1. This lecture was conducted during the Nephrology Unit Grand Ground by Medical Student rotated under Nephrology Division under the supervision and administration of Prof. Jamal Al Wakeel, Head of Nephrology Unit, Department of Medicine and Dr. Abdulkareem Al Suwaida, Chairman of Department of Medicine. Nephrology Division is not responsible for the content of the presentation for it is intended for learning and /or education purpose only.

2. Presented by: Dr. Rinda Mousa Medical Student August 2008

3. Objectives 1-RENAL ROLE IN ACID-BASE BALANCERENAL ROLE IN ACID-BASE BALANCE Reabsorption of bicarbonate Acid excretion 2-PROXIMAL RTAPROXIMAL RTA 3-DISTAL RTADISTAL RTA 4-TYPE 4 RENAL TUBULAR ACIDOSISTYPE 4 RENAL TUBULAR ACIDOSIS

4. The lungs and the kidneys are responsible for the maintenance of acid- base balance within the body. Alveolar ventilation removes carbon dioxide. while the kidneys reabsorb filtered bicarbonate and excrete a daily quantity of hydrogen ion equal to that produced by the metabolism of dietary protein.

5. Dietary acid load increases ammonium excretion Ammonium excretion increased almost four-fold despite a minimal fall in the plasma bicarbonate concentration.

6. RENAL ROLE IN ACID-BASE BALANCE RENAL ROLE IN ACID-BASE BALANCE Reabsorption of bicarbonate And Acid excretion

7. the factors that determine H+ excreted and HCO3- reabsorption. 1- The extracellular pH (ABG) is the major physiologic regulator. 2- the effective circulating volume and Aldosterone 3- the plasma K+ concentration 4- other less important factors such as parathyroid hormone, Hypochloremia and nonreabsorbable anion

8. 1-The extracellular pH

9. The intracellular pH changes either due to. An elevation in the PCO2 will induce rapid acidification in the cells, because CO2 can freely cross cell membranes. Alterations in the plasma HCO3- concentration are less direct, since transcellular diffusion of this anion is limited by the lipid bilayer of the cell membrane. However, the carrier-mediated HCO3- exit steps in the basolateral membrane of the proximal tubule (Na+-3HCO3- cotransport) and in the distal nephron (Cl--HCO3- exchange) are affected by the transmembrane HCO3- gradient.

10. Acidemia is manifested in the proximal tubule by 3 changes Enhanced luminal Na+-H+ exchange. It is sensitive to inhibition by the diuretic drug amiloride, and has affinity for Li+ in addition to Na+ and H+. Increased activity of the Na:3HCO3- cotransporter in the basolateral membrane. Increased NH4+ production from glutamine. glutamine

11. Acidemia is manifested In the collecting tubules H+-ATPase pumps the increase in acidification appears to involve the insertion of preformed cytoplasmic. the diffusion of interstitial NH3 into the lumen where it will be trapped as NH4+. Cl--HCO3- exchange The net effect of increase in acid excretion is enhanced generation of HCO3- by the tubules that is returned to the peritubular capillary.

12. In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3 diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of the lumen. Note that each NH4+ ion that is excreted is associated with the generation of a new HC03- ion that is returned to the peritubular capillary.

13. These adaptive changes in cell pH are determined by the extracellular pH itself, not by the HCO3- concentration or PCO2 alone. Thus, there is no alteration in the cell pH if both the HCO3- concentration and PCO2 are lowered or raised to a similar degree, so that the extracellular pH remains constant. I The importance of this local effect, which is independent of other circulating factors, is though to be mediated by activation of pH-sensitive proteins.

14. 2-the effective of circulating volume and Aldosterone

15. Ion transport in collecting tubule cell. Aldosterone, leads to enhanced Na reabsorption and potassium secretion by increasing both the number of open Na channels and the number of Na-K-ATPase pumps in the intercalated cells in the cortical collecting tubule, and the cells in the outer and inner medullary collecting tubule†. Atrial natriuretic peptide inhibits sodium reabsorption by closing the Na channels. The potassium-sparing diuretics act by closing Na channels, amiloride and triamterene directly and spironolactone by competing with aldosterone.

16. Ion transport in thick ascending limb of the loop of Henle The entry of filtered NaCl into the cells is mediated by a neutral Na-K-2Cl cotransporter in the apical (luminal) membrane. Reabsorbed Na is pumped out of the cell by the Na-K-ATPase pump in the basolateral (peritubular) membrane. Although K plays an important role in this process, the concentration of K in the filtrate and tubular fluid is much less than that of Na and Cl; thus, K must recycle back into the lumen through K channels in the apical membrane to allow continued NaCl reabsorption. The ensuing lumen electropositivity creates an electrical gradient that promotes the passive reabsorption of cations - Na, and, to a lesser degree, Ca, and Mg - via the paracellular pathway between the cells. The loop diuretics inhibit Na, K, and Cl (and Ca and Mg) reabsorption by competing for the Cl site on this transporter.

17. 3-the plasma K+ concentration

18. Reciprocal cation shifts of K, H, and Na between the cells, (including renal tubular cells) and the extracellular fluid. In the presence of hypokalemia K moves out of the cells down a concentration gradient. Since the cell anions (primarily proteins and organic phosphates) are unable to cross the cell membrane, electroneutrality is maintained by the entry of Na and H into the cell(alkalosis). The increase in renal cell H concentration may be responsible for the increased H secretion and HCO3 reabsorption ( alkalosis) seen with hypokalemia. hyperkalemia K moves in causes H and Na to leave the cells( acidosis), in renal cell resulting in a fall in H secretion and HCO3 reabsorption.

19. 4-Hypochloremia and nonreabsorbable anion

20. both H+ and Cl- ions are lost in most patients, such as those with vomiting or diuretic therapy. The reduction in the filtered Cl- concentration, can enhance H+ secretion and HCO3- reabsorption

21. Effect of nonreabsorbable anion on potassium and hydrogen secretion Events occurring after Na reabsorption across the luminal membrane in the cortical collecting tubule. the presentation of Na with a nonreabsorbable anion such as SO4(2-) enhances H and K secretion. In contrast, if NaCl is presented to this segment, Na will be reabsorbed with Cl, with little effect on H and K secretion

22. 5-parathyroid hormone

23. Parathyroid hormone (PTH) diminishes proximal HCO3- reabsorption by reducing the activity of Na+-H+ exchanger in the luminal membrane and the Na+-3HCO3- cotransporter in the basolateral membrane. However, the extra HCO3- delivered out of the proximal tubule is mostly picked up in the loop of Henle and more distal segments. Although there may be a slight increase in HCO3- excretion, this is generally counteracted by enhanced excretion of phosphate which can increase net acid excretion.

25. Refers to the development of metabolic acidosis because of a defect in the ability of the renal tubules to perform their functions. Impaired hydrogen ion secretion is the primary defect in distal RTA while impaired ammoniagenesis is the primary defect in type 4 RTA and renal failure All forms of RTA are characterized by a normal anion gap (hyperchloremic) metabolic acidosis. This form of metabolic acidosis usually results from either 1-the net retention of hydrogen chloride. 2-the net loss of sodium bicarbonate.sodium bicarbonate However, The major cause of a normal anion gap acidosis in patients without renal failure is diarrhea

26. Type 1 or distal RTA It is associated with a defect in distal hydrogen ion excretion

27. Major causes of type I (distal) renal tubular acidosis

28. In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3 diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of the lumen. Note that each NH4+ ion that is excreted is associated with the generation of a new HC03- ion that is returned to the peritubular capillary.

29. Distal RTA results from one of several defects in distal hydrogen ion secretion. 1-Decreased proton pump (H-ATPase) activity 2-Increased luminal membrane permeability with backleak of hydrogen ions 3-Diminished distal tubular sodium reabsorption which reduces the electrical gradient for proton secretion 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

30. Several patients with Sjögren's syndrome have been described in whom immunocytochemical analysis of tissue obtained by renal biopsy showed complete absence of H-ATPase pumps in the intercalated cells. How immunologic injury leads to this change is not known. Mutations in the gene for the chloride-bicarbonate exchanger (AE1 or band 3) have been described in autosomal dominant (most common) and autosomal recessive type 1 RTA. Other mutations in AE1 can lead to hereditary spherocytosis. Mutations have also been described in the genes encoding the B1 and alpha4 subunits of the H-ATPase pump defects of either subunit may be associated with sensorineural deafness, suggesting that the pump is required for normal function of the inner ear. The presence of high titers of an autoantibody directed against carbonic anhydrase II as observed in patients with Sjögren's syndrome ; inhibition of this enzyme would reduce the number of hydrogen ions generated within the cell for secretion into the lumen.

31. Increased luminal membrane permeability amphotericin B i enhance membrane permeability lead to both the fall in hydrogen secretion and increased membrane permeability to potassium.amphotericin B Diminished sodium reabsorption in the adjacent principal cells indirectly influences net hydrogen secretion by the intercalated cells. The transport of sodium makes the lumen electronegative, an effect that promotes the secretion both of potassium and hydrogen. Thus, impairing sodium reabsorption will tend to induce both metabolic acidosis and hyperkalemia. urinary tract obstruction sickle cell disease, lupus nephritis, and with any cause of marked volume depletion

32. Hyperkalemic type 1 RTA can be differentiated from type 4 RTA in which hypoaldosteronism leads to a rise in the plasma potassium concentration. In type 1 RTA, however, aldosterone levels are normal and the acidifying defect is more severe, leading to a urine pH that is above 5.30 and a plasma bicarbonate concentration that is often below 15 meq/L. In comparison, the urine pH is typically below 5.3 and the plasma bicarbonate concentration is generally above 17 meq/L in type 4 RTA.

33. Major causes of type I (distal) renal tubular acidosis Primary 1-Idiopathic, sporadic 2-Familial 3-Autosomal dominant 3-Autosomal recessive Secondary Sjögren's syndrome, Rheumatoid arthritis, SLE Hypercalciuria Hyperglobulinemia Ifosfamide Amphotericin B Cirrhosis Renal trasplant Sickle cell anemia (may be hyperkalemic) Obstructive uropathy (may be hyperkalemic) Lithium carbonate

34. DIAGNOSIS high urine pH (greater than 5.5 in the presence of acidosis). plasma bicarbonate concentration that may fall below 10 meq/L. hypercalciuria due to the effects of chronic acidosis on both bone resorption and the renal tubular reabsorption of calcium. Hypercalciuria contributes to the development of nephrolithiasis and nephrocalcinosis. Hypokalemia, sometimes severe, is frequently seen in distal RTA and may produce muscle weakness, potassium secretion must be enhanced to maintain electroneutrality as sodium is reabsorbed.

35. treatment correction of the acidemia has the advantages of minimizing new stone formation and nephrocalcinosis and lowering inappropriate urinary potassium losses. The aim of alkali therapy is to achieve a relatively normal plasma bicarbonate concentration (22 to 24 meq/L). Bicarbonate wasting is negligible in adults who can generally be treated with 1 to 2 meq/kg of sodium bicarbonate or sodium citrate (Bicitra™, which is usually better tolerated). Children, however, may require as much as 4 to 8 meq/kg per day in divided doses because the urine pH and fixed bicarbonate losses may be higher than in adults. sodium bicarbonatesodium citrate Potassium citrate, alone or with sodium citrate (Polycitra™), is indicated for persistent hypokalemia or for calcium stone disease. Potassium citratesodium citrate

36. Type 2 or proximal RTA It is characterized by a reduction in proximal bicarbonate reabsorption capacity

37. Inherited defects in the gene for the sodium bicarbonate cotransporter (SLC4A4) results in autosomal recessive type 2 RTA (with concurrent ocular abnormalities).sodium bicarbonate while mutations in the gene for one of the plasma membrane sodium-hydrogen exchangers may be responsible for autosomal dominant disease. Defective carbonic anhydrase activity and, in cystinosis, ATP depletion have been described among patients with type 2 RTA. The distal nephron has substantial bicarbonate reabsorptive capacity; thus, even if proximal function is severely impaired, the plasma bicarbonate concentration does not fall below 12 meq/L.

38. In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3 diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of the lumen. Note that each NH4+ ion that is excreted is associated with the generation of a new HC03- ion that is returned to the peritubular capillary.

39. Proximal (type 2) RTA may occasionally present as an isolated defect, but is more commonly associated with generalized proximal tubular dysfunction called the Fanconi syndrome. In addition to bicarbonaturia, generalized proximal dysfunction may be associated with one or more of the following: glucosuria, phosphaturia, uricosuria, aminoaciduria, and tubular proteinuria. The most common causes of Fanconi syndrome in adults are the excretion of light chains due to multiple myeloma (which may be occult) and the use of a carbonic anhydrase inhibitor (such as acetazolamide) or the anticancer drug ifosfamide.acetazolamideifosfamide

40. Primary disorders Acquired disorders Multiple myeloma Ifosfamide Carbonic anhydrase inhibitors Amyloidosis Heavy metals Lead Cadmium Mercury Copper Vitamin D deficiency Renal transplantation Paroxysmal nocturnal hemoglobinuria Idiopathic, sporadic Familial disorders Cystinosis Tyrosinemia Hereditary fructose intolerance Galactosemia Glycogen storage disease (type I) Wilson's disease Lowe's syndrome

41. Potassium balance — depending whether the patient is being treated with alkali therapy. Once there has been a sufficient reduction in the filtered bicarbonate load in untreated patients, all of the filtered bicarbonate can again be reabsorbed as in normal subjects. At this time, the plasma bicarbonate concentration is stable (usually between 12 and 20 meq/L), the urine pH may be normally acid, and the plasma potassium concentration is relatively normal. There may still be some tendency to potassium wasting, since metabolic acidosis alone diminishes proximal sodium reabsorption. As a result, there is increased distal delivery of sodium and sodium-wasting-induced secondary hyperaldosteronism, both of which promote potassium secretion. The findings are dramatically different once alkali therapy is begun to correct the acidemia. The ensuing marked elevation in distal sodium and water delivery can substantially enhance distal potassium secretion. Thus, many patients must be treated with a combination of potassium and sodium bicarbonate (or citrate).sodium bicarbonate

42. The diagnosis of proximal RTA measurement of the urine pH fractional bicarbonate excretion during a bicarbonate infusion. The hallmark is a urine pH above 7.5 and the appearance of more than 15 percent of the filtered bicarbonate in the urine when the serum bicarbonate concentration is raised to a normal level

43. treatment Correction of the acidemia will allow normal growth to occur and will promote healing of rickets or osteomalacia. phosphate and vitamin D supplementation may be necessary to normalize the plasma phosphate concentration.vitamin D bicarbonaturia also enhances urinary potassium losses by increasing sodium and water delivery to the distal potassium secretory site.

44. Type 3 RTA The term is now most often applied to a rare autosomal recessive syndrome (resulting from carbonic anhydrase II deficiency) with features of : Both type 1 and type 2 RTA Oesteopetrosis cerebral calcification mental retardation.

45. Type 4 RTA or hypoaldosteronism It is associated with hyperkalemia and a mild metabolic acidosis

46. Estimation of the transtubular potassium concentration gradient (TTKG) is often of greater value in hyperkalemic patients, since it may distinguish hypoaldosteronism from other causes of hyperkalemia. The TTKG can be calculated using the following formula: TTKG = [Urine K ÷ (urine osmolality / serum osmolality)] ÷ serum K Hyperkalemia should be associated with increases in aldosterone release and distal potassium secretion, leading to a high TTKG above 10 in normal subjects. A value below 7 and particularly below 5 is highly suggestive of hypoaldosteronism. The TTKG is relatively accurate as long as the urine osmolality exceeds that of serum and the urine sodium concentration is above 25 meq/L (to ensure adequate distal distal sodium delivery).

47. Major causes of hypoaldosteronism 1-Aldosterone deficiency 2-Aldosterone resistance

48. Aldosterone deficiency Primary 1-Primary adrenal insufficiency 2-Congenital adrenal hyperplasia, particularly 21-hydroxylase deficiency 3-Isolated aldosterone synthase deficiency 4-Heparin and low molecular weight heparin Hyporeninemic hypoaldosteronism 1-Renal disease, most often diabetic nephropathy 2-Volume expansion, as in acute glomerulonephritis 3-Angiotensin converting enzyme inhibitors 4-Nonsteroidal antiinflammatory drugs 5-Cyclosporine HIV infection 6-Some cases of obstructive uropathy

49. Aldosterone resistance 1-Drugs which close the collecting tubule sodium channel Amiloride Spironolactone Triamterene Trimethoprim (usually in high doses) Pentamidine 2-Tubulointerstitial disease 3-Pseudohypoaldosteronism 4-Distal chloride shunt

50. In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3 diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of the lumen. Note that each NH4+ ion that is excreted is associated with the generation of a new HC03- ion that is returned to the peritubular capillary.

51. DIAGNOSIS OF HYPOALDOSTERONISM

52. Patients suspected to have hypoaldosteronism should be questioned about the use of any drug or the presence of a disease that can impair aldosterone release, If none of these findings is present, then evaluation for some other causes of hypoaldosteronism : 1. hyporeninemic hypoaldosteronism 2. primary adrenal insufficiency 3. adrenal enzyme defect 4. the rare genetic disorders type 1 and type 2 pseudohypoaldosteronism.

53. These disorders can be differentiated by measurement of plasma renin activity (PRA)and serum aldosterone and cortisol Hyporeninemic hypoaldosteronism most often occurs in patients 50 to 70 years of age with diabetic nephropathy or chronic interstitial nephritis who have mild to moderate renal insufficiency. It is associated with low PRA, a low serum aldosterone concentration, and a normal serum cortisol concentration. primary adrenal insufficiency have low serum aldosterone and cortisol concentrations, but high PRA due to volume depletion and hypotension. adrenal enzyme deficiency, adrenal androgen synthesis increased, leading to virilization syndrome of aldosterone resistance (pseudohypoaldosteronism) have high PRA and serum aldosterone concentration

54. The cortical collecting tubule contains two cell types with very different functions principal cells increased function in Liddle's syndrome and decreased function in pseudohypoaldosteronism The intercalated cells

55. Treatment Treat the cause

57. In the proximal tubule, glutamine is taken up by the cells and metabolized into NH4+ and alpha-ketoglutarate. Utilization of the latter results in the generation of HCO3-, whereas NH4+ substitutes for H+ on the Na+-H+ exchanger and is then secreted directly into the lumen. The mechanism is different in the collecting tubules; nonpolar, lipid-soluble NH3 diffuses from the interstitial fluid into the lumen, where it combines with secreted H+ to form NH4+. Ammonium is lipid-insoluble and is therefore unable to back-diffuse out of the lumen. Note that each NH4+ ion that is excreted is associated with the generation of a new HC03- ion that is returned to the peritubular capillary.