Optimization of de novo belatacept-based immunosuppression administered to renal transplant recipients

Kidney transplant recipients administered belatacept-based maintenance immunosuppression present with a more favorable metabolic profile, reduced incidence of de novo donor-specific antibodies (DSAs), and improved renal function and long-term patient/graft survival relative to individuals receiving calcineurin inhibitor (CNI)-based immunosuppression. However, the rates and severity of acute rejection (AR) are greater with the approved belatacept-based regimen than with CNI-based immunosuppression. Although these early co-stimulation blockade-resistant rejections are typically steroid sensitive, the higher rate of cellular AR has led many transplant centers to adopt immunosuppressive regimens that differ from the approved label. This article summarizes the available data on these alternative de novo belatacept-based maintenance regimens. Steroid-sparing, belatacept-based immunosuppression (following T cell–depleting induction therapy) has been shown to yield AR rates comparable to those seen with CNI-based regimens. Concomitant treatment with belatacept plus a mammalian target of rapamycin inhibitor (mTORi; sirolimus or everolimus) has yielded AR rates ranging from 0 to 4%. Because the optimal induction agent and number of induction doses; blood levels of mTORi; and dose, duration, and use of corticosteroids have yet to be determined, larger prospective clinical trials are needed to establish the optimal alternative belatacept-based regimen for minimizing early cellular AR occurrence.     

Early post‐transplant conversion from tacrolimus to belatacept for prolonged delayed graft function improves renal function in kidney transplant recipients

Prolonged delayed graft function (DGF) in kidney transplant recipients imparts a risk of poor allograft function; tacrolimus may be detrimental in this setting. We conducted a retrospective single center analysis of the first 20 patients converted to belatacept for prolonged DGF as part of a clinical protocol as a novel treatment strategy to treat prolonged DGF. Prior to conversion, patients underwent an allograft biopsy to rule out rejection and confirm tubular injury. The primary outcome was the estimated glomerular filtration rate (eGFR) at 12 months post‐transplant; secondary outcome was the change in eGFR 30 days post‐belatacept conversion. At 1 year post‐transplant, the mean eGFR was 54.2 (SD 19.2) mL/min/1.73 m². The mean eGFR on the day of belatacept conversion was 16 (SD 12.7) mL/min/1.73 m² and rose to 43.1 (SD 15.8) mL/min/1.73 m² 30 days post‐conversion (P<.0001). The acute rejection rate was 20% with 100% patient survival at 12 months post‐transplant. There was one graft loss in the setting of an invasive Aspergillus infection that resulted in withdrawal of immunosuppression and transplant nephrectomy. Belatacept conversion for prolonged DGF is a novel treatment strategy that resulted in an improvement in eGFR. Additional follow‐up is warranted to confirm the long‐term benefits of this strategy.     

Predicting long-term graft survival in adult kidney transplant recipients

The ability to accurately predict a population's long-term survival has important implications for quantifying the benefits of transplantation. To identify a model that can accurately predict a kidney transplant population's long-term graft survival, we retrospectively studied the United Network of Organ Sharing data from 13,111 kidney-only transplants completed in 1988- 1989. Nineteen-year death-censored graft survival (DCGS) projections were calculated and compared with the population's actual graft survival. The projection curves were created using a two-part estimation model that (1) fits a Kaplan-Meier survival curve immediately after transplant (Part A) and (2) uses truncated observational data to model a survival function for long-term projection (Part B). Projection curves were examined using varying amounts of time to fit both parts of the model. The accuracy of the projection curve was determined by examining whether predicted survival fell within the 95% confidence interval for the 19-year Kaplan-Meier survival, and the sample size needed to detect the difference in projected versus observed survival in a clinical trial. The 19-year DCGS was 40.7% (39.8-41.6%). Excellent predictability (41.3%) can be achieved when Part A is fit for three years and Part B is projected using two additional years of data. Using less than five total years of data tended to overestimate the population's long-term survival, accurate prediction of long-term DCGS is possible, but requires attention to the quantity data used in the projection method.     

Risk of malignancy with long-term immunosuppression in renal transplant recipients

BACKGROUND: Improvements in immunosuppressive regimens have significantly enhanced patient and graft survival in renal transplant recipients. However, susceptibility to neoplastic disorders is increased as a consequence of prolonged immunosuppression. Available data pertaining to cancer risks in renal transplant recipients have been inconsistent, and much of it is derived from international studies, which may not be truly representative of the United States population. METHODS: We studied a total of 1979 transplants performed in 1739 patients from a single center in the United States with a mean follow-up of 6.1 years, and a total of 9852 person-years' follow-up. RESULTS: The mean age at the time of diagnosis of cancer was 50 years, and the mean interval between transplant and diagnosis of cancer was 95 months. Older patients receiving a transplant had a significantly higher risk for developing cancer as opposed to younger patients (RR 6.2 for >60 years compared with <40 years). When compared with the general population using data from the Surveillance, Epidemiology and End Results (SEER) registry, the overall risk for nonskin malignancies was modestly increased in our transplant recipients, with a standardized incidence ratio (SIR) of 1.4 (P= 0.01). When stratified by age groups, younger age at transplant (<40 years) had the highest SIR, at 2.3 (P < 0.001). Similarly, duration post-transplant >10 years had an SIR of 2.4 (P < 0.001). CONCLUSION: We believe that this study is representative of the United States' renal transplant population, and highlights the need for reduced immunosuppression in the long-term and increased vigilance for cancers in younger patients receiving renal transplantation.     

肾移植术后6个月血清肌酐水平对移植肾长期存活的影响

目的探讨肾移植术后半年肾功能对移植肾长期存活的影响。方法回顾性分析自1992年4月至2001年3月在本中心进行首次单纯尸体肾移植病例794例的临床资料。根据术后6个月时间点血清肌酐(Scr)水平,分为肾功能异常组(Scr>133μmol/L)与肾功能正常组(Scr≤133μmol/L)。通过Kaplan-Meier方法分别计算包括急性排斥(AR)、延迟复功(DGF)和不包括AR、DGF时两组患者带功和排除带功死亡时移植肾短期和长期存活率。结果两组在受体移植时年龄、淋巴毒、冷/热缺血时间及免疫抑制剂方案无显著性差异;而男女性别比例、受体体重、随访时间、术后6个月内AR和DGF发生率、术后6个月或12个月环孢素A(CsA)剂量、随访期间及Scr水平等差异有显著性意义。肾功能异常组与正常组相比有较高的AR和DGF的发生率,但不管是否存在AR和DGF,肾功能异常组带功和排除带功死亡时移植肾的长期存活均明显低于肾功能正常组。结论术后6个月Scr水平影响移植肾的长期存活。     

Predictors of renal function improvement following tacrolimus conversion in cyclosporine-treated kidney transplant recipients

The objective of this study was to evaluate the relationship between variability of cyclosporine (CsA) absorption and tacrolimus (TAC) conversion seeking factors that predict improvement in allograft function after TAC conversion. We performed a retrospective study of 44 adult kidney transplant recipients undergoing conversion from CsA to TAC-based immunosuppression. Before TAC conversion, patients had complete, consecutive, 6 monthly C2 levels and a follow-up duration beyond 6 months after TAC conversion. The patients were divided into 2 groups: one (n=23) with low variability of CsA absorption and one (n=21) with high variability of CsA absorption. At TAC conversion, the estimated glomerular filtration rate (eGFR) was similar in both patient groups. Six months after TAC conversion, eGFR improved in both groups. Stepwise regression analysis revealed the DeltaSCr6 (change in serum creatinine level at 6 months) to be independently associated with the preconversion serum creatinine (SCr; P<.0001) and the percent coefficient of variation (%CV) of SCr (P=.0034). DeltaSCr6 was inversely associated with posttransplantation years (P=.0033), and 6-month TAC blood levels (P=.0053). The DeltaSCr6 was not associated with variability of oral CsA absorption. The cutoff value of baseline SCr at TAC conversion differentiated an increase in or reduction of SCr to be about 1.0 mg/dL. Our study of CsA-treated kidney transplant recipients who underwent TAC conversion showed that a preconversion SCr>1.0 mg/dL, a high variability of SCr, and early TAC conversion predicted greater short-term benefit on graft function.     

Safe conversion of mycophenolate mofetil to azathioprine in kidney transplant recipients with sirolimus-based immunosuppression

Aim:   Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The long-term use of MMF may bring increased risk of for infection and malignancy and also increased cost of transplantation. The search for minimization of immunosuppressive protocol has led to an open randomized clinical trial of conversion from MMF to azathioprine (AZA).
Methods:   A total of 50 kidney allograft recipients treated with prednisone, sirolimus and MMF were randomized into two groups: converted (AZA group) and continuing (MMF group). The average duration of MMF therapy prior to conversion was 43 months in each group. Inclusion criteria included: patients with serum creatinine levels of less than 200 µmol/L; no past history of acute vascular rejection or recent acute rejection 6 months before randomization; and normal liver function tests.
Results:   Baseline demographics were similar in the two groups. During the 12 month observation period, there were no acute rejection episodes in either group. There were no significant differences in overall patient or graft survival or function. AZA-treated patients had a lower incidence of gastrointestinal complications ( P  = 0.03). Daily cost reduction in the AZA group was more than $US8.79/day per patient.
Conclusion:   In general, replacing MMF with AZA in stable renal transplant recipients is well tolerated and was cost effective with no increased risk of rejection. As the this study was on relatively small samples, larger and longer follow-up studies will be needed to confirm these expected advantages for the long-term outcome and to assess the long-term safety of this minimization of immunosuppressive therapy.     

Hyperuricemia in kidney transplant recipients with intact graft function

Objectives

The aim of this study was to investigate the prevalence of hyperuricemia and factors predicting its occurrence, and to establish the relationship over time between serial changes in estimated glomerular filtration rate (eGFR) and uric acid (UR) concentration in kidney transplant (KT) recipients with eGFR >60 mL/min/1.73 m².

Methods

Adult patients who underwent KT at the Asan Medical Center between 1990 and 2008 and maintained eGFR >60 mL/min/1.73 m² were retrospectively assessed. Clinical and laboratory data were obtained from inpatient and outpatient charts and from the hospital electronic database.

Results

Of 356 patients, 301 (84.55%) had normal UR levels and 55 (15.45%) had hyperuricemia. After multivariate adjustment, transplant duration, male gender, eGFR, diabetes mellitus (DM), and calcium level were associated with higher mean UR levels. Mean UR level increased significantly and mean eGFR decreased significantly during the first year after transplantation, but there were no significant differences over the next 4 years. Serial UR and eGFR levels changed almost simultaneously.

Conclusions

Transplantation duration, male gender, eGFR level, DM, and serum calcium level were risk factors for hyperuricemia in kidney recipients with intact graft function. Increased uric acid after KT did not significantly affect graft function.     

Initial immunosuppression in liver transplant recipients with impaired renal function

Acute renal failure (ARF) after liver transplantation is a factor of poor prognosis associated with a high mortality. Selection of the donor, recipient, and intraoperative and postoperative treatment has crucial importance in the management of these critical patients. Thus, optimization of the use of calcineurin inhibitors (CNI), the main nephrotoxic substances in the immediate postoperative period, may decrease ARF incidence, allowing for early recovery of renal function in this period. Most protocols are based on the reduction or late introduction of CNI, based on the use of mycophenolate mofetil (MMF) with/without antiCD25 (basilximab/daclizumab). Recently, thymoglobulin (ATG) is also being tested to further delay the use of the CNI. A 20%-30% acute rejection incidence with the usual protocols allows recovery of renal function in more than 80% of patients without increasing the incidence of infections or adverse effects. However, it is still unknown whether there is a long-term negative effect of chimeric-humanized monoclonal antibodies and MMF combination on reinfection with hepatitis C virus in transplant recipients.     

Frailty and delayed graft function in kidney transplant recipients

The ability to predict outcomes following a kidney transplant is limited by the complex physiologic decline of kidney failure, a latent factor that is difficult to capture using conventional comorbidity assessment. The frailty phenotype is a recently described inflammatory state of increased vulnerability to stressors resulting from decreased physiologic reserve and dysregulation of multiple physiologic systems. We hypothesized that frailty would be associated with delayed graft function, based on putative associations between inflammatory cytokines and graft dysfunction. We prospectively measured frailty in 183 kidney transplant recipients between December 2008 and April 2010. Independent associations between frailty and delayed graft function were analyzed using modified Poisson regression. Preoperative frailty was independently associated with a 1.94-fold increased risk for delayed graft function (95% CI, 1.13-3.36; P = .02). The assessment of frailty may provide further insights into the pathophysiology of allograft dysfunction and may improve our ability to preoperatively risk-stratify kidney transplant recipients.     

个体化免疫抑制治疗在肾移植的疗效观察

目的：探讨个体化免疫抑制治疗对肾移植患者的临床价值。方法：将肾移植患者分为个体化组(42例)和常规组(50例),分别采用个体化免疫抑制治疗和常规免疫抑制治疗,并对术后两组的临床指标进行比较。结果：个体化组比较常规组,术后肝功能损害、高血糖、胃肠功能紊乱、呼吸系统感染、急性排斥反应发生率均明显降低(P＜0．05);而巨细胞病毒感染发生率及移植肾切除人数无差异(P＞0．05)。结论：个体化免疫抑制治疗既能维持免疫抑制效果,又能最大限度减少药物不良反应,对肾移植患者有较好治疗价值。     

Long-term survival in renal transplant recipients with graft function

Long-term survival in renal transplant recipients with graft function. BACKGROUND: Death with graft function (DWGF) is a common cause of graft loss. The risks and determinants of DWGF have not been studied in a recent cohort of renal transplant recipients. We performed a population-based survival analysis of U.S. patients with end-stage renal disease (ESRD) transplanted between 1988 and 1997. METHODS: Registry data were used to evaluate long-term patient survival and cause-specific risks of DWGF in 86,502 adult (>/=18 years) renal transplant recipients. RESULTS: Out of 18,482 deaths, 38% (N = 7040) were deaths with graft function. This accounts for 42. 5% of all graft loss. Patient survival with graft function was 97, 91, and 86% at 1, 5, and 10 years, respectively. The risk of DWGF decreased by 67% (RR = 0.33, P < 0.001) between 1988 and 1997. The adjusted rate of DWGF was 4.6, 0.8, 2.2, and 1.4 deaths per 1000 person-years for cardiovascular disease, stroke, infections, and malignancy, respectively. The suicide rate was 15.7 versus 9.0 deaths per 100,000 person-years in the general population (P < 0. 001). In multivariate analysis, the following factors were independently and significantly predictive of DWGF: white recipient, age at transplantation, ESRD caused by hypertension or diabetes mellitus, length of pretransplant dialysis, delayed graft function, acute rejection, panel reactive antibody> 30%, African American donor race, age> 45 years, and donor death caused by cerebrovascular disease. CONCLUSIONS: Patients with graft function have a high long-term survival. Although DWGF is a major cause of graft loss, the risk has declined substantially since 1990. Cardiovascular disease was the predominant reported cause of DWGF. Other causes vary by post-transplant time period. Attention to atherosclerotic risk factors may be the most important challenge to further improve the longevity of patients with successful renal transplants.     

The impact of reduced immunosuppression on graft outcomes in elderly renal transplant recipients

Abstract: Optimal immunosuppression (IS) for elderly kidney transplant recipients is unknown. We conducted a retrospective cohort study of recipients aged 60 yr or older to examine the impact of reduced IS on graft outcomes. Group 1 patients (n = 101) were initiated on mycophenolate mofetil 2 g/d and tacrolimus, target level 10–12 ng/mL; Group 2 patients (n = 88) with 1 g/d and 8–10 ng/mL, respectively. Dose adjustments were made as required. The groups were comparable except for diabetes, end‐stage renal disease duration, and induction. Mycophenolate mofetil dose was reduced in 62% and 38% of the patients, respectively (p < 0.01). Patients were followed for 23.8 ± 14.2 and 21.3 ± 11.8 months post‐transplant (p = 0.2). Twenty‐seven cases in Group 1 (26.7%) and eight in Group 2 (9.1%) lost their grafts (p = 0.01); 19 (18.8%) and 7 (8.0%) cases in each group because of death, respectively (p = 0.09). Sixteen patients in Group 1 (15.8%) and 18 in Group 2 (20.5%) experienced acute rejection (p = 0.36). Patients in Group 2 had a lower risk of graft loss compared with those in Group 1 [adjusted hazard ratio (HR): 0.27, p = 0.006, 95% CI: 0.11–0.69]. There were no significant differences between the groups regarding graft function, BK virus nephropathy, and CMV infection. Our results suggest that reduction in overall IS in this group was associated with improved graft and patient survival.     

Favorable graft survival in renal transplant recipients with polycystic kidney disease

Graft survival in the autosomal dominant polycystic kidney disease (ADPKD) transplant population at our center was compared to other end stage renal disease (ESRD) transplant recipients (excluding diabetics). There were 1512 adult cadaveric renal transplants carried out at our center between 1989 and 2002. After exclusions, 1372 renal grafts were included in the study. Using Kaplan-Meier methods, patient and graft survival were determined and compared between the two groups. Mean age at transplant was significantly older for the ADPKD group of patients. The age adjusted graft survival at 5 years was 79% for ADPKD patients compared to 68% in the controls. Patient survival for ADPKD patients improved from 89% at 5 years to 95% when age adjusted. Using the Cox proportional hazards models to compare ADPKD with other causes of ESRD (including recipient age and other variables) in a multifactorial model, ADPKD was significant at the 5% level (p=0.036). This study demonstrates a graft and patient survival advantage in ADPKD patients when age-matched compared to other ESRD patients.     

Basiliximab improves graft survival in renal transplant recipients with delayed graft function

The aim of this study was to evaluate the use of basiliximab in first renal transplant recipients with delayed graft function, defined by the need for dialysis in the first week posttransplantation. Among 148 patients in the study, 90 received basiliximab (60.8%) with 58 comprising the control group. There were no significant differences between the 2 groups related to the evaluated variables, except that the control group received more blood transfusions pretransplantation. There was a lower incidence of steroid-resistant rejection (6% vs 20.9%; P = .017) and humoral rejections (0% vs 7%; P = .038) in the basiliximab group. Also, graft survival was significantly higher in basiliximab group compared with the control one (92.8% vs 80.4%; P = .028). There were no significant differences in the other outcomes. In conclusion, this study confirmed the beneficial effects of addition of basiliximab to the immunosuppressive schema of patients with delayed graft function.     

A calcineurin antagonist-free induction strategy for immunosuppression in cadaveric kidney transplant recipients at risk for delayed graft function

BACKGROUND: Avoidance of calcineurin antagonists for a prolonged period de novo after cadaver donor renal transplantation may facilitate recovery from delayed graft function. The present study examined the benefit of prolonging the calcineurin antagonist-free interval by administering sirolimus (SRL) in combination with chimeric (c-) anti-interleukin-2 receptor (IL-2R) monoclonal antibodies (mAb). METHODS: Three contemporaneous but nonrandomized cohorts were compared for acute rejection episodes, patient and graft survival rates, renal function, and adverse reaction profiles for 12 months. Patients with delayed graft function were treated with either SRL/c-IL-2R mAb/prednisone (Pred) with inception of cyclosporine (CsA) once the serum creatinine value was < or =2.5 mg/dl (n=43; group 1) or anti-lymphocyte preparations/Pred/delayed CsA for 7 to 14 days (n=18; group 3). A third cohort displayed immediate function and was treated de novo with CsA/c-IL-2R mAb/Pred (n=21; group 2). RESULTS: The incidence of acute rejection episodes was significantly lower among group 1 (16%) compared with groups 2 (52%, P=0.004) or 3 (39%, P=0.05). Among the seven rejection episodes in group 1, six of seven occurred among African-American or retransplant recipients, and a separate cluster of six of seven occurred among patients who displayed SRL trough concentrations < or =9 ng/ml. Furthermore, additional antilymphocyte antibody treatment was required to reverse either steroid-resistant or Banff grades II or III acute rejection episodes among 14%, 55% (P=0.08), and 71% (P=0.03) of patients in each group, respectively. Patient and graft survival rates, as well as mean serum creatinine values, were similar at 12 months among the three groups. However, group 1 patients displayed higher serum cholesterol and triglyceride values, as well as lower hemoglobin, platelet, and leukocyte values compared with the other two groups. CONCLUSION: This pilot study suggests that a SRL/c-IL-2R mAb/Pred induction regimen provides excellent acute rejection prophylaxis.     

Conversion to belatacept maintenance immunosuppression in HIV-positive kidney transplant recipients

There are only scattered case reports documenting belatacept use in HIV + kidney transplant recipients. We performed a retrospective review to describe short-term outcomes following conversion to belatacept in a cohort of HIV + patients. Patients were included if they were converted to belatacept between May 2015 and May 2019, had an HIV- donor, and received ≥4 doses of belatacept. All patients were treated with non-depleting induction and triple maintenance immunosuppression. Allograft and HIV-related outcomes were collected from the date of belatacept infusion until May 2020. Ten HIV + kidney transplant recipients were identified, who were converted to belatacept a median of 364 days post-transplant. At last follow-up (median 3.3 years), 8 patients remained on belatacept therapy, and all patients were alive with functioning allografts. Mean estimated glomerular filtration rates (eGFR) improved from 31.6 mL/min at baseline to 42.8 mL/min at 1 year (P = .03). Two patients developed acute rejection, with one necessitating conversion back to tacrolimus. All patients maintained undetectable HIV-1 viral loads at last follow-up. One patient each developed pneumocystis pneumonia and Kaposi sarcoma following conversion, which were responsive to standard medical therapy. In our cohort of stable HIV + kidney transplant recipients, conversion to belatacept was associated with excellent early patient and allograft survival and improved eGFR at 1 year.     

Steroid avoidance immunosuppression in low-risk kidney transplant recipients

Recent clinical trials have documented the short-term safety of steroid avoidance (SA) in kidney transplant recipients. Since July 2003, we have used a SA immunosuppression protocol for low-risk kidney transplant recipients. Eligibility criteria are age > or = 18, primary transplant (living or deceased donor), and tacrolimus started by postoperative day 3. Recipients were excluded if peak/current PRA was >50%/20%, or if they had a positive flow crossmatch, or if they had the recent use of corticosteroids (<6 months). All recipients received induction with rabbit anti-thymocyte globulin, total dose 6 mg/kg, or basiliximab. Recipients received 5 daily doses of corticosteroid and mycophenolate mofetil 1 gm twice daily starting on the day of transplantation. Tacrolimus was started when the serum creatinine level decreased by 20%, or by postoperative day 3. The goal for trough tacrolimus levels was 10-15 ng/mL for the first month, 8-12 ng/mL for months 2-3, and 5-10 ng/mL after month 3. Protocol biopsies (bx) were performed at reperfusion, 1 month, 4 months, and 12 months. Ninety-four kidney transplantations were performed during the study period. Sixty-seven recipients (71%) were eligible and enrolled in SA. Characteristics of the 67 SA recipients: mean age, 53 years (range, 26-70); 41% female; 67% Caucasian; 24% Hispanic; 15% African American; and 5% Native American. Also, 77% received a living donor kidney. The mean follow-up was 180 days (range, 10-360). At last follow-up, 91% remained steroid-free. Biopsy-proven acute rejection (BPAR) occurred in 5 recipients (7.5%). Three recipients (4.5%) had clinical BPAR and 2 had subclinical. One recipient died with pneumonia 4 months following transplantation. Posttransplantation diabetes mellitus (PTDM) occurred in 2 (5%) of 38 recipients. In the initial 41 recipients, 27 had protocol bx at 1 month and 13 at 4 months available for analysis. Chronic allograft nephropathy (CAN) was present on protocol bx in 48% at 1 month and 69% at 4 month. Actuarial (Kaplan-Meier method) patient and graft survival rates at 351 days were 97.8% and 96.8%, respectively. SA with anti-thymocyte globulin induction in low-immunologic risk kidney transplant recipients is safe and is associated with a low risk of BPAR. The incidence of PTDM appears to be lower.