CsA Withdrawal Research Articles

Minimizing the Risk of Posttransplant Malignancy

Recent improvements in immunosuppressive therapies have reduced the incidence of acute rejection and increased patient survival. These agents may however contribute to higher rates of mortality due to an increased risk of cardiovascular disease or malignancy. Transplant patients are immunocompromised with a reduced ability to combat the development of malignancy. The higher risk for the activity of oncoviruses may also contribute to the higher incidence and determine specific tumor types. Some immunosuppressants seem to have direct oncogenic effects. In vitro data have demonstrated that calcineurin inhibitors (CNIs) may show direct effects on tumor growth and the development of metastases. In contrast, mTOR inhibitors have demonstrated anti-tumoral properties in vitro and perhaps potent anti-angiogenic effects thereby. Recent studies and registry analyses have confirmed that mTOR inhibitors are associated with a reduced incidence of malignancies. UNOS data demonstrated that an mTOR inhibitor, with or without a CNI, is associated with a reduced incidence of tumors compared to regimens without mTOR inhibitors. The Rapamune Maintenance Regimen study demonstrated that patients receiving sirolimus-based, CNI-free therapy after CsA withdrawal at 3 months showed a reduced incidence of malignancy at 5 years posttransplant, compared with those who continued on a regimen that included CsA. In the CONVERT study, patients converted to sirolimus revealed a significantly lower malignancy rate at 24 months (3.1%) compared with those who continued CNI-based therapy (9.8%, P < .001). The elimination of CNIs and the introduction of sirolimus may, therefore, have a role to reduce the risk of cancer among posttransplant patients.

Allogeneic Hematopoietic Stem Cell Transplantation in HIV-Positive Patients with High Risk Hematologic Malignancies

Recent studies have shown that Autologous Stem cell Transplantation (ASCT) in HIV+ patients (pts) with associated lymphoma along with highly active antiretroviral therapy (HAART) have similar results to those observed in immunocompetent pts. However there have been few reports describing Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) in HIV+ pts with high risk hematologic malignancies. The main difficulties associated to this procedure are infections and pharmacological interactions. We present the results of three HIV+ pts with hematologic malignancies treated with HAART and AlloHSCT.Pt # 1: 37 years old male diagnosed with HIV infection (AIDS-C3) in 1988, on HAART since 1996. In 1998 a diffuse large B cell lymphoma (DLBCL) IV-B was diagnosed. He achieved complete remission (CR) after CHOPx6, but relapsed one month later. After ESHAP he underwent AlloHSCT from an HLA-identical sibling in chemo-sensitive relapse. TBI+Cy was administered as conditioning treatment (CT) and Cyclosporine (CsA) as Graft versus Host Disease (GvHD) prophylaxis. HAART (3TC, NFV, EFV, d4T) was maintained during transplantation. The patient died on day (d) +6 due to respiratory distress without engraftment. Autopsy showed pulmonary aspergillosis with no evidence of toxicity or lymphoma.Pt # 2: 45 years old female. AIDS-C3 in 1994, on HAART since 1996. Diagnosed with high risk common acute lymphoblastic leukemia in 2005. She reached CR after Hyper-CVAD+Rituximab (R) x2 and received an AlloHSCT from an HLA-identical sibling using TBI+Cy as CT and CsA + Methotrexate (MTX) as GvHD prophylaxis. HAART (T20, d4T, ABC, 3TC) was maintained throughout the procedure. Engraftment occurred on +17d and full donor chimerism (FCh) on +26d. During transplantation Herpes Zoster infection, febrile neutropenia and CMV infection were observed and suitably treated. Acute GvHD grade III occurred on +30d, successfully treated with steroids, CsA and mycophenolate mofetil. Four months (m) after transplantation the patient showed extensive chronic GvHD (cGvHD) also treated with steroids and CsA. Despite adequate immunologic recovery since +6m (CD4+: 450 cells/mm3 and serum IgG: 683mg/dl) she developed Streptococcal pneumonia (+9m) encephalitis of unknown etiology (+12m) and streptococcal sepsis together with pneumonia (+20m). The patient remains in CR with negative HIV-viral load and no cGvHD 30m after transplant.Pt # 3: 44 years old male.AIDS-C3 on HAART since 2000. He developed DLBCL-IVA in 2004 and reached CR after CHOP+R x6. Relapsed in 2006, showing refractoriness to ESHAP+R x5 and reaching 2nd CR after ASCT with BEAM as CT. He relapsed again in 2007, and received MINE-R x3 and GIFOX-R x1 obtaining partial remission. An AlloHSCT from an HLA-identical sibling was designed using reduced CT (90Y-Ibritumomab-tiuxetan, Rituximab, Fludarabine and Melphalan) and CsA + MTX as GvHD prophylaxis. HAART (DDI, T20, 3TC) was maintained during treatment, but stopped for 7 days due to mucositis. Engraftment was observed on +13d, with FCh on +32d. During transplantation the patient developed febrile neutropenia and CMV infection, successfully resolved. After CsA withdrawal on +70d, the patient showed two acute grade II GvHD episodes responsive to steroids and CsA. The patient remains in CR with cGVHD, on immunosupression, 9 months after transplant. He shows negative HIV-Viral load, CD4+ 65 cells/mm3 and serum IgG 559mg/dl. These pts show that AlloHSCT is a feasible treatment in HIV+ pts with high risk hematologic malignancies. Moreover we have not found significant interactions between immunosuppressive agents and HAART. Nevertheless early diagnosis of infection is critical in this setting.

Effect on Kidney Graft Survival of Reducing or Discontinuing Maintenance Immunosuppression After the First Year Posttransplant

Data are scarce concerning the impact of maintenance immunosuppression dose reductions posttransplant. Graft survival according to dose reduction or discontinuation of calcineurin inhibitors or mycophenolate mofetil (MMF) after the first year posttransplant was evaluated in 25,045 patients undergoing kidney transplantation during 1996 to 2005. No patient in this analysis had experienced a rejection and all had good graft function before dose reduction. Reduction of cyclosporine (CsA) dose to less than or equal to 150 mg/day, tacrolimus to less than or equal to 2 mg/day, or MMF to less than or equal to 1.0 g/day in patients on CsA or less than or equal to 0.5 g/day in patients on tacrolimus during the second year posttransplant was associated with a statistically significant reduction in graft survival (hazard ratios between 1.37 and 1.65). Withdrawal of CsA, tacrolimus, or MMF during year 2 was also associated with an increase in the risk of graft loss compared with continuing treatment (hazard ratio 1.52-1.73). This observational analysis indicates that in kidney transplant patients with good graft function, withdrawing maintenance CsA, tacrolimus or MMF, or reducing the dose of these agents below certain thresholds after the first year posttransplant is associated with a significant risk of graft loss.

Accuracy and variability of equations to estimate glomerular filtration rates in renal transplant patients receiving sirolimus and/or calcineurin inhibitor immunosuppression*

Measured glomerular filtration rates (mGFRs) were obtained by (99)mTc-DPTA, (125)I-iothalamate, iohexol, (51)Cr-EDTA, non-radiolabeled iothalamate, or inulin clearance from centers agreeing to perform mGFR in six completed and one ongoing Wyeth Research multicenter trials evaluating sirolimus (SRL) in regimens with or without a calcineurin inhibitor (CNI). Estimated GFRs (eGFRs) were calculated by the Cockcroft-Gault (eGFR(CG)), Nankivell (eGFR(NK)), and simplified Modification of Diet in Renal Disease (eGFR(MDRD)) equations. Bias, precision, and accuracy for each of these equations were estimated by tertiles and by regimen. For the Rapamune Maintenance Regimen (RMR) trial, eGFR outcomes were also compared between treatments {[SRL-cyclosporine (CsA) versus SRL]} using the three eGFR formulas. In the lowest mGFR tertile (6-40 ml/min), eGFR(MDRD) gave the best accuracy with the least bias whereas eGFR(NK) and eGFR(CG) performed better in the highest mGFR tertile (58-139 ml/min). At 24 months in the RMR study, mean differences in eGFR between treatments were 13.6, 14.2, and 13.5 ml/min/1.73 m(2) for eGFR(CG), eGFR(NK), and eGFR(MDRD), respectively, favoring CsA withdrawal (P-values for all <0.001). The accuracy of the three eGFR equations was affected by mGFR range but not by immunosuppressive regimens utilizing SRL, SRL-CNI or CNI-based therapy.

Incidence of anemia in sirolimus-treated renal transplant recipients: the importance of preserving renal function

Sirolimus (SRL) has a concentration-related effect on hematopoiesis. In this study, 430 renal transplant recipients were randomized (1:1) 3 months post-transplantation to continue SRL-cyclosporine (CsA)-steroids (ST) or to have CsA withdrawn (SRL-ST). Over 5 years, on therapy calculated glomerular filtration rate (GFR), hematological indices, erythropoietin (EPO) use, and rates of mild, moderate, and severe anemia were determined. Longitudinal analyses using linear mixed models examined covariates predicting hemoglobin (Hgb) levels. Mean Hgb was significantly lower with SRL-ST at 6 months; but subsequently became significantly higher (at 2 years, 129 vs. 135 g/l, SRL-CsA-ST vs. SRL-ST, P<0.001). Mean corpuscular volume was low with both therapies, and significantly lower with SRL-ST. EPO use was similar in the two groups, approximately 30% during the first year and 10% thereafter. The incidence of anemia was significantly higher with SRL-CsA-ST>or=2 years. At year 5, only 39.1% of SRL-CsA-ST patients had normal Hgb vs. 68.5% of SRL-ST patients. GFR and recipient age as well as the interaction term x treatment time were significant covariates predicting Hgb. CsA withdrawal followed by SRL immunotherapy resulted in significantly less anemia than SRL-CsA-ST, despite twofold higher SRL exposure. This suggests that the improvement in GFR accompanying CsA withdrawal may mitigate the effect of SRL on hematopoiesis. (ClinicalTrials.gov number: NCT00428064).

Maintenance Immunosuppression With Mycophenolate Mofetil and Corticosteroids in Pediatric Kidney Transplantation: Temporary Benefit but Not Without Risk

Aiming at reducing cyclosporine toxicity, we investigated safety and efficacy of mycophenolate mofetil (MMF) as an immunosuppressive drug in pediatric kidney transplantation compared with cyclosporine (CsA), both in combination with corticosteroids. One year after kidney transplantation, children on triple immunosuppression, having experienced no more than one, steroid-sensitive, acute rejection episode, were randomized to withdrawal of either CsA or MMF and were followed for 2 yr. In each group, two patients had an acute rejection episode during withdrawal. Treatment failure occurred in 3 of 21 MMF and 5 of 23 CsA patients. Final analysis was for 18 patients in either group. A larger than 10 mL/min 1.73 m decrease in glomerular filtration rate was observed in more patients on CsA than on MMF (73% vs. 29%, P=0.019). No differences in blood pressure or nightly decrease of blood pressure were noted. Hypercholesterolism improved in the MMF (-16%), but not the CsA group (+5%, P<0.05), over the first, but not over both study years. Differences in triglycerid levels between groups were not shown. At study end, MMF patients tended to have lower hemoglobin levels than patients on CsA. Two MMF patients experienced a first acute rejection episode during the second study year, resulting in chronic transplant glomerulopathy with graft loss in one and deterioration of kidney function in the other. In pediatric kidney transplantation, maintenance immunosuppression with MMF together with corticosteroids has short-term benefits for kidney function and lipid pattern compared with CsA but is not without risk of complications.

Factors influencing glomerular filtration rate in renal transplantation after cyclosporine withdrawal using sirolimus‐based therapy: a multivariate analysis of results at five years1

Changes in calculated glomerular filtration rate (GFR) from baseline to five yr were analyzed in relation to risk factors among renal transplant recipients. At three months after transplantation (baseline), 430 eligible patients receiving sirolimus (SRL), cyclosporine (CsA), and steroids (ST) were randomly assigned (1:1) to continue SRL-CsA-ST or have CsA withdrawn and SRL trough levels increased (SRL-ST group). For each risk factor, changes from baseline were compared within each treatment using a t-test and between treatments using ANCOVA. Univariate then multivariate robust linear regression analyses were also performed. In the SRL-ST group, changes from baseline were not significantly different for any risk factor. With the exception of cold ischemia time >24 h, GFR values declined significantly for all risk factors in SRL-CsA-ST patients. For all risk factors, except second transplant or cold ischemia time >24 h, renal function was significantly different between groups. By order of significance in the multivariate analysis, treatment (p < 0.001), donor age (p < 0.001), proteinuria (p < 0.001), and biopsy-confirmed rejection (p = 0.010) were significant predictors of GFR change from baseline. In conclusion, patients with risk factors for reduced renal function benefit from SRL maintenance therapy without CsA vs. those remaining on CsA.

Randomized Study Comparing Cyclosporine With Azathioprine One Year After Renal Transplantation–15-Year Outcome Data

The introduction of cyclosporine (CsA) improved 1-year graft survival and reduced the incidence of acute rejection episodes after renal transplantation compared to azathioprine (Aza). However, CsA has many side effects and reducing exposure of this drug after the first year may benefit long-term patient and graft survival. We report 15-year outcome data from a single center, randomized controlled study comparing CsA withdrawal and conversion to Aza with continuation of CsA 1-year posttransplant. Two hundred sixteen patients who showed a serum creatinine less than 300 mumol/L with no acute rejection episodes in the preceding 6 months were enrolled (CsA 114, Aza 102). There was no difference in patient survival at 15 years: 62.4% in the CsA group and 64.4% in the Aza group (P=0.6). Fifteen-year transplant survival was 41.9% for the CsA group and 48.8% for the Aza group (P=0.8). Fifteen-year graft survival censoring for death with a functioning graft was 58% in the CsA group and 72% in the Aza group (P=0.5). Predictors of patient survival were younger recipient age (P<0.001) and lower systolic blood pressure at randomization (P=0.01). Predictors of graft survival were older recipient age (P<0.001) and better renal function at randomization (P=0.01). Assigned drug showed no effect on graft or patient survival. Patients assigned to CsA showed significantly worse renal function up to 10 years posttransplantation and required more anti-hypertensive treatment throughout the study period. In a selected group of patients, either Aza or low-dose CsA is safe and effective. Despite lower estimated glomerular filtration rate (eGFR) up to 10 years posttransplantation and increased use of anti-hypertensive agents, low-dose CsA was not associated with a worse patient or graft survival.

Cyclosporine Sparing with Mycophenolate Mofetil, Daclizumab and Corticosteroids in Renal Allograft Recipients: The CAESAR Study

Although the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are highly effective immunosuppressants, they are associated with serious side effects. There is great interest in immunosuppressive regimens that permit reduction or elimination of CNIs, while maintaining adequate immunosuppression and acceptable acute rejection rates. Patients (n = 536) receiving their first renal allograft were randomized to one of three immunosuppressant regimens: daclizumab, mycophenolate mofetil (MMF), corticosteroids (CS) and low-dose CsA (target trough levels of 50-100 ng/mL), weaned from month 4 and withdrawn by month 6; daclizumab, MMF, CS and low-dose CsA; or MMF, CS and standard-dose CsA. Mean GFR 12 months after transplantation (primary end point) was not statistically different in the CsA withdrawal and low-dose CsA groups (both 50.9 mL/min/1.73 m(2)) vs. the standard-dose CsA group (48.6 mL/min/1.73 m(2)). At 12 months, the incidence of biopsy-proven acute rejection was significantly higher in the CsA withdrawal group (38%) vs. the low- or standard-dose CsA groups (25.4% and 27.5%, respectively; p < 0.05). In summary, a regimen of continuous low-dose CsA with MMF, CS and daclizumab induction is a clinically safe and effective immunosuppressive regimen in renal transplant recipients.

Renal outcome after ciclosporin-induced nephrotoxicity

Renal outcome after ciclosporin (CsA) is not clear in most studies involving patients with many renal comorbid conditions. We first report on renal function recovery after CsA in previously healthy kidney patients. Uveitis patients, enroled in a unique single centre cohort follow-up study initiated in 1987, were prospectively evaluated for plasma creatinine and glomerular filtration rate (GFR) before, during (>2 years) and after (>6 months) CsA therapy. We hypothesized that CsA alters renal function progressively over time according to two additive exponential components (irreversible and reversible) and used a mixed linear model with exponential speed parameters maximizing the likelihood. Twenty-seven patients treated for 60+/-34 months (CsA 5.1+/-2.5 mg/kg/day) were followed up for 56+/-42 months after CsA withdrawal. Baseline creatinine was 0.92+/-0.15 mg/dl. The reversible effect of CsA was quantified as a 0.11+/-0.07 mg/dl increase in creatinine/100 mg CsA/day (P<0.001) and a 6.0+/-3.7 ml/min/1.73 m(2) decrease in GFR/100 mg CsA/day (P<0.0001). The irreversible effect was quantified as a 0.03+/-0.05 mg/dl increase in creatinine/100 g cumulative CsA received (P<0.007) and a decrease of 3.3+/-3.9 ml/min/1.73 m(2) GFR/100 g CsA. Although significant decrease in GFR is induced by low-dose CsA therapy in previously healthy kidney patients, renal function recovery is possible after CsA withdrawal and best predicted by CsA daily dosage. Irreversible loss in GFR is correlated to cumulated CsA exposure. The lowest CsA dosage and shortest exposure time effect as well as unlimited renal monitoring are required in order to provide the best long-term renal outcome.

Conversion to Sirolimus in Renal Transplant Recipients with Skin Cancer

Conversion to Sirolimus in Renal Transplant Recipients with Skin Cancer

Assessment of the Risk of Chronic Allograft Dysfunction after Renal Transplantation in a Randomized Cyclosporine Withdrawal Trial

We report the two-year follow-up of a trial comparing the three-month postgraft discontinuation of either cyclosporine (CsA) or mycophenolate mofetil (MMF) from a triple-drug regimen after de novo renal transplantation. One hundred and eight patients were enrolled in this study and randomized to be withdrawn from CsA (MMF group, n=54) or MMF (CsA group, n=54). Despite an increased risk of acute rejection and a lower, but nonsignificant, two-year graft survival, CsA withdrawal induced a sustained improvement of the renal function. At one year, the chronic allograft damage index was similar in both the MMF and CsA groups. However, CsA elimination resulted in a higher incidence of C4d deposits, irrespective of the occurrence of a prior acute rejection. While this finding could suggest a risk of chronic rejection in the MMF group, the outcome did not appear to be related to the C4d status. Moreover, logistic regression analysis showed that only two factors, acute rejection and the one-year glomerular filtration rate level, were predictive of a significant decline of the renal function at two years. These results point out the need to secure the minimization of the calcineurin inhibitors after renal transplantation, in order to reduce the risk of acute rejection in these patients, because this strategy allows the improvement of the one-year renal function which is predictive of a chronic allograft dysfunction.

Conversion to a proliferation signal inhibitor in a patient with coronary artery disease—a case report

The calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus are currently an important part of immunosuppressive regimens, but are associated with increased cardiovascular risk factors, including hyperlipidaemia, hypertension and diabetes mellitus. Conversion from CNI-based regimens to proliferation signal inhibitors or mammalian target of rapamycin inhibitors, such as everolimus and sirolimus, has been associated with an improvement in cardiovascular risk. This case study describes a 59-year-old renal transplant recipient who presented with angina pectoris while receiving immunosuppression with CsA, azathioprine and steroids. The patient developed angina pectoris 5 years after receiving a cadaveric renal transplant. At the time, the patient was obese, with hypertension controlled with diuretics and calcium channel blockers, and hyperlipidaemia controlled with statins. A scintigram revealed plurisegmental myocardial ischaemia, and a coronary angiogram showed the presence of occlusions in the left anterior descending artery and circumflex coronary artery. The patient also had 70% stenosis of the right coronary artery, which was corrected by angioplastic percutaneous intervention. The patient was converted from azathioprine to sirolimus 2 mg/day (trough blood level, 6-10 ng/ml), while the CsA dose was tapered and withdrawn. The angina pectoris subsequently resolved, no progression of coronary artery disease (CAD) has been observed during follow-up and stable renal function has been maintained throughout. Conversion to an immunosuppressive regimen of sirolimus with CsA withdrawal, along with angioplastic percutaneous correction of right coronary artery stenosis, therefore led to the complete resolution of angina pectoris and no progression of the CAD was noticed in this obese renal transplant patient with drug-controlled hypertension and hyperlipidaemia.

Cyclosporine-Associated Leukoencephalopathy in Organ Transplant Recipients: Experience of Three Clinical Cases

Leukoencephalopathy is a structural alteration of cerebral white matter mainly involving damage to myelin. Several reports have linked cyclosporine (CsA) with this alteration. The clinical features vary from qualitative alterations of consciousness to neurological deficits. Magnetic resonance imaging (MRI) of the brain demonstrates the damage to the white matter, which is essential for the differential diagnosis. We describe three clinical cases of leukoencephalopathy. The first case is a 43-year-old man received a cadaveric kidney transplant using immunosuppression with of mycophenolate mofetil, prednisone, and CsA. Four months later he developed meningism and bilateral sixth nerve palsy. The second case is a 50-year-old man with a cadaveric kidney transplant received immunosuppressive treatment with azathioprine and prednisone. As a result of gouty arthritis of the ankle, azathioprine was replaced with CsA to allow addition of allopurinol. Two weeks later he developed confusion and personality changes. The third case is a 16-year-old man received a orthotopic liver transplant. Postoperatively he suffered generalized tonic-clonic seizures. In all patients the CsA levels were toxic and signs of neurological alterations were present on MRI. All patients recovered rapidly after CsA withdrawal.

Sirolimus Therapy after Early Cyclosporine Withdrawal Reduces the Risk for Cancer in Adult Renal Transplantation

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi's sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.

Cyclosporine‐responsive thrombocytopenia in a patient with chloramphenicol‐associated myelodysplastic syndrome

A 64-yr-old patient with myelodysplastic syndrome (MDS), with refractory cytopenia with multilineage dysplasia subtype following chloramphenicol exposure received immunosuppressive treatment with antithymocyte globulin and cyclosporine (CsA). Complete remission was achieved and CsA was tapered after 2.5 yr. Shortly after CsA withdrawal, the patient relapsed with thrombocytopenia but responded to restoration of CsA. This case illustrates that immune-mediated mechanisms of cytopenia in MDS may be dependent on continued immunosuppressive treatment similar to aplastic anemia.

Conversion to Sirolimus From Cyclosporine May Induce Nephrotic Proteinuria and Progressive Deterioration of Renal Function in Chronic Allograft Nephropathy Patients

Antiproliferative and non-nephrotoxic properties of sirolimus have been exploited for treatment of patients with chronic graft dysfunction. In this paper we point to the possible association of nephrotic syndrome and renal impairment with rapid conversion from cyclosporine (CsA) to sirolimus in patients with chronic nephropathy. Five male patients, ages 34 to 56 years, with chronic renal failure in the course of glomerulonephritis, were transplanted between 1997 and 1999. For the first 49 to 65 months, the immunosuppressive regimen consisted of CsA, azathioprine (AZA), and prednisone. Thereafter, due to chronic nephropathy evidenced by biopsy, conversion to sirolimus was performed with sharp withdrawal of CsA. The serum creatinine level prior to conversion was 1.9 ± 0.3 mg/dL. Trace to 86 mg/dL proteinuria was found in 3 patients, while 2 patients had about 200 mg/dL. After 2 to 4 months of sirolimus treatment the proteinuria progressed (558 ± 183 mg/dL); edema, hypoproteinemia, hypoalbuminemia, and hyperlipidemia developed; and the serum creatinine increased to 3.5 ± 0.8 mg/dL. Biopsies performed in three patients revealed new pathologic changes. After 4 to 5 months, we performed reconversion to calcineurin inhibitor. Proteinuria decreased to 0 to 150 mg/dL; nevertheless the serum creatinine was continuously rising. Six to 15 months after the conversion, 3 patients returned to dialysis. The fourth patient, who was earlier reconverted, has a serum creatinine level of 2.0 mg/dL after 15 months. In conclusion, conversion from CsA to sirolimus may induce nephrotic syndrome with progressive deterioration of renal function. Converted patients require careful monitoring of proteinuria and renal function. Early reconversion to calcineurin inhibitor may prevent progressive deterioration of graft function.

Successful Reversal of Acute Vascular Rejection and Cyclosporine-Associated Nephrotoxicity in Renal Allograft With Combined Sirolimus and Mycophenolate Mofetil as Immunotherapy

Cyclosporine (CsA) has substantially improved patient and graft survival rates in solid organ transplantation. In clinical studies, sirolimus has been shown to be as effective as CsA to maintain survival of renal and cardiac allografts without causing nephrotoxicity. Herein we describe a patient with biopsy-proven CsA-associated nephrotoxicity and refractory renal allograft rejection who was converted from steroids, CsA, and azathioprine to steroids, sirolimus (RAPA), and low-dose mycophenolate mofetil (MMF). The follow-up period was 60 months. We observed substantial improvement, even normalization in renal function. Our patient did not give consent to repeat biopsy after conversion. We also observed a beneficial effect of CsA withdrawal on blood pressure control. The spectrum of adverse events induced by sirolimus seemed to be mild relative to the potency of the immunosuppressive effect. The excellent response to combined RAPA and MMF in this patient was probably due to “concerted actions” of these agents on both B- and T-cell functions. The combination enhanced therapeutic efficacy while minimizing the toxicity of individual drugs used in the regimen. These findings suggest that sirolimus, when used as a base therapy in combination with low-dose MMF in a renal allograft recipient, may be an alternative to CsA-based therapy, providing potent immunosuppression of a renal allograft. Sirolimus administration facilitated steroids dose reduction.

The Use of PET Scans To Direct Immunotherapy Following Reduced Intensity Stem Cell Transplants in Adults with Lymphoid Malignancies.

FDG PET scanning is increasingly being used to establish poor response and early relapse in patients with lymphoid malignancies in order to direct early intensification of treatment. We have performed a prospective study to assess the role of PET scans in directing immune manipulation (withdrawal of immune suppression and donor lymphocyte infusions (DLI)) following reduced intensity transplants (RIT) in patients with lymphoid malignancies. 34 patients (8 Hodgkin's lymphoma, 3 Mantle cell lymphoma, 23 Non-Hodgkin's Lymphoma), median age 44 years (range 20 to 64 years) have been entered since May 2002 and have > 3months follow up. PET and CT scans were performed pre-RIT and at 3, 6, 9, 15 and 24 months post RIT. Patients were conditioned with fludarabine (30mg/m2x5) and melphalan (140mg/m2x1) and in vivo alemtuzumab. Cyclosporin (CSA) was given day −1 to 3 months after RIT. Progression was defined as persistent and/or increasing PET positivity. Relapse was defined as either new PET positive imaging (PET+), progression on CT scan (CT+) or clinical progression. DLI was subsequently given to patients who progressed or relapsed at escalating doses of 1 x 106/kg T cells up to 1 x 108/kg. Patients with active GVHD were excluded from DLI.Results: 17 patients had positive PETs pre-treatment. 9 of these became PET negative, showing an anti-lymphoma effect of the conditioning regime. There were 7 TRMs, leaving 27 of 34 patients evaluable to assess the role of PET in post-transplant management. Of these 27 patients, 6 have had positive CT scans (CT+) with negative PET scans (PET-), with no evidence of clinical relapse. 10/27 patients have subsequently progressed on PET scan (PET+): 2 with PET+ and CT+ disease were not eligible for DLI (GVHD). Both progressed and died at 9 months. One patient is too early to evaluate. The remaining 7 patients received immunotherapy: 4/7 had CT negative (−) disease at PET+ relapse. One patient responded to CSA withdrawal, 6 responded to escalating DLI +/− rituximab (n=3): 3/7 having never developed CT+ disease. 2 patients have subsequently relapsed at 18 and 30 months and are being re-treated. In summary, negative PET scans prevented 6 patients from either undergoing invasive investigations or receiving potentially harmful DLI because of persistently abnormal CT scans. PET scans became positive before CT scans in 4 of 7 patients who relapsed, allowing earlier treatment with immunotherapy, resulting in PET remissions all 7 patients, 3 without CT or clinical relapse. There were no cases of CT relapse before PET relapse. The use of regular PET scanning therefore altered therapy (either delayed or initiated immunotherapy) in 10/27 (37%) evaluable patients in this study. The use of PET scans in identifying early relapse in patients undergoing RIT for lymphoid malignancies, where early DLI can be beneficial is very promising and needs further evaluation, with larger event numbers and longer follow-up.

Superior Outcomes in Renal Transplantation after Early Cyclosporine Withdrawal and Sirolimus Maintenance Therapy, Regardless of Baseline Renal Function

It has become increasingly important to refine therapeutic strategies according to individual patient characteristics. We evaluated the long-term impact of renal function at the time of withdrawing cyclosporine (CsA) in renal allograft recipients receiving sirolimus (SRL), CsA, and steroids (ST). At 3 months+/-2 weeks, 430 of 525 patients were eligible to be randomized to remain on triple-therapy (SRL-CsA-ST, n=215) or to have CsA withdrawn (SRL-ST, n=215). Patients were divided into quartiles according to their baseline (last value before randomization) calculated GFR: <or=45 ml/min (quartile 1, n=104), >45 to 56 ml/min (quartile 2, n=105), >56 to 67 ml/min (quartile 3, n=112), and >67 ml/min (quartile 4, n=107). All data were included (ITT analysis). At 4 years, calculated GFR for SRL-CsA-ST vs. SRL-ST was 22.1 vs. 37.7 ml/min (P=0.017), 38.6 vs. 56.6 ml/min (P<0.001), 50.7 vs. 66.8 ml/min (P=0.006), and 62.7 vs. 71.4 ml/min (P=0.436), for quartiles 1 to 4, respectively. Death-censored graft loss ranged from 21.2% vs. 7.7% (SRL-CsA-ST vs. SRL-ST, P=0.092) in quartile 1 to 5.5% vs. 1.9% (P=0.618) in quartile 4. The incidence of death and biopsy-confirmed acute rejection also decreased with increasing baseline GFR, but was not significantly different between treatments. Overall, more patients remained on therapy in the SRL-ST group (46.3% vs. 57.9%, P=0.020). Early and complete withdrawal of CsA from a combination of SRL, CsA, and steroids was preferable to continuing on this regimen, regardless of baseline renal function. The benefit was most marked in patients with a baseline calculated GFR<or=45 ml/min.