Biopsy-confirmed Acute Rejection Episodes Research Articles

De-novo use of generic tacrolimus (Adoport) in renal transplant recipients: A single center experience from Türkiye

Objective: Renal transplantation is the best treatment for end-stage kidney disease, and tacrolimus has become an important immunosuppressive treatment for kidney transplant patients since it was introduced. After the first generic tacrolimus has been approved by the FDA, studies have begun to compare the effectiveness and safety of generic tacrolimus with the original tacrolimus. When using generic immunosuppressive therapies, it is also necessary to ensure that it provides adequate immunosuppression and does not cause severe toxicity. This study aims to compare clinical outcomes, including acute rejection, graft loss and adverse reactions, in patients receiving brand tacrolimus (Prograf, Astellas Pharma, U.S.) or generic tacrolimus (Adoport, Sandoz, UK) from the start of kidney transplant therapy. Study Design: Renal transplant recipients between 1 January 2015-1 March 2020 were screened retrospectively. All patients receiving de novo generic tacrolimus (n:51) and randomly selected 102 control renal transplant recipients receiving original tacrolimus were included in this study. Materials and Methods: We evaluated and recorded demographic, clinical and laboratory data including age, gender, primary kidney disease, donor type (live or dead), induction and death regimen, tacrolimus dose, tacrolimus through levels, serum creatinine, biopsy-confirmed acute rejection episodes, delayed transplant function, positive BK polyomavirus in the urine, BK polyomavirus-related nephropathy, cytomegalovirus infection in 1-year follow-up. Results: Most of the patients were male (64.1%) with a mean age of 38.3 years. There was no significant difference in demographic characteristics between the original and generic tacrolimus groups. No differences were found in terms of creatinine levels, total daily dose of tacrolimus and tacrolimus trough levels at discharge and the first year. Additionally, biopsy-confirmed acute rejection in the following year after transplantation, BKPyV positivity in urine, BKPyVAN, CMV viremia and adverse reactions related to tacrolimus were similar between the two groups. Conclusion: With this study, we aimed to contribute to the literature with our experience on the use of generic tacrolimus from our country. As a result of our study, we noted that generic tacrolimus can be safely preferred for de-novo use with close drug-level monitoring because it is an immunosuppressant agent with a narrow therapeutic index. There is a continuing need for randomized prospective-designed and multi-centric studies with a wide range of patients.

Regulatory cell therapy in kidney transplantation (The ONE Study): a harmonised design and analysis of seven non-randomised, single-arm, phase 1/2A trials

Use of cell-based medicinal products (CBMPs) represents a state-of-the-art approach for reducing general immunosuppression in organ transplantation. We tested multiple regulatory CBMPs in kidney transplant trials to establish the safety of regulatory CBMPs when combined with reduced immunosuppressive treatment. The ONE Study consisted of seven investigator-led, single-arm trials done internationally at eight hospitals in France, Germany, Italy, the UK, and the USA (60 week follow-up). Included patients were living-donor kidney transplant recipients aged 18 years and older. The reference group trial (RGT) was a standard-of-care group given basiliximab, tapered steroids, mycophenolate mofetil, and tacrolimus. Six non-randomised phase 1/2A cell therapy group (CTG) trials were pooled and analysed, in which patients received one of six CBMPs containing regulatory T cells, dendritic cells, or macrophages; patient selection and immunosuppression mirrored the RGT, except basiliximab induction was substituted with CBMPs and mycophenolate mofetil tapering was allowed. None of the trials were randomised and none of the individuals involved were masked. The primary endpoint was biopsy-confirmed acute rejection (BCAR) within 60 weeks after transplantation; adverse event coding was centralised. The RTG and CTG trials are registered with ClinicalTrials.gov, NCT01656135, NCT02252055, NCT02085629, NCT02244801, NCT02371434, NCT02129881, and NCT02091232. The seven trials took place between Dec 11, 2012, and Nov 14, 2018. Of 782 patients assessed for eligibility, 130 (17%) patients were enrolled and 104 were treated and included in the analysis. The 66 patients who were treated in the RGT were 73% male and had a median age of 47 years. The 38 patients who were treated across six CTG trials were 71% male and had a median age of 45 years. Standard-of-care immunosuppression in the recipients in the RGT resulted in a 12% BCAR rate (expected range 3·2-18·0). The overall BCAR rate for the six parallel CTG trials was 16%. 15 (40%) patients given CBMPs were successfully weaned from mycophenolate mofetil and maintained on tacrolimus monotherapy. Combined adverse event data and BCAR episodes from all six CTG trials revealed no safety concerns when compared with the RGT. Fewer episodes of infections were registered in CTG trials versus the RGT. Regulatory cell therapy is achievable and safe in living-donor kidney transplant recipients, and is associated with fewer infectious complications, but similar rejection rates in the first year. Therefore, immune cell therapy is a potentially useful therapeutic approach in recipients of kidney transplant to minimise the burden of general immunosuppression. The 7th EU Framework Programme.

Efficacy and Safety of Delayed Prolonged-Release Tacrolimus Initiation in De Novo Hepatitis C Virus-Negative Orthotopic Liver Transplant Recipients: A Single-Center, Single-Arm, Prospective Study.

BackgroundDelaying initiation of tacrolimus after liver transplantation (LT) is a potential renal-sparing strategy. We assessed safety and efficacy of delayed initiation of prolonged-release tacrolimus (PR-T) in de novo LT.Material/MethodsThis was a single-center, single-arm, prospective, 12-month observational study of hepatitis C virus-negative orthotopic LT patients. Immunosuppression included PR-T (initially 0.1 or 0.2 mg/kg/day) initiated on Day 3 post LT, basiliximab (20 mg) on post-transplantation Day 0 and Day 4, and intraoperative corticosteroids (500 mg). Patients received maintenance corticosteroids and mycophenolate mofetil (MMF) according to center protocol. MMF dose was adjusted according to thrombocyte count. The primary endpoint was the estimated glomerular filtration rate (eGFR) measured using the Modification of Diet in Renal Disease 4-variable formula at 12 months. Secondary endpoints included biopsy-confirmed acute rejection (BCAR) and dialysis requirement. Adverse events were recorded.ResultsSixty-nine patients (mean age 55.0 years) were included. Most patients started MMF on Day 1 (60.9%) or Day 2 (10.1%), and PR-T on Day 3 (55.1%) or Day 4 (29.0%). Mean tacrolimus trough levels (ng/mL) were: Day 7, 9.5±6.3; Day 10, 9.4±5.4; Month 1, 8.0±3.1; Month 3, 7.8±3.7; Month 6, 8.0±4.1; and Month 12, 7.2±3.1. Mean 12-month eGFR was 77.2±24.5 mL/min/1.73 m2; 72.5% of patients had eGFR >60 mL/min/1.73 m2 at 12 months; 89.9% had no eGFR measurements <40 mL/min/1.73 m2 during the study. Renal insufficiency (any eGFR <60 mL/min/1.73 m2) was diagnosed in 27.5% of patients; one patient required dialysis. There were no BCAR episodes; the infection rate was 36.2%, and 3 patients died. Overall, 19 patients (27.5%) developed de novo diabetes mellitus, 18 patients (26.1%) had hypercholesterolemia, and 12 patients (17.4%) had hypertriglyceridemia.ConclusionsQuadruple therapy with delayed administration of PR-T was well tolerated and efficacious, and was associated with acceptable renal function over 12 months.

Clinical and economic analysis of short-course versus standard-course antithymocyte globulin (rabbit) induction therapy in deceased-donor renal transplant recipients

The immunosuppressive effects of and costs associated with short-course antithymocyte globulin rabbit (ATG [rabbit]) therapy versus standard-course ATG (rabbit) therapy in deceased-donor renal transplant recipients were evaluated. The records of 84 consecutive patients who received a deceased-donor renal transplant at the Montefiore Einstein Center for Transplantation in 2008 were retrospectively reviewed. Donor and recipient characteristics, including rates of biopsy-confirmed acute rejection, serum creatinine (SCr) levels, and frequency of complications, and drug costs were collected. Patients were excluded if they had donor-specific antibodies identified before transplantation or hepatitis-C-positive serology or were under 18 years of age. A total of 60 patients were included in the study, with 28 receiving short-course ATG (rabbit) therapy and 32 receiving standard-course ATG (rabbit) therapy. Baseline patient demographic characteristics were similar between groups. Six months after transplantation, biopsy-confirmed acute rejection episodes did not significantly differ between the short-course ATG (rabbit) and standard-course ATG (rabbit) groups (17.8% versus 12.5%, respectively), nor did SCr concentrations (1.56 mg/dL versus 1.85 mg/dL). The frequency of therapy-related leukopenia was greater in patients receiving standard-course ATG (rabbit). Patients treated with short-course ATG (rabbit) received a total mean dose of 4.6 mg/kg, compared with 7.3 mg/kg for patients in the standard-course ATG (rabbit) group, resulting in a mean cost saving of $2548 per patient. After six months, there were no significant differences in biopsy- confirmed acute rejection episodes or SCr levels between deceased-donor renal transplant recipients receiving short-course versus standard-course ATG (rabbit) induction therapy. The mean cost saving associated with short-course therapy was $2548 per patient.

Advagraf De Novo in Liver Transplantation: A Single-Center Experience

Advagraf, a prolonged release formulation of tacrolimus, is administered once daily in the morning. The aim of this study was to show the results obtained in our center, analyzing the safety, efficacy, blood trough levels, and drug doses. Methods We analyzed 50 consecutive recipients of a first liver transplantation with 6 months follow-up. Efficacy and safety variables were collected as the incidence of acute rejection episodes, patient and graft survivals, kidney function as well as incidences of diabetes mellitus and arterial hypertension de novo. Results The incidence of biopsy proven acute rejection episodes was 10% ( n = 5), none 7 of which were steroid resistant and all resolved favorably. The rate of diabetes mellitus de novo was 22% ( n = 11), 7 of whom required insulin. Hypertension developed in 9 patients (18%), all of whom were treated with a single drug. The mean serum creatinine level was 1.08 ± 0.25 mg/dL, with 3 patients (6%) displaying a value ≥ 1.5 mg/dL. Patient and graft survivals were 100%. Conclusion Advagraf is an effective immunosuppressant in liver transplantation with a low incidence of biopsy-confirmed acute rejection episodes. The good results for patient and graft survival with few side effects make it a useful drug for de novo liver transplantation.

The Use of Explanted Internal Iliac Artery Grafts in Renal Transplants With Multiple Arteries

The use of renal allografts with multiple arteries is challenging, particularly with respect to live kidney donation. With an ongoing shortage of cadaveric organs available, live donor programs continue to be an increasingly important source of kidneys for transplantation. The prevalence of multiple renal arteries in some series is estimated between 18% and 30% and is believed to be bilateral in 15% of cases (1). Previously, multiple arteries were considered as a relative contraindication to live donation and renal transplantation; however, there is now increasing evidence that transplantation of kidneys with multiple arteries is safe with no significant increase in immediate or long-term complications (2–4). We present a series of seven cases where we have successfully used explanted recipient internal iliac artery grafts in live donor renal transplants with multiple arteries. The use of internal iliac artery grafts has been described before (4, 5); however, only small numbers have been reported as part of larger series and no consecutive series have been described. We describe a slightly different technique, which we have successfully reproduced in consecutive renal transplants with multiple arteries. Technique The operative bed is prepared in the usual manner. The internal iliac artery and suitable branches are dissected and then explanted from the recipient after clamping the main trunk of the vessel. On the back table, under cold storage conditions, the internal iliac graft can then be anastomosed to the renal allograft. The individual arteries are anastomosed end-to-end in turn to the branches of the explanted arterial graft over silastic catheters. The kidney is then implanted by reanastomosis of the internal iliac trunk to its parent main stem. Other similar techniques describe the use of end-to-side anastomosis with the external iliac artery rather than to parent internal iliac artery. Patients Seven kidneys of 41 retrieved from live donors by laparoscopic nephrectomy over a 10-month period had multiple arteries. Six of the renal allografts had two renal arteries and one had three arteries. All allografts had single vein and ureter. The mean follow-up was 149 days (range 53–277 days). Demographic details of the seven patients are shown in Table 1.TABLE 1: Patient and transplant demographicsNo intraoperative complications were reported. Table 1 shows the anastomotic and cold ischemic times. There were no immediate vascular complications, and, in all cases, recovery room Doppler ultrasound imaging reported good perfusion throughout the transplanted kidneys. Primary graft function was established in all cases. Since transplantation, two of the seven recipients reported ipsilateral buttock claudication. Neither of these patients had had the contralateral internal iliac artery used previously. One of the recipients has had hypertension that was difficult to control, requiring multiple anti-hypertensive medications. No urological complications have been documented since transplantation. There have been no biopsy-confirmed acute rejection episodes. Summary In summary, this series demonstrates that explanted internal iliac artery grafts can be used successfully to anastomose renal allografts with multiple renal arteries. The main advantage of the technique is that the difficult anastomosis of small vessels can be performed on the back table under hypothermic conditions, and there is no pressure on the surgeon to consider the anastomotic warm time at that point. This technique, literally, takes the heat out of a difficult operative situation. Louisa C. Firmin Michael L. Nicholson Department of Transplant Surgery Leicester General Hospital Leicester, United Kingdom

Conversion Therapy to Everolimus in Renal Transplant Recipients: Results After One Year

Background Two new diagnoses have been causing graft loss during long-term follow-up, namely, chronic nephropathy and anticalcineurinic toxicity. The advent of the mammalian target of rapamycin (m-TOR) obviates anticalcineurine toxicity and reduces posttransplant malignancy incidence with good inmunosuppressive potential. We examinated the renal and metabolic behavior in renal transplant recipients who required conversion from an anticalcineurinic (cyclosporine or tacrolimus) to an m-TOR inhibitor (everolimus) as part of their immunosuppressive maintenance therapy. Materials and Methods Twenty-one first renal transplant recipients had everolimus added to their inmunosuppressive therapy combined with an antimetabolite (mycophenolate mofetil or sodium mycophenolate). The mean age of the patients was 35 ± 17 years (range, 6 to 65). The prevalence of male recipients was 57%; the overall mean weight, 64 kg (range, 48 to 95). All patients were hispanic with 15 transplants from cadaveric donors (71%). The mean follow-up posttransplant was 18 months (range, 3 to 40) and the mean follow-up on everolimus, 10 months (range, 2 to 22). Results There was no mortality or graft loss, but there were 3 (17%) biopsy-confirmed acute rejection episodes. There were no significant changes in metabolic function pre- or postconversion. Regarding renal function, the mean creatinine serum showed a trend to decline: preconversion 1.7 mg/dL; postconversion 1.5 mg/dL. In 10 patients, it was possible to discontinue at least one antihypertensive medication (48%). Conclusions Everolimus was an effective medication to manage renal transplant patients. It produced metabolic stability and low myelotoxicity, despite combination with an antimetabolite (mycophenolic acid). Also, reduction of antihypertensive medications was an additional benefits for many patients.

Statins Benefit Outcomes of Renal Transplant Recipients on a Sirolimus-Cyclosporine Regimen

Background Statins offer a strategy to address dyslipidemia commonly experienced by immunosuppressed transplant recipients. Methods This single-center, retrospective study of 325 recipients (mean posttransplant follow-up of over 6 years; 75.0 ± 26.0 months) correlated four adverse outcomes—biopsy-confirmed acute rejection episodes, biopsy-confirmed chronic rejection/allograft nephropathy, graft loss, or death—with demographic and posttreatment variables. Patients were treated with a combination of sirolimus (SRL), cyclosporine (CsA), and various durations of steroids. Statins were prescribed for 259/325 (79%) recipients whose serum cholesterol exceeded 240 mg/dL and discontinued when the creatine phosphokinase increased fivefold (3.4%) or the liver function, threefold (3.0%) above normal. Results Upon univariate (hazard ratio [HR] 0.16; P < .001) and multivariate analysis (HR 0.38; P = .02), statins were markedly protective against acute rejection episodes. They reduced occurrence of chronic nephropathy/chronic rejection (HR 0.60; P = .03 and HR 0.52; P = .01, respectively). Incidences of graft loss were diminished (HR 0.26; P < .001 and HR 0.49; P = .01, respectively). Finally, the mortality rate was decreased (HR 0.21, P = .001 and HR 0.26, P = .01, respectively). Upon multivariate analysis, a reduced incidence of acute rejection was correlated with greater exposure to SRL (HR 0.78, P = .016) and CsA (HR 0.39; P = .006). Conclusions This study demonstrated compelling effects of statins against all adverse outcomes among patients treated with SRL-based, CsA-containing regimens. The profoundly dyslipidemic properties of SRL may explain these unique findings compared with previous studies on patients treated with CsA-based regimens.

A Single-dose Daclizumab Induction Protocol in Renal Allograft Recipients: A Chinese Single Center Experience

This study prospectively compared immunoprophylaxis with a single dose of daclizumab versus no induction in kidney transplant recipients treated with a cyclosporine, mycophenolate mofetil, and prednisone-based immunosuppression regimen seeking to observe the impact of a single-dose regimen for prevention of acute rejection among Chinese renal allograft recipients. A total of 118 renal transplant recipients were randomized into a daclizumab induction therapy group (daclizumab group, n = 58) and a no induction group (control group, n = 60). The daclizumab group received a single-dose (1 mg/kg of ideal body weight by intravenous infusion) 2 hours before the operation. There was no induction therapy in the control group. There was no significant difference in the baseline parameters at randomization between the two groups. The mean time to the first episode of acute rejection was 41.2 ± 3.2 days for the daclizumab group versus 11.2 ± 4.6 days for the control group. The number of first biopsy-confirmed acute rejection episodes during the 6-months after transplantation was significantly different in the daclizumab (7,12.1%) versus the control group (14,23.3%; P < .001). At the end of 12 months, patient and graft survivals were 100% in the groups with or without daclizumab. We noted that the incidence of infection, including serious infection was similar, in the daclizumab group to that in the control group, 17.2% and 20.0%, respectively. This study showed that a single-dose of daclizumab effectively prevented acute rejection in Chinese renal allograft recipients.

Comparative Study of Muromonab-CD3 (OKT3) Versus Daclizumab (Zenapax) in Cardiac Transplantation at Our Center

Recent studies support the addition of new immunosuppressive drugs as cytolytic induction therapy in cardiac transplantation. We carried out a comparative study comprising 52 patients who had undergone cardiac transplantation at our center. Thirty patients received muromonab-CD3 (OKT3, Janssen-Cilag, The Netherlands) as the induction therapy, whereas 22 patients received Daclizumab (Zenapax, Hoffman-La Roche, Nutley, NJ, USA) instead. All patients received cyclosporine or tacrolimus, mycophenolate, and steroids. Over an average follow-up period of 23.21 ± 18 months, we analyzed retrospectively the incidence of grade ≥3A biopsy-confirmed acute rejection episodes, the presence of infectious processes at 1 and 6 months, the occurrence of significant secondary effects, and the necessity to modify the immunosuppressive therapy during the follow-up. The results suggest that daclizumab is linked to a decreased incidence of grade ≥3A biopsy-confirmed acute rejection and to a reduced necessity to modify the immunosuppressive therapy during the medium-term follow-up.

Sirolimus (rapamycin) reduces the incidence of acute rejection episodes in renal transplantation: An initial experience in Taiwan

Background Acute rejection is the major cause of graft loss in renal transplantation. Sirolimus (rapamycin) inhibits the effects of cytokines on T and B cells; therefore, it provides prophylaxis against acute renal rejection. This open-label trial assessed the incidence of biopsy-confirmed acute rejection episodes, variation in renal function, as well as graft and patient survival rates up to 12 months posttransplantation when using sirolimus in combination with cyclosporine and prednisolone as immunosuppressants. Methods Ten kidney transplant recipients received sirolimus 2 mg daily after a 6-mg loading dose. Doses were then adjusted to keep the whole-blood trough level between 5 and 20 mg/mL. All patients received sirolimus in combination with cyclosporine and prednisolone. Results At 12 months after renal transplantation, the graft and patient survival rates were 90% and 90%, respectively. One patient died at 2 months due to sepsis with a functioning graft. The mean serum creatinine levels at 1, 3, and 6 months were 1.59 mg/dL, 1.71 mg/dL, and 1.65 ml/dL, respectively. There was no biopsy-confirmed acute rejection episode within 12 months. Conclusions Sirolimus in combination with cyclosporine and prednisolone significantly protected kidney transplant recipients from acute rejection for up to 1 year of follow-up.

Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification.

The incidence of acute humoral rejection (AHR) in renal allograft biopsies has been difficult to determine because widely accepted diagnostic criteria have not been established. C4d deposition in peritubular capillaries (PTC) of renal allografts has been proposed as a useful marker for AHR. This study was designed to test the relative value of C4d staining, histology, and serology in the diagnosis of AHR. Of 232 consecutive kidney transplants performed at a single institution from July 1995 to July 1999, all patients (n = 67) who developed acute rejection within the first 3 mo and had a renal biopsy with available frozen tissue at acute rejection onset, as well as posttransplant sera within 30 d of the biopsy, were included in this study. Hematoxylin and eosin and periodic acid-Schiff stained sections were scored for glomerular, vascular, and tubulointerstitial pathology. C4d staining of cryostat sections was done by a sensitive three-layer immunofluorescence method. Donor-specific antibodies (DSA) were detected in posttransplant recipient sera using antihuman-globulin-enhanced T cell and B cell cytotoxicity assays and/or flow cytometry. Widespread C4d staining in PTC was present in 30% (20 of 67) of all acute rejection biopsies. The initial histologic diagnoses of the C4d(+) acute rejection cases were as follows: AHR only, 30%; acute cellular rejection (ACR) and AHR, 45%; ACR (CCTT types 1 or 2) alone, 15%; and acute tubular injury (ATI), 10%. The distinguishing morphologic features in C4d(+) versus C4d(-) acute rejection cases included the following: neutrophils in PTC, 65% versus 9%; neutrophilic glomerulitis, 55% versus 4%; neutrophilic tubulitis, 55% versus 9%; severe ATI, 75% versus 9%; and fibrinoid necrosis in glomeruli, 20% versus 0%, or arteries, 25% versus 0%; all P < 0.01. Mononuclear cell tubulitis was more common in the C4d(-) group (70% versus 100%; P < 0.01). No significant difference between C4d(+) and C4d(-) acute rejection was noted for endarteritis, 25% versus 32%; interstitial inflammation (mean % cortex), 27.2 +/- 27% versus 38 +/- 21%; interstitial hemorrhage, 25% versus 15%; or infarcts, 5% versus 2%. DSA were present in 90% (18 of 20) of the C4d(+) cases compared with 2% (1 of 47) in the C4d(-) acute rejection cases (P < 0.001). The pathology of the C4d(+) but DSA(-) cases was not distinguishable from the C4d(+), DSA(+) cases. The C4d(+) DSA(-) cases may be due to non-HLA antibodies or subthreshold levels of DSA. The sensitivity of C4d staining is 95% in the diagnosis of AHR compared with the donor-specific antibody test (90%). Overall, eight grafts were lost to acute rejection in the first year, of which 75% (6 of 8) had AHR. The 1-yr graft failure rate was 27% (4 of 15) for those AHR cases with only capillary neutrophils versus 40% (2 of 5) for those who also had fibrinoid necrosis of arteries. In comparison, the 1-yr graft failure rates were 3% and 7%, respectively, in ACR 1 (Banff/CCTT type 1) and ACR 2 (Banff/CCTT type 2) C4d(-) groups. A substantial fraction (30%) of biopsy-confirmed acute rejection episodes have a component of AHR as judged by C4d staining; most (90%), but not all, have detectable DSA. AHR may be overlooked in the presence of ACR or ATI by histology or negative serology, arguing for routine C4d staining of renal allograft biopsies. Because AHR has a distinct therapy and prognosis, we propose that it should be classified separately from ACR, with further sub-classification into AHR 1 (neutrophilic capillary involvement) and AHR 2 (arterial fibrinoid necrosis).

Sirolimus and ciclosporin for renal transplantation

Rapamycin was isolated from fungi found in soil samples brought from Rapa Nui (Easter Islands) by the Canadian Medical Research Expedition (December, 1964, to February, 1965). But despite being discovered at about the same time as ciclosporin, 1 Borel JF Feurer C Gubler HJ Stahelin H Biological effects of cyclosporin A: a new antilymphocytic agent. Agents and Actions. 1976; 6: 468-475 Crossref PubMed Scopus (1199) Google Scholar rapamycin, which was initially noted to have antifungal properties, 2 Vézina C Kudelski A Sehgal SN Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 1975; 28: 721-726 Crossref PubMed Scopus (1266) Google Scholar , 3 Sehgal SN Baker H Vézina C Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J Antibiot (Tokyo). 1975; 28: 727-732 Crossref PubMed Scopus (812) Google Scholar took nearly two decades longer to be developed as an immunosuppressive agent. The pivotal clinical trial of rapamycin in renal transplantation reported by Barry Kahan and colleagues in this issue of The Lancet highlights many novel features of this drug. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre studyUse of sirolimus reduced occurrence and severity of biopsy-confirmed acute rejection episodes with no increase in complications. Further studies are needed to establish the optimum doses for the combined regimen. Full-Text PDF

Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study

Acute rejection episodes after renal transplantation are an important clinical challenge, despite use of multidrug immunosuppressive regimens. We did a prospective, multicentre, randomised, double-blind trial to investigate the impact of the addition of sirolimus, compared with azathioprine, to a cyclosporin and prednisone regimen. 719 recipients of primary HLA-mismatched cadaveric or living-donor renal allografts who displayed initial graft function were randomly assigned, after transplantation, sirolimus 2 mg daily (n=284) or 5 mg daily (n=274), or azathioprine (n=161). We assessed the primary composite endpoint of efficacy failure, occurrence of biopsy-confirmed acute rejection episodes, graft loss, or death, and various secondary endpoints that characterise these episodes at 6 months and 12 months. Analyses were done by intention to treat. The rate of efficacy failure at 6 months was lower in the two sirolimus groups (2 mg 18.7%, p=0.002; 5 mg 16.8%, p<0.001) than in the azathioprine group (32.3%). The frequency of biopsy-confirmed acute rejection episodes was also lower (2 mg 16.9%, p=0.002; 5 mg 12.0%, p<0.001; azathioprine 29.8%). At 12 months, survival was similar in all groups for grafts (97.2%, 96.0%, and 98.1%) and patients (94.7%, 92.7%, and 93.8%). Patients on sirolimus showed a delay in the time to first acute rejection episode and decreased frequency of moderate and severe histological grades of rejection episodes and related antibody treatment, compared with the azathioprine group. Rates of infection and malignant disorders were similar in all groups. Use of sirolimus reduced occurrence and severity of biopsy-confirmed acute rejection episodes with no increase in complications. Further studies are needed to establish the optimum doses for the combined regimen.

Screening for basiliximab exposure–response relationships in renal allotransplantation

The immunosuppressant basiliximab--a chimeric monoclonal antibody specific to the interleukin-2 receptor on activated T-lymphocytes--significantly reduces the incidence of acute cellular rejection following renal transplantation. Screening for exposure-response relationships was performed within a randomized, blinded, placebo-controlled efficacy trial in which patients received 40 mg basiliximab (20 mg on days 0 and 4) by intravenous infusion in addition to cyclosporine and corticosteroids. In a subset of patients, serum samples were collected pre-transplant and once in weeks 2, 3 and 4 for determination of basiliximab concentrations. A population pharmacostatistical model was used to derive individual empirical Bayes estimates of each patient's pharmacokinetic parameters. Biopsy-confirmed acute rejection episodes were recorded to month 6 post-transplant. Forty basiliximab-treated patients were evaluated, 30 men and 10 women, aged 48 +/- 12 yr (range, 24-73) and weighing 72.4 +/- 12.9 kg (range, 52.5-107.5). The basiliximab distribution volume was 7.5 +/- 1.7 L, the half-life 7.5 +/- 2.5 d and the clearance 33 +/- 12 mL/h. There was no clinically relevant influence of weight, age, or gender on basiliximab disposition. Receptor-saturating serum basiliximab concentrations (> 0.2 microgram/mL) were maintained for 41 +/- 23 d. Twenty-five patients remained rejection-free over the 6-month observation period, while a total of 26 biopsy-confirmed acute rejection episodes occurred in the remaining 14 patients. Of these episodes, 12 occurred during receptor blockade. No apparent relationship to basiliximab concentration on the day of onset was observed range, 0.1-9.0 microgram/mL) nor did the time of suppression offset represent a period of increased risk for rejection episodes. Fourteen rejection episodes occurred after basiliximab had cleared from the serum. The durations of receptor suppression preceding these events did not differ compared with those in patients who remained rejection-free: 32 +/- 11 versus 45 +/- 26 d, respectively (p = 0.1269). Given the durations of receptor saturation achieved with the chosen basiliximab regimen, this screen for exposure-response relationships did not identify the duration of receptor saturation in peripheral blood as a predictive factor for acute rejection episodes. Further exploration for exposure-effect relationships in a larger population is warranted.

Basiliximab.

The chimaeric monoclonal antibody basiliximab specifically binds the alpha subunit of the interleukin-2 (IL-2) receptor on activated T lymphocytes. Through competitive antagonism of IL-2, basiliximab supplements standard immunosuppressive therapy after renal transplantation. < or =24 Hours after a single intravenous dose of basiliximab 2.5 to 25 mg, approximately 90% of available IL-2 receptors on T lymphocytes were complexed with the drug. This level of basiliximab binding was maintained for 4 to 6 weeks when renal transplant patients received basiliximab 20 mg 2 hours before and then 4 days after transplantation surgery. In 2 large, well-designed trials, the percentage of patients with biopsy-confirmed acute rejection episodes after renal transplantation was significantly lower with basiliximab 20 mg (administered 2 hours before and then 4 days after transplantation surgery; 30 or 33%, respectively) than placebo (44 or 46%) at 6 months after surgery. Basiliximab was well tolerated during clinical trials. The incidence of infections (including active cytomegalovirus infection) and post-transplant lymphoproliferative disorders was similar with basiliximab and placebo. Cytokine release syndrome was not observed in patients who received basiliximab.