asnjournals.org/content/clinjasn/early/2015/01/30/CJN.08880914.full.pdf?with-ds=yes%3Fversioned%3DtrueRemarkably, licorice has been used in dialysis patients to lower potassium in patients in this short term trial. Glycyr-rhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patientsAnimal studies on pregnant rats demonstrating the reset osmostat as predicted by Roger. Osmoregulation during Pregnancy in the Rat: EVIDENCE FOR RESETTING OF THE THRESHOLD FOR VASOPRESSIN SECRETION DURING GESTATION

Chapter 6 part 1In this review of vasopressin, you can find an excellent discussion of basic stimuli and vasopressin receptors: Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems | Physiological ReviewsX-Linked Nephrogenic diabetes insipidus is very rare and there was theory that all patients originated from the same family and traveled to the US on the Hopewell ship JCI - X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis.  This report describes another family from the Netherlands with nephrogenic DI including the finding that the urine osmolarity never exceeds 200 mOsm/kg. Hereditary Nephrogenic Diabetes Insipidus - GeneReviews®  (and here’s a family with central diabetes insipidus  https://academic.oup.com/jcem/article/81/1/192/2649423?login=true )Although we have all learned that thiazides should be used with diabetes insipidus, to induce mild volume depletion, several case reports and animal data have found that acetazolamide might be the best diuretic for the job. Clinicians from Boston Medical Center tried it out in this report:    ​​Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus | NEJM based on exciting data in mice! https://jasn.asnjournals.org/content/27/7/2082.shortADH appears to have an effect on potassium excretion. This was investigated by Giebesch who found, with clearance and micropuncture studies in rats plus isolated perfused tubules, ADH increased potassium secretion  Influence of ADH on renal potassium handling: A micropuncture and microperfusion study   A corollary should be that inhibition of ADH would increase the risk of hyperkalemia but this was not observed in the SALT-1 and SALT-2 trials. 5% of patients developed hyperkalemia in both the tolvaptan group and the placebo group Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia | NEJMV1 vasopressin as a pressor Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature ReviewWe wondered/debated on our observation that hyponatremia is not reliably seen in patients receiving vasopressin in the ICU. In the VASST trial, Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock,  1 patient in each study arm of nearly 400 patients developed hyponatremia. Note that patients with hyponatremia (<130 mEq/L) were excluded from the study.Excellent review! Vasopressin and the Regulation of Aquaporin-2This report looks at the PET scan in individuals who are thirsty.  Neuroimaging of genesis and satiation of thirst and an interoceptor-driven theory of origins of primary consciousnessHere’s a little discussion of Dr. Grant Liddle. In addition to his eponymous syndrome, he coined the term “ectopic” and developed the dexamethasone suppression test. Grant Liddle (1921–1989) : The EndocrinologistThis is the sad case of licorice gluttony in NEJM which led to hypokalemia and a cardiac arrest. Case 30-2020: A 54-Year-Old Man with Sudden Cardiac ArrestIn this review of the principal and intercalated cells, check out Figure 8 which has an excellent figure of the aldosterone paradox. https://cjasn.asnjournals.org/content/clinjasn/early/2015/01/30/CJN.08880914.full.pdf?with-ds=yes%3Fversioned%3DtrueRemarkably, licorice has been used in dialysis patients to lower potassium in patients in this short term trial. Glycyr-rhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patientsAnimal studies on pregnant rats demonstrating the reset osmostat as predicted by Roger. Osmoregulation during Pregnancy in the Rat: EVIDENCE FOR RESETTING OF THE THRESHOLD FOR VASOPRESSIN SECRETION DURING GESTATION

References for Chapter 5--the Distal NephronRoger pointed out the fact that the distal nephron can achieve very low urinary sodium as evidenced by observations in people from the Yanomamo tribe Blood pressure and electrolyte excretion in the Yanomamo Indians, an isolated population in this report, 84% of the participants had urinary sodium < 1mmol/24 hours. Information about the Yanomamo Tribe. It looks like they’re starting to make chocolate, now! YanomamiThe Yanomami are great observers of natureThe Amazon's Yanomami utterly abandoned by Brazilian authorities: ReportYanomami Amazon reserve invaded by 20,000 miners; Bolsonaro fails to actI believe this is the original study looking at urine sodium and blood pressure in the Yanomamo Indians, but the INTERSALT trial linked above I believe had more robust urine dataThis study mentions the average lipid profile for men and women along with BMI. I didn’t mention in the “Voice of God” overview, but there is some interest looking at the Yanomamo and rate of cancer as it relates to the correlation with intracellular potassium to sodium ratiosJosh referred back to his notes and realized that the tightest junctions are in the TOAD not FROG bladders Physiology and Function of the Tight JunctionAn excellent review from McCormick and Ellison on the Distal convoluted tubule in Comprehensive Physiology.We flirt with the disorder of Gordon’s syndrome: Familial Hyperkalemic Hypertension | American Society of Nephrology and its alter ego, Gitelman syndrome: Gitelman Syndrome | HypertensionJC spoke about this beautiful report on how calcineurin inhibitors lead to hyperkalemia (and mimic Gordon’s syndrome). The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertensionThis superb review of the DCT includes all the highlights of Rose’s chapter 5 with a modern lens including “braking” from DCT hypertrophy Distal Convoluted Tubule | American Society of NephrologyEchos of the lessons learned in the DCT can be seen in this review: Diuretic Treatment in Heart Failure | NEJMAnna reminds us of the ALL HAT trial which showed that chlorthalidone was superior to the lisinopril and amlodipine groups (and the alpha blocker dropped out earlier) ​​Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs DiureticNice review of drug induced Hyperuricemia with a deep dive into the mechanisms of diuretic induced Hyperuricemia. Drug-induced hyperuricaemia and goutPlus, despite the concerns that thiazides are weaker than loop diuretics and may not work in CKD, this report suggests that it can still be of use. Chlorthalidone for poorly controlled hypertension in chronic kidney disease: an interventional pilot studyIf you love diuretics, you will love this classic paper from Craig Brater on diuretics Diuretic Therapy | NEJM which also includes the t1/2 of various diuretics and points out that chlorthalidone’s half life is 24-55 hours so eliminated after 4-10 days. The hypercalcemia seen in some patients who take thiazides may be the unmasking of primary hyperparathyroidism Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two DecadesAs we discussed the relative importance of DCT vs Proximal tubule for the hypercalcemia seen with thiazides, Amy reminded us of about the TRPV5 knockout mice: JCI - Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5 JC mentioned the defect in TRPM6 that can cause severe hypomagnesemia:  Novel TRPM6 Mutations in 21 Families with Primary Hypomagnesemia and Secondary HypocalcemiaWe enjoyed talking about Liddle syndrome Hypertension caused by a truncated epithelial sodium channel γ subunit: genetic heterogeneity of Liddle syndromeWe wondered about the role of pendrin which was discovered after this book was published. Here’s a nice review: The role of pendrin in renal physiology and also a potential therapeutic target for pendrin: Pendrin—A New Target for Diuretic Therapy? | American Society of NephrologyBradykinen Bradykinin B2 receptor antagonist increases chloride and water absorption in rat medullary collecting ductMore Bradykinen Chronic Overexpression of Bradykinin in Kidney Causes Polyuria and Cardiac HypertrophyWe ended on a high note when we considered the urothelium of the American black bear. These magnificent creatures have aquaporins 1 &3 that allow them to reabsorb their own urine during hibernation. The urothelium of a hibernator: the American black bear

Show notes with a full set of references are available here: http://www.rosebook.club/episodes/2021/6/22/chapter-fourAlso, please fill out our listener survey: https://forms.gle/DVdcJikKZkzY56mXA

Chapter Three: How the proximal tubule is like Elizabeth Warren and other truths my friends from Boston taught me

The exciting conclusion to Chapter Two: Renal Circulation and Glomerular Filtration Rate

Back by popular demand…all two of you…the second chapter of The Clinical Physiology of Acid Base and Electrolyte Disorders.

The Channel Gang discusses the name of their new podcast and then discuss chapter one of The Book.