Weaning of maintenance immunosuppressive therapy in lupus nephritis (WIN-Lupus): results of a multicentre randomised controlled trial.

OBJECTIVES: Lupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE). Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST, to target remission and avoid relapses. The optimal duration of maintenance IST is unknown. The WIN-Lupus trial tested whether IST discontinuation after 2‒3 years was non-inferior to IST continuation for two more years in proliferative LN. METHODS: WIN-Lupus was an investigator-initiated multicentre randomised controlled trial. Patients receiving maintenance IST with azathioprine or mycophenolate mofetil for 2-3 years, and hydroxychloroquine, were randomised (1:1) into two groups: (1) IST continuation and (2) IST discontinuation. The primary endpoint was the relapse rate of proliferative LN at 24 months. Main secondary endpoints were the rate of severe SLE flares, survival without renal relapse or severe flare, adverse events. RESULTS: Between 2011 and 2016, 96 patients (out of 200 planned) were randomised in WIN-Lupus: IST continuation group (n=48), IST discontinuation group (n=48). Relapse of proliferative LN occurred in 5/40 (12.5%) patients with IST continuation and in 12/44 (27.3%) patients with IST discontinuation (difference 14.8% (95% CI -1.9 to 31.5)). Non-inferiority was not demonstrated for relapse rate; time to relapse did not differ between the groups. Severe SLE flares (renal or extrarenal) were less frequent in patients with IST continuation (5/40 vs 14/44 patients; p=0.035). Adverse events did not differ between the groups. CONCLUSIONS: Non-inferiority of maintenance IST discontinuation after 2‒3 years was not demonstrated for renal relapse. IST discontinuation was associated with a higher risk of severe SLE flares. TRIAL REGISTRATION NUMBER: NCT01284725.

SARS-CoV-2 Antibody Response After a Third Dose of the BNT162b2 Vaccine in Patients Receiving Maintenance Hemodialysis or Peritoneal Dialysis.

RATIONALE & OBJECTIVE: Recent studies showed that antibody titers after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the dialysis population are diminished as compared with the general population, suggesting the possible value of a third booster dose. We characterized the humoral response after 3 doses of the BNT162b2 vaccine in patients treated with either maintenance hemodialysis (HD) or peritoneal dialysis (PD). STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 69 French patients (38 HD and 31 PD) treated at a single center who received 3 doses of the BNT162b2 vaccine. FINDINGS: Humoral response was evaluated using plasma levels of anti-SARS-CoV-2 spike protein S1 immunoglobulin measured after the second dose and at least 3 weeks after the third dose of the BNT162b2 vaccine. Patients (median age 68 years [interquartile range (IQR), 53-76 years], 65% men) had a median anti-S1 antibody level of 284 [IQR, 83-1190] AU/mL after the second dose, and 7,554 [IQR, 2,268-11,736] AU/mL after the third dose. Three patients were nonresponders (anti-S1 antibody level < 0.8 AU/mL), and 12 were weak responders (anti-S1 antibody level 0.8-50 AU/mL) after the second vaccine dose. After the third dose, 1 of the 3 initial nonresponders produced anti-spike antibody, and all the 12 initial weak responders increased their antibody levels. Patients with a greater increase in anti-S1 antibody levels after a third dose had lower antibody levels after the second dose, and a longer time interval between the second and the third dose. Adverse events did not seem to be more common or severe after a third vaccine dose. LIMITATIONS: Observational study, small sample size. Relationship between antibody levels and clinical outcomes is not well understood. CONCLUSIONS: A third dose of the BNT162b2 vaccine substantially increased antibody levels in patients receiving maintenance dialysis and appeared to be as well tolerated as a second dose.

Rituximab alone as induction therapy for membranous lupus nephritis: A multicenter retrospective study.

The optimal treatment for pure membranous lupus nephritis (MLN) remains undetermined. Rituximab constitutes a promising therapeutic option for lupus nephritis and is currently being evaluated for use in idiopathic membranous nephritis. We retrospectively analysed the efficacy and tolerance of rituximab as a monotherapy in the induction treatment of pure MLN.We retrospectively investigated SLE patients with biopsy-proven pure class V lupus nephritis presenting with a protein-to-creatinine ratio of at least 2 g/g and treated with rituximab as monotherapy. A background low dose of corticosteroids (≤20 mg/day) was allowed, as was hydroxychloroquine; higher doses of steroids and/or immunosuppressive drugs fell under the exclusion criteria. Remission status was evaluated at baseline and 6, 12, and 24 months after rituximab.The study included 15 patients (13 women, median age 37 years, 27% with extra-renal manifestations, median SLE duration 1.5 years). The median protein-to-creatinine ratio was 4.9 g/g, 80% of the patients had nephrotic-range proteinuria, the median serum albumin was 24 g/L, the median serum creatinine was 0.7 mg/dL, and the median eGFR was 122 mL/min/1.73 m. The median follow-up was 29 months (6-112 months). Treatment failure occurred in 2 patients. However, remission was recorded in the remaining 13 (87%, complete remission in 8 patients) with a median time to remission of 5 months. Median proteinuria decreased from 4.9 g/g to 0.16 g/g at month 12 and to 0.11 g/g at month 24. Median serum albumin increased to 36.5 g/L at month 24, and all patients had serum albumin levels greater than 30 g/L at month 12. Renal function remained stable in all patients. Relapse of proteinuria was recorded in 3 patients (at 12, 29, and 34 months). No patients experienced serious adverse events.Rituximab as monotherapy may represent an effective treatment for pure MLN with an excellent tolerance profile.

ANCA-associated diseases and lung carcinomas: a five-case series.

Microscopic polyangiitis, granulomatosis with polyangiitis, Churg-Strauss syndrome and focal necrotizing glomerulonephritis are severe systemic vasculitides associated with circulating antineutrophil cytoplasmic antibodies (ANCA). Several studies reported that some malignancies can develop in these patients during follow-up, but few studies have considered the association and role of pre-existing cancers, at least in a fraction of patients. Herein, we report five patients with ANCA-associated diseases who had associated lung carcinomas or were diagnosed within 2 years after vasculitis onset. We discuss the putative role of tumor antigen in driving the auto-immune response.

Focal segmental glomerulosclerosis plays a major role in the progression of IgA nephropathy. II. Light microscopic and clinical studies.

It is well known that lesions morphologically identical with focal segmental glomerulosclerosis (FSGS) may appear in IgA nephropathy (IgAN). Capsular adhesions without underlying abnormalities in the tuft, often the first sign of FSGS, are frequent in IgAN. In this retrospective study, a new cohort of 128 adult patients with IgAN was used to validate the new Oxford classification system of IgAN, and shown to have highly significant associations with clinical and outcome parameters. We then used these patients to determine the extent to which IgAN could be accounted for in terms of FSGS. Some form of lesion consistent with FSGS, notably hyalinosis and collapsing glomerulopathy, was found in 101 of these patients. No glomerular lesions were found in 16 patients, and 11 had mild lesions not definable as FSGS. Those with FSGS had significantly worse renal survival at 80 months than those without. Comparison of pure forms of FSGS (excluding collapsing glomerulopathy) with cases of FSGS having other glomerular lesions (mesangial hyperplasia, endocapillary hypercellularity, glomerular necroses, extracapillary proliferation) revealed that those with FSGS and other superimposed lesions did significantly worse than cases of pure FSGS at 80 months following diagnosis. Importantly, patients with pure FSGS had relatively poor survival even without other superimposed glomerular abnormalities. Thus, the majority of cases of IgAN can be interpreted as representing one or another variant of FSGS. Hence, interpreting IgAN in terms of FSGS emphasizes the role that podocyte lesions may play in the pathogenesis and progression of this disease.

Rituximab treatment for membranous nephropathy: a French clinical and serological retrospective study of 28 patients.

The development of well-tolerated and effective therapies that target the pathogenesis of membranous nephropathy (MN) would be useful. Our objective was to evaluate the efficacy of rituximab in MN. We analyzed the outcome of 28 patients treated with rituximab for idiopathic MN. Anti-PLA(2)R antibodies in serum and PLA(2)R antigen in kidney biopsy were assessed in 10 and 9 patients, respectively. Proteinuria was significantly decreased by 56, 62 and 87% at 3, 6 and 12 months, respectively. At 6 months, 2 patients achieved complete remission (CR) and 12 partial remission (PR; overall renal response, 50%). At 12 months (n = 23), CR was achieved in 6 patients and PR in 13 patients (overall renal response, 82.6%). Three patients suffered a relapse of nephrotic proteinuria 27-50 months after treatment. Univariate analysis suggested that the degree of renal failure (MDRD estimated glomerular filtration rate <45/ml/min/1.73 m(2)) is an independent factor that predicts lack of response to rituximab. Anti-PLA(2)R antibodies were detected in the serum of 10 patients, and PLA(2)R antigen in immune deposits in 8 of 9 patients. Antibodies became negative in all 5 responsive patients with available follow-up sera. In this retrospective study, a high rate of remission was achieved 12 months after treatment.

Glycaemic control in type 2 diabetic patients on chronic haemodialysis: use of a continuous glucose monitoring system.

BACKGROUND: The proportion of diabetic patients undergoing haemodialysis is rapidly increasing. Glucose control among such patients is difficult to assess. We aimed to evaluate the clinical performance of a continuous glucose monitoring system (CGMS) in type 2 diabetic patients on chronic haemodialysis. METHODS: We used a 4-day CGMS to monitor glucose levels in 19 haemodialysed type 2 diabetic patients (HD T2) including 2 days with and 2 days without dialysis session, and 39 non-HD T2 in a double-centre study. RESULTS: The glucose concentration according to the glucose meter and CGMS were correlated in HD T2 patients (r = 0.90, P < 0.0001) and in non-HD T2 patients (r = 0.81, P < 0.0001). The relative absolute difference (RAD) between glucose determined by a glucose meter and glucose determined by the CGMS did not differ between HD T2 and non-HD T2 patients (9.2 +/- 10.5 vs. 8.2 +/- 7.6%; P = 0.165). Glycated haemoglobin (A1c) and mean glucose concentration were strongly correlated in non-HD T2 patients (r = 0.71; P < 0.0001) but weakly correlated in HD T2 patients (r = 0.47; P = 0.042). Fructosamine was correlated with the mean glucose concentration in non-HD T2 (r = 0.67; P < 0.0001) but not in HD T2 patients (r = 0.04; P = 0.88). CONCLUSION: CGM is a validated marker of glycaemic control in HD diabetic patients. This tool showed that A1c and fructosamine, despite being good markers of glycaemic control in non-HD diabetic patients, are of poor value in HD diabetic patients.

Antiphospholipid syndrome nephropathy in systemic lupus erythematosus.

In the course of the antiphospholipid syndrome (APS), the existence of vaso-occlusive lesions capable of affecting numerous organs is now well established. The renal involvement attributable to primary APS, APS nephropathy (APSN), corresponds to vaso-occlusive lesions of the intrarenal vessels, associating side-by-side, acute thromboses with chronic arterial and arteriolar lesions, leading to zones of cortical ischemic atrophy. A retrospective study of 114 lupus patients undergoing renal biopsy was undertaken to determine the following: (1) if APSN can be found in the course of systemic lupus erythematosus (SLE); (2) if certain clinical and biologic factors can permit the prediction of the presence of APSN; and (3) if APSN is a superadded renal morbidity factor in lupus patients. This study shows the following: (1) APSN occurs in SLE (32% of patients with renal biopsies) in addition to, and independently of, lupus nephritis; (2) APSN is statistically associated with lupus anticoagulant but not with anticardiolipin antibodies; (3) APSN is associated with extrarenal APS, mainly arterial thromboses and obstetrical fetal loss, but not with the venous thromboses of APS; (4) APSN is an independent risk factor, over and above lupus nephritis, that contributes to an elevated prevalence of hypertension, elevated serum creatinine, and increased interstitial fibrosis. Thus, it seems likely that, because of its associations with hypertension, elevated serum creatinine, and increased interstitial fibrosis, APSN may worsen the prognosis in these patients. APSN may also have therapeutic significance in that its recognition should permit a better balance between immunosuppressor and antithrombotic and/or vasoprotective therapy. Finally, this study suggests that APSN should be considered as an element to be included in the classification criteria of APS.