Transplant Trial Watch

Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients: The FAVORIT Trial.

Park M, Katz R, et al.

Am J Transplant. 2017; 17(10):2640-9.

The aim of the multicenter double-blind, randomized controlled FAVORIT trial was to determine if lowering homocysteine levels with vitamin therapy reduced CVD events in stable KTRs. This case-cohort substudy of the FAVORIT trial assessed whether higher urine concentrations of four markers are associated with risk of cardiovascular disease (CVD) events and death in stable kidney transplant recipients (KTRs) independent of chronic kidney disease (CKD) and CVD risk factors, baseline eGFR, and urine albumin-to-creatinine ratio (ACR).

Participants in the FAVORIT trial were randomized to either a standard multivitamin with high doses of folic acid, vitamin B6, and B12 or a multivitamin containing no folic acid and low doses of vitamin B6 and vitamin B12. For this study, urine markers of fibrosis (a1m, MCP-1, PINP, and PIIINP) were measured in duplicate in spot urine samples obtained at the FAVORIT baseline study visit.

513 participants from the FAVORIT trial were included in the subcohort for this study. Members of the subcohort were selected at random irrespective of whether or not they experienced CVD or death during follow-up. Among these 513 subcohort participants, 23 had CVD events and 36 deaths occurred, with 31 participants experiencing both. Among the cases included in the study, there were 300 CVD cases and 371 deaths, with 143 cases of both CVD events and death.

Outcomes assessed or utilized in this substudy were urine markers of fibrosis, urine injury biomarkers (urine NGAL, KIM-1, IL-18, and L-FABP), eGFR, urine ACR, CVD risk factors, CVD events (defined as a composite of CVD death, myocardial infarction, resuscitated sudden death, and stroke) and death. Statistical models were used to test associations between markers and events.

Median 3.46 years follow-up.

CET Conclusions
This paper represents another ancillary analysis of the FAVORIT study, which we have previously assessed as a very good quality study with adequate randomisation, blinding and follow up. Four urinary proteins known to correlate with interstitial fibrosis were evaluated for their association with cardiovascular events and death. Higher levels of urinary alpha-1-microglobulin, MCP-1 and PINP were associated with significantly increased hazard ratio for cardiovascular events and death. The paper gives a thorough description of methods and analysis. The authors speculate on the mechanistic relationship between these markers and the primary outcome but this study itself does not help to explain this.

Jadad score

Data analysis
Per protocol analysis

Allocation concealment

Quality notes
SCORE BASED ON ‒ Bostom AG, Carpenter MA, Kusek JW, et al. Circulation, 2011; 123:1763-70.

Trial registration - NCT00064753

Funding source
Non-industry funded