Cyclosporine Withdrawal Research Articles

Cyclosporine withdrawal in post‐renal transplant thrombotic microangiopathy

Thrombotic microangiopathy (TMA) is a well known complication of cyclosporine (CsA)-treated renal transplantation but optimum treatment strategies are not clearly defined. All patients transplanted between January 1996 and December 2001 at our center who had biopsy-proven TMA and in whom CsA was withdrawn were studied retrospectively. The TMA was found in nine of 688 patients (1.3%). All except one donor were living related. HLA matching was one haplotype in all except one where both haplotypes were different. There were five males and four females and the mean age was 24.9 +/- 9 yr. All of them developed TMA within 3 months of transplant. Five of nine had evidence of microangiopathic hemolysis on peripheral film. Serum creatinine at the time of diagnosis of TMA was 3.1 +/- 1.3 mg/dL. Cyclosporine was discontinued in all and mycophenolate mofetil was substituted for azathioprine. No episode of acute rejection occurred after CsA withdrawal. Graft function did not improve in four who eventually became dialysis-dependent after a mean duration of 12.6 +/- 8.3 months. Remaining patients showed stabilization or improvement in function and all had serum creatinine below 2 mg/dL after a mean follow up of 24 months. The CsA withdrawal in cases with TMA at a stage when significant functional deterioration has not taken place can salvage the graft.

Targeted Deletion of Fgl-2/Fibroleukin in the Donor Modulates Immunologic Response and Acute Vascular Rejection in Cardiac Xenografts

Xenografts ultimately fail as a result of acute vascular rejection (AVR), a process characterized by intravascular thrombosis, fibrin deposition, and endothelial cell activation. We studied whether targeted deletion of Fgl-2, an inducible endothelial cell procoagulant, (Fgl-2-/-) in the donor prevents AVR in a mouse-to-rat cardiac xenotransplantation model. By 3 days after transplant, Fgl-2+/+ grafts developed typical features of AVR associated with increased levels of donor Fgl-2 mRNA. Grafts from Fgl-2-/- mice had reduced fibrin deposition but developed cellular rejection. Treatment with a short course of cobra venom factor and maintenance cyclosporine resulted in long-term acceptance of both Fgl-2+/+ and Fgl-2-/- grafts. On withdrawal of cyclosporine, Fgl-2+/+ grafts developed features of AVR; in contrast, Fgl-2-/- grafts again developed acute cellular rejection. Rejecting Fgl-2+/+ hearts stained positively for IgG, IgM, C3, and C5b-9, whereas rejecting Fgl-2-/- hearts had minimal Ig and complement deposition despite xenoantibodies in the serum. Furthermore, serum containing xenoantibodies failed to stain Fgl-2-/- long-term treated hearts but did stain wild-type heart tissues. Treatment of Fgl-2-/- xenografts with mycophenolate mofetil and tacrolimus, a clinically relevant immune suppression protocol, led to long-term graft acceptance. Deletion of Fgl-2 ameliorates AVR by downregulation of xenoantigens and may facilitate successful clinical heart xenotransplantation.

Predictive Factors of Acute Rejection after Early Cyclosporine Withdrawal in Renal Transplant Recipients Who Receive Mycophenolate Mofetil

The aim of this randomized, open-labeled trial was to compare the incidence of acute rejection after an early (3 mo posttransplantation) withdrawal of cyclosporine (CsA) or mycophenolate mofetil (MMF) in renal transplantation. Among 218 eligible recipients, 108 nonsensitized, rejection-free patients who were under a triple drug regimen (CsA-MMF-prednisone) and had received a first kidney from a deceased donor were enrolled. At 3 mo after graft, they were gradually withdrawn from CsA (MMF group, n = 54) or MMF (CsA group, n = 54). A graft biopsy and a pharmacokinetic study of CsA and mycophenolic acid were systematically performed before the randomization. At 1 yr, graft and patient survival rates were 100% in each group. Renal function was improved in the MMF group compared with the CsA group (Cockcroft calculated clearance 64.7 +/- 18.7 versus 56.5 +/- 18.0 ml/min; P = 0.023). However, the probability of acute rejection was higher in the MMF group (18.5 versus 5.6%; P = 0.045). The 10 patients who developed acute rejection after CsA withdrawal had a significantly higher incidence of borderline changes on the randomization biopsy than the 44 rejection-free patients (five of 10 versus eight of 44; P = 0.034), and they displayed a lower area under the curve of mycophenolic acid (43 +/- 9 versus 58 +/- 22 mg/h per L; P = 0.045). Multivariate analysis confirmed that borderline changes and area under the curve of mycophenolic acid were significant risk factors of acute rejection after CsA discontinuation. It is concluded that a systematic graft biopsy and a pharmacokinetic study of mycophenolic acid are needed to reduce the risk for acute rejection after CsA withdrawal.

Cyclosporine Withdrawal from a Mycophenolate Mofetil–Containing Immunosuppressive Regimen

Maintenance immunosuppression with cyclosporine (CsA) is associated with nephrotoxicity, hyperlipidemia, and hypertension. This long-term study (core study + 4 yr of follow-up) investigated the long-term efficacy and safety of CsA withdrawal from a mycophenolate mofetil (MMF)-based regimen. Seventy-seven patients were maintained on CsA, MMF, and steroids (CsA-MMF group), and 74 were given a CsA-free regimen of MMF and steroids (MMF group). Serum creatinine and creatinine clearance were measured at 6-month intervals. Patient and graft survival, acute rejection episodes, malignancies, BP, and lipid profile were also recorded. At 5 yr, patient and graft survival was 93 and 88%, respectively, for the MMF group and 95 and 92%, respectively, for the CsA-MMF group. During follow-up, seven MMF patients experienced acute rejection episodes compared with one CsA-MMF patient (P = 0.0283). Nine grafts were lost to chronic rejection in the MMF group versus three in the CsA-MMF group. No demographic or immunologic characteristics were associated with acute or chronic rejection in the MMF group, but the doses of both MMF and steroids decreased significantly between 1 and 5 yr. The MMF group showed a trend toward improved creatinine clearance (67.4 versus 61.7 ml/min; P = 0.0500). Withdrawal of CsA from an MMF-containing immunosuppressive regimen resulted in an increased risk for acute rejection episodes and graft loss as a result of rejection throughout the 5-yr study period. The creatinine clearance-confirmed improvement in renal function observed at year 1 was maintained at 5 yr BP and cholesterol levels were well controlled in both groups.

Differential Effects of Cyclosporine and Tacrolimus on Mycophenolate Pharmacokinetics in Patients With Impaired Kidney Function

In a single-center prospective randomized controlled study, the impact of calcineurin inhibitor (CNI) reduction or withdrawal on the pharmacokinetics of mycophenolic acid (MPA) was studied in a group of renal transplant recipients with impaired renal function. Mycophenolate mofetil (MMF) was added to a baseline regimen of prednisolone and CNI. Afterwards the patients were randomized into “CNI withdrawal” and “CNI continuation” groups. The dosage of CNIs, cyclosporine or tacrolimus, was gradually reduced and withdrawn within 6 weeks from patients in the withdrawal group. The continuation group was maintained on therapy with CNI, MMF, and steroids. These regimens were maintained until the ninth month. In contrast to the withdrawal of tacrolimus, which has no significant effect on MPA pharmacokinetics, cyclosporine withdrawal was associated with a significant increase in the trough levels and areas under the curve of MPA. Serum creatinine and urine albumine levels stabilized on average after CNI withdrawal in this population. The results are consistent with the hypothesis that cyclosporine attenuates the enterohepatic recirculation of MPA. The withdrawal of CNI has a positive effect on renal function in chronic allograft dysfunction.

Cyclosporine A, Alpha-Interferon and Interleukin-2 Following Chemotherapy with BCNU, DTIC, Cisplatin, and Tamoxifen: A Phase II Study in Advanced Melanoma

Preclinical data suggest that one method of inducing autoimmunity to tumor is the administration and subsequent withdrawal of cyclosporine A following chemotherapy and that this effect may be enhanced with interferon and interleukin-2. Consequently, we performed a phase II trial in patients with advanced melanoma to explore this approach. Thirty-three patients were treated with BCNU (150 mg/m2 iv every 8 weeks), cisplatin (25 mg/m2 iv days 1–3) every 4 weeks, DTIC (220 mg/m2 iv days 1–3 every 4 weeks) along with tamoxifen (10 mg po BID days 1–4). Cyclosporine A at 3 mg/kg/day in two divided doses was given on days 4–21, alpha-interferon 1 million units/m2 subcutaneously every other day on days 4–21 and interleukin-2 1 million units/m2 BID subcutaneously days 21–28 were also given. Of the 33 patients, 3 patients (9%) had complete response and 8 patients (24%) had a partial response for a total response rate of 33% (95% confidence interval 18–52%). Median duration of response was 17 months (range 3 + to 24 + months). Six patients continue to show no signs of tumor progression for 3 +, 5 +, 10 +, 24 +, 60 +, and 72 + months. Toxicity was generally well tolerated and included myelosuppression and fatigue. This regimen is feasible and generally tolerable and has produced an antitumor response rate comparable with inpatient biochemotherapy regimens.

Non-Hodgkin's Lymphoma Manifest as Gingival Hyperplasia in a Renal Transplant Recipient

Gingival hyperplasia is a frequent complication in transplant patients who receive cyclosporine or calcium channel blockers. We studied an unusual case involving a renal transplant recipient with post-transplant non-Hodgkin's lymphoma that manifested as gingival hyperplasia. We initially consider that it was a side effect of cyclosporine and nifedipine. The lesion did not respond to dose reductions or the withdrawal of cyclosporine and nifedipine, and the gingival hyperplasia progressed in a localized fashion, becoming ulcerated and bleeding easily. Histological examination revealed the presence of malignant lymphoma.

Cyclosporine A, Alpha-Interferon and Interleukin-2 Following Chemotherapy with BCNU, DTIC, Cisplatin, and Tamoxifen: A Phase II Study in Advanced Melanoma

Preclinical data suggest that one method of inducing autoimmunity to tumor is the administration and subsequent withdrawal of cyclosporine A following chemotherapy and that this effect may be enhanced with interferon and interleukin-2. Consequently, we performed a phase II trial in patients with advanced melanoma to explore this approach. Thirty-three patients were treated with BCNU (150 mg/m2 iv every 8 weeks), cisplatin (25 mg/m2 iv days 1–3) every 4 weeks, DTIC (220 mg/m2 iv days 1–3 every 4 weeks) along with tamoxifen (10 mg po BID days 1–4). Cyclosporine A at 3 mg/kg/day in two divided doses was given on days 4–21, alpha-interferon 1 million units/m2 subcutaneously every other day on days 4–21 and interleukin-2 1 million units/m2 BID subcutaneously days 21–28 were also given. Of the 33 patients, 3 patients (9%) had complete response and 8 patients (24%) had a partial response for a total response rate of 33% (95% confidence interval 18–52%). Median duration of response was 17 months (range 3 + to 24 + months). Six patients continue to show no signs of tumor progression for 3 +, 5 +, 10 +, 24 +, 60 +, and 72 + months. Toxicity was generally well tolerated and included myelosuppression and fatigue. This regimen is feasible and generally tolerable and has produced an antitumor response rate comparable with inpatient biochemotherapy regimens.

Cardiovascular risk profile in patients treated with sirolimus after renal transplantation

Renal transplant patients are inherently predisposed to cardiovascular disease (CVD) as a result of prolonged exposure to multiple cardiovascular risk factors. Approximately one half of all late graft losses are due to death with a functioning graft, and CVD is the most frequent cause of death with a functioning graft among these patients. Immunosuppressive therapies associated with a reduced burden of risk for CVD would therefore greatly decrease post-transplantation morbidity and mortality. The nephrotoxic effects observed with the use of calcineurin inhibitors (CNIs), such as cyclosporine (CsA), run counter to the goal of renal transplant therapy. Sirolimus, a more recent immunosuppressive agent with a unique mechanism of action, offers an alternative to CsA. Recent data from a 4-year study investigating early CsA withdrawal from a sirolimus-CsA-steroid (SRL-CsA-ST) combination demonstrated significantly better renal function, lower blood pressure, and improved graft survival after CsA withdrawal. During that trial, the increase in serum lipids induced by sirolimus was generally manageable with lipid-lowering therapy. Further investigation is warranted to evaluate the value of CNI-free therapy compared with CNI-based regimens in reducing cardiovascular risk factors and improving patient and graft survival.

Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation

We report the 48-month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL-CsA-ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL-CsA-ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL-ST, n = 215). SRL-ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL-ST. Differences in the incidences of biopsy-proven acute rejection after randomization (6.5% vs. 10.2%, SRL-CsA-ST versus SRL-ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL-CsA-ST-treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL-ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL-CsA-ST regimen rapidly improves renal function and ultimately results in better graft survival.

A Randomized Controlled Trial of Cyclosporine Withdrawal in Renal-Transplant Recipients: 15-Year Results

In renal transplantation, the immunosuppressive efficacy of cyclosporine is counterbalanced by its nephrotoxicity. Although cyclosporine improves short-term graft survival, its long-term effects are unclear. Recipients of first cadaver renal transplants were randomized into three groups between 1983 and 1986: azathioprine and prednisolone alone (AP, n = 158), long term cyclosporine alone (Cy, n = 166), and short-term cyclosporine followed by azathioprine and prednisolone (CyAP, n = 165). All groups received methylprednisolone induction. There were no significant differences in patient survival at 15 years (48 vs. 56 vs. 51%, P = 0.14), and 15-year graft survival (censored for death) in those patients in the CyAP group (47 vs. 44 vs. 59%, P = 0.06) was not significantly different statistically. When deaths or graft losses before 12 months were censored, the differences in 15-year graft survival between the groups were significant (58%, 51%, 70%, P = 0.01). The CyAP group also had lower mean serum creatinine at all time points beyond 3 months posttransplant out to 10 years (143 vs. 169 vs. 131 micromoles/L, P = 0.04). Per protocol analysis, after censoring patients at change in therapy, increased the observed differences in 15-year graft survival between the groups (54 vs. 38 vs. 65%, P = 0.01). Survival and function of first cadaveric kidney transplants is improved by use of short-term cyclosporine followed by azathioprine and prednisolone. Long-term cyclosporine use reduces long-term graft survival.

FATE OF DONOR KIDNEY: LAPAROSCOPIC VERSUS OPEN TECHNIQUE

Laparoscopic donor nephrectomy (LDN) is an increasingly accepted modality for procuring donor kidneys for transplantation. We analyzed and compared the short and long-term outcomes of living transplant allografts from kidneys procured by laparoscopic or open donor (ODN) technique and managed with a single immunosuppression regimen in each group. Records of recipients who underwent living (laparoscopic or open) donor nephrectomy were reviewed from August 1999 to July 2001 for LDN and from January 1994 to December 1999 for ODN. Patients included were on a single immunosuppression regimen particular to each group. Sirolimus, mycophenolate mofetil and prednisone were given to the LDN group, and calcineurin inhibitor (FK-506 or cyclosporine), mycophenolate mofetil and prednisone were given to the ODN group. Excluded from study were patients with prior kidney transplant or patients not receiving immunosuppression as previously described. Also excluded from study were patients lost to followup before 1 year. Data were retrieved retrospectively from case notes or from the transplant database and analyzed using SAS software (SAS Institute, Cary, North Carolina). A total of 71 patients from the LDN group and 60 patients from the ODN group qualified for the study. Demographic data are comparable in both groups except for the significantly longer followup in the ODN group. Serum creatinine was 2.2 and 1.8 mg/dl at postoperative day 4, 1.3 and 1.3 mg/dl at day 10, and 1.3 and 1.4 mg/dl at 1 month in the LDN and ODN groups, respectively. Time to achieve nadir serum creatinine was 8.7 versus 6.6 days for LDN and ODN groups, respectively (p = not significant). Delayed graft function was noted in 5 of 71 (7%) in the LDN group and 3 of 60 (5%) in the ODN group (p = 0.5). In the LDN group 13 (18%) patients had a serum creatinine of greater than 1.5 mg/dl at postoperative day 30 compared to 6 (10%) in the ODN group (p = 0.06). Mean serum creatinine at 1 year was lower for LDN recipients (p = not significant). But at last followup this difference became statistically significant in favor of LDN. Mean followup was 939 versus 2,046 days for LDN versus ODN, respectively (p <0.0001). Recipient mean hospital stay was 5.2 versus 6.7 days for LDN versus ODN, respectively (p = 0.08). There were 8 of 78 (10.2%) episodes of acute rejection in the LDN group compared to 22% in the ODN group (p = 0.08). The complication rate (ureteral vascular, lymphocele, acute rejection and wound) was 11% in LDN compared to 15% in the ODN group. Long-term graft function, graft survival and patient survival in the LDN group were comparable to the ODN group. Early graft recovery is slower in LDN allografts, although not statistically significant, but long-term function in the LDN group is significantly better compared to the ODN group. Laparoscopic donor kidneys take longer to achieve nadir serum creatinine, but this does not influence long-term outcome and results.

ABO Incompatible Allogeneic Stem-Cell Transplantation Following Reduced-Intensity Conditioning: Close Association with Thrombotic Microangiopathy.

Thrombotic microangiopathy (TM) is a severe complication of stem cell transplantation (SCT) associated with high mortality rates. One of the major risk factors for the development of TM is the toxic effect of high-dose chemo-radiotherapy, heavy pretreatment and the use of unrelated donors (URD) grafts. To reduce transplant related mortality in patients at risk non myeloablative conditioning regimens have been introduced.We reviewed data on 83 consecutive patients given sibling (n=44) and URD (n=39) SCT after reduced intensity conditioning and graft versus host (GvHD) prophylaxis with CsA and mycophenolate mofetil with respect to occurence of TM. Diagnoses consisted of ALL (n=5), AML (n=31), CML (n=8), MDS (n=6), MM (n=11), NHL (n=17), renal cell cancer (n=4) and n. ovarii (n=1). A group of 565 patients undergoing high-dose conditioning followed by sibling (n=372) an URD (n=193) SCT served as control. The majority of these patients received CsA and MTX as GvHD prophylaxis. The diagnoses of TM was confirmed by renewed thrombocytopenia, coombs negative hemolysis, increased LDH-levels and fragmented red cells in peripheral blood smears. TM occured in 9 of 83 patients (11%) after RIC compared to 25 of 565 patients (4,4%) after high-dose conditioning, respectively. All but one patient in the RIC group received an ABO-incompatible stem cell graft (p< 0.05). The median time of onset of TM was 62 days after SCT (range, 9 to 906 days) in this group. Donor source (sibling/URD) had no influence on the risk of developing TM (p=0.07). TM was associated with severe acute GvHD (n=2), chronic extensive GvHD (n=3), sepsis (proteus mirabilis n=1), herpes virus infection (n=1), severe hemolysis after minor ABO-incompatible SCT (n=1) and computed tomography approven atypical pneumonia (n=1). First line treatment consisted of withdrawal of cyclosporine A and plasmaexchange treatment (median exchange procedures 14, range 8 to 30). Overall, 5of 9 (55%) patients responded, 3 patients died due to GvHD and TM, 1 of multi- organ failure. One patient who responded to plasmaexchange died 1 year later due to relapse.Posttransplant TM is a common severe complication and seems to increase after reduced-intensity conditioning. Fludarabin, a major constitute of RIC, is not reported to cause TM. How far GvHD-prophylaxis without MTX plays a role in the development of TM remains unclear. Of particular importance is that patients receiving ABO-incompatible stem cell grafts have a significant higher risk to develop TM after allogeneic SCT following reduced-intensity conditioning.

Early Cyclosporine A Withdrawal in Kidney-Transplant Recipients Receiving Sirolimus Prevents Progression of Chronic Pathologic Allograft Lesions

Nephrotoxicity of calcineurin inhibitors (CNIs) is partially responsible for the development of chronic allograft nephropathy (CAN). Sirolimus has demonstrated its potential to substitute for CNIs because it lacks significant nephrotoxicity and shows a short-term immunosuppressive capacity comparable with that of cyclosporine. This results in the maintenance of better renal function when cyclosporine is eliminated, but it has not been demonstrated whether this benefit is associated with an improvement in the pathologic substrate and a reduction in CAN. We analyzed pretransplant and 1-year renal-allograft biopsies from 64 patients enrolled in a multicenter trial. Patients received cyclosporine and sirolimus during the first 3 months after transplant and were then randomly assigned to continue with cyclosporine or have it withdrawn. Histologic chronic allograft lesions were compared between groups. The percentage of patients in whom chronic pathologic lesions progressed was lower in the group of cyclosporine elimination. Significant differences were observed in chronic interstitial and tubular lesions (70% vs. 40.9% [P<0.05] and 70% vs. 47.8% [P<0.05], respectively), whereas no differences were observed in acute lesions (subclinical rejection). Prevalence of CAN at 1 year was lower in this group, as was the severity and incidence of new cases (P<0.05). Early cyclosporine withdrawal associated with sirolimus administration is followed by an improvement in renal function, a reduction in the progression of chronic pathologic allograft lesions, and a lower incidence of new cases and severity of CAN during the first year after transplantation. This benefit may result in better long-term graft outcome.

Prognostic factors for survival in renal cell cancer patients undergoing allogeneic stem cell transplantation: A report from the EBMT Solid Tumours Working Party

6666 Background: An immune-mediated graft-versus-tumor (GVT) effect has been reported to occur in patients with metastatic renal carcinoma receiving allogeneic transplantation. However, the onset of GVT effect is typically delayed by months from the time of the transplant, and usually follows cyclosporine withdrawal. Indeed, most patients show a tumor progression soon after the transplant, and it is questionable if patients with rapidly progressive tumor should be included in allografting protocols. Methods: We identified poor prognosis patients as those with four or more out of ten analysed prognostic factors. Prognostic factors examined were: ECOG PS; time interval from diagnosis to occurence of metastases; number of metastatic sites; liver metastases; mediastinal metastases; Hb; CRP; LDH; neutrophils; and calcium. We report the data on 53 patients with clear-cell renal carcinoma transplanted in Europe with various fludarabine-based, reduced-intensity conditioning regimens. Survival was measured from transplant date to death or last follow-up. Results: Median survival for poor-prognosis patients was 140 days, vs 820 days for good-prognosis patients. Conclusions: Identification of prognostic subgroups can assist in result evaluation and clinical decision making about allografting in renal cell carcinoma. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Funded by the Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research), a non-profit cancer-funding agency

Prognostic factors for survival in renal cell cancer patients undergoing allogeneic stem cell transplantation: A report from the EBMT Solid Tumours Working Party

6666 Background: An immune-mediated graft-versus-tumor (GVT) effect has been reported to occur in patients with metastatic renal carcinoma receiving allogeneic transplantation. However, the onset of GVT effect is typically delayed by months from the time of the transplant, and usually follows cyclosporine withdrawal. Indeed, most patients show a tumor progression soon after the transplant, and it is questionable if patients with rapidly progressive tumor should be included in allografting protocols. Methods: We identified poor prognosis patients as those with four or more out of ten analysed prognostic factors. Prognostic factors examined were: ECOG PS; time interval from diagnosis to occurence of metastases; number of metastatic sites; liver metastases; mediastinal metastases; Hb; CRP; LDH; neutrophils; and calcium. We report the data on 53 patients with clear-cell renal carcinoma transplanted in Europe with various fludarabine-based, reduced-intensity conditioning regimens. Survival was measured from transplant date to death or last follow-up. Results: Median survival for poor-prognosis patients was 140 days, vs 820 days for good-prognosis patients. Conclusions: Identification of prognostic subgroups can assist in result evaluation and clinical decision making about allografting in renal cell carcinoma. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Funded by the Associazione Italiana per la Ricerca sul Cancro (Italian Association for Cancer Research), a non-profit cancer-funding agency

Sirolimus-Based Therapy Following Early Cyclosporine Withdrawal Provides Significantly Improved Renal Histology and Function at 3 Years

Graft function and histology are predictive of renal transplant survival. The Rapamune Maintenance Regimen study demonstrated that early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen improved renal function and blood pressure. We report the protocol-mandated biopsy findings from that study. Renal transplant patients (n = 430) receiving SRL-CsA-ST were randomized at 3 months after transplantation to remain on SRL-CsA-ST, or to have CsA withdrawn (SRL-ST group). Protocol-mandated biopsies were performed at engraftment and at 12 and 36 months. Two pathologists blindly evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. At 36 months among patients with serial biopsies (n = 63), the mean CADI score was significantly lower with SRL-ST(4.70 vs. 3.20, p = 0.003), as was the mean tubular atrophy score (0.77 vs. 0.32, p < 0.001). All six components of the CADI score were numerically lower in SRL-ST group; moreover, inflammation and the tubular atrophy scores decreased significantly in the SRL-ST group between 12 and 36 months. The calculated glomerular filtration rate at 36 months was significantly better in the CsA-withdrawal group (54.8 vs. 68.2 mL/min, p = 0.009). In conclusion, withdrawing CsA from the SRL-CsA-ST regimen resulted in improved renal histology and function.

Withdrawal of Cyclosporine or Tacrolimus After Addition of Mycophenolate Mofetil in Patients With Chronic Allograft Nephropathy

There has been a need for a prospective, randomized, controlled trial to determine whether the addition of mycophenolate mofetil (MMF) to a calcineurin inhibitor (CNI)-based regimen or MMF addition followed by CNI withdrawal is an effective treatment for chronic allograft nephropathy (CAN). We conducted the first randomized, prospective study to compare the introduction of MMF with or without CNI withdrawal in long-term transplant recipients with histologically proven CAN and deteriorating renal function. The primary endpoint was renal function as indicated by the slope of the inverse serum creatinine vs. time at 32 weeks after randomization. After an interim analysis found a greater-than-expected difference between groups in the slopes of the inverse serum-creatinine, the study was stopped for ethical reasons. There were 20 patients in the MMF/CNI continuation and 19 patients in the MMF/CNI withdrawal groups (mean time post-transplant 7 years). Renal function improved in the dual-therapy compared with the triple-therapy group (p = 0.002). Blood pressure decreased in the dual-therapy group with a significant difference between groups at 35 weeks (p = 0.04). No acute rejections occurred. Long-term patients with CAN experience a significant improvement in renal function and blood pressure when CNIs are replaced by MMF.

Thrombotic microangiopathy following stem cell transplantation

Stem cell transplantation associated microangiopathy (TA-TMA) occurs in about 7% of all transplantations. While it resembles in all its features idiopathic TTP or HUS, response to plasma therapy is poor. The overall mortality of patients afflicted with TA-TMA is about 80%. Comparative studies aimed at discovering risk factors for the development of TA-TMA and defined different entities according to clinical, laboratory and outcome parameters. It is thought to be of multifactorial aetiology with the central event of endothelial damage. Intensive chemotherapy and radiation for bmt-preparation, infection in the immunocompromised host and graft versus host disease in conjunction with immunosuppressive therapy i. e. cyclosporine turn the haemostatic balance into a procoagulant state. Therapeutic strategies deduced from idiopathic TTP were disappointing with the only consensus in the withdrawal of cyclosporine from TA-TMA patients. Future trials are directed to ameliorate endothelial dysfunction.

Thrombotische Mikroangiopathie nach Stammzelltransplantation

ZusammenfassungDie Stammzelltransplantation-assoziierte thrombotische Mikroangiopathie (TA-TMA) tritt bei ca. 7% aller Transplantationen auf. Während sie alle Zeichen der idiopathischen TTP oder des HUS aufweist, zeigt die Plasmatherapie kaum Erfolg. Insgesamt versterben mehr als 80% der TA-TMA-Patienten. Der Vergleich von Fallberichten konnte Risikofaktoren für die Entwicklung einer TA-TMA aufdecken und unterschiedliche Varianten der Erkrankung anhand klinischer und labordiagnostischer Parameter sowie der therapeutischen Beeinflussbarkeit definieren. Es wird eine multifaktorielle Ätiologie angenommen, deren zentrale Gemeinsamkeit die Endothelschädigung ist. Das Gerinnungssystem wird durch intensive chemo- und strahlentherapeutische Konditionierungsbehandlung, Infektionen und Graft-versus-host-Reaktion in Verbindung mit der immunsuppressiven Therapie (v. a. Cyclosporin A) in Richtung prokoagulanter Status verschoben. Die bisherigen von der idiopathischen TTP übernommenen Therapieansätze verliefen enttäuschend. Das Absetzen von Cyclosporin ist der einzige Konsens in diesem Zusammenhang. Zukünftige Behandlungsansätze zielen auf Minimierung des Endothelschadens.