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CLINICAL STUDIES

Rosuvastatin Increases {alpha}-1 Microglobulin Urinary Excretion in Patients With Primary Dyslipidemia

Michael S. Kostapanos, MD, Haralampos J. Milionis, MD, Irene Gazi, MD, Christine Kostara, PhD, Eleni T. Bairaktari, PhD and Moses Elisaf, MD, FRSH, FASA

From the Department of Internal Medicine (Dr Kostapanos, Dr Milionis, Dr Gazi, Prof Elisaf) and the Laboratory of Clinical Chemistry (Dr Kostara, Dr Bairaktari), School of Medicine, University of Ioannina, Ioannina, Greece.

Address for reprints: Moses S. Elisaf, MD, FRSH, FASA, Department of Internal Medicine, School of Medicine, University of Ioannina, 451 10 Ioannina, Greece; e-mail: hmilioni{at}cc.uoi.gr.


   ABSTRACT
TOP
 ABSTRACT
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The renoprotective effect of statins has been recently disputed because of observations of proteinuria associated with rosuvastatin treatment, the newest drug of the class. Statin-induced proteinuria findings were mainly based on crudely quantitative dipstick assays. The authors quantitatively evaluated the effect of rosuvastatin at the recommended starting dose of 10 mg/d, on urine protein excretion in patients with primary dyslipidemia. Serum lipid and nonlipid parameters as well as urinary electrolyte, creatinine, and protein (total, albumin, immunoglobulin G, and {alpha}-1 microglobulin) levels were measured in 40 patients treated with rosuvastatin and 30 controls at baseline and after 12 weeks. The protein-to-creatinine ratios were used to assess urinary protein excretion. Rosuvastatin improved the lipid profile, produced no deterioration of kidney function, but induced a small but significant increase in the excretion of {alpha}-1 microglobulin (by 16%, P < .05) indicating that statin-related proteinuria involves low-molecular-weight proteins and is of proximal tubular origin.

Key Words: Rosuvastatin • proteinuria • albumin • alpha-1 microglobulin

3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) are the cornerstone in the management of hypercholesterolemia.1-3 Statin treatment has proved to be efficacious and well tolerated, with infrequent reports of muscle toxicity being the major reason for clinicians to be cautious about their use.4,5 Besides their lipid-lowering capacity, statins exhibit a variety of favorable antiatherogenic actions, including anti-inflammatory properties in atherosclerotic plaques, antiproliferative effects in vascular smooth muscle cells, and anticoagulation properties.6-8 Experimental evidence and a limited body of clinical data suggest that statins may slow the progression of renal impairment and decrease proteinuria in patients with renal disease.9-12 Recently, the renoprotective action of this class of drugs has been disputed because of observations of statin-induced proteinuria.13,14 Concerns have been raised because of reports of urine abnormalities, specifically proteinuria and hematuria, associated with rosuvastatin treatment, which had not been previously reported with these drugs.15,16

Statin-induced proteinuria findings were based on dipstick assays on random urine samples (ie, dipstick-positive proteinuria defined as a shift from no protein or trace at baseline to ++ or more).15 These tests are crudely quantitative, subject to investigator reading errors, and are relatively inaccurate (with a false positive rate of 10%) and nonspecific.17 To date, there are no data concerning the effects of statins on proteinuria using accurate quantitative measures.

The aim of this study was to evaluate the effect of rosuvastatin at the recommended starting dose of 10 mg/d on urine protein excretion in patients with primary dyslipidemia.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Participants
Forty patients with primary dyslipidemia type IIa (primary hypercholesterolemia, low-density lipoprotein cholesterol [LDL-C] >160 mg/dL, triglycerides [TG] <200 mg/dL) or IIb (combined dyslipidemia, LDL-C >160 mg/dL and TG 200-350 mg/dL) according to the classification of Friedrickson, who consecutively attended the Outpatient Lipid Clinic of the University Hospital of Ioannina, Ioannina, Greece, participated in the present study.

Exclusion criteria were (1) age less than 18 years, (2) renal function impairment as defined by serum creatinine levels greater than 1.8 mg/dL (159 µmol/L) and/or total protein urinary (UTpr) excretion greater than 150 mg/24h, (3) diabetes mellitus (coded as fasting glucose levels >126 mg/dL on more than one occasion or relevant treatment), (4) raised thyroid-stimulating hormone levels (>5 IU/mL), (5) liver disease (as defined by alanine and/or aspartate aminotransferase levels >3 times the upper limit of normal in more than 2 consecutive measurements), (6) childbearing potential for women, (7) antihypertensive therapy (especially with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) modified 12 or fewer weeks prior to enrollment, or (8) lipid-lowering therapy (including other statins, fibric acid derivatives, nicotinic acid, cholestyramine, ezetimibe, or {omega}-3 fatty acids) for at least 4 weeks before rosuvastatin initiation.

After a 6 weeks' dietary lead-in, eligible patients were prescribed rosuvastatin 10 mg/d. A food record rating score was calculated from 3-day diaries kept by participants to assess compliance throughout the study.

To validate for urinary laboratory parameters (ie, protein excretion) and changes potentially induced by statin treatment, we also evaluated a control group of 30 subjects who were selected among volunteers attending a Primary Care Family Screening Program, which was conducted in the Outpatient Lipid Clinic during the study period. Exclusion criteria 1 to 5 were also applied to the control group. None of the controls received anti-hypertensive or lipid-lowering treatment during the study period.

All patients gave informed consent and the study protocol was approved by the Institutional Ethics Committee.

Laboratory Investigations
Blood samples were obtained at baseline and after 12 weeks after a 12-hour overnight fast to determine serum lipid and nonlipid metabolic parameters. First morning urine samples were also collected from all eligible subjects before and after 12 weeks. Urine samples were centrifuged at 3000 revolutions per minute for 15 minutes to remove any solid sediment and were stored in deep freeze at -80°C until analysis (within a month).

All serum laboratory measurements were performed by standardized methods using an Olympus AU 600 clinical chemistry analyzer (Olympus Diagnostica, Hamburg, Germany). Specifically, serum samples were analyzed by using ion-sensitive electrodes for sodium (SNa+), potassium (SK+), chloride (SCl-), and calcium (SCa2+), and by photometric assays for phosphorus (SPO43-) and magnesium (SMg2+). The glutamate dehydrogenase (GLDH) method was used for the determination of serum urea (SUre) levels and a modification of the Jaffé method for creatinine (SCr). Serum total protein (STpr) concentrations were measured by the Biuret method and serum albumin (SAlb) by the bromocresol green (BCG) method. Serum glucose levels (SGlc) were measured by the hexokinase method.

LDL-C levels were calculated using the Friedewald formula. Serum levels of apolipoproteins (apo) A1 and B were measured by immunonephelometry using a Behring Nephelometer BN100 (Behring Diagnostics, Frankfurt, Germany).

Biochemical analysis of urine samples, for the determination of UTpr, creatinine (UCr), sodium (UNa+), potassium (UK+), calcium (UCa2+), phosphate (UPO43-), magnesium (UMg2+), and chloride (UCl-) levels, was carried out on an Olympus AU 600 analyzer. In addition, the fractional excretion (FE) of the electrolytes (A) was calculated using the formula: FEA(%) = (UrineA/SerumA)/(UrineCr/SerumCr) x 100.

The urinary proteins (ie, albumin [UAlb], immunoglobulin G [UIgG], and {alpha}-1 microglobulin [U{alpha}1m]) were measured by a Behring Nephelometer BN ProSpec using reagents (antibodies and calibrators) from Dade Behring Holding Gmbh (Liederbach, Germany).

Urinary excretion of high- and low-molecular-weight proteins was expressed as the ratio of protein to creatinine concentration: UTpr/UCr, UAlb/UCr, U{alpha}1m/UCr, and UIgG/UCr.18-21 Furthermore, to assess the impact of rosuvastatin therapy on renal function, we determined the glomerular filtration rate (GFR) by using the abbreviated Modification of Diet in Renal Disease (MDRD) formula: MDRD GFR = 186 x (SCr in mg/dL)-1.154 x (age in years)-0.203 x (0.742 if female).22

Statistical Analysis
Preliminary analysis was performed to ensure no violation of the assumptions of linearity and normality. The Shapiro-Wilk test was used to evaluate whether each parameter followed a Gaussian distribution. Data are expressed as mean ± SD, except for non-Gaussian parameters, which are presented as median (range). Differences of study parameters between baseline and posttreatment values were evaluated by paired samples t test (or Wilcoxon rank test when appropriate). Significance was defined as P < .05. All analyses were carried out with SPSS 13.0 (SPSS Inc, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
All 40 patients (21 men and 19 women; mean age, 51.5 ± 14.5 years) completed the study protocol. The baseline clinical characteristics of the study population are shown in Table I. There were no withdrawals due to treatment-related serious adverse events. Clinically significant elevations in alanine aminotransferase (ALT, values >3 times the upper limit of normal on 2 consecutive occasions) or in creatine kinase (CK) activities (values >10 times the upper limit of normal) were not observed during follow-up.


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  		Table I Demographic and Clinical Characteristics of the Study Population

 

The antihypertensive treatment was not modified in any patient during the follow-up. No significant differences between baseline and follow-up systolic and diastolic blood pressure (BP) measurements were noted (120.5 ± 4.5 vs 119 ± 8.9, P = not significant and 78 ± 4 vs 80.3 ± 9.5 mm Hg, P = not significant, respectively).

The effects of rosuvastatin on lipid parameters are shown in Table II. Specifically, total cholesterol (TC), LDL-C, apo B, and TG levels were reduced by 30.7% (P < .001), 40.7% (P < .001), 32.2% (P < .001), and 14.9% (P < .01), respectively, and the ratio apoB/apoA1 was decreased by 30% (P < .001). A small but not significant increase was observed in HDL-C and apo A1 levels following rosuvastatin treatment.


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  		Table II Changes in the Serum Lipid Profile From Baseline to Week 12 in the Study Population

 

There were no significant alterations in nonlipid serum metabolic measurements, including SCr, SUre, SAlb, STpr, SGlc, and SUA levels (Table III) as well as in the FE of the electrolytes and uric acid (Table IV).


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  		Table III Changes in Nonlipid Serum Metabolic Parameters From Baseline to Week 12 in the Study Population

 

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  		Table IV Changes in Urinary Parameters From Baseline to Week 12

 

Rosuvastatin treatment did not affect the calculated UTpr, UAlb, and UIgG excretions (Table IV). However, a significant increase by 15.7% (P < .05) in the calculated U{alpha}1m urinary excretion was noted (Table IV). This increase was not accompanied by a significant change in the GFR, (GFR-MDRD, 83.1 ± 17.9 vs 83.1 ± 17.3 mL/min/1.73 m2, P = not significant) or the SCr levels (Table III).


   DISCUSSION
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
In the present study, we evaluated the effects of rosuvastatin at the recommended starting dose of 10 mg/d in hyperlipidemic, nondiabetic patients with no evidence of renal dysfunction at baseline. Rosuvastatin treatment improved lipid abnormalities and was associated with an increase in the urinary excretion of {alpha}1m.

There is an interesting body of literature with regard to the effect of statins on renal function and proteinuria, especially in patients with no evidence of renal function impairment prior to treatment initiation.23,24 Moreover, statin treatment has been shown to either lower9,10 or stabilize11,12 proteinuria and retard25,26 the progression of renal damage in patients with renal disease. These effects have been attributed to the normalization of the deleterious impact of dyslipidemia on the kidney function as well as to lipid independent pleiotropic actions.27,28

However, short-term high dose statin therapy has been reported to be complicated with the development of proteinuria.13,14 In vitro studies showed that statins (HMG-CoA reductase inhibitors) reduce the synthesis of mevalonate, which plays an important role on the normally filtered low-molecular-weight proteins' reabsorption by the proximal tubular cells.29,30 Statin-induced proteinuria has been shown to correlate with the HMG-CoA inhibitory effect and subsequently their lipid-lowering action; however, this increase in protein excretion has not been associated with any structural damage of proximal tubular cells.29,30 It must be noted that tubular proteinuria is seen with all statins and directly relates to the potency of LDL reduction at a given dose.15,16,31

Rosuvastatin, the newest statin available, has been shown to be the most potent in terms of its lipid-lowering capacity.32-34 Even though, this statin seems to share some of the pleiotropic actions of the class,35,36 with a safety profile comparable to that of other statins,31 its exact role on renal function remains controversial. In fact, in a large pooled analysis of data from a phase II/III development program,15 a significant statin-induced proteinuria appeared in subjects on rosuvastatin 40 mg/d more often than in those on placebo or other statins groups. Moreover, with the highest dose of rosuvastatin tested in clinical trials (80 mg/d) a high incidence of proteinuria and hematuria was seen and was accompanied by isolated cases of renal failure, some of which were associated with myopathy.15,37 However, no evidence of renal impairment with the recommended doses of rosuvastatin (10 to 40 mg/d) has been reported.15,38

In the present study, we determined protein excretion before and after rosuvastatin administration using accurate quantitative laboratory methods. Rosuvastatin 10 mg/d induced an increase in the {alpha}1m urinary excretion. In line with our findings, Vidt et al,15 based on results from urinary protein gel electrophoresis, showed that rosuvastatin therapy may be associated with an increase in excretion of proteins with a molecular weight less than that of albumin. These findings indicate that rosuvastatin-induced proteinuria is of tubular rather than of glomerular origin.

It is well known that {alpha}1m is a low-molecular-weight protein that is normally filtered by renal glomeruli and reabsorbed by the proximal tubular cells.39 In the clinical setting, U{alpha}1m excretion is proposed to be a marker of the proximal tubular functionality.40-43 Therefore, we could hypothesize that rosuvastatin-induced increase in U{alpha}1m might be associated with a proximal tubular harm. According to our findings, there was no evidence of significant proximal tubular damage following rosuvastatin treatment, as reflected by the absence of alterations in the fractional excretions of electrolytes and uric acid. Thus, the increase in U{alpha}1m excretion could be the result of the pharmacologic action of rosuvastatin because of its highly effective inhibition of HMG-CoA reductase.

No significant variations in renal function parameters (namely, SCr levels and GFR-MDRD) were observed during the follow-up period. This finding is in agreement with recent studies in patients with primary hyperlipidemia,38,44 type 2 diabetes,45 as well as patients with chronic kidney disease.46 Moreover, rosuvastatin did not affect the urinary excretion of albumin and IgG, which are known to be related with the function of the glomeruli.47,48

There is evidence that long-term statin treatment may improve renal function.25,49 For example, in the Heart Protection Study, simvastatin at 40 mg (compared with placebo) was associated with less deterioration in the estimated GFR in patients at high-risk for vascular events over a 5-year follow-up.49 In addition to short-term studies with rosuvastatin,50 including the present one, renal function, as assessed by mean GFR, did not deteriorate in patients who received long-term (over 96 weeks) treatment with rosuvastatin at any dose, irrespective of age, gender, the presence of diabetes or hypertension, level of renal function at baseline, or evidence of proteinuria before or during the treatment period.15

Study Limitations
In this small, prospective, open-label, noncomparative study, we attempted to evaluate quantitatively the short-term effects of rosuvastatin therapy on renal function parameters and proteinuria of either glomerular or tubular origin. The short duration of the follow-up period and the lack of dose-titration of treatment may represent study limitations. Studies with larger populations are needed to confirm our findings as well as to compare between statins and to evaluate the effects of dose titration of single agents.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
Financial disclosure: None declared.

DOI: 10.1177/0091270006292629


   REFERENCES
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 ABSTRACT
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

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M. S. Kostapanos, H. J. Milionis, and M. S. Elisaf
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Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2008; 13(3): 157 - 174.
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M. S. Kostapanos, H. J. Milionis, V. G. Saougos, K. G. Lagos, C. Kostara, E. T. Bairaktari, and M. S. Elisaf
Dose-Dependent Effect of Rosuvastatin Treatment on Urinary Protein Excretion
Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2007; 12(4): 292 - 297.
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