• Renal tubular acidosis (RTA) is 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 a normal plasma anion
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 daily acid load cannot be excreted as free H+
• Secreted H+ ions are excreted by binding to either
buffers, such as HPO42- and creatinine, or to NH3 to
• The extracellular pH is the primary physiologic
regulator of net acid excretion.
Renal acid-base homeostasis may be broadly
divided into 2 processes
Proximal tubular absorption of HCO 3(Proximal acidification)
Distal Urinary acidification.
Reabsorption of remaining HCO3- that
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 transporter and by HCO3reabsorption.
• 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.
Proximal tubule physiology
Multiple factors are of primary importance in
normal bicarbonate reabsorption
The sodium-hydrogen exchanger in the
The Na-K-ATPase pump
The enzyme carbonic anhydrase II & IV
The electrogenic sodium-bicarbonate
• Ammonium synthesis and excretion is one of
the most important ways kidneys eliminate
• 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
• 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
Distal Urinary Acidification
• The thick ascending limb of Henle’s loop
reabsorbs about 15% of the filtered HCO3load by a mechanism similar to that present in
the proximal tubule, i.e., through Na+-H+
• The collecting tubule (CT) is the major site of
H+ secretion and is made of 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.
• Alpha-Intercalated Cells are thought to be the
main cells involved with H+ secretion in the
• 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.
• Beta-Intercalated Cells in contrast to the above
have a luminal Cl-/HCO3- exchanger and a
• They play a role in bicarbonate secretion into
the lumen that is later reabsorbed by the CA
IV rich luminal membrane of medullary
• 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
Aldosterone and Renal acidification
• Favors H+ and K+ secretion through enhanced
• Recruits more amiloride sensitive sodium
channels in the luminal membrane of the
• Enhances H+-ATPase activity in cortical and
medullary collecting tubules.
• Aldosterone also has an effect on NH4+
excretion by increasing NH3 synthesis
• 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
• 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
• 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.
• This leads to bicarbonaturia, kaliuresis and
• Thus patients will generally present with
hypokalemia and a Hyperchloremic metabolic
• Isolated defects in PCT function are rarely
found. Most patients with a pRTA will have
multiple defects in PCT function with
subsequent Fanconi Syndrome.
• In children, cystinosis is the most common.
• 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
Cause of hyokalemia in Type 2 RTA
Metabolic acidosis in 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
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
• 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
• Distal RTA (dRTA) is a disorder leading to
HCMA secondary to impaired distal H+
• 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
• In children, type 1 RTA is most often a
primary, hereditary condition.
• The term incomplete distal RTA has been
proposed to describe patients with
nephrolithiasis but without metabolic acidosis.
• Hypocitraturia is the usual underlying cause.
Secretory defects causing Distal RTA
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, CAH, Lithium and
• 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-KATPase activity.
Type 4 RTA (Hyperkalemic RTA)
• This disorder is characterized by modest
HCMA with normal AG and association with
• 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
Mechanism of action
• In contrast to hyperkalemic distal RTA, the
ability to lower urine ph in response to
systemic acidosis is maintained.
• Nephrocalcinosis is absent in this disorder.
Physiology of Renal Acidification.
Types of RTA and characteristics
Lab diagnosis of RTA
Approach to a patient with RTA
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 HCO3losses and who is not taking acetazolamide or
ingesting exogenous acid.
Functional evaluation of proximal
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.
Functional Evaluation of Distal Urinary
Acidification and Potassium Secretion
Urine anion gap
Urine osmolal gap
• 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
• Urine sodium should be known and urine
should not be infected.
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
• 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
• When there is increased excretion of
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.
• 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.
• 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
• This formula is relatively accurate as long as the
urine osmolality exceeds that of the plasma
urine sodium concentration is above 25 meq/L
• 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
• 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
• Bicarbonate wasting is negligible in adults who can
generally be treated with 1 to 2 meq/kg of sodium
citrate (Bicitra) 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, highsodium, low-potassium diet plus a thiazide or loop
diuretic if necessary.
• Treatment and prognosis depends on the
• Potassium-retaining drugs should always be
• 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.