Serum Phosphorus Affects Long-Term Kidney Transplant Outcomes

Serum phosphorus levels have a significant impact on outcomes after kidney transplantation—especially the risk of transplant failure, suggests a study in the American Journal of Kidney Diseases.

Despite a “marginal” effect on the risk of cardiovascular disease (CVD) events, higher phosphorus levels are associated with substantial increases in the risk of dialysis-dependent transplant failure and all-cause mortality, according to analysis of prospective data from a large sample of kidney transplant participants.

The study included data on more than 3000 kidney transplant participants enrolled in the “Folic Acid for Vascular Outcome Reduction in Transplantation” (FAVORIT) Trial—a randomized trial of homocysteine-lowering therapy with high-dose vitamin B. The lead author and senior author, respectively, were Basma Merhi, MD, and Andrew Bostom, MD, both of Rhode Island Hospital.

The primary results, published in Circulation in 2011, showed no significant difference in fatal and nonfatal CVD events, transplant failure, or mortality for kidney transplant participants assigned to high-dose versus low-dose B vitamins. That was so even though high-dose vitamin B successfully lowered homocysteine levels.

The new analysis examined associations between posttransplant hyperphosphatemia and the risk of adverse graft and patient outcomes. As kidney disease advances, patients often develop deranged calcium-phosphorus metabolism, which is not fully reversed after kidney transplantation.

The study included 3138 FAVORIT subjects with complete data, representing about three-fourths of the study sample. Mean age was about 52 years and mean time since transplantation was 4 years. Thirty-nine percent of patients had a history of diabetes while 19% had a history of CVD.

Mean serum phosphorus level was 3.07 mg/dL, with a range of 0.79 to 8.32 mg/dL. Patients with higher phosphorus levels differed in some important baseline characteristics, including lower estimated glomerular filtration rate (eGFR) and higher urine albumin/creatinine ratio (UACR). They also had a longer time since transplantation and a higher rate of cadaveric transplant. Hyperphosphatemia was also associated with older age, male sex, and higher rates of smoking, higher blood pressure, and higher cholesterol.

During follow-up, a total of 436 CVD events occurred, including 135 deaths. There were also 238 transplant failure events and 348 total deaths. On unadjusted analysis, the risk of incident or first recurrent CVD—the primary outcome—was 25% higher per 1 mg/dL increase in serum phosphorus.

However, on an initial multivariable analysis, the increase in CVD risk significantly weakened: to 14% per increment in phosphorus level. After further adjustment for eGFR and UACR, the association became nonsignificant. The association became nonsignificant after further adjustment for eGFR and UACR.

In contrast, serum phosphorus was more strongly related to the risk of transplant failure. Risk increased by 72% per 1 mg/dL increment in phosphorus in the “almost fully adjusted” model, and remained significant at 36% after further adjustment for kidney measures. From the lowest quintile to the highest decile of serum phosphorus—2.51 mg/dL or less versus 3.83 mg/dL or higher—risk for transplant failure increased by 215%.

Serum phosphorus was also associated with all-cause mortality, with risk increases of 43% and 34% in the mostly and fully adjusted models. An association with cardiovascular death became nonsignificant after adjustment for eGFR and UACR. For a composite outcome of transplant failure and death, the hazard ratio in the fully adjusted model was 1.25. The pattern of associations was significant on competing risk analysis.

The authors note that their findings are consistent with the “phosphate toxicity hypothesis,” as previously reported in CKD patients who have not undergone transplantation. However, the pathways responsible for the cytotoxic effect of extracellular phosphate remain far from clear. One possible mechanism that warrants further study is the formation of insoluble calciprotein particles, formed by combination of extracellular phosphorus with calcium and fetuin A.

The FAVORIT investigators also point out some key weaknesses of their study—including the lack of data on other FGF-23, parathyroid hormone, and vitamin D status. While the study adjusted for eGFR and UACR, there may be residual confounding from other measures of kidney function.

Of course, given its observational nature, the study permits no conclusions about the potential benefits of phosphorus-lowering therapy for kidney transplant recipients.

“Our data suggest that kidney transplant participants merit a randomized controlled clinical trial that assesses the potential impact of phosphorus-lowering therapy on hard outcomes in this CKD population, such as CVD, all-cause mortality, and the development of kidney transplant failure—the last outcome, especially,” the authors said.

July 2017 (Vol. 9, Number 6)

References

1. Bostom AG, et al. Homocysteine-lowering and cardiovascular disease outcomes in kidney transplant recipients: primary results from the Folic Acid for Vascular Outcome Reduction in Transplantation Trial. Circulation 2011; 123:1763–1770.

2. Kuro-O MA phosphate-centric paradigm for pathophysiology and therapy of chronic kidney disease. Kidney Int Suppl 2011; 3:420–426.