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BACKGROUND: A renewed interest for activity and chronicity indices as predictors of lupus nephritis (LN) outcome has emerged. Revised National Institutes of Health activity and chronicity indices have been proposed to classify LN lesions, but they should be validated by future studies. The aims of this study were (1) to detect the histologic features associated with the development of kidney function impairment (KFI), and (2) to identify the best clinical-histologic model to predict KFI at time of kidney biopsy. METHODS: Patients with LN who had more than ten glomeruli per kidney biopsy specimen were admitted to the study. Univariate and multivariate logistic regression and Cox proportional hazards models were used to investigate whether activity and chronicity indices could predict KFI development. RESULTS: Among 203 participants with LN followed for 14 years, correlations were found between the activity index, and its components, and clinical-laboratory signs of active LN at baseline. The chronicity index was correlated with serum creatinine. Thus, serum creatinine was significantly and directly correlated with both activity and chronicity indices. In the multivariate analysis, glomerulosclerosis (OR, 3.05; 95% CI, 1.17 to 7.91; P=0.02) and fibrous crescents (OR, 6.84; 95% CI, 3.22 to 14.52; P

Mechanisms for the generation of anti-dsDNA autoantibodies are still not completely elucidated. One theory states that dsDNA interacts for mimicry with antibodies raised versus other antigens but molecular features for mimicry are unknown. Here we show that, at physiological acid-base balance, anti-Annexin A1 binds IgG2 dsDNA in a competitive and dose-dependent way with Annexin A1 and that the competition between the two molecules is null at pH 9. On the other hand, these findings also show that dsDNA and Annexin A1 interact with their respective antibodies on a strictly pH-dependent basis: in both cases, the binding was minimal at pH 4 and maximal at pH9-10. The anionic charge of dsDNA is mainly conferred by the numerous phosphatidic residues. The epitope binding site of Annexin A1 for anti-Annexin A1 IgG2 was here characterized as a string of 34 amino acids at the NH2 terminus, 10 of which are anionic. Circulating levels of anti-dsDNA and anti-Annexin A1 IgG2 antibodies were strongly correlated in patients with systemic lupus erythematosus (n 496) and lupus nephritis (n 425) stratified for age, sex, etc. These results show that dsDNA competes with Annexin A1 for the binding with anti-Annexin A1 IgG2 on a dose and charged mediated base, being able to display an inhibition up to 75%. This study provides the first demonstration that dsDNA may interact with antibodies raised versus other anionic molecules (anti-Annexin A1 IgG2) because of charge mimicry and this interaction may contribute to anti-dsDNA antibodies generation.

Lupus nephritis (LN) is a frequent and severe manifestation of SLE. Along the decades, the epidemiology of LN and its clinical presentation have been changing. However, even though retrospective cohort studies report a decreased mortality rate and an improvement in the disease prognosis, the percentage of patients progressing into end stage renal disease (ESRD) keeps steady despite the improvements in therapeutic strategies. Current in-use medications have been available for decades now, yet over the years, regimens for optimizing their efficacy and minimizing toxicity have been developed. Therapeutic research is now moving towards the direction of precision medicine and several new drugs, targeting selectively different pathogenetic pathways, are currently under evaluation with promising results. In this review, we address the main changes and persistent unmet needs in LN management throughout the past decades, with a focus on prognosis and upcoming treatments.

Background: Belimumab (Benlysta) is currently approved for the treatment of active Lupus despite standard therapy. Few data are available on the efficacy of this drug in lupus nephritis (LN). Methods: 17 LN female followed in two Nephrology Italian Unit received belimumab for a median period of 36 months (range 6–42 months). The indications were: arthralgia in 3 patients, cutaneous manifestations in 2, residual proteinuria in 8, and the need to reduce steroids for severe side effects in 4. Of interest, 1 patient started therapy during Peritoneal Dialysis and continued after kidney transplantation due to non-responsive arthralgias. Results: Arthralgia and skin manifestations resolved in all patients. Proteinuria normalized in three patients and stabilized in all but one of the others. Steroids were indefinitely stopped in six patients (35%) and reduced to around 40% of the basal dosage in the other patients. During belimumab therapy, three extrarenal and one renal SLE flares were diagnosed accounting for a rate of renal flares of 0.02/patient/year. No major adverse events leading to therapy withdrawal occurred. Clinical case: Arthralgia resolved, immunological parameters improved and prednisone could be reduced within few months in the patient who started belimumab during peritoneal dialysis. After kidney transplantation belimumab was stopped but due to arthralgias unresponsive to standard immunosuppressive therapy it was restarted with success. Conclusions: Belimumab allows the achievement of complete response together with the withdrawal or the reduction of corticosteroids in almost all our patients. Of interest its satisfactory use in a patient in peritoneal dialysis and after kidney transplantation.

ObjectiveTo investigate second kidney biopsy as predictor of end-stage kidney disease (ESKD) in active lupus nephritis (LN).MethodsPatients with biopsy-proven LN (International Society of Nephrology/Renal Pathology Society 2003) who had undergone a second kidney biopsy between January 1990 and December 2018 were included. Clinical and histological findings at first and at second biopsy were analysed with Cox proportional hazard models to predict ESKD, defined as start of kidney replacement therapy. Survival curves were calculated with Kaplan-Meier method.ResultsNinety-two patients with LN were included, 87% females, mean follow-up 17.9±10.1 years. Reasons for second kidney biopsy encompassed nephritic flares (n=28, 30.4%), proteinuric flares (n=46, 50%) or lack of renal response (n=18, 19.5%). Class switch from first biopsy occurred in 50.5% of cases, mainly from non-proliferative towards proliferative classes. Class IV remained stable in over 50% of cases. Twenty-five patients (27.2%) developed ESKD, mostly belonging to the nephritic flare group (17/28, 60.7%). Independent predictors of ESKD at second biopsy were activity index (AI; (HR 95% CI) 1.20 (1.03 to 1.41), p=0.022), chronicity index (CI; 1.41 (1.09 to 1.82), p=0.008) and 24h-proteinuria (1.22 (1.04 to 1.42), p=0.013). AI≥2 (log-rank p=0.031), CI >4 (log-rank p=0.001) or proteinuria ≥3.5 g/day (log-rank=0.009) identified thresholds for higher ESKD risk. In a subgroup analysis, glomerular activity and tubular chronicity mostly accounted for AI and CI association with ESKD. No histological or laboratory predictors emerged at first biopsy (95% CI): AI: 0.88 to 1.19; CI: 0.66 to 1.20; proteinuria 0.85 to 1.08.ConclusionsFindings at second but not at first kidney biopsy in patients with persistently active or relapsing LN inform about ESKD development in a long-term follow-up.

Due to complex comorbidity, high infectious complication rates, an elevated risk of relapsing for primary renal disease, as well as inferior recipient and allograft survivals, individuals with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAVs) are often considered as poor transplant candidates. Although several aspects of recurrent and de novo AAVs remain unclear, recent evidence suggests that kidney transplantation (KT) represents the best option, which is also the case for this particular subgroup of patients. Special counselling and individualized approaches are strongly recommended at the time of enlistment and during the entire post-transplant follow-up. Current strategies include avoiding transplantation within one year of complete clinical remission and thoroughly assessing the recipient for early signs of renal or systemic vasculitis. The main clinical manifestations of allograft AAV are impaired kidney function, proteinuria, and hematuria with ANCA positivity in most cases. Mixed results have been obtained using high-dose steroids, mycophenolate mofetil, or cyclophosphamide. The aim of the present review was to summarize the available literature on AAVs in KT, particularly focusing on de novo pauci-immune glomerulonephritis.

We aimed to identify the rates and predictors of chronic damage accrual and mortality in lupus nephritis (LN).We retrospectively measured SLICC/ACR Damage Index (SDI) in biopsy proven active LN with at least 5 years follow-up. We searched for the predictors of first SDI increase and death at univariate and multivariate regression analysis. Then, we considered clinical/biochemical/histological features at diagnosis, corticosteroids dose and proportion of follow-up in complete renal remission.187 patients (91.4% females, age 28.1 years, 95.7% Caucasians) were included. After a median follow-up of 18.6 years, 26 patients (13.9%) died, 116 (62%) accrued damage. SDI annual rate has significantly reduced over the last decades (from a mean of 0.14±0.17 in 1970-1985, to 0.09±0.21 in 1986-2001, to 0.07±0.1 in 2002-2019; p=0.0032). SDI increases occurred more frequently in renal (22.5%), ocular (18.2%), cardiovascular, neuropsychiatric (13.4% both) and malignancy (12.8%) domains. First SDI increase free survival was 73.3%, 59.8%, 49.9% and 38% at 5,10,15 and 20 years. At multivariate analysis, hypertension (HR:1.699, CI:1.126-2.457, p=0.011), presentation with acute renal dysfunction (HR:1.587,CI:1.082-2.327, p=0.018) and average prednisone dose5mg/day (HR:3.378, CI:1.984-5.751, p0.0001) independently predicted damage. Achievement of complete renal remission (HR:0.993, CI:0.987-0.999, p0.039) reduced the risk of damage. Age (HR:1.063, CI:1.027-1.099, p=0.0004), hypertension (HR:3.096, CI:1.211-7.912, p=0.019), and no immunosuppressors as maintenance therapy (HR:4.168, CI:1.212-14.336, p=0.024) predicted mortality at multivariate analysis.Besides arterial hypertension, presentation with acute renal dysfunction and corticosteroids dose predict SDI increase in LN, while achieving renal remission prevents damage. Aggressive therapy to induce remission in the acute phases of LN and low corticosteroids dose in maintenance therapy may prevent the increase of chronic damage.

Objectives Serum anti-dsDNA and anti-nucleosome IgGs have been proposed as signatures for SLE and LN in limited numbers of patients. We sought to show higher sensitivity and specificity of the same antibodies with the IgG2 isotype and included IgG2 antibodies vs specific intracellular antigens in the analysis. Methods A total of 1052 SLE patients with (n = 479) and without (n = 573) LN, recruited at different times from the beginning of symptoms, were included in the study. Patients with primary APS (PAPS, n = 24), RA (RA, n = 24) and UCTD (UCTD, n = 96) were analysed for comparison. Anti-nucleosome (dsDNA, Histone2A, Histone3), anti-intracellular antigens (ENO1), anti-annexin A1 and anti-C1q IgG2 were determined by non-commercial techniques. Results The presence in the serum of the IgG2 panel was highly discriminatory for SLE/LN vs healthy subjects. Serum levels of anti-dsDNA and anti-C1q IgG2 were more sensitive than those of IgGs (Farr radioimmunoassay/commercial assays) in identifying SLE patients at low–medium increments. Of more importance, serum positivity for anti-ENO1 and anti-H2A IgG2 discriminated between LN and SLE (ROC T0–12 months), and high levels at T0–1 month were detected in 63% and 67%, respectively, of LN, vs 3% and 3%, respectively, of SLE patients; serum positivity for each of these was correlated with high SLEDAI values. Minor differences existed between LN/SLE and the other rheumatologic conditions. Conclusion Nephritogenic IgG2 antibodies represent a specific signature of SLE/LN, with a few overlaps with other rheumatologic conditions. High levels of anti-ENO1 and anti-H2A IgG2 correlated with SLE activity indexes and were discriminatory between SLE patients limited to the renal complication and other SLE patients. Trial registration The Zeus study was registered at https://clinicaltrials.gov, NCT02403115.

Objectives Circulating anti-ENO1 and anti-H2A IgG2 have been identified as specific signatures of LN in a cross-over approach. We sought to show whether the same antibodies identify selected population of patients with LN with potentially different clinical outcomes. Methods Here we report the prospective analysis over 36 months of circulating IgG2 levels in patients with newly diagnosed LN (n=91) and SLE (n=31) and in other patients with SLE recruited within 2 years from diagnosis (n=99). Anti-podocyte (ENO1), anti-nucleosome (DNA, histone 2 A, histone 3) and anti-circulating proteins (C1q, AnnexinA1-ANXA1) IgG2 antibodies were determined by home-made techniques. Results LN patients were the main focus of the study. Anti-ENO1, anti-H2A and anti-ANXA1 IgG2 decreased in parallel to proteinuria and normalized within 12 months in the majority of patients while anti-dsDNA IgG2 remained high over the 36 months. Anti-ENO1 and anti-H2A had the highest association with proteinuria (Heat Map) and identified the highest number of patients with high proteinuria (68% and 71% respectively) and/or with reduced estimated glomerula filtration rate (eGFR) (58% for both antibodies) compared with 23% and 17% of anti-dsDNA (agreement analysis). Anti-ENO1 positive LN patients had higher proteinuria than negative patients at T0 and presented the maximal decrement within 12 months. Conclusions Anti-ENO1, anti-H2A and anti-ANXA1 antibodies were associated with high proteinuria in LN patients and Anti-ENO1 also presented the maximal reduction within 12 months that paralleled the decrease of proteinuria. Anti-dsDNA were not associated with renal outcome parameters. New IgG2 antibody signatures should be utilized as tracers of personalized therapies in LN. Trial registration The Zeus study was registered at https://clinicaltrials.gov (study number: NCT02403115).

In 178-kidney transplanted patients (KTxp), the prevalence of hypovitaminosis-D, the presence and novel development of left ventricular hypertrophy(LVH) and the correlations between native Vitamin-D (25OHD) and LVH were evaluated during the 1st year of transplantation (KTx). Clinical and instrumental data were recorded at pre-KTx and at one (T1) and 12 (T12) months after KTx. 25OHD levels were considered sufficient (s25OHD, ≥ 30 ng/dL) or insufficient (i25OHD

Background: Central venous catheter use is rising in chronic and acute hemodialysis. Catheter-related bloodstream infections are a major complication of central venous catheter use. This article examines clinical factors associated with catheter-related bloodstream infections incidence. Methods: In this retrospective, single-center study, 413 patients undergoing extracorporeal treatments between 1 February 2014 and 31 January 2017 with 560 central venous catheters were recruited. Clinical parameters, such as gender, age, kidney disease status, diabetes, immunosuppression, and vintage dialysis, were collected at study entry. An incidence rate ratio (95% confidence interval) was calculated to assess the association between catheter-related bloodstream infections incidence rate and each clinical variable/central venous catheter type. Significant associations at the univariate analyses were investigated with multivariate Cox models. Results: During a cumulative time of 66,686 catheter-days, 54 catheter-related bloodstream infections (incidence rate: 0.81) events occurred. Gram negative bacteria were more frequent in patients with age Conclusion: Central venous catheter characteristics and acute kidney injury are independently associated with higher catheter-related bloodstream infections rate.

The ideal long-term maintenance therapy of Lupus Nephritis (LN) is still a matter of debate. The present study was aimed at comparing the efficacy/safety profile of cyclosporine (CsA), mycophenolate mofetil (MMF) and azathioprine (AZA) in long-term maintenance therapy of LN.We performed a retrospective study of patients with biopsy-proven active LN. After induction therapy, all patients received maintenance therapy with CsA, MMF or AZA based on medical decision. Primary endpoint was complete renal remission (CRR) after 8 years (defined as proteinuria 0.5 g/24 h, eGFR 60 ml/min/1.73 mq); secondary endpoints were: CRR after 1 year, renal and extrarenal flares, progression of chronic kidney disease (CKD stage 3 or above) and side-effects.Out of 106 patients, 34 received CsA, 36 MMF and 36 AZA. Clinical and histological characteristics at start of induction therapy were comparable among groups. At start of maintenance therapy, CsA patients had significantly higher proteinuria (P = 0.004) or nephrotic syndrome (P = 0.024) and significantly lower CRR (23.5% vs 55.5% on MMF and 41.7% on AZA, P = 0.024). At one year, CRR was similar in the three groups (79.4% on CsA, 63.8% on MMF, 58.3% on AZA, P = 0.2). At 8 years, the primary endpoint was achieved by 79.4% of CsA vs 83.3% of MMF and 77.8% of AZA patients (P = 0.83); 24 h proteinuria, serum creatinine, eGFR were similar. CKD stage 3 or above developed in 8.8% of CsA, in 8.3% of MMF and in 8.3% of AZA patients (P = 0.92). Flares-free survival curves and incidence of side-effects were not different.This is the first study comparing CsA, MMF and AZA on long-term LN maintenance therapy. All treatments had similar efficacy in achieving and maintaining CRR, despite more severe baseline clinical features in patients treated with CsA.

ObjectivesShort-term predictive endpoints of chronic kidney disease (CKD) are needed in lupus nephritis (LN). We tested response to therapy at 1 year.MethodsWe considered patients with LN who underwent renal biopsy followed by induction therapy between January 1970 and December 2016. LN was assessed using the International Society of Nephrology/Renal Pathology Society (2003) criteria and the National Institute of Health (NIH) activity and chronicity index. The renal outcome was CKD. Response was defined according to EULAR/European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations:complete:proteinuria partial:≥50% proteinuria reduction to subnephrotic levels, (near) normal eGFR; andno response:all the other cases. Logistic regression analysis was employed for 12-month response and Cox regression for CKD prediction.ResultsWe studied 381 patients (90.5% Caucasians). After 12-month therapy, 58%, 26% and 16% of patients achieved complete, partial and no response, respectively, according to EULAR/ERA-EDTA. During a median follow-up of 10.7 (IQR: 4.97–18.80) years, 53 patients developed CKD. At 15 years, CKD-free survival rate was 95.2%, 87.6% and 55.4% in patients with complete, partial and no response at 12 months, respectively (pConclusionsLack of EULAR/ERA-EDTA response at 12 months predicts CKD.

There is little information about very long-term outcomes of kidney allograft recipients exposed to calcineurin inhibitors. In this single-centre retrospective study with 20-year follow-up, we analyzed data from 644 patients who underwent primary renal transplantation between 1983 and 1993. Participants were treated with a cyclosporine-based immunosuppressive scheme and had allograft function at 1 year. After 20 years, 15.2% patients died, 39.7% experienced allograft loss, 26.8% were alive with a functioning transplant, and 18.2% were lost to follow-up. Cardiovascular disease (30.8%), malignancy (26.6%) and infection (17.0%) were the main causes of death. Age, new-onset proteinuria > 1 g/day, major acute cardiovascular event (MACE), and malignancy were independent predictors of mortality at time-dependent multivariate analysis. Chronic rejection (63.3%), recurrent glomerulonephritis (14.0%), and nonspecific interstitial fibrosis/tubular atrophy (13.2%) were the leading cause of allograft loss. Basal disease, hepatitis C, difference between 1 year and nadir serum creatinine, new-onset proteinuria > 1 g/day, and MACE were independent predictors of transplant failure. Among patients with 20-year allograft function, we recorded the following complications: hypertension (85%), malignancy (13%), diabetes (9%), and cardiovascular disease (9%). Median serum creatinine and proteinuria were 1.4 mg/dL and 0.6 g/day, respectively. Prolonged use of cyclosporine may expose to several dose-related adverse events and may contribute to the development of allograft dysfunction but it does not necessarily cause relentless, progressive transplant failure if patients are carefully and consistently monitored during the follow-up.

Rationale & Objective Idiopathic retroperitoneal fibrosis (IRF) is a rare disorder of unknown cause. Medical therapy can induce remission, but disease relapses are common. This study sought to characterize long-term outcomes of IRF and the factors associated with disease recurrences. Study Design Retrospective cohort study. Setting & Participants Retrospective analysis of 50 patients with IRF prospectively followed up for 8.9 (IQR, 4.7-12.7) years at a tertiary-care referral center. Exposures Demographic, clinical, treatment, and laboratory parameters, including measures of autoimmunity. Outcome Disease relapse. Analytical Approach Proportional hazards analysis for the subdistribution of competing risks. Results 49 patients received medical treatment and 35 underwent interventional procedures. All patients experienced a clinical response (defined as regression of disease-related symptoms and hydronephrosis, and decrease in the maximal transverse diameter of the retroperitoneal mass on computed tomography of >50%), 44 of whom responded within 1 year. The remaining 6 responded over a median of 2.95 years after starting therapy. 40 patients were alive at last observation, 1 receiving maintenance dialysis and 15 with estimated glomerular filtration rate Limitations Small sample size and variable approaches to therapy. Conclusions IRF relapses were common and were experienced more frequently by male patients. Corticosteroids alone or with tamoxifen were associated with a lower rate of relapse. The strong association of antinuclear antibody positivity with relapse supports the hypothesis of an autoimmune pathogenesis of IRF.

Lupus nephritis (LN) treatment requires an initial intensive period of therapy followed by a long-term maintenance treatment in order to stabilize disease control and eventually reach renal remission. In this section, Authors discuss the feasibility of safely lowering and even suspending maintenance therapy in LN patients having entered remission, highlighting hurdles in predicting the depth and durability of disease quiescence together with the need for minimizing potentially toxic therapies. Even though no firm conclusions can still be drawn, the treating physician has to find the wise balance between disease control and treatment-related drawbacks by following patients closely and recognizing as early as possible the ones who are likely to reach a deep and durable renal remission; there is consensus that is these are the only patients in whom a potential safe complete withdrawal can be foreseen so far.

Twenty-yr patient and death-censored graft survival of 348 kidney transplant recipients with primary glomerulonephritis (GN) and of 696 matched controls were 82.2% in GN patients and 75% in controls (p = 0.037) and 49.5% and 54%, respectively (p = 0.013). GN patients had a higher incidence of graft failure than controls even considering death as a competing risk (p = 0.004). In the GN group, graft survival of deceased and of living donor recipients was similar. At multivariate analysis, GN as primary disease (RR: 1.47), delayed graft function recovery (RR: 2.34), acute rejection (RR: 2.36), and any PRA positivity (RR: 1.01) were predictive of graft loss. GN recurred in 85 of 348 grafts (24.4%), and 43 were lost for recurrence. In non-recurrent patients, graft survival at 20 yr was significantly better than in recurrent patients (59.4% vs. 24.4%, p = 0.000), but not different from that of controls (59.4 vs. 54%, p = 0.9). At multivariate analysis, young age at transplantation (RR: 0.97), shorter duration of dialysis (RR: 1.05 per each dialysis year), and graft from living donors (RR: 1.668) were independent predictors of recurrence. Patients with primary GN have reduced graft survival in comparison with controls, and this is mainly due to recurrence of original disease. However, the most frequent recurrence in living recipients does not compromise graft survival.