Sirolimus in de novo heart transplant recipients with severe renal impairment

Two patients with end-stage heart failure and advanced renal dysfunction (under chronic dialysis therapy) underwent heart transplantation. In order to avoid further renal impairment, a calcineurine inhibitor-free immunosuppression regimen based on the sirolimus was used. Although temporary perioperative support with hemofiltration and dialysis was needed, both patients eventually regained a reasonable renal function with no episodes of clinical rejection and normal cardiac function at 13 and 11 months, respectively, after transplantation. Sirolimus-based immunosuppression might be an interesting alternative to calcineurine inhibitors in the management of patients with significant renal impairment.     

Pharmacokinetics of sirolimus in heart transplant recipients with chronic renal impairment

BACKGROUND: A common clinical problem following organ transplantation is the development of renal failure due to calcineurin inhibitors. Sirolimus offers the potential of providing appropriate immunosuppression without nephrotoxicity. This study evaluates the impact of sirolimus monotherapy on renal function in patients late following heart transplantation and correlates trough sirolimus levels with area-under-the-concentration time curve measurements. METHODS: Six male patients with renal impairment late following heart transplantation (mean 8 years) were offered sirolimus therapy. Calcineurin inhibition was discontinued in all patients on commencing sirolimus. Patients started on sirolimus 2 to 5 mg/d orally. Venous blood samples for pharmacokinetic studies and repeat creatinine clearance were performed before and 6 weeks after commencement of sirolimus in all subjects. RESULTS: Sirolimus trough levels accurately reflected sirolimus area-under-the-concentration time curve measurements. There was no change in renal function. Mean creatinine clearance prior to commencing sirolimus was 26.7 (12.2) mL/min and the post-sirolimus creatinine clearance performed 6 weeks later was 23.4 (11.7) mL/min (P = .64). CONCLUSIONS: Trough levels of sirolimus correlate with drug exposure and may be used to monitor sirolimus therapy. No improvement in renal function following calcineurin inhibitor withdrawal occurred in this cohort.     

Sirolimus interferes with iron homeostasis in renal transplant recipients

BACKGROUND: Sirolimus is an immunosuppressive drug whose use is frequently associated with anemia. A pathogenic link between sirolimus-induced anemia and the appearance of an inflammatory state was recently suggested. Because inflammation-related anemia is characterized by a functional iron deficiency, we investigated whether sirolimus may influence iron homeostasis and serum levels of hepcidin, a key mediator of inflammation-related anemia. METHODS: To this purpose, 42 consecutive transplanted patients with biopsy-proven chronic allograft nephropathy were randomized (2:1 ratio) to receive either a 40% cyclosporine reduction (group A, 14 patients) or immediate cyclosporine withdrawal and sirolimus introduction (group B, 28 patients). Hemoglobin levels and iron status were evaluated 6 months before and after randomization. RESULTS: The two groups had similar hemoglobin levels and iron status at baseline. We did not observe any significant change in hemoglobin and iron status in group A patients after randomization. On the contrary, we observed a significant reduction of hemoglobin without any change of red blood cell count after sirolimus introduction, with a significant reduction of mean corpuscular volume and mean corpuscular hemoglobin. Serum iron and transferrin saturation (TSAT) levels were markedly reduced after the switch, while ferritin serum concentrations remained stable. Although sirolimus-induced anemia was recently suggested to resemble inflammation-related anemia, hepcidin serum levels were similar in the two groups after randomization. None of group A and eight of group B patients presented a TSAT <20 and were given iron supplementation after randomization, in all of them oral iron therapy did not influence either hemoglobin or serum iron levels. CONCLUSION: We demonstrated that sirolimus-induced anemia is independent of the drug antiproliferative effect and does not present the features of inflammation-related anemia. This event may be due to the direct influence of sirolimus on iron homeostasis.     

Sirolimus therapy in orthotopic liver transplant recipients with calcineurin inhibitor related chronic renal insufficiency

Calcineurin inhibitor-related renal toxicity affects patient and graft survival in transplant recipients. Our clinical experience has revealed sirolimus to be an effective agent in treating renal insufficiency related to calcineurin inhibitor toxicity. METHODS: We performed a retrospective review of the medical records of OLT recipients suffering from chronic renal insufficiency and treated with sirolimus at the University of Miami. RESULTS: Fourteen patients (nine men and five women) of mean age 57 years who had been treated with tacrolimus for at least 30 days were converted to sirolimus after developing nephrotoxicity. Mean creatinine clearances collected on day 0, 30, 60, and 90 after conversion were 40.1 mL/min, 49.6 mL/min, 53.9 mL/min, and 51.4 mL/min, respectively. Episodes of acute cellular rejection were not increased during the sirolimus conversion. CONCLUSION: This retrospective review suggests that OLT patients suffering from tacrolimus-related renal insufficiency successfully converted to sirolimus may benefit from this therapy.     

Sirolimus immunosuppression in pediatric heart transplant recipients: a single-center experience.

BACKGROUND: Sirolimus has been used in heart transplant recipients for treatment of rejection, alternative immunosuppression (IS) and promotion of regression and prevention of graft vasculopathy (coronary artery disease [CAD]). This study reports on our center's experience with 16 children who underwent heart transplantation. METHODS: Data were obtained by retrospective review. RESULTS: Median age at time of review was 12.3 years (n = 16, 5.1 to 18.0 years; 9 boys, 7 girls), and at time of transplant 7.5 years (6 months to 18.0 years). Median time of sirolimus introduction was 2.7 years (1 month to 8.2 years) post-transplant. Fifteen patients were on steroids, 10 on tacrolimus (FK) and mycophenolate mofetil (MMF), 5 on FK and 1 on MMF with no calcineurin inhibitors (CNIs). The average dose of sirolimus was 0.25 mg/kg or 7.0 mg/m(2) to maintain a target level of 5 to 15 mug/liter. Sirolimus was started for CAD in 6 patients (38%), rejection in 5 (31%), and in 5 with combinations of CNI intolerance, CAD, renal dysfunction and rejection. All 6 who received sirolimus for rejection (International Society for Heart and Lung Transplantation [ISHLT] Grade 3A) showed improvement on follow-up biopsies. Two of 3 who received sirolimus for renal dysfunction showed improvement (glomerular filtration rate [GFR] 43 to 67 and 32 to 106 ml/min per 1.73 m(2), respectively). Side effects included hyperlipidemia (38%), abdominal pain (31%), mouth ulcers (26%), anemia or neutropenia (12.5%), persistent pericardial effusion (6%) and interstitial lung disease (6%). Sirolimus therapy was discontinued in 3 patients due to side effects. CONCLUSIONS: In this study sirolimus was found to be a valuable IS agent for the management of rejection, significant renal dysfunction and CNI side effects. These results support the need for prospective studies of the role of sirolimus in primary rejection prophylaxis, primary CAD prophylaxis and CAD regression. There also exists a need to establish an adverse event profile for this drug.     

Risk factors for chronic renal dysfunction in lung transplant recipients

Several factors predispose to renal dysfunction (RD), a common complication of solid organ transplants. We evaluated the impact of clinical and laboratory parameters on the decline of renal function in lung and heart-lung transplant recipients. We enrolled 45 patients who survived more than 6 months after transplantation, had normal renal function and urinalysis before the surgery. The prognostic value of variables for the occurrence of RD was calculated by univariate analysis. Thirty patients developed RD, defined as doubling of serum creatinine or creatinine steadily >1.5 mg/dL after a median time of 12 months. Serum creatinine above 0.9 mg/dL during the month preceding lung transplant, systolic blood pressure above 130 mmHg, and pretransplant idiopathic pulmonary hypertension were significantly associated with the development of RD. Our findings indicate that increased systolic blood pressure, reduced glomerular filtration rate, and idiopathic pulmonary hypertension are risk factors for chronic RD in lung transplant recipients.     

Sirolimus delays recovery from posttransplant renal failure in kidney graft recipients

The aim of this study was to evaluate the impact of sirolimus and cyclosporine (CsA) combined therapy on the incidence and duration of delayed graft function (DGF), and the impact of the latter on 1-year graft function. The study entailed 23 cadaveric renal recipients treated with sirolimus-CsA-prednisone regimen (sirolimus group). The reference group entailed 23 patients treated with CsA-azathioprine-prednisone. In the sirolimus group the frequency of DGF was 39% and was essentially the same as in reference group (34.8%). The duration of DGF was significantly longer in SRL group and lasted 21.2 +/- 12.2 days versus 6.8 +/- 2.5 in reference group (P = .004). Serum creatinine level decreased below 3.0 mg/dL after 36 +/- 22 days in sirolimus group versus 16.8 +/- 6 days in reference group (P < .04). Cold ischemia was slightly longer and donors were older in DGF patients in both groups. Sirolimus dose during first month was higher in DGF patients (3.5 versus 2.6 mg), whereas level of CsA was lower (230 versus 310 ng/mL). Biopsy-proven acute rejection (AR) occurred in most of DGF patients and during the DGF period. Serum creatinine level at the 12th month posttransplant was higher in DGF versus non-DGF patients (2.0 +/- 0.5 versus 1.5 +/- 0.4 mg/dL). One-year patient and graft survival was 100% in sirolimus group and 100% and 95% in reference group. In conclusion, sirolimus significantly retards the recovery from posttransplant renal failure; however, it does not increase the incidence of DGF. Patients who suffered from posttransplant acute renal failure had worse renal function at 1 year after transplantation, independent of the treatment protocol.     

Respiratory viruses and chronic rejection in lung transplant recipients.

BACKGROUND; Chronic rejection manifested as obliterative bronchiolitis (OB) and bronchiolitis obliterans syndrome (BOS) continue to be major causes of morbidity and mortality after lung transplantation. Community respiratory virus (CRV) infection, including respiratory syncytial virus, parainfluenza virus, and influenza virus, can infect and also cause morbidity in lung transplant recipients. Because CRV and OB/BOS affect the small airways, we sought to determine whether CRV infections predisposed patients to OB/BOS. METHODS: To determine whether CRV predisposed to OB/BOS, a proportional hazards regression analysis of time to OB/BOS was performed with CRV as a time-dependent covariate. To determine the influence of OB/BOS on the subsequent development of CRV infection, we reversed the outcome and time-dependent covariate. To illustrate the effect of CRV on OB/BOS and the effect of OB/BOS on CRV, landmark plots were generated at specific time points. Time to development of OB/BOS was then compared using the Kaplan-Meier method. RESULTS: In our institution, we documented 40 infections caused by CRV in 33 lung transplant recipients during an 11-year period. Community respiratory virus infections occurred predominantly during seasonal community outbreaks, except for parainfluenza infections, which occurred throughout the year. The diagnosis of OB/BOS occurred throughout the year and was not associated with seasonal outbreaks of CRV. Community respiratory virus infection involving both upper and lower respiratory tracts did not predispose to OB or BOS (relative risk [RR], 1.1; 95% confidence interval [CI], 0.52-2.3; p = 0.81). However, patients with documented CRV infection of the lower respiratory tract were predisposed to high-grade BOS development (RR, 2.3; 95% CI, 1.1-4.9; p = 0.04). In addition, a patient with pre-existing OB or BOS was predisposed to developing both upper and lower respiratory tract infection with CRV (RR, 4.2; 95% CI, 1.9-9.4; p < 0.001). CONCLUSIONS: Patients with CRV infection of the lower respiratory tract were predisposed to high-grade BOS development, and patients with OB and BOS were predisposed to CRV infections.     

西罗莫司在肝移植术后钙调素类抑制剂相关肾损病人中的应用

目的 探讨西罗莫司对肝移植术后钙调素类免疫抑制剂相关肾功能损害病人的肾功能的改善作用及安全性.方法 对11例肝移植术后出现钙调素类免疫抑制剂相关肾损害病人进行西罗莫司转换治疗,同时减少或完全停止钙调素类免疫抑制剂的应用.观察转换治疗后病人的肾功能、肝功能、急性排斥反应的发生及药物副作用等情况.结果 随访至今所有病人均存活,随访时间6～23个月.转化治疗后所有病人的肾功能均有不同程度的改善,6个月后血肌酐从(163.8±47.9)μmol/L降为(108.1±26.6)μtmol/L(P<0.05);除1例病人出现转氨酶升高,加用钙调素类免疫抑制剂后恢复正常外,其余病人肝功能无明显变化;药物副作用有高脂血症、贫血、溃疡型口疮等.结论 西罗莫司可以安全地应用于肝移植术后钙调素类免疫抑制剂相关肾功能损害的病人,改善病人的肾功能,同时对移植肝功能无明显影响.     

Individualization of immunosuppressive therapy: I. Sirolimus improves outcomes in African-American renal transplant recipients

INTRODUCTION: African-American renal transplant recipients are prone to acute rejection episodes and graft loss owing to genetic, pharmacokinetic, cultural, and socioeconomic factors. While more intense exposures to antirejection agents can mitigate this propensity, heightened immunosuppressive regimens are accompanied by an array of toxicities. Our study sought to examine the impact of a combination of sirolimus (SRL) and cyclosporine (CsA) on the outcomes of African-Americans vs Caucasians. MATERIALS AND METHODS: The outcomes of African-Americans treated with either CsA-prednisone (Pred, n = 90) or SRL-CsA-Pred (n = 86) were compared with 148 SRL-CsA-Pred-treated Caucasians. RESULTS: The addition of SRL to a CsA-Pred regimen reduced the rate of acute rejection episodes within 2 years in African-Americans from 43.3% to 17% (P = .004), a value similar to that observed in Caucasian patients (18%). At 2 years, the graft survival rate of 79% among African-American patients treated with SRL-CsA-Pred was similar to that in the Caucasian cohort (80%). The respective patient survival rates also were similar: 93% and 90%, respectively. Multivariate analysis of 5-year outcomes among patients treated with SRL-CsA-Pred revealed the hazard ratios of African-Americans vs Caucasians to actually be reduced for acute rejection (.22; P = .01) and for death (.15; P = .01), but similar for chronic rejection (.77; P = NS) and graft loss (1.03; P = NS). CONCLUSION: The use of SRL-based regimens mitigated the otherwise enhanced risk for acute rejection episodes or graft loss otherwise experienced by CsA-treated African-American renal transplant recipients.     

L-arginine supplementation in young renal allograft recipients with chronic transplant dysfunction.

AIMS: L-arginine (LA), the precursor of nitric oxide (NO), was suggested to be beneficial in many forms of renal disease: hypertension, ureteral obstructive nephropathy and cyclosporin A (CsA) nephrotoxicity. METHODS: Thus, we investigated the effects of LA supplementation on renal function, proteinuria and blood pressure (BP) in young renal allograft recipients with chronic renal transplant dysfunction treated with CsA. Eleven CsA-treated renal allograft recipients with chronic transplant dysfunction, aged 11-22 years, were randomly assigned to a 6-week treatment period with placebo (P), followed by 2 subsequent 6-week periods with LA supplementation (0.1 g/kg body weight/day) or a 6-week treatment period with LA, followed by 2 subsequent 6-week periods with P. At the end of each treatment period 24-hour BP recordings were made, and GFR (Inutest), RPF (PAH clearance) and the urinary excretion of protein, albumin, nitrate, cGMP and urea were evaluated. RESULTS: In comparison to placebo, LA treatment did not significantly change GFR, RPF, proteinuria and albuminuria, mean systolic or diastolic BP. The urinary excretion of urea and NO3 increased after LA supplementation (uUrea: LA 26.3 +/- 4.6 compared to P 23.5 +/- 4.7 g/day/1.73 m3, p < 0.05, uNO3: LA 514 +/- 152 compared to P 95 +/- 41 mM/day/1.73 m3, p < 0.05), whereas urinary excretion of cGMP remained unchanged. CONCLUSION: LA supplementation did not improve renal function and did not decrease proteinuria in CsA-treated renal allograft recipients with chronic transplant dysfunction possibly because of inhibition of NO-cGMP forming mechanism.     

Early experience with sirolimus in lung transplant recipients with chronic allograft rejection.

BACKGROUND: Chronic lung allograft rejection, commonly manifest as obliterative bronchiolitis (OB/BOS), hinders long-term survival after lung transplantation (LT). OB/BOS is traditionally treated with augmented immunosuppression and results in short-term stabilization in pulmonary function for most patients. However, peribronchiolar fibroproliferation and airway obstruction usually recur despite initial improvements seen with increases in immunosuppression. In this observational, uncontrolled study, the effect of sirolimus, a novel immunosuppressant with anti-proliferative activity, was assessed in LT patients with OB/BOS. METHODS: Between June 1999 to November 2000, LT recipients with newly diagnosed or progressive OB/BOS received sirolimus in combination with a calcineurin inhibitor (CI) and prednisone. Pulmonary function, laboratory data and adverse effects were monitored for the first 24 weeks of therapy. RESULTS: Sirolimus was utilized in 12 LT recipients with OB/BOS. After drug initiation, 58% of patients required a reduction in CI dose to maintain appropriate CI trough concentrations. Despite CI dose reduction, serum creatinine rose in 75% of patients. Unexpected adverse effects included anemia of chronic disease (100%), edema (50%) and malignancy (17%). For the group, the rate of change in FEV(1) and FEF(25%-75%) was unchanged with sirolimus, but individual responses varied. CONCLUSIONS: For the group, the decline in pulmonary function was not affected by the addition of sirolimus. However, among individuals with rapidly declining pulmonary mechanics, sirolimus resulted in stabilization or improvement in pulmonary function. Significant adverse effects resulted from combination sirolimus plus CI therapy. Until optimal dosing strategies and a more complete adverse effect profile are established, combination therapy should be utilized cautiously in these patients.     

Alloreactivity in renal transplant recipients with and without chronic allograft nephropathy

The pathogenesis of chronic allograft nephropathy (CAN) involves both immunologic (antigen-dependent) and nonimmunologic (antigen-independent) mechanisms. In order to provide further insight into the immunologic basis of this disease, a cross-sectional analysis of cellular and humoral immunity in human renal allograft recipients with or without deteriorating renal function and biopsy proven CAN was performed. Interferon-gamma enzyme-linked immunosorbent spot assays were used to assess cellular immunity to donor, or fully mismatched third-party stimulator cells (direct pathway), and to synthetic peptides derived from donor HLA molecules (indirect pathway). Anti-HLA antibodies were evaluated by flow cytometry using HLA-coated beads. Both the mean frequencies of donor-reactive peripheral blood lymphocytes and the number of individuals who responded to donor antigens per group were statistically higher in CAN patients versus control subjects (P < 0.02). Calculated ratios of donor/third-party enzyme-linked immunosorbent spot responses showed mean values of 2.61 +/- 3.0 in the CAN group, with ratios of 0.50 to 0.72 +/- 0.42 in control subjects (P < 0.001), confirming that direct, donor-specific cellular immunity predominated in patients with CAN. Fifty percent of CAN patients studied exhibited donor peptide reactivity compared with only 28.6% in control subjects. Finally, 33% of patients in the CAN group developed new posttransplantation anti-HLA antibodies compared with only 4% in the control group (P < 0.05). Overall, the results suggest that persistent cell-mediated and humoral alloimmunity contribute to the development of CAN and further demonstrate that anti-donor immunity in patients with CAN is heterogeneous. Immune monitoring to predict long-term outcome should include multiple measures of cellular and humoral immunity.     

Sirolimus is associated with new-onset diabetes in kidney transplant recipients

New-onset diabetes (NOD) is associated with transplant failure. A few single-center studies have suggested that sirolimus is associated with NOD, but this is not well established. With the use of data from the United States Renal Data System, this study evaluated the association between sirolimus use at the time of transplantation and NOD among 20,124 adult recipients of a first kidney transplant without diabetes. Compared with patients treated with cyclosporine and either mycophenolate mofetil orazathioprine, sirolimus-treated patients were at increased risk for NOD, whether it was used in combination with cyclosporine (adjusted hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.36 to 1.90),tacrolimus (adjusted HR 1.66; 95% CI 1.42 to 1.93), or an antimetabolite (mycophenolate mofetil orazathioprine; adjusted HR 1.36; 95% CI 1.09 to 1.69). Similar results were obtained in a subgroup analysis that included the 16,861 patients who did not have their immunosuppressive regimen changed throughout the first posttransplantation year. In conclusion, sirolimus is independently associated with NOD. Given the negative impact of NOD on posttransplantation outcomes, these findings should be confirmed in prospective studies or in meta-analyses of existing trials that involved sirolimus.     

Sirolimus inhibits oxidative burst activity in transplant recipients

Increased susceptibility to bacterial infection is a recognized side-effect of sirolimus treatment after transplantation, which could be caused by inhibition of neutrophil activation. Blood from 24 healthy subjects was equilibrated with 0 to 50 ng/mL sirolimus or 60 microg/mL propofol. Blood was also collected from 23 transplant recipients (13 kidney, 10 liver) with renal impairment, randomized to remain on calcineurin inhibitors (n=12) or to be switched to sirolimus monotherapy (n=11). Phorbol myristate acetate (PMA)-stimulated oxidative burst was measured by flow cytometry at 0 and 3 months after randomization. There was a linear relationship between inhibition of neutrophil activation in vitro and sirolimus concentrations spanning the therapeutic range (P=0.01). Neutrophil activation was decreased significantly in transplant recipients 3 months after switching from calcineurin inhibitors to sirolimus therapy (mean percentage change -24.4%; 95% confidence interval -7.5, -41.2%, P=0.009), but no changes were observed in patients who remained on calcineurin inhibitors.