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1.  Genetics of kidney disease and related cardiometabolic phenotypes in Zuni Indians: the Zuni Kidney Project 
The objective of this study is to identify genetic factors associated with chronic kidney disease (CKD) and related cardiometabolic phenotypes among participants of the Genetics of Kidney Disease in Zuni Indians study. The study was conducted as a community-based participatory research project in the Zuni Indians, a small endogamous tribe in rural New Mexico. We recruited 998 members from 28 extended multigenerational families, ascertained through probands with CKD who had at least one sibling with CKD. We used the Illumina Infinium Human1M-Duo version 3.0 BeadChips to type 1.1 million single nucleotide polymorphisms (SNPs). Prevalence estimates for CKD, hyperuricemia, diabetes, and hypertension were 24%, 30%, 17% and 34%, respectively. We found a significant (p < 1.58 × 10-7) association for a SNP in a novel gene for serum creatinine (PTPLAD2). We replicated significant associations for genes with serum uric acid (SLC2A9), triglyceride levels (APOA1, BUD13, ZNF259), and total cholesterol (PVRL2). We found novel suggestive associations (p < 1.58 × 10-6) for SNPs in genes with systolic (OLFML2B), and diastolic blood pressure (NFIA). We identified a series of genes associated with CKD and related cardiometabolic phenotypes among Zuni Indians, a population with a high prevalence of kidney disease. Illuminating genetic variations that modulate the risk for these disorders may ultimately provide a basis for novel preventive strategies and therapeutic interventions.
PMCID: PMC4311707  PMID: 25688259
single nucleotide polymorphisms; association; kidney function; serum uric acid; triglycerides
2.  Troponin I and NT-proBNP and the Association of Systolic Blood Pressure With Outcomes in Incident Hemodialysis Patients: The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) Study 
There is uncertainty regarding treatment of hypertension in hemodialysis patients due to the observed J-shaped association between blood pressure (BP) and death. We hypothesized that this association reflects confounding by cardiovascular disease (CVD) and that stratification by CVD biomarkers, cardiac troponin I (cTnI) and N-terminal fragment of prohormone brain natriuretic peptide (NT-proBNP), might change this association.
Study Design
National prospective cohort study.
Setting & Participants
446 incident hemodialysis patients.
Predialysis systolic BP.
Mortality (all-cause and CVD) and first CVD event assessed using Cox regression adjusted for demographics, comorbidities and clinical factors.
Participants with cTnI ≥0.1 ng/mL or NT-proBNP ≥9,252 pg/mL classified as the high biomarker group; remaining participants included in the low biomarker group.
Participants in the high biomarker group (n=138 [31%]) were older (61 versus 57 years) and had higher prevalence of CVD (67% versus 23%) but similar baseline BP (152 versus 153 mm Hg). There were 323 deaths (143 from CVD) and 271 CVD events. The high-biomarker group had higher risk of mortality than low biomarker group (HR, 1.75; 95% CI, 1.37–2.24). The association between BP and outcomes differed among the two biomarker groups (p for interaction of 0.01, 0.16 and 0.07 for all-cause mortality, CVD mortality and first CVD event, respectively). In the low biomarker group, BP was associated with a greater risk: HR per 10–mm Hg higher BP of 1.07 [95% CI, 1.01–1.14], 1.10 [95% CI, 0.96–1.25], and 1.04 [95% CI, 0.96–1.13] for all-cause mortality, CVD mortality, and first CVD event, respectively. Importantly, lower BP was not associated with an increased risk of outcomes in stratified models including among those with high biomarkers.
BP measurements not standardized.
The observed J-shaped association between BP and outcomes in hemodialysis patients is due to confounding by subclinical CVD. A stratification approach based on cTnI and NT-proBNP has the potential to inform BP treatment in hemodialysis patients.
PMCID: PMC4143435  PMID: 24787760
End-Stage Renal Disease (ESRD); Hypertension; Troponin I; N-terminal pro–brain natriuretic peptide (NT-proBNP); Dialysis; Epidemiology; Hemodialysis; Mortality; Outcomes; systolic blood pressure
3.  Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND) 
PLoS Genetics  2015;11(8):e1005352.
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.
Author Summary
Type 2 diabetes is the most common cause of severe kidney disease worldwide and diabetic kidney disease (DKD) associates with premature death. Individuals of non-European ancestry have the highest burden of type 2 DKD; hence understanding the causes of DKD remains critical to reducing health disparities. Family studies demonstrate that genes regulate the onset and progression of DKD; however, identifying these genes has proven to be challenging. The Family Investigation of Diabetes and Nephropathy consortium (FIND) recruited a large multi-ethnic collection of individuals with type 2 diabetes with and without kidney disease in order to detect genes associated with DKD. FIND discovered and replicated a DKD-associated genetic locus on human chromosome 6q25.2 (rs955333) between the SCAF8 and CNKSR genes. Findings were supported by significantly different expression of genes in this region from kidney tissue of subjects with, versus without DKD. The present findings identify a novel kidney disease susceptibility locus in individuals with type 2 diabetes which is consistent across subjects of differing ancestries. In addition, FIND results provide a rich catalogue of genetic variation in DKD patients for future research on the genetic architecture regulating this common and devastating disease.
PMCID: PMC4549309  PMID: 26305897
4.  Twice-Weekly and Incremental Hemodialysis Treatment for Initiation of Kidney Replacement Therapy 
Mortality is highest in the first months of maintenance hemodialysis (HD). 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 more 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 paper 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/day), volume status, cardiovascular symptoms, body size, potassium and phosphorus levels, nutritional status, hemoglobin, comorbid conditions, hospitalizations, and health related quality of life. These ten clinical criteria may identify which patients might benefit from beginning maintenance HD 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 vs. 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. Such incremental and individualized HD therapy may prove to be the most appropriate approach for transitioning to dialytic therapy.
PMCID: PMC4111970  PMID: 24840669
Transition of care; residual kidney function; incremental dialysis; incremental hemodialysis; end-stage renal disease; kidney replacement therapy; renal replacement therapy
5.  Management of Hypertension in In-Center Hemodialysis Patients – An Opinion–Based Update 
Seminars in dialysis  2014;27(2):146-153.
Hypertension is highly prevalent in hemodialysis patients but its management remains a matter of debate. In this review, we discuss the observational studies on the association of blood pressure with outcomes, measurement of blood pressure in hemodialysis patients and present an opinion-based approach to treating hypertension.
PMCID: PMC3956305  PMID: 24494716
6.  Increased CD36 Expression Signals Monocyte Activation Among Patients With Type 2 Diabetes 
Diabetes Care  2010;33(9):2065-2067.
To explore the hypothesis that CD36, a scavenger receptor and fatty acid translocase, is upregulated in peripheral blood mononuclear cells (PBMCs) among patients with type 2 diabetes and is a biomarker of PBMC activation and inflammation.
We used a cross-sectional observational design to study a multi-racial/ethnic population sample consisting of Caucasians, Hispanics, and Native Americans with type 2 diabetes (n = 33) and nondiabetic control subjects (n = 27). PBMC CD36 mRNA/protein and plasma high sensitivity (hs) C-reactive protein (hsCRP), hs–interleukin-6 (hsIL-6), and adiponectin were measured.
Unadjusted PBMC CD36 mRNA and protein were 1.56- and 1.63-fold higher, respectively, among type 2 diabetic subjects versus control subjects. PBMC CD36 protein was directly associated with CD36 mRNA, plasma hsCRP, and hsIL-6 and inversely associated with plasma adiponectin in both groups.
Increased CD36 expression is a biomarker of PBMC activation and inflammation and may become a useful tool in cardiovascular disease risk stratification.
PMCID: PMC2928364  PMID: 20551015
7.  Heritability of Measures of Kidney Disease Among Zuni Indians: The Zuni Kidney Project 
The long-term goal of the GKDZI (Genetics of Kidney Disease in Zuni Indians) Study is to identify genes, environmental factors, and genetic-environmental interactions that modulate susceptibility to renal disease and intermediate phenotypes.
Study Design
A community-based participatory research approach was used to recruit family members of individuals with kidney disease.
Setting & Participants
The study was conducted in the Zuni Indians, a small endogamous tribe located in rural New Mexico. We recruited members of extended families, ascertained through a proband with kidney disease and at least 1 sibling with kidney disease. 821 participants were recruited, comprising 7,702 relative pairs.
Predictor Outcomes & Measurements
Urine albumin-creatinine ratio (UACR) and hematuria were determined in 3 urine samples and expressed as a true ratio. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease (MDRD) Study equation modified for American Indians. Probands were considered to have kidney disease if UACR was ≥0.2 in 2 or more of 3 spot urine samples or estimated GFR was decreased according to the CRIC (Chronic Renal Insufficiency Cohort) Study criteria.
Kidney disease was identified in 192 participants (23.4%). There were significant heritabilities for estimated GFR, UACR, serum creatinine, serum urea nitrogen, and uric acid and a variety of phenotypes related to obesity, diabetes, and cardiovascular disease. There were significant genetic correlations of some kidney-related phenotypes with these other phenotypes.
Limitations include absence of renal biopsy, possible misclassification bias, lack of direct GFR measurements, and failure to include all possible environmental interactions.
Many phenotypes related to kidney disease showed significant heritabilities in Zuni Indians, and there were significant genetic correlations with phenotypes related to obesity, diabetes, and cardiovascular disease. The study design serves as a paradigm for the conduct of research in relatively isolated, endogamous, underserved populations.
PMCID: PMC3030616  PMID: 20646805
Genetics; heritability; American Indians; kidney diseases; risk factors; glomerular filtration rate; urine albumin-creatinine ratio (UACR); creatinine; serum urea nitrogen (SUN); uric acid
8.  A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND) 
PLoS ONE  2013;8(12):e81888.
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.
Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.
The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.
The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
PMCID: PMC3866106  PMID: 24358131
9.  Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study 
American Journal of Nephrology  2011;33(5):381-389.
Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.
A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations.
Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies.
These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.
PMCID: PMC3078269  PMID: 21454968
Albuminuria; Diabetes mellitus; Renal failure; End-stage renal disease; Linkage; Allelic association
10.  Computerized Decision Support for EPO Dosing in Hemodialysis Patients 
Anemia management in hemodialysis patients poses significant challenges. The present study explored the hypothesis that computerized dosing of intravenous erythropoietin (EPO) would increase the percentage of hemoglobin (Hb) values within the target range and reduce staff time spent on anemia management.
Study Design
Retrospective cohort
Setting and Participants
In-center hemodialysis patients who received EPO at Dialysis Clinic Inc dialysis units for at least 3 months between Oct 1, 2005 and April 30, 2006
Quality Improvement Plan
Computerized decision support (CDS) for EPO dosing is compared with manual physician-directed dosing.
Outcomes and Measurements
Achieved monthly Hb values, quantity of EPO administered, and time spent by dialysis unit personnel
Monthly Hb values and the quantity of EPO administered to 1118 patients from 18 dialysis units treated by CDS and 7823 patients from 125 dialysis units treated by manual dosing.
There was no difference in the likelihood of a monthly Hb of 11–12 g/dl or 10–12 g/dl with CDS as compared with manual dosing. The likelihood of Hb > 12 g/dL decreased and the likelihood of Hb < 10g/dl increased with CDS. EPO use was 4% lower with CDS, although the difference was not statistically significant. CDS was associated with a nearly 50% reduction (p<0.001) in the time spent by dialysis unit staff on anemia management.
Retrospective, non-randomized
The number of monthly Hb values in a 11 (and 10)–12 g/dl target range and EPO use did not differ with EPO dosing by a CDS as compared with manual dosing. The staff resources devoted to anemia management declined significantly with CDS.
PMCID: PMC2788058  PMID: 19781831
Anemia; hemoglobin; hemodialysis; ESRD; erythropoietin; quality improvement; decision support; computer
11.  Genome-wide linkage scans for type 2 diabetes mellitus in four ethnically diverse populations; significant evidence for linkage on chromosome 4q in African Americans: the Family Investigation of Nephropathy and Diabetes (FIND) Research Group 
Previous studies have shown that, in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations.
Phenotypic and genotypic data were obtained from African American (AA; total number of individuals (N)=1004), American Indian (AI; N=883), European American (EA; N=537), and Mexican American (MA; N=1634) individuals from the Family Investigation of Nephropathy and Diabetes. Nonparametric linkage analysis, using an average of 4,404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM.
Statistically significant evidence for linkage was observed on chromosomes 4q21.1 (LOD=3.13; genome-wide p=0.04) in AA. In addition, a total of eleven regions showed suggestive evidence for linkage (estimated at LOD>1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD=2.02) and 22q12.3 (LOD=2.38) in AA, 2p11.1 (LOD=2.23) in AI, 6p12.3 (LOD=2.77) in EA, and 13q21.1 (LOD=2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD>1.71 have been identified in previously published studies.
The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA, 6p in EA, 2p in AI, and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population.
PMCID: PMC2783577  PMID: 19795399
FIND; Type 2 Diabetes; linkage analysis; ethnicity
12.  Heritability of the Severity of Diabetic Retinopathy: The FIND-Eye Study 
Diabetic retinopathy (DR) and diabetic nephropathy (DN) are serious microvascular complications of diabetes mellitus. Correlations between severity of DR and DN and computed heritability estimates for DR were determined in a large, multiethnic sample of diabetic families. The hypothesis was that (1) the severity of DR correlates with the presence and severity of nephropathy in individuals with diabetes mellitus, and (2) the severity of DR is under significant familial influence in members of multiplex diabetic families.
The Family Investigation of Nephropathy and Diabetes (FIND) was designed to evaluate the genetic basis of DN in American Indians, European Americans, African Americans, and Mexican Americans. FIND enrolled probands with advanced DN, along with their diabetic siblings who were concordant and discordant for nephropathy. These diabetic family members were invited to participate in the FIND-Eye study to determine whether inherited factors underlie susceptibility to DR and its severity. FIND-Eye participants underwent eye examinations and had fundus photographs taken. The severity of DR was graded by using the Early Treatment Diabetic Retinopathy Study Classification (ETDRS). Sib–sib correlations were calculated with the SAGE 5.0 program FCOR, to estimate heritability of retinopathy severity.
This report summarizes the results for the first 2368 diabetic subjects from 767 families enrolled in FIND-Eye; nearly 50% were Mexican American, the largest single ethnicity within FIND. The overall prevalence of DR was high; 33.4% had proliferative DR; 7.5%, 22.8%, and 9.5% had severe, moderate, and mild nonproliferative DR, respectively; 26.6% had no DR. The severity of DR was significantly associated with severity of DN, both by phenotypic category and by increasing serum creatinine concentration (χ2 = 658.14, df = 20; P < 0.0001). The sib–sib correlation for DR severity was 0.1358 in the total sample and 0.1224 when limited to the Mexican-American sample. Broad sense heritabilities for DR were 27% overall and 24% in Mexican-American families. The polygenic heritability of liability for proliferative DR approximated 25% in this FIND-Eye sample.
These data confirm that the severity of DR parallels the presence and severity of nephropathy in individuals with diabetes mellitus. The severity of DR in members of multiplex diabetic families appears to have a significant familial connection.
PMCID: PMC2583147  PMID: 18765632

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