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.

43rd European Renal Association/European Dialysis and Transplant Association Congress

Glasgow, United Kingdom / July 15-18, 2006

As explained by Dr. David C. Wheeler, Senior Lecturer in Nephrology, University College Medical School, London, UK, “For many years, we focused on treatment to try to stop bone disease [in dialysis patients]. However, it has become clear in the last five to eight years that in doing that, we have noticed a deposition of calcium in the arteries of our patients.”

Investigators met here this week to explore this issue and to see whether newer therapies may allow physicians to treat bone disease without causing cardiovascular calcification.

DCOR Trial Evidence

Dr. David J.A. Goldsmith, Consultant Nephrologist and Honorary Senior Lecturer, Renal Unit, Guy’s Hospital, London, UK, presented data from the DCOR (Dialysis Clinical Outcomes Revisited) study, the first large-scale study to compare clinical outcomes in patients randomized to different phosphate binders. DCOR prospectively randomized 2103 hemodialysis patients in 75 US centres to sevelamer or to a calcium-based phosphate binder. The primary outcome was all-cause mortality.

Researchers found no significant difference in all-cause mortality between the two groups (relative risk [RR] 0.91; 95% CI, 0.77-1.08, P=0.3). In a subgroup analysis of patients aged 65 and older, however, the risk of all-cause mortality was lower in patients in the sevelamer group (RR 0.78; 95% CI, 0.62-0.97; P=0.03). Also, starting at two years and onward, there was a significant decrease in mortality in the non-calcium group (RR 0.66; 95% CI, 0.48-0.94; P=0.02).

“We are only at the very beginning [of our knowledge about coronary calcification and renal disease],” Dr. Goldsmith told listeners. “When we have a patient in front of us, that patient does not just have a serum calcium, phosphate, or PTH [parathyroid hormone] level. Managing bone or mineral metabolism remains a phenomenally difficult balancing act between too much of this and too much of that, and even now remains one of the greatest challenges for all of us.”

Bone Biopsy Study

A one-year bone biopsy study of hemodialysis patients randomized to either sevelamer or calcium carbonate revealed a trend to less suppression of bone turnover and improvement in microarchitecture in patients randomized to sevelamer. Discussing these findings, Dr. Anibal Ferreira, Department of Nephrology, Hospital de Curry Cabral, Lisbon, Portugal, told the audience that they sought to evaluate bone turnover, bone mineralization and bone volume, and to compare the effects of sevelamer and calcium in their dialysis patients. The team randomized adult patients in 16 dialysis centres in Portugal to the two types of phosphate binders. The patients received bone biopsies one year apart.

A total of 33 patients in the calcium group and 35 patients in the sevelamer group completed the study. Serum phosphorus, calcium and PTH levels were well controlled in both groups, although serum calcium was consistently lower and serum PTH higher in the sevelamer-treated group. “Calcium treatment resulted in higher calcium levels, a higher incidence of hypercalcemia and greater suppression of PTH,” Dr. Ferreira reported. A total of 9% of patients in the sevelamer-treated group vs. 31% in the calcium carbonate-treated group moved from normal levels of bone turnover to below normal levels.

RIND Extended Study

As discussed by Dr. Geoffrey Alan Block, Assistant Professor of Medicine, University of Colorado Health Sciences Center and Director, Division of Clinical Research, Denver Nephrologists, Colorado, both the previously published 18-month data from the RIND (Renagel in New Dialysis) study (Block et al. Kidney Int 2005;68(4):1815-24) and the new extended data on sevelamer vs. calcium-containing phosphate binders showed that among patients just starting dialysis, initial coronary calcification score (CCS) was linked to survival. The more recent RIND results were obtained from an additional 42-month-long extended study of 114 patients from the original RIND cohort. Patients had an average age of 60 at study entry; 60% were men and 60% had diabetes.

At some point during the first 18 months of the initial study, in the calcium-treated group, 54% had a serum calcium over 2.55 mmol/L and 24% had a calcium over 2.75 mmol/L. “It is very difficult to manage and prevent hypercalcemic episodes using calcium as a phosphate binder,” noted Dr. Block.

The median CCS was equivalent in the two treatment groups at the start of the extended study phase. Over time, the scores in the sevelamer group increased slightly, but among the patients on calcium, the CCS doubled at 12 months and tripled at 18 months. Patients who were non-calcified at the start of the trial, however, remained non-calcified at the end, independent of therapy type.

“The patients randomized to calcium had twice the mortality after adjusting for age, race, sex and diabetes. I think that whether calcium made them worse or sevelamer protected them is irrelevant. If you have a choice, patients should not receive calcium-containing binders,” Dr. Block stated.

Canadian Perspective

Commenting on these presentations, Dr. David C. Mendelssohn, Associate Professor of Medicine, University of Toronto, Ontario, noted that the RIND study showed a lower progression of existing vascular calcification in sevelamer-treated new dialysis patients. At five years, the CCS predicted mortality. “Most impressive, given the small numbers treated, the study showed a marked and statistically significant survival benefit for the sevelamer-treated patients,” he noted.

Dr. Mendelssohn also indicated that DCOR was carried out in patients already on dialysis. Its main outcome showed a trend in favour of sevelamer. One prespecified end point (patients ³65 years) did reach statistical significance, as did one non-prespecified end point (sevelamer use ³two years). The study was underpowered, yet important biologically sensible signals were still seen.

Taken together, these two studies are “remarkable,” Dr. Mendelssohn added, since they are the first two randomized controlled trials in end-stage renal disease to show that it is possible to modify the tragically high mortality rates in this population. Further clinical trials in these patients are warranted.

Other Promising Studies

Other findings presented here during the scientific sessions included an international study evaluating the safety and efficacy of phosphate binder therapy in 143 peritoneal dialysis patients (Abstract MP580). In a crossover study of 58 patients, it was revealed that sevelamer treatment was associated with a delayed and sustained increase in serum levels of the calcification inhibitor fetuin A (Abstract SP386). In another presentation, the CORD (Calcification Outcome in Renal Disease) epidemiological study found extensive calcification in the abdominal aorta among 796 dialysis patients (Abstract MP327). Researchers also presented an evaluation of 36 patients new to dialysis that showed that of 13 patients with no coronary calcium at baseline, 12 patients remained unchanged after 30 months (Abstract MP440).

Fabry Disease Therapy

In another session, Dr. Stephen Waldek, Consultant Nephrologist, Hope Hospital Manchester, UK, discussed preservation of renal function in patients with Fabry disease. “[Agalsidase beta] 1 mg/kg every two weeks can prevent renal progression if started early,” he stated. Some older patients with more sclerosis and proteinuria show disease progression and should receive therapy with an ACE inhibitor, an angiotensin II receptor blocker or both, together with statins. “The key has to be to detect early,” he stressed. “We know that even at age 13 and 14, boys have evidence of renal dysfunction. Therefore, we must do all we can to detect these families, detect the disease early and treat patients with an adequate dose of enzyme.”