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.     

Calcineurin inhibitor minimization protocols in liver transplantation

Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay – with induction therapy for bridging – followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.     

Long-term efficacy and safety of a calcineurin inhibitor-free regimen in live-donor renal transplant recipients

Calcineurin inhibitor (CNI) nephrotoxicity is a major concern after renal transplantation. To investigate the safety and efficacy of a CNI-free immunosuppressive regimen, 132 live-donor renal transplant recipients were included in a prospective, randomized controlled trial. All patients received induction therapy with basiliximab and steroids. The patients were randomized to a maintenance immunosuppression regimen that included steroids, sirolimus, and either low-dose tacrolimus or mycophenolate mofetil (MMF). Over a mean follow-up period of approximately 5 yr, patient and graft survival did not significantly differ between the two maintenance regimens. Patient survival was 93.8% and 98.5% in the tacrolimus/sirolimus and MMF/sirolimus groups, respectively, and graft survival was 83% and 88%, respectively. However, the MMF/sirolimus group had significantly better renal function, calculated by Cockcroft-Gault, from the second year post-transplant until the last follow-up. In addition, this group was less likely to require a change in their primary immunosuppression regimen than the tacrolimus/sirolimus group (20.8% versus 53.8%, P = 0.001). The safety profile was similar between groups. In summary, after long-term follow-up, a CNI-free maintenance regimen consisting of sirolimus, MMF, and steroids was both safe and efficacious among low to moderate immunologic risk renal transplant recipients.     

Individualization of immunosuppressive therapy. II. Sirolimus as a less nephrotoxic alternative to calcineurin inhibitors

The nephrotoxic effects of chronic administration of calcineurin inhibitors have created a demand for a potent immunosuppressive drug free of this side effect. Sirolimus (SRL) clearly displays fewer and a lesser degree of adverse effects on renal function by itself. However, in combination with calcineurin antagonists, it tends to augment the nephrotoxicity due, at least in part, to a pharmacokinetic interaction. The use of SRL for de novo immunosuppression (even with adjunctive mycophenolate mofetil) is probably not sufficient to avert alloimmune reactions. A useful combination with SRL can be achieved by reducing calcineurin inhibitor exposure by 80% for immediately functioning kidneys or by delaying its inception until renal graft recovery. SRL proffers additional benefits as an inhibitor of endothelial and smooth muscle cell proliferation, serving as the foundation of chronic immunosuppressive therapy.     

An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients

As the risk of graft loss due to acute rejection has declined, the goal of post-transplant management has switched to long-term preservation of organ function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective. Everolimus is a mammalian target of rapamycin inhibitor/proliferation-signal inhibitor with potent immunosuppressive and anti-proliferative effects. It has been widely investigated in large randomized clinical studies that have shown it to have similar anti-rejection efficacy compared with standard-of-care regimens across organ transplant indications. With demonstrated potential to facilitate the reduction of CNI therapy and preserve renal function, everolimus is an alternative to the current standard-of-care CNI-based regimens used in de novo and maintenance solid organ transplantation recipients.Here, we provide an overview of the evidence from the everolimus clinical study program across kidney, liver, heart, and lung transplants, as well as other key data associated with its use in CNI reduction strategies in adult transplant recipients.     

Immunosuppressive treatment and progression of histologic lesions in kidney allografts

Renal transplantation is the best therapeutic option for patients with end-stage renal disease. Although short-term results are excellent, long-term graft survival has not improved substantially in recent times. Chronic allograft nephropathy (CAN) and death with a functioning graft are the most important causes of graft loss. Recent evidence shows that nephrotoxicity of calcineurin inhibitors contributes to CAN, and the introduction of non-nephrotoxic drugs such as mycophenolate mofetil (MMF) and mammalian target of rapamycin inhibitors may provide new immunosuppressive strategies to improve long-term results after renal transplantation. MMF decreases the risk of developing chronic allograft failure and is useful for treating established CAN, because it has a beneficial effect on allograft fibrosis. Treatment with sirolimus (SRL), a basic immunosuppressive drug given in association with MMF, may offer better renal function, decrease the prevalence of CAN, and downregulate expression of genes responsible for the progression of CAN than treatment with cyclosporine A (CsA). SRL also permits an early elimination of CsA from SRL-CsA-steroid regimens and shows better renal function and improved renal histology without risk of rejection. Notably, this approach improves graft survival at 4 years. Further multicenter studies are needed to determine whether both approaches produce similar results by comparing immunosuppression caused by SRL-based and tacrolimus (TAC)-based treatments. Because TAC is the most commonly used anticalcineurin drug, it is important to compare the effects of steroid-TAC-SRL treatment with and without elimination of TAC. Finally, although caution is needed, the use of non-nephrotoxic immunosuppressive treatment may change the natural history of CAN.     

Optimal immunosuppression to prevent chronic allograft dysfunction

Prevention of chronic allograft dysfunction is currently one of the main goals in renal transplantation for the improvement of kidney graft survival. For this purpose, refinements in immunosuppressive regimens, both controlling alloimmune responses and avoiding calcineurin inhibitor (CNI)-derived nephrotoxicity, are mandatory. The majority of trials aiming to avoid CNI-related nephrotoxicity have only reported short-term data, with different rates of acute rejection depending on the strategy performed. First attempts of CNI-free strategies in micophenolate mofetil-based regimens showed unsatisfactory results in terms of increased acute rejection events. With the advent of mammalian target of rapamycin inhibitors, a new optimistic perspective seemed to appear. Despite an increased risk of rejection, better graft function and graft parenchyma preservation seem to be associated with such a strategy, at least in the short term, with a potential benefit in terms of less cardiovascular-related adverse events and malignancies. New biological agents such as belatacep have been developed as another interesting strategy for CNI avoidance. Importantly, in any case, longer-term analyses of all these CNI-avoidance strategies are warranted in order to confirm whether persistent immune-mediated graft damage can be safely overcome.     

Sirolimus and mycophenolate mofetil as calcineurin inhibitor-free immunosuppression in a cardiac transplant patient with chronic renal failure.

Chronic renal failure triggered by calcineurin inhibitor (CNI)-based immunosuppression is a common complication after cardiac transplantation. Sirolimus and mycophenolate mofetil (MMF) are 2 newer immunosuppressive agents with no documented nephrotoxic side effects. This case report describes a patient with ongoing chronic renal failure 10 months after cardiac transplantation on cyclosporine-based immunosuppressive therapy. Conversion of the immunosuppressive regimen from cyclosporine to sirolimus and MMF resulted in freedom from acute rejection, excellent cardiac graft function and consistently improved renal function. This case illustrates the beneficial potential of sirolimus and MMF as CNI-free and safe long-term immunosuppression in a patient with chronic renal failure after heart transplantation.     

Outcomes at 3 years of a prospective pilot study of Campath-1H and sirolimus immunosuppression for renal transplantation

Campath-1H (alemtuzumab) induction was used for renal transplantation in combination with sirolimus as immunosuppression. We previously reported a high (28%) rate of early rejection with this regimen, and now report 3-year outcomes. Twenty-nine patients were recipients of either deceased donor or non-HLA (Human Leukocyte Antigen) identical living donor primary renal allografts. Clinical parameters including infection, malignancy, kidney function, and kidney histology were followed prospectively for 3 years. Three-year cumulative graft and patient survival were 96% and 100%, respectively. Twenty patients were maintained on steroid-free immunosuppressive regimens, and 15 patients were maintained on monotherapy for immunosuppression (12 on sirolimus). No serious infectious complications were observed and two patients developed basal cell skin cancer. The 3-year results of our initial pilot study demonstrate good graft (96%) and patient (100%) outcomes. Campath-1H induction has yielded a high proportion of patients maintained on immunosuppressive monotherapy (57%) without serious infectious- and no malignancy-related complications. The reported regimen yielded novel insights into both Campath-1H and sirolimus therapy in renal transplantation. Because of the higher incidence of early rejection, we recommend a modified strategy of immunosuppression including a brief course of a calcineurin inhibitor.     

Sirolimus and everolimus: inhibitors of mammalian target of rapamycin in liver transplantation

Sirolimus (SRL) and everolimus are members of a relatively new class of immunosuppressants that impair cell cycle proliferation by inhibition of the mammalian target of rapamycin. These agents have been evaluated and licensed for use in kidney transplantation where they are used predominantly as maintenance immunosuppression because they lack the nephrotoxicity associated with calcineurin inhibitors. Neither SRL nor its newer analogue everolimus are currently licensed for use in liver transplantation, but both have been used with varying degrees of success and efficacy in this setting. Concern has been expressed about a potential association between de novo use of SRL and both a high incidence of hepatic artery thrombosis after liver transplantation and impaired wound healing, and thus, subsequent development has focused on the use of SRL in response to calcineurin inhibitor toxicity in patients with established liver transplants as well as using its potential antitumor effects in patients transplanted for malignancy. This article reviews the reported experience of mammalian target of rapamycin inhibitor therapy in liver transplantation.     

Trends in maintenance immunosuppressive drugs used in taiwanese kidney transplant recipients: an analysis of the national health insurance research database

Trends in maintenance immunosuppressive drugs used among Taiwanese kidney transplant recipients have not been reported before. We examined the National Health Insurance Research Database to analyze trends in maintenance immunosuppressive drugs used in Taiwanese kidney transplant recipients for the years 2002-2009. The new case number of kidney transplant recipients ranged from 302 to 673 per year. In 2009, 5276 kidney transplant recipients received immunosuppressive therapy. The 5-year renal graft survival rate of kidney transplant recipients was 93%. In 2009, the most common immunosuppressive therapy among Taiwanese kidney transplant recipients was a triple regimen that included tacrolimus, mycophenolate mofetil, and corticosteroid. There was a significant increase in the use of a tacrolimus-based regimen from 35.1%-58.2%, while the use of cyclosporine decreased from 62.2%-24.8% (P < .05). The percentage of calcineurin inhibitor-free regimen increased from 2.7%-17%. Moreover, the use of Rapamune dramatically increased from 8.2%-22.6% in 2002-2004. However, the percentage of kidney transplant recipients using Rapamune maintained 23 ± 1.6% in 2004-2009. The use of mycophenolic acid remained stable at about 74.9 ± 3.2% in 2002-2009. As predicted, the use of Imuran decreased from 6.9%-3.5%. In summary, although calcineurin inhibitors remained the mainstay of immunosuppressive drugs, these findings suggest a general trends toward individualized regimens and the use of calcineurin inhibitor-free and mammalian target of rapamycin inhibitors-based regimens in Taiwanese kidney transplant recipients.     

BK virus replication following kidney transplant: does the choice of immunosuppressive regimen influence outcomes?

The increasing prevalence of BK virus nephropathy (BKVN) observed in recent years, with its consequent impact on kidney allograft survival rates, has focused attention on the relationship between immunosuppression regimens and risk of BK virus reactivation. The adoption of more potent immunosuppressive regimens over the last two decades, notably tacrolimus with mycophenolic acid and corticosteroids, appears to be associated with higher rates of BK activation. There is also evidence of a specific increase in risk for tacrolimus-based immunosuppression vs. cyclosporine, which in vitro data suggest may be at least partly due to differences in antiviral activity. Early concerns that mammalian target of rapamycin (mTOR) inhibitor use was associated with development of BKVN do not appear to have been borne out. Protocol-driven BK virus screening is recommended to facilitate early diagnosis and intervention, which primarily comprises the controlled reduction or discontinuation of immunosuppressive drugs. Although a consensus on the optimal strategy for immunosuppression modification is still lacking, early diagnosis of BK reactivation and pre-emptive modification of immunosuppression has resulted in a marked improvement in graft outcomes. Typically, intervention consists of reducing calcineurin inhibitor exposure before or after antimetabolite dose reduction, withdrawal of one agent from a triple therapy regimen, or switching between agents within a therapeutic class. A benefit for antiviral therapy is not yet confirmed. While more data are required, the current evidence base is adequate to justify routine screening with early modification of the intensity and nature of the immunosuppression regimen to reduce the toll of BKVN in the kidney transplant population.     

肝移植受者雷帕霉素靶蛋白抑制剂临床应用中国专家共识（2023版）

肝移植受者的长期存活和生存质量很大程度上取决于术后中长期健康管理和免疫抑制方案。长期服用免疫抑制剂可导致受者出现肾损伤、代谢性疾病和新发恶性肿瘤等严重并发症,甚至增加肝癌肝移植术后肿瘤复发风险。目前肝移植受者常用的免疫抑制方案以钙调磷酸酶抑制剂（CNI）为基础,但是CNI引起的肾脏毒性、神经毒性和促进肿瘤复发等问题极大地影响了受者预后,近年来临床逐渐减少其用量并寻求替代药物。近年来使用以哺乳动物雷帕霉素靶蛋白抑制剂（mTORi）为基础的免疫抑制方案逐渐增多,国内外多部指南均对肝移植受者使用mTORi给出了指导意见。为了更好地为国内肝移植临床医师提供参考,中国器官移植发展基金会组织国内经验丰富的移植专家,结合已发表的国内外指南、共识和研究进展,经广泛征求意见,共同制订本专家共识。     

Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy

Rapamycin is a new immunosuppressive agent approved for maintenance therapy after kidney transplantation. It may allow calcineurin-inhibitor-free, non-nephrotoxic immunosuppression. We report, however, on four kidney-transplant recipients who developed post-transplantation glomerulonephritis after conversion from a calcineurin-inhibitor-based immunosuppression to rapamycin. In all four patients nephrotic-range proteinuria occurred 2–9 months after conversion to rapamycin. Renal biopsy confirmed membrano-proliferative glomerulonephritis type 1 in one case, membranous glomerulonephritis in another and IgA-nephropathy in two cases, respectively. Calcineurin-inhibitor-based immunosuppression was reintroduced and resulted in complete remission of proteinuria and in stabilised renal function in all patients. We conclude that in the case of rapamycin-associated post-transplantation glomerulonephritis an attempt should be made to replace rapamycin by a calcineurin inhibitor.     

BK‐Virus and the Impact of Pre‐Emptive Immunosuppression Reduction: 5‐Year Results

A 1‐year, single‐center, randomized trial demonstrated that the calcineurin inhibitor or adjuvant immunosuppression, independently, does not affect BK‐viruria or viremia and that monitoring and pre‐emptive withdrawal of immunosuppression was associated with resolution of BK‐viremia and absence of clinical BK‐nephropathy without acute rejection or graft loss. A retrospective 5‐year review of this trial was conducted. In cases of BK viremia, the antimetabolite was withdrawn and for sustained viremia, the calcineurin inhibitor was minimized. Five‐year follow‐up was available on 97% of patients. Overall 5‐year patient survival was 91% and graft survival was 84%. There were no differences in patient‐survival by immunosuppressive regimen or presence of BK‐viremia. Immunosuppression and viremia did not influence graft survival. Acute rejection occurred in 12% by 5‐years after transplant, was less common with tacrolimus versus cyclosporine (9% vs. 18%; p = 0.082), and was lowest with the tacrolimus‐azathioprine regimen (5%, p = 0.127). Tacrolimus was associated with better renal function at 5‐years (eGFR 63 FK vs. 52 CsA mL/min, p = 0.001). Minimization of immunosuppression upon detection of BK‐viremia was associated with excellent graft survival at 5‐years, low rejection rates and excellent renal function. It is a safe, short and long‐term strategy that resulted in freedom from clinically evident BK‐virus nephropathy.     

South American Heart Transplantation Registry of Patients Receiving Everolimus in Their Immunosuppressive Regimens

The increasing number of heart transplant recipients receiving immunosuppression with mammalian target of rapamycin inhibitors prompted the implementation of a South American Transplant Physicians Group to register these patients in a database. Everolimus (EVL) is a signal proliferation inhibition that reduces graft vascular disease when used de novo. Recently, its administration has expanded to subjects with resistant rejection or with side effects due to other immunosuppressive drugs (calcineurin inhibitors and/or steroids), allowing for better regulation of the immunosuppressive regimen. Herein we have shown the data collected from patients receiving EVL in ten South American Heart Transplant Centers. We have concluded that the administration of EVL is a useful adjunctive therapy that allows the reduction or suspension of other immunosuppressive drugs that caused unwanted side effects, without a loss of immunosuppressive efficacy, with manageable side effects, and constituting a valuable therapeutic option.     

Fish oil treatment for kidney transplant recipients: a meta-analysis of randomized controlled trials

BACKGROUND: Calcineurin inhibitors have adverse effects that contribute to nephrotoxicity and cardiovascular risk profile, and these may be reduced by administration of fish oil. The aim of this review was to assess the benefits and harms of fish oil supplementation in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. METHODS: The Cochrane Controlled Trials Registry, MEDLINE, and EMBASE were searched for randomized controlled trials of fish oil treatment in kidney transplant recipients on a calcineurin inhibitor-based immunosuppressive regimen. Trials comparing fish oil to both placebo and statins were included. Data were extracted for patient and graft survival, acute rejection, calcineurin inhibitor toxicity, cardiovascular events, adverse effects, compliance, renal function, blood pressure, and lipid profile. Dichotomous outcomes were reported as relative risk and continuous outcome measures as weighted mean differences (WMD), with 95% confidence intervals. RESULTS: Sixteen suitable trials were analyzed. Fish oil treatment was associated with a lower diastolic blood pressure (WMD 4.5 mmHg, P=0.004) and higher high-density lipoprotein (HDL) cholesterol (WMD 0.12 mmol/L, P=0.01) but did not affect the other outcomes. Fishy aftertaste and gastrointestinal upset were common but did not result in significant dropout. Fish oil effects on lipids were not significantly different than low-dose statins. CONCLUSION: There is insufficient evidence from currently available randomized controlled trials to recommend fish oil therapy to improve renal function, rejection rates, and patient or graft survival. Improvements in HDL cholesterol and diastolic blood pressure were too modest to recommend routine use.     

Sirolimus-Induced Thrombotic Microangiopathy is Associated with Decreased Expression of Vascular Endothelial Growth Factor in Kidneys

The aim of this study was to examine the clinical characteristics, the histological features and the renal expression of vascular endothelial growth factor (VEGF) of five patients with sirolimus-associated thrombotic microangiopathy (TMA). Sirolimus-induced TMA occurs preferentially in kidneys with concomitant endothelial injury: it was observed in three patients with acute cellular rejection on calcineurin inhibitor-free regimen, in one patient with chronic graft rejection on a calcineurin inhibitor-free protocol and in one patient with chronic calcineurin inhibitor nephrotoxicity. We found that renal VEGF expression during sirolimus-induced TMA was significantly lower than VEGF expression in normal transplanted kidneys (p < 0.01). Decreased expression of VEGF seems to be a consequence of sirolimus treatment since (i) analysis of two biopsies performed after the switch of sirolimus to calcineurin inhibitor showed reappearance of VEGF expression, (ii) no decreased expression of VEGF was found in five kidneys with classical TMA and, (iii) an increased expression of VEGF was observed in seven kidneys with acute cellular rejection on a sirolimus-free immunosuppressive regimen (p < 0.01). The potential role of sirolimus-induced downregulation of VEGF as a predisposing factor to the development of TMA is discussed.     

Calcineurin inhibitor-free immunosuppression in dual kidney transplantation from elderly donors

BACKGROUND: Kidneys from expanded-criteria donors may be particularly susceptible to calcineurin inhibitor (CI)-mediated vasoconstriction and nephrotoxicity. In the early post-transplant phase, using CI may prolong ischemic injury and, in the long term, chronic CI nephrotoxicity is an even greater concern. To avoid the acute and chronic consequences of CI in kidneys from marginal donors, CI-free protocols have been introduced for maintenance immunosuppressive therapy. A CI-free protocol of anti-thymocyte globulin (ATG) induction, sirolimus, mycophenolate mofetil (MMF) and steroids has been adopted at our center in recipients of dual kidney transplantation (DKT) from elderly donors (EDs). METHODS: Dual kidney transplantations performed since April 2003 on CI-free immunosuppression (group 1 = 31) were compared with earlier DKTs in recipients treated with CI-based therapy (group 2 = 25), retrospectively analyzing patient and graft survival, surgical and medical complications, rejection episodes and renal function. RESULTS: No deaths occurred after a mean follow-up of 10.1 +/- 7.6 (group 1) and 48.2 +/- 17.4 months (group 2). Graft loss occurred in one patient in group 1 (bilateral renal vein thrombosis) and in three patients in group 2 (one primary non-function [PNF], one chronic rejection, one Kaposi's sarcoma). The incidence of acute rejection was 19% in group 1 and 16% in group 2. Delayed graft function (DGF) was recorded in 16% and 48%, respectively. Renal function was better in group 1, with a mean S-Cr of 135 +/- 48 vs. 210 +/- 141 micromol/L at one month and 116 +/- 30 vs. 149 +/- 49 micromol/L at six months. CONCLUSIONS: After DKT from EDs, a CI-free immunosuppressive regimen including ATG induction, sirolimus, MMF and steroids affords excellent results, with a lower DGF rate and a better renal function.     

Unlocking the Potential of Purinergic Signaling in Transplantation

Purinergic signaling has been recognized as playing an important role in inflammation, angiogenesis, malignancy, diabetes and neural transmission. Activation of signaling pathways downstream from purinergic receptors may also be implicated in transplantation and related vascular injury. Following transplantation, the proinflammatory “danger signal” adenosine triphosphate (ATP) is released from damaged cells and promotes proliferation and activation of a variety of immune cells. Targeting purinergic signaling pathways may promote immunosuppression and ameliorate inflammation. Under pathophysiological conditions, nucleotide‐scavenging ectonucleotidases CD39 and CD73 hydrolyze ATP, ultimately, to the anti‐inflammatory mediator adenosine. Adenosine suppresses proinflammatory cytokine production and is associated with improved graft survival and decreased severity of graft‐versus‐host disease. Furthermore, purinergic signaling is involved both directly and indirectly in the mechanism of action of several existing immunosuppressive drugs, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. Targeting of purinergic receptor pathways, particularly in the setting of combination therapies, could become a valuable immunosuppressive strategy in transplantation. This review focuses on the role of the purinergic signaling pathway in transplantation and immunosuppression and explores possible future applications in clinical practice.