Risk Of Late Acute Rejection Research Articles

Etiologies and Outcomes Associated With Tacrolimus Levels Out of a Typical Range That Lead to High Variability in Kidney Transplant Recipients.

High tacrolimus intrapatient variability (tac IPV) is associated with poor outcomes in kidney transplantation, including rejection, donor-specific antibodies, and graft loss. A common cause of high tac IPV is related to patient nonadherence, but this is yet to be conclusively demonstrated. This was a longitudinal cohort study comprising adult kidney recipients, who received transplants between 2015 and 2017, with follow-ups through February 2020. The goal of this study was to identify the most common etiologies of tac levels outside the typical range, which lead to high tac IPV, and assess the etiology-specific associations between high tac IPV and graft outcomes. Multivariate Cox regression was used to assess time-to-event analyses. In total, 537 adult kidney recipients were included; 145 (27%) were identified as having a high tac IPV (>40%) 3-102 months post-transplant. Common etiologies of tac levels significantly outside the standard goal range (6-12 ng/mL) leading to high tac IPV included patient nonadherence (20%), infections (19%), tac-related toxicities (17%), and undocumented issues (27%). In multivariable Cox modeling, those with high tac IPV because of nonadherence had a 3.5 times higher risk of late acute rejection (P = 0.019) and 2.2 times higher risk of late graft loss (P = 0.044). No other etiologies in the typical tac level range were significantly associated with either acute rejection or graft loss. Although high tac IPV has many causes, only high tac IPV caused by nonadherence is consistently associated with poor allograft outcomes.

Does Calcineurin Inhibitor Plus Mycophenolate Mofetil Combination Therapy Decrease the Risk of Late Acute Rejection after Liver Transplantation?

Does Calcineurin Inhibitor Plus Mycophenolate Mofetil Combination Therapy Decrease the Risk of Late Acute Rejection after Liver Transplantation? Kwan-Woo Kim, M.D., Sung-Gyu Lee, M.D., Shin Hwang, M.D., Ki-Hun Kim, M.D., Chul-Soo Ahn, M.D., Deok-Bog Moon, M.D., Tae-Yong Ha, M.D., Gi-Won Song, M.D., Dong-Hwan Jung, M.D., Nam-Kyu Choi, M.D., Jeong-Ik Park, M.D., Gil-Chun Park, M.D., Young-Dong Yu, M.D., Pyung-Jae Park, M.D. and Young-Il Choi, M.D.

Sirolimus monotherapy as maintenance immunosuppression: a multicenter experience

The aim of this study was to retrospectively evaluate safety and feasibility of sirolimus (SRL) monotherapy in kidney transplant recipients. Patients older than 18 years, with monotherapy prescribed for more than 1 month and at least 6 months of follow-up were included. We analysed the data from 138 patients. Mean time period between transplantation and start of monotherapy was 6.5 +/- 4.1 years.The most frequent reason was minimization of immunosuppression followed by malignancy. Acute rejection rate was 1.4% at 12 months (two episodes). Graft and patient survival were 94.2% and 97.1% respectively. Mean follow-up after initiation of monotherapy was 29.4 months. Two patients died as a result of cardiovascular diseases and two because of malignancy. Percentage of withdrawal from monotherapy was 14%. SRL trough levels were 10.2 +/- 2.3 ng/ml at baseline and 9.6 6 +/- 3.3 ng/ml at 12 months. Mean glomerular filtration rate was 48.4 ml/min/1.73 m(2) at baseline and 47.7 ml/min/1.73 m(2) at 12 months. Proteinuria was 499.7 mg/24 h at baseline and 543 +/- 794 mg/24 h at 12 months. No significant changes in lipids, glucose, or hemoglobin occurred, although the percentage of patients treated with statins and Epo increased at the end of the follow-up. SRL monotherapy is suitable as long-term immunosuppression in selected patients with no significantly increased risk of late acute rejection.

Association of MCP‐1 and CCR2 polymorphisms with the risk of late acute rejection after renal transplantation in Korean patients

Among the factors modulating transplant rejection, chemokines and their respective receptors deserve special attention. Increased expression of monocyte chemoattractant protein-1 (MCP-1) and its corresponding receptor (chemokine receptor-2, CCR2) has been implicated in renal transplant rejection. To determine the impact of the MCP-1-2518G and CCR2-64I genotypes on renal allograft function, 167 Korean patients who underwent transplantation over a 25-year period were evaluated. Genomic DNA was genotyped using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Fifty-five (32.9%) patients were homozygous for the MCP-1-2518G polymorphism. Nine (5.4%) patients were homozygous for the CCR2-64I polymorphism. None of the investigated polymorphism showed a significant shift in long-term allograft survival. However, a significant increase was noted for the risk of late acute rejection in recipients who were homozygous for the MCP-1-2518G polymorphism (OR, 2.600; 95% CI, 1.125–6.012; P = 0.022). There was also an association between the MCP-1-2518G/G genotype and the number of late acute rejection episodes (P = 0.024). Although there was no difference in the incidence of rejection among recipients stratified by the CCR2-V64I genotype, recipients with the CCR2-V64I GG genotype in combination with the MCP-1-2518G/G genotype had a significantly higher risk of acute or late acute rejection among the receptor-ligand combinations (P = 0.006, P = 0.008, respectively). The MCP-1 variant may be a marker for risk of late acute rejection in Korean patients.

Does mycophenolate mofetil reduce the risk of late acute rejection after liver transplantation?

Does mycophenolate mofetil reduce the risk of late acute rejection after liver transplantation?

Mycophenolate Mofetil Use Is Associated with Decreased Risk of Late Acute Rejection in Adult Liver Transplant Recipients

Mycophenolate mofetil (MMF) used in a triple-drug regimen has been shown to decrease acute rejection rates, compared to a double-drug regimen. The impact of MMF on late acute rejection (LAR) episodes has not been well described. To investigate the risk of LAR (rejection > or = 6 months post-transplantation) data from the Scientific Registry of Transplant Recipients (SRTR) were used. We studied adult primary liver transplant recipients transplanted between June 1, 1995, and April 30, 2004, with hepatitis C virus (HCV) (n = 3356), hepatitis B virus (HBV) (n = 550) or a nonviral (n = 5740) primary cause of liver disease who were recorded as receiving continuous 3-(MMF + Tacro + steroids) versus 2-drug (Tacro + steroids) therapy for at least 6 months immediately post transplantation. Kaplan-Meier analysis showed significantly lower LAR rates 4 years post-transplant in 3- versus 2-drug HCV, HBV and nonviral disease patients. Multivariate regression confirmed 3- versus 2-drug therapy to be associated with a decreased risk of LAR. Late graft survival was significantly lower at 4 years post-transplant for patients with LAR 6-12 months post-transplantation versus patients with early rejection (78.0% vs. 87.0%, p < 0.001) and no rejection (88.1%, p < 0.001). Three-drug versus 2-drug therapy for a minimum of 6 months may offer a better treatment strategy to avoid the consequences and expense of LAR episodes.

Sirolimus-Based Therapy With or Without Cyclosporine: Long-Term Follow-up in Renal Transplant Patients

This open-label, phase 3b, extension trial in renal transplant recipients (Sirolimus Study 311) assessed the long-term safety of sirolimus (SRL) administered with cyclosporine (CsA) (SRL + CsA group, n = 98) or without CsA (SRL group, n = 69). Renal transplant recipients who had either completed one of seven previous SRL studies sponsored by Wyeth Research or had participated for ≥3 months and reached a protocol-designated endpoint were eligible for enrollment. Data were available for 167 patients, all of whom initially received steroids. Mean total SRL exposure was 1526 days, including previous study participation. After enrollment in the extension study, there were significantly more acute rejections in the SRL + CsA group (6.1% vs 0%, P < .05). Differences in rates of graft loss (3.1% vs 1.4%) and death (6.1% vs 1.4%) were not significantly different between SRL + CsA and SRL groups, respectively. At 48 months after transplantation, calculated GFR (53.4 vs 70.9 mL/min) and hemoglobin (124.9 vs 136.6 g/L) were significantly better in the SRL group. Lipid values were not significantly different between groups at 48 months. The incidence of treatment-emergent increased creatinine, anemia, hypertension, headache, epistaxis, abnormal kidney function, and upper respiratory infection were significantly higher in the SRL + CsA group, whereas no adverse events were significantly higher in the SRL group. Malignancies were reported more frequently (11.2% vs 0%) with SRL + CsA. Results from this extension study indicate that SRL-based therapy without CsA is a safe alternative to combination therapy with CsA, offering long-term improvement in renal function with no increased risk of late acute rejection.

SIROLIMUS USED WITH OR WITHOUT CYCLOSPORINE IN RENAL TRANSPLANT PATIENTS: RESULTS FROM AN ONGOING LONG-TERM EXTENSION STUDY

P745 Aims: To evaluate the long-term safety of sirolimus (SRL) used with cyclosporine (CsA) (SRL+CsA group) or without CsA (SRL group). Methods: Renal transplant recipients who had either completed a previous SRL study sponsored by Wyeth Research or had participated for >3 months and reached a protocol-designated endpoint were eligible to be selected for inclusion in this extension study of SRL-based therapy. Results: Data were available for 167 patients, all of whom initially received steroids. Three patients (4.3%) in the SRL+CsA group (n=69) converted to tacrolimus + SRL. Nine (9.2%) patients in the SRL group (n= 98) received azathioprine, 4 (4.1%) received MMF, and 3 (3.1%) received both azathioprine and MMF, at different times. Mean total SRL exposure was 1651 days, including previous study participation. Graft loss censored for death (3.1% vs 1.4%) and death (6.1% vs 1.4%) were not significantly different, SRL+CsA vs SRL, respectively. After enrollment in the extension study, there were significantly more acute rejections in the SRL+CsA group (6.1% vs 0%). At 48 months after transplantation, calculated GFR (53.4 vs 70.9 mL/min), fasting glucose (5.9 vs 5.3 mmol/L) and hemoglobin (124.9 vs 136.6 g/L) were significantly better with SRL. Fasting cholesterol (5.9 vs 6.0 mmol/L) and triglycerides (2.9 vs 2.3 mmol/L), SRL+CsA vs SRL, respectively, were not significantly different. Increased creatinine, anemia, hypertension, skin hypertrophy, headache, thrombocytopenia, epistaxis, abnormal kidney function, pneumonia, flu syndrome, and upper respiratory infection occurred significantly more often in the SRL+CsA group. In addition, the incidence of malignancy (11.2% vs 0%) was significantly higher in the SRL+CsA group. No adverse event was reported significantly more often in the SRL group. Conclusions: This open-label extension study adds to the growing evidence that SRL-based therapy without CsA is a safe alternative to combination therapy with CsA, offering long-term improvement in renal function with no increased risk of late acute rejection.

Long-term outcome of a prospective trial of steroid withdrawal after kidney transplantation

Background: Steroid withdrawal (SW) after kidney transplantation is desirable to avoid associated serious side effects. We studied the long-term outcome of a group of kidney transplant recipients who underwent SW. Methods: Between 1991 and 1993, kidney transplant recipients (N = 12) who had posttransplantation diabetes were entered in a prospective trial of SW. These patients were compared with a demographically similar comparison cohort (N = 66). End points of the study were patient and graft survival, incidence of late acute and chronic rejection, and changes in diabetes management. Results: Previously published data from the SW group at 15 months of follow-up indicated improvement in diabetes control without any adverse effect on patient or graft actuarial survival. At long-term follow-up (mean, 56 months) the improvement in diabetes management was not detectable. The incidence of late acute rejection in SW and cohort groups was 42% and 8%, respectively (P = .006). Likewise, the incidence of chronic rejection in the SW versus cohort group was 42% and 12%, respectively (P = .014). Conclusions: Although SW appeared to be successful initially, our long-term data indicate that SW significantly increases the risk of late acute rejection and chronic rejection episodes without benefits in posttransplantation diabetes management. Steroid withdrawal in patients with posttransplantation diabetes should be approached with caution. (Surgery 1999;125:155-9.)

Long-term outcome of a prospective trial of steroid withdrawal after kidney transplantation

Background: Steroid withdrawal (SW) after kidney transplantation is desirable to avoid associated serious side effects. We studied the long-term outcome of a group of kidney transplant recipients who underwent SW. Methods: Between 1991 and 1993, kidney transplant recipients (N = 12) who had posttransplantation diabetes were entered in a prospective trial of SW. These patients were compared with a demographically similar comparison cohort (N = 66). End points of the study were patient and graft survival, incidence of late acute and chronic rejection, and changes in diabetes management. Results: Previously published data from the SW group at 15 months of follow-up indicated improvement in diabetes control without any adverse effect on patient or graft actuarial survival. At long-term follow-up (mean, 56 months) the improvement in diabetes management was not detectable. The incidence of late acute rejection in SW and cohort groups was 42% and 8%, respectively ( P = .006). Likewise, the incidence of chronic rejection in the SW versus cohort group was 42% and 12%, respectively ( P = .014). Conclusions: Although SW appeared to be successful initially, our long-term data indicate that SW significantly increases the risk of late acute rejection and chronic rejection episodes without benefits in posttransplantation diabetes management. Steroid withdrawal in patients with posttransplantation diabetes should be approached with caution. (Surgery 1999;125:155-9.)