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Renal tubular acidosis [keywords]
- Impaired expression of key molecules of ammoniagenesis underlies renal acidosis in a rat model of chronic kidney disease. [JOURNAL ARTICLE]
- Nephrol Dial Transplant 2014 Dec 18.
Advanced chronic kidney disease (CKD) is associated with the development of renal metabolic acidosis. Metabolic acidosis per se may represent a trigger for progression of CKD. Renal acidosis of CKD is characterized by low urinary ammonium excretion with preserved urinary acidification indicating a defect in renal ammoniagenesis, ammonia excretion or both. The underlying molecular mechanisms, however, have not been addressed to date.We examined the Han:SPRD rat model and used a combination of metabolic studies, mRNA and protein analysis of renal molecules involved in acid-base handling.We demonstrate that rats with reduced kidney function as evident from lower creatinine clearance, lower haematocrit, higher plasma blood urea nitrogen, creatinine, phosphate and potassium had metabolic acidosis that could be aggravated by HCl acid loading. Urinary ammonium excretion was highly reduced whereas urinary pH was more acidic in CKD compared with control animals. The abundance of key enzymes and transporters of proximal tubular ammoniagenesis (phosphate-dependent glutaminase, PEPCK and SNAT3) and bicarbonate transport (NBCe1) was reduced in CKD compared with control animals. In the collecting duct, normal expression of the B1 H(+)-ATPase subunit is in agreement with low urinary pH. In contrast, the RhCG ammonia transporter, critical for the final secretion of ammonia into urine was strongly down-regulated in CKD animals.In the Han:SPRD rat model for CKD, key molecules required for renal ammoniagenesis and ammonia excretion are highly down-regulated providing a possible molecular explanation for the development and maintenance of renal acidosis in CKD patients.
- Mutations in exons 3 and 7 resulting in truncated expression of human ATP6V1B1 gene showing structural variations contributing to poor substrate binding- causative reason for distal renal tubular acidosis with sensorineural deafness. [JOURNAL ARTICLE]
- J Biomol Struct Dyn 2014 Dec 17.:1-29.
Abstract Distal renal tubular acidosis (dRTA) is an Autosomal recessive syndrome results defect in either proximal tubule bicarbonate reabsorption or in distal tubule H(+) secretion and is characterized by severe hyperchloraemic metabolic acidosis in childhood. dRTA is associated with functional variations in the ATP6V1B1 gene encoding β1 subunit of H(+) -ATPase, key membrane transporters for net acid excretion of α-intercalated cells of medullary collecting ducts. In the present study a 13 year old male patient suffering with nephropathy and sensorineural deafness was reported in the Department of Nephrology. We predicted improper functioning of ATP6V1B1 gene could be the reason for diseased condition. Therefore, exon 3, 4 and 7 contributing active site of ATP6V1B1 gene was amplified and sequenced (Accession number: KF571726, KM222653). The obtained sequence was BLAST searched against the wild type ATP6V1B1 gene which showed novel mutations c.307 A > G, c.308 C > A, c.310 C > G, c.704 T > C, c.705 G > T, c.709 A > G, c.710 A > G, c.714 G > A, c.716 C > A, c.717delC, c.722 C > G, c.728insG, c.741insT, c.753G > C. These mutations resulted in the expression of truncated protein terminating at Lys 209. The mutated ATP6V1B1structure was superimposed with wild type showed extensive variations with RMSD 1.336 Å and could not bind to substrate ADP leading to non functional ATPase. These results conclusively explain these mutations in ATP6V1B1 gene resulted in structural changes causing accumulation of H(+) ions contributing to dRTA with sensorineural deafness.
- [Rhabdomyolysis: role of the nephrologist]. [English Abstract, Journal Article]
- G Ital Nefrol 2014 Nov-Dec; 31(6)
Rhabdomyolysis is characterized by skeletal muscle necrosis resulting in release of large amounts of toxic muscle cell components, including electrolytes, myoglobin, and other sarcoplasmic proteins into circulation. Creatinine phosphokinase (CPK) and myoglobin serum levels constitute the diagnostic hallmark. Nowadays, drugs have become one of the most frequent cause of rhabdomyolysis and acute kidney injury (AKI) is a potential life-threatening complication. The mechanisms involved in the development of AKI in rhabdomyolysis are intrarenal vasoconstriction, direct and ischemic tubule injury and tubular obstruction. According to some clinical series, the mortality rate in patients who develop AKI due to rhabdomyolysis is highly variable. The cornerstone in managing this condition is the early, aggressive repletion of fluids. The composition of replacement fluid remains controversial. Saline and sodium bicarbonate, especially in patients with metabolic acidosis, seem to be a reasonable approach. When AKI produces refractory hyperkalemia, acidosis or volume overload, renal replacement therapy is indicated.
- Effects of chronic lithium administration on renal acid excretion in humans and rats. [Journal Article]
- Physiol Rep 2014 Dec 1; 2(12)
Lithium therapy's most common side effects affecting the kidney are nephrogenic diabetes insipidus (NDI) and chronic kidney disease. Lithium may also induce a distal renal tubular acidosis. This study investigated the effect of chronic lithium exposure on renal acid-base homeostasis, with emphasis on ammonia and citrate excretion. We compared 11 individuals on long-term lithium therapy with six healthy individuals. Under basal conditions, lithium-treated individuals excreted significantly more urinary ammonia than did control subjects. Following an acute acid load, urinary ammonia excretion increased approximately twofold above basal rates in both lithium-treated and control humans. There were no significant differences between lithium-treated and control subjects in urinary pH or urinary citrate excretion. To elucidate possible mechanisms, rats were randomized to diets containing lithium or regular diet for 6 months. Similar to humans, basal ammonia excretion was significantly higher in lithium-treated rats; in addition, urinary citrate excretion was also significantly greater. There were no differences in urinary pH. Expression of the critical ammonia transporter, Rhesus C Glycoprotein (Rhcg), was substantially greater in lithium-treated rats than in control rats. We conclude that chronic lithium exposure increases renal ammonia excretion through mechanisms independent of urinary pH and likely to involve increased collecting duct ammonia secretion via the ammonia transporter, Rhcg.
- Calcium phosphate stone morphology can reliably predict distal renal tubular acidosis. [JOURNAL ARTICLE]
- J Urol 2014 Dec 10.
Calcium stones account for 85-90% of all urinary calculi including a variety of crystalline composition and etiologic conditions. Calcium phosphate (CaP) account for 10-15% of cases. They are mainly related to three groups of risk factors: calcium or phosphate metabolism disturbance, renal acidification defects and urinary tract infection. Identifying the stone etiology often requires extensive metabolic evaluation. We assessed whether stone analysis including morphological typing in addition to stone composition could be a valuable help for the diagnosis.Among 60,564 stones analysed by morphological examination and infrared spectroscopy in our laboratory, 6439 (10.6%) were mainly composed of carbapatite. Among them, we included 1093 patients with available etiological diagnosis and stones containing at least 70% of calcium phosphate without struvite.Among the 1093 CaP stones, 12.8% exhibited a peculiar morphology, termed IVa2, characterized by a smooth aspect, a glazed brown-yellow appearance with tiny cracks, which was associated to inherited distal renal tubular acidosis (dRTA) in 96.1% of cases. By contrast, the other stones, showing similar composition, but different morphology, were related to dRTA in only 3.9% of cases. In addition, IVa2 stones were found in 65% of CaP stones associated to Sjögren syndrome and in 35% of CaP stones found in medullary sponge kidney patients, two conditions related with mild to moderate distal acidification defect.Recognition of IVa2 stone morphology is clinically relevant as it should prompt clinicians to search for a complete or incomplete distal acidosis in order to initiate specific therapy to reduce recurrence.
- Investigation of ATP6V1B1 and ATP6V0A4 genes causing hereditary hearing loss associated with distal renal tubular acidosis in Iranian families. [Journal Article]
- J Laryngol Otol 2014 Dec; 128(12):1056-9.
Hearing defects are the most common sensory disorders, affecting 1 out of every 500 newborns. ATP6V1B mutations are associated with early sensorineural hearing loss, whereas ATP6V0A4 mutations are classically associated with either late-onset sensorineural hearing loss or normal hearing. ATP6V1B1 and ATP6V0A4 genetic mutations cause recessive forms of distal renal tubular acidosis.Ten unrelated deaf Iranian families with distal renal tubular acidosis were referred to the Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran. All exons of the ATP6V1B1 and ATP6V0A4 genes were sequenced in affected family members.We identified a previously reported ATP6V1B1 frameshift mutation (P385fsX441) in two families and a nucleotide substitution in exon 10 (P346R) in three families. In addition, one patient was homozygous for a novel nucleotide substitution in exon 3.ATP6V1B1 genetic mutations were detected in more than half of the families studied. Mutations in this gene therefore seem to be the most common causative factors in hearing loss associated with distal renal tubular acidosis in these families.
- Inhibitory effect of atenolol on urinary excretion of metformin via down-regulating multidrug and toxin extrusion protein 1 (rMate1) expression in the kidney of rats. [JOURNAL ARTICLE]
- Eur J Pharm Sci 2014 Dec 5.
Renal tubular secretion is an important pathway for the elimination of many clinically used drugs. Metformin, a commonly prescribed first-line antidiabetic drug, is secreted primarily by the renal tubule. Many patients with type 2 diabetes mellitus (T2DM) receiving metformin may together be given selective β1 blockers (e.g., atenolol). Therefore, it is of great use to evaluate the effect of atenolol on metformin urinary excretion for exploring drug interactions and predicting the adverse effect of drugs. The aim of this study was to investigate the effect of atenolol on the pharmacokinetic of metformin and plasma lactate (LCA) level in rats, for high LCA is a serious adverse reaction ofmetformin after long-term metformin treatment. In this study, rats were treated with metformin alone or in combination with atenolol. Plasma, urine and tissue concentration of metformin was determined by HPLC method, while Western blotting and immunohistochemical analysis were used to evaluate the renal expression of rat organic cation transporter 2 (rOct2) and multidrug and toxin extrusion protein 1 (rMate1). The results showed that, after 7days drug treatment, the AUC0→t of metformin in atenolol and metformin co-administration group was significantly increased by 19.5% compared to that in metformin group, while the 24h cumulative urinary excretion of metformin was significantly decreased by 57.3%. In addition, atenolol treatment significantly decreased the renal expression of rMate1, but had no effect on rOct2 expression, renal blood perfusion and glomerular filtration. Moreover, plasma LCA level in atenolol and metformin co-administration group rats was significantly increased by 83.3% compared to that in metformin group after 60days drug treatment. These results indicated that atenolol can inhibit urinary excretion of metformin via decreasing renal rMate1 expression, and long-term atenolol and metformin co-administration may induce potential lactic acidosis. Our results, for the first time, provided an important experimental evidence that rMate1 is the target of transporter-mediated drug interactions concerning metformin and atenolol.
- Clinical profile and outcome of renal tubular disorders in children: A single center experience. [Journal Article]
- Indian J Nephrol 2014 Nov; 24(6):362-6.
Tubular disorders form a significant proportion of pediatric kidney diseases and are an important differential diagnosis of failure to thrive (FTT) in children. Data regarding their outcome is scarce from India. We evaluated the clinical profile of these children and studied the outcome in terms of their growth and renal failure. This is a retrospective longitudinal study of all children with renal tubular disorders attending a tertiary care pediatric nephrology center from 2005 to 2010. Growth and renal outcomes were assessed by Z scores and estimated glomerular filtration rate at diagnosis and. The common disorders encountered were distal renal tubular acidosis (d-RTA) (44%), Bartter-like (Bartter's and Gitelman) syndromes (22%) followed by hereditary Fanconi syndrome (cystinosis and idiopathic Fanconi syndrome) (13%) and few cases of nephrogenic diabetes insipidus, hypophosphatemic rickets and idiopathic hypercalciuria. Male: female ratio was 1.22. The median age at diagnosis was 1.5 (range 0.13-11) years. Growth failure was the presenting feature in 86% of children followed by polyuria (60%) and bone deformities (47%). In 60% of children with hereditary Fanconi syndrome, nephropathic cystinosis was diagnosed, all of whom progressed to stage III chronic kidney disease (CKD) within 3.41 ± 1.42 years. With appropriate therapy, catch-up growth was noted in d-RTA and Bartter syndrome. Renal tubular disorders usually present with FTT. d-RTA is the most common etiology followed by Bartter-like syndrome. Renal function is preserved in all these disorders except for nephropathic cystinosis, who ultimately progressed to CKD. With appropriate and inexpensive therapy, these children do grow well.
- Metabolic Evaluation and Recurrence Prevention for Urinary Stone Patients: EAU Guidelines. [JOURNAL ARTICLE]
- Eur Urol 2014 Nov 20.
An optimum metabolic evaluation strategy for urinary stone patients has not been clearly defined.To evaluate the optimum strategy for metabolic stone evaluation and management to prevent recurrent urinary stones.Several databases were searched to identify studies on the metabolic evaluation and prevention of stone recurrence in urolithiasis patients. Special interest was given to the level of evidence in the existing literature.Reliable stone analysis and basic metabolic evaluation are highly recommended in all patients after stone passage (grade A). Every patient should be assigned to a low- or high-risk group for stone formation. It is highly recommended that low-risk stone formers follow general fluid and nutritional intake guidelines, as well as lifestyle-related preventative measures to reduce stone recurrences (grade A). High-risk stone formers should undergo specific metabolic evaluation with 24-h urine collection (grade A). More specifically, there is strong evidence to recommend pharmacological treatment of calcium oxalate stones in patients with specific abnormalities in urine composition (grades A and B). Treatment of calcium phosphate stones using thiazides is only highly recommended when hypercalciuria is present (grade A). In the presence of renal tubular acidosis (RTA), potassium citrate and/or thiazide are highly recommended based on the relative urinary risk factor (grade A or B). Recommendations for therapeutic measures for the remaining stone types are based on low evidence (grade C or B following panel consensus). Diagnostic and therapeutic algorithms are presented for all stone types based on the best level of existing evidence.Metabolic stone evaluation is highly recommended to prevent stone recurrences.In this report, we looked at how patients with urolithiasis should be evaluated and treated in order to prevent new stone formation. Stone type determination and specific blood and urine analysis are needed to guide patient treatment.
- Etiologic and Therapeutic Analysis in Patients with Hypokalemic Non-periodic Paralysis. [JOURNAL ARTICLE]
- Am J Med 2014 Oct 15.
Hypokalemic non-periodic paralysis represents a group of heterogeneous disorders with a large potassium (K(+)) deficit. Rapid diagnosis of curable causes with appropriate treatment is challenging to avoid the sequelae of hypokalemia. We prospectively analyzed the etiologies and therapeutic characteristics of hypokalemic non-periodic paralysis.Over an eight-year period, patients with hypokalemic non-periodic paralysis were enrolled by excluding those with hypokalemic periodic paralysis due to acute shift of K(+) into cells. Blood and spot urine samples were collected for the measurements of electrolytes, pH, and biochemistries. Intravenous potassium chloride (KCl) at rate of 10-20 mmol/hour was administered until muscle strength recovered.We had identified 58 patients with hypokalemic non-periodic paralysis from 208 consecutive patients with hypokalemic paralysis and their average K(+) concentration was 1.8 0.2 mmol/L. Among patients with low urinary K(+) excretion (n=17), chronic alcoholism, remote diuretic use, and anorexia/bulimia nervosa were the most common causes. Among patients with high urinary K(+) excretion (n=41) and metabolic acidosis, renal tubular acidosis and chronic toluene abuse were the main causes while primary aldosteronism, Gitelman's syndrome and diuretics were the leading diagnoses with metabolic alkalosis. The average KCl doses needed to restore muscle strength was 3.8 0.8 mmol/kg. Initial lower plasma K(+), volume depletion, and high urinary K(+) excretion were associated with higher recovery KCl dosage. During therapy, patients with paradoxical hypokalemia (n=32) who required more KCl supplementation than patients without (4.1 0.7 vs 3.4 0.7 mmol/kg, p < 0.001) often exhibited significantly higher plasma renin activity and received more volume of normal saline prior to its appearance.Understanding the common etiologies of hypokalemic non-periodic paralysis may aid in early diagnosis. Patients with initial lower plasma K(+), renal K(+) wasting, and hypovolemia required higher recovery K(+) dosage. Paradoxical hypokalemia is prone to develop in hypovolemic patients even during K(+) supplementation with volume repletion.