Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increasing urinary net acid (titratable acid + NH4 - HCO-3) excretion is accompanied by an increased urinary Ca excretion because of reduced renal tubular reabsorption of filtered Ca. The relationships between urinary Ca excretion rates and urinary net acid excretion rates are reviewed for data: (1) among healthy adults eating constant diets when net acid excretion is increased by increasing dietary protein, administering NH4Cl, or withdrawal of dietary KHCO3 or reduced by administering KHCO3; (2) among healthy adults eating constant diets providing varying amounts of protein and potassium, and (3) among healthy adults and Ca stone formers with and without idiopathic hypercalciuria eating ad libitum. The results show that urinary Ca excretion varies directly with net acid excretion by 0.035 mmol/mEq. The urinary net acid excretion increases by 0.10-0.15 mEq/mmol urinary urea, and urinary Ca increases by about 0.04 mmol/g dietary protein, while the urinary net acid excretion decreases as the ratio of urinary K/urea, a reflection of the dietary K relative to dietary protein, increases. The relationships between net acid excretion and both urinary urea and K/urea are similar among Ca stone formers without and with idiopathic hypercalciuria, but those with idiopathic hypercalciuria exhibit increased rates of urinary Ca excretion at all levels of net acid excretion.
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PMID:Relationship between urinary calcium and net acid excretion as determined by dietary protein and potassium: a review. 987 10

Loss of function mutations of the renal chloride channel, ClC-5, have been implicated in Dent's disease, a genetic disorder characterized by low weight proteinuria, hypercalciuria, nephrolithasis and, in some cases, eventual renal failure. Recently, our laboratory used an RT-PCR/RACE cloning strategy to isolate an amphibian cDNA from the renal epithelial cell line A6 that had high homology to human ClC-5. We now report a full-length native ClC-5 clone (xClC-5, containing 5' and 3' untranslated regions) isolated by screening a cDNA library from A6 cells that was successfully expressed in Xenopus oocytes. In addition, we compared the properties of xClC-5 and hClC-5 using isogenic constructs of xClC-5 and hClC-5 consisting of the open reading frame subcloned into an optimized Xenopus expression vector. Expression of the full-length "native" xClC-5 clone resulted in large, strongly rectifying, outward currents that were not significantly affected by the chloride channel blockers DIDS, DPC, and 9AC. The anion conductivity sequence was NO-3 > Cl- = I- > HCO-3 >> glutamate for xClC-5 and NO-3 > Cl- > HCO-3 > I- >> glutamate for hClC-5. Reduction of the extracellular pH (pHo) from 7.5 to 5.7 inhibited outward ClC-5 currents by 27 +/- 9% for xClC-5 and 39 +/- 7% for hClC-5. The results indicate that amphibian and mammalian ClC-5 have highly similar functional properties. Unlike hClC-5 and most other ClC channels, expression of xClC-5 in oocytes does not require the removal of its untranslated 5' and 3' regions. Acidic solutions inhibited both amphibian and human ClC-5 currents, opposite to the stimulatory effects of low external pH on other ClC channels, suggesting a possibly distinct regulatory mechanism for ClC-5 channels.
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PMID:Comparison of amphibian and human ClC-5: similarity of functional properties and inhibition by external pH. 1019 59

We identified the human ortholog of soluble adenylyl cyclase (hsAC) in a locus linked to familial absorptive hypercalciuria and cloned it from a human cDNA library. hsAC transcripts were expressed in multiple tissues using RT-PCR and RNA blotting. RNA blot analysis revealed a predominant 5.1-kb band in a multiple human tissue blot, but three splice transcript variants were detected using RT-PCR and confirmed by performing sequence analysis. Immunoblot analysis showed 190- and 80-kDa bands in multiple human cell lines from gut, renal, and bone origins in both cytosol and membrane fractions, including Caco-2 colorectal adenocarcinomas, HEK-293 cells, HOS cells, and primary human osteoblasts, as well as in vitro induced osteoclast-like cells. The specificity of the antiserum was verified by peptide blocking and reduction using sequence-specific small interfering RNA. Confocal immunofluorescence cytochemistry localized hsAC primarily in cytoplasm, but some labeling was observed in the nucleus and the plasma membrane. Cytoplasmic hsAC colocalized with microtubules but not with microfilaments. To test the function of hsAC, four constructs containing catalytic domains I and II (aa 1-802), catalytic domain II (aa 231-802), noncatalytic domain (aa 648-1,610), and full-length protein (aa 1-1,610) were expressed in Sf9 insect cells. Only catalytic domains I and II or full-length proteins showed adenylyl cyclase activity. Mg(2+), Mn(2+), and Ca(2+) all increased adenylyl cyclase activity in a dose-dependent manner. While hsAC had a minimal response to HCO(3)(-) in the absence of divalent cations, HCO(3)(-) robustly stimulated Mg(2+)-bound hsAC but inhibited Mn(2+)-bound hsAC in a dose-dependent manner. In summary, hsAC is a divalent cation and HCO(3)(-) sensor, and its HCO(3)(-) sensitivity is modulated by divalent cations.
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PMID:Cloning and characterization of the human soluble adenylyl cyclase. 1565 11

Although acute nonoliguric renal failure is a well-known nephrotoxic effect of aminoglycoside antibiotics, less recognized is acquired Bartter-like syndrome. Herein, we describe four female patients who presented with marked paresthesia, muscle weakness, and tetany following gentamicin therapy with total dose ranging from 1.2 g to 2.6 g. All were normotensive. Biochemical abnormalities included hypokalemia (K+ 1.8-2.3 mmol/L), metabolic alkalosis (HCO(3-) 31.9-34.2 mmol/L), hypomagnesemia (Mg2+ 0.9-1.2 mg/dL), hypermagnesiuria (fractional excretion of Mg 3-6%), hypocalcemia (free Ca2+ 2.0-4.1 mg/dL), and hypercalciuria (molar ratio of Ca2+/creatinine 0.23-0.53), all consistent with Bartter-like syndrome. Serum immunoreactive parathyroid hormone concentration was low despite the hypocalcemia. The Bartter-like syndrome lasted for 2 to 6 weeks after cessation of gentamicin, coupled with supplementation of K+, Ca2+, and Mg2+. These biochemical abnormalities resembled those seen in patients with gain-of-function mutations in the calcium-sensing receptor. We hypothesize that gentamicin, a polyvalent cationic molecule, induces the action of calcium-sensing receptor on the thick ascending loop of Henle and distal convoluted tubule to cause renal wasting of Na+, K+, Cl-, Ca2+, and Mg2+.
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PMID:Acquired bartter-like syndrome associated with gentamicin administration. 1576 21

Mutations in the human gene that encodes the AE1 Cl(-)/HCO(3)(-) exchanger (SLC4A1) cause autosomal recessive and dominant forms of distal renal tubular acidosis (dRTA). A mouse model that lacks AE1/slc4a1 (slc4a1-/-) exhibited dRTA characterized by spontaneous hyperchloremic metabolic acidosis with low net acid excretion and, inappropriately, alkaline urine without bicarbonaturia. Basolateral Cl(-)/HCO(3)(-) exchange activity in acid-secretory intercalated cells of isolated superfused slc4a1-/- medullary collecting duct was reduced, but alternate bicarbonate transport pathways were upregulated. Homozygous mice had nephrocalcinosis associated with hypercalciuria, hyperphosphaturia, and hypocitraturia. A severe urinary concentration defect in slc4a1-/- mice was accompanied by dysregulated expression and localization of the aquaporin-2 water channel. Mice that were heterozygous for the AE1-deficient allele had no apparent defect. Thus, the slc4a1-/- mouse is the first genetic model of complete dRTA and demonstrates that the AE1/slc4a1 Cl(-)/HCO(3)(-) exchanger is required for maintenance of normal acid-base homeostasis by distal renal regeneration of bicarbonate in the mouse as well as in humans.
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PMID:Distal renal tubular acidosis in mice lacking the AE1 (band3) Cl-/HCO3- exchanger (slc4a1). 1740 10

Claudin-16 is defective in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Claudin-16 knockdown (CLDN16 KD) mice show reduced cation selectivity in the thick ascending limb. The defect leads to a collapse of the lumen-positive diffusion voltage, which drives Ca(2+) and Mg(2+) absorption. Because of the reduced tight junction permeability ratio for Na(+) over Cl(-), we proposed a backleak of NaCl into the lumen. Systemic analysis had revealed lower blood pressure and a moderately increased plasma aldosterone concentration. In this study, we measured the amiloride-sensitive equivalent short-circuit current in isolated, perfused collecting ducts and found it increased by fivefold in CLDN16 KD mice compared with wild-type (WT) mice. Amiloride treatment unmasked renal Na(+) loss in the thick ascending limb of the nephron. Under amiloride treatment, CLDN16 KD mice developed hyponatremia and the renal fractional excretion of Na(+) was twofold higher in CLDN16 KD compared with WT mice. The loss of claudin-16 also resulted in increased urinary flow, reduced HCO(3)(-) excretion, and lower urine pH. We conclude that perturbation in salt and acid-base metabolism in CLDN16 KD mice has its origin in the defective cation permselectivity of the thick ascending limb of the nephron. This study has contributed to the still incomplete understanding of the symptoms of FHHNC patients.
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PMID:Salt and acid-base metabolism in claudin-16 knockdown mice: impact for the pathophysiology of FHHNC patients. 1878 60

Congenital chloride diarrhea is due to mutations in the intestinal Cl(-)/HCO(3)(-) exchange (SLC26A3) which results in sodium chloride and fluid depletion leading to hypochloremic and hypokalemic metabolic alkalosis. Although treatment with sodium and potassium chloride offers protection from renal involvement in childhood, the long-term renal outcome remains unclear. Here we describe two cases of congenital chloride diarrhea-associated end-stage renal disease with transplantation. Further, we show that there is a high incidence of mild chronic kidney disease in 35 other patients with congenital chloride diarrhea. The main feature of the renal injury was nephrocalcinosis, without hypercalciuria or nephrolithiasis with small sized kidneys and commensurately reduced glomerular filtration rates. This suggests that diarrhea-related sodium chloride and volume depletion, the first signs of non-optimal salt substitution, promote urine supersaturation and crystal precipitation. The poor compliance with salt substitution along with long-lasting hypochloremic and hypokalemic metabolic alkalosis is likely to induce progressive calcification and renal failure. Both our patients developed nephrocalcinosis in the transplanted kidneys suggesting that this complication is a consequence of intestinal SLC26A3 deficiency. Interestingly, the transporter is expressed in the distal nephron but the recurrence of nephrocalcinosis in the transplanted kidney suggests that it does not play a significant renal role in this syndrome.
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PMID:The impact of sodium chloride and volume depletion in the chronic kidney disease of congenital chloride diarrhea. 1882

Renal tubular acidosis (RTA) represents a group of diseases characterized by (1) a normal anion gap metabolic acidosis; (2) abnormalities in renal HCO3- absorption or new renal HCO3- generation; (3) changes in renal NH4+, Ca2+, K+, and H2O homeostasis; and (4) extrarenal manifestations that provide etiologic diagnostic clues. The focus of this review is to give a general overview of the pathogenesis of the various clinical syndromes causing RTA with a particular emphasis on type I (hypokalemic distal RTA) and type II (proximal) RTA while reviewing their pathogenesis from a physiological "bottom-up" approach. In addition, the factors involved in the generation of metabolic acidosis in both type I and II RTA are reviewed highlighting the importance of altered renal ammonia production/partitioning and new HCO3- generation. Our understanding of the underlying tubular transport and extrarenal abnormalities has significantly improved since the first recognition of RTA as a clinical entity because of significant advances in clinical acid-base chemistry, whole tubule and single-cell H+/base transport, and the molecular characterization of the various transporters and channels that are functionally affected in patients with RTA. Despite these advances, additional studies are needed to address the underlying mechanisms involved in hypokalemia, altered ammonia production/partitioning, hypercalciuria, nephrocalcinosis, cystic abnormalities, and CKD progression in these patients.
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PMID:Renal Tubular Acidosis: H+/Base and Ammonia Transport Abnormalities and Clinical Syndromes. 3013 60

Homozygous autosomal recessive distal renal tubular acidosis (dRTA) is a rare entity. The intercalated cells in the collecting ducts are defective in apical proton secretion or basolateral bicarbonate reabsorption, due to mutations in genes encoding for proteins in a4 and B1 subunits of the V-ATPase and the anion exchanger Cl-/HCO- (kAE1). This results in decreased ammonium (NH4+) excretion and defective urine acidification. dRTA is characterized by hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria, hypocitranuria, and nephrocalcinosis. Autosomal recessive dRTA is associated with mutation in ATP6V1B1 (2p13) or ATP6V0A4 (7q34) genes. ATP6V1B1 mutation is associated with early - onset sensory neural hearing loss (SNHL), whereas ATP6V0A4 gene mutation may be associated with early-to late-onset SNHL. We report the case of a 30-year-old married woman diagnosed with dRTA at three months of age with mild SNHL, showing homogygous nonsense mutation in exon 3 of the ATP6V0A4 gene that resulted in a stop codon and premature truncation of the protein at codon 6.
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PMID:A rare case of autosomal recessive ATP6V0A4 variant of distal renal tubular acidosis in a young female with recurrent nephrolithiasis. 3192 93