Alternative biomarkers for assessing response to treatment in patients with LN

Measuring proteinuria is a commonly used approach for monitoring response to treatment and disease progression in patients with lupus nephritis (LN); however, proteinuria is not an ideal marker for kidney disease given the lack of correlation between proteinuria and the level of inflammation. Also, this approach is limited by an inability to differentiate between chronic damage and inflammation that may be treatable as well as different classes of kidney disease.

Kidney biopsy, whilst more informative, is not suitable for frequent sampling due to the invasive nature of the procedure, the number of contraindications that prohibit its use, and the timeframe of sample analysis. There remains a need for sensitive biomarkers to monitor inflammation and kidney damage in patients with LN.

During the American College of Rheumatology (ACR) annual meeting (ACR Convergence 2022), Fava presented data on urinary biomarkers that predict response to treatment in patients with LN that outperformed proteinuria.

Study design

For this study, 225 patients with systematic lupus erythematosus (SLE) who were undergoing a kidney biopsy due to proteinuria levels were enrolled, along with ten healthy donors. The study design is shown in Figure 1.

eGFR, estimated glomerular filtrate rate; SLE, systematic lupus erythematosus; UPCR, urine protein creatinine ratio.
*Adapted from Fava, et al.¹

Results

Classification of the kidney biopsy samples are presented in Table 1, demonstrating that most patients had proliferative, pure membranous, or mixed class.

Table 1. Classification of kidney biopsy samples*

*Adapted from Fava, et al.1 †ISN/RPS class
Histopathological classification, %†
Mesangial only (I–II)	9
Pure membranous (V)	25
Mixed (III or IV +/− V)	24
Proliferative (III or IV)	38
Advanced sclerosis (VI)	4

Identifying biomarkers

The investigators also evaluated whether response to treatment could be determined from urine proteomics data at the time of biopsy, with no difference found between responders and non-responders.

However, assessing urine proteomics at 3 months showed a decline in several proteins in responders compared with non-responders. This protein signature was similar to a previously identified urine protein signature that correlated with the degree of histological activity in the kidney at the time of biopsy (Figure 2).

IL, interleukin.
*Adapted from Fava, et al.¹

The protein signature persisted at 6 and 12 months. Pathway enrichment analysis demonstrated that an initial decrease in factors associated with the destruction of the extracellular matrix at 3 months was followed by a greater reduction in inflammatory markers at 6 and 12 months.

Assessing value of identified biomarkers

An assessment of the validity of these biomarkers found protein signatures at 3 months had a greater predictive power of 12-month treatment response than proteinuria. In particular, urinary CD206 significantly outperformed proteinuria as a biomarker for treatment response at 1 year, with an area under the curve of 91% (Table 2). The performance of these biomarkers was particularly striking in patients with proliferative LN.

CD206 and CD163 are both M2 macrophage markers that are shed during inflammation.

Table 2. AUC for urinary biomarkers*

AUC, area under the curve; UPCR, urine protein creatinine ratio. *Adapted from Fava, et al.1
Biomarker	AUC	p value
UPCR decrease	0.78	0.0037
uCD163 decrease	0.86	0.00026
uCD206 decrease	0.91	2.9 ×10−5

Conclusion

This study found that urinary biomarkers were a better predictor of 12-month response than proteinuria in patients with LN, especially in cases of proliferative LN. Biomarkers of internal inflammation were shown to change in parallel to treatment response, allowing for earlier detection of treatment response or failure and enabling earlier intervention where treatment plans may need to be changed. While longitudinal studies are required to confirm the results of this study, and to assess the decline of kidney function at 3–5 years, these biomarkers could be suitable as surrogate endpoints for clinical trials.