Using mTOR Inhibitors in the Prevention of BK Nephropathy

The incidence of BK viremia, an early complication after renal transplantation and the associated rates of graft loss resulting from BK nephropathy have been steadily rising since a series of cases that were reported in the mid-1990's. While this is at least partly related to the introduction of newer immunosuppressive agents, recent United Network for Organ Sharing (UNOS) data analyses suggest that there is a continuing rise in the incidence of BK viremia and associated nephropathy with a 3.5% incidence rate in 2009 representing a dramatic rise from just 0.9% only 4 years earlier. Single center data reports have suggested much lower rates of BK viremia and nephropathy in cohorts treated with mTOR (mammalian target of rapamycin) based immunosuppressive regimens when compared to the overall national incidence rates. Recent data has demonstrated that calcineurin inhibitors at concentrations routinely used in clinical practice interfere with the BK virus specific T cell responses; an interference that is not seen to occur with mTOR inhibitors. Further, recent evidence that inhibition of the mTOR pathway has a direct and consequential negative impact on BK infected cells provides additional insight into the observed benefit associated with mTOR inhibitors. The growing problem of BK viremia among renal transplant patients is further compounded by the absence of effective management strategies that have been tested in a rigorous or controlled setting - a fact that was highlighted in a recent systematic review. The cornerstone for management so far has been the reduction of immunosuppression, largely based on the outcome of a single center study of screening patients for viremia and following with preemptive lowering of immunosuppression. Conversion from calcineurin inhibitors to mTOR inhibitors has been reported in small case series to be an effective measure that appears to be superior to merely lowering immunosuppression; however, this approach has not been tested with a robust clinical study design.

Currently, the diagnosis of BK nephropathy requires a renal biopsy, an invasive procedure with its own risks. In addition, identification of patients with viremia who progress to nephropathy and subsequent graft failure i.e. prognostication does not appear possible with the renal biopsy results at present. Validation of potential non-invasive biomarkers provides a unique opportunity for both detection and risk stratification of patients with BK viremia subsequent failure, which could lead to more informed therapeutic interventions while supporting the development of newer therapies.

Inclusion criteria

• Renal transplant recipients age 18 years or over

Exclusion criteria

• Patients with multiorgan transplants
• Patients on immunosuppressive regimens that include steroids or Sirolimus at the time of detection of viremia
• ABO incompatible renal transplants
• Three or more previous renal transplants
• Patients with contraindications to tacrolimus, sirolimus, mycophenolate mofetil or mycophenolic acid.