Sirolimus and mycophenolate mofetil as calcineurin inhibitor-free immunosuppression in a cardiac transplant patient with chronic renal failure.

Chronic renal failure triggered by calcineurin inhibitor (CNI)-based immunosuppression is a common complication after cardiac transplantation. Sirolimus and mycophenolate mofetil (MMF) are 2 newer immunosuppressive agents with no documented nephrotoxic side effects. This case report describes a patient with ongoing chronic renal failure 10 months after cardiac transplantation on cyclosporine-based immunosuppressive therapy. Conversion of the immunosuppressive regimen from cyclosporine to sirolimus and MMF resulted in freedom from acute rejection, excellent cardiac graft function and consistently improved renal function. This case illustrates the beneficial potential of sirolimus and MMF as CNI-free and safe long-term immunosuppression in a patient with chronic renal failure after heart transplantation.     

Correlation between human leukocyte antigen antibody production and serum creatinine in patients receiving sirolimus monotherapy after Campath-1H induction

BACKGROUND: In this study, we determined whether Campath-1H induction followed by sirolimus monotherapy inhibited alloantibody production in renal transplantation. Second, we evaluated the correlation between human leukocyte antigen (HLA) antibody production and serum creatinine levels. METHODS: Sera were taken 1 to 24 months after transplantation from 24 patients treated with Campath-1H and sirolimus and tested for serum creatinine and HLA-specific antibody by using flow cytometry and enzyme-linked immunosorbent assay. RESULTS: Ten (42%) of the 24 patients treated with Campath-1H and sirolimus produced HLA antibodies. Six of these 10 developed both donor-specific antibodies (DSAs) and non-donor-specific antibodies (NDSAs), whereas only NDSAs were detected in the other four patients. In patients with biopsy-diagnosed humoral rejection (C4d+), serum levels of both DSA and NDSA significantly correlated with patient serum creatinine levels. Rejection treatment successfully reduced both DSAs and NDSAs and reversed humoral rejection. CONCLUSIONS: The numeric relationship between serum creatinine and DSA levels suggests a causal relationship between alloantibody and transplant rejection.     

Living-related donor renal transplantation in HIV+ recipients using alemtuzumab preconditioning and steroid-free tacrolimus monotherapy: a single center preliminary experience

BACKGROUND: End-stage renal disease (ESRD) is an increasing problem in patients infected with the human immunodeficiency virus (HIV). The use of highly active antiretroviral therapy (HAART) has decreased the morbidity associated with HIV and has prompted renewed interest in renal transplantation. METHODS: We performed four cases of deceased donor renal transplantation in HIV+ recipients and three cases where laparoscopic live donor nephrectomy (LLDN) was utilized to obtain the kidney for transplantation into living-related HIV+ recipients. In the four deceased donor cases, conventional tacrolimus-based immunosuppression, without antibody induction was used. In the three living-related cases, the immunosuppressive regimen was based on two principles: recipient pretreatment and minimal posttransplant immunosuppression. Alemtuzumab 30 mg (Campath 1-H) was used for preconditioning followed by low-dose tacrolimus monotherapy. RESULTS: Of the four deceased donor cases, one patient continues to have good graft function, and another is not yet on dialysis but has significant graft dysfunction. Rejection was observed in three patients (75%). Infectious complications occurred in one patient (25%), all non-acquired immunodeficiency syndrome (AIDs) defining. In the three living-related cases, all had good graft function, and none have experienced acute rejection. HIV viral loads remain undetectable. CD4 counts are slowly recovering. No infectious or surgical complications occurred. There were no deaths in either group. CONCLUSIONS: These data suggest that living-related donor renal transplantation with steroid-free tacrolimus monotherapy in a "tolerogenic" regimen can be efficacious. However, long-term follow-up is needed to confirm this observation.     

Campath-1H Induction Plus Rapamycin Monotherapy for Renal Transplantation: Results of a Pilot Study

Campath-1H, an anti-CD52 monoclonal antibody, was used as induction therapy (40 mg i.v. total dose) in 29 primary human renal transplants, and the patients were maintained on rapamycin monotherapy (levels 8-15 ng/mL) post-transplant. Campath-1H profoundly depletes lymphocytes long-term and more transiently depletes B cells and monocytes. All patients are alive and well at 3-29 months of follow up. One graft was lost because of rejection. There have been no systemic infections and no malignancies. Eight of 29 patients have experienced rejection, which was successfully treated in seven of eight patients. Five of these patients had pathological evidence of a humoral component of their rejection. Seven of the 29 patients were converted to standard triple therapy on account of rejection. Rapamycin was generally well tolerated in that there were no significant wound-healing problems; two lymphoceles required surgical drainage; and most patients were treated with a lipid-lowering agent. Flow crossmatch testing post-transplant revealed evidence of alloantibody in two patients tested with previous combined cellular and humoral rejection. Biopsies have shown no chronic allograft nephropathy to date. In view of the relatively high incidence of early humoral rejection, we plan to modify the immunosuppressive regimen in subsequent pilot studies. This clinical trial provides insight into the use of Campath-1H induction in combination with rapamycin maintenance monotherapy.     

Steroid-free tacrolimus monotherapy after pretransplantation thymoglobulin or Campath and laparoscopy in living donor renal transplantation

Living donor renal transplantation was performed under a regimen of recipient pretreatment and low-dose postoperative immunosuppression with subsequent weaning. From October 9, 2002, to December 31, 2004, 196 consecutive, unselected laparoscopic live donor nephrectomies resulting in 196 living donor renal transplantations were performed. Recipients were pretreated with rabbit antithymocyte globulin (thymoglobulin; 24 patients or [12%]) or Campath 1H (alemtuzumab; 166 patients [85%]), or were not in protocol (6 patients [3%]), and were given postoperative steroid-free low-dose tacrolimus immunosuppressive monotherapy with subsequent weaning. There was no donor mortality. Major and minor donor morbidities were 2.6% and 4.2%, respectively. Laparoscopic live donor nephrectomy recipient outcomes with a mean follow-up of 401 days included (1) recipient and graft survival of 99.0% and 97.4%, respectively; (2) no ureteral stenosis; (3) 0.5% delayed graft function, from recurrent focal segmental glomerulosclinosis; and (4) no vascular thrombosis. The incidence of acute rejection at 30, 90, and 401 days was 1.5%, 3.8%, and 11.2% (all 196 recipients), 0%, 25%, and 29.2% (thymoglobulin recipients), and 1.8%, 3.9%, and 8.4% (Campath 1H recipients), respectively. Sixty-six patients (33.7%) are receiving spaced-dose immunosuppressive monotherapy. The mean creatinine concentration in all recipients was 1.5 +/- 1.1 mg/dL. There were no instances of cytomegalovirus tissue invasive disease or posttransplantation lymphoproliferative disease. The incidence of new-onset posttransplantation insulin-dependent diabetes was 0.5%. At current follow-up, the use of Campath 1H rather than thymoglobulin for pretreatment seems to have significantly improved the efficacy of our regimen.     

Intestinal transplantation before and after the introduction of sirolimus

INTRODUCTION: Small bowel transplantation has been limited by high rates of rejection and graft loss. In June 2000, we began using sirolimus, an immunosuppression agent with proven efficacy in kidney transplantation. We reviewed results among intestinal transplant recipients before and after the introduction of sirolimus. METHODS: Thirty-one intestinal transplants were performed in 29 patients at our center between July 1998 and April 2001. All patients were followed for at least 30 days posttransplant. In the first 19 transplants (group 1), patients received tacrolimus, steroids, and antibody induction therapy (either daclizumab or OKT3). In the next 12 consecutive transplants (group 2), patients received tacrolimus, steroids, basiliximab, and sirolimus. RESULTS: Eighteen children (7 males and 11 females, mean age 2.1+/-2.2 years) and 11 adults (9 males and 2 females, mean age 38.1+/-12.4 years) underwent transplantation. All patients survived transplantation. The overall reoperation rate was 1.7 procedures per patient in group 1 and 1.1 procedures per patient in group 2. The most common indications were abscess (n=7), planned second look (n=7), leaks/fistulas (n=6), dehiscence (n=6), obstruction (n=4), ischemic bowel (n=3), perforations (n=3), stomal complications (n=3), and graft removal (n=3). The incidence of biopsy-proven rejection in the first 30 days was 73.7% in group 1 and 16.7% in group 2 (P<0.002). Sirolimus was temporarily held or discontinued in 66.7% of patients. Actuarial 1-year graft survival was 91.7% with sirolimus and 57.9% without sirolimus (P<0.04). Actuarial 1-year patient survival was 91.7% with sirolimus and 79% without sirolimus (P=0.12). CONCLUSIONS: An immunosuppressive regimen that includes sirolimus has improved graft survival. Furthermore, this regimen has significantly decreased the incidence of early rejection and has eliminated early graft loss caused by fulminant rejection.     

亲属活体供肾移植与尸体供肾移植的临床疗效比较

目的比较HLA配型和免疫抑制方案相同情况下亲属活体供肾移植与尸体供。肾移植的临床效果。方法对12例亲属活体供肾移植供、受者的临床资料进行回顾性分析，并与22例同期进行的、HLA配型情况相近的尸体供肾移植的临床资料进行对比，分析各组术后人／肾1年及3年存活率、1年内急性排斥反应发生率及3年内的。肾功能。结果12例供者均无手术并发症，术后肾功能正常，生活及工作未受明显影响。术后1年内的急性排斥反应发生率，亲属活体供。肾组和尸体供。肾组分别为16．7％和22．7％（P〈0．05）；人／肾1年和3年存活率，亲属活体供肾组分别为100％（12／12）／91．7％（11／12）和91．7％（11／12）／83．3％（10／12），尸体供。肾组分别为100％（22／22）／90．9％（20／22）和95．4％（21／22）／86．4％（19／22），两组比较，差异无统计学意义（P〉0．05）；3年内的。肾功能，亲属活体供肾移植组明显优于尸体供肾移植组（P〈0．05）。结论在HLA配型和免疫抑制方案相同的情况下，亲属活体供。肾移植的临床效果优于尸体供。肾移植。     

BK Nephropathy in Kidney Transplant Recipients Treated with a Calcineurin Inhibitor-Free Immunosuppression Regimen

Recently, polyomavirus-associated nephropathy (PVAN) has been reported more frequently and is emerging as an important cause of renal allograft dysfunction and graft loss. Susceptibility appears to be related to the type and intensity of pharmacologic immunosuppression but some reports have suggested a link among the development of PVAN, the treatment of rejection or maintenance with a tacrolimus-based immunosuppressive regimen. We report three cases of PVAN in patients who never received immunosuppression with calcineurin inhibitors (CNIs). Two patients received induction immunosuppression consisting of an IL-2 receptor antagonist while 1 received thymoglobulin. These 3 patients were maintained on prednisone, sirolimus and mycophenolate mofetil (MMF) and none was treated for rejection. All three patients presented with an elevated serum creatinine and demonstrated polyomavirus infection on biopsy and by blood PCR. These cases demonstrate that, unlike reports linking tacrolimus and PVAN, polyomavirus infection may develop in patients maintained on CNI-free immunosuppressive regimens and have not had episodes of rejection.     

Sequential quadruple immunosuppression including sirolimus in extended criteria and nonheartbeating donor kidney transplantation

The aim was to evaluate feasibility and safety of calcineurin inhibitor-free immunosuppression in high-risk donor kidney transplantation with sequential sirolimus introduction. Kidney transplant patients (n=76) with a donor aged >60 years, donor with acute renal failure, or a nonheartbeating donor were included. Immunosuppression consisted of antithymocyte globulin or basiliximab, mycophenolate mofetil, prednisone, and sequential introduction of sirolimus. One-year patient survival was 96.2% and 95.8%; graft survival was 94.2% and 91.7%; acute rejection rates were 21.2% and 12.4%; delayed graft function was 21.2% and 66.7%; and creatinine clearance was 58+/-20 mL/min and 56+/-21 mL/min for the brain-dead donor group and the nonheartbeating donor group, respectively. Most adverse events were infections, but also three lymphoceles, three urinary fistulas, three wound seromas. Sequential sirolimus introduction in high-risk donor kidney transplantation was found to lead to good patient and graft survival and incidence of acute rejection and delayed graft function.     

Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients

Calcineurin inhibitor (CNI) nephrotoxicity is a major concern after renal transplantation. To investigate the safety and efficacy of a CNI-free immunosuppressive regimen, 132 live-donor renal transplant recipients were included in a prospective, randomized controlled trial. All patients received induction therapy with basiliximab and steroids. The patients were randomized to a maintenance immunosuppression regimen that included steroids, sirolimus, and either low-dose tacrolimus or mycophenolate mofetil (MMF). Over a mean follow-up period of approximately 5 yr, patient and graft survival did not significantly differ between the two maintenance regimens. Patient survival was 93.8% and 98.5% in the tacrolimus/sirolimus and MMF/sirolimus groups, respectively, and graft survival was 83% and 88%, respectively. However, the MMF/sirolimus group had significantly better renal function, calculated by Cockcroft-Gault, from the second year post-transplant until the last follow-up. In addition, this group was less likely to require a change in their primary immunosuppression regimen than the tacrolimus/sirolimus group (20.8% versus 53.8%, P = 0.001). The safety profile was similar between groups. In summary, after long-term follow-up, a CNI-free maintenance regimen consisting of sirolimus, MMF, and steroids was both safe and efficacious among low to moderate immunologic risk renal transplant recipients.     

Campath-1H (alemtuzumab) as an induction agent for the prevention of graft rejection and preservation of renal function in kidney transplant patients: Philippine 3-year follow-up

OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of induction with Campath-1H with low-dose cyclosporine (CsA) monotherapy using outcome measures of acute rejection episodes (ARE), chronic allograft nephropathy (CAN), graft and patient survivals, as well as malignancies and infections. MATERIALS AND METHODS: Fourteen kidney transplant recipients were randomized to receive either Campath 1H induction with CsA monotherapy (9 patients) or immunosuppression with CsA, azathioprine, and steroids (5 patients). Campath (20 mg IV) was administered within 6 hours after the anastomosis and repeated 24 hours later. Cyclosporine was started 72 hours after the first Campath dose (10 mg/kg on the first day, then 4 mg/kg/d), seeking to achieve target trough CsA levels of 90 to 110 ng/mL. This is a 3-year follow-up of the 9 patients who received Campath-1H induction. RESULTS: Six of 9 (67%) patients developed ARE (borderline ARE to Banff IB) in the Campath group compared with 1 of 5 (20%) in the other group (ARE Banff IIA). They all received methylprednisolone for 3 days with good responses. One of the 6 patients in the Campath group with ARE also displayed CAN and was converted to sirolimus; 2 others had mycophenolate mofetil and steroids added to their immunosuppression after the ARE. Creatinine levels ranged from 1 to 1.7 mg/dL at 24 to 36 months posttransplantation in both groups. Among the Campath group, 1 patient died 6 months posttransplantation with sepsis secondary to infectious diarrhea. Upper respiratory tract infections comprised the majority of infections at 24 to 36 months. No malignancies were observed. CONCLUSIONS: Three years posttransplantation, patients given Campath induction with CsA monotherapy showed a greater incidence of ARE, although renal function remained comparable to CsA-azathioprine-prednisone therapy. AREs were easily reversed with steriods. Infections were minor.     

Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36months after transplantation

Early conversion to a calcineurin‐inhibitor (CNI)‐free maintenance immunosuppression with sirolimus (SRL), mycophenolate mofetil (MMF) and steroids was associated with an improved 1‐year renal function as compared with a cyclosporine (CsA)‐based regimen (SMART core‐study). This observational follow‐up describes 132 patients followed up within the SMART study framework for 36 months. At 36 months, renal function continued to be superior in SRL‐treated patients [ITT‐eGFR_@36m: 60.88 vs. 53.72 (CsA) ml/min/1.73 m², P = 0.031]. However, significantly more patients discontinued therapy in the SRL group 59.4% vs.42.3% (CsA). Patient [99% (SRL) vs.97% (CsA) and graft 96% (SRL) vs.94% (CsA)] survival at 36 months was excellent in both arms. There was no difference in late rejection episodes. Late infections and adverse events were similar in both arms except of a higher rate of hyperlipidemia in SRL and a higher incidence of malignancy in CsA‐treated patients. In a multivariate analysis, donor age >60 years, S‐creatinine at conversion >2 mg/dl, CMV naïve(‐) recipients and immunosuppression with CsA were predictive of an impaired renal function at 36 months. Early conversion to a CNI‐free SRL‐based immunosuppression is associated with a sustained improvement of renal function up to 36 months after transplantation. Patient selection will be key to derive long‐term benefit and avoid treatment failure using this mTOR‐inhibitor‐based immunosuppressive regimen.     

Late conversion of tacrolimus to sirolimus in a prednisone‐free immunosuppression regimen in renal transplant patients

Chhabra D, Grafals M, Cabral B, Leventhal J, Parker M, Gallon L. Late conversion of tacrolimus to sirolimus in a prednisone‐free immunosuppression regimen in renal transplant patients.
Clin Transplant 2009: DOI: 10.1111/j.1399‐0012.2009.01047.x
© 2009 John Wiley & Sons A/S. Abstract: Background: One of the most important causes of graft loss is chronic nephrotoxicity from calcineurin inhibitors. The aim of this study was to evaluate the feasibility and to assess the impact on rejection risk, graft loss and renal allograft function of converting patients from tacrolimus (Tac) to sirolimus (SRL) at one yr post‐transplantation (Tx) using a prednisone‐free immunosuppressive regimen. Methods: Two hundred fifty‐five kidney transplant patients were induced with Alemtuzumab and maintained on a steroid‐free regimen with Tac and mycophenolate mofetil. Thirty‐seven stable patients (14%) were converted from Tac to SRL at one yr post‐Tx. Results: The two groups were demographically similar. Mean post‐tx follow‐up was 2.8 ± 0.2 yr. Patient and graft survival were not statistically different. There was no significant difference in acute rejection episodes between the SRL and Tac groups (21% vs. 15%, p = 0.2). Calculated glomerular filtration rate (GFR), in the SRL group at 2.8 yr post‐tx, was 69 ± 13 mL/min from the one month post‐tx GFR of 53 ± 19 and 59 ± 23 mL/min from the one month post‐tx GFR of 56 ± 21 mL/min in the Tac group. Conclusions: Using a prednisone‐free regimen, the conversion of Tac to SRL at one yr post‐Tx was not associated with an increased risk of acute rejection or graft loss.     

Sirolimus in kidney transplantation from marginal donors

Nephrotoxicity caused by calcineurin inhibitors can lead to either delayed graft function or long-term decline of renal function after kidney transplantation. Therefore, recipients of renal transplants from marginal donors require non-nephrotoxic immunosuppression. Eighteen patients received kidney transplants from marginal donors, with a calcineurin inhibitor-free immunosuppressive regimen, based on basiliximab, mycophenolate mofetil, steroids, and sirolimus. Renal graft biopsy was performed in all cases before surgery. Mean follow-up was 11.8 months. We report immediate renal function in 9 patients, delayed graft function in 5 and acute tubular necrosis in 4 patients. One patient was successfully treated for biopsy-proven acute rejection. Hypercholesterolemia and hypertriglyceridemia were the most common adverse effects (n = 13) associated with arthralgia (n = 2) and thrombocytopenia (n = 2). Five patients underwent a switch to tacrolimus, due to sirolimus-induced side effects. Immunosuppression without the use of calcineurin inhibitors is a safe and effective regimen in kidney transplantation, although sirolimus-related side effects still represent a morbidity factor in these patients.     

Campath-1H诱导在小肠移植免疫抑制中的作用

目的探讨Campath-1H诱导在小肠移植免疫抑制中的作用。方法回顾性总结1例小肠移植患者的临床资料。结果术中采用Campath-1H静脉注射诱导,术后予以FK506加MMF加激素三联免疫抑制方案。Campath-1H诱导后淋巴细胞及白细胞数目明显减少．经提升白细胞治疗和调整免疫抑制剂用量后逐渐恢复正常。术后早期,患者未发生急性排斥反应及移植物抗宿主病（GVHD）,无严重感染症状,患者顺利渡过围手术期,康复出院。结论Campath-1H术中诱导．术后小剂量FK506加MMF加激素三联免疫抑制方案．可有效控制小肠移植术后早期排斥反应和GVHD的发生。     

Immunosuppression minimization protocols: how should they be monitored?

This Practice Point commentary discusses the experience of Shapiro et al. with renal allograft recipients at a single center who underwent significant minimization of immunosuppressive treatment with alemtuzumab induction and tacrolimus monotherapy (weaned to three times weekly by 1 year after transplantation). Donor-specific antibodies (DSAs) against human leukocyte antigen were monitored after transplantation in some patients. Although 44% of patients did not develop acute rejection or DSAs and had excellent 2-year graft survival (96%), spaced weaning was not attempted in 20% of patients, generally those with early rejection and poor allograft function. During tapering, 20% of patients developed acute rejection and 15% developed DSAs. Two-year graft survival was 63% in patients for whom weaning was not attempted and 78% in patients who experienced acute rejection. Alemtuzumab preconditioning with tacrolimus monotherapy and spaced weaning increased the risk of acute rejection and development of DSAs. Patients should be carefully selected for this protocol and monitored closely for DSAs. Results of a long-term controlled trial that includes protocol biopsies are required to reach more-definitive conclusions.     

Alemtuzumab Induction and Prednisone-Free Maintenance Immunotherapy in Kidney Transplantation: Comparison with Basiliximab Induction—Long-Term Results

This study examined alemtuzumab (anti-CD 52, Campath-1H) and basiliximab (anti-CD 25, Simulect) as induction immunosuppression in kidney transplantation. We used a single-center, nonrandomized, retrospective, sequential study design to evaluate outcomes in kidney transplant recipients given either alemtuzumab (n = 123) or basiliximab (n = 155) induction in combination with a prednisone-free maintenance protocol using tacrolimus and mycophenolate mofetil. Kaplan-Meier analyses of long-term patient and graft survivals and rejection rates were determined according to induction agent, donor source and recipient ethnicity. Secondary endpoints included the quality of renal allograft function and the etiology of infectious complications. Overall long-term patient and graft survival rates did not significantly differ between patients treated with alemtuzumab and basiliximab. A lower rate of early (<3 months) rejection was observed in the alemtuzumab (4.1%) versus the basiliximab (11.6%) group, but the rates for both groups were equivalent at 1 year. Patient and kidney survival and rejection rates were nearly identical between Caucasians and African Americans that received alemtuzumab. Quality of renal function and incidence of infectious complications were similar in the two groups. Alemtuzumab induction therapy was similar in efficacy to basiliximab in a prednisone-free maintenance immunosuppressive protocol for an ethnically diverse population of kidney transplant recipients.     

A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 1 year

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.     

Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation

BACKGROUND: The adoption of calcineurin inhibitors (CNI) as the mainstay of immunosuppression has resuited in a significant decrease of acute rejection and improvement of short-term graft survival. However, because of the irreversible nephrotoxicity associated with the chronic use of the CNI, the magnitude of the improvement of long-term graft survival has been more modest. Therefore, an effective immunosuppression regimen that does not rely on CNI may result in improvement of long-term outcome and simplification of the management of transplant recipients. METHODS: Ninety-eight patients of primary cadaver or living donor kidneys at low immunologic risk were enrolled in a CNI avoidance study. The immunosuppression regimen consisted of daclizumab, a humanized monoclonal antibody that binds to the alpha chain of the interleukin-2 receptor (IL-2Ralpha), administered for a total of five doses at biweekly intervals; 3 gm/day mycophenolate mofetil for the first 6 month and 2 gm thereafter; and conventional corticosteroid therapy. Patients who underwent rejection episodes could be started on CNI. The primary efficacy end-point was biopsy-proven rejection during the first 6 months posttransplant. RESULTS: Biopsy-proven rejection was diagnosed in 48% of patients during the first 6 months after transplantation. The majority of rejection episodes were Banff grade I and IIA and were fully reversed with corticosteroid therapy. The median time to the first biopsy-proven rejection among patients who experienced this event during the first 6 months was 39 days. In 22 patients with delayed graft function, the proportion of patients with biopsy-proven rejection was 50% at 6 months. However in the first 2 weeks posttransplant, only 1 of 22 patients with delayed graft function developed biopsy-proven rejection. At 1 year, patient survival was 97% and graft survival was 96%. Only two grafts were lost secondary to rejection. At 1-year posttransplant, 62% of patients had received CNI for more than 7 days. At 1-year posttransplant, the mean serum creatinine in the nonrejectors with no CNI use was 113 micromol/L (95%, confidence interval [CI], 100.7 to 125.3 micromol/L) and in the rejectors or patients with CNI use (more than 7 days) was 154 micromol/L (95% CI, 135.0 to 173.0 micromol/L). In selected patients with rejection, analysis of circulating and intragraft lymphocytes revealed complete IL-2Ralpha saturation. CONCLUSIONS: This CNI avoidance study in immunologic low-risk patients, while only partially successful in preventing acute rejection, provided benefits to a sizable minority of patients who have not required chronic CNI therapy. However, wide acceptance of a CNI-sparing immunosuppression regimen may require a lower rate of acute rejection, possibly through the addition of a non-nephrotoxic dose of CNI. However, because complete IL-2Ralpha blockade was present during rejection, it can be assumed that alternative pathways, such as IL-15, may be responsible for the rejection; thus, the incorporation of non-nephrotoxic immunosuppressive agents, such as sirolimus, may provide a more strategic approach.