Low-dose Calcineurin Inhibitors Research Articles

Calcineurin inhibitor sparing in renal transplantation

Purpose of review The aim of this review is to report on the current state of calcineurin inhibitor-sparing therapies. The influence of mammalian target of rapamycin inhibitors in combination with low-dose or no calcineurin inhibitors on long-term allograft survival and function are discussed. Calcineurin inhibitor-sparing therapies without mammalian target of rapamycin inhibitors are also discussed. Recent findings The withdrawal of calcineurin inhibitors 3 months after transplantation and continuous therapy with sirolimus and prednisolone gives an adequate long-term allograft survival rate 4 years after transplantation. Low-dose calcineurin inhibitors together with everolimus seems to be superior to a full-dose calcineurin inhibitor-based therapy 3 years after transplantation, but adequately powered studies with hard endpoints are still needed. If mammalian target of rapamycin inhibitors are not tolerated (up to 30% of patients), other strategies such as antimetabolite (mycophenolate mofetil, azathioprine)-based therapy or antibody therapies (that is belatacept) may be utilized to facilitate calcineurin inhibitor withdrawal. Summary New immunosuppressive regimens have made it possible to withdraw or completely avoid cyclosporine or tacrolimus in selected patients at high risk of chronic allograft nephropathy and calcineurin inhibitor toxicity.

The use of induction agents in liver transplantation

Purpose of review Despite improvements in early graft survival, late graft loss through chronic rejection and morbidity and mortality as a result of long-term treatment with immunosuppressive medications is a major concern. New drugs have facilitated new treatment protocols with the delayed or reduced application of calcineurin inhibitors or steroid avoidance. This review focuses on recent data concerning the use of induction agents in liver transplantation. Recent findings Clinical studies using induction agents have demonstrated their safety and efficacy, and show promise for a beneficial outcome in liver transplant patients. IL-2 receptor antibodies allow a reduction of maintenance immunosuppression and reduce side effects, such as diabetes or renal impairment. Several studies using IL-2 receptor antibodies have also shown a lower incidence of acute rejection episodes in paediatric patients. Thymoglobulin has been used primarily in hepatitis C-positive patients, and studies have shown a positive effect on virus replication without significant recurrence of hepatitis C. Alemtuzumab has shown promising results regarding acute rejection episodes and renal function in a low-dose calcineurin inhibitor protocol. Summary The use of induction agents in liver transplantation is a promising strategy to reduce acute rejection episodes, maintenance immunosuppression, and prevent side effects without affecting patient and graft survival.

Cyclosporine Withdrawal Improves Renal Function in Heart Transplant Patients on Reduced-Dose Cyclosporine Therapy

Renal failure is a major cause of morbidity after heart transplantation. It is unclear whether calcineurin inhibitor (CNI) free immunosuppression provides more nephroprotection than low-dose CNI therapy. Thirty-nine patients with renal failure on low-dose cyclosporine A (CsA) were studied (62.9 +/- 8.7 years, five female, 8.2 +/- 4.3 years posttransplant, serum creatinine: 1.9 +/- 0.3 mg/dL, calculated GFR (cGFR): 48.2 +/- 18.3 mL/min, CsA C0 level: 64.0 +/- 19.9 ng/mL). All patients had been treated with low-dose CsA >6 months, renal function was stable or slowly decreasing (creatinine 1.7-3.5 mg/dL). Nineteen patients were randomized to discontinuation of CsA and overlapping rapamycin therapy initiation (RAPA), 20 patients continued low-dose CsA (control). Three patients (16%) discontinued rapamycin medication for side effects (diarrhea, skin rash), two patients developed pneumonia and pulmonary embolism, respectively, no rejection or other infectious complications were seen. After 6 months, renal function in the control group was unchanged. In the RAPA group, renal function markedly improved (creatinine: 2.08 +/- 0.15 to 1.67 +/- 0.13 mg/dL, cGFR: 48.5 +/- 21.4 to 61.7 +/- 21.4 mL/min (p < 0.001 within and between groups)). In carefully selected late survivors following heart transplantation who are at low risk of rejection, CNI-free rapamycin-based immunosuppression improves cGFR even in those already receiving low-dose CsA therapy. The results of this study warrant further confirmation in larger clinical trials that are powered to assess clinical outcomes.

Current issues in pediatric transplantation

Pediatric solid organ transplantation is so successful that >80% of children will survive to become teenagers and adults. Therefore, it is essential that these children maintain a good quality life, free of significant long-term side effects. While intensive immunosuppressive regimens (containing CsA, tacrolimus, MMF, and steroids) effectively reduce acute or chronic rejection, they can produce long-term side effects including viral infection, renal dysfunction, hypertension, and stunting. The development of effective methods of diagnosis, prevention, and treatment of CMV means that this is no longer a significant cause of mortality, but morbidity remains high. In contrast, infection rates of EBV remain high in EBV-negative pre-transplant patients. However, pre-emptive reduction of immunosuppression or treatment with rituximab or adoptive T-cell therapy is effective in preventing/treating post-transplant lymphoproliferative disease. Recent protocols have concentrated on reducing CsA immunosuppression, to prevent unacceptable cosmetic effects, and to reduce the hypertension, hyperlipidemia, and nephrotoxicity. Both CsA and tacrolimus cause a 30% reduction in renal function, with 4-5% of patients developing severe chronic renal failure. The use of IL-2 inhibitors for induction therapy with low-dose calcineurin inhibitors, in combination with renal-sparing drugs such as MMF or sirolimus for maintenance immunosuppression, should prevent significant renal dysfunction in the future. The concept of steroid-free immunosuppression with IL-2 inhibitors, tacrolimus, and MMF is an attractive option, which may reduce stunting and renal dysfunction. However, these regimens may be associated with the increased development of de-novo autoimmune hepatitis in 2-3% of children. The most important challenge to long-term survival in transplanted children is the management of non-adherence and other adolescent issues, particularly when transferring to adult units, as this is the time when many successful transplant survivors lose their grafts.

Treatment strategies in pediatric solid organ transplant recipients with calcineurin inhibitor‐induced nephrotoxicity

Although short-term kidney allograft survival has improved significantly since the introduction of the calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus, long-term transplant survival remains a major concern, chronic allograft nephropathy (CAN) being the principal reason for graft loss after the first post-transplant year. This is particularly major for pediatric renal transplant recipients because of their higher life expectancy compared with adults. The mechanisms leading to CAN are multiple, including acute and chronic alloimmune responses and nephrotoxicity of CNIs. CNI-induced nephrotoxicity is also a long-term concern in other pediatric solid organ transplant recipients, such as liver and heart. Prevention of allograft nephropathy requires a balance of maintaining adequate immunosuppression, while avoiding the toxic effects of CNIs. Regimens that are based on mycophenolate mofetil (MMF) alone or in combination with newer agents may allow for reduced reliance on CNIs and thus may represent an effective treatment paradigm for long-term maintenance of a renal allograft. From the available data it appears that the currently safest treatment strategy in pediatric renal and heart transplant recipients with CNI toxicity is an MMF-based therapy with low-dose CNIs +/- low-dose steroids, while in pediatric liver transplant recipients, CNI-free MMF-based immunosuppressive therapy with or without steroids appears feasible in a significant subset of patients. In renal transplant recipients, the benefit of a CNI-free MMF/steroid therapy on renal function is gained at the cost of increased rejection in a subset of patients, although the relative importance of rejection vs. overall renal function requires further clinical investigation. The introduction of mammalian target of rapamycin (mTOR) inhibitors provides an opportunity for unique CNI-sparing regimens that combine two antiproliferative agents (MMF and TOR inhibitors). It is possible that a sirolimus-based CNI-free immunosuppressive regimen in terms of renal transplant survival is superior to CNI minimization, where the detrimental effects of CNIs on allograft function and structure are still operative, albeit to a lesser degree. Substitution of CNIs by mTOR inhibitors is therefore promising, but requires validation in long-term studies in large cohorts.

134 Impact of combined mycophenolate mofetil and low dose calcineurin inhibitor therapy on T cell function

Complications of Calcineurin inhibitor (CNI), in particular nephrotoxicity, have a major effect on morbidity and mortality within the transplant setting. We randomized liver transplant patients with renal dysfunction under CNI treatment to either a) receive mycophenolate mofetil (MMF) up to a dose fo 2 g/day followed by consecutive reduction of CNI (CNI reduction group) or b) to continue their current CNI dose (control group). Peripheral blood mononuclear cell (PBMC) were isolated from patient blood at baseline and after conversion to MMF/low dose CNI regimen. The expression of CD3, CD4, CD8 on PBMC and the expression of activation marker was determined by FACS analysis. In in vitro experiments freshly isolated PBMC from healthy volunteers were treated with mycophenolic acid (MPA) (1 up to 10 μM), cyclosporine A (CsA) (25-100 ng/mL), tacrolimus (Tac) (2-10 ng/mL) and combined CsA/MPA or Tac/MPA. T cell proliferation was measured by carboxfluorescein diacetate succinimidyl ester and FACS analysis. T cell cycle analysis was performed by bromodexoxyuridine staining and FACS. Furthermore activation marker and nuclear factor of activated T cell (NFAT)-regulated cytokine expression was analyzed by FACS. The expression of cytokine mRNA was measured by real- time RT PCR. Combined MMF and low dose CNI therapy leads to reduction of percentages of CD8+ T cells, CD4+CD45RO+ T cells, CD3+CD56+ T cells and inhibition of activation marker expression. In vitro experiments have demonstrated that 1 μM MPA completely blocks the proliferation of CD4 and CD8 T cells. MPA stops the cell cycle of activated T cells at G0/G1 phase and this effect is dose-dependent. Both MPA and CNI inhibit the expression of activation T cell markers and this effect is potentiated by combined exposure to MPA and CNI. MPA has no detectable effect on NFAT-regulated genes such as IL-2, IL-4, IFN-γ and their protein expression. Our results suggest that FACS analysis and assessment of cytokine expression of PBMC represent important tools for monitoring and optimizing the immunosuppressive regimen within the liver transplant setting. Adjustment of the MMF dosage by detection of the AUC may be required to avoid over-immunosuppression. Combined MMF and low dose CNI exhibit anti-proliferative effects in T cells by a) blocking the S phase of the cell cycle, b) decreasing NFAT-regulated gene and activation marker expression.

Use of Sirolimus and Low-dose Calcineurin Inhibitor in Lung Transplant Recipients With Renal Impairment: Results of a Controlled Pilot Study

Use of Sirolimus and Low-dose Calcineurin Inhibitor in Lung Transplant Recipients With Renal Impairment: Results of a Controlled Pilot Study

Use of IL‐2 receptor antagonists to reduce delayed graft function following renal transplantation: a review

Delayed graft function (DGF) occurs in approximately 30% of renal transplant patients, and significantly increases risk of long-term graft loss. This article reviews the potential for use of interleukin-2 receptor (IL-2R) antagonists to reduce the burden of DGF. IL-2R antagonists decrease incidence of acute rejection without increasing risk of cytomegalovirus infection or malignancy, and show equivalent efficacy to lymphocyte-depleting antibody agents in standard risk patients with immediate graft function. The nephrotoxicity associated with calcineurin inhibitors (CNIs) has led to use of delayed or low-dose CNI regimens with induction therapy in patients with DGF. In this setting, use of an IL-2R antagonist with mycophenolate mofetil and steroids with delayed cyclosporine appears to be associated with a low incidence of biopsy-proven rejection and comparable renal function to patients with immediate function. Additionally, there is intriguing evidence to suggests that IL-2R antagonists may reduce risk of DGF occurring. A number of large-scale and smaller studies have reported a trend to reduced incidence of DGF or improved early renal function using IL-2R antagonists compared with placebo, although data are not entirely consistent. In conclusion, the ability of IL-2R antagonists to reduce acute rejection with no additional safety concerns makes them an attractive option for patients with DGF.

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

Improvement of Renal Function in Pediatric Heart Transplant Recipients Treated with Low-Dose Calcineurin Inhibitor and Mycophenolate Mofetil

Renal dysfunction is a major complication in heart transplant recipients treated with calcineurin inhibitors. The goal of the study was to investigate the effect of a reduction of calcineurin inhibitor dosage with the concomitant introduction of mycophenolate mofetil on both renal function and cardiac allograft function. Fourteen of 52 consecutive pediatric cardiac allograft recipients experienced a progressive decrease of renal function. A renal biopsy was performed before the dose of calcineurin inhibitors was reduced by 50% and azathioprine was replaced by mycophenolate mofetil. Renal function was evaluated by inulin clearance and maximal urinary osmolality before and yearly after the therapeutic changes. Acute rejection was monitored clinically, by echocardiography and endomyocardial biopsies. Inulin clearance in the fourteen children decreased from 84.2 mL/min/1.73 m at one year posttransplantation to 46.5+/-9.6 mL/min/1.73 m at the time of the change in immunosuppressive therapy. Significant renal lesions were observed in the renal biopsies performed before the change. At 1 year, inulin clearance had increased by 67%. In six patients who had a second determination 2 years after the switch, inulin clearance was not significantly different from the value at 1 year. There were three reversible acute rejection episodes in three patients. The incidence of rejection episodes was not different from a control group of patients whose treatment was not changed. The reduction of calcineurin inhibitor dosage and replacement of azathioprine by mycophenolate mofetil is a safe way to improve renal function in children with heart transplants and calcineurin inhibitor induced nephrotoxicity.

Use of sirolimus and low-dose calcineurin inhibitor in lung transplant recipients with renal impairment: Results of a controlled pilot study

Renal failure induced by calcineurin-inhibitor agents is a common complication of lung transplantation. Sirolimus, a macrolide immunosuppressant with a distinct mechanism of action, may prevent renal failure but was found to have a high infectious and toxicity rate in the only relevant study conducted so far. The aim of the present prospective pilot study was to assess the benefit of sirolimus combined with low-dose calcineurin inhibitors in this patient population. Sixteen lung transplant recipients with post-transplantation renal dysfunction were allocated to receive the standard immunosuppression regimen or a combination sirolimus/low-dose calcineurin-inhibitor regimen. Target trough levels of sirolimus were 4 to 8 ng/mL. Tacrolimus was tapered down to target trough levels of 4 to 8 ng/mL and cyclosporine to 80 to 120 ng/mL. Duration of follow-up was 18 months. At the end of follow-up, the sirolimus group showed a significant improvement in creatinine clearance (42.6 mL/min vs. 32.5 mL/min, P= 0.05), whereas the control group showed a significant reduction (32.3 mL/min vs. 40.3 mL/min, P= 0.02). The difference between the groups was statistically significant (P < 0.0001). Acute rejection episodes occurred in 2 patients in the sirolimus group and 1 patient in the control group (P= NS). Pneumonia developed in 6 study patients and 4 controls; all responded to antibiotics. Sirolimus combined with low-dose calcineurin inhibitors appears to be a safe and effective alternative immunosuppressive therapy to sirolimus alone in lung transplant recipients with renal failure. Graft function is preserved, and infection and drug toxicity rates are low.

Investigation of Pediatric Renal Transplant Recipients with Heavy Proteinuria after Sirolimus Rescue

Little is known about the incidence and evolution of proteinuria as a complication of sirolimus rescue in children. This study describes pediatric renal transplant (Tx) recipients who were treated with sirolimus and who developed heavy proteinuria. Risk factors for the development of proteinuria and its time course are explored. Data at various time points after sirolimus introduction were abstracted from the records of children treated at the author's center. The repeated measures general linear model and the Student's paired t test were used to analyze changes in laboratory values over time. Of the 13 children on sirolimus, 12 developed heavy proteinuria after a mean interval of 1 month. The mean urine protein (Up)-to-creatinine (c) ratio increased from 1.1 to a peak value of 3.9 (P=0.003) at 4.6 months after the start of sirolimus. Although not statistically significant, children on no calcineurin inhibitor (CNI) had a greater increase in the Up/c than those on low-dose CNI. At last follow-up, with the use of angiotensin receptor blockers (ARB), the Up/c declined to 2.2. No predictors could be identified for the development of proteinuria. Heavy proteinuria is common after the use of sirolimus as rescue therapy in children with renal Tx. Whether this is attributable to a toxic effect of the sirolimus itself or to lower CNI exposure is uncertain. Early detection of proteinuria is important to enable prompt intervention. Most children have a reduction in their Up/c with the use of ARB and can therefore be continued on sirolimus.

Impact of combined mycophenolate mofetil and low-dose calcineurin inhibitor therapy on renal function, cardiovascular risk factors, and graft function in liver transplant patients: Preliminary results of an open prospective study

As liver transplantation (LT) is now being performed with excellent 1-year graft survival rates of 85% to 90%, attention has been shifted to reducing long-term complications of calcineurin inhibitors (CNI). We randomized LT patients (2:1) who displayed renal dysfunction under CNI treatment to either mycophenolate mofetil (MMF) (1000 mg twice a day) followed by stepwise reduction of CNI ( n = 21; Tac trough levels <4 ng/mL, CsA trough levels <50 ng/mL); or continue their current CNI dose ( n = 11; control group). Three months after study entry, we observed significantly decreased mean values in the CNI reduction group of serum creatinine (1.88 ± 0.36 versus 1.58 ± 0.33 mg/dL, P < .001) and BUN (39.2 ± 11.8 versus 29.9 ± 9.59 mg/dL, P < .001) with a significantly increased GFR (51.4 ± 10.8 versus 61.6 ± 14.1 mL/min, P < .001). Improved renal function in these long-term LT recipients (5.6 ± 3.6 years posttransplant; range, 2 to 13 years) suggests at least a partial reversibility of CNI-induced renal damage. Furthermore, we found an improved lipid profile as well as a significantly decreased mean systolic (140 ± 19 versus 130 ± 14 mm Hg, P < .01) and diastolic (82 ± 9 to 74 ± 8 mm Hg, P < .001) blood pressure 3 months after introduction of MMF therapy. Additionally, transaminases significantly improved in the CNI reduction group within this time period (ALT 37.9 ± 25.9 versus 25.2 ± 13.2, P < .05). MMF and CNI-reduced immunosuppressive regimens may improve long-term patient survival, suggesting a broad application within the liver transplant setting.

SIROLIMUS IN HEART TRANSPLANTATION: A STRATEGY TO IMPROVE RENAL FUNCTION AND REDUCE THE RISK OF RENAL FAILURE

P625 Aims: The predominant cause of chronic renal disease after heart transplantation is the long-term use of calcineurin inhibitors (CI)-either cyclosporine or tacrolimus. Sirolimus (S) has been administered successfully in the management of this complication in other solid organs recipients. We report our experience with (S) administered with low doses of CI or as primary therapy in combination with steroids and mycophenolate mophetil (MM) in heart transplant recipients who developed renal insufficiency after transplantation. Methods: Fifty four (54) patients (pts) have received an orthotopic heart transplant in the Puerto Rico Heart Transplant Program since June 1999 to March 2004. The initial immunosuppressive regimen consisted of MM, steroids, and a CI (50 cyclosporine and 2 tacrolimus). Renal function was monitored closely with creatinine clearance (CC) determination each 3-6 months. If CC decreased below 49 ml/min per 1.73 Kgs per M2, the CI dosage was reduced to the minimal dose to control rejection and CC was reexamined. If renal function remained unchanged, (S) was started, MM discontinued and CI dose reduced in 50% (Group I). After this approach, if CC continued < 49 ml/min CI was discontinued, MM restarted and (S) was continued, (Group II). Results: Among 54 pts, 41males, 13 females, mean age 47 years (11 to 62 years), 20 (37%) has diabetes mellitus (DM), and 34 (63%) hypertension. None had acute perioperative renal failure or hepatitis C, and all were receiving either an ACE inhibitor or an ARB agent. In twenty (20) pts, (S) was introduced in its immunosuppressive regime to manage renal insufficiency (CC<49 mls/min). Ten (10) required (S), low dose CI, plus prednisone (Group I); and ten (10) (S), MM, plus prednisone (Group II), at a mean time of 22 months post transplantation. The average CC increased from 38.6 mls/min to 63.5 mls/min (p<0.05) in Group I, and from 38.4 mls/min to 67.4 mls/min (p<0.5) in Group II after (S) administration. No significant change in left ventricular ejection fraction, or in episodes of rejection were observed since one year before and one year after Sirolimus. None of our patients has required renal dialysis. Renal function improvement sustained one year after Sirolimus (S) in heart transplant patients: Conclusions: Our heart transplant recipients have a high incidence of DM, and renal insufficiency with CC < 49mls /min, post transplant in 37%; and 38% respectively. Sirolimus has offered a flexible opportunity to manage this complication. Either in combination with a CI at lower doses (50% dose reduction) or as a substitution therapy for the CI, we have observed a significant improvement in renal function with Sirolimus without graft function deterioration or increase in rejection.Figure

“PROPE” TOLERANCE AFTER INTESTINAL TRANSPLANTATION IN MAN.

P608 Aims: Current protocols for Intestinal Transplantation (Itx) use heavy immunosuppression (IS) but this causes infection, lymphoma and drug toxicity. “Prope” or “almost” tolerance refers to a state of graft acceptance maintained by low, non-toxic immunosuppression. To establish prope tolerance, we developed an immuno-modulatory protocol including: 1) Donor-Specific Blood Transfusion (DSBT induces regulatory cells); 2) low-dose calcineurin-inhibitor (CI) (high-dose CI prevents DSBT-induced regulatory cells generation); and 3) no steroids bolus (shown to break tolerance in a DSBT-induced tolerance model). Methods: 2 females (55 and 57 years old) with short gut and liver failure received an Itx in addition to a new liver. 300cc donor whole blood was transfused in the recipient after reperfusion. For induction IS, no iv steroids bolus were given, but only 2 doses of anti-IL-2 RA (20mg Simulect days1/4). Patients received postTx maintenance IS with very low Tac levels for this type of Tx (15ng/ml 1stmth; 5-10ng/ml 2nd-3rdmth; ∼5ng/ml thereafter), low-dose azathioprine (1mg/kg 1st–3rd mth; .5mg/kg thereafter) and low-dose steroids (medrol 8mgx2 daily tapered to 2mgx2 by the 3rdmth). Standard anti-bacterial, -fungal and -viral prophylaxis was given. Patients were monitored for rejection, GVHD, infection and PTLD. Protocol biopsies were taken from the ileal stomy. Results: Despite exposure to low IS, clinical, endoscopic and histologic signs of rejection were absent. Chimerism (donor HLA-type cells in peripheral blood) was transiently identified at day 28 in patient 1 but was self-limiting. GVHD was absent in both patients. Under this low IS, patients remained free of systemic opportunistic infections, lymphoma (no increased copies of EBV genome by PCR), and drug toxicity. Both patients are nutritionally independent and well 3 and 1.5 year postTx. Last follow-up biopsies show normal intestinal mucosa. Conclusions: The herein described immuno-modulatory protocol allowed development of “prope” tolerance and restored nutritional independence in 2 consecutive Itx recipients, a form of Tx that usually requires profound IS. Maintenance IS in these patients is less than after kidney Tx or in certain patients with chronic inflammatory bowel disease. Mechanisms of graft acceptance in these patients - in particular the development of regulatory cells - are under investigation.

Complete immunosuppressive withdrawal as a uniform approach to post-transplant lymphoproliferative disease in pediatric liver transplantation.

Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) in pediatric liver transplant recipients is associated with a high mortality (up to 60%) and the younger age groups, who are predominantly EBV-naïve, are at highest risk for development of this disease. The aim of this study is to assess, in this high-risk group, patient outcome and graft loss to rejection when complete withdrawal of immunosuppressive agents (IMS) is instituted as the mainstay of treatment in addition to the use of standard therapy. A retrospective analysis of 335 pediatric patients whose liver transplants were performed by our team between September 1988 and September 2002, was carried out through review of computer records, database and patient charts. Fifty patients developed either EBV or PTLD; 80% were < or =2 yr of age. Of these 50 patients, 19 had a positive tissue diagnosis for PTLD and 31 were diagnosed with EBV infection, 14 of whom had positive tissue for EBV. Fifty-eight percent of patients who developed PTLD and 51.6% of patients with EBV received antibody for induction or treatment of rejection prior to onset of disease. Forty-six patients (92%) received post-transplant antiviral prophylaxis with ganciclovir or acyclovir. Antiviral treatment included ganciclovir in 76%, acyclovir in 20% and Cytogam (in addition to one of the former agents) in 44%. In those with PTLD, treatment included chemotherapy (n = 1), Rituximab (n = 2), and ocular radiation (n = 1). IMS was stopped in all patients with PTLD and in 19 with EBV infection and was held as long as there was no allograft rejection. Eight patients have remained off IMS for a mean of 1535.5 +/- 623 days. Of the 21 patients who were restarted on IMS for acute rejection, 18 responded to steroids and/or reinstitution of low-dose calcineurin inhibitors. The mean time to rejection while off IMS in this group was 107.43 +/- 140 days (range: 7-476). Two patients were re-transplanted for chronic rejection; one had chronic rejection that existed prior to discontinuing IMS. The mortality rate in our series was 31.6% in those with PTLD and 6% in those with EBV disease. The cause of death was related to PTLD or sepsis in all cases; no deaths were due to graft loss from acute or chronic rejection. PTLD is associated with high mortality in the pediatric population. Based on this report, we advocate aggressive management of PTLD that is composed of early cessation of IMS, the use of antiviral therapy, and chemotherapy when indicated. Episodes of rejection that occur after stopping IMS can be successfully treated with standard therapy without graft loss to acute rejection.

Sirolimus-based immunosuppression with reduce dose cyclosporine or tacrolimus after renal transplantation

Sirolimus (SRL), a fermentation product of Streptomyces hygroscopicus, complexes with the FKBP12 to inhibit cyclin dependent kinase(s), collectively termed the target of rapamycin (TOR), causing G 1–S phase cell cycle arrest. Safety and efficacy have been documented in clinical renal transplantation, but concerns were raised due to important biologically relevant side effects. Hyperlipidemia was identified, beginning with early clinical experiences, and the unexpected findings that SRL may exacerbate CsA associated nephrotoxicity was observed during the pivotal phase III studies. This report details results of our experience using SRL (target trough concentration, 10–15 ng/mL) with low dose CsA (target trough concentration, 50–100 ng/mL), seeking to determine whether this approach might provide effective immunosuppression while reducing associated nephrotoxicity. Among 121 renal transplant recipients, 62 received the SRL based regimen and 59 received MMF with all patients receiving CsA and prednisone. Similar to earlier clinical experiences, hematopoeitic abnormalities and hyperlipidemia were observed among patients who received SRL, and those abnormalities were readily controlled. However, unlike observations from the phase III SRL studies, renal function was not adversely affected. These findings support the growing body of evidence indicating that SRL based immunosuppression in combination low dose calcineurin inhibitors and corticosteroids is safe, efficacious, and without associated renal toxicity.

Long-term mycophenolate mofetil monotherapy in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplantation.

Calcineurin inhibitors (CNIs) are the first-line immunosuppressive agents administered after liver transplantation, but they cause renal impairment. Two recent randomized trials report cellular rejection and liver graft loss when mycophenolate mofetil (MMF) monotherapy was used as a renal-sparing agent. Our experience with MMF in the same setting but with longer follow-up is described. In 45 patients with serum creatinine more than 120 micromol/L or creatinine clearance less than 50 mL/min, 2 g MMF per day was administered (median 29 months, 1-49 months) either as monotherapy (with all other immunosuppression withdrawn in 1 month) in 16 patients (group I) or in combination with low-dose CNI (trough tacrolimus </=5 ng/mL, cyclosporin A </=50 ng/mL) in 29 patients (18 patients without [group II] and 11 patients with [group III] previous refractory rejection [rejection after two episodes of treated rejection]). In group I (median interval receiving MMF, 33 months), only one patient (6%) experienced cellular rejection, and serum creatinine normalized in five of eight patients long term. In group II (median follow-up 26.5 months), none of 18 experienced rejection, and serum creatinine normalized in 6 of 10 long term. In group III (median follow-up 34 months), 5 of 11 patients (45%) experienced further rejection, one was not steroid responsive, and serum creatinine normalized in four of eight patients long term. There was no graft loss or death as a result of rejection. Our cohort with prolonged follow-up showed significant improvement in renal function with both MMF monotherapy and in combination with low-dose CNI with minimal rejection (five of six steroid responsive) and no graft loss. MMF substitution is a therapeutic strategy that deserves more extensive use in liver transplantation.

Effect of low-dose calcineurin inhibitors on acute rejection and graft survival

Effect of low-dose calcineurin inhibitors on acute rejection and graft survival

Concomitant basiliximab with low-dose calcineurin inhibitors in children post-liver transplantation.

Orthotopic liver transplantation (OLT) is effective therapy for end-stage liver disease but immunosuppression with calcineurin inhibitors (CNI) leads to significant nephrotoxicity, resulting in either a reduction of dosage to below the therapeutic level or omission of the drug altogether. Basiliximab (Bx) is a human/mouse chimeric monoclonal antibody that inhibits binding of interleukin-2 (IL-2) to IL-2 receptors and thus prevents proliferation of T cells, which is the main step in the development of acute cellular rejection. The aim of this study was to identify the role of Bx in the prevention of acute cellular rejection and in the reduction of nephrotoxicity in children post-liver transplantation. We evaluated three children (19 months, 22 months, and 11 yr of age; one male, two female) who were treated with Bx post-OLT on compassionate grounds. The indications were: nephrotoxicity in two children, requiring re-transplantation for hepatic artery thrombosis and recurrent giant cell hepatitis, respectively; and nephrotoxicity secondary to chemotherapy for hepatoblastoma in the third child. All patients received 10 mg of Bx, at OLT and on Day 4. Tacrolimus (0.15 mg/kg/day) was started at 48 h (n = 2) and cyclosporin (5 mg/kg/day) at 2 weeks (n = 1). Trough levels of tacrolimus were maintained at 5-8 ng/mL and trough levels of cyclosporin at 100-150 mg/L for the first 3 months. All patients received methylprednisolone (2 mg/kg) with azathioprine (1.5 mg/kg) (n = 2) and/or mycophenolate mofetil (20 mg/kg) (n = 1). The glomerular filtration rate (cGFR) was calculated using the Schwartz formula before and 10 weeks after transplant. Bx was found to be easy to administer and no major side-effects were reported. One child had two episodes of mild acute rejection at 5 and 9 weeks post-OLT and one developed chronic rejection requiring re-transplantation at 9 weeks post-OLT. One child did not develop rejection. The mean pretransplant cGFR was 58.1 (54.6-64.1) mL/min/m2. Within 10 weeks of transplantation, the cGFR had improved by 69% to a mean of 116 (88-157.6) mL/min/m2. To conclude, Bx was well tolerated in all children and had a renal sparing effect. It was effective in preventing early acute rejection, but the combination of Bx and low-dose CNI drugs did not prevent late acute or chronic rejection. Further studies to evaluate the appropriate levels of CNI immunosuppression with Bx are required.