Blood pressure and renal failure in the Fawn-Hooded rat: combining physiology and genetics

The question why not all patients with hypertension develop end-stage renal failure (ESRF) has become a major issue in nephrology and hypertension research over the past decade. There are indications for a relationship between hypertension and impaired renal fimction in individuals with no underlying renal disease.31 It is widely believed that genetic factors play an important role in the susceptibility to hypertension-induced renal failure.18.IOO Epidemiological studies indicate that the risk for hypertension-associated renal failure varies with the ethnic background. 14.28 For instance, the presence of ESRF in an AfricanAmerican individual results in a nine-fold increased risk of ESRF in a firstdegree relative, even after controlling hypertension in the relative.32 Most information on familial clustering of renal failure and hypertension is derived from studies in patients with diabetic nephropathy, for which Seaquist et al. recently showed the involvement of genetic factors in its pathogenesis. I08 Other studies have reported a greater prevalence of hype11ension and/or cardiovascular disease in the parents of children who developed diabetic nephropathy later in Iife.27 • 133 Furthermore, Schmidt et al. found that a familial history of hypertension is not only more frequent in patients who develop chronic renal failure caused by diabetes but also in patients with different histologic types of primary glomel1llonephritis. lo7 The factors responsible for an association between blood pressure and renal failure are not known, but an increased blood pressure is: (a) necessmy and sufficient to cause ESRF, or (b) necessmy but not sufficient to cause ESRF, or (c) neither nec~ssmy nor sufficient to cause ESRF; it accelerates the risk in individuals who are otherwise predisposed. Renal failure is hypertension-induced in the first two suppositions and hypertension-associated in the latter. 12 In this context, we have to consider the possibility that hypertension and the predisposition to develop glomel1llar damage due to hypertension are influenced by different genes. Gene-gene and gene-environment interactions determine the final phenotype. It could be that hype11ension alone and renal failure due to hypertension are two different phenotypes. The genetic basis of complications in human diseases deserves more attention, and it would be usefill to asce11ain a large number of hypertensive affected sibpairs to study whether risk of renal failure correlates between these sib-pairs and, if so, to map human susceptibility factors. Using the candidate gene approach, an insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene was recently discovered, significantly influencing circulating ACE levels. These levels might playa role in the development of target organ damage, such as left ventricular hYfelirophy in essential hypeliension and microalbuminuria in diabetes mellitus. I .29.83 However, simple comparisons do not provide answers to these complex problems. Combining physiology and genetics, we might be able to dissect the susceptibility to hypeliension and renal damage.

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