Tubular Toxicity in Sirolimus- and Cyclosporine-Based Transplant Immunosuppression Strategies: An Ancillary Study From a Randomized Controlled Trial
Received 8 December 2008; accepted 9 September 2009. published online 18 November 2009.
Refers to article:
Why Do Patients Develop Proteinuria With Sirolimus? Do We Have the Answer?
Jeremy R. Chapman, Gopala K. Rangan
American Journal of Kidney Diseases
February 2010 (Vol. 55, Issue 2, Pages 213-216) Full Text |
Full-Text PDF (237 KB)
Background
Sirolimus has been promoted as an agent to provide immunosuppression for kidney transplant recipients that, in contrast to calcineurin inhibitors, would not be nephrotoxic. However, several reports have observed proteinuria in patients treated with sirolimus, ranging from low grade to nephrotic range. Accordingly, we compared markers of tubular and glomerular damage in an ancillary study of a randomized trial comparing sirolimus and cyclosporine.
Patients undergoing cadaveric or living donor kidney transplant at the University Hospital in Basel, Switzerland, between January 2001 and July 2004.
Intervention
Immunosuppression regimen consisting of cyclosporine, mycophenolate mofetil, and prednisone versus sirolimus, mycophenolate mofetil, and prednisone.
Outcomes
The primary outcome was kidney function, assessed using serum creatinine level. Secondary outcomes included patient and graft survival, number of rejections, and evidence of kidney damage, assessed using glomerular and tubular urine biomarker levels.
Measurements
Urine and serum were collected at 0, 7, 30, and 90 days. Kidney function was estimated using serum creatinine level. Urinary markers included α1-microglobulin and retinol-binding protein (tubular), transferrin and albumin (glomerular), and semiquantitative assessment of glucosuria. Protocol kidney biopsies were performed at days 90 and 180.
Results
There were 63 patients randomly assigned to cyclosporine-based regimens, and 64, to sirolimus-based regimens. Kidney function was similar in both groups, whereas levels of markers associated with glomerular damage (albumin, 19.5 vs 8.96 mg/mmol creatinine; P < 0.001; transferrin, 13.1 vs 5.7 mg/mmol creatinine; P < 0.001) and those associated with tubular damage (α1-microglobulin, 11 vs 7.6 mg/mmol creatinine; P = 0.004; retinol-binding protein, 19.6 vs 9.6 mg/mmol creatinine; P = 0.002) were higher beginning at day 7 in patients randomly assigned to sirolimus therapy, with similar findings through day 90. Glucosuria incidence was higher in patients randomly assigned to sirolimus therapy beginning by day 30 (65% vs 30% on day 30; P = 0.002; 51% vs 22% on day 90; P < 0.001). On histologic examination, the overall severity of tubular lesions was significantly higher in patients randomly assigned to sirolimus therapy.
Limitations
Small sample size, short-term follow-up likely insufficient to appreciate calcineurin-associated nephropathy.
Conclusion
Compared with a cyclosporine-based immunosuppression regimen, a sirolimus-based regimen is associated with de novo low-grade glomerular proteinuria, increased excretion of markers associated with tubular damage, and evidence of tubular damage on kidney biopsy.
1Clinic for Transplantation Immunology and Nephrology, University Hospital, Basel, Switzerland
2Laboratory Medicine, University Hospital, Basel, Switzerland
3Institute of Clinical Pathology, University Hospital, Basel, Switzerland
Address correspondence to Michael Dickenmann, MD, Clinic for Transplantation Immunology and Nephrology, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland
ABSTRACT