Current data suggests that statins might have beneficial effects on renal outcomes. Beneficial effects of statin treatment on renal progression in advanced chronic kidney disease (CKD) are obviously controversial. In a retrospective, controlled study, the authors have evaluated the effects of 53-week treatment with simvastatin, versus no treatment on proteinuria and renal function among 51 patients with CKD stages III-IV. By the end of the 53-week treatment, urine protein excretion decreased from 0.96 (IQR 0.54, 2.9) to 0.48 (IQR 0.18, 0.79) g/g creatinine (
Chronic kidney disease (CKD) is a common condition and its prevalence is increasing worldwide [
Use of statins is beneficial for most patients with CKD who are at high cardiovascular risk [
The research employed a retrospective cohort-based design that randomly used medical records from April 2012 to March 2013 on CKD patients who routinely visited an outpatient facility including stable blood pressure and blood glucose within 3 months. Inclusion criteria of the study included age, 18 years or older, proteinuric CKD > 300 mg/day, and urinary protein creatinine ratio (UPCR) test before and after initiating simvastatin for 53 weeks. Treatment group of patients received simvastatin 10–40 mg daily. The other patients in the normal care group were treated according to their physician’s standard of care. Normal care included life style changes, such as low fat diet, weight loss, and exercise, in addition to all necessary drug treatment without statins. Exclusion criteria included active malignancy, severe heart, lung, or liver disease, stroke, chronic infection, for example, tuberculosis, within one year of starting the study, and any immunological or inflammatory disorders.
From their clinical data, we determined the effects of statins on renal parameters after a 53-week period. At the time of entry, all patients were also taking standard antihypertensive agents including angiotensin receptor blockers, angiotensin converting enzyme inhibitors, calcium channel blocker, beta-blockers, alpha-blockers, and diuretics. A complete medical history was taken and physical examination was performed on all subjects. All subjects fasted for at least 12 hours overnight before all blood drawing. Complete blood counts, blood urea nitrogen, serum creatinine, and comprehensive serum chemistries were measured. The serum concentration of creatinine using the enzymatic method was determined with reagents from Roche Diagnostics (Mannheim, Germany) and the calibrator was IDMS standardized. Glomerular filtration rate (GFR) was estimated from calibrated serum creatinine with the 2009 CKD-EPI creatinine equation [
Results are expressed as the mean ± SD, as medians with interquartile ranges, or as a percentage in categorical variables. Differences between groups mean or median values were evaluated using the independent Student’s
Patient characteristics are shown in Table
Patients’ characteristics.
Simvastatin |
Nonsimvastatin |
|
|
|
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Male (%) | 17 (68%) | 20 (76.9%) | 0.556 |
Age (year) | 62 ± 19.86 | 60.04 ± 21.31 | 0.735 |
Weight (kg) | 67.80 ± 13.92 | 63.34 ± 13.80 | 0.256 |
Primary renal diseases, |
0.612 | ||
Glomerular diseases | 11 | 9 | |
CTIN | — | 1 | |
Unknown | 14 | 16 | |
Diabetes mellitus (%) | 17 (68%) | 8 (30.8%) | 0.012 |
Hypertension (%) | 21 (84%) | 17 (65.4%) | 0.199 |
Atherosclerosis (%) | 6 (24.0%) | 5 (19.2%) | 0.743 |
Current antihypertensive agents (%) | |||
ACEI/ARB | 17 (68.0%) | 18 (69.2%) | 0.572 |
Diuretics | 9 (36.0%) | 5 (19.2%) | 0.220 |
Alpha-blockers | 9 (36.0%) | 5 (19.2%) | 0.220 |
Beta-blockers | 5 (20.0%) | 3 (11.5%) | 0.171 |
CCB | 7 (28.0%) | 5 (19.2%) | 0.258 |
SBP (mmHg) | 139.08 ± 17.24 | 137.38 ± 17.88 | 0.732 |
DBP (mmHg) | 79.44 ± 14.22 | 77.27 ± 13.26 | 0.575 |
UPCR (g/g creatinine) | 0.96 (0.54, 2.9) | 1.41 (0.66, 2.41) | 0.445 |
GFR (mL/min/1.73 m2) | 41.12 ± 28.97 | 39.77 ± 23.55 | 0.856 |
BUN (mg/dL) | 27.75 ± 12.68 | 30.60 ± 15.16 | 0.472 |
Serum creatinine (mg/dL) | 1.97 ± 0.72 | 1.97 ± 0.73 | 0.995 |
Cholesterol (mg/dL) | 211.72 ± 123.80 | 185.62 ± 57.15 | 0.335 |
Triglyceride (mg/dL) | 158.48 ± 154.03 | 143.04 ± 112.93 | 0.684 |
HDL (mg/dL) | 52.24 ± 15.05 | 57.19 ± 27.02 | 0.425 |
LDL (mg/dL) | 134.04 ± 93.90 | 109.00 ± 42.80 | 0.232 |
Non-HDL (mg/dL) | 157.56 ± 126.09 | 122.27 ± 55.55 | 0.199 |
AST (mg/dL) | 24.80 ± 11.39 | 23.69 ± 10.88 | 0.724 |
ALT (mg/dL) | 23.44 ± 19.07 | 21.04 ± 13.36 | 0.604 |
Values expressed as mean ± SD or median with interquartile ranges, ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin type 1 receptor blocker; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; CCB: calcium channel blockers; DBP: diastolic blood pressure; HDL: high density lipoprotein; LDL: low density lipoprotein; GFR: glomerular filtration rate; SBP: systolic blood pressure; UPCR: urine protein creatinine ratio.
Both systolic and diastolic blood pressure remain unaltered during the observation period. However, lipid profiles improved after 53 weeks of simvastatin treatment. Mean changes of total cholesterol (−52.44 ± 106.05 versus −6.65 ± 36.88 mg/dL,
Changes of metabolic profiles after 53 weeks of statin treatment.
Variables | Mean changes |
|
|
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Simvastatin | Nonsimvastatin | ||
SBP (mmHg) | −5.72 ± 21.88 | −0.77 ± 20.19 | 0.405 |
DBP (mmHg) | −1.84 ± 13.89 | −4.50 ± 13.64 | 0.493 |
Cholesterol (mg/dL) | −52.44 ± 106.05 | −6.65 ± 36.88 | 0.045 |
Triglyceride (mg/dL) | −34.68 ± 140.77 | −15.81 ± 83.44 | 0.561 |
HDL (mg/dL) | 0.36 ± 15.95 | 1.65 ± 20.31 | 0.802 |
LDL (mg/dL) | −41.28 ± 79.96 | −3.81 ± 25.44 | 0.033 |
Non-HDL (mg/dL) | −56.04 ± 111.34 | −8.50 ± 29.78 | 0.049 |
AST (U/L) | −2.12 ± 7.57 | 5.15 ± 18.83 | 0.079 |
ALT (U/L) | 3.36 ± 28.03 | 10.96 ± 44.41 | 0.470 |
Data are expressed as mean changes of 53 weeks ± SD; ALT: alanine aminotransferase; AST: aspartate aminotransferase; DBP: diastolic blood pressure; HDL: high density lipoprotein; LDL: low density lipoprotein; SBP: systolic blood pressure.
Renal function did not significantly change in both groups. Finally, mean changes of serum creatinine (0.1 ± 0.62 versus 0.1 ± 0.68 mg/dL,
Individual CKD patients with proteinuria >300 mg/day receiving simvastatin had a statistically significant decreased UPCR from 0.96 (IQR 0.54, 2.9) to 0.48 (IQR 0.18, 0.79) g/g creatinine (
Renal outcomes after 53 weeks of statin treatment.
Variables | Simvastatin | Nonsimvastatin |
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( |
( |
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Baseline | At 53 weeks | Mean differences |
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Baseline | At 53 weeks | Mean differences |
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Mean UPCR (g/g creatinine) | 2.26 ± 2.99 | 0.83 ± 0.95 | −1.4 ± 2.8 | 0.019 | 1.79 ± 1.47 | 1.77 ± 2.68 | −0.02 ± 2.4 | 0.969 | 0.049 |
Median UPCR (g/g creatinine) | 0.96 (0.54, 2.9) | 0.48 (0.18, 0.79) | <0.001 | 1.41 (0.66, 2.41) | 1.21 (0.19, 1.56) | 0.485 | |||
GFR (mL/min/1.73 m2) | 41.12 ± 28.97 | 39.88 ± 29.74 | −1.2 ± 7.2 | 0.396 | 39.77 ± 23.55 | 36.46 ± 18.82 | −3.3 ± 11.9 | 0.168 | 0.458 |
Serum creatinine (mg/dL) | 1.97 ± 0.73 | 2.06 ± 0.72 | 0.1 ± 0.62 | 0.315 | 1.97 ± 0.72 | 2.07 ± 0.67 | 0.1 ± 0.68 | 0.458 | 0.308 |
Values expressed as mean ± SD or median with interquartile ranges; GFR: glomerular filtration rate; UPCR: urine protein creatinine ratio; (#) comparisons within groups; (&) comparisons between groups.
No unexpected safety concerns were identified and similar incidences of adverse events were experienced in each of the treatment groups. No serious adverse effects such as persistent elevations in liver function enzymes and creatine phosphokinase values were observed in those using simvastatin.
The present study reported that simvastatin was associated with lipid lowering and antiproteinuric benefits in patients with moderate to advanced CKD. They seemed to be safe with CKD, with respect to the risk of hepatotoxicity. However, the present study could not clearly confirm evidence of any renoprotective effect of statins in patients with CKD, as indicated by no difference found in GFR and serum creatinine between simvastatin and control groups.
Patients with higher levels of proteinuria have an increased risk of severe CKD and as a predictor of future decline in GFR [
The beneficial effect of statins on proteinuria seen in our study may be potentially explained by cholesterol dependent effects and cholesterol independent effects. Experimental studies have documented that dyslipidemia contributes to glomerular and interstitial injury and the severity of the hypercholesterolemia correlates with proteinuria [
Our findings are consistent with a recent study, reporting that urinary protein losses had fallen, but renal function was stable among CKD patients at the end of one year of therapy with intensified lipid-lowering statin [
One possible explanation of estimated GFR improvement in previous studies may be related to the intensity of statin therapy. Improvement in estimated GFR occurred with low-dosage atorvastatin (10 mg/day), but high-dosage atorvastatin (80 mg/day) demonstrated significantly greater improvement in estimated GFR than that achieved by low-dosage atorvastatin [
Our study had limitations that should be considered. First, this was a retrospective controlled study, and the limitations of it are well described. Thus, other confounding factors and change of metabolic parameters might have affected the proteinuria in the simvastatin group during the follow-up period. Although a significant reduction of urinary protein excretion in the statin treated group and mean changes of urine protein between the statin treated and nonstatin treated groups were observed, differences in baseline data of comorbid diseases included type 2 diabetes, hypertension, and medications between both groups. Second, renal outcomes in the current study were estimated using the CKD-EPI-GFR formula and UPCR, which are less accurate than nuclear isotope estimates of GFR and 24-hour urine protein. Finally, this study enrolled a small sample size and had a short duration of follow-up. However, our study revealed that individuals with moderate to severe kidney disease may derive clinically relevant proteinuric benefits from the use of simvastatin, especially those with proteinuria. These findings should be confirmed by a large randomized trial conducted specifically among this patient population.
This study has showed that treatment with statins in addition to a regimen with ACE inhibitors or ARBs can reduce proteinuria in patients with proteinuric CKD and hyperlipidemia. The benefits appear to occur in addition to those treated with standard CKD management.
None of the authors have conflict of interests to declare in relation to this work.
This work was supported by a grant from the Department of Medicine, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand.