Steroid minimization for sirolimus-treated renal transplant recipients.

Steroids are associated with a myriad of post-transplant side effects. Therefore, as new immunosuppressive drugs have been developed, attempts have been made to minimize steroid exposure. Sirolimus (SRL) has been demonstrated to have efficacy in early and late post-transplant immunosuppression. Accordingly, numerous trials have studied steroid minimization (early and late post-transplant) in the context of SRL-containing protocols (either with or without a calcineurin inhibitor). We herein review these trials and show that recent studies have determined that both late steroid withdrawal and early rapid discontinuation can be successful with SRL immunosuppression.

Comparison of the portal vein and kidney subcapsule as sites for primate islet autotransplantation.

To date, the portal vein has been the primary site for clinical islet transplantation. Despite success, potential complications such as portal vein thrombosis still exist. The kidney subcapsule has been used successfully in rodent models of islet transplantation. We hypothesized that the kidney subcapsule as a site for islet transplantation in the nonhuman primate model would be as effective as the portal vein. Diabetes was induced in the primate Macaca fascicularis via a total pancreatectomy. Animals were kept under anesthesia during the isolation procedure. Islet isolation was performed using intraductal infusion with Liberase HI and mechanical digestion in the Ricordi chamber, and were purified using a continuous Ficoll gradient. Purified islets were autotransplanted either into the portal vein (n = 6) or the left kidney subcapsule (n = 5) of pancreatectomized animals. Intravenous glucose tolerance tests were performed prior to pancreatectomy and 10 days following transplantation. Three animals underwent pancreatectomy and served as diabetic controls. Of the six animals receiving islets in the portal vein, one developed portal vein thrombosis. All remaining autotransplanted animals in this group remained normoglycemic with glucose-induced insulin secretion that was not different from that prior to pancreatectomy. Of the five animals undergoing transplantation into the kidney subcapsule, only one maintained normoglycemia and elicited insulin secretion in response to glucose stimulation. The other four animals remained hyperglycemic. We conclude that the portal vein is superior to the kidney subcapsule as a site for islet transplantation in nonhuman primates 10 days posttransplantation.

Peritubular capillary C4d staining in late acute renal allograft rejection--is it relevant?

BACKGROUND: In the early post-transplant period, renal allograft rejection with diffuse peritubular capillary (PTC) C4d deposition predicts poor graft survival. In the late post-transplant setting, that is, one or more yr after transplantation, the implication of diffuse PTC C4d deposition is still a topic of debate. The purpose of our study was to see if diffuse PTC C4d deposition, in late acute rejection (LAR), occurring more than one yr post-transplant, has any impact on graft survival and function. METHODS: We selected cases, both cadaveric as well as living donor renal transplant recipients, in whom acute rejection with PTC C4d deposition was first detected after the first year post-transplant. Recipients with multiple acute rejection episodes during the first year post-transplant were excluded from the study. The first biopsy diagnosed with LAR was considered the index biopsy (n = 40). We formed two groups: group 1, C4d-positive LAR (n = 20), and group 2, C4d-negative LAR (n = 20). Groups were matched for maintenance and post-rejection immunosuppressive therapy, baseline serum creatinine levels before the time of the index biopsy, time from transplant to index biopsy, as well as chronic allograft damage index (CADI) score in the index biopsies. We compared the rate of graft loss, and the graft function of the surviving grafts at the end of the study period, as well as histologic parameters in the index biopsy specimens between the two groups. The mean follow-up period was 20 months. RESULTS: No significant differences in the rate of graft loss or graft function were found between groups 1 and 2 at the end of the follow-up period. Histologically, PTC margination and transplant glomerulopathy were more common in the C4d-positive group, and this difference was statistically significant. There was no statistically significant difference in the degree of plasma cell infiltrates. CONCLUSIONS: Unlike in the acute setting, the presence or absence of PTC C4d staining in renal allografts with LAR may not have a predictive value regarding graft outcome.

Steroid-free maintenance immunosuppression with rapamune and low-dose neoral in pancreas transplant recipients.

BACKGROUND: Steroid-free immunosuppression is an attractive option because it avoids the many side effects of chronic corticosteroid use. It is especially attractive in pancreas recipients because it avoids the diabetogenic effects of steroids. METHODS: We evaluated the outcome of a steroid-free maintenance immunosuppressive protocol in pancreas transplant recipients. Between August 2003 and May 2006, a total of 97 pancreas transplant recipients received steroid-free maintenance immunosuppression, consisting of induction with thymoglobulin and prednisone for the first 5 days. Patients were maintained on sirolimus adjusted to a target rapamycin trough level and reduced-dose cyclosporine adjusted to target C2 levels. All pancreas transplants (n=124) performed in the previous 3 years and maintained on a steroid-based immunosuppressive protocol with cyclosporine and mycophenolate mofetil were used for comparison. RESULTS: One-year patient and death censored pancreas graft survival were 93.8% and 94.8% for the steroid free group versus 95.2% and 87.9% for the comparator group, respectively. The incidence of acute rejection was 9.3% in the steroid-free group versus 28.3% in the comparator group (P<0.01). No pancreas loss in the steroid-free group was caused by acute rejection, whereas seven (5.6%) patients in the comparator group lost their pancreases because of acute rejection (P<0.05). At 1 year after transplant, the mean serum glucose and creatinine levels were not different between the two groups. CONCLUSION: We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of sirolimus and cyclosporine.

Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.

BACKGROUND: FTY720, a novel immunomodulator, displays potent immunosuppressive activity in a variety of preclinical transplant models. This study examined the safety, pharmacodynamics, and pharmacokinetics of multiple doses of FTY720 in stable renal transplant patients. METHODS: This randomized, multicenter, double-blind, placebo-controlled, phase I study included adults who had been maintained on a regimen of cyclosporine A (CsA) microemulsion and prednisone (or its equivalent) for at least 1 year after renal transplantation. Patients received once-daily doses of 0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg FTY720, or placebo for 28 days. After completion of study drug administration, the patients were monitored until day 56 by serial laboratory tests, clinical examinations, and recording of adverse events. The study includes 76 treatment courses (61 FTY720 and 15 placebo), with 65 patients enrolled once and 11 reenrolled. RESULTS: FTY720 doses greater than or equal to 1.0 mg/day produced a significant reduction in peripheral blood lymphocyte count by up to 85%, which reversed within 3 days after discontinuation of study medication. Compared with placebo-treated patients, FTY720 subjects did not show a major increase in adverse events or a change in renal function. Pharmacokinetic measurements revealed that FTY720 displayed linear relations of doses and concentrations over a wide range, but had no effect on CsA exposure. CONCLUSIONS: At doses up to 5.0 mg/day for 28 days, stable renal transplant patients treated with FTY720 in combination with CsA and prednisone displayed a dose-dependent, reversible decline in peripheral blood lymphocytes without an enhanced incidence of collateral toxicities, except possibly bradycardia.

Patient survival after renal transplantation III: the effects of statins.

BACKGROUND: Kidney transplant recipients have high cardiovascular risk and an unfavorable cardiovascular risk profile, which frequently includes hyperlipidemia. Although the use of HMG-CoA reductase inhibitors (statins) is associated with improved survival in the general population, the effects of these drugs on the survival of kidney transplant recipients have not been established. METHODS: In this study, we determined which factors were associated with the use of statins in a population of 1,574 adult, kidney allograft recipients, transplanted in one institution. A risk factor analysis of patient survival was done with a primary focus on the possible relationship between statin use and survival. RESULTS: The percent of patients treated with statins increased progressively from 1982 to 1996. Statins were used significantly more often in whites (30%) than in blacks (20%, P = 0.001) and in older individuals. These differences in statin use were not due to differences in lipid levels among the patient groups. As expected, the group of patients treated with statins had significantly higher serum lipid levels than untreated patients. Patient survival was significantly better in patients treated with statins than in untreated patients. That relationship became apparent, however, only after controlling for three additional factors: recipient age, transplant year, and serum cholesterol levels. In a multivariable Cox survival model, patient survival was associated significantly with statin use (hazard ratio [HR] = 0.76; confidence interval [CI], 0.6 to 0.96; P = 0.02), recipient age (HR = 1.05; CI, 1.04 to 1.06; P < 0.0001), and transplant year (HR = 1.05; CI, 1.01 to 1.08; P = 0.001). The serum cholesterol level was not associated significantly with patient survival in this model, but cholesterol significantly modified the relationship between statin use and patient survival. CONCLUSIONS: Renal transplant recipients treated with statins have a 24% better survival than patients who do not receive these drugs.

Determinants of quality of life changes among long-term cardiac transplant survivors: results from longitudinal data.

BACKGROUND: Cross-sectional analyses have identified significant associations between quality of life (QOL), and comorbidities and adverse effects in cardiac transplant recipients. However, little is known about factors that influence changes in QOL over time. This study examines both cross-sectional and longitudinal data from long-term survivors to identify factors that affect differences in QOL among recipients and individual changes in QOL during a 1-year period. METHODS: Self-selected enrollees completed questionnaires, including QOL scales, at 3-month intervals. Repeated measures multiple regression analysis was used to examine the association between the QOL scales and comorbidities, adverse effects, and compliance measures, controlling for other factors. RESULTS: We included 569 participants in the analysis, with a mean time since transplantation of 8.6 years. Cross-sectional results showed that the number of comorbidities, treatment non-compliance, and several adverse effects were associated with low QOL. In longitudinal results, waiting to take medications and taking less medication because of lifestyle restrictions were associated with decreases in QOL over time. Hair loss, changes in face shape, and decreased sexual interest or ability also had the largest adverse effects on changes in QOL. CONCLUSIONS: These findings provide new opportunities for interventions to address factors related to decreases in QOL. Clinicians should actively solicit information about compliance with medication regimens. In addition, information about the adverse effects of medications should be considered when making therapeutic decisions.

Twenty years of renal transplantation at Ohio State University: the results of five eras of immunosuppression.

Over the past 20 years, more than 4,000 patients have undergone an abdominal solid organ transplant at Ohio State University. The 20-year period can be divided into five eras, each defined by an immunosuppressive protocol used during that period. With each successful era came a new immunosuppressive protocol that produced an incremental improvement in outcomes of patients and graft survival resulting from the application of the newest and most sophisticated combination of immunosuppressive drugs. The incidence of acute rejection episodes and graft survival from each era are compared and demonstrate the substantial improvement in results that has been achieved over the past 20 years.

Prospective, randomized trial of steroid withdrawal in kidney recipients treated with mycophenolate mofetil and cyclosporine.

UNLABELLED: Our transplant centre began a prospective, randomized trial of steroid withdrawal in low risk renal transplant recipients on triple immunosuppression consisting of mycophenolate mofetil (MMF), microemulsion cyclosporine (CSA), and prednisone. One hundred and twenty patients were randomized either to discontinue or remain on steroids (60 patients per group). Study design consisted of analyses of 1-yr outcomes after study entry. This report includes the 1-yr results plus results at last follow-up (mean follow-up 3.7 yr). There were no significant differences in rates of patient and graft survival at 1 yr or at last follow-up. Additionally, the incidences of acute and chronic rejection as well as graft function were the same at 1 yr and at last follow-up. Significant improvement was noted in total serum cholesterol and bone density at 1 yr and last follow-up. Initial improvement in patient weight at 1 yr was not sustained at last follow-up. No significant impact of steroid withdrawal on serum triglycerides, blood pressure, or post-transplant diabetes mellitus was observed. To date, we have observed no immunologic risk, and some significant benefit in regards to side effects, of steroid withdrawal between 6 and 36 months after transplantation in low risk renal transplant recipients maintained on prednisone, MMF, and microemulsion CSA. CONCLUSION: Steroid withdrawal in low risk kidney transplant recipients is safe and ameliorates many of the unwanted sides effects of steroid use.

Excellent clinical outcomes in primary kidney transplant recipients treated with steroid-free maintenance immunosuppression.

Steroid-free maintenance immunosuppression is desirable to eliminate the side effects of chronic corticosteroid use. Complete steroid avoidance or rapid post-transplant steroid withdrawal has recently been used in renal transplant recipients with encouraging results. The present study evaluated the outcome of a steroid-free maintenance immunosuppressive protocol in kidney transplant recipients with at least one-yr follow up. Between April 2002 and October 2004, a total of 301 primary kidney transplant recipients received steroid-free maintenance immunosuppression. The regimen consisted of induction with thymogobulin and prednisone for the first five d. Patients were maintained on Sirolimus and Neoral. Neoral dose was adjusted to target C2 levels and the Sirolimus dose was adjusted to a target rapamycin trough level. All primary kidney transplants (n = 502) performed in the two yr (starting January 2000) prior to institution of the steroid-free regimen and thus maintained on a steroid-based immunosuppressive protocol were used for comparison. One-year patient and death censored graft survival were 93.1% and 98.1% for the steroid-free group vs. 95.2% and 95.2% for the comparator groups (p = ns). The incidence of biopsy-proven acute rejection was 4.9% in the steroid-free group vs. 9.4% in the comparator group (p < 0.01). Two (0.7%) of 301 patients in the steroid-free group lost their grafts because of acute rejection compared with nine (1.8%) patients in the comparator group (p < 0.05). At one-yr post-transplant the mean serum creatinine level was not different between the two groups. There were no significant differences in mean serum cholesterol and triglycerides levels as well as the percentage of patients on lipid lowering agents between the groups. White blood cell counts, daily doses of Neoral and weight gain were significantly lower in the steroid-free group vs. the comparator group. However, more patients in the steroid-free group required erythropoietin and iron therapy for anemia (p < 0.001). We conclude that excellent graft survival with a significantly lower incidence of acute rejection can be achieved using a steroid-free maintenance immunosuppressive protocol consisting of Neoral and Sirolimus.

Pulmonary cytomegalovirus reactivation causes pathology in immunocompetent mice.

OBJECTIVE: Cytomegalovirus (CMV) is a ubiquitous herpes virus that persists in the host in a latent state following primary infection. We have recently observed that CMV reactivates in lungs of critically ill surgical patients and that this reactivation can be triggered by bacterial sepsis. Although CMV is a known pathogen in immunosuppressed transplant patients, it is unknown whether reactivated CMV is a pathogen in immunocompetent hosts. Using an animal model of latency/reactivation, we studied the pathobiology of CMV reactivation in the immunocompetent host. DESIGN: Laboratory study. SETTING: University laboratory. SUBJECTS: Cohorts of immunocompetent BALB/c mice with or without latent murine CMV (MCMV+/MCMV-). INTERVENTIONS: Mice underwent cecal ligation and puncture. Lung tissue homogenates were evaluated after cecal ligation and puncture for tumor necrosis factor-alpha, interleukin-1beta, neutrophil chemokine KC, and macrophage inflammatory protein-2 messenger RNA by polymerase chain reaction and real-time quantitative reverse transcription-polymerase chain reaction. Because pulmonary tumor necrosis factor-alpha expression is known to cause pulmonary fibrosis, trichrome-stained sections of lung tissues were analyzed using image analysis to quantitate pulmonary fibrosis. In a second experiment, a cohort of MCMV+ mice received ganciclovir (10 mg/kg/day subcutaneously) following cecal ligation and puncture. Tumor necrosis factor-alpha messenger RNA and pulmonary fibrosis were evaluated as described previously. MEASUREMENTS AND MAIN RESULTS: All MCMV+ mice had CMV reactivation beginning 2 wks after cecal ligation and puncture. Following reactivation, these mice had abnormal tumor necrosis factor-alpha, interleukin-1beta, neutrophil chemokine KC, and macrophage inflammatory protein-2 messenger RNA expression compared with controls. Image analysis showed that MCMV+ mice had significantly increased pulmonary fibrosis compared with MCMV- mice 3 wks after cecal ligation and puncture. Ganciclovir treatment following cecal ligation and puncture prevented MCMV reactivation. Furthermore, ganciclovir-treated mice did not demonstrate abnormal pulmonary expression of tumor necrosis factor-alpha messenger RNA. Finally, ganciclovir treatment prevented pulmonary fibrosis following MCMV reactivation. CONCLUSIONS: This study shows that CMV reactivation causes abnormal tumor necrosis factor-alpha expression, and that following CMV reactivation, immunocompetent mice have abnormal pulmonary fibrosis. Ganciclovir blocks MCMV reactivation, thus preventing abnormal tumor necrosis factor-alpha expression and pulmonary fibrosis. These data may explain a mechanism by which critically ill surgical patients develop fibroproliferative acute respiratory distress syndrome. These data suggest that human studies using antiviral agents during critical illness are warranted.

Evolution of immunosuppression in kidney transplantation: the Ohio State University experience.

The goals and outcomes of immunosuppression in renal transplantation have changed significantly over the last 30 years. When graft survival rates were relatively low and acute rejection was a frequent occurrence in the early era of transplantation, the goal of immunosuppression was to improve survival and reduce the rate of acute rejection. Today, with excellent graft survival rates and a low incidence of acute rejection, the goal of immunosuppression has shifted toward not only eliminating acute rejection, but also toward reducing the side effects of medications, and maintaining long-term graft function by decreasing chronic nephropathy. Between September 1982-December 2004, 3,211 primary kidney transplant procedures were performed at The Ohio State University. We excluded from analysis all combined transplants as well as patients who were involved in clinical research protocols. Our immunosuppressive protocol changed substantially over this 24-year period, which can be divided into 5 eras in time. Each era is defined by a distinct immunosuppressive protocol that resulted in an incremental improvement in outcomes of patient and graft survival rates. In the present study, the outcomes of each era in patients with previous kidney transplant only are compared and future directions are discussed. The incidence of acute rejection episodes and graft survival from each era are compared and demonstrate the substantial improvement in results that have been achieved over the past 24 years.

Hand-assisted laparoscopic versus open nephrectomies in living donors.

UNLABELLED: Shortages of cadaveric kidneys for transplant into rising numbers of patients with end-stage renal failure have increased the demand for kidneys from live donors. The morbidity associated with traditional open donor nephrectomies (ODN) may discourage many candidates. The newer laparoscopic technique has been promoted as having less morbidity. OBJECTIVES: To evaluate outcomes of hand-assisted laparoscopic nephrectomies (HALN) and prospectively compare HALN and ODN. METHODS: After retrospectively reviewing donor and recipient outcomes in 33 HALN (December through August, 2000), we prospectively compared another 47 with 30 ODN performed from September 2000 through April 2001. RESULTS: All 80 HALN were successful, with no requirement to convert to an open procedure. Four donors experienced surgery-related complications: wound infection, retroperitoneal hematoma, prolonged ileus and early small-bowel obstruction, respectively. Two recipients had ureteral complications (1 stricture, 1 leak); 5 experienced delayed graft function, 2 requiring dialysis; and 2 kidneys were lost from infarction. The prospective comparison showed the operative time for HALN (mean 184 min, standard deviation [SD] 39 min) was significantly longer (143 [SD 27] min, p < 0.01), but resulted in less blood loss (p < 0.05). Lengths of time to warm ischemia/early graft function, resumption of oral intake/first bowel movement, and hospital discharge were similar. The abdominal-wall laxity and loss of cutaneous sensation from the flank incision experienced by many ODN patients after was uncommon in the HALN group. Three months after nephrectomy, donor complaints of incisional pain were less common after HALN (p < 0.01). CONCLUSIONS: HALN had good outcomes for donors and recipients, with quicker, more complete recoveries 3 months afterward.

Sexual functioning following renal transplantation.

This study describes the prevalence of and investigates variables associated with problems in sexual functioning for a sample of 347 individuals following renal transplantation. Sexual problem was conceptualized through three continuous variables: lack of interest in sex; lack of enjoyment of sex; and difficulty becoming sexually aroused. Between 50 percent and 55 percent of respondents reported no sexual difficulties. The remaining respondents indicated from mild to severe problems. Multiple regression was used to examine predictors of problems with sexual functioning. Variables in the final model associated with sexual problems were older age and lower patient perceptions of physical and mental well-being. Assessment of and education regarding sexual functioning must be a routine component of psychosocial intervention. Future research warrants investigation of the meaning of sexual function for this population.

Intra-abdominal bacterial infection reactivates latent pulmonary cytomegalovirus in immunocompetent mice.

Critically ill surgery patients are susceptible to pulmonary reactivation of latent cytomegalovirus (CMV), but what triggers this reactivation is unknown. Immunosuppression and bacterial sepsis are thought to stimulate reactivation of CMV, and in this study it was hypothesized that immunosuppressive effects of surgery with or without concomitant bacterial infection may reactivate latent CMV. Mice infected with CMV were allowed to develop latent infections. Latently infected mice underwent a laparotomy with cecal ligation and puncture (CLP; n=30), a laparotomy alone (sham; n=10), or no surgery (control; n=5). Lung tissue homogenates were evaluated for viral activity, and, 2 and 3 weeks after CLP, lungs of 7 of 7 and 5 of 5 mice, respectively, showed reactivation of latent CMV. In contrast, lungs from all sham-operated animals and controls showed no viral reactivation. These findings demonstrate that surgery with subsequent intra-abdominal bacterial infection reactivated CMV in lungs of latently infected mice. The mechanism of this reactivation is unknown but likely involves cytokines induced by sepsis.

The relationship between donor age and cadaveric renal allograft survival is modified by the recipient's blood pressure.

Increasing donor age correlates with reduced renal allograft survival. In this study we analyzed variables that may modify this relationship. The study included 1285 cadaveric kidney allograft recipients followed for 7.2 + 4.5 years. By Cox, increasing donor age beyond 30 years was associated with significant increases in the hazard ratio for graft loss [age 31-46, hazard ratio (HR) = 1.4, p = 0.02; 46-60, HR = 1.55, p = 0.008; > 60, HR = 1.68, p = 0.03]. Increasing donor age was significantly associated with: older and heavier recipients; higher creatinine and blood pressure (BP) 6 months post-transplant; and lower total cyclosporine dose during the first year. Of interest, the 6-month serum creatinine and the BP level modified significantly the relationship between age and survival. Thus, increasing donor age was significantly related to reduced graft survival only in patients with a 6-month creatinine < 2 mg/dL. Furthermore, donor age related significantly to graft survival only among patients with higher BP levels 6 month post transplant. It is concluded that increasing donor age is associated with reduced cadaveric graft survival, but that relationship is significantly modified by graft function and BP. These data suggest that poorly functioning kidneys have reduced survival irrespective of age. Furthermore, elevated BP levels may have a particularly negative effect on the survival of older grafts.

Patient survival after renal transplantation: IV. Impact of post-transplant diabetes.

BACKGROUND: The development of de novo diabetes mellitus is a serious complication of kidney transplantation. This study examined the cardiovascular risk profile of patients with post-transplant diabetes (PTDM) and assessed the impact of PTDM on patient survival. METHODS: This analysis included 1811 adult, renal allograft recipients, transplanted in a single institution between 1983 and 1998. Patient survival was analyzed by univariable and multivariable Cox regression considering PTDM as a time dependent variable. RESULTS: After a follow-up period of 8.3 +/- 4.5 years, 293 patients (20%) developed PTDM, 14% lost their graft, and 20% died. Compared to patients without DM (NoDM, N = 1186) patients with PTDM were significantly older (40 +/- 14 vs. 48 +/- 12 years, P < 0.001), heavier (76 +/- 23 vs. 86 +/- 25 kg, P < 0.001), and included more African Americans (18 vs. 28%, P = 0.001). In addition, the incidence of PTDM was significantly higher in patients who were transplanted after 1995 than prior to that year. In contrast, there were no significant differences between PTDM and patients who had DM before the transplant (DM; N = 332). Compared to NoDM, patients with PTDM had significantly higher total serum cholesterol and triglycerides (TG), higher systolic blood pressure and higher pulse pressure throughout the post-transplant period. Of interest, all of these abnormalities preceded the development of PTDM. Hypertriglyceridemia was particularly pronounced in PTDM and elevated TG levels correlated with the subsequent development of PTDM, independent of other risk factors (P = 0.001 by multivariate Cox). Compared to NoDM (16% mortality) a significantly higher percent of DM (31%, P < 0.001) and PTDM (22%, P = 0.005) patients died. By Cox regression, PTDM correlated with reduced patient survival (hazard ratio = 1.80, CI 1.35 to 2.41, P = 0.001), and that relationship was independent of other correlates of reduced survival that included: increasing age; transplant year; reduced serum albumin; and male sex. CONCLUSION: s: PTDM is associated with an unfavorable cardiovascular risk profile that precedes the development of hyperglycemia. PTDM is an independent predictor of reduced survival in renal allograft recipients.

Clinical significance of MHC-reactive alloantibodies that develop after kidney or kidney-pancreas transplantation.

The purpose of this study was to determine the relationships between acute rejection, anti-major histocompatibility complex (MHC) class I and/or class II-reactive alloantibody production, and chronic rejection of renal allografts following kidney or simultaneous kidney-pancreas transplantation. Sera from 277 recipients were obtained pretransplant and between 1 month and 9.5 years post-transplant (mean 2.6years). The presence of anti-MHC class I and class II alloantibodies was determined by flow cytometry using beads coated with purified MHC molecules. Eighteen percent of recipients had MHC-reactive alloantibodies detected only after transplantation by this method. The majority of these patients produced alloantibodies directed at MHC class II only (68%). The incidence of anti-MHC class II, but not anti-MHC class I, alloantibodies detected post-transplant increased as the number of previous acute rejection episodes increased (p = 0.03). Multivariate analysis demonstrated that detection of MHC class II-reactive, but not MHC class I-reactive, alloantibodies post-transplant was a significant risk factor for chronic allograft rejection, independent of acute allograft rejection. We conclude that post-transplant detectable MHC class II-reactive alloantibodies and previous acute rejection episodes are independent risk factors for chronic allograft rejection. Implementing new therapeutic strategies to curtail post-transplant alloantibody production, and avoidance of acute rejection episodes, may improve long-term graft survival by reducing the incidence of chronic allograft rejection.

The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) has proven to be a very effective drug for the prevention of acute rejection following renal transplantation when dosed as prescribed at 2 or 3 g/d. However, circumstances arise in clinical transplantation where the dose must be lowered, either to avoid drug toxicity or because of concurrent infection. The impact on the incidence of acute rejection and graft survival when the MMF dose must be lowered has not previously been investigated. METHODS: In this study, a cohort of 721 kidney transplant recipients who received immunosuppression using MMF in conjunction with cyclosporine and prednisone and OKT3 (n = 425) or Simulect (n = 296) induction were evaluated. Clinical outcomes were compared and contrasted between patients with and without MMF dose changes within the first year post-transplantation. RESULTS: The majority of patients (70.3%, n = 507) had at least one dose change within the first post-transplant year. Compared with the 214 patients who did not have a dose change, these patients had a much higher incidence of acute rejection within the first post-transplant year (23.3% vs. 3.7%, p < 0.001). This resulted in a significantly decreased 3-yr death-censored graft survival (76.3% vs. 88.3%, p = 0.003). The incidence of acute rejection for patients who had a dose change was highest if the dose change occurred within the first post-transplant month (34.4%). The incidence of acute rejection for the dose change patients was influenced by recipient ethnicity (African-American vs. Caucasian) and the type of induction agent used (OKT3 vs. Simulect). CONCLUSION: Altering the dose of MMF within the first post-transplant year correlated with a significantly worse clinical outcome in this cohort of renal transplant recipients. These data suggest that avoidance of MMF dose changes within the first year after renal transplantation would result in improved graft survival.