Clinical management strategies for recipients with renal graft loss / 器官移植

With the maturity of kidney transplantation, introduction of new immunosuppressive drugs and improvement of immunosuppressive regimen, the short-term survival rate of kidney transplant recipients has been significantly improved, whereas the long-term survival rate has not been significantly elevated. Kidney transplant recipients may have the risk of renal graft loss. Clinical management after renal graft loss is complicated, including the adjustment of immunosuppressive drugs, management of renal graft and selection of subsequent renal replacement therapy. These management procedures directly affect clinical prognosis of patients with renal graft loss. Nevertheless, relevant guidelines or consensuses are still lacking. Clinical management of patients after renal graft loss highly depend upon clinicians’ experience. In this article, the adjustment of immunosuppressive drugs, management of renal graft and selection of subsequent renal replacement therapy were reviewed, aiming to provide reference for prolonging the survival and improving the quality of life of these patients.

Allograft nephrectomy vs. no nephrectomy for failed renal transplants.

The role of allograft nephrectomy (AN) in failed renal transplants is a topic of debate, owing to controversial results reported in the literature and the fact that most of the studies are limited by a retrospective design and small numbers of participants. Allograft nephrectomy is most likely of benefit in the patient with recurrent allograft intolerance syndrome (AIS) following pulse steroids. Immunosuppression weaning in the presence of clinical signs related to a chronic inflammatory state is also reasonable grounds to pursue AN. Studies are mainly inconclusive but suggest that AN has no overall benefit for allograft survival after retransplant. This topic is still of interest in the transplant field and is particularly relevant for patients who are likely to require retransplantation within their lifetime. Further assessment is needed in the form of randomized controlled trials that control for various AN indications and immunosuppression regimens, and have clearly defined survival outcomes.

Management of patients with a failed kidney transplant: what should we do?

The number of kidney transplant recipients returning to dialysis after graft failure is steadily increasing over time. Patients with a failed kidney transplant have been shown to have a significant increase in mortality compared with patients with a functioning graft or patients initiating dialysis for the first time. Moreover, the risk for infectious complications, cardiovascular disease and malignancy is greater than in the dialysis population due to the frequent maintenance of low-dose immunosuppression, which is required to reduce the risk of allosensitization, particularly in patients with the prospect of retransplantation from a living donor. The management of these patients present several controversial opinions and clinical guidelines are lacking. This article aims to review the leading evidence on the main issues in the management of patients with failed transplant, including the ideal timing and modality of dialysis reinitiation, the indications for an allograft nephrectomy or the correct management of immunosuppression during graft failure. In summary, retransplantation is a feasible option that should be considered in patients with graft failure and may help to minimize the morbidity and mortality risk associated with dialysis reinitiation.

Pembrolizumab-induced severe rejection and graft intolerance syndrome resulting in renal allograft nephrectomy.

INTRODUCTION: Pembrolizumab is a selective anti-programmed cell death protein-1 (PD-1) humanized monoclonal antibody that inhibits PD-1 activity by binding to the PD-1 receptor that is found on activated T-cells. The goal of the treatment is to allow the immune system to target and destroy cancer cells by preventing cancer cells from binding to PD-1 receptors, leading to decreased tumor growth. The activation of T-cells by pembrolizumab not only leads to the destruction of malignant cells but also attacks the donor alloantigens that are present in a renal transplant, resulting in graft rejection. CASE REPORT: We present a case of a 46-year-old African American female with history of renal transplant who was treated with pembrolizumab for stage IV B endometrial adenocarcinoma and experienced renal transplant rejection and severe graft intolerance syndrome.Management and outcome: Due to ongoing graft intolerance, a transplant nephrectomy was performed. Allograft pathology was consistent with non-viable kidney with tubulitis, interstitial fibrosis and necrosis consistent with transplant rejection without any evidence of malignancy. DISCUSSION: As emphasized in our case, there is a very high risk of graft rejection in patients who need to be placed on immunomodulators such as pembrolizumab, so the risk versus benefit needs to be assessed and discussed. Our case is unique because pembrolizumab not only caused graft rejection but also severe graft intolerance syndrome which led to transplant nephrectomy. Further guidelines are needed in renal transplant patients requiring PD-1 inhibitors to establish the ideal treatment plan of immunosuppression management and anti-cancer treatments.

Multi-disciplinary team on acute heart failure complicated with respiratory failure after allograft nephrectomy / 器官移植

Objective To evaluate the effect of multi-disciplinary team (MDT) on acute heart failure (AHF) complicated with respiratory failure after allograft nephrectomy. Methods MDT discussion was performed on a patient with hemorrhagic shock caused by sudden renal graft hemorrhage, who developed acute myocardial infarction (AMI) with AHF, acute pulmonary congestion, pulmonary infection and acute respiratory failure 2 weeks after allograft nephrectomy. And treatment plan was formulated and effect evaluation was conducted. Results Based on the opinions of MDT discussion, the patient was given nasal high-flow oxygen therapy, continuous veno-venous hemodiafiltration (CVVHDF) to reduce cardiac load, anticoagulant, dilating blood vessels, reducing myocardial oxygen consumption, improving myocardial remodeling, lipid regulation, anti-infection, nutritional support, and other comprehensive treatment. The clinical outcome of the patient was good and regular hemodialysis treatment was resumed. Conclusions Application of MDT pattern helps to formulate a comprehensive and effective individualized treatment plan for patients with AHF and respiratory failure after allograft nephrectomy, which can enhance clinical treatment effects and improve prognosis of patient.

Dialysis after graft loss: a Swiss experience.

BACKGROUND: Patients returning to dialysis after graft loss have high early morbidity and mortality. METHODS: We used data from the Swiss Transplant Cohort Study to describe the current practice and outcomes in Switzerland. All patients who received a renal allograft between May 2008 and December 2014 were included. The patients with graft loss were divided into two groups depending on whether the graft loss occurred within 1 year after transplantation (early graft loss group) or later (late graft loss group). Patients with primary non-function who never gained graft function were excluded. RESULTS: Seventy-seven out of 1502 patients lost their graft during follow-up, 40 within 1 year after transplantation. Eleven patients died within 30 days after allograft loss. Patient survival was 86, 81 and 74% at 30, 90 and 365 days after graft loss, respectively. About 92% started haemodialysis, 62% with definitive vascular access, which was associated with decreased mortality (hazard ratio = 0.28). At the time of graft loss, most patients were on triple immunosuppressive therapy with significant reduction after nephrectomy. One year after graft loss, 77.5% (31 of 40) of patients in the early and 43.2% (16 out of 37) in the late-loss group had undergone nephrectomy. Three years after graft loss, 36% of the patients with early and 12% with late graft loss received another allograft. CONCLUSION: In summary, our data illustrate high mortality, and a high number of allograft nephrectomies and re-transplantations. Patients commencing haemodialysis with a catheter had significantly higher mortality than patients with definitive access. The role of immunosuppression reduction and allograft nephrectomy as interdependent factors for mortality and re-transplantation needs further evaluation.

The Failing Kidney Transplant Allograft. Transplant Nephrectomy: Current State-of-the-Art.

PURPOSE OF REVIEW: This review provides a critical literature overview of the risks and benefits of transplantectomy in patients with a failed allograft. Additionally, it offers a summary of related problems, primarily alloantibody sensitization in the event of nephrectomy and immunosuppression weaning. RECENT FINDINGS: Transplant nephrectomy has high morbidity and mortality rates. The morbidity of transplant nephrectomy (4.3 to 82%) is mostly due to hemorrhage or infection. Mortality rates range from 1.2 to 39%, and most are due to sepsis. Transvascular graft embolization has been described as a less invasive alternative technique for the management of symptomatic graft rejection, with minimal complications compared with transplantectomy. The number of patients with a failed allograft returning to dialysis is increasing. The role of allograft nephrectomy in the management of asymptomatic transplant failure is still controversial and up today continues to depend on the usual clinical practice of each institution. The less invasive transvascular embolization could have applicability in asymptomatic patients with the obvious lower morbidity and mortality rate.

Indications, risks and impact of failed allograft nephrectomy.

In this review, we describe the indications, surgical aspects, benefits and risks of nephrectomy after graft failure. There is a great variation in the number of allograft nephrectomies performed among different centers. Nephrectomy of a failed allograft is associated with significant morbidity and mortality with a complication rate of 20-30% and mortality rates between 0% and 11%. A systematic review through Medline (Pubmed) and Embase identified thirteen retrospective studies that compared patients with and patients without allograft nephrectomy prior to retransplantation. Allograft nephrectomy associates with an increased risk of HLA antibody development. With two recent studies that used the more sensitive HLA antibody detection methods disproving the hypothesis of intragraft adsorption of HLA antibodies, the mechanism leading to the increased HLA antibody levels is not clear, but the role of immunosuppression withdrawal is becoming clear and needs further investigation. In nine of the thirteen studies that evaluated the impact of allograft nephrectomy on outcome in retransplantation, retransplant graft survival was not significantly different among patients with and patients without allograft nephrectomy. Only three studies showed significantly worse retransplant graft survival if prior allograft nephrectomy was performed. Most studies did not observe a significant difference in patient survival after retransplantation with versus without prior allograft nephrectomy. All studies were affected by the retrospective design, indication bias, and selection bias. On the basis of the available literature on this topic, we did not identify a clear advantage or disadvantage of allograft nephrectomy, in terms of outcome after repeat transplantation. Nevertheless, the significantly increased risk of HLA antibody sensitization, especially in patients at high immunological risk like high donor-recipientHLA epitope mismatch load and HLA-DQB1 mismatches, argues against routine allograft nephrectomy and immunosuppression withdrawal in asymptomatic patients who are eligible for repeat transplantation.

Pathological assessment of allograft nephrectomy: An Iranian experience.

BACKGROUND: The aim of this study was to determine the pathologic causes of renal allograft failure in transplant nephrectomy specimens. MATERIALS AND METHODS: In this cross-sectional study performed in the referral transplant center of Isfahan, Iran, medical files of all patients who underwent nephrectomy in 2008-2013 were studied. Age at transplantation, sex, donor's characteristics, causes of primary renal failure, duration of allograft function, and pathologic reasons of nephrectomy were extracted. Slides of nephrectomy biopsies were evaluated. Data were analyzed using SPSS. RESULTS: Medical files of 39 individuals (male: 56.4%; mean age: 35.1 ± 16.0 years) were evaluated. The main disease of patients was hypertension (17.9%), and most cases (64.1%) were nephrectomized < 6 months posttransplantation. Renal vein thrombosis (RVT) (51.3%) and T-cell-mediated rejection (TCMR) (41.0%) were the most prevalent causes of transplanted nephrectomy. Cause of primary renal failure was correlated to nephrectomy result (P = 0.04). TCMR was the only pathologic finding in all of patients nephrectomized >2 years posttransplantation. There were 14 cases in which biopsy results showed a relationship between primary disease of patients and pathologic assessment of allograft (P = 0.04). A significant relationship between transplantation-nephrectomy interval and both the nephrectomy result and histopathologic result existed (P < 0.0001). A relationship between primary allograft biopsy appearance and further assessment of nephrectomized specimen (P < 0.001) existed as well. CONCLUSION: The most pathologic diagnoses of nephrectomy in a period of less than and more than 6 months posttransplantation were RVT and TCMR, respectively. Early obtained allograft protocol biopsy is suggested, which leads to better diagnosis of allograft failure.

Anti-HLA sensitization after kidney allograft nephrectomy: changes one year post-surgery and beneficial effect of intravenous immunoglobulin.

The analysis of anti-HLA sensitization at the time of and following allograft nephrectomy may help clinicians to define better both the indications for nephrectomy and preventive therapeutic strategies. We carried out a retrospective analysis of anti-HLA antibodies in 63 clinically indicated nephrectomies (baseline and three and 12 months after) according to the time elapsed since transplantation (six months) and clinical background. An intervention study included 10 patients without donor-specific antibodies (DSA) at the time of nephrectomy treated with high-dose intravenous immunoglobulin (IVIG) (1.5 g/kg). Early nephrectomies were performed in 15 patients (24%). Among the late nephrectomies, 14 patients (22%) were asymptomatic and 34 (54%) had graft intolerance syndrome (GIS). At baseline, anti-HLA sensitization was significantly lower in the early and late asymptomatic groups than in the GIS group, but increased considerably within the three months following surgery. In the group of 10 patients treated with IVIG, only the number of class I non-DSA increased in the three months after surgery, whereas in the control group (N = 13), all anti-HLA variables increased significantly. All patients undergoing a clinically indicated allograft nephrectomy become highly sensitized within the 12 months after surgery. In patients without DSA before nephrectomy, high doses of IVIG may prevent anti-HLA sensitization.

Dynamics and epitope specificity of anti-human leukocyte antibodies following renal allograft nephrectomy.

BACKGROUND: A considerable proportion of patients awaiting kidney transplantation is immunized by previous transplantation(s). We investigated how allograft nephrectomy (Nx) and withdrawal of maintenance immunosuppression (WD-MIS) in patients with a failed renal allograft contribute to allosensitization. METHODS: HLA antibodies (HLAabs) were analyzed before and after Nx and/or WD-MIS using a single antigen bead assay. Patients were grouped as follows: (A) Nx and concomitant WD-MIS (n = 28), (B) Nx (n = 14) and (C) WD-MIS (n = 12). In a subgroup of patients, the epitope specificity of HLAabs was determined by adsorption and elution of sera with recombinant single HLA allele-expressing cell lines. RESULTS: Following Nx and/or WD-MIS, HLAabs were detectable in 100, 100 and 92% of patients in Groups A, B and C, respectively. In patients of all groups, de novo donor-specific HLAabs (DSAs) were found. After Nx, an increase in the breadth [percent panel reactive antibody (%PRA)] and mean fluorescence intensity of class I HLAabs was predominant. In contrast, an increase of class II HLAabs prevailed following WD-MIS. Experimental analysis of the epitope specificities revealed that 64% of the class I HLAabs classically denoted as non-DSA were donor epitope-specific HLAabs (DESA). CONCLUSIONS: Both Nx and WD-MIS contribute to alloimmunization with differing patterns concerning class I and II HLAabs. Nx preferentially increased class I HLAabs and most of the observed class I HLAabs were DESA. Considering that class I, but not class II, HLA molecules are constitutively expressed, our results support the hypothesis that the increase of HLAabs following Nx might have been caused by removal of the adsorbing donor tissue (sponge hypothesis).

De novo papillary carcinoma in a renal allograft: the pros and cons of immunosuppression.

We present a case of a multifocal kidney transplant renal cell carcinoma in a 35-year-old lady, presenting 16 years after kidney transplantation, diagnosed during investigation of recurrent urinary tract infections. The patient underwent a graft nephrectomy and subsequently maintained on haemodialysis. She remained disease-free after 4 years of surveillance and thus reactivated on the transplant list. This case reinforces the fact that immunosuppressive therapy has made kidney transplantation possible; however, it is accompanied by a higher incidence of malignancy. It also reinforces the importance of lifelong screening of both native and renal transplant grafts.

Management of patients with a failed kidney transplant: Dialysis reinitiation, immunosuppression weaning, and transplantectomy.

The number of patients reinitiating dialysis after a failed transplant increases over time and has more than doubled between the year 1988 and 2010 (an increase from 2463 to 5588). More importantly, patients returning to dialysis have been shown to have a greater than three-fold increase in the annual adjusted mortality rates compared with those with a functioning graft. Continuation of immunosuppression to preserve residual graft function has been implicated to be a contributing factor, seemingly due to immunosuppression-associated cardiovascular and infectious complications and malignancy risk, among others. Nonetheless, maintenance low-dose immunosuppression has been suggested to confer survival benefit in patients returning to peritoneal dialysis. Whether early vs late reinitiation of dialysis or whether transplantectomy has an impact on patient survival remains poorly defined. Consensus guidelines for the management of a failed allograft are lacking. In this article, we present a literature overview on the ideal timing of dialysis reinitiation after graft loss, the management of immunosuppression after graft failure, and the risks and benefits of transplantectomy. The authors' perspectives on the management of this special patient population are also discussed.

Humoral Immune Response and Allograft Function in Kidney Transplantation.

HLA antibodies can damage a kidney transplant. In January 2013, consensus guidelines from The Transplantation Society were published regarding technical aspects of HLA antibody determination, as well as their potential significance in the pre- and posttransplantation periods. During the past 2 years, new studies have been reported, but controversies remain. In this article, these new data related to HLA antibodies in kidney transplantation are reviewed and compared to relevant prior research. Pretransplantation sensitization issues are discussed, including the new more sensitive assays (flow cytometry and solid-phase immunoassays such as Luminex single-antigen bead assays). A positive complement-dependent cytotoxicity crossmatch remains an absolute contraindication to transplantation, although a positive flow cytometry crossmatch is only a relative contraindication. Positivity only by solid-phase assays increases the risk for acute rejection and transplant loss, but acceptable cutoffs are not defined. The sensitizing effect of red blood cell transfusions is substantiated. Following allograft failure, continued immunosuppression decreases the risk of sensitization, whereas overall, the effect of nephrectomy remains uncertain. Regarding the posttransplantation period, new data are available concerning the timing and significance of donor-specific antibodies (DSA). Whereas some centers report DSA appearance after years, others detect DSA within months. The prominence of class II DSA, especially DQ, in the posttransplantation period is noted. The relevance of non-HLA antibodies is discussed, including anti-endothelial cell antibodies, major histocompatibility complex class I chain-related protein A antibodies, and angiotensin II type 1 receptor autoantibodies.

Kidney retransplantation for BK virus nephropathy with active viremia without allograft nephrectomy.

BK virus nephropathy is an important cause of kidney allograft failure. Retransplantation has been successfully performed for patients with previous allograft loss due to BK virus nephropathy; however, whether allograft nephrectomy and viral clearance are required prior to retransplantation is controversial. Some recent studies have suggested that retransplantion can be successfully achieved without allograft nephrectomy if viremia is cleared prior to retransplant. The only published experience of successful retransplantation in the presence of active viremia occurred in the presence of concomitant allograft nephrectomy of the failing kidney. In this report, we describe a case of successful repeat kidney transplant in a patient with high-grade BK viremia and fulminant hepatic failure without concomitant allograft nephrectomy performed under the setting of a simultaneous liver-kidney transplant.

Extensive emphysematous pyelonephritis in a renal allograft: case report and review of literature.

Emphysematous pyelonephritis (EPN) is an acute, severe necrotizing infection of the renal parenchyma and perirenal tissue, which results in the presence of gas within the renal parenchyma, collecting system, or perinephric tissue. EPN of renal allograft is rare, with only 23 cases reported in Western literature. Here, we report a patient treated successfully with surgery. We also review the literature, focusing on old and new suggested classification systems for EPN.

Renal retransplantation after kidney and pancreas transplantation using the renal vessels of the failed allograft: pitfalls and pearls.

Renal retransplantation after a failed prior kidney and pancreas transplant is being increasingly performed. In these complex cases, both iliac fossae have been used for prior transplants, and the placement of the new allograft can be problematic. We describe our experience with an alternative technique for renal retransplantation (RRTx) in the setting of severe bilateral aortoiliac atherosclerosis or scarring and fibrosis on the iliac vessels. Nephrectomy of the failed allograft is performed, and the renal vessels of the failed allograft (RVFA) are preserved. The new kidney is implanted on RVFA at the same operative time. This technique was attempted and successfully accomplished in a total of six patients (mean operative time = 240 ± 63 min). One postoperative complication occurred: poor arterial inflow to the allograft, being corrected reoperatively. Hospitalizations ranged from five to eight d. Five of the six patients were alive with a functioning allograft at last follow-up (a single graft failure occurred 21 months postoperatively in the setting of post-transplant lymphoproliferative disease that also led to patient death). Renal vessels of the failed allograft seem to be suitable alternative vascular conduits for renal retransplantation after prior kidney and pancreas transplants.

A Retrospective Analysis on Reasons for Allograft Nephrectomy after Kidney Transplantation / 대한이식학회지

PURPOSE: Allograft nephrectomy has been done in considerable proportion due to many reasons after kidney transplantation. This study was undertaken to determine the incidence, causes, and time of allograft nephrectomy after kidney transplantation. METHODS: A total 141 kidney transplantations were performed between 1993 and 2003 Kyung Hee University Hospital. We found 22 cases of allograft nephrectomy in the same period and a retrospective analysis was conducted on 22 allograft nephrectomy. The patients records were reviewed for age, causes, and time of allograft nephrectomy after kidney transplantation. RESULTS: The pathological causes of allograft nephrectomy were chronic rejection in 18 cases (81.8%), acute rejection in 3 cases (13.6%), accelerated rejection in 2 cases (9.1%) and allograft infection, renal vessel thrombosis, cyclosporin toxicity, GVHD in each one case (4.5%). Of 18 cases with chronic rejection, acute rejection episode was occurred in 12 cases (66.7%). The interval from kidney transplantation to allograft nephrectomy was more than 5 years in most patients (63.6%). CONCLUSION: In our studies, allograft nephrectomy was performed in 22 cases, chronic rejection was major cause of allograft nephrectomy, and acute rejection episide was occurred in most chronic rejection. We suggested that early detection and aggressive treatment of acute rejection might be considered to lower the incidence of allograft nephrectomy after kidney transplantation.