Immunosuppressive Sirolimus Research Articles

Refractory autoimmune hemolytic anemia after intestinal transplant responding to conversion from a calcineurin to mTOR inhibitor

AIHA is a rare and serious complication of solid organ transplantation. Herein, we report four cases of warm or mixed AIHA in pediatric patients following combined liver, small bowel and pancreas transplant. The hemolysis was refractory to multiple treatment modalities including steroids, rituximab, IVIG, plasmapheresis, cytoxan, discontinuation of prophylactic penicillin, and a change in immunosuppression from tacrolimus to cyclosporine. All patients had resolution or marked improvement of hemolysis after discontinuation of maintenance of CNI and initiation of sirolimus immunosuppression. One patient developed nephrotic syndrome but responded to a change in immunosuppression to everolimus. Three of the four patients continue on immunosuppression with sirolimus or everolimus without further hemolysis, evidence of rejection or medication side effects. Based on our experience and review of similar cases in the literature, we have proposed a treatment algorithm for AIHA in the pediatric intestinal transplant patient population that recommends an early change in immunosuppressive regimen from CNIs to sirolimus therapy.

Profiling Sirolimus-Induced Inflammatory Syndrome: A Prospective Tricentric Observational Study

BackgroundThe use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive.Methods30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch.Results66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model.ConclusionsSirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.

Synergistic immunosuppressive effects of the mTOR inhibitor sirolimus and the phytochemical curcumin

The immunosuppressant sirolimus and curcumin, the main principle of the turmeric spice, have shown antiproliferative effects on many human and not-human cell lines. Whereas the antiproliferative effect of sirolimus is mainly mediated by inhibition of mTOR, curcumin is described to affect many molecular targets which makes it unpredictable to appraise if the effects of these both substances on cell proliferation and especially on immunosuppression are additive or synergistic. To answer this question we investigated the interaction of both these substances on OKT3-induced human peripheral blood mononuclear cell (PBMC) proliferation. OKT3-induced human PBMC proliferation was determined by measuring 3H-thymidine incorporation. Influence of curcumin on interleukin-2 (IL-2) release and IκB-phosphorylation in PBMC was determined by ELISA and western blot, respectively. Curcumin-induced apoptosis and necrosis was analyzed by FACS analysis. Whereas curcumin completely inhibited OKT3-induced PBMC proliferation in a dose-dependent manner with an IC50 of 2.8μM, sirolimus could reduce PBMC proliferation dose-dependently only to a minimum of 28% at a concentration of 5ng/ml (IC50 1.1ng/ml). When curcumin was combined at concentrations of 1.25–2.5μM with sirolimus at concentrations from 0.63 to 1.25ng/ml the effects were synergistic. Combination of curcumin (1.25–2.5μM) with sirolimus (5ng/ml) showed additive effects. The effects after combination of curcumin at 5μM with each sirolimus concentration and sirolimus at 10ng/ml with each curcumin concentration were presumably antagonistic. We conclude that the immunosuppressive effects of curcumin and sirolimus in low concentrations are synergistic in OKT3-activated PBMC. Whether curcumin and sirolimus have also synergistic antiproliferative effects in tumor cells has to be shown in further experiments including animal models.

Sirolimus Induced Phosphaturia is Not Caused by Inhibition of Renal Apical Sodium Phosphate Cotransporters

The vast majority of glomerular filtrated phosphate is reabsorbed in the proximal tubule. Posttransplant phosphaturia is common and aggravated by sirolimus immunosuppression. The cause of sirolimus induced phosphaturia however remains elusive. Male Wistar rats received sirolimus or vehicle for 2 or 7 days (1.5mg/kg). The urine phosphate/creatinine ratio was higher and serum phosphate was lower in sirolimus treated rats, fractional excretion of phosphate was elevated and renal tubular phosphate reabsorption was reduced suggesting a renal cause for hypophosphatemia. PTH was lower in sirolimus treated rats. FGF 23 levels were unchanged at day 2 but lower in sirolimus treated rats after 7 days. Brush border membrane vesicle phosphate uptake was not altered in sirolimus treated groups or by direct incubation with sirolimus. mRNA, protein abundance, and subcellular transporter distribution of NaPi-IIa, Pit-2 and NHE3 were not different between groups but NaPi-IIc mRNA expression was lower at day 7. Transcriptome analyses revealed candidate genes that could be involved in the phosphaturic response. Sirolimus caused a selective renal phosphate leakage, which was not mediated by NaPi-IIa or NaPi-IIc regulation or localization. We hypothesize that another mechanism such as a basolateral phosphate transporter may be responsible for the sirolimus induced phosphaturia.

Kinetic Nomograms Assist Individualization of Drug Regimens

Therapeutic drug monitoring is applied to a range of drugs. To predict an appropriate dosing regimen, models based on Bayesian techniques have been used. However, this approach requires a well trained professional and sophisticated software. The objectives of this study were first to develop kinetic nomograms as a useful tool to achieve individual drug blood concentrations within the therapeutic window, using few samples and in a short period of time; and second to evaluate the performance of these nomograms in dosage adjustment and compare them with the Bayesian procedure by use of simulation. Kinetic nomograms involve collection of concentration-time profiles following repeated administrations of a fixed identification protocol and targeting of a steady-state concentration. The profiles divide the concentration-time space into several areas, each of them corresponding to a given adjusted drug dose. Kinetic nomograms are grounded on the statistical description of the interindividual variability provided by population pharmacokinetic approaches. To use them, the assayed drug concentration in a blood sample is first located in the kinetic nomogram and then the dose corresponding to the area containing this location is read. Evaluation of performance and comparison with the traditional Bayesian procedure were done by a simulation study using the immunosuppressant drug sirolimus (rapamycin). All calculations were performed by use of Matlab software. The simulation study confirmed the need for individual dosage adjustment; 71.6% of individuals underwent modification of the identification protocol of 1 mg twice daily in order to reach steady-state trough concentrations of 8 ng/mL. When the regimens were adjusted by kinetic nomograms and the Bayesian procedure, the steady-state trough concentrations of sirolimus showed low variability (coefficients of variation [CVs] of 23.4% and 24.0%, respectively) as compared with those obtained by standard recommended protocols of 4 mg once daily (CV 68.6%). The doses adjusted by kinetic nomograms and the Bayesian procedure were linearly linked and highly correlated (r = 0.96), and both provided simultaneous control of minimum and maximum drug concentrations (63.9% and 68.7% of cases between 6 and 20 ng/mL, respectively). Kinetic nomograms allow rapid and reliable dosage adjustment after the start of drug therapy. They are interesting alternatives to the cumbersome Bayesian procedure, and they provide dosage adjustment even for drugs that exhibit large intraindividual variability. In the clinical context, kinetic nomograms render individual dosage adjustment a simplified bedside application, and they could assist population studies aiming at dose individualization.

Hypersensitivity to Rabbit Antithymocyte Globulin in an Islet Transplant Recipient: A Case Report

Objective The aim was to describe a case of hypersensitivity to rabbit antithymocyte globulin (rATG) occurring in the context of islet transplantation. Methods A 36-year-old woman with type 1 diabetes was admitted for islet transplantation. rATG was administered the first day (1.5 mg/kg) with methylprednisolone (2 mg/kg), and on the second day (1.5 mg/kg) without glucocorticoid to avoid potential toxicity to the anticipated islet transplant. Results At the end of the rATG infusion on the second day she developed hives over her face, chest, and back and tender erythema at her intravenous site (Arthus reaction). Islet transplantation was not performed. She reported exposure to a pet rabbit for 2 years in childhood. Overnight, fever developed and the rash evolved into an erythematous morbilliform eruption affecting the torso. Serum high-sensitivity C-reactive protein (hsCRP) and the erythrocyte sedimentation rate (ESR) were elevated; serum complements C3 and C4 were normal. She received prednisone (50 mg) with subsequent resolution of the rash. Nine days after her initial reaction, she developed a recurrence of the rash and fever with arthralgias; levels of C3 and C4 had fallen. Methylprednisolone (125 mg, twice) was required for symptom improvement, and was gradually tapered as prednisone over the next 4 weeks with resolution of the complement, ESR, and hsCRP abnormalities. Five months after the initial attempt at islet transplantation, she returned to receive 7,879 IE/kg via portal vein infusion under basiliximab, etanercept, tacrolimus, and sirolimus immunosuppression and has required no to low-dose (0.1 U/kg/d) insulin to maintain near-normal glycemic control for > 12 months after transplantation. Conclusions Our patient's initial hypersensitivity reaction to rATG was followed by immune-complex type 3 hypersensitivity (serum sickness) requiring high-dose glucocorticoids. Canceling the initial islet infusion proved to be wise, and the patient subsequently did well with islet transplantation under an alternative induction agent.

A patient presenting with a perivascular epithelioid cell tumor in the broad ligament: a case report

IntroductionPerivascular epithelioid cell tumors are a family of rare mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. They can originate in any visceral organ or soft tissue and include a range of lesions such as angiomyolipoma, clear cell 'sugar' tumor of the lung, lymphangioleiomyomatosis and clear cell myomelanocytic tumors of the falciparum ligament/ligament teres. Due to their rarity and varied sites and presentation, management of these tumors remains highly challenging.Case PresentationA 46-year-old para 2 Caucasian woman initially presented to the general surgeons at our hospital in North West London with abdominal pain. Laparoscopy revealed a right broad ligament hematoma, which was thought to be iatrogenic in origin, from insertion of the Veress needle at the time of surgery, and was managed conservatively. Upon her re-presentation two months later with severe pain, ultrasound scanning revealed the hematoma had increased in size and she underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. Histology results from necrotic tissue from the hematoma led to a diagnosis of perivascular epithelioid cell tumor. She was then referred to a tertiary oncology center, where she underwent several further operations in an attempt to debulk the tumor for symptomatic relief of her pain, with limited success. She is now taking the immunosuppressive drug sirolimus, which has produced a modest reduction in tumor size. She is now 47 months on from initial presentation.ConclusionsA literature search has revealed only six other case reports of broad ligament perivascular epithelioid cell tumors, with varied presentations and management. The longest duration of follow-up was 21 months. Only five other cases of perivascular epithelioid cell tumor managed with sirolimus have been reported. We therefore feel that this report highlights some of the difficulties in diagnosing perivascular epithelioid cell tumors, and sheds light on management strategies for a very rare gynecological tumor in addition to sharing our experience in the use of sirolimus in its treatment.

Tacrolimus and Sirolimus Induce Reproductive Abnormalities in Female Rats

Immunosuppression medications contribute to posttransplant diabetes mellitus in patients and can cause insulin resistance in male rats. Tacrolimus (TAC)-sirolimus (SIR) immunosuppression is also associated with appearance of ovarian cysts in transplant patients. Because insulin resistance is observed in patients with polycystic ovary syndrome, we hypothesized that TAC or SIR may induce reproductive abnormalities. We monitored estrus cycles of adult female rats treated daily with TAC, SIR, and combination of TAC-SIR, or diluent (control) for 4 weeks. Animals were then challenged with oral glucose to determine their glucose and insulin responses, killed, and their blood and tissues, including ovaries and uteri harvested. TAC and TAC-SIR treatments increased mean random glucose concentrations (P<0.05). TAC, SIR, and TAC-SIR treatments also increased the glucose response to oral glucose challenge (P<0.05). The insulin response to glucose was significantly higher in rats treated with SIR compared with TAC (P<0.05). TAC, SIR and TAC-SIR treatments reduced number of estrus cycles (P<0.05). The ovaries were smaller after SIR and TAC-SIR treatment compared with controls. The TAC and TAC-SIR treatment groups had fewer preovulatory follicles. Corpora lutea were present in all groups. Ovarian aromatase expression was reduced in the SIR and TAC-SIR treatment groups. A significant (P<0.05) reduction in uterine size was observed in all treatment groups when compared with controls. In a model of immunosuppressant-induced hyperglycemia, both TAC and SIR induced reproductive abnormalities in adult female rats, likely through different mechanisms.

Laparoscopic Incisional Hernia Repair After Solid-Organ Transplantation

Background Incisional hernias are a frequent problem after liver transplantation. Mesh repair techniques including laparoscopic repair have been employed in order to address this problem. We have introduced intraperitoneal onlay mesh repair (IPOM) in 2008 because of advantages that had been reported in the literature. To perform a structured comparison of methods and outcomes, we compared patients who have been treated with IPOM and those who have been treated conventionally. Methods We included 29 consecutive patients (15 IPOM, 14 conventional hernia repair [CHR] who have been analyzed and have been examined clinically and sonographically during their follow-up. Results Recurrence rate was 6% (IPOM) and 50% (CHR), complication rate was 33% (IPOM) and 21% (CHR), mean hospital stay was 7.2 (IPOM) and 9.7 (CHR) days. None of the 29 patients had an impaired wound healing or infectious complications. Of the 29 patients, 10 received sirolimus for immunosuppression, which was switched preoperatively to a calcineurin inhibitor. Conclusion IPOM results in a shorter hospital stay. The complication rate with IPOM was higher compared with CHR, recurrence rate was considerably lower. The role of perioperative sirolimus switch needs to be interpreted with caution, but should be further investigated because of potential advantages with respect to fewer wound healing complications.

Steroid minimization for sirolimus‐treated renal transplant recipients

Steroids are associated with a myriad of post-transplant side effects. Therefore, as new immunosuppressive drugs have been developed, attempts have been made to minimize steroid exposure. Sirolimus (SRL) has been demonstrated to have efficacy in early and late post-transplant immunosuppression. Accordingly, numerous trials have studied steroid minimization (early and late post-transplant) in the context of SRL-containing protocols (either with or without a calcineurin inhibitor). We herein review these trials and show that recent studies have determined that both late steroid withdrawal and early rapid discontinuation can be successful with SRL immunosuppression.

The Incidence of Cancer and Potential Role of Sirolimus Immunosuppression Conversion on Mortality Among a Single-Center Renal Transplantation Cohort of 1,816 Patients

Introduction The chronic use of immunosuppressive drugs in renal transplant recipients increases the risk of developing de novo malignancies. Herein we analyze the incidence of de novo tumors and the potential role of sirolimus to improve cancer-specific survival among a cohort at a single center. Methods This retrospective analysis of our 1,816 patients allografted between January 1983 and December 2009 sought subjects who developed de novo tumors. Epidemiological and clinical data were examined using Mann-Whitney and Pearson's chi-square or Fisher exact tests for statistical comparisons of continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to determine cancer-specific survival according to type of neoplasia and immunosuppressive regimen, namely, conversion to sirolimus. Results One hundred patients (5.5%) were diagnosed with a de novo malignancy. The 110 different cancers were diagnosed at a median interval of 73 months after kidney transplantation. The overall cancer-specific survivals at 1 and 5 years after cancer diagnosis were 87.0% and 76.9%, respectively. The 15 patients converted to sirolimus showed no difference in survival. Conclusion The observed frequencies of cancer in our center are consistent with the literature. Among our cohort, sirolimus did not significantly impact survival among subjects who had de novo malignancies.

Pulmonary alveolar proteinosis in a kidney transplant: a rare complication of sirolimus

Pulmonary alveolar proteinosis (PAP) has been associated with the immunosuppressant sirolimus in transplant patients. PAP is a progressive lung disease characterized by the accumulation of surfactant-like material in the lungs leading to decreased pulmonary function with shortness of breath and cough as common symptoms. We report a rare case of sirolimus-associated PAP in a kidney transplant recipient with a history of end-stage renal disease secondary to haemolytic uraemic syndrome (HUS) and review of the literature. Discontinuation of sirolimus and initiation of tacrolimus led to resolution of PAP without recurrence of HUS.

Pharmacokinetic and Pharmacodynamic Interactions Between the Immunosuppressant Sirolimus and the Lipid-Lowering Drug Ezetimibe in Healthy Volunteers

Organ transplant recipients who have dyslipidemia related to immunosuppression may benefit from cholesterol-lowering therapy with ezetimibe, a substrate of ABCB1, ABCC2, and OATP1B1. Adverse pharmacokinetic interactions are hypothesized with sirolimus, which is a substrate of OATP1B1 and OATP1B3 and an inhibitor of ABCB1, OATP1B1, and OATP1B3 but not of ABCC2. However, competition between sirolimus and ezetimibe for ABCB1 and OATP1B1 is not of major clinical relevance, as confirmed in our randomized, controlled, single-dose study in healthy subjects.

Impact of Sirolimus on the Recurrence of Hepatocellular Carcinoma After Liver Transplantation

Tumor recurrence after liver transplantation for hepatocellular carcinoma is associated with a poor prognosis. Because immunosuppression is a well-known risk factor for tumor growth, it is surprising that its possible role in the outcome of liver transplantation has been poorly evaluated. We performed a case-control review of prospectively collected data and compared 2 groups of patients according to the type of immunosuppression after liver transplantation for hepatocellular carcinoma at a single center. One hundred six patients received tacrolimus and mycophenolate mofetil, and 121 received sirolimus. Patients in the sirolimus group had significantly higher recurrence-free survival rates than patients in the tacrolimus group (P = 0.0003). The sirolimus group also had significantly higher patient survival rates than the tacrolimus group at 1 year (94% versus 79%), 3 years (85% versus 66%), and 5 years (80% versus 59%; P = 0.001). Sirolimus was well tolerated, and the patients in this study did not have the increase in surgical complications noted by other investigators. Leukopenia was the most common side effect, but it typically resolved with dose reduction. Dyslipidemia and mouth ulcers were common but were easily controlled. In summary, the data suggest a beneficial effect of sirolimus immunosuppression on recurrence-free survival, which translates into patient survival benefits.

Current Status and Challenges Associated with Targeting mTOR for Cancer Therapy

The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival, and proliferation. Inappropriate activation of PI3K/Akt/mTOR signaling can promote a cellular environment that is favorable for transformation. In fact, dysregulation of this pathway, as a result of genetic mutations and amplifications, is implicated in a variety of human cancers. Therefore, mTOR has emerged as a key target for the treatment of cancer, particularly in the treatment of tumors that exhibit increased mTOR signaling as a result of genetic lesions. The immunosuppressant sirolimus (rapamycin) directly inhibits mTOR activity and suppresses the growth of cancer cells in vitro and in vivo. As a result, a number of sirolimus derivatives have been developed as anti-cancer therapies, and these compounds are currently under investigation in phase I-III clinical trials. In this review, we summarize the use of sirolimus derivatives in clinical trials and address some of the challenges associated with targeting mTOR for the treatment of human cancer.

Multiple hepatic nodules in a renal transplant recipient

A 55-year-old female received a cadaveric renal transplant in 2003. Sixteen months later, multiple liver nodules were found in a routine abdominal sonogram follow-up. Serial studies were all negative for malignancy. She was placed on a quadruple immunosuppressive regimen, including prednisolone, cyclosporine, mycophenolate mofetil and sirolimus. Her graft function was stable with serum creatinine of 1.0 mg/dl and there had been no rejection since transplantation. Liver function and lipid profile were within normal limits. Serum ferritin level was 1,466 ng/ml. Two liver biopsies, 4 months apart, showed fatty metamorphosis of the liver and no tumor. She was closely watched and no malignancy was found in the subsequent 3 years. Cyclosporine and sirolimus were tapered and corticosteroid withdrawn gradually. Serum ferritin level gradually declined to 600 - 800 ng/ml in subsequent years. Interestingly, the liver nodules gradually disappeared and there were only a few left on the last follow-up in April, 2008.

No Major Neurologic Complications With Sirolimus Use in Heart Transplant Recipients

To determine whether sirolimus therapy is associated with neurologic complications, including stroke, among heart transplant recipients. We retrospectively studied patients who underwent heart transplant at Mayo Clinic's site in Rochester, MN, from January 1, 1988, through June 30, 2006. Of 313 patients in the cohort, the medical regimen in 116 patients (37%) was switched from cyclosporine-based therapy to sirolimus. The hazard ratio of sirolimus for any neurologic or psychiatric event was 1.94 (95% confidence interval, 0.67-4.29). This hazard ratio was driven mainly by the association between sirolimus and the development of tremor and depression. Cerebrovascular events occurred with a cumulative incidence of 14% but did not occur in any of the patients who received sirolimus therapy. There were no cases of posterior reversible encephalopathy syndrome with sirolimus use. No early or late episodes of major neurotoxicity occurred in heart transplant recipients using sirolimus immunosuppression. The absence of stroke and transient ischemic attacks in these high-risk transplant recipients treated with sirolimus is notable but needs confirmation in future studies.

No Major Neurologic Complications With Sirolimus Use in Heart Transplant Recipients

To determine whether sirolimus therapy is associated with neurologic complications, including stroke, among heart transplant recipients.We retrospectively studied patients who underwent heart transplant at Mayo Clinic's site in Rochester, MN, from January 1, 1988, through June 30, 2006.Of 313 patients in the cohort, the medical regimen in 116 patients (37%) was switched from cyclosporine-based therapy to sirolimus. The hazard ratio of sirolimus for any neurologic or psychiatric event was 1.94 (95% confidence interval, 0.67-4.29). This hazard ratio was driven mainly by the association between sirolimus and the development of tremor and depression. Cerebrovascular events occurred with a cumulative incidence of 14% but did not occur in any of the patients who received sirolimus therapy. There were no cases of posterior reversible encephalopathy syndrome with sirolimus use.No early or late episodes of major neurotoxicity occurred in heart transplant recipients using sirolimus immunosuppression. The absence of stroke and transient ischemic attacks in these high-risk transplant recipients treated with sirolimus is notable but needs confirmation in future studies.

Sirolimus-associated lymphoedema: eight new cases and a proposed mechanism

Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is increasingly used as an agent for post-transplant immunosuppression and the treatment of solid organ and haematological malignancies and hamartomas. Its advantages include a lack of nephrotoxicity and a lower incidence of nonmelanoma skin cancers; adverse effects include delayed wound healing, increased lymphocoele formation and rarely lymphoedema. We report a series of eight cases of severe, sustained, unilateral and bilateral lymphoedema in patients receiving sirolimus for post-transplant immunosuppression, classify their lymphoscintigraphy findings and propose a mechanism of aetiology based on the interaction of mTOR with key mediators of lymphangiogenesis.

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.