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.

40th Annual Meeting and Scientific Exhibition of the American Society of Nephrology

San Francisco, California / November 2-5, 2007

Epidemiological evidence in both healthy and chronic kidney disease (CKD) patients points to a relationship between increasing levels of serum phosphate and cardiovascular disease (CVD). In the Framingham cohort, for example, those with serum phosphorus levels within the upper quartile of normal were 55% more likely to develop CVD over 20 years of follow-up than those in the lowest quartile, “so higher phosphate levels are bad for your CV health even in people with normal glomerular filtration rates (GFRs),” confirmed Dr. Craig Langman, Professor of Kidney Diseases, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

DCOR Observations

DCOR (Dialysis Clinical Outcomes Revisited) was a prospective, randomized clinical trial carried out among 2103 dialysis patients (Suki et al. Kidney Int 2007;72(9):1130-7). Findings showed that in older patients, a non-calcium-containing binder does confer a survival benefit over that seen with calcium-containing binders. Patients were randomized in equal numbers to either sevelamer or a calcium-based binder. At study end point 44 months later, neither all-cause nor cause-specific mortality was significantly different between the two groups in the 1068 completers. In patients over age 65, the mortality rate per 100 patient-years was 18.2 deaths and 23.4 deaths in the sevelamer and calcium-based binder groups, respectively (P=0.02).

Given the greater burden of calcification in older hemodialysis patients, it may simply have been that any effect calcium had on mortality could be observed over a relatively short follow-up compared with younger patients, who had less of a calcification burden at treatment outset.

Investigators also noted a trend for a lesser need for hospitalization in those receiving sevelamer both in the number of hospitalizations per patient-year and the number of days in hospital. Again, this difference was most pronounced in older patients.

Cascade to Calcification

Tonnelli et al. also showed that the risk of all-cause mortality, fatal and non-fatal myocardial infarction (MI) and new heart failure over five years in patients who already had coronary artery disease rose in a graded, independent way as baseline phosphorus levels went from <2 mg/dL to ³4 mg/dL (Circulation 2005;112:2627-33). Among CKD patients, Kesenbaum et al. reported that serum phosphate levels in excess of 3.5 mg/dL were associated with a significant increase in mortality risk which rose linearly with each additional 0.5 mg/dL increase in phosphate levels. (J Am Soc Nephrol 2005;16:520-8). “A significant proportion of CKD patients already have evidence of coronary calcification prior to or at the beginning of dialysis,” Dr. Langman added, “and 100% of patients in stage 3 to 5 CKD will have evidence of pathological calcification.”

The link between high phosphate levels and calcification is complex. As we lose kidney function, we lose the ability to make the active vitamin D hormone, calcitriol. Chronic vitamin D deficiency that frequently accompanies CKD exacerbates the loss of calcitriol and these decreasing levels lead to a fundamental change in the biology of the parathyroid glands and eventually cause secondary hyperparathyroidism. “At the same time, patients develop hyperphosphatemia as they lose GFR,” Dr. Langman explained. Hyperphosphatemia in turn triggers yet more release of parathyroid hormone (PTH) and finally renal osteodystrophy. It is the combination of lack of calcitriol, excess phosphate and secondary hyperparathyroidism that together creates a toxic environment that culminates in calcification and subsequent CVD.

Coronary Artery Calcium Scores and Mortality

Results from the Treat-to-Goal study suggest that the process can be attenuated depending on the phosphate binder used (Kidney Int 2002;62:245-52). In the study, 99 patients were randomized to sevelamer 6.5 g/day and another 101 received either calcium acetate 4.6 g/day or calcium carbonate 3.9 g/day. Over the following 52 weeks, mean serum phosphorus levels were virtually identical in all groups and all achieved Kidney Disease Outcomes Quality Initiative (K/DOQI) targets for CKD stage 5 patients. However, by study end, the median change in the coronary artery and aortic calcium scores was significantly greater among calcium-based binder recipients at 25% and 28% than among sevelamer-treated patients at 6% and 5% (both P=0.02), respectively.

The parent RIND (Renagel in New Dialysis) trial also examined the relationship between phosphate binder choice and coronary artery calcium (CAC) in 127 new hemodialysis patients. Fifty-five patients in the calcium binder arm and 54 patients in the sevelamer arm were available for the electron beam computed tomography analysis. Identical levels of phosphorus control over the 18-month study were reported. The median absolute increase in the CAC scores was 11-fold greater in calcium-treated patients with a baseline CAC score >30, and these patients were significantly more likely to experience both moderate and severe hypercalcemia than sevelamer-treated patients, as Dr. Langman noted.

A pre-determined secondary end point in RIND Outcomes (Kidney Int 2007;71(5):438-41) assessed the relationship between the phosphate binder used, CAC and all-cause mortality after a median follow-up of 44 months. At study end, investigators observed that baseline CAC scores were a strong predictor of mortality such that after adjustment for multiple confounders, a baseline CAC score of ³400 was associated with a fourfold increase in mortality. The use of a calcium-containing phosphate binder was also associated with a 2.2-fold increase in mortality compared with sevelamer. “This was the first trial showing baseline CAC scores and choice of phosphate binder are independent predictors of mortality in subjects new to hemodialysis, and it confirmed the finding that severity of CAC at the time of hemodialysis initiation is an important predictor of long-term survival and it also supports guidelines to use sevelamer in the presence of calcification,” Dr. Langman concluded.

A new carbonate formulation of sevelamer is expected in the near future. In an equivalency study reviewed by Dr. Langman, phosphate control was found to be similar with both formulations but serum bicarbonate levels increased to K/DOQI targets with the carbonate formulation and there were fewer gastrointestinal side effects with it than with the hydrochloride formulation.

Snapshot Adherence

In the largest hemodialysis sample ever reported in Canada, Dr. David Mendelssohn, Associate Professor of Medicine, University of Toronto, Ontario, and colleagues generated a “snapshot” of adherence to K/DOQI mineral metabolism guidelines with the help of the PhotoGraph software program. Similar to DOPPS (Dialysis Outcomes and Practice Patterns Study), the snapshot showed there is still room for improvement in reaching K/DOQI targets but that Canadian centres have improved over time relative to DOPPS II data, and that this improvement may be attributable to increased use of newer medications. For example, close to 60% of 2337 hemodialysis patients were achieving K/DOQI targets for serum phosphorus, although fewer patients were within K/DOQI ranges for serum calcium and intact PTH (iPTH). “Provinces that have easier access [to new drugs] seem to have better performance relative to targets than provinces that don’t,” Dr. Mendelssohn observed, suggesting that improving access to new drugs may improve K/DOQI target achievement.

A relatively encouraging “snapshot” was again seen among peritoneal dialysis (PD) patients. As presented by Dr. Steven Soroka, Medical Director, Dialysis and Predialysis Program, Dalhousie University, Halifax, Nova Scotia, 65% of the 317 PD patients analyzed by the program were within K/DOQI targets for serum phosphorus, with fewer PD patients again achieving either calcium or iPTH targets. “The question is, do we achieve more targets by spending more time talking to patients about the importance of taking their medication or by getting better access to medications for patients?” Dr. Soroka asked. “These are the kinds of questions raised by this data.”

Meanwhile, the PhotoGraph software program has been modified to allow nephrologists to track bone mineral metabolism trends in pediatric CKD patients. “The program doesn’t make them take their binders,” acknowledged Dr. Colin White, Clinical Assistant Professor of Medicine, University of British Columbia, Vancouver, “but it is quite useful for visualizing where bone mineral metabolism parameters are. We need to do a better job of maintaining calcium and phosphate balance in our children because they are going to live with CKD for the rest of their lives, which hopefully will be long ones.”