1. Renal Tubular Acidosis

2. Normal Renal Function Proximal Tubule Distal 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
90% HCO (H+ secretion drives)
carbonic anhydrase
CA inhibitors – block PT reab of HCO3 and therefore useful for alkalinizing urine
calcium

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 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).

9. .

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
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
90% HCO (H+ secretion drives)
carbonic anhydrase
CA inhibitors – block PT reab of HCO3 and therefore useful for alkalinizing urine
calcium

24. TYPES OF RTA Proximal RTA (type 2) Distal RTA (type 1)
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
One proximal type and 2 distal types

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).

28. .

29. Isolated defects in PCT function are rarely found
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
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. Type 2 RTA Causes: Primary Fanconi’s Syndrome Acquired
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

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 Dec; 146(12):

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 Secondary – 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
A 37-year-old man was referred for evaluation of distal renal tubular acidosis. Laboratory evaluation revealed a serum potassium level of 3.3 mmol per liter, a bicarbonate level of 16 mmol per liter, a calcium level of 9.3 mg per deciliter (2.3 mmol per liter), a phosphate level of 2.1 mg per deciliter (0.7 mmol per liter), a creatinine level of 3.0 mg per deciliter (265 {micro}mol per liter), a parathyroid hormone level of 62 pg per milliliter, and an estimated glomerular filtration rate of 25 ml per minute per 1.73 m2 of body-surface area. He had been given a diagnosis of renal tubular acidosis at 9 years of age on the basis of metabolic acidosis with a high urinary pH and hypokalemia associated with nephrocalcinosis. At that time, there was evidence of bilateral nephrocalcinosis on plain abdominal radiography. The patient was treated with sodium bicarbonate and potassium supplementation and had normal growth but did not undergo medical follow-up or treatment between 15 and 37 years of age. The plain film of the abdomen obtained during the referral visit (see figure) revealed bilateral symmetric calcification of the renal parenchyma, sparing only the renal pelvis. This finding contrasts with those classically associated with type 1 distal renal tubular acidosis, in which nephrocalcinosis is present but is limited to the renal medulla. Three years after sodium bicarbonate and potassium supplementation was restarted, the patient's renal function has remained stable.
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

51. Renal Tubular Acidosis
Type 2 RTA
Type 1 RTA
LOW serum K+
Type 4 RTA
HIGH serum K+
One proximal type and 2 distal types

52. Type 4 RTA Acquired Causes  Renin: Normal renin, Aldo:
Diabetic nephropathy
NSAIDS
Interstitial Nephritis
Normal renin, Aldo:
ACEs, ARBs
Heparin
Primary adrenal response
response to Aldo:
Medications: K+ sparing drugs (Sprinolactone), TMP-SMX, pentamidine, tacrolimus
Tubulointerstitial ds: sickle cell, SLE, amyloid, diabetes

53. What happened to Type 3 RTA?
Very rare
Used to designate mixed dRTA and pRTA of uncertain etiology
Now describes genetic defect in Type 2 carbonic anhydrase (CA2), found in both proximal, distal tubular cells and bone

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

55. Lab diagnosis of RTA
RTA should be suspected when metabolic acidosis is accompanied by hyperchloremia and a normal plasma anion gap (Na+ - [Cl- + HCO3-] = 8 to 16 mmol/L) in a patient without evidence of gastrointestinal HCO3- losses and who is not taking acetazolamide or ingesting exogenous acid.

56. Functional evaluation of proximal bicarbonate absorption
Fractional excretion of bicarbonate
Urine ph monitoring during IV administration of sodium bicarbonate.
FEHCO3 is increased in proximal RTA >15% and is low in other forms of RTA
(FEHCO3 = fractional excretion of HCO3)

57. Functional Evaluation of Distal Urinary Acidification and Potassium Secretion
Urine pH
Urine anion gap
Urine osmolal gap
Urine pCO2
TTKG (transtubular potassium gradient)
Urinary citrate

58. Urine ph
In humans, the minimum urine pH that can be achieved is 4.5 to 5.0.
Ideally urine ph should be measured in a fresh morning urine sample.
A low urine ph does not ensure normal distal acidification and vice versa.
The urine pH must always be evaluated in conjunction with the urinary NH4+ content to assess the distal acidification process adequately .
Urine sodium should be known and urine should not be infected.

59. Urine Anion Gap Urine AG = Urine (Na + K - Cl).
The urine AG has a negative value in most patients with a normal AG metabolic acidosis.
Patients with renal failure, type 1 (distal) renal tubular acidosis (RTA), or hypoaldosteronism (type 4 RTA) are unable to excrete ammonium normally. As a result, the urine AG will have a positive value.

60. There are, however, two settings in which the urine AG cannot be used.
When the patient is volume depleted with a urine sodium concentration below 25 meq/L.
When there is increased excretion of unmeasured anions

61. Urine osmolal gap
When the urine AG is positive and it is unclear whether increased excretion of unmeasured anions is responsible, the urine ammonium concentration can be estimated from calculation of the urine osmolal gap.
UOG=Uosm - 2 x ([Na + K]) + [urea nitrogen]/2.8 + [glucose]/18.
UOG of >100 represents intact NH4 secretion.

62. Urine pCO2 Measure of distal acid secretion.
In pRTA, unabsorbed HCO3 reacts with secreted H+ ions to form H2CO3 that dissociate slowly to form CO2 in MCT.
Urine-to-blood pCO2 is <20 in pRTA.
Urine-to-blood pCO2 is >20 in distal RTA reflecting impaired ammonium secretion.

63. TTKG
TTKG is a concentration gradient between the tubular fluid at the end of the cortical collecting tubule and the plasma.
TTKG   =   [Urine K  ÷  (Urine osmolality / Plasma osmolality)]  ÷  Plasma K.
Normal value is 8 and above.
Value <7 in a hyperkalemic patient indicates hypoaldosteronism.
This formula is relatively accurate as long as the urine osmolality exceeds that of the plasma urine sodium concentration is above 25 meq/L

64. Urine citrate
The proximal tubule reabsorbs most (70-90%) of the filtered citrate.
Acid-base status plays the most significant role in citrate excretion.
Alkalosis enhances citrate excretion, while acidosis decreases it.
Citrate excretion is impaired by acidosis, hypokalemia,high–animal protein diet and UTI.

65. Table - Renal Tubular Acidosis
Primary defect
Serum K+
Urine pH
Other
Causes
Type 1
distal
H+ secretion decreased
Low-nl
> 5.5
Renal stones
Autoimmune (SLE, Sjogrens)
Hypercalciuria
Drugs (Ampho B, Ifosfamide, lithium)
Hypergammaglobulinemia
Type 2
proximal
HCO3- reab decreased
< 5.5, although high initially
Multiple Myeloma
Acetazolamide
Heavy Metal Poisonings (Lead, Copper, Mercury, Calcium)
Amyloidosis
Disorders of protein, Carb, AA metabolism
Type 4
Aldosterone deficiency, cation exchange decreased
High
< 5.5
Aldosterone deficiency
Diabetic nephropathy Spirinolactone
Interstitial nephritis
Obstructive uropathy
Renal transplant

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

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

70. Treatment Proximal RTA
A mixture of Na+ and K+ salts, preferably citrate, is preferable.
10 to 15 meq of alkali/kg may be required per day to stay ahead of urinary losses.
Thiazide diuretic may be beneficial if large doses of alkali are ineffective or not well tolerated.
Vit D

71. Distal RTA
Bicarbonate wasting is negligible in adults who can generally be treated with 1 to 2 meq/kg of sodium citrate or bicarbonate. Sodium citrate tolerated better than sodium bicarb
Potassium citrate, alone or with sodium citrate, is indicated for persistent hypokalemia or for calcium stone disease.
For patients with hyperkalemic distal RTA, high-sodium, low-potassium diet plus a thiazide or loop diuretic if necessary.

72. Treatment and prognosis depends on the underlying cause.
Hyperkalemic RTA
Treatment and prognosis depends on the underlying cause.
Potassium-retaining drugs should always be withdrawn..
Fludrocortisone therapy may also be useful in hyporeninemic hypoaldosteronism, preferably in combination with a loop diuretic such as furosemide to reduce the risk of extracellular fluid volume expansion
Dietary restriction of sodium

73. Take Home Points Distinguish RTA Types 1, 2 and 4
See Table(slide no. 65) + Some clues:
Type 1: renal stones, hypercalciuria, high urine pH despite metabolic acidosis
Type 2: think acetazolamide and bicarbonate wasting; Fanconi syndrome
Type 4: aldosterone deficiency and hyperkalemia
Mainstay of treatment of RTA
Bicarbonate therapy

74. THANK YOU !