Renal Tubular Acidosis

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Renal Tubular Acidosis
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Normal Renal Function

• Proximal 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

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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

• 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.

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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

• 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.

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Distal Urinary Acidification

• The thick ascending limb of Henles 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).

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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-/HCO3- exchanger 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
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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

• 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..

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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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Renal Tubular Acidosis
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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)

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Renal Tubular Acidosis
Type 2 RTA
Type 1 RTA Type 4 RTA
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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(lt5.5) mostly but
  becomes alkaline when bicarbonate losses are
  corrected.
• FEHCO3 increases(gt15)with administration of
  alkali for correction of acidosis
• (FEHCO3 fractional excretion of HCO3)

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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.

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• 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 lt 5.5, although high initially
• K low to normal

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Type 2 RTA

• Causes
• Primary
• Idiopathic, sporadic
• Familial Cystinosis, Tyrosinemia, Hereditary
  Fructose intolerance, Galactosemia, Glycogen
  storage disease (type 1), Wilsons disease,
  Lowes syndrome
• Fanconis 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

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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(lt5.5) under the stimulus of systemic
  acidemia. The serum HCO3- levels are very low lt12
  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
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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)

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• 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
  NH4trapping. 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 Dickens 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. 1992 Dec 146(12)
1403-7.
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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 gt 5.5
• Hypercalciuria
• Renal stones

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Type 1 RTA

• Causes
• Primary
• Idiopathic, sporadic
• Familial AD, AR
• Secondary
• Autoimmune (SLE, Sjogrens, RA)
• Hereditary hypercalciuria, hyperparathyroidism,
  Vit D intoxication
• Hypergammaglobulinemia
• Drugs (Amphotericin B, Ifosfamide, Lithium)
• Chronic hepatitis
• Obstructive uropathy
• Sickle cell anemia
• Renal transplantation

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A 37-year-old man was referred for evaluation of
distal renal tubular acidosis
Serrano A and Batlle D. N Engl J Med 2008359e1
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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
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• 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 lt 5.5

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Renal Tubular Acidosis
Type 2 RTA
Type 1 RTA LOW serum K Type 4 RTA HIGH serum K
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Type 4 RTA

• Acquired Causes
• ? Renin
• 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

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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

• 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.

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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 gt15 and is
  low in other forms of RTA
• (FEHCO3 fractional excretion of HCO3)

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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.
• UOGUosm - 2 x (Na K) urea nitrogen/2.8
  glucose/18.
• UOG of gt100 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 lt20 in pRTA.
• Urine-to-blood pCO2 is gt20 in distal RTA
  reflecting impaired ammonium secretion.

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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 lt7 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

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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,highanimal protein diet and UTI.

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Table - Renal Tubular Acidosis
Primary defect Serum K Urine pH Other Causes
Type 1 distal H secretion decreased Low-nl gt 5.5 Renal stones Autoimmune (SLE, Sjogrens) Hypercalciuria Drugs (Ampho B, Ifosfamide, lithium) Hypergammaglobulinemia
Type 2 proximal HCO3- reab decreased Low-nl lt 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 lt 5.5 Aldosterone deficiency Diabetic nephropathy Spirinolactone Interstitial nephritis Obstructive uropathy Renal transplant
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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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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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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
• 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.

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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

• 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

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