The course of diabetic glomerulopathy in patients with type I diabetes: A 6-year follow-up with serial biopsies

Diabetic nephropathy is a severe complication and few studies have described the early morphological changes over time. Two kidney biopsies were performed, within a 6-year interval, in 29 primarily normoalbuminuric patients, aged 24 years at the second biopsy. These were examined with light and electron microscopy. Glomerular filtration rate, and effective renal plasma flow were determined with inulin and para-aminohippurate clearances. Urinary albumin excretion rate and the 24 ambulatory blood pressure were determined. Ten patients had developed microalbuminuria and/or hypertension; of these, six were treated with antihypertensive medication for 2 years or more. Significant increases were found in night time diastolic blood pressure and decreases in systolic and diastolic dipping. The glomerular volume, mesangial volume, mesangial matrix volume fraction and foot process width increased significantly. The group that was treated later for complications had the worst long-term metabolic control, thicker basement membranes and larger mesangial matrix and volume at the first biopsy, than the persistent normoalbuminuric group. During the follow-up, the untreated group with complications and the persistent normoalbuminuric group showed an increase in morphological parameters, whereas no progression occurred in the treated patients who also improved their metabolic control. In conclusion, the morphological parameters deteriorated in the normoalbuminuric patients and in those with complications, but were unchanged in the small antihypertensive-treated group with improved metabolic control

Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

BACKGROUND: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. METHOD: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. RESULTS: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. CONCLUSION: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.UK funding includes Cancer Research UK and NIH.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s13058-016-0718-

Normal 25-Hydroxyvitamin D Levels Are Associated with Less Proteinuria and Attenuate Renal Failure Progression in Children with CKD

Angiotensin-converting enzyme inhibitors (ACEi) for renin-angiotensin-aldosterone system (RAAS) blockade are routinely used to slow CKD progression. However, vitamin D may also promote renoprotection by suppressing renin transcription through cross-talk between RAAS and vitamin D-fibroblast growth factor-23 (FGF-23)-Klotho pathways. To determine whether vitamin D levels influence proteinuria and CKD progression in children, we performed a post hoc analysis of the Effect of Strict Blood Pressure Control and ACE Inhibition on Progression of CKD in Pediatric Patients (ESCAPE) cohort. In 167 children (median eGFR 51 ml/min per 1.73 m2), serum 25-hydroxyvitamin D (25(OH)D), FGF-23, and Klotho levels were measured at baseline and after a median 8 months on ACEi. Children with lower 25(OH)D levels had higher urinary protein/creatinine ratios at baseline (P=0.03) and at follow-up (P=0.006). Levels of 25(OH)D and serum vitamin D-binding protein were not associated, but 25(OH)D /=50 nmol/L and 50% in those with lower 25(OH)D levels (P/=50 nmol/L was associated with greater preservation of renal function. This effect was present but attenuated with concomitant ACEi therapy

Early Proteinuria Lowering By Angiotensin-Converting Enzyme Inhibition Predicts Renal Survival In Children With Ckd

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