Modification Of Disease

Environmental factors, most of which probably remain unknown, that influence the development or progression of renal disease in subjects with diabetes are likely to be shared with other family members resulting in concordance of renal disease. Therapeutic manipulations of several factors alter the course of diabetic renal disease in individuals, but it will take family studies to see if the response to therapies is also genetic or influenced by other environmental factors.

Various treatments, which will be discussed in detail in subsequent chapters, may alter the familial aggregation of renal disease. Reichard et al. [35] showed that intensive insulin therapy in type 1 diabetes can reduce the development of microvascular complications including diabetic kidney disease. Similar results were reported by the Diabetes Control and Complications Trial [36]. The results of the United Kingdom Prospective Diabetes Study, also, showed that intensive blood glucose control decreases the risk of microvascular complications, in patients with type 2 diabetes [37].

Figure 4. Prevalence of proteinuria according to parental hypertension and diabetes, adjusted for age, sex, diabetes duration and post-load plasma glucose Adapted from Nelson et al. [33].

Dietary protein may induce glomerular hyperfiltration [38], and beneficial effects of dietary protein restriction have been described [39-43]. As the renal effects differ with different types of protein [44], familial aggregation of renal disease may be due to a common diet rather than to genetics. Likewise, the beneficial effects of protein restriction may differ in different families depending, not only on genetic differences, but also on the type and the amount of protein consumed before the intervention.

Mother Father Mother Father

Parental Hypertension

Parental Diabetes

Treatment of hypertension in subjects with diabetic nephropathy retards the progression of the renal disease [45], especially when drugs that block the renin-angiotensin system are used [46]. In several randomized trials, angiotensin converting enzyme inhibitors and angiotensin receptor blockers were shown to slow the progression of renal disease and reduce mortality in subjects with proteinuria, regardless of hypertension [47-54]. It is of interest to note that there is evidence suggesting that ACE insertion/deletion polymorphism may be involved in the responsiveness to the ACE inhibitors [55,56].

In summary, much of the intriguing information regarding the familial occurrence of diabetic renal disease suggests a genetic component for this disorder but is also consistent with environmental effects. The epidemiology of renal disease is complicated by the fact that several forms of therapy currently employed to treat hyperglycemia, proteinuria and hypertension can alter the progression of renal disease and may, in some cases, even prevent its development. Selective prevention of renal disease will likely alter the familial aggregation of the disease. If there are important genes providing susceptibility to renal disease or influencing the response to treatment, even if the contribution is small, their identification could increase the clinician's knowledge about the risk for a given patient and help identify those for whom intensive therapy may be most beneficial.

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