Dyslipidaemia and the progression of renal disease in chronic renal failure patients
Ziad A. Massy1,3,
Thao Nguyen Khoa1,2,
Bernard Lacour2,
Béatrice Descamps-Latscha3,
Nguyen Khoa Man3 and
Paul Jungers1
1 Service de Néphrologie,
2 Service de Biochimie A, and
3 INSERM U507, Hôpital Necker, Paris, France
Correspondence and offprint requests to:
Ziad A. Massy MD, INSERM U 507, Necker Hospital, 161 rue de Sèvres, F-75730 Paris Cedex 15, France.
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Abstract
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Background. Dyslipidaemia is common in patients with chronic renal failure (CRF), and there is increasing evidence to support the role of dyslipidaemia as a contributing factor in the progression of chronic renal disease. However, few prospective studies have been carried out which address the possible relationship between dyslipidaemia and the rate of progression of renal disease in patients with renal failure.
Methods. Between January 1985 and December 1997, we prospectively assessed the risk of CRF progression to dialysis in a cohort of 138 patients. Forty CRF patients reached end-stage renal disease (ESRD) and had to start supportive therapy during the follow-up period [group ESRD(+)]. The remaining 98 CRF patients served as controls [group ESRD(-)]. Potential clinical and laboratory risk factors for more rapid CRF decline to dialysis, including lipid abnormalities and baseline creatinine clearance were determined at the start of the follow-up period.
Results. Several significant differences were found in univariate analysis between the two groups of CRF, ESRD(+) and ESRD(-), namely a shorter follow-up period, a lower level of baseline creatinine clearance, a faster rate of creatinine clearance decline, a higher level of serum triglycerides, fibrinogen, total homocyst(e)ine and proteinuria, and a lower level of serum high-density lipoprotein in the ESRD(+) group than in the ESRD(-) group. However, by multivariate Cox analysis proteinuria [relative risk (95% confidence interval) 1.32 (1.161.50) for each g/day P=0.001], baseline creatinine clearance [0.53 (0.400.70) for each 10 ml/min, P=0.001] and chronic interstitial nephritis and hypertensive nephrosclerosis [0.38 (0.170.84) for presence, P=0.005] were the only significant risk factors for CRF progression to dialysis. Hypertriglyceridaemia and male gender were selected in the final model, but were of borderline significance.
Conclusions. These results suggest a limited role for dyslipidaemia in the progression of chronic renal disease to dialysis in CRF patients, in contrast with the powerful influence of proteinuria, baseline creatinine clearance and nephropathy type in predicting this progression.
Keywords: chronic renal failure; creatinine clearance; fibrinogen; homocyst(e)ine; lipids; lipoprotein(a)
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Introduction
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Hyperlipidaemia is common in patients with renal failure. In addition, atherogenic changes in lipoprotein composition occur in most of these patients [1]. It has long been hypothesized that lipoproteins play a role in renal injury similar to their putative involvement in atherosclerosis [2]. A number of experimental investigations have provided relevant evidence that lipids may contribute to progressive renal damage [3], and several observational studies in humans have also supported this latter role [411]. However, there are only a few prospective studies that have addressed the possible relationship between dyslipidaemia observed in patients with renal failure and the rate of progression in kidney disease [12,13]. Therefore, additional prospective studies are warranted.
In our nephrology division, we prospectively determined clinical and laboratory parameters relevant to atherogenesis in a cohort of pre-dialysis chronic renal failure (CRF) patients, and evaluated the incidence and risk factors of cardiovascular events over a 10-year period [14]. In this paper we extend this follow-up period to 31 December 1997. Data from our study provide an opportunity to examine prospectively the role of dyslipidaemia, as well as of other factors, as predictors of rapid progression towards end-stage renal disease (ESRD).
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Patients and methods
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Between January 1985 and December 1997, 223 patients (147 male, 76 female, all Caucasian) with progressive CRF, defined by a creatinine clearance (Ccr) of 2070 ml/min, were referred to our nephrology division. Of these, 147 (99 male, 48 female), had a regular follow-up at our division from baseline Ccr until the start of haemodialysis (HD), or until the end of the follow-up period, and gave their informed consent to participate in a study of risk factors of atherosclerosis. The recruitment of patients started in January 1985 and terminated in April 1994. The remaining 76 patients who lived outside the Paris area, and were usually followed by their nephrologists, were referred to our nephrology division for consultations when needed. By consequence, they were not able to participate in such regular follow up and were excluded. However, age, sex and primary renal disease were not significantly different between the patients who participated in the present study and those who did not. Nine of the 147 patients who participated in the present study were on lipid-lowering therapy and were also excluded. Thus, only 138 patients were included in the current evaluation. All were ambulatory and managed as outpatients. Among them, 40 patients reached ESRD and had to start supportive therapy during the follow-up period [group ESRD(+)]. The decision to start dialysis was based on Ccr values between 58 ml/min or on the presence of severe clinical manifestation. The remaining 98 CRF patients had not yet reached ESRD and served as controls [group ESRD(-)]. Among them six patients died and six did not complete the follow-up period.
Primary renal disease was chronic glomerulonephritis [30 and 11% of patients, for ESRD(+) and ESRD(-) groups, respectively], chronic interstitial nephritis (25 and 41%), hypertensive nephrosclerosis (23 and 31%), polycystic kidney disease (20 and 14%) and diabetic nephropathy (2 and 3%). We classified renal diagnosis into three categories according their potential rate of Ccr decline over time: glomerular disease including diabetic nephropathy (CGN), polycystic kidney disease (PKD) and chronic interstitial nephritis or hypertensive nephrosclerosis (CPN+HTN).
Each patient had at least two visits per year, or at more frequent intervals according to the degree of CRF, with assessment of blood pressure, antihypertensive medication [i.e furosemide, beta-blockers, calcium-channel blockers and angiotensin-converting enzyme (ACE) inhibitors], body weight and serum creatinine at each visit. The majority of patients treated with ACE inhibitors had this treatment at the start of follow-up (>90%). Cardiovascular events considered were myocardial infarction, evidence of coronary artery stenosis on coronary angiography or coronary revascularisation procedure. Cerebrovascular disease considered was ischaemic stroke. Peripheral arterial disease (subocclusive or occlusive artery disease and/or aneurysm of the abdominal aorta) was not taken into account because the time of onset could not be determined [14]. Ccr was estimated for each subject from serum creatinine concentration using the Gault and Cockroft formula, which takes into account age, body weight and gender, and which has been shown to closely reflect glomerular filtration rate, as measured by inulin clearance and technetium-dietlylene triamine pentacetic acid (Tc-DTPA) in subjects with impaired renal function and renal transplant recipients [15]. Assuming that the rate of Ccr decline in a group of CRF patients is approximately linear [16], we calculated Ccr decline as follows: (Ccr at the beginning of follow-upCcr at the end of follow-up) (ml/min)/duration of follow-up period (years). It should be noted that there was no significant change of body weight throughout the follow-up period. Protein intake was calculated using the formula of Maroni et al [17]. Fasting fresh serum triglycerides, total cholesterol, high-density lipoprotein (HDL) cholesterol, apolipoprotein (apo) A-I, apo B, lipoprotein (a) [Lp(a)], fibrinogen and total homocyst(e)ine (Hcy) levels were determined according to previously described methods [18,19]. Clinical and laboratory parameters taken into account for correlation analysis were the baseline values at the start of the follow-up.
Results have been expressed as mean±SD, except for serum Lp(a) and proteinuria which have been also expressed as median values. Differences between groups were tested using Student's t-test, analysis of variance (ANOVA) and Chi-squared test. The SpearmanPearson test was used to evaluate the relationship between numeric variables. Possible risk factors for ESRD (presence or absence of ESRD, i.e. renal death, during the follow-up period) were examined using univariate Cox proportional hazard analysis. Since the increase of relative risk throughout the four quartiles of age was not fairly consistent, age was encoded into two classes according to the median from the sample. Renal diagnosis was entered as two binary covariates for each group (present or not), and evaluated first by nested Cox proportional hazard analysis. Covariates that tended to correlate with endpoints on univariate analysis (P<0.15) were also examined using multivariate Cox analysis. Interaction between variables was tested by using nested Cox proportional hazard analysis. Since we did not have a comparable baseline Ccr value within the ESRD(-) group for each ESRD(+) patient, we carried out the multivariate Cox analysis by adjusting for baseline Ccr. When necessary, differences between groups were tested using an adjusted survival curve obtained from the multivariate Cox analysis. Final results of multivariate Cox analysis were considered significant for P<0.05. Since only two-thirds of patients had plasma Hcy determinations, we did not include plasma Hcy in the final Cox proportional hazard models. Statistical comparisons were performed using SAS statistical software (SAS Institute Inc., Cary, NC, USA).
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Results
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The characteristics of the patients at baseline are given in Table 1
according to aetiology groups. Patients with CGN or PKD were younger than those with CPN and HTN. Daily protein intake, as well as body mass index were similar in the three groups. The rate of Ccr decline was markedly influenced by the type of nephropathy. Thus, it was significantly more rapid in the CGN and PKD groups than in the CPN+HTN group. Proteinuria was strikingly lower in the PKD group than in the CGN group. The use of ACE inhibitors was more frequent in CGN and PKD patients than in CPN+HTN patients. There were more patients who reached ESRD in the CGN and PKD groups than in the CPN+HTN group.
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Table 1. Clinical data on patients in three renal diagnosis groups: glomerular disease including diabetic nephropathy (CGN), polycystic kidney disease (PKD), and chronic interstitial nephritis or hypertensive nephrosclerosis (CPN+HTN)
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Tables 2 and 3
show that among the clinical and laboratory parameters assessed, several significant differences were found between the two groups of CRF, respectively ESRD(+) and ESRD(-), namely a shorter follow-up period, a lower level of baseline Ccr, a faster rate of Ccr decline, a higher level of serum triglycerides, fibrinogen, total Hcy, and proteinuria, and a lower level of serum HDL in the ESRD(+) group. A more frequent use of antihypertensive medication in the ESRD(+) group than in the ESRD(-) group was of borderline significance. In contrast, there was no significant difference in the levels of systolic blood pressure, diastolic blood pressure, cigarette consumption, serum total cholesterol or serum apo B.
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Table 2. Comparison of baseline clinical data between the two groups of chronic renal failure patients who did (+) or did not (-) reach end-stage renal disease (ESRD)
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Table 3. Comparison of baseline laboratory data between the two groups of chronic renal failure patients who did (+) or did not (-) reach end-stage renal disease (ESRD)
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Multivariate Cox analysis identified proteinuria, baseline Ccr and the absence of CPN+HTN, as significant risk factors for developing ESRD (Table 4
). Hypertriglyceridaemia and male gender were selected in the final model but were of borderline significance (Table 4
). Systolic blood pressure, cigarette smoking, HDL cholesterol, fibrinogen, protein intake and antihypertensive medication were not predictive of ESRD in CRF patients by multivariate Cox analysis, although they were selected by univariate Cox analysis. The adjusted survival-curve obtained from a Cox proportional hazard analysis shows that patients with baseline triglycerides levels above 1.45 mM (median levels of the whole group; Figure 1
), as well as patients with PKD+GNC (Figure 2
) had a high risk of progression of CRF to dialysis.

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Fig. 1. Adjusted survival-curve obtained from a Cox proportional hazard analysis for chronic interstitial nephritis or hypertensive nephrosclerosis (CPN+HTN) and glomerular disease including diabetic nephropathy or polycystic kidney disease (PKD+GNC).
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Fig. 2. Adjusted survival-curve obtained from a Cox proportional hazard analysis for two levels of baseline triglycerides (Tg).
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When baseline Ccr was excluded from the final model, we identified proteinuria (relative risk 1.38 for each g/day P=0.001), the absence of CPN+HTN (0.47 for presence, P=0.023) and HDL cholesterol (0.30 for each 1 mM, P=0.005) as risk factors for developing ESRD. When proteinuria was excluded from the final model, we identified baseline Ccr (0.53 for each 10 ml/min P=0.001), the absence of CPN+HTN (0.29 for presence, P=0.002), gender (2.43 for presence of male, P=0.006) and triglycerides (1.38 for each 1 mM, P=0.092) as risk factors for developing ESRD. When the absence of CPN+HTN was excluded from the final model we identified baseline Ccr (0.55 for each 10 ml/min P=0.001), proteinuria (1.43 for each g/day P=0.001), gender (2.26 for presence of male, P=0.039) and the use of antihypertensive medication (4.41 for presence, P=0.043) as risk factors for developing ESRD.
It should be noted that proteinuria was found to be positively correlated with systolic blood pressure (r=0.2, P<0.02), diastolic blood pressure (r=0.17, P<0.05), triglycerides (r=0.3, P<0.01) and fibrinogen (r=-0.41, P<0.01), but not with HDL cholesterol or with baseline Ccr. A negative correlation was found between baseline Ccr and fibrinogen (r=-0.20, P<0.03), but not with triglycerides nor with HDL cholesterol. Triglycerides were found to be positively correlated with total cholesterol (r=0.38, P<0.01) and apo B (r=-0.75, P<0.01), and negatively with HDL cholesterol (r=-0.53, P<0.01). A positive correlation was found between age and systolic blood pressure (r=0.32, P<0.01). Systolic blood pressure was positively correlated with diastolic blood pressure (r=0.54, P<0.01).
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Discussion
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Our prospective, casecontrol study in patients with moderate CRF shows that a limited association exists between dyslipidaemia and the rate of progression of CRF to dialysis, in contrast with the prominent value of proteinuria, renal function and renal diagnosis in predicting this progression. In addition, it underlines the lack of apparent influence of treated blood pressure, fibrinogen, cigarette smoking and protein intake in the rate of progression of CRF to dialysis in such patients.
Several observational studies in patients have supported the role of lipids as contributors to progressive renal damage [411]. However, there are only a few prospective studies that have addressed this issue in CRF patients [12,13]. In the recent analysis of the Modification of Diet in Renal Disease (MDRD) Study, it was demonstrated that low HDL cholesterol concentrations is one of six co-variants related to the subsequent rate of decline in the glomerular filtration rate [12]. In another prospective study, the decline of renal function over 3 years was significantly associated with baseline concentrations of cholesterol, LDL cholesterol and apo B, but not with that of triglycerides [13]. In the present study, we could not demonstrate a significant role for dyslipidaemia in the rate of progression of CRF to dialysis, and only a weak association was observed between triglycerides and this progression. Several differences between our study and that of Samuelsson and colleagues [13] may explain the observed discrepancy, including a different population, use of a different end-point (renal death in our study vs decrease in glomerular filtration rate in the other study), use of a different multivariate analysis method (Cox proportional hazard analysis vs multiple linear regression, respectively) and a different method of determinating renal function (Gault and Cockcroft formula vs 51Cr-EDTA clearance). Moreover, we did not evaluate different complex apo-B-containing lipoproteins, which have been shown to be a better predictor of renal disease progression [13]. Nevertheless, we previously demonstrated that dyslipidaemia, particularly HDL cholesterol, is a significant risk factor for cardiovascular events in the same cohort of patients [14]. Thus, it appears that dyslipidaemia is a better predictor for cardiovascular events than for renal disease progression in such patients.
Serum Lp(a) concentrations were not correlated with CRF progression in our study. A previous study similarly failed to demonstrate a close relationship between serum Lp(a) concentrations and the rate of progression of CRF [20]. However, in view of the skewed distribution of serum Lp(a) concentrations the small number of subjects in each group (<100 subjects) may preclude a definitive conclusion.
In agreement with the results of others, proteinuria was found to be an independent risk factor for progression of CRF [12,13,2123]. The fact that in multivariate analysis, baseline proteinuria, renal function and renal disease independently predicted the risk of progression of CRF towards ESRD in the present study is in favour of a direct role of proteinuria in renal injury [24].
Several studies stressed the importance of the underlying disease as a factor determining the rate of CRF progression [12,21,25,26]. Our results suggest that renal diagnosis may influence directly the rate of CRF decline, since the CPN+HTN group was an independent protective factor for CRF progression to dialysis in multivariate analysis. Indeed, the rate of Ccr decline was twice as high in patients with GNC or PKD than in patients with CPN+HTN. The fact that patients with PKD had a high rate of CRF decline is in accordance with three studies [12,21,27], but not with another one [26].
Treated blood pressure levels appeared to have no influence on the rate of CRF progression in the present study. Others have also failed to demonstrate such influence [22,25,26]. However, the MDRD study recently showed a slower rate of renal function decline in patients whose blood pressure values were reduced to below the recommended normal values during the period of follow-up, especially in those with higher baseline proteinuria [28]. Our patients were all on antihypertensive medication, but were not submitted to a policy of stringent blood pressure control. Therefore, we cannot exclude that a more aggressive blood pressure control would have exerted a better protective effect.
As in all epidemiological studies, the present observations should be interpreted with caution. Although we used multivariate statistical analysis, it is difficult to eliminate the possibility of confounding between variables in discerning cause and effect relationships. In addition, we did not examine putative risk factors for the progression of CRF not leading to dialysis, and all putative risk factors for the progression of CRF to dialysis. Nevertheless, the results of our analysis suggest that baseline proteinuria, renal function and renal diagnosis, but not dyslipidaemia, were significant risk factors for the rate of Ccr decline to dialysis in CRF patients. Such findings are of potential relevance in the management of CRF patients as proteinuria is presently amenable to specific therapeutic interventions. It has been demonstrated that ACE inhibitors are capable of decreasing proteinuria and preserving renal function in CRF patients [29]. Correcting dyslipidaemia, however, does not appear to be an essential strategy to prevent the progression of CRF to dialysis in such patients. It remains possible that lipid-lowering treatment prescribed for cardiovascular prevention could help to preserve the renal function in CRF patients.
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Acknowledgments
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The authors gratefully acknowledge the critical advise of Paul Landais and Christine Le Bihan.
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Received for publication: 17. 4.98
Accepted in revised form: 26. 5.99