Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices.

We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term "endocapillary proliferation" is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific descriptor. We also make recommendations on issues for which there are limited data at present and that can best be addressed in future studies (phase 2). We propose to proceed to these investigations, with clinicopathologic studies and tests of interobserver reproducibility to evaluate the applications of the proposed definitions and to classify lupus nephritis lesions.

Validation of the Systemic Lupus International Collaborating Clinics classification criteria in a cohort of patients with full house glomerular deposits.

In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) presented a new classification for systemic lupus erythematosus (SLE). In this classification, biopsy-confirmed lupus nephritis with positive antinuclear or anti-double-stranded DNA antibodies became a stand-alone criterion. Because of the unknown diagnostic performance among patients from nephrology clinics, we aimed to test the validity of the SLICC classification, compared with the American College of Rheumatology classification, in a cohort of patients whose renal biopsies would raise the clinicopathologic suspicion of lupus nephritis. All patients with a renal biopsy showing full house glomerular deposits and clinical follow-up in our center were included and reevaluated, after which clinicians and a pathologist reached a consensus on the reference-standard clinical diagnosis of SLE. The diagnostic performance and net reclassification improvement were assessed in 149 patients, 117 of whom had clinical SLE. Compared with the American College of Rheumatology classification, the SLICC classification had better sensitivity (100 vs. 94%); although, this was at the expense of specificity (91 vs. 100%; net reclassification improvement -0.03). Excluding the stand-alone renal criterion, the specificity of the SLICC classification reached 100%, with a significant net reclassification improvement of 0.06 compared with the American College of Rheumatology classification. The SLICC classification performed well in terms of diagnostic sensitivity among patients with full house glomerular deposits; whereas, the stand-alone renal criterion had no additional value and compromised the specificity. Thus, presumed patients with lupus nephritis in nephrology clinics reflect a distinct SLE disease spectrum warranting caution when applying SLE classification criteria.

Clinical and Histopathologic Characteristics Associated with Renal Outcomes in Lupus Nephritis.

BACKGROUND AND OBJECTIVES: The prognostic significance of histopathologic (sub)classes in the current classification of lupus nephritis (LN) is controversial. We analyzed clinical and histopathologic predictors of renal outcome in LN outside the framework of the classification. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Variables (50 histopathologic and ten clinical) were tested in mixed, linear, and Cox regression models for their association with renal flare, ESRD, and eGFR during follow-up (1, 5, and 10 years) in 105 patients with LN who underwent biopsy from 1987 to 2011. The Cockcroft-Gault (normalized to a body surface area of 1.73 m2) and Schwartz formulas were used to calculate eGFR for adults and children, respectively. RESULTS: During median follow-up of 9.9 years (25th-75th percentile, 5.9-13.8), 47 patients experienced a renal flare and 21 progressed to ESRD. Renal flare was predicted by fibrinoid necrosis (hazard ratio [HR], 1.04 per %; 95% confidence interval [95% CI], 1.00 to 1.07) and nonwhite race (HR, 2.23; 95% CI, 1.23 to 4.04). ESRD was predicted by fibrinoid necrosis (HR, 1.08 per %; 95% CI, 1.02 to 1.13), fibrous crescents (HR, 1.09 per %; 95% CI, 1.02 to 1.17), interstitial fibrosis/tubular atrophy (IF/TA) ≥25% (HR, 3.89; 95% CI, 1.25 to 12.14), eGFR at baseline (HR, 0.98 per ml/min per 1.73 m2; 95% CI, 0.97 to 1.00), and nonwhite race (HR, 7.16; 95% CI, 2.34 to 21.91). A higher mean eGFR during follow-up was associated with normal glomeruli (+0.2 ml/min per 1.73 m2 per %; 95% CI, 0.1 to 0.4). Like ESRD, a lower eGFR during follow-up was associated with fibrous crescents, IF/TA≥25%, and nonwhite race, as well as with cellular/fibrocellular crescents (-0.4 ml/min per 1.73 m2 per %; 95% CI, -0.6 to -0.2) and age (-0.8 ml/min per 1.73 m2 per year; 95% CI, -1.2 to -0.4). CONCLUSION: The LN classification should include an index of evidence-based prognosticators. Awaiting validation of a formal index, we suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings.

Idiopathic non-lupus full-house nephropathy is associated with poor renal outcome.

Background: Full-house immunofluorescence in combination with various histopathologic lesions in the renal biopsies of patients without overt systemic lupus erythematosus (SLE) poses a diagnostic challenge. In this setting, the biopsy findings are sometimes termed non-lupus 'full-house nephropathy' (FHN). It is presently unknown whether idiopathic non-lupus FHN is clinicopathologically and prognostically distinct from lupus FHN. Methods: We included non-lupus FHN patients and lupus FHN controls (four or more American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria) who were biopsied between 1968 and 2014 at the Leiden University Medical Centre. Non-lupus FHN patients were studied for progression to SLE and/or the presence of other conditions with FHN. The clinicopathologic characteristics and prognosis of idiopathic non-lupus FHN patients were compared with those of lupus FHN patients. Results: Of 149 included patients, 32 had non-lupus FHN. During the median follow-up of 20 years, no non-lupus FHN patients developed SLE. In all, 20 non-lupus FHN patients had idiopathic non-lupus FHN, and in 12 patients, secondary non-lupus FHN was considered due to membranous nephropathy (anti-PLA2R-positive, n = 1; cancer-associated, n = 3), IgA nephropathy ( n = 4), infection-related glomerulonephritis ( n = 2) or anti-neutrophil cytoplasmic antibody-associated glomerulonephritis ( n = 2). Idiopathic non-lupus FHN patients were more often male (P < 0.001) than lupus FHN patients and their renal biopsies more often showed a mesangial (P = 0.04) or membranous pattern of injury (P = 0.02) and less intense C1q staining (P = 0.002). Clinically, they presented with lower-range erythrocyturia (P = 0.04), more proteinuria (P < 0.01) and less complement consumption in the classical pathway (P < 0.001) than lupus FHN patients. By multivariable Cox regression analysis of patients with a lupus nephritis class III/IV pattern of injury, idiopathic non-lupus FHN compared with lupus FHN was an independent risk factor for end-stage renal disease [hazard ratio 5.31 (95% confidence interval 1.47-19.24)]. Conclusions: Our results show that the clinical recognition of idiopathic non-lupus FHN as a diagnostic category is critical.

Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement.

OBJECTIVES: Neuropsychiatric (NP) involvement is a poorly understood manifestation of SLE. We studied post-mortem histopathology in relation to clinical NPSLE syndromes and complement deposition in brains of NPSLE and SLE patients and controls. Furthermore, we investigated the correlation between cerebral post-mortem histopathology and ex vivo 7 T MRI findings in SLE and NPSLE. METHODS: A nationwide search for autopsy material yielded brain tissue from 16 NPSLE and 18 SLE patients. Brains obtained from 24 patients who died of acute cardiac events served as controls. Apart from a histopathological evaluation, paraffin-embedded cortical tissue was stained for components of the classical, lectin and terminal complement pathways. RESULTS: Diffuse vasculopathy, microinfarction, macroinfarction, vasculitis and microthrombi occurred significantly more often in NPSLE than SLE patients and were absent in controls. Focal vasculopathy was found in both SLE patients and controls. Complement deposition was strongly associated with both SLE and NPSLE, but not with controls (P < 0.001). Microthrombi were found uniquely in NPSLE and were associated with C4d and C5b-9 deposits (P < 0.05). A 7 T MRI was unable to detect most small vessel injury that was visible histopathologically. CONCLUSION: Our study demonstrates that histopathological lesions in NPSLE represent a continuum, ranging from non-specific lesions such as focal vasculopathy, to more specific lesions including C4d- and C5b-9-associated microthrombi and diffuse vasculopathy related to clinical syndromes defining NPSLE. Complement deposition may be a key factor in the interaction between circulating autoantibodies and thromboischaemic lesions observed in NPSLE. Therefore, complement inhibition may have novel therapeutic potential in NPSLE.

Tissue microchimerism is increased during pregnancy: a human autopsy study.

Microchimerism is the occurrence of small populations of cells with a different genetic background within an individual. Tissue microchimerism is considered to be primarily pregnancy-derived and is often studied relative to female-dominant autoimmune diseases, pregnancy complications, malignancies, response to injury, and transplantation outcomes. A particular distribution pattern of chimeric cells across various organs was recently described in a model of murine pregnancies. Our aim was to determine the frequency and distribution of tissue microchimerism across organs during and after pregnancy in humans. We performed in situ hybridization of the Y chromosome on paraffin-embedded autopsy samples of kidneys, livers, spleens, lungs, hearts and brains that were collected from 26 women who died while pregnant or within 1 month after delivery of a son. Frequencies of chimeric cells in various tissues were compared with those of a control group of non-pregnant women who had delivered sons. Tissue microchimerism occurred significantly more frequently in the lungs, spleens, livers, kidneys and hearts of pregnant women compared with non-pregnant women (all P < 0.01). We showed that some of the chimeric cells were CD3+ or CD34+. After correction for cell density, the lung was most chimeric (470 Y chromosome-positive nuclei per million nuclei scored), followed by the spleen (208 Y+/10(6) nuclei), liver (192 Y+/10(6) nuclei), kidney (135 Y+/10(6) nuclei), brain (85 Y+/10(6) nuclei) and heart (40 Y+/10(6) nuclei). Data from this unique study group of women who died while pregnant or shortly after delivery provide information about the number and physiologic distribution of chimeric cells in organs of pregnant women. We demonstrate that during pregnancy, a boost of chimeric cells is observed in women, with a distribution across organs, that parallels findings in mouse models.