Renal tubular acidosis (RTA):RecognizeTheAmmonium defect and pHorget the urine pH

To maintain acid-base balance, the kidney must generate new bicarbonate by metabolizing glutamine and excreting ammonium (NH₄ ⁺). During chronic metabolic acidosis, the kidney should respond by increasing the rate of excretion of NH₄ ⁺ to 200–300 mmol/day. If the rate of excretion of NH₄ ⁺ is much lower, the kidney is responsible for causing or perpetuating the chronic metabolic acidosis. Thus, the first step in the assessment of hyperchloraemic metabolic acidosis is to evaluate the rate of excretion of NH₄ ⁺. It is important to recognize that the urine pH may be misleading when initially assessing the cause of this acidosis, as it does not necessarily reflect the rate of excretion of NH₄ ⁺. If proximal renal tubular acidosis (RTA) is excluded, low NH₄ ⁺ excretion disease may be broadly classified into problems of NH₄ ⁺ production and problems of NH₄ ⁺ transfer to the urine; the latter being due to either interstitial disease or disorders of hydrogen ion secretion. The measurement of the urine pH at this stage may identify which problem predominates. This approach returns the focus of the investigation of RTA from urine pH to urine NH₄ ⁺.     

An analysis of renal tubular acidosis by the Stewart method

Renal tubular acidosis (RTA) comprises a group of disorders characterized by a low capacity for net acid excretion and persistent hyperchloremic, metabolic acidosis. To investigate the role of chloride, we performed hypotonic (0.45%) saline-loading experiments in 12 children with alkali-treated distal RTA (dRTA) and compared the results with data obtained from 17 healthy control subjects. In patients, but not in controls, saline loading induced both hyperchloremia and metabolic acidosis. Hyperchloremia was associated with high total and high distal fractional reabsorption of chloride [C_H20/(C_H20+C_Cl)]. The increase in plasma chloride varied inversely with the fractional excretion of chloride (C_Cl) and correlated with the decrease in blood pH. However, the urinary excretion of bicarbonate did not correlate with either changes in blood pH or plasma bicarbonate concentration. Our findings suggest that the mechanism of hyperchloremia was enhanced Cl^–/HCO₃^– exchange by the distal tubule. The resulting metabolic acidosis is better explained by changes in the strong ion difference (the Stewart theory) than by changes in the urine bicarbonate excretion (the traditional theory).     

Renal tubular acidosis and osteopetrosis with carbonic anhydrase II deficiency: pathogenesis of impaired acidification

Renal tubular acidosis with osteopetrosis is an autosomal recessive disorder due to deficiency of carbonic anhydrase II (CAII). A 3.5-year-old Egyptian boy with osteopetrosis and cerebral calcification had a persistent normal anion gap type of metabolic acidosis (plasma pH 7.26) and a mild degree of hypokalemia. A baseline urine pH was 7.0; ammonium (NH₄ ⁺) excretion was low at 11 μmol/min per 1.73 m²; fractional excretion of bicarbonate HCO₃ (FE_HCO3) was high at 9%, when plasma HCO₃ was 20 mmol/l; citrate excretion rate was high for the degree of acidosis at 0.35 mmol/mmol creatinine. Intravenous administration of sodium bicarbonate led to a urine pH of 7.6, a FE_HCO3 of 14%, a urine-blood PCO₂ difference of 7 mmHg, NH₄ ⁺ excretion fell to close to nil, and citrate excretion remained at 0.38 mmol/mmol creatinine. Intravenous administration of arginine hydrochloride caused the urine pH to fall to 5.8, the FE_HCO3 to fall to 0, the NH₄ ⁺ excretion rate to rise to 43 μmol/min per 1.73 m², and citrate excretion to fall to <0.01 mmol/mmol creatinine. These results show that our patient had a low rate of NH₄ ⁺ excretion, a low urine minus blood PCO₂ difference in alkaline urine, and a low urinary citrate excretion, but only when he was severely acidotic. He failed to achieve a maximally low urine pH. These findings indicate that his renal acidification mechanisms were impaired in both the proximal and distal tubule, the result of his CA_II deficiency. Received October 24, 1996; received in revised form and accepted February 20, 1997     

Atypical presentation of distal renal tubular acidosis in two siblings

Primary distal renal tubular acidosis (dRTA) is an inherited disease characterized by the inability of the distal tubule to lower urine pH <5.50 during systemic acidosis. We report two male siblings who presented with severe hyperchloremic metabolic acidosis, high urinary pH, nephrocalcinosis, growth retardation, sensorineural hearing loss, and hypokalemic paralysis. Laboratory investigations revealed proximal tubular dysfunction (low molecular weight proteinuria, generalized hyperaminoaciduria, hypophosphatemia with hyperphosphaturia, and hypouricemia with hyperuricosuria). There was significant hyperoxaluria and laboratory evidence for mild rhabdomyolysis. Under potassium and alkali therapy, proximal tubular abnormalities, muscular enzymes, and oxaluria normalized. A homozygous mutation in the ATP6V1B1 gene, which is responsible for dRTA with early hearing loss, was detected in both siblings. In conclusion, proximal tubular dysfunction and hyperoxaluria may be found in children with dRTA and are reversible under appropriate therapy.     

The syndrome of renal tubular acidosis and nerve deafness. Discordant manifestations in dizygotic twin brothers

The syndrome of renal tubular acidosis (RTA) and nerve deafness is a distinct nosological entity that is inherited as an autosomal recessive trait. We studied a pair of dizygotic twin brothers both with nerve deafness but only one with RTA. Distal RTA was diagnosed in twin A because of inappropriately high urinary pH (6.9) and low net acid excretion (40.0 Eq/min per 1.73 m²) in the presence of hyperchloraemic metablic acidosis, and fractional bicarbonate excretion of 1.6% at a normal serum bicarbonate concentration. The urine minus bloodPCO₂ differences (U-BPCO₂) during a neutral sodium phosphate load and in alkaline urine induced by bicarbonate supplementation were: 11 and 0 mm Hg, respectively. Twin A developed nephrocalcinosis and, after a 9.5-year follow-up period, was 5.3 cm taller than his brother. Twin B remained asymptomatic. Periodic determinations of blood pH and serum bicarbonate were normal and urine pH decreased to 4.6 in the face of ammonium chloride-induced metabolic acidosis. The U-BPCO₂ assessed in alkaline urine was 33.5 mm Hg. Audiograms demonstrated bilateral nerve deafness in both brothers. The presence of deafness without RTA has not been previously reported in this syndrome. This report also shows that a primary distal acidification defect is responsible for the RTA observed in this syndrome.     

Distal RTA with nerve deafness: clinical spectrum and mutational analysis in five children

Distal renal tubular acidosis (RTA) with nerve deafness is caused by mutations in the ATP6V1B1 gene causing defective function of the H⁺-ATPase proton pump. We report five acidotic children (four males) from four unrelated families: blood pH 7.21–7.33, serum bicarbonate 10.8–14.7 mEq/l, minimum urinary pH 6.5–7.1 and fractional excretion of bicarbonate in the presence of normal bicarbonatemia 1.1–5.7%. Growth retardation and nephrocalcinosis, but not hypercalciuria, were common presenting manifestations. Hearing was normally preserved in one of the patients whose sister was severely deaf. One child was homozygous for a known mutation in exon 1: C>T (R31X). Three children were homozygous for a splicing mutation, intron 6 + 1G>A. The other patient was a compound heterozygote, having this mutation and a previously unreported mutation in exon 10: G>A (E330K). Our report shows that hearing loss is not always present in the syndrome of distal renal tubular acidosis with nerve deafness and the absence of hypercalciuria at diagnosis and describes a new mutation responsible for the disease in the ATP6V1B1 gene.     

NBCn1 Increases NH4+ Reabsorption Across Thick Ascending Limbs,the Capacity for Urinary NH4+ Excretion,and Early Recovery from Metabolic Acidosis

BackgroundThe electroneutral Na⁺/HCO₃⁻ cotransporter NBCn1 (Slc4a7) is expressed in basolateral membranes of renal medullary thick ascending limbs (mTALs). However, direct evidence that NBCn1 contributes to acid-base handling in mTALs, urinary net acid excretion, and systemic acid-base homeostasis has been lacking.MethodsMetabolic acidosis was induced in wild-type and NBCn1 knockout mice. Fluorescence-based intracellular pH recordings were performed and NH₄⁺ transport measured in isolated perfused mTALs. Quantitative RT-PCR and immunoblotting were used to evaluate NBCn1 expression. Tissue [NH₄⁺] was measured in renal biopsies, NH₄⁺ excretion and titratable acid quantified in spot urine, and arterial blood gasses evaluated in normoventilated mice.ResultsBasolateral Na⁺/HCO₃⁻ cotransport activity was similar in isolated perfused mTALs from wild-type and NBCn1 knockout mice under control conditions. During metabolic acidosis, basolateral Na⁺/HCO₃⁻ cotransport activity increased four-fold in mTALs from wild-type mice, but remained unchanged in mTALs from NBCn1 knockout mice. Correspondingly, NBCn1 protein expression in wild-type mice increased ten-fold in the inner stripe of renal outer medulla during metabolic acidosis. During systemic acid loading, knockout of NBCn1 inhibited the net NH₄⁺ reabsorption across mTALs by approximately 60%, abolished the renal corticomedullary NH₄⁺ gradient, reduced the capacity for urinary NH₄⁺ excretion by approximately 50%, and delayed recovery of arterial blood pH and standard [HCO₃⁻] from their initial decline.ConclusionsDuring metabolic acidosis, NBCn1 is required for the upregulated basolateral HCO₃⁻ uptake and transepithelial NH₄⁺ reabsorption in mTALs, renal medullary NH₄⁺ accumulation, urinary NH₄⁺ excretion, and early recovery of arterial blood pH and standard [HCO₃⁻]. These findings support that NBCn1 facilitates urinary net acid excretion by neutralizing intracellular H⁺ released during NH₄⁺ reabsorption across mTALs.     

Role of the kidney in acid–base balance

Correction of disturbances in acid–base balance is achieved by: physicochemical buffering by extracellular and intracellular buffer systems (instantaneous), alveolar ventilation to control pCO₂ (rapid), and renal compensation (long term). Buffering and changes in ventilation limit changes in pH, but cannot return acid–base status to normal. The kidney has a pivotal role: disturbances can be completely corrected through changes in H⁺ secretion and HCO₃^? reabsorption and production. HCO₃^? reabsorption is modified by changes in glomerular filtration rate (filtered load), changes in extracellular volume and by hormones which modify Na⁺ reabsorption via the Na⁺–H⁺ exchanger in renal tubular cells. Changing the activity of this exchanger influences H⁺ secretion and, hence, HCO₃^? reabsorption. Chronic (but not acute) changes in pCO₂ influence HCO₃^? reabsorption through changes in the filtered load and, in chronic acidosis, by the insertion of more H⁺ transport proteins in renal tubular cells. Renal HCO₃^? production is linked to H⁺ excretion: acid buffer salts (phosphate, creatinine), their availability and pK and tubular fluid pH. Formation and excretion of NH₄⁺ buffer salts are important – acidosis stimulates secretion of NH₄⁺ (proximal tubule) and NH₃ (collecting duct). There is a reciprocal relationship between extracellular K⁺ and NH₄⁺ excretion, hence HCO₃^? production.     

Atypical distal renal tubular acidosis confirmed by mutation analysis

In autosomal dominant distal renal tubular acidosis type I (dRTA) impaired hydrogen ion secretion is associated with metabolic acidosis, hyperchloremic hypokalemia, hypercalciuria, nephrocalcinosis, and/or nephrolithiasis. A retardation of growth is commonly observed. In this report we present a family with autosomal dominant dRTA with an atypical and discordant clinical picture. The father presented with severe nephrocalcinosis, nephrolithiasis, and isosthenuria but metabolic acidosis was absent. His 6-year-old daughter, however, suffered from metabolic acidosis, hypokalemia, and hypercalciuria. In addition, sonography revealed multiple bilateral renal cysts but no nephrocalcinosis. Mutation analysis of the AE1 gene coding for the renal Cl^–/HCO₃ ^–- exchanger AE1 displayed a heterozygous Arg589Cys exchange in both patients but not in the healthy family members. This point mutation is frequently associated with autosomal dominant dRTA. Diagnosis of autosomal dominant dRTA is supported in this family by results of AE1 mutation analysis. Received: 13 April 2000 / Revised: 23 June 2000 / Accepted: 26 June 2000     

Role of the kidney in acid–base balance

Correction of disturbances in acid–base balance is achieved by: physicochemical buffering by extracellular and intracellular buffer systems (instantaneous), alveolar ventilation to control pCO₂ (rapid), and renal compensation (long term). Buffering and changes in ventilation limit changes in pH but cannot return acid–base status to normal. The kidney has a pivotal role: disturbances can be completely corrected through changes in H⁺ secretion and HCO₃^? reabsorption and production. HCO₃^? reabsorption is modified by changes in GFR (filtered load), changes in extracellular volume and by hormones which modify Na⁺ reabsorption via the Na⁺–H⁺ exchanger in renal tubular cells. Changing the activity of this exchanger influences H⁺ secretion and, hence, HCO₃^? reabsorption. Chronic (but not acute) changes in pCO₂ influence HCO₃^? reabsorption through changes in the filtered load and, in chronic acidosis, by the insertion of more H⁺ transport proteins in renal tubular cells. Renal HCO₃^? production is linked to H⁺ excretion: acid buffer salts (phosphate, creatinine), their availability and pK and tubular fluid pH. Formation and excretion of NH₄⁺ buffer salts are important – acidosis stimulates secretion of NH₄⁺ (proximal tubule) and NH₃ (collecting duct). There is a reciprocal relationship between extracellular K⁺ and NH₄⁺ excretion, hence HCO₃^? production.     

Acquired alterations in vitamin D metabolism in the acidotic state

Summary Classic (type I) renal tubular acidosis in children is attended by growth retardation and rickets, abnormalities that can be corrected by alkali therapy alone. We have employed the NH₄Cl-treated rachitic chick as a model to investigate vitamin D metabolism in the acidotic state. NH₄Cl ingestion for 96 h was associated with a rise in serum calcium, a significant decrease in blood pH (7.42+0.08 vs 7.30±0.08,P<0.005), decreased [³H]1,25(OH)₂D₃ following [³H]25OHD D₃ injections, and enhanced metabolic clearance of administered [³H]1,25(OH)₂D₃. The data collectively suggest that metabolic acidosis in the chick alters the production and degradation of 1,25(OH)₂D₃.     

Proximal renal tubular dysfunction in primary distal renal tubular acidosis

Low-molecular-weight (LMW) proteinuria has been described in patients with primary distal renal tubular acidosis (dRTA). However, other proximal renal tubular dysfunctions have rarely been reported. In this report we describe reversible and multiple proximal renal tubular cell dysfunctions in a patient with dRTA. A 4-year-old girl was admitted to our hospital for investigation of short stature and proteinuria. Laboratory studies revealed a hyperchloremic metabolic acidosis without aciduria, hypokalemia, hypouricemia with uricosuria, hypercalciuria, LMW proteinuria, phosphaturia, and generalized aminoaciduria. The patient was diagnosed as having dRTA with multiple proximal renal tubular dysfunctions. All proximal renal tubular dysfunction subsided 1.5 years after starting alkali therapy. The precise pathogenic mechanisms underlying the development of multiple proximal renal tubular dysfunctions in dRTA remained unclear. However, proximal renal tubular endosomal dysfunction resulting from a profound intracellular acidosis caused by vacuolar H⁺-ATPase dysfunction or hypokalemic nephropathy might contribute to the development of proximal renal tubular dysfunctions in patients with dRTA.     

Acid–base metabolism: implications for kidney stosne formation

The physiology and pathophysiology of renal H⁺ ion excretion and urinary buffer systems are reviewed. The main focus is on the two major conditions related to acid–base metabolism that cause kidney stone formation, i.e., distal renal tubular acidosis (dRTA) and abnormally low urine pH with subsequent uric acid stone formation. Both the entities can be seen on the background of disturbances of the major urinary buffer system, . On the one hand, reduced distal tubular secretion of H⁺ ions results in an abnormally high urinary pH and either incomplete or complete dRTA. On the other hand, reduced production/availability of is the cause of an abnormally low urinary pH, which predisposes to uric acid stone formation. Most recent research indicates that the latter abnormality may be a renal manifestation of the increasingly prevalent metabolic syndrome. Despite opposite deviations from normal urinary pH values, both the dRTA and uric acid stone formation due to low urinary pH require the same treatment, i.e., alkali. In the dRTA, alkali is needed for improving the body’s buffer capacity, whereas the goal of alkali treatment in uric acid stone formers is to increase the urinary pH to 6.2–6.8 in order to minimize uric acid crystallization.     

Permeability defect with bicarbonate leak as a mechanism of immune-related distal renal tubular acidosis

We present a 15-year-old girl with distal renal tubular acidosis (dRTA) appearing in what is probably a very early stage of primary Sj?gren's syndrome. On the basis of tests evaluating renal handling of H+, we attempt to explain the mechanism of the urine acidification disorder. The inability to decrease urinary pH during systemic acidosis, together with the normal increase of urinary carbon dioxide partial pressure (pCO2) values after sodium bicarbonate and neutral phosphate loading, suggest a gradient-type dRTA. The inability to lower urinary pH in response to furosemide, accompanied by markedly increased urinary excretion of NH4, HCO3, Na, and K, points to a collecting tubule permeability disorder with bicarbonate leak to the tubular lumen. This patient had never been exposed to amphotericin B. To our knowledge, immune-related dRTA as a result of a gradient defect with bicarbonate leak into the tubular lumen has not been described.     

Effect of ammonium-chloride-induced metabolic acidosis on renal electrolyte handling in human neonates

The present study was undertaken to determine the relative contribution of altered glomerular and tubular functions to the metabolic-acidosis-induced increase of renal electrolyte excretion in healthy preterm and full-term neonates and in older infants. Studies were performed in 10 premature infants (mean birth weight 1618 g, gestational age 30.8 weeks) weekly for 6 consecutive weeks, in 11 full-term neonates (mean birth weight 3085 g, gestational age 38.6 weeks) on the 7th day of life and in 25 older control infants (mean age 6.5 months, body weight 6802 g), before and after NH₄Cl loading. Blood acid-base parameters, plasma and urine electrolyte and creatinine concentrations were measured, endogenous creatinine clearance and fractional electrolyte excretion (FE) calculated. It was demonstrated that the significant reduction in blood pH and total CO₂ content induced by NH₄Cl administration was associated with significant increases in glomerular filtration rate (GFR), urine flow rate, FE_Na and FE_Cl, in each group studied, irrespective of maturity, postnatal age or pre-load values. FE_K also tended to increase, but the change reached statistical significance only in older infants and in premature babies during the 1st, 2nd and 5th week of post-natal life. FE_Ca and FE_PO4 increased slightly in preterm and full-term newborns and became significant in older infants. Prior to NH₄Cl administration, FE_Ca correlated positively with FE_Na in each group. NH₄Cl metabolic acidosis, however, dissociated FE_Ca from FE_Na in the full-term newborns and older infants but not in the preterm neonates. We conclude that changes in urinary excretory response of human neonates to NH₄Cl administration may be accounted for by the combined effect of increased GFR and decreased electrolyte reabsorption.     

Clinical and genetic analysis of distal renal tubular acidosis in three Chinese children

Objective: Primary distal renal tubular acidosis (dRTA) is a rare genetic disease characterized by distal tubular dysfunction leading to metabolic acidosis and alkaline urine. Growth retardation is a major concern in these children. The disease is caused by defects in at least three genes (SLC4A1, ATP6V0A4, and ATP6V1B1) involved in urinary distal acidification. Several series of dRTA patients from different ethnic backgrounds have been genetically studied, but genetic studies regarding Chinese population is rare. Our aim was to investigate the clinical features and genetic basis of primary dRTA in Chinese children.

Methods: Three unrelated patients with dRTA participated in our study. Next-generation sequencing was performed, and the findings were validated using the Sanger sequencing method.

Results: All patients exhibited hyperchloraemic metabolic acidosis, abnormally high urine pH, hypokalemia, and nephrocalcinosis. Growth retardation was observed in all patients. During the follow-up (range 1–4 years), alkali replacement therapy corrected the systemic metabolic acidosis, and two patients demonstrated normal growth. rhGH therapy was administered to patient-3 at the age of 6?years, and his growth rate was significantly improved (growth velocity 9.6?cm/yr). In total, 5 mutations were identified in our cohort of three patients, and four mutations were novel.

Conclusions: We report the clinical and molecular characteristics of dRTA patients from China. The four novel mutations detected in our study extend the spectrum of gene mutations associated with primary dRTA. Furthermore, our study confirms the effect of early treatment in improving growth for dRTA patient and provides insight into the effects of rhGH on dRTA patients who were diagnosed late and exhibiting a persistent growth delay despite appropriate therapy.     

Renal tubular acidosis

The term renal tubular acidosis (RTA) is applied to a group of transport defects in the reabsorption of bicarbonate (HCO ₃ ^– ), the excretion of hydrogen ions, or both. On clinical and pathophysiological grounds, RTA can be separated into three main types: distal RTA (type 1), proximal RTA (type 2) and hyperkalaemic RTA (type 4). Some patients present combined types of proximal and distal RTA or of hyperkalaemic and distal RTA. Diagnosis of RTA should be suspected when a patient presents a normal plasma anion gap, and hyperchloraemic metabolic acidosis. A normal plasma anion gap (Na⁺–[Cl^–+HCO₃ ^–]=8–16 mEq/l) reflects loss of HCO₃ ^– from the extracellular fluid via the gastro-intestinal tract or the kidney, dilution of extracellular buffer or administration of hydrochloric acid (HCl) or its precursors. Distinction of RTA from other disorders is greatly facilitated by the study of the urine anion gap (Na⁺+K⁺–Cl^–). This index estimates the urinary concentration of ammonium in a patient with hyperchloraemic metabolic acidosis. A negative urine anion gap (Cl^–Na⁺+K⁺) suggests the presence of gastro-intestinal or renal loss of HCO₃ ^–, while a positive urine anion gap (Cl^–++K⁺) is indicative of a distal acidification defect. Determination of plasma potassium, of urine pH at low plasma HCO₃ ^– concentration, and of urineP co ₂ and fractional excretion of HCO₃ ^– at normal plasma HCO₃ ^– concentration permits the differentiation between the various types of RTA.     

Oral Sodium Bicarbonate Reduces Proximal Renal Tubular Peptide Catabolism,Ammoniogenesis, and Tubular Damage in Renal Patients

Oral sodium bicarbonate (NaHCO₃) is widely used to treat acidosis in patients with renal failure. However, no data are available in man on the effects on proximal renal tubular protein catabolism or markers of tubular injury. We have developed methods to allow such studies, and both increased tubular catabolism of ^99mTc-labelled aprotinin (Apr^*), as well as tubular damage were found in association with increased ammonia (NH₃) excretion in patients with nephrotic range proteinuria.

We now examine the effects of reducing renal ammoniogenesis, without altering proteinuria, using oral NaHCO₃ in 11 patients with mild/moderate renal impairment and proteinuria. Renal tubular catabolism of Apr^* was measured before and after NaHCO₃ by renal imaging (Kidney uptake, K % of dose) and urinary excretion of free ^99mTcO₄ (metabolism, Met % of dose/h) over 26 h. Fractional degradation (Frac) was calculated from Met/K (/h). Fresh urine was also analyzed for NH₃ excretion every fortnight from 6/52 before treatment. Total urinary N-acetyl-β-D-glucoseaminidase (NAG) and the more tubulo-specific NAG “A2” were measured. ⁵¹CrEDTA clearance and 99mTc- MAG 3 TER were also assessed.

After NaHCO₃ Met over 26 h was significantly reduced (from 1.3 ± 0.2 % of dose/h to 0.9 ± 0.1 % dose/hrp <0.005), as was Frac of Apr^* (from 0.06 ±. 006/h to 0.04 ± 0.005/hrp <0.003). NH₃ excretion also fell significantly (from 0.9 ± 0.2 mmol/h to 0.2 ± 0.05 mmol/hp <0.007), as did both total urinary NAG (from 169 μmol/24 h, 74-642 μmol/24 h to 79 μmol/ 24 h, 37-393 μmol/24 hp <0.01), and the NAG ‘A2’ isoenzyme (from 81.5 μmol/24 h, 20–472 μmol/24 h to 35.0 μmol/24 h, 6–388 μmol/24 hp <0.001). Proteinuria remained unaltered, and there was no change in blood pressure nor in glomerular haemodynamics. Oral NaHCO₃ may thus pro-tect the proximal renal tubule and help delay renal disease progression.     

Why is hypercalciuria absent at diagnosis in some children with ATP6V1B1 mutation?

We try to explain why hypercalciuria is absent at diagnosis in some children with an ATP6V1B1 mutation. A 5-month-old girl presented with distal renal tubular acidosis (dRTA) and sensorineural hearing loss. Direct sequencing of the ATP6V1B1 genes disclosed a new homozygous mutation (452 delT) in exon 13. In particular, an absence of hypercalciuria and a normal level of parathyroid hormones were noted. After alkaline therapy, the signs of nephrocalcinosis improved on ultrasound during follow-up. After a review of the literature regarding patients with ATP6V1B1 gene mutations, a young age seemed to be an important factor for normocalciuria. The probable mechanism of normocalciuria and a dynamic mode of calcium excretion in patients with dRTA is proposed. The determinant factors include the degree of systemic acidosis, urine pH, genetic polymorphisms, age, dietary factors, and volume status. Low sodium intake may be a major determinant of normocalciuria in these patients. It is suggested that hypercalciuria is usually absent at diagnosis of dRTA in young infants. Blood pH, plasma bicarbonate concentration, urinary citrate levels, and growth catch-up may be better indicators of adequate alkali therapy in normocalciuric children. Volume contraction, low salt content in infant formula, and alkaline urine in young infants are likely to account for the increased calcium reabsorption.     

Severe renal tubular acidosis in a renal transplant recipient with repeated acute rejections and chronic allograft nephropathy

Renal tubular acidosis in renal transplant recipients usually is asymptomatic and subclinical. The authors report a case of severe renal tubular acidosis manifested as muscle weakness in a renal transplant recipient. The patient received a renal transplant 30 months ago and had a history of successive episodes of acute rejection during the past 2 months. On admission, arterial blood (arterial blood pH, 7.11; pco₂, 12.8 mm Hg; and bicarbonate, 4 mEq/L [4 mmol/L]) and urine gas analysis were compatible with distal renal tubular acidosis. The graft biopsy findings showed superimposed acute rejection on chronic allograft nephropathy, and immunohistochemical staining and electron microscopic findings showed the reduced immunoactivity of H⁺ATPase pump and anion exchanger 1. The patient was treated successfully with intravenous bicarbonate and oral steroid pulse therapy. This finding suggests that rejection-related renal tubular acidosis should be considered a cause of severely affected metabolic acidosis in renal transplant recipients. Am J Kidney Dis 41:E6.