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PubMed1993

Latent distal renal tubular acidosis (dRTA) in primary biliary cirrhosis (PBC) and chronic autoimmune hepatitis (CAH).

In an attempt to evaluate the latent distal renal tubular acidosis (dRTA7) in patients with primary biliary cirrhosis (PBC), and chronic autoimmune hepatitis (CAH), and differences between them in relation to the sodium urinary excretion ([Na]u), thirty four patients divided in two groups were studied. Group A: 17 patients who fulfilled criteria for PBC diagnosis (clinical and humoral evidence antimitochondrial antibody titles of 1/80 or above by indirect immunofluorescence technique, and liver biopsy). Group B: 17 patients who fulfilled criteria for CAH diagnosis (clinical and humoral evidence, antinuclear and smooth muscle antibody titles of 1/80 or above and liver biopsy). Patients with ascitis and/or edema were excluded from the study. Ability to acidify urine was evaluated by gradient between pC02 in urine and blood (U-BpC02) after alkali infusion. Five patients in Group A (29.4%7) and six in Group B(35.2%) had dRTA, (p = 0.49). When analyzing patients with dRTA in both groups, the mean [Na]u in Group A was 152.2 +/- 33.8, versus 50.8 +/- 8.1 mEq/l, in Group B. (p = 0.00016). We concluded that the prevalence of dRTA was similar in patients with PBC and CAH but the urinary acidifications impairment of the former did not correlate with [Na]u, as it did with the latter.

Acidosis, Renal Tubular↗
PubMed2005

A primary Sjögren's syndrome patient with distal renal tubular acidosis, who presented with symptoms of hypokalemic periodic paralysis: Report of a case study and review of the literature.

Although renal tubular acidosis (RTA), secondary to autoimmune interstitial nephritis, develops in a large proportion of patients with Sjögren's syndrome (SS), most of the subjects are asymptomatic. Here, we shall present a 39-year-old female patient who came to us with hypokalemic periodic paralysis (HPP), and who was later diagnosed with distal RTA. The patient, who had xerostomia and xerophthalmia for a long period of time, was diagnosed with primary SS from serologic and histologic findings. The patient recovered by being prescribed potassium replacement therapy. Although renal biopsy was not performed, corticosteroids were administered because HPP indicated severe interstitial nephritis. HPP did not reoccur during a 2-year follow-up period. We also review cases with SS-related distal RTA and HPP.

Acidosis, Renal Tubular↗
PubMed1990

[Renal tubular acidosis and perception deafness. Apropos of a familial form].

We report a case of primary distal tubular acidosis with sensorineural deafness in two children from the same family. Failure to thrive at age one month was the first manifestation. Administration of bicarbonates allowed rapid resumption of normal growth. Inheritance is recessive and autosomal, contrary to isolated distal tubular acidosis. Early detection of deafness, a common feature that can easily be treated by hearing aids, should avoid delays in development of speech.

Acidosis, Renal Tubular↗
PubMed2004

A novel missense mutation in AE1 causing autosomal dominant distal renal tubular acidosis retains normal transport function but is mistargeted in polarized epithelial cells.

Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron. In this study we report a novel missense mutation, G609R, causing dominant dRTA in affected members of a large Caucasian pedigree who all exhibited metabolic acidosis with alkaline urine, prominent nephrocalcinosis, and progressive renal impairment. To investigate the potential disease mechanism, the consequent effects of this mutation were determined. We first assessed anion transport function of G609R by expression in Xenopus oocytes. Western blotting and immunofluorescence demonstrated that the mutant protein was expressed at the oocyte cell surface. Measuring chloride and bicarbonate fluxes revealed normal 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid-inhibitable anion exchange, suggesting that loss-of-function of kAE1 cannot explain the severe disease phenotype in this kindred. We next expressed epitope-tagged wild-type or mutant kAE1 in Madin-Darby canine kidney cells. In monolayers grown to polarity, mutant kAE1 was detected subapically and at the apical membrane, as well as at the basolateral membrane, in contrast to the normal basolateral appearance of wild-type kAE1. These findings suggest that the seventh transmembrane domain that contains Gly-609 plays an important role in targeting kAE1 to the correct cell surface compartment. They confirm that dominant dRTA is associated with non-polarized trafficking of the protein, with no significant effect on anion transport function in vitro, which remains an unusual mechanism of human disease.

Acidosis, Renal Tubular↗
PubMed2004

Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype-phenotype correlation.

The carbonic anhydrase II (CA II) deficiency syndrome is an autosomal recessive disorder that produces osteopetrosis, renal tubular acidosis, and cerebral calcification. Other features include developmental delay, short stature, cognitive defects, and a history of multiple fractures by adolescence. With one exception, all patients with osteopetrosis and renal tubular acidosis examined have proven to have CA II deficiency. All CA II-deficient patients analyzed have been found to have mutations in the CA2 gene. Previously, we used single strand conformational (SSCP) analysis to identify exons to be sequenced from CA II-deficient patients. In this report, we amplified all seven exons by PCR from genomic DNA and directly sequenced the amplified products. Application of this method allowed identification of eleven new mutations in 21 patients referred for confirmation of the diagnosis of CA II deficiency. These mutations were scattered over the genome from exon 2 to 7. In two opportunities for prenatal diagnosis, one from cultured amniocytes and one from chorionic villus biopsy, we demonstrated the general utility of the direct sequencing method for prenatal DNA diagnosis. These studies expand our knowledge of the heterogeneity in mutations underlying the CA II deficiency syndrome.

Acidosis, Renal Tubular↗
PubMed2006

Vacuolar H+ -ATPase B1 subunit mutations that cause inherited distal renal tubular acidosis affect proton pump assembly and trafficking in inner medullary collecting duct cells.

Point mutations in the B1 subunit of vacuolar H+ -ATPase are associated with impaired ability of the distal nephron to secrete acid (distal renal tubular acidosis). For testing of the hypothesis that these mutations interfere with assembly and trafficking of the H+ -ATPase, constructs that mimic seven known point mutations in inherited distal renal tubular acidosis (M) or wild-type (WT) B1 were transfected into a rat inner medullary collecting duct cell line to express green fluorescence protein (GFP)-B1WT or GFP-B1M fusion proteins. In co-immunoprecipitation studies, GFP-B1WT formed complexes with other H+ -ATPase subunits (c, H, and E), whereas GFP-B1M did not. Proteins that were immunoprecipitated with anti-GFP antibody from GFP-B1WT cells had ATPase activity, whereas proteins from GFP-B1M cells did not. Proton pump-mediated intracellular pH transport was inhibited in GFP-B1M-transfected cells but not in GFP-B1WT cells. GFP-B1WT and GFP-B1M are present in the apical membrane and increased with cellular acidification. In GFP-B1WT cells, the apical membrane fraction of GFP-B1, endogenous B1, and the 31-kD subunits of the H+ -ATPase increased with cell acidification. In GFP-B1M cells, the endogenous B1 and 31-kD subunits did not increase with acidification. B1 point mutations prevent normal assembly of the H+ -ATPase and also may act as an inhibitor of H+ -ATPase function by competing with endogenous intact H+ -ATPase for trafficking in inner medullary collecting duct cells.

Acidosis, Renal Tubular↗
PubMed1978

Inactive form of erythrocyte carbonic anhydrase B in patients with primary renal tubular acidosis.

Evidence was found for an inactive form of carbonic anhydrase type B in the erythrocytes of two children with primary renal tubular acidosis. The addition of zinc chloride to hemolysates from these patients resulted in a marked increase in the activity of this enzyme. No such effect was noted with hemolysates of control subjects. No significant differences were observed in the zinc levels of hemolysates of these patients and of normal individuals. However, the level of zinc in the carbonic anhydrase B isolated from one of these patients was low, suggesting a modified form of the enzyme. The restoration of activity upon the addition of zinc was reversed by ethylenediamine tetraacetate, but no such effects were noted for the carbonic anhydrase B of normal individuals. Thus the abnormal carbonic anhydrase B has decreased zinc binding. The ultraviolet difference spectrum of the carbonic anhydrase B of normal individuals and that of a patient showed a peak at 305 nm which decreased upon the addition of zinc. The abnormal form of carbonic anhydrase B was not distinguishable from that of normal individuals by either immunological or electrophoretic criteria.

Acidosis, Renal Tubular↗
PubMed2004

Novel compound heterozygous SLC4A1 mutations in Thai patients with autosomal recessive distal renal tubular acidosis.

BACKGROUND: Mutations in the SLC4A1 gene have been found to cause either autosomal dominant (AD) or autosomal recessive (AR) distal renal tubular acidosis (dRTA). The SLC4A1 mutations causing AD dRTA were reported in white patients, whereas those associated with AR dRTA were often found in Southeast Asia. Here, the authors report additional novel SLC4A1 mutations in 3 patients with AR dRTA from 2 unrelated Thai families. METHODS: The patients and members of their families were clinically studied. Red cell morphology and sulfate influx were examined. The SLC4A1 gene was screened, analyzed, and confirmed for mutations by molecular genetic techniques. RESULTS: In the first family, the patient had dRTA, rickets, failure to thrive, nephrocalcinosis, and hypokalemic-hyperchloremic metabolic acidosis with a urine pH level of 7.00. He had novel compound heterozygous SLC4A1 G701D/S773P mutations, inherited from clinically normal heterozygous mother and father. In the second family, the patient and his sister had dRTA and Southeast Asian ovalocytosis (SAO) with different clinical severity. The patient had proximal muscle weakness, rickets, nephrocalcinosis, hypokalemia, normal anion gap metabolic acidosis, and urine pH level of 6.80. His sister was asymptomatic but the urine pH level could not be lowered to below 5.50 after a short acid load. Both siblings had compound heterozygous SLC4A1 SAO/R602H mutations. CONCLUSION: Two novel compound heterozygous SLC4A1 G701D/S773P and SAO/R602H mutations were identified in Thai patients with AR dRTA.

Acidosis, Renal Tubular↗
PubMed2000

Hypokalemic muscular paralysis causing acute respiratory failure due to rhabdomyolysis with renal tubular acidosis in a chronic glue sniffer.

CASE REPORT: A 34-year-old male was admitted to the emergency department with the development of quadriparesis and respiratory failure due to hypokalemia after prolonged glue sniffing. The patient was subsequently given mechanical ventilatory support for respiratory failure. He was weaned from the ventilator 4 days later after potassium replacement. Toluene is an aromatic hydrocarbon found in glues, cements, and solvents. It is known to be toxic to the nervous system, hematopoietic system, and causes acid-base and electrolyte disorders. Acute respiratory failure with hypokalemia and rhabdomyolysis with acute renal failure should be considered as potential events in a protracted glue sniffing.

Acidosis, Renal Tubular↗
PubMed1974

Enzymatically inactive red cell carbonic anhydrase B in a family with renal tubular acidosis.

An inactive mutant form of red cell carbonic anhydrase B is described in three members of a large kindred who manifest infantile renal tubular acidosis and nerve deafness. A combination of enzymatic and immunologic investigations permitted its detection, despite the fact that both antigenic and electrophoretic properties of the mutant were identical to those of the normal form.

Acidosis, Renal Tubular↗
PubMed2001

[A case of Sjögren's syndrome presenting with hypokalemic myopathy due to renal tubular acidosis].

A 37-year-old woman was admitted to our university hospital because of severe flaccid quadriplegia. Her laboratory data, lip biopsy and muscle biopsy findings were compatible with hypokalemic myopathy due to renal tubular acidosis(RTA) type I associated with primary Sjögren's syndrome. Kidney biopsy revealed chronic tubulointerstitial nephritis(TIN), consisting of focal mononuclear cell infiltration with tubulitis, interstitial fibrosis and tubular atrophy. Immunohistochemical analysis of the renal biopsy specimens showed that the infiltrating mononuclear cells were predominantly CD8+T cells, and CD68+ cells(macrophages), whereas CD4+ T cells were fewer in number. Following potassium administration and alkali therapy, hypokalemia and metabolic acidosis were ameliorated and limb palsy gradually subsided. Finally, RTA improved with prednisolon and short term cyclophosphamide treatment without supplemental potassium and alkali therapy.

Acidosis, Renal Tubular↗
PubMed2004

Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin.

Cyclosporin A (CsA), a widely used immunosuppressant, causes distal renal tubular acidosis (dRTA). It exerts its immunosuppressive effect by a calcineurin-inhibitory complex with its cytosolic receptor, cyclophilin A. However, CsA also inhibits the peptidyl prolyl cis-trans isomerase (PPIase) activity of cyclophilin A. We studied HCO(3)(-) transport and changes in beta-intercalated cell pH on luminal Cl(-) removal in isolated, perfused rabbit cortical collecting tubules (CCDs) before and after exposure to media pH 6.8 for 3 h. Acid incubation causes adaptive changes in beta-intercalated cells by extracellular deposition of hensin (J Clin Invest 109: 89, 2002). Here, CsA prevented this adaptation. The unidirectional HCO(3)(-) secretory flux, estimated as the difference between net flux and that after Cl(-) removal from the lumen, was -6.7 +/- 0.2 pmol.min(-1).mm(-1) and decreased to -1.3 +/- 0.2 after acid incubation. CsA in the bath prevented the adaptive decreases in HCO(3)(-) secretion and apical Cl(-):HCO(3)(-) exchange. To determine the mechanism, we incubated CCDs with FK-506, which inhibits calcineurin activity independently of the host cell cyclophilin. FK-506 did not prevent the acid-induced adaptive decrease in unidirectional HCO(3)(-) secretion. However, [AD-Ser](8) CsA, a CsA derivative, which does not inhibit calcineurin but inhibits PPIase activity of cyclophilin A, completely blocked the effect of acid incubation on apical Cl(-):HCO(3)(-) exchange. Acid incubation resulted in prominent "clumpy" staining of extracellular hensin and diminished apical surface of beta-intercalated cells [smaller peanut agglutinin (PNA) caps]. CsA and [AD-Ser](8) CsA prevented most hensin staining and the reduction of apical surface; PNA caps were more prominent. We suggest that hensin polymerization around adapting beta-intercalated cells requires the PPIase activity of cyclophilins. Thus CsA is able to prevent this adaptation by inhibition of a peptidyl prolyl cis-trans isomerase activity. Such inhibition may cause dRTA during acid loading.

Acidosis, Renal Tubular↗
PubMed1985

Proximal renal tubular acidosis in methylmalonic acidemia.

A patient with methylmalonic acidemia was found to have a persistent hyperchloremic acidosis. Investigation documented the presence of a proximal renal tubular acidosis. Between 14 and 18 months of age the urinary pH was as high as 8.0 when the serum bicarbonate was 17 mEq/liter and the threshold for bicarbonate was at 16-17 mEq/liter. When restudied at 33 months of age, the threshold had risen to 20 mEq/liter, but this was still abnormal and supplemental treatment was required to keep the serum concentration of bicarbonate above 20 mEq/liter. It is postulated that organic acid metabolites which accumulate in this and related disorders may interfere with renal tubular function as has been shown for maleic acid in experimental animals.

Acidosis, Renal Tubular↗
PubMed2003

Evaluation of failure to thrive: diagnostic yield of testing for renal tubular acidosis.

BACKGROUND: Failure to thrive (FTT) poses a diagnostic dilemma for pediatricians. The kidney disorder that is considered most often is renal tubular acidosis (RTA). However, the prevalence of RTA may be overestimated, leading to unnecessary referrals for subspecialty evaluation. Moreover, preliminary data suggest that venous blood gas (VBG) testing may provide a more accurate measurement of the serum bicarbonate concentration than routine biochemical testing. OBJECTIVE: 1) To compare the results of bicarbonate measurements by using VBG and routine clinical biochemistry methods under a variety of in vitro conditions; 2) to determine the frequency of RTA as a cause of FTT; and 3) to assess the utility of VBG measurement of serum bicarbonate in the clinical assessment of RTA. EXPERIMENTAL DESIGN AND METHODS: In blood samples collected from healthy volunteers, bicarbonate was measured by using a VBG apparatus and a clinical biochemistry analyzer under a variety of in vitro conditions including variation in time until sample processing (0-4 hours), variations in temperature (room temperature versus on ice), addition of sodium fluoride, or addition of heparin. A retrospective chart review was also performed of all children referred to the renal clinic for evaluation of FTT during the 5-year period of 1997 to 2002. The following data were collected for each case: demographic and clinical information and laboratory testing including serum bicarbonate determined by both routine biochemical testing and VBG analysis. Data are reported as mean +/- standard deviation. RESULTS: In the in vitro studies, VBG determination of bicarbonate concentration consistently yielded a value that was 3 to 6 mmol/L higher than routine biochemical analysis regardless of whether the sample was processed immediately or up to 4 hours later, maintained at room temperature or on ice until the measurement was performed, or the sample tube contained sodium fluoride or heparin. Thirty-six children were referred to exclude a renal etiology of FTT with a presumptive diagnosis of RTA in all cases. The patient group was comprised of 16 males and 20 females whose ages ranged from 4 to 156 months (mean: 27 +/- 33 months). The serum bicarbonate concentration determined by biochemical testing was 18 +/- 4 mmol/L, whereas the bicarbonate level by VBG was 24 +/- 3 mmol/L. The mean difference between the bicarbonate by VBG and bicarbonate by routine biochemistry measurements was 5.6 +/- 4.4. Only 1 child (2.8%) was confirmed to have RTA. CONCLUSIONS: RTA is a rare renal cause of FTT in children. VBG determination of serum bicarbonate yielded a significantly higher value than the result obtained by routine biochemical testing under both in vitro and in vivo conditions. These data suggest that reliance on routine biochemical testing results in an overestimation of the importance of RTA as a cause of FTT. We recommend the use of a VBG determination of serum bicarbonate concentration for the evaluation of a child with FTT who is thought to have a metabolic acidosis. Adoption of this practice will reduce the number of children suspected of having RTA and decrease the need for referral to a nephrologist for further evaluation.

Acidosis, Renal Tubular↗