Effects of Add-on Fluvastatin Therapy in Patients with Chronic Proteinuric Nephropathy on Dual Renin-Angiotensin System Blockade

Abstract

Background and objectives:This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade.Design, setting, participants, & measurements: After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat.Results: During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated.Conclusions: In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating.

Mechanisms and Treatment of CKD

“…Patients were all then maintained on dual RAS inhibitor therapy and prospectively followed-up. Their GFR decline over the following 6 years was significantly slower than in matched reference patients receiving single drug RAS blockade with full dose of an ACE inhibitor 75 More recently, the ESPLANADE trial 76 showed that, in 186 patients with chronic proteinuric nephropathies, the larger reduction in proteinuria achieved by combined therapy with benazepril and valsartan compared with benazepril alone, was associated with concomitant reduction in total, LDL, and HDL cholesterol, and apoB and apoA levels, an effect that in the long term might translate into reduced cardiovascular risk.…”

“…it/remission/) and applied to all CKD patients with heavy proteinuria despite therapy. 75 This multimodal intervention strategy included lifestyle modifications such as sodium 93 and protein 30 intake restriction, smoking cessation, body weight loss, 94 optimal BP (target systolic/diastolic ,130/80 mmHg) and metabolic control (target hemoglobin A1C ,7.5%) in patients with diabetes, correction of metabolic acidosis 95 and hyperphosphatemia, 96 use of statins, 76,97,98 and dual RAS blockade with maximum tolerated doses of ACE inhibitors and ARBs, probably the mainstay of proteinuria management in this setting. 99 In a matched-cohort study, we compared the outcome of 56 CKD patients receiving the Remission Clinic approach because of persistent 24-hour proteinuria .3 g despite standard antihypertensive doses of an ACE inhibitor with that of 56 matched historical reference patients who had received ACE inhibitor therapy titrated to target BP.…”

Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis

“…22 In light of these findings, all attempts have been made to reduce proteinuria by any therapeutic means, including RAAS-blocking agents, low salt intake, 44 smoking cessation, optimal metabolic control, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. 45 Multiple therapies aimed at reducing proteinuria may slow the progression of kidney disease to a greater extent than any single treatment. This was demonstrated effectively by a multimodal intervention strategy, the Remission Clinic program, that used all available lifestyle recommendations and pharmacologic tools to further reduce proteinuria in patients with CKD and severe proteinuria already treated with RAAS-blocking agents.…”

The Efficacy and Safety of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors in Chronic Kidney Disease, Dialysis, and Transplant Patients

“…Taylor and coworkers (38) also reported on the ARBITER 6-HALTS trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) that addition of ezetimibe was no more effective compared with niacin in decreasing the progression of carotid intima-media thickness in patients receiving statin therapy ( Table 7). The Statins in Proteinuric Nephropathies (ESPLANADE) study assessed the effect of fluvastatin plus angiotensinconverting-enzyme inhibitors or angiotensin II receptor blockers in reducing proteinuria in patients with CKD and diabetic nephropathy (39). Patients were randomized to fluvastatin versus placebo and were followed for 6 months.…”