The Effect of Sirolimus on Prostate‐Specific Antigen (PSA) Levels in Male Renal Transplant Recipients Without Prostate Cancer

In kidney recipients, the immunosuppressant sirolimus has been associated with a decreased incidence of de novo posttransplant malignancies (including prostate cancer). But the effect of sirolimus on the prostate‐specific antigen (PSA) blood level, an important prostate cancer screening tool, remains unknown. We studied male kidney recipients >50 years old (transplanted from January 1994 to December 2006) without clinical evidence for prostate cancer. Pre‐ and posttransplant PSA levels were analyzed for 97 recipients (n = 19 on sirolimus, n = 78 on tacrolimus [control group]). Pretransplant PSA was similar for sirolimus versus tacrolimus recipients (mean, 1.8 versus 1.7 ng/mL, p = 0.89), but posttransplant PSA was significantly lower for recipients on sirolimus (mean, 0.9 versus 1.9 ng/mL, respectively, p < 0.001). The mean difference between pretransplant and posttransplant PSA was −0.9 ng/mL (50.0%, p = 0.006) for the sirolimus group versus +0.2 ng/mL (+11.8%, p = 0.24) for the tacrolimus group. By multivariate analysis, only pretransplant PSA and immunosuppression with sirolimus independently impacted posttransplant PSA. Our data strongly suggest that sirolimus is associated with a significant PSA decrease in kidney recipients. Future studies must investigate the clinical implications of our findings for the use of PSA for prostate cancer screening in male kidney recipients on sirolimus.

[1]  L. Salomon,et al.  Prostate cancer in renal transplant recipients. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[2]  A. Marks.  Cellular functions of immunophilins. , 1996, Physiological reviews.

[3]  S. Sehgal,et al.  Activity of rapamycin (AY-22,989) against transplanted tumors. , 1984, The Journal of antibiotics.

[4]  J. Lowell,et al.  Influence of end-stage renal disease and renal transplantation on serum prostate-specific antigen. , 1995, British journal of urology.

[5]  M. Castagneto,et al.  Gonadal function and immunosuppressive therapy after renal transplantation. , 2005, Transplantation proceedings.

[6]  A. Iranmanesh,et al.  Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. , 2000, The Journal of clinical endocrinology and metabolism.

[7]  Cecka Jm.  The OPTN/UNOS renal transplant registry. , 2005 .

[8]  L. Rostaing,et al.  Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview , 2007, Transplant international : official journal of the European Society for Organ Transplantation.

[9]  J. Kaldor,et al.  Cancer incidence before and after kidney transplantation. , 2006, JAMA.

[10]  E. Feuer,et al.  SEER Cancer Statistics Review, 1975-2003 , 2006 .

[11]  H. Klocker,et al.  Androgen receptors in prostate cancer. , 2003, Endocrine-related cancer.

[12]  M. Barry.  Prostate-Specific–Antigen Testing for Early Diagnosis of Prostate Cancer , 2001 .

[13]  H. Lilja,et al.  Rapid elimination by glomerular filtration of free prostate specific antigen and human kallikrein 2 after renal transplantation. , 2004, The Journal of urology.

[14]  J. Cecka,et al.  The OPTN/UNOS renal transplant registry. , 2004, Clinical transplants.

[15]  M. Zargar,et al.  Effects of renal transplantation on serum-free and total PSA levels. , 2007, Transplantation proceedings.

[16]  G. Mayer,et al.  Serum tumor markers after renal transplantation. , 1996, Transplantation.

[17]  J. Crowley,et al.  Prevalence of prostate cancer among men with a prostate-specific antigen level < or =4.0 ng per milliliter. , 2004, The New England journal of medicine.

[18]  K. Inoki,et al.  mTOR pathway as a target in tissue hypertrophy. , 2007, Annual review of pharmacology and toxicology.

[19]  K. Budde,et al.  Testosterone Concentrations and Sirolimus in Male Renal Transplant Patients , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[20]  S. Sehgal,et al.  Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. , 1975, The Journal of antibiotics.

[21]  B. Kasiske,et al.  Cancer after Kidney Transplantation in the United States , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[22]  A. De Benedetti,et al.  Post-transcriptional regulation of the androgen receptor by Mammalian target of rapamycin. , 2005, Cancer Research.

[23]  G. Russ,et al.  Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. , 2006, Journal of the American Society of Nephrology : JASN.

[24]  M. Castagneto,et al.  Sirolimus Impairs Improvement of the Gonadal Function after Renal Transplantation , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  I. Tannock,et al.  Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells and xenografts. , 2005, Cancer research.

[26]  R. Martel,et al.  Inhibition of the immune response by rapamycin, a new antifungal antibiotic. , 1977, Canadian journal of physiology and pharmacology.

[27]  S. Sehgal,et al.  Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. , 1975, The Journal of antibiotics.

[28]  A. Guay,et al.  Testosterone treatment in hypogonadal men: prostate-specific antigen level and risk of prostate cancer. , 2000, Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists.

[29]  F. Kaper,et al.  Mutations in the PI3K/PTEN/TSC2 pathway contribute to mammalian target of rapamycin activity and increased translation under hypoxic conditions. , 2006, Cancer research.

[30]  V. Ashby,et al.  Kidney and Pancreas Transplantation in the United States, 1997–2006: The HRSA Breakthrough Collaboratives and the 58 DSA Challenge , 2008, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[31]  B. Kahan,et al.  Maintenance Immunosuppression with Target-of-Rapamycin Inhibitors is Associated with a Reduced Incidence of De Novo Malignancies , 2005, Transplantation.

[32]  H. Meier‐Kriesche,et al.  Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. , 1999, Transplantation.

[33]  F. Guillemin,et al.  Excess risk of cancer in renal transplant patients , 2006, Transplant international : official journal of the European Society for Organ Transplantation.

[34]  J. Patard,et al.  Diagnosis and treatment of prostate cancers in renal-transplant recipients , 2003, Transplantation.

[35]  B. Meiser,et al.  Sirolimus Impairs Gonadal Function in Heart Transplant Recipients , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[36]  E. Crawford,et al.  Testosterone therapy in hypogonadal men and potential prostate cancer risk: a systematic review , 2009, International Journal of Impotence Research.