Calcineurin Inhibitor Initiation Research Articles

#1103 Delayed initiation or reduced initial dose of calcineurin-inhibitors for kidney transplant recipients: a systematic review and meta-analysis

Abstract Background and Aims Delayed graft function (DGF) is more common in donors after cardiac death, especially expanded criteria donors and those with longer cold ischaemia time, older or with an increased serum creatinine. There is no agreement on the optimal immunosuppressive approach in patients at increased risk of DGF, with strategies including a delayed introduction of calcineurin inhibitors (CNI) or initial low dose CNI. Our aim was to evaluate the benefits and harms of delayed initiation of CNI or reduced CNI dose as initial immunosuppression therapy for kidney transplant (KT) recipients at high risk of DGF. Method We searched the Cochrane Kidney and Transplant Register of Studies up to 07 March 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. We included all randomized controlled trials (RCTs) and quasi-RCTs evaluating early vs delayed initiation of CNI or reduced vs standard initial dose of CNI in kidney transplant (KT) recipients at high risk of DGF. Three authors independently assessed study eligibility, and two assessed the risk of bias, certainty of evidence, extracted the data, and performed the analysis. Results were reported as risk ratios with 95% confidence intervals for dichotomous outcomes and as mean difference with 95% CI for continuous outcomes. Statistical analysis was performed using the random-effects model. Risk of bias was assessed with RoB2 and the certainty of the evidence according to GRADE methods. Results Thirteen studies were included (2386 randomized participants). Incidence of DGF (RR 1.09, 95% CI 0.89 to 1.32; I2 = 18%) and acute rejection (RR 0.98, 95% CI 0.72 to 1.33; I2 = 54%) were similar between early and delayed introduction of CNI, as well as between low vs standard dose of CNI (DGF: RR 1.16, 95% CI 0.90 to 1.50; I2 = 9%; acute rejection: RR 0.70, 95% CI 0.43 to 1.14; I2 = 58%). There were also no differences in secondary outcomes such as graft function, graft loss, risk of death, or infection. Conclusion In patients at high risk of DGF, the strategy of delaying CNI introduction or starting at a lower dose does not reduce the risk of DGF.

Myeloablative Haploidentical Donor Hematopoietic Transplantation Using Post-Transplantation Cyclophosphamide and Antithymocyte Globulin

Haploidentical donor (haplo-) hematopoietic stem cell transplantation (HSCT) with post-transplantation cyclophosphamide (PTCy) is now performed on a large scale worldwide. Our patient outcomes did not completely reflect the results published by other groups. We herein present the results of 60 patients with hematologic malignancies treated homogeneously on a modified version of the standard protocol by adding ATG as an additional graft-versus-host disease (GVHD) prophylaxis measure. This was a retrospective analysis of 60 haplo-HSCT recipients using a myeloablative conditioning regimen with antithymocyte globulin and PTCy for GVHD prophylaxis. At 5 years, overall survival was 59.2%, relapse-free survival (RFS) was 48.6%, and chronic GVHD (cGVHD) and relapse-free survival was 40%. The median time to neutrophil and platelet engraftment was 16 days and 28.5 days, respectively. The rates of grade II-IV acute GVHD and extensive cGVHD were 46.7% and 23.3%, respectively. The cumulative incidence of relapse was 30%, nonrelapse mortality was 21.6%, and transplantation-related mortality was 11%. Higher Disease Risk Index and 50% HLA match were associated with lower RFS. Female donor to male recipient and older donor age were associated with an elevated risk of cGVHD. The use of PTCy might not yield the same results in different populations. Many remaining questions need to be addressed in randomized trials, including optimal graft source and donor, date of calcineurin inhibitor initiation, personalized or targeted dose of PTCy, immune reconstitution, and others.

Delayed Initiation of Calcineurin Inhibitor Is Critical for Tolerance Induction By Posttransplant Cyclophosphamide

[Introduction] We have previously shown that T-cell exhaustion of donor alloreactive T cells plays a critical role in tolerance induction after mouse allogeneic hematopoietic cell transplantation (allo-HCT) (Asakura S: JCI 2010). Emerging evidence indicates that T-cell exhaustion is a multistep process, including precursors of exhausted T cells (pTex) with stem cell-like properties, pTex-derived transitory exhausted T cells (transitory-Tex) with potent effector-like functions, and terminally exhausted T cells (terminal-Tex) with the expression of multiple inhibitory receptors and severely impaired functions. We have demonstrated, for the first time, that calcineurin inhibitors (CNIs) inhibit tolerance induction by suppressing the terminal exhaustion of donor T cells while inducing transitory-Tex after allo-HCT in mice (Senjo H: Blood 2023). In contrast, post-transplantation cyclophosphamide (PTCy) efficiently induces tolerance with low incidence of chronic GVHD. In the current study, we evaluated the mechanisms by which PTCy could induce tolerance even with the use of CNIs. [Methods] In mouse haploidentical HCT model,B6D2F1 recipients (H-2 b/d) were lethally irradiated and transplanted with 2 × 10 6 T cells together with T-cell-depleted bone marrow cells from C57BL/6 (H-2 b) donors on day 0. CSP (25 mg/kg) was administered from either day 0 (early-CSP) or day 5 (late-CSP), and PTCy (50 mg/kg) was i.p. injected on day 3 after HCT. In clinical study, peripheral blood mononuclear cells were prospectively collected from patients who underwent PTCy-based haplo-PBSCT at our institutions after approval of institutional review. [Results] We have shown that Ly6C is a specific marker for transitory-Tex in mice (Senjo H: Blood 2023). In mice, early-CSP followed by PTCy (CSP→PTCy) significantly expanded Ly6C +PD-1 +TOX low CD8 + T cells and Ly6C +PD-1 +GZMB + CD4 + T cells on day 14, while late-CSP following PTCy (PTCy→CSP) induced T-cell differentiation towards Ly6C -PD-1 +TOX high terminally exhausted T cells. When CSP→PTCy recipients were injected with anti-PD-L1 monoclonal antibodies, transitory-Tex demonstrated vigorous proliferation, while terminal-Tex did not respond to PD-1 blockade. These findings indicate that CSP administration after PTCy promotes tolerance induction, whereas CSP administered before PTCy inhibits tolerance induction. Next, we explored the specific markers for human transitory-Tex using scRNA-seq of T cells from the patients who underwent PTCy haplo-PBSCT, in which tacrolimus (TAC) was started either from day -1 (early-TAC) or day 5 (late-TAC). UMAP analysis showed that early-TAC expanded cluster 5 (C5) out of six CD8 + clusters (C1-C6) and C8 out of three CD4 + clusters (C7-C9) (Fig.1). C5 highly expressed exhaustion markers such as Tox and Pdcd1, together with effector molecules such as Prf1, Gzmb and Cx3cr1, while C8 was characterized with high expression of Gzmb, indicating that C5 and C8 are the human counterparts of transitory-Tex. Analysis of differentially expressed genes showed that Fcgr3a (CD16A) was selectively expressed in C5, while Gzmb and Cd74 were selectively expressed in C8. These two populations showed robust proliferative responses to TCR stimulation in vitro. ScTCR-seq demonstrated that C5 and C8 clusters showed less TCR diversity compared to other clusters, suggesting that C5 and C8 were enriched with alloreactive donor T cells that clonally expanded post-transplant. FCM confirmed that both CX3CR1 +CD16 + CD8 + T cells and GZMB +CD74 +CD4 + T cells were significantly increased in the early-TAC group compared to the late-TAC group on day 28 (Fig. 2). In the early-TAC group, 2/9 patients developed moderate and severe chronic GVHD, and only 1/9 patient was off-immunosuppressants (Fig 2). In sharp contrasts, in the late-TAC group, no patient developed chronic GVHD, and 7/9 patients were off-immunosuppressants. Importantly, two patients who developed chronic GVHD had a particularly high proportions of CX3CR1 +CD16 +CD8 + and GZMB +CD74 +CD4 + transitory-Tex on day 28 after HCT (Fig.2). [Conclusion] Our study demonstrated that early initiation of CNIs before PTCy induced transitory-Tex and inhibited tolerance induction after PTCy haplo-PBSCT. Administration of CNIs after PTCy is critical for tolerance reduction without chronic GVHD.

A Multi-Modal Approach to Islet and Pancreas Transplantation With Calcineurin-Sparing Immunosuppression Maintains Long-Term Insulin Independence in Patients With Type I Diabetes.

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1years, including one patient 9years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1mL/min to 50.2 ± 27.1mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants

While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.

Pre-transplant immune cell function assay as a predictor of early cardiac allograft rejection.

ImmuKnow, an immune cell function assay that quantifies overall immune system activity can assist in post-transplant immunosuppression adjustment. However, the utility of pre-transplant ImmuKnow results representing a patient's baseline immune system activity is unknown. This study sought to assess if pre-transplant ImmuKnow results are predictive of rejection at the time of first biopsy in our cardiac transplant population. This is a single center, retrospective observational study of consecutive patients from January 1, 2018 to October 1, 2020 who underwent orthotopic cardiac transplantation at NYU Langone Health. Patients were excluded if a pre-transplant ImmuKnow assay was not performed. ImmuKnow results were categorized according to clinical interpretation ranges (low, moderate, and high activity), and patients were divided into two groups: a low activity group versus a combined moderate-high activity group. Pre-transplant clinical characteristics, induction immunosuppression use, early postoperative tacrolimus levels, and first endomyocardial biopsy results were collected for all patients. Rates of clinically significant early rejection (defined as rejection≥1R/1B) were compared between pre-transplant ImmuKnow groups. Of 110 patients who underwent cardiac transplant, 81 had pre-transplant ImmuKnow results. The low ImmuKnow activity group was comprised of 15 patients, and 66 patients were in the combined moderate-high group. Baseline characteristics were similar between groups. Early rejection occurred in 0 (0%) patients with low pre-transplant ImmuKnow levels. Among the moderate- high pre-transplant ImmuKnow group, 16 (24.2%) patients experienced early rejection (P=.033). The mean ImmuKnow level in the non-rejection group was the 364.9ng/ml of ATP compared to 499.3ng/ml of ATP for those with rejection (P=.020). Patients with low pre-transplant ImmuKnow levels had lower risk of early rejection when compared with patients with moderate or high levels. Our study suggests a possible utility in performing pre-transplant ImmuKnow to identify patients at-risk for early rejection who may benefit from intensified upfront immunosuppression as well as to recognize those where slower calcineurin inhibitor initiation may be appropriate.

Timing of Initiation of Calcineurin Inhibitors in Pediatric Haploidentical Transplantation with Post-Transplantation Cyclophosphamide: Effects on Survival, Relapse, and Cytokine Release Syndrome

Background: The use of unmanipulated haploidentical hematopoietic stem cell transplantations (haplo-HSCT) with post-transplant cyclophosphamide (PTCY) in children has emerged as an acceptable alternative to the patients without a matched donor. However, the timing of calcineurin inhibitors (CNIs) used in combination with PTCY is increasingly becoming a topic of controversy. Method: We evaluated 49 children with acute leukemia who underwent unmanipulated haplo-HSCT with PTCY according to the initiation day of CNIs (pre- or post-cyclophosphamide [CY]). Results: There were no significant differences in the overall survival analysis between the 2 groups. The cumulative incidence of relapse at 2 years was 21.2% in the pre-CY group and 38.9% in the post-CY group (p = 0.33). Cytokine release syndrome (CRS) was observed more frequently in the post-CY group (p = 0.04). The overall survival and event-free survival at 2 years in patients with and without CRS in the pre-CY group were 42.9% versus 87.5% (p = 0.04) and 38.1% versus 87.5% (p = 0.04), respectively. Conclusion: Our study shows that the argument for starting CNI administration after CY is tenuous, and the rationale for not starting CNIs before CY needs to be reconsidered.

Is There a Place for Induction Therapy With Polyclonal Antibodies to Improve Renal Function After Liver Transplantation?

Is There a Place for Induction Therapy With Polyclonal Antibodies to Improve Renal Function After Liver Transplantation?

SY4.3. Therapeutic considerations in myasthenia gravis

Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by fatigable muscle weakness. Treatment of MG has depended largely on high-dose corticosteroids for decades. Although this procedure remarkably reduced the mortality rate of MG, it highlighted issues such as the adverse effects of steroids and reduction in quality of life. A number of alternative therapeutic options have become available. Disease-modifying therapies for MG include immunosuppression with azathioprine, cyclosporine, or tacrolimus other than oral prednisolone (PSL). More aggressive exacerbation of generalized MG often requires additional immunomodulatory treatments with intravenous immunoglobulin (IVIg), plasma exchange (PE)/plasmapheresis (PP) and steroid pulse therapy. The Japanese clinical guidelines for MG were published in 2014, and they proposed a novel treatment strategy utilizing these therapeutic options, which might replace high-dose steroids. In the Japanese clinical guidelines, the first goal in MG treatment is minimal manifestations (MM) with PSL 5 mg/day or below (MM-or-better-5mg). Immunotherapy should be initiated from early stages in order to shorten the period of time during which MG symptoms interfere with daily activities. One suggested strategy to increase success rate is reduction of oral steroid dose and early initiation of calcineurin inhibitors, followed by fast-acting treatments such as IVIg, PE/PP and steroid pulse therapy to resolve remaining symptoms quickly. Despite the availability of an increasing variety of disease-modifying therapies for use in the new strategy, the proportion of patients with generalized MG who achieved MM-or-better-5mg remained approximately 50-60% in our latest survey. Therefore, we need further development of new treatment to increase the success rate of generalized MG patients to the treatment goal. In this symposium, I will review positive clinical trials in the previous literatures and guidance/guideline for management of MG in individual countries. In addition, I will introduce further development of new treatment options based on novel mechanisms of action for MG treatment. Especially, I will discuss monoclonal antibodies to prevent complement-mediated damage at the endplate of neuromuscular junction in MG with acetylcholine receptor antibody (Eculizumab, Ravulizumab and Zilucoplan) and neonatal Fc receptor antibodies which would be rational therapeutic agents for decreasing the levels of pathogenic autoantibodies with IgG isotypes (Efgartigimod and Rozanolixizumab).

Abstracts of the 30th Annual Pediatric Pharmacy Association (PPA) Meeting April 21 to 25, 2021

Abstracts of the 30th Annual Pediatric Pharmacy Association (PPA) Meeting April 21 to 25, 2021

Basiliximab Induction with Delayed Calcineurin Inhibitors for High-Risk Lung Transplant Candidates.

PurposeCalcineurin inhibitor (CNI) use has improved lung transplantation outcomes. However, significant perioperative complications in patients receiving CNI can deteriorate the early course of lung transplantation. To date, there is no consensus regarding the optimal agent for the induction regimen after lung transplantation. We aimed to determine the efficacy of basiliximab induction with delayed CNI initiation in the prevention of acute complications without compromising immunosuppression in high-risk patients.Materials and MethodsBetween January 2013 and December 2019, 236 patients at a single lung transplant center were retrospectively reviewed. Forty-one patients (17.4%) received basiliximab induction, and 195 patients (82.6%) received a routine triple-drug regimen without induction. The primary endpoint was postoperative acute kidney injury with several other postoperative outcomes as secondary end-points.ResultsPreoperatively, the induction group had a higher proportion of patients who were admitted before transplantation (95.1% vs. 47.7%, p<0.001) and received intensive unit care (90.2% vs. 33.8%, p<0.001) and extracorporeal membrane oxygenation (ECMO) (87.8% vs. 20.0%, p<0.001) compared to the non-induction group. No significant differences were observed in the incidence of acute rejection between groups (p=0.657), although lower incidence of postoperative complications, including acute kidney injuries or culture-proven infections, were observed in the induction group. However, the differences were not statistically significant. A subgroup analysis of high-risk and preoperative ECMO support groups showed similar results.ConclusionBasiliximab induction with delayed CNI initiation for high-risk patients might decrease the incidence of perioperative complications, including acute renal failure, without increasing the risk of acute rejection.

Evaluation of the Efficacy and Safety of Dual Induction versus Induction Monotherapy in Orthotopic Heart Transplant Recipients

The goal of induction therapy with rabbit anti-thymocyte globulin (rATG) and basiliximab in cardiac transplant is to minimize incidence of biopsy-proven acute cellular rejection (BPAR). However, rATG has been associated with increased risk for hematologic and infectious complications. At Mayo Clinic, dual induction, consisting of rATG cumulative doses less than 6 mg/kg and basiliximab, has been utilized in recipients experiencing complications from rATG. The impact of dual induction in cardiac transplant recipients is unknown. The goal of this study was to evaluate the clinical outcomes associated with dual induction. This Institutional Review Board approved study was a retrospective review of cardiac transplant recipients who received induction therapy with rATG and/or basiliximab at Mayo Clinic in Florida between January 1, 2013 and December 31, 2017. The primary endpoint was time to first incidence of BPAR within 12 months following cardiac transplant. Secondary outcomes included time to first incidence of infectious complication, antibody-mediated rejection, and death within 12 months post-cardiac transplant. Additional secondary outcomes included time to first incidence of hematologic complication within 90 days post-cardiac transplant, time to first incidence of cytokine release syndrome and calcineurin inhibitor initiation within 14 days post-cardiac transplant. 102 cardiac transplant recipients were included. BPAR occurred in 79% patients receiving rATG induction, 90% patients receiving basiliximab induction, and 83% patients receiving dual induction. Basiliximab (HR, 1.85; 95% CI 1.06 to 3.23)and dual induction (HR, 1.81; 95% CI 1.04 to 3.15) were associated with higher risks of BPAR compared to rATG. Dual induction demonstrated an increased risk of infection, compared to both rATG (HR, 2.02; 95% CI 1.05 to 3.90) and basiliximab (HR, 3.46; 95% CI 1.31 - 9.1). Basiliximab was associated with a reduced risk of hematologic complication, compared to rATG (HR, 0.44; 95% CI 0.22 - 0.91), but an increased risk of mortality (HR, 4.32; 95% CI 1.2 to 16.1). Use of dual induction was associated with an increased risk of BPAR and infection post-transplant. Use of basiliximab demonstrated reduced risk of hematologic complications but increased risk of BPAR and mortality following transplant.

Evaluation of Targeted Basiliximab Induction Therapy in Lung Transplant

Antibody induction therapy has been shown to reduce acute rejection episodes in organ transplantation. Universal basiliximab (BAS) induction therapy was discontinued at our center due to lack of efficacy versus no induction. Targeted induction therapy with BAS was developed for patients with acute kidney injury. This study compares the incidence of acute and chronic rejection in lung transplant (txp) recipients who received basiliximab for acute kidney injury (AKI). Patients transplanted between 2008-2018 were retrospectively divided into two groups (grps): (1) BAS vs (2) no induction. Maintenance IS included a calcineurin inhibitor, mycophenolate or azathioprine, and prednisone. Acute rejection (AR) was defined as ISHLT grade A2 or greater. Variables examined included baseline characteristics, incidence of AR, infections within 12 months (mo), serum creatinine (Scr) pre- and post-txp, antibody mediated rejection, post-transplant lymphoproliferative disorder (PTLD), time to CLAD development, and patient survival. 318 patients qualified for analysis: 59 patients received BAS. The groups were comparable in regards to gender, age, diagnosis, and CMV status. Grp 2 had more single transplants (p= 0.032). Overall, AR at 12 mo was similar in both groups (15.6% vs. 19.6%, p=NS). Pre-txp Scr and Scr at 30 days post-txp were similar in both groups. Freedom from CLAD was similar in both groups at 2 years (grp 1= 36 v. grp 2= 178 pts, p= 0.163). No difference was observed between the groups regarding secondary outcomes shown in the table. However, patients receiving BAS therapy trended toward worse survival at 12 mo when compared to no induction. In conclusion, our single-center experience demonstrated similar outcomes in patients with AKI who received targeted basiliximab induction therapy in conjunction with delayed calcineurin inhibitor initiation.

SAT-373 PRIMARY MEMBRANOUS NEPHROPATHY MANAGEMENT WITH CALCINEURIN INHIBITORS AND ITS ASSOCIATED REMISSION AND LONG-TERM RELAPSE RATE: MEMBRANOUS G-COHORT STUDY

Majority of the studies on primary membranous nephropathy (PMN) based the relapse rate associated with calcineurin inhibitors (CNI) on relatively short-term follow-up (<2years). We look to identify the efficacy of calcineurin inhibitors in inducing and maintaining remission over long term follow-up of 2years or more. Retrospective data was collected using the regional electronic database (eMED) on patients identified with PMN (n=31). Patients on initial immunosuppressive therapy with CNIs were included and data were assessed for remission induction, either complete remission (CR) or partial remission (PR) and subsequent relapses over a mean follow up period of 10±7 years from onset of diagnosis of PMN (n=16). CR was defined as urine protein to creatinine ratio (uPCR) <30mg/mmol and PR as >50% reduction from baseline in proteinuria and uPCR between 30 and 350 mg/mmol with stable eGFR. Relapse was defined as recurrence of uPCR > 350 mg/mmol after remission. Ciclosporin (CyA) with prednisolone was used in 14 patients (87.5%), Tacrolimus (Tac) monotherapy in 2 patients (12.5%). All patients achieved remission. PR occurred in 10 patients (62.5%) and complete remission in 6 patients (37.5%). Mean uPCR at the initiation of CNI was 783 ± 287 mg/mmol. At least one or more relapses were observed in 11 patients (68.8%) during the long term follow up. Mean duration of treatment was 3.6±2.2 years. Six patients (54.5%) relapsed while weaning off treatment while 5 patients (45.5%) off all treatment of which 3 patients were off treatment for more than 10 years.Tabled 1Patient CharacteristicsVariables ( n=16)Male11Female5Ethnicity - Irish - Non-IrishIrish : 11 Non Irish : 5Age at presentation in years41 ± 12eGFR at initiation of CNI ( ml/min/1.73m2)64 ± 14Urine Protein to Creatinine Ratio at initiation of CNI (mg/mmol)783 ± 287Gout6 (37.5%)Hypertension11 (68.8%)Ischaemic Heart Disease (IHD)4 (25%)Hyperlipidaemia6 (37.5%)Diabetes Mellitus3 (18.8%) Open table in a new tab Tabled 1Summary of results tableCiclosporin (CyA) with prednisolone, n (%)14 (87.5%)Tacrolimus (Tac) monotherapy, n (%)2 (12.5%)uPCR at initiation of CNI (mg/mmol)1783±287Follow up110±7 yearsDuration of treatment (years)13.6±2.2Partial remission, n (%)10 (62.5%)Complete remission, n (%)6 (37.5%)Relapse while weaning, n (%)6 (54.5%)Relapse while off treatment, n(%)5 (45.5%)Total relapse, n(%)11(68.8%)1-Mean± standard deviation, uPCR-Urine Protein to Creatinine ratio Open table in a new tab 1-Mean± standard deviation, uPCR-Urine Protein to Creatinine ratio CNIs are potent agents in remission induction in PMN. However, the relapse rate associated with CNIs in PMN is higher than previously documented when patients are followed for a prolonged duration. Majority of the patient's relapse when treatment is stopped or is being weaned off.

Neurotoxicity including posterior reversible encephalopathy syndrome after initiation of calcineurin inhibitors in transplanted methylmalonic acidemia patients: Two case reports and review of the literature.

IntroductionNew neurological symptoms in methylmalonic acidemia (MMA) patients after liver and/or kidney transplantation (LKT) are often described as metabolic stroke‐like‐events. Since calcineurin inhibitors (CNIs) are a well‐known cause of new neurological symptoms in non‐MMA transplanted patients, we investigated the incidence of CNI‐induced neurotoxicity including posterior reversible encephalopathy syndrome (PRES) in post‐transplanted MMA patients.MethodsWe report the two MMA patients treated with LKT in our center. Additionally, we performed a systematic review of case reports/series of post‐transplanted MMA patients and determined if CNI‐induced neurotoxicity/PRES was a likely cause of new neurological symptoms. Definite CNI‐induced neurotoxicity was defined as new neurological symptoms during CNI treatment with symptom improvement after CNI dose reduction/discontinuation. PRES was defined as CNI‐induced neurotoxicity with signs of vasogenic edema on brain magnetic resonance imaging (MRI)‐scan post‐transplantation.ResultsOur two MMA patients both developed CNI‐induced neurotoxicity, one had PRES. In literature, 230 transplanted MMA patients were identified. Neurological follow‐up was reported in 54 of them, of which 24 were excluded from analysis since no anti‐rejection medication was reported. Thirty patients, all using CNI, were included. Sixteen patients (53%) had no new neurological symptoms post‐transplantation and five patients (17%) had definite CNI neurotoxicity of whom two had PRES. Including our cases this results in a pooled incidence of 22% (7/32) definite CNI neurotoxicity and 9% PRES (3/32) in post‐transplanted MMA patients on CNI.ConclusionIn MMA post‐transplanted patients with new neurological symptoms CNI‐induced neurotoxicity/PRES should be considered. Early recognition of CNI‐induced neurotoxicity is essential to initiate dose reduction/discontinuation of CNI to minimize persistent neurologic damage and improve outcome.Concise one sentence take home messageIn all post‐transplanted MMA patients with new neurological symptoms CNI‐induced neurotoxicity/PRES should be considered, and directly reducing the dose/discontinuation of CNI is essential.

A Single-Center Experience of the Optimal Initial Immunosuppressive Strategy for Preventing Early Acute Cellular Rejection in Orthotopic Heart Transplantation Associated With Renal Dysfunction.

Renal dysfunction is a common complication following heart transplantation that may be worsened by the early initiation of calcineurin inhibitors. Antithymocyte globulin (ATG) or basiliximab has been used to delay or avoid calcineurin inhibitors. The most effective strategy for preventing early acute cellular rejection in this context is uncertain. We retrospectively reviewed all heart transplant cases between January 2012 and June 2017. The standard therapy consisted of mycophenolate mofetil, prednisolone, and tacrolimus. In patients at high risk of post-transplant renal dysfunction, an early calcineurin inhibitor-free regimen with basiliximab and/or ATG was used. Patients were assigned to cohorts based on the initial immunosuppressive strategy. The primary end point was the freedom rate of acute cellular rejection within 4 weeks post-transplant. Of 93 cases, 21 patients received standard therapy, 64 patients received an initial calcineurin inhibitor-free regimen with basiliximab, and 8 patients received ATG and basiliximab. Freedom from acute rejection was greater in the ATG plus basiliximab group (all rejection free), compared to 40 (63%) of 64 patients treated with basiliximab and 10 (48%) of 21 patients treated with standard therapy (P < .05, log rank test). In patients treated with basiliximab, early administration (<24 hours) was associated with a higher freedom from acute rejection compared to ≥24 hours, (72% vs 29%, P < .05). The combination of ATG and basiliximab was more effective in preventing acute cellular rejection. In those patients treated with basiliximab, rejection rates were no worse than standard therapy; however, it was only effective when administered within 24 hours.

Some Aspects of Aging Are Advantageous: Elderly Organ Recipients May Get Away With Less Immunosuppression

Aging impacts health care broadly. In organ transplantation, most patients currently waiting for an organ transplant are older than 55 years, with >20% of transplant recipients being over the age of 65.1 Demographic changes are also relevant for the deceased donor population with approximately 20% of donors being older than 50 years and approximately 5% >65 years old.2 Markedly are geographic differences with close to 50% of donors being older than 60 years in Spain.3 Although relevance and necessity of age-specific aspects of immunosuppression in the elderly have been recognized, clinical immunosuppressive trials in organ transplantation have mostly excluded older patients. The aging immune system is characterized by reduced amounts of naïve T cells because of limited thymic outputs, an accumulation of less effective memory T cells, and a constricted T-cell receptor repertoire. Additional age specifics of T-cell metabolisms have started to be appreciated. The effects of immunosenescence on B-cell responses are less well understood. The efficacy of B cells may be influenced through compromised T cell function, with additional limitations in class switch recombinations playing a role.4 Clearly, understanding immunosuppression in the elderly is of clinical relevance. It is important to understand that an optimization of immunosuppression in aging may not be as simple as applying less of the same immunosuppression. Immunosuppressants that work effectively in young recipients may operate differently in the elderly. Tacrolimus, for example, has been more efficient at lower doses with age-specific effects based on lower calcineurin levels in older human CD-4 T cells. Moreover, mammalian target of rapamycin inhibition has been more effective in experimental models with reduced proinflammatory interferon-γ production and augmented amounts of interleukin (IL)-10 by old CD4+ T cells.5 Studying age-specific aspects of clinical immunosuppression appears, therefore, timely and relevant. While previous studies have compared the application of the polyclonal antibody Thymoglobulin (ATG) and Basiliximab (BSX) targeting the IL-2 receptor on activated T cells as induction treatments, those regimens have not been compared in the elderly. Masset et al6 from France showed that both ATG and BSX were effective in immunological low risk older (≥65 y) recipients. Three-year graft survival was different (74% for ATG- and 68% for BSX-treated recipients), however, not reaching statistical significant difference. BSX-treated patients also had higher rates of acute T-cell–mediated rejections. As the most prominent finding of this study, the occurrence of posttransplant diabetes (PTD) had been significantly higher in BSX compared to ATG-treated recipients (23% versus 15%, P = 0.04), potentially related to higher tacrolimus trough levels in the BSX group (BSX 9.48 versus ATG 7.30 ng/mL, P = 0.023). As T-cell–mediated rejections had been significantly higher in BSX-treated recipients, those patients may have also had an additional corticosteroid burden. A few additional aspects, including center-specific approaches of protocol versus for-cause biopsies and an overall small cohort, need to be contemplated. Moreover, conclusions of this study are based on a retrospective analysis with a broad center-specific variance of immunosuppressive treatments and only a small albeit significant difference for the incidence of PTD. Do those results confirm that less is more when it comes to immunosuppression in the elderly, or are there additional aspects to consider? We have come to understand that alloimmunity is determined by the sum of recipient’s alloimmune responses. The immunogenicity of the graft itself is playing an additional role. In aging, this constellation appears of particular relevance: older organs elicit more frequent acute rejections linked to activated intragraft dendritic cells.7-9 Remarkably, the frequency of acute rejections when transplanting older organs is blunted when older organs are transplanted into older recipients. Of additional clinical relevance, older recipients are more likely to receive an older organ that is, in turn, more likely to develop a delayed graft function,10 emphasizing the importance to postpone the initiation of calcineurin inhibitors. Immunosuppressive protocols for the elderly will thus need to have those complexities in mind. Although more frequent rates of PTD may very well be linked to increased tacrolimus trough levels, this finding may not necessarily make an argument for a BSX induction in elderly transplant recipients. A reduced Thymoglobulin dosage in parallel to a reduced tacrolimus dosage, initiated days after transplantation, may be a preferable alternative. Masset et al6 have helped us to focus on the elderly in transplantation with the goal to work toward an optimized immunosuppression in this growing transplant population. Future prospective immunosuppressive studies in the aging population with an additional detailed evaluation of alloimmune responses may provide further clarification for a clinically pressing problem in organ transplantation (Figure 1).FIGURE 1.: Future immunosuppressive trials in the elderly may address dosing of established immunosuppressants in addition to age-specific effects and alloimmune responses. ATG, antibody thymoglobulin.

Amlodipine and calcineurin inhibitor-induced nephrotoxicity following allogeneic hematopoietic stem cell transplant.

Studies in the renal transplant population have suggested calcium-channel blockers (CCBs) may protect against calcineurin inhibitor (CNI)-induced nephrotoxicity. However, this has not been evaluated in the hematopoietic stem cell transplant (HSCT) population. This retrospective study reviews data from 350 consecutive patients who underwent allogeneic HSCT to determine whether amlodipine improved renal outcomes. Subject data included up to one year from CNI initiation. Patients in the amlodipine group (n=130) received an average of 143days treatment with amlodipine and experienced a smaller decrease in creatinine clearance (CrCl) through day 180. At day 30, change in CrCl was -17.4mL/min in the amlodipine cohort and -33.8mL/min in the control (P<0.001). At day 180, change in CrCl was -40.9 and -50.6mL/min, respectively (P=0.005). Incidence of hospitalization with acute kidney injury (AKI) was significantly lower in patients receiving amlodipine, 7.7% (10/132) vs 16.4% (36/220) (hazard ratio [HR] 0.44; 95% confidence interval [CI] 0.22-0.89). Median blood pressure in the amlodipine group remained <132/78 through day 360. Our data support the use of amlodipine for hypertension in the allogeneic HSCT population and provide evidence suggesting that CCBs protect against CNI-induced nephrotoxicity.

Delayed calcineurin inhibitor introduction and renal outcomes in liver transplant recipients receiving basiliximab induction.

To investigate the impact of delayed calcineurin inhibitor (CNI) initiation in liver transplant recipients (LTR) with peri-operative renal insufficiency receiving basiliximab induction, we compared renal outcomes of LTR stratified by the degree of achieved post-operative renal recovery (RR) prior to CNI initiation. All adult LTR transplanted between 01/2007 and 12/2015 who received basiliximab were included. Patients who received multi-organ transplantations, were repeat transplant recipients, or expired prior to post-operative day (POD) 90 were excluded. The primary outcome of our retrospective analysis was renal function at POD 90. A total of 210 patients were included in our final analysis. Most patients were Caucasian males undergoing liver transplantation for liver disease secondary to hepatitis C virus. Baseline characteristics were similar among the evaluable population. Estimated GFR was significantly higher among patients with the greatest degree of post-operative renal recovery at POD 90; however, this difference did not persist at POD 180. There was no significant difference in incidence or severity of biopsy-proven acute rejection (BPAR) at any measured time point. Delayed CNI initiation following liver transplantation in patients with post-operative renal insufficiency who receive basiliximab induction does not adversely affect the incidence of BPAR or long-term renal outcomes.

The Optimal Initial Immunosuppressive Strategy for Orthotopic Heart Transplantation in Renal Dysfunction - A Comparison of Commonly Used Regimes

Renal dysfunction is a common complication following orthotopic heart transplantation (OHTx) that may be worsened by the early initiation of calcineurin inhibitors (CNI), especially in patients with pre-existing renal impairment. As a result, delayed initiation of CNI or CNI-free immunosuppression regimes are sometimes unavoidable, and temporizing strategies involving anti-thymocyte globulin (ATG) or basiliximab are used as an adjunct to immunosuppressive protocols. However, the most effective strategy for preventing acute cellular rejection (ACR) in this context is uncertain.