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Saudi Journal of Kidney Diseases and Transplantation
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REVIEW ARTICLE Table of Contents   
Year : 1997  |  Volume : 8  |  Issue : 3  |  Page : 235-246
Renal Tubular Acidosis in Children

Department of Pediatrics, Virginia Commonwealth University's Medical College of Virginia, Richmond, Virginia, USA

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How to cite this article:
Saborio P, Krieg RJ, Ahmad TM, Chan JC. Renal Tubular Acidosis in Children. Saudi J Kidney Dis Transpl 1997;8:235-46

How to cite this URL:
Saborio P, Krieg RJ, Ahmad TM, Chan JC. Renal Tubular Acidosis in Children. Saudi J Kidney Dis Transpl [serial online] 1997 [cited 2021 Apr 21];8:235-46. Available from: https://www.sjkdt.org/text.asp?1997/8/3/235/39350

   Introduction Top

Renal tubular acidosis (RTA), was first described by Lightwood, et al [1] , and its presence in adults, by Baines, et al [2] . Its identification as a renal tubular disorder was done by Albright, et al [3] . Subsequently, RTA was first defined by the incapacity to lower urinary pH below 5.5, despite the degree of acidemia present, and later the concept of tubular impairment in the bicarbonate reabsorption was added [4] . In recent years, it was discovered that impaired renal acidification may be present in patients with hyperkalemia associated with aldosterone deficiency [5],[6],[7],[8] .

RTA is a clinical syndrome characterized by growth failure, polyuria, constipation and muscular weakness associated with the presence of hypokalemic and hyperchloremic metabolic acidosis [8],[9] . This entity can be diagnosed with the use of biochemical and laboratory tests usually available in the majority of the hospitals [9] . However, the prevalence of RTA is low in most countries in the world, excepting the endemic forms [10] . The physician should be familiar with the clinical presentation, and the correct management of the illness, in order to prevent or ameliorate nephrocalcinosis, rickets or growth failure.

   Acid-base Balance Top

The range of the free hydrogen ion concentration in the extracellular fluid is 35 to 45 nanomoles per liter, which when converted in its negative logarithm, corresponds to pH of 7.35 to 7.45. This narrow range of the extracellular pH is maintained by different processes of buffering and excretion [11]. In normal conditions, 0.8 to 1 mmol of non­volatile acids per kilogram is generated daily mostly due to breakdown of dietary protein for energy. This is blunted by the reclamation of filtered bicarbonate and the excretion of protons with phosphate buffers (titratable acid) and ammonium. The proximal tubule reabsorbs 70 co 80% of the filtered bicarbonate. The secretion of hydrogen ion in the proximal tubule is dependent on a Na-K exchanger. The energy necessary for H+ secretion is obtained from basolateral sodium-potassium ATPase pumps, which maintain a low concentration of intracellular sodium and create a chemical gradient for passive sodium entry from the tubular lumen. For each sodium absorbed, one hydrogen ion is secreted to the tubule, maintaining electro­neutrality. The bicarbonate combines with the hydrogen ion in the lumen to form carbonic acid, which later dissociates to CO2 and water. The carbon dioxide diffuses across the membrane and is hydrated in the presence of carbonic anhydrase to form carbonic acid. This acid dissociates in the cell into hydrogen ion which diffuses to the basolateral membrane and bicarbonate which is exchanged with sodium across the brush border membrane. Ammonium ions generated by degration of glutamite are transported from the proximal cell into the lumen in exchange with sodium ions [11],[12] .

The urine that comes to the distal tubule contains 10-20% of the filtered bicarbonate, which is reabsorbted by a similar process to that in the proximal tubule. After reclamation of bicarbonate is complete, hydrogen secretion to the tubular lumen and bicarbonate incorporation to the blood continues. Hydrogen ions diffuse to the tubular lumen where they are buffered mainly by the phosphate and ammonia. Monohydrogen phosphate binds with hydrogen ion to form dihydrogen phosphate. Ammonia diffuses into the tubular lumen which binds with hydrogen ion to form ammonium. These compounds are poorly permeable across the membrane, and thus get eliminated with the hydrogen ions in the urine [11] .

The kidney preserves the acid-base homeostasis by reabsorption of bicarbonate and excretion of acid. The acid excretion consists of ammonium and titratable acid ([TA + NH4+ ] - HCO3 ).In renal tubular acidosis, the impairments involved are in acid excretion, bicarbonate reabsorption, generation of NH4+or buffer deficiency [11],[12] .

   The Types of Renal Tubular Acidosis Top

Type I renal tubular acidosis (distal RTA) is characterized by hyperchloremic metabolic acidosis associated with hypokalemia [12] . The urinary pH is in excess of 5.5 and net acid excretion less than 70 µEq/min/1.73m2. Several mechanisms have been postulated in the pathogenesis of distal RTA.

a) The existence of a secretory defect for the hydrogen ion in the collecting tubule has been well described. Patients with distal RTA are unable to elevate urinary pCO2 above that in the blood. Halperin, et al [13] have interpreted this as indicating an absence of, or diminished H+ secretion in the collecting ducts, because in alkaline urine, there is a favorable gradient for secretion.

b) Gradient defect: This hypothesis suggest san increased back diffusion of H+ or H2CO3. Experiments on turtle bladders have shown that impairment in urine acidification was a result of back leak of H+ from lumen to cell. From the bicarbonate loading experiments it is possible to argue that the failure to elevate PCO2may be secondary to defective H+ secretion or increased back diffusion of H+ orH2CO3.

c) Voltage dependent RTA: Urinary acidification defect can result from inability to generate sufficient negative transepithelial difference in the distal nephron. This mechanism has been described in patients with obstructive uropathy and sickle cell nephropathy [14],[15] .

d) Deficiency of carbonic anhydrase: An inhability to generate intracellular bicarbonate can result in a failure to excrete hydrogen ion. Carbonic anhydrase deficiency may be responsible for some reported cases of RTA. [16],[17] .

e) Rate dependent RTA: This concept includes patients in whom urinary pH is appropriately low during systemic acidosis but who present a low gradient of PCO2 in alkaline urine, interpreted as demonstrating a defect in the rate of secretion of hydrogen [8] .

Type II renal tubular acidosis is due to a bicarbonate reabsorption defect [12] . Because the distal tubular ability to acidify is intact, the urinary pH can be less than 5.5 and net acid excretion in excess of 70 (J.Eq/min/1.73m2 when the child is acidotic. At normal plasma bicarbonate concentrations, more than 15% of the filtered bicarbonate load escapes reabsorption by the proximal nephron resulting in an increased amount of bicarbonate delivered to the distal tubule. Bicarbonaturia occurs, net acid excretion is stopped and the metabolic acidosis gets aggravated. Increased concentrations of sodium at the proximal nephron induces the secretion of potassium in the cortical collecting tubule, promoting hyperkaliuria and reflected systemically as hypokalemia. By virtue of the fact that there is a defect in tubular maximum reabsorption of bicarbonate (TmHCO3 ), type II renal tubular acidosis is a transient phenomena. In most children with type II renal tubular acidosis, the T111HCO3 improved and the defect disappears in the first decade of life. The pathogenic mechanism responsible for the proximal tubule defect are not well understood. Some of the postulated mechanisms are as follows:

a) Defect in pump secretion or function: Alterations in the function of the proton pumps will impair bicarbonate reabsorption.

b) Carbonic anhydrase deficiency: a deficiency of inhibition of this enzyme will result in bicarbonate wasting. Inherited deficiency has been reported in some children [16],[17] .

c) Structural damage to the luminal membrane with increased amount of bicarbonate into the lumen [11] .

Type III RTA is a hybrid of type I and type II RTA with distal acidification defect and mild (less than 15%) bicarbonaturia on correction of metabolic acidosis. This has now been reclassified as a subtype of type I RTA, occurring primarily in premature infants [12] .

Type IV RTA is characterized by hyperkalemic metabolic acidosis and therefore, is markedly different than the hypokalemic metabolic acidosis of the other types of RTA [18] . Type IV RTA is secondary to aldosterone resistance as may occur after obstructive uropathy [19] and/or aldosterone deficiency [20] , as seen in congenital adrenogenital syndrome secondary to 21-­hydroxylase deficiency. The exact pathogenesis is unclear. Some postulated mechanisms are:

a) Selective destruction of the juxtaglomerular cells.

b) Decreased sympathetic innervation of the juxtaglomerular apparatus.

c) Decreased production of prostacyclin, subsequently followed by a decrease in the renin-angiotensm production.

d) Primary hypoaldosteronism.

e) Secondary hypoaldosteronism from the chronic use of heparin.

   Rate Dependent Distal Renal Tubular Acidosis Top

Recently, the rate dependent distal RTA has been increasingly recognized [21],[22] . This subtype of distal RTA is similar in clinical presentation to the classic, distal RTA in children with almost the same incidence of failure to thrive, nephrocalcinosis or nephrolithiasis. The failure to make an early diagnosis is due to the fact that the rate dependent distal RTA can lower the minimum urinary pH to less than 5.5 in the presence of metabolic acidosis similar to that seen in normal subjects as well as those with proximal RTA [21],[22] . However, the use of urine minus blood partial pressure of CO2 (U-B PCO2) clearly distinguishes this type of distal RTA from normal subjects and patients with proximal RTA [22] . In both gradient dependent RTA and the classic distal RTA, the urine minus blood partial pressure of CO2 is less than 20 mm Hg [21],[22] . Recently, Bonilla, et al [23] , evaluated the acidification mechanism in 20 patients with idiopathic hypercalciuria. They found that 20% of the children had a partial defect in distal acidification. All these patients presented with nephrolithiasis in comparison to none in the normal distal acidification group. They suggest that calcium deposition may induce tubular damage causing an impairment in the distal acidifiction mechanism.

   Age, Gender, Differences of RTA Top

The earlier data of Brenner, et al [24] indicated that type I RTA occurred more frequently in patients older than 18 years of age and had a female predominance. Type II RTA occurred primarily in the pediatric group aged less than 18 years with a male predominance. In this earlier report, type IV RTA was thought to be the second most common type of RTA. However, with increasing recognition of type IV RTA secondary to aldosterone resistance as in obstructive uropathy, or to aldosterone deficiency, and with more patients with obstructive uropathy from congenital posterior urethral valve or in elderly men with prostatic hypertrophy, type IV RTA is now widely regarded as the most common type of RTA [25] .

   Diagnosis Top

The untreated child with RTA has nonspecific symptoms such as failure to thrive, polydipsia, polyuria, anorexia, vomiting, constipation and listlessness [9],[26],[27],[28],[29] . There are also signs and symptoms which are more specific to some types of RTA; metabolic bone disease is frequent in type II RTA secondary to Fanconi syndrome, in association with hypophosphatemia and hypocalce-mia. Nephrocalcinosis is common in patients with distal RTA. Muscle weakness is frequent in hypokalemic patients with type I or type II RTA associated with the Fanconi syndrome [9],[30] .

The diagnosis of RTA may be considered in a patient with hyperchloremic metabolic acidosis in whom non-renal causes of acidosis have been ruled out [9] .

In infants and children, the normal values for blood pCO2, plasma bicarbonate, and total CO2 concentrations are lower than in adults. Bicarbonate varies directly with pCO2 and inversely with the concentration of protein and the net acid in the diet [31],[32] . In the evaluation of acid-base status, it is necessary to obtain arterial or arterialized venous blood samples for determination of pH, PCO2, and total CO2. Warming the extremity with a heating pad for 15 minutes, arterialized blood can be obtained. Simultaneously, one should obtain an urine sample for measurement of pH, and urinary anion gap.

Urine pH

It was the traditional method for the assessment of patients in whom RTA was suspected. The diagnosis depends upon demonstrating an inappropriately high urine pH during metabolic acidosis [33] . Urine pH alone, is not adequate to show the urine net acid excretion in acidosis. For example, during metabolic acidosis, the urine pH initially decreases, but several days later, increases to a high value, despite the persistence of acidosis [34] .

Urine Anion Gap

It has been proposed that the urine concentration of NH4"" can be estimated by the urine anion gap ([Na + ] + [K + ] - [CV]). In urine, with a pH less than 6.5, bicarbonate concentration is very low, and can be ignored in the calculation of the anion gap. It is based upon the principle that the sum of all the anions must equal the sum of the cations in urine [35],[36],[37] . If the anions and cations not usually measured are ignored, the urinary anion gap is proportional to the negative value of the urine concentration of NH + [35] . In normal subjects, urinary anion gap is positive, approximately 30-35 mEq/L [38] . In patients with RTA, urinary anion gap is zero or positive, showing that excretion of ammonia is relatively low during acidosis [39] . This method can underestimate NH4 + excretion during ketoacidosis, acetylsalicylic acid intoxication, lactic acidosis and with the use of penicillin [38] . There is no correlation among urinary anion gap and NH4+ excretion in neonates or infants within the first few weeks of life [40] .

Ammonium Chloride Loading Test

This test explores the ability of the distal tubule to eliminate hydrogen ions in free form (urinary pH) as well as combined with, the two major urinary buffers, ammonia and phosphate.

The basis of the test is the measure of the maximal acid excretion and the lowest urinary pH during an episode of acutely induced metabolic acidosis.

An ammonium chloride load normally induces a metabolic acidosis by a compensatory depression of the urinary pH below 6 and a net acid excretion elevation above 70 iEq/min/1.73m2 - Because a distal renal tubular defect prevents urinary acidification, the absence of the compensatory responses confirm a diagnosis of type I RTA [41].

The fractional excretion of bicarbonate is defined as the bicarbonate filtered through, the glomeruli and not reabsorbed by the renal tubules.

The formula requires that the plasma bicarbonate be normal. In patients with RTA, it is necessary to correct the bicarbonate to normal levels to apply this concept. Bicarbonaturia greater than 15%, confirms type II RTA.

Urine to Blood PCO2 Gradient

Urine to blood carbon dioxide tension gradient during maximal urine alkalinization is a reliable test in the assessment of distal RTA. The test measures the ability of the partial pressure of carbon dioxide in urine to increase during maximal urine alkalinization. Values less than 20 mm Hg are consistent with the presence of distal RTA. Recently, Alon, et al [42] utilized oral acetazolamide in the evaluation of the PCO2 gradient and obtained good correlation with the bicarbonate test, at a lesser cost, and better acceptance by the patients.

Phosphate Loading Test

This test evaluates the secretion of H+after the administration of 50 mg/kg/day of elemental phosphorus in a three-day period. Normally, when urinary pH is close to 6.8 the difference between urine and blood PCO2 is more than 20 mm Hg.

This test is utilized to specify the mechanism which causes subnormal acidification in some patients with distal RTA.

Furosemide Test

This test analyses the acidification of the distal tubule and the urinary excretion of potassium under increased delivery of sodium and chloride mediated by the use of furosemide. In normal patients, administration capability of furosemide results in a decrease of urinary pH lower than 5.5 and increase in urinary excretion of potassium. In patients with abnormal H+secretion due to decreased delivery of sodium or reversible, impaired sodium reabsorption in the distal tubule, the furosemide test may be useful.

Potassium Metabolism

Renal tubular acidosis also teaches us a lot about potassium metabolism. Sebastian et al [43],[44] indicated that even in non­renal tubular acidosis patients and normal volunteers, when the serum potassium is less than 3.8 mmol/L, the urinary potassium excretion is markedly conserved with values of 40 mmol/day or less. However, in patients with RTA, the potassium wasting continues, even with severe hypokalemia. Thus, the daily potassium requirements decreases with correction of acidosis in type I, distal, classic RTA. Whereas, the daily potassium requirements increase with correction in type II, proximal RTA. Gill, et al [45] , showed that, when sufficient sodium bicarbonate or neutral phosphate is given to increase the sodium-hydrogen exchange in the distal tubule, the decreased concentration of serum potassium are corrected. They found that maintenance of the correction of acidosis results in a positive potassium and sodium balances. Treatment with alkali therapy in type I RTA ameliorates the hypokalemia [9] . The explanation of this correction is based on the concept that sodium bicarbonate expands the extracellular volume and suppresses the renin-aldosterone secretion. Thus, hydrogen secretion is facilitated with bicarbonate therapy which decreases the concentration gradient. In type II RTA, during the initial phase of treatment, loss of potassium is more severe, due to increased sodium delivery in the distal tubule. Despite alkali therapy, sometimes in both proximal and distal RTA, loss of potassium may persist in the presence of sustained correction of sodium and bicarbonate wasting [8],[46],[47],[48] . In fact, the presence of hyperaldosteronism in these patients is a consistent finding.

It is suggested that patients in hypokalemic and polyuric states induce the activation of prostaglandin E synthesis, thus increasing the blood renin levels, with the consequent exacerbation of potassium wasting [48],[49] . Raymond, et al [50] , in a rabbit model of potassium depletion found that it is temporally correlated with elevated levels of urinary PGE excretion, and may be responsible for the attenuated ADH response through stimulation of the inhibitor guanine nucleotide regulatory protein, resulting in decreased vasopressin adenylate cyclase activity in the cortical collecting tubules. Indomethacin and meclofenamate corrected the ADH unresponsiveness of perfused cortical collecting tubules and increased the urinary osmolality. In fact, successful treatment with indomethacin has been reported in the literature in patients with renal tubular defects, including RTA, which showed metabolic disturbances and increased levels of prostaglandin E in the urine [49],[51],[52],[53],[54],[55],[56] .

Mineral and Vitamin D Metabolism

It has been shown repeatedly that sub­optimum calcium balances are found in children with RTA [57],[58] and that correction of the acidosis gives rise to markedly improved calcium retention. This may be due by suppression of lcc-hydroxylase vitamin D system by metabolic acidosis as shown by ammonium chloride induced experimental acidosis [59] . However, this may not apply to the human child, because the data of Chesney and associates [60] indicated that 1,25-­dihydroxyvitamin D were in the normal ranges in children with RTA. In addition, normal volunteers made acidotic by the ingestion of ammonium chloride responded appropriately to parathyroid hormone challenges by increasing their serum 1,25­-dihydroxyvitamin D concentrations [61] . Thus, the clear evidence in the acidotic animals of inhibition of 1,25-­dihydroxyvitamin D [59] cannot be reconciled with the human data in which there appeared to be no interference with vitamin D metabolism in the presence of metabolic acidosis [60],[61] . The sub-optimum calcium balances repeatedly shown by many different investigators in children with RTA [57],[58] cannot simply be assumed to be due to interference with vitamin D metabolism at this point. Indeed, chronic metabolic acidosis stimulates 1,25-dihydroxyvitamin D production in normal volunteers [62] .

To test the hypothesis that metabolic acidosis might interfere with calcium absorption by inhibition of 1,25-dihydroxyvitamin D formation, Chan [58] analyzed metabolic balances in four children with RTA and growth failure. After the correction of metabolic acidosis, there was a marked increase in the calcium absorption across the intestinal tract, with 50% reduction in stool calcium loss. Probably, acidosis interferes with calcium absorption in the gastrointestinal tract. Correction of acid-base disturbances results in optimum calcium balance and catch-up growth [58],[63] . Pre-minger, et al [64] , confirmed these results in nine adult patients treated with alkali. They found that 1,25­dihydroxyvitamin D3 synthesis may not be disturbed in distal RTA and suggested that hypercalciuria and impaired intestinal calcium absorption was a vitamin D-independent process [64] .


The urinary excretion of calcium in patients with classic RTA is 10-20 mg/Kg/day [11] . It is suggested that the hypercalciuria was secondary to the metabolic acidosis, like the calciuric response seen in normal subjects given ammonium chloride load [8] . Recently. Houillier, et al [65] induced metabolic acidosis by ammonium chloride administration in 34 stone formers and nine control subjects. In all the patients, they observed an increase in the urinary calcium excretion, due to a decrease in magnesium and calcium tubular reabsorption, probably by affecting the thick ascending limb of the loop of Henle.

Hypercalciuria, hyperphosphaturia, hypocitraturia and a high urinary pH are the main events that predispose RTA patients to develop renal stones [8],[11],[47],[48] . The state of chronic metabolic acidosis that is present in patients with RTA. reduces the renal excretion of citrate and contributes to hypercalciuria [11] . Urinary citrate is an inhibitor of the crystal aggregation and precipitation. When citrate excretion is reduced, less calcium is chelated thus, aggravating urolithiasis and nephrocalcinosis [66] . Intracellular acidosis promotes citrate uptake from the tubular lumen and its metabolism in renal cell mitochondria, resulting in less citrate available for urinary excretion. Metabolic acidosis, hypokalemia, starvation, hypercalcemia and volume expansion are the main causes of hypocitraturia. Patients with proximal RTA have high urinary levels of citrate contrast to the low levels observed in patients with distal acidification defects. This is one of the reasons why distal RTA is associated with nephrocalcinosis [8],[11],[47],[48],[67],[68] .

Nephrocalcinosis is a distinct risk in patients with type I, Classic RTA because the accumulation of hydrogen ion stimulates bone dissolution. Metabolic acidosis stimulates mitochondria-citrate oxidation, thus reducing the renal excretion of these calcium chelators [69] . The hypocitraturia, therefore, aggravated by the hypercalciuria, plays a significant role in the development of nephrocalcinosis in type I distal RTA. Data from Rodriguez-Soriano, et al [27] demonstrated that the urinary excretion of calcium was directly correlated with the degree of metabolic acidosis. The data also indicated that with correction of acidosis, in the majority of children with RTA, the urinary calcium excretion was decreased to the normal range, less than 4 mg/kg/day.

Sulfate Excretion

It has been shown that there is significant sulfate excretion in children with renal tubular acidosis in the acidotic state. Chan [70] measured the excretion of sulfate in patients with RTA and showed significant statistical difference between RTA patients and controls. This sulfate loss may result in a subclinical sulfate deficiency, which may contribute to the development of growth failure in these patients. The persistence of elevated excretion of sulfate in the children after the correction of acidosis, suggest a primary defect, and not likely to be related to the metabolic acidosis [70] . It has been suggested that urinary sulfate excretion may be used, together with urinary citrate excretion [67] , as additional markers of RTA.


The treatment of RTA is the use of sodium bicarbonate or Shohl's Solution or Bicitra and for those who need potassium supplementation, Polycitra and Polycitra K [Table - 1].

In infants and children, alkali therapy can be initiated at 3 mEq/kg/day, and increased at 2-4 day intervals until plasma CO2 is in the normal range. In the next months after the therapy, the dose of alkali must be readjusted due to increased growth in these patients in response to the treatment. The administration of the medicament should be in 4 divided doses per day in children and 4-6 doses with feeds in infants. Less than 4 times per day may present variable fluctuations in plasma TCO2, with the consequent alkali loss and bicarbonate wasting in the renal tubules. In older children, with alkali requirement less than 3 mEq/kg/day, the treatment can be given 3 times per day.

Initially, due to hypokalemia. some of the alkali load may be given as potassium citrate, but after the correction, the majority of the patients do not require potassium supplements [9] . Severe hypokalemia should be corrected with KC1 infusion, 1-3 mEq/kg. six to twelve hours before starting alkali treatment. The acidosis may be corrected slowly, in a two to three day­period, because rapid correction can increase the hypokalemia and induce tetany in hypocalcemic patients [9] . In stable patients, correction of the acidosis may be safely done with oral sodium bicarbonate or sodium citrate [9],[25],[47] .

When long-term therapy with potassium and alkali is required, the best option is to give a mixture of sodium and potassium citrate, reducing the osmotic charge and consequently, the polyuria too [9],[25] . The adequate percentages of both alkali and potassium in the mixture, are dependent upon the amount of K+necessary to prevent hypokalemia. It is recommended, that the concentration of sodium in the solution does not exceed 1000 mEq/L. In the ederaatous patients with RTA, dietary restriction of sodium and KC1 prescription restore the hypokalemic state and decreases the sodium reabsorption which is augmented in hypokalemic patients recovering from metabolic acidosis [25],[71] .

The determination of the total amount of alkali necessary for the correction of the acidosis is done by the loss of renal bicarbonate at normal concentrations of TCO2. Santos and Chan [29] indicated that the dosage of alkali therapy required to achieve a sustained correction of metabolic acidosis in infants and children are the same. Their data indicated that the average dose required to have sustained correction of metabolic acidosis is 3-4 mEq/kg/day.

In some patients, specially those with type II RTA associated with Fanconi syndrome, the urinary excretion of bicarbonate at normal TCO2 is very high. The use of sodium restriction, or hydrochlorothiazide at 1.5-2 mg/kg/day may be useful in these patients to decrease the alkali requirements [72] .

It has been suggested that urinary excretion of calcium is a good indicator of the regulation of the alkali therapy [8],[27] . At normal concentrations of bicarbonate, fractional excretion of sodium correlates with calciuria. Hypercalciuric patients in whom natriuresis is considerable, are at great risk to develop nephrocalcinosis [8],[27] . Rodriguez Soriano, et al [8],[27] suggest that in patients with RTA, the achievement of sustaining correction of the acidosis, is associated with decreased calciuria to normal levels. However, Santos and Chan [29] , in a prospective review of 24 cases of distal tubular acidosis, failed to find a good linear correlation between urinary calcium excretion and the degree of acidosis. Hypercalciuria was not uniformely present in all the patients.

Indomethacin may be useful in RTA patients with metabolic disturbances and concentrating inability who are unresponsive to the conventional therapy. This drug enhances proximal tubular reabsorption and the effect of vasopressin by the collecting tubules [50],[55] . Patients with different tubulopathies like Fanconi syndrome, proximal tubular acidosis and incomplete distal RTA improve their metabolic problems (hyperuricemia, hypokalemia, hypophosphatemia, glucosuria) with indomethacin therapy [49],[51],[52],[53],[54],[55],[56] .

The treatment of the type IV RTA includes many modalities. If the patient has no intrinsic renal disease, and the pathology is a deficiency of aldosterone, miner alocorticoids (9, alfafluorocortisone) at doses of 0.05-0.2 mg/day are useful in the correction of the acidosis and hyperkalemia [9],[47] . In patients with renal insufficiency and hyporeninemic hypoaldosteronism, the use of furosemide alone or with fluorocortisone may ameliorate these conditions [9],[73] . In addition, potassium binding resins and dietary restriction of potassium coupled with the use of hydrochlorothiazide may be effective in correcting the hyperkalemia [74] . When the type IV RTA is associated with obstructive uropathy, hydrochlorthiazide given alone or with alkali therapy can correct the acid-bases and potassium disturbances [9] . In patients with classical pseudo hypoaldosteronism, administration of supplemental doses of sodium chloride will correct the acidosis, sodium wasting and hyperkalemia [9] . In addition, when the type IV RTA is characterized by incomplete end-organ resistance to aldosterone, treatment with alkali therapy is successful [18] .

Treatment of Bone Disease

The treatment of rickets or osteomalacia in patients with type I RTA consists of vitamin D 2000-5000 IU/day until the resolution of the bone disease, but the risk of nephrocalcinosis needs careful monitoring [9] . In patients with type II RTA associated with Fanconi syndrome, who have rickets or osteomalacia, vitamin D is given at a dose of 5000 IU/day, with monthly increments to a maximum of 4000­5000 IU/kg/day if there is no biochemical or clinical response. The use of 1-a hydroxyvitamin D, 0.25-1 lig per day is advocated if there is no satisfactory response with the parent vitamin D treatment [9],[47] . Additional treatment with phosphate is necessary in a dose of 1-3 g of elemental phosphorous per day, given in 4-5 divided doses [9] . Carefully monitoring of alkaline phosphatase. serum calcium and calciuria is necessary to prevent hypercalcemia in these patients [9] .

In summary, treatment in RTA is oriented to correction of the mineral and acid-base disturbances and to prevent nephrocalcinosis. In this manner it is possible to achieve improvement in growth velocity, adequate puberal development and adult height near that of the normal parent height [75] . The initial presence of rickets is a poor prognostic sign on the ultimate height, and the presence of renal insufficiency is associated with a poor prognosis [75] .

   Effects on Growth Top

The data of Santos, et al [29] indicate that both weight and height percentile of normal for age, improved with sustained correction of metabolic acidosis. The reason for the wide range of response seen in practice could be related to the likelihood of medical non-compliance in some patients.

Caldas. et al [75] indicate that the presence of rickets at the time of presentation is a poor prognostic sign and these children do not grow as well as those who do not have rickets at the time of presentation. Adequate puberal development can be reached with alkali therapy in RTA patients [75] .

Mechanism of Growth Failure in Patients with Metabolic Acidosis

McSherry, et al [76] , in an earlier abstract presentation 17 years ago, suggested that the growth hormone response to clonidine challenge was blunted in children with RTA. These data were never published and new-information on the importance of spontaneous growth hormone secretion, made it essential to investigate the status of spontaneous growth hormone secretion in the presence of acidosis [77] . The recent data of Challa, et al [78] clearly indicate that ammonium chloride induced experimental metabolic acidosis in rats suppressed total growth hormone secretion, as well as the pulse amplitude and the pulse frequency. Challa, et al [79] also showed that serum IGF-I was significantly reduced in acidotic and pair-fed animals. There was significant suppression in hepatic IGF-I mRNA in acidotic and pair-fed animals and it appeared that acidosis was specific in inhibiting hepatic growth hormone receptor mRNA as compared to the pair-fed and control animals. Brungger. et al [80] , showed a reduction in serum IGF-I in human volunteers made acidotic by ammonium chloride ingestion. They concluded that the feedback regulation for the control of growth hormone/IGF-I axis had been impaired by metabolic acidosis in these volunteers.

Hanna, et al [81] , showed that acidotic animals had a significant reduction in the width of the tibial epiphyseal growth plate as well as its IGF-I mRNA compared to that of pair-fed and control animals. The quantity of IGF-I mRNA was decreased in chondrocytes and tibial epiphyseal growth plate, both in the proliferative zone and the hypertrophy zone in acidotic animals compared to pair-fed and control animals.

Thus, these data suggest that the mechanism of growth failure in acidosis may be related to a dysfunction of the growth hormone/IGF axis including the growth hormone receptor mRNA and IGF-I mRNA [78],[79] .

   References Top

1.Lightwood R, Maclagan NF, Williams JG. Persistent acidosis in a infant: cause not yet ascertained. Proc R Soc Med 1936;29:143i.  Back to cited text no. 1    
2.Baines GH, Barclay GA, Cooke WT. Nephrocalci- nosis associated with hyperchloremia and low plasma bicarbonate. Q J Med 1945;14:113.  Back to cited text no. 2    
3.Albright F, Burnett CH, Parson W, Reifenstein EC, Roos A. Osteomalacia and late rickets. Medicine 1946;25:399.  Back to cited text no. 3    
4.Rodriguez-Soriano J, Boichis H, Stark H, Edelman CM. Proximal renal tubular acidosis: a defect in bicarbonate reabsorption with normal urinary acidification. Pediatr Res 1967; 1:81,  Back to cited text no. 4    
5.Di Telia P, Sodhi B, McCreary J, et al. The mechanism of metabolic acidosis of selective mineralocorticoid deficiency. Kidney Int 1978;14:446.  Back to cited text no. 5    
6.Perez GO, Oster JR, Vaamonde CA. Renal acidosis and renal potassium handling in selective hypoaldosteronism. Am J Med 1974;57:809.  Back to cited text no. 6    
7.Sebastian A, Schambelan M, Lindenfeld S, et al. Amelioration of metabolic acidosis with fludrocortisone therapy in hyporenimic hypoaldosteronism. N Engl J Med 1977;297:576.  Back to cited text no. 7    
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74.Santos F, Kainer G, Chan JCM. Renal tubular acidosis. Chapter 12, 2nd ed. In Masry SG, Suki WN (eds): Therapy of renal diseases and related disorders. Boston, Martinus Nijhoff Publishers 1991;207-21.  Back to cited text no. 74    
75.Caldas A, Broyer M, Dechaux M, Kleinknecht C. Primary distal tubular acidosis in childhood: clinical study and long-term follow-up of 28 patients. J Pediatr 1992;121:233-41.  Back to cited text no. 75    
76.McSherry E, Kaplan JS, Grumbach MM. The 79. effect of acidosis on human growth hormone (hGH)release with non-azotemic renal tubular acidosis (RTA). Clin Res 1980;28:535.  Back to cited text no. 76    
77.Kuemmerle N, Krieg RJ Jr, Latta K, Chaila A, 80. Hanna JD, Chan JCM. Growth hormone and insuline like growth factor in non-uremic acidosis and uremic acidosis. Kidney Int 1997;51:S102-S5.  Back to cited text no. 77    
78.Chaila A, Krieg RJ Jr, Thabet MA, Veldhuis JD, Chan JCM. Metabolic acidosis inhibits growth 81. hormone secretion in the rat: Mechanism of growth retardation. Am J Physiol 1993;265:E547-E53.  Back to cited text no. 78    
79.Chaila A, Chan W, Krieg RJ Jr, et al. Effect of metabolic acidosis on the expression of insulin-like growth factor and growth hormone receptor. Kidney Int 1993;44:1224-27.  Back to cited text no. 79    
80.Brungger M, Hatler HN, Knaft R. Effect of chronic metabolic acidosis on the growth hormone/ IGF-I endocrine axis: new cases of growth hormone insensitivity in humans. Kidney Int 1997;51:216-21.  Back to cited text no. 80    
81.Hanna JD, Chaila A, Chan JCM, Han VKM. Insulin-like growth factor-I gene expression in the tibial epiphyseal growth plate of acid otic and nutritionally limited rat. Pediatr Res 1995;37:363A.  Back to cited text no. 81    

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