Renal Tubular Acidosis

1. Renal Tubular Acidosis

2. Normal Renal Function • Proximal Tubule • Reabsorption: • HCO3- (90%) – carbonic anhydrase • calcium • glucose • Amino acids • NaCl, water • Distal Tubule • Na+ reabsorbed • H+ (NH4+ or phosphate salts) excreted • molar competition between H+ and K+ • Aldosterone

3. OUTLINE • Renal tubular acidosis (RTA) is applied to a group of transport defects in the reabsorption of bicarbonate (HCO3-), the excretion of hydrogen ion (H+), or both. • The RTA syndromes are characterized by a relatively normal GFR and a metabolic acidosis accompanied by hyperchloremia and a normal plasma anion gap.

4. OBJECTIVES • Physiology of Renal acidification. • Types of RTA and characteristics • Lab diagnosis of RTA • Approach to a patient with RTA • Treatment

5. Physiology of Renal Acidification • Kidneys excrete 50-100 meq/day of acid generated daily. • This is achieved by H+ secretion at different levels in the nephron. • The daily acid load cannot be excreted as free H+ ions. • Secreted H+ ions are excreted by binding to either buffers, such as HPO42- and creatinine, or to NH3 to form NH4+. • The extracellular pH is the primary physiologic regulator of net acid excretion.

6. Renal acid-base homeostasis may be broadly divided into 2 processes • Proximal tubular absorption of HCO3- (Proximal acidification) • Distal Urinary acidification. • Reabsorption of remaining HCO3- that escapes proximally. • Excretion of fixed acids through buffering & Ammonia recycling and excretion of NH4+.

7. Proximal tubule physiology • Proximal tubule contributes to renal acidification by H+ secretion into the tubular lumen through NHE3 transporter and by HCO3- reabsorption. • Approx. 85% of filtered HCO3- is absorbed by the proximal tubule. • The remaining 15 % of the filtered HCO3- is reabsorbed in the thick ascending limb and in the outer medullary collecting tubule.

8. Proximal tubule physiology Multiple factors are of primary importance in normal bicarbonate reabsorption • The sodium-hydrogen exchanger in the luminal membrane(NHE3). • The Na-K-ATPase pump • The enzyme carbonic anhydrase II & IV • The electrogenic sodium-bicarbonate cotransporter(NBC-1).

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10. Ammonia recycling • Ammonium synthesis and excretion is one of the most important ways kidneys eliminate nonvolatile acids. • Ammonium is produced via catabolism of glutamine in the proximal tubule cells. • Luminal NH4+ is partially reabsorbed in the thick ascending limb and the NH3 then recycled within the renal medulla

11. Ammonia Recycling

12. The medullary interstitial NH3 reaches high concentrations that allow NH3 to diffuse into the tubular lumen in the medullary collecting tubule, where it is trapped as NH4+ by secreted H+.

13. Distal Urinary Acidification • The thick ascending limb of Henle’s loop reabsorbs about 15% of the filtered HCO3- load by a mechanism similar to that present in the proximal tubule, i.e., through Na+-H+ apical exchange(NHE3).

14. H+ secretion • The collecting tubule (CT) is the major site of H+ secretion and is made up of the medullary collecting duct (MCT) and the cortical collecting duct (CCT). • Alpha and Beta-intercalated cells make up 40% of the lining while Principal cells and collecting tubule cells make up the remainder.

15. Alpha-Intercalated Cells are thought to be the main cells involved with H+ secretion in the CT. • This is accomplished by an apically placed H+-K+-ATPase and H+-ATPase with a basolateral Cl-/HCO3- exchanger and the usual basolateral Na+ - K+ ATPase.

17. Beta-Intercalated Cells in contrast to the above have a luminal Cl-/HCO3- exchanger and a basolateral H+-ATPase. • They play a role in bicarbonate secretion into the lumen that is later reabsorbed by the CA IV rich luminal membrane of medullary collecting duct.

18. CCT H+ secretion is individually coupled to Na+ transport. Active Na+ reabsorption generates a negative lumen potential favoring secretion of H+ and K+ ions. • In contrast the MCT secretes H+ ions independently of Na+. • Medullary portion of the Collecting duct is the most important site of urinary acidification

19. Principal cells

20. Aldosterone and Renal acidification • Favors H+ and K+ secretion through enhanced sodium transport. • Recruits more amiloride sensitive sodium channels in the luminal membrane of the collecting tubule. • Enhances H+-ATPase activity in cortical and medullary collecting tubules. • Aldosterone also has an effect on NH4+ excretion by increasing NH3 synthesis

21. Summary of renal physiology • H+ secretion, bicarbonate reabsorption and NH4+ production occur at the proximal tubule. Luminal CA IV is present in the luminal membrane at this site and in MCT. • NH4+ reabsorption occurs at TAL of loop of Henle and helps in ammonia recycling that facilitates NH4+ excretion at MCT. • H+ secretion occurs in the CCT either dependent or independent of Na availability and in the MCT as an independent process..

22. OBJECTIVES • Physiology of Renal Acidification. • Types of RTA and characteristics • Lab diagnosis of RTA • Approach to a patient with RTA • Treatment

23. Renal Tubular Acidosis

24. TYPES OF RTA Proximal RTA (type 2) • Isolated bicarbonate defect • Fanconi syndrome Distal RTA (type 1) • Classic type • Hyperkalemic distal RTA • Hyperkalemic RTA (Type 4)

25. Renal Tubular Acidosis Type 2 RTA Type 1 RTA Type 4 RTA

26. PROXIMAL RTA • Proximal RTA (pRTA) is a disorder leading to HCMA secondary to impaired proximal reabsorption of filtered bicarbonate. • Since the proximal tubule is responsible for the reabsorption of 85-90% of filtered HCO3- a defect at this site leads to delivery of large amounts of bicarbonate to the distal tubule.

27. This leads to bicarbonaturia, kaliuresis and sodium losses. • Thus patients will generally present with hypokalemia and a HCMA (hyperchloremic metabolic acidosis).

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29. Isolated defects in PCT function are rarely found. Most patients with a pRTA will have multiple defects in PCT function with subsequent Fanconi Syndrome. • The most common causes of Fanconi syndrome in adults are multiple myeloma and use of acetazolamide. • In children, cystinosis is the most common.

30. pRTA is a self limiting disorder and fall of serum HCO3- below 12 meq/l is unusual, as the distal acidification mechanisms are intact.. • Urine ph become remains acidic(<5.5) mostly but becomes alkaline when bicarbonate losses are corrected. • FEHCO3 increases(>15%)with administration of alkali for correction of acidosis (FEHCO3 = fractional excretion of HCO3)

31. Cause of hypokalemia in Type 2 RTA • Metabolic acidosis in and of itself decreases pRT Na+ reabsorption leading to increased distal tubule delivery of Na+ which promotes K+ secretion. • The pRTA defect almost inevitably leads to salt wasting, volume depletion and secondary hyperaldosteronism. • The rate of kaliuresis is proportional to distal bicarbonate delivery. Because of this alkali therapy tends to exaggerate the hypokalemia.

32. Patients with pRTA rarely develop nehrosclerosis or nephrolithiasis. This is thought to be secondary to high citrate excretion. • In children, the hypocalcemia as well as the HCMA will lead to growth retardation, rickets, osteomalacia and an abnormal vitamin D metabolism. In adults osteopenia is generally seen.

33. To summarise Type 2 RTA • Proximal defect • Decreased reabsorption of HCO3- • HCO3- wasting, net H+ excess • Urine pH < 5.5, although high initially • K+: low to normal

34. Causes: Primary Idiopathic, sporadic Familial: Cystinosis, Tyrosinemia, Hereditary Fructose intolerance, Galactosemia, Glycogen storage disease (type 1), Wilson’s disease, Lowe’s syndrome Fanconi’s Syndrome Generalized proximal tubule dysfunction Proximal loss of phos, uric acid, glucose, AA Acquired Multiple Myeloma Carbonic anhydrase inhibitors (Acetazolamide) Other drugs (Ampho B, 6-mercaptopurine) Heavy Metal Poisonings (Lead, Copper, Mercury, Calcium) Amyloidosis Disorders of protein, Carb, AA metabolism Hypophosphatemia, hypouricosuria, renal glycosuria with normal serum glucose Type 2 RTA

35. DISTAL RTA • Distal RTA (dRTA) is a disorder leading to HCMA secondary to impaired distal H+ secretion. • It is characterized by inability to lower urine ph maximally(<5.5) under the stimulus of systemic acidemia. The serum HCO3- levels are very low <12 meq/l. • It is often associated with hypercalciuria, hypocitraturia, nephrocalcinosis, and osteomalacia.

36. The term incomplete distal RTA has been proposed to describe patients with nephrolithiasis but without metabolic acidosis. • Hypocitraturia is the usual underlying cause.

37. The most common causes in adults are autoimmune disorders, such as Sjögren's syndrome, and other conditions associated with chronic hyperglobulinemia. • In children, type 1 RTA is most often a primary, hereditary condition.

38. Secretory defects causing Distal RTA

39. Non secretory defects causing Distal RTA • Gradient defect: backleak of secretd H+ ions. Ex. Amphotericin B • Voltage dependent defect: impaired distal sodium transport ex. Obstructive uropathy, sickle cell disease, Congenital Adrenal Hyperplasia, Lithium and amiloride etc. • This form of distal RTA is associated with hyperkalemia(Hyperkalemic distal RTA)

40. A high urinary pH (5.5) is found in the majority of patients with a secretory dRTA. • Excretion of ammonium is low as a result of less NH4+trapping. This leads to a positive urine anion gap. • Urine PCO2 does not increase normally after a bicarbonate load reflecting decreased distal hydrogen ion secretion. • Serum potassium is reduced in 50% of patients. This is thought to be from increased kaliuresis to offset decreased H+ and H-K-ATPase activity.

41. What Charles Dicken’s character is theorized to have suffered from RTA? Tiny Tim • Growth retardation • Bone disease • Intermittent muscle weakness (hypokalemia) • Kidney stones • Progressive renal failure • Death Lewis DW, Am J Dis Child. 1992 Dec; 146(12): 1403-7.

42. To summarise Type 1 RTA • First described, classical form • Distal defect  decreased H+ secretion • H+ builds up in blood (acidotic) • K+ secreted instead of H+ (hypokalemia) • Urine pH > 5.5 • Hypercalciuria • Renal stones

43. Type 1 RTA Causes: • Primary • Idiopathic, sporadic • Familial – AD, AR • Secondary – • Autoimmune (SLE, Sjogren’s, RA) • Hereditary hypercalciuria, hyperparathyroidism, Vit D intoxication • Hypergammaglobulinemia • Drugs (Amphotericin B, Ifosfamide, Lithium) • Chronic hepatitis • Obstructive uropathy • Sickle cell anemia • Renal transplantation

45. A 37-year-old man was referred for evaluation of distal renal tubular acidosis Serrano A and Batlle D. N Engl J Med 2008;359:e1

46. Type 4 RTA (Hyperkalemic RTA) • This disorder is characterized by modest HCMA with normal AG and association with hyperkalemia. • This condition occurs primarily due to decreased urinary ammonium excretion. • Hypoaldosteronism is considered to be the most common etiology. Other causes include NSAIDS, ACE inhibitors, adrenal insufficiency etc.

47. Mechanism of action

49. In contrast to hyperakalemic distal RTA, the ability to lower urine ph in response to systemic acidosis is maintained. • Nephrocalcinosis is absent in this disorder.

50. To summarise Type 4 RTA • Aldosterone deficiency or distal tubule resistance to Aldosterone  • Impaired function of Na+/K+-H+ (cation) exhange mechanism • Decreased H+ and K+ secretion plasma buildup of H+ and K+ (hyperkalemia) • Urine pH < 5.5