Tubulo-interstitial inflammation increases the risk of graft loss after the recurrence of IgA nephropathy.

Background: Immunoglobulin A nephropathy (IgAN) is the most frequent recurrent disease in kidney transplant recipients and its recurrence contributes to reducing graft survival. Several variables at the time of recurrence have been associated with a higher risk of graft loss. The presence of clinical or subclinical inflammation has been associated with a higher risk of kidney graft loss, but it is not precisely known how it influences the outcome of patients with recurrent IgAN. Methods: We performed a multicentre retrospective study including kidney transplant recipients with biopsy-proven recurrence of IgAN in which Banff and Oxford classification scores were available. 'Tubulo-interstitial inflammation' (TII) was defined when 't' or 'i' were ≥2. The main endpoint was progression to chronic kidney disease (CKD) stage 5 or to death censored-graft loss (CKD5/DCGL). Results: A total of 119 kidney transplant recipients with IgAN recurrence were included and 23 of them showed TII. Median follow-up was 102.9 months and 39 (32.8%) patients reached CKD5/DCGL. TII related to a higher risk of CKD5/DCGL (3 years 18.0% vs 45.3%, log-rank 7.588, P = .006). After multivariate analysis, TII remained related to the risk of CKD5/DCGL (HR 2.344, 95% CI 1.119-4.910, P = .024) independently of other histologic and clinical variables. Conclusions: In kidney transplant recipients with IgAN recurrence, TII contributes to increasing the risk of CKD5/DCGL independently of previously well-known variables. We suggest adding TII along with the Oxford classification to the clinical variables to identify recurrent IgAN patients at increased risk of graft loss who might benefit from intensified immunosuppression or specific IgAN therapies.

Long-Term Evolution of the Adaptive NKG2C+ NK Cell Response to Cytomegalovirus Infection in Kidney Transplantation: An Insight on the Diversity of Host-Pathogen Interaction.

Human CMV infection is frequent in kidney transplant recipients (KTR). Pretransplant Ag-specific T cells and adaptive NKG2C+ NK cells associate with reduced incidence of infection in CMV+ KTR. Expansions of adaptive NKG2C+ NK cells were reported in posttransplant CMV-infected KTR. To further explore this issue, NKG2C+ NK, CD8+, and TcRγδ T cells were analyzed pretransplant and at different time points posttransplant for ≥24 mo in a cohort of CMV+ KTR (n = 112), stratified according to CMV viremia detection. In cryopreserved samples from a subgroup (n = 49), adaptive NKG2C+ NK cell markers and T cell subsets were compared after a longer follow-up (median, 56 mo), assessing the frequencies of CMV-specific T cells and viremia at the last time point. Increased proportions of NKG2C+ NK, CD8+, and TcRγδ T cells were detected along posttransplant evolution in viremia(+) KTR. However, the individual magnitude and kinetics of the NKG2C+ NK response was variable and only exceptionally detected among viremia(-) KTR, presumably reflecting subclinical viral replication events. NKG2C+ expansions were independent of KLRC2 zygosity and associated with higher viral loads at diagnosis; no relation with other clinical parameters was perceived. Increased proportions of adaptive NKG2C+ NK cells (CD57+, ILT2+, FcεRIγ-) were observed after resolution of viremia long-term posttransplant, coinciding with increased CD8+ and Vδ2- γδ T cells; at that stage CMV-specific T cells were comparable to viremia(-) cases. These data suggest that adaptive NKG2C+ NK cells participate with T cells to restore CMV replication control, although their relative contribution cannot be discerned.

COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium.

Kidney transplant recipients may be at a high risk of developing critical coronavirus disease 2019 (COVID-19) illness due to chronic immunosuppression and comorbidities. We identified hospitalized adult kidney transplant recipients at 12 transplant centers in the United States, Italy, and Spain who tested positive for COVID-19. Clinical presentation, laboratory values, immunosuppression, and treatment strategies were reviewed, and predictors of poor clinical outcomes were determined through multivariable analyses. Among 9845 kidney transplant recipients across centers, 144 were hospitalized due to COVID-19 during the 9-week study period. Of the 144 patients, 66% were male with a mean age of 60 (±12) years, and 40% were Hispanic and 25% were African American. Prevalent comorbidities included hypertension (95%), diabetes (52%), obesity (49%), and heart (28%) and lung (19%) disease. Therapeutic management included antimetabolite withdrawal (68%), calcineurin inhibitor withdrawal (23%), hydroxychloroquine (71%), antibiotics (74%), tocilizumab (13%), and antivirals (14%). During a median follow-up period of 52 days (IQR: 16-66 days), acute kidney injury occurred in 52% cases, with respiratory failure requiring intubation in 29%, and the mortality rate was 32%. The 46 patients who died were older, had lower lymphocyte counts and estimated glomerular filtration rate levels, and had higher serum lactate dehydrogenase, procalcitonin, and interleukin-6 levels. In sum, hospitalized kidney transplant recipients with COVID-19 have higher rates of acute kidney injury and mortality.

Use of tocilizumab in kidney transplant recipients with COVID-19.

Acute respiratory distress syndrome associated with coronavirus infection is related to a cytokine storm with large interleukin-6 (IL-6) release. The IL-6-receptor blocker tocilizumab may control the aberrant host immune response in patients with coronavirus disease 2019 (COVID-19) . In this pandemic, kidney transplant (KT) recipients are a high-risk population for severe infection and showed poor outcomes. We present a multicenter cohort study of 80 KT patients with severe COVID-19 treated with tocilizumab during hospital admission. High mortality rate was identified (32.5%), related with older age (hazard ratio [HR] 3.12 for those older than 60 years, P = .039). IL-6 and other inflammatory markers, including lactic acid dehydrogenase, ferritin, and D-dimer increased early after tocilizumab administration and their values were higher in nonsurvivors. Instead, C-reactive protein (CRP) levels decreased after tocilizumab, and this decrease positively correlated with survival (mean 12.3 mg/L in survivors vs. 33 mg/L in nonsurvivors). Each mg/L of CRP soon after tocilizumab increased the risk of death by 1% (HR 1.01 [confidence interval 1.004-1.024], P = .003). Although patients who died presented with worse respiratory situation at admission, this was not significantly different at tocilizumab administration and did not have an impact on outcome in the multivariate analysis. Tocilizumab may be effective in controlling cytokine storm in COVID-19 but randomized trials are needed.

COVID-19 in elderly kidney transplant recipients.

The SARS-Cov-2 infection disease (COVID-19) pandemic has posed at risk the kidney transplant (KT) population, particularly the elderly recipients. From March 12 until April 4, 2020, we diagnosed COVID-19 in 16 of our 324 KT patients aged ≥65 years old (4.9%). Many of them had had contact with healthcare facilities in the month prior to infection. Median time of symptom onset to admission was 7 days. All presented with fever and all but one with pneumonia. Up to 33% showed renal graft dysfunction. At infection diagnosis, mTOR inhibitors or mycophenolate were withdrawn. Tacrolimus was withdrawn in 70%. The main treatment combination was hydroxychloroquine and azithromycin. A subset of patients was treated with anti-retroviral and tocilizumab. Short-term fatality rate was 50% at a median time since admission of 3 days. Those who died were more frequently obese, frail, and had underlying heart disease. Although a higher respiratory rate was observed at admission in nonsurvivors, symptoms at presentation were similar between both groups. Patients who died were more anemic, lymphopenic, and showed higher D-dimer, C-reactive protein, and IL-6 at their first tests. COVID-19 is frequent among the elderly KT population and associates a very early and high mortality rate.

Pretransplant adaptive NKG2C+ NK cells protect against cytomegalovirus infection in kidney transplant recipients.

Cytomegalovirus (CMV) infection constitutes a complication for kidney transplant recipients (KTR) and CMV-specific T cells reduce the risk of viral replication in seropositive patients. CMV promotes the adaptive differentiation and expansion of an NK cell subset, hallmarked by expression of the CD94/NKG2C receptor with additional characteristic features. We previously reported an association of pretransplant NKG2C+ NK cells with a reduced incidence of CMV infection. We have strengthened the analysis in cryopreserved peripheral blood mononuclear cells from an enlarged KTR cohort (n = 145) with homogeneous immunosuppression, excluding cases at low risk of infection (ie, CMV D-R-) or receiving antiviral prophylaxis. Moreover, adaptive NKG2C+ NK cell-associated markers (ie, NKG2A, CD57, Immunoglobulin-like transcript 2 [LIR1 or LILRB1], FcεRI γ chain, and Prolymphocytic Leukemia Zinc Finger transcription factor) as well as T lymphocyte subsets were assessed by multicolor flow cytometry. The relation of NKG2C+ NK cells with T cells specific for CMV antigens was analyzed in pretransplant patients (n = 29) and healthy controls (n = 28). Multivariate Cox regression and Kaplan-Meier analyses supported that NKG2C+ NK cells bearing adaptive markers were specifically associated with a reduced incidence of posttransplant symptomatic CMV infection; no correlation between NKG2C+ NK cells and CMV-specific T cells was observed. These results support that adaptive NKG2C+ NK cells contribute to control CMV infection in KTR.

Impact of preformed and de novo anti-HLA DP antibodies in renal allograft survival.

The influence of antibodies against HLA-DP antigens detected with solid-phase assays on graft survival after kidney transplantation (KT) is uncertain. We evaluated with Luminex® the prevalence of pre- and posttransplant DP antibodies in 440 KT patients and their impact on graft survival. For 291 patients with available pretransplant samples, DP antibodies were present in 39.7% KT with pretransplant HLA antibodies and 47.7% with DSA. Graft survival of KT with pretransplant class-II DSA was worse than with non-DSA (p=0.01). DP antibodies did not influence graft survival. Of 346 patients monitored post-KT, 17.1% had HLA class-II antibodies, 56% with DP antibodies. Class-II DSA was detected in 39%, 60.9% of them had DP antibodies. Graft survival was worse in patients with class-II DSA (p=0.022). DP antibodies did not change these results. The presence of isolated DP antibodies was a rare event both pre- and posttransplantation (1.03 and 0.86%). The presence of pretransplant and posttransplant DSA is associated with a negative impact on graft survival. However, the presence of DP antibodies does not modify this impact significantly.

Clinical relevance of pretransplant anti-HLA donor-specific antibodies: does C1q-fixation matter?

UNLABELLED: Anti-HLA donor-specific antibodies (DSA) identified by single antigen bead array (SAB) are questioned for their excess in sensitivity and lack of event prediction after transplantation. POPULATION AND METHODS: We retrospectively evaluated specific types of preformed DSA (class I, class II or C1q-fixing) and their impact on graft survival. Kidney transplantations performed across negative CDC-crossmatch were included (n=355). Anti-HLA antibodies were tested using SAB to identify DSA and their capacity to fix C1q. RESULTS: Twenty-eight patients with pretransplant DSA(+) with MFI>2000 were selected to assess C1q fixation. DSA were C1q+ in 15 patients and C1q- in 13, without significant differences in demographics, acute rejection, graft loss or renal function. The maximum MFI of DSA in patients with C1q-fixing DSA was significantly higher (p=0.008). Patients with DSA class-I suffered more antibody-mediated rejection (AMR) and had worse graft survival than class-II. The capacity of DSA I to fix C1q did not correlate with rejection, graft function or graft loss. CONCLUSIONS: C1q testing in pretransplant sera with DSA was unable to predict acute antibody-mediated rejection or early graft loss, but the presence of DSA class I compared to DSA only class II did. Despite non-fixing complement in vitro, pretransplant C1q-negative DSA I can mediate rejection and graft loss.

Chagas' disease and kidney donation.

Due to current trends in human population movements, there has been an increase in the number of individuals with Chagas’ disease (CD) living in non-endemic regions; as such, there is a high probability that we will face an increase in cases of CD, both in patients requiring renal replacement therapy and in potential donors. We present the case of an organ donor with positive serology for Trypanosoma cruzi, whose kidneys were implanted into two different recipients. Prophylaxis was administered with benznidazole for 3 weeks. Over the course of two years of serological and clinical follow-up, no evidence of Chagas’ transmission or infection was observed. This positive evolution suggests that renal transplants derived from donors with positive serology results and no signs of acute or chronic disease may be acceptable. We also provide a review of the evidence supporting this conclusion and the available recommendations in the medical literature.

Enfermedad de Chagas y donación renal / Chagas' disease and kidney donation

Debido a los movimientos poblacionales que se desarrollan actualmente, existe un incremento en el número de individuos con enfermedad de Chagas (EC) que viven en regiones no endémicas; por tanto, existe una gran probabilidad de que nos enfrentemos a un aumento de casos de EC, tanto en pacientes que requieren tratamiento renal sustitutivo como en potenciales donantes. Presentamos el caso de un donante de órganos con serología Trypanosoma cruzi positiva, cuyos riñones se implantaron en sendos receptores. Se realizó profilaxis con benznidazol durante 3 semanas. En dos años de seguimiento serológico y clínico no se ha objetivado ninguna evidencia de transmisión ni afectación chagásica. La buena evolución sugiere que el trasplante de riñones procedentes de donantes con serología positiva sin signos de enfermedad aguda o crónica puede ser aceptable. Revisamos las evidencias que lo sustentan y las recomendaciones disponibles en la literatura (AU)

Due to current trends in human population movements, there has been an increase in the number of individuals with Chagas' disease (CD) living in non-endemic regions; as such, there is a high probability that we will face an increase in cases of CD, both in patients requiring renal replacement therapy and in potential donors. We present the case of an organ donor with positive serology for Trypanosoma cruzi, whose kidneys were implanted into two different recipients. Prophylaxis was administered with benznidazole for 3 weeks. Over the course of two years of serological and clinical follow-up, no evidence of Chagas' transmission or infection was observed. This positive evolution suggests that renal transplants derived from donors with positive serology results and no signs of acute or chronic disease may be acceptable. We also provide a review of the evidence supporting this conclusion and the available recommendations in the medical literature (AU)

Chronic renal allograft injury: early detection, accurate diagnosis and management.

Chronic renal allograft injury (CRAI) is a multifactorial clinical/pathological entity characterised by a progressive decrease in glomerular filtration rate, generally associated with proteinuria and arterial hypertension. Classical views tried to distinguish between immunological (sensitization, low HLA compatibility, acute rejection episodes) and non-immunological factors (donor age, delayed graft function, calcineurin inhibitors [CNI] toxicity, arterial hypertension, infections) contributing to its development. Defining it as a generic idiopathic entity has precluded more comprehensive attempts for therapeutic options. Consequently, it is necessary to reinforce the diagnostic work-up to add etiopathogenetic diagnosis in any case of graft dysfunction, specially transplant vasculopathy and transplant glomerulopathy, reserving the term interstitial fibrosis and tubular atrophy (IFTA) when a case of CRAI is unspecific and no clear contributing factors or a specific etiology is possible in diagnosis. Earlier detection and intervention of CRAI remain as key challenges for transplant physicians. Changes in SCr levels and proteinuria often occur late in disease progression and may not accurately represent the underlying renal damage. Deterioration of renal function over time, determined through slope analysis, is a more accurate indicator of CRAI, and earlier identification of renal deterioration may prompt earlier changes in immunosuppressive therapies. The crucial point is probably to distinguish between nonimmunological or toxic CRAI and immunological-derived CRAI cases. Conversion to nonnephrotoxic immunosuppressants, such as mTOR inhibitors, holds promise in reducing the impact of toxic CRAI by both avoiding and reducing the impact of CNIs and reducing smooth muscle cell proliferation in the kidney. CRAI due to chronic antibody mediated rejection is an important entity, better and better defined that carries a bad prognosis and is associated with graft loss. The best prevention is adequate immunosuppression and tight patient monitoring, from the clinical, analytical and histological standpoint. While clinical trial evidence is needed for early detection and intervention in patients with CRAI, this review represents the current knowledge upon which clinicians can base their strategies. New prospective, ideally well-controlled trials are needed to establish the usefulness of different potentially therapeutic regimens. These evidences should demonstrate the benefits before extended uncontrolled use of drugs such as rituximab, bortezomib or eculizumab, which are expensive and frequently iatrogenic.