Can We Predict Graft Intolerance Syndrome After Kidney Transplant Failure? External Validation of a Previously Developed Model.

Previously we established a prediction model for graft intolerance syndrome requiring graft nephrectomy in patients with late kidney graft failure. The aim of this study is to determine generalizability of this model in an independent cohort. The validation cohort included patients with late kidney graft failure between 2008 and 2018. Primary outcome is the prognostic performance of our model, expressed as the area under the receiver operating characteristic curve (ROC-AUC), in the validation cohort. In 63 of 580 patients (10.9%) a graft nephrectomy was performed because of graft intolerance. The original model, which included donor age, graft survival and number of acute rejections, performed poorly in the validation cohort (ROC-AUC 0.61). After retraining of the model using recipient age at graft failure instead of donor age, the model had an average ROC-AUC of 0.70 in the original cohort and of 0.69 in the validation cohort. Our original model did not accurately predict the graft intolerance syndrome in a validation cohort. However, a retrained model including recipient age at graft failure instead of donor age performed moderately well in both the development and validation cohort enabling identification of patients with the highest and lowest risk of graft intolerance syndrome.

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.

Renal artery embolization of non-functioning graft: an effective treatment for graft intolerance syndrome.

BACKGROUND: Percutaneous renal artery embolization is a valid non-invasive technique alternative to nephrectomy for patients with symptomatic non-functioning allograft (graft intolerance syndrome-GIS). The purpose of this article is to report the experience of our centre. METHODS: We analysed retrospectively 15 patients with symptomatic non-functioning renal allograft treated with percutaneous embolization from 2003 to 2017. Occlusion was obtained with the injection of calibrated microspheres of increasing size (from 100 to 900 µm) and completed with 5 to 8 mm metal coils placement in the renal artery. RESULTS: Technical success was achieved in all cases at the end of the procedure. Clinical success was obtained in 11 patients (73%). In four cases, nephrectomy was necessary: in one case because of septic fever and in three cases because of GIS persistence. In one case, it was possible to perform another procedure to embolize a perirenal collateral from a lumbar artery. Four patients (27%) reported minor complications which spontaneously resolved during the hospital stay. CONCLUSIONS: According to the scientific literature, we believe that, in selected patients, percutaneous renal artery embolization is a valid treatment option for GIS thanks to its efficacy, repeatability, minimal invasiveness and the absence of severe complications.

Graft intolerance syndrome requiring graft nephrectomy after late kidney graft failure: can it be predicted? A retrospective cohort study.

Graft nephrectomy is recommended in case of early graft failure. When the graft fails more than 3-6 months after transplantation, it is current practice to follow a wait-and-see policy. A common indication for graft removal is the graft intolerance syndrome. We aimed to create a risk prediction model for the occurrence of graft intolerance resulting in graft nephrectomy. We collected data of kidney transplantations performed in our center between 1980 and 2010 that failed at least 6 months after transplantation. We evaluated the association between baseline characteristics and the occurrence of graft nephrectomy because of graft intolerance using a competing risk regression model. Prognostic factors were included in a multivariate prediction model. In- and exclusion criteria were met in 288 cases. In 48 patients, the graft was removed because of graft intolerance. Donor age, the number of rejections, and shorter graft survival were predictive factors for graft nephrectomy because of the graft intolerance syndrome. These factors were included in a prediction rule. Using donor age, graft survival, and the number of rejections, clinicians can predict the need for graft nephrectomy with a reasonable accuracy.

Sensitization trends after renal allograft failure: the role of DQ eplet mismatches in becoming highly sensitized.

Sensitization following renal allograft failure (AF) is highly variable. Some patients remain non-sensitized (NS), while others become highly sensitized (HS). We studied 66 NS patients who experienced AF after initial kidney transplantation. Post-failure, two main groups of NS panel reactive antibody (PRA) class I and II <10% and HS patients (PRA class I or II ≥80%) were identified. The impact of acute rejection (AR), immunosuppression withdrawal (ISW) at AF, allograft nephrectomy, graft intolerance syndrome (GIS), and both standard serologic and eplet-based mismatches (MM) in inducing HS status after failure was examined. Late PRA testing post-failure revealed 18 patients remained NS and 34 patients became HS. African American recipients, ISW at AF, DQB1 eplet MM, and presence of GIS were associated with becoming HS. Presence of total zero eplet MM, zero DQA1/B1 eplet MM, continuation of immunosuppression after failure, and a hyporesponsive immune status characterized by recurrent infections were features of NS patients. DQ eplet MM represents a significant risk for becoming HS after AF. Studies comparing ISW vs. continuation in re-transplant candidates with high baseline DQ eplet MM burden should be performed. This may provide insights if sensitization post-AF can be lessened.

Sensitization, pathologic, and imaging findings comparing symptomatic and quiescent failed renal allografts.

Late allograft failure (LAF) is a common cause of end stage renal disease. These patients face interrelated challenges regarding immunosuppression management, risk of graft intolerance syndrome (GIS), and sensitization. This retrospective study analyzes sensitization, pathology, imaging, and transfusion requirements in 33 LAFs presenting either with GIS (22) or grafts remaining quiescent (11). All patients underwent immunosuppression weaning to discontinuation at LAF. Profound increases in sensitization were noted for all groups and occurred in the GIS group prior to transplant nephrectomy (TxN). Patients with GIS experienced a major upswing in sensitization at, or before the time of their symptomatic presentation. For both GIS and quiescent grafts, sensitization appeared to be closely linked to immunosuppression withdrawal. Most transfusion naïve patients became highly sensitized. Fourteen patients in the GIS group underwent TxN which revealed grade II acute cellular rejection or worse, with grade 3 chronic active T-cell-mediated rejection. Blinded comparisons of computed tomography scan of GIS group revealed swollen allografts with fluid collections compared with the quiescent allografts (QAs), which were shrunken and atrophic. The renal volume on imaging and weight of explants nearly matched. Future studies should focus on interventions to avoid sensitization and GIS.

Challenges in the Management of the Patient with a Failing Kidney Graft: A Narrative Review.

Patients with a failed kidney allograft have steadily increase in recent years and returning to dialysis after graft loss is one of the most difficult transitions for chronic kidney disease patients and their assistant physicians. The management of these patients is complex and encompasses the treatment of chronic kidney disease complications, dialysis restart and access planning, immunosuppression withdrawal, graft nephrectomy, and evaluation for a potential retransplant. In recent years, several groups have focused on the management of the patient with a failing renal graft and expert recommendations are arising. A review of Pubmed, ScienceDirect and the Cochrane Library was performed focusing on the specific care of these patients, from the management of low clearance complications to concerns with a subsequent kidney transplant. Conclusion: There is a growing interest in the failing renal graft and new approaches to improve these patients' outcomes are being defined including specific multidisciplinary programs, individualized immunosuppression withdrawal schemes, and strategies to prevent HLA sensitization and increase retransplant rates.

Embolization of the renal artery before graft nephrectomy: a comparing study to evaluate the possible benefits.

The graft nephrectomy is burdened by immunological and surgical complications. The main surgical complications of graft nephrectomy are hemorrhage, infections, vascular injury and death. The mortality is high, with percentages varying between 1.3 and 38%. Therefore, graft nephrectomy should be recommended only in selected cases. We conducted a retrospective study, comparing the data of 26 patients undergoing an allograft nephrectomy (2009-2013), without embolization of the renal artery (NO EMBO group) with the data of 40 patients undergoing an allograft nephrectomy (2014-2019), with embolization of the renal artery (EMBO group). We included only graft nephrectomies performed at least 6 months after transplantation. The patients included in the study were consecutive because until 2013 we did not perform the embolization of the renal graft artery. Afterwards, from 2014, instead, we routinely carry out embolization to all patients to be subjected to graft nephrectomy. We, therefore, wanted to analyze whether this surgical approach compared to the previous technique can lead to an improvement in morbidity and mortality, reducing the risk of bleeding and operating times. The examination of our data highlights that embolization of renal artery reduces the operating times of the explant, in addition the group subjected to embolization had less changes in hemoglobinemia and less blood loss.

[A rare presentation of kidney allograft intolerance syndrome: Bullous pemphigoid]. / Une présentation rare du syndrome d'intolérance au greffon renal : la pemphigoïde bulleuse.

Bullous pemphigoid is an autoimmune bullous cutaneous disease. We report the case of a 60 year-old male patient whose kidney allograft failed and was on hemodialysis for the previous 16 months. After tapering immunosuppressive medication, he presented simultaneous bullous eruption and kidney allograft intolerance syndrome. Investigation showed a positive BP180 anti-basement membrane zone antibody and skin biopsy was consistent with bullous pemphigoid. The patient was treated with corticotherapy and bullous pemphigoid resolved. The development of new onset diabetes and concerns over long term immunosuppression, halted the decision to continue corticotherapy and the patient underwent graft nephrectomy, with resolution of the kidney allograft intolerance syndrome without recurrence of the bullous disease. The occurrence of bullous pemphigoid in patients with failed renal allograft is rare, with only eleven cases reported in literature. This case illustrates how graft nephrectomy can provide a definitive cure to bullous pemphigoid in this setting.

Impact of dialysis modality on morbimortality of kidney transplant recipients after allograft failure. Analysis in the presence of competing events. / Impacto de la modalidad de diálisis sobre la morbimortalidad tras el fracaso del injerto renal: análisis con eventos competitivos.

BACKGROUND AND OBJECTIVE: The number of patients who start dialysis due to graft failure increases every day. The best dialysis modality for this type of patient is not well defined and most patients are referred to HD. The objective of our study is to evaluate the impact of the dialysis modality on morbidity and mortality in transplant patients who start dialysis after graft failure. MATERIAL AND METHODS: A multicentre retrospective observation and cohort study was performed to compare the evolution of patients who started dialysis after graft failure from January 2000 to December 2013. One group started on PD and the other on HD. The patients were followed until the change of dialysis technique, retransplantation or death. Anthropometric data, comorbidity, estimated glomerular filtration rate (eGFR) at start of dialysis, the presence of an optimal access for dialysis, the appearance of graft intolerance and retransplantation were analysed. We studied the causes for the first 10 hospital admissions after starting dialysis. For the statistical analysis, the presence of competitive events that hindered the observation of the event of interest, death or hospital admission was analysed. RESULTS: 175 patients were included, 86 in DP and 89 in HD. The patients who started PD were younger, had less comorbidity and started dialysis with lower eGFR than those on HD. The mean follow-up was 34 ± 33 months, with a median of 24 months (IQR 7 - 50 months), Patients on HD had longer follow-up than patients on PD (35 vs. 18 months, p = < 0.001). The mortality risk factors were age sHR 1.06 (95% CI: 1.033 - 1.106, p = 0.000), non-optimal use of access for dialysis sHR 3.00 (95% CI: 1.507 - 5.982, p = 0.028) and the dialysis modality sHR (PD / HD) 0.36 (95% CI: 0.148 - 0.890, p = 0.028). Patients on PD had a lower risk of hospital admission sHR [DP / HD] 0.52 (95% CI: 0.369-0.743, p = < 0.001) and less probability of developing graft intolerance HR 0.307 (95% CI 0.142-0.758, p = 0.009). CONCLUSIONS: With the limitations of a retrospective and non-randomized study, it is the first time nationwide that PD shows in terms of survival to be better than HD during the first year and a half after the kidney graft failure. The presence of a non-optimal access for dialysis was an independent and modifiable risk factor for mortality. Early referral of patients to advanced chronic kidney disease units is essential for the patient to choose the technique that best suits their circumstances and to prepare an optimal access for the start of dialysis.

Impact of dialysis modality on morbimortality of kidney transplant recipients after allograft failure. Analysis in the presence of competing events.

BACKGROUND AND OBJECTIVE: The number of patients who start dialysis due to graft failure increases every day. The best dialysis modality for this type of patient is not well defined and most patients are referred to HD. The objective of our study is to evaluate the impact of the dialysis modality on morbidity and mortality in transplant patients who start dialysis after graft failure. MATERIAL AND METHODS: A multicentre retrospective observation and cohort study was performed to compare the evolution of patients who started dialysis after graft failure from January 2000 to December 2013. One group started on PD and the other on HD. The patients were followed until the change of dialysis technique, retransplantation or death. Anthropometric data, comorbidity, estimated glomerular filtration rate (eGFR) at start of dialysis, the presence of an optimal access for dialysis, the appearance of graft intolerance and retransplantation were analyzed. We studied the causes for the first 10 hospital admissions after starting dialysis. For the statistical analysis, the presence of competitive events that hindered the observation of the event of interest, death or hospital admission was analyzed. RESULTS: 175 patients were included, 86 in DP and 89 in HD. The patients who started PD were younger, had less comorbidity and started dialysis with lower eGFR than those on HD. The mean follow-up was 34 ± 33 months, with a median of 24 months (IQR 7-50 months), Patients on HD had longer follow-up than patients on PD (35 vs. 18 months, p = < 0.001). The mortality risk factors were age sHR 1.06 (95% CI: 1.03-1.106, p = 0.000), non-optimal use of access for dialysis sHR 3.00 (95% CI: 1.507-5.982, p = 0.028) and the dialysis modality sHR (PD/HD) 0.36 (95% CI: 0.148-0.890, p = 0.028). Patients on PD had a lower risk of hospital admission sHR [DP/HD] 0.52 (95% CI: 0.369-0.743, p = < 0.001) and less probability of developing graft intolerance HR 0.307 (95% CI 0.142-0.758, p = 0.009). CONCLUSIONS: With the limitations of a retrospective and non-randomized study, it is the first time nationwide that PD shows in terms of survival to be better than HD during the first year and a half after the kidney graft failure. The presence of a non-optimal access for dialysis was an independent and modifiable risk factor for mortality. Early referral of patients to advanced chronic kidney disease units is essential for the patient to choose the technique that best suits their circumstances and to prepare an optimal access for the start of dialysis.

A Case of Transplant Nephrectomy due to Chronic Graft Intolerance Syndrome.

We report a case of graft intolerance syndrome in which transplant nephrectomy was performed 11 years after kidney transplantation. A 46-year-old man was admitted to our hospital in February 2018 with a mild fever, left lower abdominal pain, and gross hematuria with enlargement of the transplanted kidney. Urinary tract infection was ruled out. Because the symptoms developed after the immunosuppressants had been stopped after kidney graft loss, graft intolerance syndrome was suspected. He had lost his graft in 2016 and had stopped all immunosuppressants since January of 2017. Immunosuppressive therapy was intensified, and steroid half-pulse therapy was added for 3 days. After the steroid pulse therapy, the C-reactive protein (CRP) decreased from 6.47 mg/dL to 0.76 mg/dL, but there was little improvement in the symptoms, and the CRP then increased to 4.44 mg/dL. Transplant nephrectomy was performed in March 2018. Postoperatively, the symptoms disappeared without the administration of immunosuppressants, and the CRP decreased. Pathologically, the resected kidney graft showed persistent active allograft rejection with severe endarteritis, transplant glomerulopathy, and diffuse interstitial fibrosis. Massive thrombi occluded the large arteries, and there was extensive hemorrhagic cortical necrosis. Transplant nephrectomy is uncommon in patients >6 months after transplantation. However, even if more time has passed since transplantation, as in this case, transplant nephrectomy may be a valid option in some cases of severe graft intolerance syndrome.

Embolización transcatéter del injerto renal en pacientes con síndrome de intolerancia: reporte de tres casos en un grupo de trasplantes

Introducción el síndrome de intolerancia es un proceso inflamatorio que ocurre hasta en un tercio de los pacientes con pérdida del injerto. Cuando no se obtiene una mejoría de los síntomas con el manejo médico, se indica la realización de nefrectomía del riñón trasplantado, sin embargo, este es un procedimiento invasivo que puede estar asociado a mayor morbilidad y mortalidad. Dada la fragilidad de estos pacientes, se plantea la embolización transcatéter del injerto como una alternativa válida y menos invasiva para el tratamiento de este síndrome. Objetivo describir el uso de la embolización transcatéter como tratamiento al síndrome de intolerancia del injerto. Presentación del caso se reportan tres casos clínicos de pacientes con sintomatología de entre 15 y 20 días de evolución, consistentes en dolor y tumefacción sobre riñón trasplantado y otros signos y síntomas reportados fueron fiebre, hiporexia, pérdida de peso y hematuria macroscópica. Se describe la evolución de los síntomas que en ninguno de los casos expuestos tuvieron mejoría con el ajuste inmunosupresor, descartando en todos los casos etiología infecciosa y estableciéndose así la sospecha síndrome de intolerancia del injerto. Los pacientes fueron manejados con embolización transcatéter de la arteria del riñón trasplantado y el éxito del tratamiento se definió por la resolución de los síntomas. Discusión y conclusión entre las primeras 24-48 horas posprocedimiento, los pacientes presentaron una evolución satisfactoria y, finalmente, egreso. La embolización transcatéter del injerto es una alternativa segura a la nefrectomía del trasplante y que es menos invasiva para el tratamiento del síndrome de intolerancia del injerto.

Background The renal graft intolerance syndrome is an inflammatory process that occurs in one third of the kidney transplant patients with graft loss. If medical treatment for intolerance graft syndrome is not effective, there is an indication of graft nephrectomy. However, graft nephrectomy has higher morbidity and mortality compared to non-invasive techniques. Due to a high fragility in kidney transplant patients, the renal arterial embolization has become a useful minimally invasive therapeutic option for intolerance graft syndrome. Objective We aim to describe the use of renal arterial embolization for renal graft intolerance syndrome. Case presentation We report three clinical cases who were admitted to the emergency department for a history of twenty days of graft pain and swelling. These patients had fever, hyporexia, weight loss and macroscopic hematuria. None of the cases had clinical improvement with immunosuppression adjustment and a diagnosis of renal graft intolerance syndrome was made dismissing infection. Patients were treated with renal arterial embolization and its procedure success were determined as the symptom's resolution. Discussion and conclusion After 24- and 48-hours post-embolization, patients were successfully recovered and discharged in the hospital. Renal graft arterial embolization is a safe and non-invasive alternative to graft nephrectomy to treat renal intolerance syndrome.