Intragraft transcriptional profiling of renal transplant patients with tubular dysfunction reveals mechanisms underlying graft injury and recovery.Azevedo H, Renesto PG, et al.
Hum Genomics 2016; 10(1): 2.
To investigate intragraft transcriptional profiles in renal transplant patients with Proximal tubular dysfunction (PTD)
Participants were initially treated with cyclosporine (CsA), prednisone and azathioprine. At enrolment, participants were randomized to continue to receive the initial protocol, or an alternative protocol consisting of reduced CsA dosage and mycophenolate mofetil introduction.
33 renal transplant recipients > 1 year of surgery, diagnosed with PTD according to three consecutive monthly measurements of urinary retinol-binding protein (uRBP) >0.4 mg/L.
The primary outcome measured was transcriptional profiles from paired biopsies at enrolment and 12 months. Other measured outcomes were serum creatine, creatine clearance, and uRBP levels.
This is an interesting study based on the assumption that proximal tubular dysfunction is associated with poorer renal graft outcome, for which there is some evidence. Proximal tubular dysfunction was diagnosed in 33 renal transplant patients who were at least one year post-transplant by demonstrating a raised level of the low molecular weight protein (urinary retinal binding protein URBP) in the urine as an indication of proximal tubular injury. All patients were on cyclosporine, azathioprine and steroids. After randomisation 18 patients had their immunosuppression changed in that cyclosporine dosage was reduced and azathioprine was replaced with mycophenolate. The control group continued on the same immunosuppression. Biopsies were performed at the time of randomisation and again at 12 months, and the follow-up was carried out over 12 months. The alternative immunosuppression scheme did result in better renal function and less evidence of tubular proteinuria at 12 months of follow up, presumably due to the reduction in cyclosporine dose. In their molecular studies they were able to show that there was more evidence of autophagy, extra-cellular matrix and adaptive immunity in the patients who had had modified immunosuppression. They were also able to show the gene expression in a group who remained on the same immunosuppression was related to fibrosis, endocytosis and endoplasmic reticulum stress. The authors suggest that the molecular networks associated with control of endocytosis, autophagy, protein overload, fibrosis and adaptive immunity may be involved in improvement of graft function. This is a carefully done study but small and really underpowered to make a lot of the conclusions valid, but it certainly points the direction for further studies in this area.