Forms Of dRTA Research Articles

#2830 Treatment of primary and secondary distal renal tubular acidosis with a prolonged release formulation of potassium citrate and potassium bicarbonate

Abstract Background and Aims Distal renal tubular acidosis (dRTA) is a rare kidney disease. It can be inherited, i.e. primary (PdRTA), or acquired i.e. secondary (SdRTA). Secondary dRTA is more prevalent in the adult population and is usually caused by underlying autoimmune diseases (e.g. Sjogren syndrome). Both forms of dRTA are characterized by alkaline urine, kidney stone formation, nephrocalcinosis, chronic kidney disease, while metabolic acidosis can be variable. The treatment is based on the substitution of alkali substances. Our clinical study aims to describe a cohort of adult dRTA patients (both PdRTA and SdRTA) treated for 18 months by a prolonged-release alkalizing formulation of potassium citrate and potassium bicarbonate, in terms of electrolyte disbalance correction, metabolic control, nephrolithiasis complications and kidney function. Method Data from seven patients with dRTA (3 with PdRTA and 4 with SdRTA, mean age 44 years, women 71%) taking prolonged-release alkalizing formulation of potassium citrate and potassium bicarbonate in our center, were retrospectively collected and analyzed. The patients were previously treated with alkalizing agents (mostly sodium bicarbonate and potassium citrate). Patients were followed up for up to 18 months after inducing prolonged-release alkalizing formulation of potassium citrate and potassium bicarbonate was introduced. Kidney function, metabolic acidosis control (serum bicarbonate), serum electrolytes, urinary calcium excretion, and urinary citrate were measured. Nephrolithiasis complications and patient compliance were also evaluated. The urine and blood samples were analyzed two weeks after introducing the new drug and every 3 months afterward. Data are presented as mean ± standard error of the mean. Student T-test was used to calculate p values. Results The patients were taking on average 48 mEq of the drug (range 32-72 mEq), the dosage remained the same during the follow-up period (p = 0.365). The average follow-up period was 10 months (range 3-18 months). The metabolic acidosis was well controlled (serum bicarbonate was 24 ± 1.71 mmol/l at baseline, 24.4 ± 1.5 mmol/l at the end of follow-up, p = 0.680). Kidney function remained stable (GFR 73.5 ± 22.67 ml/min/1.73 m2 at baseline, 73 ± 22.69 ml/min/1.73 m2 at the end, p = 0.977). Serum potassium was also well controlled (4.07 ± 0.45 mmol/l at baseline, 4.32 ± 0.40 mmol/l at the end, p = 0.344), as well as calcium in 24-hour urine (2.75 ± 0.59 mmol/24-hour urine at baseline, 2.35 ± 0.12 mmol/24-hour urine at the end, p = 0.222). Urinary citrate levels (calculated as citrate/creatinine ratio) remained in the lower part of the reference range during the follow-up period (103.3 ± 68.3 mmol/mol at baseline, 114.6 ± 64.9 mmol/l at the end, p = 0.775). Two patients had acute renal colic caused by nephrolithiasis, without the need for surgical intervention. Safety and adherence to treatment remained good with no gastrointestinal side effects, one patient discontinued the drug due to headaches. Conclusion Our data show that treatment with a prolonged-release alkalizing formulation of potassium citrate and potassium bicarbonate in adult dRTA patients can achieve good control of metabolic acidosis and electrolyte disbalance with stable kidney function without the need to escalate the dose of the drug during the follow-up period. The adherence to the treatment remained good with no gastrointestinal side effects.

Genotypic analysis of SLC4A1 A858D mutation in Indian population associated with distal renal tubular Acidosis (dRTA) coupled with hemolytic anemia.

Although distinctive, distal renal tubular acidosis (dRTA) and Hereditary Spherocytosis (HS) shares a common protein, the anion exchanger1 (AE1) encoded by SLC4A1gene. In spite of this, the co-existence of dRTA and HS has rarely been observed. To date, 23 mutations have been identified in SLC4A1 gene causing both autosomal recessive (AR) and autosomal dominant (AD) forms of dRTA. We have assessed the applicability of the High Resolution Melting curve (HRM) method for the detection of SLC4A1 (A858D) mutation in 12 Indian families having AR dRTA coupled with HS. The reliability of the HRM analysis was verified by comparing the results of the HRM method with those of conventional methods such as Polymerase Chain Reaction-Restriction Fragment-Length Polymorphism (PCR-RFLP) and Sanger sequencing thereby confirming the diagnosis. We here described the clinical, hematological and genetic data of 16 individuals from 12 families having AR dRTA coupled with HS. All patients carried homozygous SLC4A1 (A858D) mutation, whereas their family members had heterozygous A858D obtained by HRM analysis and confirmed by RFLP and Sanger sequencing. Our data indicates that a missense mutation of A858D in SLC4A1 gene is the most common cause of dRTA coupled with HS in the Indian population. HRM analysis can be used as a rapid screening method for common SLC4A1 mutations that cause AR dRTA in the Indian population.

Deficiency in NBCe2 causes distal renal tubular acidosis (891.2)

The pathogenesis of distal renal tubular acidosis (dRTA) is not fully understood. Here we show that the electrogenic Na/HCO3 cotransporter NBCe2 is involved in the pathophysiology of dRTA by reabsorbing HCO3 in the collecting duct (CD). NBCe2 knockout (KO) and wild type (WT) mice were fed with acid water for 7‐10 days and placed in metabolic cages. Immunohistochemistry (IHC) and Western blot were used to examine the expressions of NBCe2 and H‐ATPase B1 in the kidneys. IHC showed NBCe2 was expressed mostly at the apical membrane of Type A intercalated cells (α‐IC) of the CD. The H‐ATPase B1 expression was higher in the plasma membrane of α‐IC in NBCe2 KO than WT, suggesting compensation for NBCe2 defect. As compared with WT, NBCe2‐KO exhibited significantly lower plasma pH, [HCO3] and [K], while the urine pH, K clearance and transtubular K gradient were increased. NBCe2 expression was also examined in cultured MDCK‐C11 cells by immunocytochemistry (ICC), which showed that NBCe2 was expressed selectively at the apical membrane in C11 cells. The intracellular pH (pHi) recovery rate in C11 cells was recorded using BCECF. Knocking down of NBCe2 expression by siRNA significantly decreased the pHi recovery rate in C11 cells. In conclusion, NBCe2 plays an important role in reabsorbing HCO3 in the CD. NBCe2 deficiency leads to hypokalemic acidosis and is another form of dRTA.Grant Funding Source: NIDDK

Acidose tubulaire rénale distale primitive

Renal tubular acidosis are forms of metabolic acidosis characterized by an impairment of urinary acidification due to a lack of urine excretion of protons or loss of bicarbonates. Primary distal renal acidosis (dRTA) is characterized by hyperchloremic metabolic acidosis due to failure in proton excretion, variably severe nephrocalcinosis and/or nephrolithiasis associated with hypercalciuria and hypocitraturia. When the metabolic acidosis is compensated, dRTA can be diagnosed by the failure of urinary acidification after oral ammonium chloride or furosemide administration. dRTA is inherited as either an autosomal dominant or autosomal recessive trait. An autosomal dominant form results from a SLC4A1 gene mutation leading to dysfunction of the anionic exchanger type 1 (AE1). Otherwise, recessive forms are due to mutations of ATP6V1B1 gene encoding the B1-subunit of H+-ATPase expressed in the apical membrane of the alpha intercalated cells in collecting duct and in the cochlea. Those mutations lead to dRTA accompanied by sensorineural deafness. Also, mutations in ATP6V0A4 gene encode the accessory subunit a4 of the H+ATPase, leading to recessive forms of dRTA with preserved hearing or delayed signs of deafness. Molecular approach can identify mutations which are responsible for this pathology. The medical treatment is simple and involves an alkali load which allows curing the metabolic acidosis. Long-term outcome is usually good unless the patient's compliance is low or alkalizing treatment is insufficient.

Defective kidney anion-exchanger 1 (AE1, Band 3) trafficking in dominant distal renal tubular acidosis (dRTA).

dRTA (distal renal tubular acidosis) results from the failure of the a-intercalated cells in the distal tubule of the nephron to acidify the urine. A truncated form of AE1 (anion-exchanger 1; Band 3), kAE1 (kidney isoform of AE1), is located in the basolateral membrane of the intercalated cell. Mutations in the AE1 gene cause autosomal dominant and recessive forms of dRTA. All the dominant dRTA mutations investigated cause aberrant trafficking of kAE1, resulting in its intracellular retention or mistargeting to the apical plasma membrane. Therefore the intracellular retention of hetero-oligomers containing wild-type and dRTA mutants, or the mistargeted protein in the apical membrane neutralizing acid secretion, explains dominant dRTA. The kAE1 (Arg(901)-->stop) mutant has been studied in more detail, since the mistargeting kAE1 (Arg(901)-->stop) from the basolateral to the apical membrane is consistent with the removal of a basolateral localization signal. The C-terminal amino acids deleted by the Arg(901)-->stop mutation, contain a tyrosine motif and a type II PDZ interaction domain. The tyrosine residue (Tyr(904)), but not the PDZ domain, is critical for basolateral localization. In the absence of the N-terminus of kAE1, the C-terminus was not sufficient to localize kAE1 to the basolateral membrane. This suggests that a determinant within the kAE1 N-terminus co-operates with the C-terminus for kAE1 basolateral localization. Interestingly, Tyr(359), in the N-terminal domain, and Tyr(904) in the C-terminus of AE1 are phosphorylated in red blood cells. A potential scheme is suggested where successive phosphorylation of these residues is necessary for correct localization and recycling of kAE1 to the basolateral membrane.

Defects in processing and trafficking of the AE1 Cl-/HCO3- exchanger associated with inherited distal renal tubular acidosis.

Distal renal tubular acidosis (dRTA) results from impaired urinary acidification by the renal collecting duct. Acquired dRTA can be secondary to diverse pathological processes, including diabetic, ischemic, fibrosing, or immunological processes; less frequently it presents as a familial disorder with either an autosomal recessive or dominant pattern of transmission. Mutations in the SLC4A1/AE1/band 3 Cl(-)/HCO(3)(-) exchanger gene have been identified as causes for both dominant and recessive forms of dRTA. These mutations comprise a group almost entirely distinct from the SLC4A1 mutations that underlie the familial hemolytic anemia of hereditary spherocytosis. Why does one group of mutations express almost exclusively an isolated erythroid phenotype, whereas the second group of mutations expresses almost exclusively a phenotype explicable entirely by defective function of renal collecting duct type A intercalated cells? This review summarizes current research addressing this central question in the pathobiology of inherited dRTA associated with mutations in the SLC4A1 gene. Studying dRTA-associated mutant AE1 polypeptides can provide novel insights into the biology of the intercalated cell and the collecting duct as well as more generally into mechanisms by which epithelial cells generate and maintain functional polarity.

The association between familial distal renal tubular acidosis and mutations in the red cell anion exchanger (band 3, AE1) gene

In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen ion in the distal nephron is impaired, leading to the development of metabolic acidosis, frequently accompanied by hypokalemia, nephrocalcinosis, and metabolic bone disease. The condition can be familial, when it is usually inherited as an autosomal dominant, though there is a rarer autosomal recessive form associated with nerve deafness. It has been shown that the autosomal dominant form of dRTA is associated with a defect in the anion exchanger (AE1) of the renal collecting duct intercalated cell. This transporter is a product of the same gene (AE1) as the erythrocyte anion exchanger, band 3. In this review we will look at the evidence for this association. Studies of genomic DNA from families with this disorder have shown, both by genetic linkage studies and by DNA sequencing, that affected individuals are heterozygous for mutations in the AE1 gene whilst unaffected family members have a normal band 3 sequence. Mutations have been found in the region of proposed helices 6 and 7 of the membrane domain of band 3 and involve amino acids Arg-589 and Ser-613, and in the COOH-terminal domain of band 3. Studies of red cell band 3 from these families have provided information on the effect these mutations have on the structure and function of erythrocyte band 3. Expression studies of the erythroid and kidney isoforms of the mutant AE1 proteins, in Xenopus laevis oocytes, have shown that they retained chloride transport activity, suggesting that the disease in the dRTA families is not related simply to the anion transport activity of the mutated proteins. A possible explanation for the dominant effect of these mutant AE1 proteins in the kidney cell is that these mutations affect the targeting of AE1 from the basolateral to the apical membrane of the alpha-intercalated cell.Key words: erythrocyte, kidney, acidosis.

The association between familial distal renal tubular acidosis and mutations in the red cell anion exchanger (band 3, AE1) gene.

In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen ion in the distal nephron is impaired, leading to the development of metabolic acidosis, frequently accompanied by hypokalemia, nephrocalcinosis, and metabolic bone disease. The condition can be familial, when it is usually inherited as an autosomal dominant, though there is a rarer autosomal recessive form associated with nerve deafness. It has been shown that the autosomal dominant form of dRTA is associated with a defect in the anion exchanger (AE1) of the renal collecting duct intercalated cell. This transporter is a product of the same gene (AE1) as the erythrocyte anion exchanger, band 3. In this review we will look at the evidence for this association. Studies of genomic DNA from families with this disorder have shown, both by genetic linkage studies and by DNA sequencing, that affected individuals are heterozygous for mutations in the AE1 gene whilst unaffected family members have a normal band 3 sequence. Mutations have been found in the region of proposed helices 6 and 7 of the membrane domain of band 3 and involve amino acids Arg-589 and Ser-613, and in the COOH-terminal domain of band 3. Studies of red cell band 3 from these families have provided information on the effect these mutations have on the structure and function of erythrocyte band 3. Expression studies of the erythroid and kidney isoforms of the mutant AE1 proteins, in Xenopus laevis oocytes, have shown that they retained chloride transport activity, suggesting that the disease in the dRTA families is not related simply to the anion transport activity of the mutated proteins. A possible explanation for the dominant effect of these mutant AE1 proteins in the kidney cell is that these mutations affect the targeting of AE1 from the basolateral to the apical membrane of the alpha-intercalated cell.