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Abstract
Introduction One third of lupus nephritis (LN) patients develop irreversible kidney damage despite achieving a clinical response based on resolution of proteinuria. Furthermore, per protocol kidney biopsies showed clinically significant histological activity in 50% of patients with proteinuria < 0.5 g/g. We hypothesized that persistence of intrarenal inflammation (=LN histological activity) after treatment leads to accrual of kidney damage. We have previously identified several urinary biomarkers that correlate with the NIH Activity Index (histological activity). Here, we tested whether the elevation of these candidate biomarkers of LN immunological activity at 6 and 12 months from the diagnostic kidney biopsy predict loss of kidney function at 3 years.
Methods We quantified 1200 biomarkers (Kiloplex, RayBiotech) in urine samples collected on the day of (73%) or within 3 weeks (27%) of kidney biopsy and week 12, 24, or 52 in LN patients (ISN class III, IV, V, or mixed) with proteinuria > 1 g/d. Glomerular filtration rate (GFR) was estimated using the CKD-EPI equation. Significant GFR loss was defined as a decline of >15 ml/min below 90 ml/min at 3 years from biopsy or end-stage kidney disease (ESKD) by year 3 requiring dialysis or transplant.
Results We included 73 patients: 85% female, 46% identified as Black, 40% as White, 10% as Asian, and 4% as Other. ISN classification included 25% pure proliferative (III or IV), 40% pure membranous (V), and 35% mixed (III or IV + V). Mean GFR at biopsy was 85 (SD 34.7) ml/min. There were 32/73 (44%) patients who developed significant GFR loss. Figure 1 shows the associations of candidate urinary biomarkers at 6 and 12 months with significant GFR loss at 3 years. Most urinary biomarkers of histological activity were higher at 6 and 12 months in patients who ultimately lost GFR at 3 years. For example, IL-16 outperformed UPCR both at 6 and 12 months (figure 1) and was independent of proteinuria (not shown). UPCR at 12 months predicted 3-year GFR loss with AUC 0.79, but albuminuria did not. In a multivariable model, the combination of CD163 (macrophage activation), PRTN3 (degranulation), and IL-16 (cellular inflammation in LN) urinary levels at 12 months predicted GFR loss at 3 years with an AUC of 0.96.
Conclusions Elevation of urinary biomarkers of histological activity after 6 or 12 months of treatment predict GFR loss at 3 years better than proteinuria, especially IL-16. These findings suggest that insufficient immunosuppression results in persistent intrarenal immunological activity in LN that increases the risk of kidney function loss. The ultimate treatment goal in LN is long term preservation of kidney function. Therefore, clinical trials endpoints should include response definitions that best associate with GFR preservation. Because noninvasive urinary biomarkers of immunological activity parallel intrarenal inflammation and predict future GFR, they could be used to 1) monitor treatment response/failure, 2) allow early treatment changes, and 3) they could serve as surrogate endpoints in clinical trials.
Association of candidate urinary biomarkers of histological activity with significant GFR loss. Urinary abundance (pg/mgcreatinine) of urinary biomarkers selected a priori based on their correlation with histological activity (NIH Activity Index) in a matching kidney biopsy of LN according to GFR loss at 3 years. Urine protein and albumin to creatinine ratios are reported for reference as clinically used biomarkers.
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