RESUMO
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.
Assuntos
Acetazolamida/uso terapêutico , Acidose Tubular Renal/induzido quimicamente , Calcinose/tratamento farmacológico , Calcinose/genética , Fatores de Crescimento de Fibroblastos/genética , Neoplasias/complicações , Poliaminas/uso terapêutico , Acetazolamida/efeitos adversos , Acidose Tubular Renal/genética , Calcinose/complicações , Quelantes/efeitos adversos , Quelantes/uso terapêutico , Pré-Escolar , Análise Mutacional de DNA , Diuréticos/efeitos adversos , Diuréticos/uso terapêutico , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Hiperfosfatemia/complicações , Hiperfosfatemia/genética , Lactente , Mutação/fisiologia , Neoplasias/genética , Neoplasias/metabolismo , Linhagem , Fosfatos/metabolismo , Poliaminas/efeitos adversos , Sevelamer , Irmãos , Resultado do TratamentoRESUMO
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.
Assuntos
Acidose Tubular Renal/induzido quimicamente , Cloreto de Amônio/toxicidade , Rim/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidose Tubular Renal/complicações , Acidose Tubular Renal/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Hipertrofia/etiologia , Hipertrofia/metabolismo , Hipertrofia/patologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Rim/efeitos dos fármacos , Masculino , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Sódio/urina , Tirosina/metabolismoRESUMO
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.
Assuntos
Acidose Tubular Renal/induzido quimicamente , Inibidores da Anidrase Carbônica/efeitos adversos , Frutose/análogos & derivados , Acidose Tubular Renal/diagnóstico , Feminino , Frutose/efeitos adversos , Humanos , Pessoa de Meia-Idade , TopiramatoRESUMO
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.
Assuntos
Feminino , Humanos , Pessoa de Meia-Idade , Acidose Tubular Renal/induzido quimicamente , Inibidores da Anidrase Carbônica/efeitos adversos , Frutose/análogos & derivados , Acidose Tubular Renal/diagnóstico , Frutose/efeitos adversosRESUMO
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)
Assuntos
Acidose Tubular Renal/induzido quimicamente , Lítio/toxicidade , Animais , Bicarbonatos/urina , Concentração de Íons de Hidrogênio , Túbulos Renais Distais/efeitos dos fármacos , Túbulos Renais Distais/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Cinética , Masculino , Potenciais da Membrana , Ratos , Ratos Endogâmicos , Sódio/urinaRESUMO
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
Assuntos
Ratos , Animais , Masculino , Acidose Tubular Renal/induzido quimicamente , Lítio/farmacologia , Sódio/metabolismo , Túbulos Renais Proximais/fisiopatologia , Punções , Ratos EndogâmicosRESUMO
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.
Assuntos
Equilíbrio Ácido-Base/fisiologia , Rim/fisiologia , Acidose Tubular Renal/induzido quimicamente , Acidose Tubular Renal/fisiopatologia , Animais , Transporte Biológico/fisiologia , Humanos , Concentração de Íons de Hidrogênio , Capacidade de Concentração Renal/fisiologiaRESUMO
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.
Assuntos
Acidose Tubular Renal/induzido quimicamente , Gentamicinas/efeitos adversos , Túbulos Renais Distais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Netilmicina/efeitos adversos , Alcalose/metabolismo , Animais , Dióxido de Carbono/sangue , Ratos , Análise de RegressãoRESUMO
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