RENAL TUBULAR ACIDOSIS

RENAL TUBULAR ACIDOSIS

1. RENAL TUBULAR ACIDOSIS
Dept of Urology
Govt Royapettah Hospital and Kilpauk Medical College
Chennai

2. Moderators:
Professors:
•Prof. Dr. G. Sivasankar, M.S., M.Ch.,
•Prof. Dr. A. Senthilvel, M.S., M.Ch.,
Asst Professors:
•Dr. J. Sivabalan, M.S., M.Ch.,
•Dr. R. Bhargavi, M.S., M.Ch.,
•Dr. S. Raju, M.S., M.Ch.,
•Dr. K. Muthurathinam, M.S., M.Ch.,
•Dr. D. Tamilselvan, M.S., M.Ch.,
•Dr. K. Senthilkumar, M.S., M.Ch.
Dept of Urology, GRH and KMC, Chennai. 2

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 GFRand a metabolic
acidosis accompanied by hyperchloremia and a
normal plasma anion gap.
3Dept of Urology, GRH and KMC, Chennai.

4. •First described clinically in
1935
•Confirmed as a renal
tubular disorder in 1946
•Designated as RTA in 1951
•All types produce
hyperchloremicmetabolic
acidosis with a normal
anion gap.(NAGMA)
4Dept of Urology, GRH and KMC, Chennai.

5. •Anion gap = [Na
+
] –{[Cl
–
] + [HCO3
–
]}
•normal AG : 8-16 mEq/L
•Predominant unmeasured anions
include albumin , phosphate, sulfate
and organic anions.
•Major unmeasured cationsinclude
calcium, magnesium, potassium and
gamma globulins.
5Dept of Urology, GRH and KMC, Chennai.

6. ACID LOADS
Ammonium chloride
Hyperalimentation
Ketoacidosiswith renal
ketoneloss
Bicarbonate Losses
Diarrhea
Pancreatic, biliary, or small
bowel drainage
Ureterosigmoidostomy,
Jejunalor ilealLoop
DRUGS
Cholestyramine
Calcium chloride
Magnesium sulfate
Post hypocapnia
Defects in Renal Acidification
Proximal: decreased HCO
3
-
reclamation
Distal: decreased net acid excretion
Primary mineralocorticoiddeficiency
Hyperreninemichypoaldosteronism
Mineralocorticoid-resistant
hyperkalemia
Dilutional
HyperchloremicMetabolic Acidosis (Normal Anion Gap )
6Dept of Urology, GRH and KMC, Chennai.

7. OBJECTIVES
•Physiology of Renal acidification.
•Types of RTA and characteristics
•Lab diagnosis of RTA
•Approach to a patient with RTA
•Treatment
7Dept of Urology, GRH and KMC, Chennai.

8. Physiology of Renal Acidification
•Kidneys excrete 50-100 meq/day of non carbonic
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 HPO4
2
-and creatinine, or to NH3 to
form NH4+.
•The extracellular pH is the primary physiologic
regulator of net acid excretion.
8Dept of Urology, GRH and KMC, Chennai.

9. Renal acid-base homeostasis may be broadly
divided into 2 processes
1.Proximal tubular absorption of HCO
3
-
(Proximal acidification)
2.Distal Urinary acidification.
➢Reabsorption of remaining HCO
3
-
that
escapes proximally.
➢Excretion of fixed acids through buffering &
Ammonia recycling and excretion of NH
4
+
.
9Dept of Urology, GRH and KMC, Chennai.

10. Proximal tubule physiology
•Proximal tubule contributes to renal
acidification by H+ secretion into the tubular
lumenthrough NHE3 transporter and by
HCO3-reabsorption.
•Approx. 85% of filtered HCO
3
-
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.
10Dept of Urology, GRH and KMC, Chennai.

11. 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).
11Dept of Urology, GRH and KMC, Chennai.

12. .
12Dept of Urology, GRH and KMC, Chennai.

13. 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
13Dept of Urology, GRH and KMC, Chennai.

14. Ammonia Recycling
14Dept of Urology, GRH and KMC, Chennai.

15. •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+.
15Dept of Urology, GRH and KMC, Chennai.

16. 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).
16Dept of Urology, GRH and KMC, Chennai.

17. 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.
17Dept of Urology, GRH and KMC, Chennai.

18. •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
-
/HCO
3
-
exchanger and the usual basolateral
Na
+
-K
+
ATPase.
18Dept of Urology, GRH and KMC, Chennai.

19. 19Dept of Urology, GRH and KMC, Chennai.

20. •Beta-Intercalated Cells in contrast to the above
have a luminal Cl
-
/HCO
3
-
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.
20Dept of Urology, GRH and KMC, Chennai.

21. •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
21Dept of Urology, GRH and KMC, Chennai.

22. Principal cells
22Dept of Urology, GRH and KMC, Chennai.

23. 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
23Dept of Urology, GRH and KMC, Chennai.

24. Summary
•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.
24Dept of Urology, GRH and KMC, Chennai.

25. OBJECTIVES
•Physiology of Renal Acidification.
•Types of RTA and characteristics
•Lab diagnosis of RTA
•Approach to a patient with RTA
•Treatment
25Dept of Urology, GRH and KMC, Chennai.

26. TYPES OF RTA
Proximal RTA (type 2)
•Isolated bicarbonate defect
•Fanconisyndrome
Distal RTA (type 1)
•Classic type
•Hyperkalemicdistal RTA
HyperkalemicRTA (Type 4)
26Dept of Urology, GRH and KMC, Chennai.

27. 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 HCO
3
-
a
defect at this site leads to delivery of large
amounts of bicarbonate to the distal tubule.
27Dept of Urology, GRH and KMC, Chennai.

28. •This leads to bicarbonaturia, kaliuresis and
sodium losses.
•Thus patients will generally present with
hypokalemia and a HCMA.
28Dept of Urology, GRH and KMC, Chennai.

29. .
29Dept of Urology, GRH and KMC, Chennai.

30. •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.
30Dept of Urology, GRH and KMC, Chennai.

31. I. Primary isolated proximal RTA
1. hereditary (persistent)
a. autosomal dominant
b. autosomal recessive associated with mental retardation and ocular
abnormalities
2. sporadic (transient in infancy)
II. Secondary proximal RTA
1. in the context of Fanconisyndrome (cystinosis, galactosemia, fructose
intolerance, tyrosinemia, Wilson disease, Lowe syndrome, metachromatic
leukodystrophy, multiple myeloma, light chain disease)
2. drugs and toxins (acetazolamide, outdated tetracycline, aminoglycoside
antibiotics, valproate, 6-mercaptopurine, streptozotocin, iphosphamide, lead,
cadmium, mercury)
3. associated to other clinical entities (vitamin D deficiency,
hyperparathyroidism, chronic hypocapnia, Leigh syndrome, cyanotic
congenital heart disease, medullary cystic disease, Alportsyndrome,
corticoresistantnephroticsyndrome, renal Transplantation, amyloidosis,
recurrent nephrolithiasis 31Dept of Urology, GRH and KMC, Chennai.

32. •pRTAis a self limiting disorder and fall of
serum HCO3_ below 12 meq/l is unusual, as
the distal acidification mechanisms are intact..
•Urine phremains acidic(<5.5) mostly but
becomes alkaline when bicarbonate losses are
corrected.
•FEHCO3 increases(>15%)with administration
of alkali for correction of acidosis
32Dept of Urology, GRH and KMC, Chennai.

33. Cause of hyokalemia in Type 2 RTA
➢Metabolic acidosis →decreases pRTNa
+
reabsorption →increased distal tubule
delivery of Na
+
which promotes K
+
secretion.
➢The pRTAdefect almost inevitably leads to salt
wasting, volume depletion and secondary
hyperaldosteronism.
➢The rate of kaliuresisis proportional to distal
bicarbonate delivery. Because of this alkali
therapy tends to exaggerate the hypokalemia.
33Dept of Urology, GRH and KMC, Chennai.

34. •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.
34Dept of Urology, GRH and KMC, Chennai.

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.
35Dept of Urology, GRH and KMC, Chennai.

36. •The term incomplete distal RTA has been proposed to
describe patients with nephrolithiasis but without
metabolic acidosis.
•Hypocitraturiais the usual underlying cause.
Hypocitraturiaresults from
•increased citrate utilization in proximal tubule cells due
to intracellular acidosis, resulting in an increased
gradient for tubular reabsorption,
•due to the high luminal pH favoring conversion of
citrate3-to the readily reabsorbablecitrate
36Dept of Urology, GRH and KMC, Chennai.

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.
37Dept of Urology, GRH and KMC, Chennai.

38. I. Primary distal RTA
1. persistent
a. “classic” form (sporadic or inherited as autosomal dominant or autosomal recessive)
b. with neurosensory deafness (autosomal recessive)
c. with bicarbonate wasting (in infants and young children)
d. incomplete distal RTA
2. transient (in infancy?)
II. Secondary distal RTA
1. Genetic diseases (osteopetrosis, sickle-cell disease, Ehlers-Danlossyndrome, hereditary ovalocytosis, Wilson
disease, hereditary fructose intolerance with nephrocalcinosis, primary hyperoxaluriatype 1, carnitine
palmitoyltransferase-1 deficiency, X-linked hypophosphatemia, cogenitaladrenal hyperplasia)
2. Calcium disorders (primary hyperparathyroidism, hypercalcemichyperthyroidism, vitamin D intoxication, idiopathic
hypercalciuriawith nephrocalcinosis, familial hypomagenesemia-hypercalciuriawith nephrocalcinosis)
3. Dysproteinemicsyndromes (hypergammaglobulinemia, cryoglobulinemia, amyloidosis)
4. Autoimmune diseases (systemic lupus erythematosus, Sjo¨grensyndrome, chronic active hepatitis, primary biliary
cirrhosis, thyroiditis, fibrosingalveolitis, rheumatoid arthritis)
5. Renal diseases (renal transplant rejection, medullary sponge kidney, obstructive and reflux nephropathy, Balkan
nephropathy)
6. Hyponatriuricstates (nephroticsyndrome, hepatic cirrhosis)
7. Drugs and toxins (amphotericin B, lithium, analgesic abuse, toluene, amiloride, trimethoprim, pentamidine,
vanadium)
38Dept of Urology, GRH and KMC, Chennai.

39. Secretory defects causing Distal RTA
39Dept of Urology, GRH and KMC, Chennai.

40. Non secretory defects causing Distal RTA
•Gradient defect: backleakof secreted H+
ions. Ex. Amphotericin B
•Voltage dependent defect: impaired distal
sodium transport ex. Obstructive uropathy,
sickle cell disease, CAH, Lithium and
amilorideetc.
•This form of distal RTA is associated with
hyperkalemia(Hyperkalemicdistal RTA)
40Dept of Urology, GRH and KMC, Chennai.

41. •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 NH
4
+
trapping. This leads to a positive
urine anion gap.
•Urine PCO
2 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.
41Dept of Urology, GRH and KMC, Chennai.

42. 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.
42Dept of Urology, GRH and KMC, Chennai.

43. Mechanism of action
43Dept of Urology, GRH and KMC, Chennai.

44. 44Dept of Urology, GRH and KMC, Chennai.

45. •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.
45Dept of Urology, GRH and KMC, Chennai.

46. OBJECTIVES
•Physiology of Renal Acidification.
•Types of RTA and characteristics
•Lab diagnosis of RTA
•Approach to a patient with RTA
•Treatment
46Dept of Urology, GRH and KMC, Chennai.

47. 47Dept of Urology, GRH and KMC, Chennai.

48. Lab diagnosis of RTA
•RTA should be suspected when metabolic
acidosisis accompanied by hyperchloremia
and a normal plasma anion gap in a patient
without evidence of gastrointestinal HCO3-
losses and who is not taking acetazolamide or
ingesting exogenous acid.
48Dept of Urology, GRH and KMC, Chennai.

49. 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.
49Dept of Urology, GRH and KMC, Chennai.

50. Functional Evaluation of Distal Urinary
Acidification and Potassium Secretion
•Urine anion gap
•Urine osmolalgap
•Urine ph
•Urine Pco2
•TTKG
•Urinary citrate
50Dept of Urology, GRH and KMC, Chennai.

51. 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.
51Dept of Urology, GRH and KMC, Chennai.

52. •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
52Dept of Urology, GRH and KMC, Chennai.

53. 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.
Urine osmolalgap = Measured osmolality –Calculated osmolality
(The early morning urine osmolality is measured directly by an
osmometerand calculated as given below:
•Calculated urine osmolality = 2 [Na
+
+ K
+
] + urea / 6 + glucose / 18
(Urinary levels of electrolytes are in mEq/l and urea and glucose are in
mg/dl).
•UOG of >100 represents intact NH4 secretion.
53Dept of Urology, GRH and KMC, Chennai.

54. 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.
54Dept of Urology, GRH and KMC, Chennai.

55. 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.
55Dept of Urology, GRH and KMC, Chennai.

56. TTKG
•TTKG is a concentration gradient between the
tubular fluid at the end of the cortical collecting
tubule and the plasma.
•TTKG=[Urine KxPlasma osmolality)]÷[Plasma K
xUrine osmolality]
•Normal value is 8 and above.
•Value <7 in a hyperkalemicpatient 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
56Dept of Urology, GRH and KMC, Chennai.

57. 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.
•< 2mg/kg/day
•Calcium > 4mg/kg/day
57Dept of Urology, GRH and KMC, Chennai.

58. OBJECTIVES
•Physiology of Renal acidification.
•Types of RTA and characteristics
•Lab diagnosis of RTA
•Approach to a patient with RTA
•Treatment
58Dept of Urology, GRH and KMC, Chennai.

59. 59Dept of Urology, GRH and KMC, Chennai.

60. 60Dept of Urology, GRH and KMC, Chennai.

61. 61Dept of Urology, GRH and KMC, Chennai.

62. OBJECTIVES
•Physiology of Renal acidification.
•Types of RTA and characteristics
•Lab diagnosis of RTA
•Approach to a patient with RTA
•Treatment
62Dept of Urology, GRH and KMC, Chennai.

63. Treatment
Proximal RTA
•A mixture of Na+ and K+ salts, preferably
citrate, is preferable.
•10 to 15 meqof 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.
63Dept of Urology, GRH and KMC, Chennai.

64. Distal RTA
•Bicarbonate wasting is negligible in adults who can
generally be treated with 1 to 2 meq/kg of sodium
citrate or bicarbonate.
•Potassium citrate, alone or with sodium citrate
(Polycitra), is indicated for persistent hypokalemia or
for calcium stone disease.
•For patients with hyperkalemicdistal RTA, high-
sodium, low-potassium diet plus a thiazide or loop
diuretic if necessary.
64Dept of Urology, GRH and KMC, Chennai.

65. HyperkalemicRTA TYPE 4
•Treatment and prognosis depends on the
underlying cause.
•Potassium-retaining drugs should always be
withdrawn..
•Fludrocortisone therapy may also be useful in
hyporeninemichypoaldosteronism, preferably
in combination with a loop diuretic such as
furosemide to reduce the risk of extracellular
fluid volume expansion.
65Dept of Urology, GRH and KMC, Chennai.

66. Proximal RTADistal RTARTA IV
Type of
Acidosis
Hyperchloremic
metabolic
acidosis
Hyperchloremic
metabolic
acidosis
Hyperchloremic
metabolic
acidosis
Serum
Potassium
low low high
Urine pH< 5.5 >5.5 < 5.5
Urine
bicarbonate
loss
66Dept of Urology, GRH and KMC, Chennai.

67. Feature Type 1 Type 2 Type 4
Nephro-
lithiasis
present absent Absent
Nephro-
calcinosis
present absent Absent
Osteo-
malacia
present present Absent
Growth
failure
+++ ++ +++
Hypokalemic
muscle
weakness
++ + -
Alkali
therapy
Low dose (2
–4 meq/kg)
High dose (
2-14 meq/kg)
Low dose ( 2-
3 meq/kg)
Response to
therapy
good fair fair

Features of the RTA Syndromes
67Dept of Urology, GRH and KMC, Chennai.

68. Features of the RTA SyndromesFeature Type 1 Type 2 Type IV
Plasma HCO3

Variable,
may be <10
meq/L
14- 18 meq/L

15-29 meq/L
Plasma Cl- increased Increased Increased
Plasma K+ Mildly to
severely
decreased
Mildly
decreased
Mildly to
severely
decreased
Plasma anion
gap
Normal Normal Normal
GFR Normal or
slightly
decreased
Normal of
slightly
decreased
Normal to
moderately
decreased
Fractional
Excretion of
HCO3
<5% > 15% <5%
Urine pH
during
acidosis
>6.0 </= 5.5 </= 5.5


68Dept of Urology, GRH and KMC, Chennai.