Background/Purpose: Persistent intrarenal inflammation despite immunosuppression drives kidney damage and functional decline in lupus nephritis (LN). Yet, current guidelines do not recommend repeat biopsy to assess treatment response, relying instead on proteinuria, which does not reflect histological activity in >50% of cases. Urinary biomarkers are emerging as a promising alternative to assess histological activity and predict long-term renal outcomes. We evaluated candidate biomarkers previously linked to histological activity and risk of renal function loss in LN patients undergoing per-protocol repeat kidney biopsies one year after treatment initiation.

Methods: Twenty LN patients enrolled in Belgium and Sweden underwenta diagnostic and a per-protocol kidney biopsy one year after diagnosis. Treatment was discretionary. Urine samples were collected at time of diagnosis and one-year repeat biopsy, and profiled using Olink Explore HT (5416 proteins). Four candidate biomarkers were selected based on prior associations with histological activity (IL16, soluble CD163), renal function loss (Tenascin C), or B cell activity (BAFF).

Results: At baseline, 18/20 (90%) had ISN/RPS class III or IV +/- V LN and 2/20 (10%) pure class V (Table 1). Paired biopsies at one year were available for 18 patients (16 proliferative): one biopsy was unsuccessful, and one patient declined repeat biopsy. After one year of treatment, only 6/16 (37%) patients transitioned from proliferative to non-proliferative classes, but the NIH Activity Index declined in all proliferative LN patients (Figure 1). Although the NIH Chronicity Index increased in several patients, the median value remained unchanged because of improved scores in a subset. At one year, 10/16 (62%) patients still had persistent proliferative LN but only 6/16 (37%) had an activity index >=2. Proteinuria did not correlate with histological activity at baseline or at one year (Figure 2). At baseline, urinary IL-16 and sCD163 correlated with histological activity, especially in proliferative LN, but these associations diminished at follow-up. In contrast, urinary Tenascin C (a marker of myofibroblast activation) and BAFF were associated with histological activity at one year .

Conclusion: Urinary IL16 and sCD163 correlated with histological activity at diagnosis, whereas Tenascin C and BAFF associated with histological activity at one year, suggesting a potential temporal shift in dominant inflammatory pathways—from macrophage-driven inflammation to stromal activation and B cell persistence. Notably, urinary sCD163 at one year has been shown to predict future renal function loss but it was not correlated with one-year histological activity, highlighting a disconnect between histological and urinary predictors of outcome. This underscores the value of urinary biomarkers as complementary tools that may capture molecular activity missed by biopsy. Given the limited sample size, these findings require validation in larger cohorts. Together, these results support urinary biomarkers as a noninvasive strategy to complement histologic and clinical assessment, offering insight into disease activity not always reflected by traditional measures.

Table 1. Patient demographics and histological features at baseline and one-year repeat biopsy.

(A) Demographic and (B) clinical characteristics including ISN/RPS class, NIH Activity and Chronicity indices, urine protein-to-creatinine ratio (UPCR), and estimated glomerular filtration rate (eGFR) at baseline (T0) and one-year follow-up (T1). *Paired biopsies at 1 year were available for 18 patients: one biopsy was unsuccessful, and one patient declined repeat biopsy.

Figure 1. Transition of lupus nephritis (LN) class and histologic indices from baseline to one-year repeat biopsy.

(A) Alluvial plot shows individual transitions in ISN/RPS class from T0 to T1, highlighting class change from proliferative to non-proliferative LN. (B) Individual paired trajectories of NIH activity index, showing reduction at T1 for all patients with Activity Index >0 at baseline. (C) Chronicity index at T0 and T1. The medians of the NIH Activity and Chronicity Indices at T0 and T1 are shown by the pink dashed line. Only patients with paired biopsies included (n=18)

Figure 2. Correlation between urinary biomarkers and histologic activity at baseline (T0) and follow-up (T1). (A) All patients. (B) Subset with proliferative lupus nephritis. Proteins are expressed as normalized protein expression (NPX) and normalized by plate-controls. Correlation with NIH Activity Index was assessed using Spearman’s rank correlation. P.adjust indicates the p value after adjusting for urine creatinine (linear model). For BAFF, most of the variability contributing to the correlation was in the lower range and not well visualized on the scale shown; the scale was kept unchanged for consistency across plots. UPCR: urine protein-to-creatinine ratio.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-urinary-biomarkers-with-histological-features-in-diagnostic-and-per-protocol-repeat-kidney-biopsies-in-lupus-nephritis/