TUBULAR TUBULAR FUNCTIONFUNCTIONTUBULAR TUBULAR FUNCTIONFUNCTION

• 2/3 of glomerular ultra 2/3 of glomerular ultra filtrate is reabsorbed from filtrate is reabsorbed from the PTthe PT

• 60% of 60% of NaNa ia absorbed in the ia absorbed in the PT & 25% in the ALH &15% PT & 25% in the ALH &15% in the DT.in the DT.

• All filterd All filterd KK is reabsorbed in is reabsorbed in PT & excretion occur in DT PT & excretion occur in DT and collecting ducts.and collecting ducts.

• HH excretion occur in early excretion occur in early parts of PT and also DT.parts of PT and also DT.

• CaCa reabsorption occur in reabsorption occur in parallel with Na reabsorptionparallel with Na reabsorption

• Majority of Majority of PHPH is reabsorbed is reabsorbed in the PT.in the PT.

• The process of K and H ion The process of K and H ion excretion and Na excretion and Na reabsorption iall stimulated reabsorption iall stimulated by aldosteron.by aldosteron.

• 85% of 85% of bicarbonatebicarbonate is is reabsorbed in PT and the reabsorbed in PT and the remaining 15% reabsorbed in remaining 15% reabsorbed in the DTthe DT

Acidosis & anion gapAcidosis & anion gap Acidosis & anion gapAcidosis & anion gap• ==[Na] – [Cl + Hco3][Na] – [Cl + Hco3]

• < 12 = normal or absence of anion gap < 12 = normal or absence of anion gap as in bicarbonate loss in as in bicarbonate loss in {diarhea ,RTA,carbonic anhydrase inhibitor , {diarhea ,RTA,carbonic anhydrase inhibitor , ureterosigmoidostomy, dilutional acidosis, ureterosigmoidostomy, dilutional acidosis, pancreatic fistula}pancreatic fistula}

• >20 =increased anion gap >20 =increased anion gap as in as in{ lactic acidosis, DKA, { lactic acidosis, DKA, inborn errors of metabolism, uremia, inborn errors of metabolism, uremia, poisoning with poisoning with (salicylate,methanol,ethanol)}(salicylate,methanol,ethanol)}

Normal Urinary Normal Urinary AcidificationAcidification

• Urinary acidification involves two processesUrinary acidification involves two processes: : bicarbonate bicarbonate reabsorption and hydrogen ion excretion .reabsorption and hydrogen ion excretion .

• In infants, bicarbonate reabsorption is less efficient, and In infants, bicarbonate reabsorption is less efficient, and renal bicarbonate excretion may occur at serum renal bicarbonate excretion may occur at serum concentrations less than 22 mmolconcentrations less than 22 mmol//LL. .

• The hydrogen ion in the tubular lumen binds with The hydrogen ion in the tubular lumen binds with bicarbonate and, under the influence of carbonic bicarbonate and, under the influence of carbonic anhydrase, is converted to carbon dioxide and water. anhydrase, is converted to carbon dioxide and water.

• Secretion of the daily acid load Secretion of the daily acid load ((approximately 1 mEqapproximately 1 mEq//kgkg//24 24 hr produced during normal cellular processeshr produced during normal cellular processes) ) is is accomplished by hydrogen ion secretion .accomplished by hydrogen ion secretion .

• Approximately 85%The remaining 15% of bicarbonate is Approximately 85%The remaining 15% of bicarbonate is reabsorbed distally of the filtered bicarbonate is reabsorbed distally of the filtered bicarbonate is reabsorbed in the proximal tubule .reabsorbed in the proximal tubule .

DEFINITIONDEFINITION

• Renal tubular acidosis (RTA) refers to the Renal tubular acidosis (RTA) refers to the development of a metabolic acidosis due to a development of a metabolic acidosis due to a defect at the level of the renal tubule.defect at the level of the renal tubule.

• All forms of RTA are All forms of RTA are non-anion gapnon-anion gap or or hyperchloremic metabolic acidosishyperchloremic metabolic acidosis resulting from loss of bicarbonate (inability to resulting from loss of bicarbonate (inability to reabsorb HCO3) or retention of hydrogen ion reabsorb HCO3) or retention of hydrogen ion (inability to excrete).(inability to excrete).

• In addition to the hyperchloremic metabolic In addition to the hyperchloremic metabolic acidosis, RTAs can also present with varying acidosis, RTAs can also present with varying degrees of renal insufficiency degrees of renal insufficiency

TYPES OF RTAsTYPES OF RTAs

• Distal RTADistal RTA (Type I): (Type I): loss of hydrogen ion loss of hydrogen ion secretion into urine due to defect in distal secretion into urine due to defect in distal tubule. tubule.

• Proximal RTAProximal RTA (Type II): (Type II): loss of bicarbonate loss of bicarbonate reabsorption due to defect in the proximal tubulereabsorption due to defect in the proximal tubule

• Hypoaldosteronism or hyperkalemic Hypoaldosteronism or hyperkalemic (Type IV):(Type IV): aldosterone deficiency or distal tubule resistance aldosterone deficiency or distal tubule resistance to aldosterone leading to loss of potassium to aldosterone leading to loss of potassium excretion. Ensuing hyperkalemia leads to excretion. Ensuing hyperkalemia leads to suppression of ammonia excretion. suppression of ammonia excretion.

Proximal Proximal ((Type IIType II) ) Renal Renal Tubular AcidosisTubular Acidosis• PathogenesisPathogenesis

Proximal RTA results from impaired proximal tubule Proximal RTA results from impaired proximal tubule bicarbonate reabsorptionbicarbonate reabsorption. . Isolated forms of inherited or Isolated forms of inherited or acquired proximal RTA occur, although they are generally acquired proximal RTA occur, although they are generally rarerare. . Isolated autosomal dominant forms, as well as an Isolated autosomal dominant forms, as well as an autosomal recessive form associated with ocular autosomal recessive form associated with ocular abnormalities, have been reportedabnormalities, have been reported. . More typically, proximal More typically, proximal RTA occurs as a component of global proximal tubule RTA occurs as a component of global proximal tubule dysfunction or Fanconi syndrom dysfunction or Fanconi syndrom . . Both autosomal dominant Both autosomal dominant and autosomal recessive forms of primary Fanconi and autosomal recessive forms of primary Fanconi syndrome occursyndrome occur. . In addition, secondary Fanconi syndrome In addition, secondary Fanconi syndrome may occur as a component of one of several inherited renal may occur as a component of one of several inherited renal tubular disorders or in acquired disease statestubular disorders or in acquired disease states..

Proximal (Type II) Renal Proximal (Type II) Renal Tubular AcidosisTubular Acidosis

Causes Causes IsolatedIsolated• Sporadic Sporadic • Hereditary Hereditary

Fanconi SyndromFanconi Syndrom• PrimaryPrimary• Sporadic Sporadic • Hereditary Hereditary • Cystinosis Cystinosis • Lowe syndrome Lowe syndrome • Galactosemia Galactosemia • Tyrosenemia Tyrosenemia • Fructosemia Fructosemia • Fanconi-Bickel syndrome Fanconi-Bickel syndrome • Wilson disease Wilson disease • Mitochondrial diseases Mitochondrial diseases • Dent disease (X-linked nephrolithiasis) Dent disease (X-linked nephrolithiasis)

• secondarysecondary • Heavy metals Heavy metals • Outdated tetracycline Outdated tetracycline • Gentamicin Gentamicin • Ifosfamide Ifosfamide • Cyclosporine/tacrolimus Cyclosporine/tacrolimus

•CCyyssttiinnoossiiss •LLoowwee ssyynnddrroommee •GGaallaaccttoosseemmiiaa •TTyyrroosseenneemmiiaa •FFrruuccttoosseemmiiaa •FFaannccoonnii--BBiicckkeell ssyynnddrroommee •WWiillssoonn ddiisseeaassee •MMiittoocchhoonnddrriiaall ddiisseeaasseess •DDeenntt ddiisseeaassee ((XX--lliinnkkeedd nneepphhrroolliitthhiiaassiiss))

Clinical Manifestations of Clinical Manifestations of Proximal RTA and Fanconi Proximal RTA and Fanconi SyndromeSyndrome . .

• Patients with isolated, sporadic, or inherited proximal Patients with isolated, sporadic, or inherited proximal RTA commonly present with RTA commonly present with growth failuregrowth failure in the first in the first year of life. Additional symptoms may include year of life. Additional symptoms may include polyuriapolyuria, , dehydrationdehydration (due to sodium losses), (due to sodium losses), anorexiaanorexia, , vomitingvomiting,, constipationconstipation, and, and hypotonia hypotonia. Patients with primary . Patients with primary Fanconi syndrome will have additional symptoms Fanconi syndrome will have additional symptoms secondary to phosphate wasting such assecondary to phosphate wasting such as rickets rickets. Those . Those with systemic diseases will present with additional signs with systemic diseases will present with additional signs and symptoms specific to their underlying disease. A and symptoms specific to their underlying disease. A non-anion gap metabolic acidosis will be present. non-anion gap metabolic acidosis will be present. Urinalysis in patients with isolated proximal RTA is Urinalysis in patients with isolated proximal RTA is generally unremarkable. The urine pH is acidic (<5.5), generally unremarkable. The urine pH is acidic (<5.5), because distal acidification mechanisms are intact in because distal acidification mechanisms are intact in these patients. In contrast, urinary indices in patients these patients. In contrast, urinary indices in patients with Fanconi syndrome demonstrate varying degrees ofwith Fanconi syndrome demonstrate varying degrees of phosphaturiaphosphaturia, , aminoaciduriaaminoaciduria, , glycosuriaglycosuria, , uricosuriauricosuria, and , and elevated urinary sodium or potassiumelevated urinary sodium or potassium. Depending on the . Depending on the nature of the underlying disorder, laboratory evidence of nature of the underlying disorder, laboratory evidence of chronic renal insufficiency, including chronic renal insufficiency, including elevated serum elevated serum creatininecreatinine, may be present. , may be present.

Distal (Type I) Renal Tubular Distal (Type I) Renal Tubular AcidosisAcidosis

PathogenesisPathogenesis Distal RTA occurs as the result of impaired distal urinary acidification (hydrogen ion secretion). Primary or secondary causes can result in damaged or impaired functioning of one or more transporters or proteins involved in the acidification process, including the H+/ATPase, the HCO3-/Cl- anion exchangers or the components of the aldosterone pathway. Because of impaired hydrogen ion excretion, urine pH cannot be reduced below 5.5, despite the presence of severe metabolic acidosis. Loss of sodium bicarbonate results in hyperchloremia and hypokalemia. Hypercalciuria is usually present and may lead to nephrocalcinosis or nephrolithiasis. Chronic metabolic acidosis also impairs urinary citrate excretion. Hypocitraturia further increases the risk of calcium deposition in the tubules. Bone disease is common, resulting from mobilization of organic components from bone to serve as buffers to chronic acidosis. Both primary sporadic or inherited forms occur. As with proximal RTA, distal RTA can also occur as a complication of either inherited or acquired diseases of the distal tubules.

Distal (Type I) Renal Tubular Distal (Type I) Renal Tubular AcidosisAcidosis

CausesCauses primaryprimary• Sporadic Sporadic • Hereditary Hereditary secondarysecondary• Interstitial nephritisInterstitial nephritis • Obstructive uropathy Obstructive uropathy • Vesicoureteral reflux Vesicoureteral reflux • Pyelonephritis Pyelonephritis • Transplant rejection Transplant rejection • Sickle cell nephropathy Sickle cell nephropathy • Ehlers-Danlos syndrome Ehlers-Danlos syndrome • Lupus nephritis Lupus nephritis • Nephrocalcinosis Nephrocalcinosis • Medullary sponge kidney Medullary sponge kidney • Hepatic cirrhosis Hepatic cirrhosis • Toxines\medicationsToxines\medications• Amphotericin B Amphotericin B • Lithium Lithium • Toluene Toluene • Cisplatin Cisplatin

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Distal (Type I) Renal Tubular Distal (Type I) Renal Tubular AcidosisAcidosis

Clinical ManifestationsClinical Manifestations

Patients with distal RTA share common features Patients with distal RTA share common features with those of proximal RTA, including non-anion with those of proximal RTA, including non-anion gap metabolic acidosis and growth failure. gap metabolic acidosis and growth failure. However, distinguishing features of distal RTA However, distinguishing features of distal RTA include include nephrocalcinosis nephrocalcinosis and and hypercalciuriahypercalciuria. The . The phosphate and massive bicarbonate wasting phosphate and massive bicarbonate wasting

characteristic of proximal RTA is generally absentcharacteristic of proximal RTA is generally absent..

Hyperkalemic (Type IV) Renal Hyperkalemic (Type IV) Renal Tubular Acidosis Tubular Acidosis• PathogenesisPathogenesis..

Type IV RTA occurs as the result of impaired aldosterone production Type IV RTA occurs as the result of impaired aldosterone production (hypoaldosteronism) or impaired renal responsiveness to aldosterone (hypoaldosteronism) or impaired renal responsiveness to aldosterone ("pseudo" hypoaldosteronism). Because aldosterone has a direct effect on ("pseudo" hypoaldosteronism). Because aldosterone has a direct effect on the H+ ATPase responsible for hydrogen secretion, acidosis results. In the H+ ATPase responsible for hydrogen secretion, acidosis results. In addition, aldosterone is a potent stimulant for potassium secretion in the addition, aldosterone is a potent stimulant for potassium secretion in the collecting tubule. Loss of aldosterone effect results in hyperkalemia. This collecting tubule. Loss of aldosterone effect results in hyperkalemia. This further affects acid-base status by inhibiting ammoniagenesis and, thus, further affects acid-base status by inhibiting ammoniagenesis and, thus, hydrogen ion excretion. Aldosterone deficiency typically occurs as a result hydrogen ion excretion. Aldosterone deficiency typically occurs as a result of adrenal gland disorders such as Addison disease or congenital adrenal of adrenal gland disorders such as Addison disease or congenital adrenal hyperplasia (CAH). In children, aldosterone unresponsiveness is a more hyperplasia (CAH). In children, aldosterone unresponsiveness is a more common cause of type IV RTA. This may occur transiently, during an common cause of type IV RTA. This may occur transiently, during an episode of acute pyelonephritis or acute urinary obstruction, or chronically, episode of acute pyelonephritis or acute urinary obstruction, or chronically, particularly in infants and children with a history of obstructive uropathy. particularly in infants and children with a history of obstructive uropathy. The latter patients may have significant hyperkalemia, even in instances The latter patients may have significant hyperkalemia, even in instances when renal function is normal or only mildly impaired. Rare examples of when renal function is normal or only mildly impaired. Rare examples of inherited forms of type IV RTA have been identified. inherited forms of type IV RTA have been identified.

Hyperkalemic (Type IV) Renal Hyperkalemic (Type IV) Renal Tubular Acidosis Tubular Acidosis

CausesCauses• primaryprimary• Sporadic Sporadic • Hereditary Hereditary • secondarysecondary• Hypoaldosteronism Hypoaldosteronism • Addison disease Addison disease • Congenital adrenal hyperplasia Congenital adrenal hyperplasia • Prolonged heparinization Prolonged heparinization • Pseudohypoaldosteronism (type I or II) Pseudohypoaldosteronism (type I or II) • Obstructive uropathy Obstructive uropathy • Pyelonephritis Pyelonephritis • Interstitial nephritis Interstitial nephritis • Diabetes mellitus Diabetes mellitus • Sickle cell nephropathy Sickle cell nephropathy • Trimethoprim/sulfamethoxazole Trimethoprim/sulfamethoxazole • Angiotensin-converting enzyme inhibitors Angiotensin-converting enzyme inhibitors • Cyclosporine Cyclosporine

Hyperkalemic (Type IV) Renal Hyperkalemic (Type IV) Renal Tubular Acidosis Tubular Acidosis

Clinical ManifestationsClinical Manifestations..

Patients with type IV RTA, like those with types I Patients with type IV RTA, like those with types I and II RTA, may present with growth failure in the and II RTA, may present with growth failure in the first few years of life. Polyuria and dehydration first few years of life. Polyuria and dehydration (from salt wasting) are common. Rarely, patients (from salt wasting) are common. Rarely, patients (especially those with pseudohypoaldosteronism (especially those with pseudohypoaldosteronism type 1) will present with life-threatening type 1) will present with life-threatening hyperkalemia. Patients with obstructive hyperkalemia. Patients with obstructive uropathies may present acutely with signs and uropathies may present acutely with signs and symptoms of pyelonephritis, such as fever, symptoms of pyelonephritis, such as fever, vomiting, and foul-smelling urine. Laboratory vomiting, and foul-smelling urine. Laboratory tests reveal a hyperkalemic non-anion gap tests reveal a hyperkalemic non-anion gap metabolic acidosis. Urine may be alkaline or metabolic acidosis. Urine may be alkaline or acidic. Elevated urine sodium levels with acidic. Elevated urine sodium levels with inappropriately low urine potassium levels reflect inappropriately low urine potassium levels reflect the absence of aldosterone effectthe absence of aldosterone effect . .

Diagnosis of RTADiagnosis of RTA

• confirm the presence of and nature of the metabolic confirm the presence of and nature of the metabolic acidosis.acidosis.

• assess renal function.assess renal function.• rule out other causes of metabolic acidosis, such as rule out other causes of metabolic acidosis, such as

diarrhea diarrhea ( which is extremely common) .( which is extremely common) .

• identify electrolyte abnormalities (K,Na,Cl)identify electrolyte abnormalities (K,Na,Cl)• blood urea nitrogen, calcium, phosphorus, and blood urea nitrogen, calcium, phosphorus, and

creatinine and pHcreatinine and pH NOTE:NOTE:

blood should be obtained by blood should be obtained by venous puncture. Traumatic blood draws (such as heel stick venous puncture. Traumatic blood draws (such as heel stick specimens) or prolonged specimen transport time can lead to specimens) or prolonged specimen transport time can lead to falsely falsely low bicarbonate levelslow bicarbonate levels, often in association with an , often in association with an elevated serum elevated serum potassium value. potassium value.

Diagnosis of Diagnosis of RTARTA ## the anion gap should be calculated using the formula the anion gap should be calculated using the formula [Na+] - [Na+] - [Cl- + HCO3-].[Cl- + HCO3-]. Values of less than 12 demonstrate the absence Values of less than 12 demonstrate the absence of an anion gap.of an anion gap.

# # True hyperkalemic acidosis is consistent with type IV RTA, True hyperkalemic acidosis is consistent with type IV RTA, whereas the finding of normal or low potassium suggests type I whereas the finding of normal or low potassium suggests type I or II .or II .

# # urine pH may help distinguish distal from proximal causes urine pH may help distinguish distal from proximal causes. . A A urine pH of urine pH of less than 5.5less than 5.5 in the presence of acidosis suggests in the presence of acidosis suggests proximal RTA, whereas patients with distal RTA typically have a proximal RTA, whereas patients with distal RTA typically have a urine pH of urine pH of more than 6.0more than 6.0..

# # The urine anion gap The urine anion gap ([([Urine Na + Urine K] - Urine Cl)Urine Na + Urine K] - Urine Cl) is is sometimes calculated to confirm the diagnosis of distal RTA. A sometimes calculated to confirm the diagnosis of distal RTA. A positive gap suggests distal RTA. A negative gap is consistent positive gap suggests distal RTA. A negative gap is consistent with proximal tubule bicarbonate wasting (or gastrointestinal with proximal tubule bicarbonate wasting (or gastrointestinal bicarbonate wasting). bicarbonate wasting).

# # acid loading test with use of acid loading test with use of ammonium chlorideammonium chloride with finding with finding of further fall in serum bicarbonate without decline of urine PH of further fall in serum bicarbonate without decline of urine PH below 6.0 without development of –ve urine anion gap is proof below 6.0 without development of –ve urine anion gap is proof of distal RTAof distal RTA

## A urinalysis should also be obtained to determine the presence A urinalysis should also be obtained to determine the presence of glycosuria, proteinuria, or hematuria suggesting the of glycosuria, proteinuria, or hematuria suggesting the possibility of more global tubular damage or dysfunction .possibility of more global tubular damage or dysfunction .

##Random or 24-hr urine calcium and creatinine measurements Random or 24-hr urine calcium and creatinine measurements will identify hypercalciuria .will identify hypercalciuria .

# # A renal ultrasound should be obtained to identify underlying A renal ultrasound should be obtained to identify underlying structural abnormalities such as obstructive uropathies as well structural abnormalities such as obstructive uropathies as well as to determine the presence of nephrocalcinosis. as to determine the presence of nephrocalcinosis.

Ultrasound examination of a child with distal renal Ultrasound examination of a child with distal renal tubular acidosis demonstrating medullary tubular acidosis demonstrating medullary nephrocalcinosisnephrocalcinosis

Treatment of RTATreatment of RTA• Patients with proximal RTA often require large quantities of Patients with proximal RTA often require large quantities of

bicarbonate, up to bicarbonate, up to 20 mEq/kg/24 hr20 mEq/kg/24 hr in the form of sodium in the form of sodium bicarbonate or sodium citrate solution (Bicitra or Shohl's bicarbonate or sodium citrate solution (Bicitra or Shohl's solution). Also we have( polycitra solution) which same as solution). Also we have( polycitra solution) which same as bictra with adding of potassium citrate.bictra with adding of potassium citrate.

• The base requirement for distal RTAs is generally in the range The base requirement for distal RTAs is generally in the range of of 2-4 mEq/kg/24 hr2-4 mEq/kg/24 hr, although patient requirements may vary ., although patient requirements may vary .

• Patients with Fanconi syndrome generally require phosphate Patients with Fanconi syndrome generally require phosphate supplementation .supplementation .

• Patients with distal RTA should be monitored for the Patients with distal RTA should be monitored for the development of hypercalciuria. Those with symptomatic development of hypercalciuria. Those with symptomatic hypercalciuria (e.g., recurrent episodes of gross hematuria), hypercalciuria (e.g., recurrent episodes of gross hematuria), nephrocalcinosis, or nephrolithiasis may require thiazide nephrocalcinosis, or nephrolithiasis may require thiazide diuretics to decrease urine calcium excretion. diuretics to decrease urine calcium excretion.

Treatment of RTA contTreatment of RTA cont..• Patients with type IV RTA may require chronic Patients with type IV RTA may require chronic

treatment for hyperkalemia with sodium-potassium treatment for hyperkalemia with sodium-potassium exchange resin (Kayexalate®). exchange resin (Kayexalate®).

• Rickets may be present in primary renal tubular Rickets may be present in primary renal tubular acidosis (RTA), particularly in type II or proximal RTA. acidosis (RTA), particularly in type II or proximal RTA. Administration of sufficient bicarbonate to reverse Administration of sufficient bicarbonate to reverse acidosis stops bone dissolution and the hypercalciuria acidosis stops bone dissolution and the hypercalciuria that is common in distal RTA. Proximal RTA is treated that is common in distal RTA. Proximal RTA is treated with both bicarbonate and oral phosphate with both bicarbonate and oral phosphate supplements to heal bone disease. Doses of supplements to heal bone disease. Doses of phosphate similar to those used in familial phosphate similar to those used in familial hypophosphatemia or Fanconi syndrome should be hypophosphatemia or Fanconi syndrome should be used . Vitamin D is needed to offset the secondary used . Vitamin D is needed to offset the secondary hyperparathyroidism that complicates oral phosphate hyperparathyroidism that complicates oral phosphate therapy therapy

• The mainstay of therapy in all forms of RTA is The mainstay of therapy in all forms of RTA is bicarbonate replacement .bicarbonate replacement .

THE ENDTHE END