Albuminuria and allograft failure, cardiovascular disease events, and all-cause death in stable kidney transplant recipients: a cohort analysis of the FAVORIT trial

Authors: WEINER, DANIEL - Tufts Medical Center; PARK, MEYEON - University Of California; TIGHIOUART, HOCINE - Tufts Medical Center; JOSEPH, ALIN - Tufts Medical Center; CARPENTER, MYRA - University Of North Carolina; GOYAL, NINTENDER - Tufts Medical Center; HOUSE, ANDREW - London Health Sciences Centre; HSU, CHI-YUAN - University Of California; IX, JOACHIM - University Of California; JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; KEW, CLILFTON - University Of Alabama; KIM, S. - Toronto General Hospital; KUSEK, JOHN - National Institute Of Diabetes And Digestive And Kidney Diseases; PESAVENTO, TODD - The Ohio State University; PFEFFER, MARC - Brigham & Women'S Hospital; SMITH, STEPHEN - Duke University; WEIR, MATTHEW - University Of Maryland; LEVEY, ANDREW - Tufts Medical Center; BOSTOM, ANDREW - Rhode Island Hospital

Submitted to: American Journal of Kidney Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/23/2018
Publication Date: 7/20/2018
Citation: Weiner, D.E., Park, M., Tighiouart, H., Joseph, A.A., Carpenter, M.A., Goyal, N., House, A.A., Hsu, C., Ix, J.H., Jacques, P.F., Kew, C.E., Kim, S.J., Kusek, J.W., Pesavento, T.E., Pfeffer, M.A., Smith, S.R., Weir, M.R., Levey, A.S., Bostom, A.G. 2018. Albuminuria and allograft failure, cardiovascular disease events, and all-cause death in stable kidney transplant recipients: a cohort analysis of the FAVORIT trial. American Journal of Kidney Diseases. 73(1):51-61. https://doi.org/10.1053/j.ajkd.2018.05.015.
DOI: https://doi.org/10.1053/j.ajkd.2018.05.015

Interpretive Summary: Kidney transplant recipients (KTRs) face many health challenges. There have been improvements in decreasing kidney transplant rejections soon after surgery, but the number of transplanted kidney that are rejected over a longer term is still too high. KTR also experience a much higher risk of cardiovascular disease (CVD) than the general population. In addition to higher prevalence of traditional CVD risk factors among KTRs, such as diabetes, reduced kidney function following transplantation is also independently associated with increased cardiovascular risk. An important indicator of kidney damage in the general population (who have not undergone kidney transplantation) is high urinary levels of the protein albumin (called albuminuria). The relationship between albuminuria and kidney disease and other health outcomes is established in persons without kidney transplants. However, it is not clear that albuminuria in KTRs reflects the same disease processes as seen in the general population. Specifically, the relationship between albuminuria and the development of CVD and kidney disease outcomes in KTRs is unknown. To address this gap in our understanding of the relationship between albuminuria and kidney health in KTRs, we examined transplant failure, CVD, and death among patients enrolled in the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial, which was designed to test whether high-dose folic acid and B vitamins reduced CVD events in KTRs. Our results, which included approximately 3,500 FAVORIT participants, showed that albuminuria in KTRs was independently associated with transplant failure, CVD, and death. Future research should look at whether reducing albuminuria would help improve these outcomes.

Technical Abstract: RATIONALE & OBJECTIVE: Cardiovascular disease (CVD) is common and overall graft survival is suboptimal among kidney transplant recipients. Although albuminuria is a known risk factor for adverse outcomes among persons with native chronic kidney disease, the relationship of albuminuria with cardiovascular and kidney outcomes in transplant recipients is uncertain. STUDY DESIGN: Post hoc longitudinal cohort analysis of the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) Trial. SETTING & PARTICIPANTS: Stable kidney transplant recipients with elevated homocysteine levels from 30 sites in the United States, Canada, and Brazil. PREDICTOR: Urine albumin-creatinine ratio (ACR) at randomization. OUTCOMES: Allograft failure, CVD, and all-cause death. ANALYTICAL APPROACH: Multivariable Cox models adjusted for age; sex; race; randomized treatment allocation; country; systolic and diastolic blood pressure; history of CVD, diabetes, and hypertension; smoking; cholesterol; body mass index; estimated glomerular filtration rate (eGFR); donor type; transplant vintage; medications; and immunosuppression. RESULTS: Among 3,511 participants with complete data, median ACR was 24 (Q1-Q3, 9-98) mg/g, mean eGFR was 49 +/- 18 (standard deviation) mL/min/1.73m^2, mean age was 52 +/- 9 years, and median graft vintage was 4.1 (Q1-Q3, 1.7-7.4) years. There were 1,017 (29%) with ACR less than 10mg/g, 912 (26%) with ACR of 10 to 29mg/g, 1,134 (32%) with ACR of 30 to 299mg/g, and 448 (13%) with ACR greater than or equal to 300mg/g. During approximately 4 years, 282 allograft failure events, 497 CVD events, and 407 deaths occurred. Event rates were higher at both lower eGFRs and higher ACR. ACR of 30 to 299 and greater than or equal to 300mg/g relative to ACR less than 10mg/g were independently associated with graft failure (HRs of 3.40 [95% CI, 2.19-5.30] and 9.96 [95% CI, 6.35-15.62], respectively), CVD events (HRs of 1.25 [95% CI, 0.96-1.61] and 1.55 [95% CI, 1.13-2.11], respectively), and all-cause death (HRs of 1.65 [95% CI, 1.23-2.21] and 2.07 [95% CI, 1.46-2.94], respectively). LIMITATIONS: No data for rejection; single ACR assessment. CONCLUSIONS: In a large population of stable kidney transplant recipients, elevated baseline ACR is independently associated with allograft failure, CVD, and death. Future studies are needed to evaluate whether reducing albuminuria improves these outcomes.