1Division of Nephrology, 3Division of Clinical Care Research, New England Medical Center, Tufts University School of Medicine, Boston, MA, 4University of Texas at Southwestern, Dallas, TX and 8Merck Research Laboratories, West Point, NJ, USA, 2Department of Community Health Sciences and Medicine, The Aga Khan University, Karachi, Pakistan, 5Instituto di Richerche, Farmacologiche Mario Negri, Bergamo and 6Divisione di Nefrologia, Ospedale Civile Maggiore, Verona, Italy, 7The Royal Melbourne Hospital, Melbourne, Australia, 9University of Groningen, Groningen, The Netherlands and 10Herlev Hospital University of Copenhagen, Copenhagen, Denmark
Correspondence and offprint requests to: Tazeen H. Jafar, MD MPH, Department of Medicine and Community Health Sciences, The Aga Khan University, Stadium Road, PO Box 3500, Karachi, Pakistan. Email: tazeen.jafar{at}aku.edu
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Abstract |
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Methods. We analysed a pooled database of patients with non-diabetic renal disease enrolled in 11 randomized controlled trials evaluating the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) for slowing renal disease progression. The primary end point was the combined outcome of doubling of baseline serum creatinine or onset of end-stage renal disease (ESRD). The secondary end point was the onset of ESRD alone. We performed multivariable Cox proportional hazards analysis to study the independent effect of gender on these end points after adjusting for baseline patient characteristics, and changes from baseline to follow-up systolic blood pressure (SBP) and urine protein (UP) excretion.
Results. The total number of patients was 1860: 645 (35%) females and 1215 (65%) males. Mean duration of follow-up was 2.2 years. The proportions randomized to ACEI (51%), mean baseline serum creatinine (2.2 mg/dl) and mean age (52 years) were similar for both genders. Mean baseline SBP was greater in women than in men: 151 vs 147 mmHg (P < 0.001). Mean baseline UP was significantly lower in women compared with men: 1.3 vs 2.1 g/day (P < 0.001). A total of 311 (16.7%) patients developed the primary end point, and 176 (9.5%) developed the secondary end point. The unadjusted relative risk (RR) with 95% confidence interval (CI) for the primary end point in women vs men was 0.98 (0.771.24). It became 1.32 (1.031.69) after adjusting for the baseline variables and interaction between ACEIs and baseline UP, and 1.36 (1.061.75) after adjusting for baseline variables and changes in SBP and UP during follow-up. Similar results were found for the outcome of ESRD.
Conclusions. Our findings suggest that the rate of renal disease progression may not be slower, and may even be faster in women compared with men, after adjusting for other factors associated with a faster rate of progression. We caution that most women in our database were of post-menopausal age, and thus our findings may not extend to younger women.
Keywords: chronic renal disease; gender; renal disease progression
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Introduction |
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A number of studies suggest that renal disease progression is faster in men than women [35], while others have reported no differences between men and women [68]. However, these studies have not always accounted for other factors, such as the level of blood pressure or proteinuria, whose mean values are often higher in men than women in clinical studies [8,9]. Thus, it is not clear whether sex is independently associated with renal disease progression, or whether the association reflects confounding by imbalances between men and women of other factors associated with renal disease progression.
We used the data from the ACE Inhibition in Progressive Renal Disease Study (AIPRD) Study Group database [10] to assess whether there are differences in the rates of progression between men and women with non-diabetic renal disease, after adjustment for differences in baseline characteristics, as well as differences in response to treatment.
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Subjects and methods |
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Outcomes
The primary outcome was the combined outcome of a 2-fold increase (doubling) of baseline serum creatinine or the onset of end-stage renal disease (ESRD), defined as the initiation of chronic dialysis therapy. Secondary outcome was the outcome of ESRD, and is a well-defined hard clinical outcome. Doubling of baseline serum creatinine is a well-accepted surrogate outcome of the progression of renal disease, and would be expected to occur more frequently than ESRD, resulting in higher statistical power for analyses using this outcome.
Non-renal events were defined as a combined end point consisting of any of the following: (i) all-cause mortality; (ii) non-fatal cardiovascular disease events leading to withdrawal from study, including myocardial infarction, congestive heart failure, stroke, transient ischaemic attacks and claudication; (iii) non-fatal side effects possibly due to ACEIs leading to withdrawal, including hyperkalaemia, cough, angio-oedema, rash and acute renal failure; and (iv) other non-fatal events leading to withdrawal, including malignancy, pneumonia, cellulitis, headache and gastrointestinal disturbance.
Statistical analysis
SAS (SAS Institute Inc., Cary, NC) and S-Plus were used for all statistical analyses. The same models as reported earlier were built [10]. Univariate analysis was performed to look for associations between the co-variates and outcomes. Baseline patient characteristics included treatment assignment (ACEI vs control), age (logarithmic transformation), race, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure, serum creatinine (reciprocal transformation) and urine protein (UP) excretion. Study characteristics included blinding, the type of antihypertensive regimen in the control group, the planned duration of follow-up, whether or not dietary protein or sodium was restricted, year of publication and terms for study effects. Baseline patient characteristics and study characteristics were introduced as fixed co-variates. Since renal biopsy was not performed in most cases, and since criteria for classification of cause of renal disease were not defined, the cause of renal disease was not included as a variable in the analysis. The changes in BP and UP during follow-up were adjusted as time-dependent co-variates, with the value recorded at the beginning of each time segment used for that segment. This convention was used so that each outcome would be determined only by prior exposure.
Cox proportional hazard regression models, as reported previously [10], were used to determine the association of gender with the risk of the primary and secondary outcomes. Briefly, multivariable models were built by using candidate predictors that were associated with outcomes (P < 0.2) in bivariate analysis [10]. Clinically significant variables were forced in the model. Since we previously reported a significant interaction between UP excretion and treatment effect of ACEI, this interaction term was also added in the model. Interactions between gender and baseline and follow-up co-variates were tested. All P-values were based on two-sided tests, and significance was set at a P-value <0.05 for main effects and P < 0.1 for interactions. Associations are expressed as relative risk (RR) with 95% confidence intervals (CIs). Residual diagnostics were performed on the final models as described previously [10].
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Results |
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Renal disease progression
Table 2 shows that a total of 311 (16.7%) patients developed the combined outcome of a doubling of serum creatinine and onset of ESRD: 102 (15.8%) women vs 209 (17.2%) men (P = 0.44). A total of 176 (9.5%) patients developed ESRD only: 67 (10.4%) women vs 109 (9.0%) men (P = 0.32).
Table 3 shows the unadjusted and the adjusted RRs and 95% CIs for the primary and secondary outcomes in women vs men. As shown in Table 3, middle column, the unadjusted RR (95% CI) for the primary outcome in women compared with men was 0.98 (0.771.24). Of all baseline factors, adjustment for UP had the largest effect on the RR; it rose to 1.17 (0.921.49) (data not shown). The adjusted RR (95% CI) was 1.32 (1.031.69) after adjusting for the significant baseline characteristics and the interaction between treatment with ACEIs and baseline UP, and 1.36 (1.061.75) after also including changes in SBP and UP during follow-up.
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As reported previously [10], other factors significantly associated with the primary and secondary outcomes included ACEI treatment, age, baseline serum creatinine, baseline SBP, baseline UP, and changes in SBP and UP. Adjustment also included the interaction between treatment with ACEIs and baseline UP, as well as fixed effects for studies. Consistent with our previous findings [10], the benefit of ACEI was modified by baseline UP excretion (interaction P < 0.001), with a greater benefit at higher levels of UP excretion.
No significant interaction was detected between sex and the effect of treatment (ACEIs vs control) on the combined outcome of doubling of serum creatinine or ESRD (P = 0.18), ESRD (P = 0.24) alone, or between sex and other baseline and follow-up changes in SBP and DBP (P > 0.1 for each).
Non-renal events
As shown in Table 2, a total of 1131 patients (60.8%) completed the studies; 392 (60.7%) women and 739 (60.8%) men. A total of 212 patients had non-renal events: 65 (10.1%) women vs 147 (12.1%) men (P = 0.19). The unadjusted RR (95% CI) in women vs men was 0.86 (0.6481.15), and was 0.89 (0.661.22) when adjusted for baseline characteristics.
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Discussion |
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There are substantial differences regarding the effect of gender on renal disease progression among the reported studies [3,4,5,7]. We believe these differences may reflect lack of adjustment for confounding factors at baseline, and possibly differential changes in the response to treatment [8,20]. As shown by us and others, several patient characteristics at baseline, such as age, race, levels of BP, UP excretion and renal function, influence the rate of renal disease progression [7,10,21]. In addition, the response to antihypertensive therapy, such as BP and UP during follow-up, and the type of antihypertensive regimen used (ACEI vs non-ACEI) also affects renal disease progression [10,18].
We found significant differences in baseline characteristics between women and men. For instance, as shown in Table 2, the mean baseline SBP was higher in women than in men (151 vs 147 mmHg, P < 0.001). The level of proteinuria at baseline in women (1.3 g/day) was lower compared with men (2.1 g/day) (P < 0.001). Imbalances in baseline characteristics may simply reflect differential effects of recruitment or eligibility and exclusion criteria in men and women. As shown in Table 3, imbalances in baseline proteinuria had the largest effect on the RR of renal disease progression in women vs men. The unadjusted RR of 0.98 for the primary outcome rose to 1.17 after adjusting for baseline UP excretion, and remained elevated in magnitude after adjusting for all other baseline variables. Similar results were observed for the outcome of ESRD.
We did not find differential effects of treatment on BP, UP or renal disease progression in men and women. Therefore, it appears that the major source of confounding in our study was imbalances in baseline factors, particularly proteinuria. However, the sample size in our study may not have been large enough to rule out conclusively small differences in the response to treatment between men and women.
Our results conflict with a meta-analysis by Neugarten et al. [4] of eight studies of 2229 patients with non-diabetic chronic renal disease in which men were reported to be at higher risk of progression than women. There are reasons for this discrepancy in findings. The study by Neugarten et al. [4] was a meta-analysis of group data, which had some important methodological limitations. First, the definition of outcomes differed by study, and thus a variety of surrogate outcomes of renal disease progression were used to calculate the effect sizes. Secondly, Neugarten et al. were not able to adjust for possible confounding effects of baseline factors at the individual patient level, nor did they adjust for these factors at the study level. Indeed, some of the studies included in that meta-analysis showed faster renal disease progression in men that did not remain significant after adjustment for imbalances of baseline factors [8]. The two studies that did suggest faster renal disease progression in men even after adjusting for baseline factors were retrospective studies and, therefore, suffer from their inherent limitations [22,23]. In contrast, our study is a meta-analysis of individual patient data solely from prospective studies with comparable data on factors and outcomes from all studies. Thus, we suspect that the discrepancy between our study and that of Neugarten et al. [4] is due to imbalances in baseline proteinuria and other factors.
Our analysis has limitations. First, the studies included in our database were not designed primarily to compare the risk of progression in men vs women. Thus they may not have collected data on all relevant confounding factors. For example, we do not know the menopausal status of women in our pooled analysis. The MDRD study showed a slower renal disease progression in glomerular filtration rate (GFR) in younger vs older women, and a significantly slower rate of GFR decline in younger women vs men [8]. Sex hormones are speculated to play a protective role in renal disease progression in pre-menopausal women [24]. Since most women in our database belonged to the post-menopausal age group, our findings may not extend to younger women.
Secondly, our database included patients recruited to enter randomized controlled trials to slow progression. Therefore, it is possible that patients were selected because they had faster rates of progression. This may have occurred differentially in women vs men. Rigorous evaluation of this hypothesis would require comparing characteristics of enrolled vs non-enrolled men and of enrolled vs non-enrolled women. We do not have data on subjects screened but not enrolled in these studies. However, comparison of characteristics of enrolled men vs enrolled women suggests that women generally had lower levels of risk factors for progression.
Thirdly, the risk of doubling serum creatinine is affected by factors in addition to the rate of decline in GFR, notably the baseline level of GFR and the rate of creatinine generation [25]. In principle, for a given rate of decline in GFR, a lower baseline GFR and a higher creatinine generation rate are associated with a faster rise in serum creatinine. In general, women have lower average rates of creatinine generation, due to lower muscle mass and meat intake. If the rate of GFR decline were similar in women and men in our database, a lower creatinine generation rate in women would be expected to be associated with lower, rather than faster, mean rate of rise in serum creatinine. However, it is likely that women in our database also had lower mean baseline GFR than men, since we observed no difference in mean baseline serum creatinine. Altogether, it can be difficult to infer differences in rates of change in GFR between women and men based on differences in risk of doubling of serum creatinine. We speculate that the higher RR in women of onset of ESRD compared with the combined end point of doubling of serum creatinine or ESRD may be due, in part, to lower baseline GFR in women compared with men. GFR measurements were not performed in all studies in our pooled analysis. However, the MDRD study, which did measure GFR decline, found a faster GFR decline in men, which remained significant after adjustment for baseline proteinuria, mean arterial pressure, race, cause of renal disease and serum transferrin, but not after adjustment for high-density lipoprotein (HDL) cholesterol concentration [8]. Pooling studies that measured GFR declines may provide additional data to answer this question.
In summary, in contrast to some other studies, our findings do not suggest that female sex is protective against the progression of renal disease. However, these findings may be limited to post-menopausal women. After adjustment for confounding factors, women appear to have as high, or higher, a rate of renal disease progression as men, as measured by doubling of serum creatinine or onset of ESRD. This suggests the lack on an independent effect of female sex on slowing renal disease progression. Thus, women should not receive less intensive intervention, as may have been implied by studies suggesting the risk is lower [3,4]. We caution that women in our study as well as those reported earlier were from a biased sample with characteristics dictated by study protocol and inclusion criteria, rather than from a representative population sample.
In addition, there may be other factors associated with female gender that are modifiable. More prospective, population-based studies are needed to study those factors, and to confirm our findings.
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Acknowledgments |
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Conflict of interest statement. S. Shahinfar is an employee of Merck & Co. Inc. and holds stock options in the company. No other author has declared any conflict of interest.
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References |
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