Rituximab as maintenance therapy for ANCA-associated vasculitides: pooled analysis and long-term outcome of 277 patients included in the MAINRITSAN trials.

OBJECTIVE: To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively). METHODS: The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84. RESULTS: 277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25). CONCLUSIONS: According to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.

Non-myeloma light chain cast nephropathy: a multicenter retrospective study on clinicopathological characteristics.

Not available.

Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves TRPC6-mediated Calpain Activation Impairing Autophagy.

SIGNIFICANCE STATEMENT: Autophagy protects podocytes from injury in diabetic kidney disease (DKD). Restoring glomerular autophagy is a promising approach to limit DKD. This study demonstrates a novel regulatory mechanism of autophagy that blocks this critical protection of the glomerular filtration barrier. We demonstrated that TRPC6 induced in podocytes in mouse models of diabetes mediates calpain activation, thereby impairing podocyte autophagy, causing injury and accelerating DKD. Furthermore, this study provides proof of principle for druggable targets for DKD because restoration of podocyte autophagy by calpain inhibitors effectively limits glomerular destruction. BACKGROUND: Diabetic kidney disease is associated with impaired podocyte autophagy and subsequent podocyte injury. The regulation of podocyte autophagy is unique because it minimally uses the mTOR and AMPK pathways. Thus, the molecular mechanisms underlying the impaired autophagy in podocytes in diabetic kidney disease remain largely elusive. METHODS: This study investigated how the calcium channel TRPC6 and the cysteine protease calpains deleteriously affect podocyte autophagy in diabetic kidney disease in mice. We demonstrated that TRPC6 knockdown in podocytes increased the autophagic flux because of decreased cysteine protease calpain activity. Diabetic kidney disease was induced in vivo using streptozotocin with unilateral nephrectomy and the BTBR ob/ob mouse models. RESULTS: Diabetes increased TRPC6 expression in podocytes in vivo with decreased podocyte autophagic flux. Transgenic overexpression of the endogenous calpain inhibitor calpastatin, as well as pharmacologic inhibition of calpain activity, normalized podocyte autophagic flux, reduced nephrin loss, and prevented the development of albuminuria in diabetic mice. In kidney biopsies from patients with diabetes, we further confirmed that TRPC6 overexpression in podocytes correlates with decreased calpastatin expression, autophagy blockade, and podocyte injury. CONCLUSIONS: Overall, we discovered a new mechanism that connects TRPC6 and calpain activity to impaired podocyte autophagy, increased podocyte injury, and development of proteinuria in the context of diabetic kidney disease. Therefore, targeting TRPC6 and/or calpain to restore podocyte autophagy might be a promising therapeutic strategy for diabetic kidney disease.

Proteinuria and hematuria after remission induction are associated with outcome in ANCA-associated vasculitis.

In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), hematuria and proteinuria are biomarkers reflecting kidney involvement at diagnosis. Yet, the prognostic value of their persistence after immunosuppressive induction therapy, reflecting kidney damage or persistent disease, remains uncertain. To study this, our post hoc analysis included participants of five European randomized clinical trials on AAV (MAINRITSAN, MAINRITSAN2, RITUXVAS, MYCYC, IMPROVE). Urine protein-creatinine ratio (UPCR) and hematuria of spot urine samples collected at the end of induction therapy (four-six months after treatment initiation) were correlated with the occurrence of a combined end point of death and/or kidney failure, or relapses during follow-up. Among 571 patients (59% men, median age 60), 60% had anti-proteinase 3-ANCA and 35% had anti-myeloperoxidase-ANCA, while 77% had kidney involvement. After induction therapy, 157/526 (29.8%) had persistent hematuria and 165/481 (34.3%) had UPCR of 0.05 g/mmol or more. After a median follow-up of 28 months (interquartile range 18-42), and adjustment for age, ANCA type, maintenance therapy, serum creatinine and persistent hematuria after induction, a UPCR of 0.05 g/mmol or more after induction was associated with significant risk of death/kidney failure (adjusted Hazard Ratio [HR] 3.06, 95% confidence interval 1.09-8.59) and kidney relapse (adjusted subdistribution HR 2.22, 1.16-4.24). Persistent hematuria was associated with significant kidney relapse (adjusted subdistribution HR 2.16, 1.13-4.11) but not with relapse affecting any organ nor with death/kidney failure. Thus, in this large cohort of patients with AAV, persistent proteinuria after induction therapy was associated with death/kidney failure and kidney relapse, whereas persistent hematuria was an independent predictor of kidney relapse. Hence, these parameters must be considered to assess long-term kidney prognosis of patients with AAV.

The spectrum of glomerular and vascular kidney pathology associated with myeloproliferative neoplasms.

A high prevalence of chronic kidney disease (CKD) occurs in patients with myeloproliferative neoplasms (MPN). However, MPN-related glomerulopathy (MPN-RG) may not account for the entirety of CKD risk in this population. The systemic vasculopathy encountered in these patients raises the hypothesis that vascular nephrosclerosis may be a common pattern of injury in patients with MPN and with CKD. In an exhaustive, retrospective, multicenter study of MPN kidney biopsies in four different pathology departments, we now describe glomerular and vascular lesions and establish clinicopathologic correlations. Our study encompassed 47 patients with MPN who underwent a kidney biopsy that included 16 patients with chronic myeloid leukemia (CML) and 31 patients with non-CML MPN. Fourteen cases met a proposed definition of MPN-RG based on mesangial sclerosis and hypercellularity, as well as glomerular thrombotic microangiopathy. MPN-RG was significantly associated with both myelofibrosis and poorer kidney survival. Thirty-three patients had moderate-to-severe arteriosclerosis while 39 patients had moderate-to-severe arteriolar hyalinosis. Multivariable models that included 188 adult native kidney biopsies as controls revealed an association between MPN and chronic kidney vascular damage, which was independent of established risk factors such as age, diabetes mellitus and hypertension. Therefore, MPN-RG is associated with myelofibrosis and has a poor kidney prognosis. Thus, our findings suggest that the kidney vasculature is a target during MPN-associated vasculopathy and establish a new link between MPN and CKD. Hence, these results may raise new hypotheses regarding the pathophysiology of vascular nephrosclerosis in the general population.

Glomerular diseases in pregnancy: pragmatic recommendations for clinical management.

Our understanding of the various aspects of pregnancy in women with kidney diseases has significantly improved in the last decades. Nevertheless, little is known about specific kidney diseases. Glomerular diseases are not only a frequent cause of chronic kidney disease in young women, but combine many challenges in pregnancy: immunologic diseases, hypertension, proteinuria, and kidney tissue damage. An international working group undertook the review of available current literature and elicited expert opinions on glomerular diseases in pregnancy with the aim to provide pragmatic information for nephrologists according to the present state-of-the-art knowledge. This work also highlights areas of clinical uncertainty and emphasizes the need for further collaborative studies to improve maternal and fetal health.

Stiripentol and Lumasiran as a Rescue Therapy for Oxalate Nephropathy Recurrence After Kidney Transplantation in an Adult Patient With Primary Hyperoxaluria Type 1.

Primary hyperoxaluria type 1 is a rare cause of kidney failure. Stiripentol, an inhibitor of lactate dehydrogenase A, and lumasiran, a small interfering RNA targeting glycolate oxidase, have been proposed as therapeutic options, but clinical data are scarce, especially in adults and transplanted patients. We describe the case of a 51-year-old patient with a biopsy-proven recurrence of oxalate nephropathy after a kidney-only transplantation. He received stiripentol and lumasiran without adverse events. Fourteen months after transplantation, graft function, serum, and urinary oxalate levels have remained stable, and kidney biopsy showed a complete regression of oxalate crystals. Further studies are needed to assess whether this strategy is effective and could replace liver-kidney transplantation.

C3 Glomerulopathy With Concurrent Thrombotic Microangiopathy: Clinical and Immunological Features.

RATIONALE & OBJECTIVE: C3 glomerulopathy (C3GN) and atypical hemolytic uremic syndrome (aHUS) are 2 distinct rare kidney diseases caused by dysregulation of the alternative complement pathway. Patients with C3GN and concurrent kidney lesions of thrombotic microangiopathy (TMA) have been rarely reported. We characterized the clinical features and underlying immunological abnormalities in these patients. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients with C3GN and concomitant TMA lesions on biopsy registered from 2009 to 2019 in the French National Registry of C3GN. FINDINGS: Among 278 registered patients with C3GN, 16 (6%) had biopsy-proven glomerular and/or vascular TMA lesions. Their median age at diagnosis was 39 years (range, 7-76), and 59% were female. Fourteen of the 16 patients (88%) had an estimated glomerular filtration rate of<30mL/min/1.73m2 and 3 of 16 (19%) required dialysis. Twelve of the 14 evaluated patients (86%) showed evidence of mechanical hemolysis. Fifty percent of the patients had low C3 levels. Six of the 14 evaluated patients had a rare variant in complement genes, and 4 of the 16 patients (25%) had monoclonal gammopathy. Among the 16 patients, 10 (63%) received eculizumab, 5 (31%) received immunosuppressive therapy, and 4 (25%) received clone-targeted chemotherapy. Median kidney survival was 49 months. LIMITATIONS: Small retrospective case series with a limited number of biopsies including electron microscopy. CONCLUSIONS: Concomitant C3GN and TMA is extremely rare and is associated with poor kidney outcomes. Genetic or acquired abnormalities of the alternative complement pathway are common as is the presence of monoclonal gammopathy, which may inform the selection of treatment approaches.

Dysregulation of neutrophil oxidant production and interleukin-1-related cytokines in granulomatosis with polyangiitis.

OBJECTIVES: Neutrophils play a key role in ANCA-associated vasculitis, both as targets of autoimmunity and facilitators of vascular damage. In granulomatosis with polyangiitis (GPA), data regarding the production of reactive oxygen species (ROS) in neutrophils are unclear. Further, recent data suggests that ROS production could have an anti-inflammatory effect through the regulation of the inflammasome and IL-1-related cytokines. We aimed to analyse the ROS production in neutrophils from patients with GPA and investigate its association with IL-1-related cytokines and the autoantigen proteinase 3 (PR3). METHODS: Seventy-two GPA patients with disease flare were included in the NEUTROVASC prospective cohort study. ROS production was evaluated in whole blood of patients with active GPA and compared with the same patients in remission or healthy controls. Associations between ROS production, PR3 membrane expression on neutrophils, serum levels of IL-1-related cytokines as well as inflammasome-related proteins were analyzed. RESULTS: We observed a robust defect in ROS production by neutrophils from patients with active GPA compared with healthy controls, independent of glucocorticoid treatment. Serum levels of IL-1-related cytokines were significantly increased in GPA patients, particularly in patients with kidney involvement, and levels of these cytokines returned to normal after patients achieved remission. Further, inflammasome-related proteins were significantly dysregulated in the cytosol of neutrophils as well as the serum from GPA patients. CONCLUSION: Our data suggests that ROS production and regulation of the inflammasome in neutrophils from patients with GPA are disturbed and may be a potential therapeutic target. CLINICAL TRIAL REGISTRATION NUMBER: NCT01862068, clinicaltrials.gov, https://www.clinicaltrials.gov.

Induction failure in granulomatosis with polyangiitis: a nationwide case-control study of risk factors and outcomes.

OBJECTIVE: To identify characteristics of granulomatosis with polyangiitis (GPA) associated with induction failure, describe salvage therapies and their efficacy. METHODS: We conducted a nationwide retrospective case-control study of GPA with induction failure between 2006 and 2021. Each patient with induction failure was randomly paired to three controls matched for age, sex and induction treatment. RESULTS: We included 51 patients with GPA and induction failure (29 men and 22 women). At induction therapy, median age was 49 years. Twenty-seven patients received intravenous cyclophosphamide (ivCYC) and 24 rituximab (RTX) as induction therapy. Patients with ivCYC induction failure more frequently had PR3-ANCA (93% vs 70%, P = 0.02), relapsing disease (41% vs 7%, P < 0.001) and orbital mass (15% vs 0%, P < 0.01) compared with controls. Patients with disease progression despite RTX induction therapy more frequently had renal involvement (67% vs 25%, P = 0.02) with renal failure (serum creatinine >100 µmol/l in 42% vs 8%, P = 0.02) compared with controls. After salvage therapy, remission was achieved at 6 months in 35 (69%) patients. The most frequent salvage therapy was switching from ivCYC to RTX (or vice versa), showing an efficacy in 21/29 (72%). Remission was achieved in nine (50%) patients with inappropriate response to ivCYC, while in patients with progression after RTX induction, remission was achieved in four (100%) who received ivCYC (with or without immunomodulatory therapy), but only in three (50%) after adding immunomodulatory therapy alone. CONCLUSION: In patients with induction failure, characteristics of GPA, salvage therapies and their efficacy vary according to induction therapy and failure modality.

Nephrosclerosis in young patients with malignant hypertension.

BACKGROUND: Nephrosclerosis is one of the histopathological consequences of severe or malignant hypertension (MH), some of the pathophysiology of which has been extrapolated from essential polygenetic arterial hypertension. Despite our recent description of unsuspected ciliopathies with MH, causes of MH in young patients with severe renal impairment are poorly understood. METHODS: To refine and better describe the MH phenotype, we studied clinical and prognostic factors in young patients receiving a kidney biopsy following their first episode of MH. Patients were identified retrospectively and prospectively from eight centres over a 35-year period (1985-2020). Keywords were used to retrospectively enrol patients irrespective of lesions found on renal biopsy. RESULTS: A total of 114 patients were included, 77 (67%) of whom were men, average age 34 years, 35% Caucasian and 34% African origin. An isolated clinical diagnosis of severe nephrosclerosis was suggested in only 52% of cases, with 24% primary glomerulopathies. Only 7% of patients had normal renal function at diagnosis, 25% required emergency dialysis and 21% were eventually transplanted. Mortality was 1% at the last follow-up. Independent prognostic factors significantly associated with renal prognosis (6-month dialysis) and predictive of end-stage renal disease were serum creatinine on admission {odds ratio [OR] 1.56 [95% confidence interval (CI) 1.34-1.96], P < .001} and renal fibrosis >30% [OR 10.70 (95% CI 1.53-112.03), P = .03]. Astonishingly, the presence of any thrombotic microangiopathy lesion on renal biopsy was an independent, protective factor [OR 0.14 (95% CI 0.02-0.60), P = .01]. The histopathological hallmark of nephrosclerosis was found alone in only 52% of study patients, regardless of ethnicity. CONCLUSIONS: This suggests that kidney biopsy might be beneficial in young patients with MH.

Prognosis and long-term outcomes in type I cryoglobulinemia: A multicenter study of 168 patients.

Type I cryoglobulinemia (CG) accounts for 10%-15% of all cryoglobulinemias and are exclusively seen in clonal proliferative hematologic conditions. In this multicenter nationwide cohort study, we analyzed the prognosis and long-term outcomes of 168 patients with type I CG (93 (55.4%) IgM and 75 [44.6%] IgG). Five- and 10-year event-free survivals (EFS) were 26.5% (95% CI 18.2%-38.4%) and 20.8% (95% CI 13.1%-33.1%), respectively. In multivariable analysis, factors associated with poorer EFS were renal involvement (HR: 2.42, 95% CI 1.41-4.17, p = .001) and IgG type I CG (HR: 1.96, 95% CI 1.13-3.33, p = 0.016), regardless of underlying hematological disorders. IgG type I CG patients had higher cumulative incidence of relapse (94.6% [95% CI 57.8%-99.4%] vs. 56.6% [95% CI 36.6%-72.4%], p = .0002) and death at 10 years (35.8% [19.8%-64.6%] vs. 71.3% [54.0%-94.2%], p = .01) as compared to IgM CG, respectively. Overall, complete response of type I CG at 6 months was 38.7%, with no significant difference between Igs isotypes. In conclusion, renal involvement and IgG CG were identified as independent poor prognostic factors of type I CG.

Kidney Histopathology Can Predict Kidney Function in ANCA-Associated Vasculitides with Acute Kidney Injury Treated with Plasma Exchanges.

BACKGROUND: Data from the PEXIVAS trial challenged the role of plasma exchange (PLEX) in ANCA-associated vasculitides (AAV). We aimed to describe kidney biopsy from patients with AAV treated with PLEX, evaluate whether histopathologic findings could predict kidney function, and identify which patients would most benefit from PLEX. METHODS: We performed a multicenter, retrospective study on 188 patients with AAV and AKI treated with PLEX and 237 not treated with PLEX. The primary outcome was mortality or KRT at 12 months (M12). RESULTS: No significant benefit of PLEX for the primary outcome was found. To identify patients benefitting from PLEX, we developed a model predicting the average treatment effect of PLEX for an individual depending on covariables. Using the prediction model, 223 patients had a better predicted outcome with PLEX than without PLEX, and 177 of them had >5% increased predicted probability with PLEX compared with without PLEX of being alive and free from KRT at M12, which defined the PLEX-recommended group. Risk difference for death or KRT at M12 was significantly lower with PLEX in the PLEX-recommended group (-15.9%; 95% CI, -29.4 to -2.5) compared with the PLEX not recommended group (-4.8%; 95% CI, 14.9 to 5.3). Microscopic polyangiitis, MPO-ANCA, higher serum creatinine, crescentic and sclerotic classes, and higher Brix score were more frequent in the PLEX-recommended group. An easy to use score identified patients who would benefit from PLEX. The average treatment effect of PLEX for those with recommended treatment corresponded to an absolute risk reduction for death or KRT at M12 of 24.6%. CONCLUSIONS: PLEX was not associated with a better primary outcome in the whole study population, but we identified a subset of patients who could benefit from PLEX. However, these findings must be validated before utilized in clinical decision making.

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.

Patients of 75 years and over with ANCA-associated vasculitis have a lower relapse risk than younger patients: A multicentre cohort study.

BACKGROUND: Little is known about antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) in older patients. We aim to study relapse risk of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in patients diagnosed after 75 years and compare it with those of patients aged 65-75 years. METHODS: Data from AAV patients aged ≥65 years were extracted from the French Vasculitis Study Group (FVSG) database and from a call for observation to FVSG members. Cox and Fine-Gray models were used to assess relapse risk, taking death into account either as a censoring or a competing event, respectively. RESULTS: The analysis included 219 patients aged ≥75 years (median 79) and 80 patients aged 65-75 years (median 70), of those 155 had GPA (52%), 136 MPA (45%), with 95 (32%) anti-proteinase 3 positivity and 179 (61%) anti-myeloperoxidase. Patients aged ≥75 years had a lower relapse risk in multivariate analysis (cause-specific hazards ratio [CSHR] 0.54, 95% CI [0.33-0.89], p = 0.016, Cox model; subdistribution hazard ratio [SHR] 0.46, 95% CI [0.29-0.74], p = 0.001, Fine-Gray model) after taking into account vasculitis type. Patients aged ≥75 years had a lower probability of being treated for remission maintenance with a combination of glucocorticoids and immunosuppressants (vs. glucocorticoids alone, HR 0.28, 95% CI [0.11-0.68], p = 0.005) after adjusting to Five Factor Score, although relapse-free survival was significantly longer when receiving such combination (CSHR 0.40, 95% [CI 0.24-0.67], p < 0.001). CONCLUSIONS: AAV patients ≥75 years have a lower relapse risk than patients aged 65-75 years despite a lower probability of having received maintenance therapy with a combination of glucocorticoids and immunosuppressants, but they still benefit from such treatment regimen.

Renal and vascular outcomes in patients with isolated antiphospholipid syndrome nephropathy.

BACKGROUND: Antiphospholipid syndrome (APS) nephropathy (APSN) is a rare pattern with specific features resulting from microvascular lesions. The prognosis of APSN, outside of lupus nephritis, is unknown. The aim of this study was to describe the renal, vascular and overall outcomes of patients with APSN. METHODS: Retrospective multicenter study of patients with antiphospholipid antibodies (aPL) associated with histological APSN lesions and no other nephropathy, identified through a national call for medical records. End-stage renal disease (ESRD)-free survival, thrombosis recurrence-free survival and overall survival were assessed. RESULTS: Thirty patients were included (19 women) with a median age of 40 years (34-52 years). Fifteen patients had APS, 26/28 had lupus anticoagulant, and 15/26 had triple positivity for aPL. Median eGFR was 50 (31-60) mL/min/1.73 m2. Glomerular thrombotic microangiopathy was found in 12/24 cases, fibrous intimal hyperplasia in 12/22 cases and focal cortical atrophy in 17/29 cases. Nineteen patients had moderate to severe interstitial fibrosis (>25%). Six patients developed ESRD at a median follow-up of 6.2 (1.8-9.1) years. The ESRD-free survival rates at 5 and 10 years were 80.0% (95% CI 57.6%-91.4%) and 72.7% (95% CI, 46.9%-87.4%) respectively. None of the histological factors considered was significantly associated with a decrease in eGFR at 12 months. Thrombosis recurrence-free survival was 77.8% (95% CI 48.2%-91.6%) at 10 years. Overall survival was 94% at 10 years (95% CI 65.0%-99.2%). CONCLUSIONS: The renal prognosis of isolated APSN is poor. The severe fibrotic lesions observed are suggestive of late diagnosis.

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.

ANCA-Negative Pauci-immune Necrotizing Glomerulonephritis: A Case Series and a New Clinical Classification.

RATIONALE & OBJECTIVE: Pauci-immune necrotizing glomerulonephritis (PING) is usually associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). However, a minority (2%-3%) of patients with PING do not have detectable ANCA. We assessed the clinical spectrum and outcome of patients with ANCA-negative PING. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 74 patients with ANCA-negative PING diagnosed in 19 French nephrology centers between August 2006 and December 2018 were included in the series. Patients' medical files were reviewed, and kidney biopsies were centrally reexamined by pathologists who were masked to the diagnosis. FINDINGS: Median age at diagnosis was 69 (IQR, 61-76) years. The clinical and pathological features were remarkable for a high frequency of extrarenal manifestations (54%), nephrotic syndrome (32%), and endocapillary hypercellularity (31%). Three main subtypes of ANCA-negative PING were observed: infection-associated (n=9[12%]), malignancy-associated (n=6[8%]), and primary (n=57[77%]). For patients with primary PING, induction treatment included mainly corticosteroids (n=56[98%]), cyclophosphamide (n=37[65%]), and rituximab (n=5[9%]). Maintenance treatment consisted mainly of corticosteroids (n=42[74%]), azathioprine (n=18[32%]), and mycophenolate mofetil (n=11[19%]). After a median follow-up period of 28 months, 28 (38%) patients had died and 20 (27%) developed kidney failure (estimated glomerular filtration rate<15mL/min/1.73m2). Eleven (21%) patients (9 with primary and 2 with malignancy-associated PING) relapsed. LIMITATIONS: Retrospective study and limited number of patients; electron microscopy was not performed to confirm the absence of glomerular immune deposits. CONCLUSIONS: Within the spectrum of ANCA-negative PING, infection and malignancy-associated forms represent a distinct clinical subset. This new clinical classification may inform the management of ANCA-negative PING, which remains a severe form of vasculitis with high morbidity and mortality rates despite immunosuppressive treatments.

Bartonella and Coxiella infections presenting as systemic vasculitis: case series and review of literature.

OBJECTIVES: Coxiella and Bartonella spp. display particular tropism for endothelial or endocardial tissues and an abnormal host response to infections with induced autoimmunity. We aimed, through a case series combined with a comprehensive literature review, to outline characteristics of Coxiella and Bartonella infections presenting as systemic vasculitis. METHODS: We retrospectively included cases of definite Coxiella and Bartonella infections presenting with vasculitis features and performed a comprehensive literature review. RESULTS: Six cases of Bartonella infections were added to 18 cases from literature review. Causative pathogens were mainly B. henselae. Bartonella infection mimicked ANCA-associated vasculitis in 83% with PR3-ANCA and presented as cryoglobulinaemic vasculitis in 8%. GN was present in 92%, and 88% had endocarditis. Complement fractions were low in 82% and rheumatoid factor positive in 85%. Kidney biopsies showed cell proliferation, mostly crescentic, with pauci-immune GN in 29%. Outcome was favourable, with the use of antibiotics alone in one-third. Five cases of Coxiella infections were added to 16 from literature review. Sixteen had small-vessel vasculitides, mainly cryoglobulinaemia vasculitis in 75%. One patient had polyarteritis nodosa-like vasculitis and four large-vessel vasculitis. Outcome was good except for one death. A highly sensitive next generation sequencing analysis on three Coxiella- and two Bartonella-related vasculitides biopsies did not find any bacterial DNA. CONCLUSION: Coxiella and Bartonella are both able to induce vasculitis but display distinct vasculitis features. Bartonella mimics PR3-ANCA-associated vasculitis in the setting of endocarditis, whereas Coxiella may induce vasculitis involving all vessel sizes.

Management of severe renal disease in anti-neutrophil-cytoplasmic-antibody-associated vasculitis: the place of rituximab and plasma exchange?

OBJECTIVE: The optimal induction therapy for severe glomerulonephritis of ANCA-associated vasculitis (AAV) is debated. We compared the efficacy of glucocorticoid and rituximab (RTX) or CYC induction therapy for severe AAV-related glomerulonephritis and evaluated the potential benefit of plasma exchange (PE) as adjunct therapy to CYC. METHODS: This retrospective, multicentre study included AAV patients with severe renal active disease (serum creatinine level ≥350 µmol/l and/or estimated glomerular filtration ratio ≤15 ml/min/1.73 m2). Propensity-score analysis was used to adjust for potential confounders. RESULTS: Between 2005 and 2017, 153 patients with AAV-related glomerulonephritis were studied (96 [60%] men; mean [s.d.] age 63 [13.1] years): 19 (12%) were treated with RTX and 134 (88%) with CYC. Remission rates did not differ between RTX- and CYC-treated groups. Although more patients with RTX than CYC were dialysis-free at month (M) 12 (79% vs 68%), the difference was not significant after adjustment. Among 134 patients with CYC-treated glomerulonephritis, 76 (57%) also had PE. M3 and M6 remission rates were comparable for weighted CYC groups with or without PE. For weighted groups, the dialysis-free survival rate with CYC was higher with than without PE at M6 (72% vs 64%; odds ratio 2.58) and M12 (74% vs 60%; odds ratio 2.78) reaching statistical significance at M12. CONCLUSION: We could not find any difference between RTX and CYC as induction therapy for patients with severe AAV-related glomerulonephritis. In patients receiving CYC induction regimen, the addition of PE conferred short-term benefits with higher dialysis-free rate at M12.