|Year : 2003 | Volume
| Issue : 3 | Page : 305-313
|Renal Tubular Acidosis in the Arab World
Sami A Sanjad
Professor of Pediatrics, Assistant Dean, Faculty of Medicine & Medical Center, American University of Beirut, Beirut, Lebanon
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|How to cite this article:|
Sanjad SA. Renal Tubular Acidosis in the Arab World. Saudi J Kidney Dis Transpl 2003;14:305-13
Renal tubular acidosis (RTA) is a rare disorder characterized by hyperchloremic metabolic acidosis secondary to impaired urinary acidification. This may be due to: (a) transport defects in bicarbonate reabsorption (proximal RTA), (b) abnormalities in hydrogen ion excretion (distal RTA), at times associated with hyperkalemia and (c) mixed RTA, combining elements of (a) and (b). The clinical entity was originally described almost 70 years ago ,, but the term "renal tubular acidosis" was not used until many years later  In infants and children, the clinical manifestations of proximal and distal RTA are similar, namely growth failure, vomiting and recurrent bouts of dehydration. Hypokalemia occurs in about 30% of patients with distal RTA. Muscle weakness, sometimes progressing to skeletal or respiratory muscle paralysis may occur if hypokalemia is severe. Potassium depletion will also cause impaired urinary concentration resulting in polyuria and polydypsia. Rickets or osteomalacia are frequently observed in untreated distal RTA. Hypocitraturia, together with the alkaline urine and hypercalciuria in patients with distal RTA play an important role in the pathogenesis of nephrocalcinosis and nephrolithiasis commonly seen in older, untreated patients with distal RTA. These complications are not observed with proximal RTA, but hypophosphatemic rickets and hypokalemia occur frequently as part of the Fanconi syndrome. Both-hereditary and acquired forms of RTA are recognized. This review will focus on the inherited forms of RTA, with particular emphasis on their occurrence in the Arab world.
The past five years have witnessed major advances in molecular biology that have led to a better understanding and classification of the hereditary forms of RTA at the cellular and subcellular level. , In infants and children, the autosomal recessive forms of RTA are more prevalent, whereas in adults the less severe, dominant forms are more common. In many parts of the Arab world and non-Arab Middle East where consanguineous marriages are prevalent, recessive forms of RTA are relatively common, indicating the frequency of mutant genes in the various communities. In fact, many of the international collaborative studies on hereditary RTA involve large cohorts of Arab patients. ,,, Since the vast majority of cases of inherited RTA are secondary to mutations in the genes responsible for bicarbonate reabsorption or hydrogen secretion, a brief review of the physiology of renal acidification is in order.
| Pathophysiology of Renal Acidification|| |
The kidney's contribution to acid-base homeostasis is effected through two major mechanisms, both involving tubular phenomena of exchanging filtered sodium from the tubular lumen with secreted hydrogen from the tubular cells.
Proximal Bicarbonate Reabsorption [Figure - 1]
In the proximal tubular cells, a specific electroneutral Na + -H + exchanger (NHE-3) at the luminal basement membrane, together with basolateral transport of bicarbonate by an electrogenic Na + -HCO3 - co-tranporter (NBC-1), account for the reabsorption of 85% of the filtered bicarbonate back to the plasma. The remaining 15% of the filtered bicarbonate is reabsorbed in the more distal segments of the tubule, primarily by the thick ascending limb of Henle's loop (TALH). NHE-3 is the main isoform of the NHE family responsible for the Na+ exchange with H + . It is localized exclusively in the apical cells of the proximal tubules and the cells of the TALH. The human NHE-3 gene (SLC9A3) maps to chromosome 5p15.3 . Filtered bicarbonate combines with hydrogen (exchanged for sodium) to form carbonic acid (H2CO3) which is rapidly dehydrated to CO2 and water, a process catalyzed by luminal carbonic anhydrase (CA IV) in the brush border of the proximal tubular cell. Luminal CO2 diffuses freely into the cell and is rehydrated by cellular carbonic anhydrase (CA II) to form carbonic acid, which dissociates into H + and HCO3 - . Both CA IV and CA II are maximally stimulated in chronic metabolic acidosis.  The regenerated bicarbonate is returned to the blood via the NBC-1 to maintain normal bicarbonate levels. About one third of the hydrogen secreted and exchaged for sodium is derived from an electrogenic H + -ATPase pump in the luminal basement membrane. Proximal RTA (type 2 RTA) could occur if any of the forces involved in bicarbonate reabsorption, singly, or in combination, became defective. These might be secondary to mutations in NHE3, NBC-1, carbonic anhydrase II or IV, or the H + -ATPase pump. An abnormality in the Na + -K + -ATPase pump causes impaired reabsorption of all solutes ordinarily co-transported with sodium and results in the Fanconi sydrome. Bicarbonate reabsorption in the proximal tubule is a high capacity, low gradient process that bears an inverse proportion to changes in extracellular fluid volume. Other factors influencing HCO3 - reabsorption include intraluminal flow rate, tubular and peritubular HCO3 - concentration, parathyroid hormone, pCO2, chloride and potassium concentrations.
Distal Hydrogen Secretion: Urinary Acidification [Figure - 2]
The second mechanism also involves the exchange of luminal sodium for cellular hydrogen ions secreted in the distal collecting tubules by the H + -ATPase pump at the luminal membrane of the alpha-intercalated cells. Hydrogen ions combine with filtered buffers (mainly phosphate), and are excreted in the final urine as titratable acid (TA). As this is not enough to excrete the daily acid load, a new buffer, NH 3 , derived from the deamination of glutamine in the proximal tubular cells, diffuses passively into the lumen and combines with H+, also secreted from the tubular cells. The resulting NH4 + ion is "trapped" in the lumen and excreted in the final urine. Net acid excretion (NAE) is the sum of TA and NH4 + minus any HCO3 - that may be excreted. The steady state NAE is equal to hydrogen ion generated from endogenous and exogenous (diet) sources which is equal to the net addition of HCO3 - by the kidneys to the plasma (40-60 mEq/m 2 /day). This occurs by a Cl - /HCO3 - exchanger, AE1, at the basolateral membrane. Hydrogen ion secretion in the distal tubule establishes a much steeper hydrogen gradient than the NHE mechanism prevailing in the proximal tubule. Thus, a 1000 fold gradient (3 pH units) may be attained between plasma and urine at maximum urine acidity with a pH of 4.4.
| Proximal Renal Tubular Acidosis (Type 2 RTA)|| |
Proximal RTA is caused by defective bicarbonate reabsorption in the proximal tubules. It is most often seen in association with other transport defects as part of the Fanconi syndrome, but may also occur as an isolated condition and referred to as primary proximal RTA. ,, In proximal RTA, impaired renal bicarbonate reabsorption results in large excretion of the filtered load of bicarbonate with a concomitant fall in its plasma level. This excess bicarbonate floods the distal tubules impairing urinary acidification. The urine pH becomes alkaline and remains so until plasma bicarbonate falls below the renal threshold, after which it becomes bicarbonate free and properly acidified by the intact distal secretion of hydrogen ion. During acidemia in untreated patients, the urine pH is always less than 5.5.
Proximal RTA in Association with the Fanconi Syndrome
The hereditary forms of the renal Fanconi syndrome are usually secondary to autosomal recessive metabolic diseases, the most common being cystinosis, glycogen storage disease and tyrosinemia type- 1. Our experience with these and other conditions associated with the Fanconi syndrome in the Kingdom of Saudi Arabia were reviewed in this journal recently.  Renal bicarbonate wasting in the Fanconi syndrome occurs as part of a generalized proximal tubular transport defect. This is the result of a dysfunctional basolateral Na + -K + ATPase pump which is the driving source of energy for solute reabsorption.  Glycogen storage disease appears to be a relatively common cause of the Fanconi syndrome in Saudi Arabia. This particular form is known as the Fanconi-Bickel syndrome  and accounted for almost one half of the cases seen at the King Faisal Specialist Hospital over an eight-year period. We had originally described decreased or absent activity of the enzyme phosphorylase-b kinase (PBK) in several patients with this syndrome.  Subsequent mutational analysis on several of our affected members revealed no abnormalities in any of the coding sequences of the three subunits of the PBK gene. We identified, however, a homozygous missense mutation (Pro417Leu) in the glucose tranporter gene GLUT2  confirming previous description of mutations in this gene by Santer et al.  The low PBK activity in our patients probably represents a secondary phenomenon related to intracellular glucose retention caused by GLUT2 deficiency.
Isolated Proximal RTA
The clinical features of isolated proximal RTA are those of failure to thrive and vomiting usually detected in early infancy, but the disease may not be diagnosed until early childhood. Unlike patients with the Fanconi syndrome, rickets and hypercalciuria are not seen with this disease but hypokalemia may be observed in some patients. Most reported cases have been a) sporadic, b) autosomal dominant or c) autosomal recessive with ocular abnormalities.
Sporadic Proximal RTA
Most cases of sporadic proximal RTA occur in early infancy and may be explained on an immature NHE3 or NBC1 transporter systems. Patients with this condition require therapy with alkalinizing agents; however, most recover with time. 
Autosomal Dominant Proximal RTA
This RTA variant is extremely rare and was reported once in a Costa Rican family 25 years ago. Affected members had moderately severe hyperchloremic acidosis and growth retardation. Family pedigree was compatible with an autosomal dominant pattern of inheritance. 21 Molecular studies have not been performed but the gene encoding the NHE3 appears to be a good candidate.  Studies in knockout mice lacking the gene encoding NHE3 (SLC9A3) reveal significant reduction in proximal tubular reabsorption of bicarbonate but with only a mild degree of metabolic acidosis. 
Autosomal Recessive Proximal RTA
This entity was first described about 30 years ago by Donckerwolcke et al.  This is another rare disorder, invariably associated with ocular abnormalities including glaucoma, cataracts and band keratopathy and at times, physical and mental retardation, basal ganglia calcification and enamel defects. , The metabolic abnormalities reveal severe hyperchloremic, hyopokalemic metabolic acidosis. The few patients described have been mostly from Europe and Japan. At the molecular level, several inactivating mutations in the gene encoding NBC-1 (SLC4A4) have been identified. ,
| Distal Renal Tubular Acidosis (Type I RTA)|| |
Until recently, all patients with distal RTA were thought to have an inability of the distal nephron to generate and maintain steep pH gradients between peritubular blood and urine. The implication was that the distal tubular cells were capable of proton secretion but, because of a leaky membrane, hydrogen ions back-diffused to the circulation leaving behind a relatively alkaline urine. This was referred to as gradient defect RTA. The prototype of such a defect in acidification is seen in patients treated with amphotericin B.
In recent years, the cellular and molecular aspects of renal acidification have been refined significantly to allow for a precise classification of distal RTA. The alpha-intercalated cells of the the distal collecting ducts play a pivotal role in the fine regulation of acid-base balance by the human kidney. This is accomplished by the H + -ATPase pump at the luminal membrane, which secretes H + , and by the HCO3 - /Cl (AE1) exchanger at the basolateral membrane which is responsible for bicarbonate regeneration [Figure - 2]. Failure of either mechanism underlies the cellular and molecular etiology of distal RTA. Several mutations in the genes responsible for these transport systems have been identified recently; which has revolutionized our understanding of the molecular basis of distal RTA. Both autosomal dominant and recessive modes of inheritance are recognized in patients with distal RTA.
Autosomal Dominant Distal RTA
Randall and Targgart were the first to report RTA with nephrocalcinosis and osteomalacia in successive generations suggesting an autosomal dominant transmission.  Subsequent reports confirmed this mode of transmission in several families. , Clinical manifestations and the degree of acidosis in reported patients have been milder and therefore detected much later in life than in those with autosomal recessive distal RTA.
Chaabani and colleagues  were the first from the Arab world to report a large kindred with RTA with evidence of autosomal dominant transmission. As in previous cases, metabolic acidosis was well tolerated and often asymptomatic. Only three of 28 patients, with both parents affected, developed hypercalciuria, nephrocalcinosis and growth retardation. Linkage analysis to several genetic markers failed to show linkage to the RTA locus. Hamed et al  reported a large kindred with evidence of autosomal dominant absorptive hypercalciuria with several members developing nephrocalcinosis and distal RTA as a complication of hypercalciuria. More recently, molecular studies in several kindreds with autosomal dominant RTA have consistently revealed mutations in SLC4A1 gene encoding the Cl - /HCO3 - exchanger AE1. These have been mostly missense mutations in codon Arg 589 suggesting an important role for this residue in the normal acidification process.  It has been shown that these mutations are not associated with loss of function of the Cl - /HCO3 - exchanger and that they probably affect the acidification process by targeting of AE1 from the basolateral to the luminal membrane of the alpha intercalated cell.  Mutations in the erythrocyte isoform of the AE1 are associated with hemolytic anemias due to ovalocytosis or spherocytosis, but seldom with RTA. 
Autosomal Recessive Distal RTA
This entity appears to be fairly common in the Arab world as well as non-Arab Middle Eastern countries. Karet et al ,,, have elucidated the mechanisms responsible for the acidification defect in patients with recessive distal RTA. Molecular studies involving genome-wide linkage analysis in a cohort of several, mostly consanguineous, kindreds with distal RTA localized two genes, one on chromosome 2p  associated with sensory neural deafness (SND), the other on chromosome 7q , associated with normal hearing. Both genes encode kidney-specific subunits of the proton pump of the alpha-intercalated cell. The majority of patients in both groups were of Arab or Turkish descent. Patients with distal RTA and SND were found to have several mutations in the gene encoding the B-1 subunit of the H+-ATPase, ATP6V1B1, which is localized on chromosome 2p. Most of these mutations were found to disrupt the structure or alter the production of the normal B-1 subunit protein. It was also demonstrated that ATP6V1B1 messenger RNA was expressed in the fetal and adult cochlea as well as the endolymphatic sac, findings that may explain the SND in these patients.  The clinical, biochemical and genetic features in seven Arab patients with this syndrome are presented in [Table - 1].
In patients with distal RTA and normal hearing, linkage analysis led to a defective gene on chromosome  . This gene (ATP6V0A4) encodes a newly identified kidney-specific a4 isoform of the H + -ATPase pump subnit. The clinical and biochemical manifestations are indistinguishable from patients with RTA with SND. Long-term follow up however, has revealed that many patients in this group develop mild hearing loss in later life. Stover and colleagues  have recently demonstrated that the ATP6V0A4 gene is also expressed within the human cochlea, again providing an explanation for the hearing defect.
Recent reports from the Far East have identified different mutations in the AE1 in association with autosomal recessive distal RTA with or without ovalocytosis. , This appears to be confined to Thailand and has not been documented in Caucasians.
| Mixed RTA|| |
Renal tubular acidosis combining features of both proximal and distal acidification defects may be observed in infants and children as a transient defect (previously known as type 3 RTA) and could be related to immaturity of one or more of the several transport systems described above.
A unique syndrome of mixed RTA associated with osteopetrosis, cerebral calcification and carbonic anhydrase II (CA II) deficiency has been reported in several families from the Arab world. The syndrome is inherited as an autosomal recessive trait and is characterized clinically by failure to thrive, recurrent fractures, mental retardation and cranial nerve abnormalities. Over 75% of the cases have been from Middle Eastern and North African countries where genetic heterogeneity is suggested by a more severe variant of the disease. Of the 70 cases reported, more than half have been from Saudi Arabia. ,,,, Of interest is a recent study by Fathallah and colleagues  who document evidence for a founder effect in 24 patients with osteopetrosis and CAII deficiency from 14 Tunisian families. A filiation study led to the tracing of a gene to a common Arabic tribe that settlled in the Maghreb in the 10 th century. Awad et al  have recently published a long-term follow up of 35 Saudi patients from 10 families with this syndrome. In two-thirds of the patients, distal RTA was the prevalent renal abnormality, but the authors do not provide data that excludes a combined RTA.
The gene locus for CAII has been mapped to chromosome 8q22 with several mutations identified, the most common being the Arabic one, which is a splice junction mutation in intron 2.  More recently, mutations in the gene OC16, encoding the a3 subunit of the osteoclast V H+-ATPase have been shown to cause infantile malignant osteopetrosis. 
| Hyperkalemic RTA|| |
The hereditary forms of hyperkalemic RTA are extremely rare and are usually seen in association with pseudo-hypoaldosteronism of which two types are recognized.
Type I pseudo-hypoaldosteronism (PHA-1):
Patients present in early infancy with renal salt wasting, hypovolemia, hyperchloremic acidosis and hyperkalemia. Plasma and urinary aldosterone are elevated. Two modes of inheritance are recognized. The autosomal dominant variety is relatively mild and the defect is restricted to the kidneys. It is caused by heterozygous mutations in the mineralocorticoid receptor gene.  The autosomal recessive form is much more serious and associated with severe renal salt wasting and potentially lethal hyperkalemia. At the molecular level, there are loss of function mutations in the alpha, beta and gamma subunits of the sodium epithelial channel, ENaC.  In addition to the kidney, the salivary glands, the colon and the lungs are involved.
Type II pseudohypoaldosteronism (PHA-2, Gordon's syndrome):
This is a very rare autosomal dominant disease characterized by hyperkalemic acidosis, hypertension secondary to plasma volume expansion, and low renin levels. It has been proposed recently that gain of function mutations in the genes encoding the WNK1 and WNK4 kinases may have a causative role by enhancing the transcellular and paracellular conductance of chloride. 
The hereditary and molecular bases of the different forms of RTA are summarized in [Table - 2].
| Treatment of RTA|| |
Treatment of proximal RTA usually requires large and frequent doses of sodium bicarbonate or citrate (5-20 mEq/kg/day). Potassium supplements may be necessary especially with large doses of bicarbonate, as this will aggravate potassium wasting by the kidney. In patients requiring large doses of alkali therapy, a thiazide diuretic may be used to reduce ECV expansion and enhance bicarbonate reabsorption by the proximal tubules.
The treatment of distal RTA consists of adequate alkali replacement to normalize plasma bicarbonate. Infants with the classical variety require 2-3 mEq/kg/daily in 3 divided doses.
This corresponds to the endogenous acid production. In patients with severe rachitic bone disease a short course of vitamin D will accelerate the healing process.
In patients with hyperkalemic RTA, treatment is directed at the disease process. For patients with PHA1, treatment consists of adequate salt intake to replace urinary losses and a mineralocorticoid supplement if necessary. Patients with PHA2 usually respond to thiazide or loop diuretics.
For patients with mixed RTA due to CAII deficiency and osteopetrosis, there are promising results from gene therapy  and bone marrow transplantation. 
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Sami A Sanjad
Professor of Pediatrics, American University of Beirut, Bliss Street, P.O. Box 11-0236, Beirut
[Figure - 1], [Figure - 2]
[Table - 1], [Table - 2]
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