1-4. Acid-base disorders. Elena Levtchenko (eng)


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IPNA-ESPN teaching course "Pediatric nephrology: Evidence-based statements and open questions", Moscow, Russia, October 22-24, 2013.

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1-4. Acid-base disorders. Elena Levtchenko (eng)

  1. 1. Acid-base disorders metabolic acidosis October 22, 2013
  2. 2. Outline of the lecture • Renal regulation of acid-base homeostasis • Diagnostic approach in patients with acidosis • Renal tubular acidosis (RTA) – Distal renal tubular acidosis (dRTA), type 1 – Proximal renal tubular acidosis (pRTA), type 2 – dRTA with hyperkalemia, type 4 • Diagnostic algorithm in patients with RTA • Take home message
  3. 3. Maintanance of acid-base homeostasis • Aim: maintain arterial pH 7.35-7.45 • Metabolism: production of acids (Manz et al. 2004) • Systems involved in pH regulation: – Extracellular and intracellular buffering – Lung: excretion of CO2 – Kidney Bidani et al. 2002
  4. 4. Renal regulation of acid-base homeostasis • Bicarbonate reabsorption (~4000 mmol/1.73 m2/24 hrs) • Acids and ammonium (NH4+) excretion Net acid excretion (NAE) NAE = NH4 + TA – HCO3 + _ TA: titratable acid L. Lee Hamm et al. 2008
  5. 5. Renal proximal tubule (PT) NBC1 • Reabsorption of ~ 80 % HCO3 _ • Different transport rate and mechanism in S1, S2 and S3 (highest in S1) • NHE 8 on the apical membrane (Goyal et al. 2003, 2005) 3 Na+ Citrate 2NHE 3, amiloride sensitive H+-ATP-ase L. Lee Hamm et al. 2008
  6. 6. Renal ammonium generation and transport RhCG (apical) NH4+ generation in PT cells RhBG (basolateral) (Knepper 2008) L. Lee Hamm et al. 2008
  7. 7. Role of Rhesus factor proteins in renal ammonium excretion and male fertility Rh-factor family of proteins: homology to ammonia (NH3) -transport proteins in bacteria, fungi, plants, invertebrates Rhbc -/- mouse model (Biver et al. 2008) : - reduced body weight - decreased urinary ammonium excretion - reduced urine acidification capacity after acid load - reduced male fertility due to impaired ammonia secretion in epididymus Non-erythroid members (RhCG and RhBG) are expressed in the kidney Rhbg -/- mouse model: no acid-base abnormalities (Chambrey et al. 2005) (Knepper 2008)
  8. 8. Regulation of PT acid-base transport Acidosis: insertion of NHE3 and H+-ATP-ase function of NBC1 (alkalosis: opposite effects) secretion of endothelin – 1 secretion of cortisol K+: PTH: _ increases HCO3 reabsorption _ acute effect: decreases HCO3 via cAMP PKA phosphorylation of NHE 3 inhibition chronic acidosis: excretion ATII: _ PTH net acid increases HCO3 reabsorption L. Lee Hamm et al. 2008
  9. 9. Thick ascending loop of Henle (TAL) • Reabsorption of ~ 20 % HCO3 _ _ • Acidosis: increases HCO3 reabsorption, alkalosis: no effect •Loop diuretics: increases HCO3 reabsorption _ L. Lee Hamm et al. 2008
  10. 10. Cortical collecting duct (CCD) intercalated cells intercalated cells L. Lee Hamm et al. 2008
  11. 11. Regulation of CCD acid-base transport • • • Acute acidosis: H+ secretion, _ HCO3 reabsorption in type A IC _ Chronic acidosis: HCO3 secretion in type B IC (some type B cells transform into type A cells), role of hensin (Schwartz et al. 2005) _ Na CL : AE1 in type A IC, _ HCO3 secretion in type B IC • K+: K + / H+ ATPase (K + reabsorption, H+ excretion), increase H+ATPase insertion to the apical membrane • Mineralocorticoids: rapid nongenomic stimulation of H+ATPase (independent of Na +) (toevoegen genomic effects) • ET-1: in acidosis increase of ET-1 in renal interstitium, and Na +/ H+ exchange • PTH: stimulates distal nephron acidification _ HCO3 secretion
  12. 12. Diagnostic approach in patients with acidosis • Step 1: obtain arterial (capillary) blood gas _ _ analysis and plasma HCO3 , Na +, K +, CL • Step 2: distinguish simple from mixed type acidbase disorders • Step 3: calculate blood Anion Gap_ (AG): _ – – – AG = (Na+ + K +) - (CL + HCO3 ) AG: unmeasured anions in plasma (albumin, and globulins): • 1 g/dl albumin 2.5 - 4 meq/L AG Ca2+, Mg2+, Li+ (intoxication) – High IgG (cationic) • AG AG Step 4: calculate urine Anion Gap (AG): – AG = (Na+ + K +) - CL _ Emmet et al. 2002
  13. 13. Clinical causes of high and normal AG acidosis High AG acidosis Ketoacidosis Normal AG acidosis Gastrointestinal loss of HCO3 _ negative urine AG: U (Na+ + K +) < U Cl diarrhea Diabetic (acetoacetate) Alcoholic ( -hydroxybutyrate) Starvation Renal tubular acidosis hyperchloremic, positive urine AG : U (Na+ + K+) > Cl Proximal tubular acidosis (pRTA) Lactic acid acidosis Distal tubular acidosis (dRTA) (low K +) Acetazolamide, topiramate (inhibitor of CA) Generalized distal renal tubular defect (high K +) Toxins Ethylene glycol, propylene glycol, methylalcohol, salicylate Miscellaneous NH4+Cl ingestion Sulfur ingestion
  14. 14. Distal renal tubular acidosis: type 1 dRTA • Dysfunction of acid urine • Clinical diagnosis: pH urine > 5.5 when arterial pH < 7.34, normal AG, normal GFR • NH4+Cl loading (100 mg/kg): failure to reduce urine pH < 5.3 during the following 6 hrs (Wrong and Davis 1959) • Other features: hypokalemia, metabolic bone disease, nephrocalcinosis, nephrolithiasis • In adults: mostly secondary, associated with autoimmune disease (Sjögren syndrome) (Wrong et al. 1993) • Children: inherited forms intercallated cells ( IC or type A IC): failure to produce
  15. 15. Inherited forms of type 1 dRTA Autosomal dominant dRTA (Karet et al. 2009) Autosomal recessive dRTA (Karet et al. 2009) • Mutations in 3 genes: • Mutations in AE1 ( SLC4A1 gene) (most common mutation: R588 (arginin) in 6th transmembrane domain SLC4A1 gene (other mutations than in AD dRTA); in some kindreds in combination with hemolytic anemia Mutations in H+ ATPase subunits CAII CO2 + H2O AR dRTA with deafness: mutations in B1-subunit (ATP6V1B1 gene) mutations: mostly loss of function. In inner ear: expression in cochlea and endolymphatic sac (high K+ 150 mM and pH 7.4 due to H+ ATPase) H+ + HCO3 - • Dominant-negative mechanism: depending on mutation’s sort : mutated AE1 prevents expression of wild-type AE1 on basolateral membrane, ER retention (Quilty et al. 2002, Toye et al. 2002) • Expression on the apical membrane (R901X, G609R) AR dRTA with late onset hearing loss: (Devonald et al. 2003). Mutations in a4-subunit ATP6V0A4 gene) (expression kidney, cochlea) CAII deficiency (McMahon et Other genes? al. 2001) Combination dRTA and osteopetrosis •More severe disease in these individuals (Rungroj et al. 2004)
  16. 16. Proximal renal tubular acidosis: type 2 pRTA • Defect in PT capacity to reabsorb HCO3_ (Rodriguez Soriano 1967, 2002) • Normal distal capacity to acidify urine (urine pH < 5.5 when plasma HCO3_ < 15 meq/L) • Patients maintain normal acid-base balance with HCO3_ supplements • Hypokalemia not always present (reduced PT fluid reabsorption, hyperaldosteronism, increased fluid and alcali delivery to distal nephron; mostly absent in metabolic acidosis and aggravated by base suppletion) • Hypercalciuria/nephrocalcinosis: absent or less severe (Lemann et al. 2000) Rodriguez Soriano et al. 1972
  17. 17. Proximal renal tubular acidosis: type 2 pRTA • NBC1 Most commonly: part of generalized proximal tubular dysfunction (renal Fanconi syndrome), combined with aminoaciduria, glucosuria, phosphaturia, LMW proteinuria • Isolated pRTA NBC1 mutations (SLC4A4 gene): AR, severe metabolic acidosis (pH 7.1-7.2), bicarbonate +10 mEq/L (Igarashi et al. 2002) In acidotic state: urinary pH < 5.5; short stature, ocular abnormalities (glaucoma, cataract) in all patients; basal ganglia calcifications; abnormal dentition Most mutants are retained in ER 3 Na+ Citrate 2- CAII: osteopetrosis (also distal acidification defect), defective bone resorption by osteoclasts NHE 3, amiloride sensitive H+-ATP-ase NHE3 mutations: not yet idenitfied in humans; NHE3 KO mice: mild metabolic acidosis (Schultheis et al. 1998) Transient pRTA of infants (Rodriguez Soriano 1967), growth retardation, good responce to alcali therapy
  18. 18. Hyperkalemic renal tubular acidosis: type 4 dRTA • Aldosterone action: – – Na + reabsorption lumen negative potential required for K+ and H+ secretion Direct activation of distal H+ ATPase (Winter et al. 2004) True hypoaldosteronism: hyporeninemic hypoaldosteronism (diabetes, amiloidosis, TIN due to NSAID), adrenal dysfunction, ACE inhibition, ATII receptor antagonists, inhibition of aldosterone synthesis by heparin (Kutyrina et al. 1987) Functional hypoaldosteronism: antagonists of MR (spironolactone), ENaC blockers (amiloride, triamterene, trimethoprim), cyclosporine therapy (interference with basolateral Na +/ K+ ATPase, NKCC2 and distal K+ channels (Karet 2009) Karet 2009
  19. 19. Mendelian forms of type 4 dRTA • Pseudohypoaldosteronism type 1 (PHA 1) – Renal Na+ waisting, hyperkalemia, hyponatremia and metabolic acidosis – Elevated renin and aldosterone levels – Mineralocorticoid receptor (MR) mutations: • AD, haploinsufficiency (mutant RNA degraded) – • (Geller et al. 2009) ENaC mutations • AR, loss of function (alpha, beta, gamma subunits), extremely rare (Geller 2009) Pseudohypoaldosteronism type 2 (PHA 2) (Gordon syndrome) – Hyperkalemic hypertension associated with (mild) acidosis – Impaired removal of distal NaCl cotransporter in DCT and increased expression of ENaC and decreased expression of ROMK in CD – Mutations in WNK 1 and 4 (with no lysine [K] kinase), regulating NCC, ROMK, ENaC (Kahle et al. 2009)
  20. 20. Diagnostic algorithm in patients with RTA Hyperchloremic normal AG metabolic acidosis Mesure urine AG (Na+K)-CL Positive (CL < Na+K) pH< 5.5 Nl of laag K+ pH> 5.5 Nl of laag K+ pRTA Increased FE Bicarb (10-15%) dRTA Check for renal stones and nephrocalcinosis Negative (Cl> Na+K) pH < 5.5 Hoog K+ Fractional excretion of bicarbonate Type 4 RTA Decreased (< 5%) = gastro-intestinaal losses of bicarbonate (urine pH <6.5) Fractional excretion of bicarbonate (%) = {[HCO3]u / [HCO3]p} x {Pcr / Ucr} X 100
  21. 21. Treatment of RTA • Correction of acidosis: – Na or K citrate or bicarbonate supplements • pRTA 10-15 meq/kg/day; • dRTA 2-4 meq/kg/day in 4 doses) – Further treatment depending on the cause
  22. 22. Take home message • In patients with acidosis: – Anamnesis (diarrhea, medication use, intoxication, family history) – Clinical examination (growth parameters, blood pressure, exclude autoimmune disease, bone disease) – Arterial (capillary) blood gas analysis simultaneously with blood and urine electrolytes, renal function, bicarbonate, albumin prior to alkali supplements – Follow steps 1-4 determine sort of metabolic acidosis (high AG or normal AG, renal or extrarenal) • Renal RTA – primary or secondary (medications, autoimmune disorder, other renal disease) – distal or proximal; low/normal K+ or high K+ – MAKE DIAGNOSIS (DNA analysis, genetic counselling) – FOLLOW PATIENT (acidosis might be transient!)
  23. 23. Fons Sapientiae by Jef Claerhout