Urine Measurements of the Renin-Angiotensin System-Regulated Proteins Predict Death and Graft Loss in Kidney Transplant Recipients Enrolled in a Ramipril versus Placebo Randomized Controlled Trial

The
renin-angiotensin system (RAS) is involved in kidney fibrosis.
We previously identified six RAS-regulated proteins (RHOB, BST1, LYPA1,
GLNA, TSP1, and LAMB2) that were increased in the urine of patients
with kidney allograft fibrosis, compared to patients without fibrosis.
We hypothesized that these urinary RAS-regulated proteins predicted
primary outcomes in kidney transplant recipients enrolled in the largest
RAS inhibitor randomized controlled trial. Urine excretion of 10 peptides
corresponding to the six RAS-regulated proteins was quantified using
parallel reaction monitoring mass spectrometry assays (normalized
by urine creatinine) in a subset of patients in the trial. Machine
learning models predicting outcomes based on urine peptide excretion
rates were developed and evaluated. Urine samples (n = 111) from 56 patients were collected at 0, 6, 12, and 24 months.
Twenty-four primary outcomes (doubling of serum creatinine, graft
loss, or death) occurred in 17 patients. Logistic regression utilizing
eight peptides of TSP1, BST1, LAMB2, LYPA1, and RHOB, from the last
urine sample prior to outcomes, predicted a graft loss with an AUC
of 0.78 (p = 0.00001). A random forest classifier
utilizing BST1 and LYPA1 peptides predicted death with an AUC of 0.80
(p = 0.0016). Urine measurements of RAS-regulated
proteins may predict outcomes in kidney transplant recipients, although
further prospective studies are required.