Chronic thiazide treatment is associated with high BMD. We report that patients and mice with null mutations in the thiazide-sensitive NaCl cotransporter (NCC) have higher renal tubular Ca reabsorption, higher BMD, and lower bone remodeling than controls, as well as abnormalities in Ca metabolism, mainly caused by Mg depletion.Introduction: Chronic thiazide treatment decreases urinary Ca excretion (UVCa) and increases BMD. To understand the underlying mechanisms, Ca and bone metabolism were studied in two models of genetic inactivation of the thiazide-sensitive NaCl cotransporter (NCC): patients with Gitelman syndrome (GS) and Ncc knockout (Ncc

Rationale & Objective. Chronic kidney disease (CKD) characterized by decreased glomerular filtration rate (GFR) is often accompanied by various degrees of impaired tubular function in the cortex and medulla. Assessment of tubular function may, therefore, be useful in establishing the severity of kidney disease and in identifying those at greater risk of CKD progression. We explored reductions in urinary concentrating ability, a well-known feature of CKD, as a risk factor for GFR decline and end-stage kidney disease (ESRD). StudyDesign. Prospective longitudinal cohort study. Setting and participants. 2,084 adult patients with CKD stages 1 to 4 from the French NephroTest Cohort Study. Predictor. Fasting urinary osmolality (Uosm) measured by delta cryoscopy. Outcomes. End-stage renal disease (ESRD), mortality prior to ESRD, and measured GFR (mGFR) assessed by 51 Cr-EDTA renal clearance. Analytical Approach. Cause-specific hazards models were fit to estimate crude and adjusted associations of urinary osmolality with ESRD and death prior to ESRD. Linear mixed models with random intercepts were fit to evaluate the association of urinary osmolality with slope of decline in mGFR. Results. At baseline, mean age was 58.7±15.2 (SD) years with a median mGFR of 40.2 [IQR, 29.1-54.5] ml/min and a median fasting Uosm of 502.7 ± 151.7 mOsm/kg H2O. Baseline fasting Uosm was strongly associated with mGFR (R=0.54, p<0.001). 380 ESRD events and 225 deaths prior to ESRD occurred during a median follow-up of 5.9 years [3.8-8.2]. Patients with lower baseline fasting Uosm had a higher adjusted risk of 4ESRD but not of mortality (HRs of 1.9 [95% CI, 1.2-3.0] and 0.99 [95% CI, 0.68-1.44], respectively, for the lowest versus highest tertile). Based on a mixed linear model, adjusted for baseline mGFR and clinical characteristics, patients in the lowest tertile of baseline Uosm had a steeper decline in kidney function (-4.9% ± 0.9% per year, p<0.001) compared to patients in the highest tertile.Limitations. Fasting was self-reported.Conclusions. Fasting Uosm may be a useful tool, in addition to GFR and albuminuria, for assessing non-glomerular damage in patients with CKD who are at higher risk of CKD progression.

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