Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

No abstract

Introduction: Glomerular filtration rate (GFR) is the most widely used indicator of kidney function in patients with renal disease, although it does not invariably reflect functional status after renal injury. The concept of renal functional reserve (RFR) as the ability of the kidney to increase GFR following a protein load was introduced in the 1980s. In this study we evaluated the RFR test in 26 children who had developed hemolytic-uremic syndrome (HUS) at least 2 years before the first evaluation, then 8 years later. At the beginning of the study they had no signs of proteinuria, hypertension or renal insufficiency. RFR was also evaluated in 15 healthy control children. Methods: Proteinuria and creatinine in serum and urine were tested. Functional reserve index (FRI) was defined in order to evaluate RFR. Patients with FRI level >1.36 were considered as responders (R) and with FRI <1.36 as non-responders (NR). Results: R and NR groups failed to show any significant differences when basal creatinine clearance (C_Cr) was evaluated. The NR group presented a significant low initial FRI that persisted unchanged at the end of the study. These patients developed proteinuria and a renal protector treatment with protein restriction was indicated. Although the proteinuria diminished, it remained within pathological range. The lack of RFR response in the NR group was significantly related to the presence of oliguria lasting longer than 8 days during the acute phase of disease. Conclusions: Those patients with a previous history of HUS with normal basal C_Cr should be evaluated by the RFR test to detect those at risk of developing glomerular hyperfiltration.

The acute effect of angiotensin-converting enzyme inhibition (ACEi) on proximal convoluted tubule (PCT) function is well documented. However, the effect of chronic treatment is less known. The aim of this work was to evaluate the effect of chronic ACEi on PCT acidification (J(HCO(3)(-))). Rats received enalapril (10 mg.kg(-1).day(-1), added to the drinking water) during 3 mo. Micropuncture experiments were performed to measure the effect of chronic ACEi on J(HCO(3)(-)). Nitric oxide (NO.) synthesis in kidney cortex homogenates was assessed by quantifying the conversion of [(14)C]-L-arginine to [(14)C]-L-citrulline. Western blot analysis was performed to determine the abundances of V-H(+)ATPase and NHE3 isoform of the Na(+)/H(+) exchanger in proximal brush-border membrane vesicles (BBMV). Enalapril treatment induced an approximately 50% increase in J(HCO(3)(-)). Luminal perfusion with ethyl-isopropyl amiloride (EIPA) 10(-4)M or bafilomycin 10(-6)M decreased J(HCO(3)(-)) by approximately 60% and approximately 30%, respectively, in both control and enalapril-treated rats. The effect of EIPA and bafilomycin on absolute J(HCO(3)(-)) was larger in enalapril-treated than in control rats. Acute inhibition of NO. synthesis with N(G)-nitro-L-arginine methyl ester abolished the enalapril-induced increase in J(HCO(3)(-)). Cortex homogenates from enalapril-treated rats displayed a 46% increase in nitric oxide synthase (NOS) activity compared with those from untreated animals. Enalapril treatment did not affect the abundances of NHE3 and V-H(+)ATPase in BBMV. Our results suggest that PCT acidification is increased during chronic ACEi probably due to an increase in NO. synthesis, which would stimulate Na(+)/H(+) exchange and electrogenic proton transport.

No abstract