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Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that causes a breakdown of immune tolerance. Current treatments mainly involve general immunosuppression, increasing the risk of infections. On the other hand, Bacillus Calmette-Guérin (BCG) has been investigated as a potential therapy for autoimmune diseases in recent years, prompting an ongoing investigation. This study aimed to evaluate the effect of BCG vaccination on early and late clinical presentation of SLE in a murine disease model. MRL/MPJ-Fas lpr mice were immunized with BCG or treated with PBS as a control. The progress of the disease was evaluated at 27 days post-immunization (dpi) (early) and 56 dpi (late). Clinical parameters and proteinuria were monitored. Blood samples were collected for measurement of antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA), and cytokine determination was performed using ELISA. Samples collected from mice were analyzed by flow cytometry and histopathology. We observed a clinical improvement in BCG-treated mice, reduced proteinuria in the latter stages of the disease, and decreased TNF-α. However, BCG did not elicit significant changes in ANAs, anti-dsDNA, histopathological scores, or immune cell infiltration. BCG was only partially beneficial in an SLE mouse model, and further research is needed to determine whether the immunity induced by this vaccine can counteract lupus's autoimmune response.

Background and Purpose: Reports of patients who have autoimmune nodopathies concurrent with nephrotic syndrome are increasing. We investigated whether proteinuria could be a biomarker of autoimmune nodopathies., Methods: Qualitative urinalysis results were retrospectively obtained from 69 patients who were diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) at a hospital in Japan. Proteinuria was graded as mild to severe (i.e., mild, 30-99; moderate, 100-299; severe, 300 mg/dL or more) according to the results of the urine dipstick test. Autoantibodies against the paranodal proteins contactin 1 (CNTN1), neurofascin 155 (NF155), and contactin-associated protein 1 (Caspr1) and the nodal protein neurofascin 186 (NF186) were measured, and the predominant IgG subclass was determined by enzyme-linked immunosorbent assay in sera from the 69 patients., Results: Four patients (6%), five patients (7%), and one (1%) patient were positive for anti-CNTN1, anti-NF155, and anti-Caspr1 IgG4 antibodies, respectively. No patients had IgG4 antibodies against NF186. Proteinuria of mild or greater levels was found in three patients with anti-CNTN1 IgG4 and two patients with anti-NF155 IgG4 antibodies. The autoantibody-positive patients more frequently had proteinuria of mild or greater levels than the seronegative patients (p = 0.01)., Conclusions: Proteinuria is a possible biomarker of autoimmune nodopathies associated with autoantibodies targeting CNTN1 or NF155. Urinalysis results should be carefully checked for quick differentiation of autoimmune nodopathies from CIDP. Patients who present with nephrotic syndrome should be tested for anti-CNTN1 IgG4 antibodies, and patients who exhibit mild proteinuria should be tested for anti-NF155 IgG4 antibodies., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

HLA donor specific antibodies (DSA) are implicated in antibody-mediated rejection (AMR), graft dysfunction and failure in kidney transplant (KT) recipients. Non-HLA antibodies including angiotensin II type 1 receptor (AT1R) may also play a role in AMR, impact graft function and survival. Data is limited in paediatric KT cohorts. We aimed to assess the prevalence and effect of pre-transplant AT1R antibodies on rejection, graft function and survival in paediatric KT recipients. This was a retrospective cohort study conducted across two paediatric centres including KT recipients with a pre-transplant AT1R antibody level. Outcomes included rejection, de novo DSA formation, graft function, failure, proteinuria and hypertension. Of 71 individuals, 72% recorded a positive pre-transplant AT1R Ab level (≥17 U/mL). Over a median follow-up of 4.7 years, AT1R Ab positivity demonstrated a trend towards increased risk of rejection however was not statistically significant (HR 3.45, 95% CI 0.97-12.35, p-value 0.06). Sensitivity analysis with AT1R Ab levels of ≥25 U/mL (HR 2.05 95% CI 0.78-5.39, p-value 0.14) and ≥40 U/mL (HR 1.32, CI 95% 0.55-3.17, p-value 0.53) validated this. De novo DSA formation occurred more frequently with AT1R Ab positivity (41% vs. 20%, p-value 0.9). AT1R Ab was not associated with hypertension, proteinuria, graft failure or dysfunction. In conclusion, this cohort study demonstrated a high prevalence of pre-transplant AT1R Ab positivity (72%). AT1R Ab positivity demonstrated a trend towards increased risk of rejection and de novo DSA formation however did not meet statistical significance. There was no association between AT1R Ab and hypertension, proteinuria, graft failure or dysfunction., (© 2024 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)

The aetiology and progression of systemic lupus erythematosus (SLE) resulted from a complex sequence of events generated both from genetic and epigenetic processes. In the current research, the effect of methyl-supplemented nutrition on the development of SLE was studied in the pristane-induced mouse model of the disease. The results clearly demonstrated decreased anti-dsDNA antibody and proteinuria levels, modulation of cytokines and protected renal structures in the group of treated mice. An additional increase in the DNA methylation of mouse B lymphocytes was also observed. The beneficial effect of the diet is due to the methyl-containing micronutrients with possible anti-inflammatory and immunomodulating effects on cell proliferation and gene expression. Since these components are responsible for maintaining the physiological methylation level of DNA, the results point to the central role of methylation processes in environmentally triggered lupus. As nutrition represents one of the major epigenetic factors, these micronutrients may be considered novel agents with significant therapeutic outcomes., (© 2024 John Wiley & Sons Ltd.)

Macrophages are a rich source of macrophage migration inhibitory factor (MIF). It is well established that macrophages and MIF play a pathogenic role in anti-glomerular basement membrane crescentic glomerulonephritis (anti-GBM CGN). However, whether macrophages mediate anti-GBM CGN via MIF-dependent mechanism remains unexplored, which was investigated in this study by specifically deleting MIF from macrophages in MIF f/f-lysM-cre mice. We found that compared to anti-GBM CGN induced in MIF f/f control mice, conditional ablation of MIF in macrophages significantly suppressed anti-GBM CGN by inhibiting glomerular crescent formation and reducing serum creatinine and proteinuria while improving creatine clearance. Mechanistically, selective MIF depletion in macrophages largely inhibited renal macrophage and T cell recruitment, promoted the polarization of macrophage from M1 towards M2 via the CD74/NF-κB/p38MAPK-dependent mechanism. Unexpectedly, selective depletion of macrophage MIF also significantly promoted Treg while inhibiting Th1 and Th17 immune responses. In summary, MIF produced by macrophages plays a pathogenic role in anti-GBM CGN. Targeting macrophage-derived MIF may represent a novel and promising therapeutic approach for the treatment of immune-mediated kidney diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Li, Huang, Bucala, Xu and Lan.)

Anti-phospholipase A2 receptor autoantibody (PLA2R-Ab) plays a critical role in the pathogenesis of primary membranous nephropathy (PMN), an autoimmune kidney disease characterized by immune deposits in the glomerular subepithelial spaces and proteinuria. However, the mechanism of how PLA2R-Abs interact with the conformational epitope(s) of PLA2R has remained elusive. PLA2R is a single transmembrane helix receptor containing ten extracellular domains that begin with a CysR domain followed by a FnII and eight CTLD domains. Here, we examined the interactions of PLA2R-Ab with the full PLA2R protein, N-terminal domain truncations, and C-terminal domain deletions under either denaturing or physiological conditions. Our data demonstrate that the PLA2R-Abs against the dominant epitope (the N-terminal CysR-CTLD1 triple domain) possess weak cross-reactivities to the C-terminal domains beyond CTLD1. Moreover, both the CysR and CTLD1 domains are required to form a conformational epitope for PLA2R-Ab interaction, with FnII serving as a linker domain. Upon close examination, we also observed that patients with newly diagnosed PMN carry two populations of PLA2R-Abs in sera that react to the denatured CysR-CTLD3 (the PLA2R-Ab 1 ) and denatured CysR-CTLD1 (the PLA2R-Ab 2 ) domain complexes on Western blots, respectively. Furthermore, the PLA2R-Ab 1 appeared at an earlier time point than PLA2R-Ab 2 in patients, whereas the increased levels of PLA2R-Ab 2 coincided with the worsening of proteinuria. In summary, our data support that an integrated folding of the three PLA2R N-terminal domains, CysR, FnII, and CTLD1, is a prerequisite to forming the PLA2R conformational epitope and that the dominant epitope-reactive PLA2R-Ab 2 plays a critical role in PMN clinical progression., Competing Interests: Conflict of interest H. T. holds a patent to use the findings for developing diagnostic tests to monitor PMN clinical progress and prognosis, predict patient response to treatment, and developing new therapies for patient treatment. R. Z. is a student intern at ImmunoWork., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Collapsing glomerulopathy represents a special variant of the proteinuric kidney disease focal segmental glomerulosclerosis (FSGS). Histologically, the collapsing form of FSGS (cFSGS) is characterized by segmental or global condensation and obliteration of glomerular capillaries, the appearance of hyperplastic and hypertrophic podocytes and severe tubulointerstitial damage. Clinically, cFSGS patients present with acute kidney injury, nephrotic-range proteinuria and are at a high risk of rapid progression to irreversible kidney failure. cFSGS can be attributed to numerous etiologies, namely, viral infections like HIV, cytomegalovirus, Epstein-Barr-Virus, and parvovirus B19 and also drugs and severe ischemia. Risk variants of the APOL1 gene, predominantly found in people of African descent, increase the risk of developing cFSGS. Patients infected with the new Corona-Virus SARS-CoV-2 display an increased rate of acute kidney injury (AKI) in severe cases of COVID-19. Besides hemodynamic instability, cytokine mediated injury and direct viral entry and infection of renal epithelial cells contributing to AKI, there are emerging reports of cFSGS associated with SARS-CoV-2 infection in patients of mainly African ethnicity. The pathogenesis of cFSGS is proposed to be linked with direct viral infection of podocytes, as described for HIV-associated glomerulopathy. Nevertheless, there is growing evidence that the systemic inflammatory cascade, activated in acute viral infections like COVID-19, is a major contributor to the impairment of basic cellular functions in podocytes. This mini review will summarize the current knowledge on cFSGS associated with viral infections with a special focus on the influence of systemic immune responses and potential mechanisms propagating the development of cFSGS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Muehlig, Gies, Huber and Braun.)

Full-dose prednisone (FP) regimen in the treatment of high-risk immunoglobulin A nephropathy (IgAN) patients, is still controversial. The pulsed intravenous methylprednisolone combined with alternative low-dose prednisone (MCALP) might have a more favorable safety profile, which has not been fully investigated. Eighty-seven biopsy-proven IgAN adult patients and proteinuria between 1 and 3.5 g/24 h after ACEI/ARB for at least 90 days were randomly assigned to 6-month therapy: (1) MCALP group: 0.5 g of methylprednisolone intravenously for three consecutive days at the beginning of the course and 3rd month respectively, oral prednisone at a dose of 15 mg every other day for 6 months. (2) FP group: 0.8-1.0 mg/kg/days of prednisone (maximum 70 mg/day) for 2 months, then tapered by 5 mg every 10 days for the next 4 months. All patients were followed up for another 12 months. The primary outcome was complete remission (CR) of proteinuria at 12 months. The percentage of CR at 12th and 18th month were similar in the MCALP and FP groups (51% vs 58%, P = 0.490, at 12th month; 60% vs 56%, P = 0.714, at 18th month). The cumulative dosages of glucocorticoid were less in the MCALP group than FP group (4.31 ± 0.26 g vs 7.34 ± 1.21 g, P < 0.001). The analysis of the correlation between kidney biopsy Oxford MEST-C scores with clinical outcomes indicated the percentages of total remission was similar between two groups with or without M1, E1, S1, T1/T2, and C1/C2. More patients in the FP group presented infections (8% in MCALP vs 21% in FP), weight gain (4% in MCALP vs 19% in FP) and Cushing syndrome (3% in MCALP vs 18% in FP). These data indicated that MCALP maybe one of the choices for IgAN patients with a high risk for progression into ESKD.Trial registration: The study approved by the Chinese Clinical Trial Registry (registration date 13/01/2018, approval number ChiCTR1800014442, https://www.chictr.org.cn/ )., (© 2022. The Author(s).)

Background: The Oxford classification of IgA nephropathy (IgAN) was revised in 2016 which lacked sufficient evidence for prognostic value of subclassification of focal segmental glomerular sclerosis (S lesion), and the proper proportion of S lesion for subclassification remains undetermined., Aim: This study aimed to explore the predictive value of the new subclassification of S score on renal outcomes of IgAN patients., Methods: 348 patients with IgAN-associated S lesion were enrolled. According to the optimal cut-off of 25% established by receiver operating characteristic (ROC) curves, we divided S1 patients into two groups: S1a group (S lesion < 25%) and S1b group (S lesion ≥ 25%). IgAN patients with mild lesion (M0E0S0T0C0) were set as the control group. The clinical features at renal biopsy, pathological findings, and follow-up parameters (follow-up time ranged from 1 to 5 years) were collected. We used univariate and multivariate analyses to assess whether the subclassification of S score could refine risk prediction and clinical utility., Results: We demonstrated that S lesion ≥ 25% was associated with a more rapid GFR loss and a lower rate of complete remission of proteinuria even adjusted for multiple clinic pathological variables, compared to S1a group (All p values <.05). And the ratio of glomeruli with T lesion and crescents were higher in patients with S lesion ≥ 25%. Data showed that IgAN patients with S lesion ≥ 25% were at an increased risk of poor renal outcomes even with immunosuppression., Conclusion: This study might recommend new subclassification of S scores (S0 (no S lesion), S1 (S lesion <25% of glomeruli), and S2 (S lesion ≥ 25% of glomeruli)) for the Oxford classification. This model may also help to evaluate pros and cons of immunosuppressive therapy in IgAN patients with different level of S lesion.KEY MESSAGESS lesion ≥ 25% is an independent risk factor for poor renal outcome in IgAN patients.This new subclassification of S scores may help to evaluate pros and cons of immunotherapy in IgAN patients with different level of S lesion.

Children with idiopathic nephrotic syndrome (INS) usually have podocyte injury, and recent studies suggest a B cell dysfunction in INS. Therefore, this study attempts to screen and identify the podocyte autoantibodies in patients. Two-dimensional electrophoresis and mass spectrometry were used to screen and identify the pathogenic podocyte autoantibodies in children with INS. The positive rate, expression pattern, and clinical correlation of these podocyte autoantibodies in children with INS were determined by clinical study. At least 66% of INS children have podocyte autoantibodies. Seven podocyte autoantibodies closely related to INS were screened and identified for the first time in this study. These podocyte autoantibodies are positively correlated with proteinuria, and its titer will decrease rapidly after effective treatment. In this study, a group of new disease subgroup-"autoimmune podocytes" were identified by podocyte autoantibodies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is a major cause of patient mortality and a major risk multiplier for the progression to chronic kidney disease (CKD). The mechanism of the AKI to CKD transition is complex but is likely mediated by the extent and length of the inflammatory response following the initial injury. Lymphatic vessels help to maintain tissue homeostasis through fluid, macromolecule, and immune modulation. Increased lymphatic growth, or lymphangiogenesis, often occurs during inflammation and plays a role in acute and chronic disease processes. What roles renal lymphatics and lymphangiogenesis play in AKI recovery and CKD progression remains largely unknown. To determine if the increased lymphatic density is protective in the response to kidney injury, we utilized a transgenic mouse model with inducible, kidney-specific overexpression of the lymphangiogenic protein vascular endothelial growth factor-D to expand renal lymphatics. "KidVD" mouse kidneys were injured using inducible podocyte apoptosis and proteinuria (POD-ATTAC) or bilateral ischemia reperfusion. In the acute injury phase of both models, KidVD mice demonstrated a similar loss of function measured by serum creatinine and glomerular filtration rate compared to their littermates. While the initial inflammatory response was similar, KidVD mice demonstrated a shift toward more CD4+ and fewer CD8+ T cells in the kidney. Reduced collagen deposition and improved functional recovery over time was also identified in KidVD mice. In KidVD-POD-ATTAC mice, an increased number of podocytes were counted at 28 days post-injury. These data demonstrate that increased lymphatic density prior to injury alters the injury recovery response and affords protection from CKD progression., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Ambiguities remain regarding the role of clinicopathological characteristics in the early prediction of the prognosis of lupus nephritis (LN). Systemic lupus erythematosus (SLE) patients who completed routine follow-up were identified and retrospectively reviewed for eligible cases. Poor prognosis was defined as all-cause mortality or a persistent decrease of eGFR greater than half the baseline level or progression to end-stage renal disease (ESRD). An optimal Cox regression model was constructed for the early prediction of a poor prognosis for LN. Among the 2163 SLE patients, 376 eligible LN cases were enrolled in the study, with a median follow-up time of 55 [27.0, 87.0] months. The male-to-female ratio was 1:7.2, and 37 patients (9.8%) progressed to the composite endpoint. The ISN/RPS class was significantly associated with proteinuria levels (P-value < 0.001), and class IV/IV + V patients, but not class V patients, had the most severe proteinuria. Our optimal multivariate Cox regression model indicated that sex, ISN/RPS class, tubular atrophy/interstitial fibrosis, serum albumin, tertiles of proteinuria, and their interaction were independently associated with a poor prognosis. ROC analysis and external validation demonstrated that our model was efficient and robust for distinguishing LN patients with a poor prognosis. Our study constructed a robust and early predictive model for convenience in clinical practice to identify poor prognosis in LN patients. We found a significant interaction effect between proteinuria and serum albumin for the prediction of poor prognosis. LN patients with low-level proteinuria and hypoalbuminemia exhibit an increased hazard of progression to poor outcomes.

Abstract: To investigate the clinicopathological features and outcomes of primary IgA nephropathy with nephrotic-range proteinuria in Chinese children. Patients with biopsy-proven IgA nephropathy and nephrotic-range proteinuria between January 2011 and December 2017 were included, and their proteinuria and renal function were followed up. A total of 90 patients were enrolled, and 21.1% (19/90) of them had decreased renal function at diagnosis. Complete remission, partial remission, and no response of proteinuria occurred in 88.6% (70/79), 10.1% (8/79), and 1.3% (1/79), respectively, of the 79 patients who were followed up for 6 to 104 months. 73.7% (14/19) of the patients with decreased renal function at diagnosis recovered to normal level while 26.3% (5/19) of them did not recover or progressed to end-stage renal disease. Two patients with normal renal function at diagnosis progressed to renal insufficiency during follow-up period. By multivariate analysis, the risk for renal function deterioration was significantly higher in the partial remission and no response groups than in the complete remission group. Remission of proteinuria was important for improving renal prognosis in children with IgA nephropathy and nephrotic-range proteinuria. The outcomes for pediatric patients appeared to be better than that reported in adults., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The novel coronavirus (SARS-CoV-2) has turned into a life-threatening pandemic disease (Covid-19). About 5% of patients with Covid-19 have severe symptoms including septic shock, acute respiratory distress syndrome, and the failure of several organs, while most of them have mild symptoms. Frequently, the kidneys are involved through direct or indirect mechanisms. Kidney involvement mainly manifests itself as proteinuria and acute kidney injury (AKI). The SARS-CoV-2-induced kidney damage is expected to be multifactorial; directly it can infect the kidney podocytes and proximal tubular cells and based on an angiotensin-converting enzyme 2 (ACE2) pathway it can lead to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy and mitochondrial impairment. The SARS-CoV-2-driven dysregulation of the immune responses including cytokine storm, macrophage activation syndrome, and lymphopenia can be other causes of the AKI. Organ interactions, endothelial dysfunction, hypercoagulability, rhabdomyolysis, and sepsis are other potential mechanisms of AKI. Moreover, lower oxygen delivery to kidney may cause an ischaemic injury. Understanding the fundamental molecular pathways and pathophysiology of kidney injury and AKI in Covid-19 is necessary to develop management strategies and design effective therapies., (© 2020 John Wiley & Sons Ltd.)

Pathogens such as the Epstein Barr virus (EBV) have long been implicated in the etiology of systemic lupus erythematosus (SLE). The Epstein Barr virus nuclear antigen I (EBNA-1) has been shown to play a role in the development of anti-nuclear antibodies characteristic of SLE. One mechanism by which EBV may play a role in SLE is molecular mimicry. We previously generated two monoclonal antibodies (mAbs) to EBNA-1 and demonstrated that they cross-react with double-stranded DNA (dsDNA). In the present study, we demonstrate that these mAbs have pathogenic potential. We show that they can bind to isolated rat glomeruli and that binding can be greatly diminished by pretreatment of glomeruli with DNase I, suggesting that these mAbs bind dsDNA in the kidney. We also demonstrate that these antibodies can deposit in the kidney when injected into mice and can induce proteinuria and elicit histopathological alterations consistent with glomerulonephritis. Finally, we show that these antibodies can cross-react with laminin and collagen IV in the extracellular matrix suggesting that direct binding to the glomerular basement membrane or mesangial matrix may also contribute to the antibody deposition in the kidney. In summary, our results indicate that EBNA-1 can elicit antibodies that cross-react with dsDNA, that can deposit in the kidney, and induce kidney damage. These results are significant because they support the role of a viral protein in SLE and lupus nephritis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Systemic-lupus-nephritis is a chronic autoimmune disease characterized by immune complex deposition and a flare of autoantibodies and leading to renal injury., Objectives: To expose anti-Dense-Fine-Speckled-70 (DFS70)-antibodies to genetically-prone-lupus-mice., Methods: NZBXW/F1 female mice were monitored for the onset of glomerulonephritis by proteinuria upon infusion of anti-DFS70 (40 μg/mouse), commercial-human-IgG (cIgG) or phosphate-buffered-saline (PBS) as controls. The survival time was detected by mice death. Circulating anti-dsDNA were tested by ELISA. Proteinuria, was defined by a standard semi-quantitative-Bayer-Multistix-dipstick. Kidney histology was analyzed by periodic-acid-Schiff-PAS staining., Results: A significantly higher percentage of anti-DFS70-infused mice exhibited prolonged survival time as compared with cIgG and PBS-subjected mice (p < 0.022). One mouse out of 10 mice injected with anti-DFS70-antibodies died at week 36, whereas, 6 out of 10 mice subjected with PBS found dead at this time. Eighty percent of anti-DFS70 injected mice did not show severe glomerulonephritis by histology., Conclusions: anti-DFS70 attenuated the progression of glomerulonephritis and prolonged the survival time. Circulating anti-DFS70-autoantibodies may confer a protective role against renal injury in murine-lupus-nephritis. Our data may propose a novel therapy approach for lupus patients.

Systemic lupus erythematosus (SLE) is a multifactorial and heterogeneous autoimmune disease involving multiple organ systems and tissues. Lupus nephritis occurs in approximately 60% of patients with SLE and is the leading cause of morbidity. Diffuse alveolar hemorrhage (DAH) is a rare but very serious complication of SLE with a greater than 50% associated mortality. The etiology of SLE is unclear but has proposed genetic, hormonal, and environmental aspects. Pristane is a saturated terpenoid alkane and has become the most popular laboratory model for inducing lupus in mice. The pristane model of SLE has the capacity to reproduce many components of the human presentation of the disease. Previous studies have demonstrated that virus-derived immune-modulating proteins have the potential to control inflammatory and autoimmune disorders. Serp-1, a 55 kDa secreted and highly glycosylated immune modulator derived from myxoma virus (MYXV), has potent immunomodulatory activity in models of vasculitis, viral sepsis, collagen-induced arthritis, and transplant rejection. This chapter describes the mouse preclinical pristane lupus model as a method to examine virus-derived protein efficacy for treating autoimmune diseases and specifically lupus nephritis and DAH.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the main contributors to organ damage are antibodies against autoantigens, such as double-stranded DNA (dsDNA). Calorie restriction and intermittent fasting (IF) have been shown to improve autoimmune disease symptoms in patients and animal models. Here, we tested the hypothesis that IF might improve symptoms in MRL/lpr mice, which spontaneously develop an SLE-like disease. Groups of mice were fed every other day (IF) or provided food ad libitum (controls), and various lupus-associated clinicopathological parameters were analyzed for up to 28 weeks. Contrary to expectations, anti-dsDNA antibody levels, immune complex deposition in the kidney, and glomerular injury were higher in the IF group than the control group, although there were no differences in spleen and lymph node weights between groups. Proteinuria was also worsened in the IF group. IF also increased the abundance of B cells, plasmablasts, and plasma cells and elevated autophagy in plasma cells in the spleen and lymph nodes. Secretion of anti-dsDNA antibody by splenocytes in vitro was reduced by chloroquine-induced inhibition of autophagy. These results suggest that IF exacerbates lupus nephritis in MRL/lpr mice by increasing autoantibody immune complex formation.

Background: Previous reports suggest initial presentation of IgA nephropathy (IgAN) in children is different from adults. No systematic comparison of clinical, biological, and histological childhood- and adult-onset IgAN is currently available., Methods: We compared pediatric and adult clinical and histological characteristics at IgAN diagnosis. Data on 211 consecutive patients from two different centers in Paris (82 children, 129 adults) were reviewed. Kidney biopsies were scored for Oxford classification and podocytopathic (P1) features., Results: We report higher eGFR at diagnosis in children compared to adults (89.5 vs. 64 ml/min/1.73 m 2 ; p = 0.0001) but no difference in proteinuria. Histological analysis of kidney biopsy found higher proportions of mesangial (M1) and endocapillary (E1) hypercellularity in children compared with adults (M1 [80.7% vs. 27.9%, p = 0.0001]; E1 [71.3% vs. 30%, p = 0.0001]). Focal glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis ≥ 25% (T1), and P1 were more frequent in adults (S1 [81.5% vs. 61.3%, p = 0.0012], T1 [49.5% vs. 1.35%, p = 0.0001], P1 [33.8% vs. 16.4%, p = 0.008). Proteinuria associated with M1, E1, and C1 in children (M1, p = 0.0001; E1, p = 0.0005; C1, p = 0.0014) but S1, P1, and T1 in adults (S1, p = 0.0001; P1, p = 0.0001; T1, p = 0.001). After steroid treatment (41 children and 28 adults), proteinuria decreased in children (p < 0.001, follow-up 38 months) and adults (p < 0.001, follow-up 76.9 months), whereas eGFR remained stable in adults but increased significantly in children (90.6 to 110 ml/min/1.73m 2 )., Conclusion: Proteinuria in children with IgAN is a marker of glomerular proliferative lesions whereas its presence in adults often reflects the presence of chronic lesions. This suggests the need for histological assessment.

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) cytokine family and an inflammation-associated protein. Here, we investigated the role of GDF15 in murine anti-glomerular basement membrane (GBM) glomerulonephritis. Glomerulonephritis induction in mice induced systemic expression of GDF15. Moreover, we demonstrate the protective effects for GDF15, as GDF15-deficient mice exhibited increased proteinuria with an aggravated crescent formation and mesangial expansion in anti-GBM nephritis. Herein, GDF15 was required for the regulation of T-cell chemotactic chemokines in the kidney. In addition, we found the upregulation of the CXCR3 receptor in activated T-cells in GDF15-deficient mice. These data indicate that CXCL10/CXCR3-dependent-signaling promotes the infiltration of T cells into the organ during acute inflammation controlled by GDF15. Together, these results reveal a novel mechanism limiting the migration of lymphocytes to the site of inflammation during glomerulonephritis.

Background: Angiotensin II type 1 receptors (AT1Rs) are expressed on podocytes, endothelial and other cells, and play an essential role in the maintenance of podocyte function and vascular homeostasis. The presence of AT1R antibodies (AT1R-Abs) leads to activation of these receptors resulting in podocyte injury and endothelial cell dysfunction. We assessed the correlation between AT1R-Abs and the risk of post-transplant FSGS., Methods: This is a retrospective study, which included all kidney transplant recipients with positive AT1R-Abs (≥ 9 units/ml), who were transplanted and followed at our center between 2006 and 2016. We assessed the development of biopsy proven FSGS and proteinuria by urine protein to creatinine ratio of ≥1 g/g and reviewed short and long term outcomes., Results: We identified 100 patients with positive AT1R-Abs at the time of kidney transplant biopsy or proteinuria. 49% recipients (FSGS group) had biopsy-proven FSGS and/or proteinuria and 51% did not (non-FSGS group). Pre-transplant hypertension was present in 89% of the FSGS group compared to 72% in the non-FSGS group, p = 0.027. Of the FSGS group, 43% were on angiotensin converting enzyme inhibitors or angiotensin receptor blockers prior to transplantation, compared to 25.5% in the non-FSGS group, p = 0.06. Primary idiopathic FSGS was the cause of ESRD in 20% of the FSGS group, compared to 6% in the non-FSGS group, p = 0.03. The allograft loss was significantly higher in the FSGS group 63% compared to 39% in non-FSGS. Odds ratio and 95% confidence interval were 2.66 (1.18-5.99), p = 0.017., Conclusions: Our data suggest a potential association between AT1R-Abs and post-transplant FSGS leading to worse allograft outcome. Therefore, AT1R-Abs may be considered biomarkers for post-transplant FSGS.

Purpose of Review: Immune dysfunction, including severe combined immunodeficiency, has been described in genetic disorders affecting the metabolism of the vitamins cobalamin (vitamin B12) and folate. We have reviewed reports of clinical findings in patients with a number of inborn errors of cobalamin or folate metabolism, specifically looking for immune problems., Recent Findings: There is little evidence that immune function is affected in most of the disorders. Exceptions are Imerslund-Gräsbeck syndrome and hereditary folate malabsorption (affecting intestinal absorption of cobalamin and folate, respectively), transcobalamin deficiency (affecting transport of cobalamin in blood and cellular cobalamin uptake), and methylenetetrahydrofolate dehydrogenase 1 deficiency (catalyzing cytoplasmic interconversion of reduced folate coenzyme derivatives)., Summary: Although some inborn errors of cobalamin or folate can be associated with immune dysfunction, the degree and type of immune dysfunction vary with no obvious pattern.

Objective: This study is aimed at investigating the efficacy of CTLA4-Ig abatacept in normalizing proteinuria and its possible mechanism in adriamycin-induced nephropathy (AIN) rats., Methods: A total of 32 healthy male Sprague-Dawley rats were randomly divided into a normal group, an AIN group, an abatacept group, and a prednisone group. Adriamycin (6.5 mg/kg) was injected once via the tail vein of rats to induce nephrotic syndrome. After adriamycin treatment, the abatacept group rats were given abatacept (0.5 mg/kg) once by intraperitoneal injection on day 14. In addition, the prednisone group rats were given prednisone (12.5 mg/kg) daily consecutively by gavage from day 14 to day 21. Blood, urine, and kidney tissue specimens were collected when sacrificed on day 21. The 24-hour urinary protein, serum albumin, cholesterol, creatinine, and urea nitrogen were then detected. An enzyme-linked immunosorbent assay was used to determine the level of urine CD80 and serum IL-17. Flow cytometry was used to investigate the prevalence of circulating Treg. Hematoxylin-eosin staining and electron microscopy were used for a renal histological study. Immunofluorescence staining was performed to confirm the CD80 expression of renal tissue., Results: The 24-hour urinary protein of the abatacept group was significantly lower than that of the prednisone group and the AIN group. The level of urine CD80 of the abatacept group was significantly lower than that of the AIN group. Compared with the AIN group and the prednisone group, the circulating Treg prevalence of the abatacept group was significantly higher, while the level of serum IL-17 was lower. A negative kidney staining of CD80 expression was demonstrated in each group in this study. The 24-hour urinary protein had a negative correlation with the circulating Treg prevalence and Treg/IL-17 and a positive correlation with the urine CD80 and serum IL-17. Urinary CD80 had a positive correlation with serum IL-17 and no correlation with the circulating Treg prevalence., Conclusions: CTLA4-Ig abatacept can reduce proteinuria of adriamycin-induced nephropathy rats, possibly at least partially as a result of regulating circulating Treg/IL-17. CTLA4-Ig abatacept could be a promising regimen for idiopathic nephrotic syndrome., Competing Interests: No conflicts of interest, financial of otherwise, are declared by the authors., (Copyright © 2020 Lanjun Shuai et al.)

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disorder. Renal involvement usually develops in the first few years of illness and should be detected early by periodic urine analysis and quantitation of proteinuria. The aim of our work was to evaluate the biological marker [anti-complement 1q antibodies (anti-C1q Ab)] in lupus nephritis (LN) patients and its correlation to SLE disease activity. Sixty-five subjects were divided into four groups; Group I: SLE patients with LN (proteinuria >0.5 g/day), Group II: SLE patients without LN (all of them had a lupus flares rather than nephritis; active nonrenal), Group III: SLE patients without any activity (inactive disease), and Group IV: Control group. All subjects underwent urine analysis, complete blood picture, liver function tests, kidney function tests, albumin/ creatinine ratio, antinuclear antibody, anti-double stranded DNA (anti-dsDNA) antibody, C3, C4, and anti-C1q Ab. All patients in the first group underwent renal biopsy and pathological diagnosis showed: Class II in two patients, Class III and IV in nine patients, and Class V in four patients. Anti-C1q Ab were found in the serum of SLE patients and not in the control group and showed an association with active lupus with much higher concentration in active renal group, specifically those with severe renal histological lesions (proliferative form). There was significant statistical positive correlation between anti-C1q Ab with anti-dsDNA and SLE disease activity index in both active groups. There was statistically significant negative correlation between anti-C1q Ab with C3 and C4 in both active groups. Anti-C1q Ab could be used as useful marker for active lupus, especially with nephritis., Competing Interests: None

Background: The present study aims to compare the relative efficacy and safety of different uses of cyclophosphamide (CYC) in lupus nephritis (LN)., Methods: We searched the Cochrane Library, EMBASE, Global Health, MEDLINE and PubMed for articles from the database till June 2018., Results: 12 randomized controlled trials with 994 participants were included. The meta-analysis indicated that the short-interval lower-dose intravenous CYC regime remarkably reduced 24-hour proteinuria [mean difference (MD) -0.45; 95% confidence interval (CI) -0.62 to -0.27; I2 0%], incidence of major infections [odds ratio (OR) 0.62, 95% CI 0.40 to 0.95; I2 42%], gonadal toxicity (OR 0.41, 95% CI 0.27 to 0.62; I2 0%), and leukopenia (OR 0.55, 95% CI 0.33 to 0.94, I2 0%), while high-dose regime had an obvious lower probability of doubling of serum creatinine (Scr) level (OR 2.43; 95% CI 1.19 to 4.95; I2 0%). However, the difference in the complete and total remission rates between the two regimens was not observed., Conclusion: The result suggested that the short-interval lower-dose CYC regime remarkably reduced 24-hour proteinuria and the incidence of adverse events, while the long-course high-dose regime played a significant role in reducing the rate of doubling Scr level., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Immune checkpoint inhibitors have dramatically improved cancer therapy for many patients. These humanized monoclonal antibodies against various immune checkpoints (receptors and ligands) effectively treat a number of malignancies by unleashing the immune system to destroy cancer cells. These drugs are not excreted by the kidneys or liver, have a long half-life, and undergo receptor-mediated clearance. Although these agents have greatly improved the prognosis of many cancers, immune-related end organ injury is a complication that has come to light in clinical practice. Although less common than other organ involvement, kidney lesions resulting in acute kidney injury and/or proteinuria are being described. Acute tubulointerstitial nephritis is the most common lesion seen on kidney biopsy, while acute tubular injury and glomerular lesions occur less commonly. Clinical findings and laboratory tests are suboptimal in predicting the underlying renal lesion, making kidney biopsy necessary in the majority of cases to definitely diagnose the lesion and potentially guide therapy. Immune checkpoint inhibitor discontinuation and corticosteroid therapy are recommended for acute tubulointerstitial nephritis. Based on a handful of cases, re-exposure to these drugs in patients who previously developed acute tubulointerstitial nephritis has been mixed. Although it is unclear whether re-exposure is appropriate, it should perhaps be considered in patients with limited options. When this approach is taken, patients should be closely monitored for recurrence of acute kidney injury. Treatment of cancer in patients with a kidney transplant with immune checkpoint inhibitors risks the development of acute rejection in some patients and requires close surveillance., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Crescent formation in immunoglobulin A nephropathy (IgAN) has been demonstrated to be a risk factor for worse outcomes. For IgAN patients with 0-25% crescentic glomeruli (C1), whether corticosteroids (CS) can improve the prognosis remains unclear. We tried to investigate the need for using CS in IgAN patients with C1 in different proteinuria levels., Methods: A total of 120 eligible IgAN patients with C1 from two academic medical centers were retrospectively studied, and 57 (47.5%) received CS. Patients were grouped according to with or without CS. The outcomes were the rate of estimated glomerular filtration rate (eGFR) decline (ml/min per 1.73 m 2 /year) and a composite outcome (50% decrease in eGFR, end stage renal disease (ESRD) or death due to kidney disease). The progression of adverse outcome among them were analyzed in Kaplan-Meier curve. The independent significance of CS on renal outcome or eGFR decline rate were analyzed by multivariable Cox regression or linear regression., Results: Unadjusted Kaplan-Meier showed that the outcome of treated patients was better than that of the untreated patients. Multiple Cox regression and linear regression analysis found that CS independently protected the renal outcome and decreased the eGFR decline rate. In the subgroup analysis, multivariate linear regression showed that CS decreased the eGFR decline rate both in proteinuria ≥ 1 g/day and < 1 g/day., Conclusions: CS protected the renal outcome and slowed the eGFR decline rate of IgAN patients with C1, it also decreased the eGFR decline rate even in those with initial proteinuria < 1 g/day.

The discovery in 2009 of the M-type phospholipase A2 receptor (PLA2R) as the primary target in membranous nephropathy (MN) greatly advanced basic and clinical research. Primary MN is now considered a renal-limited autoimmune disease, with antibodies against PLA2R (aPLA2Rab) identified in 70-80 % of patients of various ethnic groups. Although the use of aPLA2Rab as a diagnostic and prognostic biomarker is now widely accepted, many questions related to the development of the auto-immune response, the role of IgG subclasses and antigenic epitopes, and the pathways to podocyte injury remain unresolved. PLA2R-associated MN most likely develops governed by factors such as genetic susceptibility, loss of tolerance, alterations in antigen expression with a role for environmental factors like air pollution, smoking, and infections. More detailed knowledge of genetic factors, the relevant B- and T-cell epitopes, and the mechanisms of podocyte injury is needed to identify patients at risk for disease progression and to develop optimized, targeted treatment strategies. In this review we highlight unresolved issues, addressing initiation of antibody formation, the timeline of antibody production, the role of IgG subclass, and the pathogenicity of the antibodies in concert with complement to produce glomerular pathology and proteinuria., (Copyright © 2019 International Society of Nephrology. All rights reserved.)

Antibodies against THSD7A (thrombospondin type 1 domain-containing protein 7A) have been proposed to play a causal role in the development of nephrotic syndrome in patients with THSD7A antibody-positive membranous nephropathy. We hypothesized that removal of these antibodies from plasma could lead to a rapid reduction in proteinuria. Using immunoadsorption to reduce THSD7A antibodies led to a rapid reduction in proteinuria in 2 patients with THSD7A antibody-positive membranous nephropathy. Moreover, our findings support and strengthen the pathogenic role of the antibodies in the development of nephrotic syndrome in patients with THSD7A antibody-positive membranous nephropathy. Taken together, these 2 cases suggest that immunoadsorption could be a useful tool in the treatment of patients with THSD7A antibody-positive membranous nephropathy., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin A nephropathy (IgAN) is characterized by mesangial IgA and IgG co-deposition. As the clinical course of IgAN is highly variable, a lot of patients will eventually develop to end-stage renal disease (ESRD) within years. Hirudin, a potent and specific thrombin inhibitor, has been reported to treat IgAN with hematuria, but the mechanism is unclear. Our study aims to explore the potential of hirudin and the underlying mechanism in the treatment of IgAN. The establishment of IgAN model was set up in rats through oral and intravenous immunization with bovine gamma-globulin (BGG). Results suggested that hirudin could reduce the increased level of proteinuria, serum creatinine and urea nitrogen in IgAN models. Besides that, hirudin ameliorated the elevated number of apoptotic bodies and expressions of apoptosis-related proteins (caspase-3 and caspase-9) in IgAN model. The fibrosis indexes (transforming growth factor β-1 (TGF-β1), Collagen-IV (CoI-IV) and Fibronectin-1) of kidney were remarkably suppressed in IgAN rats treated with hirudin compared with IgAN rats with no further treatment. IgAN rats exhibited remarkably increased inflammatory factors (IL-1β, IL-6, and IL-18), while hirudin treatment significantly alleviated these alterations. Moreover, the reduced levels of CD4 + CD25 + Foxp3 + Treg and CD4 + IFN-γ + Th1/CD4 + IL-4 + Th2 could be reversed by hirudin in IgAN model. Furthermore, in the process of IgAN, hirudin could inactivate various pathways (IκBα, NF-κB, TNF-α, and VCAM-1) compared with IgAN model group. Taken together, our study indicated that hirudin could ameliorate IgAN through suppressing fibrosis and inflammatory response. These findings provide a new therapeutic method to treat IgAN.

Objective: To identify risk factors associated with unfavorable outcomes in children with IgA vasculitis with nephritis (Henoch-Schőnlein purpura nephritis)(IgA-VN)., Methods: PubMed, Embase, and Web of Science databases were searched for studies, published in English through February 2019. The data were extracted to perform pooled analysis, heterogeneity testing, subgroup analysis, sensitivity analysis, and publication bias analysis., Results: This meta-analysis showed that, older age at onset (WMD 1.77, 95% CI 0.35-3.18, p = 0.014), lower glomerular filtration rate (GFR; WMD -23.93, 95% CI -33.78- -14.09, p<0.0001), initial renal manifestations with nephrotic syndrome (OR 1.74, 95% CI 1.12-2.70, p = 0.013), with nephritic-nephrotic syndrome (OR 4.55, 95% CI 2.89-7.15, p<0.0001) and renal biopsy with crescentic nephritis (International Study of Kidney Disease in Children [ISKDC] grades III-V) (OR 3.85, 95% CI 2.37-6.28, p<0.0001) were significant risk factors associated with poor outcomes in IgA-VN, whereas initial clinical features with hematuria (OR 0.33, 95% CI 0.16-0.69, p = 0.003) and mild proteinuria±hematuria (OR 0.46, 95% CI 0.28-0.75, p<0.0001) were associated with progression to good outcomes. By contrast, gender, hypertension and initial renal manifestations of acute nephritic syndrome were not significantly associated with poor outcomes in IgA-VN., Conclusion: This meta-analysis showed that older age at onset, lower GFR, initial renal features of nephrotic syndrome and nephritic-nephrotic syndrome and renal biopsy with crescentic nephritis (ISKDC grades III-V) were predictive of poor prognosis in children with IgA-VN., Competing Interests: The authors have declared that no competing interests exist.

Proteinuria is an adverse prognostic feature in renal diseases. In proteinuric nephropathies, filtered proteins exert an injurious effect on the renal tubulointerstitium, resulting in inflammation and fibrosis. In the present study, we assessed to what extent complement activation via the lectin pathway may contribute to renal injury in response to proteinuria-related stress in proximal tubular cells. We used the well-established mouse model of protein overload proteinuria (POP) to assess the effect of lectin pathway inhibition on renal injury and fibrotic changes characteristic of proteinuric nephropathy. To this end, we compared experimental outcomes in wild type mice with MASP-2-deficient mice or wild type mice treated with MASP-2 inhibitor to block lectin pathway functional activity. Multiple markers of renal injury were assessed including renal function, proteinuria, macrophage infiltration, and cytokine release profiles. Both MASP-2-deficient and MASP-2 inhibitor-treated wild type mice exhibited renoprotection from proteinuria with significantly less tubulointerstitial injury when compared to isotype control antibody treated mice. This indicates that therapeutic targeting of MASP-2 in proteinuric nephropathies may offer a useful strategy in the clinical management of proteinuria associated pathologies in a variety of different underlying renal diseases., (Copyright © 2019 Alghadban, Kenawy, Dudler, Schwaeble and Brunskill.)

Purpose: HLA antibodies have been shown to be associated with late graft loss. In this study, we defined the incidence and profiles of anti-HLA antibodies and their impact on graft outcome in long-term kidney recipients., Methods: The sera of 118 kidney transplant recipients were screened for anti-HLA antibody presence. The antigen specificity of the detected HLA class I and class II antibodies was identified using a Luminex assay (Luminex Corp, Austin, TX, United States). Presence of donor specific antibodies (DSA) was examined in individuals with anti-HLA antibodies using the Luminex method., Results: Anti-HLA class I and/or class II antibodies were detected in serum of 16.1% of the kidney transplant patients. The antibodies were directed against HLA class I antigens in 4 patients (21.1%), HLA class II antigens in 9 patients (47.4%), and both class I and class II antigens in 6 patients (31.6%). The overall prevalence of DSA was 10.2%. Anti-HLA antibodies were significantly associated with higher rate of cyclosporine use. Presence of DSA was associated with a lower rate of tacrolimus use, a higher rate of cyclosporine use, and lower donor age. Presence of anti-HLA antibodies was associated with higher acute cellular rejection and higher chronic active humoral rejection rates. Presence of DSA was associated with chronic active humoral rejection., Conclusion: The presence of either HLA antibodies or DSA significantly correlated with lower graft survival, poor transplant function, and proteinuria., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To study the prevalence of Hepatitis B seroprotection in children (>1 y) with nephrotic syndrome vaccinated against Hepatitis B vaccine as per the Universal Immunization Program schedule (0,6,10,14 wk); to compare the Hepatitis B seroprotection rates and anti-HBs titers among different phenotypes of nephrotic syndrome; to evaluate the association between Hepatitis B seroprotection status and the immunosuppressive agents; and to study the correlation between anti-HBs titres and proteinuria., Methods: Hepatitis B serology and anti-HBs titers were analyzed in 100 children (age-1-18 y) with different clinical phenotypes of nephrotic syndrome (cases) and 100 healthy controls., Results: The proportion of seroprotected children among the cases and controls was 37% (n=37) and 61% (n=61), respectively (P<0.04). The median (IQR) anti- HBs antibodies titers among the cases was 75 (62.5, 81) mIU/mL and 112 (56, 367) mIU/mL among the controls (P=0.001). The proportion of seroprotected children among the steroid sensitive nephrotic syndrome, steroid-resistant nephrotic syndrome and controls was 40% (n=28), 30% (n=9) and 61% (n=61), respectively (P<0.01). No differences in the anti-HBs titers between children receiving steroids versus steroids along with other immunosuppressants were found. Weak negative correlation was noted between proteinuria and protective titers (r = -0.155; P=0.039)., Conclusions: Children with nephrotic syndrome, in general, and steroid-resistant nephrotic syndrome in particular, show poor seroprotection with Hepatitis B vaccination.

Properdin is known as the only positive regulator of the complement system. Properdin promotes the activity of this defense system by stabilizing its key enzymatic complexes: the complement alternative pathway (AP) convertases. Besides, some studies have indicated a role for properdin as an initiator of complement activity. Though the AP is a powerful activation route of the complement system, it is also involved in a wide variety of autoimmune and inflammatory diseases, many of which affect the kidneys. The role of properdin in regulating complement in health and disease has not received as much appraisal as the many negative AP regulators, such as factor H. Historically, properdin deficiency has been strongly associated with an increased risk for meningococcal disease. Yet only recently had studies begun to link properdin to other complement-related diseases, including renal diseases. In the light of the upcoming complement-inhibiting therapies, it is interesting whether properdin can be a therapeutic target to attenuate AP-mediated injury. A full understanding of the basic concepts of properdin biology is therefore needed. Here, we first provide an overview of the function of properdin in health and disease. Then, we explore its potential as a therapeutic target for the AP-associated renal diseases C3 glomerulopathy, atypical hemolytic uremic syndrome, and proteinuria-induced tubulointerstitial injury. Considering current knowledge, properdin-inhibiting therapy seems promising in certain cases. However, knowing the complexity of properdin's role in renal pathologies in vivo, further research is required to clarify the exact potential of properdin-targeted therapy in complement-mediated renal diseases.

Glomerulonephritis (GN) is a common cause of end-stage kidney disease and is characterized by glomerular inflammation, hematuria, proteinuria, and progressive renal dysfunction. Transforming growth factor (TGF)-β is involved in glomerulosclerosis and interstitial fibrosis. TGF-β activates multiple signaling pathways, including the canonical SMAD pathway. We evaluated the role of SMAD signaling in renal injury and proteinuria in a murine model of GN. SMAD3 +/+ or SMAD3 -/- mice received anti-glomerular basement membrane antibodies to induce GN. We confirmed previous reports that demonstrated that SMAD3 is an important mediator of glomerulosclerosis and renal interstitial fibrosis. Proteinuria was highly SMAD3 dependent. We found differential effects of SMAD3 deletion on podocytes and glomerular endothelial cells. GN led to podocyte injury, including foot process effacement and loss of podocyte-specific markers. Interestingly, these changes were not SMAD3 dependent. Furthermore, there were significant changes to glomerular endothelial cells, including loss of fenestrations, swelling, and basement membrane reduplication, which were SMAD3 dependent. Despite ongoing markers of podocyte injury in SMAD3 -/- mice, proteinuria was transient. Renal injury in the setting of GN involves TGF-β and SMAD3 signaling. Cell populations within the glomerulus respond differently to SMAD3 deletion. Proteinuria correlated more with endothelial cell changes as opposed to podocyte injury in this model.

Therapeutic plasma exchanges (TPE) is considered as one of the treatment modalities that is used in systemic autoimmune diseases. This study aimed to describe the early and late effect of TPE in patients with systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) presented with acute kidney injury (AKI). Retrospective study comprised patients with SLE and AAV with AKI seen between January 2000 and June 2014 at King Faisal Specialist Hospital and Research Center in Riyadh. All patients underwent TPE. Retrospectively, all patients were assessed for early and late renal outcome at 12- month and 24-month intervals. Renal outcome was assessed according to serum creatinine level, glomerular filtration rate, active urine sediment, and proteinuria. P <0.05 was considered significant. A total of 68 patients were included, 58 patients (51 females) had SLE and 10 patients (7 females) had AAV completed TPE. All patients had active disease and had AKI. At the first 12 months, 18 patients (17 SLE and 1 AAV) showed complete response and 14 patients had partial response while 22 patients did not show therapeutic benefit. The nonresponders (22 patients) entered the late assessment interval (24 months) without any therapeutic response. Statistically, there was no significant difference between the patient's response to TPE at the first and second assessment intervals and the baseline serum creatinine level. TPE might be an alternative rescue treatment in lupus nephritis with AKI.

Proteinuria has been identified as prognosticator of renal outcome in patients with ANCA-associated glomerulonephritis, but whether proteinuria is related to podocyte abnormalities in these patients is largely unknown. We here investigate podocyte foot process width and number of podocytes positive for the podocyte marker WT-1 in diagnostic renal biopsies of 25 Caucasian patients with ANCA-associated glomerulonephritis in relation to proteinuria. Control tissue was used from pre-transplantation donor kidney biopsies. Proteinuria at 10 weeks follow-up correlated significantly with foot process width ( P = 0.04). Biopsies with foot process width ≥600 nm belonged more often to the crescentic or mixed class, whereas biopsies with a foot process width <600 nm were most often categorized as focal class ( P = 0.03). The mean number of podocytes based upon expression of WT-1 was significantly lower in patients compared to controls (15 vs. 34 podocytes per glomerulus; P < 0.0001). The significant decrease in expression of the podocyte WT-1 marker in ANCA-associated glomerulonephritis is considered indicative of actual podocyte loss or at least, of a loss of functionality. Furthermore, our study indicates that podocyte foot process width at baseline could be indicative for proteinuria at short term follow up. For prognostic purposes, we therefore suggest to include a description of the foot process width in the diagnostic report of a biopsy with ANCA-associated glomerulonephritis.

In mice, the initial stage of nephrotoxic serum-induced nephritis (NTN) mimics antibody-mediated human glomerulonephritis. Local immune deposits generate tumor necrosis factor (TNF), which activates pro-inflammatory pathways in glomerular endothelial cells (GECs) and podocytes. Because TNF receptors mediate antibacterial defense, existing anti-TNF therapies can promote infection; however, we have previously demonstrated that different functional domains of TNF may have opposing effects. The TIP peptide mimics the lectin-like domain of TNF, and has been shown to blunt inflammation in acute lung injury without impairing TNF receptor-mediated antibacterial activity. We evaluated the impact of TIP peptide in NTN. Intraperitoneal administration of TIP peptide reduced inflammation, proteinuria, and blood urea nitrogen. The protective effect was blocked by the cyclooxygenase inhibitor indomethacin, indicating involvement of prostaglandins. Targeted glomerular delivery of TIP peptide improved pathology in moderate NTN and reduced mortality in severe NTN, indicating a local protective effect. We show that TIP peptide activates the epithelial sodium channel(ENaC), which is expressed by GEC, upon binding to the channel's α subunit. In vitro, TNF treatment of GEC activated pro-inflammatory pathways and decreased the generation of prostaglandin E2 and nitric oxide, which promote recovery from NTN. TIP peptide counteracted these effects. Despite the capacity of TIP peptide to activate ENaC, it did not increase mean arterial blood pressure in mice. In the later autologous phase of NTN, TIP peptide blunted the infiltration of Th17 cells. By countering the deleterious effects of TNF through direct actions in GEC, TIP peptide could provide a novel strategy to treat glomerular inflammation., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: To investigate the relationship between serum anti-ribonucleic acid polymerase III (anti-RNAP3) autoantibodies (Abs) and proteinuria severity in lupus patients., Methods: Serum antibodies reacting with anti-RNAP3 were measured in 49 systemic lupus erythematosus (SLE) patients (29 cases of SLE with proteinuria and 20 cases of SLE without proteinuria) and 10 healthy controls (HCs). For the patients, we recorded demographic data, daily urinary protein loss, serum anti-double strand deoxyribonucleic acid (anti-ds-DNA) antibodies, serum creatinine (Cr), estimated glomerular filtrating rate (eGFR), complement 3 (C3), and C4., Results: Fewer anti-RNAP3 antibodies were found in the SLE patients than in the HCs (p = 0.061). In the SLE with proteinuria group, positive correlations were observed among anti-RNAP3 antibodies and daily urinary protein loss, serum C3, C4, and eGFR, and negative correlations were observed between anti-RNAP3-Abs and anti-ds-DNA-Abs and serum Cr levels. However, these correlations were nonsignificant (p > 0.05)., Conclusion: This study demonstrated the possible role of anti-RNAP3 antibodies in SLE patients with proteinuria, as evidenced by their positive and negative relationships with daily urinary protein loss, eGFR, C3, C4, serum Cr, and anti-ds-DNA-Abs. Although these correlations were nonsignificant, our study builds a foundation for future tailored studies, and more in-depth studies with larger samples are warranted to provide more information.

Soluble urokinase receptor (suPAR) is a circulatory molecule that activates αvβ3 integrin on podocytes, causes foot process effacement, and contributes to proteinuric kidney disease. While active integrin can be targeted by antibodies and small molecules, endogenous inhibitors haven't been discovered yet. Here we report what we believe is a novel renoprotective role for the inducible costimulator ligand (ICOSL) in early kidney disease through its selective binding to podocyte αvβ3 integrin. Contrary to ICOSL's immune-regulatory role, ICOSL in nonhematopoietic cells limited the activation of αvβ3 integrin. Specifically, ICOSL contains the arginine-glycine-aspartate (RGD) motif, which allowed for a high-affinity and selective binding to αvβ3 and modulation of podocyte adhesion. This binding was largely inhibited either by a synthetic RGD peptide or by a disrupted RGD sequence in ICOSL. ICOSL binding favored the active αvβ3 rather than the inactive form and showed little affinity for other integrins. Consistent with the rapid induction of podocyte ICOSL by inflammatory stimuli, glomerular ICOSL expression was increased in biopsies of early-stage human proteinuric kidney diseases. Icosl deficiency in mice resulted in an increased susceptibility to proteinuria that was rescued by recombinant ICOSL. Our work identified a potentially novel role for ICOSL, which serves as an endogenous αvβ3-selective antagonist to maintain glomerular filtration.

Objective: To describe the clinical and laboratory characteristics of patients with meticulously typed light chain (AL) amyloidosis., Patients and Methods: Patients (N=592) with biopsy-proven, mass spectrometry-confirmed AL amyloidosis diagnosed from January 1, 2008, through August 31, 2015, were included., Results: The median patient age at diagnosis was 63 years. Thirty-four percent of patients (n=204) had isolated organ involvement, mostly heart (19% [n=115]) followed by kidney (9% [n=53]). In contrast, 25% (n=146) had more than 2 involved organs. Patients with isolated cardiac involvement had similar cardiac dysfunction compared with those with nonisolated cardiac amyloidosis. In contrast, isolated renal involvement was associated with increased proteinuria and higher estimated glomerular filtration rate compared with nonisolated renal amyloidosis. Serum and urine immunofixation electrophoresis results were positive in 80% and 88% of patients, respectively, with 94% of patients having at least 1 positive immunofixation electrophoresis result (serum or urine). The serum free light chain ratio was abnormal in 91% of patients. When all monoclonal protein studies were combined, only 1 patient (0.2%) had normal results. The 1- and 5-year survival rates were 65% and 46%, respectively. Survival of patients with cardiac amyloidosis was not influenced by the number of involved organs (1 vs >1 organ), emphasizing the prognostic significance of cardiac involvement., Conclusion: When mass spectrometry is used to definitively type amyloid, only a fraction of a percent of patients with AL have negative monoclonal protein studies, unlike historical reports. Patient characteristics and outcomes of accurately typed patients are described., (Copyright © 2018 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Dysfunction of decidual macrophages (DMs) is considered a critical event in the pathogenesis of pre-eclampsia (PE). T cell immunoglobulin mucin 3 (Tim-3) is an important negative regulatory molecule that induces immune tolerance by interacting with its ligand Galectin-9 (Gal-9) and thus modulating function of various immune cells, including macrophages. However, the regulatory effects of Tim-3/Gal-9 signaling on DMs polarization and its role in PE remain unclear. In this study, we established a PE-like rat model by administering 1.0 μg/kg lipopolysaccharide (LPS) to normal pregnant Sprague-Dawley rats via the tail vein at embryonic day 5 (E5). Apart from the pre-eclamptic manifestations, increased M1 subtype and decreased M2 subtype were observed at the maternal-fetal interface, as well as increased pro-inflammatory cytokines (TNF-α and IL-1β) and reduced anti-inflammatory cytokines (TGF-β and IL-10). Moreover, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were reduced. After administration of recombinant Galectin-9 (rGal-9) protein, we found that liver and renal injuries and maternofetal placental functional deficiency, including inadequate trophoblast cells invasion, impaired spiral artery remodeling and fetal capillary development, were reversed. In addition, the polarization of DMs was inclined to M2 subtype, which was similar to the polarization of DMs in the control rats but contrary to the PE-like rats. Interestingly, at E9, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were significantly increased in the rGal-9 protein intervention group. Taken together, our findings show that administration of rGal-9 protein can alleviate the PE-like rat manifestations induced by LPS. This finding may be related to the activation of the Tim-3/Gal-9 signaling pathway, which promotes DMs polarization dominantly shifting to M2 subtype. Moreover, upregulation of Tim-3 in DMs and Gal-9 at the maternal-fetal interface at E9 suggests that Tim-3/Gal-9 pathway may play some important roles in early pregnancy and even embryo development.

Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and macrophage activation are important contributors to disease pathogenesis. Bruton's tyrosine kinase (BTK) plays an important role in both B cell and FcgammaR mediated myeloid cell activation. In the current study, we examined the efficacy of BI-BTK-1, a recently described irreversible BTK inhibitor, in the classical NZB × NZW F1 (NZB/W) and MRL/lpr spontaneous mouse models of SLE. NZB/W mice were randomly assigned to a treatment (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) or control group and began treatment at 22 weeks of age. The experimental setup was similar in MRL/lpr mice, but with a single treated (10 mg/kg, beginning at 8-9 weeks of age) and control group. A separate experiment was performed in the MRL/lpr strain to assess the ability of BI-BTK-1 to reverse established kidney disease. Early treatment with BI-BTK-1 significantly protected NZB/W and MRL/lpr mice from the development of proteinuria, correlating with significant renal histological protection, decreased anti-DNA titers, and increased survival in both strains. BI-BTK-1 treated mice displayed a significant decrease in nephritis-associated inflammatory mediators (e.g. LCN2 and IL-6) in the kidney, combined with a significant inhibition of immune cell infiltration and accumulation. Importantly, BI-BTK-1 treatment resulted in the reversal of established kidney disease. BTK inhibition significantly reduced total B cell numbers and all B cell subsets (immature, transitional, follicular, marginal zone, and class switched) in the spleen of NZB/W mice. Overall, the significant efficacy of BI-BTK-1 in ameliorating multiple pathological endpoints associated with kidney disease in two distinct murine models of spontaneous lupus nephritis provides a strong rationale for BTK inhibition as a promising treatment approach for lupus nephritis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Monoclonal gammopathies are a rare diagnosis in pediatric patients. A 19-year-old female patient with past medical history of hypogammaglobulinemia and natural killer cell deficiency and stage III follicular lymphoma, in remission, presented with a right-sided pneumonia, noted to have acute kidney injury and proteinuria. Complement C3 and C4 levels were normal. Anti-double-stranded DNA antibodies, antinuclear antibodies, anti-extractable nuclear antigen antibodies, and antineutrophil cytoplasmic antibodies were negative. A renal biopsy showed numerous fractured tubular casts that were periodic acid-Schiff and silver-stain negative and fuchsinophilic on trichrome stain, with associated giant cells, tubulitis, acute tubular injury, and tubular rupture. The tubular casts had 3+ staining for lambda light chains and 0-1+ staining for kappa light chains. These findings were consistent with light chain cast nephropathy (LCCN). Serum free light chains, serum immunofixation, urine protein electrophoresis, and urine immunofixation studies supported the renal biopsy diagnosis of LCCN. A bone marrow biopsy showed normal trilineage hematopoiesis and also revealed an atypical B cell population detected by flow cytometry. Pathology specimens from lesions in the distal small bowel were characteristic of diffuse large B cell lymphoma (DLBCL). Chemoreduction therapy followed by chemotherapy was initiated for the DLBCL. Three months after initiation of chemotherapy, the patient's creatinine has improved by > 50%. The likely cause of her LCCN was the new diagnosis of a DLBCL. Other risk factors include her history of hypogammaglobulinemia, natural killer (NK) cell deficiency, community-acquired pneumonia, and prior follicular lymphoma. Our patient may be the youngest reported case of LCCN. Treatment of LCCN is based on treating the underlying clonal plasma cell or B cell proliferation, typically with chemotherapy.

We evaluated the heat shock system 70 (HSP70) in patients with chronic glomerulonephritis (CGN). Seventy-six patients with CGN patients were included in our study. Ten patients with mild proteinuria (median 0.48 [0.16-0.78] g/24 h) and ten healthy subjects served as positive and negative controls, respectively. Urinary levels of HSP70, interleukin-10, and serum levels of anti-HSP70 were measured by ELISA. The immunohistochemical peroxidase method was used to study the expression of HSP70 and Foxp3+ in kidney biopsies. Treg FoxP3+ cells in the interstitium were determined morphometrically. Median urinary HSP70 levels in patients with nephrotic syndrome (NS) [6.57 (4.49-8.33) pg/mg] and subnephrotic range proteinuria [5.7 (4.12-6.9) pg/mg] were higher (p < 0.05) than in positive [3.7 (2.5-4.82) pg/mg] and negative [3.78 (2.89-4.84) pg/mg] controls. HSP70 expression index in tubular cells positively correlated with urinary HSP70 (Rs = 0.948, р < 0.05) and proteinuria (Rs = 0.362, p < 0.05). The number of Treg Foxp3+ cells in the kidney interstitium and interleukin-10 excretion were lower in patients with NS. Anti-HSP70 antibody serum levels in patients with NS [21.1 (17.47-29.72) pg/ml] and subnephrotic range proteinuria [24.9 (18.86-30.92) pg/ml] were significantly higher than in positive [17.8 (12.95-23.03) pg/ml] and negative [18.9 (13.5-23.9) pg/ml] controls. In patients with CGN, increasing proteinuria was associated with higher HSP70 renal tissue and urinary levels. However, activation of HSP70 in patients with nephrotic syndrome did not lead to an increase in tissue levels of Treg Foxp3+ cells or to the release of IL-10.

We have previously reported that co-transplantation of the kidney with vascularized donor thymus from α-1,3-galactosyltransferase gene knockout pigs with an anti-CD154 with rituximab-based regimen led to improved xenograft survival in baboons with donor-specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy. Study 1 confirmed high urinary CD80 excretion in nephrotic animals with renal xenografts showing CD80 expression in glomeruli. In Study 2, baboons receiving xenografts received CTLA4-Ig once a week from the second postoperative week or no CTLA4-Ig. The non-CTLA4-Ig group developed severe proteinuria with modest mesangial expansion with high urinary excretion of CD80 and documented CD80 expression in glomerular podocytes. All of the recipients in non-CTLA4-Ig groups had to be euthanized before POD 60. In contrast, CTLA4-Ig group showed a marked reduction in proteinuria and survived significantly longer, up to 193 days. These results demonstrate that anti-CD80 targeted therapy represents a promising strategy for reduction of proteinuria following renal xeno-transplantation with improved survival., (© 2018 Steunstichting ESOT.)

Objective: To explore the effects of SERPINB3 administration in murine lupus models with a focus on lupus-like nephritis. Methods: 40 NZB/W F1 mice were subdivided into 4 groups and intraperitoneally injected with recombinant SERPINB3 (7.5 μg/0.1 mL or 15 μg/0.1 mL) or PBS (0.1 mL) before (group 1 and 2) or after (group 3 and 4) the development of proteinuria (≥100 mg/dl). Two additional mice groups were provided by including 20 MRL/ lpr mice which were prophylactically injected with SERPINB3 (10 mice, group 5) or PBS (10 mice, group 6). Time of occurrence and levels of anti-dsDNA and anti-C1q antibodies, proteinuria and serum creatinine, overall- and proteinuria-free survival were assessed in mice followed up to natural death. Histological analysis was performed in kidneys of both lupus models. The Th17:Treg cell ratio was assessed by flow-cytometry in splenocytes of treated and untreated MRL/ lpr mice. Statistical analysis was performed using non parametric tests and Kaplan-Meier curves, when indicated. Results: Autoantibody levels and proteinuria were significantly decreased and time of occurrence significantly delayed in SERPINB3-treated mice vs. controls. In agreement with these findings, proteinuria-free and overall survival were significantly improved in SERPINB3-treated groups vs. controls. Histological analysis demonstrated a lower prevalence of severe tubular lesions in kidneys of group 5 vs. group 6. SERPINB3-treated mice showed an overall trend toward a reduced prevalence of severe lesions in both strains. Th17:Treg ratio was significantly decreased in splenocytes of MRL/ lpr mice treated with SERPINB3, compared to untreated control mice. Conclusions: SERPINB3 significantly improves disease course and delays the onset of severe glomerulonephritis in lupus-prone mice, possibly inducing a more tolerogenic immune phenotype.