thesis
Blood pressure and renal failure in the Fawn-Hooded rat: combining physiology and genetics
- Publication date
- 21 April 1999
- Publisher
- 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.