Chapter Nineteen: Metabolic Acidosis, part 3 | 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