Urinary soluble PD-1 as a biomarker of checkpoint inhibitor-induced acute tubulointerstitial nephritis.

Background: Acute interstitial nephritis (AIN) related to immune checkpoint inhibitors (ICI-AIN) has a not completely understood pathophysiology. Our objectives were to analyze possible biomarkers for the differentiation between acute tubular necrosis (ATN) and AIN, especially in cancer patients, and to study the participation of the immune checkpoint pathway in ICI-AIN. Methods: We performed an observational study. We recruited patients with incident diagnosis of ICI-AIN (n = 19). We measured soluble PD-1 (sPD-1), sPD-L1, and sPD-L2 in serum and urine at diagnosis and compared to it patients with non-ICI-related AIN (non-ICI-AIN) (n = 18) and ATN (n = 21). The findings were validated in an independent cohort from another institution (n = 30). Also, we performed PD-L1 and PD-L2 immunostaining of kidney biopsies from patients with ICI-AIN and compared to patients with non-ICI-AIN. Results: Urinary sPD-1 (usPD-1) was higher in patients with AIN compared to ATN (P = .03). Patients with AIN also showed higher serum sPD-1 (ssPD-1) than patients with ATN (P = .021). In cancer patients, usPD-1 <129.3 pg/ml had a 71.43% sensitivity and 94.44% specificity to differentiate ATN from ICI-AIN, with a likelihood ratio of 12.86. In the external validation cohort, the same cutoff showed a sensitivity of 80%. In kidney biopsies, patients with ICI-AIN showed higher density of PD-L1 positive tubules than patients with non-ICI-AIN (P = .02). The proportion of patients having >2.64/mm2 PD-L2 positive tubules was higher among patients with ICI-AIN compared to non-ICI-AIN (P = .034). There was a positive correlation (P = .009, r = 0.72) between usPD-1 and the number of PD-L1 positive tubules. Conclusions: UsPD-1 and ssPD-1 are higher in AIN than ATN. Moreover, there was a strong correlation between usPD-1 and renal tubular PD-L1 expression. Our findings suggest a role of usPD-1 as non-invasive biomarker to differentiate ICI-AIN from ATN, especially in cancer patients, which has been confirmed in an external validation cohort.

Evaluating Single-Nucleotide Polymorphisms in Inflammasome Proteins and Serum Levels of IL-18 and IL-1ß in Kidney Interstitial Damage in Anti-Neutrophilic Cytoplasmic Antibody-Associated Vasculitis.

The inflammasome regulates the innate inflammatory response and is involved in autoimmune diseases. In this study, we explored the levels of IL-18 and IL-1ß in serum and urine and the influence of various single-nucleotide polymorphisms (SNPs) on kidney lesions at diagnosis in patients with ANCA-associated vasculitis (AAV) and their clinical outcomes. Ninety-two patients with renal AAV were recruited, and blood and urine were collected at diagnosis. Serum and urine cytokine levels were measured by ELISA. DNA was extracted and genotyped using TaqMan assays for SNPs in several inflammasome genes. Lower serum IL-18 (p = 0.049) and the IL-18 rs187238 G-carrier genotype (p = 0.042) were associated with severe fibrosis. The IL-18 rs1946518 TT genotype was associated with an increased risk of relapse (p = 0.05), whereas GG was related to better renal outcomes (p = 0.031). The rs187238 GG genotype was identified as a risk factor for mortality within the first year after AAV diagnosis, independent of the requirement for dialysis or lung involvement (p = 0.013). We suggest that decreased cytokine levels could be a surrogate marker of scarring and chronicity of the renal lesions, together with the rs187238 GG genotype. If our results are validated, the rs1946518 TT genotype predicts the risk of relapse and renal outcomes during follow-up.

Immune checkpoint inhibitors induce acute interstitial nephritis in mice with increased urinary MCP1 and PD-1 glomerular expression.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) induce acute interstitial nephritis (AIN) in 2-5% of patients, with a clearly higher incidence when they are combined with platinum derivatives. Unfortunately, suitable disease models and non-invasive biomarkers are lacking. To fill this gap in our understanding, we investigated the renal effects of cisplatin and anti-PD-L1 antibodies in mice, assessing PD-1 renal expression and cytokine levels in mice with AIN, and then we compared these findings with those in AIN-diagnosed cancer patients. METHODS: Twenty C57BL6J mice received 200 µg of anti-PD-L1 antibody and 5 mg/kg cisplatin intraperitoneally and were compared with those receiving cisplatin (n = 6), anti-PD-L1 (n = 7), or saline (n = 6). After 7 days, the mice were euthanized. Serum and urinary concentrations of TNFα, CXCL10, IL-6, and MCP-1 were measured by Luminex. The kidney sections were stained to determine PD-1 tissue expression. Thirty-nine cancer patients with AKI were enrolled (AIN n = 33, acute tubular necrosis (ATN) n = 6), urine MCP-1 (uMCP-1) was measured, and kidney sections were stained to assess PD-1 expression. RESULTS: Cisplatin and anti PD-L1 treatment led to 40% AIN development (p = 0.03) in mice, accompanied by elevated serum creatinine and uMCP1. AIN-diagnosed cancer patients also had higher uMCP1 levels than ATN-diagnosed patients, confirming our previous findings. Mice with AIN exhibited interstitial PD-1 staining and stronger glomerular PD-1 expression, especially with combination treatment. Conversely, human AIN patients only showed interstitial PD-1 positivity. CONCLUSIONS: Only mice receiving cisplatin and anti-PDL1 concomitantly developed AIN, accompanied with a more severe kidney injury. AIN induced by this drug combination was linked to elevated uMCP1, consistently with human AIN, suggesting that uMCP1 can be potentially used as an AIN biomarker.

The coexistence of diabetic retinopathy and diabetic nephropathy is associated with worse kidney outcomes.

Background: Up to 50-60% of patients with diabetes have non-diabetic kidney disease (NDKD) on kidney biopsy. Diabetic retinopathy (DR) is a microvascular complication of diabetes frequently associated with diabetic nephropathy (DN). The objective of the current study was to investigate the kidney outcomes and survival in patients with biopsy diagnoses of DN and NDKD according to the presence of DR. Methods: We conducted an observational, multicentre and retrospective study of the pathological findings of renal biopsies from 832 consecutive patients with diabetes from 2002 to 2014 from 18 nephrology departments. The association of DR with kidney replacement therapy (KRT) or survival was assessed by Kaplan-Meier and Cox regression analyses. Results: Of 832 patients with diabetes and renal biopsy, 768 had a retinal examination and 221/768 (22.6%) had DR. During a follow-up of 10 years, 288/760 (37.9%) patients with follow-up data needed KRT and 157/760 (20.7%) died. The incidence of KRT was higher among patients with DN (alone or with NDKD) and DR [103/175 (58.9%)] than among patients without DR [88/216 (40.7%), P < .0001]. The incidence of KRT was also higher among patients with only NDKD and DR than among those without DR [18/46 (39.1%) versus 79/331 (23.9%), P < .0001]. In multivariate analysis, DR or DN were independent risk factors for KRT {hazard ratio [HR] 2.48 [confidence interval (CI) 1.85-3.31], P < .001}. DN (with or without DR) was also identified as an independent risk factor for mortality [HR 1.81 (CI 1.26-2.62), P = .001]. Conclusions: DR is associated with a higher risk of progression to kidney failure in patients with histological DN and in patients with NDKD.

Diagnosis and treatment of lupus nephritis: a summary of the Consensus Document of the Spanish Group for the Study of Glomerular Diseases (GLOSEN).

Lupus nephritis (LN) is the most frequent serious manifestation of patients with systemic lupus erythematosus (SLE). Up to 60% of SLE patients develop LN, which has a significant impact on their quality of life and prognosis. Recent advances have improved the diagnostic approach to LN, and new drugs that block specific pathways and kidney damage progression have been developed. Several randomized and well-powered clinical trials have confirmed the efficacy of these agents in terms of proteinuria remission and preservation of kidney function in the medium and long term, with an acceptable safety profile and good tolerance. The combination of different therapies allows for reduction of the dose and duration of corticosteroids and other potentially toxic therapies and leads to an increase in the number of patients achieving complete remission of the disease. This consensus document carried out by the Spanish Group for the Study of Glomerular Diseases (GLOSEN) provides practical and updated recommendations, based on the best available evidence and clinical expertise of participating nephrologists.

Final Stage of Chronic Kidney Disease with Conservative Kidney Management or Renal Replacement Therapy: A Primary-Care Population Study.

BACKGROUND: Studies focus on the incidence and risk factors (RFs) associated with reaching the final stage of chronic kidney disease (CKD-G5) and receiving kidney replacement therapy (KRT). Analysis of those related to reaching CKD-G5 while receiving conservative kidney management (CKM) has been neglected. METHODS: Retrospective cohort study analysing electronic health records of individuals aged ≥ 50 with eGFR < 60 mL/min/m2. Cumulative incidence rates of CKD-G5, with and without KRT, were calculated. Multinomial regression models determined odds ratios (ORs) for CKD-G5 progression with KRT, CKM, or death. RESULTS: Among 332,164 patients, the cumulative incidence of CKD-G5 was 2.79 cases per 100 person-years. The rates were 1.92 for CKD-G5 with KRT and 0.87 for CKD-G5 with CKM. Low eGFR and albuminuria were the primary RFs. Male gender and uncontrolled blood pressure had a greater impact on KRT (OR = 2.63 CI, 1.63) than on CKD-G5 with CKM (OR = 1.45 CI, 1.31). Increasing age and rurality reduced the probability of KRT but increased the probability of CKD-G5 with CKM. Higher incomes decreased the likelihood of developing CKD-G5 with and without KRT (OR = 0.49 CI). CONCLUSION: One-third of CKD-G5 cases receive CKM. Those are typically older, female, rural residents with lower incomes and with lesser proteinuria or cardiovascular RF. The likelihood of receiving KRT is influenced by location and socioeconomic disparities.

Consensus document of the Spanish Group for the Study of the Glomerular Diseases (GLOSEN) for the diagnosis and treatment of lupus nephritis.

A significant number of patients with systemic lupus erythematosus (between 20% and 60% according to different reported series) develop lupus nephritis in the course of its evolution, which directly influences their quality of life and vital prognosis. In recent years, the greater knowledge about the pathogenesis of systemic lupus and lupus nephritis has allowed relevant advances in the diagnostic approach and treatment of these patients, achieving the development of drugs specifically aimed at blocking key pathogenic pathways of the disease. Encouragingly, these immunomodulatory agents have shown in well-powered, randomized clinical trials good clinical efficacy in the medium-term, defined as proteinuria remission and preservation of kidney function, with an acceptable safety profile and good patient tolerability. All this has made it possible to reduce the use of corticosteroids and other potentially more toxic therapies, as well as to increase the use of combined therapies. The present consensus document carried out by the Glomerular Diseases Working Group of the Spanish Society of Nephrology (GLOSEN), collects in a practical and summarized, but rigorous way, the best currently available evidence about the diagnosis, treatment, and follow-up of lupus nephritis patients, including cases of special situations, with the main objective of providing updated information and well-founded clinical recommendations to treating physicians, to improve the diagnostic and therapeutic approach to our patients.

Combining neutrophil and macrophage biomarkers to detect active disease in ANCA vasculitis: a combinatory model of calprotectin and urine CD163.

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 < .0001). According to the ROC curves, sCalprotectin and suCD163 were accurate biomarkers to discern activity [area under the curve 0.73 (0.59-0.86), P = .015 and 0.88 (0.79-0.97), P < .0001]. The combinatory model with the best performance in terms of sensitivity, specificity and likelihood ratio included sCalprotectin, suCD163 and haematuria. Regarding the inception and the validation cohort, we obtained a sensitivity, specificity and likelihood ratio of 97%, 90% and 9.7, and 78%, 94% and 13, respectively. Conclusions: In patients with ANCA vasculitis, a predictive model combining sCalprotectin, suCD163 and haematuria could be useful in detecting active kidney disease.

Documento de consenso del Grupo de Estudio de Enfermedades Glomerulares de la Sociedad Española de Nefrología (GLOSEN) para el diagnóstico y tratamiento de la nefritis lúpica / Consensus document of the Spanish Group for the Study of the Glomerular Diseases (GLOSEN) for the diagnosis and treatment of lupus nephritis

Un número importante de pacientes con lupus eritematoso sistémico (entre 20 a 60%, según diferentes series) desarrolla nefritis lúpica en el curso de su evolución, lo que influye directamente en su calidad de vida y pronóstico vital. En años recientes, el mayor conocimiento sobre la patogénesis del lupus sistémico y de la nefritis lúpica ha permitido avances relevantes en el abordaje diagnóstico y en el tratamiento de estos pacientes, lográndose desarrollar fármacos dirigidos específicamente a bloquear vías patogénicas claves de la enfermedad. Alentadoramente estos agentes inmunomoduladores han demostrado en ensayos clínicos aleatorizados, y bien ponderados, buena eficacia clínica a mediano plazo, definida como remisión de proteinuria y preservación de la función renal, con un aceptable perfil de seguridad y buena tolerabilidad del paciente. Todo esto ha permitido reducir el uso de corticoides y de otras terapias potencialmente más tóxicas, así como incrementar el uso de terapias combinadas. El presento documento de consenso realizado por el Grupo de Trabajo de Enfermedades Glomerulares de la Sociedad Española de Nefrología (GLOSEN) recoge de manera práctica y resumida, pero rigurosa, la mejor evidencia actual disponible acerca del diagnóstico, tratamiento y seguimiento del paciente con nefritis lúpica, incluyendo casos de situaciones especiales, con el objetivo principal de brindar información actualizada y recomendaciones clínicas bien fundamentadas a los médicos tratantes, para mejorar el enfoque diagnóstico y terapéutico a nuestro pacientes. (AU)

A significant number of patients with systemic lupus erythematosus (between 20% to 60% according to different reported series) develop lupus nephritis in the course of its evolution, which directly influences their quality of life and vital prognosis. In recent years, the greater knowledge about the pathogenesis of systemic lupus and lupus nephritis has allowed relevant advances in the diagnostic approach and treatment of these patients, achieving the development of drugs specifically aimed at blocking key pathogenic pathways of the disease. Encouragingly, these immunomodulatory agents have shown in well-powered, randomized clinical trials good clinical efficacy in the medium-term, defined as proteinuria remission and preservation of kidney function, with an acceptable safety profile and good patient tolerability. All this has made it possible to reduce the use of corticosteroids and other potentially more toxic therapies, as well as to increase the use of combined therapies. The present consensus document carried out by the Glomerular Diseases Working Group of the Spanish Society of Nephrology (GLOSEN), collects in a practical and summarized, but rigorous way, the best currently available evidence about the diagnosis, treatment, and follow-up of lupus nephritis patients, including cases of special situations, with the main objective of providing updated information and well-founded clinical recommendations to treating physicians, to improve the diagnostic and therapeutic approach to our patients. (AU)

Th1 Cytokines Signature in 2 Cases of IgA Nephropathy Flare after mRNA-Based SARS-CoV-2 Vaccine: Exploring the Pathophysiology.

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.

The Role of Inflammasomes in Glomerulonephritis.

The inflammasome is an immune multiprotein complex that activates pro-caspase 1 in response to inflammation-inducing stimuli and it leads to IL-1ß and IL-18 proinflammatory cytokine production. NLRP1 and NLRP3 inflammasomes are the best characterized and they have been related to several autoimmune diseases. It is well known that the kidney expresses inflammasome genes, which can influence the development of some glomerulonephritis, such as lupus nephritis, ANCA glomerulonephritis, IgA nephropathy and anti-GBM nephropathy. Polymorphisms of these genes have also been described to play a role in autoimmune and kidney diseases. In this review, we describe the main characteristics, activation mechanisms, regulation and functions of the different inflammasomes. Moreover, we discuss the latest findings about the role of the inflammasome in several glomerulonephritis from three different points of view: in vitro, animal and human studies.

Urinary Cytokines Reflect Renal Inflammation in Acute Tubulointerstitial Nephritis: A Multiplex Bead-Based Assay Assessment.

BACKGROUND: Acute tubulointerstitial nephritis (ATIN) diagnosis lays on histological assessment through a kidney biopsy, given the absence of accurate non-invasive biomarkers. The aim of this study was to evaluate the accuracy of different urinary inflammation-related cytokines for the diagnostic of ATIN and its distinction from acute tubular necrosis (ATN). METHODS: We included 33 patients (ATIN (n = 21), ATN (n = 12)), and 6 healthy controls (HC). We determined the urinary levels of 10 inflammation-related cytokines using a multiplex bead-based Luminex assay at the time of biopsy and after therapy, and registered main clinical, analytical and histological data. RESULTS: At the time of biopsy, urinary levels of I-TAC/CXCL11, CXCL10, IL-6, TNFα and MCP-1 were significantly higher in ATIN compared to HC. A positive correlation between the extent of the tubulointerstitial cellular infiltrates in kidney biopsies and the urinary concentration of I-TAC/CXCL11, MIG/CXCL9, CXCL10, IL17, IFNα, MCP1 and EGF was observed. Notably, I-TAC/CXCL11, IL-6 and MCP-1 were significantly higher in ATIN than in ATN, with I-TAC/CXCL11 as the best discriminative classifier AUC (0.77, 95% CI 0.57-0.95, p = 0.02). A combinatory model of these three urinary cytokines increased the accuracy in the distinction of ATIN/ATN compared to the individual biomarkers. The best model resulted when combining the three cytokines with blood eosinophil and urinary leukocyte counts (LR = 9.76). Follow-up samples from 11ATIN patients showed a significant decrease in I-TAC/CXCL11, MIG/CXCL9 and CXCL10 levels. CONCLUSIONS: Urinary I-TAC/CXCL11, CXCL10, IL6 and MCP-1 levels accurately distinguish patients developing ATIN from ATN and healthy individuals and may serve as novel non-invasive biomarkers in this disease.

Acute Tubulointerstitial Nephritis in Clinical Oncology: A Comprehensive Review.

Acute kidney injury in patients who suffer a malignancy is a common complication. Due to its high prevalence and effective treatment, one of the most frequent causes that both oncologists and nephrologists must be aware of is acute tubulointerstitial nephritis (ATIN). ATIN is an immunomediated condition and the hallmark of the disease, with the presence of a tubulointerstitial inflammatory infiltrate in the renal parenchyma. This infiltrate is composed mainly of T lymphocytes that can be accompanied by macrophages, neutrophils, or eosinophils among other cells. One of the major causes is drug-related ATIN, and some antineoplastic treatments have been related to this condition. Worthy of note are the novel immunotherapy treatments aimed at enhancing natural immunity in order to defeat cancer cells. In the context of the immunosuppression status affecting ATIN patients, some pathogen antigens can trigger the development of the disease. Finally, hematological malignancies can also manifest in the kidney leading to ATIN, even at the debut of the disease. In this review, we aim to comprehensively examine differential diagnosis of ATIN in the setting of a neoplastic patient.

Acute tubulointerstitial nephritis induced by checkpoint inhibitors versus classical acute tubulointerstitial nephritis: are they the same disease?

BACKGROUND: The incidence of acute tubulointerstitial nephritis (ATIN) related to drugs has dramatically increased over recent years. A new subtype of ATIN, apparently different from classical drug-related ATIN, has emerged that has been related to the administration of immune checkpoint inhibitors (ICIs). We investigated these differences between ICI-related ATIN (ICI ATIN) and non-ICI-related ATIN in terms of clinical features, response to treatment with steroids and the evolution of kidney function. METHODS: A total of 47 patients diagnosed with ATIN from two centres were recruited. Of these, 13 patients presented with ATIN during ICI treatment and 34 were diagnosed with ATIN attributed to other drugs. The main demographic, clinical and analytical variables such as gender, age and current medication were recorded. The type of malignancy, oncological treatment, ICI dose and presence of extrarenal immune-related adverse events were also reviewed. Renal biopsy diagnosis, time to drug withdrawal and ATIN-specific treatment, as well as laboratory data during follow-up, were also studied. RESULTS: Patients diagnosed with ICI ATIN presented with lower creatinine (ICI ATIN 3.8 ± 1.03 versus classical ATIN 5.98 ± 4.15 mg/dL, P = 0.007) at diagnosis and higher urinary leucocyte counts (ICI ATIN 263.2 ± 418.04 versus classical ATIN 133.55 ± 284.62, P = 0.048) compared with patients with non-ICI-related ATIN. Time from initiation of the culprit drug to ATIN diagnosis was longer in patients with ICI ATIN than in those with classical ATIN (197.07 ± 184.99 versus 114.4 ± 352.16 days, P = 0.006). In addition, during follow-up, the slope of decreasing creatinine over time was lower for ICI ATIN compared with non-ICI-related ATIN. CONCLUSIONS: In this study, we analysed differences between ICI ATIN and classical ATIN. We found that patients with ICI ATIN presented with a larger latency period after culprit drug initiation, milder acute kidney injury and slower creatinine amelioration compared with those with classical ATIN. These results may, in part, be ascribed to potential differences in the pathological mechanisms involved in ATIN development, suggesting that ICI and classical ATIN may be different diseases with similar renal histologies.

Extracapillary proliferation scoring correlates with renal outcome and contributes to stratification in adult patients with immunoglobulin A nephropathy.

BACKGROUND: The revised Oxford classification of diagnostic renal biopsies has been proposed to aid in the prediction of renal outcome. We aimed to validate the histological crescents and interstitial fibrosis and tubular atrophy (IFTA) subgrouping, and to investigate the additional value of the proportion of crescents (CatPE) in the prediction of renal outcome. METHODS: Data were retrospectively collected over 10 years, from the time of diagnosis, by systematic review of medical records from 90 patients with renal biopsies recruited to cohorts from two hospitals in Spain. Patients were classified into three groups for the analysis: CatPE >25% (C2), CatPE <25% (C1) and without this type of lesion (C0). The end point was renal survival defined by either >50% reduction in glomerular filtrate rate or end-stage renal disease. RESULTS: Renal survival at 5 years was 90% in group C0, 81% in group C1 and 31% in group C2 (P = 0.013). The presence of >25% crescents in the sample was associated with more severe disease when compared with <25%, as demonstrated by more interstitial fibrotic change and by lower estimated glomerular filtration rate at diagnosis, as well as worse renal function at 2 and 5 years. At the time of diagnosis and at 24 months, the group with IFTA >50% had poorer renal function compared with the other groups. CONCLUSIONS: We have confirmed the predictive value for renal survival of the revised Oxford classification in a two-centre study. We found worse renal outcome in patients with severe tubulointerstitial fibrosis and atrophy. Patients with extracapillary lesions >25% and IFTA >50% had a worse renal prognosis due to more severe kidney injury. These results contribute to patient stratification in immunoglobulin A nephropathy for therapeutic, epidemiological and basic research.

A Comprehensive Phenotypic and Functional Immune Analysis Unravels Circulating Anti-Phospholipase A2 Receptor Antibody Secreting Cells in Membranous Nephropathy Patients.

INTRODUCTION: Primary membranous nephropathy (MN) is characterized by the presence of antipodocyte antibodies, but studies describing phenotypic and functional abnormalities in circulating lymphocytes are limited. METHODS: We analyzed 68 different B- and T-cell subsets using flow cytometry in 30 MN patients (before initiating immunosuppression) compared with 31 patients with non-immune-mediated chronic kidney disease (CKD) and 12 healthy individuals. We also measured 19 serum cytokines in MN patients and in healthy controls. Lastly, we quantified the ex vivo production of phospholipase A2 receptor (PLA2R)-specific IgG by plasmablasts (measuring antibodies in culture supernatants and by the newly developed FluoroSpot assay [AutoImmun Diagnostika, Strasberg, Germany]) and assessed the circulating antibody repertoire by phage immunoprecipitation sequencing (PhIP-Seq). RESULTS: After adjusting for multiple testing, plasma cells and regulatory B cells (BREG) were significantly higher (P < 0.05) in MN patients compared with both control groups. The percentages of circulating plasma cells correlated with serum anti-PLA2R antibody levels (P = 0.042) and were associated with disease activity. Ex vivo-expanded PLA2R-specific IgG-producing plasmablasts generated from circulating PLA2R-specific memory B cells (mBCs) correlated with serum anti-PLA2R IgG antibodies (P < 0.001) in MN patients. Tumor necrosis factor-α (TNF-α) was the only significantly increased cytokine in MN patients (P < 0.05), whereas there was no significant difference across study groups in the autoantibody and antiviral antibody repertoire. CONCLUSION: This extensive phenotypic and functional immune characterization shows that autoreactive plasma cells are present in the circulation of MN patients, providing a new therapeutic target and a candidate biomarker of disease activity.

New Biomarkers in Acute Tubulointerstitial Nephritis: A Novel Approach to a Classic Condition.

Acute tubulointerstitial nephritis (ATIN) is an immunomediated cause of acute kidney injury. The prevalence of ATIN among the causes of acute kidney injury (AKI) is not negligible, especially those cases related to certain drugs. To date, there is a lack of reliable non-invasive diagnostic and follow-up markers. The gold standard for diagnosis is kidney biopsy, which shows a pattern of tubulointerstitial leukocyte infiltrate. The urinalysis findings can aid in the diagnosis but are no longer considered sensitive or specific. Atthe present time, there is a rising attentiveness tofinding trustworthy biomarkers of the disease, with special focus in urinary cytokines and chemokines that may reflect kidney local inflammation. Cell-based tests are of notable interest to identify the exact drug involved in hypersensitivity reactions to drugs, manifesting as ATIN. Certain single-nucleotide polymorphisms in HLA or cytokine genes may confer susceptibility to the disease according to pathophysiological basis. In this review, we aim to critically examine and summarize the available evidence on this topic.

Risk factors for non-diabetic renal disease in diabetic patients.

BACKGROUND: Diabetic patients with kidney disease have a high prevalence of non-diabetic renal disease (NDRD). Renal and patient survival regarding the diagnosis of diabetic nephropathy (DN) or NDRD have not been widely studied. The aim of our study is to evaluate the prevalence of NDRD in patients with diabetes and to determine the capacity of clinical and analytical data in the prediction of NDRD. In addition, we will study renal and patient prognosis according to the renal biopsy findings in patients with diabetes. METHODS: Retrospective multicentre observational study of renal biopsies performed in patients with diabetes from 2002 to 2014. RESULTS: In total, 832 patients were included: 621 men (74.6%), mean age of 61.7 ± 12.8 years, creatinine was 2.8 ± 2.2 mg/dL and proteinuria 2.7 (interquartile range: 1.2-5.4) g/24 h. About 39.5% (n = 329) of patients had DN, 49.6% (n = 413) NDRD and 10.8% (n = 90) mixed forms. The most frequent NDRD was nephroangiosclerosis (NAS) (n = 87, 9.3%). In the multivariate logistic regression analysis, older age [odds ratio (OR) = 1.03, 95% CI: 1.02-1.05, P < 0.001], microhaematuria (OR = 1.51, 95% CI: 1.03-2.21, P = 0.033) and absence of diabetic retinopathy (DR) (OR = 0.28, 95% CI: 0.19-0.42, P < 0.001) were independently associated with NDRD. Kaplan-Meier analysis showed that patients with DN or mixed forms presented worse renal prognosis than NDRD (P < 0.001) and higher mortality (P = 0.029). In multivariate Cox analyses, older age (P < 0.001), higher serum creatinine (P < 0.001), higher proteinuria (P < 0.001), DR (P = 0.007) and DN (P < 0.001) were independent risk factors for renal replacement therapy. In addition, older age (P < 0.001), peripheral vascular disease (P = 0.002), higher creatinine (P = 0.01) and DN (P = 0.015) were independent risk factors for mortality. CONCLUSIONS: The most frequent cause of NDRD is NAS. Elderly patients with microhaematuria and the absence of DR are the ones at risk for NDRD. Patients with DN presented worse renal prognosis and higher mortality than those with NDRD. These results suggest that in some patients with diabetes, kidney biopsy may be useful for an accurate renal diagnosis and subsequently treatment and prognosis.

Clinical features and outcomes in a cohort of patients with immunoglobulin G4-related disease at a university hospital in Spain.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a fibro-inflammatory, immune-mediated disorder, which characteristically affects the glandular tissue but has the potential to affect any organ. METHODS: We retrospectively reviewed clinical, laboratory, histological characteristics and treatment response during 12 months of follow-up of a cohort of patients with IgG4-RD diagnosed at a tertiary public hospital. Disease activity was assessed by means of the IgG4-RD responder index (IgG4-RD RI). RESULTS: In all, 15 patients have been diagnosed at our Institution and herein studied (80% men), with a median age of 60.7 years and a mean affectation of 2.8 organs per patient. We identified six patients with definitive diagnosis and nine with possible IgG4-RD, according to the Japanese diagnostic algorithm. IgG4-RD RI decreased from a median of 11.3 at baseline to 4.0 after 6 months and 6.2 after 12 months. Relapse occurred in five patients and was associated with lower cumulative steroid doses. Five patients (33.3%) required additional immunosuppressive (IS) drugs. Five adverse events were seen during follow-up: three infections, one deep vein thrombosis and one gastrointestinal bleeding. One patient died of pneumonia. CONCLUSIONS: IgG4-RD is an inflammatory disease that can affect any organ. Glucocorticoids were an effective first line of treatment; however, this treatment is associated with important adverse events and relapses occurred in patients with low cumulative doses. As an alternative, IS treatment with rituximab could be an interesting option in those patients.

Exploring Frequencies of Circulating Specific Th17 Cells against Myeloperoxidase and Proteinase 3 in ANCA Associated Vasculitis.

: Background: The role of the T helper 17 (Th17) cell subset in anti-neutrophil cytoplasm antibodies (ANCA) associated vasculitis (AAV) is controversial. We hypothesized that a specific Th17 response to myeloperoxidase (MPO) or proteinase 3 (PR3) is detectable in AAV patients and is different among the disease phases. METHODS: We analyzed 43 AAV patients with renal involvement (21 acute and 22 remission patients), and 12 healthy controls. Peripheral blood mononuclear cells (PBMCs) were cultured with PR3/MPO over 48 h. Thereafter, frequencies of MPO/PR3-specific Th17 cells were assessed using an enzyme-linked immunosorbent spot (ELISpot) assay. Supernatant IL-17 concentration was quantified using ELISA. Finally, specific Th17 response after depletion of T regulatory lymphocytes (T-regs) in some remission patients was compared to the non T-reg-depleted response. RESULTS: Specific Th17 cell number was higher in acute patients compared to remission (p = 0.004). Specific Th17 cell number performed well in the disease activity detection (ROC curve area under the curve (AUC) = 0.87; p = 0.0001) with an optimal cut-off of 6 spots/million. Patients above this cut-off showed higher serum creatinine (p = 0.004), C-reactive protein (CRP) (p = 0.001) and ANCA titer (p = 0.032). Supernatant IL-17 concentration was higher in acute patients compared to remission (p = 0.035) and did not normalize to healthy control levels (p = 0.01). CONCLUSIONS: A specific Th17 cell response is present in AAV patients. This response is more pronounced in the acute phase, but persists in remission.