Familial Aggregation Of Diabetic Nephropathy

The strongest evidence for an inherited susceptibility to diabetic nephropathy comes from studies showing that some families in particular have an increased risk of renal disease. A family history of nephropathy (or premature cardiovascular disease as its surrogate) continues to be the most accurate and available marker for identifying patients most at risk, with familial aggregation now described for nephropathy in both type 17-8 and type 2 diabetes.9,10 The diabetic offspring of parents with diabetes and proteinuria have three to four times the prevalence of nephropathy compared to the siblings of diabetic parents without renal disease.7,8 The risk appears to be further increased if both parents have diabetic nephropathy, as opposed to only one parent with albuminuria (Figure 4.1).9 This has led to the suggestion that the predisposition to diabetic nephropathy may be inherited as a dominant trait.7,11 In addition to proteinuria, familial aggregation has also been demonstrated in the severity and pattern of diabetic glomerular structural lesions, independently of glycaemic control.12

As yet, it is unclear exactly what this 'susceptibility' trait represents. It is conceivable that any number of shared environmental factors may contribute independently to the development of disease with or without the interaction of any shared genes. It is also possible that clustering of other traits in the family of patients with nephropathy contributes to the development and severity of diabetes rather than renal disease directly. Such factors include hypertension, glucose tolerance, insulin resistance and body habitus. However, even after adjusting for a family record of hypertension and poor glycaemic control, a family history of albuminuria remains strongly linked to a risk of nephropathy in patients both with type 113 and type 2 diabetes.14

An inherited susceptibility to nephropathy may not even be specific to diabetic renal disease. The risk of albuminuria may be inherited independently of diabetes. The non-diabetic offspring of parents with diabetic nephropathy have a higher albumin excretion rate14 and an exaggerated albuminuric response to physical exercise (at least in type 2 diabetes) than patients with no family history of nephropathy.15 It has been suggested that a genetic predisposition may exist to renal disease of any cause. Non-diabetic renal disease also o 30-

Number of parents with diabetic nephropathy

Figure 4.1 Increased prevalence of nephropathy with increasing number of family members with known nephropathy. Adapted with permission from Pettitt 1990.

exhibits familial aggregation.16 Thompson et al,17 in a two-by-two factorial study of proteinuria in Polynesians, examined 90 people with a first-degree relative with end-stage renal disease (ESRD) and diabetes. They were compared with 90 people with a relative having non-diabetic ESRD, 90 people with a relative with diabetes but no known nephropathy, and a further 90 people with no known relatives with either diabetes or nephropathy (Figure 4.2). Subjects with a family history of ESRD had an increased mean albumin creatinine ratio (P=0.01), particularly in the presence of diabetes. However, a family history of diabetes per se was not an independent factor associated with albuminuria (P=0.09). Similar data have been described in African-American patients with type II diabetes and ESRD, who are nearly twice as likely to have a relative with ESRD as patients without nephropathy.1018

The identification and early management of albuminuric patients with diabetes is a comparatively recent phenomenon. Historically, the earliest manifestation of nephropathy was a premature cardiovascular event. Diabetic nephropathy is associated with an increased risk of cardiovascular disease compared to diabetes of similar duration but without nephropathy.19 As a result, parental history of cardiovascular disease appears to provide an appropriate surrogate for identifying patients at increased risk of diabetic nephropathy. This has now been demonstrated in studies of patients with type 1 and type 2 diabetes.20-22 While the association between a familial history of cardiovascular disease and diabetic nephropathy may reflect undiagnosed nephropathy parents, the cosegregation of other traits, including hypertension, dyslipidaemia and activity of the renin-angiotensin system, may also be an important contributor.

The prevalence of diabetic nephropathy varies significantly among different ethnic groups For example, African-American, Indo-Asian and Polynesian patients have a much greater risk of nephropathy than matched Caucasian patients.23 Among Jews developing type 1 diabetes, the non-Ashkenazi ethnic group are at a higher risk of the development of nephropathy.24 One of the highest rates of nephropathy is described in Pima Indians, who have a cumulative incidence of persistent proteinuria of 80% after 25 years of diabetes. In addition, Pima Indians have a 61% cumulative incidence of ESRD 15 years after the onset of proteinuria, in contrast to only 17% in a comparable Caucasian population.4

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