Using mTOR Inhibitors in the Prevention of BK Nephropathy
| Status: | Completed |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease, Infectious Disease |
| Therapuetic Areas: | Immunology / Infectious Diseases, Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 7/20/2017 |
| Start Date: | March 2012 |
| End Date: | December 2016 |
BK virus infections after kidney transplant are increasing and can result in damage to the
transplanted kidney. Currently, the universally accepted treatment is to decrease the
strength of the antirejection medications but it is unclear what medications should be
lowered and to what extent. The investigators propose to perform a study with patients who
have BK virus detected in their blood during routine screening that appears to be increasing.
The investigators will use two different strategies that involve different combinations of
standard anti-rejection medications at lower dosages. Patients will be assigned to one of the
two groups in a random manner across the two hospitals participating in the study. Patients
will be followed for at least a year to determine if one strategy was more effective than the
other in preventing an increase in the number of viruses in the blood stream and whether
either one was more effective in reducing the negative impact of the infection on the
functioning of the transplanted kidney.
transplanted kidney. Currently, the universally accepted treatment is to decrease the
strength of the antirejection medications but it is unclear what medications should be
lowered and to what extent. The investigators propose to perform a study with patients who
have BK virus detected in their blood during routine screening that appears to be increasing.
The investigators will use two different strategies that involve different combinations of
standard anti-rejection medications at lower dosages. Patients will be assigned to one of the
two groups in a random manner across the two hospitals participating in the study. Patients
will be followed for at least a year to determine if one strategy was more effective than the
other in preventing an increase in the number of viruses in the blood stream and whether
either one was more effective in reducing the negative impact of the infection on the
functioning of the transplanted kidney.
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.
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:
1. Patients with multiorgan transplants
2. Patients on immunosuppressive regimens that include steroids or Sirolimus at the time
of detection of viremia
3. ABO incompatible renal transplants
4. Three or more previous renal transplants
5. Patients with contraindications to tacrolimus, sirolimus, mycophenolate mofetil or
mycophenolic acid.
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