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Normal Anion Gap Acidoses Renal Tubular Acidosis

Normal Anion Gap Acidoses Renal Tubular Acidosis. Jai Radhakrishnan, MD, MS, MRCP, FACC, FASN Associate Professor of Clinical Medicine Columbia University. Disclosures. None. Objective. Physiology of renal acid handling Diagnostic approach to Metabolic Acidosis with normal anion gap.

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Normal Anion Gap Acidoses Renal Tubular Acidosis

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  1. Normal Anion Gap AcidosesRenal Tubular Acidosis Jai Radhakrishnan, MD, MS, MRCP, FACC, FASN Associate Professor of Clinical Medicine Columbia University

  2. Disclosures • None

  3. Objective • Physiology of renal acid handling • Diagnostic approach to Metabolic Acidosis with normal anion gap. • Case-based diagnostic workup of the RTA’s

  4. Chemistry: Carbonic Acid • Carbonic Acid. • [ H+ ] x [ HCO3- ] = k1 x H2CO3 = k2 x [ CO2 ] x [ H2O ] • Simplified • H2CO3 is not of clinical interest • [H2O] is constant in-vivo • PCO2 is more familiar than [CO2]: • [ H+ ] x [ HCO3- ] = k x PCO2 • [ Modified Henderson Equation. ] • HasselbalchModification

  5. Alb- Alb- HCO3- HCO3- Na+ Na+ Cl- Cl- Nl Anion gap M acidosis Metabolic Acidosis: The “Anion Gap”  [Na+] - ([Cl-] + [HCO3-]) ~ 10-12 mM/L

  6. Etiology of “normal anion gap” (A.K.A. “hyperchloremic”) metabolic acidosis 1. GI bicarbonate loss (typically also with low K): diarrhea villous adenoma pancreatic, biliary, small bowel fistulae uretero-sigmoidostomy obstructed uretero-ileostomy

  7. HCO3- HCO3- HCO3- Cl- Cl- HCO3- K+ GI Loss of HCO3- Pancreas Pancreas Ileum Ileum Colon Colon Cl- Normal Diarrhea

  8. Na+ Na+ K+ K+ HCO3- Cl- K+ Flooding the colon with HCO3- instead of Cl- drives K+ secretion

  9. Cl- Uretero-ileostomy Causes a Normal Anion Gap Acidosis HCO3- Skin ileal loop

  10. Causes of a “normal anion gap” (A.K.A. “hyperchloremic”) metabolic acidosis 2. Ingestions & infusions ammonium chloride hyperalimentation (arginine/lysine-rich) • 3. Renal bicarbonate (or equivalent) loss • proximal RTA • distal RTA • type IV RTA • early renal failure • acetazolamide • hydrated DKA

  11. Na+ (1) Na+ HCO3- H+ H+ (3) HCO3- + CO2 H2O Na+ Defective Na+ - dependent resorption = Fanconi’s Syndrome Proximal RTA (“Type II”) HCO3- glucose amino acids urate phosphate

  12. Na+ Na+ K+ K+ Aldosterone ATP Cl- H+ HCO3- HCO3- ADP + Pi Cl- Cl- ATP H+ ADP + Pi Cl- Distal RTA Principal cell a IC cell b IC cell

  13. NH4+ NH3 Not titratable; need to measure + H2PO4- HPO4-- + + HCO3- Titratable acid H2CO3 Present in Prox RTA Net acid excretion = urinary NH4+ + urinary “titratable acid” (H2PO4-) - urinary HCO3- H+

  14. Na+ Na+ K+ K+ Aldosterone ATP Cl- H+ HCO3- HCO3- ADP + Pi Cl- Cl- ATP H+ ADP + Pi Cl- Hyperkalemic distal RTA: Principal cell a IC cell b IC cell

  15. Na+ (1) Na+ HCO3- H+ H+ (3) HCO3- Failed CCD K+ secretion + CO2 H2O K+ H+ 3. K+ entry into proximal tubule cells 4. Alkalinization of prox tubule cell by K+/H+ exchange ACIDOSIS IN HYPORENINEMIC HYPOALDOSTERONISM 5. Total Body K+ Excess Decreases Proximal Tubule Acidification and Ammoniagenesis via Intracellular Alkalosis 2. Total body K+ excess

  16. DIAGNOSTIC APPROACH

  17. Urine pH vs. Plasma bicarbonate in RTA Normal Proximal RTA Urine pH Distal RTA Plasma [HCO3-] mM (Oxford Textbook of Nephrology - Soriano et al, 1967)

  18. Urinary Anion Gap • Urine (Na+K) – Cl • Proton is partially excreted as NH4 (unmeasured cation) • The gap is usually Zero or Negative • In dRTA the anion gap will remain zero or positive • In other acidoses, the gap will become more negative. Unmeasured anions-unmeasured cations

  19. A positive urine anion gap ~ no NH4+Cl excretion (i.e. low renal tubule acidification) Normal acidotic: closed circles Diarrhea: closed triangles Type 1 or IV RTA: open circles Battle et al, NEJM 1988

  20. Na+ Na+ K+ K+ HCO3- Cl- K+ Proximal RTA: Hypokalemia Flooding the distal tubule with HCO3- instead of Cl- in Proximal RTA drives K+ secretion

  21. Na+ Na+ K+ K+ Aldosterone ATP Cl- H+ HCO3- HCO3- ADP + Pi Cl- Cl- ATP H+ ADP + Pi Cl- Distal RTA: Hypokalemia H + no longer shunts Na + current so K+ must do so Principal cell a IC cell b IC cell

  22. HyperkalemicDistal RTA Na+ Na+ K+ K+ Aldosterone ATP Cl- H+ HCO3- HCO3- ADP + Pi Cl- Cl- ATP H+ ADP + Pi Cl- Principal cell Low Aldosterone Voltage defect a IC cell b IC cell

  23. Nephrocalcinosis/Kidney Stones • Distal RTA (High Incidence) • Alkaline urine: Calcium phosphate precipitation • Acidosis: Increased citrate reabsorption by proximal nephron • Proximal RTA (Not Seen): • Urine pH not high • Citrate not absorbed

  24. Na+ (1) Na+ HCO3- H+ H+ (3) HCO3- + CO2 H2O Na+ Defective Na+ - dependent resorption = Fanconi’s Syndrome FANCONI’S SYNDROME only in Proximal RTA HCO3- glucose amino acids urate phosphate

  25. Fractional excretion of HCO3-

  26. Fractional excretion of HCO3- Daily HCO3 Requirements • Proximal • >4 meq/kg • Distal • 1-2 meq/kg • Hyperkalemic • 1-2 meq/kg

  27. J Am Soc Nephrol 13:2160-2170, 2002

  28. Urine pH < 5.5 & high[K+] Urine pH > 5.5 & low/nl[K+] Distal RTA (“Type I”): secretory or gradient defect Hypo- aldosteronism RTA(type IV) Positive Urinary anion gap Urine pH & plasma [K+]

  29. Case 1 • A 55-year-old woman presents with complaints of lethargy, thirst, muscle weakness and generalized body pains. Previous ED visits with hypokalemia. • Her serum potassium level was 2.6 mmol/l. • Other Electrolytes: • sodium 138 mmol/l • chloride 116 mmol/l • HCO3 17 mmol/l • BUN/Creatinine normal • Glucose 75mg/dL • Urine analysis: pH 5.4, 2+ glucose • Urine anion gap: -20 Proximal RTA • ABG: • pH 7.25 • pCO2 28 • pO 2 100 • total bicarbonate 15.1 mmol/l • base excess –13.7 mmol/l

  30. Case 1: Proximal RTA

  31. FEHCO3 • Intravenous infusion of sodium bicarbonate at a rate of 0.5 to 1.0 meq/kg per hour •                      UHCO3   x   PCrFEHCO3    =    ———————————    x    100                              PHCO3   x   UCr • Proximal RTA: FE HCO3>15-20%

  32. Clinical Features of Proximal RTA • Urine pH depends on plasma [HCO3-] • Fractional HCO3- excretion high (15-20%) at nl plasma [HCO3-] • Plasma [K+] reduced, worsens with HCO3- therapy • Dose of daily HCO3- required: 10-15 mEq/kg/d • Non-renal: rickets or osteomalacia

  33. Causes of Proximal RTA • Primary isolated proximal RTA • hereditary (persistent)       • a. autosomal dominant       • b. autosomal recessive associated with mental retardation and ocular abnormalities     • Sporadic (transient in infancy) • Secondary proximal RTA    • in the context of Fanconi syndrome (cystinosis, galactosemia, fructose intolerance, tyrosinemia, Wilson disease, Lowe syndrome, metachromatic leukodystrophy, multiple myeloma, light chain disease)      • drugs and toxins (acetazolamide, outdated tetracycline, aminoglycoside antibiotics, valproate, 6-mercaptopurine, streptozotocin, iphosphamide, lead, cadmium, mercury)      • other clinical entities (vitamin D deficiency, hyperparathyroidism, chronic hypocapnia, Leigh syndrome, cyanotic congenital heart disease, medullary cystic disease, Alport syndrome, corticoresistant nephrotic syndrome, renal transplantation, amyloidosis, recurrent nephrolithiasis) J Am Soc Nephrol 13:2160-2170, 2002

  34. Case 2 Distal RTA • A 38-year-old woman was admitted with severe weakness (3rd episode) • PMH: artificial tears for dry eyes • Laboratory • Urine pH 7.1 • sodium 141 mEq/L • potassium 3.0 mEq/L • carbon dioxide 14 mEq/L • chloride 114 mEq/L • S creatinine 0.8 mg/dL (70.7 µmol/L) • Albumin 4.3 • Urinary anion gap +4 Arch Intern Med. 2004;164:905-909

  35. Case 2: Distal RTA Arch Intern Med. 2004;164:905-909

  36. Nephrocalcinosis/Recurrent StonesConsider Distal RTA

  37. Furosemide/Fludrocortisone Test • Baseline urine sample • Oral administration of furosemide (40 mg) and fludrocortisone (1 mg). • Fluid intake ad libitum. • Urine q1h x 6 h after the baseline sample. • Failed to acidify their urine to pH<5.3 Kidney International (2007) 71, 1310–1316

  38. Schirmer’s test positive • antibodies to the Ro/SSA and La/SSB + • Cryocrit +

  39. Causes of distal RTA J Am Soc Nephrol 13:2160-2170, 2002

  40. Case 3 50 year old male with NIDDMhas been prescribed a low Na diet for HTN. He presents to the ER with marked weakness. Labs: 130|98|18 280 8.0 |20|1.3 Urine pH 5.0, 1+ proteinUrine Na130, K 15, Cl 120

  41. Case 3 50 year old male with NIDDMhas been prescribed a low Na diet for HTN. He presents to the ER with marked weakness. Labs: 130|98|50 280 8.0 |20|1.3 Urine pH 5.0, 1+ protein

  42. Type IV RTA: Etiology • Aldosterone • Hyporenin/hypoaldo (CKD) • Addison • Congenital :enzymes • Voltage • PHA • Drugs: TMP, K-sparing, pentamidine CNI (Na-K ATPas) • Multiple: Tubulointerstitial disease

  43. RTA

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