Familial tumoral calcinosis caused by a novel FGF23 mutation: response to induction of tubular renal acidosis with acetazolamide and the non-calcium phosphate binder sevelamer.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is an uncommon disease characterized by periarticular calcifications produced by the deposition of amorphous extraosseous calcifications of hydroxyapatite. It is associated with hyperphosphatemia due to increased tubular phosphate reabsorption, despite normal renal function and normal plasma PTH levels. The disease can be caused by inactivating mutations in either the fibroblast growth factor 23 (FGF23) gene, the UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene or in human KLOTHO (KL) gene. Herein, we describe a Caucasian 3-year-old girl with tumoral calcinosis who presented with elevated serum phosphorus levels and a large calcified mass at her left elbow which led to ulceration of the skin. Treatment with the phosphate binder sevelamer and the carbonic anhydrase inhibitor acetazolamide successfully reduced the serum phosphate levels and led to a reduction of the calcified mass. This medical management has not been described previously. Her 7-month-old sister also had elevated serum phosphate levels, but did not have ectopic calcifications. Sequencing analysis revealed a novel homozygous FGF23 missense mutation (c.367G>T, p.Gly123Trp) in both siblings while the parents were carriers of the mutation.

Effects of NH4Cl intake on renal growth in rats: role of MAPK signalling pathway.

BACKGROUND: There is a surprising lack of experimental data on the mechanisms of NH4Cl-induced chronic metabolic acidosis which causes kidney hypertrophy. The NH4Cl treatment results in an absolute increase in kidney mass. Despite findings to indicate a close interaction between NH4Cl-induced chronic metabolic acidosis and renal enlargement, the role of the stimulated serine kinase cascade, mediated by the stepwise activation of extracellular signal-regulated kinase (ERK) signalling, on kidney hypertrophy has not yet been investigated. METHODS: To test this hypothesis, the present study was undertaken to further explore the possible involvement of mitogen-activated protein kinase (MAPK) signalling pathway in renal growth in chronic NH4Cl-treated rats by western blot analysis. RESULTS: Our major findings are as follows: (1) Urinary sodium excretion significantly increased during the early phases of NH4Cl-induced acidosis, (2) This occurrence is associated with sustained renal hypertrophy, and (3) sustained basal phosphorylation of IRS-1, Shc, and MAPK/ERKs in acidotic kidneys. CONCLUSIONS: The present study confirms that NH4Cl-induced acidosis causes disturbances in renal sodium handling. In addition, these findings demonstrate a sustained pre-stimuli activation of kidney MAPK/ERKs signalling pathways in the NH4Cl-treated rats that may correlate with an increased rate of kidney hypertrophy and a transient renal tubule inability to handle sodium. Thus, the altered renal electrolyte handling may result from a reciprocal relationship between the level of renal tubule metabolic activity and ion transport. In addition, the study shows that the appropriate regulation of tyrosine kinase protein phosphorylation, and its downstream signal transduction pathway, plays an important role on renal growth in the NH4Cl-treated rats.

Topiramate and severe metabolic acidosis: case report.

Topiramate infrequently induces anion gap metabolic acidosis through carbonic anhydrase inhibition on the distal tubule of the nephron--a type 2 renal tubular acidosis. We report on a 40 years old woman previously healthy that developed significant asymptomatic metabolic acidosis during topiramate therapy at a dosage of 100 mg/day for three months. Stopping medication was followed by normalization of the acid-base status within five weeks. This infrequent side effect appears unpredictable and should be given careful attention.

Topiramate and severe metabolic acidosis: case report

Topiramato pode produzir raramente uma acidose metabólica através da inibição da anidrase carbônica no túbulo distal do néfron - acidose tubular renal do tipo 2. Relatamos o caso de mulher de 40 anos previamente saudável que desenvolveu quadro de acidose metabólica assintomática grave, sem outra etiologia identificável, durante uso de topiramato na dose de 100mg/dia por três meses. Este efeito colateral, embora infrequente, parece ser imprevisível e requer atenção cuidadosa.

Renal acidification defect induced by lithium in control and acidotic rats.

1. The aim of this work was to contribute to a better understanding of the mechanism by which Li+ administration impairs renal tubular acidification. 2. The kinetics of tubular acidification in the mid-proximal and distal convoluted tubules were studied by measuring intratubular pH using Sb microelectrodes during stopped-flow microperfusion with Krebs-Ringer bicarbonate (30 mmol/l) buffer. Four groups of male Wistar rats were utilized in this study: control, control plus lithium (C + Li+; one intraperitoneal injection of LiCl of 4 mmol l-1 day-1 kg-1 for 4 days), acidotic and acidotic plus lithium (A + Li+). 3. In C + Li+ rats, the half-time of acidification was significantly higher than in control rats (P less than 0.01), in both the mid-proximal tubule (11.3 +/- 0.34 vs 6.73 +/- 0.22 s) and the distal convoluted tubule (17.5 +/- 0.31 vs 11.5 +/- 1.02 s), and net HCO3- reabsorption was lower in both the mid-proximal tubule and the distal convoluted tubule. The effects of Li+ on tubular acidification kinetics were similar in acidotic rats. 4. A net Na+ flux, as measured by the Gertz split-droplet method, was significantly decreased in the mid-proximal tubule (P less than 0.01) in C + Li+ rats compared with control rats (2.14 +/- 0.17 vs 4.07 +/- 0.39 nmol s-1 cm-2). 5. The transepithelial potential difference in the distal convoluted tubule was significantly lower (P less than 0.01) in C + Li+ rats than in control rats (-7.50 +/- 1.50 vs -20.5 +/- 1.12 mV).(ABSTRACT TRUNCATED AT 250 WORDS)

Impairment of the renal tubular acidification kinetics by lithium

We studied the kinetics of HCO-3 reabsorption in the middle proximal (MPT) and distal convoluted tubules (DCT) by measuring continuously intratubular pH with Sb-microelectrodes in stopped-flow microperfusion (HCO-3, 30 mM Ringer) experiments. Male Wistar rats (240-280 g) were injected ip with LiCl (4mEqkg-1 day-1) for 4 days (Li) and were compared to controls (C). Steady-state pH increased in MPT from 6.64 + or - 0.02(57) to 6.89 + or - 0.02(45), mean + or - SEM (number of measurements) on tissue from 13 rats in each group, and from 6.87 + or - 0.5(30) to 7.08 + or - 0.01(63) in DCT. HCO-3 reabsorption decreased from 1.32 + or - 0.08(57) to 0.96 + or - 0.4(45) nmol cm-2 s-1 in MPT and from 0.85 + or - 0.07(30) to 0.45 + or - 0.04(63) in DCT. These data indicate that lithium affected the acidification mechanism in MPT and DCT, probably through an impairment of the Na+ -H+ antiport in both tubular segments

Role of the kidney in controlling acid-base balance.

The kidney is responsible for the maintenance of an important sector of the regulation of acid-base balance, i.e., that related to the maintenance of the alkaline reserve of the body and to excretion of fixed acids. In this review, the basic mechanisms of H-ion secretion along the nephron, responsible for bicarbonate reabsorption, titratable acid formation and ammonia excretion, are discussed. The mechanisms responsible for tubule acidification along proximal tubule, thick ascending limb, cortical distal tubule and collecting duct are reviewed, having in mind the function of the apical and basolateral membranes. Finally, the pathophysiological aspects of urinary acidification are discussed, focusing on renal tubular acidosis models (induced by maleate and amphotericin B treatment) and their cellular mechanisms, as well as the role of adrenal steroids in urinary acidification.

Evaluation of distal tubular function in aminoglycoside-induced nephropathy.

Acute metabolic acidosis potentiates the nephrotoxicity of aminoglycosides by impairing the adequate excretion of ammonium and titratable acidity. The present study assesses distal tubular function after aminoglycoside administration in the rat. Two aminoglycosides, gentamicin and netilmycin were given to rats either in low doses equivalent to those used clinically (BG4 and BN5 groups) or in doses ten times higher (BG40 and BN50). The rats were subjected to acute metabolic alkalosis and the pCO2 of urine was continuously evaluated. The regression lines obtained by plotting the differences between urine and blood pCO2 as a function of urinary HCO3- in low dose models were similar to those obtained for the control group. However, the slopes obtained for BG40 and BN50 were significantly different from the control, suggesting an impairment of H+ secretion.

Evaluation of distal tubular function in aminoglycoside induced nephropathy

Acute metabolic acidosis potentiates the nephrotixicity of aminoglycosides by impairing the adequate excretion of ammonium and titratable acidity. The present study assesses distal tubular function after aminoglycoside administration in the rat. Two aminoglycosides, gentamicin and netilmicin were given to rats either in low doses equivalent to those used clinically (BG4 and BN5 groups) or in doses ten times higher (BG40 and BN50). The rats were subjected to acute metabolic alkalosis and the pCO2 of urine was continuously evaluated. the regression lines obtained by plotting the differences between urine and blood pCO2 as a function of urinary HCO3 in low dose models were simsilar to those obtained for the control group. However, the slopes obtained for BG40 and BN50 were significantly different from the control, suggesting an impairment of H+ secretion

Renal transport and metabolism of glutamine

The experiments described in this thesis were designed to investigate the mechanism of glutamine transport and the effect of acute acidosis on glutamine transport and metabolism in the rat kidney. The experiments done with kidney slices investigated the effect of several amino acids chosen from different structural groups on uptake of glutamine. Proline (an ammino acid) and glycine (at inhibitory concentrations) were found to inhibit ammonia production and glutamine uptake significantly. When a sodium free incubation buffer was used the inhibitory effect of proline and glycine on glutamine uptake disappeared, indicating that the inhibition by proline was sodium dependent. In similar experiments with isolated kidney proximal tubules in a sodium containing buffer, proline also caused a decrease in glutamine uptake and ammonia production. Intracellular/extracellular glutamine distributions ratios in tubules however, showed a marked increase in the presence of proline. The explanation for this is not that proline shares a transport site with glutamine but rather that it is metabolised to glutamate which causes an inhibition of phosphate dependent glutaminase and hence decreased glutamine utilisation. This decreased utilisation leads to an accumulation of glutamine within the renal cell and subsequently increased intracellular/extracellular glutamine distribution ratios. The inhibitory effect of proline on glutamine uptake was much less in experiments with kidney slices from chronically acidotic rats. Isolated tubules from acutely acidotic rats showed increased intracellular/extracellular glutamine distribution ratios, increased ammonia production and glutamine uptake in tubules. When tubules from normal rats were incubated in sera from acutely acidotic rats there was a similar increase in intracellular/extracellular glutamine distribution ratios, ammonia production and glutamine uptake. The effect of the serum however, was not due to the accumulation of glutamate because glutamate levels in tubules were unchanged after incubation in sera from the acutely acidotic rats (AU)

[Nephrotoxicity caused by amphotericin B]. / Nefrotoxicidad por anfotericina B.

A six-year-old child with coccidioidomycosis is reported. The patient was given amphotericin B, that brought about disturbances in renal function with renal failure, which turned reversible on discontinuance of treatment. The earliest manifestations of nephrotoxicity were observed following administration of a total dose of 1,000 mgs. The findings were: glycosuria, cylindruria, high urinary pH followed by metabolic acidosis, hypokalemia, decreased capacity of renal concentration and clearance of endogenous creatinine. Oral administration of postassium bicarbonate and interruption of amphotericin B were followed by reversal of kidney lesion manifestations.

Renal tubular acidosis and skeletal demineralization in patients on long-term anticonvulsant therapy.

Three children ranging from seven to 12 years of age from unrelated families were given long-term anticonvulsant therapy including acetazolamide (Diamox). These children had rickets and renal tubular acidosis. Investigations have suggested (1) secondary hyperparathyroidism due to hypocalcemia of rickets and (2) prolonged acetazolamide therapy were responsible for acidosis as a result of reduction of bicarbonate reabsorption in the kidney. A clear-cut recovery from acidosis and rickets was seen in two patients following medication with high doses of vitamin D, an oral supplement of phosphorus, and discontinuance of acetazolamide therapy.