3/19/2009. The task of the kidney in acid-base balance Excretion of the daily acid load. Buffering of an acid load. A o B - + H + B - A o +OH - C +

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1 The task of the kidney in acid-base balance Excretion of the daily acid load Buffering of an acid load Oxidation of amino acids, fats and carbohydrates often lead to acid production. On an average American diet we produce about 1 of meq / kg /day Pitts. Harvey Lect. 48: Chemical reactions of metabolism Buffering of produced acid consumes HCO 3 A o B - + B - A o +OH - C + A o + HCO 3 + H 2 CO 3 CO 2 + H 2 CO 3 CO 2 + OH - HCO - 3 OH - + Glucose o CO 2 + Glucose o Lactate - + Lactate - CO + OH - 2 The Henderson Hasselbalch Equation [HCO 3 ] ph = pk + log αpco 2 HCO 3 pk = 6.1 at 37 o C and 0.15 M salt α =

2 HCO 3 Reabsorption by secretion Secretion in the Proximal Tubule HCO - 3 CO 2 + OH - Lumen + HCO 3 CA IV CO 2 + Na + HCO 3 CO 2 +OH NHE 3 Na:H Exchanger translocating ATPase NBC Na:HCO 3 cotransporter Na + Pitts JCI 28: NBC1 HCO 3 reabsorption / secretion occurs in the Proximal and Collecting tubules PCT DCT Cell Types of the Collecting Tubule Principal Na + absorption ENaC Water absorption Aquaporin 2 K + secretion ROMK Intercalated Transport ATPase ThAL CD 2

3 secretion in the Collecting Tubule HCO - +OH - 3 CO 2 Cl - translocating ATPase + HCO 3 CA IV CO 2 + AE1 Cl:HCO 3 exchanger Regulation of Transport HCO 3 CO 2 + OH - pco 2 Aldosterone K Acid-Base status NH 3 ph Gradient Membrane Potential ph CO 2 stimulates Exocytosis of ATPase Vesicles Regulation of Secretion in the Collecting Tubule CO 2 ph i Ca i LUMEN HCO 3 CO 2 + OH - Rate of H + Secretion + Aldosterone Proximal and collecting Tubules Trans-epithelial membrane Potential mv 3

4 Regulation of Secretion in the Collecting Tubule by Urine ph NH 3 Secretion + Aldosterone Cl - HCO - 3 CO 2 + OH - + NH 3 NH 4 + Rate of Urine ph Gluconeogenesis NH 3 NH 3 Glutamine Glutamate αketo-glutarate PEP Glucose The Membrane Potential Generated by Na Absorption Regulates and K + Secretion in Collecting Tubules Acid Ingestion increases Ammonia Synthesis and Excretion by a saturable mechanism meq ingested Na K Na K NH Days Net acid excretion Net acid production about 60 meq 1 Liter of Urine at ph 5.0 = 10 μeq Hence, acid excretion must occur by means other than naked protons Net Acid Excretion = NH 4 +Titratable Acid HCO 3 NH 3 + NH 4 + HPO 4 = + H + H 2 PO 4 - NH 3 Production in Renal Disease 1. If the remaining nephrons are normal; they should be able to increase their NH 3 production. Glomerular Diseases typically have normal tubules 2. If the remaining nephrons are diseased, then their NH 3 production will remain low. Tubulo-interstitial diseases typically y have atrophic tubules. When the number of functioning nephrons falls below 20% (Cr = 4); The daily NH 3 production falls below what is needed to maintain Acid-base balance even when each nephron is synthesizing NH 3 at its maximal capacity 4

5 Approach to Acid Base Abnormalities Measure arterial ph, HCO 3 and pco 2 You need all three measurements! ph = pk + If ph < 7.4 ph > 7.4 [HCO 3 ] αpco 2 Acidosis Alkalosis Metabolic Acidosis Anion Gap = Na - ( Cl + HCO 3 ) ACIDOSIS Unmeasured Anion Lactic Acidosis Lactate Diabetic Ketoacidosis β-oh butyrate Renal Failure Toxins Salicylate Lactate, Salicylate Methanol Formate Ethylene Glycol Oxalate Paraldehyde? Normal Anion Gap Metabolic Acidosis Hyperchloremic Non-renal HCO 3 Loss Diarrhea Uretero-sigmoidostomy Renal HCO 3 Wasting Carbonic anhydrase inhibitors Distal RTA Proximal RTA Type IV RTA Metabolic Acidosis Low ph Low HCO 3 Low pco 2 Increased Metabolic Acid Production Lactic or ketoacids HCO 3 Losses renal RTA non-renal, mostly GI Renal Failure Acid Ingestion Renal Tubular Acidosis Proximal 6 Distal Type IV Normal Plasma [HCO 3 ], meq / L 5

6 Type IV Renal Tubular Acidosis Interstitial Renal Disease Hyperkalemia Hypo-reninemic Hypoaldosteronsim Proximal Renal Tubular Acidosis 1. Hereditary Cystinosis; Hereditary Fructose Intolerance; CLC5 mutations; Lowe s syndrome[(ptdins[4,5]p2) 5-phosphatase deficiency]; Wilson s disease Phosphorylase kinase deficiency; Pyruvate carboxylase deficiency CAII - autosomal dominant 2. Toxins Lead; Mercury; Cadmium;Outdated tetracycline 3. Multiple Myeloma 4. Renal Transplant Rejection 5. Hyperparathyroidism 6. Auto-immune Diseases Sjogren s syndrome Distal Renal Tubular Acidosis 1. Mutations in: AE1 - autosomal dominant and recessive ATPase autosomal recessive CAII - autosomal dominant Mineraldocorticoid receptor Epithelial Na channel 2. Toxins Amphotericin B, Li, toluene 3. Nephrocalcinosis 4. Sickle Cell Disease 5. Urinary Obstruction 6. Auto-immune Diseases Sjogren s syndrome 6