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Background and Aims Renal involvement is a severe manifestation of ANCA-associated vasculitis. Patients often progress to end-stage renal disease. The potential for renal recovery after a first flare has seldom been studied. Our objectives were to describe the evolution of the estimated glomerular filtration rate (eGFR) and identify factors associated with the change in eGFR between diagnosis and follow-up at 3 months (ΔeGFRM0–M3) in a cohort of patients with a first flare of pauci-immune glomerulonephritis. Methods This was a retrospective study over the period 2003–2018 of incident patients in the Nord-Pas-de-Calais (France). Patients were recruited if they had a first histologically-proven flare of pauci immune glomerulonephritis with at least 1 year of follow up. Kidney function was estimated with MDRD-equation and analysed at diagnosis, 3rd, 6th and 12th months. The primary outcome was ΔeGFRM0–M3. Factors evaluated were histological (Berden classification, interstitial fibrosis, percentage of crescents), clinical (extra-renal manifestations, sex, age) or biological (severity of acute kidney injury, dialysis, ANCA subtype). Results One hundred and seventy-seven patients were included. The eGFR at 3 months was significantly higher than at diagnosis (mean ± standard deviation, 40 ± 24 vs 28 ± 26 ml/min/1.73 m2, p < 0.001), with a ΔeGFRM0–M3 of 12 ± 19 ml/min/1.73 m2. The eGFR at 12 months was higher than at 3 months (44 ± 13 vs 40 ± 24 ml/min/1.73m2, p = 0.003). The factors significantly associated with ΔeGFRM0–M3 in univariate analysis were: sclerotic class according to Berden classification, percentage of interstitial fibrosis, percentage of cellular crescents, acute tubular necrosis, neurological involvement. The factors associated with ΔeGFRM0–M3 in multivariate analysis were the percentage of cellular crescents and neurological involvement. The mean increase in eGFR was 2.90 ± 0.06 ml/min/1.73m2 for every 10-point gain in the percentage of cellular crescents. ΔeGFRM0–M3 was not associated with the risks of end-stage renal disease or death in long-term follow-up. Conclusions Early renal recovery after a first flare of pauci-immune glomerulonephritis occurred mainly in the first three months of treatment. The percentage of cellular crescents was the main independent predictor of early renal recovery.

Background and Aims Interstitial fibrosis / tubular atrophy (IFTA) is a common, irreversible and progressive form of chronic allograft injury, and it is considered a critical predictor of kidney allograft outcomes. Inflammation, both microvascular and interstitial, is on the contrary regarded as a reversible form of graft injury. Since treatments for rejection and other causes of graft dysfunction bear substantial toxicity and could have limited efficacy, the extent of irreversible graft scarring is a crucial information for the clinician, to evaluate risks and benefits of specific therapies. The diagnosis of kidney graft pathology is acquired through graft biopsy, which is an invasive procedure and can be subjected to sampling bias. Magnetic resonance imaging (MRI), especially with functional techniques, has emerged as a possibility for non-invasive estimation of tissue fibrosis; nevertheless, functional MRI is not widely available. Texture analysis MRI (TA-MRI) is a radiomic technique that provides a quantitative assessment of tissue heterogeneity from standard MRI images, generating features that can be fitted into a machine-learning model to assess their ability to predict clinical or histological parameters. Method Single-center cross-sectional observational cohort study enrolling kidney transplant recipients who underwent graft biopsy and graft MRI imaging within 6 months from biopsy, both on clinical indication, at the “Azienda Ospedaliero-Universitaria di Modena”, Italy. The study was approved by the local Ethical Committee (AOU0010167/20). The primary outcome was to identify the best TA-MRI features subset for estimation of IFTA > 50% in graft biopsy. Secondary outcomes were estimation of: IFTA > 25%, presence of total inflammation (ti) and microvascular inflammation (glomerulitis + peritubular capillaritis [g+ptc]). Graft biopsy was reported according to Banff 2017 system. Radiomic analysis was performed on axial T2 pre-contrast and T1 fat-suppressed post-contrast sequences. The whole renal parenchyma (PAR) was segmented and labelled on T2 and T1, renal cortex (COR) only on T2. After imaging preprocessing, PyRadiomics was used to extract radiomic features. After removal of shape features, 93 features were included and reduced using LASSO regression to produce radiomic signatures. These were introduced in Machine Learning (ML) models to test the association with outcomes. Results are reported as AUC and a value of sensitivity and specificity. Results Sixty patients were included in the study, and 67 graft biopsy – graft MRI pairs were available for analysis. Demographic and clinical characteristics of enrolled patients are depicted in table 1; histological diagnosis and main Banff histological parameters from graft biopsies in table 2. Among ML models, three showed an acceptable performance. T2 COR “firstorder_minimum/firstorder_range/glrlm_run_entropy” for IFTA>50% (AUC=0.77, sensitivity=73%, specificity=71%), T1 PAR “firstorder_energy” for IFTA>25% (AUC=0.71, sensitivity=74%, specificity=51%), T1 PAR “firstorder_energy/gldm_small_dependence_low_gray_level_emphasis” for g+ptc >0 (AUC=0.74, sensitivity= 78%, specificity=68%); see figures 1–3. No acceptable prediction was detected for ti >0. Conclusion Our study shows that TA-MRI feature signatures can predict the degree of IFTA in graft biopsies, with an acceptable diagnostic performance. These results suggest to further investigating TA-MRI from standard MRI sequences as potential tool to assess graft chronic parenchymal injury. Moreover, since graft biopsy results can be jeopardized by limited sample size, we hypothesize that evaluation of IFTA through TA-MRI could provide more comprehensive information regarding the whole parenchyma. To test this hypothesis, we are currently evaluating the association of TA-MRI radiomic features and baseline eGFR and eGFR variation over time.

Background and Aims Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in older white adults, with an incidence of 12 cases per millions of people per year. Primary MN (PMN, 75%-80% of MNs) is an organ-specific autoimmune disease caused by antibodies anti-PLA2R and anti-THSD7A. Regardless of treatment one third of patients progresses to end-stage renal disease and two third develop non-progressive chronic kidney disease. Renal biopsy is the gold standard for MN diagnosis. Several clinical and biochemical markers have been associated with the risk of progressive loss of kidney function while contrasting results have been obtained by the few studies which have examined the prognostic value of histologic findings. In this study the clinical outcome of patients with PMN has been considered based on the prognostic value of histological findings. Method Forty-nine patients with PMN of our Nephrology Unit at Padova University Hospital from 2003 to 2018 were considered. 16 patients were excluded from the study due to missing data. Age, comorbidities, proteinuria (g/day) and renal function (eGFR, CKD-EPI) were collected. eGFR decline and decrease of proteinuria were used as clinical outcomes. The follow-up was considered from renal biopsy to the last visit (in absence of GFR decline or decrease in proteinuria). Histological grading (0-3) was assigned to parameters (glomerulosclerosis (GS), tubular atrophy (TA), interstitial fibrosis (IF), vascular hyalinosis (VH)) and were evaluated separately or in combination (as GSTIV score). Morphometric analysis was used to quantify IF and expressed in percentage as the mean of area covered by pixel. Statistical analysis was performed using Fisher’s exact test and Mann-Whitney U-test where appropriate. Cox regression analyses (univariate and multivariate) were performed to identify variables associated with both renal outcomes and p ROC curves were used to determine interstitial fibrosis cut-off values predictive for both outcomes. Area under the curve (AUC) between 0.8 and 1.0 was considered as significant. Diagnostic accuracy was assessed by Specificity (Sp), Sensibility (Se), positive (PPV) and negative (NPV) predictive values and positive (LR+) and negative (LR-) likelihood ratios. Results Patients with no decrease of proteinuria had a greater degree of IF vs those with a full response (p=0.006). Univariate Cox analyses identified age ≥65 years (HR 4.92), pre-existing CKD (HR 12.98) and IF (HR3.05) as significant predictors of renal function decline in all patients. Multivariate Cox analysis confirmed these variables (age ≥65 years HR 3.05, CKD HR 6.35, IF HR 3.03). In patients without CKD only IF was significantly associated with eGFR decline in both Cox univariate and multivariate analysis (HR 4.34 and 5.05 respectively). ROC analysis showed that IF threshold of 17.80% identified patients with eGFR reduction (AUC 0.65, Se 0.50, Sp 0.79, PPV 0.75, NPV 0.45, LR+ 2.38, LR-0.63) and IF threshold of 18.04% the lack of proteinuria reduction (AUC 0.78, Se 0.70, Sp 0.83, PPV 0.67, NPV 0.80, LR+ 4.12, LR- 0.36). Conclusion Our study shows that IF could be used as a histologic predictor of renal and proteinuria outcomes. Biopsy report should therefore also include quantitative IF data that could be helpful for the choice of a more appropriate therapeutic approach.

Background and Aims Kidney biopsy is the gold standard for establishing the diagnosis of ANCA-associated glomerulonephritis (GN). Previous studies have validated the prognostic significance of histopathological classification for the development of end stage renal disease (ESRD). We sought to evaluate the prognostic value of the EUVAS histopathological classification in terms of renal and overall survival (OS) in a single center retrospective cohort study. Method Forty-six consecutive patients (mean age 69, range; 29-84 years) with biopsy-proven ANCA-associated GN diagnosed at our hospital between January 2003 and January 2019 were included in the study. All biopsies had ≥10 glomeruli and were reviewed by two independent pathologists blinded to clinical data. Renal morphology was classified as sclerotic (if ≥50% globally sclerotic glomeruli), focal (if ≥50% normal glomeruli), crescentic (if ≥50% crescents with cellular component) and mixed. Probabilities of renal and overall survival were estimated using Kaplan-Meier method. Cumulative incidence function for ESRD was estimated using death as competing risk. Results Three biopsies were classified as focal (6%), twenty-nine as crescentic (63%), ten as mixed (22%) and four as sclerotic (9%). With a median follow-up of 39 months the 3-year probability of renal survival was 100% for the focal class, 66,37% for the crescentic class, 64% for the mixed class and 50% for the sclerotic class (p>0.05). Other parameters associated with increased probability of ESRD were interstitial fibrosis (IF) and eGFR at time of diagnosis. IF of ≥40% at diagnosis was associated with high incidence of ESRD, while IF of 20-40% and 0.05). Conclusion Our results suggest that the focal class has the best and the sclerotic the worst outcome, while both crescentic and mixed subtype are of intermediate risk. Although our results did not reach statistical significance, due to primarily the small number of patients included, the incidence of ESRD and the probability of renal survival in each histopathological subtype in our cohort are comparable to those reported by larger studies. Thus, the EUVAS histological classification of ANCA-associated glomerulonephritis appears to be a useful predictor of renal outcome at the time of diagnosis. As previously reported, no significant prognostic difference was observed between the crescentic and mixed subtype. Thus, this classification system should be optimized by inclusion of other histological characteristics, such as the specific percentage of normal glomeruli, tubular atrophy and interstitial fibrosis. These characteristics may prove useful in highlighting significant differences between mixed and crescentic classes.

Background and Aims Transgelin (SM22) is a cytoskeletal actin-binding protein involved in differentiation of smooth muscle cells, osteoblasts and adipocytes. It is present in fibroblasts, some epithelium, immune cells and acts as a tumor suppressor. It was found as a marker of interstitial fibrosis and glomerulosclerosis. Transgelin upregulation depends on the etiology of the disease in various cells (glomerular parietal or visceral, or tubular interstitial cells). Elevated SM22 expression was detected in glomerular and in tubulointerstitial injury. Among patients with multiple myeloma (MM) up to 50% suffer from renal insufficiency (RI) in early stages. Free light chains (FLCs), potential nephrotoxic substances, where lambda light chains are more commonly associated with renal damage, appear to have a prognostic value in MM and indicate the stages of MM. The aim of the study was to analyse the utility of transgelin in case of renal impairment in MM patients and investigate its relationship with acclaimed parameters of renal failure and markers of MM stages. Method The analysis included 126 patients (73 women and 53 men) in mean age 66 ± 10 years. Symptomatic MM was diagnosed in 119 patients, including 84 (67%) with ISS stage 1, 20 (16%) with stage 2 and 15 (12%) with stage 3; 7 (6%) patients had smoldering MM. Mean baseline eGFR (CKD-EPICr) was 74 ± 24 ml/min/1.73 m2 and 31 (25%) patients had eGFR Results Median serum transgelin in the whole studied group was 84.1 (IQR: 65.4; 116.4) ng/ml. Transgelin concentrations were higher in men (median 96.2 versus 78.8 ng/ml; p=0.022) and in patients with smoldering MM (median 149.2 versus 82.4 ng/ml; p=0.003). Transgelin did not differ according to ISS stage (p=0.3) or disease state (regression, stable disease or progression) (p=0.3). Significant correlations were detected between transgelin and serum creatinine (R=0.29; p=0.001), eGFR (CKD-EPICr) (R=-0.25; p=0.007), uric acid (R=0.19; p=0.036), alanine (R=0.18; p=0.048) and aspartate (R=0.26; p=0.003) aminotransferases, ferritin (R=-0.22; p=0.049), hepcidin (R=-0.25; p=0.033), and urine cystatin C (R=0.19; p=0.042). Moreover, after exclusion of patients with smoldering MM, transgelin significantly correlated with serum FLC lambda (R=0.18; p=0.047) and serum periostin (R=-0.22; p=0.013). After median follow-up of 21 (IQR: 15; 24) months, eGFR decreased in 47 (37%) of patients and increased in 71 (56%) patients (no follow-up data were available in 8, i.e. 6% of patients). Patients in whom eGFR decreased had higher transgelin (median 106.6 versus 83.9 ng/ml), although the difference was marginally significant (p=0.05). However, baseline transgelin positively correlated with serum creatinine after follow-up (R=0.37; p Conclusion Transgelin may be useful in investigating renal damage because of its proven role in regulation of fibrosis, especially in kidney. As a biomarker it may indicate diagnosis and etiology of MM-related chronic kidney disease, which can lead to beginning of early therapeutic interventions and improved overall survival and quality of life in patients with MM. Moreover, elevated transgelin at the beginning of the disease may induce future development of chronic kidney disease.

Background and Aims According to the data of the Turkish Society of Nephrology-Glomerular Diseases Working Group (TSN-GOLD Working Group), IgA nephropathy is the most common primary glomerular disease in Turkey. The purpose of this study was to investigate the epidemiological and clinical data of IgA nephropathy patients in Turkey. Method 4399 patients with primary glomerular diseases from 47 centers who were followed up between May 2009 and May 2019 were included in the study conducted by TSN-GOLD Working Group. 524 patients were excluded due to lack of pathological data. Among the remaining patients, demographic, clinical and laboratory data of 994 patients with IgA nephropathy were analyzed. Results The median age of the patients was 37 (28-47) years, and 37.3% of them were female. The laboratory and clinical data at the time of diagnosis is presented in Figure-1, and biopsy indications are described in Figure-2. The median number of glomeruli was 16 (IQR: 3.5-4.3), sclerotic glomeruli was 2 (IQR: 1-5), and segmental sclerotic glomeruli was 1 (IQR: 1-2). Exudative changes, subendothelial and subepithelial deposition were present in 566 patients (56.9%), 46 patients (4.6%) and in 38 patients (3.8%), respectively. 662 (66.1%) and 611 of the patients (61.4%) had tubular atrophy and interstitial fibrosis in varying degrees, respectively. 672 (%67.6) and 416 patients (%41.9) had interstitial inflammation and vascular changes, respectively. In immunofluorescence staining, 18%, 30.1%, 4.4%, 68% of the patients had IgG, IgM, C1q and C3 positivity, respectively. Crescentic glomeruli were detected in 227 patients (3.3 ± 3.1 glomeruli). Patients with crescentic glomeruli had significantly higher proteinuria and lower eGFR than the patients without [2203 mg/day (15-26078) vs 1807 mg/day (15-29112); p=0.001; 55.3 ml/min/1.73 m2 (3.72-141.9) vs 72 ml/min/1.73 m2 (3.84-150.81); p Conclusion In this study we found that, the most common presentation of IgA nephropathy patients in our country was asymptomatic urinary abnormalities followed by nephritic and nephrotic syndrome. Higher proteinuria and lower eGFR values in patients with crescentic glomeruli, support the adoption of crescentic lesions in the new Oxford classification (MEST-C) to predict more precise outcome of IgA nephropathy patients. The high number of patients to whom the Oxford classification was applied provided us with the opportunity to examine the clinical reflections of pathological features. Evaluation of the follow-up data of the patients will give us the possibility to reveal the effect of initial clinical and pathological features on clinical findings and renal outcome.

Background and Aims Membranoproliferative glomerulonephritis (MPGN) may be caused by disturbances in the complement system. Hypocomplementemia is a characteristic of MPGN. Among these patients frequency of hypocomplementemia and their relation with clinical and histopathological findings are still not clearly known. The aim of this study is to evaluate the hypocomplementemia frequency among the primary MPGN patients in Turkey and its relation with histopathological subtypes, findings and demographic characteristics. Method The data was obtained from national multicentered (47 centers) records of primary glomerular diseases in Glomerulonephritis Study Group of the Turkish Society of Nephrology database from May 2009 to June 2019. Primary MPGN cases were evaluated and divided into 2 groups with and without hypocomplementemia. Results In total, 193 cases were included in the study. The indications for renal biopsy were isolated nephrotic syndrome (55.4%), nephritic syndrome (21.2%), nephrotic syndrome with a nephritic component (6.2%) and asymptomatic urinary findings (17.2%). 34.2% of the cases were reported as immune complex type, another 34.2% of the cases were reported as C3 glomerulopathy. 31.6% of patients were not specified. 82 (42.4%) of the cases presented hypocomplementemia. Hypocomplementemic patients were younger (34±14 vs 41±15, p=0.002) and most frequently female (56% vs 41%, p=0.03). At same time, serum albumin and hemoglobin levels were lower and anemic patient rates were higher (p Conclusion This multicenter study provided important data about the epidemiology of MPGN with importance of hypocomplementemia in Turkey. Hypocomplementemia is associated with both subtypes of MPGN patern, anemia and nephrotic syndrome. At the same time, hypocomplementemia is a valuable parameter for active MPGN pattern in the histopathological evaluation. This may be important in determining the treatment.

Background and Aims Rapidly progressive glomerulonephritis (RPGN) is a clinical condition that develops due to different etiologic causes, characterized by a rapid and progressive decrease in renal function and progresses to end-stage renal failure in weeks to months if not treated. In our study, diagnostic and demographic characteristics of patients diagnosed with RPGN by biopsy, clinical and laboratory findings in our country were investigated. Method Data were obtained from national multicenter (47 centers) data entered into the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) Working Group database between May 2009 and June 2019. Demographic characteristics such as age, sex, indications for biopsy, diagnosis of the glomerular diseases, comorbidities, laboratory and biopsy findings of all patients were recorded. The data presented is cross-sectional and includes application data for the biopsy period. According to their types, RPGN patients were classified as type 1 (anti-GBM related), type 2 (immunocomplex related) and type 3 (immune-negative; “pauci-immune”). Results After exclusion of 46 patients with missing data, 200 patients (mean age 47.9 ± 16.7 years, 44% female) were included in the study which constitutes 5.2% of the total glomerulonephritis database (total number of patients: 3875). Hypertension was present in 62 patients (31.0%) and diabetes was present in 18 patients (9.0%). Renal biopsy was performed in 147 (73.5%) patients due to nephritic syndrome (RPGN included). 80.2% of the patients' biopsies were performed in nephrology clinics and 19.8% of them were performed in radiology clinics. ANCA positivity was found in 121 (60.5%) patients (proteinase 3-ANCA was positive in 55 and myeloperoxidase-ANCA positive in 66 patients). Type 1 RPGN was detected in 11 (5.5%), type 2 RPGN in 42 (21%) and type 3 RPGN in 147 (73.5%) patients. In 21 patients (10.5%), biopsy revealed RPGN with advanced chronic changes (fibrous global sclerotic glomeruli, advanced interstitial fibrosis and tubular atrophy). Mean serum creatinine was 4.2 ± 3.4 mg/dl, median glomerular filtration rate was 18 (10-37) ml/min and proteinuria 2100 (1229-3526) mg/day according to CKD-EPI formula. The mean number of glomeruli in the biopsies was 18.8 ± 10.6 and the number of crescentic glomeruli was 9.9 ± 7.7 (ratio: 52.7%) (Figure). The patients were divided into 3 groups according to their crescentic glomeruli ratios. The proportion of crescentic glomeruli is 10-50% in group 1, 50-80% in group 2, and >80% in group 3. The demographic, laboratory and histopathological characteristics of the groups are given in Figure. It was observed that urea and creatinine increased and calcium and hemoglobin decreased with increasing crescentic glomerular ratio. Conclusion Our study provides valuable demographic, clinical, laboratory and histopathological data about RPGN in our country. Our data are generally compatible with the literature. In our study, advanced chronic histopathological findings were prominent in the biopsy of 21 patients. Early biopsy should be performed to confirm the diagnosis of RPGN and to avoid unnecessary intensive immunosuppressive therapy. In addition to the treatments applied, detailed data, including patient and renal survival are needed.

Background and Aims Lupus nephritis (LN) is a frequent manifestation of Systemic Lupus Erythematosus (SLE). The therapeutic strategy relies on the result of kidney biopsy, which differentiates proliferative LN (PLN) from non-proliferative LN (NPLN). The analysis of the urinary peptidome has led to the identification of prognostic biomarkers in chronic kidney disease (CKD, namely the CKD273 classifier), or, as a liquid biopsy, for the diagnosis of glomerulonephritides. We verified whether urinary peptidomics could predict the severity of renal pathological injury and damage in LN. Method Urine samples, collected before kidney biopsy, were analyzed by capillary-electrophoresis coupled to mass-spectrometry (CE-MS). Urinary peptide profiles were compared between PLN and NPLN. Predictive values for chronic pathological lesions (glomerulosclerosis and interstitial fibrosis/tubular atrophy (IF/TA)), response to therapy and development of CKD were also assessed. Clinical characteristics, routine laboratory parameters and immunological SLE markers were collected at inclusion and prospectively for at least 24 months. Results We collected 100 urinary samples from patients with LN, forming a discovery (n=67) and an independent validation (n=33) cohort. Overall there were 69 patients with PLN (class III or IV +/-V with active lesions) and 31 patients with NPLN (class II or V or chronic lesions). In the discovery cohort, the abundance of 36 urinary peptides differed between PLN and NPLN (Mann-Whitney test). However, these peptides did not resist multiple testing correction. Among them, 17 could be sequenced (fragments of collagen-I, -II, -III, apolipoprotein A-I, Fibrinogen alpha chain and Histone H2B). Of the 17 sequenced peptides, 7 were also part of the CKD273 classifier. A mathematical model combining the 36 peptides classified PLN and NPLN patients from the validation cohort with an AUC of 0.75 and sensitivity and specificity of 0.81 and 0.53, respectively. Positivity of anti-dsDNA antibodies had the best sensitivity (0.96) and sterile pyuria the best specificity (0.68) to differentiate PLN from NPLN, and including the CKD273 score did not improve the accuracy of the predictive models. No urinary peptidomics profile was identified to predict early response to therapy in patients with LN. Glomerulosclerosis was observed in 63/100 biopsies. In the discovery cohort, the abundance of 38 urinary peptides (including 22 sequenced) differed between patients with vs without glomerulosclerosis (Mann-Whitney test). Again, these peptides did not resist multiple testing correction. Of the 22 sequenced peptides, 7 (different from the peptides associated with PLN) belonged to the CKD273 classifier. A mathematical model combining the 38 peptides classified patients from the validation cohort with an AUC of 0.75 and sensitivity and specificity of 0.82 and 0.54, respectively, for the presence of glomerulosclerosis. Although the quantification of IF/TA was correlated to the pre-existing CKD273 classifier, including the CKD273 score did not improve the prediction of IF/TA when tested in combination with simple clinical parameters. Only 3 patients developed CKD after a mean follow-up of 4 years, therefore contribution of urinary peptidomics for the prediction of CKD in LN could not be evaluated. Conclusion Different urinary peptidomics signatures were identified among patients with LN, according to the presence of active proliferative lesions or chronic lesions. However, these panels did not resist multiple testing correction, and did not improve the diagnostic accuracy when combined with clinical or immunological markers. The contribution of urinary peptidomics to predict CKD in patients with LN, or as an early predictor of renal flares, could not be evaluated. Kidney biopsy remains central for the care of patients with LN.

Background and Aims One of the most limiting factors of long-term graft survival is chronic renal allograft dysfunction (CAD). The major hallmarks of CAD are interstitial fibrosis and tubular atrophy (IFTA). MicroRNAs (miRNAs) are 19-25 nucleotides, small, noncoding molecules involved in the regulation of gene expression. MiRNAs have a role in various immunological processes, including inflammation and fibrosis. Particularly, microRNA-21-5p (miR-21) is reported to be strongly associated with pathogenesis regarding tubulointerstitium. The aim of this study was to analyse expression levels of urinary miR-21 in the renal transplant recipients and evaluate their application in the assessment of IFTA and kidney allograft function. Method The expression levels of urinary miR-21 were measured in 31 renal transplant recipients with biopsy-evaluated IFTA (IFTA 0+I: n=17; IFTA II+III: n=14) by quantitative PCR. Protocolar biopsies were performed 1 or 2 years after renal transplantation. Urine samples were collected at the time of biopsy procedure. MicroRNA-191-5p was used as reference gene. Correlations between the clinicopathological parameters and the level of expression of miR-21 were assessed. Results Relative expression level of miR-21 was significantly increased in IFTA II+III group compared to IFTA 0+I group. MiR-21 correlated positively with serum concentration of creatinine and negatively with eGFR. ROC analysis showed diagnostic value of miR-21 with an area under curve (AUC) of 0.80, high sensitivity and specificity. Conclusion MiR-21 is associated with IFTA and dysfunction of kidney allograft. It may be considered as potential non-invasive biomarker of renal allograft function.

Background and Aims Chronic kidney disease (CKD) is a major health issue closely related to metabolic syndrome. Although a potential link between ectopic lipid-induced ER stress and the progression of CKD has been suggested, the underlying mechanism has not yet been fully elucidated. SGLT2 inhibitors have been reported to be effective in reducing fat accumulation. However the effect on lipid-associated kidney disease remains unclear. The aim of this study was to investigate the role of ectopic lipid and ER stress in the development of CKD, and evaluate the efficacy of an SGLT2 inhibitor. Method FLS-ob/ob mice, a model that shows significant ectopic lipid deposition and closely imitate the pathophysiology of non-alcoholic steatohepatitis, were treated with vehicle or an SGLT2 inhibitor, Ipragliflozin (1 mg/kg body weight) for 12 weeks. Metabolic characteristics, histology of the kidney, ER stress and apoptotic signals were evaluated. Results Ipragliflozin significantly reduced the serum triglyceride level. Ectopic lipid deposition in renal tubules found in FLS-ob/ob mice was prevented by Ipragliflozin, accompanied by reduced interstitial fibrosis. Both GRP78, a master regulator or ER stress, and CHOP, a downstream mediator of ER stress, were significantly downregulated in mice treated with Ipragliflozin. Apoptotic signal in kidney tissue was also reduced. Conclusion Ipragliflozin improved the pathogenesis of CKD by reducing ER stress through preventing ectopic lipid deposition in the kidney. SGLT2 inhibitors may have therapeutic effect on lipid-associated kidney disease.

Background and Aims The recent decades have witnessed significant changes in the epidemiology and clinical course of infection-related glomerulonephritis (IRGN). We analyzed the clinicopathological features and long-term outcome of adult patients with biopsy-proven IRGN followed in a large Italian referral centre. Method We included patients with biopsy-proven IRGN diagnosed from 2000 to 2018. Clinical and laboratory findings, histological features, possible risk factors and therapy were assessed for both renal and patient outcome. Results Forty-one patients met the inclusion criteria (male:female ratio 3:1, mean age 61±16 years). Smoke habit (47.2%), alcoholism (30.6%), and diabetes (27.5%) were the most common risk factors. The most frequently identified sites of infection were skin, lung and heart (Table 1). Staphylococci spp. accounted for 76.5% of positive cultures (Figure 1). Hypocomplementaemia emerged in 48.5% of cases. The most frequent histologic patterns were diffuse proliferative (56.0%) and membranoproliferative (29.3%) glomerulonephritis. Haemodialysis was required by 22.5% of patients at inception. Two thirds of patients developed chronic kidney disease; half of them reached end-stage renal disease (ESRD). By multivariate analysis ESRD was associated with diabetes (HR 13.7; 95% CI, 1.6-121.0; p=0.018), crescents (HR 25.2; 95% CI, 2.7-235.7; p=0.005), and interstitial fibrosis (HR 31.0; 95% CI, 3.3-287.3; p=0.003). Male gender (HR 12.7; 95% CI, 10.8-14.6; p=0.008) hypertension (HR 40.8; 95% CI, 38.6-43.1; p=0.001), gross haematuria (HR 11.8; 95% CI, 9.4-14.2; p=0.047), need for haemodialysis at onset (HR 16.3; 95% CI, 14.7-17.8; p Conclusion While traditionally considered a “benign” disease with a favorable course in children, IRGN is a potentially severe disease in adults, particularly when a background of major comorbidities and older age are present. A significant proportion of patients does not recover renal function, with a remarkable risk of ESRD.

Background and Aims Renal inflammation is a protective response to several types of renal insults. Resolution is the ideal outcome of acute inflammation, however fail in resolution leads to chronic inflammation, progressive renal fibrosis and finally to end-stage renal failure. Recently is has been established that resolution of inflammation is mediated not only by disappearance of pro-inflammatory signals (including lipid mediators such as leukotrienes and prostaglandins) but also by activation of specialized pro-resolving mediators (SPM) including lipid mediators such as protectins (PD) and resolvins (Rvs) derived from omega-3 fatty acids precursors. Several authors have explored the role of different SPM in the treatment of experimental nephropathies. In the experimental model of bilateral ischemia/reperfusion pro-resolving mediators such as RvDs and PD1 were endogenously produced in the kidney in response to the injury. In this model, administration of RvD1 or PD1 before the ischemia or after the reperfusion showed a renoprotective effect. Moreover in the unilateral ureteral obstruction model RvE1 and RvD1administration inhibited interstitial fibrosis. One of the key mediators of renal injury is Angiotensin II (AngII) that participates in the pathogenesis of renal diseases through the regulation of two key processes, inflammation and fibrosis. Therefore, the aim of this study was to investigate the effect of the pro-resolving mediator Resolvin D2 (RvD2) in AngII-induced renal injury Method We used C57BL/6 mice that were infused with AngII (1440 µg/kg/day o 1000 ng/Kg/min). After 7 days of AngII treatment, when hypertension was already established, mice were treated with RvD2 (100ng/mouse ip) every two days for additional 7 days. At day 14 mice were sacrificed and kidneys were removed for protein and gene expression analysis and for histological examination. Results In our experimental model RvD2 ameliorated renal injury assessed by expression of NGAL both at mRNA and protein levels. In addition AngII-treated mice presented significant reduction in glomerular size that was increased by RvD2 treatment reaching values comparable to control. In addition, RvD2 inhibited the activation of inflammatory markers including COX-2, IL-6 and MCP-1 induced by AngII and reduced the number of F4/80+ infiltrated macrophages. We next evaluated the effect of RvD2 in the activation of NFκB, a key signaling pathway in inflammation. We observed that RvD2 inhibited AngII-induced NFkB activation. Moreover, RT-PCR analysis indicated that Ang II increased the expression of Tenascin C, a component of the fibrogenic niche in kidney fibrosis, as well as Type-I Collagen and Fibronectin and these levels were significantly reduced by the treatment with RvD2. These results were also confirmed by Masson-Goldner trichrome staining. Importantly, these effects were independent of changes in blood pressure. We finally studied whether the effects of RvD2 might be related to the modulation of RvDs endogenous biosynthesis pathway or RvD2 receptor GPR-18. mRNA analysis showed that AngII did not modified the expression levels of RvD2 biosynthesis enzymes including LOX-5 and LOX-15 nor GPR-18. However, RvD2 treatment increased the expression of LOX-15 and GPR-18 and downregulated LOX-5 indicating a possible auto-regulatory mechanism of RvD2 Conclusion Our results evidence a dual beneficial effect of the pro-resolvin mediator RvD2 in Ang II-induced renal injury as RvD2 treatment reversed not only renal inflammation but also tubulo-interstitial fibrosis. Hence, synthetic pro-resolving mediators would be an interesting therapeutic option for renal diseases.

Traditional Chinese herbal medicine remains very popular in Taiwan. Here, Western medicine is readily available at affordable price, yet many local population choose Chinese herbal medicine as an alternative or complementary source of health-care even at a higher cost. The preference of Chinese herbal medicine comes from the generalized belief that herbs are natural, more gentle, and less toxic than synthetic Western medicine. Incidents of herbal poisoning are rare, mild, and obviously underestimated in literature [1]. Recently, Professor Vanherweghem and colleagues [2] reported rapidly progressive interstitial renal fibrosis in nine young women who had followed a slimming regimen including Chinese herbs. The report raised concern about nephrotoxicity of a cocktail of Chinese herbs. Several components were suspected to respond to the interstitial fibrosis, although no one was certain [3]. In addition, any herbal products can be contaminated during production and processing, especially by heavy metals or mycotoxin [3]. We report on a young woman who took a cocktail of Chinese herbs contaminated by cadmium and developed a unique syndrome of multiple renal tubular dysfunction not fully explained by cadmium-induced tubulopathy [4].

Heart failure (HF) is one of the main causes of morbidity and mortality in patients with chronic kidney disease (CKD). Decreased glomerular filtration rate is associated with diffuse deposition of fibrotic tissue in the myocardial interstitium [i.e. myocardial interstitial fibrosis (MIF)] and loss of cardiac function. MIF results from cardiac fibroblast-mediated alterations in the turnover of fibrillary collagen that lead to the excessive synthesis and deposition of collagen fibres. The accumulation of stiff fibrotic tissue alters the mechanical properties of the myocardium, thus contributing to the development of HF. Accumulating evidence suggests that several mechanisms are operative along the different stages of CKD that may converge to alter fibroblasts and collagen turnover in the heart. Therefore, focusing on MIF might enable the identification of fibrosis-related biomarkers and targets that could potentially lead to a new strategy for the prevention and treatment of HF in patients with CKD. This article summarizes current knowledge on the mechanisms and detrimental consequences of MIF in CKD and discusses the validity and usefulness of available biomarkers to recognize the clinical–pathological variability of MIF and track its clinical evolution in CKD patients. Finally, the currently available and potential future therapeutic strategies aimed at personalizing prevention and reversal of MIF in CKD patients, especially those with HF, will be also discussed.