Albuminuria and Allograft Failure, Cardiovascular Disease Events, and All-Cause Death in Stable Kidney Transplant Recipients: A Cohort Analysis of the FAVORIT Trial

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/1.73m², 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 < 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 ≥ 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 ≥300mg/g relative to ACR < 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.

Keywords: Albuminuria; allograft failure; biomarker; cardiovascular disease (CVD); death; end-stage renal disease (ESRD); graft survival; kidney failure; kidney transplant outcomes; protein excretion; renal transplantation; urinary albumin-creatinine ratio (UACR).

Figure 1.

Derivation of the study population

Figure 2.. Adjusted event rates per 1000 patient years by eGFR and urine albumin-creatinine ratio strata.

Rates are presented per 1,000 person-years of clinical outcomes calculated using Poisson regression. Data are presented as the number of individuals with an event/number in the eGFR/ACR stratum followed by the adjusted rate (95% confidence interval). For CVD, mortality, and the composite of allograft failure and mortality outcomes, as compared to the lowest group, green shading indicates a 1 to 1.5 fold increased event rate; yellow a 1.5–2 fold increased rate; orange a 2–3 fold increased rate; red a 3–5 fold increased rate, and dark red a 5+ fold increase. For allograft failure, green shading indicates a 1–2 fold increased rate; yellow 2–5; orange, 5–10; red, 10–20 and dark red, 20+. For the composite of allograft failure and death, green shading indicates a 1–2 fold increased rate; yellow 2–5; orange, 5–10; red, 10–20 and dark red, 20+. Models adjust for age, sex, race, study allocation, country, graft vintage, donor type, calcineurin inhibitor use, sirolimus use, diabetes, history of cardiovascular disease, smoking status, systolic blood pressure, diastolic blood pressure, body mass index, HDL cholesterol, LDL cholesterol, triglycerides, angiotensin converting enzyme inhibitor or angiotensin receptor blocker use, aspirin use, and statin use. ACR, albumin-creatinine ratio in mg/g; eGFR, estimated glomerular filtration rate in mL/min/1.73m².

Figure 3.

Event rates stratified by urine ACR level