Faculty Bibliography

Genome-wide association studies (GWASs) have identified multiple loci associated with cross-sectional eGFR, but a systematic genetic analysis of kidney function decline over time is missing. Here we conducted a GWAS meta-analysis among 63,558 participants of European descent, initially from 16 cohorts with serial kidney function measurements within the CKDGen Consortium, followed by independent replication among additional participants from 13 cohorts. In stage 1 GWAS meta-analysis, single-nucleotide polymorphisms (SNPs) at MEOX2, GALNT11, IL1RAP, NPPA, HPCAL1, and CDH23 showed the strongest associations for at least one trait, in addition to the known UMOD locus, which showed genome-wide significance with an annual change in eGFR. In stage 2 meta-analysis, the significant association at UMOD was replicated. Associations at GALNT11 with Rapid Decline (annual eGFR decline of 3 ml/min per 1.73 m(2) or more), and CDH23 with eGFR change among those with CKD showed significant suggestive evidence of replication. Combined stage 1 and 2 meta-analyses showed significance for UMOD, GALNT11, and CDH23. Morpholino knockdowns of galnt11 and cdh23 in zebrafish embryos each had signs of severe edema 72 h after gentamicin treatment compared with controls, but no gross morphological renal abnormalities before gentamicin administration. Thus, our results suggest a role in the deterioration of kidney function for the loci GALNT11 and CDH23, and show that the UMOD locus is significantly associated with kidney function decline.

Mitochondrial function is altered with age and variants in mitochondrial DNA (mtDNA) modulate risk for several age-related disease states. However, the association of mtDNA copy number, a readily available marker which reflects mitochondrial depletion, energy reserves, and oxidative stress, on aging and mortality in the general population has not been addressed. To assess the association between mtDNA copy number and two primary outcomes--prevalent frailty and all-cause mortality--we utilize data from participants who were from two multicenter, multiethnic, community-based, prospective studies--the Cardiovascular Health Study (CHS) (1989-2006) and the Atherosclerosis Risk in Communities (ARIC) study (1987-2013). A total of 4892 participants (43.3% men) from CHS and 11,509 participants (44.9% men) from ARIC self-identifying as white or black were included in the analysis. mtDNA copy number, the trait of interest, was measured using a qPCR-based method in CHS and an array-based method in ARIC from DNA isolated from whole blood in participants from both cohorts. In race-stratified meta-analyses, we observe a significant inverse association of mtDNA copy number with age and higher mtDNA copy number in women relative to men. Lower mtDNA copy number was also significantly associated with prevalent frailty in white participants from CHS (OR 0.91, 95% CI 0.85-0.97). Additionally, mtDNA copy number was a strong independent predictor of all-cause mortality in an age- and sex-adjusted, race-stratified analysis of 16,401 participants from both cohorts with a pooled hazard ratio of 1.47 (95% CI 1.33-1.62) for the lowest quintile of mtDNA copy number relative to the highest quintile. Key messages: Mitochondrial DNA (mtDNA) copy number is associated with age and sex. Lower mtDNA copy number is also associated with prevalent frailty. mtDNA copy number is a significant predictor of all-cause mortality in a multiethnic population.

Significant advances are needed to improve the diagnosis, prognosis, and management of persons with CKD. Discovery of new biomarkers and improvements in currently available biomarkers for CKD hold great promise to achieve these necessary advances. Interest in identification and evaluation of biomarkers for CKD has increased substantially over the past decade. In 2009, the National Institute of Diabetes and Digestive and Kidney Diseases established the CKD Biomarkers Consortium (http://www.ckdbiomarkersconsortium.org/), a multidisciplinary, collaborative study group located at over a dozen academic medical centers. The main objective of the consortium was to evaluate new biomarkers for purposes related to CKD in established prospective cohorts, including those enriched for CKD. During the first 5 years of the consortium, many insights into collaborative biomarker research were gained that may be useful to other investigators involved in biomarkers research. These lessons learned are outlined in this Special Feature and include a wide range of issues related to biospecimen collection, storage, and retrieval, and the internal and external quality assessment of laboratories that performed the assays. The authors propose that investigations involving biomarker discovery and validation are greatly enhanced by establishing and following explicit quality control metrics, including the use of blind replicate and proficiency samples, by carefully considering the conditions under which specimens are collected, handled, and stored, and by conducting pilot and feasibility studies when there are concerns about the condition of the specimens or the accuracy or reproducibility of the assays.

BACKGROUND:Whether the association of chronic kidney disease (CKD) with cardiovascular risk differs based on diabetes mellitus (DM) and hypertension (HTN) status remains unanswered. METHODS:We investigated 11,050 participants from the Atherosclerosis Risk in Communities Study (fourth examination (1996-1998)) with follow-up for cardiovascular outcomes (coronary disease, heart failure and stroke) through 2009. Using the Cox regression models, we quantified cardiovascular risk associated with estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR) in individuals with and without DM and/or HTN and assessed their interactions. RESULTS:Individuals with DM and HTN generally had higher cardiovascular risk relative to those without at all the levels of eGFR and ACR. Cardiovascular risk increased with lower eGFR and higher ACR regardless of DM and HTN status (e.g. adjusted hazards ratio (HR) for eGFR 30-44 vs. 90-104 ml/min/1.73 m(2), 2.32 (95% CI, 1.66-3.26) in non-diabetics vs. 1.83 (1.25-2.67) in diabetics and 2.45 (2.20-5.01) in non-hypertensives vs. 1.51 (1.27-1.81) in hypertensives and corresponding adjusted HR for ACR 30-299 vs. <10 mg/g, 1.70 (1.45-2.00) vs. 1.34 (1.10-1.64) and 1.42 (1.10-1.85) vs. 1.57 (1.36-1.81), respectively). Only the ACR-DM interaction reached significance, with a shallower relative risk gradient among diabetics than among non-diabetics (p = 0.02). Analysis of individual cardiovascular outcomes showed similar results. CONCLUSION/CONCLUSIONS:Although individuals with DM and HTN generally had higher cardiovascular risk relative to those without these complications, both low eGFR and high ACR were associated with cardiovascular diseases regardless of the presence or absence of DM and HTN. These findings reinforce the importance of CKD in cardiovascular outcomes.

Accurate assessment of cognitive impairment requires comparison of cognitive performance in individuals to performance in a comparable healthy normative population. Few prior studies have included a large number of black participants and few have excluded participants from the normative sample with subclinical/latent neurological disease or dementia. This study provides age, race, and education-specific normative data for 8 cognitive tests derived from 320 black and 392 white participants aged 61 to 82 years (mean 71 y) in the Atherosclerosis Risk in Communities (ARIC) study without clinical or subclinical/latent neurological disease. Normative data are provided for the Delayed Word Recall Test, Logical Memory Parts I and II, the Word Fluency Test, Animal Naming, the Trail Making Test Parts A and B and the Digit Symbol Substitution Test. Age, race, and education-specific mean and -1.5 SD scores are given in tabular form and graphically, as well as regression-based equations to derive adjusted score cut-points. These robust normative data should enhance comparison across studies of cognitive aging, where these measures are widely used, and improve interpretation of performance on these tests for the diagnosis of cognitive impairment not only within the ARIC cohort, but also among older blacks and whites with similar demographics.