Scott G. Satko

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: Approximately23% 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 reviewFamily 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 findingsGenetic 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. SummaryFamily 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.

Genes and renal disease.

The identification of genetic linkage between polymorphic markers and common kidney diseases, including focal and segmental glomerulosclerosis and diabetic nephropathy, clearly demonstrates that inherited factors contribute to renal failure susceptibility. These breakthroughs reveal the powerful contribution that molecular genetic techniques can make in the search for inherited factors that initiate renal failure and lead to its progression. Additionally, the environmental factors predisposing to nephropathy will be more readily detectable when evaluated in genetically similar populations. This manuscript reviews the developments in genetic epidemiology and molecular genetics of chronic renal failure.

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.

IgA Nephropathy and Reiter’s Syndrome

Immunoglobulin A (IgA) nephropathy is the commonest type of primary glomerulonephritis worldwide. It has previously been reported in association with the seronegative spondyloarthropathies (ankylosing spondylitis, Behcet’s syndrome, psoriatic arthritis, Reiter’s syndrome and the postenteritic arthritides). Since this condition was first described in 1968, 5 previous case reports of biopsy-proven IgA nephropathy associated with Reiter’s syndrome have been published in the English-language literature. Here we report 2 more such cases, along with a review of the literature describing the association of IgA nephropathy and a number of other immune-complex-mediated glomerulonephritides with the seronegative spondyloarthropathies.

Screening for Subclinical Nephropathy in Relatives of Dialysis Patients

Despite the availability of improved medical therapy to slow the progression of nephropathy, a worldwide epidemic of end‐stage renal disease (ESRD) exists. Many patients are not diagnosed until the late stages of disease, as early kidney disease may be asymptomatic. Ideally all adults would be routinely screened for evidence of early kidney disease and associated risk factors such as hypertension and diabetes mellitus. Unfortunately this would be a massive and expensive undertaking. A more practical, cost‐effective solution might be to direct screening at those individuals who are known to be at high risk for the development of nephropathy. The familial clustering of ESRD has been reported for many types of renal disease. We propose that the routine screening of first‐ and second‐degree relatives of ESRD patients for nephropathy might be an efficient way to detect subclinical renal disease. Early detection and intensive treatment of renal disease may help to curb the current epidemic of ESRD.

Looking Beyond "Fistula First" in the Elderly on Hemodialysis.

Vascular access preparation, a pervasive challenge in hemodialysis (HD), is emerging as a multidimensional subject in geriatric nephrology. Previously published guidelines declared arteriovenous fistulas (AVF) as the preferred vascular access for all patients on HD. In this article, the benefit–risk evidence for using AVF versus an alternative access (arteriovenous graft [AVG] or tunneled central venous catheter [TCVC]) in the elderly is pondered. Compared to their younger counterparts, the elderly have significantly lower survival rates independent of the vascular access used for HD. Recent studies point to comparable dialysis survival rates between AVF and AVG or TCVC in subgroups of elderly patients, as well as lower rates of access‐related infections, and lower catheter dependence after AVG compared to AVF construction in these patients. Comprehensive and longitudinal assessments that integrate comorbidities, physical function, cognitive status, and quality of life to estimate prognosis and assist with vascular access selection ought to be employed. In circumstances where patient survival is limited by comorbidities and functional status, AVF is unlikely to confer meaningful benefits compared to AVG or even TCVC in the ill elderly.

Consultants for the American Journal of Nephrology 2005

Sandra Garber Cybele Ghossein Richard Glassock Alan Go Laurence Greenbaum Karen Griffi n S. Grigoryev Krishnamurthy Gudehithlu Peter Hart Koichi Hayashi Peter Heering Susan Hou John Hoyer Randall Hudson Todd Ing Eunice John Richard Johnson Michelle Josephson Pradeep Kadambi Ramesh Khanna Orly Kohn Jeff Kopp Mark Kraus Jerome Lane Craig Langman James Lash David Leehey Oliver Lenz Edgar Lerma Jerrold Levine Wilfred Lieberthal Stuart Linas Jill Lindberg Natalia Litbarg Gerard London Rodger Loutzenhiser Friedrich Luft K. Matsumoto Peter McCullough Patrick Murray Naoyuki Nakao Kevin Abbott Rajiv Agarwal Sharon Anderson Gema Ariceta John Asplin Simon Atkinson Asad Bakir George Bakris Vinod Bansal Amelia Bartholomew Amy Barton Pai Daniel Batlle Vecihi Batuman Enrico Benedetti Angelito Bernardo Anil Bidani Peter Blake Anthony Bleyer W. Kline Bolton Michael Braun Carolyn Brecklin Harold Bregman Ellen Brooks Vito Campese Sule Cataltepe Nina Clark Jay Cohn Richard Cohn Judith Cook Andrey Cybulsky Mohamed Daha Farhard Danesh Janice Douglas George Dunea Lance Dworkin Beatrice Edwards Leon Ferder Steven Fishbane Kenneth Fisher Mary Foster Barry Freedman