Trans-ethnic genome-wide association study of blood metabolites in the Chronic Renal Insufficiency Cohort (CRIC) study.

Metabolomics genome wide association study (GWAS) help outline the genetic contribution to human metabolism. However, studies to date have focused on relatively healthy, population-based samples of White individuals. Here, we conducted a GWAS of 537 blood metabolites measured in the Chronic Renal Insufficiency Cohort (CRIC) Study, with separate analyses in 822 White and 687 Black study participants. Trans-ethnic meta-analysis was then applied to improve fine-mapping of potential causal variants. Mean estimated glomerular filtration rate was 44.4 and 41.5 mL/min/1.73m2 in the White and Black participants, respectively. There were 45 significant metabolite associations at 19 loci, including novel associations at PYROXD2, PHYHD1, FADS1-3, ACOT2, MYRF, FAAH, and LIPC. The strength of associations was unchanged in models additionally adjusted for estimated glomerular filtration rate and proteinuria, consistent with a direct biochemical effect of gene products on associated metabolites. At several loci, trans-ethnic meta-analysis, which leverages differences in linkage disequilibrium across populations, reduced the number and/or genomic interval spanned by potentially causal single nucleotide polymorphisms compared to fine-mapping in the White participant cohort alone. Across all validated associations, we found strong concordance in effect sizes of the potentially causal single nucleotide polymorphisms between White and Black study participants. Thus, our study identifies novel genetic determinants of blood metabolites in chronic kidney disease, demonstrates the value of diverse cohorts to improve causal inference in metabolomics GWAS, and underscores the shared genetic basis of metabolism across race.

Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2.

BACKGROUND: The Modification of Diet in Renal Disease (MDRD) Study equation underestimates measured glomerular filtration rate (GFR) at levels>60 mL/min/1.73 m2, with variable accuracy among subgroups; consequently, estimated GFR (eGFR)>or=60 mL/min/1.73 m2 is not reported by clinical laboratories. Here, performance of a more accurate GFR-estimating equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, is reported by level of GFR and clinical characteristics. STUDY DESIGN: Test of diagnostic accuracy. SETTING & PARTICIPANTS: Pooled data set of 3,896 people from 16 studies with measured GFR (not used for the development of either equation). Subgroups were defined by eGFR, age, sex, race, diabetes, prior solid-organ transplant, and body mass index. INDEX TESTS: eGFR from the CKD-EPI and MDRD Study equations and standardized serum creatinine. REFERENCE TEST: Measured GFR using urinary or plasma clearance of exogenous filtration markers. RESULTS: Mean measured GFR was 68+/-36 (SD) mL/min/1.73 m2. For eGFR<30 mL/min/1.73 m2, both equations have similar bias (median difference compared with measured GFR). For eGFR of 30-59 mL/min/1.73 m2, bias was decreased from 4.9 to 2.1 mL/min/1.73 m2 (57% improvement). For eGFR of 60-89 mL/min/1.73 m2, bias was decreased from 11.9 to 4.2 mL/min/1.73 m2 (61% improvement). For eGFR of 90-119 mL/min/1.73 m2, bias was decreased from 10.0 to 1.9 mL/min/1.73 m2 (75% improvement). Similar or improved performance was noted for most subgroups with eGFR<90 mL/min/1.73 m2, other than body mass index<20 kg/m2, with greater variation noted for some subgroups with eGFR>or=90 mL/min/1.73 m2. LIMITATIONS: Limited number of elderly people and racial and ethnic minorities with measured GFR. CONCLUSIONS: The CKD-EPI equation is more accurate than the MDRD Study equation overall and across most subgroups. In contrast to the MDRD Study equation, eGFR>or=60 mL/min/1.73 m2 can be reported using the CKD-EPI equation.

Estrogen replacement increased the citrate and calcium excretion rates in postmenopausal women with recurrent urolithiasis.

PURPOSE: Epidemiological data indicate a sharp increase in urinary calcium stone formation after menopause. We investigated the role of menopausal estrogen replacement therapy on the urinary constituents and characteristics that may influence recurrent calcium oxalate stone disease. MATERIALS AND METHODS: Urinary constituents in 28 postmenopausal women on estrogen replacement therapy for more than 6 months were compared with those in 41 women who had never been exposed to estrogen after menopause. These 2 groups had a history of recurrent calcium oxalate urolithiasis. A group of age matched, nonstone forming volunteers who were and were not on estrogen served as controls. RESULTS: The 24-hour urine collection revealed significantly higher mean calcium plus or minus standard deviation (188.8 +/- 101.5 versus 129.2 +/- 80.9 mg./24 hours, p <0.01), citrate (576.6 +/- 237.9 versus 306.2 +/- 209.9 mg./24 hours, p <0.001) and agglomeration inhibition (203 +/- 106 versus 159 +/- 81 minutes, p <0.05) in stone forming women who were versus were not on estrogen. CONCLUSIONS: Higher urinary citrate and higher agglomeration inhibition in women exposed to estrogen may decrease the risk of subsequent calcium stone formation.