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Background CD163 and calprotectin have been proposed as biomarkers of active renal vasculitis. This study aimed to determine whether the combination of serum/urine calprotectin (s/uCalprotectin) and urinary soluble CD163 (suCD163) increases their individual performance as activity biomarkers. Methods We included 138 patients diagnosed with ANCA vasculitis (n = 52 diagnostic phase, n = 86 remission). The study population was divided into the inception (n = 101) and the validation cohorts (n = 37). We determined the s/uCalprotectin and suCD163 concentration using enzyme-linked immunoassay at the diagnostic or at the remission phase. Receiver operating characteristic (ROC) curves were conducted to assess the biomarkers’ classificatory values. We elaborated a combinatorial biomarker model in the inception cohort. The ideal cutoffs were used in the validation cohort to confirm the model's accuracy in the distinction between active disease and remission. We added the classical ANCA vasculitis activity biomarkers to the model to increase the classificatory performance. Results The concentrations of sCalprotectin and suCD163 were higher in the diagnostic compared with the remission phase (P = .013 and P Conclusions In patients with ANCA vasculitis, a predictive model combining sCalprotectin, suCD163 and haematuria could be useful in detecting active kidney disease.

Cellular mechanisms involved in human renal recovery after an episode of acute kidney injury (AKI) are understudied. We aim to characterize the urinary immune cell phenotype of patients with AKI and evaluate its ability to predict renal recovery.A prospective study of critically ill patients with stage ≥ 2 AKI by KDIGO and sterile leukocyturia at admission was performed. Urine samples were collected fresh at day 0 and 2 and samples were analyzed by flow cytometry for different leukocytes. Patients were categorized in renal recovery or no-recovery groups.28 patients were included, all with sepsis, 60.7% of which recovered renal function. The main urinary leukocytes present were neutrophils, followed by mononuclear phagocytic cells and B cells. Patients who recovered renal function had more M2 macrophages at day 2 (p = 0.043) and less B cells at admission (p = 0.006). M2 macrophages had an AUC-ROC of 0.796 (0.601-0.990) for recovery prediction and B cells an AUC-ROC of 0.743 (0.560-0.926) for no recovery. B regulatory cells were found in the urine of AKI patients.The urinary immune cell phenotype of severe AKI patients was composed essentially of neutrophils, mononuclear phagocytic cells and B cells. Our data suggest that M2 macrophages may promote and B cells preclude renal recovery. More studies are needed to validate our results and further explore the role of immune cells in renal recovery.

Acute graft pyelonephritis (AGP) is the leading cause of bloodstream infection in kidney transplant (KT) recipients. The prevalence of urinary tract infections caused by multidrug-resistant (MDR) Gram-negative bacilli is increasing. This 14-year prospective observational study sought to determine the clinical characteristics, risk factors, and outcomes of AGP with bacteremia due to MDR Gram-negative bacilli. Overall, 278 episodes of AGP with bacteremia due to MDR Gram-negative and non-MDR Gram-negative bacilli were identified and compared in 214 KT recipients; MDR Gram-negative bacilli were the cause in 28.4%. Overall 30-day mortality was low (1.1%). Risk factors independently associated with AGP due to MDR Gram-negative bacilli were male sex (OR 3.08; 95%CI 1.60–5.93), previous episode of bacteremic AGP (OR 2.11, 95%CI 1.09–4.09), prior antibiotic therapy in the preceding month (OR 2.47, 95%CI 1.33–4.57), and nosocomial acquisition (OR 2.03, 95%CI 1.14–3.62). Forty-three percent of MDR Gram-negative episodes received inappropriate empirical antibiotic therapy. The risk factors identified in this study may help physicians when selecting empirical antibiotic treatment for AGP. Previous antibiotic use was the main modifiable factor. Its presence highlights the importance of avoiding unnecessary antibiotics in order to bring down the high rates of MDR Gram-negative bacilli infections in this population.

While great progress has been made in transplantation medicine, long-term graft failure and serious side effects still pose a challenge in kidney transplantation. Effective and safe long-term treatments are needed. Therefore, evidence of the lasting benefit-risk of novel therapies is required. Demonstrating superiority of novel therapies is unlikely via conventional randomized controlled trials, as long-term follow-up in large sample sizes pose statistical and operational challenges. Furthermore, endpoints generally accepted in short-term clinical trials need to be translated to real-world (RW) care settings, enabling robust assessments of novel treatments. Hence, there is an evidence gap that calls for innovative clinical trial designs, with RW evidence (RWE) providing an opportunity to facilitate longitudinal transplant research with timely translation to clinical practice. Nonetheless, the current RWE landscape shows considerable heterogeneity, with few registries capturing detailed data to support the establishment of new endpoints. The main recommendations by leading scientists in the field are increased collaboration between registries for data harmonization and leveraging the development of technology innovations for data sharing under high privacy standards. This will aid the development of clinically meaningful endpoints and data models, enabling future long-term research and ultimately establish optimal long-term outcomes for transplant patients.

mRNA-based vaccines have dramatically shifted the course of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. IgA nephropathy (IgAN) flare is the most reported renal adverse effect after the administration of these vaccines. Unraveling the mechanistic pathways leading to these flares is necessary to confirm a causal association. Herein, we report 2 cases of IgAN flare after SARS-CoV-2 vaccination in patients previously diagnosed with IgAN. We describe and compare the clinical and analytical features of the disease at the time of the diagnostic with the post-vaccine flare. In addition, we obtained serum and urine of these patients at the moment of the flare and determined the levels of IL-2, TNF-α, and IFNγ using a multiplex bead-based assay. As diseased controls, we included n = 13 patients diagnosed with IgAN who had available serum and urine samples at the moment of the diagnostic stored in our biobank. We also included 6 healthy controls. Compared to the first episode, postvaccination flares were more severe in terms of peak serum creatinine, albuminuria, and urinary erythrocyte count. The histological lesions found at the biopsy performed during the post-vaccine flare were similar to those found at the diagnostic. One of the patients who suffered a post-vaccine flare showed increased serum IL-2 and TNFα compared to the IgAN-diseased controls and the healthy controls. In conclusion, although several cases of post-vaccine IgAN flares have been reported, there are no mechanistic studies on the occurrence of these flares. We here suggest that hyperactivation of the Th1 pathway may be involved, but larger studies with more refined methods for numerical and functional Th1 lymphocytes evaluation are required.

Background : Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD). Cinacalcet use is controversial in non-dialysis patients. Methods : This retrospective observational study recruited patients receiving cinacalcet (off-label use) in 2010 and 2011. Patients were followed for three years from the beginning of treatment using an intention-to-treat approach. Results : Forty-one patients were studied: 14 CKD stage 3 (34.1%), 21 CKD stage 4 (51.2%), and 6 CKD stage 5 (14.6%). Median baseline parathyroid hormone (PTH) was 396 (101-1,300) pg/mL. Upon cinacalcet treatment (22 ± 12 months), PTH levels decreased by ≥ 30% in 73.2% of patients (P < 0.001; 95% confidence interval [CI], 59-87%), with a mean time for response of 18.7 months (95% CI, 15.4-22.1). Sixteen patients were followed for 36 months and treated for 32 ± 9 months. Mean reduction in their PTH levels was 50.1% (P < 0.001; 95% CI, 33.8-66.4%) at 36 months, with 62.5% of patients (P < 0.001; 95% CI, 35.9-89.1%) presenting reductions of ≥ 30%. Serum calcium levels decreased from 9.95 ± 0.62 mg/dL to 9.21 ± 0.83 and 9.12 ± 0.78 mg/dL at 12 and 36 months, respectively (P < 0.001). Serum phosphorus levels increased from 3.59 ± 0.43 to 3.82 ± 0.84 at 12 months (P = 0.180), remaining so at 36 months (P = 0.324). At 12 and 36 months, 2 (12.5%) patients experienced hypocalcemia. Meanwhile, 1 (6.3%) and 4 (25.0%) patients reported hyperphosphatemia at 12 and 36 months, respectively. Conclusion : Cinacalcet remained effective for at least 36 months in non-dialysis patients with SHPT. Electrolytic disturbances were managed with concurrent use of vitamin D and its analogs or phosphate binders.

Long-term adaptive immune memory has been reported among immunocompetent individuals up to eight months following SARS-CoV-2 infection. However, limited data is available in convalescent patients with a solid organ transplant. To investigate this, we performed a thorough evaluation of adaptive immune memory at different compartments (serological, memory B cells and cytokine [IFN-γ, IL-2, IFN-γ/IL2 and IL-21] producing T cells) specific to SARS-CoV-2 by ELISA and FluoroSpot-based assays in 102 convalescent patients (53 with a solid organ transplants (38 kidney, 5 liver, 5 lung and 5 heart transplant) and 49 immunocompetent controls) with different clinical COVID-19 severity (severe, mild and asymptomatic) beyond six months after infection. While similar detectable memory responses at different immune compartments were detected between those with a solid organ transplant and immunocompetent individuals, these responses were predominantly driven by distinct COVID-19 clinical severities (97.6%, 80.5% and 42.1%, all significantly different, were seropositive; 84% vs 75% vs 35.7%, all significantly different, showed IgG-producing memory B cells and 82.5%, 86.9% and 31.6%, displayed IFN-γ producing T cells; in severe, mild and asymptomatic convalescent patients, respectively). Notably, patients with a solid organ transplant with longer time after transplantation did more likely show detectable long-lasting immune memory, regardless of COVID-19 severity. Thus, our study shows that patients with a solid organ transplant are capable of maintaining long-lasting peripheral immune memory after COVID-19 infection; mainly determined by the degree of infection severity., Graphical abstract

Background: In December 2019, the novel SARS-CoV-2 virus triggered a large-scale pandemic of coronavirus disease 2019 (COVID-19) Kidney transplant recipients m

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune condition that commonly causes kidney impairment and can be fatal. The key participation of B-lymphocytes as ANCA producers and neutrophils as target of these antibodies is widely described as the mechanism of endothelial damage in this disease. There has been a rising interest in the role of T-lymphocytes in AAV in recent years. Evidence is strong from animal models, and T-lymphocytes can be found infiltrating kidney tissue and other tissue sites in AAV patients. Furthermore, the different subsets of T-lymphocytes are also key players in the aberrant immune response observed in AAV. Polarization towards a predominant Th1 and Th17 response in the acute phase of the disease has been described, along with a decline in the number of T-regulatory lymphocytes, which, in turn, show functional impairment. Interactions between different T-cell subsets, and between T-cells and neutrophils and B-cells, also enhance the inflammatory response, constituting a complex network. Novel therapies targeting T-cell immunity are emerging in this scenario and may constitute an interesting alternative to conventional therapy in selected patients. This review aims to summarize the available evidence regarding T-cell imbalances and functional impairment, especially focusing on renal involvement of AAV.

Background Calprotectin is produced by neutrophils and macrophages, and released during the acute phase of the ANCA vasculitis. The aim of our study was to determine if serum and urine calprotectin are disease activity and prognosis biomarkers in ANCA vasculitis patients during remission. Methods Forty-two ANCA vasculitis patients were included. Twenty-seven patients were in remission phase under immunosuppressive therapy, and 15 patients were in the acute phase. Four healthy controls were included. We determined calprotectin in serum and urine samples at the time of the inclusion. We recorded the incidence of relapse and the evolution of GFR, proteinuria, hematuria, and C reactive protein and ANCA titer during 24 months of follow-up. Results In remission phase, serum calprotectin was higher than in healthy controls but lower compared to acute patients (p = 0.05). Serum calprotectin at inclusion was higher in patients who increased proteinuria during follow-up (p = 0.04), with hematuria (p = 0.08), and with non-decreasing ANCA titer (p = 0.0019). Serum calprotectin at inclusion in stable patients who subsequently decreased GFR during follow-up was higher compared with those with a stable or improving GFR (p = 0.03). Urine calprotectin was lower in patients with sclerotic histology in remission (p = 0.03) and acute phase (p = 0.12) compared to the rest of histologies. Conclusions Worsening of renal function, hematuria, rising proteinuria and non-decreasing ANCA correlated with higher levels of serum calprotectin at recruitment. Low urine calprotectin was found in patients with sclerotic histology. Calprotectin during remission in ANCA vasculitis may be useful to identify subclinical inflammation and worse renal prognosis patients.

Renal failure is a frequent complication in liver transplant recipients and is associated with increased morbidity and mortality. A variety of risk factors for the development of renal failure in the pre- and post-transplantation periods have been described, as well as at the time of surgery. To reduce the negative impact of renal failure in this population, an active approach is required for the identification of those patients with risk factors, the implementation of preventive strategies, and the early detection of progressive deterioration of renal function. Based on published evidence and on clinical experience, this document presents a series of recommendations on monitoring RF in LT recipients, as well as on the prevention and management of acute and chronic renal failure after LT and referral of these patients to the nephrologist. In addition, this document also provides an update of the various immunosuppressive regimens tested in this population for the prevention and control of post-transplantation deterioration of renal function.

Introduccion: La calcifilaxis es una enfermedad poco prevalente (1-4% de insuficiencia renal cronica terminal) y con elevada mortalidad (60-80%). Existen casos en pacientes sin insuficiencia renal. Este estudio pretende ser un analisis de factores de riesgo, mortalidad y tratamiento de esta afeccion. Material y metodos: Se trata de un estudio observacional retrospectivo de datos demograficos, factores de riesgo, mortalidad y tratamiento de los casos diagnosticados de calcifilaxis mediante biopsia en el Hospital de Bellvitge en el periodo 2005 a 2014. Se obtuvieron los casos a traves del registro de farmacia hospitalaria de administracion de tiosulfato sodico en los ultimos 10 anos. Resultados: Un total de 19 pacientes recibieron tiosulfato sodico por diagnostico de calcifilaxis. El 85% de los pacientes eran afectos de IRC, con una media de meses en dialisis de 50 (±62,26). De estos, el 28,57% se encontraba en tratamiento con dialisis peritoneal, mientras que el 71,43% restante se encontraba en hemodialisis. El 73% de los casos fueron mujeres. La edad media al diagnostico fue 67,32 ± 12,41 anos. El calcio serico medio al diagnostico fue de 2,26 ± 0,28 mmol/L; el fosfato de 1,44 ± 0,43mmol/L y la PTH de 27,63 pmol/L con un rango entre 3,2 y 93,8. La totalidad de los casos se trataron con tiosulfato sodico, mientras que se practico paratiroidectomia total o subtotal en un 21,05% y se administro cinacalcet a diferentes dosis en el 52,65%. La mortalidad fue del 52,65%, 4 de las 10 muertes registradas se debieron a sepsis. No se encontraron diferencias estadisticamente significativas en la mortalidad de los pacientes segun si fueron tratados o no con cinacalcet (p = 0,2471). En uno de los casos se diagnostico calcifilaxis peritoneal por biopsia. Conclusiones: La mortalidad por calcifilaxis en nuestra poblacion es similar a la descrita en la literatura. El uso de cinacalcet no ocasiono diferencias en la tasa de mortalidad al comparar con el tratamiento clasico con paratiroidectomia.

RESUMO: Este documento apresenta um conjunto de estudos científicos que têm como objetivo enriquecer o conhecimento atual sobre recuperação renal após um episódio de LRA. A introdução, adequadamente suportada por um artigo de revisão, é uma oportunidade para revisitar a relevância da LRA e da recuperação renal, revendo a sua definição, epidemiologia, patogénese e elevados custos para a saúde e em termos financeiros. De seguida, três tópicos principais são explorados. O primeiro tópico é a importância da predição da recuperação renal. Ser capaz de identificar os doentes que vão recuperar, permitir-nos-ia estudar as suas características e eventualmente replicá-las no futuro, melhorando o prognóstico. De uma perspectiva clinica e prática, a predição da recuperação renal permitir-nos-ia otimizar os recursos e adequar a abordagem terapêutica, a curto e longo prazo. O segundo tópico são os fatores clínicos associados à recuperação renal. As características basais dos doentes, as particularidades do episódio de LRA e a abordagem terapêutica adoptada, são tudo grupos de fatores que influenciam a recuperação renal. Contudo, existem ainda enormes lacunas de conhecimento no que respeita ao verdadeiro impacto de cada um destes fatores na recuperação. Alguns dos trabalhos aqui apresentados ajudam a preencher estas lacunas. Numa revisão retrospectiva de doentes com insuficiência hepática aguda, foi caracterizado o impacto da duração da LRA no prognóstico, demostrando que a LRA persistente estava associada a um pior prognóstico renal e do doente. Num segundo estudo, é apresentada uma população previamente saudável de doentes referenciados para terapêutica com ECMO, em que todos os doentes que sobreviveram recuperaram completamente a função renal apesar da LRA se ter desenvolvido num contexto de choque séptico e disfunção muti-orgânica. Um caso clínico é também descrito, realçando que os doentes são frequentemente únicos, com vários fatores interligados que contribuem simultaneamente para a recuperação renal, em direções opostas. O terceiro tópico são os mecanismos celulares e moleculares associados à recuperação renal. Há certamente outros fatores para além das variáveis clinicas visíveis que contribuem para a recuperação renal. Os fatores imunológicos são explorados em trabalhos aqui apresentados. Foi realizada uma revisão retrospectiva de biópsias de protocolo de rins transplantados que demonstrou uma associação entre a leucocitúria estéril e alterações estruturais e funcionais renais. Um segundo estudo retrospectivo caracterizou o impacto da leucocitúria estéril na recuperação renal após um episódio de LRA. Os doentes com LRA e leucocitúria estéril evoluíram com pior prognóstico renal e associaram-se a fatores de risco clínicos caracterizados por uma menor capacidade regenerativa. É apresentado um estudo prospectivo que caracteriza os diferentes tipos de leucócitos presentes na urina de doentes com LRA grave e leucocitúria estéril. O fenótipo urinário dos doentes que recuperaram a função renal caracterizou-se por mais macrófagos M2 e menos células B. Por fim, foi realizada uma reflexão sobre os principais resultados desta compilação de trabalhos e sobre as perspectivas futuras. ABSTRACT: This document presents a series of scientific studies that aim to enrich the current knowledge about renal recovery after an episode of AKI. The introduction, adequately supported by a review paper, is an opportunity to revisit the relevance of AKI and renal recovery, reviewing its definition, epidemiology, pathogenesis and high burden of health and financial costs. Three main topics are then explored. The first topic is the importance of prediction of renal recovery. To be able to identify which patients will recover, would allow us to study their characteristics and eventually replicate them in future patients, improving outcome. From a clinical and practical perspective, prediction of renal recovery would allow optimization of resources and adequacy of the therapeutic approach, both on short and long-term. The second topic are the clinical factors associated with renal recovery. The baseline characteristics of patients, the particularities of the AKI episode and the adopted therapeutic approach, are all groups of factors that influence renal recovery. Nevertheless, there are still tremendous gaps of knowledge on the real impact of each of these factors on recovery. Some of the studies that are presented here help to fulfil these gaps. In a retrospective review of patients with ALD, the impact of AKI duration on outcomes was characterised, showing that persistent AKI was associated with negative renal and patient outcomes. In a second contribution, a population of previously healthy patients referenced to ECMO therapy is presented, showing complete renal recovery in all surviving patients albeit AKI was developed in the context of septic shock and multi-organ failure. A case report is also described, highlighting that patients are frequently unique, with several interconnected factors contributing simultaneously to renal recovery in opposing directions. The third topic are the cellular and molecular mechanisms associated with renal recovery. There are certainly other factors besides the visible clinical variables that contribute to renal recovery. Immunological factors are explored in the studies presented here. A retrospective review of protocol allograft biopsies was performed, demonstrating the association of sterile leukocyturia with negative structural and functional renal outcomes. A second retrospective study characterized the impact of sterile leukocyturia in renal recovery after AKI. It is shown that patients with AKI and leukocyturia had worse renal outcomes and were associated with known clinical factors characterized by a lower regenerative ability. A prospective study is presented that characterizes the different types of leukocytes present in the urine of patients with severe AKI and sterile leukocyturia. The urinary phenotype of patients who recovered renal function was characterized by more M2 macrophages and less B cells. Finally, a reflection is made about the major results of this compilation of studies and the future perspectives that lie ahead.