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Pedrinelli R, Penno G, Dell-Omo G, Bandinelli S, et al

Transvascular and urinary leakage of albumin in atherosclerotic and hypertensive men

Hypertension (Aug) 32:318-323 1998

The abstract of this paper is available from the National Library of Medicine's PubMed site: click here .


MICROALBUMINURIA AS A MARKER FOR FUTURE CARDIOVASCULAR EVENTS REFLECTS LOSS OF RENAL FUNCTIONAL RESERVE

Genjiro Kimura, M.D. Chief, Division of Nephrology National Cardiovascular Center Suita, Osaka 565-8565, Japan

We read with interest the recent a rticle "Transvascular and Urinary Leakage of Albumin in Atherosclerotic and Hypertensive Men" by Pedrinelli et al 1. This study clearly illustrated that microalbuminuria did not reflect transvascular leakage of albumin. Transcapillary escape rate of album in was higher in arteriopathic patients, independently of blood pressure (BP). In contrast, albuminuria was elevated only in hypertensive subgroups. Furthermore, no correlation existed between transcapillary escape rate of albumin and albuminuria. Microal buminuria has been considered important as a prognostic indicator for renal mortality as well as for cardiovascular events.

Essentially, there are two implications on how microalbuminuria is related with cardiovascular diseases: one as reflection of syste mic vascular endothelial dysfunction causing capillary leaky to macromolecules such as albumin, and the other as a cardiovascular overload due to early renal dysfunction. Pedrinelli and his colleagues showed that the former did not the case, and furthermo re glomerular capillary permeability of albumin did not correlate with its systemic capillary permeability 1. There are several prognostic indicators other than microalbuminuria. These include non-dipping 2 and sodium sensitivity 3. Close interrelationshi p among microalbuminuria, sodium sensitivity and non-dipping, as will be discussed below, is consistent with ideas of Pedrinelli et al, suggesting that microalbuminuria derives locally from early damaged kidneys and does not reflect systemic vascular dama ge.

We recently showed that sodium sensitivity of BP was a risk predictor leading to cardiovascular events independent of classical ones 3. We have postulated on theoretical basis that sodium sensitive types of hypertension are caused by either reduced gl omerular ultrafiltration coefficient or enhanced tubule sodium reabsorption, and that glomerular capillary pressure is elevated in either case to compensate for the impaired sodium excretion capacity 4. In fact, we quantitatively estimated that ultrafiltr ation coefficient was reduced and glomerular capillary pressure was elevated in patients with sodium sensitive type of essential hypertension 5. In addition, we showed that renal function reserve in response to chronic protein load was lost in this type o f hypertension 5, consistent with reduced ultrafiltration coefficient. It is reported that glomerular capillary pressure was elevated in black patients with sodium sensitive hypertension 6, and that urinary albumin excretion rate, which may be a marker of glomerular capillary hypertension, is greater in sodium sensitive type of essential hypertension than in the non-sodium sensitive type. It is well established in advanced chronic renal failure that BP rises and becomes sodium sensitive. Sodium sensitivit y is enhanced even when glomerular filtration rate remains normal in patients with chronic glomerulonephritis 7, and becomes much greater as glomerular filtration rate declines and as BP is elevated. Similarly, animal model of glomerulonephritis indicates that even when glomerular filtration rate remains normal, the ultrafiltration coefficient is reduced, with glomerular capillary pressure rising in compensation. Thus, it is evident that there is a direct link between sodium sensitivity and microalbuminur ia, and microalbuminuria seems to reflect glomerular capillary hypertension caused by loss of renal functional reserve. On the other hand, in some patients with essential hypertension, BP fails to fall during night and they have been called "non-dipper". It is reported that non-dippers are associated with more serious target organ damages by hypertension including microalbuminuria 8, and therefore, non-dipping phenomenon predicts worse cardiovascular morbidity 2. Recently, we found that nocturnal BP fall was diminished in patients with sodium sensitive type of essential hypertension, especially on high sodium diet 9. We further demonstrated that in patients with non-dipper type of essential hypertension, circadian rhythm of natriuresis was also disturbed 10. Sodium restriction normalized both diminished nocturnal BP decline and enhanced nocturnal natriuresis, resulting in circadian rhythms with nocturnal drops in urinary sodium excretion and BP 9,10. When sodium intake is low, the defect in renal function to excrete sodium may remain latent, allowing BP during night lowered.

These speculations, together with well known fact that in patients with renal dysfunction the nocturnal BP fall is lost and they manifest as non-dipper, suggest that circadian rhythm of BP is determined at least in part by kidneys. Importance of kidneys in the genesis of circadian BP rhythm is consistent with recent reports that circadian BP rhythm is normalized after kidney transplantation. Thus, it is also evident that there is an a nother link between sodium sensitivity and non-dipping, and non-dipping phenomenon seems to be caused by loss of renal functional reserve. Finally, it should be noted again there is a close interrelationship among microalbuminuria, sodium sensitivity and non-dipping. All of them predict worse cardiovascular morbidity, while are determined by kidneys. Data by Pedrinelli et al 1 and the close interrelationship discussed above suggest that microalbuminuria represents the loss of renal functional reserve rath er than systemic vascular dysfunction. Now, further studies are required to clarify the mechanisms how loss of renal functional reserve causes cardiovascular events.

REFERENCES

1. Pedrinelli R, Penno G, Dell'Omo G, Bandinelli S, Giorgi D, Di Bello V, Nann ipieri M, Navalesi R, Mariani M: Transvascular and urinary leakage of albumin in atherosclerotic and hypertensive men. Hypertension 1998;32:318-323

2. Verdecchia P, Porcellati C, Schillaci G, Borgioni C, Ciucci A, Battistelli M, Guerrieri M, Gatteschi C, Zampi I, Santucci A, Santucci C, Reboldi G: Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension. Hypertension 1994;24:793-801

3. Morimoto A, Uzu T, Fujii T, Nishimura M, Kuroda S, Nakamura S, Inenaga T, Kimura G: Sod ium sensitivity and cardiovascular events in patients with essential hypertension. Lancet 1997;350:1734-1737

4. Kimura G, Brenner BM: The renal basis for salt sensitivity in hypertension, in Laragh JH, Brenner BM (eds): Hypertension: Pathophysiology, Diag nosis and Management. New York, Raven Press, 1995;pp 1569-1588

5. Sanai T, Kimura G: Renal function reserve and sodium sensitivity in essential hypertension. J Lab Clin Med 1996;128:89-97

6. Campese VM, Parise M, Karubian F, Bigazzi R: Abnormal renal hemo dynamics in black salt-sensitive patients with hypertension. Hypertension 1991;18:805-812

7. Cianciaruso B, Bellizzi V, Minutolo R, Colucci G, Bisesti V, Russo D, Conte G, De Nicola L: Renal adaptation to dietary sodium restriction in moderate renal failu re resulting from chronic glomerular disease. J Am Soc Nephrol 1996;7:306-313

8. Bianchi S, Bigazzi R, Baldari G, Sgherri G, Campese VM: Diurnal variations of blood pressure and microalbuminuria in essential hypertension. Am J Hypertens 1994;7:23-29

9. Uzu T, Ishikawa K, Fujii T, Nakamura S, Inenaga T, Kimura G: Sodium restriction shifts circadian rhythm of blood pressure from nondipper to dipper in essential hypertension. Circulation 1997;96:1859-1862 10. Fujii T, Uzu T, Nishimura M, Takeji M, Kuroda S, Nakamura S, Inenaga T, Kimura G: Circadian rhythm of natriuresis is also disturbed in non-dipper type of essential hypertension. Am J Kidney Dis 1998;(in press)

Genjiro Kimura, M.D. (genki@hsp.ncvc.go.jp)
Suita, Osaka - Friday, September 18, 1998 at 22:34:55 (PDT)