Faculty Bibliography

INTRODUCTION/BACKGROUND:Activation of the complement pathway by immune complexes is a key feature of systemic lupus erythematosus (SLE) and SLE glomerulonephritis, which translates into low levels of C3 and C4 during active disease. C3 glomerulonephritis (C3GN) is part of a broader group of rare renal diseases, the C3 glomerulopathies, characterized by prominent C3 accumulation in the glomeruli with minimal to no immunoglobulin (Ig) deposition secondary to dysregulation of the alternative pathway of the complement system. Distinguishing lupus nephritis from other complement-mediated kidney disorders, including C3GN, represents a diagnostic challenge with potential therapeutic implications. METHODS:We report an unusual case of a 55-year-old woman with SLE and previous biopsy-proven class IV lupus nephritis, subsequently diagnosed with C3GN. Furthermore, we review the available literature published from January 2010-March 2021 on the clinical features and management of C3GN in the setting of SLE. RESULTS:In addition to our case, very few reports exist in the literature regarding C3GN in association with SLE. The underlying pathogenic mechanism of C3GN consists of dysregulation of the alternative pathway of the complement system, either due to genetic variation in complement-related genes or to acquired autoantibodies targeting C3 or C5 convertases; the latter mechanism could explain the occurrence of C3GN in the setting of autoimmune diseases, although it was not definitively identified in our patient or others with SLE. Similar to some of the previous reports, after suboptimal renal response on mycophenolate mofetil and rituximab, our patient has been successfully treated with eculizumab, thus far with >50% improvement in proteinuria. CONCLUSIONS:C3GN represents an additional mechanism of renal injury in SLE mediated by alternative complement pathway dysregulation. Although rare, patients with SLE and persistent proteinuria with very low C3 would benefit from expedited renal biopsy to evaluate for C3GN as well as genetic testing, since this entity could require a different therapeutic approach.

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INTRODUCTION:Successful ST-segment elevation myocardial infarction (STEMI) management is time-sensitive and is based on prompt reperfusion mainly to reduce patient mortality. It has evolved from a single hospital care to an integrated regional network approach over the last decades. This prospective study, named the China STEMI Care Project (CSCAP), aims to show how implementation of different types of integrated regional STEMI care networks can improve the reperfusion treatment rate, shorten the total duration of myocardial ischaemia and lead to mortality reduction step by step. METHODS AND ANALYSIS:The CSCAP is a prospective, multicentre registry study of three phases. A total of 18 provinces, 4 municipalities and 2 autonomous regions in China were included. Patients who meet the third universal definition of myocardial infarction and the Chinese STEMI diagnosis and treatment guidelines are enrolled. Phase 1 (CSCAP-1) focuses on the in-hospital process optimisation of primary percutaneous coronary intervention (PPCI) hospitals, phase 2 (CSCAP-2) focuses on the PPCI hospital-based regional STEMI care network construction together with emergency medical services and adjacent non-PPCI hospitals, while phase 3 (CSCAP-3) focuses on the whole-city STEMI care network construction by promoting chest pain centre accreditation. Systematic data collection, key performance index assessment and subsequent improvement are implemented throughout the project to continuously improve the quality of STEMI care. ETHICS AND DISSEMINATION:The study has been reviewed and approved by the Ethics Committee of Peking University First Hospital. Ranking reports of quality of care will be generated available to all participant affiliations. Results will be disseminated via peer-reviewed scientific journals and presentations at congresses. TRIAL REGISTRATION NUMBER:NCT03821012.

The molecular and cellular processes that lead to renal damage and to the heterogeneity of lupus nephritis (LN) are not well understood. We applied single-cell RNA sequencing (scRNA-seq) to renal biopsies from patients with LN and evaluated skin biopsies as a potential source of diagnostic and prognostic markers of renal disease. Type I interferon (IFN)-response signatures in tubular cells and keratinocytes distinguished patients with LN from healthy control subjects. Moreover, a high IFN-response signature and fibrotic signature in tubular cells were each associated with failure to respond to treatment. Analysis of tubular cells from patients with proliferative, membranous and mixed LN indicated pathways relevant to inflammation and fibrosis, which offer insight into their histologic differences. In summary, we applied scRNA-seq to LN to deconstruct its heterogeneity and identify novel targets for personalized approaches to therapy.

Renal involvement is an uncommon extra-glandular manifestation in Sjogren's syndrome (SS). We present the case of a young male who presented with nephrotic range proteinuria and advanced irreversible renal disease, with positive anti-Ro antibody (Ab) and antineutrophil cytoplasmic antibody (ANCA) with myeloperoxidase (MPO) specificity. He was initially treated with steroids for suspected ANCA vasculitis but treatment was discontinued as there was no response and renal biopsy revealed interstitial lymphocytic infiltrates, advanced glomerular disease with immune complex mediated glomerulonephritis more suspicious for SS. SS usually affects exocrine glands and patients rarely have renal involvement in which cases it is commonly tubulo-interstitial nephritis. This report describes a rare case of anti-Ro Ab and MPO-ANCA positive patient with advanced irreversible renal disease due to immune-complex mediated glomerulonephritis felt to be due to SS and without any classic sicca symptoms.

OBJECTIVE:To study membrane attack complex in lupus nephritis as a potential biomarker for disease intensity and prognostic indicator for response to treatment. METHODS:Immunohistochemistry was performed using unconjugated, murine anti-human complement C9 on kidney biopsies from 30 SLE patients who fulfilled 4 ACR or SLICC criteria. Clinical parameters were assessed at time of biopsy, 6 and 12 months. RESULTS:30 renal biopsies were obtained from patients with Class II (2), III (5), IV (8), V (5), III+V (8) and IV+V (2). 13/30 (43.3%) biopsies stained positive for glomerular C9. Patients with positive C9 had significantly higher blood pressure, trend towards lower C3, and male gender. There was no significant difference for ISN/RPN class, activity or chronicity indices between C9 positive and negative groups. 5/11 (45.5%) patients positive for C9 did not respond to therapy at 6 months compared with 2/15 (13.3%) patients negative for C9. C9 positive patients were more likely to be a non-responder at 6 months (OR = 5.4, 95% CI: 0.8, 36.4) compared to C9 negative patients. After adjusting for systolic blood pressure, compliance to treatment and proteinuria in a multivariate logistic model, C9 positive patients remained more likely to be non-responders (OR = 4.6, 95% CI: 0.3, 70.9). CONCLUSION/CONCLUSIONS:This study suggests that MAC deposition measured as C9 staining may be a biomarker for more intense disease and poor response to treatment in lupus nephritis. MAC staining may be useful in routine studies of lupus biopsies and identify patients at risk for aggressive disease who may be candidates for novel therapies targeting terminal complement pathway.

Interstitial nephritis (IN) is a relatively rare entity in children and adolescents that can be caused by a range of disorders including infection, medications, inflammatory bowel disease, and sarcoid. There is no proven therapy for this condition. We present 2 cases of biopsy-proven interstitial nephritis, of which 1 case was with granulomatous features that presented with unusual sonographic findings of discrete mass lesions in the kidney parenchyma bilaterally. Although a precise cause could not be identified in either case, 1 patient progressed to end-stage kidney disease (ESKD) and the other is in the early stages of treatment. We suggest that recognition of the atypical imaging features of interstitial nephritis may enable early recognition of this condition and avoid confusion with neoplastic or infectious processes.