Linkage Consortium for End-Stage Renal Disease

The Family Investigation of Nephropathy and Diabetes (FIND)Study is a multi-center consortium. The charge of the consortium is to acquire sets of families with well-characterized diabetic nephropathy, establish a secure master FIND database, and perform a genome scan to identify chromosomal regions linked with diabetic nephropathy.

Diabetic Nephropathy (DN) is undoubtedly a multifactorial disease, and a large proportion of patients affected with either type 1 or type 2 diabetes develop diabetic nephropathy and progress to end stage renal disease (ESRD). When poor prognostic factors such as hypertension and chronic hyperglycemia are aggressively treated, the rate of progression of diabetic nephropathy can be slowed. However, no interventions have been shown to reliably halt the progression of diabetic nephropathy. Numerous studies have suggested that genetic predisposition to diabetic nephropathy exists, but genes for nephropathy have not yet been isolated. It is anticipated that a comprehensive analysis of a large number of uniformly phenotyped ESRD families will be necessary to isolate genes for ESRD. Such a database of families may not be available at any single institution. The FIND study has established a centralized Genetic Analysis and Data Coordinating Center (GADCC) that, together with eight participating investigation centers (PICs), three minority recruitment centers, and the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), will use the emerging high-throughput genetic technologies to enable identification of diabetic nephropathy susceptibility or protection genes. The charge of the consortium is to acquire sets of families with well-characterized diabetic nephropathy, establish a secure master FIND database, and perform a genome scan to identify chromosomal regions linked with diabetic nephropathy. The FIND study population includes participants from European American (EA), Native American (NA), African American (AA) and Mexican American (AA) populations.

Two analytic approaches are utilized in FIND. The Family Study approach involves the enrollment of probands, affected or discordant sibling and their affected family members. Analytic methods include affected sibling pair (ASP), discordant sibling pair (DSP) affected relative pair (ARP), and discordant relative pair (DRP) linkage analyses for the Family Study. The Mapping by Admixture and Linkage Disequilibrium (MALD) approach involves the enrollment of probands and a population based control for both the AA and MA studies. In addition, a spousal control (diad) and when available, a child 18 years or older, will be recruited (triad)for the AA MALD study only.

• Diabetes
• Diabetic Nephropathy

Inclusion Criteria:

For the Family protocol, proband must meet diagnostic criteria for diabetes and have nephropathy that meets one of the following:

• diabetic nephropathy diagnosed from a kidney biopsy and a history of overt proteinuria.
• ESRD considered due to diabetic nephropathy because
• diabetes is present for ≥ 5 years prior to the initiation of renal replacement therapy and diabetic retinopathy has been diagnosed at any time; or
• diabetes is present ≥ 5 years prior to the initiation of replacement therapy and either a 24 hour urine collection contains ≥ 3 gm protein/24 hours or a random urine protein (mg/dl)/ creatinine (mg/dl) ratio is ≥ 3.0; or
• diabetic retinopathy is present and either a previous 24 hour urine collection contains ≥ 3 gm protein/24 hours or a random urine protein (mg/dl)/ creatinine (mg/dl) ratio is ≥ 3.0.
• nephropathy without ESRD that is considered to be diabetic nephropathy because (a) diabetic retinopathy and a 24 hr urine collection with either ≥ 1 gram proteinuria/24 hours or a urine protein (mg/dl)/ creatinine (mg/dl) ratio ≥ 1.0; or (b) at a time when diabetes duration is ≥ 10 years, either a urine collection of ≥ 3 grams protein/24 hours or a urine protein (mg/dl) /creatinine (mg/dl) ratio ≥ 3.0.

African-American patients with chronic renal failure are as MALD cases by meeting criteria for diabetic nephropathy, as described for Family probands, or having nephropathy (serum creatinine ≥ 2.0 mg/dl) not due to diabetes or known monogenic renal disease. Mexican-Americans recruited as MALD cases must meet criteria for diabetic nephropathy as defined for the Family probands. Phenotype criteria for probands entered into the Family or MALD protocols must be confirmed by medical record review.

Eligibility of family members and MALD control subjects is based on laboratory tests obtained at the time of screening. Entry of a proband with diabetic nephropathy into the Family protocol also requires participation of either two living parents or at least one full sibling with diabetes. To be enrolled as having nephropathy, the diabetic sib must meet one of the following criteria:

• renal biopsy consistent with a diagnosis of diabetic nephropathy;
• urinary albumin excretion ≥ 30 mg/24hr or a urine albumin (mg/dl)/creatinine (mg/dl) ratio ≥ 0.03;
• a serum creatinine concentration ≥ 1.6 mg/dl for men or ≥ 1.4 mg/dl for women; or
• ESRD. Unaffected sibs are recruited if they have had diabetes for ≥ 10 years, have normal serum creatinine and albumin excretion (< 30 mg albumin/24 hours, or a urine albumin (mg/dl)/creatinine (mg/dl) ratio < 0.03) and no historical evidence of kidney disease.

The criteria for MALD control subjects differ by ethnic group. For the African-American MALD protocol, two different control samples are recruited. First, an adult offspring with or without renal disease and the other parent of the offspring, who cannot have evidence of renal disease, are collected as controls for African-American probands with either diabetic or non-diabetic nephropathy. Together with the probands, this forms a sample of triads (offspring and other parent) or dyads (spouse only). A second group of African-American control subjects consists of unrelated individuals with diabetes duration ≥ 10 years and without nephropathy (as defined above for diabetic sibs). For Mexican Americans, a single unrelated control population is recruited with diabetes duration ≥ 10 years but without nephropathy (as defined above for diabetic sibs).

Exclusion Criteria:

A. Did not sign the informed consent: refusal to participate. B. Diagnosis not confirmed. C. Appropriate siblings not available. D. Judged not likely or unable to follow study protocol. E. Ethnicity of parents or grandparent not suitable. F. Spouse not available.