Philip G. Zager

Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: The Family Investigation of Nephropathy and Diabetes (FIND)

The Family Investigation of Nephropathy and Diabetes (FIND) was initiated to map genes underlying susceptibility to diabetic nephropathy. A total of 11 centers participated under a single collection protocol to recruit large numbers of diabetic sibling pairs concordant and discordant for diabetic nephropathy. We report the findings from the first-phase genetic analyses in 1,227 participants from 378 pedigrees of European-American, African-American, Mexican-American, and American Indian descent recruited from eight centers. Model-free linkage analyses, using a dichotomous definition for diabetic nephropathy in 397 sibling pairs, as well as the quantitative trait urinary albumin-to-creatinine ratio (ACR), were performed using the Haseman-Elston linkage test on 404 microsatellite markers. The strongest evidence of linkage to the diabetic nephropathy trait was on chromosomes 7q21.3, 10p15.3, 14q23.1, and 18q22.3. In ACR (883 diabetic sibling pairs), the strongest linkage signals were on chromosomes 2q14.1, 7q21.1, and 15q26.3. These results confirm regions of linkage to diabetic nephropathy on chromosomes 7q, 10p, and 18q from prior reports, making it important that genes underlying these peaks be evaluated for their contribution to nephropathy susceptibility. Large family collections consisting of multiple members with diabetes and advanced nephropathy are likely to accelerate the identification of genes causing diabetic nephropathy, a life-threatening complication of diabetes.

Changing Relationship of Blood Pressure with Mortality over Time among Hemodialysis Patients

High BP is a major risk factor for atherosclerotic cardiovascular disease mortality in the general population. Surprising, studies that have been conducted among hemodialysis (HD) patients have yielded conflicting data on the relationship between BP and mortality. This study explores two hypotheses among HD patients: (1) The relationship between BP and mortality changes over time, and (2) mild to moderate hypertension is well tolerated. Incident HD patients who were treated at Dialysis Clinic Inc. facilities between 1993 and 2003 were studied. Primary end points were atherosclerotic cardiovascular disease and all-cause mortality. The relationship between BP and mortality was analyzed in two sets of Cox proportional hazards models. Model-B explored the relationship between baseline BP and mortality in sequential time periods. Model-TV assessed the relationship between BP, treated as time-varying, and mortality. The study sample (n = 16,959) was similar in characteristics to the United States Renal Data Systems population, although black patients were slightly overrepresented. Model-B demonstrated that the relationship between baseline BP and mortality changes over time. Low systolic BP (<120 mmHg) was associated with increased mortality in years 1 and 2. High systolic BP (> or =150 mmHg) was associated with increased mortality among patients who survived > or =3 yr. Low pulse pressure was associated with increased mortality. Model-TV demonstrated that mild to moderate systolic hypertension may be relatively well tolerated. In conclusion, the relationship between baseline BP and mortality changes over time. Mild to moderate systolic hypertension was associated with only modest increases in mortality.

Which Targets in Clinical Practice Guidelines Are Associated with Improved Survival in a Large Dialysis Organization

Professional organizations have developed practice guidelines in the hope of improving clinical outcomes. The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) has set targets for dialysis dosage (single-pool Kt/V), hematocrit, serum albumin, calcium, phosphorus, parathyroid hormone, and BP for hemodialysis (HD) patients. Several guidelines are largely based on results from observational studies. In contrast to other parameters, BP values within the KDOQI guidelines have been associated with increased mortality. Therefore, it was postulated that having multiple parameters that satisfy the current guidelines, except those for BP, is associated with improved survival among HD patients. A retrospective analysis was conducted of incident HD patients who were treated at facilities operated by Dialysis Clinic Inc., a not-for-profit dialysis provider, between January 1, 1998, and December 31, 2004 (n = 13,792). Cox proportional hazards models were used to assess the association between satisfying guidelines and mortality. Values within guidelines for single-pool Kt/V, hematocrit, serum albumin, calcium, phosphorus, and parathyroid hormone were associated with decreased mortality (P < or = 0.0001). The largest survival benefit was found for serum albumin (hazard ratio [HR] 0.27; 95% confidence interval [CI] 0.24 to 0.31). Satisfying these six guidelines simultaneously was associated with an 89% reduction in mortality (HR 0.11; 95% CI 0.06 to 0.19]). Conversely, BP values satisfying the guideline were associated with increased mortality (HR 1.90; 95% CI 1.73 to 2.10). Because this target was largely extrapolated from the general population, a randomized, controlled trial is needed to identify the optimal BP for HD patients.

Twice-Weekly and Incremental Hemodialysis Treatment for Initiation of Kidney Replacement Therapy

Mortality is highest in the first months of maintenance hemodialysis (HD) therapy. In many Western countries, patients who transition to kidney replacement therapy usually begin thrice-weekly HD regardless of their level of residual kidney function (RKF). RKF is a major predictor of survival. RKF may decline more rapidly with thrice-weekly HD treatments, is associated with a reduced need for dialytic solute clearance, and is an important factor in the prescription of peritoneal dialysis. In this article, we review the concept of incremental HD, in which weekly dialysis dose, in particular HD treatment frequency, is based on a variety of clinical factors, such as RKF (including urine output > 0.5 L/d), volume status, cardiovascular symptoms, body size, potassium and phosphorus levels, nutritional status, hemoglobin level, comorbid conditions, hospitalizations, and health-related quality of life. These 10 clinical criteria may identify which patients might benefit from beginning maintenance HD therapy twice weekly. Periodic monitoring of these criteria will determine the timing for increasing dialysis dose and frequency. We recognize that twice-weekly HD represents a major paradigm shift for many clinicians and jurisdictions. Therefore, we propose conducting randomized controlled trials of twice-weekly versus thrice-weekly HD to assess the potential of twice-weekly HD to improve survival and health-related quality of life while simultaneously reducing costs, protecting fragile vascular accesses, and optimizing resource use during the first year of hemodialysis therapy. Such incremental and individualized HD therapy may prove to be the most appropriate approach for transitioning to dialytic therapy.

Genome-Wide Scan for Estimated Glomerular Filtration Rate in Multi-Ethnic Diabetic Populations The Family Investigation of Nephropathy and Diabetes (FIND)

OBJECTIVE— Diabetic nephropathy, the most common cause of end-stage renal disease, aggregates in families and specific ethnic groups. Deconstructing diabetic nephropathy into intermediate, quantitative phenotypes may increase feasibility of detecting susceptibility loci by genetic screens. Glomerular filtration rate (GFR), which characterizes diabetic nephropathy, was employed as a quantitative trait in a preliminary whole-genome scan. RESEARCH DESIGN AND METHODS— Estimated GFR (eGFR) was calculated for 882 diabetic sibpairs (mean age 57 years) of African-American (25.6% of total), American Indian (8.6%), European-American (14.2%), and Mexican-American (51.6%) descent enrolled in the initial phase of the Family Investigation of Nephropathy and Diabetes (FIND). A whole-genome scan was performed using 404 microsatellite markers (average spacing 9 cM) and model-free linkage analysis. RESULTS— For all ethnicities combined, strong evidence for linkage was observed on chromosomes 1q43 (P = 3.6 × 10−3), 7q36.1 (P = 2.1 × 10−4), 8q13.3 (P = 4.6 × 10−4), and 18q23.3 (P = 2.7 × 10−3). Mexican-American families, who comprised the major ethnic subpopulation in FIND, contributed to linkage on chromosomes 1q43, 2p13.3, 7q36.1, 8q13.3, and 18q23.3, whereas African-American and American-Indian families displayed linkage peaks on chromosomes 11p15.1 and 15q22.3, respectively. CONCLUSIONS— We have demonstrated multiple chromosomal regions linked to eGFR in a multi-ethnic collection of families ascertained by a proband with diabetic nephropathy. Identification of genetic variants within these loci that are responsible for the linkage signals could lead to predictive tests or novel therapies for subsets of patients at risk for diabetic nephropathy.

Age, Race, Diabetes, Blood Pressure, and Mortality among Hemodialysis Patients

Observational studies involving hemodialysis patients suggest a U-shaped relationship between BP and mortality, but the majority of these studies followed large, heterogeneous cohorts. To examine whether age, race, and diabetes status affect the association between systolic BP (SBP; predialysis) and mortality, we studied a cohort of 16,283 incident hemodialysis patients. We constructed a series of multivariate proportional hazards models, adding age and BP to the analyses as cubic polynomial splines to model potential nonlinear relationships with mortality. Overall, low SBP associated with increased mortality, and the association was more pronounced among older patients and those with diabetes. Higher SBP associated with increased mortality among younger patients, regardless of race or diabetes status. We observed a survival advantage for black patients primarily among older patients. Diabetes associated with increased mortality mainly among older patients with low BP. In conclusion, the design of randomized clinical trials to identify optimal BP targets for patients with ESRD should take age and diabetes status into consideration.

Comparison of Oxidative Stress Markers After Intravenous Administration of Iron Dextran, Sodium Ferric Gluconate, and Iron Sucrose in Patients Undergoing Hemodialysis

Study Objective. To compare non–transferrin‐bound iron and markers of oxidative stress after single intravenous doses of iron dextran, sodium ferric gluconate, and iron sucrose.

Genome-Wide Scan for Estimated GFR in Multi-Ethnic Diabetic Populations: The Family Investigation of Nephropathy and Diabetes

OBJECTIVE— Diabetic nephropathy, the most common cause of end-stage renal disease, aggregates in families and specific ethnic groups. Deconstructing diabetic nephropathy into intermediate, quantitative phenotypes may increase feasibility of detecting susceptibility loci by genetic screens. Glomerular filtration rate (GFR), which characterizes diabetic nephropathy, was employed as a quantitative trait in a preliminary whole-genome scan. RESEARCH DESIGN AND METHODS— Estimated GFR (eGFR) was calculated for 882 diabetic sibpairs (mean age 57 years) of African-American (25.6% of total), American Indian (8.6%), European-American (14.2%), and Mexican-American (51.6%) descent enrolled in the initial phase of the Family Investigation of Nephropathy and Diabetes (FIND). A whole-genome scan was performed using 404 microsatellite markers (average spacing 9 cM) and model-free linkage analysis. RESULTS— For all ethnicities combined, strong evidence for linkage was observed on chromosomes 1q43 (P = 3.6 × 10−3), 7q36.1 (P = 2.1 × 10−4), 8q13.3 (P = 4.6 × 10−4), and 18q23.3 (P = 2.7 × 10−3). Mexican-American families, who comprised the major ethnic subpopulation in FIND, contributed to linkage on chromosomes 1q43, 2p13.3, 7q36.1, 8q13.3, and 18q23.3, whereas African-American and American-Indian families displayed linkage peaks on chromosomes 11p15.1 and 15q22.3, respectively. CONCLUSIONS— We have demonstrated multiple chromosomal regions linked to eGFR in a multi-ethnic collection of families ascertained by a proband with diabetic nephropathy. Identification of genetic variants within these loci that are responsible for the linkage signals could lead to predictive tests or novel therapies for subsets of patients at risk for diabetic nephropathy.

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Oral Intradialytic Nutritional Supplement Use and Mortality in Hemodialysis Patients

BACKGROUND Hemodialysis patients have high mortality rates, potentially reflecting underlying comorbid conditions and ongoing catabolism. Intradialytic oral nutritional supplements may reduce this risk. STUDY DESIGN Retrospective propensity-matched cohort. SETTING & PARTICIPANTS Maintenance hemodialysis patients treated at Dialysis Clinic Inc facilities who were initiated on a nutritional supplement protocol in September to October 2010 were matched using a propensity score to patients at facilities at which the protocol was not used. PREDICTORS Prescription of the protocol, whereby hemodialysis patients with serum albumin levels ≤3.5g/dL would initiate oral protein supplementation during the dialysis procedure. Sensitivity analyses matched on actual supplement intake during the first 3 study months. Covariates included patient and facility characteristics, which were used to develop the propensity scores and adjust multivariable models. OUTCOMES All-cause mortality, ascertained though March 2012. RESULTS Of 6,453 eligible patients in 101 eligible hemodialysis facilities, the protocol was prescribed to 2,700, and 1,278 of these were propensity matched to controls. Mean age was 61 ± 15 (SD) years and median dialysis vintage was 34 months. There were 258 deaths among protocol assignees versus 310 among matched controls during a mean follow-up of 14 months. In matched analyses, protocol prescription was associated with a 29% reduction in the hazard of all-cause mortality (HR, 0.71; 95% CI, 0.58-0.86); adjustment had minimal impact on models. In time-dependent models incorporating change in albumin level, protocol status remained significant but was attenuated in models incorporating a 30-day lag. Similar results were seen in sensitivity analyses of 439 patients receiving supplements who were propensity-matched to controls, with 116 deaths among supplement users versus 140 among controls (HR, 0.79; 95% CI, 0.60-1.05), achieving statistical significance in adjusted models. LIMITATIONS Observational design, potential residual confounding. CONCLUSIONS Prescription of an oral nutritional supplement protocol and use of oral protein nutritional supplements during hemodialysis are associated with reduced mortality among in-center maintenance hemodialysis patients, an effect likely not mediated by change in serum albumin levels.