Recent Advances In Immunosuppression Research Articles

Donor specific antibody surveillance among pediatric kidney transplant programs: A report from the improving renal outcome collaborative.

Kidney transplantation (KT) is the preferred treatment for children with end-stage kidney disease. Recent advances in immunosuppression and advances in donor specific antibody (DSA) testing have resulted in prolonged allograft survival; however, standardized approaches for surveillance DSA monitoring and management of de novo (dn) DSA are widely variable among pediatric KT programs. Pediatric transplant nephrologists in the multi-center Improving Renal Outcomes Collaborative (IROC) participated in a voluntary, web-based survey between 2019 and 2020. Centers provided information pertaining to frequency and timing of routine DSA surveillance and theoretical management of dnDSA development in the setting of stable graft function. 29/30 IROC centers responded to the survey. Among the participating centers, screening for DSA occurs, on average, every 3 months for the first 12months post-transplant. Antibody mean fluorescent intensity and trend most frequently directed changes in patient management. Increased creatinine above baseline was reported by all centers as an indication for DSA assessment outside of routine surveillance testing. 24/29 centers would continue to monitor DSA and/or intensify immunosuppression after detection of antibodies in the setting of stable graft function. In addition to enhanced monitoring, 10/29 centers reported performing an allograft biopsy upon detection of dnDSA, even in the setting of stable graft function. This descriptive report is the largest reported survey of pediatric transplant nephrologist practice patterns on this topic and provides a reference for monitoring dnDSA in the pediatric kidney transplant population.

Chronic kidney disease progression in kidney transplant recipients: A focus on traditional risk factors.

Kidney transplant recipients are a subset of patients with chronic kidney disease (CKD) that remain at high risk for progression to dialysis and mortality. Recent advances in immunosuppression have only partially improved long-term graft and patient survival. Discovery of new immunosuppressive regimens is a slow and resource-intensive process. Hence, recognition and management of modifiable allogeneic and non-allogeneic risk factors for progression to CKD among kidney transplant recipients is of major interest for improving long-term outcomes. Graft survival is mainly determined by the quality of the allograft and by the patient's alloimmune response, which is influenced by human leukocyte antigen matching and the presence of donor-specific antibodies. Alloimmune responses manifest as acute and chronic forms of cell- and antibody-mediated rejection, which can be worsened by patient non-adherence or under-immunosuppression. However, donor and patient ages, glomerular disease recurrence, time on dialysis, pre-existing cardiovascular burden, medication side-effects and traditional risk factors, such as hypertension, proteinuria, anaemia, dyslipidaemia, diabetes and bone mineral disorder, which can ultimately lead to severe endothelial derangement, also contribute to graft loss and mortality. These traditional risk factors, common to pre-dialysis patients, often are considered of secondary importance when compared to alloimmunity and immunosuppression concerns. In this review article, we focus on the epidemiological, pathophysiological and therapeutic features of non-allogeneic traditional risk factors for CKD. We also discuss the benefit of adopting a multidisciplinary approach to pursue the same therapeutic targets recommended for pre-dialysis patients.

Total Recall: Can We Reshape T Cell Memory by Lymphoablation?

Despite recent advances in immunosuppression, donor-reactive memory T cells remain a serious threat to successful organ transplantation. To alleviate damaging effects of preexisting immunologic memory, lymphoablative induction therapies are used as part of standard care in sensitized recipients. However, accumulating evidence suggests that memory T cells have advantages over their naive counterparts in surviving depletion and expanding under lymphopenic conditions. This may at least partially explain the inability of existing lymphoablative strategies to improve long-term allograft outcome in sensitized recipients, despite the well-documented decrease in the frequency of early acute rejection episodes. This minireview summarizes the insights gained from both experimental and clinical transplantation as to the effects of existing lymphoablative strategies on memory T cells and discusses the latest research developments aimed at improving the efficacy and safety of lymphoablation.

Recent advances in immunosuppression and acquired immune tolerance in renal transplants.

the primary challenge in organ transplantation continues to be the need to suppress the host immune system long term to ensure prolonged allograft survival ([21][1]). In organ transplantation, immunosuppressive agents inhibit one or more steps of the alloimmune response that would otherwise

Recent advances in immunosuppression for kidney transplantation

Objective To perform a systematic review on the recent advances in immunosuppression for kidney transplantation and how these recent strategies over the past decades have led to significant improvements in the field of renal transplantation. Data sources MEDLINE, EMBASE, and Cochrane databases were searched. The search was performed on 1 November 2013 and included articles published ahead of print, with no language restrictions. Study selection The initial search presented 500 articles, of which 20 fulfilled the inclusion criteria. The articles studied whether transplantation is the ideal treatment for kidney failure, presenting details on graft immunology and the mechanism of action of immunosuppressants, with a focus on novel mechanisms. Data synthesis Because of heterogeneity in the postoperative follow-up periods and outcome measures reported, it was not possible to pool the data and carry out a meta-analysis. Comparisons were performed by a structured review. Conclusion Excellent outcomes have been achieved in the field of renal transplantation. A significant reduction in acute rejection has been achieved at many renal transplant centers using currently available immunosuppressives, consisting of an induction agent, a calcineurin inhibitor, and an antiproliferative agent with or without a corticosteroid. Despite improvements with these regimens, chronic allograft injury and adverse events still persist. The perfect immunosuppressive regimen would limit or eliminate calcineurin inhibitors and/or corticosteroid toxicity while resulting in enhanced allograft outcomes. The aim of this review is to consolidate the published evidence of the effectiveness and safety of investigational immunosuppressive agents in renal transplant recipients.

Current Issues in ABO-Incompatible Kidney Transplantation

Organ shortage is a critical issue in Korea as well as in other countries. In Korea, in 2013, the number of end-stage renal disease patients on the waiting list was 14,600; however, only 1,759 patients received transplantation during 2013. Recent advances in immunosuppression and antibody removal protocols have made ABO-incompatible kidney transplantation (ABO IKT) feasible, and have increased the opportunities for patients to undergo transplantation, especially for patients who do not have an ABO-compatible donor. The first ABO IKT was reported in 1955, but was unsuccessful due to the absence of an effective preparation protocol for antibody removal. In the 1980s, Alexandre used a protocol for removal of anti-ABO antibodies for the first time; however, the outcome was still inferior to that of ABO-compatible KT. Since 2000, with the advancement of immunosuppression and plasmapheresis, the outcome of ABO IKT has shown significant improvement and is now comparable to that of ABO-compatible KT. However, there are still several undetermined issues in ABO IKT. For example, issues regarding anti-ABO antibody titer, pretransplant desensitization method, immune suppressant regimen, and the role of C4d have still not been established. In this article, we reviewed the current status and protocol of ABO IKT and addressed to the undetermined issues in this field.

Outcomes in kidney transplantation

It is estimated that there are greater than 100,000 kidney transplant recipients with a functioning graft in the United States. Recent advances in immunosuppression have improved short-term graft survival rates and decreased early mortality by decreasing the incidence and therapy for acute rejection episodes. For those accepted on the waiting list, transplant prolongs patient survival compared with remaining on dialysis. During the 1990s, 3 new immunosuppressive drugs were introduced in clinical kidney transplantation. All were approved for use by the Food and Drug Administration after large, controlled, randomized trials. Mycophenolate mofetil (MMF), when combined with cyclosporine (CSA) and prednisone, lowered acute rejection rates by nearly 50% compared with control. Tacrolimus compared with CSA also significantly reduced acute rejection rates in kidney transplant recipients, but was associated with a significant increase in posttransplant diabetes mellitus (PTDM) in the early trials. When evaluated in combination with MMF, the incidence of PTDM was much lower. At the end of the decade, sirolimus was shown in several randomized trials to lower acute rejection rates and is believed to be less nephrotoxic compared with calcineurin inhibitors. All of the randomized trials were not statistically powered to assess long-term superiority. Registry analyses have been performed that appear to show some long-term benefit of immunosuppressive therapy with MMF. Other outcome assessments in kidney transplant recipients include risk factors for chronic allograft nephropathy, hypertension, hyperlipidemia, and bone disease. Although there are few randomized trials, understanding of the significance of these common complications has progressed and strategies for therapy and intervention have been developed. This article focuses on the randomized trials of immunosuppressive therapy and complications associated with use of these drugs. In addition, we review the current management and intervention for the comorbidities associated with the long-term clinical management of the kidney transplant recipient.

Reversal of steroid- and anti-lymphocyte antibody-resistant rejection using intravenous immunoglobulin (IVIG) in renal transplant recipients.

Despite the recent advances in immunosuppression, steroid-resistant rejection remains a difficult problem in renal transplant recipients. We reviewed our experience with i.v. immunoglobulin (IVIG) in the treatment of steroid- and antilymphocyte antibody-resistant rejection in renal transplant patients. Between September 1996 and March 1999, 17 patients were treated with IVIG to reverse steroid- or antilymphocyte antibody-resistant rejection. A total of 2 g/kg of IVIG was administered to patients during each treatment course. With a mean follow-up of 21.5+/-9.5 months from the time of IVIG administration, patient and graft survival rates were 94% (16/17) and 71% (12/17), respectively. The baseline mean serum creatinine level prior to rejection was 2.2+/-0.7 mg/dl and peaked at 3.3+/-1.1 mg/dl at the time of the diagnosis of refractory rejection. IVIG therapy was associated with a fall in the mean creatinine to 2.8+/-1.1 mg/dl. The most recent serum creatinine in patients with functioning grafts was 2.8+/-1.6 mg/dl. In 82% of allograft biopsies after IVIG, reversal or reduction in the severity of rejection was demonstrated. In addition, IVIG therapy rescued three of four patients with antilymphocyte antibody-resistant rejection. IVIG rescue therapy for steroid- or antilymphocyte antibody-resistant rejection is associated with resolution or improvement of rejection severity, stable renal function, and reasonable graft survival.

Recent advances in immunosuppressive therapy for renal transplantation.

Recent advances in immunosuppression have focused on more effective, safer, and targeted therapies that have resulted in improved short- and intermediate-term renal allograft survival. During the past decade there has been a marked decrease in acute rejection rates following renal transplantation because of the use of newer immunosuppressive agents. Recent data indicate that the average yearly reduction in the relative hazard of graft failure beyond 1 year was 4.2% for all recipients (0.4% for those recipients who had an acute rejection episode and 6.3% for those who did not have an acute rejection). Despite these improvements the currently available immunosuppressive agents are associated with significant cardiovascular risk factors, an increased risk of infection, and the development of malignancies in the long term. Predictive parameters of donor-specific hyporesponsiveness are needed so as to allow identification of patients in whom immunosuppressive therapy can be safely reduced. Immunosuppressive agents that have recently been approved for use in the United States and those that are in clinical and preclinical studies are discussed.

Elevated blood pressure predicts the risk of acute rejection in renal allograft recipients

Acute rejection (AR) is a strong predictor of renal allograft survival. Recent advances in immunosuppression have reduced considerably the incidence of AR. Still, approximately 25% of patients have AR early post-transplant, and the factors that predispose to AR have not been fully clarified. The study includes 1641 adults, recipients of first cadaveric (CAD, N = 1195) or living related renal grafts (LRD, N = 446), transplanted in one institution. The variables associated with the occurrence of AR during the first year post-transplant were identified. By univariate analyses, AR was associated with the following variables: younger (P < 0.001); heavier (P = 0.003); and African American recipients (P = 0.002); CAD transplants (P = 0.001); higher number of HLA mismatches (P = 0.001); delayed graft function (DGF, P = 0.001); higher levels of serum creatinine post-transplant (P = 0.003); and higher levels of systolic and/or diastolic blood pressure (BP) post-transplant (P < 0.001). Higher BP levels were also associated with earlier AR episodes (P < 0.0001). By multivariable analysis AR was significantly associated with recipient age, number of HLA mismatches, DGF, pre-PRA and systolic BP. Analysis of BP measured weekly post-transplant indicated that elevated BP levels, even three weeks prior to the AR episode, were significantly associated with AR. For every level of BP, the use of BP medications was associated with a lower incidence of AR (P < 0.0001). Furthermore, the use of calcium channel blockers was also associated with lower incidence of AR (P = 0.001). Of note, 81% of recipients whose BP increased after the transplant had AR. In contrast, 22% of patients whose BP declined post-transplant had AR. Elevated BP levels post-transplant identify patients at high risk of AR independently of graft function. Treatment of BP and reduction of BP levels appears to be associated with a decreased risk of AR. We hypothesize that high BP may be an indicator of a particular type of allograft damage, perhaps ischemic, that may predispose to AR.

Biliary atresia and biliary cysts

The authors present a review of the classification, aetiology, presentation, treatment and long-term outcome of children and adults with biliary atresia and choledochal cyst disease. Biliary atresia should be suspected in any infant with jaundice beyond the second week of life. Although the aetiology and pathogenesis remain unclear, early management with portoenterostomy has significantly improved the course of this disease. Recent advances in immunosuppression have made liver transplantation a valuable and necessary adjunct to biliary bypass. With choledochal cyst disease, adults, unlike children, often present with acute biliary tract symptoms or pancreatitis. The treatment of choice remains extrahepatic cyst excision and biliary bypass. This treatment has excellent long-term results that minimize the development of malignancy.

Recent advances in immunosuppression

T THE PRESENT time, cyclosporin A (CsA) and FK506 (tacrolimus; Prograf, Fujisawa USA, Deerfield, IL) are both used as immunosuppressive agents in the transplant setting. The introduction of CsA to the clinical arena in the late 1970s heralded an increased success not only in solid organ transplantation, but also in bone marrow transplantation. However, chronic administration of CsA is not without potential and at times serious side effects including hypertension, neurologic toxicity, and nephrotoxicity. Isolated in 1984, FK506 is 10- to 100-fold more potent than CsA in inhibiting T cell function in vitro. However, its use is still accompanied by serious side effects including decreased renal function, glucose intolerance, and infectious and neurologic complications. Thus, efforts to develop new agents with less toxicity, but equal or improved immunosuppressive efficacy are ongoing. Rapamycin is a novel immunosuppressant whose use in clinical transplantation is beginning to be explored. Although structurally similar to FK506, rapamycin has a distinct mechanism of action. This article focuses on the mechanisms by which these drugs exert their biological effects. An understanding of the mechanisms involved in immunosuppression is helpful'in anticipating the clinical course of patients maintained on these

The Cardiopulmonary Response to OKT3 in Orthotopic Cardiac Transplant Recipients

Improvement in the outcome from cardiac transplantation can be attributed to recent advances in immunosuppression, including the use of OKT3, a new monoclonal antibody. The first dose of OKT3 induces side effects such as dyspnea in other transplant populations. We studied cardiopulmonary responses to OKT3 in 23 recipients of cardiac transplants. Despite pretreatment including antihistamines, hydrocortisone, and acetaminophen, OKT3 administered within 72 hours of transplantation, as part of prophylactic immunosuppression, induced a biphasic systemic response. Within the first hour, patients developed fever, hyperdynamia, hypertension, and tachycardia. By five to seven hours after the dose, there was mild hypotension, hypoxemia, and decreased indices of vascular resistance. Eighteen of the 23 patients required supplemental oxygen or vasopressor support (or both). Our findings define a complex cardiovascular response to OKT3 exhibited by the delayed noncoincident onset of hemodynamic instability, hypoxemia, and fever. Close observation in an ICU is recommended during the initial administration of OKT3 for prompt intervention when reactions occur.

Surgical treatment of the short bowel syndrome

Long-term survival after massive intestinal resection is now possible with parenteral nutritional support. The expense, morbidity, and inconvenience of this therapy, however, has led to continued interest in alternatives for the treatment of the short bowel syndrome. The goals of surgical therapy in the short bowel syndrome are to increase the area of absorption, slow intestinal transit, and reduce gastric hyperacidity. Selected patients with dilated bowel segments benefit from intestinal tapering or lengthening. Growing neomucosa to increase surface area is not yet clinically efficacious. The results of transplantation remain unsatisfactory despite recent advances in immunosuppression. Antiperistaltic segments, colon interposition, and intestinal valves may benefit patients with sufficient absorptive area but rapid intestinal transit. Recirculating loops are associated with prohibitive morbidity and mortality. Intestinal pacing is currently being investigated. Surgical treatment of the short bowel syndrome is not sufficiently safe and effective to recommend its routine use. Operations should be performed only on selected patients to achieve specific goals. Adjunct procedures should not be carried out at the initial intestinal resection. Most important is continued emphasis on the prevention of intestinal resection and conservation of the intestine when massive resection is necessary.

Surgical alternatives for the short bowel syndrome.

Since the introduction of total parenteral nutrition an increasing number of patients are surviving massive intestinal resection. However, the expense, morbidity, and inconvenience of this therapy have created interest in surgical alternatives for the treatment of the short bowel syndrome. The goals of surgical therapy in the short bowel syndrome are to slow intestinal transit, increase the area of absorption, and reduce gastric hyperacidity. Antiperistaltic segments or colon interposition benefit patients with sufficient absorptive area, but rapid intestinal transit. Intestinal valves yield inconsistent results. Recirculating loops are associated with prohibitive morbidity and mortality. Experience with intestinal pacing is limited. Patients with dilated bowel segments may benefit from intestinal tapering or lengthening. Growing neomucosa holds promise but has not been evaluated clinically. Despite recent advances in immunosuppression the results of transplantation remain unsatisfactory. Gastric hyperacidity can be effectively controlled by H2 receptor antagonists. None of the operations for treatment of the short bowel syndrome is sufficiently safe and effective to recommend their routine use. Operations should be performed only on selected patients to achieve specific goals. Although investigation continues, our emphasis should continue to be prevention of intestinal resection and conservation of as much of the intestine as possible when massive resection is necessary.