Tubular Acidosis




(1)
Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

 



Keywords

Proximal RTADistal RTAIncomplete RTADistal RTA with hyperkalemiaNet acid excretionUrine pHUrine anion gapUrine osmolal gap


Renal tubular acidosis (RTA) comprises a group of different renal tubular disorders that are characterized by the inability to excrete H+ in the urine. As a result, there is a positive H+ balance, causing metabolic acidosis. The net acid excretion (NAE) is decreased, and some of the patients are unable to lower their urine pH <5.5. Despite severe acidosis, the anion gap (AG) remains normal because the decrease in serum [HCO3 −] is compensated for by a proportionate increase in serum [Cl−].


Types of RTAs


Distal RTA was the first one to be described and is, therefore, called type I or classic RTA. It is called distal RTA because the urinary acidification is impaired in the distal segment of the nephron. HCO3 − loss in the urine is minimal. Subsequently proximal tubular disorder was described and named proximal RTA or type II RTA. In this type, there is HCO3 − wasting but the distal acidification mechanism is intact. Type III RTA patients share characteristics of both type I and type II and is referred to as incomplete RTA. All these three types have hypokalemia. The term type IV RTA was coined in 1976 to describe patients with hyperchloremic metabolic acidosis, hyperkalemia, hyporeninemia, aldosterone deficiency, and moderate renal insufficiency. These patients were able to acidify their urine (unlike type I patients) and do not have HCO3 − wasting (unlike type II patients). In 1981, however, a subset of patients with hyperkalemia and metabolic acidosis were unable to acidify their urine. These patients had obstructive uropathy and did not have aldosterone deficiency. They were unable to create a lumen-negative voltage gradient in the cortical collecting duct so that both K+ and H+ are not secreted into the lumen. These patients were classified as having voltage-dependent RTA. In order to avoid confusion in terminology, it is better to combine both type IV RTA and voltage-dependent RTA and call “distal RTA with hyperkalemia.” Thus, RTA can be classified into the following four types:


  1. 1.

    Proximal RTA (type II RTA)


     

  2. 2.

    Distal RTA (classic or type I RTA)


     

  3. 3.

    Incomplete RTA (type III RTA)


     

  4. 4.

    Distal RTA with hyperkalemia


     

In order to understand the various types of RTA, it is important to recapitulate the mechanisms of renal acidification and NAE. As discussed in Chap. 2, HCO3 − reabsorption and H+ secretion are important mechanisms to maintain urine pH <5.5 in a normal individual. In order to maintain acid urine, the excretion of HCO3 − should be minimal, and H+ secretion should be normal in the urine. This urinary acidification is impaired in most of the conditions of RTAs.


Briefly, reabsorption of HCO3 − in the proximal tubule occurs because of H+ secretion into the tubular lumen by Na/H exchanger and H-ATPase. The secreted H+ combines with the tubular HCO3 − to form carbonic acid (H2CO3), which dissociates into CO2 and H2O in the presence of carbonic anhydrase IV. CO2 diffuses into the cell where it combines with H2O to form H2CO3, which is degraded into H+ and HCO3 −. This reaction is catalyzed by carbonic anhydrase II. H+ is secreted into the lumen, and HCO3 − is transported into the blood via basolateral Na/HCO3 cotransporter. Thus, 80% of the HCO3 is reabsorbed in the proximal tubule (Fig. 2.​1).


The remaining 20% of HCO3 − is reabsorbed (regenerated) in the remaining segments of the nephron. Of these segments, the collecting duct plays an important role in renal acidification. The collecting duct includes the cortical portion and outer and inner medullary segments. This cortical collecting duct contains principal cells and intercalated cells. The latter cells are responsible for acid–base transport. The intercalated cells in the cortical collecting duct are of three types: type A, type B, and type C cells. Type A intercalated cells contain H-ATPase and K/H exchanger in the apical membrane. H+ that is formed inside the cell from dehydration of H2CO3 is secreted into the lumen by these transporters. HCO3 − exit is facilitated by the Cl/HCO3 exchanger (Fig. 2.​2).


In contrast, type B intercalated cells secrete HCO3 − into the lumen (Fig. 2.​3). These cells possess pendrin, a Cl/HCO3 exchanger, in the apical membrane and H-ATPase in the basolateral membrane.


Type C (formerly non A, non B) cells express H-ATPase and pendrin (Cl/HCO3 exchanger) in the apical membrane. These cells also participate in HCO3 − handling.


The cellular mechanisms of HCO3 − reabsorption in the cortical collecting duct have been discussed above. The intercalated cells of the outer medullary and inner medullary collecting duct reabsorb HCO3 − and secrete protons similar to the type A cell mechanisms (Fig. 2.​2). The cells of outer medullary and inner medullary collecting duct do not secrete HCO3 − into the lumen.


Thus, all filtered HCO3 − is reabsorbed in all segments of the nephron leaving minimal amount in the urine.


Net Acid Excretion


As stated in Chap. 2, the H ions that are generated as fixed acids must be excreted daily in the urine to maintain normal acid–base balance. These H+ are not excreted as free ions. Instead, they are excreted in the form of titratable acidity (TA) and NH4 +. Only a small amount of H+ is excreted as free ions. Each liter of urine contains approximately 0.04 mmol of free H+. Because of this negligible amount of free H+, the urine pH is maintained between 4.5 and 6.0. Another reason for the maintenance of acid urine pH is the relatively low concentration of HCO3 − (<3 mEq/L of urine). Urinary loss of HCO3 − greater than 5 mEq would generally raise the pH above 6.0 and make the urine alkaline. HCO3 − loss in the urine is generally equated as a gain of H+ to the body.


The excretion of H+ as TA and NH4 + is quantified as net acid excretion (NAE). NAE is defined as the sum of TA and NH4 + minus any H+ that is added to the body because of urinary loss of HCO3 −. Therefore, NAE is calculated as follows:



$$ NAE= TA+{NH_4}^{+}-{HCO_3}^{-}. $$
In a normal individual, NAE is increased in response to an acid load. Metabolic acidosis increases NAE because the excretion of both TA and NH4 + increases. Thus, NAE reflects the amount of H+ excretion in the form of urinary buffers. Determination of NAE in a patient with hyperchloremic metabolic acidosis can help determine the etiology of this disorder.

NAE is difficult to estimate. However, simple laboratory tests such as urine pH, urine anion gap (UAG), and urine osmolal gap are helpful during the workup of a patient with RTA. Of these three tests, the first two are easy and routinely performed.


Urine pH






  • Normal urine pH varies between 4.5 and 6.0, implying appropriate NAE.



  • In patients with proximal RTA, urine pH can be acidic or alkaline (see further).



  • In patients with distal RTA, urine pH is always >6.5.



  • In type III RTA, urine pH is >6.5.



  • In patients with hyperkalemic RTA (type IV) with aldosterone deficiency, urine pH is usually <5.5.



  • In hyperkalemic distal RTA with variable levels of aldosterone, urine pH is always >6.5.


Urine Anion Gap (UAG)






  • UAG (UNa + UK − UCl) is an indirect measure of NH4 + excretion. It is the best measure to distinguish RTA from hyperchloremic metabolic acidosis due to nonrenal causes such as chronic diarrhea.



  • When UCl > (UNa + UK), the UAG is negative, indicating adequate NH4 + excretion. On the other hand, when UAG is positive [UCl < (UNa + UK)], NH4 + excretion is decreased.



  • In conditions such as diabetic ketoacidosis, Cl− is excreted mostly with ketoanions than with Na+, K+, or NH4 +; therefore, the UAG becomes falsely positive. Therefore, a direct measurement of NH4 + is needed.



  • UAG should be determined in patients with urinary Na+ > 25 mEq/L.



  • Since direct measurement of NH4 + is not available in many clinical laboratories, an indirect measurement can be obtained by calculating the urine osmolal gap.


Urine Osmolal Gap (UOG)






  • Like serum osmolal gap, UOG is the difference between the measured and calculated urine osmolalities. UOG detects unmeasured anions or cations, and it is an indirect test for NH4 + excretion. The UOG is expressed as mOsm/kg H2O and calculated as follows:






$$ {\mathrm{U}}_{OG}=2\left({Na}^{+}+{\mathrm{K}}^{+}\right)+\mathrm{Urea}+\mathrm{Glucose}\ \left(\mathrm{all}\ \mathrm{in}\ \mathrm{mmol}/\mathrm{L}\right) $$




  • Normal UOG values range from 10 to100 mOsm/kg H2O.



  • UNH4 excretion is half of UOG due the accompanying anions.



  • When UOG is <100 mOsm in metabolic acidosis, it indicates impaired NH4 + excretion.



  • UOG is thus useful in the differential diagnosis of hyperchloremic metabolic acidosis.


Proximal RTA (Type II RTA)


Definition of Proximal RTA


Proximal RTA is a condition of impaired HCO3 − reabsorption in the proximal tubule, which is due to a defect in H+ secretion (decreased activity of either Na/H exchanger or H-ATPase or both), decreased carbonic anhydrase activity, or a defect in HCO3 − exit. It can occur as an isolated defect of HCO3 − reabsorption or in association with other solute defects in the proximal tubule, which is collectively referred to as renal Fanconi syndrome. These characteristics of proximal RTA are given below.


Pathophysiology of Proximal RTA


As discussed above and from Chap. 2 regarding HCO3 − handling in the kidney, all the filtered HCO3 − is reabsorbed by the kidney. For example, 4320 mEq (serum [HCO3 −] 24 × daily GFR 180 L = 4320) of HCO3 − are filtered daily in a normal individual. All of this HCO3 − is reabsorbed, and virtually none appears in the urine. Approximately 80% of filtered HCO3 − is reabsorbed in the proximal tubule. In proximal RTA, HCO3 − reabsorption is reduced. This results in more HCO3 − delivery to the distal tubules, and all HCO3 − not being reabsorbed. This causes loss of HCO3 − in the urine, and urine pH becomes alkaline (>6.5). This suggests that there is a certain threshold for HCO3 − reclamation in the proximal tubule in patients with proximal RTA. When the filtered load of HCO3 − is reduced because of low serum [HCO3 −] of ~18–20 mEq/L, patients with proximal RTA with normal renal function can reabsorb all HCO3 −, and urine is free of HCO3 − with a pH <5.5 (acid). This acidic pH is due to increased NAE, suggesting that distal acidification is intact. Thus, acidification of urine depends on serum [HCO3 −] in patients with proximal RTA. Table 8.1 explains HCO3 − handling and urine pH in proximal RTA, which occurs in two phases: initial and steady-state phases.


Table 8.1

Handling of HCO3 − in normal subjects and patients with proximal RTA










































Subjects

Amount (mEq) of filtered HCO3 −


Amount (mEq) reabsorbed in the proximal tubule

Amount (mEq) delivered to distal segments

Amount (mEq) of HCO3 − excreted

Urine pH

Normal

4320

3456 (80%)

864 (20%)

<3

<5.5


Proximal RTA


 Initial phase

4320

2808 (65%)

1512 (25%)a


1134

>6.5


 Steady state

3600b


2880 (76%)

864 (24%)

<3

<5.5



aMaximum reabsorption


bCalculated at serum [HCO3 −] of 20 mEq/L


Causes of Proximal RTA


Proximal RTA can be either hereditary (primary) or acquired (secondary). As stated, it can occur as an isolated defect in HCO3 − transport only (called isolated proximal RTA) or in association with multiple tubular transport defects (called renal Fanconi syndrome). Table 8.2 shows the causes of proximal RTA.


Table 8.2

Causes of proximal RTA













































































Primary (hereditary) causes

Secondary (acquired) causes

Isolated proximal RTA not associated with renal Fanconi syndrome


Dysproteinemic states


Genetic

Multiple myeloma


Autosomal recessive

Light-chain deposition disease


Autosomal dominant

Amyloidosis


Sporadic

Tubulointerstitial diseases


Carbonic anhydrase (CA) II deficiency

Sjögren’s syndrome


CA IV deficiency

Posttransplantation rejection


Proximal RTA associated with renal Fanconi syndrome


Medullary cystic disease


Inherited disorders

Secondary hyperparathyroidism with chronic hypocalcemia


Cystinosis

Vitamin D deficiency or resistance


Wilson’s disease

Vitamin D dependency


Tyrosinemia

Others


Hereditary fructose intolerance

Nephrotic syndrome


Lowe syndrome

Paroxysmal nocturnal hemoglobinuria


Galactosemia

Drugs


Dent disease

CA inhibitors (acetazolamide, topiramate)

 

Anticancer drugs (ifosfamide, cisplatin, carboplatin, streptozotocin, azacitidine, suramin, mercaptopurine)

 

Antibacterial drugs (outdated tetracyclines, aminoglycosides)

 

Anticonvulsants (valproic acid, topiramate)

 

Antiviral agents (DDI, adefovir, cidofovir, tenofovir)

 

Calcineurin inhibitor (tacrolimus)

 

Others (fumarate, ranitidine, salicylates, alcohol, cadmium)


Renal Fanconi Syndrome


Definition


It is defined as a proximal tubular dysfunction, leading to excessive urinary excretion of HCO3 −, glucose, phosphate, uric acid, amino acids, and to a lesser extent Na+, K+, and Ca2+.


Pathogenesis


The pathogenesis of renal Fanconi syndrome is not completely understood because several mechanisms may exist, particularly for drug-induced syndrome. However, mitochondrial cytopathy and disruption of cellular energy production as well as impaired proximal tubular endocytosis seem to cause dysfunction of proximal tubule.


Laboratory and Clinical Manifestations


The urinary losses of solutes lead to acidosis, electrolyte abnormalities (hypokalemia, hypophosphatemia, hypouricemia), dehydration with resultant increase in renin-AII-aldosterone production, rickets, osteomalacia, growth, and mental retardation.


Characteristics of Proximal RTA


Based on the above discussion, the characteristics of proximal RTA include the following:


  1. 1.

    Hyperchloremic (non-AG) metabolic acidosis


     

  2. 2.

    HCO3 − wasting in early or initial phase when serum [HCO3 −] is 20 mEq/L and urine pH is usually >6.5


     

  3. 3.

    Urine pH <5.5 in chronic (steady) phase (serum [HCO3 −] is <18–20 mEq/L


     

  4. 4.

    Hypokalemia is extremely common because of excess urinary loss of K+. This is due to the increased delivery of Na+ and HCO3 − to the distal nephron, where Na+ and K+ exchange occurs. Also, volume depletion-induced aldosterone may contribute to K+ wastage


     

  5. 5.

    Positive UAG


     

  6. 6.

    Intact distal tubule acidification


     

  7. 7.

    Abnormalities associated with renal Fanconi syndrome


     

Causes of Proximal RTA


Table 8.2 shows both genetic and acquired causes of proximal RTA associated with renal Fanconi syndrome. The most common genetic cause of renal Fanconi syndrome is cystinosis in children and adolescents, whereas multiple myeloma and drugs are important causes in adults.


Diagnosis of Proximal RTA






  • Suspect proximal RTA in an adult with chronic hyperchloremic metabolic acidosis, hypokalemia, and urine pH <5.5 with serum [HCO3 −] <20 mEq/L



  • Confirmatory tests include:


    1. 1.

      Positive UAG


       

    2. 2.

      Fractional excretion of HCO3 − >15% (even >5% may be sufficient in some patients)


       

    3. 3.

      HCO3 − titration test (definitive test): a marked increase in urinary excretion of HCO3 − and pH occurs, as serum [HCO3 −] is raised to normal levels (i.e., above renal threshold) by i.v. administration of NaHCO3


       


  • Glucosuria in the presence of normal serum glucose levels, phosphaturia, or other solute excretion establishes the diagnosis of renal Fanconi syndrome.



  • Growth retardation and rickets in children and osteopenia as well as pseudofractures in adults should alert the physician to consider proximal RTA as one of the diagnoses.


Clinical Manifestations of Proximal RTA






  • Skeletal abnormalities and osteomalacia are common due to chronic metabolic acidosis and vitamin D deficiency. Hypophosphatemia may also contribute to skeletal abnormalities.



  • Vitamin D deficiency is due to decreased formation of 1,25(OH)2D3 from 25(OH)D3, as proximal tubular production of 1α-hydroxylase is reduced.



  • Osteopenia and pseudofractures occur in adults.



  • Nephrocalcinosis and nephrolithiasis are rather uncommon, except in patients treated for epilepsy with topiramate. This drug inhibits carbonic anhydrase and causes hypercalciuria, hypocitraturia, and alkaline urine pH with resultant formation of calcium phosphate stones.


Specific Causes of Isolated Proximal RTA


Autosomal Recessive Proximal RTA






  • Caused by mutations in Na/HCO3 cotransporter isoform 1 located in the basolateral membrane of the proximal tubule and eyes. Described initially in 2- and 16-year-old females.



  • Clinical manifestations include short stature, mental retardation, cataracts, bilateral glaucoma, and band keratopathy. Low HCO3 −, non-AG acidosis, and acid urine were observed. However, both parents were normal.



  • Treatment includes lifelong alkali therapy.


Autosomal Dominant Proximal RTA






  • Described only in two brothers belonging to a single Costa Rican family.



  • Gene mutation is unknown.



  • Clinical manifestations include growth retardation and reduced bone density. Both brothers had low serum [HCO3 −] with acid urine.



  • Treatment is lifelong alkali therapy.


Sporadic Form






  • A transient form of inherited proximal RTA, requiring alkali therapy initially, and then discontinuation after several years.


Carbonic Anhydrase (CA) Deficiency






  • Two isoforms of CA have been described.



  • CA II is cytoplasmic and found in the proximal and distal tubule.



  • CA IV is located in the apical membrane of the proximal tubule.



  • CA II deficiency is caused by mutations in CA II gene and inherited as an autosomal recessive disease.



  • CA II deficiency patients are usually Arabic in origin.



  • Early manifestations include growth and mental retardation, osteopetrosis, cerebral calcification, hypokalemia, proximal muscle weakness, and other features of both proximal and distal (type III) RTAs.



  • CA IV deficiency impairs HCO3 − reabsorption in the proximal tubule, but a genetic mutation has not been described.


Specific Causes of Renal Fanconi Syndrome


Cystinosis






  • Cystinosis is an important cause of renal Fanconi syndrome in children.



  • It is caused by inactivating mutations in CTNS which encodes a lysosomal membrane protein called cystinosin. It is a membrane transporter that is responsible for cystine export from lysosomes.



  • Because of this mutation, transport of cystine is impaired, with resultant accumulation of cystine in renal tubules and other organs.



  • Nephropathic cystinosis manifests in the first year of life with failure to thrive, increased thirst, polyuria, and hypophosphatemic rickets. Several other nonrenal manifestations can occur in cystinosis.



  • Increased urinary loss of Na+, Ca2+, and Mg2+ occurs in cystinosis. Renal calcification is rather common. ESRD occurs by 10 years of age, and cystinosis does not recur in transplanted kidney.



  • Specific therapy of renal Fanconi syndrome depends on the underlying cause. Supportive therapy is crucial with replacement of fluids and electrolytes.



  • Cysteamine, a cystine-depleting agent, converts cystine into a mixed disulfide cysteamine-cysteine molecule that exits lysosomes via the lysine transporter. This agent has been shown to improve renal function once it is started after the diagnosis of cystinosis is confirmed.


Lowe Syndrome (Oculocerebrorenal Syndrome)






  • Lowe syndrome is an X-linked recessive syndrome.



  • Characterized by a triad of congenital cataracts, mental retardation, and renal dysfunction.



  • Caused by a mutation in the OCRL1 gene that encodes the enzyme phosphatidylinositol 4,5-bisphosphate phosphatase, which localizes in the Golgi complex and involved in protein trafficking.



  • Aminoaciduria with sparing of branch-chain amino acids (leucine, isoleucine, proline, and valine) is characteristic of Lowe syndrome.



  • Renal function is normal at birth. By 1 year of age, proximal tubular dysfunction and proteinuria are common. Renal histology is characterized by both glomerular and interstitial fibrosis with renal failure during the fourth and fifth decades of life.



  • Hypophosphatemic rickets and osteopenia and growth retardation may be seen.



  • Treatment is symptomatic and supportive care with replacement of fluids and electrolytes.


Dent Disease






  • Dent disease is an X-linked recessive disease with associated renal Fanconi syndrome.



  • It is caused by inactivating mutations in the CLCN5 gene, which encodes a renal chloride channel, CLC-5.



  • The disease is characterized by varying degrees of low molecular weight proteinuria, hypercalciuria, nephrolithiasis, hyperphosphaturia, and rickets.



  • Renal failure gradually develops in patients with Dent disease. Renal biopsy shows chronic tubulointerstitial disease with calcium deposits. Glomeruli are normal.



  • Treatment of Dent disease is largely supportive.


Treatment of Proximal RTA


The physician should address the cause of proximal RTA and take appropriate steps to improve acidosis and skeletal abnormalities.



  • Alkali therapy is indicated in all the patients (Table 8.3).



  • In children, the aim is to prevent growth abnormalities. Administration of NaHCO3 or its metabolic equivalent (citrate) to maintain serum [HCO3 −] to near-normal levels (22–24 mEq/L) is desirable to reestablish normal growth.



  • Maintenance of normal serum [HCO3 −] exacerbates kaliuresis; therefore, high doses of K+ supplements are necessary.



  • Alkali therapy restores growth and volume with suppression of renin-AII-aldosterone system.



  • In adults, it is not necessary to maintain normal serum [HCO3 −].



  • Adults require between 50 and 100 mEq of alkali daily.



  • NaHCO3 and baking soda are inexpensive. Both of them may cause osmotic diarrhea; therefore, small and dividing doses may lower this adverse effect.



  • Diuretics such as amiloride may be helpful in some patients by preventing K+ loss.



  • Thiazide and loop diuretics also help in lowering HCO3 − requirements by volume depletion and increasing HCO3 − reabsorption in the proximal tubule, but hypokalemia may be aggravated.



  • Polycitra-K provides both K and HCO3 and is recommended by many physicians.



  • Active vitamin D3 and phosphate supplementation help skeletal growth and acidification in patients with low serum phosphate levels.



  • Note that citrate increases aluminum absorption.




Table 8.3

Alkali preparations



































Preparation

Amount of HCO3 − or its equivalent

NaHCO3


4 mEq/325 mg tablet or 8 mEq/650 mg tablet


Baking soda (NaHCO3)

60 mEq/teaspoon (4.5 g) of powder


K-Lyte (K+ HCO3/K+ citrate)

25–50 mEq/tablet


Urocit-K (K+ citrate)

5–10 mEq/tablet


Kaon (K+ gluconate)

5 mEq/mL or 1.33 mEq/mL


Shohl’s solution, Bicitra (Na+ citrate/citric acid)

1 mEq/mL


Polycitra (Na+ citrate/K+ citrate/citric acid)

2 mEq/mL


Polycitra-K (K+ citrate/citric acid)

2 mEq/mL


Distal (Classic or Type I) RTA


Characteristics of Distal RTA


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Oct 20, 2020 | Posted by in NEPHROLOGY | Comments Off on Tubular Acidosis

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