It has been shown, mostly through observational studies, that higher levels of serum phosphorus are associated with    increased mortality in patients with late stage CKD. Clinical trials have also demonstrated how various phosphate binder treatments can decrease the level of serum phosphorus. However, until recently, evidence has been lacking that closes the loop linking phosphate binder treatment directly to reduced mortality. In Part 1 of this article, we examine this issue in more detail, while in Part 2 we discuss a number of key questions generated by recent research.
Closing the phosphate binder “evidence loop”
There have been two recent studies that have investigated the association between phosphate binder therapy and reduced mortality.
A 2009 study  by Isakova et al. observed a significant survival advantage in over 10,000 incident hemodialysis patients in the US that were treated with phosphate binders. The mortality rate was found to be 25% lower for patients on phosphate binders as compared to those not receiving treatment (HR=0.75, propensity-matched). Importantly, the clear survival benefit remained even when the data were adjusted for patient age and other established risk factors.
Interestingly, the survival benefit appeared to be independent of both baseline and follow-up serum phosphate levels, and it was also found in subgroups with serum phosphorus concentrations inside the range recommended by both the European Best Practice Guidelines and KDOQI (Kidney Disease Outcomes Quality Initiative). This raises the possibility that phosphate binders have additional protective mechanisms, and the authors suggested improved control of fibroblast growth factor 23 (FGF-23) as one possible explanation.
Adding further to our understanding was a recent study  by Lopes et al. published in March 2012, in which data was analyzed from nearly 24,000 maintenance hemodialysis patients from the 12-country DOPPS study. As with the Isakova study, patients prescribed phosphate binders were found to have 25% lower mortality than untreated patients; however this association was only observed at serum phosphorus concentrations ≥ 3.5 mg/dL.
In this more recent study, the authors also attempted to explain the independence of serum phosphorus and mortality found in both the Isakova results and their own. They also identified a possible mechanism behind the effect of phosphate binders on mortality risk, beyond their control of serum phosphorus. They hypothesized that patients who eat more are more likely to maintain better nutritional status and so are more likely to be prescribed phosphate binders because of a higher tendency toward hyperphosphatemia. This association between improved nutritional state and phosphate binder user could be contributing to the observed survival benefit.
In fact, the study results support this hypothesis. When adjusted for nutritional indicators the mortality benefit of phosphate binder use was reduced from 25% to 12% (HR=0.75 vs. HR=0.88). However, the authors highlighted that more research was needed to understand and explain this effect.
Furthermore, the Lopes study also addresses one of the traditional shortcomings of observational analysis: the potential for bias caused by confounding by indication. The study also performed facility-level analysis on the DOPPS records, and such analysis may reduce this bias. The fact that this analysis also showed a survival advantage should be viewed as additional corroborating evidence on the survival benefit of phosphate binder use.
Opportunities for further investigation
Given that investigations into the survival benefit of phosphate binder therapy are relatively recent, it is clear that more research is still needed. Indeed these, and other recent studies, have thrown up several topics for further investigation. We will examine these in our next post on mortality risk.
1. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis. JASN. 2004 Aug 1;15(8):2208–18.
2. Floege J, Kim J, Ireland E, Chazot C, Drueke T, De Francisco A, et al. Serum iPTH, Calcium and Phosphate, and the Risk of Mortality in a European Haemodialysis Population. Nephrol. Dial. Transplant. 2011 Jun 1;26(6):1948–55.
3. Tentori F, Blayney MJ, Albert JM, Gillespie BW, Kerr PG, Bommer J, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am. J. Kidney Dis. 2008 Sep;52(3):519–30.
4. Isakova T, Gutiérrez OM, Chang Y, Shah A, Tamez H, Smith K, et al. Phosphorus Binders and Survival on Hemodialysis. JASN. 2009 Feb 1;20(2):388–96.
5. Lopes AA, Tong L, Thumma J, Li Y, Fuller DS, Morgenstern H, et al. Phosphate Binder Use and Mortality Among Hemodialysis Patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): Evaluation of Possible Confounding by Nutritional Status. American journal of kidney diseases: the official journal of the National Kidney Foundation [Internet]. 2012 Feb 29 [cited 2012 May 2]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/22385781