Background

Hyperlipidemia of the nephrotic syndrome is a risk factor for the development of systemic atherosclerosis, but it also may aggravate glomerulosclerosis and enhance the progression of glomerular disease. HMG-CoA reductase inhibitors are effective in reducing cardiovascular morbiditiy and mortality. Whether they may influence the progression of glomerular disease is not clear. The Simvastatin in Nephrotic Syndrome Study addressed the question of whether or not cholesterol lowering by the HMG-CoA reductase inhibitor simvastatin was superior to placebo treatment in limiting the decline of GFR and reducing proteinuria in nephrotic patients with primary glomerulonephritis.

Methods

This was a prospective, two-year, double-blind trial that included 56 patients with primary glomerulonephritis, hypercholesterolemia due to the nephrotic syndrome (proteinuria> 3 g/24 hr), and a creatinine clearance> 40 ml/min/1.73 m². They were randomly assigned to treatment with simvastatin or placebo targeted to achieve low density lipoprotein (LDL) cholesterol levels below 120 mg/dl. The objectives were to determine the efficacy and safety of simvastatin, the rate of GFR decline as measured by inulin clearance, and the change in proteinuria over a two-year treatment period.

Results

Simvastatin produced a mean change in cholesterol, LDL cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides of -39%, - 47%, + 1%, and -30%, respectively. Serum lipoprotein(a) [Lp(a)] was not affected. No major simvastatin related events occurred. Minor events included elevations in serum creatine kinase without clinical symptoms. The course of renal function and of proteinuria during the study are still under evaluation and are not given here.

Conclusions

Long-term treatment with simvastatin in nephrotic patients with hypercholesterolemia is effective and safe.

PATIENTS

Patients with focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, or IgA nephropathy were recruited from 40 renal clinics in Germany. Inclusion criteria were: proteinuria >3 g/24 hr at least during the last 6 months prior to inclusion; creatinine clearance >40 ml/min/1.73 m²; low density lipoprotein (LDL) cholesterol >4.2 mmol/liter (160 mg/dl) prior to randomization while off all lipid-lowering drugs; and adhearing to an appropriate diet for at least four weeks. The primary exclusion criteria were: systolic blood pressure >160 mm Hg or diastolic blood pressure >95 mm Hg despite treatment; concurrent use of corticosteroids, immunosuppressive drugs, or nonsteroidal anti-inflammatory drugs; diabetes mellitus; concurrent use of other lipid lowering drugs; unstable renal function defined as changes in serum creatinine> 176 mol/liter (>2 mg/dl) in the previous four months. Concurrent use of dihydropyridine calcium channel-blockers was an exclusion criterion, since experimental and preliminary clinical evidence indicated its detrimental effect on renal function. At the time of study planning, there was preliminary evidence for an ameliorating effect of ACE inhibitors on the progression of glomerular diseases. Hence, we accepted individual decisions of investigators to introduce ACE inhibitor therapy six months prior to randomization. Initiation of ACE inhibitor treatment during later study periods was an exclusion criterion. Enalapril was the recommended ACE inhibitor.

STUDY DESIGN

This was a multicenter, two-year, double blind, placebo controlled study with the option of an extension based on a decision of the steering committee after a one year interim analysis. It consisted of a 20-week baseline period, followed by a 4-week placebo baseline period, and the active treatment period Figure 1. The rationale of the long baseline was to identify patients going into remission, to establish the pretreatment course of renal function, and to identify patients with rapidly progressive disease. During the baseline measurement period all patients met the inclusion/exclusion criteria. The cholesterol intake was reduced to 200 mg/day and protein intake to 0.6 to 0.8 g per kg body weight per day by appropriate counseling and repeated reinforcement. Protein intake was monitored by examining urine urea excretion, and 90% of the patients had a protein intake between 0.7 and 0.9 g/kg/day during the study period. At six, four, and two months prior to randomization the patients underwent clinical and laboratory examinations including safety parameters, proteinuria, creatinine clearance, lipid levels and blood pressure. At the end of the placebo baseline period all eligible patients were randomized to receive one tablet of 10 mg simvastatin or placebo. At the follow-up visits the dosage of simvastatin was adjusted in 10 mg and 20 mg increments, to lower the LDL-cholesterol to less than 120 mg/dl. The maximum dosage was 40 mg of simvastatin. The lipid values were measured by the core laboratory and were not provided to either the investigator or the patient. The increase in dosage was issued by the core laboratory. For each increase in the simvastatin group, a matched patient in the placebo group received an appropriate increase in the placebo dose. Follow-up visits were scheduled in monthly intervals during the first three months and in six week intervals thereafter. The inulin single-shot plasma clearance was measured at the end of the placebo baseline period and in six month intervals thereafter¹¹.

Figure 1.

Disposition of patients showing each phase of screening and study.

Full figure and legend (29K)

PATIENT RECRUITMENT, BASELINE CHARACTERISTICS, AND FOLLOW-UP

Between May 1991 and June 1994 approximately 800 patients with a nephrotic syndrome were screened and 102 patients were included in the six-month baseline period. Thereafter, 56 patients were randomized; 46 patients were not eligible according to study criteria. Thirteen patients had to be excluded from the per-protocol population Figure 1. After two years 43 patients completed the study. Only 14 patients entered the third study year. Data are given for the two-year study period. The baseline characteristics of the groups were similiar Table 1. All patients except two in the simvastatin group were on antihypertensive treatment. Twenty-seven patients (13 in the simvastatin group) received enalapril throughout the study. The mean diastolic blood pressure, averaged over all follow-up visits, was 86 5 mm Hg in the simvastatin group and 88 6 mm Hg in the placebo group. The corresponding values of the systolic pressure were 137 13 mm Hg and 138 7 mm Hg, respectively. Blood chemistry including liver enzymes, bilirubin, alkaline phosphatase, serum electrolytes, uric acid, TSH, cholinesterase, thyroxin, T4, and a complete blood count were in normal ranges throughout the study.

Table 1 - Baseline characteristics of randomized patients according to study group.

Full table

LIPID VALUES AND ADVERSE EVENTS

After nine months on the study drug, the patients received on average 35 mg of simvastatin in order to achieve the treatment goal of serum LDL cholesterol below 3.1 mmol/liter (120 mg/dl). The mean changes from baseline in total, LDL, and high density lipoprotein (HDL) cholesterol, and serum triglycerides were -39%, -47%, +1%, and -30%. Serum Lp(a) was not affected in either group. Simvastatin was well tolerated and no major drug related events or deaths occurred. A number of minor events were reported, including elevations in serum creatine. Overall, creatine kinase values were fluctuating in simvastatin and placebo treated patients, but elevations of the enzyme were not accompanied by clinical symptoms

DISCUSSION

Simvastatin decreased the total and LDL cholesterol by -39% and -47%, respectively. The drop in serum lipids exceeded that reported with statin therapy in other studies, including patients with a nephrotic syndrome and constant proteinuria^8,9 and in patients of the 4S Group¹⁰. The surprisingly high decrease of -30% in triglycerides was not related to the dietary counseling, since the placebo group with identical dietary advice had a change in triglycerides of only -5% at two years. Further analysis of the data should provide evidence as to whether simvastatin has a potent triglyceride lowering action in nephrotic syndrome. The effective long-term lowering of LDL is providing a solid base to assess the effect of a cholesterol lowering therapy on renal function and proteinuria. Despite major efforts, including the screening of approximately 800 patients with a nephrotic syndrome, only 56 patients could be randomized due to the stringent inclusion and exclusion criteria, and only 43 patients completed the two-year study period. The small number of patients may be a limitation of the study. It was our goal to have at least 40 patients in each group at the end of the study. Blood pressure was well controlled during the study. Dihydropyridine calcium channel blockers were excluded from antihypertensive treatment, since some studies have shown increasing proteinuria and little protection against glomerulosclerosis in nondiabetic chronic renal disease¹². At the time of study planning, ample experimental but no clinical evidence existed for an ameliorating effect of ACE inhibitors on the progression of glomerular diseases; hence, the protocol accepted individual decisions of the investigators to introduce ACE inhibitor therapy before randomization took place. Approximately 60% of the patients in both groups received the ACE inhibitor enalapril. The concomitant treatment with enalapril may confound the effect of LDL reduction by simvastatin on the progression of nephrotic glomerular diseases.

However, the course of renal function and of proteinuria during the study are still under evaluation and are not included in the current study. Despite the lack of information on lipid lowering and progression of renal diseases, patients with a nephrotic syndrome and elevated serum LDL should receive lipid lowering therapy to decrease the risk of coronary heart disease.

References

1. Kasiske, BL, O'Donnell, MP, Cleary, MP, Keane, WF: Treatment of hyperlipidemia reduces glomerular injury in obese Zucker rats. Kidney Int 1988 33:667–672,  | PubMed | ISI | ChemPort |
2. Kasiske, BL, O'Donnell, MP, Garvis, WJ, Keane, WF: Pharmacologic treatment of hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure. Circ Res 1988 62:367–374,  | PubMed | ISI | ChemPort |
3. Harris, Kpg, Purkerson, ML, Yates, J, Klahr, S: Lovastatin ameliorates the development of glomerulosclerosis and uremia in experimental nephrotic syndrome. Am J Kidney Dis 1990 15:16–23,  | PubMed | ISI | ChemPort |
4. Diamond, JR, Hanchak, NA, McCarter, MD, Karnovsky, MJ: Cholestyramine resin ameliorates chronic aminonucleoside nephrosis. Am J Clin Nutr 1990 51:606–611,  | PubMed | ISI | ChemPort |
5. Hirano, T & Morohoshi, T: Treatment of hyperlipidemia with probucol suppresses the development of focal and segmental glomerulosclerosis in chronic aminonucleoside nephrosis. Nephron 1992 60:443–447,  | PubMed | ISI | ChemPort |
6. O'Donnell, MP, Kasiske, BL, Kim, Y, Schmitz, PG, Keane, WF: Lovastatin retards the progression of established glomerular disease in obese Zucker rats. Am J Kidney Dis 1993 22:83–89,
7. Rabelink, AJ, Hen, RJ, Erkelenz, DW, Joles, JA, Koomans, HA: Partial remission of nephrotic syndrome in patients on long-term simvastatin. Lancet 1990 335:1045–1046,  | Article | PubMed | ISI | ChemPort |
8. Chan, Pck, Robinson, JD, Yeung, WC, Cheng, KP, Yeung, Hwd, Tsang, Mts: Lovastatin in glomerulonephritis patients with hyperlipidemia and heavy proteinuria. Nephrol Dial Transplant 1992 7:93–99,  | PubMed | ISI | ChemPort |
9. Thomas, ME, Harris, Kpg, Ramaswamy, C, Hattersley, JM, Wheeler, DC, Varghese, Z, Williams, JD, Walls, J, Moorhead, JF: Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria. Kidney Int 1993 44:1124–1129,  | PubMed | ISI | ChemPort |
10. Scandinavian Simvastatin Survival Study Group: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994 344:1383–1389,
11. Gretz, N, Ecker-Tschirner, KH, Kühnle, HF, Dahl, K, Kirschfink, M, Drescher, P, Lasserer, JJ, Strauch, M: Practicability of the inuline plasma single-shot clearance. Contrib Nephrol 1990 81:220–228,  | PubMed | ChemPort |
12. Ter Wee, PM, De Micheli, AG, Epstein, M: Effects of calcium antagonists on renal hemodynamics and progression of nondiabetic chronic renal disease. Arch Intern Med 1994 154:1185–1191,  | Article | PubMed | ChemPort |