[Renal glucosuria]. / Glucosurie rénale.

The occurrence of glucosuria in the absence of hyperglycemia is distinctive for renal glucosuria. SGLT2 mutations provoke familial renal glucosuria characterized by persistent glucosuria in the absence of any other renal tubular dysfunction. Renal glucosuria associated with others proximal tubular dysfunctions points to Fanconi syndrome. This generalized dysfunction of proximal tubule needs to be treated and may progress regarding its aetiology to chronic renal failure. The development and study of models of Fanconi syndrome has recently contributed to a better knowledge of the mechanisms implicated in the tubular transport of glucose and low-molecular-weight-proteins. This article reviews these recent developments.

Can we generate new hypotheses about Dent's disease from gene analysis of a mouse model?

In humans, Dent's disease, an X-linked renal tubular disorder, is characterized by low molecular weight proteinuria, aminoaciduria, glycosuria, hyperphosphaturia, hypercalciuria, nephrolithiasis, progressive renal failure and sometimes rickets or osteomalacia. The aetiology of X-linked Dent's disease is established to be caused by mutations of the CLCN5 gene. The protein product of this gene is the voltage-gated chloride-proton exchanger CLC-5. Previous studies by the Johns Hopkins group (Guggino) and the Hamburg group (Jentsch) have established that the Clcn5 knockout mouse recapitulates the renal attributes of Dent's disease. In order to understand the changes in kidney function that accompany the knockout of the Clcn5 gene, we examined gene expression profiles from dissected proximal segment 1 (S1) and segment 2 (S2) tubules of mouse kidneys. Overall, 725 genes are expressed differentially in the proximal tubules of the Dent Clcn5 knockout mouse model compared with those of control wild-type mice. A major finding is the change in the cholesterol synthesis pathway. Some interesting changes also occur in genes encoding transport proteins. One of these transport proteins, the sodium bile cotransporter gene, Slc10a2, has transcripts increased by 17-fold in the Clcn5 knockout mouse. The Clc-3 protein encoded by Clcn3, a chloride-proton exchanger related to Clc-5, has a 1.9-fold increase in transcripts. The Npt2c protein, a proximal tubule sodium phosphate cotransporter encoded by Slc34a3, has a 0.6-fold decrease in the number of transcripts. The sodium-proton exchanger-like protein, Nhe10/sperm, encoded by Slc9a10, has a 0.5-fold decrease in transcript number. These genes are discussed with regard to the possible physiological outcomes of their transcript or protein changes.

Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion.

INTRODUCTION: Familial renal glucosuria (FRG) is a rare renal tubular disorder caused by mutations within the SLC5A2 gene. It is characterized by persistent glucosuria in the absence of hyperglycaemia and any other signs of generalized tubular dysfunction. In small series of patients previously reported, the molecular and phenotypic findings in FRG families, including first hints of extracellular volume depletion and activation of the renin-angiotensin-aldosterone system induced by natriuresis, have been described. We have now extended this analysis to another 21 consecutive cases from 17 pedigrees, including 11 cases with severe glucose excretion. METHODS: Mutation analysis was performed by direct sequencing of the genomic coding segments of the SLC5A2 gene. In two cases with severe glucosuria, basal plasma renin activity and serum aldosterone concentrations were determined. RESULTS: Within the 17 pedigrees, we have identified a total of 20 different SLC5A2 mutations. Fifteen have not been previously reported. In all glucosuric individuals tested, at least one SLC5A2 mutation could be identified. Heterozygous individuals were found to have only mild glucose excretion whereas homozygous or compound heterozygous patients had severe glucosuria, ranging from 10 to 86.5 g/1.73 m(2)/24 h. In two patients of the latter group, basal plasma renin activity and serum aldosterone concentration were determined and found to be raised to an average of 4.6-fold and 3.1-fold of the upper limit of the normal range, respectively. Discussion. The identification of at least one mutated allele in every affected individual in this cohort of 17 consecutively investigated families strongly suggests that genetic heterogeneity is not prevalent in FRG. Although 5 of the detected alleles have been described previously, 15 are novel, confirming that most mutations in FRG are private. Our finding of an activation of compensatory mechanisms for salt loss may warrant more detailed studies of long-term hormonal and metabolic imbalances in patients with FRG.

Increased Muscle Mass Protects Against Hypertension and Renal Injury in Obesity.

Background Obesity compromises cardiometabolic function and is associated with hypertension and chronic kidney disease. Exercise ameliorates these conditions, even without weight loss. Although the mechanisms of exercise's benefits remain unclear, augmented lean body mass is a suspected mechanism. Myostatin is a potent negative regulator of skeletal muscle mass that is upregulated in obesity and downregulated with exercise. The current study tested the hypothesis that deletion of myostatin would increase muscle mass and reduce blood pressure and kidney injury in obesity. Methods and Results Myostatin knockout mice were crossed to db/db mice, and metabolic and cardiovascular functions were examined. Deletion of myostatin increased skeletal muscle mass by ≈50% to 60% without concomitant weight loss or reduction in fat mass. Increased blood pressure in obesity was prevented by the deletion of myostatin, but did not confer additional benefit against salt loading. Kidney injury was evident because of increased albuminuria, which was abolished in obese mice lacking myostatin. Glycosuria, total urine volume, and whole kidney NOX-4 levels were increased in obesity and prevented by myostatin deletion, arguing that increased muscle mass provides a multipronged defense against renal dysfunction in obese mice. Conclusions These experimental observations suggest that loss of muscle mass is a novel risk factor in obesity-derived cardiovascular dysfunction. Interventions that increase muscle mass, either through exercise or pharmacologically, may help limit cardiovascular disease in obese individuals.

Effect of camostat mesilate on heavy proteinuria in various nephropathies.

Camostat mesilate, a developed derivative of gabexate mesilate for oral use, was administered in a daily dose of 600 mg for 4 weeks to 17 patients with heavy proteinuria due to various nephropathies. Five patients had glomerulonephritis (3 patients with IgA nephropathy, one each with membranoproliferative GN and membranous nephropathy) and 3 had systemic vasculitis. These patients had been treated with glucocorticoid, cyclophosphamide, anticoagulants, and dipyridamole. Five patients had diabetic nephropathy and had been treated with conventional therapy including angiotensin converting enzyme inhibitors. Two cases with benign nephrosclerosis, one with Alport syndrome, and the rest with end-stage renal failure of undetermined cause were also included in this study. Urinary protein decreased promptly within 2 weeks (from 5.2 +/- 0.7 to 3.5 +/- 0.5, mean +/- SE, p less than 0.005), and serum total protein and albumin levels increased significantly. Serum creatinine levels did not change. Decreases in urinary protein excretion of more than 50% were observed in five out of eight patients with glomerulonephritis or systemic vasculitis, two out of five with diabetic nephropathy, and one with chronic renal failure. However, urinary protein excretion values remained at the same level in two patients with benign nephrosclerosis and a patient with Alport syndrome. We suggest that camostat mesilate caused a change in glomerular capillary permeability for macromolecules through its inhibitory effects on the kallikrein-kinin system, complement system, coagulation system, and platelet function, which contributed to the treatment of the various nephropathies.

[Renal diabetes. Apropos of 103 cases]. / Le diabète rénal. A propos de 103 observations.

Three main concepts came out of this prospective study of 103 cases (51 girls and 52 boys) of renal diabetes followed up from 1955 to 1975 and reviewed in 1984: contrary to what is still sometimes written, renal diabetes does not evolve to diabetes mellitus; renal diabetes does not seem to progress over the years; the mode of genetic transmission, when present, which is rare, is obscure but it seems to occur in a recessive rather than a dominant fashion.

Type O renal glucosuria.

We observed a 7-year-old boy with virtual absence of renal tubular glucose reabsorption (type O renal glucosuria). Glucose titration studies in his family revealed severe type A renal glucosuria in a younger brother, a mild type A defect in the mother and normal glucose reabsorption in the father; thus a spectrum of renal glucose transport defects was observed in members of the same family.

Glucose transporters.

The recent cloning of families of glucose transporters has made it possible to study their structure and their role in an increasing number of disease states. Two classes of glucose transporters transfer glucose across the plasma membrane of human cells. In epithelial cells lining the jejunum and proximal renal tubules, Na+/glucose cotransporters concentrate glucose inside cells using the transmembrane electrochemical potential of Na+. Molecular defects of different transporters of this class cause familial glucose-galactose malabsorption and renal glycosuria. In the basolateral membrane of epithelial cells and in nonepithelial cells, glucose flows down its concentration gradient through a family of facilitative glucose transporters. Reduced numbers of different facilitative glucose transporters may contribute to both defective insulin secretion and insulin resistance in diabetes mellitus and to neurological diseases associated with decreased cerebrospinal fluid glucose.