Clinicopathological features of "Full-House" Non-lupus nephropathy in a long term follow-up study

BACKGROUND: A subset of patients without overt systemic lupus erythematosus (SLE) present with biopsy findings typically seen in lupus nephritis (LN). However, it remains unclear the rate of evolution to overt SLE of these patients. Similarly, uncertainty still exists on how to classify or treat these patients. AIM: The objective of this study was to investigate the clinicopathological characteristics and the long-term outcome of the subset of cases that are linked to the pathological characteristics of LN yet do not exhibit any clinical signs of SLE. PATIENTS: This study involved a retrospective review of all native kidney biopsies accessioned in the Nephrology Division of San Giovanni Bosco and University of Torino from 2012 to 2022. The purpose of the review was to identify any results compatible with lupus-like (LL) pathology. The present study utilized for the definition of LL-like features (LL-fx) the presence of positive staining for all immunoglobulins (Ig) and complements with an intensity of at least 1+ on a scale ranging from 0 to 3+ using immunofluorescence (IF) techniques. RESULTS: From January 2012 to December 2022, 1014 patients underwent native renal biopsies that were accessioned at San Giovanni Bosco. Of these patients, 91 (9%) patients with either LN or LL-fx were studied. Of the 91 patients with LN or LL-fx, 85 had LN and 6 LL-fx. LL-fx patients had a mean age of 28 years (range: 21 - 55), they were all females and were most frequently Caucasian (5 of 6 patients (83.4%). The most common indication for kidney biopsy was nephrotic proteinuria accompanied by renal impairment. At the time of kidney biopsy mean serum creatinine was 2.06 mg/dl (range 1.4 – 2.8 mg/dl) and mean eGFR calculated with 2021 CKD-EPI equation was 34.6 ml/min (range 24 – 54 ml/min). Five of 6 (83.4%) patients presented with a full-blown nephrotic syndrome. Anti-double-stranded DNA antibody and ENA were absent in all LL-fx. Three patients with LL-fx presented with ANA positivity (low-to medium titer, up to 1:160, often inconsistently determined) and reduced C3. Five patients (83.4%) presented with a Membranous GN, considered with features in line with of class V LN. One patient (16.7%) presented with prolipherative GN, with histological findings compatible with class III LN. Of note, two patients having Membranous GN had also extra-capillary proliferation. Mean follow-up from time of biopsy was 7.5 year (88.8 months), (range 3 – 10 years; 36 – 120 months). None of the cases develop additional clinical symptoms leading to a diagnosis of overt SLE. Two patients with ANA positivity at the time of presentation, maintained a complete negativity for ENA and anti-dsDNA during follow up. During follow up, 5 of 6 patients developed End Stage Kidney Disease (ESKD) with the need of Renal Replacement Therapy (RRT), either peritoneal of hemodialysis. Mean time from kidney biopsy to the start of RRT was 54.4 months (range 4 – 90 months). The two patients with extra capillary proliferation at kidney biopsy did not respond to therapy and progressed to irreversible ESKD within 4 and 10 months from presentation, respectively. CONCLUSION: Our study suggested that a not negligible number of patients may present with biopsy findings similar to LN and yet do not exhibit clinical evidence of SLE. In our cohort, these patients were often female, Caucasian, and were more likely to present with nephrotic proteinuria (particularly nephrotic syndrome) and impairment of kidney function. They do appear to have worse prognosis than those with LN, despite aggressive IS therapy. Future studies are needed to understand if the pathologic features of LL-fx may be a manifestation of a complex autoimmune process overlapping with SLE or expression of other multiple possible etiologies.