Combination Of Sirolimus Research Articles

Sirolimus in Combination with Tacrolimus Is Associated with Worse Renal Allograft Survival Compared to Mycophenolate Mofetil Combined with Tacrolimus

Cyclosporine (CsA) nephrotoxicity is enhanced by sirolimus (SRL). Tacrolimus is perceived to be less nephrotoxic than CsA, and therefore, CsA has been largely replaced by tacrolimus (TAC) when calcineurin inhibitors are used with SRL. We analyzed 44 915 adult renal transplants in the Scientific Renal Transplant Registry (SRTR) from 2000 to 2004. Three thousand five hundred twenty-four (7.8%) patients received a baseline immunosuppressive regimen of TAC/SRL, with an inferior overall (log-rank p<0.001) and death-censored graft survival (p<0.001) as compared to TAC/MMF (N=27 007). This effect was confirmed in multivariate Cox models; the adjusted hazard ratio (AHR) for overall graft loss with TAC/SRL was 1.47 (95% CI=1.32, 1.63) and for CsA/SRL 1.38 (95% CI=1.20, 1.59) relative to TAC/MMF. These effects were most apparent in high-risk transplants. Six-month acute rejection rates were low (11.5-12.6%) and not different between groups. In summary, national data indicate that TAC/SRL as compared to TAC/MMF is associated with significantly worse renal allograft survival in all subgroups of patients and, in particular, higher-risk transplants. These results have to be interpreted in the context of the inherent limitations of any retrospective database analysis and evaluated in context with data from prospective clinical trials.

Immunosuppression in Pediatric Liver and Intestinal Transplantation: A Closer Look at the Arsenal

Immunosuppression in Pediatric Liver and Intestinal Transplantation: A Closer Look at the Arsenal

A Prospective, Randomized Trial of Tacrolimus in Combination with Sirolimus or Mycophenolate Mofetil in Kidney Transplantation: Results at 1 Year

This is the 1-year report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Prior to transplantation, recipients were randomized to receive tacrolimus plus corticosteroids with either sirolimus (n=185) or MMF (n=176). The incidence of biopsy-confirmed acute rejection at 6 months was the primary endpoint of the study. Patient and graft survival, renal function, study drug dosing and discontinuations were evaluated at 1 year. At 1 year, there was no difference in patient survival (95.7% sirolimus vs. 97.2% MMF; P=0.45) or graft survival (90.8% sirolimus vs. 94.3% MMF; P=0.22). Patients without delayed graft function (DGF) receiving MMF had significantly better graft survival (99% vs. 93%; P=0.01). Patients receiving a transplant from a live donor had a trend towards better graft survival with MMF as compared to sirolimus (98% vs. 91%; P=0.07). Patients receiving sirolimus had a significantly higher incidence of study drug discontinuation (26.5% vs. 14.8% MMF; P=0.006). Patients receiving MMF had significantly better renal function as shown by median serum creatinine levels (1.3 mg/dL vs. 1.5 mg/dL; P=0.03) and a trend towards higher calculated creatinine clearance (CrCl), (58.4 ml/min vs. 54.3 ml/min; P=0.06). More patients in the sirolimus group had a serum creatinine >2.0 mg/dL, (20.4% vs. 11.0%; P=0.02). Tacrolimus is safe and effective in live and deceased donor kidney transplantation when given in combination with sirolimus or MMF. Patient and graft survival were excellent in both arms. Renal function is superior for patients treated with tacrolimus + MMF combination.

Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft‐versus‐host disease

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid-resistant cGVHD. Thirty-five patients who developed GVHD after day 100 post-transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count > or = 100 x 10(9)/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD-free survival are warranted.

Sirolimus in combination with tacrolimus for the treatment of resistant chronic graft-versus-host disease

6657 Introduction: Chronic graft versus host disease (cGVHD) remains a major complication in hematopoietic transplant recipients. We conducted a phase II trial of sirolimus in combination with tacrolimus for patients with steroid-refractory cGVHD. Patients and Methods: The median age of the 35 patients was 45 years (19–69). The median number of prior treatments for chronic GVHD was 3 (range 2–6). Chronic GVHD was defined as GVHD present beyond day 100 post-transplantation. The patients were divided into two groups. One group had continuous or recurrent manifestations of acute GVHD (late acute GVHD group). The remaining 23 patients had clinical manifestations of chronic GVHD (true chronic GVHD group). Results: Six patients had a complete remission and 16 had a partial remission for an overall response rate (ORR) of 63%. Skin was the organ most often involved (n= 29) and had an ORR of 65%. Eight patients with sclerodermatous skin involvement responded to therapy (73%). Responses were also seen in patients with GVHD of the lower GI tract (67%), liver (33%), eye (64%), and oral mucosa (75%). Major adverse events related to sirolimus were hyperlipidemia and cytopenias. Median survival was 15 months, and estimated actuarial survival at 2 years was 41% (95% CI 20–61). A significantly worse non-relapse mortality was noted in patients who had a platelet count of less than 100,000/mm3 (p < 0.0001) or late acute GVHD features (p = 0.001). Actuarial survival at 1 year was 25% in the late acute GVHD group, and 76% in the true chronic group (p = 0.0003). Corresponding estimates at 2 years were 12% (95% CI 1–40) and 62% (95% CI 34–80) (p = 0.0005). Non-relapse mortality at 2 years post initiation of therapy was significantly higher in patients with late acute GVHD (75%, 95% CI 49–99%) than in those with true chronic GVHD (35%, 95% CI 17–64%, p = 0.003). Conclusions: The addition of sirolimus to tacrolimus and methylprednisolone was effective for the treatment of resistant chronic GVHD with an ORR of 63%. It was most effective in patients with true chronic features and sclerodermatous skin involvement. Differentiating between late acute GVHD and true chronic GVHD may result in better interpretation of studies intended to target chronic GVHD. No significant financial relationships to disclose.

De Novo Immunosuppression With Sirolimus and Tacrolimus in Heart Transplant Recipients Compared With Cyclosporine and Mycophenolate Mofetil: A One-Year Follow-Up Analysis

Background Limited data exist regarding the safety and efficacy of sirolimus in combination with a calcineurin inhibitor in heart transplant recipients. Methods From January 2001 to June 2002, 31 de novo heart transplant recipients (treatment group) received a combination of sirolimus, tacrolimus, low-dose rabbit antithymocyte globulin, and glucocorticoids. Outcomes, such as actuarial survival, rate of rejection, incidence of infection, probability of developing diabetes mellitus, renal function, platelet and white blood cell counts, and incidence of coronary artery disease at 1 year, were compared with a cohort of 25 patients (control group) who underwent transplantation primarily in 2000 and in early 2002 treated with cyclosporine, mycophenolate mofetil, and glucocorticoids. All patients were followed up for at least 12 months. Results Kaplan-Meier actuarial 1-year survival rates were equivalent between groups (97% for the treatment group and 88% for the control group), as was freedom from allograft rejection (48% and 42% for treatment and control groups, respectively). No cases of transplant arteriopathy were noted within the first posttransplantation year. Renal function was not significantly affected in either group. There was a striking increased incidence of mediastinitis in the treatment group (19%) versus 0% in the control group ( P = .02). Tacrolimus-sirolimus therapy was associated with a nearly 11-fold increased incidence of new-onset diabetes mellitus as well ( P = .004). Conclusion Tacrolimus, sirolimus, and steroids (following low-dose rabbit antithymocyte globulin) were associated with an increased incidence of mediastinitis and posttransplantation diabetes mellitus. No obvious long-term benefit on survival, arteriopathy, or renal function was noted.

Gonadal Function and Immunosuppressive Therapy After Renal Transplantation

End-stage renal disease is associated with disorders in hypothalamic-pituitary-gonadal function. Immunosuppressive therapies may influence the restoration of normal levels of gonadal hormones after renal transplantation. The aim of the present study was to evaluate the hormonal status of successful renal transplant recipients who were treated with different immunosuppressive agents. Methods Testosterone, luteinizing hormone (LH), and follicle stimulating hormone (FSH) were measured in 59 male renal transplant recipients with stable graft function with serum creatinine <2.5 mg/dL. Patients were treated with three different immunosuppressive regimens: group I, calcineurin inhibitors (CI; n = 15), group II, sirolimus without calcineurin inhibitors (SRL; n = 15), group III, sirolimus in combination with calcineurin inhibitors (SRL * CI; n = 29). Results Testosterone was significantly lower in group II versus group I (3.12 ± 1.23 versus 4.39 ± 1.53 ng/mL; P < .0197). Group III had higher testosterone values than group II, but lower than group I. FSH and LH were also higher in the SRL group, but the differences were not statistically significant, perhaps because of the small number of patients. No relationship was found between testosterone blood levels and age, posttransplant follow-up, renal function, time on dialysis, body mass index, steroid use, or posttransplant diabetes. Conclusion Sirolimus seems to impair the improvement of gonadal function after renal transplantation. Further prospective studies are needed to confirm these data before patients are advised of this potential side effect.

Impact of Sirolimus on Early Graft Function after Deceased-Donor Kidney Transplantation

We recently described the de novo use of sirolimus in combination with antibody therapy selected based upon recipient immune responder risk (1) as a more effective prophylaxis of acute rejection episodes among cadaveric renal allografts than de novo mycophenolate mofetil (2). Table 4 in our article (1) documented a direct relationship between renal function early posttransplant and sirolimus concentrations in 145 patients. In their comment, McTaggart et al. suggest that the observed renal function was “impaired” based upon serum creatinine values. Because the transplant community accepts glomerular filtration rates (GFR) to be a superior measure of function, these at-risk kidneys showed quite reasonable function: 1-week mean calculated GFR values of 19, 21, and 30 mL/min and 1-month values of 55, 56, and 71 mL/min among patients stratified by sirolimus exposures of less than 7, 7 to 15, or greater than 15 ng/mL. Furthermore, our donors had a similar Novartis DGF score (mean 3.2±2.8, median 3, range 0–12) to those analyzed by McTaggart et al. (3). Their concern that excluding 10 nonfunctioning grafts at 1 month from among 145 patients biased the results is banal; re-analysis of the data including these patients did not affect the conclusions. Their retrospective analysis of DGF incidence and recovery among only 55 sirolimus-treated patients versus 77 receiving other regimens (3) was not stratified by early postoperative concentrations of sirolimus nor by the time of inception of cyclosporine or tacrolimus (or any conversions between the agents). Because they used low doses of sirolimus, the 55 patients were likely to have initial C0 values less than 7 ng/mL, the cohort that we have shown to display the highest incidence and poorest recovery from DGF (1). We attribute our favorable experience with sirolimus to the practice of delaying introduction of a calcineurin antagonist until the serum creatinine level is 2.5 mg/dL or less. Only then do we introduce cyclosporine at a dose of 1.5 mg/kg per day or less. Our recent experience with de novo treatment of 894 patients (4) revealed that only approximately 5% experience prolonged recovery from DGF beyond 6 weeks. The low incidence of, and prompt recovery from, DGF among our cohort was not intended to represent a comparison of sirolimus therapy versus other regimens: we presented these data at the XX International Congress of the Transplantation Society (5). Demographically matched cohorts of patients free of acute rejection episodes were treated de novo with (n=2,674) versus without (n=2,752) sirolimus. There was only a slight difference in DGF rates, namely, 31.7% versus 25.7%, probably reflecting physician preference to treat patients at increased risk of DGF with the relatively non-nephrotoxic agent, sirolimus. Indeed, recovery of renal function was similar: the incidence of 1-year mean GFR values above 55 mL/min was 42% versus 47.2%, respectively (P=NS). Furthermore, in a randomized trial of 361 patients, the DGF rate with tacrolimus-sirolimus (22.7%) was lower than that with tacrolimus-mycophenolate mofetil (31.3%; P=0.07) (6). Our findings suggest that sirolimus mitigates ischemia-reperfusion injuries among human renal allografts primarily by inhibiting receptor-dependent cascades triggered by toxic humoral factors, including cytokines, rather than exacerbating apoptosis or blocking tubular cell proliferation. Richard J. Knight Barry D. Kahan Division of Immunology and Organ Transplantation University of Texas Medical School at Houston Houston, TX

356 Dramatic antitumoral effect of metronomic dosing of sirolimus in combination with chemotherapy to treat hepatocellular carcinoma: Inhibition of angiogenesis and regulation of P21WAF1/CIP1

356 Dramatic antitumoral effect of metronomic dosing of sirolimus in combination with chemotherapy to treat hepatocellular carcinoma: Inhibition of angiogenesis and regulation of P21WAF1/CIP1

Effect of the immunosuppressive regime of Edmonton protocol on the long-term in vitro insulin secretion from islets of two different species and age categories

The success of the new immunosuppressive regime known as the Edmonton protocol in islet allotransplantation may suggest that it is also possible that this regime may prevent the rejection of xenografts. This protocol applies a combination of Tacrolimus, Sirolimus and Daclizumab at low doses. This combination may have some toxicity that affects the function and viability of the pancreatic islets. The choice of species or age category, whose islets can tolerate the toxicity of this immunosuppressive combination, may become important for the graft survival. It was the aim of this study to investigate the long-term effect of this regime on insulin secretion from pancreatic islets isolated from two species (rats and pigs) and from two age categories (day 7 postnatal [P7] and adult rat). Islets were cultured for three weeks in medium containing Tacrolimus in a concentration of 5 ng/ml, while the concentration of Sirolimus was 15 ng/ml. Daclizumab was added at the beginning of culture and once weekly in a final concentration of 10 ng/ml. In immunosuppressive-treated groups, Glucose was able to stimulate increases of insulin secretion over the basal value after 1 and 3 weeks in adult rat islets, and could not stimulate this secretion in P7 islets, while it stimulated the secretion only after 1 week, but not 3 weeks, in porcine islets. The immunosuppressive regimen caused significant reductions of glucose-stimulated insulin secretion magnitude in adult rat and porcine islets after 3 weeks, while it reduced both basal and stimulated secretions after 1 and 3 weeks in P7 rat islets. There was no difference in DNA contents between control and immunosuppressive-treated groups after 1 or 3 weeks in any of the islet preparations. DNA decreased considerably with the time in culture. The change in DNA content over 3 weeks was higher in the Edmonton group of adult porcine and P7 rat than in adult rat islets. Comparison of the responses of islets from different age categories and species leads to conclude that in vitro cultures of adult rat islets are more tolerant to this immunosuppressive combination toxicity than P7 islets, and there is variable responses of islets from different adult species to this toxicity.

Sirolimus: a new option in transplantation

This review of immunosuppression in renal transplantation has allowed us to highlight the deleterious effect of calcineurin inhibitor nephrotoxicity and to emphasise the importance of sirolimus. Now, a whole new set of possibilities has opened up in immunosuppression: sirolimus-based immunosuppression without calcineurin inhibitors; sirolimus in combination with calcineurin inhibitors in reduced doses; early calcineurin inhibitor withdrawal from a regimen that combines sirolimus, calcineurin inhibitors and steroids; and calcineurin inhibitor conversion to sirolimus when the first signs of graft nephrotoxicity appear. These new strategies in immunosuppression in renal transplantation are associated with good results in graft and patient survival in year 1, and with better renal function. Therefore, we can hope for better long-term results in transplantation, with a significant increase in the graft half-life and in the patient survival.

Addition of Sirolimus to Cyclosporine in Long-Term Kidney Transplant Recipients to Withdraw Steroid

The aim of this study was to evaluate the feasibility of a steroid-free maintenance immunosuppression regimen in long-term renal transplant (KTx) recipients after addition of sirolimus (SRL) to cyclosporine (CsA)-based immunosuppression. A multicenter, prospective pilot study of steroid withdrawal (SW) was initiated for KTx patients. SW was divided into three phases: (A) conversion to a SRL + CsA + steroid regimen; (B) steroid tapering and withdrawal; and (C) maintenance with SRL + CsA. Primary endpoints of the study were incidence of acute biopsy-proven rejection (AR) and safety. In the A and B phases of the study 42 KTx patients (132 ± 75 months post-Tx) were entered into the study, 18 of 42 (43%) with severe, acute side effects due to the CsA + SRL combination. These side effects were reversible with reduction of CsA or with suspension of the SRL/CsA combination. An amendment was introduced in the protocol to drastically reduce the CsA exposure to <50 ng/mL (trough) at the time of SRL addition. After this amendment, 39 other KTx patients entered the study and only 3 of 39 (8%) were discontinued because of toxic side effects. In the overall cohort of 81 KTx patients, the incidence of AR after SW was low (n = 5, 6.1%), all occurring within the first 3 months after SW. These findings indicate: (1) addition of SRL to very low-maintenance CyA exposure allows safe SW in KTx; (2) with the SRL + CsA combination, the incidence of AR after SW is low in long-term KTx patients; and (3) in the first 3 months after SW strict monitoring for early diagnosis and treatment of AR is mandatory.

Combination therapy with sirolimus (rapamycin) and tacrolimus (FK-506) in treatment of refractory minimal change nephropathy, a clinical case report

Minimal change nephropathy (MCN) is the dominant cause of idiopathic nephrotic syndrome in childhood and accounts for 25% of cases of adult nephrotic syndrome [1]. Each new episode of nephrotic syndrome adversely affects quality of life and is associated with complications including infection, thromboembolism and urinary loss of binding transport proteins. Proteinuria usually remits with high dose corticosteroid treatment; however, a significant minority responds incompletely or relapses frequently, providing a difficult therapeutic challenge. Furthermore, the management of frequent relapses with multiple courses of corticosteroids is associated with appreciable morbidity, including muscle atrophy, skin fragility and growth retardation. We report the use of sirolimus (rapamycin) in combination with tacrolimus (FK-506) to induce and maintain remission successfully in a case of chronic resistant MCN. To our knowledge, this is the first report of sirolimus/tacrolimus combination therapy in the treatment of MCN.

Clinical application of sirolimus in renal transplantation: an update

In addition to an analysis of the final results of phase I/II and phase III clinical trials of sirolimus (SRL), this review focuses on the recent results of several studies in renal transplantation, which include diverse combinations of SRL with other immunosuppressive agents. While SRL was initially introduced as an adjunctive agent to calcineurin inhibitors, it is now serving as the base for therapies that spare or avoid these nephrotoxic drugs. However, to optimize the use of SRL as base therapy, further work is necessary to determine target concentrations, requirement for concomitant steroids and/or nucleoside synthesis blockers, and countermeasure therapy to overcome the drug's adverse effects.

The combination of sirolimus and tacrolimus for primary immunosuppression after heart transplantation-is it worth the effort

Introduction: This combination has hardly been considered for immunosuppression since both compounds compete for the same binding protein. Methods: In a controlled, prospective pilot study 33 patients (pts) were treated with a combination of tacrolimus (tac), sirolimus (sir) and prednisone. Prednisone was completely withdrawn after six months. Mean follow up time was 931 226 days. Results: Survival during follow up was 100%. All but three pts. tolerated the combination well: one pt. was switched to tac/azathioprine, two pts. to sir/mycopehnolate mofetil. Only one pt. revealed an acute rejection episode (ARE) on day 54 after transplantation (0.004ARE/100pt.days). Mean tac/sir trough levels achieved were 8.28 1.74 and 6.27 1.02ng/ml, respectively. The infection incidence (1.5 1.39/pat) was comparable to that of alternative regimes with remarkable less viral infections (0.19 0.4). There were no cases of pneumonitis or wound healing disturbances but 3 cases of pericardial, 1 case of pleural effusion. In 1 patient the trough level of sir had to be decreased because of permanent diarrhea. Non significant adverse events were temporary. Mean cholesterol levels decreased after cessation of steroids, mean creatinine-levels increased slightly. At time of baseline angiography an cav-score of 0.46 1.25 was detected. At one year after transplantation this score was 1.38 3.19 and after two years 1.70 3.50 (p ns). Conclusion: This combination seems to be extremely effective preventing AREs at low trough levels, while infection-incidence proved to be comparable to alternative regimes. Adverse events were non-significant and decreased over time. Therefore, this combination seems to offer an option to decrease target trough levels of each drug, which could not be achieved for each compound in combination with other, less potent agents. Furthermore, due to antiproliferative effects of sir, the combination resulted in a decrease of the incidence of graft vessel disease compared to other immunosuppressive regimes.

The Portal Immunosuppressive Storm

Outcomes in clinical islet transplantation improved substantially with the introduction of combined sirolimus and tacrolimus immunosuppression. However, multiple islet preparations are often required to achieve insulin independence, suggesting that islet engraftment may not be optimal when these agents are absorbed via the portal vein. The current study was designed to assess the differential concentrations of immunosuppressive drugs within the portal and systemic circulations of a large animal model, to assess the local concentrations of drugs to which islets are exposed early after implantation. Chronic catheters were placed in the portal vein and carotid artery of 6 mongrel dogs, and immunosuppressants were administered orally. Blood samples were drawn simultaneously from portal and systemic catheters, and drug concentrations were analyzed. Peak immunosuppressant levels as well as area under the curve were dramatically elevated in portal blood relative to systemic levels for all drugs tested. This "portal storm" of immunosuppression may be relevant to intrahepatic islet transplantation.

Benefit-Risk Assessment of Sirolimus in Renal Transplantation

Sirolimus (rapamycin) is a macrocyclic lactone isolated from a strain of Streptomyces hygroscopicus that inhibits the mammalian target of rapamycin (mTOR)-mediated signal-transduction pathways, resulting in the arrest of cell cycle of various cell types, including T- and B-lymphocytes. Sirolimus has been demonstrated to prolong graft survival in various animal models of transplantation, ranging from rodents to primates for both heterotopic, as well as orthotopic organ grafting, bone marrow transplantation and islet cell grafting. In human clinical renal transplantation, sirolimus in combination with ciclosporin (cyclosporine) efficiently reduces the incidence of acute allograft rejection. Because of the synergistic effect of sirolimus on ciclosporin-induced nephrotoxicity, a prolonged combination of the two drugs inevitably leads to progressive irreversible renal allograft damage. Early elimination of calcineurin inhibitor therapy or complete avoidance of the latter by using sirolimus therapy is the optimal strategy for this drug. Prospective randomised phase II and III clinical studies have confirmed this approach, at least for recipients with a low to moderate immunological risk. For patients with a high immunological risk or recipients exposed to delayed graft function, sirolimus might not constitute the best therapeutic choice--despite its ability to enable calcineurin inhibitor sparing in the latter situation--because of its anti-proliferative effects on recovering renal tubular cells. Whether lower doses of sirolimus or a combination with a reduced dose of tacrolimus would be advantageous in these high risk situations remains to be determined. Clinically relevant adverse effects of sirolimus that require a specific therapeutic response or can potentially influence short- and long-term patient morbidity and mortality as well as graft survival include hypercholesterolaemia, hypertriglyceridaemia, infectious and non-infectious pneumonia, anaemia, lymphocele formation and impaired wound healing. These drug-related adverse effects are important determinants in the choice of a tailor-made immunosuppressive drug regimen that complies with the individual patient risk profile. Equally important in the latter decision is the lack of severe intrinsic nephrotoxicity associated with sirolimus and its advantageous effects on arterial hypertension, post-transplantation diabetes mellitus and esthetic changes induced by calcineurin inhibitors. Mild and transient thrombocytopenia, leukopenia, gastrointestinal adverse effects and mucosal ulcerations are all minor complications of sirolimus therapy that have less impact on the decision for choosing this drug as the basis for tailor-made immunosuppressive therapy. It is clear that sirolimus has gained a proper place in the present-day immunosuppressive armament used in renal transplantation and will contribute to the development of a tailor-made immunosuppressive therapy aimed at fulfilling the requirements outlined by the individual patient profile.

Cardiovascular risk profile in patients treated with sirolimus after renal transplantation

Renal transplant patients are inherently predisposed to cardiovascular disease (CVD) as a result of prolonged exposure to multiple cardiovascular risk factors. Approximately one half of all late graft losses are due to death with a functioning graft, and CVD is the most frequent cause of death with a functioning graft among these patients. Immunosuppressive therapies associated with a reduced burden of risk for CVD would therefore greatly decrease post-transplantation morbidity and mortality. The nephrotoxic effects observed with the use of calcineurin inhibitors (CNIs), such as cyclosporine (CsA), run counter to the goal of renal transplant therapy. Sirolimus, a more recent immunosuppressive agent with a unique mechanism of action, offers an alternative to CsA. Recent data from a 4-year study investigating early CsA withdrawal from a sirolimus-CsA-steroid (SRL-CsA-ST) combination demonstrated significantly better renal function, lower blood pressure, and improved graft survival after CsA withdrawal. During that trial, the increase in serum lipids induced by sirolimus was generally manageable with lipid-lowering therapy. Further investigation is warranted to evaluate the value of CNI-free therapy compared with CNI-based regimens in reducing cardiovascular risk factors and improving patient and graft survival.

Mycophenolate mofetil inhibits intimal hyperplasia and attenuates the expression of genes favouring smooth muscle cell proliferation and migration

Aim Intimal hyperplasia remains the leading cause of late graft failure following heart transplantation. The immunosuppressive drug mycophenolate mofetil has been shown to inhibit the development of intimal hyperplasia. This study aimed to assess the efficacy of a combination of mycophenolate mofetil, calcineurin inhibition, and sirolimus on the development of intimal hyperplasia. Methods Male Sprague-Dawley rats received mycophenolate mofetil (30 mg/kg per day) and either tacrolimus (0.1 mg/kg per day), cyclosporine (5 mg/kg per day), or sirolimus (0.05 mg/kg per day) and were compared to an untreated control group. All animals underwent left common carotid artery balloon angioplasty. Morphometric analysis was performed on representative transverse sections, and intima medial ratios calculated at 2 weeks. Profibrotic gene expression was assessed with competitive RT-PCR at 2 weeks for metalloproteinase-2, metalloproteinase-9, TIMP-1, collagen III, and TGF-β. Sections were stained with sirius red, and extracellular matrix deposition was quantified. Results Mycophenolate mofetil in combination with rapamycin was associated with the greatest reduction in intimal thickening (intima medial ratio 0.79; range 0.45–0.86), compared to its combination with either cyclosporine (1.41; range 1.06–1.68, P < .02) or tacrolimus (0.93; range 0.81–1.37, P < .05) and controls (1.47; range 1.02–2.04, P < .005). Mycophenolate mofetil and rapamycin significantly inhibited all profibrotic genes studied compared to controls ( P < .01) but there were no differences between tacrolimus and cyclosporine. Mycophenolate mofetil and sirolimus significantly attenuated extracellular matrix deposition compared to tacrolimus and cyclosporin ( P < .023). Conclusion The benefits of mycophenolate mofetil in combination with sirolimus are preferential over those with cyclosporine or tacrolimus. Randomised trials are warranted to assess if mycophenolate mofetil should be an alternative agent to calcineurin-inhibitors when used in combination with sirolimus.

Recovery of Chronic Renal Impairment With Sirolimus After Lung Transplantation

Background Standard immunosuppression after lung transplantation includes calcineurin inhibitors, azathioprine, and steroids. Calcineurin inhibitor administration is associated with an increased renal impairment. Sirolimus shows no renal toxicity and could be used in selected patients. Methods We have prospectively administered sirolimus as an alternative to calcineurin inhibitors in 15 lung transplantation recipients with persistent drug nephrotoxicity. Eight patients had also bronchiolitis obliterans syndrome. The mean serum creatinine and azotemia were 2.7 ± 1.1 mg/dL and 111 ± 39 mg/dL. After starting sirolimus, azathioprine was reduced to 50%–25% of baseline, calcineurin inhibitors were gradually reduced and eventually stopped, and steroids were maintained stable. Patients started sirolimus with 2 to 5 mg/d orally; adjustments were made according to trough levels (4 to 12 ng/mL for combined sirolimus + calcineurin inhibitors; 12 to 20 ng/mL as monotherapy), toxicity, and perceived efficacy. Patients were monitored for renal and graft function and clinical status. Results A significant creatinine decrease was observed after 6 months of treatment ( p < 0.02); azotemia decreased after 1 month and remained stable ( p < 0.01). Pulmonary function tests did not show any significant modification from before sirolimus baseline in patients without bronchiolitis obliterans syndrome. There were eight infectious complications and 10 episodes of toxicity (4 dermatitis, 2 epistaxis, 1 headache, 1 diarrhea, 1 nausea, 1 laryngeal cancer). Moderate leukocytopenia (n = 3) and hypertriglyceridemia (n = 6) responded to dose reduction. One patient was lost to follow-up. Three patients died of complications related to bronchiolitis obliterans. One patient underwent transplantation again. Conclusions Sirolimus administration allows amelioration of renal function with a relatively low morbidity and is useful for chronic renal impairment rescue after lung transplantation.