C4d-positive acute humoral renal allograft rejection: rescue therapy by immunoadsorption in combination with tacrolimus and mycophenolate mofetil

OBJECTIVE: We investigated the efficacy of immunoadsorption (IA) in combination with tacrolimus (FK506) and mycophenolate mofetil (MMF) rescue therapy for C4d-positive acute humoral rejection (AHR) of renal transplants. METHODS: Six of 185 cadaveric renal allograft recipients developed AHR at a mean of 4.8 +/- 0.8 days after the operation. C4d deposits were observed in peritubular capillaries (PTC) with accumulation of granulocytes. IA with staphylococcal protein A and FK506-MMF combination therapy were administered. RESULTS: After treatment with IA for 6.3 +/- 1.03 sessions combined with FK506 (0.14 to 0.16 mg.kg(-1).d(-1)) and MMF (1.5 g/d) therapy, renal function recovered in all the patients. The mean duration of treatment to a serum creatinine decrease was 14 +/- 2.9 days. The pre-IA panel reactive antibody reactivity (PRA) peaked at 50.2% +/- 6.1%, and was significantly reduced to 8.3% +/- 2.9% after IA. In four of six patients repeat allograft biopsy revealed a remission of AHR. With a mean follow-up of 18.8 +/- 5.46 months, patient and allograft survival are 100% and renal function remains stable with a mean serum creatinine of 1.2 +/- 0.22 mg/dL. CONCLUSION: The optimal treatment for alloantibody-mediated AHR remains uncertain. Our findings suggest that a therapeutic approach combining IA and FK506-MMF rescue improves the outcome of AHR.     

免疫吸附联合他克莫司和霉酚酸酯逆转肾移植后急性体液性排斥反应

目的探讨免疫吸附(IA)联合他克莫司(FK506)和霉酚酸酯(MMF)治疗C4d阳性的急性体液性排斥反应(AHR)的临床效果。方法1999年4月至2003年6月间行同种异体尸肾移植490例,其中9例受者发生AHR,其诊断均依据Banff 97标准,Banff分级为Ⅱ级5例,Ⅲ级4例。患者发生AHR后均采用免疫吸附联合FK506 MMF 激素治疗,同时辅以连续性血液净化。治疗前、后行移植肾活检,分别进行病理观察、免疫荧光和免疫组织化学检测,同时检测患者血清HLA、免疫球蛋白水平以及肝、肾功能。结果治疗后,9例AHR患者中有8例得到逆转;1例治疗无效,转而采用血液透析治疗。患者的HLA-Ⅰ、Ⅱ水平较治疗前明显下降,分别为(5.9±2.9)%和(2.2±0.6)%;血清总的免疫球蛋白水平也明显降低;患者移植肾肾小管周围毛细血管C4d沉积强度较治疗前明显减轻,其中5例患者C4d转阴;肾小球浸润细胞明显减少,肾小管炎症减轻,间质浸润细胞减少,血管炎减轻。患者在接受免疫吸附治疗过程中均未出现严重并发症。结论免疫吸附联合FK506 MMF可有效地逆转C4d阳性的急性体液性排斥反应。     

C4d-positive acute humoral renal allograft rejection: effective treatment by immunoadsorption.

There is increasing evidence for an important pathogenetic role of alloantibodies in acute renal allograft rejection. Acute humoral rejection (AHR) has been reported to be associated with a poor transplant survival. Although treatment modalities for cellular rejection are fairly well established, the optimal treatment for AHR remains undefined. Ten of 352 kidney allograft recipients transplanted at the authors' institution between November 1998 and September 2000 were diagnosed as having AHR, supported by severe graft dysfunction, C4d deposits in peritubular capillaries (PTC), and accumulation of granulocytes in PTC. AHR was diagnosed 18.9 +/- 17.5 d posttransplantation. All patients were subjected to immunoadsorption (IA) with protein A (median number of treatment sessions, 9; range, 3 to 17). Seven recipients with additional signs of cellular rejection (according to the Banff classification) received also antithymocyte globulin. In nine of ten patients, AHR was associated with an increase in panel reactive antibody reactivity. A pathogenetic role of alloantibodies was further supported by a positive posttransplant cytotoxic crossmatch in all tested recipients (n = 4). In nine of ten recipients, renal function recovered after initiation of anti-humoral therapy. One patient lost his graft shortly after initiation of specific therapy. Another recipient with partial reversal of AHR returned to dialysis 8 mo after transplantation. Mean serum creatinine in functioning grafts was 2.2 +/- 1.2 mg/dl after the last IA session (n = 9) and 1.5 +/- 0.5 mg/dl after a follow-up of 14.2 +/- 7.1 mo (n = 8). In conclusion, this study suggests that AHR, characterized by severe graft dysfunction, C4d staining, and peritubular granulocytes, can be effectively treated by timely IA. In the majority of patients, IA treatment can restore excellent graft function over a prolonged time period.     

Late developing C4d-positive humoral renal allograft rejection associated with withdrawal of mycophenolate mofetil

In renal transplantation, C4d-positive acute humoral rejection (AHR) usually develops in the early stage posttransplantation. It is clear C4d can be detected late after the operation, when it is associated with chronic renal allograft rejection. We report a case of a renal allograft recipient who experienced C4d-positive acute renal allograft rejection associated with withdrawal of mycophenolate mofetil (MMF) at 10 months after transplantation. This 21-year-old single male patient received his first cadaveric renal allograft under immunosuppression with cyclosporine, MMF, and prednisolone. The serum creatinine recovered to the normal range within 4 days. A protocol biopsy performed at 1 month after transplantation revealed no signs of rejection. The graft function was stable until 10 months postoperation, when MMF was converted to mizoribin. Three days later a biopsy showed a C4d-positive rejection. Patient had no response to the MMF combined with tacrolimus and steroid bolus therapy, which generally improves 85% of AHR among Chinese. He finally returned to dialysis. Our report suggested that C4d positive AHR may occur late after transplantation. MMF is important to suppress the body's humoral response to allograft; when MMF was converted to a weaker immunosuppressant, the dose of the other immunosuppressants (cyclosporine for example) must be adjusted properly.     

Novel rescue therapy for C4d-positive acute humoral renal allograft rejection

OBJECTIVE: To investigate the efficacy of immunoadsorption (IA) in combination with tacrolimus (TAC) and mycophenolate mofetil (MMF) rescue therapy for C4d-positive acute humoral rejection (AHR) of renal transplants. METHODOLOGY: Six of 185 cadaveric renal allograft recipients transplanted at our institute developed AHR over a mean period of 4.8 +/- 0.8 d after operation. The ages ranged from 35 to 51 yr (mean 42.6 +/- 5.6 yr). C4d deposits in peritubular capillaries (PTC) and accumulation of granulocytes in PTC were observed. IA with staphylococcal protein A and TAC-MMF combination therapy were given. RESULTS: After subjected to IA for 6.3 +/- 1.03 sessions combined with TAC (0.14-0.16 mg/kg/d) and MMF (1.5 g/d) therapy, renal function recovered in all the patients. The mean duration of treatment when serum creatinine decreased was 14 +/- 2.9 d. The pre-IA panel reactive antibody reactivity was as high as 50.2 +/- 6.1%, and was significantly reduced to 8.3 +/- 2.9% after IA. Repeated allograft kidney biopsy in four of six patients revealed a favorable remission of AHR. With a mean follow-up of 18.8 +/- 5.46 months, patient and allograft survival are 100%, renal function remained stable with a mean serum creatinine of 1.2 +/- 0.22 mg/dL. CONCLUSION: The optimal treatment for alloantibody-mediated AHR remains undefined. Our findings suggest that a therapeutic approach combining IA and TAC-MMF rescue has excellence to improve the outcome of AHR.     

Tacrolimus combined with mycophenolate mofetil can effectively reverse C4d-positive steroid-resistant acute rejection in Chinese renal allograft recipients.

BACKGROUND: Tacrolimus (TAC) combined with mycophenolate mofetil (MMF) has been suggested to play a critical role in the reversal of C4d-positive acute humoral rejection (AHR) in renal transplantation, but the efficacy of using only TAC-MMF without immunoadsorption or plasmapheresis has not been investigated. On the other hand, Chinese recipients of renal grafts usually need lower doses of immunosuppressants, and their optimal treatment for acute humoral rejection has not been established. METHODS: Since 1999, we have used TAC-MMF to treat steroid-resistant acute rejection (AR). C4d staining was retrospectively performed in 32 patients with steroid-resistant AR, and the treatments of 19 patients with C4d-positive steroid-resistant AR were investigated. RESULTS: Thirteen of 19 patients received TAC-MMF treatment only; 11 episodes of rejection in them were reversed (7 completely, 4 partially) and only 2 recipients lost their graft. Another 6 patients received immunoadsorption also. One of them failed to respond and lost her graft. Four of 5 patients treated with immunoadsorption and TAC-MMF recovered (3 completely, 1 partially), but 3 of them had severe pneumonia, a complication rate statistically higher than in patients treated with only TAC-MMF (P<0.05). AR occurring during the first two weeks after transplantation had a statistically better outcome than that occurring later (P = 0.003). CONCLUSION: Our study suggests that the combination of TAC and MMF is a potentially safe and economic treatment for most Chinese renal allograft recipients with C4d-positive steroid-resistant AR, especially for rejections developing within the first two weeks after transplantation.     

Treatment of early mixed cellular and humoral renal allograft rejection with tacrolimus and mycophenolate mofetil

This prospective study investigated the efficiency of the tacrolimus (Tac) combined with mycophenolate mofetil (MMF) alone without immunoadsorption (IA) or plasmapheresis (PPH) as treatment for early (within 2 weeks) acute humoral rejection (AHR) in non-sensitized renal allograft recipients. Of 160 patients enrolled in this prospective study, 11 patients had histologically and clinically confirmed early steroid-resistant acute rejection with an antibody response and received Tac-MMF therapy. No other aggressive rescue methods such as IA, PPH were used, according to the study design. Patients (n=11) were followed for 13.8+/-3.5 months; nine were females. The complement-dependent cytotoxicity crossmatch was negative before transplantation in all patients and only positive for panel-reactive antibody in one patient. Most of the rejection episodes were mixed with cellular rejection (four patients met Banff IIA criteria, five patients met Banff IIB, one patient met Banff IB, and one patient met Banff borderline). After 16.19+/-6.16 days of treatment, all rejection episodes were successfully reversed and all graft functions were stable, with a mean serum creatinine level of 1.12+/-0.32 mg/dl during follow-up. No patient suffered from severe infectious complications (except one case of urinary infection). Our investigation suggests that Tac combined with MMF alone is adequate to reverse early mixed cellular and humoral C4d-positive rejection in non-sensitized renal allograft recipients.     

Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection

BACKGROUND: In renal transplantation, chronic rejection is a major cause of late allograft loss. Recent studies indicate that a subset of chronic rejection is associated with anti-HLA donor specific antibodies (DSA) and complement C4d deposition in peritubular capillaries (PTC). Since rescue therapy with tacrolimus and mycophenolate mofetil has been found to limit antidonor B-cell responses in recipients with acute humoral rejection, we sought to determine whether a similar immunosuppressive regimen might be effective in patients with 'chronic humoral rejection'. METHODS: Four renal allograft recipients with 'chronic humoral rejection' were prospectively identified. The diagnosis was based on: (1) progressive rise in serum creatinine over 12 months; (2) typical pathologic features by light microscopy (transplant arteriopathy and glomerulopathy); (3) widespread C4d deposits in PTC by immunofluorescence; (4) detection of 'de novo' DSA at the time of biopsy. Maintenance immunosuppression was CsA, prednisone and azathioprine (n=3) or prednisone and azathioprine (n=1). Rescue therapy with tacrolimus and mycophenolate mofetil was initiated in all patients, 12 hr after cyclosporine and azathioprine discontinuation. RESULTS: At diagnosis, the mean serum creatinine was 3.9 mg/dl (range: 3.3 to 5.4 mg/dl). DSA was an IgG directed against HLA class II (n=3) or class I (n=2), that is one patient had both anti-HLA class I and class II antibodies. Pretreatment antibody titers varied between 1:8 and 1:128. Rescue therapy was associated with a rapid and sustained decrease in antibody titers. In two patients, DSA became undetectable after 9 months and a repeat biopsy performed after 12 months revealed a decrease in C4d deposition in PTC. CONCLUSION: These results suggest that a decrease in DSA production can be induced in renal allograft recipients with 'chronic humoral rejection' by using an immunosuppressive regimen that combines tacrolimus and mycophenolate mofetil. Limitation of antidonor antibody synthesis may be important for the treatment or the prevention of chronic rejection in organ transplantation.     

Treatment of C4d-positive acute humoral rejection with plasmapheresis and rabbit polyclonal antithymocyte globulin

BACKGROUND: Alloantibody-mediated acute rejection is a major cause of renal allograft loss despite aggressive therapy. Patients with humoral rejection can be identified with high sensitivity and specificity by the presence of peritubular capillary C4d staining on renal biopsy and donor-specific anti-human leukocyte antigen antibodies. Standard therapy for acute humoral rejection (AHR) has been removal of donor-specific antibodies by plasmapheresis (PPH) in conjunction with intravenous immunoglobulin therapy. We describe a series of seven patients with C4d positive AHR who received combined therapy with PPH and polyclonal rabbit antithymocyte globulin (rATG). METHODS: PPH (1.4 volume exchange) was initiated on diagnosis of AHR on an alternate day basis for a mean number of 6.8 treatments, in conjunction with rATG (0.75 mg/kg/day 5-10 days) until the serum creatinine returned to 120% of nadir. RESULTS: The nadir posttreatment creatinine was significantly lower than pretreatment creatinine (1.0+/-1.2 vs. 2+/-1.4, P <0.007) with only one episode of graft loss. On follow-up there was no difference in renal allograft survival between the AHR group and the 60 patients without AHR who underwent transplantation during the same period. We describe the ability of rATG to induce apoptosis in vitro peripheral blood and activated B cells. CONCLUSION: Combination therapy using PPH and rATG is an effective means of reversing AHR in renal allografts.     

Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients

INTRODUCTION: A previous trial in renal transplantation comparing sirolimus (rapamycin) to cyclosporine (CsA) in a triple-drug therapy regimen with azathioprine and corticosteroids found that the incidence of acute rejection was similar (approximately 40%) with a trend for better renal function with sirolimus. METHODS: In 14 European centers, first cadaveric renal allograft recipients were randomized to receive sirolimus (n = 40) or CsA (n = 38) in an open-label design. All patients received corticosteroids and mycophenolate mofetil 2 g/day. Sirolimus and CsA were concentration controlled; trough levels of mycophenolic acid and prednisolone were also measured. RESULTS: At 12 months, graft survival (92.5% sirolimus vs. 89.5% CsA), patient survival (97.5% sirolimus vs. 94.7% CsA), and the incidence of biopsy-proven acute rejection (27.5% sirolimus vs. 18.4% CsA) were not statistically different. The use of antibodies to treat suspected rejection episodes was also similar (7.5% sirolimus vs. 5.3% CsA). More sirolimus patients received bolus steroid therapy (20 vs. 11, P = 0.068). From month 2 onward, the calculated glomerular filtration rate was consistently higher in sirolimus-treated patients. The adverse events reported more frequently with sirolimus were thrombocytopenia (45% vs. 8%) and diarrhea (38% vs. 11%). In the CsA group, increased creatinine (18% vs. 39%), hyperuricemia (3% vs. 18%), cytomegalovirus infection (5% vs. 21%), and tremor (5% vs. 21%) were observed significantly more often. DISCUSSION: Patient and graft survival and the incidence of biopsy-proven acute rejection at 12 months were comparable between sirolimus and CsA, whereas safety profiles were different. These data suggest that sirolimus may be used as primary therapy for the prevention of acute rejection.     

Age-dependency of mycophenolate mofetil dosing in combination with tacrolimus after pediatric renal transplantation

BACKGROUND: Dosing of mycophenolate mofetil (MMF) must be lower in combination therapy with Tacrolimus (Tac) than with Cyclosporine. One study with mostly adolescent recipients recommended an MMF dose of 250 mg/m2 BID. Because this dose resulted in low area-under-the-curve (AUC) in our infant population, we retrospectively analyzed all available pharmacokinetic (PK) profiles in pediatric renal transplant patients on MMF plus Tac therapy to propose appropriate MMF dosing in pediatric patients of all ages. PATIENTS AND METHODS: Forty-four PK profiles were performed in 27 patients (median age, 11.6 years; range, 1.8-20.7 years). The investigations were performed at a median of 299 days (range, 24-3424) after transplantation. Ten patients were converted to Tac plus MMF, all others received this as primary therapy. For patients with repeated measurements, we calculated the average AUC and doses. We used first-order PK modeling to calculate the doses for a mycophenolic acid (MPA) AUC of 60 ug*h/mL and a Tac AUC of 150 ng*h/mL. RESULTS: The mean Tac dose was 2.6 +/- 1.2 mg/m2/d or 0.086 +/- 0.038 mg/kg/d, resulting in an average AUC of 120.6 +/- 30.4 ng*h/mL. The MMF dose was not normally distributed; the median dose was 549 mg/m2/d (range, 146-1413) and the median MPA AUC was 49.8 ug*h/mL (range, 26.7-156.0). The mean dose for a Tac AUC of 150 ng*h/mL was 3.50 +/- 1.77 mg/m2/d (0.117 +/- 0.058 mg/kg) and was independent of age or time after transplantation. By contrast, we found a negative relationship between the dose per m2 (r2 = 0.29; P = 0.0038) or per kg (r2 = 0.58; P < .0001) required for an MPA AUC of 60 ug*h/mL and patient age. Converted and primary patients behaved identically. The dosing requirement decreased from 500 mg/m2 BID in 2-year-old patients to 250 mg/m2 in adolescents. There was substantial interpatient variability of 44%. CONCLUSIONS: Higher MMF doses are required for young children. Our data suggest a starting dose for infants of 500 mg/m2 BID, with PK monitoring of MPA due to substantial interpatient variability.     

Hepatitis C, acute humoral rejection, and renal allograft survival

The effect of recipient hepatitis C virus (HCV) infection on renal allograft loss and acute rejection in kidney transplantation remains controversial. We studied 354 renal allograft recipients transplanted during 1996 to 2001 who had HCV antibodies (Ab) measured before transplantation. The primary outcome was death-censored allograft loss and the secondary outcome was acute humoral rejection (AHR). Compared with HCV Ab-negative patients, those with positive HCV Ab had longer time on dialysis before transplantation, higher percentage of panel-reactive antibodies (PRA), were more likely to receive a cadaveric transplant, and were more likely to develop delayed graft function (DGF). In univariate analyses, predictors of renal allograft loss included HCV, cadaveric graft, PRA >20%, HLA mismatch > or =5, retransplantation, DGF, induction therapy, and AHR. When adjusted for PRA >20%, HLA mismatch > or =5, and multiple transplant status, HCV was not a statistically significant predictor of allograft loss. HCV was also associated with AHR but lost significance when adjusted for PRA >20%. HCV Ab-positive patients were more likely to have longer duration of dialysis before transplantation prior to kidney transplants, higher PRA, and to receive cadaveric transplants. These characteristics likely resulted in more DGF and AHR after transplantation. After adjusting for these confounding factors, the association between HCV Ab positivity and renal allograft loss was notably attenuated and no longer statistically significant.     

Combination therapy of mycophenolate mofetil and rapamycin in prevention of chronic renal allograft rejection in the rat

BACKGROUND: Chronic rejection is the leading cause of long-term allograft loss. Until now, no therapy has been recognized as being efficient in its prevention. In addition to their immunosuppressive activity, mycophenolate mofetil (MMF) and rapamycin (RAPA) show diverse properties against vascular smooth muscle cell activity, cell-adhesion molecule expression, and ischemia-reperfusion injury. The combination effect of MMF and RAPA was tested to prevent chronic renal allograft rejection in the rat in this study. METHODS: Nephrectomized Lewis recipients underwent orthotopic transplantation with Fisher (F344) kidneys (allograft groups) or Lewis kidneys (isograft control). The initial episode of acute rejection was controlled with a short course of cyclosporine A (CsA) (1.5 mg/kg/day for 10 days). From weeks 4 to 20, animals were thereafter treated every other day either with vehicle, MMF (20 mg/kg), RAPA (0.8 mg/kg), or MMF (20 mg/kg) plus RAPA (0.8 mg/kg) in combination. Animals were sequentially killed at serial intervals over a follow-up of 50 weeks, and histologic study was performed on harvested kidneys according to the Banff working classification for allograft pathology. RESULTS: Animals treated with MMF or RAPA alone showed a Banff sum score similar to the allograft control group (6.31+/-1.01 and 7.27+/-1.14 vs. 7.21+/-1.14, respectively; P>0.05). When the recipient rats were treated with MMF and RAPA in combination, it resulted in a clinically and statistically significant reduction of Banff sum score (4.21+/-0.79, P<0.01), with specific inhibition of vascular fibrous intimal thickening, allograft glomerulopathy, and interstitial fibrosis. CONCLUSION: Over a 50-week study, concomitant therapy of MMF and RAPA prevents chronic renal allograft rejection, probably through reduction of ischemic and cytotoxic degenerative changes. These results warrant further investigation in the combination of MMF and RAPA as anti-chronic rejection therapy in clinical transplantation.     

Combination therapy with tacrolimus and mycophenolate mofetil: effects of early and late minimization of mycophenolate mofetil after renal transplant

The objectives of the study were: (i) to compare the efficacy and safety of minimizing mycophenolate mofetil (MMF) early (30 d) or late (90 d) after renal transplantation, when used in combination with tacrolimus; (ii) to retrospectively investigate factors associated with early, acute rejections and (iii) to investigate the pharmacokinetic interaction between tacrolimus and diltiazem. A prospective, randomized, multicenter, open-label study was conducted in 124 de novo kidney transplant recipients. Efficacy and safety outcomes were assessed for 180 d after transplantation and subjects were followed-up for a mean duration of 5.1 yr. The efficacy and safety outcomes were comparable whether the dose of MMF was minimized early or late. The incidence of early, acute rejection episodes was higher for recipients who were younger, received a graft from an unrelated donor or failed to achieve adequate tacrolimus concentrations (trough > 10 ng/mL) in the first seven d after transplant. Concomitant use of diltiazem had a tacrolimus-sparing effect in some subjects. Based on these results, we support the achievement of a high target tacrolimus concentration within the first week after renal transplant and suggest that early minimization of MMF can be achieved when used in combination with tacrolimus.     

Detectable circulating antiendothelial cell antibodies in renal allograft recipients with C4d-positive acute rejection: a report of three cases

It is suggested that non-HLA endothelial antigens may also cause C4d-positive acute rejection, but this is very rare. We report on three renal allograft recipients who developed C4d-positive acute rejection with detectable circulating antiendothelial cell antibodies (AECAs). All patients had severe dialysis-dependent graft dysfunction. Histologic manifestations include neutrophils infiltration on peritubular capillaries and glomeruli. Endoarteritis can be seen in all the patients. Two patients lost grafts after the rescue therapy including immunoadsorption, mycophenolate mofetil with or without tacrolimus. The titer variation of AECAs might be associated with the graft outcome. In patients those who lost grafts, AECAs titer increased from 1:10 to 1:80 in one patient, and was kept positive during the treatment in the other patient. In the recovered patient, however, the titer became negative from 1:40. From our report, it appears that persisting circulating AECAs during the rescue treatment of C4d-positive acute rejection may be associated with a poor outcome.     

Double-blind comparison of two corticosteroid regimens plus mycophenolate mofetil and cyclosporine for prevention of acute renal allograft rejection

BACKGROUND: Renal transplant recipients experience adverse events attributed to corticosteroid therapy. METHODS: This was a multicenter, randomized, double-blind, 6-month, controlled steroid dose-reduction study in renal transplant recipients with an unblinded 6-month follow-up. In the low/stop arm, corticoste. roids were given at half the dosage of control for 3 months from the date of transplantation, and then withdrawn. Both arms received mycophenolate mofetil and cyclosporine. The primary endpoint was the incidence of biopsy-proven acute rejection at 6 months posttransplantation. RESULTS: There were 248 patients in the control group and 252 in the low/stop group. At 6 months the low/stop group had more biopsy-proven acute rejection episodes than the control (23% vs. 14%; P=0.008). At 12 months this increased to 25% vs. 15%. Most rejections were Banff grade I. Twelve-month graft loss was 5% in the low/stop group vs. 4% in the control. At 6 and 12 months serum cholesterol (P<0.01, P<0.01), triglycer. ides (P<0.01, P<0.01), and systolic blood pressure (P<0.001, P<0.001) were lower in the low/stop group. Diastolic pressure was lower (P<0.01) and lumbar spine bone density was greater (P<0.01) in the low/ stop group at 12 months. CONCLUSIONS: In renal transplant recipients treated with mycophenolate mofetil and cyclosporine, reduction and early withdrawal of the prophylactic corticosteroid dose is feasible without an unacceptable increase in serious rejection episodes. This is accompanied by a significant reduction of steroid-related adverse events.