Statins can significantly improve the lipid profile and reduce cardiovascular events. However, beneficial effects of statins on renal function are still controversial. PubMed, the Cochrane Central Register of Controlled Trials, Web of Knowledge, and ClinicalTrials.gov Web sites were searched for randomized controlled trials. The selected studies reported renal function during treatment with statins and control. Forty-one studies with a total of 88,523 participants were included in this analysis. Compared with statins, placebo group had significantly decreased estimated glomerular filtration rate (eGFR): the standardized mean difference (SMD) of eGFR in change from baseline was 0.15 (95% confidence interval [CI] 0.07 to 0.23, p = 0.0004) in patients with eGFR >60 ml/min and 0.09 (95% CI 0.01 to 0.17, p = 0.02) in patients with eGFR 30 to 60 ml/min. Compared with placebo, statin group had significantly greater reduction of proteinuria: the SMD of proteinuria in change from baseline was −1.12 (95% CI −1.95 to −0.30, p = 0.008) in patients with urinary protein excretion 30 to 300 mg/day and −0.77 (95% CI −1.35 to −0.18, p = 0.01) in patients with urinary protein excretion > 300 mg/day. eGFR was significantly greater with high-intensity statins than with moderate-intensity statins (SMD 0.12, 95% CI 0.08 to 0.16, p = 0.00001). Placebo group had significantly decreased eGFR for 1 to 3 years (SMD 0.05, 95% CI 0.02 to 0.08, p = 0.003) and >3 years (SMD 0.14, 95% CI 0.04 to 0.25, p = 0.007) of statin therapy. The beneficial effect of statins on renal function may be dosage related and duration dependent. In conclusion, statins appear to decrease the rate of reduction of eGFR and slow the progression of pathologic proteinuria moderately.
Statins are the most widely prescribed drugs for the treatment of atherosclerosis, and they substantially reduce cardiovascular disease morbidity and mortality in prevention. However, it has not been established whether statins provide similar beneficial effects on the kidney. There is a growing affirmation that statins may offer renoprotective effects as illustrated in a number of cohort studies, other meta-analyses, and statements by professional organizations. In contrast, some studies failed to demonstrate renoprotection from statins. Concerns about these conflicting results make physicians reluctant to prescribe statins in patients with chronic kidney disease (CKD). To assess whether statins had beneficial effects on kidney, we performed this meta-analysis to investigate the effects of statins on estimated glomerular filtration rate (eGFR) and urinary protein excretion between statin and control groups.
Methods
Our meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. We searched the PubMed, the Cochrane Central Register of Controlled Trials, Web of Knowledge, and ClinicalTrials.gov Web sites to identify the published or unpublished randomized controlled trials (RCTs) in any language from 1987 to 2013. The following terms were used: hydroxymethylglutaryl-CoA reductase inhibitors, atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, pitavastatin, statin, kidney, renal, glomerular filtration rate, nephropathy, albuminuria, and proteinuria.
Two investigators independently identified reports according to the inclusion criteria. Disagreements were resolved by discussion and consensus. Study quality was estimated using the Cochrane classification for assessing the risk of bias (sequence generation, allocation concealment, blinding, selective reporting, and intention-to-treat analysis).
The inclusion criteria were (1) RCTs of statins versus control (placebo, another statin, or usual care); (2) participants aged >18 years; (3) report of baseline and at end of follow-up data on kidney function (eGFR, creatinine clearance, or urinary protein excretion); and (4) report of change from baseline on renal function and damage (eGFR, creatinine clearance, or urinary protein excretion). The exclusion criteria were (1) participants aged <18 years; (2) studies without kidney function; (3) participants with contrast-induced nephropathy or dialysis; and (4) reviews, nonhuman studies, case reports, and abstracts.
The characteristics of the study were extracted from the included studies: author, year, sample size, age, design, follow-up duration, statin and dosage, type of renal disease, eGFR, and urinary protein excretion.
The change from baseline in eGFR in milliliters per minute per year was calculated in this analysis. In our meta-analysis, creatinine clearance is regarded as an eGFR. Twenty-five studies ( Supplementary References 3,5,6,9,11–14,16–22,24,27,28,30–35,37 ) enrolled patients with eGFR >60 ml/min/1.73 m 2 . Nine studies ( Supplementary References 1,4,6,7,10,25,26,29,38 ) enrolled patients with eGFR <60 ml/min/1.73 m 2 .
In our analysis, albuminuria and proteinuria were considered together. Three studies ( Supplementary References 2,22,36 ) enrolled patients with urinary protein (or albumin) excretion <30 mg/day. Six studies ( Supplementary References 8,9,15,23,33,35 ) enrolled patients with urinary protein (or albumin) excretion 30 to 300 mg/day. Thirteen studies ( Supplementary References 1,7,9–13,19,20,21,25,32,34 ) enrolled patients with urinary protein (or albumin) excretion >300 mg/day.
“High-intensity,” “moderate-intensity,” and “low-intensity” statin therapy definitions were derived from the recent American College of Cardiology/American Heart Association guidelines. We analyzed our data by comparing high-intensity statins versus moderate-intensity statins. We also investigated the effect of high-intensity, moderate-intensity, and low-intensity statins on eGFR and urinary protein excretion. Eight studies ( Supplementary References 1,6,27,28,30,39–41 ) adopted high-intensity statins. Twenty-five studies ( Supplementary References 2–5,7,9,11,12,16–18,22–24,26,27,29,31,34,35,37–41 ) adopted moderate-intensity statins. Twelve studies ( Supplementary References 8,10,13–15,19–21,25,32,33,36 ) adopted low-intensity statins.
Nikolic et al found that the benefit of statins may depend on the duration of treatment. So we investigated the relation between the duration of treatment (<1 year, 1 to 3 years, and >3 years) and the effect of statins on renal function. The duration of statin therapy in 15 studies ( Supplementary References 4,8,9,12,15,19–21,26,27,31–34,38 ) was <1 year. The duration of statin therapy in 11 studies ( Supplementary References 1,2,10,13,23,25,28–30,35,36 ) was from 1 to 3 years. The duration of statin therapy in 12 studies ( Supplementary References 3,5,6,7,11,14,16–18,22,24,37 ) was >3 years.
The I 2 statistic was used to assess heterogeneity. I 2 >50% and p <0.10 indicated statistically significant heterogeneity. A funnel plot was used to assess publication bias. In the present study, 2-sided p <0.05 was considered significant.
The change from baseline in eGFR in milliliters per minute per year and in urinary protein excretion was calculated using the standardized mean difference (SMD). Missing mean was replaced with median. Missing SD was imputed using the width of interquartile ranges divided by 1.35 or on the basis of p values. The meta-analysis was performed using Review Manager software (version 5.0; Cochrane Collaboration, Oxford, United Kingdom).
Results
Initially, 8,660 studies were searched, consisting of 366 potentially relevant studies and 8,294 studies that were removed after reading titles and abstracts. Of 366 potentially relevant studies, 325 failed to match the inclusion criteria. Finally, 41 studies with a total of 88,523 participants were included in this meta-analysis. Flowchart for identification of studies is presented in Figure 1 . The baseline characteristics of studies in the meta-analysis are given in Table 1 .
| Studies | Treatment | Control | No. of Patients | Mean Age (Years) | Baseline eGFR (ml/min/1.73 m 2 ) | Baseline Urinary Protein Excretion (mg/d) | Follow up (Months) | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Treatment | Control | Treatment | Control | Treatment | Control | Treatment | Control | ||||
| Bianchi S1 | A 40 mg | Placebo | 28 | 28 | 56.5 | 56.8 | 50.8 ± 9.5 | 50.0 ± 10.1 | 2500 ± 1900 | 1900 ± 1400 | 12 |
| Dalla Nora S2 | A 10 mg | Placebo | 12 | 13 | 66 | 63 | NR | NR | 5.76 ± 16 | 7.2 ± 12 | 12 |
| Athyros S3 | A 24 mg | Placebo | 800 | 800 | 58 | 59 | 76 ± 13 | 77 ± 12 | NR | NR | 36 |
| Goicoechea S4 | A 20 mg | Placebo | 44 | 19 | 66.2 | 70 | 42.8 ± 24.9 | 44.2 ± 25.9 | NR | NR | 6 |
| Colhoun S5 | A 10 mg | Placebo | 447 | 437 | 61.5 | 61.8 | 64.5 ± 10.0 | 64.9 ± 10.0 | NR | NR | 46.8 |
| Koren S6 | A 40.5 mg | Placebo | 235 | 158 | 65.6 | 64.8 | 51.3 ± 7.8 | 51.1 ± 8.5 | NR | NR | 54.3 |
| A 40.5 mg | Placebo | 811 | 564 | 59.8 | 60.2 | 79.4 ± 15.2 | 79.1 ± 15.6 | NR | NR | 54.3 | |
| Fassett S7 | A 10 mg | Placebo | 58 | 65 | 60 | 60.3 | 31.9 ± 11.0 | 29.1 ± 12.8 | 1430 ± 2280 | 1180 ± 1610 | 36 |
| Lintott S8 | F 40 mg | Placebo | 32 | 10 | 57 | 63 | NR | NR | 200 ± 537 | 297 ± 403 | 3 |
| Buemi S9 | F 40 mg | Placebo | 8 | 13 | 36 | 38 | 90 ± 44 | 90 ± 40 | Proteinuria 845 ± 699 Albuminuria 296 ± 244 | Proteinuria 837 ± 523 Albuminuria 293 ± 183 | 6 |
| Yasuda S10 | F 20 mg | Placebo | 39 | 41 | 57 | 58 | 59 ± 31 | 60 ± 26 | 800 ± 1248 | 700 ± 640 | 12 |
| Fellstrom S11 | F 40–80 mg | Placebo | 1050 | 1052 | 49.5 | 50 | 60.2 ± 20.8 | 60.3 ± 20.7 | 500 ± 1400 | 400 ± 700 | 60 |
| Ruggenenti S12 | F 40–80 mg | Placebo | 83 | 88 | 51.4 | 51.4 | 67.7 ± 45.2 | 59.4 ± 34.0 | 1200 ± 1200 | 1500 ± 1400 | 6 |
| Lam S13 | L 30 mg | Placebo | 16 | 18 | 58.9 | 53.9 | 83.1 ± 38 | 84.3 ± 21.6 | 810 ± 680 | 1140 ± 1273 | 24 |
| Kendrick S14 | L 20 mg | Placebo | 3303 | 3301 | 58–62 | 58–62 | >60 | >60 | NR | NR | 63.6 |
| Zhang S15 | P 20 mg | Placebo | 10 | 10 | 43 | 43 | NR | NR | 93.6 ± 53 | 93.6 ± 53 | 3 |
| Shepherd S16 | P 40 mg | Placebo | 3302 | 3293 | 55.3 | 55.1 | >60 | >60 | NR | NR | 58.8 |
| Sacks S17 | P 40 mg | Placebo | 2081 | 2078 | 59 | 59 | >60 | >60 | NR | NR | 60 |
| LIPID S18 | P 40 mg | Placebo | 4512 | 4502 | 62 | 62 | >60 | >60 | NR | NR | 73.2 |
| Imai S19 | P 5–10 mg | Placebo | 32 | 25 | 58.5 | 49.5 | 64.4 ± 30.5 | 54.4 ± 30.5 | 1100 ± 1358 | 1400 ± 1450 | 6 |
| Lee S20 | P 10 mg | Placebo | 31 | 32 | 50 | 47 | 85 ± 16 | 90 ± 19 | 1234 ± 490 | 1193 ± 507 | 6 |
| Lee S21 | P 10 mg | Placebo | 42 | 40 | 50 | 48 | 85 ± 16 | 90 ± 19 | 1323 ± 592 | 1207 ± 531 | 6 |
| Atthobari S22 | P 40 mg | Placebo | 400 | 388 | 52.1 | 50.9 | 75.7 ± 12.1 | 75.5 ± 12.0 | NR | NR | 48 |
| Nanayakkara S23 | P 40 mg | Placebo | 47 | 46 | 54 | 52 | NR | NR | 45 ± 854 | 71 ± 650 | 24 |
| Rahman S24 | P 40 mg | Placebo | 1342 | 1298 | 63.3 | 63.1 | 101.8 ± 12.9 | 102.4 ± 12.3 | NR | NR | 57.6 |
| P 40 mg | Placebo | 2903 | 2960 | 67 | 67 | 75.3 ± 8.0 | 75.2 ± 8.1 | NR | NR | 57.6 | |
| P 40 mg | Placebo | 779 | 778 | 70.7 | 70.6 | 50.8 ± 8.2 | 50.6 ± 8.4 | NR | NR | 57.6 | |
| Fassett S25 | P 20 mg | Placebo | 29 | 20 | 53 | 49 | 58.5 ± 18.2 | 49.9 ± 23.2 | 370 ± 490 | 220 ± 230 | 24 |
| Verma S26 | R 10 mg | Placebo | 44 | 39 | 73 | 74 | 42.3 ± 11.1 | 49.4 ± 11.9 | NR | NR | 5 |
| Kostapanos S27 | R 10 mg | Placebo | 45 | 40 | 51.7 | 52.2 | 83.4 ± 15.4 | 82.9 ± 13.2 | NR | NR | 3 |
| R 20 mg | Placebo | 45 | 40 | 52.4 | 52.2 | 82.3 ± 12.5 | 82.9 ± 13.2 | NR | NR | 3 | |
| Crouse S28 | R 40 mg | Placebo | 702 | 282 | 57 | 57 | >60 | >60 | NR | NR | 24 |
| Sawara S29 | R 2.5 mg | Placebo | 22 | 16 | 63.8 | 67.0 | 50.7 ± 18.7 | 57.3 ± 16.2 | NR | NR | 12 |
| Vidt S30 | R 20 mg | Placebo | 8143 | 8136 | 66 | 66 | 75.4 ± 17.5 | 75.4 ± 17.1 | NR | NR | 27.6 |
| Abe S31 | R 2.5–10 mg | Placebo | 52 | 52 | 64.5 | 64.9 | 70.4 ± 11.9 | 69.3 ± 9.5 | 69.3 ± 9.5 | 69.3 ± 9.5 | 6 |
| Hommel S32 | S 10–20 mg | Placebo | 12 | 9 | 41 | 35 | 64 ± 30 | 72 ± 23 | 698 ± 1313 | 755 ± 1290 | 3 |
| Nielsen S33 | S 10–20 mg | Placebo | 8 | 10 | 65 | 65 | 96.6 ± 22.6 | 97.1 ± 21.2 | 28 ± 18 | 49 ± 40 | 9 |
| Thomas S34 | S 10–40 mg | Placebo | 15 | 15 | 52 | 49 | 76.5 ± 36.5 | 75.4 ± 40.2 | 5290 ± 3490 | 4400 ± 2680 | 6 |
| Tonolo S35 | S 20 mg | Placebo | 10 | 9 | 60 | 62 | 101 ± 8 | 97 ± 7 | 73 ± 50.4 | 70 ± 45.9 | 12 |
| Fried S36 | S 10–20 mg | Placebo | 19 | 20 | 33.3 | 31.0 | NR | NR | 11 ± 8 | 15 ± 10 | 24 |
| Collins S37 | S 40 mg | Placebo | 7999 | 7697 | 40–80 | 40–80 | >60 | >60 | NR | NR | 60 |
| Panichi S38 | S 40 mg | Placebo | 28 | 27 | 60 | 55 | 40 ± 12 | 32 ± 13 | NR | NR | 6 |
| PLANETI S39 | A 80 mg | R 10 mg | 111 | 118 | NR | NR | 72.1 ± 24.9 | 68.8 ± 24.1 | NR | NR | 13 |
| R 40 mg | R 10 mg | 124 | 118 | NR | NR | 72.6 ± 25.8 | 68.8 ± 24.1 | NR | NR | 13 | |
| PLANETII S40 | A 80 mg | R 10 mg | 80 | 70 | NR | NR | 71.5 ± 30.0 | 78.3 ± 28.1 | NR | NR | 13 |
| R 40 mg | R 10 mg | 87 | 70 | NR | NR | 76.8 ± 30.4 | 78.3 ± 28.1 | NR | NR | 13 | |
| Shepherd S41 | A 80 mg | A 10 mg | 4827 | 4829 | 61.2 | 60.9 | 65.0 ± 11.2 | 65.6 ± 11.4 | NR | NR | 60 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
