Inhibitory innate receptors and their potential role in transplantation.

The regulatory arm of the immune system plays a crucial role in maintaining immune tolerance and preventing excessive immune responses. Immune regulation comprises various regulatory cells and molecules that work together to suppress or regulate immune responses. The programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) are examples of inhibitory receptors that counteract activating signals and fine-tune immune responses. While most of the discoveries of immune regulation have been related to T cells and the adaptive immune system, the innate arm of the immune system also has a range of inhibitory receptors that can counteract activating signals and suppress the effector immune responses. Targeting these innate inhibitory receptors may provide a complementary therapeutic approach in several immune-related conditions, including transplantation. In this review, we will explore the potential role of innate inhibitory receptors in controlling alloimmunity during solid organ transplantation.

Recurrence of IgA Nephropathy after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 "The Post-Transplant Glomerular Disease" study centers in Europe, North America, and South America. RESULTS: Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazard ratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence. CONCLUSIONS: In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss.

Recurrence of FSGS after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors. RESULTS: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m2; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival. CONCLUSIONS: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.

APOL1-Associated Kidney Disease in Brazil.

INTRODUCTION: Coding variants in apolipoprotein L-1 (APOL1) are associated with an increased risk of end-stage kidney disease (ESRD) in African American individuals under a recessive model of inheritance. The effect of the APOL1 risk alleles on kidney disease has been observed in studies in African American and African populations. Despite the 130 million individuals of recent African ancestry in South America, the impact of APOL1 has not been explored. METHODS: In this case-control study, we tested APOL1 genotype in 106 Brazilian HD (hemodialysis) patients with African ancestry and compared risk allele frequency with 106 healthy first-degree relatives. The association of risk alleles and ESRD was calculated with a linear mixed model and was adjusted for relatedness and additional confounders. In a broader survey, the age of dialysis initiation and APOL1 variants were analyzed in 274 HD patients. RESULTS: Two APOL1 risk alleles were 10 times more common in patients with ESRD than in controls (9.4% vs. 0.9%; odds ratio [OR]: 10.95, SE = 1.49, P = 0.0017). Carriers of 2 risk alleles initiated dialysis 12 years earlier than patients with zero risk alleles. CONCLUSION: The APOL1 risk variants were less frequent in dialysis patients of African ancestry in Brazil than in the United States. Nonetheless, carriers of 2 risk variants had 10-fold higher odds of ESRD. Age of dialysis initiation was markedly lower in 2-risk allele carriers, suggesting a more aggressive disease phenotype. The Brazilian population represents an opportunity to identify different sets of genetic modifiers or environmental triggers that might be present in more extensively studied populations.

March1-dependent modulation of donor MHC II on CD103+ dendritic cells mitigates alloimmunity.

In transplantation, donor dendritic cells (do-DCs) initiate the alloimmune response either by direct interaction with host T cells or by transferring intact donor MHC to host DCs. However, how do-DCs can be targeted for improving allograft survival is still unclear. Here we show CD103+ DCs are the major do-DC subset involved in the acute rejection of murine skin transplants. In the absence of CD103+ do-DCs, less donor MHC-II is carried to host lymph nodes, fewer allogenic T cells are primed and allograft survival is prolonged. Incubation of skin grafts with the anti-inflammatory mycobacterial protein DnaK reduces donor MHC-II on CD103+DCs and prolongs graft survival. This effect is mediated through IL-10-induced March1, which ubiquitinates and decreases MHC-II levels. Importantly, in vitro pre-treatment of human DCs with DnaK reduces their ability to prime alloreactive T cells. Our findings demonstrate a novel therapeutic approach to dampen alloimmunity by targeting donor MHC-II on CD103+DCs.

Belatacept in kidney transplantation - past and future perspectives.

Calcineurin inhibitors (CNIs) are used widely for maintenance immunosuppression in renal transplant recipients. However, their side effect profile has led researchers to attempt to find safer alternatives that can maintain effective long-term immunosuppression with less toxicity. Belatacept is a CTLA4-Ig molecule designed to block the costimulatory B7-CD28 signal needed for activation of effector T cells. While it has shown great promise in clinical trials, it has made halting progress towards replacing CNIs in actual clinical practice. The BENEFIT trial revealed some of the advantages of belatacept in terms of maintaining renal function after transplant and reducing some of the metabolic side effects of CNIs related to hypertension and dyslipidemia. Despite that, some cautionary signals have emerged as well, in that belatacept-treated patients experience higher acute rejection rates and greater risk for PTLD. Furthermore, the requirement for monthly intravenous infusions has presented logistical and cost challenges for widespread adoption.

Belatacept in kidney transplantation - past and future perspectives / Belatacept no transplante renal - perspectivas passadas e futuras

Abstract Calcineurin inhibitors (CNIs) are used widely for maintenance immunosuppression in renal transplant recipients. However, their side effect profile has led researchers to attempt to find safer alternatives that can maintain effective long-term immunosuppression with less toxicity. Belatacept is a CTLA4-Ig molecule designed to block the costimulatory B7-CD28 signal needed for activation of effector T cells. While it has shown great promise in clinical trials, it has made halting progress towards replacing CNIs in actual clinical practice. The BENEFIT trial revealed some of the advantages of belatacept in terms of maintaining renal function after transplant and reducing some of the metabolic side effects of CNIs related to hypertension and dyslipidemia. Despite that, some cautionary signals have emerged as well, in that belatacept-treated patients experience higher acute rejection rates and greater risk for PTLD. Furthermore, the requirement for monthly intravenous infusions has presented logistical and cost challenges for widespread adoption.

Resumo Os inibidores da calcineurina (INC) são amplamente utilizados para a imunossupressão de manutenção em pacientes receptores de transplante renal. No entanto, o seu perfil de efeitos colaterais tem levado os pesquisadores a tentar encontrar alternativas mais seguras, que possam manter efetiva imunossupressão de longo prazo com menos toxicidade. O Belatacept é uma molécula de CTLA4-IgG concebida para bloquear o sinal co-estimulador B7-CD28, necessário para a ativação de linfócitos T efetores. Embora tenha demonstrado grande promessa em ensaios clínicos, não tem tido progresso na substituição de INCs na prática clínica. O estudo BENEFIT revelou algumas das vantagens do belatacept em termos da manutenção da função renal após o transplante, e da redução de alguns dos efeitos secundários metabólicos dos INCs, relacionados à hipertensão e dislipidemia. Apesar disso, alguns sinais de precaução também têm surgido, quando doentes tratados com belatacept tem maiores taxas de rejeição aguda e maior risco de DLPT. Além disso, a necessidade de perfusões intravenosas mensais apresenta desafios logísticos e de custo para sua adoção generalizada.

Acute myeloid leukemia after kidney transplantation: a case report and literature review.

The incidence of malignancy is greater in kidney transplant recipients compared to the general population, though the higher risk is not equally distributed to all types of cancers. In face of the increased longevity of renal transplant recipients, certain cancers, such as acute leukemias, are becoming more prevalent. Acute myeloid leukemia (AML) typically presents with cytopenias and infections, both common findings after kidney transplantation. Therefore, the diagnosis of AML may be initially overlooked in these patients. We report the case of a 33-year-old man who presented with fever, pancytopenia and acute worsening of his renal allograft function 9 years after a living unrelated kidney transplant. After initial negative infectious work-up, a kidney biopsy revealed C4d-positive antibody-mediated rejection in combination with scattered atypical inflammatory cells. A subsequent bone marrow biopsy confirmed AML. He underwent successful induction chemotherapy with daunorubucin and cytarabine and ultimately achieved a complete remission. However, he developed a Page kidney with worsening renal function and abdominal pain three weeks after biopsy in the setting of chemotherapy-induced thrombocytopenia. Herein, we discuss the prevalence, risk factors, presentation and management of leukemia after kidney transplantation.

Acute myeloid leukemia after kidney transplantation: a case report and literature review / A leucemia mielóide aguda após transplante renal: um relato de caso e revisão da literatura

Abstract The incidence of malignancy is greater in kidney transplant recipients compared to the general population, though the higher risk is not equally distributed to all types of cancers. In face of the increased longevity of renal transplant recipients, certain cancers, such as acute leukemias, are becoming more prevalent. Acute myeloid leukemia (AML) typically presents with cytopenias and infections, both common findings after kidney transplantation. Therefore, the diagnosis of AML may be initially overlooked in these patients. We report the case of a 33-year-old man who presented with fever, pancytopenia and acute worsening of his renal allograft function 9 years after a living unrelated kidney transplant. After initial negative infectious work-up, a kidney biopsy revealed C4d-positive antibody-mediated rejection in combination with scattered atypical inflammatory cells. A subsequent bone marrow biopsy confirmed AML. He underwent successful induction chemotherapy with daunorubucin and cytarabine and ultimately achieved a complete remission. However, he developed a Page kidney with worsening renal function and abdominal pain three weeks after biopsy in the setting of chemotherapy-induced thrombocytopenia. Herein, we discuss the prevalence, risk factors, presentation and management of leukemia after kidney transplantation.

Resumo A incidência de cancer é maior em receptores de transplante renal em comparação com a população em geral, entretanto, o maior risco não é igualmente distribuído em todos os tipos de canceres. Em face do aumento da longevidade de pacientes transplantados renais, certos canceres, tais como leucemias agudas, são cada vez mais prevalentes. Leucemia mielóide aguda (LMA) normalmente se apresenta com citopenias e infecções, quadro comum após o transplante renal. Portanto, o diagnóstico da LMA pode ser inicialmente negligenciado nestes pacientes. Relatamos o caso de um homem de 33 anos de idade que se apresentou com febre, pancitopenia e agravamento agudo da função do enxerto renal de 9 anos após transplante de rim de doador vivo. Após inicial testes negativos para infecção, uma biópsia renal revelou rejeição por anticorpos com C4d positivo e dispersas células inflamatórias atípicas. A subsequente biópsia de medula óssea confirmou LMA. A quimioterapia de indução foi bem-sucedida com daunorubucin e citarabina e, finalmente, obtida uma complete remissão. No entanto, ele desenvolveu uma "Page kidney" com piora da função renal e dor abdominal, três semanas após a biópsia no contexto da trombocitopenia induzida pela quimioterapia. Aqui, discutimos a prevalência, fatores de risco, apresentação e manejo da leucemia pós-transplant renal.

Incremental prognostic value of kidney function decline over coronary artery disease for cardiovascular event prediction after coronary computed tomography.

It is unknown whether mild chronic kidney disease (CKD) is associated with adverse cardiovascular (CV) prognosis after accounting for coronary artery disease (CAD). Here we evaluated the interplay between CKD and CAD in predicting CV death or myocardial infarction (MI) and all-cause death. We included 1541 consecutive patients in the Partners registry (mean age 55 years, 43% female) over 18 years old with no known prior CAD who underwent coronary computed tomography angiography (CCTA). The results of CCTA were categorized as normal, nonobstructive (under half), or obstructive (half and over). Overall, 653 of the patients had no CAD, 583 had nonobstructive CAD, and 305 had obstructive CAD, while 1299 had eGFR over 60 ml/min per 1.73 m(2) and 242 had an eGFR under this value. The presence and severity of CAD was significantly associated with an increased rate of CV death or MI and all-cause death, even after adjustment for age, gender, symptoms, and risk factors. Similarly, reduced eGFR was significantly associated with CV death or MI and all-cause death after similar adjustment. The addition of reduced GFR to a model which included both clinical variables and CCTA findings resulted in significant improvement in the prediction of CV death or MI and all-cause death. Thus, among individuals referred for CCTA to evaluate CAD, renal dysfunction is associated with an increased rate of CV events, mainly driven by an increase in the rate of noncoronary CV events. In this group of patients, both eGFR and the presence and severity of CAD together improve the prediction of future CV events and death.