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Residual renal histopathological activity at clinical remission in Proliferative Lupus Nephritis (PLN) can predict renal flare upon immunosuppression withdrawal. Data on the role of histological renal remission in predicting extra-renal flares is lacking. We assessed renal histopathology prior to drug withdrawal and the occurrence of renal and extra-renal flares over 52 weeks after drug withdrawal in PLN patients in long-term clinical remission. This is a subgroup analysis of a non-inferiority, open-label randomized (1:1) controlled trial. Patients with biopsy-proven Class III/IV LN in the past (biopsy 1), on immunosuppressants (IS) ≥ 3 years, in clinical remission for ≥ 1 year, on stable prednisolone dose (≤ 7.5 mg/day) plus a maintenance IS and hydroxychloroquine (HCQ) were subjected to a repeat renal biopsy (biopsy 2). Individuals with biopsy 2 having activity index (AI) < 4/24 were randomised to either prednisolone or IS withdrawal. Primary end-point was the proportion experiencing a flare [SELENA-SLEDAI flare index (SFI)] at week 52. Twenty-eight eligible patients underwent biopsy 2 and randomized to prednisolone (n = 15) and IS (n = 13) withdrawal. At biopsy 1, 12 (43%) had class III, 15 (53.5%) had class IV, and 1 (3.5%) had class III + V. At biopsy 2, PLN persisted in 4 (14.2%) while 18 (64.2%) were in histological remission (AI = 0) with 6 (21.4%) in class II. Following drug withdrawal, 9/28 (32%) had flares especially musculoskeletal (55.5%), mucocutaneous (44.4%), and renal (33.3%). Among the four persistent PLN patients, one of the two (50%) with AI = 1 had extra-renal flare while both the two with AI = 2 (100%) had renal and extra-renal flares. In those with histological remission (biopsy 2), 6/18 (66.6%) experienced extra-renal flare of whom one also had renal flare. Upon drug withdrawal, renal histopathology findings with any activity index can predict renal flare while histological remission is not enough to predict extra-renal flare, thus making it an unsuitable marker for deep SLE remission.

BackgroundIscalimab (CFZ533) is a novel, anti-CD40 monoclonal antibody. This study evaluated the efficacy, pharmacokinetics and safety of iscalimab versus placebo as add-on to standard-of-care (SoC) therapy in patients with biopsy-proven active proliferative lupus nephritis (LN).MethodsThis was a phase II, randomised, double-blind, placebo-controlled, multicentre study including patients with a diagnosis of systemic lupus erythematosus with active LN. Patients were randomly assigned (2:1) to receive either intravenous iscalimab (10 mg/kg) or placebo for 24 weeks on top of SoC for LN. The primary efficacy endpoint was the ratio from baseline in urinary protein-to-creatinine ratio (UPCR) at week 24. Safety assessments included adverse events (AEs) and serious AEs (SAEs) during treatment and follow-up up to 49 weeks.FindingsOf the 57 patients (iscalimab, n=39; placebo, n=18) randomised, 31 (54.4%) completed the study. The primary efficacy endpoint was met: at week 24, the relative improvement from baseline in proteinuria (UPCR) was 63.1% and 36.3% in the iscalimab and placebo arms, respectively. UPCR to baseline at week 24 showed a statistically significant reduction of 42.1% in the iscalimab versus placebo arm. Most AEs were of mild to moderate severity in both treatment arms. Overall, seven SAEs were reported in six patients (15.4%) in the iscalimab arm versus four in three patients (16.7%) in the placebo arm.InterpretationIscalimab showed a significant improvement in proteinuria (UPCR) in patients with active LN. Iscalimab was generally well tolerated with the exception of a few severe infections and one case of macrophage-activation syndrome in immunosuppressed and comorbid patients.Trial registration numberNCT03610516.

Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), we randomized 87 proliferative LN patients to either cyclophosphamide pulses (750mg/m2, 13 pulses in 2 years) combined with oral prednisone (CY) or to azathioprine (2mg/kg/day in 2 years) combined with intravenous pulses of methylprednisolone (3 × 3 pulses of 1000mg) and oral prednisone (AZA). After a median follow-up of 5.7 years (interquartile range 4.1–7.2 years), doubling of serum creatinine was more frequent in the AZA group, although not statistically significant (relative risk (RR): 4.1, with 95% confidence interval (95% CI): 0.8–20.4). Relapses occurred more often in the AZA group (RR: 8.8, 95% CI: 1.5–31.8). Creatinine and proteinuria at last visit did not differ between the two treatment arms. Moreover, 88.4% of the patients in the AZA arm were still free of cyclophosphamide treatment. During the first 2 years, the frequency of remission was not different, but infections, especially herpes zoster virus infections (HZV) were more frequent in the AZA group. Parameters for ovarian function did not differ between the two groups. In conclusion, in this open-label randomized controlled trial, cyclophosphamide was superior to azathioprine with regard to renal relapses and HZV. At last follow-up, there were no differences in serum creatinine or proteinuria between the two groups. However, since our study lacked sufficient power, longer follow-up is needed to reveal putative differences.

Objective To evaluate the extended follow-up of the CYCLOFA-LUNE trial, a randomized prospective trial comparing two sequential induction and maintenance treatment regimens for proliferative lupus nephritis based either on cyclophosphamide (CPH) or cyclosporine A (CyA). Patients and methods Data for kidney function and adverse events were collected by a cross-sectional survey for 38 of 40 patients initially randomized in the CYCLOFA-LUNE trial. Results The median follow-up time was 7.7 years (range 5.0–10.3). Rates of renal impairment and end-stage renal disease, adverse events (death, cardiovascular event, tumor, premature menopause) did not differ between the CPH and CyA group, nor did mean serum creatinine, 24 h proteinuria and SLICC damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. Conclusion An immunosuppressive regimen based on CyA achieved similar clinical results to that based on CPH in the very long term.

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1 , were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies. Much about the kidney-resident immune populations is a black box. Hacohen and colleagues use single cell RNA sequencing of kidney, skin and urine from lupus nephritis patients to describe the transcriptional state of the immune cells present in each compartment.

ObjectiveTo update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN).MethodsFollowing the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements.ResultsThe changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease.ConclusionsWe have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

Antinephrin autoantibodies occur in adults with minimal change disease and children with idiopathic nephrotic syndrome and appear to be disease activity markers. Their binding at slit diaphragms may induce podocyte dysfunction.

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. Nephritis is a major cause of lupus morbidity. Putterman and colleagues use single-cell RNA sequencing on human renal and skin biopsies to describe the expression landscape associated with lupus nephritis.

Spatial transcriptomics measures in situ gene expression at millions of locations within a tissue 1 , hitherto with some trade-off between transcriptome depth, spatial resolution and sample size 2 . Although integration of image-based segmentation has enabled impactful work in this context, it is limited by imaging quality and tissue heterogeneity. By contrast, recent array-based technologies offer the ability to measure the entire transcriptome at subcellular resolution across large samples 3 – 6 . Presently, there exist no approaches for cell type identification that directly leverage this information to annotate individual cells. Here we propose a multiscale approach to automatically classify cell types at this subcellular level, using both transcriptomic information and spatial context. We showcase this on both targeted and whole-transcriptome spatial platforms, improving cell classification and morphology for human kidney tissue and pinpointing individual sparsely distributed renal mouse immune cells without reliance on image data. By integrating these predictions into a topological pipeline based on multiparameter persistent homology 7 – 9 , we identify cell spatial relationships characteristic of a mouse model of lupus nephritis, which we validate experimentally by immunofluorescence. The proposed framework readily generalizes to new platforms, providing a comprehensive pipeline bridging different levels of biological organization from genes through to tissues.  A method for topological automatic cell type classification across subcellular resolution spatial transcriptomic platforms is proposed, resolving cell type information and locating sparsely dispersed cells in human kidney and mouse kidney and brain.

ObjectivesTo evaluate changes in demographic, clinical and histological presentation, and prognosis of lupus nephritis (LN) over time.Patients and methodsWe studied a multicentre cohort of 499 patients diagnosed with LN from 1970 to 2016. The 46-year follow-up was subdivided into three periods (P): P1 1970–1985, P2 1986–2001 and P3 2002–2016, and patients accordingly grouped based on the year of LN diagnosis. Predictors of patient and renal survival were investigated by univariate and multivariate proportional hazards Cox regression analyses. Survival curves were compared using the log-rank test.ResultsA progressive increase in patient age at the time of LN diagnosis (p<0.0001) and a longer time between systemic lupus erythematosus onset and LN occurrence (p<0.0001) was observed from 1970 to 2016. During the same period, the frequency of renal insufficiency at the time of LN presentation progressively decreased (p<0.0001) and that of isolated urinary abnormalities increased (p<0.0001). No changes in histological class and activity index were observed, while chronicity index significantly decreased from 1970 to 2016 (p=0.023). Survival without end-stage renal disease (ESRD) was 87% in P1, 94% in P2% and 99% in P3 at 10 years, 80% in P1 and 90% in P2 at 20 years (p=0.0019). At multivariate analysis, male gender, arterial hypertension, absence of maintenance immunosuppressive therapy, increased serum creatinine, and high activity and chronicity index were independent predictors of ESRD.ConclusionsClinical presentation of LN has become less severe in the last years, leading to a better long-term renal survival.