Individuals with a family history of ESRD are a high-risk population for CKD: implications for targeted surveillance and intervention activities.

Activities intended to improve the detection, treatment, and control of chronic kidney disease (CKD) should be incorporated into existing health care systems and targeted to high-risk populations to avoid redundancy and waste of resources. One high-risk population consists of first- or second-degree family members of patients with end-stage renal disease (ESRD), who are 2 to 3 times as likely to have incident ESRD, have high rates of impaired kidney function and undetected and uncontrolled high blood pressure, and are more likely to be obese. These individuals usually are unaware of their underlying CKD and may discount their own risk of ESRD. The ESRD Network 6 Family History Project shows that the ESRD Networks, which constitute a national CKD surveillance system for patients with stage 5 CKD, may be an existing resource that can be used to identify relatives of incident patients with ESRD and provide these families with information about CKD. Nationally available resources have been developed by the National Kidney Disease Education Program for use with these at-risk families. Individuals interested in population-based CKD control activities should be aware of and use these resources.

Obesity is associated with family history of ESRD in incident dialysis patients.

BACKGROUND: Obesity is an established risk factor for chronic kidney disease and aggregates in families. The objective of this study is to examine the relationship between obesity and family history of end-stage renal disease (ESRD). METHODS: Data were collected from 25,883 incident patients with ESRD in US ESRD Network 6 (Georgia, North Carolina, and South Carolina) dialysis clinics between 1995 and 2003. Family history is defined as a first- or second-degree relative with ESRD. Body mass index (BMI) at dialysis therapy initiation was classified as underweight (BMI < 18.5 kg/m2), normal (BMI, 18.5 to <25 kg/m2), overweight (BMI, 25 to < 30 kg/m2), obese (BMI, 30 to <35 kg/m2), or morbidly obese (BMI > or = 35 kg/m2). RESULTS: Twenty-three percent of patients reported a family history of ESRD. Of patients reporting a family history of ESRD, 5.5% were underweight, 32.5% had normal BMI, 28.0% were overweight, 17.3% were obese, and 16.7% were morbidly obese. After controlling for age, race, sex, primary cause of ESRD, history of diabetes, history of hypertension, and estimated glomerular filtration rate at dialysis therapy initiation, reported family history of ESRD was associated with being overweight (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.08 to 1.26), obese (OR, 1.25; 95% CI, 1.14 to 1.37), and morbidly obese (OR, 1.40; 95% CI, 1.27 to 1.55). CONCLUSION: Obesity at dialysis therapy initiation was associated independently with reported family history of ESRD. This finding suggests that behavioral factors, adiposity-related genes, and gene-by-BMI interaction may contribute to familial risk for ESRD. This finding also suggests that management of obesity may be even more important for patients with a family history of ESRD than for the general population.

Genetic factors in end-stage renal disease.

Despite more aggressive treatment of diabetes, hypertension, and hyperlipidemia, the incidence and prevalence rates of end-stage renal disease (ESRD) continue to increase worldwide. The likelihood of developing chronic kidney disease in an individual is determined by interactions between genes and the environment. Familial clustering of nephropathy has repeatedly been observed in all population groups studied and for multiple etiologies of kidney disease. A three- to nine-fold greater risk of ESRD is observed in individuals with a family history of ESRD. Marked racial variation in the familial aggregation of kidney disease exists, with high rates in African American, Native American, and Hispanic American families. Disparate etiologies of nephropathy aggregate within African American families, as well. These data have led several investigators to search for genes linked to diabetic and other forms of nephropathy. Evidence for linkage to kidney disease has been detected and replicated at several loci on chromosomes 3q (types 1 and 2 diabetic nephropathy), 10q (diabetic and nondiabetic kidney disease), and 18q (type 2 diabetic nephropathy). Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Given the overwhelming burden of kidney disease worldwide, it is imperative that we develop a clearer understanding of the pathogenesis of nephropathy so that individuals at risk can be identified and treated at earlier, potentially reversible, stages of their illness.

The familial clustering of renal disease and related phenotypes.

This article reviews the familial aggregation of chronic kidney diseases including end-stage renal disease and albuminuria, along with variation in glomerular filtration rate. In addition to environmental influences on the progression of nephropathy, epidemiologic evidence in support of the existence of renal failure susceptibility genes is presented.

Nephropathy in siblings of African Americans with overt type 2 diabetic nephropathy.

BACKGROUND: The prevalence of abnormal proteinuria and elevated serum creatinine (sCr) concentrations in diabetic sibs of African Americans (AAs) with overt type 2 diabetic nephropathy (DN) or end-stage renal disease (ESRD) is unknown. METHODS: We measured urine albumin-creatinine (UAC) ratio, sCr, and hemoglobin A1c (HbA1c) in 211 sibs from 66 families (66 unrelated index cases with overt type 2 DN/ESRD, 132 of their diabetic sibs, and 13 of their nondiabetic sibs). Overt DN was defined as a UAC ratio of 1,000 mg/g or greater or ESRD attributed to diabetes. All index cases had at least one diabetic sib screened. RESULTS: Given similar mean ages and body mass indices, nondiabetic sibs had lower UAC ratios and HbA1c values compared with diabetic sibs and index cases (Wilcoxon's rank-sum test, all P < 0.006). More than 60% of index cases had at least one diabetic sib with a UAC ratio of 30 or greater and 300 mg/g or less. Nearly 35% of index cases had at least one sib with a UAC ratio greater than 300 mg/g. Nearly 24% of index cases had at least one sib with an elevated sCr level (> or =1.4 mg/dL [124 micromol/L] in women, > or =1.6 mg/dL [141 micromol/L] in men). CONCLUSION: Asymptomatic elevations in urinary albumin excretion and sCr levels are frequently present in diabetic sibs of AA individuals with overt type 2 DN. Diabetic sibs of AA individuals with type 2 DN should be the focus of intensive screening and intervention programs to slow the current epidemic of diabetic ESRD.

Heritability of the severity of diabetic retinopathy: the FIND-Eye study.

PURPOSE: 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. METHODS: 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. RESULTS: 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 (chi(2) = 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. CONCLUSIONS: 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.

Familial clustering of chronic kidney disease.

The incidence and prevalence rates of most forms of chronic kidney disease (CKD) had steadily been increasing for the past 30 years, although these rates now appear to have reached a plateau. It is clear that an individual's likelihood of developing progressive CKD results from complex interactions between multiple genetic and environmental factors. Familial clustering of CKD and end-stage renal disease (ESRD) is observed among all the common etiologies of nephropathy. This article reviews the epidemiology of the familial clustering of kidney disease, as well as potential environmental and genetic contributors. The related impact of familial clustering of cardiovascular disease (CVD) and the impact of CVD on the current epidemic of ESRD is also discussed. It is imperative that nephrologists and primary care physicians recognize that individuals who have relatives with advanced nephropathy are themselves at high risk for subsequent kidney disease, proteinuria, and atherosclerotic cardiovascular complications. Until kidney failure genes are identified, it is reasonable to use "family history" (FH) as a surrogate marker for risk of future nephropathy. The detection of kidney disease genes holds great promise for detecting novel pathways that initiate renal fibrosis and lead to progressive loss of renal function. These pathways are likely to offer new therapies that may slow or halt development of chronic kidney failure.

Population-based screening for family history of end-stage renal disease among incident dialysis patients.

BACKGROUND: We determined the familial aggregation of end-stage renal disease (ESRD) in a large, population-based sample of incident ESRD cases to assess the feasibility of developing a targeted screening and prevention program directed at members of families at high risk for kidney disease. METHODS: Between January 1, 1995, and December 31, 2003, incident dialysis patients in ESRD Network 6 facilities were asked to complete a voluntary questionnaire on family history (FH) of ESRD. Cases with ESRD attributed to Mendelian diseases or urologic causes were excluded. FH was considered present if first- or second-degree relatives had ESRD. De-identified FH data were collated with demographic data at dialysis initiation. RESULTS: More than 46% of eligible patients (25,883/55,929) provided FH information and 22.8% (5,901/25,883) of these reported having a FH of ESRD. FH of ESRD was positively associated with female gender, earlier age at ESRD onset, and primary cause of ESRD, and negatively associated with white race. FH associations with age, race, gender, and primary cause of renal failure remained statistically significant after simultaneous adjustment in a multivariate logistic regression model. CONCLUSIONS: Approximately 23% of incident dialysis patients have close relatives with ESRD. Far more are likely to have relatives with clinically silent proteinuria or chronic kidney disease (CKD), both risk factors for future cardiovascular events and ESRD. Physicians caring for patients with CKD should be aware of the marked familial aggregation of ESRD and consider focusing screening efforts on high-risk family members in an attempt to slow the exponential growth rate of kidney disease.

The importance of family history on the development of renal disease.

PURPOSE OF REVIEW: Family history of end-stage renal disease is an important risk factor for the subsequent development of nephropathy. Multiply-affected families with members demonstrating end-stage renal disease often contain individuals with disparate etiologies of renal disease. These observations have led to the search for nephropathy susceptibility genes. RECENT FINDINGS: Genetic loci associated with susceptibility to diabetic (3q, 18q22.3-23) and non-diabetic nephropathy (chromosome 10) have been identified. A mutation in the uromodulin gene (16p11-13) has recently been linked to medullary cystic kidney disease type 2 and familial juvenile hyperuricemic nephropathy. Familial focal segmental glomerulosclerosis is linked to the 1q25-31, 11q21-22, and 19q13 loci in different families. Several research groups are evaluating family members of individuals with nephropathy in an attempt to uncover previously undiagnosed cases of renal disease. SUMMARY: Family members of individuals with chronic kidney disease are disproportionately affected with unrecognized and asymptomatic nephropathy. Screening of these high-risk relatives for early nephropathy, and for risk factors for nephropathy, will probably lead to successful treatment for nephropathy and slow the growing worldwide epidemic of end-stage renal disease.

Clinical characterization of a family with a mutation in the uromodulin (Tamm-Horsfall glycoprotein) gene.

BACKGROUND: We have recently identified a mutation in the uromodulin gene in a large family affected with hyperuricemia, gout, and renal failure. The purpose of this investigation is to provide a comprehensive characterization of the clinical findings of this syndrome in family members who had a mutation in the uromodulin gene. METHODS: An extended family suffering from hyperuricemia and gout was identified by a local practitioner. After consent was obtained, patients provided a directed clinical history and blood and urine specimens for chemical and genetic testing. All family members were tested for the presence of uromodulin gene mutations by direct DNA sequence analysis. The clinical and biochemical characteristics of family members carrying the affected mutation were then investigated. RESULTS: Thirty-nine family members were found to have an exon 5 uromodulin gene mutation (g.1966 1922 del), and 29 unaffected family members were identified. The cardinal clinical features in individuals with the uromodulin mutation included hyperuricemia, decreased fractional excretion of uric acid, and chronic interstitial renal disease leading to end-stage renal disease (ESRD) in the fifth through seventh decade. Women did not always develop hyperuricemia or gout, but still developed progressive chronic renal failure. CONCLUSION: Mutation of the uromodulin gene resulted in hyperuricemia, reduced fractional excretion of uric acid, and renal failure. Genetic testing will be required to definitively identify individuals suffering from this condition. We are interested in studying other families that may suffer from this condition and would appreciate any such referrals.