Current Era Of Immunosuppression Research Articles

Histopathological characteristics and causes of kidney graft failure in the current era of immunosuppression.

BACKGROUNDThe histopathological findings on the failing kidney allograft in the modern era is not well studied. In this study, we present our experience working with kidney transplant recipients with graft failure within one year of the biopsy.AIMTo report the histopathological characteristics of failed kidney allografts in the current era of immunosuppression based on the time after transplant, cause of the end-stage renal disease and induction immunosuppressive medications.METHODSIn a single-center observational study, we characterized the histopathological findings of allograft biopsies in kidney transplant recipients with graft failure within one year after the biopsy.RESULTSWe identified 329 patients with graft failure that met the selection criteria between January 1, 2006 and December 31, 2016. The three most common biopsy findings were interstitial fibrosis and tubular atrophy (IFTA, 53%), acute rejection (AR, 43%) and transplant glomerulopathy (TG, 33%). Similarly, the three most common causes of graft failure based on the primary diagnosis were AR (40%), TG (17%), and IFTA (13%). Most grafts failed within two years of post-transplant (36%). Subsequently, approximately 10%-15% of grafts failed every two years: > 2-4 years (16%), > 4-6 years (13%), > 6-8 years (11%), > 8-10 years (9%) and > 10 years (16%). AR was the most common cause of graft failure in the first six years (48%), whereas TG was the most prevalent cause of graft failure after 6 years (32%) of transplant.CONCLUSIONIn the current era of immunosuppression, AR is still the most common cause of early graft failure, while TG is the most prevalent cause of late graft failure.

Practice Patterns Surrounding Surveillance Biopsies in Pediatric Kidney Transplant Patients

There have been very few advancements in the long-term outcomes of children who have had a kidney transplantation in the current era of immunosuppression. Because of this, some centers have started to perform surveillance biopsies in an attempt to diagnose and potentially treat early or subclinical findings of renal allograft injury. There is very little information on the practice patterns of pediatric nephrologists regarding these biopsies. To gain a better idea of how many centers in North American are doing surveillance biopsies, we sent out a brief survey electronically via the PedNeph email list (https://lists.uchicago.edu/web/info/pedneph), with a reminder sent 4 weeks later. Of the survey respondents, currently 34.3% (23/67) perform surveillance biopsies. We were unable to determine the actual percentage of attending pediatric nephrologists who completed the survey due to 1) membership of people in the listserv who are not physicians, 2) members who are no longer practicing who are still on the list, and 3) members whose email has changed but both of their emails are on the list. We received responses from 60% (33/50) of the top 50 ranked pediatric nephrology centers in the 2016-2017 U.S. News & World Report rankings comprising 29 different states, Canada, and Europe. The majority of responding centers, 68.4% (13/19) do continuous direct sonographic guidance. Not all centers biopsied children at the same time points. 52% (12/23) of centers biopsied patients at 3mo, 69.5% (16/23) at 6 months, 78.2% (18/23) at 1 year and 43.4% (10/23) at 2 years post-transplant. Of the 19 centers that responded to this question, 12 (63.2%) observe the patient and discharge home. Eighty-two percent (18/22) centers who answered the question and perform SB said that the pediatric nephrologist does the SB, and 68.2% (15/22) use direct sonographic guidance. Sixty two percent (13/21) have someone from pathology (technician, pathologist, etc.) present in the room during the procedure to collect the tissue and examine for adequacy. All respondents stated that their complication rates were low, but most did not have specific numbers available. Having a better understanding of the practice patterns among pediatric nephrologists is critical as this is the first step in developing protocols and future research studies. More work needs to be done to examine the finding of these biopsies.

Rates of CMV Reactivation in Non Mismatched Heart Transplant Patients

Cytomegalovirus (CMV) infection after heart transplantation poses a burden on the health care system. Society guidelines recommend prophylaxis only for patients at high risk (D+/R-) of developing CMV infection, with options for prophylaxis or pre-emptive therapy in intermediate risk patients (R+). We sought to quantify the burden of CMV viraemia in intermediate risk patients in current era of immunosuppression.

Recurrent Cytomegalovirus Infections in Heart Transplant Recipients in the Current Era of Immunosuppression

Society guidelines recommend prophylaxis for patients at high risk (D+/R−) of developing cytomegalovirus (CMV) infection following heart transplantation. We sought to quantify the burden of CMV viraemia in intermediate-risk patients (R+). We reviewed 150 consecutive heart transplant recipients (2013–2017). Intermediate-risk patients had regular laboratory monitoring to detect early viral replication. High-risk patients received ganciclovir prophylaxis within 24 hours of transplantation with subsequent valganciclovir. Patients received induction immunosuppression with basiliximab if serum creatinine >120 μmol/L (n = 118); all patients received maintenance tacrolimus and mycophenolate mofitil. Cytomegalovirus viraemia was defined as serum CMV polymerase chain reaction >712 IU/mL; sustained increase in CMV titre despite oral valganciclovir was considered persistent viraemia. There was a high prevalence of CMV viraemia in intermediate-risk patients with 55% (n = 59/107) having 31 episodes of CMV viraemia; it was 39% (n = 9/23; p = 0.163) in high-risk patients. There was no difference in the proportion of viraemic patients with persistent viraemia or clinical CMV infection requiring hospitalisation for IV ganciclovir in intermediate-risk versus high-risk patients (46% [n = 27/59] vs 67% [n = 6/9]; p = 0.242). However, presence of clinical CMV disease requiring hospitalisation was lower in intermediate-risk than in high-risk patients (17% [n = 10/59] vs 57% [n = 6/9]; p = 0.001). Mean highest CMV titre was lower in intermediate-risk than in high-risk patients (372,070 IU/mL vs 1,324,1779 IU/mL; p = 0.002). There was no observed difference in mortality, allograft rejection, or vasculopathy between groups. We identified at least an equivalent risk of CMV viraemia and hospitalisation for intravenous ganciclovir in intermediate-risk and high-risk patients, when the former are managed by pre-emptive therapy.

Acute Rejection Phenotypes in the Current Era of Immunosuppression: A Single-Center Analysis: Erratum

Acute Rejection Phenotypes in the Current Era of Immunosuppression: A Single-Center Analysis: Erratum

Acute Rejection Phenotypes in the Current Era of Immunosuppression: A Single-Center Analysis.

BackgroundBesides ‘definitive rejection’, the Banff classification includes categories for ‘suspicious for rejection’ phenotypes. The aim of this study was to determine the frequency and phenotypes of rejection episodes in 316 consecutive renal transplants from 2009 to 2014 grouped into patients without/with pretransplant HLA-DSA (ptDSAneg, n = 251; ptDSApos, n = 65).MethodsAll adequate indication (n = 125) and surveillance biopsies (n = 538) performed within the first year posttransplant were classified according to the current Banff criteria.Results‘Suspicious for rejection’ phenotypes were 3 times more common than ‘definitive rejection’ phenotypes in biopsies from ptDSAneg patients (35% vs 11%) and equally common in biopsies from ptDSApos patients (25% vs 27%). In both groups, ‘suspicious for rejection’ phenotypes were more frequent in surveillance than in indication biopsies (28% vs 16% in ptDSAneg patients, and 37% vs 29% in ptDSApos patients). ‘Borderline changes: ‘Suspicious' for acute T-cell mediated rejection’ (91%) were the dominant ‘suspicious for rejection’ phenotype in ptDSAneg patients, whereas ‘borderline changes’ (58%) and ‘suspicious for acute/active antibody-mediated rejection’ (42%) were equally frequent in biopsies from ptDSApos patients. Inclusion of ‘suspicious for rejection’ phenotypes increased the 1-year incidence of clinical (ptDSAneg patients: 18% vs 8%, P = 0.0005; ptDSApos patients: 24% vs 18%, P = 0.31) and (sub)clinical rejection (ptDSAneg patients: 59% vs 22%, P < 0.0001; ptDSApos patients: 68% vs 40%, P = 0.004).Conclusions‘Suspicious for rejection’ phenotypes are very common in the current era and outnumber the frequency of ‘definitive rejection’ within the first year posttransplant.

A New HLA Allocation Procedure of Kidneys From Deceased Donors in the Current Era of Immunosuppression

IntroductionIt has recently been proposed to replace the current Eurotransplant kidney allocation based primarily on mismatches (MM) at the 3 HLA loci by a simpler system based on full HLA-DR compatibility. The present study analyzes this system in the current era of immunosuppression. MethodsFrom 1999 to 2012, 723 renal grafts were performed on 586 patients who were treated with a calcineurin inhibitor, mycophenolate mofetil, and in most cases antilymphocyte globulins. Four groups of HLA MM were compared: (A) A+B 2-4/DR 1-2 MM (n = 397), (B) A+B 2-4 MM/DR 0 MM (n = 106), (C) A+B 0-1 MM/DR 1-2 MM (n = 138), and (D) A+B 0-1/DR 0 MM (n = 82). ResultsAcute rejection episodes were less frequent during the first post-transplantation year in group D than in the other groups (P = .018). Patient survival was lower in group A than in the other groups (P = .008). Immunologic graft survival was higher in group D than in the other groups in univariate (P = .015) and multivariate analyses (P = .033; 96.4% vs 90.1% at 10 years). ConclusionsIn the current era of immunosuppression, allocation of kidneys from deceased donors could be performed primarily according to full DR compatibility then to the best A+B matching, affording excellent graft outcome to most recipients.

Patient and graft outcome in current era of immunosuppression: a single centre pilot study

Objectives:The present single centre study aims at analyzing the impact on renal allograft outcome of the important changes which occurred in the transplant population and immunosuppressive therapy during the last two decades.Methods:From 2000 to 2013, 779 single kidney transplantations were performed on 635 patients who all received on an intent-to-treat basis steroids, a calcineurin inhibitor, mycophenolate mofetil and an induction therapy with either antithymocyte globulin or an antagonist directed to the interleukin (IL)-2 receptor. Uni- and multivariate analyses of patient and immunologic graft survival were conducted.Results:The sole factor predicting patient survival is recipient’s age: 10-year survival rates are 94·7, 81·6 and 57·9% for the <45, 45–60 and >60 years age groups, respectively (P<0·001). Peak (>50% panel reactive antibodies) anti-human leucocyte antigens (HLA) sensitization, cold ischaemia time and HLA-B and -DR mismatches (MM) influence graft outcome: at 10 years, the difference in 10-year survival rates is 5·9% between grafts from sensitized and not sensitized patients (90·9 vs 96·8%, P = 0·002), 3·8% between grafts with <18 and ≧18 hours cold ischaemia (96·6 vs 92·8%, P = 0·003), 7·3% between grafts with no MM and either B or DR MM versus those with B and DR MM (96·8 vs 89·5%, P = 0·002).Conclusion:In our single centre experience, graft survival was most strongly determined by HLA matching, offering excellent long term graft outcome to most patients.

Early Changes of Allograft Mass as Evidenced by Cardiac Magnetic Resonance (CMR) Imaging Technique in a Cohort of Post Heart Transplant Patients in the Current Era of Immunosuppression

Early Changes of Allograft Mass as Evidenced by Cardiac Magnetic Resonance (CMR) Imaging Technique in a Cohort of Post Heart Transplant Patients in the Current Era of Immunosuppression

Long-term Outcome of Kidney Retransplantation in Comparison With First Kidney Transplantation: A Report From the Thai Transplantation Registry

IntroductionKidney retransplantation is a high-risk procedure that is increasingly performed because of previous graft failure. The aim of this study was to determine the long-term outcomes of kidney retransplantations compared with first kidney transplantations under the current era of immunosuppression. MethodsSince the first retransplantation in Thailand was performed in 1993, this study included all consecutive cases registered in the Thai Transplantation Registry database from January 1993 to December 2011. A total of 3337 kidney transplantations were available for the analysis. Graft loss was defined as a return to dialysis or graft removal. Death with a functioning graft was censored. ResultsOf 3337 kidney transplantations during the study period, 113 were second and 3 were third transplantations. Among these 116 retransplantations, the most common identified causes of end-stage renal disease were chronic glomerulonephritis (38.8%), followed by hypertensive nephropathy (13.0%), diabetic nephropathy (6.0%), and lupus nephritis (1.7%). The retransplantation recipients were older (mean age, 46.2 ± 12.8 years) than the first transplantation group (mean age, 42.2 ± 12.8 years). The proportion of living-related kidney transplantations and male sex were similar between first and retransplantation recipients. Fourteen percent of retransplantation recipients showed high immunologic risk as defined by current panel reactive antibodies ≥30% compared with 3% of those in the first transplantation group (P < .001). The percentages of induction therapy with antithymocyte globulin and anti–interleukin-2 antibody in the retransplantation and first transplantation groups were 18.3% versus 4.3% and 60.0% versus 32.6%, respectively. The graft survival rates (95% confidence interval [CI]) at 1, 5, and 10 years were 88.6% (80.7–93.3), 87.3% (79.1–92.5), and 74.4% (53.7–86.9) among retransplantation, versus 95.0% (94.1–95.7), 87.0% (85.5–88.5), and 70.7% (67.4–73.8) among first transplantation groups, respectively (P = .63). Patient survival rates were not different between first and retransplantation groups (P = .42). The leading cause of graft loss in the retransplantation group was chronic allograft nephropathy (22%), whereas infection (57%) was the major cause of death in this group. ConclusionThe 10-year patient and graft survival rates of kidney retransplantation were acceptable. The combination of induction therapy with a calcineurin inhibitor and a mycophenolate mofetil/mychophenolic acid–based regimen lead to outcomes comparable to first kidney transplantations among our cohort of 3337 patients.

Mixed Chimerism Approach to Induction of Transplant Tolerance: A Review of the Massachusetts General Hospital Experience

URRENTLY, long-term immunosuppression is required for successful solid organ transplantation in humans. However, immunosuppressive regimens are associated with multiple complications, including infection, malignancies, and renal failure due to drug toxicity. In addition, although short-term allograft survival has increased significantly in the current era of immunosuppression, there has been little improvement in the rate of graft loss after the first posttransplantation year. Approximately 3% to 5% of all kidney transplants are lost in each subsequent year and chronic rejection accounts for almost half of the graft losses. 1 Many in the transplantation field believe that induction of donor-specific tolerance is the only way to control late alloimmune responses and to reduce the morbidity of immunosuppression. It has been shown that individuals with complete hematopoietic chimerism after myeloablative therapy and bone marrow transplantation will later be tolerant to solid organ transplants from the same donor. 2 However, the morbidity and mortality that result from the conditioning regimen is such that this method of tolerance induction is not appropriate for routine solid organ transplantation. Ildstad and Sachs 3 reported in 1984 that mice reconstituted with a mixture of donor and recipient strain bone marrow after ablative treatment developed mixed chimerism, where hematopoietic cells of both donor and recipient origin coexist in the recipient. These animals maintained their mixed chimerism and became tolerant to skin grafts from the donor strain. Later studies by Sharabi and Sachs 4 used nonmyeloablative protocols to achieve the same result. More recently, these studies were extended to large animal models. 5 Renal allograft tolerance through mixed chimerism has been reported in swine 6 and nonhuman primates. 7 In the monkey studies, combined hematopoietic stem cell and kidney transplants from the same donor resulted in mixed chimerism, but only for a few weeks. However, despite the loss of mixed chimerism, long-term tolerance of the kidney allograft was maintained. The low toxicity, lack of graft versus host disease (GvHD), and longterm tolerance that developed in these animals allowed similar protocols to be used in humans. The first trial of inducing renal allograft tolerance using mixed chimerism started in 1998 and involved HLA-matched bone marrow and kidney transplantation for multiple myeloma with renal failure secondary to the myeloma. 8,9 The protocol was easily justifiable for this patient population because patients with multiple myeloma are not candidates for conventional kidney transplants, and patients with end-stage renal disease (ESRD) are not candidates for conventional bone marrow transplantation (BMT). In addition, nonmyeloablative HLA-matched BMT was associated with a potent graft versus tumor effect, so this was the only treatment option available for these patients that could potentially treat their myeloma while restoring renal function. The conditioning regimen was derived from the nonhuman primate studies as well as experience with nonmyeloablative transplants for patients with hematologic malignancies. 10 Total body irradiation used in the animal studies was replaced with cyclophosphamide to provide more cytoreductive capability for the malignancy. Because the patients had renal failure, cyclophosphamide was limited to 2 doses at 60 mg/kg. Patients underwent thymic irradiation (7.0 Gy) on day 1 and antithymocyte globulin (ATG; 15 mg/kg) was given on days 1, 1, 3, and 5. Cyclosporine (CyA) was also started on day 1, with plans to discontinue it at 2 to 3 months posttransplantation. A kidney and bone marrow transplantation was performed from the same HLA- matched sibling donor on day 0. Donor leukocyte transfusions were given posttransplantation in an attempt to convert mixed chimerism to full donor chimerism to enhance the antitumor response without associated GvHD. Six such transplantations have been performed so far and

ANTIBODY INDUCTION IN THE CURRENT ERA

251 Antibody induction therapy in the current era of immunosuppression is controversial. We have studied the use of various antibodies in the early posttransplant period in a prospective fashion. This report compares the use of OKT3, HAT (Zenapax, Hoffman LaRoche), CHI (Basilaximab, Novartis), and non-induced controls in four different studies performed at our institution with the primary end point of the incidence of rejection in the first year posttransplant. Maintenance immunosuppression varied in the different studies using Azathioprine (A), Myco-phenolate (M), Sandimmune (S), Neoral (N) in combination with Prednisone (P). TableThere is a clinically relevant decrease in the incidence of rejection in each group, as well as the overall group, receiving induction therapy. Interestingly, in the humanized monoclonals there were no instances of clinical CMV episodes, resulting in a reduction in the overall incidence. With the availability of a host of new antibody preparations, the use of induction may undergo a renewed interest as the efficacy and safety profiles undergo further study. Research funded in part by OrthoBiotech, Hoffman LaRoche, and Novartis Pharmaceuticals.