RENAL TUBULAR ACIDOSIS

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

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

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.
3
Dept of Urology, GRH and KMC, Chennai.

• First described clinically in
1935
• Confirmed as a renal
tubular disorder in 1946
• Designated as RTA in 1951
• All types produce
hyperchloremic metabolic
acidosis with a normal
anion gap.(NAGMA)
4

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

ACID LOADS
Ammonium chloride
Hyperalimentation
Ketoacidosis with renal
ketone loss
Bicarbonate Losses
Diarrhea
Pancreatic, biliary, or small
bowel drainage
Ureterosigmoidostomy,
Jejunal or ileal Loop
DRUGS
Cholestyramine
Calcium chloride
Magnesium sulfate
Post hypocapnia
Defects in Renal Acidification
Proximal: decreased HCO3
-
reclamation
Distal: decreased net acid excretion
Primary mineralocorticoid deficiency
Hyperreninemic hypoaldosteronism
Mineralocorticoid - resistant
hyperkalemia
Dilutional
Hyperchloremic Metabolic Acidosis (Normal Anion Gap )
6

OBJECTIVES
• Physiology of Renal acidification.
• Types of RTA and characteristics
• Lab diagnosis of RTA
• Approach to a patient with RTA
• Treatment
7

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 HPO42- and creatinine, or to NH3 to
form NH4+.
• The extracellular pH is the primary physiologic
regulator of net acid excretion.
8

Renal acid-base homeostasis may be broadly
divided into 2 processes
1. Proximal tubular absorption of HCO3
-
(Proximal acidification)
2. Distal Urinary acidification.
➢ Reabsorption of remaining HCO3
- that
escapes proximally.
➢ Excretion of fixed acids through buffering &
Ammonia recycling and excretion of NH4
+.
9

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.
10

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).
11

.
12

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
13

Ammonia Recycling
14

• 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+.
15

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).
16

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.
17

• 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.
18

19

• 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.
20

• 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
21

Principal cells
22

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
23

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.
24

OBJECTIVES
• Physiology of Renal Acidification.
• Treatment
25

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)
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.
28

.
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

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 Fanconi syndrome (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, Alport syndrome,
corticoresistant nephrotic syndrome, renal Transplantation, amyloidosis,
recurrent nephrolithiasis 31

• 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 remains acidic(<5.5) mostly but
becomes alkaline when bicarbonate losses are
corrected.
• FEHCO3 increases(>15%)with administration
of alkali for correction of acidosis
32

Cause of hyokalemia in Type 2 RTA
➢Metabolic acidosis → decreases pRT Na+
reabsorption → 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.
33

• 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.
34

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.
35

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

• 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.
37

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-Danlos syndrome, hereditary ovalocytosis, Wilson
disease, hereditary fructose intolerance with nephrocalcinosis, primary hyperoxaluria type 1, carnitine
palmitoyltransferase-1 deficiency, X-linked hypophosphatemia, cogenital adrenal hyperplasia)
2. Calcium disorders (primary hyperparathyroidism, hypercalcemic hyperthyroidism, vitamin D intoxication, idiopathic
hypercalciuria with nephrocalcinosis, familial hypomagenesemia-hypercalciuria with nephrocalcinosis)
3. Dysproteinemic syndromes (hypergammaglobulinemia, cryoglobulinemia, amyloidosis)
4. Autoimmune diseases (systemic lupus erythematosus, Sjo¨gren syndrome, chronic active hepatitis, primary biliary
cirrhosis, thyroiditis, fibrosing alveolitis, rheumatoid arthritis)
5. Renal diseases (renal transplant rejection, medullary sponge kidney, obstructive and reflux nephropathy, Balkan
nephropathy)
6. Hyponatriuric states (nephrotic syndrome, hepatic cirrhosis)
7. Drugs and toxins (amphotericin B, lithium, analgesic abuse, toluene, amiloride, trimethoprim, pentamidine,
vanadium) 38

Secretory defects causing Distal RTA
39

Non secretory defects causing Distal RTA
• Gradient defect: backleak of secreted H+
ions. Ex. Amphotericin B
• Voltage dependent defect: impaired distal
sodium transport ex. Obstructive uropathy,
sickle cell disease, CAH, 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

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.
42

Mechanism of action
43

44

• 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.
45

OBJECTIVES
• Physiology of Renal Acidification.
• Treatment
46

47

Lab diagnosis of RTA
• RTA should be suspected when metabolic
acidosis is 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.
48

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.
49

Functional Evaluation of Distal Urinary
Acidification and Potassium Secretion
• Urine anion gap
• Urine osmolal gap
• Urine ph
• Urine Pco2
• TTKG
• Urinary citrate
50

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.
51

• 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
52

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 osmolal gap = Measured osmolality – Calculated osmolality
(The early morning urine osmolality is measured directly by an
osmometer and 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.
53

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.
54

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.
55

TTKG
• TTKG is a concentration gradient between the
tubular fluid at the end of the cortical collecting
tubule and the plasma.
• TTKG = [Urine K x Plasma osmolality)] ÷ [Plasma K
x Urine osmolality]
• 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
56

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
57

OBJECTIVES
• Treatment
58

59

60

61

OBJECTIVES
• Treatment
62

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.
63

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 hyperkalemic distal RTA, high-
sodium, low-potassium diet plus a thiazide or loop
diuretic if necessary.
64

Hyperkalemic RTA TYPE 4
• 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.
65

Proximal RTA Distal RTA RTA 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 66

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
67

Features of the RTA Syndromes
Feature 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
68

RENAL TUBULAR ACIDOSIS

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