Transcript Renal Tubular Acidosis

Renal Tubular Acidosis
Normal Renal Function
Proximal Tubule
Distal Tubule
Reabsorption:
• Na+ reabsorbed
• HCO3- (90%) – carbonic
anhydrase
• H+ (NH4+ or
phosphate salts)
excreted
• calcium
• glucose
• Amino acids
• NaCl, water
• molar competition
between H+ and K+
• Aldosterone
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.
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OBJECTIVES
Physiology of Renal acidification.
 Types of RTA and characteristics
 Lab diagnosis of RTA
 Approach to a patient with RTA
 Treatment
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Physiology of Renal Acidification
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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.
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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+.
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.
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Proximal tubule physiology
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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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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
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Ammonia Recycling
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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+.
Distal Urinary Acidification
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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).
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.
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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-/HCO3exchanger and the usual basolateral Na+ - K+ ATPase.
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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.
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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
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Principal cells
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
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Summary of renal physiology
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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..
OBJECTIVES
Physiology of Renal Acidification.
 Types of RTA and characteristics
 Lab diagnosis of RTA
 Approach to a patient with RTA
 Treatment

Renal Tubular Acidosis
TYPES OF RTA
Proximal RTA (type 2)
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Isolated bicarbonate defect
Fanconi syndrome
Distal RTA (type 1)
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Classic type
Hyperkalemic distal RTA
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Hyperkalemic RTA (Type 4)
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Renal Tubular Acidosis
Type 2 RTA
Type 1 RTA
Type 4 RTA
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.
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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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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.
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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)
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Cause of hypokalemia in Type 2 RTA
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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.
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.
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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
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Type 2 RTA
Causes:
 Primary
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Idiopathic, sporadic
Familial: Cystinosis,
Tyrosinemia, Hereditary
Fructose intolerance,
Galactosemia, Glycogen
storage disease (type 1),
Wilson’s disease, Lowe’s
syndrome
Fanconi’s Syndrome
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Generalized proximal
tubule dysfunction
Proximal loss of phos, uric
acid, glucose, AA
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Acquired
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Multiple Myeloma
Carbonic anhydrase inhibitors
(Acetazolamide)
Other drugs (Ampho B, 6mercaptopurine)
Heavy Metal Poisonings (Lead,
Copper, Mercury, Calcium)
Amyloidosis
Disorders of protein, Carb, AA
metabolism
Hypophosphatemia,
hypouricosuria, renal
glycosuria with normal serum
glucose
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.
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The term incomplete distal RTA has been proposed to
describe patients with nephrolithiasis but without
metabolic acidosis.
 Hypocitraturia is the usual underlying cause.
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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.
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Secretory defects causing Distal RTA
Non secretory defects causing Distal RTA
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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)
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.
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What Charles Dicken’s character is
theorized to have suffered from RTA?
Tiny Tim
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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.
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
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Type 1 RTA
Causes:
 Primary
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Idiopathic, sporadic
Familial – AD, AR
Secondary –
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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
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
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.
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Mechanism of action
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.
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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
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Renal Tubular Acidosis
Type 2 RTA
Type 1 RTA
LOW serum K+
Type 4 RTA
HIGH serum K+
Type 4 RTA
Acquired Causes
  Renin:
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Diabetic nephropathy
NSAIDS
Interstitial Nephritis
Normal renin, Aldo:
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ACEs, ARBs
Heparin
Primary adrenal
response
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response to Aldo:
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Medications: K+ sparing
drugs (Sprinolactone),
TMP-SMX, pentamidine,
tacrolimus
Tubulointerstitial ds:
sickle cell, SLE,
amyloid, diabetes
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
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OBJECTIVES
Physiology of Renal Acidification.
 Types of RTA and characteristics
 Lab diagnosis of RTA
 Approach to a patient with RTA
 Treatment
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Lab diagnosis of RTA
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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 HCO3losses and who is not taking acetazolamide or
ingesting exogenous acid.
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)
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
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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.
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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.
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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
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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.
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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.
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TTKG
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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
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.
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Table - Renal Tubular Acidosis
Type 1
distal
Type 2
proximal
Type 4
Primary defect
Serum
K+
Urine
pH
Other
Causes
H+ secretion
decreased
Low-nl
> 5.5
Renal
stones
Autoimmune (SLE, Sjogrens)
Hypercalciuria
Drugs (Ampho B, Ifosfamide,
lithium)
Hypergammaglobulinemia
HCO3- reab
decreased
Low-nl
< 5.5,
although
high
initially
Multiple Myeloma
Acetazolamide
Heavy Metal Poisonings (Lead,
Copper, Mercury, Calcium)
Amyloidosis
Disorders of protein, Carb, AA
metabolism
Aldosterone
deficiency, cation
exchange
decreased
High
< 5.5
Aldosterone deficiency
Diabetic nephropathy
Spirinolactone
Interstitial nephritis
Obstructive uropathy
Renal transplant
OBJECTIVES
Physiology of Renal acidification.
 Types of RTA and characteristics
 Lab diagnosis of RTA
 Approach to a patient with RTA
 Treatment

OBJECTIVES
Physiology of Renal acidification.
 Types of RTA and characteristics
 Lab diagnosis of RTA
 Approach to a patient with RTA
 Treatment

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
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Distal RTA
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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
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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, lowpotassium diet plus a thiazide or loop diuretic if necessary.
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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
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Take Home Points
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Distinguish RTA Types 1, 2 and 4
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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
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Bicarbonate therapy
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