(Hypertension. 1995;26:670-675.)
© 1995 American Heart Association, Inc.
Articles |
Effects of Hypertension and Dyslipidemia on the Decline in Renal Function
From the Department of Medicine, Helsinki (Finland) University Central Hospital.
Correspondence to Matti Mänttäri, MD, Department of Medicine, Helsinki University Central Hospital, Haartmaninkatu 4, SF 00290 Helsinki, Finland.
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Abstract |
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Abstract Experimental evidence suggests that in addition to hypertension, serum lipids might also accelerate the decline in renal function. We tested this hypothesis in 2702 dyslipidemic middle-aged men without renal disease participating in the Helsinki Heart Study, a coronary primary prevention trial. The decline in renal function was estimated from linear regression slopes based on reciprocals of 10 serum creatinine determinations over the study period. Renal function deteriorated 3% on average during the 5-year study, and hypertension accelerated this change. Subjects with an elevated ratio of low- to high-density lipoprotein cholesterol (>4.4) had a 20% faster decline than those with a ratio less than 3.2. Both the contribution of the lipoprotein ratio and the protective effect of high-density lipoprotein cholesterol alone remained significant in multiple regression analyses. In the study of joint effects the contribution of lipids was confined to subjects with simultaneous elevation of blood pressure and lipids. The results suggest that in addition to hypertension, blood lipids also modify the decline in renal function.
Key Words: cholesterol • lipoproteins, HDL cholesterol • creatinine • kidney
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Introduction |
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The decline in renal function in healthy humans begins after maturity and is reflected in a fairly consistent decrease in glomerular filtration, which in 40- to 60-year-olds averages 8 mL/min (0.6%) per decade as determined by endogenous creatinine clearance.1 Hypertension has been shown to accelerate this decline,2 3 4 5 6 whereas the effect of dyslipidemia is so far unknown and most of the evidence is based on animal experiments. It has been suggested that lipids are mainly involved in glomerular injury leading to glomerulosclerosis,7 8 9 10 11 12 13 although a causal relationship has yet to be demonstrated. Human data are sparse and mostly restricted to extreme populations, eg, the morbidly obese, in whom the predominant glomerular lesion is focal segmental glomerulosclerosis.14 Nevertheless, an association between vascular disease and age-associated changes in human kidney has been demonstrated in one study.15
The main objective of the present study was to test the hypothesis that hypertension and dyslipidemia, both major risk factors for atherosclerotic diseases, accelerate the decline in normal renal function. The study population consisted of hypercholesterolemic, middle-aged men participating in the HHS, a coronary primary prevention trial with gemfibrozil.16 Changes in renal function were estimated from semiannual determinations of serum creatinine over the 5-year study period.
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Methods |
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Study Population
The present study cohort consisted of 2702 dyslipidemic participants of the HHS. The trial design, methods, and main results have been described in detail previously16 17 but are reviewed here briefly. HHS participants were selected by screening some 19 000 middle-aged (40 to 55 years old) male employees of two government agencies and five industrial companies. To be eligible, subjects had to have dyslipidemia, defined as non–HDL-C of 5.2 mmol/L or greater at two consecutive screening examinations, and be free of coronary heart disease or any other major illness. However, hypertension and type II diabetes were not considered causes for exclusion. The lipid acceptance criterion selected subjects from the upper end of serum total cholesterol distribution, and the HDL-C distribution was similar in study participants and the screened population.18 Subjects with abnormal laboratory safety parameters (hemoglobin, leukocyte count, aspartate aminotransferase, alkaline phosphatase, bilirubin, and creatinine) were also excluded. For serum creatinine, 115 µmol/L was the upper limit, but despite this, about 30 subjects with serum creatinine in the range of 116 to 136 µmol/L slipped into the study cohort, mainly in the pilot phase. This was not considered a major protocol violation, and because of being otherwise eligible, these subjects were allowed to continue in the study.
A total of 4081 men were randomly allocated to either gemfibrozil (1200 mg/d) or matching placebo. All participants were given dietary counseling to lower elevated LDL-C. The participants attended regular follow-up visits at 3-month intervals. The selection of this particular study cohort of 2702 men (1371 on placebo and 1331 on gemfibrozil) was based on the complete availability of all the serum creatinine determinations during the study and absence of any grade of proteinuria (examined with Uristix, Ames Co) at study entry. Because major illness or a cardiovascular event during the study caused dropout from the HHS, this particular cohort consisted of hypercholesterolemic but otherwise healthy men who completed the 5-year study period. A total of 302 were taking antihypertensive medication at study entry, and 66 had type II diabetes. With the exceptions noted above, there were no major differences in any baseline variables between the 2702 men in the present study and those 1379 excluded (data not presented). Even in this selected population the original randomization16 was successful. No significant differences were detected between the placebo and gemfibrozil groups in any baseline levels of continuous variables such as age, body mass, BP, lipid levels, or serum creatinine (data not presented). The proportion of smokers was 29% in the placebo group and 32% in the gemfibrozil group (P=NS), and 37% of subjects in both treatment groups were physically active.
BP was recorded by the study nurses using calibrated mercury sphygmomanometers. The recordings were made with subjects in the sitting position after interviews and before collection of blood samples. The cuff measured 12x40 cm, and Korotkoff phase V was used to define diastolic pressure (phase IV when the sounds could be heard until the end of the scale). All recordings were made at 5–mm Hg intervals.
Laboratory Methods
Lipid levels were determined at every follow-up visit and
laboratory safety parameters semiannually, as described
previously.17 With the exception of hemoglobin and
leukocyte count, the analyses were centralized in the
Department of Biochemistry at the National Public Health Institute in
Helsinki. Serum samples were mailed daily to the laboratory and
analyzed fresh without freezing. The delay between collection
of the samples and analysis ranged from 1 to 5 days on average.
Semiannual determinations of major safety parameters
(aspartate aminotransferase, alkaline phosphatase, bilirubin, and
creatinine) were carried out with routine, in-house
analytic procedures with the use of an automated multichannel
laboratory package. Jaffe's method was used for creatinine
determinations. In contrast to the vigorous quality control procedures
for lipid analyses, the HHS protocol had no requirements for
precision in the determinations of safety parameters.
Quality control therefore depended on the routines of the laboratory, a
department of the National Public Health Institute participating in the
World Health Organization external quality assessment program.
Statistical Methods
Mean in-trial levels for lipids, BP, and other variables
were calculated from the 10 values recorded at the semiannual
visits, when serum creatinine was also determined.
Pearson's correlation coefficients were calculated to describe the
cross-sectional associations between the measured serum
creatinine levels and other variables. The decline in
renal function in each individual was estimated from the
least-squares linear regression slope based on reciprocals of the
10 creatinine determinations versus time over the
follow-up period. A linear model was considered accurate enough to
describe the change in glomerular filtration rate, which is
reflected by the reciprocal of serum
creatinine.19 20 On the basis of the slopes,
adjusted baseline and 5-year creatinine levels were
determined and the changes between these two calculated to indicate the
decline in renal function. For conceptual reasons the decline in this
article is referred to as creatinine change. Other
approaches for statistical modeling were also considered. The use of
creatinine clearance as calculated with the Cockcroft-Gault
formula21 was rejected because both of the explanatory
variables, hypertension and lipids, are related to body mass. The
use of a life-table analysis with censoring of each case
when a certain creatinine level has been reached was not
considered possible because of the variation in the measured normal
creatinine values. Either baseline or in-trial levels
of the independent variables were used in multiple linear
regression models of the Statistical Analysis System (SAS) to
evaluate their contribution on the change in serum
creatinine. ANOVA was used in the comparisons of the mean
creatinine changes between various subgroups.
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Results |
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None of the cross-sectional associations between measured serum creatinine and the BP levels or determined lipoproteins (HDL-C, LDL-C, triglycerides) were significant. The correlations between creatinine and relative weight (body mass index; kilograms divided by meters squared) or body weight (kilograms) were statistically significant, but the coefficients were only +.04 and +.08, respectively.
During the study period there was a monotonous increase in mean measured serum creatinine levels in both the gemfibrozil and placebo groups averaging 3% (Table 1). The mean creatinine changes in measured values between baseline and the final visit were 6.0±9.0 µmol/L in the gemfibrozil group and 5.4±8.7 µmol/L in the placebo group (P=NS). The mean changes in adjusted creatinine values, based on regression slopes, were 5.5±7.0 and 6.0±6.9 µmol/L, respectively (P=NS). The distributions of the creatinine levels at baseline and 5 years are presented in Fig 1. The change in serum creatinine in the entire study cohort was relatively normally distributed: the 10th percentile was at -3 µmol/L, the 25th at +1, the 50th at +5, the 75th at +9, and 90th at +13 µmol/L.
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Age had no effect on the rate of decline in renal function, with mean creatinine changes of 5.6, 6.1, and 5.8 µmol/L in the age groups of 40 to 44, 45 to 49, and 50 to 55 years, respectively (P=NS). Neither smoking nor physical activity had a significant contribution to the creatinine change. On the other hand, the relationship between the change and baseline creatinine level was an inverse one, and the change was more than threefold in subjects with baseline creatinine less than 70 µmol/L compared with those with baseline level greater than 110 µmol/L (Table 2).
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Hypertension accelerated the decline in renal function (Fig 2), but no differences emerged between gemfibrozil and placebo groups in this respect. When MAP is considered, the fastest decline, 6.4±7.3 µmol/L, was in the highest quintile, with MAP greater than or equal to 110 mm Hg; the mean decline in the lowest quintile, with MAP less than 95 mm Hg, was 5.8±6.6 µmol/L. The corresponding mean declines in the three middle quintiles were 5.6, 5.7, and 5.6 µmol/L. A study of the 302 subjects taking antihypertensive therapy at baseline showed that drug therapy itself had no influence on the rate of decline. The major determinant was the achieved BP; when mean in-trial systolic BP was less than 140 mm Hg, the mean creatinine change was 5.8±6.7 µmol/L in normotensive subjects and 5.1±7.8 µmol/L in treated hypertensive subjects (P=NS). The corresponding mean creatinine changes, when mean in-trial systolic BP remained greater than 160 mm Hg, were 8.5 µmol/L in untreated subjects and 7.8 µmol/L in treated hypertensive subjects (P=NS). A similar pattern was seen in diastolic BP (data not presented).
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No associations between mean in-trial LDL-C or triglyceride levels and the rate of decline in renal function were observed in either treatment group (Table 3). On the contrary, HDL-C level had a negative contribution, with the largest mean changes in both treatment groups (6.4 and 6.5 µmol/L) when in-trial HDL-C was low (<1.0 mmol/L) and the smallest (5.0 and 5.3 µmol/L) when HDL-C was high (>1.5 mmol/L) (Fig 3). The effect of the LDL-C/HDL-C ratio on the rate of decline was significant, with the smallest mean changes, 5.4 µmol/L in the placebo group and 5.1 µmol/L in the gemfibrozil group, at the lower end of the distribution (ratio <3.2); the corresponding maximal changes (6.2 and 6.5 µmol/L) occurred at the upper end (ratio >4.4), as illustrated in Fig 4 with both treatment groups combined.
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The independent contributions of hypertension and lipid levels to creatinine change were estimated with the use of linear regression models, with age and body mass index as covariates. At best, 1% of the variation in the decline of renal function could be explained by the models (Table 4). Inclusion of the baseline level did not basically change the results but increased the total explanatory proportions of the models. For instance, when baseline creatinine was incorporated along with the LDL-C/HDL-C ratio into a regression analysis, the total R2 of the model increased from 1% to 11% in explaining the variation in the rate of decline of renal function.
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We evaluated the effects of simultaneous elevation in BP and lipid levels on the decline in renal function by studying the joint effects with both treatment groups combined for the analyses. Because of a U-shaped association with systolic BP and creatinine change (Fig 2), we used diastolic BP levels in the analyses. However, consistent results were obtained when diastolic BP was replaced with MAP in the analyses. A significantly (P<.01) greater change in serum creatinine was observed in hypertensive subjects (diastolic BP >95 mm Hg) with an LDL-C/HDL-C ratio greater than 4.4 compared with normotensive subjects with a low lipoprotein ratio or hypertensive subjects with normal lipids (Fig 5a). In the analyses with HDL-C as the lipid variable, the difference did not quite reach statistical significance (Fig 5b). The effect of hypertension on the decline in renal function was not dependent on triglyceride levels (Fig 5c).
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Discussion |
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Our data, in accordance with previous experience, indicate that hypertension is one of the factors accelerating the rate of deterioration in renal function, even in subjects without renal disease. However, as far as we know, this is the first human data to suggest an association between the decline in renal function and serum lipids.
The loss of renal function with age is a "physiological" phenomenon in Western societies.22 The decline is suggested to occur independently of BP23 or protein-rich diets,24 but the rate of decline is accelerated by arterial hypertension.2 3 4 5 6 Racial and sex-related differences in the rate of decay have also been described.4 Measurement of renal function is problematic in population studies, with all methods being developed for clinical purposes in subjects with progressive renal failure. Although endogenous creatinine clearance approximates glomerular filtration rate, a constant inverse relationship exists between serum creatinine concentration and endogenous creatinine clearance, assuming no systematic changes in urinary volume. With these prerequisites,19 the deterioration in glomerular filtration rate, a direct measure of renal function, can be estimated from a linear reduction in the reciprocals of serum creatinine.19 20 The creatinine change in our study population was normally distributed, with some 20% of subjects having a decrease or no change. A similar distribution pattern in creatinine change has been detected in other populations.14
Even though the results were generally more consistent in
subjects on gemfibrozil, our interpretation was that there were no
major differences in the rate of creatinine change whether
the lipid level was naturally occurring, as in the placebo group, or
pharmacologically modified, as in the gemfibrozil group. Our findings
concerning joint effects rest on this assumption. Relevant comparative
data are not available from the current literature. The insignificant
role of LDL-C alone was most probably a consequence of the lipid
acceptance criterion used in the HHS (non–HDL-C 
5.2
mmol/L). This criterion selected subjects from the upper end of total
and hence LDL-C distribution. Triglycerides, either alone
or estimated jointly with other lipids, and/or hypertension showed no
association with the creatinine change. This is somewhat
unexpected, bearing in mind the close relation between
triglycerides and HDL-C as well as between
triglycerides and hypertension in the context of the
insulin resistance syndrome.25
Then how could lipids be involved in the decline of renal function? The basic pathophysiological hypothesis is that dyslipidemia, among other factors, causes glomerular injury leading to glomerulosclerosis.26 27 Experimental data support this concept, and it has even been suggested that glomerulosclerosis and atherosclerosis could share a common pathophysiological background.15 Human mesangial cells resemble modified smooth muscle cells and take up native LDL and apolipoprotein E–containing lipoproteins through a receptor-mediated pathway, and glomerular epithelial cells also express lipoprotein receptors in vitro.28 Although the kidney has a certain role in the degradation of apolipoprotein A-I,29 only indirect evidence of the role of HDL-C is available. Glomerular lipid deposits have been observed in rare metabolic disorders involving low HDL-C, such as lechitin:cholesterol acyltransferase deficiency.30 However, an exact mechanism by which glomerulosclerosis could lead to reduced creatinine clearance is so far unresolved.
The deterioration in renal function with age has mostly been studied in relation to BP levels, because hypertension is one of the major risk factors for end-stage renal failure. Our data confirm the contribution of elevated BP to the decline in renal function. However, with regard to systolic BP the effect was detected only when BP was elevated (>160 mm Hg), a finding in accordance with the Baltimore Longitudinal Study on Aging31 but in contrast to other studies.5 32 With regard to diastolic BP there was a classic dose-response pattern. The contribution of diastolic BP remained statistically significant in multiple regression analyses, but studies of the joint effects showed a significant interdependence between diastolic BP and the LDL-C/HDL-C ratio in the decline of renal function. A basically similar pattern was seen in the joint effect of hypertension and HDL-C. A purely speculative explanation for these findings is that hypertension is the primary injurious factor, and the lipids behave as suggested by the lipid hypothesis, with HDL performing a central role in reverse cholesterol transport.
Some methodological problems are encountered in the study of serum creatinine and its change with time. A major issue is the large interindividual and intraindividual variations. This offers, in addition to the relatively narrow age range, a partial explanation for why we were not able to demonstrate any cross-sectional association between age and creatinine. A second problem arises from the close correlation between the initial value and the change, an association partly explained by "regression toward the mean." The use of linear regression slopes to estimate initial and final creatinine values did not eliminate this association in our study cohort, leaving the possibility of a true effect. However, our data are insufficient for further speculations. Because of these theoretical considerations and the largest predictive power, baseline creatinine levels were not included in the main statistical models. However, incorporation of the baseline value did not change the main results but increased the total explanatory proportion of the models. Another problem arises from the relatively short follow-up period of 5 years of a variable within a "normal" range and with large intraindividual variation.
In addition to the methodological problems discussed above, our study has other shortcomings and restrictions. This was a post hoc analysis in a study population of white men, and the results may not be applicable to other races or women. Second, the population consisted of dyslipidemic, mainly hypercholesterolemic subjects, and the small variation caused by the lipid acceptance criterion reduces the relative contributions of LDL-C, the major cholesterol carrier in the human body. On the other hand, initial screening excluded subjects with renal disease, and continuous patient monitoring ensured the reliability of both laboratory and clinical data.
In conclusion, our data suggest that in addition to hypertension, blood lipids also modify the decline in renal function. In this hypercholesterolemic population both HDL-C and the LDL-C/HDL-C ratio made independent contributions to the decline. However, the decline in renal function was small during this short follow-up period of 5 years, though in accordance with previous studies. An accelerated decline was detected especially when both BP and lipids were elevated.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant from The Paavo Nurmi Foundation, Helsinki, Finland.
Received April 10, 1995; first decision May 31, 1995; accepted June 20, 1995.
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References |
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