Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 43rd Annual Meeting and Scientific Exhibition of the American Society of Nephrology (ASN)

Denver, Colorado / November 16-21, 2010

Chronic kidney disease (CKD) has a substantial adverse impact on quality of life, health services utilization and societal costs. Notably, CKD is now widely accepted as a risk factor for cardiovascular (CV) disease. Improving the long-term outcome of patients with CKD remains challenging. Early detection and risk stratification are key. As with CV disease, lifestyle measures may be preventive: Increasing body mass index and obesity are risk factors for CKD and its progression, while exercise training favourably affects a variety of metabolic parameters in patients with CKD.

New Insights into CKD Risk

Several presentations here confirmed the greater utility of the new CKD-Epidemiology (EPI) equation for determining estimated glomerular filtration rate (eGFR), noting the new equation stratifies patients by clinical risk more accurately than the Modification of Diet in Renal Disease (MDRD) formula.

The meeting also offered insight into factors that may influence CKD development and progression. One analysis of 660 patients with type 2 diabetes showed that overall, lower glycosylated hemoglobin (A1c) values reduced the risk of CKD progression. However, patients with lower A1c values associated with severe hypoglycemia had increased risk for mortality. Collectively, the data suggested that reducing A1c is helpful in managing CKD except when the treatment strategy induces severe hypoglycemia. Another presentation, based on a retrospective cohort analysis, suggested that antidiabetic treatment aimed at A1c <6.5% afforded the greatest protection against end-stage renal disease (ESRD); however, achieving this goal did not affect mortality.

A comparison of patients with type 1 and type 2 diabetes determined that for any given degree of renal dysfunction, patients with type 2 diabetes had a higher incidence of microalbuminuria. However, the rate of microalbuminuria progression was similar in both types of diabetes. In addition, a 3-year study of 1.5 million patients by investigators of the University of Alberta determined that for any level of eGFR, heavier proteinuria increases the likelihood of an adverse CV outcome.

SHARP: Value of Lipid Lowering

Patients with CKD have an atypical lipid profile characterized by normal or near-normal levels of total cholesterol (TC) and LDL-C, high triglycerides and low HDL-C. The risk of vascular disease and death in CKD has a seemingly paradoxical relationship with lipids, as patients with the lowest cholesterol levels face the greatest risk. The atypical risk profile has led to considerable uncertainty among physicians about the value of cholesterol-lowering therapy in patients with CKD.

The multicentre Study of Heart and Renal Protection (SHARP) was designed to determine the impact of lipid-lowering therapy on CV outcomes in patients with CKD; ascertaining the effect on renal function was a secondary objective. Eligible patients had established CKD (defined as blood creatinine =1.7 mg/dL [150 µmol/L] in men, =1.5 mg/dL [130 µmol/L] in women) but no history of myocardial infarction (MI) or coronary revascularization. In an effort to generate widely applicable data, the investigators enrolled patients on dialysis and those who were not on dialysis.

“The key criterion for entry into the study was that the patients’ doctors were uncertain about whether to treat with LDL-lowering therapy,” noted Dr. Colin Baigent, University of Oxford, UK, during a news briefing at the ASN meeting.

SHARP involved 9438 patients, two-thirds of whom were not on dialysis. The nondialysis patients in the trial had a median eGFR of 27 mL/min/1.73 m2 and 80% had albuminuria. The baseline lipid profile included a median TC of 4.89 mmol/L, LDL-C 2.79 mmol/L, HDL-C 1.11 mmol/L and triglycerides 2.33 mmol/L.

Investigators initially randomized the patients 4:4:1 to placebo, the combination of ezetimibe 10 mg/simvastatin 20 mg or simvastatin alone. The simvastatin monotherapy arm was included in the trial design to allow for assessment of drug safety, noted Dr. Baigent. After a year of treatment, patients in the simvastatin monotherapy arm were re-randomized to ezetimibe 10 mg/simvastatin 20 mg or placebo. After one year of treatment, the reduction in LDL-C averaged 0.78 mmol/L in the simvastatin monotherapy arm and 1.11 mmol/L with ezetimibe/simvastatin. LDL-C did not change significantly in the placebo group.

The trial’s key outcome was the composite of major atherosclerotic events, comprising coronary death, MI, nonhemorrhagic stroke or any revascularization. The primary renal outcome was progression to ESRD, defined as dialysis or transplantation. After a median follow-up of 5 years, patients treated with the combination had a 17% reduction in the major atherosclerotic events (P=0.0022) and a statistically significant 15.3% reduction in the risk of major vascular events (P=0.0012).

“We observed similar reductions in major atherosclerotic events in all subgroups studied, including nondialysis and dialysis patients,” reported Dr. Martin Landray, University of Oxford.

Assessment of safety end points showed no major differences between treatment groups, he added. Of note, the incidence of malignancy did not differ between ezetimibe 10 mg/simvastatin 20 mg and placebo arms. Some concern had arisen when results of the smaller Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial had shown more new-onset malignancies in patients treated with ezetimibe 10 mg/simvastatin 20 mg (N Engl J Med 2008;359:1343-56).

“The SHARP trial results provide clear evidence that lowering cholesterol with ezetimibe 10 mg/simvastatin 20 mg safely reduces the risk of major atherosclerotic events,” stated Dr. Landray.

Strategies to Improve Renal Outcomes

The SHARP trial did not detect a significant benefit of lipid-lowering therapy on renal outcomes. The rate of progression to ESRD was about 34% in both groups.

Other studies evaluating strategies to slow CKD progression yielded mixed results. Investigators in a multicentre, international clinical trial examined more frequent hemodialysis as a means of improving renal outcomes. The investigation comprised 2 parallel studies comparing 6-times-weekly hemodialysis with conventional 3-times-weekly dialysis in 332 patients. About three-fourths of the study participants were randomized to 6 vs. 3 in-centre dialysis sessions, and the remaining patients received 3-times-weekly hemodialysis at a centre or 6-times-weekly nocturnal hemodialysis at home.

After 12 months of treatment, more frequent in-centre dialysis was associated with a 40% reduction in the composite end point of death or increased left ventricular mass (P<0.001) and a 36% reduction in the composite of death and change in health-related quality of life (P=0.007). At-home dialysis also reduced the co-primary end points but not significantly compared with conventional in-centre hemodialysis, reported Dr. Alan Kliger, Yale University, New Haven, Connecticut.

However, more frequent hemodialysis was associated with a 71% increase in the need for interventions related to vascular access problems. “Before major changes in practice can be recommended, the net effects of frequent dialysis will need to be balanced against the added burden for the patient and societal cost,” Dr. Kliger stated at an ASN news briefing.

Two other studies had promising findings with strategies aimed at improving renal function in CKD patients. Treatment with the novel anti-inflammatory agent bardoxolone methyl significantly improved eGFR after 6 months compared with placebo (10 vs. 0.1 mL/min/1.73 m2, P<0.0001) in patients with type 2 diabetes and CKD. Almost 4 times as many patients treated with bardoxolone had improvement in CKD stage compared with placebo (59% vs 16%, P<0.001). The study involved 227 patients, all of whom had stage 3-4 CKD at baseline.

“These encouraging results suggest that bardoxolone methyl has the potential to change the treatment landscape of CKD,” Dr. Pablo Pergola, University of Texas, San Antonio, told delegates.

Dietary intervention also demonstrated potential benefits for patients with CKD. The findings came from a study of 40 patients with moderately reduced GFR related to hypertension. The patients followed a produce-rich diet for 30 days, aimed at ameliorating the acidic environment created by the typical Western diet. At the end of the study, patients had reduced urinary excretion of 3 indicators of kidney injury: albumin, transforming growth factor and N-acetyl-D-glucosamine.

“These preliminary findings support the need for larger, long-term studies to determine if this simple and relatively inexpensive intervention helps reduce the risk of subsequent worsening of kidney function in patients with hypertension-associated kidney disease,” said Dr. Nimrit Goraya, Texas A&M College of Medicine, College Station.

Summary

Lipid-lowering therapy with ezetimibe 10 mg/simvastatin 20 mg significantly reduced CV risk in patients with CKD, according to results of a large, multinational randomized clinical trial. The lipid-lowering therapy did not affect renal outcomes, a secondary end point of the trial. Other studies of strategies for improving renal function in patients with CKD yielded mixed results. More frequent hemodialysis sessions reduced the mortality risk in patients with ESRD but was associated with more vascular-access problems. Short-term treatment with the investigational anti-inflammatory drug bardoxolone improved CKD stage in almost 4 times as many patients as placebo. A small clinical study of dietary intervention showed that short-term adherence to a produce-rich diet led to modest reductions in biomarkers of kidney injury. Given the vast scope of discussions during the ASN scientific sessions, this report very briefly summarizes selected presentations focusing on CV risk and progression of CKD.

Note: The single-tablet ezetimibe/simvastatin combination is not available in Canada.