The Brenner Hypothesis

Glomerular number shows wide biological variation in both humans (400,000 -1,200,000) [27, 28] and rats (20,000 - 35,000) [11, 29]. Brenner et al, proposed that individuals with a mean glomerular number at the lower end of or below the physiological range are at increased risk of developing hypertension [5], due to a reduction in total filtration surface area. During the growth phase of a human being, hypertension may result in glomerular capillary hypertension and later on in glomerular sclerosis, which will further reduce the total glomerular filtration surface area, thus perpetuating a vicious cycle [30].

A variety of post-mortem studies in neonates have shown that intra-uterine growth retardation is associated with a reduction in glomerular number [31 -33]. These studies may not be relevant to the general population because retrospective post mortem studies in adults with a higher birth weights do not show a relationship between birth weight and glomerular number [34]. The lack of relationship between birth weight and glomerular number is also demonstrated in animal studies [35, 36] and even in the IUGR studies there is no linear relationship between birth weight and glomerular number [33].

The mechanism by which glomerular number is reduced is uncertain but exogenous factors acting on the fetus may be important. Vitamin A and its derivatives play a role in nephrogenesis [37] and vitamin A deficiency is associated with renal abnormalities [38] and reduced glomerular number [39]. Low circulating levels of Vitamin A occur in women who smoke, abuse alcohol or adopt extreme weight reducing diets [40, 41]. Whether this reduction in Vitamin A levels is sufficient to reduce glomerular number is uncertain. Maternal smoking reduces birth weight [42] and in Manalich's study [33] maternal smoking status was a stronger determinant of glomerular number than birth weight itself.

Surgical reduction in glomerular number by unilateral nephrectomy in childhood [43], and unilateral renal agenesis [44] are associated with increased risk of hypertension but the prevalence of hypertension in adults undergoing nephrectomy are small [43]. These findings suggest that the early reduction in glomerular number in the pathogenesis of hypertension but the majority of people with hypertension have not undergone nephrectomy and do not have renal agenesis.

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