Impact of rituximab‐associated B‐cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients

Levi ME, Quan D, Ho JT, Kleinschmidt‐DeMasters BK, Tyler KL, Grazia TJ. Impact of rituximab‐associated B‐cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01044.x
© 2009 John Wiley & Sons A/S. Abstract: Evidence suggests that West Nile virus (WNV) neuroinvasive disease occurs more frequently in both solid organ and human stem cell transplant recipients. The effect of concomitant anti‐B‐cell therapy with rituximab, a CD20⁺ monoclonal antibody, on WNV infection in this population, however, has not been reported. We describe a case of a patient with alpha‐1‐antitrypsin deficiency who underwent single lung transplantation in 2005 and was maintained on tacrolimus, cytoxan and prednisone. More recently, she had received two courses of rituximab for recurrent A2–A3 grade rejection with concomitant capillaritis and presented six months later with rapid, fulminant WNV meningoencephalitis. Her diagnosis was made by cerebrospinal fluid (CSF) PCR but serum and CSF WNV IgM and IgG remained negative. She received WNV‐specific hyperimmune globulin (Omr‐Ig‐Am^®) through a compassionate protocol. She experienced a rapidly progressive and devastating neurological course despite treatment and died three wk after onset of her symptoms. Autopsy revealed extensive meningoencephalomyelitis.     

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

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

Outcome of sirolimus‐based immunosuppression,fifteen years post–live‐donor kidney transplantation: Single‐center experience

In a prospective randomized controlled trial, between May 2001 and January 2003, 132 live‐donor kidney transplant recipients were randomized to receive sirolimus primary immunosuppression, either in combination with low dose tacrolimus (Tac group) or in combination with mycophenolate mofetil (MMF group). We have previously reported on 2‐ and 5‐year follow‐up results, with favorable patient and graft outcomes obtained in both groups. In view of recent published reports of increased risk of inferior outcomes among sirolimus‐treated patients, we herein present results of an observational extension of the previously randomized patients 15 years post‐transplantation. Mortality rates were 10.8% and 3% in Tac and MMF groups respectively after mean follow‐up period of 11.2‐11.8 years. Comparable graft survival rates were obtained in both groups ranging from 60% to 62.7%. The (MMF) group continued to have the advantage of remaining on primary plan of immunosuppression (56.7% of patients) as well as to maintain better graft function in terms of serum creatinine level. Herein, we presented longest term published data for sirolimus‐based immunosuppression among live‐donor kidney transplants with favorable outcome in terms of survival and graft function.     

Renal Failure Five Years After Lung Transplantation Due to Polyomavirus BK‐Associated Nephropathy

Polyomavirus‐associated nephropathy (PyVAN) is rare in nonrenal solid organ transplantation and only limited information is available from single cases. We describe a 67‐year‐old female presenting with hypertension and progressive kidney failure due to PyVAN 60 months after lung transplantation. Plasma BK virus (BKV) loads were 4.85 log₁₀ copies/mL at diagnosis and cleared slowly over 14 months after switching from tacrolimus, mycophenolate and prednisone to low‐dose tacrolimus, sirolimus and leflunomide, the latter being discontinued for anemia and diarrhea. BKV‐ and JC virus‐specific immunoglobulins were detectable prior to transplantation. Only BKV‐specific IgG and IgM increased during follow‐up. BKV‐specific T cells were detectable in blood following in vitro expansion, but cleared with reincreased sirolimus, yet BKV viremia remained undetectable. We identified eight other cases of PyVAN in nonrenal solid organ transplantation including lung (n = 1), heart (n = 6) and pancreas (n = 1). Overall, diagnosis was later than commonly seen in kidney transplants (median 18 months, interquartile range 10–29). Seven patients were male, five received triple immunosuppression consisting of tacrolimus, mycophenolate, prednisone. Immunosuppression was reduced in four cases and cidofovir and/or leflunomide administered in five and two cases, respectively. Renal function deteriorated in five requiring hemodialysis in four. We discuss mTOR inhibitors versus cidofovir and leflunomide as potential PyVAN rescue therapy.     

Successful pancreas-renal transplantation without induction therapy

Most pancreas transplant centers initially use immunosuppression with antilymphocyte induction because the pancreas appears to be a highly immunogeneic organ. Although the addition of an antilymphocyte agent provides enhanced immunosuppression in the early posttransplant period, it is associated with added costs and adverse reactions. In this study we evaluated the safety and efficacy of tacrolimus (Tac), mycophenolate mofetil (MMF), and steroid immunosuppression without induction after simultaneous kidney-pancreas transplantation (SKPT). Six patients (30%) displayed rejection episodes with a mean follow-up of 12 months (range = 4 to 18 months). No graft was lost due to rejection. The results of this series suggest that SKPT can be safely performed without induction therapy.     

Lipid metabolism in renal transplant patients receiving tacrolimus/sirolimus combination therapy

INTRODUCTION: The administration of sirolimus has been reported to be associated with high serum cholesterol and high triglyceride values. In a large prospective, multicenter 6-month study in renal transplantation, basic parameters of lipid metabolism (total serum cholesterol and triglycerides) were systematically assessed in patients who received tacrolimus/mycophenolate mofetil/steroids (Tac/MMF), tacrolimus/0.5 mg sirolimus (SIR)/steroids (Tac/0.5SIR) on tacrolimus/2 mg sirolimus/steroids (Tac/2SIR). METHODS: For purposes of analysis, lipid parameters were classified using the National Kidney Foundation Dyslipidemia Classification definitions. RESULTS: Complete sets of data at all visits (baseline, months 1, 3, and 6) were available for 211 Tac/MMF, 210 Tac/0.5SIR, and 203 Tac/2SIR patients. Total serum cholesterol in the Tac/MMF group was 193.4 at baseline and 202.9 mg/dL at month 6. Values increased from 196 mg/dL to 212.5 mg/dL in Tac/0.5SIR and from 200 mg/dL to 230.5 mg/dL in Tac/2SIR. Differences in parameters between treatment groups were statistically significant (P < .05). Serum triglycerides decreased from baseline to 6 months in Tac/MMF, increased from 176.3 mg/dL (baseline) to 191.4 mg/dL (6 months) in Tac/0.5SIR and from 203 mg/dL to 255.3 mg/dL in Tac/2SIR. Parameters differed significantly between Tac/0.5SIR versus Tac/2SIR at P = .0069, and between Tac/MMF versus Tac/2SIR at P = .0013. In the Tac/2SIR group 36.5% had "high" serum cholesterol and 8.3% had "very high" triglyceride levels at 6 months. CONCLUSION: Total serum cholesterol levels were relatively stable and serum triglycerides decreased between baseline and month 6 using a Tac/MMF regimen. Contrastingly, the Tac/SIR combinations led to increased total cholesterol values (at both sirolimus dose levels) and Tac/2SIR also led to increased triglyceride levels.     

Elective withdrawal of mycophenolate mofetil in renal transplant recipients treated with mycophenolate mofetil, cyclosporine, and prednisone

In a retrospective study we investigated the risk of acute rejection after the withdrawal of mycophenolate mofetil (MMF) in 39 adult patients treated with cyclosporine (CyA), prednisone, and MMF for at least 6 months following renal transplantation. After reaching a stable renal graft function, MMF was withdrawn and CyA and prednisone were continued. Preceding the withdrawal of MMF, four patients experienced an acute rejection. During a median follow-up of 38 months after discontinuing MMF, no acute rejection occurred. The mean serum creatinine level did not change during the first 6 months after withdrawal of MMF. We conclude that elective withdrawal of MMF in stable renal transplant recipients at 6 months after transplantation bears no important risk of an occurrence of acute rejection. Received: 24 November 1999 Revised: 11 May 2000 Accepted: 18 December 2000     

Alemtuzumab (Campath-1H) combined with tacrolimus in intestinal and multivisceral transplantation

BACKGROUND: We combined alemtuzumab (Campath-1H, Berlex Laboratories, Montville, NJ) and tacrolimus (Tac) immunosuppression for intestinal and multivisceral transplantation. MATERIALS AND METHODS: A total of 21 adult patients received 24 grafts: 14 intestinal, nine multivisceral, and one liver-intestinal graft. Alemtuzumab was administered perioperatively in four doses with low-dose Tac (levels 10-15 ng/dL) and no maintenance steroids. Tac was substituted with sirolimus in case of Tac-related complications. Suspected or mild rejections were treated with steroids. Moderate rejections were treated with steroids or OKT3. Severe rejections were treated with OKT3. RESULTS: Of the 16 patients that were followed up for an average of 9 months, 12 are alive with functioning grafts. Two patients experienced severe rejection, three experienced moderate rejection episodes, and seven experienced mild acute rejection episodes. Four patients never developed acute rejection. Infectious complications included a cytomegalovirus enteritis and four fungal infections (related to central venous access). CONCLUSIONS: The combination of alemtuzumab and Tac therapy without steroid use seems to efficiently prevent acute rejection in a significant number of patients without causing frequent opportunistic infections.     

Long-term renal transplant function in recipient of simultaneous kidney and pancreas transplant maintained with two prednisone-free maintenance immunosuppressive combinations: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus

BACKGROUND: It is not known how different steroid-free immunosuppressive combinations affect long-term kidney transplant function in recipients of simultaneous kidney and pancreas transplant (SPK). Here, we sought to evaluate, in SPK recipients, the impact on long-term renal allograft function of two Tac-based prednisone-free maintenance immunosuppressive protocols: tacrolimus (Tac)/mycophonelate mofetil (MMF) versus Tac/ sirolimus (SRL). METHODS: In this single-center, retrospective, sequential study, we analyzed 59 SPK transplant patients with at median follow up of 5 years. All patients received induction therapy with thymoglobulin and maintenance immunosuppression with Tac/MMF (n=22) or Tac/SRL (n=37). There were no differences between the two groups in regards to age, gender, race, panel reactive antibodies, degree of mismatch, donor age, incidence of delay graft function, and Tac trough levels at different time points after transplantation. RESULTS: Kaplan-Meier patient survival at 6 years after transplantation was not statistically different between the two groups. Rate of ACR was similar. Kidney survival, even if not statistically significant, was better in the Tac/MMF group than in the Tac/SRL (90.7% vs. 70.7%, P=0.09). The slope of glomerular filtration rate decline per month at 5 years after transplantation was not statistically different between the two groups. Both groups had the same decline over time in glomerular filtration rate of 0.40+/-0.06 mL/min/1.73/month. Pancreas survival at 6 years after transplantation was 100% in both treatment groups. CONCLUSIONS: Our data suggest that, in SPK recipients, long-term kidney allograft survival and function are not statistically different. A trend toward an increased rate of renal allograft loss was found in the Tac/SRL-treated group.     

Cutaneous Toxicities From Transplantation‐Related Medications

Despite the abundance of information on cutaneous malignancies associated with solid organ transplantation in the transplant literature, there is limited information regarding nonmalignant skin changes after transplantation. There are numerous skin toxicities secondary to immunosuppressive and other transplant‐related medications that can vary in presentation, severity, and prognosis. To limit associated morbidity and mortality, solid organ transplant recipient care providers should effectively identify and manage cutaneous manifestations secondary to drug toxicity. Toxicities from the following transplant‐related medications will be discussed: antithymocyte globulins, systemic steroids, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, mammalian target of rapamycin inhibitors sirolimus and everolimus, basiliximab and daclizumab, belatacept, and voriconazole.     

Autoimmune cytopaenia after paediatric intestinal transplantation: a case series

Autoimmune cytopaenia is a rare, but severe complication after solid organ transplantation. We retrospectively analysed 57 paediatric intestinal transplants performed in 49 patients between 1999 and 2009. Autoimmune cytopaenia was observed in six patients; it appeared after an average of 10 months post‐transplant. Warm autoimmune haemolytic anaemia was developed in three patients, cold autoimmune haemolytic anaemia in one and two presented a mixed type. Incidence and causes for haematological cytopaenia such as the following were investigated: immunosuppression, major blood mismatch, viral infection, malignancy, passenger lymphocyte syndrome and lymphoproliferative disorders. Initial treatment included high‐dose steroids, intravenous immunoglobulin, plasmapheresis and maintenance of body temperature above 37 °C in those with cold autoantibodies. Inclusion of the spleen in multivisceral transplants seems to be an important risk factor. All patients, except one, relapsed after classic therapy, requiring additional treatments. Sirolimus conversion was performed in four patients. One died after infection. The immunosuppressive therapies associated with other concomitant factors, such as viral infections, lymphoproliferative disorders, graft‐versus‐host disease, passenger lymphocyte syndrome and the inclusion of the spleen as part of multivisceral graft seem to play an important part in the development of autoimmune processes after intestinal transplantation. Therapy is not well established, especially in those resistant to first‐line treatment.     

Planned Randomized Conversion From Tacrolimus to Sirolimus‐Based Immunosuppressive Regimen in De Novo Kidney Transplant Recipients

Planned conversion from tacrolimus to sirolimus was evaluated in de novo kidney transplant recipients. In this multicenter, randomized, open‐label study, 297 patients were initially treated with tacrolimus, mycophenolate sodium and prednisone. Of the 283 patients reaching 3 months, 97 were converted to sirolimus (SRL), 107 were maintained on tacrolimus (TAC) and 79 were patients receiving TAC without criteria to undergo intervention at month 3 (TACex). The primary objective was to show superior estimated glomerular filtration rate (eGFR) in the SRL group at month 24. Of the 258 patients who completed 24 months, 91 (94%) were in the SRL group, 101 (94%) in the TAC group and 66 (84%) in the TACex group. In the intention‐to‐treat population there were no differences in eGFR (66.2 ± 25.3 vs. 70.7 ± 25.1, p = 0.817) or in the severity of chronic sclerosing lesions scores in 24‐month protocol biopsies. Higher mean urinary protein‐to‐creatinine ratio (0.36 ± 0.69 vs. 0.15 ± 0.53, p = 0.03) and higher incidence of treated acute rejection between months 3–24 (13.4% vs. 4.7%, p = 0.047) were observed in SRL compared to TAC group. In this population planned conversion from TAC to SRL 3 months after kidney transplantation was not associated with improved renal function at 24 months.     

Mammalian target of rapamycin inhibition after solid organ transplantation: can it,and does it,reduce cancer risk?

The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus has been increasingly used as immunosuppressants for recipients of solid organ transplants. Over the years, potential advantages unique to this class of immunosuppressants have been recognized, including chemoprevention by virtue of their antiproliferative effects. Prevention of malignancy after transplant through mTOR inhibitor‐based immunosuppression may have a specific practical application in transplant recipients with preexisting malignancy including hepatocellular carcinoma or cholangiocarcinoma. This review will reveal how the biochemistry of the mTOR pathway, as it pertains to chemoprevention, can support a clinical role for mTOR inhibitors in the prevention of malignancies, recurrent or de novo, after solid organ transplantation in selected patients.     

Tacrolimus combined with two different corticosteroid-free regimens compared with a standard triple regimen in renal transplantation: one year observational results

Krämer BK, Klinger M, Wlodarczyk Z, Ostrowski M, Midvedt K, Stefoni S, Citterio F, Pietruck F, Squifflet J‐Paul, Segoloni G, Krüger B, Sperschneider H, Banas B, Bäckman L, Weber M, Carmellini M, Perner F, Claesson K, Marcinkowski W, Vítko ?, Senatorski G, Salmela K, Nordström J. Tacrolimus combined with two different corticosteroid‐free regimens compared with a standard triple regimen in renal transplantation: one year observational results.
Clin Transplant 2010: 24: E1–E9. © 2009 John Wiley & Sons A/S. Abstract: Side effects of steroid use have led to efforts to minimize their use in transplantation. Two corticosteroid‐free regimens were compared with a triple immunosuppressive therapy. Data from the original intent‐to‐treat (ITT) population (153 tacrolimus/basiliximab [Tac/Bas], 151 tacrolimus/MMF [Tac/MMF], and 147 tacrolimus/MMF/steroids [control]) were analyzed in a 12‐month follow‐up. Percentage of graft survival were 92.8%, 95.4%, and 95.9% (KM estimates 89.9%, 95.3%, 95.9%), percentage of surviving patients were 98.7%, 98.0%, and 100% (KM estimates 95.9%, 92.8%, and 100%). During months 7–12, graft loss occurred in 3 Tac/Bas, 2 Tac/MMF, and zero control patients, patient deaths in 1 Tac/Bas, 2 Tac/MMF, and zero control, and biopsy‐proven acute rejection episodes in 4 Tac/Bas, 3 Tac/MMF, and zero control. Mean serum creatinine at month 12 was 141.9 ± 69.6 μM, 144.0 ± 82.1 μM, and 134.5 ± 71.2 μM (ns). New‐onset insulin use in previously non‐diabetic patients at month 12 was 1/138, 6/127, and 4/126. Patient and graft survival as well as renal function at 12 months were not different between patient groups, despite considerably higher rates of acute rejection occurring within the first six months after transplantation in both steroid‐free patient groups. Tac/Bas therapy might offer benefits in terms of a trend for a more favorable cardiovascular risk profile.     

Pilot conversion trial from mycophenolic acid to everolimus in ABO‐incompatible kidney‐transplant recipients with BK viruria and/or viremia

Immunosuppression using everolimus (EVR) plus low‐dose tacrolimus (Tac) is commonly used in organ transplantation. EVR has potential antiviral effects. Herein, the long‐term outcomes and impacts of Tac‐EVR on the BK virus are reported in ABO‐incompatible kidney‐transplant recipients. The initial immunosuppressive regimen combined steroids, Tac, and mycophenolic acid (MPA). At a median of 141 (34–529) days post‐transplantation, seven stable ABO‐incompatible kidney‐transplant recipients were converted from MPA to EVR because of active BK replication, and compared with a reference group of fourteen ABO‐incompatible patients receiving classical Tac plus MPA. At 1 month before conversion, at 1, 3 months after, and at last follow‐up, clinical and biological parameters were monitored. The median time from conversion to the last follow‐up was 784 (398‐866) days. Conversion to EVR caused no change to rejection episodes or immunological status (isoagglutinin titers, anti‐HLA antibodies). At last follow‐up, median eGFR was similar in the Tac‐MPA versus Tac‐EVR group (40 [range: 14–56] vs. 54.5 ml/min/1.73 m² [range: 0–128], P = 0.07). The major adverse event was dyslipidemia. Interestingly, conversion from MPA to EVR decreased BK viral load in five patients. ABO‐incompatible kidney‐transplant recipients with an active BK virus infection may benefit from conversion to EVR.     

Oxidative stress indices in rats under immunosuppression

Immunosuppressants lead to generation of reactive oxygen species (ROS). Oxidative stress (OxS) can initiate chronic allograft nephropathy (CAN). The most active antioxidant enzymes, superoxide dysmutase (SOD) and catalase (CAT), are present in erythrocytes. Glutathione peroxidase (GPx) is produced in the proximal tubules of nephrons. Malonyldialdehyde (MDA) concentrations are a marker of OxS intensity in plasma. In vitro and animal model studies have shown increased or decreased OxS during treatment with tacrolimus (Tac) or cyclosporine (CyA). Results obtained in humans after solid organ transplantation have been contradictory, because of confounding factors such as ischemia-reperfusion injury, donor and recipient ages, endothelial injury, and comorbidity. The aim of this study was to assess the intensity of OxS among rats under chronic immunosuppression (IS) without a transplantation. We examined 49 male Wistar rats. IS started at 12 weeks of age was continued for 6 months: group I were controls (n = 7); group II, Tac + sirolimus (Rapamycin [Rapa]) + corticosteroids (CS; n = 6); group III, CyA + Rapa + CS (n = 4 of which 2 died); group IV, Rapa + mycophenolate mofetil (MMF) + CS (n = 6); group V, CyA + MMF + CS (n = 6); group VI, CsA + MMF + CS for 3 months followed by conversion to Rapa (n = 6); group VII, Tac + MMF + CS (n = 6 rats); and group VIII, Tac + MMF + CS for 3 months followed by conversion to Rapa (n = 6). The drug doses were as follows: Tac 4 mg/kg/d; MMF 20 mg/kg/d; CyA 5mg/kg/d; Rapa 0.5mg/kg/d; and CS 4 mg/kg/d. Multiple regression analysis revealed that all IS drugs decreased GPx activity (P < .001) except CS, which increased it (P < .0001). Multiple regression analysis showed that CsA and Tac decreased plasma MDA concentrations (P < .01), whereas CS increased them (P < .05). In conclusion, all IS drugs except CS damage proximal tubules of nephrons.     

肾移植后胰岛素抵抗的危险因素以及与代谢综合征关系的临床研究

目的 探讨肾移植术后发生胰岛素抵抗(IR)的危险因素以及与代谢综合征的关系.方法 对133例肾移植受者进行前瞻性观察,患者移植前无糖尿病病史,入组时未发生急性排斥反应和免疫抑制剂肾毒性,无蛋白尿,肝、肾功能正常,无严重感染.术后采用环孢素A(CsA)、霉酚酸酯(MMF)和泼尼松(Pred)预防排斥反应者108例(CsA组),采用他克莫司(Tac)、MMF和Pred预防排斥反应者19例(Tac组),采用西罗莫司者6例.1年后进行血、尿生化及体格检查,并计算体重指数(BMI)和稳态模型胰岛素抵抗指数(HOMA-IR).随机抽取普通社区人群200名作为对照.结果 肾移植受者的代谢综合征发生率为33.1%(44/133),显著高于普通社区人群的15%(30/200),差异有统计学意义(P＜0.05).肾移植受者中超重/肥胖者(BMl≥24 kg/m2)39例,其HOMA-IR和代谢综合征发生率明显高于BMI正常者(P＜0.05,P＜0.01).Tac组的空腹血糖为(6.19±1.61)nmml/L,HOMA-IR为0.95±0.53,均高于CsA组的(5.50±1.17)mmol/L和0.68±0.56,差异有统计学意义(P＜0.05,P＜0.05),且HOMA-IR与血Tac浓度存在正相关(r=0.521,P＜0.05).合并代谢综合征的肾移植受者的HOMA-IR为1.01±0.56,显著高于无代谢综合征者的0.58±0.53(P＜0.01);高甘油三酯血症、高胆固醇血症以及高血压者的HOMA-IR水平明显升高(P＜0.05).结论 超重/肥胖以及使用Tac(尤其是血Tac浓度较高时)是引起肾移植受者IR的危险因素,而IR与肾移植后的代谢综合征关系密切.     

Impact of mycophenolate mofetil on recurrent rejection in kidney transplant patients

PURPOSE: Mycophenolate mofetil (MMF) has emerged as a valuable adjunctive agent in renal transplantation. However, due to intolerable adverse effects associated with MMF use in our transplant population, we have used MMF selectively in patients at high risk for recurrent graft rejection, since these patients are known to be at risk for poor long-term graft outcomes. The purpose of this study was to assess the efficacy of MMF in preventing the recurrence of acute rejection following an initial rejection episode in kidney transplant patients in the first year following transplantation. METHODS: Forty-four kidney transplant recipients were given MMF prospectively following treatment of their initial rejection episode to prevent recurrent rejection. MMF 1-2 g/d was given. Doses were adjusted based on tolerance; MMF therapy was to be continued for at least 6 months. The control group consisted of 124 consecutive kidney transplant recipients who had received standard anti-rejection therapy without the addition of MMF. Maintenance immunosuppression consisted predominantly of cyclosporine, prednisone+/-azathioprine. Anti-rejection therapy for both groups consisted of either corticosteroids (methylprednisolone 500 mg i.v. for 3 d or oral prednisone 2 mg/kg/d with rapid taper over 3 wk), OKT3 5 mg/d for 10 d or ATG 15 mg/kg/d for 10 d. All rejection episodes were confirmed by biopsy. RESULTS: The majority of rejection episodes were characterized histologically as mild or moderate. Most patients (76%) received corticosteroids for treatment of their first rejection episode. There was a 68% reduction in the incidence of recurrent rejection episodes within the first year of transplant in patients receiving MMF; only 14% of recipients receiving MMF developed recurrent rejection compared to 44% of patients in the control group (p<0.05). Approximately 50% of patients developed MMF-associated adverse effects (leukopenia, GI toxicity). Only 52% of patients remained on MMF at 6 months. One-yr graft survival was 86% in the MMF group and 89% in the control group (p>0.05). One-year patient survival was 93 and 100%, respectively (p>0.05). CONCLUSIONS: The addition of MMF to maintenance therapy for patients experiencing acute renal allograft rejection may prevent recurrent rejection episodes in the subsequent follow-up year.     

Late cytomegalovirus disease with atypical presentation in renal transplant patients: case reports

Cytomegalovirus (CMV) disease typically occurs 1 to 4 months (median 35 days) after solid organ transplantation. Recent reports documented that the natural history of CMV disease associated with solid organ transplantation has been modified as a result of the widespread use of potent immunosuppressents and antiviral prophylaxis. We herein report three pretransplant CMV seropositive recipients (with unknown donor status) who were diagnosed recently to display late and atypical CMV disease. Two men and one woman included two patients who presented with allograft dysfunction at 12 years and at 3 years after transplantation. Both patients showed increased serum creatinine approximately from baseline 200 to >400 micromol/L over 3 months in the absence of features of rejection or cyclosporine toxicity. A renal biopsy was refused by both patients. Two of the three patients presented with symptoms of enterocolitis (diarrhea, nausea, weight loss), which had persisted for more than 6 months. Other symptoms and signs of overt CMV disease (fever, leukopenia) were absent. None had pulmonary, hepatic, or other major organ involvement. In all patients IgG antibodies and CMV DNA by polymerase chain reaction were positive with negative IgM antibodies. The immunosuppressive regimen consisted of mycophenolate mofetil (MMF), steroids, and calcineurin inhibitors. The kidney function significantly improved in both patients with renal dysfunction. Gastrointestinal symptoms resolved completely with gradual weight gain. The recognition and early diagnosis of late atypical CMV disease in kidney transplant patients presenting with allograft dysfunction and/or other organ systems is important. The MMF has a red herring effect in our cases due to its GI side effects.     

A Phase I/II Randomized Open-Label Multicenter Trial of Efalizumab, a Humanized Anti-CD11a, Anti-LFA-1 in Renal Transplantation

Leukocyte function associated antigen-1 (LFA-1) has a multifaceted role in the immune response, including adhesion and trafficking of leukocytes, stabilizing the immune synapse of the MHC-TCR complex and providing costimulation signals. Monoclonal antibodies to the CD11a chain of LFA-1 have been seen to result in effective immunosuppression in experimental models. Efalizumab, a humanized IgG1 anti-CD11a, is approved for use in psoriasis and may provide effective immunosuppression in organ transplantation. Thirty-eight patients undergoing their first living donor or deceased renal transplant were randomized to receive efalizumab 0.5 or 2 mg/kg weekly subcutaneously for 12 weeks. Patients were maintained on full dose cyclosporine, mycophenolate mofetil and steroids or half dose cyclosporine, sirolimus and prednisone. At 6 months following transplant patient survival was 97% and graft survival was 95%. Clinical biopsy-proven acute rejection in the first 6 months after transplantation was confirmed in 4 of 38 patients (11%). Three patients (8%) developed post transplant lymphoproliferative disease, all treated with the higher dose efalizumab and full dose cyclosporine. The two doses of efalizumab resulted in comparable saturation and modulation of CD11a. This phase II trial suggests that efalizumab may warrant further investigation in transplantation.