Everolimus-Induced Immune Effects after Heart Transplantation: A Possible Tool for Clinicians to Monitor Patients at Risk for Transplant Rejection

Background: Patients treated with an inhibitor of the mechanistic target of rapamycin (mTORI) in a calcineurin inhibitor (CNI)-free immunosuppressive regimen after heart transplantation (HTx) show a higher risk for transplant rejection. We developed an immunological monitoring tool that may improve the identification of mTORI-treated patients at risk for rejection. Methods: Circulating dendritic cells (DCs) and regulatory T cells (Tregs) were analysed in 19 mTORI- and 20 CNI-treated HTx patients by flow cytometry. Principal component and cluster analysis were used to identify patients at risk for transplant rejection. Results: The percentages of total Tregs (p = 0.02) and CD39+ Tregs (p = 0.05) were higher in mTORI-treated patients than in CNI-treated patients. The principal component analysis revealed that BDCA1+, BDCA2+ and BDCA4+ DCs as well as total Tregs could distinguish between non-rejecting and rejecting mTORI-treated patients. Most mTORI-treated rejectors showed higher levels of BDCA2+ and BDCA4+ plasmacytoid DCs and lower levels of BDCA1+ myeloid DCs and Tregs than mTORI non-rejectors. Conclusion: An mTORI-based immunosuppressive regimen induced a sufficient, tolerance-promoting reaction in Tregs, but an insufficient, adverse effect in DCs. On the basis of patient-specific immunological profiles, we established a flow cytometry-based monitoring tool that may be helpful in identifying patients at risk for rejection.

Humoral Immune Response Following SARS-CoV-2 Vaccination in Liver Transplant Recipients

As COVID-19 remains an issue in transplantation medicine, a successful vaccination can prevent infections and life-threatening courses. The probability of poor immune response in liver transplant recipients gained attention and insecurity among those patients, leading us to investigate the humoral immune response alongside the influence of underlying diseases and immunosuppressive regimen on seroconversion rates. We included 118 patients undergoing anti-spike-protein-IgG testing at least 21 days after completed SARS-CoV-2 vaccination. Ninety-seven patients also underwent anti-spike-protein-IgA testing. The influence of baseline demographics, immunosuppressive regimen and underlying disease on seroconversion was analyzed, and 92 of 118 patients (78.0%) developed anti-spike-protein-IgG antibodies. Patients with a history of alcoholic liver disease before transplantation showed significantly lower seroconversion rates (p = 0.006). Immunosuppression also significantly influenced antibody development (p < 0.001). Patients run on a mycophenolate mofetil (MMF)-based regimen were more likely not to develop antibodies compared to patients run on a non-MMF regimen (p < 0.001). All patients weaned off immunosuppression were seropositive. The seroconversion rate of 78.0% in our cohort of liver transplant recipients is promising. The identification of alcohol-induced cirrhosis as underlying disease and MMF for immunosuppression as risk factors for seronegativity may serve to identify vaccination non-responder after liver transplantation.

Efficacy and Safety of Iguratimod Supplement to the Standard Immunosuppressive Regimen in Highly Mismatched Renal Transplant Recipients: A Pilot Study

Iguratimod (IGU) can mitigate the symptoms of rheumatoid arthritis through its anti-inflammatory effects. The objective of this study was to investigate the clinical efficacy and safety of IGU in highly HLA-mismatched renal transplant recipients, in combination with standard immunosuppressive regimen. This pilot study was designed as an open-label, blank-control, randomized clinical trial on patients recruited from a single transplant center in China. Patients who met the inclusion criteria were randomized to the IGU (n=27) and blank control (n=27) groups. IGU was administrated with the conventional triple immunosuppressive protocol for 52 weeks after kidney transplantation. The incidence of biopsy-proven acute rejection rate was 14.8% (4/27) in the IGU group and 29.6% (8/27) in the control group, P = 0.19. The clinical rejection rate was also substantially reduced in the IGU group (3.7% vs. 18.5%, P = 0.08). De novo donor-specific antibody also showed a decline trend in the IGU group after 52 weeks. The graft function and incidence of adverse events were similar between the two groups. In addition, IGU intervention significantly decreased the number of NK cells throughout the follow-up. In conclusion, our study has shown the possibility that IGU could reduce the allograft rejection rate and de novo DSA with appreciable safety in combination with conventional immunosuppressants. Formal clinical trials were warranted based on current findings.

TAFRO syndrome: a case report

A man diagnosed as TAFRO syndrome was successfully responded to a novel immunosuppressive regimen containing methylprednisolone and mycophenolate mofetil. Blood cells firstly recovered, followed by the general situation and complete recover 1 month later, highlighting the danger of TAFRO syndrome and the importance of immunosuppressive agents in reversing pathological course

Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient

Patients with previous sensitization events against anti-human leukocyte antigens (HLA) often have circulating anti-HLA antibodies. Following organ transplantation, sensitized patients have higher rates of antibody-mediated rejection (AMR) compared to those who are non-sensitized. More stringent donor matching is required for these patients, which results in a reduced donor pool and increased time on the waitlist. Current approaches for sensitized patients focus on reducing preformed antibodies that preclude transplantation; however, this type of desensitization does not modulate the primed immune response in sensitized patients. Thus, an optimized maintenance immunosuppressive regimen is necessary for highly sensitized patients, which may be distinct from non-sensitized patients. In this review, we will discuss the currently available therapeutic options for induction, maintenance, and adjuvant immunosuppression for sensitized patients.

Protocol Biopsies on de novo Renal-Transplants at 3 Months after Surgery: Impact on 5-Year Transplant Survival

Background: In many centers, a protocol kidney biopsy (PKB) is performed at 3 months post-transplantation (M3), without a demonstrated benefit on death-censored graft survival (DCGS). In this study, we compared DCGS between kidney transplant recipients undergoing a PKB or without such biopsy while accounting for the obvious indication bias. Methods: In this retrospective, single-center study conducted between 2007 and 2013, we compared DCGS with respect to the availability and features of a PKB. We built a propensity score (PS) to account for PKB indication likelihood and adjusted the DCGS analysis on PKB availability and the PS. Results: A total of 615 patients were included: 333 had a PKB, 282 did not. In bivariate Kaplan–Meier survival analysis, adjusting for the availability of a PKB and for the PS, a PKB was associated with a better 5-year DCGS independently of the PS (p < 0.001). Among the PKB+ patients, 87 recipients (26%) had IF/TA > 0. Patients with an IF/TA score of 3 had the worst survival. A total of 144 patients (44%) showed cv lesions. Patients with cv2 and cv3 lesions had the worst 5-year DCGS. Conclusions: A M3 PKB was associated with improved graft survival independently of potential confounders. These results could be explained by the early treatment of subclinical immunological events. It could be due to better management of the immunosuppressive regimen.

Increased renal function decline in fast metabolizers using extended-release tacrolimus after kidney transplantation

Fast metabolism of immediate-release tacrolimus (IR-Tac) is associated with decreased kidney function after renal transplantation (RTx) compared to slow metabolizers. We hypothesized, by analogy, that fast metabolism of extended-release tacrolimus (ER-Tac) is associated with worse renal function. We analyzed data from patients who underwent RTx at three different transplant centers between 2007 and 2016 and received an initial immunosuppressive regimen with ER-Tac, mycophenolate, and a corticosteroid. Three months after RTx, a Tac concentration to dose ratio (C/D ratio) < 1.0 ng/ml · 1/mL defined fast ER-Tac metabolism and ≥ 1.0 ng/ml · 1/mL slow metabolism. Renal function (estimated glomerular filtration rate, eGFR), first acute rejection (AR), conversion from ER-Tac, graft and patient survival were observed up to 60-months. 610 RTx patients were divided into 192 fast and 418 slow ER-Tac metabolizers. Fast metabolizers showed a decreased eGFR at all time points compared to slow metabolizers. The fast metabolizer group included more patients who were switched from ER-Tac (p < 0.001). First AR occurred more frequently (p = 0.008) in fast metabolizers, while graft and patient survival rates did not differ between groups (p = 0.529 and p = 0.366, respectively). Calculation of the ER-Tac C/D ratio early after RTx may facilitate individualization of immunosuppression and help identify patients at risk for an unfavorable outcome.

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients

Background In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. Methods This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is ‘successful transplantation’, defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. Conclusions The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. Trial registration ClinicalTrials.gov: NCT03797196, registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.