B. Baggio, G. Gambaro, G. Bertaglia

Institute of Internal Medicine and Division of Nephrology, University of Padua, Italy

The biologic price of aging includes progressive deterioration of renal function and structure. Davies and Shock demonstrated an age-dependent fall-off in both renal plasma flow using Diodrast clearances, and a lesser fall-off in GFR as measured by inulin clearance with a rise in the filtration fraction. Diodrast clearance, as a measure of renal plasma flow, fell from 613 to 290 ml/min in the ninth decade of life. The drop in inulin clearance with aging was from a mean of 122 to a mean of 65 ml/min between 30 and 90 years respectively (1) . Wesson analysed all the available literature, and showed a fall of approximately 10 per cent per decade in renal plasma flow (2).The fall-off in renal function with age parallels the anatomical changes, caracterized by the progressive glomerulosclerosis, the reasons of which in aging kidney are not clear.

Using the creatinine clearance as an index of GFR, Kampmann et al (3), Rowe et al (4) and Laine et al (5) made the same observation that GFR declines with age. One problem which arises with these data is that similar populations were not studied. Rowe (4) studied healthy age individuals, whilst Kampmann (3) studied a hospital population, but excluded any patient with a raised plasma creatinine. Cockroft and Gault (6) used hospital patients, but included as subjects, whatever their renal function. A second point is that all these data were obtained with creatinine methodology, using plasma creatinine or constructed creatinine clearance nomograms, which are not an adequate method to estimate GFR in the elderly. Finally it should be noted that almost without exception these studies have been cross-sectional and not longitudinal studies, which to date are generally lacking. Lindeman et al (7) published an important extended longitudinal study of old people in Baltimore, some of whom were followed with repeated measurements for more than 30 years. It is interesting to note that despite a mean calculated fall-off in creatinine clearance of 0.75 ml/min/year, 92 of 254 individuals studied showed no fall-off in creatinine clearance, and a few even increased their clearances. Larsson et al (8) also found no decline in GFR in individuals between the ages of 70 and 79, although serum creatinine increased from 91 to 96 micromol/1 in women and from 100 to 107 micromol/ in men. Recently, Feinfeld et al (9) reported the results of the Bronx Longitudinal Aging study, documenting that the renal function, evaluated by serum creatinine, was stable over a three-year period in the majority of the 500 people studied.

These observations suggest that age-dependent decline in renal function is not a constant, in contrast to what was thought in the past. The reasons of this variability are not yet clear, as the general mechanisms of aging are poorly understood. Researchers wonder how much of the loss in kidney function with senescence is due to age and how much to other factors, such as cardiovascular risk factors, hypertension, diabetes, hyperlipidemia, smoking and/or risk factors related to the kidney, protein intake and previous renal diseases. The question arises whether one can identify risk factors that impair renal function in the elderly. The attempt to demonstrate that the rate of decline in renal function over time is correlated with blood pressure was unable to draw any conclusions from several studies as to whether renal microvascular or parenchimal pathology is the cause of the hypertension or the hypertension is the etiology of the accelerated decline in renal function observed with age. Lindeman (10) found a significant negative correlation between the mean blood pressure and the rate of decline in creatinine clearance with time in 446 subjects in the Baltimore Longitudinal Study on Aging followed over a period of 8 or more years. On the other hand, when those subjects with hypertension were not included, the inverse relationship between mean blood pressure and the rate of decline in renal function is lost, suggesting that an accelerated loss of renal function is observed primarily because of the impact exerted by individuals with blood pressures in the hypertensive range.

Leeuw et al (11) evaluated the effects of antihypertensive treatment on renal function analysing data from a prospective, double-blind investigation of 840 patients randomly assigned to placebo or to active treatment; during a five year follow-up period, serum creatinine levels increased significantly in treated patients but not in placebo patients, suggesting that adequate treatment of hypertension may enhance rather than prevent renal impairment. Fliser (12) performed a comprehensive study to compare several aspects of renal function in a young healthy normotensive group and in three groups of elderly subjects, normotensives, treated and untreated hypertensives, and elderly patients with compensated mild to moderate heart failure. Compared to young subjects and normotensive elderly patients, the old with hypertension and heart failure showed lower values of glomerular filtration rate and renal plasma flow, and increased renovascular resistances. Preliminary results from the Italian Longitudinal Study on Aging, aimed to evaluate renal function related to age and the most common cardiovascular risk factors, exclude the hypertension as a significant variable predicting the pathological level of creatinine dearance.
Several studies have assessed the impact of hyperlipemia on renal function and progression of kidney disease and a number of experimental investigations have suggested that lipids are involved in renal injury (13).

High cholesterol diets are associated with albuminuria and glomerular injury in a variety of different animal species; however, this form of lipid-induced hypercholesterolemia is relatively modest, and glomerular disease accompanied by proteinuria is not familiar in primary hyperlipidaemias. This may reflect a need for a combination with other cardiovascular risk factors or glomerular predisposing conditions. Although elevated LDL is not regularly accompanied by renal disease, it is not known whether the normal glomerulus is susceptible to LDL damage. In a recent study project to evaluate the association betwen cardiovascular risk factors, peripheral atherosderosis and renal function, we found that renal plasma flow, as evidenced by MAG3 clearance, progressively declined in parallel with the severity of peripheral atherosderosis and that MAG3 clearance values were best explaned by the score of systemic atherosclerosis, serum LDL-cholesterol values and smoking habit. In animals models, hypercholesterolemia is associated with mesangial matrix accumulation, focal and segmental glomerulosclerosis and monocyte infiltration into preinjured glomeruli (13); hystologic analysis of scarred glomeruli displays features similar to those found in atherosclerosis(14).

Human mesangial cells express receptors for both HDL and VLDL (15). LDL and the cholesterol-ester rich VLDL stimulate mesangial cell proliferation (16). LDL has been shown to stimulate the synthesis of growth factors, cytokines and other mediators capable of indudng collagen synthesis and mesangial cell proliferation analogous to vascular smooth muscle cell proliferation in atherosclerosis. Additional support for the role of lipids in renal injury can be obtained from studies in which pharmacological interventions reduced circulating lipids and ameliorated renal damage in different models of experimental renal disease (13).
Cigarette smoking is a major risk factor for vascular disease; it induces a variety of effects on the vascular and hormonal systems and involved in the development of atherosclerosis, thrombogenesis, and vascular occlusion (17).

Preliminary report suggests that smoking-related hemodynamic events may have an acute influence on renal function (18); other studies reported adverse renal effects of smoking in dialized IDDM and NIDDM patients, where the smoking habits increased the relative risk of myocardial infarction; moreover, several studies have proposed that smoking in diabetes mellitus is associated with the development and/or progression of diabetic nephropathy (19). A recent cross-sectional study (17) carried out to evaluate the effect of chronic cigarette smoking on renal function showed that compared with nonsmokers, smokers had a renal function impairment characterized by a normal GFR and a significant reduction in renal plasma flow as reflected by MAG3 clearance.

The renal dysfunction was associated with an increase in plasma endothelin-1 concentration. This finding suggests that smoke has a significant, detrimental effect on renal function. The mechanisms of smoking-related arterial damage have not yet been defined; however, a sympathetic stimulation, with consequent release of the neurotransmitter nore-pinephrine and morphologic and functional endothelial changes, characterized by intimal smooth muscle cell proliferation and alterations in endothelial-derived vascular tone regulators, seem to play an important role.

The evidence for a direct role of smoking on the metabolism of the lipoproteins and the glycosaminoglycans (GAGS) provide some insights into mechanisms that may operate in vascular damage. Smoking induces an increased plasma concentrations and oxidative modification of LDL-cholesterol,which represents a key process in the development of atherosclerosis (20,21). Moreover, consistent evidence demonstrates that smoke, by ipoxic stress induction, has an effect on GAGS metabolism (22); these substances are the main constituents of the arterial wall, are synthesized by endotelial and smooth muscle cells and are capable to interact with lipoproteins, causing the accumulation of HDL in the arterial; moreover, GAGS are involved in vasculogenesis and angiogenesis after ischemic injury, interactions of cells with adhesive proteins and blood vessels, proliferation of smooth muscle cells during atherogenesis and interactions with growth factors, enzymes and protease inhibitors, all biologic processes which play a key role in the pathogenesis of atherosclerosis and glomerulosclerosis (14,23).

In conclusion, cross-sectional and longitudinal studies confirm that age-associated decline of renal function may be the result of intervening comorbid conditions or cardiovascular risk factors, rather than an involutional aging process. Among these, smoking and hyperlipaemia conditions seem to have an important role in the detrimental effect on renal function.

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