Basma Merhi1, Theresa Shireman2, Myra A Carpenter3, John W Kusek4, Paul Jacques5, Marc Pfeffer6, Madhumathi Rao7, Meredith C Foster7, S Joseph Kim8, Todd E Pesavento9, Stephen R Smith10, Clifton E Kew11, Andrew A House12, Reginald Gohh1, Daniel E Weiner7, Andrew S Levey7, Joachim H Ix13, Andrew Bostom14. 1. Division of Hypertension and Kidney Diseases, Department of Medicine, Rhode Island Hospital, Providence, RI. 2. Center for Gerontology and Healthcare Research, Brown University, Providence, RI. 3. Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, NC. 4. National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD. 5. Nutritional Epidemiology Program, USDA Human Nutrition Research Center on Aging, Boston, MA. 6. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA. 7. Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, MA. 8. Division of Nephrology and the Kidney Transplant Program, Toronto General Hospital, Toronto, Ontario, Canada. 9. Division of Nephrology, Department of Medicine, Ohio State University, Columbus, OH. 10. Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC. 11. Division of Nephrology, Department of Medicine, University of Alabama-Birmingham, Birmingham, AL. 12. Division of Nephrology, Department of Medicine, London Health Sciences Center, London, Ontario, Canada. 13. Division of Nephrology-Hypertension, Department of Medicine, University of California, San Diego, CA. 14. Division of Hypertension and Kidney Diseases, Department of Medicine, Rhode Island Hospital, Providence, RI. Electronic address: abostom@cox.net.
Abstract
BACKGROUND: Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. PREDICTOR: Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. RESULTS: During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). LIMITATIONS: We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. CONCLUSIONS:Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.
RCT Entities:
BACKGROUND: Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. PREDICTOR: Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. RESULTS: During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). LIMITATIONS: We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. CONCLUSIONS: Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.
Authors: Victoria Shalhoub; Edward M Shatzen; Sabrina C Ward; James Davis; Jennitte Stevens; Vivian Bi; Lisa Renshaw; Nessa Hawkins; Wei Wang; Ching Chen; Mei-Mei Tsai; Russell C Cattley; Thomas J Wronski; Xuechen Xia; Xiaodong Li; Charles Henley; Michael Eschenberg; William G Richards Journal: J Clin Invest Date: 2012-06-25 Impact factor: 14.808
Authors: Grainne M Connolly; Ronan Cunningham; Peter T McNamee; Ian S Young; Alexander P Maxwell Journal: Transplantation Date: 2009-04-15 Impact factor: 4.939
Authors: R Marcén; S Jimenez; A Fernández; C Galeano; J J Villafruela; F J Burgos; C Quereda Journal: Transplant Proc Date: 2012-11 Impact factor: 1.066
Authors: Elke S Schaeffner; Manuela Födinger; Reinhard Kramar; Gere Sunder-Plassmann; Wolfgang C Winkelmayer Journal: Transpl Int Date: 2007-03 Impact factor: 3.782
Authors: Despina Sitara; Mohammed S Razzaque; Martina Hesse; Subbiah Yoganathan; Takashi Taguchi; Reinhold G Erben; Harald Jüppner; Beate Lanske Journal: Matrix Biol Date: 2004-11 Impact factor: 11.583
Authors: Andreas Pasch; Geoffrey A Block; Matthias Bachtler; Edward R Smith; Wilhelm Jahnen-Dechent; Spyridon Arampatzis; Glenn M Chertow; Patrick Parfrey; Xiaoye Ma; Juergen Floege Journal: Clin J Am Soc Nephrol Date: 2016-12-09 Impact factor: 8.237
Authors: Faith Omede; Shiqin Zhang; Cassandra Johnson; Emily Daniel; Yan Zhang; Timothy A Fields; Joseph Boulanger; Shiguang Liu; Ishfaq Ahmed; Shahid Umar; Darren Paul Wallace; Jason R Stubbs Journal: Am J Physiol Renal Physiol Date: 2019-11-04
Authors: Julio Chevarria; Donal J Sexton; Susan L Murray; Chaudhry E Adeel; Patrick O'Kelly; Yvonne E Williams; Conall M O'Seaghdha; Dilly M Little; Peter J Conlon Journal: Clin Kidney J Date: 2020-05-22