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.

Referral and Evaluation for Kidney Transplantation Following Implementation of the 2014 National Kidney Allocation System.

RATIONALE & OBJECTIVE: The national kidney allocation system (KAS) implemented in December 2014 in the United States redefined the start of waiting time from the time of waitlisting to the time of kidney failure. Waitlisting has declined post-KAS, but it is unknown if this is due to transplant center practices or changes in dialysis facility referral and evaluation. The purpose of this study was to assess the impact of the 2014 KAS policy change on referral and evaluation for transplantation among a population of incident and prevalent patients with kidney failure. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 37,676 incident (2012-2016) patients in Georgia, North Carolina, and South Carolina identified within the US Renal Data System at 9 transplant centers and followed through December 2017. A prevalent population of 6,079 patients from the same centers receiving maintenance dialysis in 2012 but not referred for transplantation in 2012. EXPOSURE: KAS era (pre-KAS vs post-KAS). OUTCOME: Referral for transplantation, start of transplant evaluation, and waitlisting. ANALYTICAL APPROACH: Multivariable time-dependent Cox models for the incident and prevalent population. RESULTS: Among incident patients, KAS was associated with increased referrals (adjusted HR, 1.16 [95% CI, 1.12-1.20]) and evaluation starts among those referred (adjusted HR, 1.16 [95% CI, 1.10-1.21]), decreased overall waitlisting (adjusted HR, 0.70 [95% CI, 0.65-0.76]), and lower rates of active waitlisting among those evaluated compared to the pre-KAS era (adjusted HR, 0.81 [95% CI, 0.74-0.90]). Among the prevalent population, KAS was associated with increases in overall waitlisting (adjusted HR, 1.74 [95% CI, 1.15-2.63]) and active waitlisting among those evaluated (adjusted HR, 2.01 [95% CI, 1.16-3.49]), but had no significant impact on referral or evaluation starts among those referred. LIMITATIONS: Limited to 3 states, residual confounding. CONCLUSIONS: In the southeastern United States, the impact of KAS on steps to transplantation was different among incident and prevalent patients with kidney failure. Dialysis facilities referred more incident patients and transplant centers evaluated more incident patients after implementation of KAS, but fewer evaluated patients were placed onto the waitlist. Changes in dialysis facility and transplant center behaviors after KAS implementation may have influenced the observed changes in access to transplantation.

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.

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.

Community Engagement to Improve Equity in Kidney Transplantation from the Ground Up: the Southeastern Kidney Transplant Coalition.

Purpose of review: The purpose of this review is to describe the Southeastern Kidney Transplant Coalition's mission, vision, goals, and Early Transplant Access registry as an example of a community/academic collaboration dedicated to improving access to transplantation and reducing inequities in transplant access. Recent findings: The barriers and facilitators to referral and evaluation for kidney transplantation are not necessarily the same as for waitlisting and transplantation. Recent findings suggest that inequities in transplant access are multilevel and multifactorial and require continued community engagement to improve access to kidney transplantation across patients, health systems, and populations. Summary: Community-engaged approaches are critical to ensuring that inequities in transplant access - which may vary across regions -- are not only described but are addressed in practice in a sustainable manner.

Collapsing focal segmental sclerosis in an HIV-negative patient.

Collapsing focal segmental glomerulosclerosis (FSGS) is classically seen in HIV-infected patients and carries a dismal prognosis. It can also occur in HIV-negative patients in which case, early aggressive treatment with glucocorticoids may be helpful with improvement in both proteinuria and renal function.

First Reported Use of Highly Adsorptive Hemofilter in Critically Ill COVID-19 Patients in the USA.

Critically ill patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop respiratory failure and septic shock. Extracorporeal blood purification is proposed as an adjuvant therapy for sepsis and aims at controlling the dysregulated autoimmune system. We describe our experience in treating COVID-19 patients with the oXiris® hemofilter which adsorbs both cytokines and endotoxins, provides renal replacement therapy and has anti-thrombogenic properties. It was approved by the US Food and Drug Administration (FDA) under emergency use authorization for COVID-19 patients in April 2020. In our study, the use of the oXiris® filter decreased levels of inflammatory markers including interleukin-6 (IL-6), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), and improved clinical outcomes in two out of three patients.

Metastatic Calcinosis of Gastric Mucosa.

Calcinosis cutis refers to the deposition of calcium salts in the cutaneous and subcutaneous tissue and is frequently associated with inflammation. Gastric calcinosis can be classified into metastatic, dystrophic, and idiopathic; metastatic calcinosis is the most common type. In metastatic calcification, calcium salts are deposited in normal soft tissues in the setting of altered metabolism of serum calcium and phosphorus and is a rare and serious complication of chronic renal failure. The important factors contributing to the development of metastatic calcinosis are hypercalcemia, hyperphosphatemia, and an elevated calcium-phosphate product. The most striking feature of this diagnosis is the calcification around the large joints. While it mostly involves dermis of small and medium-sized vessels, it can rarely affect the mucosal layers of the gastrointestinal (GI) tract. Calcinosis presents as a marker for the presence of calcifications in other organs, such as heart or lung, which can be life-threatening. Patients rarely present with clinical symptoms of GI upset, dyspepsia, or epigastric pain that are attributed to calcinosis. If patients present with GI symptoms, infectious causes remain to be higher on the differential. We present a case of incidental finding of gastric mucosal calcinosis during the workup and treatment of dysphagia.

HLA-G and humanized mouse models as a novel therapeutic approach in transplantation.

HLA-G is a nonclassical MHC-Class I molecule whose expression, along the feto-maternal barrier contributes towards tolerance of the semiallogeneic fetus during pregnancy. In light of its inhibitory properties, recent research has established HLA-G involvement in mechanisms responsible for directing allogeneic immune responses towards tolerance during allogeneic situations such as organ transplantation. Here, we critically review the data supporting the tolerogenic role of HLA-G in organ transplantation, the various factors influencing its expression, and the introduction of novel humanized mouse models that are one of the best approaches to assess the utility of HLA-G as a therapeutic tool in organ transplantation.

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.

Dialysis facility referral and start of evaluation for kidney transplantation among patients treated with dialysis in the Southeastern United States.

Variability in transplant access exists, but barriers to referral and evaluation are underexplored due to lack of national surveillance data. We examined referral for kidney transplantation evaluation and start of the evaluation among 34 857 incident, adult (18-79 years) end-stage kidney disease patients from 690 dialysis facilities in the United States Renal Data System from January 1, 2012 through August 31, 2016, followed through February 2018 and linked data to referral and evaluation data from nine transplant centers in Georgia, North Carolina, and South Carolina. Multivariable-adjusted competing risk analysis examined each outcome. The median within-facility cumulative percentage of patients referred for kidney transplantation within 1 year of dialysis at the 690 dialysis facilities in Network 6 was 33.7% (interquartile range [IQR]: 25.3%-43.1%). Only 48.3% of referred patients started the transplant evaluation within 6 months of referral. In multivariable analyses, factors associated with referral vs evaluation start among those referred at any time differed. For example, black, non-Hispanic patients had a higher rate of referral (hazard ratio [HR]: 1.22; 95% confidence interval [CI]: 1.18-1.27), but lower evaluation start among those referred (HR: 0.93; 95% CI: 0.88-0.98), vs white non-Hispanic patients. Barriers to transplant varied by step, and national surveillance data should be collected on early transplant steps to improve transplant access.

Association of sociocultural factors with initiation of the kidney transplant evaluation process.

Although research shows that minorities exhibit higher levels of medical mistrust, perceived racism, and discrimination in healthcare settings, the degree to which these underlying sociocultural factors preclude end-stage renal disease (ESRD) patients from initiating kidney transplant evaluation is unknown. We telephone surveyed 528 adult ESRD patients of black or white race referred for evaluation to a Georgia transplant center (N = 3) in 2014-2016. We used multivariable logistic regression to examine associations between sociocultural factors and evaluation initiation, adjusting for demographic, clinical, and socioeconomic characteristics. Despite blacks (n = 407) reporting higher levels of medical mistrust (40.0% vs 26.4%, P < .01), perceived racism (55.5% vs 18.2%, P < .01), and experienced discrimination (29.0% vs 15.7%, P < .01) than whites (n = 121), blacks were only slightly less likely than whites to initiate evaluation (49.6% vs 57.9%, P = .11). However, after adjustment, medical mistrust (odds ratio [OR]: 0.59; 95% confidence interval [CI]: 0.39, 0.91), experienced discrimination (OR: 0.62, 95% CI: 0.41, 0.95), and perceived racism (OR: 0.61; 95% CI: 0.40, 0.92) were associated with lower evaluation initiation. Results suggest that sociocultural disparities exist in early kidney transplant access and occur despite the absence of a significant racial disparity in evaluation initiation. Interventions to reduce disparities in transplantation access should target underlying sociocultural factors, not just race.

A Culturally Sensitive Web-based Intervention to Improve Living Donor Kidney Transplant Among African Americans.

INTRODUCTION: There are pervasive racial disparities in access to living donor kidney transplantation, which for most patients with end-stage renal disease (ESRD) represents the optimal treatment. We previously developed a theory-driven, culturally sensitive intervention for African American (AA) patients with kidney disease called Living ACTS (About Choices in Transplantation and Sharing) as a DVD and booklet, and found this intervention was effective in increasing living donor transplant knowledge. However, it is unknown whether modifying this intervention for a Web-based environment is effective at increasing access to living donor transplantation. METHODS: We describe the Web-based Living ACTS study, a multicenter, randomized controlled study designed to test the effectiveness of a revised Living ACTS intervention in 4 transplant centers in the southeastern United States. The intervention consists of a Web site with 5 modules: Introduction, Benefits and Risks, The Kidney Transplant Process, Identifying a Potential Kidney Donor, and ACT Now (which encourages communication with friends and family about transplantation). RESULTS: This study will enroll approximately 800 patients from the 4 transplant centers. The primary outcome is the percentage of patients with at least 1 inquiry from a potential living donor among patients who receive Living ACTS as compared with those who receive a control Web site. CONCLUSION: The results from this study are expected to demonstrate the effectiveness of an intervention designed to increase access to living donor transplantation among AA individuals. If successful, the Web-based intervention could be disseminated across the >250 transplant centers in the United States to improve equity in living donor kidney transplantation.

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.

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.

HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival.

Human leukocyte antigen G (HLA-G), a nonclassic HLA class Ib molecule involved in the maintenance of maternal tolerance to semiallogeneic fetal tissues during pregnancy, has emerged as a potential therapeutic target to control allograft rejection. We demonstrate here that the level of soluble HLA-G dimer was higher in a group of 90 patients with a functioning renal allograft compared with 40 patients who rejected (RJ) their transplants. The HLA-G dimer level was not affected by demographic status. One of the potential mechanisms in tissue-organ allograft rejection involves the induction of granzymes and perforin, which are the main effector molecules expressed by CD8+ cytotoxic T lymphocytes and function to destroy allogeneic transplants. Using genomics and molecular and cellular analyses of cells from T-cell-mediated RJ and nonrejected kidney transplant patients, cells from leukocyte Ig-like receptor B1 (LILRB1) transgenic mice, humanized mice, and genetically engineered HLA-G dimer, we demonstrated a novel mechanism by which HLA-G dimer inhibits activation and cytotoxic capabilities of human CD8+ T cells. This mechanism implicated the down-regulation of Granzyme B expression and the essential involvement of LILRB1. Thus, HLA-G dimer has the potential to be a specific and effective therapy for prevention of allograft rejection and prolongation of graft survival.-Ajith, A., Portik-Dobos, V., Nguyen-Lefebvre, A. T., Callaway, C., Horuzsko, D. D., Kapoor, R., Zayas, C., Maenaka, K., Mulloy, L. L., Horuzsko, A. HLA-G dimer targets Granzyme B pathway to prolong human renal allograft survival.

Mentor vs. mentee perceptions of career mentoring partnerships and work outcomes: A multi-institutional study of faculty mentoring programs.

This article was migrated. The article was marked as recommended. Introduction: Formal mentoring programs are a professional development approach to help junior faculty develop an academic medicine career. This study investigated the perceptions of mentors versus mentees in formal career mentoring partnerships across multiple institutions. Methods: The authors implemented departmental mentoring programs for junior faculty at four academic medical centers. They collected post-program data from mentors and mentees in order to examine the predictors of mentoring satisfaction, mentee outcomes, and work-related variables. Results: The pattern of relationships between the variables differed for mentors versus mentees. Mentoring focus, mentor accessibility and mentee initiative predicted partnership satisfaction and mentee progress. Partnerships that used a mentoring agreement reported greater progress and satisfaction. There were some relationships between partnership outcomes and work-related outcomes. While partnership satisfaction predicted job and administrative/leadership satisfaction for mentors, it predicted positive perceptions of the department's mentoring culture and professional development opportunities for mentees. Conclusions: The study identified unique antecedents and consequences of mentoring partnership satisfaction and mentee outcomes. The varying perspectives of mentors versus mentees indicated a need to clearly communicate partnership expectations and desired outcomes. Overall, the positive impact of formal mentoring programs on partnership and work-related outcomes was supported with implications for future programs and research.

Racial disparities in preemptive referral for kidney transplantation in Georgia.

BACKGROUND: Racial disparities persist in access to kidney transplantation. Racial differences in preemptive referral, or referral prior to dialysis start, may explain this discrepancy. METHODS: Patient-level data on kidney transplant referrals (2005-2012) from all Georgia transplant centers were linked to the United States Renal Data System to examine racial disparities in preemptive referral, waitlisting, and living donor transplant. Adjusted logistic regression and Cox proportional hazard models determined the associations between race (African American vs white) and preemptive referral, and placement on the waitlist and receipt of a living donor kidney, respectively. RESULTS: Among 7752 adults referred for transplant evaluation, 20.38% (n = 1580) were preemptively referred. The odds of African Americans being preemptively referred for transplant evaluation were 37% (OR = 0.63; [95% CI: 0.55 0.71]) lower than white patients. Among preemptively referred patients, there was no racial difference (African Americans compared to white patients. HR = 0.96; [95% CI: 0.88, 1.04]) in waitlisting. However, African Americans were 70% less likely than white patients to receive a living donor transplant (HR = 0.30; [95% CI: 0.21, 0.42]). CONCLUSION: Racial disparities in transplant receipt may be partially explained by disparities in preemptive referral. Interventions to reduce racial disparities in kidney transplant access may need to be targeted earlier in the disease process.

Outcomes at 7 years post-transplant in black vs nonblack kidney transplant recipients administered belatacept or cyclosporine in BENEFIT and BENEFIT-EXT.

Clinical outcomes are generally worse for black vs nonblack renal allograft recipients. In BENEFIT and BENEFIT-EXT, recipients were randomized to belatacept more intense-based, belatacept less intense-based, or cyclosporine-based immunosuppression. At year 7, belatacept was associated with superior graft survival vs cyclosporine in BENEFIT (recipients of living or standard criteria deceased donor kidneys); belatacept was associated with similar graft survival vs cyclosporine in BENEFIT-EXT (recipients of extended criteria donor kidneys). In both studies, renal function was superior for belatacept-treated vs cyclosporine-treated patients. Seven-year outcomes were examined by race post hoc in each study. The effect of race and treatment on time to death or graft loss was compared using Cox regression. The interaction between treatment and race was also considered. Glomerular filtration rate (GFR) was estimated from months 1 to 84 using a repeated-measures model. In total, 8.3% (55/666) and 13.1% (71/543) of patients in BENEFIT and BENEFIT-EXT, respectively, were black. Time to death or graft loss was similar in blacks and nonblacks. For both subgroups, estimated mean GFR increased over 7 years for belatacept, but declined for cyclosporine. Outcomes were similar in belatacept-treated black and nonblack patients. Due to the small number of black patients, these results must be interpreted with caution.