IL-10-producing memory B regulatory cells as a novel target for HLA-G to prolong human kidney allograft survival.

Despite the growing interest in the role of regulatory B cells (Bregs) in autoimmunity, their distinct role and function in kidney transplant outcomes remain elusive. Here, we retrospectively analyzed the proportion of Bregs, transitional Bregs (tBregs) and memory Bregs (mBregs) and their capacity to produce IL-10 in non-rejected (NR) versus rejected (RJ) kidney transplant recipients. In the NR group, we observed a significant increase in the proportion of mBregs (CD19+CD24hiCD27+) but no difference in tBregs (CD19+CD24hiCD38+), as compared to the RJ group. We also observed a significant increase in IL-10-producing mBregs (CD19+CD24hiCD27+IL-10+) in the NR group. As our group and others have previously reported a potential role of the human leukocyte antigen G (HLA-G) in human renal allograft survival, notably through IL-10, we then investigated possible crosstalk between HLA-G and IL-10+ mBregs. Our ex vivo data suggest a role of HLA-G in enhancing IL-10+ mBreg expansion upon stimulation, which further decreased CD3+ T cell proliferation capability. Using RNA-sequencing (RNA-seq), we identified potential key signaling pathways involved in HLA-G-driven IL-10+ mBreg expansion, such as the MAPK, TNF and chemokine signaling pathways. Together, our study highlights a novel HLA-G-mediated IL-10-producing mBreg pathway that may serve as a therapeutic target to improve kidney allograft survival.

Immune Thrombocytopenia in a Kidney Transplant Recipient Treated with Romiplostim.

We present a case of immune thrombocytopenia following a living donor kidney transplant. Thrombocytopenia started two days after transplant and continued up to seven weeks after transplant, despite an extensive workup, treatment with steroids, intravenous immune globulin, and alterations in immunosuppression and other medications. In the absence of platelet transfusions, the patient's platelet count remained < 20,000/mm3. Platelet count responded to romiplistim (Nplate®, Amgen Inc.) within two weeks and has remained stable for twelve months after initiation of this agent. The patient's graft function has also been stable. This experience suggests romiplostim is safe and effective for persistent immune thrombocytopenia in kidney transplant recipients.

Massive Chylous Ascites After Living Donor Nephrectomy Successfully Treated With Lymphatic Embolization.

Chylous ascites may result from a variety of pathological conditions, most of them from nontraumatic causes, such as congenital defects of the lymphatic system, infections, liver cirrhosis, and malignancy. Rarely, chylous ascites occurs as an iatrogenic complication after left-sided laparoscopic donor nephrectomy (LDN). Injury to the cisterna chyli and its main lymphatic tributaries around the para-aortic region intraoperatively can cause the lymphatic fluid to accumulate. There is currently no standardized treatment for chylous ascites as there have only been 54 cases documented to date. Most patients can be managed with conservative therapy. Recommended guidelines include high-protein and low-fat diet with medium-chain triglycerides. Paracentesis is often used as a diagnostic and therapeutic first-line measure with total parenteral nutrition (TPN), bowel rest, and somatostatin analogue as adjunct therapies. We present a case of massive chylous ascites refractory to conservative therapy. The patient had progressive abdominal distention and unintentional weight gain 2 weeks postoperatively warranting multiple paracenteses of >7 L of chylous fluid. Ultimately, the patient was successfully treated with lymphatic embolization using N-butyl cyanoacrylate glue.

Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation.

The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient's personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient's humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses.

Anticoagulant-induced hemorrhagic cholecystitis with hemobilia after deceased donor kidney transplant and literature review.

INTRODUCTION AND IMPORTANCE: Hemobilia and hemorrhagic cholecystitis are uncommon causes of right upper quadrant abdominal pain. The development of intra-gallbladder and biliary bleeding has been primarily associated with abdominal trauma, malignancy, liver transplant, and iatrogenic injury to the biliary tree and vasculature. Spontaneous anticoagulant induced hemorrhagic cholecystitis and hemobilia are incredibly rare events and have only been documented by a handful of case reports. CASE PRESENTATION: A 55-year-old male who had recently undergone a deceased-donor kidney transplant was transferred to our academic institution for evaluation of subjective fever, right upper quadrant abdominal and back pain. The patient demonstrated localized tenderness in the right abdomen and was found to have hemorrhagic cholecystitis on imaging. He subsequently underwent urgent cholecystectomy and recovered without any subsequent complications. CLINICAL DISCUSSION: Hemorrhagic cholecystitis and hemobilia are a rare cause of right-sided or generalized abdominal pain. Diagnosis is made primarily by pathognomonic findings on CT and US imaging. Prompt diagnosis is essential in preventing mortality and/or significant morbidity. The standard treatment consists of urgent/emergent cholecystectomy. CONCLUSION: A rare sequelae of anticoagulant use, intra-biliary bleeding must be considered as a differential diagnosis in anticoagulated patients presenting with right upper quadrant abdominal pain.

Ureteric Trauma following Stent Removal in Kidney Transplant Recipient: A Unique Case of Prolonged Morbidity.

A 52-year-old African-American male patient with end-stage renal disease due to hypertension underwent deceased donor kidney transplant procedure with no immediate complications. The postprocedure complications, interventions, and course were abstracted by chart review. The ureteric stent was removed with flexible cystoscopy on postoperative day (POD) 24. 24 hours later, the patient presented with abdominal pain and inability to urinate. An urgent ultrasound and noncontrast CT scan showed grade 4 hydronephrosis of the transplanted kidney. A percutaneous nephrostomy stent was placed for urinary diversion. A large ureteric hematoma filling the lumen of the mid to distal ureter was identified on the nephrostogram and was evacuated. A follow-up nephrostogram on POD 44 revealed a distal ureter stricture and persistent well-formed midureter filling defect. A repeat nephrostogram performed at POD 72 was done with stricture dilatation, internalization of stents, and removal of a percutaneous nephrostomy tube. The patient was maintained on antibiotics for UTI prophylaxis throughout the course.

Disseminated Histoplasmosis Presenting as Weight Loss and Hypercalcemia in a Renal Transplant Patient With Prior History of Subtotal Parathyroidectomy.

Hypercalcemia and weight loss in a renal transplant patient especially with history of parathyroidectomy raises concern for an underlying malignancy, fungal infections or granulomatous disease. We present a case of 45-year-old male with history of subtotal parathyroidectomy presented with severe persistent hypercalcemia, acute kidney injury (AKI) and significant weight loss. An extensive workup revealed disseminated histoplasmosis. Hypercalcemia (which was refractory to initial medical management) and other symptoms resolved after a few weeks of initiating the antifungal treatment.

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.

Cytomegalovirus pancreatitis in an immunocompetent patient.

Cytomegalovirus (CMV) is a double-stranded DNA virus, which infects a large portion of the adult population. In immunocompetent patients, it typically is asymptomatic or manifests as mild and self-limiting flu-like illness symptoms, whereas in immunocompromised patients, CMV can cause significant disease. Herein we report an unusual case of CMV pancreatitis in an immunocompetent 75-year-old female. Patient developed severe significant pancreatic necrosis that failed non-operative management, and ultimately underwent pancreatic necrosectomy. Later on, she developed three spontaneous gastric perforations. The first two perforations were managed operatively, but after the third perforation family decided not to undergo another operation. The CMV pancreatitis diagnosis was based on pancreatic histopathology and confirms by a prompt response to ganciclovir. Patient was promptly started on intravenous (IV) ganciclovir which resulted in clinical recovery and she remained asymptomatic more than one-year post op. This is a rare case of CMV pancreatitis with gastric perforations in an immunocompetent patient. High degree of suspicion and appropriate treatment are important for such clinical scenarios.

Spontaneous Breast Haematoma after Heparin Anticoagulation.

Heparin is commonly used in clinical practice for the prevention and treatment of various thrombotic conditions. Its use can be associated with bleeding which can range from minor to life threatening. Non-traumatic causes of breast haematoma are very rare. We report a case of spontaneous bleeding into the breast in a female patient who was anticoagulated with heparin. LEARNING POINTS: Anticoagulant use can be associated with the adverse effect of bleeding at various sites.Physicians should be cautious of such bleeding which can occur at unsuspected sites.Our patient developed spontaneous breast haematoma after unfractionated heparin anticoagulation, and was successfully managed with cessation of anticoagulation, protamine, desmopressin and blood transfusion.

Severe Intraoperative Anaphylaxis Related to Thymoglobulin during Living Donor Kidney Transplantation.

Anaphylaxis secondary to thymoglobulin (anti-thymocyte globulin) is a rare condition that can be life threatening. Thymoglobulin is a rabbit-derived T-cell depleting polyclonal immunoglobulin. It is commonly used for induction immunosuppression and/or for treatment of acute rejection in renal transplantation. We report a case of a living kidney transplant recipient who developed intraoperative anaphylactic shock secondary to thymoglobulin. The patient had a history of pet rabbit exposure. This case report highlights the importance of prompt identification and management of intraoperative anaphylaxis, which is key to a successful outcome. Induction immunosuppression selection based on patient characteristics is important. Communication between the anesthesia team and surgeons played a key role in stopping the donor surgery.

Recurring Norovirus & Sapovirus Infection in a Renal Transplant Patient.

Noroviruses and sapoviruses are common causes of gastroenteritis and infectious diarrhea. Although these viruses are typically of short duration in healthy individuals, immunocompromised organ transplant recipients can develop chronic, relapsing symptoms with grave outcomes. We discuss a unique case of chronic norovirus infection with subsequent sapovirus infection in a kidney transplant recipient. Relief of norovirus symptoms occurred after the reduction of immunosuppression and treatment with nitazoxanide. Subsequently, a superimposed sapovirus infection developed. Patient developed renal transplant rejection due to reduction of immunosuppression. Findings from this case study suggest that norovirus and sapovirus are associated with chronic, relapsing symptoms and significant morbidity in immunocompromised renal transplant patients and that reduction of immunosuppression in order to overcome infection risks allograft rejection. Early detection and management are essential to reduce morbidity associated with these viruses among immunocompromised transplant recipients.

A Rare Case of Drug-Resistant Nocardia transvalensis Infection in a Renal Transplant Patient.

Nocardia transvalensis is a rare species of Nocardia and is known to be a drug-resistant organism. Multiple cases have been reported of Nocardia species causing opportunistic infections in immunocompromised hosts. To our knowledge, we report the first case of successfully treated drug-resistant Nocardia transvalensis causing pulmonary nocardiosis in a renal transplant patient. Our case validates the importance of prompt identification of Nocardia species and their drug sensitivities to improve clinical outcomes and reduce mortality.

Autoimmune Hemolytic Anemia in a Renal Transplant Patient Following Seasonal Influenza Vaccination.

Vaccines aim to prevent disease occurrence, its severity, and resultant complications. Our patient, a 58-year-old male, received seasonal influenza vaccination as part of routine health maintenance. Three days later, he presented with malaise, fever, and yellowish discoloration of eyes. His labs showed hyperbilirubinemia, anemia, elevated lactate dehydrogenase, and low haptoglobin, consistent with hemolytic anemia. Autoimmune hemolytic anemia has been associated with vaccine use and may result from phenomena of molecular mimicry and cross-reactivity with the possible role of vaccine adjuvants as well. An underlying structural defect of the red blood cell membrane may make them prone to hemolysis. The differential diagnosis and work-up of hemolytic anemia is extensive, as performed in our case. Management strategies for vaccine-induced hemolysis may involve supportive care, red blood cell transfusion, steroids, and intravenous immunoglobulin.

Crescentic IgA nephropathy along with simultaneous cellular and antibody-mediated rejection in a kidney transplant leading to rapid allograft failure.

Crescentic IgA Nephropathy in a renal transplant can lead to rapid loss of graft function despite treatment. Concurrent treatment-resistant acute cellular and antibody-mediated rejection make the prognosis even worse.

Simultaneous candida albicans and herpes simplex virus type 2 esophagitis in a renal transplant recipient.

Renal transplant recipients are prone to opportunistic infections due to iatrogenic immunosuppression. Infectious esophagitis can present as an opportunistic infection in the post-transplant period. Common pathogens are candida, herpes simplex virus (HSV) and cytomegalovirus (CMV). Having a dual infection is uncommon and the diagnoses can be missed at initial presentation. Our patient, a 29-year-old African-American woman, status post deceased-donor-kidney transplant presented with difficulty and pain in swallowing with clinical features suggestive of candida esophagitis, confirmed by fungal culture. She did not get better with antifungal treatment. On further testing, the patient was found to have HSV-2 infection of the oesophagus as well. She received both fluconazole as well as acyclovir that lead to complete resolution of her symptoms. In the right clinical setting, esophagitis can be caused by more than one organism present at the same time and a high level of suspicion is warranted.

Gastric Mucormycosis in a Renal Transplant Patient Treated with Isavuconazole Monotherapy.

Gastrointestinal mucormycosis is a rare infection in solid organ transplant recipients. Our patient, a 79-year-old male, presented with severe dysphagia and odynophagia about 2 weeks after receiving a renal transplant. An upper gastrointestinal (UGI) endoscopy revealed esophagitis and gastric ulceration, the cultures from which grew Rhizopus species. A usual treatment strategy should include Amphotericin B as monotherapy or in combination with Posaconazole or Isavuconazole for such infections. Our patient was treated with Isavuconazole monotherapy, in an effort to minimize renal toxicity from Amphotericin B to the new allograft. Unique to our case was a successful clinical response and resolution of UGI lesions with Isavuconazole monotherapy. Due to the vagueness of presenting symptoms, such infections can be easily missed in an immunocompromised patient which can have tragic outcomes. Prompt diagnosis and modulation of immunosuppression are essential to decrease mortality and morbidity. Isavuconazole is a novel agent and can be used as a monotherapy for such infections, especially in renal transplant recipients.

Prevalence and correlates of cognitive impairment in kidney transplant recipients.

BACKGROUND: There is a high prevalence of cognitive impairment in dialysis patients. The prevalence of cognitive impairment after kidney transplantation is unknown. METHODS: Study Design: Cross-sectional study. SETTING AND PARTICIPANTS: Single center study of prevalent kidney transplant recipients from a transplant clinic in a large academic center. INTERVENTION: Assessment of cognition using the Montreal Cognitive Assessment (MoCA). Demographic and clinical variables associated with cognitive impairment were also examined. Outcomes and Measurements: a) Prevalence of cognitive impairment defined by a MoCA score of <26. b) Multivariable linear and logistic regression to examine the association of demographic and clinical factors with cognitive impairment. RESULTS: Data from 226 patients were analyzed. Mean (SD) age was 54 (13.4) years, 73% were white, 60% were male, 37% had diabetes, 58% had an education level of college or above, and the mean (SD) time since kidney transplant was 3.4 (4.1) years. The prevalence of cognitive impairment was 58.0%. Multivariable linear regression demonstrated that older age, male gender and absence of diabetes were associated with lower MoCA scores (p < 0.01 for all). Estimated glomerular filtration rate (eGFR) was not associated with level of cognition. The logistic regression analysis confirmed the association of older age with cognitive impairment. CONCLUSION: Cognitive impairment is common in prevalent kidney transplant recipients, at a younger age compared to general population, and is associated with certain demographic variables, but not level of eGFR.