Immunosuppression In Renal Transplant Recipients Research Articles

The Clinical Manifestation of Immunosuppressive Therapy as a Tool to Improve Immune Monitoring in Renal Transplant Recipients

Introduction: Metrics for posttransplant immune monitoring to prevent over or under immunosuppression in renal transplant recipients (RTRs) are lacking. Methods: We surveyed 132 RTRs, 38 in the first year posttransplant and 94 >1-year posttransplant, to study the clinical expression of immunosuppressive therapy. A questionnaire administered to these RTRs was divided into physical (Q physical) and mental (Q mental) symptoms. Results: In multivariable models for the association between the calculated Q physical and Q mental scores and different clinical and biochemical variables in the 38 RTRs who filled out the questionnaire 130 times during the first year posttransplant, it was found that mycophenolic acid (MPA) and prednisone use increased the mean Q physical score by 0.59 (95% CI: 0.21–0.98, p = 0.002) and 0.53 (95% CI: 0.26–0.81, p = 0.00), respectively, while MPA use increased the mean Q mental score by 0.72 (95% CI: 0.31–1.12, p = 0.001). Among the 94 RTRs who each completed the questionnaire only once, the odds for the mean Q mental score to be above the median value were more than 3 times higher for RTRs treated versus non-treated with MPA (OR 3.38, 95% CI: 1.1–10.3, p = 0.03). MPA-treated RTRs had higher mean scores for questions related to sleep disorders (1.83 ± 1.06 vs. 1.32 ± 0.67 for not treated, p = 0.037), to difficulty falling asleep (1.72 ± 1.11 vs. 1.16 ± 0.5, p = 0.02), and to depression and anxiety. Conclusion: We concluded that prednisone and MPA use are associated with an increased Q physical and Q mental scores in RTRs. Routine monitoring of physical and mental status of RTRs should be implemented to improve the diagnosis of overimmunosuppression. Dose reduction or discontinuation of MPA should be considered in RTRs who report sleep disorders, depression, and anxiety.

Effectiveness of Retzius-Sparing Robot-Assisted Radical Prostatectomy in a Renal Transplant Recipient: a Case Report

Prostate cancer (PCa) has increased as a long-term outcome of advanced immunosuppression in renal transplant recipients (RTRs). Retzius-sparing robot-assisted radical prostatectomy (Rs-RARP) is reportedly less time-consuming and has a higher continence recovery rate than the standard RARP without increasing the risk of complications. However, only a few cases of Rs-RARP in RTRs have been reported. A 65-year-old man, who received a renal transplant 2 years prior, was diagnosed with low-risk PCa, per the D'Amico risk classification system, and underwent Rs-RARP with the da Vinci Xi robotic system. All port sites were placed contralateral to the allograft and compared with the standard RARP. The operative time was 187 min, and the estimated blood loss was 100 mL. The urethral catheter was removed on postoperative day 7 after confirming the absence of leakage using voiding cystourethrography. The patient was discharged on postoperative day 8. Pathologic findings showed localized PCa with a Gleason score of 3+3 and negative surgical margins. One year after the surgery, the patient had adequate urinary continence. His prostate-specific antigen level was <0.01 ng/mL, and his renal function was similar to that before surgery. We reported a case of PCa in an RTR, successfully treated via Rs-RARP, resulting in adequate continence without complications.

CYP3A5 polymorphism and immunosuppression in renal transplant recipients

Tacrolimus remains mainstay of immunosuppression in renal transplant recipients. Tacrolimus has narrow therapeutic window. Underdosing can precipitate rejection, whereas overdose may result in toxicity. CYP3A5 polymorphism can explain the inter individual variability in the tacrolimus pharmacokinetics. CYP3A5 expressers have faster tacrolimus metabolism as compared to nonexpressers. Using genotype-based tacrolimus dosing can help achieve therapeutic drug levels faster than weight-based dosing. However, differences in CYP3A5 expression have not translated into clinical outcomes in many studies. Further studies are needed to ascertain the role of CYP3A5 in tacrolimus toxicity. In this article, we reviewed the evidence pertaining to CYP3A5 polymorphism and its impact on tacrolimus pharmacokinetics and also their role in tacrolimus dose decision-making.

Immunological risk stratification and tailored minimisation of immunosuppression in renal transplant recipients

BackgroundThe efficacy and safety of minimisation of immunosuppression including early steroid withdrawal in kidney transplant recipients treated with Basiliximab induction remains unclear.MethodsThis retrospective cohort study reports the outcomes from 298 consecutive renal transplants performed since 1st July 2010–June 2013 treated with Basiliximab induction and early steroid withdrawal in low immunological risk patients using a simple immunological risk stratification and 3-month protocol biopsy to optimise therapy. The cohort comprised 225 low-risk patients (first transplant or HLA antibody calculated reaction frequency (CRF ≤50% with no donor specific HLA antibodies) who underwent basiliximab induction, steroid withdrawal on day 7 and maintenance with tacrolimus and mycophenolate mofetil (MMF), and 73 high-risk patients who received tacrolimus, MMF and prednisolone for the first 3 months followed by long term maintenance immunosuppression with tacrolimus and prednisolone. High-risk patients not undergoing 3-month protocol biopsy were continued on triple immunosuppression.ResultsSteroid withdrawal could be safely achieved in low immunological risk recipients with IL2 receptor antibody induction. The incidence of biopsy-proven acute rejection was 15.1% in the low-risk and 13.9% in the high-risk group (including sub-clinical rejection detected at protocol biopsy). One- year graft survival was 93.3% and patient survival 98.5% in the low-risk group, and 97.3 and 100% respectively in the high-risk group. Graft function was similar in each group at 1 year (mean eGFR 61.2 ± 23.4 mL/min low-risk and 64.6 ± 19.2 mL/min high-risk).ConclusionsImmunosuppression regimen comprising basiliximab induction, tacrolimus, MMF and prednisolone with early steroid withdrawal in low risk patients and MMF withdrawal in high risk patients following a normal 3-month protocol biopsy is effective in limiting acute rejection episodes and produces excellent rates of patient survival, graft function and complications.

Renal allograft surveillance with allospecific T-cytotoxic memory cells

Background Allo-antigen-specific T-cytotoxic memory cells (TcM) which express CD40 ligand (CD154) in overnight lymphocyte co-culture are strongly associated with acute cellular rejection (ACR) seen in “for cause” biopsies for renal allograft dysfunction. Specifically, when the likelihood of rejection is increased, donor-specific allospecific TcM exceed those induced by HLA-non-identical third-party cell by 1.15-fold or greater. Methods The performance of allospecific TcM was evaluated retrospectively in primary renal transplant recipients (RTR) at routine clinical visits, cross-sectionally at presentation for biopsies, and serially. Performance metrics were sensitivity, specificity, positive and negative predictive values (PPV and NPV). Results Twenty-two primary RTR, median age 45 years (range 19–72) were tested with allospecific CD154 + TcM. Samples were obtained at the mean ± SD time interval of 806 ± 239 days after kidney transplantation. Six of 22 patients experienced biopsy proven T- Cell Mediated Rejection (TCMR). A seventh showed antibody mediated rejection (ABMR). Of these seven patients six demonstrated increased likelihood of rejection with allospecific TcM (sensitivity 83%). Ten of these 15 patients with no rejection had a negative test (specificity 67%). False positive tests were seen in five patients. Six out of 11 patients with positive tests had ACR/ABMR with a PPV of 54%, while 10 out of 11 patients with negative tests were non-rejecters with a NPV of 91%. Conclusion Allospecific T-cytotoxic memory cells distinguished primary RTR with quiescent allografts from those with dysfunction. With serial surveillance measures, this test system may facilitate decisions to manage immunosuppression in RTR.

Symptomatic respiratory Encephalitozoon cuniculi infection in renal transplant recipients

ObjectivesEncephalitozoon spp. and Enterocytozoon bieneusi are intracellular parasitic fungi from the phylum Microsporidia, which initially localize to the intestine. As opportunistic pathogens, Encephalitozoon spp. in particular can disseminate to the respiratory tract, among other locations. Patients on life-long immunosuppression are at higher risk of such infections, mostly symptomatic. MethodsSputum samples and bronchial washings from 72 renal transplant recipients and 105 patients with various respiratory diseases were screened for Encephalitozoon spp. and E. bieneusi by microscopic examination and genus-specific nested PCR followed by genotyping. ResultsA total of 8.3% (6/72) of immunosuppressed renal transplant recipients and 1.9% (2/105) of patients with various respiratory diseases, both immunocompetent and immunosuppressed, were positive for respiratory microsporidial infection. All six transplant recipients were Encephalitozoon cuniculi-positive by PCR/sequencing and five of them suffered from respiratory symptoms. The presence of microsporidial spores was also confirmed microscopically in three of the transplant recipients. Of the two immunocompetent patients with various respiratory diseases, one had an E. cuniculi infection, while the second had an E. bieneusi infection. ConclusionsLife-long immunosuppression in renal transplant recipients increases the risk of respiratory infection by E. cuniculi. Microsporidia should be screened in respiratory samples of these patients, particularly when they have respiratory symptoms.

Summary of the Third International Workshop on Clinical Tolerance.

The Third International Workshop on Clinical Tolerance was held in Stanford, California, September 8-9, 2017. This is a summary of Workshop presentations of clinical trials designed to withdraw or minimize immunosuppressive (IS) drugs in kidney and liver transplant patients without subsequent evidence of rejection. All clinical protocols had in common the use of donor or recipient cell therapy combined with organ transplantation. Tolerance to HLA matched and mismatched living donor kidney transplants with complete withdrawal of IS drugs without subsequent rejection for up to 14 years of observation was achieved in more than 50 patients enrolled in trials in four medical centers after the establishment of transient or persistent chimerism. Complete IS drug withdrawal without chimerism was reported in a prospective trial of liver transplantation combined with injection of regulatory T cells. IS drug minimization without rejection was reported in recipients of living donor kidney transplants enrolled in the One Study consortium after injection of recipient regulatory T cells, or injection of donor regulatory monocytes or dendritic cells. In conclusion, considerable progress has been made in achieving IS drug withdrawal after cell therapy in recipients of organ transplants.

Belatacept in Solid Organ Transplant: Review of Current Literature Across Transplant Types.

Calcineurin inhibitors (CNIs) have been the backbone immunosuppressant for solid organ transplant recipients for decades. Long-term use of CNIs unfortunately is associated with multiple toxicities, with the biggest concern being CNI-induced nephrotoxicity. Belatacept is a novel agent approved for maintenance immunosuppression in renal transplant recipients. In the kidney transplant literature, it has shown promise as being an alternative agent by preserving renal function and having a minimal adverse effect profile. There are emerging studies of its use in other organ groups, particularly liver transplantation, as well as using with other alternative immunosuppressive strategies. The purpose of this review is to analyze the current literature of belatacept use in solid organ transplantation and discuss its use in current practice.

Persistent accumulation of circulating monocytic myeloid-derived suppressor cells contributes to post-infectious immunosuppression in renal transplant recipients with bacterial infection: A pilot study

IntroductionPost-infectious immunosuppression is disadvantageous to patients' long-term outcomes, especially in transplant recipients receiving large doses of immunosuppressants. A growing body of evidence indicates the immunoregulatory ability of myeloid-derived suppressor cells (MDSCs). We herein investigate the characteristics of monocytic-MDSCs (M-MDSCs) in a cohort of renal transplant recipients with/without infection to clarify the potential involvement in post-infectious immunosuppression. MethodsThe study prospectively included 28 adult recipients who underwent allogeneic ABO-compatible renal transplant. Blood samples were drawn at day 0, 7, 14, 28, 60 and 90 postoperation. The incidence of infection and treatment strategies were recorded. The frequency and absolute number of peripheral blood M-MDSCs as well as other immune cells were determined by flow cytometry. Immnosuppressive functions of M-MDSCs were analyzed by inhibition of T cells proliferation. mRNA levels of immunosuppressive molecules in sorted M-MDSCs were also examined. Results7 recipients were diagnosed with bacterial (n = 5) or viral (n = 2) infection and 3/5 of bacterial-infected recipients suffered from secondary infection during further follow-up. In the non-infected group, M-MDSCs numbers increased transiently during the early postoperative period, however, bacterial but not viral infection led to significant and persistent accumulation of M-MDSCs that remained at high levels after anti-infective treatments. M-MDSCs from infected recipients demonstrated potent ability to suppress T cells proliferation in vitro and negatively correlated with lymphocytes in vivo, yet not in the non-infected group. Inducible nitric oxide synthase (iNOS) mRNA levels were higher in sorted M-MDSCs when compared with monocytes, and suppressive activity was reversed by addition of a NOS inhibitor. ConclusionsCirculating M-MDSCs underwent significant and persistent increases after bacterial infection in renal transplant recipients, contributing to post-infectious immunodeficiency. Therefore, special attention should be given to M-MDSCs during the monitoring of immune status and infection management.

Do clinical trials reflect reality? A systematic review of inclusion/exclusion criteria in trials of renal transplant immunosuppression.

Renal transplant recipients and donors are becoming increasingly more marginal, with more expanded criteria (ECD) and donation after circulatory death (DCD) donors and older recipients. Despite this, high-risk donors and recipients are often excluded from clinical trials, leading to uncertainty about the generalizability of findings. We extracted data regarding inclusion/exclusion criteria from 174 trials of immunosuppression in renal transplant recipients published over a 5-year period and compared criteria with those specified in published trial registries. Frequently reported donor exclusion criteria were age (16.1%), donor type and cold ischaemic time (22.4%). Common recipient exclusion criteria included upper age limit (38.5%), high panel reactive antibody (PRA) (42.5%) and previous transplantation (39.7%). Inclusion/exclusion criteria recorded in trial registries matched those reported in the manuscript in only 6 (7.8%) trials. Of registered trials, 51 (66.2%) trials included additional criteria in the manuscript, 51 (66.2%) were missing criteria in the manuscript specified in the protocol, and in 19 (24.7%) key criteria changed from the protocol to the manuscript. Our findings suggest many recent immunosuppression trials have restrictive inclusion criteria which may not be reflective of current renal transplant populations. Discrepancies between trial protocols and published reports raise the possibility of selection bias.

Application of Operational Tolerance Signatures Are Limited by Variability and Type of Immunosuppression in Renal Transplant Recipients: A Cross-Sectional Study.

Renal transplant recipients (RTR) frequently develop complications relating to chronic immunosuppression. Identifying RTR who could safely reduce immunosuppression is therefore highly desirable. We hypothesized that "signatures" described in RTR who have stopped immunosuppression but maintained stable graft function ("operational tolerance") may enable identification of immunosuppressed RTR who are candidates for immunosuppression minimization. However, the effect of immunosuppression itself on these signatures and circulating B-cell populations is currently unknown. We undertook a cross-sectional study of 117 RTR to assess the effect of immunosuppression upon circulating B cell populations, humoral alloresponse and 2 previously published "signatures" of operational tolerance. Immunosuppression associated with alterations in both published "signatures." Azathioprine associated with a decrease in transitional and naive B-cell numbers and calcineurin inhibition associated with an increase in the number of circulating plasmablasts. However, only azathioprine use associated with the presence of donor-specific anti-HLA IgG antibodies. Calcineurin inhibition associated with an increase in total serum IgM but not IgG. Data were corrected for age, time since last transplant, and other immunosuppression. Current signatures of operational tolerance may be significantly affected by immunosuppressive regimen, which may hinder use in their current form in clinical practice. Calcineurin inhibition may prevent the development of long-lasting humoral alloresponses, whereas azathioprine therapy may be associated with donor specific antibody development.

Belatacept in kidney transplantation - past and future perspectives.

Calcineurin inhibitors (CNIs) are used widely for maintenance immunosuppression in renal transplant recipients. However, their side effect profile has led researchers to attempt to find safer alternatives that can maintain effective long-term immunosuppression with less toxicity. Belatacept is a CTLA4-Ig molecule designed to block the costimulatory B7-CD28 signal needed for activation of effector T cells. While it has shown great promise in clinical trials, it has made halting progress towards replacing CNIs in actual clinical practice. The BENEFIT trial revealed some of the advantages of belatacept in terms of maintaining renal function after transplant and reducing some of the metabolic side effects of CNIs related to hypertension and dyslipidemia. Despite that, some cautionary signals have emerged as well, in that belatacept-treated patients experience higher acute rejection rates and greater risk for PTLD. Furthermore, the requirement for monthly intravenous infusions has presented logistical and cost challenges for widespread adoption.

IFNγ+ Treg in-vivo and in-vitro represent both activated nTreg and peripherally induced aTreg and remain phenotypically stable in-vitro after removal of the stimulus.

BackgroundIFNγ-producing CD4+CD25+Foxp3+CD127- Treg represent the first line of Treg during an immune response. In the present study we determined whether IFNγ+ Treg in-vivo and in-vitro are Helios-positive representing activated natural (nTreg) or Helios-negative representing adaptive Treg (aTreg) and whether they originate from CD4+CD25+ and/or CD4+CD25- PBL. Furtheron, we investigated whether they are inducible by recombinant IFNγ (rIFNγ) as a single stimulus, decrease in-vitro after elimination of the stimulus, and have a demethylated Foxp3 Treg-specific demethylated region (TSDR) which is associated with stable Foxp3 expression.MethodSubsets of IFNγ+ Treg were determined in peripheral blood of healthy controls using eight-color flow cytometry and were further investigated in-vitro. Foxp3 TSDR methylation status was determined using bisulphite polymerase chain reaction (PCR) and high resolution melt (HRM) analysis.ResultsNearly all Treg in the peripheral blood were Helios+IFNγ- (1.9 ± 1.1/μl) and only few were Helios+IFNγ+ or Helios-IFNγ+ Treg (both 0.1 ± 0.1/μl). Enriched IFNγ+ Treg subsets showed in part strong Foxp3 TSDR demethylation. In-vitro, rIFNγ was unable to induce Treg. CD4+CD25+ enriched PBL stimulated with PMA/Ionomycin in the presence of rIFNγ were rather resistant to the effect of rIFNγ, in contrast to CD4+CD25- enriched PBL which showed increasing total Treg with Helios+ Treg switching from IFNγ- to IFNγ+ and increasing Helios-IFNγ+ Treg. The data indicate that rIFNγ, in combination with a polyclonal stimulus, activates nTreg and induces aTreg. When phorbol 12-myristate 13-acetate (PMA)/Ionomycin was washed out from the cell culture after 6 h stimulation, Treg induction continued for at least 96 h of cell culture, contradicting the hypothesis that removal of the stimulus results in significant decrease of IFNγ- and IFNγ+ CD4+CD25+Foxp3+CD127- Treg due to loss of Foxp3 expression.ConclusionsIFNγ+Helios- aTreg as well as IFNγ+Helios+ nTreg are detectable in the blood of healthy individuals, show in part strong Foxp3 TSDR demethylation and are inducible in-vitro. The present data provide further insight concerning the in-vivo and in-vitro characteristics of IFNγ+ Treg and help to understand their role in immunoregulation. Alloantigen-specific demethylated IFNγ+Helios+ nTreg might represent a suitable marker for monitoring graft-specific immunosuppression in renal transplant recipients.

A Randomized Trial of Everolimus and Low-dose Cyclosporine in Renal Transplantation: With or Without Steroids?

This multicenter, randomized, prospective, controlled trial (EVIDENCE study) aimed to determine short-term effects of early steroid withdrawal in renal transplant patients initially treated with everolimus, low-dose cyclosporine (CsA), and steroids. Patients were randomized to standard triple therapy with CsA, everolimus twice daily and steroids (group A), steroid-free immunosuppression (group B), or triple therapy once daily (group C). However, since patient enrollment was slower than expected, group C randomization was prematurely discontinued. The primary end point was treatment failure rate (composite end point of death, graft loss, biopsy-proven acute rejection, and loss to follow-up) between randomization and month 12. Patients evaluable for the primary end point included 139 randomized patients. According to intention-to-treat analysis, 2.8% of patients in group A and 14.7% in group B experienced treatment failure (95% upper confidence limit 19.7%). As this was higher than the predefined noninferiority limit of 10%, noninferiority could not be proved. No conclusive statements can be made on noninferiority of the steroid withdrawal regimen vs the standard regimen in these patients. Additional studies with longer follow-up are required to determine the efficacy of steroid-free immunosuppression in renal transplant recipients receiving everolimus.

Risk of posttransplant lymphoproliferative disorder associated with use of belatacept

Published evidence on a rare but serious malignancy associated with use of the first biological agent approved for long-term maintenance immunosuppression in renal transplant recipients is reviewed. Belatacept (Nulojix, Bristol-Myers Squibb) is approved by the Food and Drug Administration for use in combination therapy to prevent renal graft rejection in patients who are Epstein-Barr virus seropositive. Belatacept appears to offer some advantages over calcineurin inhibitor-based regimens (e.g., no need for therapeutic drug monitoring), but its use poses a risk of posttransplant lymphoproliferative disorder (PTLD), a rapidly progressing and often lethal malignancy. The efficacy and safety of more-intensive and less-intensive belatacept regimens were established in two Phase III clinical trials, which found that rates of patient and graft survival were comparable to those in cyclosporine users; belatacept was shown to be superior in preserving renal function. The occurrence of PTLD, particularly PTLD involving the central nervous system, in 0-4% of belatacept-treated patients in clinical trials prompted postmarketing initiatives: (1) implementation of a risk evaluation and mitigation strategy (REMS) program to help ensure the safe and proper use of belatacept, (2) longitudinal studies to better define the risks and outcomes of belatacept therapy, and (3) a manufacturer-created patient registry to track belatacept use and encourage voluntary reporting of associated adverse events. Appropriate patient selection and adherence to REMS requirements, including patient counseling and facilitation of registry enrollment, are essential in mitigating the increased risk of PTLD associated with belatacept therapy.

Outbreak of Pneumocystis Pneumonia in Renal and Liver Transplant Patients Caused by Genotypically Distinct Strains of Pneumocystis jirovecii

An outbreak of 29 cases of Pneumocystis jirovecii pneumonia (PCP) occurred among renal and liver transplant recipients (RTR and LTR) in the largest Danish transplantation centre between 2007 and 2010, when routine PCP prophylaxis was not used. P. jirovecii isolates from 22 transplant cases, 2 colonized RTRs, and 19 Pneumocystis control samples were genotyped by restriction fragment length polymorphism and multilocus sequence typing analysis. Contact tracing was used to investigate transmission. Potential risk factors were compared between PCP cases and matched non-PCP transplant patients. Three unique Pneumocystis genotypes were shared among 19 of the RTRs, LTRs, and a colonized RTR in three distinct clusters, two of which overlapped temporally. In contrast, Pneumocystis control samples harbored a wide range of genotypes. Evidence of possible nosocomial transmission was observed. Among several potential risk factors, only cytomegalovirus viremia was consistently associated with PCP (P=0.03; P=0.009). Mycophenolate mofetil was associated with PCP risk only in the RTR population (P=0.04). We identified three large groups infected with unique strains of Pneumocystis and provide evidence of an outbreak profile and nosocomial transmission. LTRs may be infected in PCP outbreaks simultaneously with RTRs and by the same strains, most likely by interhuman transmission. Patients are at risk several years after transplantation, but the risk is highest during the first 6 months after transplantation. Because patients at risk cannot be identified clinically and outbreaks cannot be predicted, 6 months of PCP chemoprophylaxis should be considered for all RTRs and LTRs.

Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

The mammalian target of rapamycin inhibitors (mTOR-I), sirolimus and everolimus, are immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2, and PI3K confers the antineoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are valid option to calcineurine inhibitors (CNIs) for maintenance immunosuppression in renal transplant recipients with chronic allograft nephropathy. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects that need to be early recognized and treated to avoid severe illness in renal transplant patients. In particular, mTOR-I may induce systemic nonnephrological side effects including pulmonary toxicity, hematological disorders, dysmetabolism, lymphedema, stomatitis, cutaneous adverse effects, and fertility/gonadic toxicity. Although most of the adverse effects are dose related, it is extremely important for clinicians to early recognize them in order to reduce dosage or discontinue mTOR-I treatment avoiding the onset and development of severe clinical complications.

Platelet activation markers after conversion from azathioprine to sirolimus based immunosuppression in renal transplant recipients

Under immunosupression with sirolimus (rapamycin) procoagulant effects and platelet activation have been controversially discussed. We evaluated patients of a prospectly designed substudy as part of a randomized trial investigating the effect of a switch from non-mTOR-based immunosuppression to sirolimus in renal transplant recipients. Our substudy consisted of 7 patients who switched therapy from azathioprine to sirolimus (conversion group) and 8 patients who remained on azathioprine (controls) before (V1) and after (V2) 3 months of treatment. In all patients we assessed flowcytometric markers of platelet activation (PAC-1), platelet degranulation (CD62P), formation of platelet leukocyte-aggregates (PLA), monocyte activation (CD11b), endogenous thrombin potential (ETP) and platelet aggregation. Both groups were similar in terms of baseline demographics and had stable transplant function for at least 6 months. CD62P increased significantly in the control group (p < 0.03). PLA were significantly reduced in the sirolimus conversion group at V2 (p < 0.02), whereas no effect was seen in the controls. Expression of PAC-1, CD11b, ETP-peak, ETP-time to peak, ETP-AUC and platelet aggregation showed no significant changes in both groups compared to V2. From clinical data, performing in depth platelet function testing, we found no evidence for increased platelet activation parameters in RTR who switched therapy from azathioprine to sirolimus.

Sirolimus in Renal Transplantation: Analysis of Safety and Efficacy in a Nonprotocol Conversion Group

BackgroundConversion to sirolimus (SRL)-based immunosuppression in renal transplant recipients is an alternative for chronic allograft dysfunction (CAD), cancer and viral infections. We sought to analyze the indications for and safety and efficacy of conversion to SRL among renal transplant patients. Methods/MaterialsWe examined a retrospective cohort, using medical records of renal transplant recipients >18 years old who had their immunosuppressive regimen converted to a SRL-based treatment. Data analysis included the indication for conversion, time posttransplant, as well as urine protein and serum creatinine at conversion and 6 months thereafter. The end points included death, graft loss and/or discontinuation of SRL. ResultsWe included 112 patients in this series who had indications for conversion: fungal, polyomavirus, or cytomegalovirus infection (n = 32), CAD (n = 30), cancer (n = 21), immunologic (n = 3), and other reasons (n = 26). Changes in immunosuppression were performed at 41 ± 57 months posttransplant or later in cancer patients. SRL was discontinued in 9 patients owing to adverse events such as edema, proteinuria, mucositis, or pneumonitis. Graft loss was observed in 19 patients, and death in 6. In 87 patients with functioning grafts, protein/creatinine ratios increased from 0.28 ± 0.03 (conversion) to 0.63 ± 0.09 (after 6 months; P < .001). Serum creatinine decreased from 2.24 ± 0.13 (conversion) to 1.89 ± 0.75 mg/dL (after 6 months; P < .001). Graft survival was 88% at 1 and 80% at 3 years after conversion. ConclusionIn, SRL was well tolerated; conversion to SRL improved graft function with a slight increase in proteinuria.

Human leukocyte antigen mismatches associated with increased risk of rejection, graft failure, and death independent of initial immunosuppression in renal transplant recipients

Human leukocyte antigen (HLA) mismatches have been shown to adversely affect renal allograft outcomes and remain an important component of the allocation of deceased donor (DD) kidneys. The ongoing importance of HLA mismatches on transplant outcomes in the era of more potent immunosuppression remains debatable. Using Australia and New Zealand Dialysis and Transplant Registry, live and DD renal transplant recipients between 1998 and 2009 were examined. The association between the number of HLA mismatches and HLA-loci mismatches and outcomes were examined. Of the 8036 renal transplant recipients, 59% had between 2 and 4 HLA mismatches. Compared with 0 HLA mismatch, increasing HLA mismatches were associated with a higher risk of graft failure and patient death in the adjusted models. HLA mismatches were associated with an incremental risk of rejection although the relative risk was higher for live donor kidney transplants. Increasing HLA-AB and HLA-DR mismatches were associated with a greater risk of acute rejection, graft failure, death-censored graft failure, and/or death. There was no consistent association between initial immunosuppressive regimen and outcomes. Our results corroborate and extend the previous registry analyses demonstrating that HLA mismatches are associated with poorer transplant outcomes independent of immunosuppression and transplant era.