Increased Blood Pressure in Adult Offspring of Families With Balkan Endemic Nephropathy: A Prospective Study

Plamen S. Dimitrov; Valeri A. Simeonov; Svetlana D. Tsolova; Angel G. Bonev; Rossitza B. Georgieva; Wilfried J. Karmaus

Disclosures

BMC Nephrology 

In This Article

Discussion

Our findings show that a decrease of the minimal kidney cortex width of 1 mm was related to an increase in systolic blood pressure of 1.4 mm Hg. There was no association between kidney length and blood pressure. A maternal history of BEN was associated with a significant increase in systolic blood pressure of 6.7 mm Hg, paternal BEN with a non-significant increase of 3.2 mm Hg, and both parents affected, a significant increase of 9.9 mm Hg. The lack of association of either kidney cortex width or a parental history of BEN with diastolic blood pressure may either stem from the larger individual variance of this parameter or may indicate that there is no such link.

In a study with healthy volunteers in England, Raman et al. did not identify a clear pattern between measurements of the right and left kidneys and blood pressure.[26] In another population-based study, Paivansalo et al. found that the kidneys of hypertensive women were slightly larger (p < 0.08).[27] To the contrary, comparing hypertensive and normotensive Turkish patients, Zumrutdal et al. found that kidney length and volume were significantly smaller in hypertensive patients.[19] Thus, it is not clear whether hypertension affects kidney dimensions or vice versa.

For adult Aboriginals in Australia, Singh et al. found that a 10 mL decrease in kidney volume was associated with a 0.5 mm Hg increase in systolic blood pressure.[16] The study of Singh et al. did not provide information on cortex width; in our study we do not have information on kidney volume. To compare results, we expressed both findings as a percent decrease in kidney dimensions. A 10 mL decrease in kidney volume in the Australian study represents approximately a 5% decrease in volume (range: 62 - 267 mL). In our study of adult Caucasian offspring from Bulgaria, a 5% decrease in the minimal cortex width (0.5 mm, range 10 - 20 mm) is associated with a 0.7 mm Hg increase in blood pressure. Thus, both studies found a similar effect of kidney dimensions on blood pressure. Singh et al. also showed a cubic-type association between kidney volume and systolic blood pressure. Similarly, we have demonstrated a cubic regression between minimal kidney cortex width and blood pressure; the threshold we detected in our model, is approximately 16 mm of cortex width. However, if we control for other variables in mixed regression models, a straight line is also appropriate ( Table 2 ).

Mackenzie et al. posited the hypothesis that the total nephron supply at birth is a factor in determining a susceptibility to increased blood pressure.[17] Given that kidney dimensions correlate with the number of nephrons,[18] our finding that minimal cortex width is significantly associated with systolic and pulse pressure supports Mackenzie's hypothesis. In addition, we found that, in offspring, maternal BEN is associated with increased systolic and pulse pressure. In a prior report of this project, we showed that a maternal but not a paternal history of BEN is related to reduced cortex width in their adult offspring.[14] The stronger role of maternal BEN in offspring susceptibilities (cortex width and average blood pressure) and the lack of paternal-related risks may indicate, in our opinion, the importance of feto-maternal interactions during pregnancy. Mothers who later develop BEN do not yet have the disease during their childbearing years. However, they are likely to have developed precursors of the disease before becoming pregnant, which, however, must be sufficient in themselves to initiate a higher risk in the offspring for having a smaller kidney cortex width and increased systolic and pulse pressure.

Hence, a maternal history of BEN may have both a direct and an indirect effect on blood pressure in offspring. Indirectly, maternal BEN seems to decrease kidney cortex width, which in turn increases blood pressure in adult offspring. Directly, maternal BEN seems to initiate regulations likely to raise the average blood pressure in affected offspring. However, hypertension is not a predominant feature in BEN offspring. Thus, it is unlikely that the reduction in kidney cortex width in BEN offspring results from hypertension.

Renal mass is considered to contribute directly to the development and maintenance of hypertension.[16,19,28] Also renal scarring, an index of chronic damage, has also been related to blood pressure.[29] Since we have previously reported a reduced kidney cortex width in BEN offspring,[14] our finding that minimal cortex width is related to blood pressure is in agreement with prior reports.

However, in BEN patients, whose kidneys shrink, the lack of increased blood pressure has been considered to be a typical characteristic before the disease reaches its final stage.[3,4,5,6,7,8,9] The reason for this unusual association has never been explained. We were surprised to find that BEN offspring had an average increased systolic blood pressure, in particular related to a maternal history of BEN. In agreement with our finding, Arsenovic et al. recently also reported an increased prevalence of hypertension (20 out of 47 persons) in BEN family members.[30]

Since our data is based on adult offspring, we are uncertain about the future development of blood pressure in this group. There are three possibilities: (I) Offspring of BEN patients will not develop BEN but maternal BEN may lead to subclinical changes such as an increase in average blood pressure. An argument against this option is that we have found reduced kidney sizes and increased protein excretion in the BEN offspring, which may be considered as early signs of BEN.[14] (II) BEN offspring will develop BEN and their higher average blood pressure will disappear with the progression of BEN. One speculation is that the juxtaglomerular cells become injured and thus the renin-angiotensin system also is impared, which may prevent hypertension. (III) A third option is that the reported lack of hypertension in BEN patients was not based on scientifically sound conclusions and needs to be revised.

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