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Subclinical inflammation in protocol biopsies relates to tacrolimus exposure and human leukocyte antigen (HLA) matching. We aimed to characterize transcripts associated with rejection and tacrolimus exposure and the latter's association with transplant outcomes. We tested whether gene expression is associated with rejection using strictly normal protocol biopsies (n = 17) and biopsies with T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) according to Banff criteria (n = 12). Subsequently, we analyzed these transcripts in a set of 4-month protocol biopsies (n = 137) to assess their association with donor and recipient characteristics, the intensity of immunosuppression, and the graft outcome. Differential expression (false discovery rate (FDR) < 0.01, fold (change (FC) > 3) between normal and rejection biopsies yielded a set of 111 genes. In the protocol biopsy cohort (n = 137), 19 out of these 111 genes correlated with tacrolimus trough levels at the time of biopsy (TAC-C0), and unsupervised analysis split this cohort into two clusters. The two clusters differed in donor age and tacrolimus trough levels. Subclinical rejection, including borderline lesions, tended to occur in the same cluster. Logistic regression analysis indicated that TAC-C0 at the time of biopsy (OR: 0.83, 95%CI:0.72-0.06, p = 0.0117) was associated with cluster 2. In a follow-up averaging 70 ± 30 months, this patient group displayed a significant decline in renal function (p = 0.0135). The expression of rejection-associated transcripts in early protocol biopsies is associated with tacrolimus exposure and a faster decline in renal function.
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Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Tacrolimo/efeitos adversos , Rejeição de Enxerto/genética , Biópsia , Terapia de Imunossupressão , Imunossupressores/efeitos adversosRESUMO
In kidney transplantation, day-zero biopsies are used to assess organ quality and discriminate between donor-inherited lesions and those acquired post-transplantation. However, many centers do not perform such biopsies since they are invasive, costly and may delay the transplant procedure. We aim to generate a non-invasive virtual biopsy system using routinely collected donor parameters. Using 14,032 day-zero kidney biopsies from 17 international centers, we develop a virtual biopsy system. 11 basic donor parameters are used to predict four Banff kidney lesions: arteriosclerosis, arteriolar hyalinosis, interstitial fibrosis and tubular atrophy, and the percentage of renal sclerotic glomeruli. Six machine learning models are aggregated into an ensemble model. The virtual biopsy system shows good performance in the internal and external validation sets. We confirm the generalizability of the system in various scenarios. This system could assist physicians in assessing organ quality, optimizing allograft allocation together with discriminating between donor derived and acquired lesions post-transplantation.
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Nefropatias , Transplante de Rim , Humanos , Rim/patologia , Transplante Homólogo , Nefropatias/patologia , BiópsiaRESUMO
SIGNIFICANCE STATEMENT: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist. BACKGROUND: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. METHODS: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively. RESULTS: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted. CONCLUSIONS: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity. CLINICAL TRIAL REGISTRATION NUMBER: NCT04294459 .
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Transplante de Rim , Humanos , Anticorpos Monoclonais Humanizados , Rim , Isoanticorpos , Soro AntilinfocitárioRESUMO
Hypertension is a common chronic medical condition. Treatment is not satisfactory in a significant proportion of patients with primary hypertension, despite the concurrent use of three or more medications with different mechanisms of action. Such treatment-resistant hypertension is a clinical challenge associated with poor prognosis and needs further investigation. The efficacy of lifestyle changes has not been established yet in patients with resistant hypertension, and educational efforts appear clinically irrelevant in patients who must achieve behavioral changes without supervision. A 6-month multidisciplinary pilot intervention enrolled 50 patients with established resistant hypertension. The aims were: (1) to examine whether intensive and supervised lifestyle changes contribute to decreasing blood pressure in this condition, and (2) to identify which components affect compliance and feasibility. The program provided intensive changes in nutrition, physical exercise, and control of sleep disturbances supervised by nutritionists, physiotherapists, and psychologists. Nurses and pharmacists followed up on adherence to the antihypertensive medication. The primary outcome was 24 h blood pressure control. Data in patients with full compliance (n = 30) indicate that lifestyle modifications in resistant hypertension significantly reduced 24 h both systolic and diastolic blood pressure (p < 0.01), body mass index (p < 0.01), medication burden (p = 0.04), improving physical fitness, and cardiovascular risk markers such as heart rate (p = 0.01) and augmentation index (p = 0.02). The adherence to the intervention was moderate, with an attrition rate of 12%. A modified version reducing visits and explorations will likely improve compliance and can be used to assess the long-term maintenance of these benefits in managing resistant hypertension by diverse healthcare providers.
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BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is associated with poorer glycemic control and a higher risk of type-2 diabetes (T2D) complications, extrahepatic and cardiovascular disease (CVD). Our study aim was to evaluate the association between NAFLD, T2D complications, and the development of overall clinical events (OCE) (CV, liver-related, and mortality) in patients with T2D. METHODS: Prospective single-center study comprising T2D subjects with no history of CVD and non-T2D matched controls. Patients were selected from the Outpatient Diabetes Clinic of Vall d'Hebron Hospital and related primary care centers. RESULTS: 186 diabetics and 57 controls were included. Amongst T2D, 124/186 subjects had NAFLD (66.6%). T2D-NAFLD subjects showed a heavier metabolic burden and higher median liver stiffness (5.6kPa [4.5-7.3] vs 4.8 [4.2-5.8]; p=0.004) compared to non-NAFLD diabetics. During a median follow-up of 5.6 years, 33 (17.7%) T2D patients developed OCE vs 4 (7.0%) controls (p=0.049). No differences were found for OCE between NAFLD and non-NAFLD diabetics (16.9% vs 19.4%; p=0.68). CV was the most reported outcome and only one liver event occurred. NAFLD diabetics showed more often chronic kidney disease (CKD), whereas T2D complications and subclinical CVD rates were similar. A higher liver stiffness, older age, and male gender were independently associated with OCE amongst the entire T2D population and NAFLD diabetics. CONCLUSIONS: NAFLD and liver stiffness were associated with CKD and clinical outcomes in diabetics, respectively. A hepatic evaluation is recommended to identify high-risk T2D patients that would benefit from early referral to specialized care.
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Doenças Cardiovasculares , Complicações do Diabetes , Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Insuficiência Renal Crônica , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Fatores de Risco , Estudos Prospectivos , Diabetes Mellitus Tipo 2/complicações , Insuficiência Renal Crônica/complicações , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologiaRESUMO
BACKGROUND: Subclinical inflammation, including borderline lesions (BL), is very common (30-40%) after kidney transplantation (KT), even in low immunological risk patients, and can lead to interstitial fibrosis/tubular atrophy (IFTA) and worsening of renal function with graft loss. Few controlled studies have analyzed the therapeutic benefit of treating these BL on renal function and graft histology. Furthermore, these studies have only used bolus steroids, which may be insufficient to slow the progression of these lesions. Klotho, a transmembrane protein produced mainly in the kidney with antifibrotic properties, plays a crucial role in the senescence-inflammation binomial of kidney tissue. Systemic and local inflammation decrease renal tissue expression and soluble levels of α-klotho. It is therefore important to determine whether treatment of BL prevents a decrease in α-klotho levels, progression of IFTA, and loss of kidney function. METHODS: The TRAINING study will randomize 80 patients with low immunological risk who will receive their first KT. The aim of the study is to determine whether the treatment of early BL (3rd month post-KT) with polyclonal rabbit antithymocyte globulin (Grafalon®) (6 mg/kg/day) prevents or decreases the progression of IFTA and the worsening of graft function compared to conventional therapy after two years post-KT, as well as to analyze whether treatment of BL with Grafalon® can modify the expression and levels of klotho, as well as the pro-inflammatory cytokines that regulate its expression. DISCUSSION: This phase IV investigator-driven, randomized, placebo-controlled clinical trial will examine the efficacy and safety of Grafalon® treatment in low-immunological-risk KT patients with early BL. TRIAL REGISTRATION: clinicaltrials.gov : NCT04936282. Registered June 23, 2021, https://clinicaltrials.gov/ct2/show/NCT04936282?term=NCT04936282&draw=2&rank=1 . Protocol Version 2 of 21 January 2022. SPONSOR: Canary Isles Institute for Health Research Foundation, Canary Isles (FIISC). mgomez@fciisc.org .
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Nefropatias , Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Rim/patologia , Nefropatias/patologia , Projetos de Pesquisa , Inflamação/etiologia , Rejeição de Enxerto/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase IV como AssuntoRESUMO
BACKGROUND: Diagnostic tools to measure the response to individual immunosuppressive drugs for transplant patients are currently lacking. We previously developed the blood-based Immunobiogram bioassay for in-vitro characterization of the pharmacodynamic response of patients' own immune cells to a range of immunosuppressants. We used Immunobiogram to examine the association between patients' sensitivity to their prescribed immunosuppressants and clinical outcome. METHODS: We conducted an international, multicenter, observational study in a kidney transplant population undergoing maintenance immunosuppressive therapy. Patients were selected by clinical course poor [PCC] N = 53 (with renal dysfunction, and rejection signs in biopsy or/and an increase in DSA strength in last 12 months) versus good [GCC] N = 50 (with stable renal function and treatment, no rejection and no DSA titers). Immunobiogram dose-response curve parameters were compared between both subgroups in patients treated with mycophenolate, tacrolimus, corticosteroids, cyclosporine A or everolimus. Parameters for which significant inter-group differences were observed were further analyzed by univariate and subsequent multivariate logistic regression. RESULTS: Clinical outcome was associated with following parameters: area over the curve (AOC) and 25% (ID25) and 50% (ID50) inhibitory response in mycophenolate, tacrolimus, and corticosteroid-treated subgroups, respectively. These statistically significant associations persisted in mycophenolate (OR 0.003, CI95% <0.001-0.258; p = 0.01) and tacrolimus (OR < 0.0001, CI95% <0.00001-0.202; p = 0.016) subgroups after adjusting for concomitant corticosteroid treatment, and in corticosteroid subgroup after adjusting for concomitant mycophenolate or tacrolimus treatment (OR 0.003; CI95% <0.0001-0.499; p = 0.026). CONCLUSIONS: Our results highlight the potential of Immunobiogram as a tool to test the pharmacodynamic response to individual immunosuppressive drugs.
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Transplante de Rim , Humanos , Transplante de Rim/efeitos adversos , Tacrolimo/uso terapêutico , Ácido Micofenólico/uso terapêutico , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/tratamento farmacológico , Testes Diagnósticos de Rotina , Imunossupressores/efeitos adversos , Ciclosporina/uso terapêutico , Terapia de Imunossupressão , Quimioterapia CombinadaRESUMO
The diagnosis of acute T cell-mediated rejection (aTCMR) after kidney transplantation has considerable relevance for research purposes. Its definition is primarily based on tubulointerstitial inflammation and has changed little over time; aTCMR is therefore a suitable parameter for longitudinal data comparisons. In addition, because aTCMR is managed with antirejection therapies that carry additional risks, anxieties, and costs, it is a clinically meaningful endpoint for studies. This paper reviews the history and classifications of TCMR and characterizes its potential role in clinical trials: a role that largely depends on the nature of the biopsy taken (indication vs protocol), the level of inflammation observed (e.g., borderline changes vs full TCMR), concomitant chronic lesions (chronic active TCMR), and the therapeutic intervention planned. There is ongoing variability-and ambiguity-in clinical monitoring and management of TCMR. More research, to investigate the clinical relevance of borderline changes (especially in protocol biopsies) and effective therapeutic strategies that improve graft survival rates with minimal patient morbidity, is urgently required. The present paper was developed from documentation produced by the European Society for Organ Transplantation (ESOT) as part of a Broad Scientific Advice request that ESOT submitted to the European Medicines Agency for discussion in 2020. This paper proposes to move toward refined definitions of aTCMR and borderline changes to be included as primary endpoints in clinical trials of kidney transplantation.
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Transplante de Rim , Biópsia , Rejeição de Enxerto/etiologia , Humanos , Inflamação/patologia , Rim/patologia , Transplante de Rim/efeitos adversos , Transplante de Rim/métodos , Linfócitos TRESUMO
Antibody-mediated rejection (AMR) is caused by antibodies that recognize donor human leukocyte antigen (HLA) or other targets. As knowledge of AMR pathophysiology has increased, a combination of factors is necessary to confirm the diagnosis and phenotype. However, frequent modifications to the AMR definition have made it difficult to compare data and evaluate associations between AMR and graft outcome. The present paper was developed following a Broad Scientific Advice request from the European Society for Organ Transplantation (ESOT) to the European Medicines Agency (EMA), which explored whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research. ESOT considers that an AMR diagnosis must be based on a combination of histopathological factors and presence of donor-specific HLA antibodies in the recipient. Evidence for associations between individual features of AMR and impaired graft outcome is noted for microvascular inflammation scores ≥2 and glomerular basement membrane splitting of >10% of the entire tuft in the most severely affected glomerulus. Together, these should form the basis for AMR-related endpoints in clinical trials of kidney transplantation, although modifications and restrictions to the Banff diagnostic definition of AMR are proposed for this purpose. The EMA provided recommendations based on this Broad Scientific Advice request in December 2020; further discussion, and consensus on the restricted definition of the AMR endpoint, is required.
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Transplante de Rim , Anticorpos , Biópsia , Rejeição de Enxerto , Antígenos HLA , Humanos , IsoanticorposRESUMO
This article outlines the evolving definition of rejection following kidney transplantation. The viewpoints and evidence presented were included in documentation prepared for a Broad Scientific Advice request to the European Medicines Agency (EMA), relating to clinical trial endpoints in kidney transplantation. This request was initiated by the European Society for Organ Transplantation (ESOT) in 2016 and finalized following discussions between the EMA and ESOT in 2020. In ESOT's opinion, the use of "biopsy-proven acute rejection" as an endpoint for clinical trials in kidney transplantation is no longer accurate, although it is still the approved histopathological endpoint. The spectrum of rejection is now divided into the phenotypes of borderline changes, T cell-mediated rejection, and antibody-mediated rejection, with the latter two phenotypes having further subclassifications. Rejection is also described in relation to graft (dys)function, diagnosed because of protocol (surveillance) or indication (for-cause) biopsies. The ongoing use of outdated terminology has become a potential barrier to clinical research in kidney transplantation. This article presents these perspectives and issues, and provides a foundation on which subsequent articles within this Special Issue of Transplant International build.
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Transplante de Rim , Anticorpos , Biópsia , Rejeição de Enxerto/etiologia , Humanos , Rim/patologia , Linfócitos TRESUMO
BACKGROUND AND OBJECTIVES: Kidney biopsy (KB) is the "gold standard" for the diagnosis of nephropathies and it is a diagnostic tool that presents a low rate of complications. Nowadays, biobank collections of renal tissue of patients with proven renal pathology are essential for research in nephrology. To provide enough tissue for the biobank collection, it is usually needed to obtain an extra kidney core at the time of kidney biopsy. The objective of our study is to evaluate the complications after KB and to analyze whether obtaining an extra core increases the risk of complications. MATERIAL AND METHODS: Prospective observational study of KBs performed at Vall d'Hebron Hospital between 2019 and 2020. All patients who accepted to participate to our research biobank of native kidney biopsies were included to the study. Clinical and laboratory data were reviewed and we studied risk factors associated with complications. RESULTS: A total of 221 patients were included, mean age 56.6 (±16.8) years, 130 (58.8%) were men, creatinine was 2.24 (±1.94) mg/dL, proteinuria 1.56 (0.506-3.590) g/24 h, hemoglobin 12.03 (±2.3) g/dL, INR 0.99 (±0.1), and prothrombin time (PT) 11.86 (±1.2) s. A total of 38 patients (17.2%) presented complications associated with the procedure: 13.1% were minor complications, 11.3% (n = 25) required blood transfusion, 1.4% (n = 3) had severe hematomas, 2.3% (n = 5) required embolization, and 0.5% (n = 1) presented arterio-venous fistula. An increased risk for complication was independently associated with obtaining a single kidney core (vs. 2 and 3 cores) (p = 0.021). CONCLUSIONS: KB is an invasive and safe procedure with a low percentage of complications. Obtaining an extra kidney core for research does not increase the risk of complications during the intervention, which remains low in concordance with previously published reports.
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INTRODUCTION: There is no consensus on the most appropriate treatment for chronic active antibody-mediated rejection (cAMR). Recent studies suggest that treatment with tocilizumab (TCZ) may stabilize graft function, decrease the intensity of donor-specific HLA antibodies (DSAs) and reduce inflammation of microcirculation. PATIENTS AND METHODS: Observational study with renal allograft recipients diagnosed with cAMR (n = 5) who had not submitted a response to traditional treatment based on the combination of plasma replacements, immunoglobulins, and rituximab. Patients were told to be treated with TCZ as compassionate use in six doses per month (8 mg/kg/month). Renal function, proteinuria, and the intensity of DSAs were monitored during follow-up. RESULTS: Five patients, average age 60 ± 13 years, three male and two retrasplants (cPRA average 55%) with preformed DSAs. Treatment with TCZ was initiated within 47 ± 52 days of biopsy. In two cases treatment was discontinued after the first dose, by severe bicitopenia with cytomegalovirus viremia and by graft failure, respectively. In the three patients who completed treatment, no stability of renal function (serum creatinine from 1.73 ± 0.70 to 2.04 ± 0.52 mg/dL, e-FGR 4 6 ± 15 to 36 ± 16 mL/min), showed increased proteinuria (3.2 ± 4.0 to 6.9 ± 11.0 g/g) and the intensity of DSAs maintain stable. No changes were observed in the degree of inflammation of microcirculation (g+pt 4.2 ± 0.8 vs. 4.3 ± 1.0) or in the degree of transplant glomerulopathy (cg 1.2 ± 0.4 vs. 1.8 ± 1.0). CONCLUSIONS: TCZ therapy does not appear to be effective in modifying the natural history of chronic active antibody-mediated rejection, does not improve the degree of inflammation of microcirculation and does not reduces the intensity of DSAs.
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Transplante de Rim , Humanos , Masculino , Pessoa de Meia-Idade , Idoso , Transplante de Rim/efeitos adversos , Isoanticorpos , Proteinúria/etiologia , Inflamação/etiologia , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/prevenção & controleRESUMO
BACKGROUND: Preimplantation scores assist with correct kidney graft allocation, but macroscopic graft features have never been evaluated in this scenario. METHODS: We designed a graft appraisal questionnaire, assessed its reproducibility by comparing the senior and junior surgeon responses and evaluated which features can predict transplant outcomes in 202 patients transplanted from 144 donors at a tertiary center. We created new prediction models in combination with validated preimplantation scores. The primary outcome was graft loss or eGFR<30 mL/min/1.73 m2 at six months and secondary outcomes were delayed graft function, early graft loss and graft function at six months. RESULTS: Interrater correlation was very good for adherent perinephric fat (kappa=0.91) and acceptable for cortical surface roughness (kappa=0.51) and cortical color (kappa=0.47). Adherent perirenal fat (Odds ratio=4.77; 95% CI: 2.10-10.85) and surface roughness (OR=2.11, 95% CI: 1.25-3.58) were independent predictors of the primary outcome, improving the kidney donor risk index efficacy model (AUC 0.71 vs. 0.82, P≤0.001), while cortical color and adherent fat improved the Irish risk model for delayed graft function (AUC 0.76 vs. 0.82, P=0.03). We created nomograms to visually assess the risk of both endpoints. CONCLUSIONS: Kidney graft macroscopic appraisal is reproducible between surgeons and can improve the accuracy of clinical preimplantational prediction scores.
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Transplante de Rim , Cirurgiões , Função Retardada do Enxerto , Sobrevivência de Enxerto/fisiologia , Humanos , Transplante de Rim/efeitos adversos , Estudos Prospectivos , Reprodutibilidade dos Testes , Medição de RiscoRESUMO
BACKGROUND: Checkpoint inhibitors (CPIs) have drastically improved metastatic cancer outcomes. However, immunotherapy is associated with multiple toxicities, including acute kidney injury (AKI). Data about CPI-related AKI are limited. Our aim was to determine risk factors for CPI-related AKI as well as its clinical characteristics and its impact on mortality in patients undergoing immunotherapy. METHODS: All patients under CPI at our centre between March 2018 and May 2019 and with a follow-up through April 2020 were included. Demographic, clinical and laboratory data were collected. AKI was defined according to the Kidney Disease: Improving Global Outcomes guidelines. We performed a logistic regression model to identify independent risk factors for AKI and actuarial survival analysis to establish risk factors for mortality in this population. RESULTS: A total of 759 patients were included, with a median age of 64 years. A total of 59% were men and baseline median creatinine was 0.80 mg/dL. The most frequent malignancy was lung cancer and 56% were receiving anti-programmed death protein 1 (PD-1). About 15.5% developed AKI during the follow-up. Age and baseline kidney function were identified as independent risk factors for CPI-related AKI. At the end of follow-up, 52.3% of patients had died. The type of cancer (not melanoma, lung or urogenital malignance), type of CPI (not cytotoxic T-lymphocyte-associated protein 4, PD-1, programmed death-ligand 1 or their combination) and the presence of an episode of AKI were identified as risk factors for mortality. CONCLUSIONS: A total of 15.5% of patients under immunotherapy presented with AKI. A single AKI episode was identified as an independent risk factor for mortality in these patients and age and baseline renal function were risk factors for the development of AKI.
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Injúria Renal Aguda , Neoplasias , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Creatinina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1 , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Checkpoint inhibitors (CPIs) are used to treat solid organ metastatic malignancies. They act by triggering a vigorous immune response against tumoural cells, preventing their proliferation and metastasis. However, this is not a selective response and can cause immune-related adverse events (irAEs). The kidney can potentially be damaged, with an incidence of irAEs of 1-4%. The most frequent type of toxicity described is acute interstitial nephritis (AIN). METHODS: We conducted a study of patients with solid organ metastatic malignancies treated with immunotherapy who developed acute renal injury and underwent kidney biopsy in the last 14 months at the Vall d'Hebron University Hospital. RESULTS: In all, 826 solid organ malignancies were treated with immunotherapy in our centre, 125 of them (15.1%) developed acute kidney injury (AKI), 23 (18.4% of AKI) visited the nephrology department and 8 underwent kidney biopsy. The most frequent malignancy was lung cancer, in five patients (62%), followed by two patients (25%) with melanoma and one patient (12%) with pancreatic cancer. Four patients (50%) had already received previous oncological therapy, and for the remaining four patients (50%), CPI was the first-line therapy. Five patients (62%) were treated with anti-programmed cell death protein 1, three patients (37%) received anti-programmed death ligand 1 and two (25%) patients were treated in combination with anti-cytotoxic T-lymphocyte antigen 4. The time between the start of CPI and the onset of the AKI ranged from 2 to 11 months. The most frequent urine findings were subnephrotic-range proteinuria, with a mean protein:creatinine ratio of 544 mg/g (standard deviation 147) and eosinophiluria. All patients were biopsied after being diagnosed with AIN. Three patients (37%) received treatment with pulses of methylprednisolone 250-500 mg/day and five patients (62%) received prednisone 1 mg/kg/day. Seven patients (87%) experienced recovery of kidney function and one patient (12%) progressed to chronic kidney disease. CONCLUSIONS: We report on eight patients with CPI-related AIN diagnosed in the last 14 months at our centre. The novel immunotherapy treatment of metastatic solid organ malignancies carries a higher risk of irAEs. The kidney is one of the most commonly affected organs, frequently presenting as an AIN and exhibiting a favourable response to steroid treatment.
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INTRODUCTION: Chronic kidney disease (CKD) patients infected with COVID-19 are at risk of serious complications such as hospitalization and death. The prognosis and lethality of COVID-19 infection in patients with established kidney disease has not been widely studied. METHODS: Data included patients who underwent kidney biopsy at the Vall d'Hebron Hospital between January 2013 and February 2020 with COVID-19 diagnosis during the period from March 1 to May 15, 2020. RESULTS: Thirty-nine (7%) patients were diagnosed with COVID-19 infection. Mean age was 63 ± 15 years and 48.7% were male. Hypertension was present in 79.5%, CKD without renal replacement therapy in 76.9%, and cardiovascular disease in 64.1%. Nasopharyngeal swab was performed in 26 patients; older (p = 0.01), hypertensive (p = 0.005), and immunosuppressed (p = 0.01) patients, those using RAS-blocking drugs (p = 0.04), and those with gastrointestinal symptoms (p = 0.02) were more likely to be tested for CO-VID-19. Twenty-two patients required hospitalization and 15.4% died. In bivariate analysis, mortality was associated with older age (p = 0.03), cardiovascular disease (p = 0.05), chronic obstructive pulmonary disease (p = 0.05), and low hemoglobin levels (p = 0.006). Adjusted Cox regression showed that low hemoglobin levels at admission had 1.81 greater risk of mortality. CONCLUSIONS: Patients with CO-VID-19 infection and kidney disease confirmed by kidney biopsy presented a mortality of 15.4%. Swab test for COVID-19 was more likely to be performed in older, hypertensive, and immunosuppressed patients, those using RAS-blocking drugs, and those with gastrointestinal symptoms. Low hemoglobin is a risk factor for mortality.
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COVID-19/complicações , Insuficiência Renal Crônica/complicações , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biópsia , COVID-19/mortalidade , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , Feminino , Hemoglobinas/análise , Hospitalização/estatística & dados numéricos , Humanos , Hipertensão/complicações , Hipertensão/epidemiologia , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Prognóstico , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/mortalidade , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/patologia , Terapia de Substituição Renal , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
A major complication of primary focal segmental glomerulosclerosis (FSGS) is its recurrence after kidney transplantation that happens in 30 to 40% of the patients. The diagnosis of these relapses is not always easy as the histological lesions are not highly specific and appear after the proteinuria increase. Currently, there are no accurate biomarkers to detect FSGS recurrence. Our group identified a modified form of Apolipoprotein A-I (ApoA-I), named ApoA-Ib, specifically present in the urine of recurrent FSGS patients after kidney transplantation. Aberrant forms of ApoA-I have also been described in the urine of native primary FSGS patients; this feature has been associated with prominent staining of ApoA-I at the apical membrane of the tubular cells. In this study, we aim to analyze the ApoA-I distribution in kidney allograft biopsies of recurrent FSGS patients. We detected ApoA-I by immunohistochemistry in kidney allograft biopsies of patients with FSGS relapse after kidney transplantation and in kidney allograft biopsies of patients with a disease different from FSGS in the native kidney (non-FSGS). In recurrent FSGS patients, ApoA-I was prominently localized at the brush border of the tubular cells, while in the non-FSGS patients, ApoA-I was found along the cytoplasm of the tubular cells. The localization of ApoA-I at the brush border of the tubular cells is a specific feature of primary FSGS in relapse. This suggests that ApoA-I staining in kidney biopsies, coupled with ApoA-Ib measurement in urine, could be used as a diagnostic tool of primary FSGS relapse after kidney transplantation due to its highly specific tubular distribution.
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The impact of corticosteroid withdrawal on medium-term graft histological changes in kidney transplant (KT) recipients under standard immunosuppression is uncertain. As part of an open-label, multicenter, prospective, phase IV, 24-month clinical trial (ClinicalTrials.gov, NCT02284464) in low-immunological-risk KT recipients, 105 patients were randomized, after a protocol-biopsy at 3 months, to corticosteroid continuation (CSC, n = 52) or corticosteroid withdrawal (CSW, n = 53). Both groups received tacrolimus and MMF and had another protocol-biopsy at 24 months. The acute rejection rate, including subclinical inflammation (SCI), was comparable between groups (21.2 vs. 24.5%). No patients developed dnDSA. Inflammatory and chronicity scores increased from 3 to 24 months in patients with, at baseline, no inflammation (NI) or SCI, regardless of treatment. CSW patients with SCI at 3 months had a significantly increased chronicity score at 24 months. HbA1c levels were lower in CSW patients (6.4 ± 1.2 vs. 5.7 ± 0.6%; p = 0.013) at 24 months, as was systolic blood pressure (134.2 ± 14.9 vs. 125.7 ± 15.3 mmHg; p = 0.016). Allograft function was comparable between groups and no patients died or lost their graft. An increase in chronicity scores at 2-years post-transplantation was observed in low-immunological-risk KT recipients with initial NI or SCI, but CSW may accelerate chronicity changes, especially in patients with early SCI. This strategy did, however, improve the cardiovascular profiles of patients.
RESUMO
The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.