Reports

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PRIORITY PRESS - World Congress of Nephrology 2011

Vancouver, British Columbia / April 8-12, 2011

By Steve Pridgeon

Here at the WCN, Dr. Michael Shlipak, University of California, San Francisco, analyzed the types of cardiovascular disease (CVD) associated with chronic kidney disease (CKD) using cystatin C, which has a linear relationship with the estimated glomerular filtration rate (eGFR) across a much wider range of values than creatinine. This allows a more accurate analysis of the relationship between eGFR and CVD from normal filtration rates to advanced CKD. In one study of an elderly population (mean age 75 years; N=4444), Dr. Shlipak found that CV mortality doubled at what are considered pre-CVD eGFR rates of 60-80 mL/min/ 1.73 m², and increased to almost three times baseline at an eGFR of <45 mL/min/1.73 m². However, although significant heart failure was seen at eGFR 60-80 mL/min/1.73 m² and continued to increase as CKD progressed, myocardial infarction (MI) only significantly increased at eGFR <45 mL/min/1.73 m₂. Stroke and peripheral arterial disease also increased only at low eGFR rates. Dr. Shlipak reported that left ventricular hypertrophy and heart failure were more significant factors in CVD across the range of declining eGFR, while atherosclerotic outcomes were strongly associated only with more advanced CKD.

The lipid profile is also often atypical in CKD, with normal total cholesterol and LDL-C, lowered HDL-C and elevated triglycerides. “CKD is associated with profound dysregulation of lipid metabolism,” confirmed Dr. Nosratola Vaziri, University of California, Irvine. Not only is HDL-C deficient, he explained, but its antioxidant and anti-inflammatory properties are approximately 3 times lower than normal. Furthermore, his work has shown that LDL-C produced by patients with renal disease is 2.5 to 3 times more pro-inflammatory and pro-atherogenic than in the general population. “The combination, obviously, is a disaster in terms of the atherogenicity,” Dr. Vaziri told delegates.

Treatment of CKD

Several types of therapy appear to offer benefit in preventing the progression of CKD, according to Dr. Johannes Mann, Friedrich Alexander University, Erlangen, Germany. In patients with proteinuria, lowering blood pressure (BP) using ACE inhibitors or ARBs reduced the end points of death, end-stage kidney disease (ESRD) and doubling of serum creatinine. No benefit of lowered BP was seen in patients with urine protein/creatinine <0.22, although this group was not at high risk of progression. “ACE inhibitors and ARBs themselves are the mainstay of treatment in people with CKD, especially those with significant proteinuria,” commented Dr. Mann. He suggested a target BP of <130/80 mm Hg on the balance of evidence.

The SHARP trial has shown LDL-C-lowering therapy using the combination of simvastatin and ezetimibe to be effective in reducing atherosclerotic CV events in patients who did not otherwise have a clear indication for lipid-lowering therapy.

Treatment of metabolic acidosis by the administration of 2 g of sodium bicarbonate yielded surprisingly large effect sizes in 2 small, open-label studies. In one (N=134), only 6% of treated patients progressed to ESRD at 2 years compared to 33% in the control group. Dietary protein intake also improved significantly. Because of the safety and high apparent benefit of this regimen, Dr. Mann recommended its addition, pending more definitive studies.

A small (N=56) trial of allopurinol yielded a slight increase in eGFR (1 mL/min/1.73 m²) at 2 years compared to a drop of 3 mL/min/1.73 m2 in the control group. The trial also demonstrated a large decrease in the risk of CV events, Dr. Mann told delegates.

The importance of a multifactorial approach was emphasized by Dr. Hans-Henrik Parving, Aarhus University, Denmark. The Steno-2 study (N=160) aimed to treat multiple modifiable risk factors in patients with type 2 diabetes and persistent microalbuminuria. Interventions included an ACE inhibitor (or an ARB if ACE inhibition was contraindicated), vitamin and mineral supplementation, ASA, dietary fat control, exercise and smoking cessation courses. Further hypoglycemic, antihypertensive and lipid-lowering therapies were administered as required. After an unusually long follow-up period of 13 years, Dr. Parving noted that compared with patients who underwent standard therapy, study patients experienced 50% less laser treatment, more than 60% less nephropathy and 50% less autonomic neuropathy. At 8 years, there was a 50% RR reduction in major CV events, which was maintained to 13 years. At 13 years, 6 patients in the control group and only 1 in the treatment group progressed to ESRD requiring dialysis. “Finally, we succeeded in demonstrating that if you have type 2 diabetes and microalbuminuria, it is feasible to avoid ESRD,” stated Dr. Parving. The hazard ratio for mortality was 0.54 (P=0.015), but this benefit did not become apparent until approximately 10 years, underscoring the need for long-term follow-up. “You can appreciate that if we had stopped the study after 4 or 5 years, you would have told me ‘there is no effect on mortality, Dr. Parving, it doesn’t work’; it works, but you have to wait,” he told WCN delegates.

LDL-C Lowering in CKD

Following the inconclusive results of the 4D and AURORA studies, the SHARP trial (N=9438) was carefully designed to determine whether or not a robust LDL-C-lowering regimen could safely provide a vascular benefit to patients with CKD, reported Dr. David Wheeler, University College London, UK. Dr. Wheeler explained that the combination of simvastatin and ezetimibe was chosen to produce a large decrease in LDL-C levels without the safety concerns of using a high statin dose. The cardiac risk profile seen in CKD is atypical, noted Dr. Wheeler. There is no clear relationship between serum cholesterol and CV risk, and the pattern of vascular disease is also atypical, with a large proportion being non-atherosclerotic.

Accordingly, the primary end point chosen for SHARP was atherosclerotic events (coronary death, MI, non-hemorrhagic stroke or any revascularization). The broader outcome of major vascular events was included as a secondary end point. The primary outcome of SHARP was a 16.5% reduction in major atherosclerotic events (P=0.0022). The benefit achieved was independent of patient baseline lipid profile. At 1 year, the ezetimibe/simvastatin combination reduced LDL-C by 1.07 mg/dL (0.03 mmol/L) compared to placebo. “A third of this was made up by ezetimibe,” noted Dr. Wheeler. “We wouldn’t have had a large reduction like this without including ezetimibe in the regimen.” At 2.5 years, the LDL-C was 0.84 mg/dL (0.02 mmol/L) compared to placebo, a 32% improvement (P<0.0001). However, Dr. Wheeler pointed out that compliance in the trial was poor, with only approximately two-thirds of patients compliant with the study protocol by the trial midpoint. He suggested that with good compliance, the study results could have been better, with lower LDL-C and improved cardiac outcomes. Extrapolating from this, Dr. Wheeler estimated that with full compliance, the 5-year benefit to non-dialysis patients could be 30 fewer major atherosclerotic events per 1000 patients, increasing to 40 per 1000 in patients receiving dialysis.

The Role of Diet

Specific dietary elements may significantly effect the progression of CKD. Diets containing high amounts of fish provide omega-3 and polyunsaturated fatty acids (PUFAs), which are considered to be beneficial to vascular health. Dr. Julie Lin, Brigham and Women’s Hospital, Boston, Massachusetts, presented the results of an observational longitudinal cohort study of 3256 Caucasian women. Average age at baseline in 2000 was 56 years. These women were a subgroup of the Nurse’s Health Study of 121,000 women that began in 1976. At baseline, 205 women had microalbuminuria. At the end of the 11-year study period, 381 participants (11.7%) had a decline in eGFR of >30%. The multivariate adjusted OR for eGFR decline =30% in women who ate 2 or more servings of fish per week compared to those who ate less than 1 serving per week was 0.71 (95% CI, 0.5-1.0). Dr. Lin noted that significant ORs were also seen for high vs. low sodium intake (OR 1.61) and for 2 or more servings of diet soda per day vs. <1 serving/month (OR 1.86) in this study. She speculated that the reduced kidney damage associated with fish consumption might be the result of the anti-inflammatory properties of PUFA or BP reduction caused by PUFA.

There were several other presentations on the effects of diet on kidney disease. One showed that high salt intake causes long-term increases in BP and kidney damage in the general population, not just in “salt-sensitive” individuals. Another, based on animal studies, indicated that kidney damage from long-term fructose ingestion is caused by elevations in uric acid.

Summary

Advances in the understanding of the processes leading to both CKD and associated CVD, as well as progress in elucidating the pathological processes that lead to CV morbidity in patients with kidney disease, are providing a stronger rationale on which to base preventive and therapeutic regimens to provide optimal outcomes for patients with renal disease. The role of lipid-lowering therapy in providing a benefit to cardiac outcomes in CKD by aggressively lowering LDL-C levels using combination simvastatin/ezetimibe was demonstrated in trial findings presented here at the WCN.