scholarly journals Preservation of intercalated cell H(+)-ATPase in two patients with lupus nephritis and hyperkalemic distal renal tubular acidosis.

1997 ◽  
Vol 8 (7) ◽  
pp. 1109-1117
Author(s):  
B Bastani ◽  
D Underhill ◽  
N Chu ◽  
R D Nelson ◽  
L Haragsim ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Renal Tubular Acidosis ◽  
Frozen Section ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Distal Renal Tubular Acidosis ◽  
Intercalated Cells ◽  
Urine Ph ◽  
Control Serum ◽  
Renal Tubular

In patients with Sjögren's syndrome and a secretory-defect distal renal tubular acidosis (dRTA), absence of vacuolar H(+)-ATPase from collecting duct intercalated cells has been reported. The H(+)-ATPase was examined in two patients with lupus nephritis and hyperkalemic (presumed voltage defect) dRTA. Both patients had a positive urine anion gap, alkaline urine despite acidemia, no rise in urine PCO2 with alkaluria, a urine pH > 5.5, and urine potassium excretion rate not significantly increased after 80 mg of intravenous furosemide. In both patients, immunocytochemistry of renal biopsy frozen sections with an anti-H(+)-ATPase monoclonal antibody showed bright staining of the proximal tubule brush border and collecting duct intercalated cells. In one patient, routine immunofluorescence analysis of a frozen section of her kidney biopsy with antihuman IgG showed staining of the collecting duct, indicative of autoantibodies to this segment. Moreover, rat kidney sections incubated with her serum showed labeling of the intercalated cells. On immunoblots of human kidney microsomal membranes performed with serum from both patients, an immunoreactive polypeptide was observed at M(r) approximately 56 kD that was not seen with control serum. Neither patient's sera reacted with affinity-purified bovine H(+)-ATPase or with lysates from 293 cell fibroblasts in which either of both isoforms of the human H(+)-ATPase B subunit (56 kD) were expressed. These findings demonstrate that the spectrum of dRTA includes the preservation of H(+)-ATPase in intercalated cells, in patients with presumed voltage defect dRTA. Moreover, some patients may have autoantibodies to the intercalated cells that are not directed to subunits of the H(+)-ATPase.

scholarly journals Idiopathic hypokalemia in lupus nephritis - A newly recognized entity

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0004352021
Author(s):  
Emmanuel A. Adomako ◽  
Saira Bilal ◽  
Yu-lun Liu ◽  
Ayesha Malik ◽  
Peter N. Van Buren ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Renal Tubular Acidosis ◽  
Serum Potassium ◽  
Serum Magnesium ◽  
Distinct Pattern ◽  
Distal Renal Tubular Acidosis ◽  
Urine Ph ◽  
Median Serum ◽  
Novel Target ◽  
Renal Tubular

Background:Various causes of hypokalemia from renal potassium wasting, including distal renal tubular acidosis, have been described in lupus nephritis (LN). We report a phenomenon of otherwise unexplained hypokalemia among a population with LN. Methods:From our population of 403 patients with LN, we identified a cohort of 20 patients with idiopathic hypokalemia (HK), defined by serum potassium < 3.5 mmol/L without any apparent explanation. This cohort is compared to 90 LN controls (CON) and 10 LN patients with distal renal tubular acidosis (RTA) from the same population. Results:The HK cases had lower median serum potassium compared to CON and RTA subjects (3.26 vs 4.00 vs 3.75 mmol/L, respectively; p < 0.001). The median serum bicarbonate was normal in HK and CON but low in RTA (26.0 vs 25.0 vs 19.4 mmol/L; p < 0.001). The median urine pH was abnormally high only in the RTA group (6.00 vs 6.25 vs 6.67; p = 0.012). The median serum magnesium was modestly lower in HK compared to the CON and RTA groups (1.73 vs 2.00 vs 1.85 mg/dL; p = 0.002). While both HK and RTA showed a higher rate of seropositivity than CON for anti-Ro/SSA (79% and 80% vs 37%, respectively; p < 0.001), only HK revealed a higher rate of seropositivity than CON for anti-RNP (84% vs 42%; p = 0.003) and only RTA showed a higher rate of seropositivity than CON for anti-La/SSB (40% vs 12%; p = 0.046). Conclusions:A syndrome of idiopathic hypokalemia was revealed in 20/403 (5%) of patients within our LN population and proved to be distinct from the renal tubular acidosis that occurs in LN. Furthermore, it was associated with a distinct pattern of autoantibodies. We speculate that idiopathic hypokalemia is the result of a novel target of autoimmunity in LN affecting renal tubular potassium transport.

scholarly journals Absence of vacuolar H(+)-ATPase pump in the collecting duct of a patient with hypokalemic distal renal tubular acidosis and Sjögren's syndrome.

1995 ◽  
Vol 6 (2) ◽  
pp. 295-301
Author(s):  
P E DeFranco ◽  
L Haragsim ◽  
P G Schmitz ◽  
B Bastani
Keyword(s):  
Renal Biopsy ◽  
Renal Tubular Acidosis ◽  
Collecting Duct ◽  
Band 3 ◽  
Distal Renal Tubular Acidosis ◽  
Hydrogen Ion ◽  
Intercalated Cells ◽  
Band 3 Protein ◽  
Ion Secretion ◽  
Renal Tubular

Distal renal tubular acidosis (dRTA) is a common complication of autoimmune connective tissue diseases. The underlying pathophysiology of renal tubular acidosis in these syndromes is frequently characterized by impaired hydrogen ion secretion, i.e., secretory defect dRTA. However, the precise molecular events leading to this disturbance remain poorly understood. An opportunity was recently afforded to examine the ultrastructural features of the collecting duct in a patient with Sjögren's syndrome and secretory defect dRTA. Immunocytochemical analysis of a renal biopsy obtained 12 months after the patient's initial presentation demonstrated a complete absence of vacuolar H(+)-ATPase in the collecting duct. Antibodies to the 31- and 56-kd kidney-specific subunits of the H(+)-ATPase pump were used to characterize pump distribution. Interestingly, although antiserum to the CI-:HCO3- anion exchanger (band-3 protein) reacted strongly with normal human kidney and the patient's red blood cells, no immunoreactivity was observed in the patient's collecting duct epithelium. Importantly, electron microscopy of the patient's renal biopsy specimen disclosed cells that ultrastructurally were indistinguishable from intercalated cells. These results suggest that the functional basis of impaired hydrogen ion secretion in this patient was secondary to the absence of intact H(+)-ATPase pumps rather than defective pump function or distribution. The presence of intercalated cells ultrastructurally, but the absence of discernible staining for band-3 protein and H(+)-ATPase, also suggests that the defect in proton secretion may represent a defect involving the assembly of at least two of the ion transport pumps essential for the normal maintenance of acid-base homeostasis by the intercalated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Inherited Proximal and Distal Renal Tubular Acidosis

2017 ◽  
Author(s):  
Patricia Valles ◽  
Jesus Moran-Farias ◽  
Daniel Batlle
Keyword(s):  
Metabolic Acidosis ◽  
Renal Tubular Acidosis ◽  
Distal Renal Tubular Acidosis ◽  
Anion Gap ◽  
Intercalated Cells ◽  
Acid Excretion ◽  
Acid Base ◽  
Urine Ph ◽  
Renal Tubular ◽  
Net Acid Excretion

Acid-base homeostasis by the kidney is maintained through proximal tubular reclamation of filtered bicarbonate and the excretion of the daily acid load by collecting duct type A intercalated cells. The impairment of either process results in renal tubular acidosis (RTA), a group of disorders characterized by a reduced net acid excretion and a persistent hyperchloremic, non–anion gap metabolic acidosis. The primary or hereditary forms of proximal (pRTA) and distal renal tubular acidosis (dRTA) have received increased attention because of advances in the understanding of the molecular mechanism, whereby mutations in the main proteins involved in acid-base transport result in either reduced bicarbonate reabsorption or reduced H+ secretion and impaired acid excretion. dRTA is characterized by reduced net acid excretion and an inability to lower urine pH despite severe acidemia (but minimal HCO3– wastage). pRTA (type 2), by contrast, is characterized by marked HCO3– wastage but preserved ability to lower urine pH when plasma HCO3– (and therefore filtered HCO3–) is below a certain threshold. In children with dRTA, growth retardation caused by chronic metabolic acidosis is the key manifestation but is fully reversible with appropriate alkali therapy if initiated early in life. A striking manifestation of many patients with dRTA is the development of severe hypokalemia that may cause muscle paralysis. In this review, we discuss these types of hereditary RTA and the mechanisms involved in the genesis of these inherited tubular disorders. This review contains 5 figures, 1 table, and 103 references. Key words: Proximal renal tubular acidosis (pRTA), Distal renal tubular acidosis (dRTA), Hyperchloremic, non–anion gap metabolic acidosis, Hypokalemia, Fractional HCO3– excretion, Urinary gap, Fanconi Syndrome.ATP6V1B1 and ATP6V0A4 gene mutations . Intercalated cells ,

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

2005 ◽  
Vol 288 (1) ◽  
pp. F40-F47 ◽  
Author(s):  
Seiji Watanabe ◽  
Shuichi Tsuruoka ◽  
Soundarapandian Vijayakumar ◽  
Gunter Fischer ◽  
Yixin Zhang ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Renal Tubular Acidosis ◽  
Cyclophilin A ◽  
Distal Renal Tubular Acidosis ◽  
Apical Surface ◽  
Intercalated Cells ◽  
Ppiase Activity ◽  
Fk 506 ◽  
Isomerase Activity ◽  
Renal Tubular

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 HCO3− transport and changes in β-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 β-intercalated cells by extracellular deposition of hensin ( J Clin Invest 109: 89, 2002). Here, CsA prevented this adaptation. The unidirectional HCO3− 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 HCO3− secretion and apical Cl−:HCO3− 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 HCO3− 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−:HCO3− exchange. Acid incubation resulted in prominent “clumpy” staining of extracellular hensin and diminished apical surface of β-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 β-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.

scholarly journals Acidosis and Deafness in Patients with Recessive Mutations in FOXI1

2017 ◽  
Vol 29 (3) ◽  
pp. 1041-1048 ◽  
Author(s):  
Sven Enerbäck ◽  
Daniel Nilsson ◽  
Noel Edwards ◽  
Mikael Heglind ◽  
Sumaya Alkanderi ◽  
...  
Keyword(s):  
Dna Binding ◽  
Inner Ear ◽  
Renal Tubular Acidosis ◽  
Cultured Cells ◽  
Collecting Duct ◽  
Sensorineural Deafness ◽  
Distal Renal Tubular Acidosis ◽  
Acid Base ◽  
Recessive Mutations ◽  
Renal Tubular

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.

scholarly journals Incomplete distal renal tubular acidosis from a heterozygous mutation of the V-ATPase B1 subunit

2014 ◽  
Vol 307 (9) ◽  
pp. F1063-F1071 ◽  
Author(s):  
Jianning Zhang ◽  
Daniel G. Fuster ◽  
Mary Ann Cameron ◽  
Henry Quiñones ◽  
Carolyn Griffith ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Renal Tubular Acidosis ◽  
Distal Renal Tubular Acidosis ◽  
Heterozygous Mutation ◽  
Wild Type ◽  
Urine Ph ◽  
293 Cells ◽  
Heterozygous Carriers ◽  
Renal Tubular ◽  
Negative Dominance

Congenital distal renal tubular acidosis (RTA) from mutations of the B1 subunit of V-ATPase is considered an autosomal recessive disease. We analyzed a distal RTA kindred with a truncation mutation of B1 (p.Phe468fsX487) previously shown to have failure of assembly into the V1domain of V-ATPase. All heterozygous carriers in this kindred have normal plasma HCO3−concentrations and thus evaded the diagnosis of RTA. However, inappropriately high urine pH, hypocitraturia, and hypercalciuria were present either individually or in combination in the heterozygotes at baseline. Two of the heterozygotes studied also had inappropriate urinary acidification with acute ammonium chloride loading and an impaired urine-blood Pco2gradient during bicarbonaturia, indicating the presence of a H+gradient and flux defects. In normal human renal papillae, wild-type B1 is located primarily on the plasma membrane, but papilla from one of the heterozygote who had kidney stones but not nephrocalcinosis showed B1 in both the plasma membrane as well as diffuse intracellular staining. Titration of increasing amounts of the mutant B1 subunit did not exhibit negative dominance over the expression, cellular distribution, or H+pump activity of wild-type B1 in mammalian human embryonic kidney-293 cells and in V-ATPase-deficient Saccharomyces cerevisiae. This is the first demonstration of renal acidification defects and nephrolithiasis in heterozygous carriers of a mutant B1 subunit that cannot be attributable to negative dominance. We propose that heterozygosity may lead to mild real acidification defects due to haploinsufficiency. B1 heterozygosity should be considered in patients with calcium nephrolithiasis and urinary abnormalities such as alkalinuria or hypocitraturia.

scholarly journals Deletion of hensin/DMBT1 blocks conversion of  - to  -intercalated cells and induces distal renal tubular acidosis

2010 ◽  
Vol 107 (50) ◽  
pp. 21872-21877 ◽  
Author(s):  
X. Gao ◽  
D. Eladari ◽  
F. Leviel ◽  
B. Y. Tew ◽  
C. Miro-Julia ◽  
...  
Keyword(s):  
Renal Tubular Acidosis ◽  
Distal Renal Tubular Acidosis ◽  
Intercalated Cells ◽  
Renal Tubular

scholarly journals Results of a Gene Panel Approach in a Cohort of Patients with Incomplete Distal Renal Tubular Acidosis and Nephrolithiasis

2021 ◽  
pp. 1-6
Author(s):  
Viola D’Ambrosio ◽  
Alessia Azzarà ◽  
Eugenio Sangiorgi ◽  
Fiorella Gurrieri ◽  
Bernhard Hess ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Genetic Testing ◽  
Renal Tubular Acidosis ◽  
Distal Renal Tubular Acidosis ◽  
Tubular Dysfunction ◽  
Urine Ph ◽  
Cross Sectional ◽  
Urinary Acidification ◽  
Stone Formers ◽  
Renal Tubular

<b><i>Background:</i></b> Distal renal tubular acidosis (dRTA) is characterized by an impairment of urinary acidification resulting in metabolic acidosis, hypokalemia, and inappropriately elevated urine pH. If not treated, this chronic condition eventually leads to nephrocalcinosis, nephrolithiasis, impaired renal function, and bone demineralization. dRTA is a well-defined entity that can be diagnosed by genetic testing of 5 genes known to be disease-causative. Incomplete dRTA (idRTA) is defined as impaired urinary acidification that does not lead to overt metabolic acidosis and therefore can be diagnosed if patients fail to adequately acidify urine after an ammonium chloride (NH<sub>4</sub>Cl) challenge or furosemide and fludrocortisone test. It is still uncertain whether idRTA represents a distinct entity or is part of the dRTA spectrum and whether it is caused by mutations in the same genes of overt dRTA. <b><i>Methods:</i></b> In this cross-sectional study, we investigated a group of 22 stone formers whose clinical features were suspicious of idRTA. They underwent an NH<sub>4</sub>Cl challenge and were found to have impaired urinary acidification ability. These patients were then analyzed by genetic testing with sequencing of 5 genes: <i>SLC4A1</i>, <i>ATP6V1B1</i>, <i>ATP6V0A4</i>, <i>FOXI1</i>, and <i>WDR72</i>. <b><i>Results:</i></b> Two unrelated individuals were found to have two different variants in <i>SLC4A1</i> that had never been described before. <b><i>Conclusions:</i></b> Our results suggest the involvement of other genes or nongenetic tubular dysfunction in the pathogenesis of idRTA in stone formers. However, genetic testing may represent a cost-effective tool to recognize, treat, and prevent complications in these patients.

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