A blood test for NELL1 membranous nephropathy, and it tracks the proteinuria

Design

assay development and validation study using a luciferase immunoprecipitation systems immunoassay, with an independent clinical evaluation cohort and longitudinal sampling

Population

validation cohort of 20 biopsy-proven NELL1-positive and 20 PLA2R-positive NELL1-negative patients; evaluation cohort of 63 membranous nephropathy cases and 20 disease controls

Primary outcome

sensitivity and specificity for NELL1-associated membranous nephropathy

Effect

90% sensitivity and 100% specificity in the validation cohort; 6 NELL1-positive cases identified among 63; antibody titres tracked proteinuria in 3 longitudinally followed patients

PLA2R serology changed membranous nephropathy: it allows diagnosis without biopsy in the right clinical setting and titre monitoring to guide treatment. NELL1-associated membranous nephropathy — around a tenth of cases, and the subtype most associated with malignancy and with certain drug exposures — has had no equivalent, relying on mass spectrometry or immunostaining of biopsy tissue.

This group built a luciferase immunoprecipitation assay, finding that an N-terminal fragment of NELL1 performed better than the full-length protein. Against a validation cohort of 20 biopsy-proven NELL1-positive and 20 PLA2R-positive, NELL1-negative patients, it achieved 90% sensitivity and 100% specificity, agreeing with ELISA but with better specificity. In an independent cohort of 63 membranous nephropathy cases and 20 disease controls it identified six NELL1-positive cases. In three patients followed longitudinally, antibody levels tracked proteinuria.

The practical significance is what a second serology would allow: a patient who is PLA2R-negative currently goes to biopsy, and a positive NELL1 result would both spare that and prompt the malignancy search the subtype warrants. The assay is not commercially available and the validation cohort was 40 patients, so this is a development to watch rather than to request. What to do now is ask the pathologist whether your laboratory can stain for NELL1 on tissue you already have.

• Ask whether your renal pathology service offers NELL1 staining — the tissue test exists even though the serology does not
• A NELL1-positive membranous nephropathy warrants an age-appropriate malignancy assessment and a drug history
• Do not expect a commercial serological assay yet; this is a research immunoassay
• Titre tracking proteinuria in three patients is a suggestion, not a validated monitoring strategy
• Specificity of 100% against 20 PLA2R-positive controls is encouraging and untested against secondary membranous nephropathy of other causes

Why it matters

A second serological subtype would spare biopsies and flag the patients who need a malignancy search.

Don't overread it

A 40-patient validation of a research assay with longitudinal data on three patients — this is not yet a clinical test.

The statistics, in plain English

Ninety per cent sensitivity and 100% specificity come from 20 cases and 20 controls, so each percentage point is one patient — the true performance could be appreciably worse. A specificity of 100% against PLA2R-positive patients also tests the easier question; the harder one is whether the assay stays specific against the other membranous subtypes and against non-membranous glomerular disease.

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