Are serum C3 levels or kidney C3 deposits useful markers for predicting outcomes in patients with ANCA-associated vasculitis?

Introduction: Complement activation emerged as a key actor of anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV). Whether serum levels of C3 (sC3) or C3 kidney deposition may help to refine the prognosis of AAV remains elusive. Methods: Retrospective multicentric study that included 154 patients with a first flare of AAV and sC3 (n = 143) or C3 kidney staining (n = 95) available at diagnosis. Clinical presentations, kidney pathology, and survival of patients with normal or low sC3 were compared using univariate analyses, Kaplan-Maier curves with log-rank comparison, or multivariate Cox' model, as appropriate. Results: 20 patients (14 %) had low sC3. sC3 (as bivariate low/normal or as a continuous variable) was associated with 5-year mortality but not with kidney survival. C3 kidney deposition (C3+) was identified in 23 patients who were characterized by more frequent chronic hypertension and lower eGFR at presentation (p = 0.04). C3+ correlated with IgG, IgM, C1q deposition (p = 0.07, p < 0.0001 and p = 0.003, respectively). Chronicity and activity scores were similar in C3+ and C3- patients. Among C3+ patients, those with C3 deposition ≥2+ had lower eGFR at presentation (p = 0.006) and were more frequently classified as sclerotic using the Berden classification (p = 0.04) and as 'high risk' using the Brix score (p = 0.03). However, eGFR improvement following induction regimen was similar between C3+ and C3- patients, and kidney survival at 5 years was similar. Conclusions: Correlation of sC3 with mortality confirms mechanistic links between complement pathways and AAV, but the lack of clear predictive sC3 cut-off and the similar kidney outcome irrespective of C3 deposition precludes their use as biomarkers of AAV outcomes and response to treatment.

Rare Variants in Complement Gene in C3 Glomerulopathy and Immunoglobulin-Mediated Membranoproliferative GN.

BACKGROUND: C3 glomerulopathy and idiopathic immunoglobulin-mediated membranoproliferative GN (Ig-MPGN) are rare complement-mediated kidney diseases. Inherited forms of C3 glomerulopathy/Ig-MPGN are rarely described. METHODS: Three hundred ninety-eight patients with C3 glomerulopathy ( n =296) or Ig-MPGN ( n =102) from a national registry were screened for three complement genes: factor H ( CFH ), factor I ( CFI ), and C3 . Patients with rare variant (minor allele frequency <0.1%) were included. Epidemiologic, clinical, and immunologic data at diagnosis and kidney outcomes of patients were retrospectively collected. RESULTS: Fifty-three different rare variants, including 30 (57%), 13 (24%), and ten (19%) in CFH , CFI , and C3 variants, were identified in 66/398 (17%) patients. Thirty-eight (72%) variants were classified as pathogenic, including 20/30 (66%) and 11/13 (84%) variants in CFH and CFI , respectively, impairing synthesis of factor H or factor I regulators. Fifteen of 53 (27%) variants were of unknown significance. At diagnosis, 69% of patients were adult (median age of 31 years). With the exception of biologic stigma of thrombotic microangiopathy, which was more frequent in patients with CFI variants (5/14 [36%] versus 1/37 [3%] and 0% in the CFH group and C3 group, respectively, P < 0.001), the clinical and histologic features were similar among the three variants groups. The kidney outcome was poor regardless of the age at onset and treatment received. Sixty-five percent (43/66) of patients with rare variant reach kidney failure after a median delay of 41 (19-104) months, compared with 28% (55/195) after a median delay of 34 (12-143) months in the nonvariant group. Among 36 patients who received a kidney transplant, 2-year recurrence was frequent, occurring in 39% (12/31), without difference between variant groups, and led to graft failure in three cases. CONCLUSIONS: In our cohort, 17% of C3 glomerulopathy/Ig-MPGN cases were associated with rare variants in the CFH , CFI , or C3 genes. In most cases, a quantitative deficiency in factor H or factor I was identified. The presence of a rare variant was associated with poor kidney survival. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_11_08_CJN0000000000000252.mp3.

Long-Term Follow-Up and Immunomonitoring of Relapsing Type 1 Autoimmune Pancreatitis Treated With Rituximab.

OBJECTIVES: To evaluate the efficacy and safety of rituximab in relapsing type 1 autoimmune pancreatitis especially the long-term clinical and immunologic impacts. METHODS: All consecutive patients with type 1 autoimmune pancreatitis were retrospectively included. The rituximab protocol was induction therapy of 375 mg·m -2 intravenous weekly for 4 weeks, followed by 500 mg intravenous every 6 months for 2 years. The follow-up included clinical examinations, biological tests, positron emission tomography scan, and immunomonitoring of lymphocyte CD 19+. RESULTS: Among the 43 patients included, 15 received rituximab induction therapy, followed by maintenance in 10 cases because of 1 or more relapses after steroids (whether or not followed by immunosuppressants) and multiple organ involvement. All patients had a clinical, biological and morphological response, a deep and persistent drop in serum immunoglobulin G4 levels, an extinction of both pancreatic and extra pancreatic hypermetabolic positron emission tomography scan signals, and a depletion of B lymphocyte CD19+. No relapse occurred during the follow-up (62.8 ± standard error of the mean of 11.1 months). CONCLUSIONS: Rituximab is an effective treatment for type 1 autoimmune pancreatitis that provides a rapid strong clinical, biological, and morphological response, which persists after discontinuation without any safety issues.

Sedimentary legacy and the disturbing recurrence of the human in long-term ecological research.

Even as new elements of a research infrastructure are added, older parts continue to exert persistent and consequential influence. We introduce the concept of sedimentary legacy to describe the relationship between infrastructure and research objects. Contrary to common accounts of legacy infrastructure that underscore lock-in, static, or constraining outcomes, sedimentary legacy emphasizes how researchers adapt infrastructure to support the investigation of new research objects, even while operating under constraining legacies. To illustrate the implications of sedimentary legacy, we track shifting objects of investigation across the history of the Long-Term Ecological Research (LTER) Network, focusing especially on recurrent ecological investigations of 'human disturbance' as researchers shift to study socioecological objects. We examine the relationship between scientific objects and the resources collected and preserved to render such objects tractable to scientific investigations, and show how the resources of a long-term research infrastructure support the assembly of certain objects of investigation, even while foreclosing others.

Results from a nationwide retrospective cohort measure the impact of C3 and soluble C5b-9 levels on kidney outcomes in C3 glomerulopathy.

C3 glomerulopathy (C3G) is a rare complement-mediated disease. Specific treatments are not yet available and factors predictive of kidney survival such as age, kidney function and proteinuria are not specific to C3G. The prognostic value of biomarkers of complement activation, which are pathognomonic of the diseases, remains unknown. In a large cohort of 165 patients from the French National registry, we retrospectively assess the prognostic value of C3, soluble C5b-9 (sC5b-9), C3 nephritic factor, and rare disease-predicting variants in complement genes in predicting clinical outcome of patients. By multivariate analysis age (adult onset), reduced kidney function (defined by estimated glomerular filtration rate under 60ml/min) and presence of rare disease-predicting variants in complement genes predicted risk of progression to kidney failure. Moreover, by multivariate analysis, normal C3/high sC5b-9 levels or low C3/normal sC5b-9 levels remained independently associated with a worse kidney prognosis, with the relative risk 3.7- and 8-times higher, respectively. Subgroup analysis indicated that the complement biomarker profiles independently correlated to kidney prognosis in patients with adult but not pediatric onset. In this subgroup, we showed that profiles of biomarkers C3 and/or sC5b-9 correlated with intra glomerular inflammation and may explain kidney outcomes. In children, only the presence of rare disease-predicting variants correlated with kidney survival. Thus, in an adult population, we propose a three-point C3G prognostic score based on biomarker profiles at risk, estimated glomerular filtration rate at presentation and genetic findings, which may help stratify adult patients into subgroups that require close monitoring and more aggressive therapy.

Clinical impact and prognosis of cryoglobulinemia and cryofibrinogenemia in systemic sclerosis.

INTRODUCTION: An association of systemic sclerosis (SSc) with cryoglobulin and/or cryofibrinogenemia has been described. However, clinical, biological, morphological and prognostic implications are unknown. The objective of this study was to describe the phenotype and evaluate the prognosis of cryoglobulinemia and/or cryofibrinogenemia in the progression of SSc. MATERIALS AND METHODS: Patients were included from the Systemic Scleroderma Toulouse Cohort (SSTC), between June 1, 2005 and May 31, 2018, and underwent a measurement of a cryoglobulin and/or cryofibrinogen in immunology laboratory at the Toulouse University Hospital Center. Patients with and without cryoglobulinemia >50 mg/l and patients with and without cryofibrinogenemia were compared to identified the impact of cryoprcipitate on the phenotype. Mortality based on cryoprecipitate was explored. RESULTS: 166 patients were included in the study. 43.3% and 46.6% had a cryoglobulinemia >50 mg/l and cryofibrinogenemia, respectively. Cryoglobulin >50 mg was not associated with microvascular damage. Cryoglobulin does not influence the phenotype. 5-and 10-years survival were 97.6% and 88.8% respectively in patients with cryoglobulinemia >50 mg/l versus 91.9% and 78.4% in patients without cryoglobulin>50 mg/l. 10-years survival was better for patients with cryoglobulinemia >50 mg/l (log-rank 0.0363). Cryofibrinogenemia was not associated with neoplasia, any clinical (in particular ischemic damage), biological or morphological features. Cryofibrinogenemia had no influence on the mortality of these patients. CONCLUSION: Cryoglobulinemia and cryofibrinogenemia are frequent in SSc. The presence of cryoprecipitate (cryoglobulin or cryofibrinogen) not influence the phenotype and has not associated with a poor survival.

Spectrum of Kidney Disorders Associated with T-Cell Immunoclones.

Large granular T-cell leukemia is a clonal hematological condition often associated with autoimmune disorders. Whether small-sized T-cell clones that are otherwise asymptomatic can promote immune kidney disorders remains elusive. In this monocentric retrospective cohort in a tertiary referral center in France, we reviewed characteristics of 29 patients with T-cell clone proliferation and autoimmune kidney disorders. Next-generation sequencing of the T-cell receptor of circulating T-cells was performed in a subset of patients. The T-cell clones were detected owing to systematic screening (mean count 0.32 × 109/L, range 0.13-3.7). Strikingly, a common phenotype of acute interstitial nephropathy was observed in 22 patients (median estimated glomerular filtration rate at presentation of 22 mL/min/1.73 m2 (range 0-56)). Kidney biopsies showed polymorphic inflammatory cell infiltration (predominantly CD3+ T-cells, most of them demonstrating positive phospho-STAT3 staining) and non-necrotic granuloma in six cases. Immune-mediated glomerulopathy only or in combination with acute interstitial nephropathy was identified in eight patients. Next-generation sequencing (n = 13) identified a major T-cell clone representing more than 1% of the T-cell population in all but two patients. None had a mutation of STAT3. Twenty patients (69%) had two or more extra-kidney autoimmune diseases. Acute interstitial nephropathies were controlled with corticosteroids, cyclosporin A, or tofacitinib. Thus, we showed that small-sized T-cell clones (i.e., without lymphocytosis) undetectable without specific screening are associated with various immune kidney disorders, including a previously unrecognized phenotype characterized by severe inflammatory kidney fibrosis and lymphocytic JAK/STAT activation.

Complement Activation and Thrombotic Microangiopathy Associated With Monoclonal Gammopathy: A National French Case Series.

RATIONALE & OBJECTIVE: Hemolytic uremic syndrome (HUS), a thrombotic microangiopathy (TMA) with kidney involvement, is a rare condition in patients with monoclonal gammopathy. In the absence of known causes of TMA, the role of complement activation in endothelial injury in patients with monoclonal gammopathy remains unknown and was the focus of this investigation. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We studied the 24 patients in the French national registry of HUS between 2000 and 2020 who had monoclonal gammopathy without other causes of secondary TMA. We provide the clinical histories and complement studies of these patients. FINDINGS: Monoclonal gammopathy-associated TMA with kidney involvement is estimated to be 10 times less frequent than adult atypical HUS (aHUS) in the French national registry. It is characterized by severe clinical features, with 17 of 24 patients requiring dialysis at disease onset, and with median renal survival of only 20 months. TMA-mediated extrarenal manifestations, particularly cutaneous and neurological involvement, were common and associated with poor overall prognosis. Complement studies identified low C3, normal C4, and high soluble C5b-9 levels in 33%, 100%, and 77% of tested patients, respectively, indicating a contribution of the alternative and terminal complement pathways in the pathophysiology of the disease. Genetic abnormalities in complement genes known to be associated with aHUS were found in only 3 of 17 (17%) who were tested. LIMITATIONS: Retrospective study without comparison group; limited number of patients, limited available blood samples. CONCLUSIONS: Within the spectrum of TMA, TMA associated with monoclonal gammopathy represents a distinct subset. Our findings suggest that HUS associated with monoclonal immunoglobulin is a complement-mediated disease akin to aHUS.

Renal diseases secondary to interferon-ß treatment: a multicentre clinico-pathological study and systematic literature review.

Background: The spectrum of interferon-ß (IFN-ß)-associated nephropathy remains poorly described and the potential features of this uncommon association remain to be determined. Methods: In this study we retrospectively analysed the clinical, laboratory, histological and therapeutic data of patients with biopsy-proven renal disease in a context of IFN-ß treatment administered for at least 6 months. Results: Eighteen patients (13 women, median age 48 years) with biopsy-proven renal disease occurring during IFN-ß therapy were included. The median exposure to IFN-ß (14 patients were treated with IFN-ß1a and 4 patients with IFN-ß1b) was 67 months (range 23-165 months). The clinical presentation consists in hypertension (HT; 83%), malignant HT (44%), proteinuria (protU) >1 g/g (94%), reduced renal function (78%), biological hallmark suggesting thrombotic microangiopathy (TMA; 61%), oedematous syndrome (17%) or nephritic syndrome (11%). The pathological findings included typical features of isolated TMAs in 11 cases, isolated focal segmental glomerulosclerosis (FSGS) lesions in 2 cases and 5 cases with concomitant TMA and FSGS lesions. An exploration of the alternative complement pathway performed in 10 cases (63%) did not identify mutations in genes that regulate the complement system. The statistical analysis highlighted that the occurrence of IFN-ß-associated TMA was significantly associated with Rebif, with a weekly dose >50 µg and with multiple weekly injections. In all cases, IFN-ß therapy was discontinued. Patients with TMA lesions received other therapies, including corticosteroids (44%), eculizumab (13%) and plasma exchanges (25%). At the end of a 36-month median follow-up, persistent HT and persistent protU were observed in 61% and 22% of patients, respectively. Estimated glomerular filtration rate <60 mL/min/1.73 m2 was present in 61% of patients. Conclusions: IFN-ß-associated nephropathy must be sought in the case of HT and/or protU onset during treatment. When TMA and/or FSGS are observed on renal biopsy, early discontinuation of IFN-ß is essential.

Sine scleroderma, limited cutaneous, and diffused cutaneous systemic sclerosis survival and predictors of mortality.

BACKGROUND: Systemic sclerosis (SSc) is associated with a variability of mortality rates in the literature. OBJECTIVE: To determine the mortality and its predictors in a long-term follow-up of a bi-centric cohort of SSc patients. METHODS: A retrospective observational study by systematically analyzing the medical records of patients diagnosed with SSc in Toulouse University Hospital and Ducuing Hospital. Standardized Mortality Ratio (SMR), mortality at 1, 3, 5, 10, and 15 years of disease and causes of death were described. Predictors of mortality using Cox regression were assessed. RESULTS: Three hundred seventy-five patients were included: 63 with diffuse cutaneous SSc, 279 with limited cutaneous SSc, and 33 with sine scleroderma. The SMR ratio was 1.88 (95% CI 1.46-1.97). The overall survival rates were 97.6% at 1 year, 93.4% at 3 years, 87.1% at 5 years, 77.9% at 10 years, and 61.3% at 15 years. Sixty-nine deaths were recorded. 46.4% were SSc related deaths secondary to interstitial lung disease (ILD) (34.4%), pulmonary hypertension (31.2%), and digestive tract involvement (18.8%). 53.6% were non-related to SSc: cardiovascular disorders (37.8%) and various infections (35.1%) largely distanced those from cancer (13.5%). Four significant independent predictive factors were identified: carbon monoxide diffusing capacity (DLCO) < 70% (HR=3.01; p=0.0053), C-reactive protein (CRP) >5 mg/l (HR=2.13; p=0.0174), cardiac involvement (HR=2.86; p=0.0012), and the fact of being male (HR=3.25; p=0.0004). CONCLUSION: Long-term data confirmed high mortality of SSc. Male sex, DLCO <70%, cardiac involvement, and CRP> 5mg/l were identified as independent predictors of mortality.

Shiga Toxin-Associated Hemolytic Uremic Syndrome in Adults, France, 2009-2017.

We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC) in 96 adults enrolled in the cohort of the National Reference Center for Thrombotic Microangiopathies network in France during 2009-2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.

Complement C5 inhibition reverses bleomycin-induced thrombotic microangiopathy.

Whether C5 blocking may improve the outcomes of patients developing chemotherapy-induced thrombotic microangiopathy (TMA) remains elusive. Lung fibrosis is a well-known complication of bleomycin, whereas TMAs are very rare (<20 cases described). Here, we report an exceptional case of a male patient that developed acute respiratory distress syndrome and TMA following administration of bleomycin, cisplatin and etoposide . Refractoriness to plasma exchanges prompted us to use eculizumab as salvage therapy. Eculizumab led to complete remission of the TMA before Day 2. However, the patient progressed towards refractory respiratory failure, suggesting that pathophysiological mechanisms of bleomycin-induced lung fibrosis and TMA differ.