Among patients with lupus membranous nephritis (LMN), those who test positive for exostosins 1 or 2 (EXT1/EXT2) in the glomerular basement membrane are less likely to experience kidney failure than patients who test negative for these enzymes, a finding that has important clinical complications for prognosis and management.
EXT1/EXT2 are glycosyltransferases possibly residing in podocytes that are responsible for synthesis of the heparan sulfate chain in the glomerular basement membrane, according to Sanjeev Sethi, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.
The investigators tested 374 biopsy-proven LMN cases and found 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. In significant results from a subset of these cases, patients who were EXT1/EXT2-negative progressed to end-stage kidney disease (ESKD) faster and more frequently compared with patients who were EXT1/EXT2-positive (18.8% vs 3.1%), Dr Sethi’s team reported in the Journal of the American Society of Nephrology. Results were consistent across analyses of LMN cases of pure class 5 or class 5 mixed with proliferative class 3 or 4.
On kidney biopsy, EXT1/EXT2-positive patients displayed significantly less glomerulosclerosis (median 3.8% vs 9.1%) and interstitial fibrosis/ tubular atrophy (median 0% vs 10%) compared with EXT1/EXT2-negative patients, despite significantly more EXT1/EXT2-positive patients presenting with proteinuria of 3.5 g/24 h or more (median 60.0% vs 43.7%). The EXT1/EXT2-positive group also had significantly lower serum creatinine levels (median 0.8 vs 0.9 mg/dL) and were significantly younger (32 vs 35 years).
Factors significantly predicting ESKD at 10 years included male sex, EXT1/EXT2-negativity, serum creatinine at presentation, 25% or more glomerulosclerosis, and 25% or more interstitial fibrosis/ tubular atrophy, according to a multivariable analysis. There were no significant between-group differences in death rate in any analysis.
EXT1/EXT2-positive disease appears to represent a subgroup with favorable kidney biopsy findings with respect to chronicity indices, according to the investigators. They suggested the presence of EXT1/EXT2 may be protective.
“We hypothesize that in patients with EXT1/EXT2-positive LMN, the increased secretion of catalytic domain EXT1/EXT2 into the [glomerular basement membrane] results in increased synthesis of the heparan sulfates, which, in turn, may offer protection from damaging events, such as leukocyte infiltration, complement activation, cytokine production, etc. EXT1/EXT2, along with heparan sulfates, may coat the immune complexes and restrict the immune deposits from generating an inflammatory response.”
The team recommended that kidney biopsy samples from patients with lupus nephritis and lupus membranous nephritis be stained for EXT1/EXT2.
Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.
Ravindran A, Casal Moura M, Fervenza FC, et al. In patients with membranous lupus nephritis, exostosin-positivity and exostosin-negativity represent two different phenotypes. Published online January 21, 2021. J Am Soc Nephrol. doi:10.1681/ASN.2020081181