Serum and Urinary Biomarkers Endothelin-1, Beta-2 Microglobulin, Cystatin C, Galectin-3 and Alpha-1-acid Glycoprotein; Can they Surrogate Clinical and Histological Staging in Lupus Nephritis Patients?

Abstract

Background: Lupus nephritis (LN) affects up to 50% of patients with Systemic lupus erythematosus (SLE) and is a major cause of morbidity. It is thus essential to identify biomarkers as indices with substantial predictive power to reduce the serious sequelae. However, criteria for disease remission have not been clearly established for these indices, except for the SLE Disease Activity Index (SLEDAI). Objectives: To investigate the relationship of non-invasively renal protein biomarkers and established measures of renal function to histologic findings in LN, and to test whether certain combinations of the above mentioned laboratory measures are diagnostic for specific histologic features of LN and to evaluate their relations to SLEDAI and chronicity. Methods: The study was conducted on 40 SLE female patients, recruited from renal unit of Internal Medicine department and Rheumatology and Rehabilitation department, and Neurology department, Assuit and Aswan University Hospitals, Egypt from May 2011 to January 2014, Renal biopsies were evaluated using the International Society of Nephrology/Renal Pathology Society classification (ISN/RPS), and scored for Activity Index and Chronicity Index; Clinical responders (CR) were required to have ≥50% reduction in proteinuria, normal or improved renal function, and inactive urinary sediment. Histopathological responders (HR) were required to have ≥50% improvement in Activity Index In addition, 40 age and sex matched healthy persons as a control group were enrolled in the study. The GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Novel serum biomarkers; Endothelin-1 (ET-1), cystatin C, beta-2 microglobulin (B2M), galectin-3 (Gal-3) and alpha-1-acid glycoprotein (AAG) were collected. Urine samples from patients were collected within 2 months of kidney biopsy and assayed for the urinary biomarkers Endothelin-1 (ET-1), α1-acid glycoprotein (AAG), Cystatin C (CysC) and beta-2 microglobulin (B2M). Renal disease activity was estimated using the British Isles Lupus Assessment Group (BILAG) index. Results: The urinary and plasma biomarkers; ET-1, AAG, Cys C and B2M and GAL-3 were statistically significantly higher in patients with LN compared to controls that is reflective of specific histologic features seen in active LN. The combination of ET-1, AAG and CRP levels plus protein: creatinine ratio was excellent in predicting LN activity. The urinary B2M together with ET-1 and AAG plus creatinine clearance was an excellent diagnostic test for LN chronicity. However, plasma and urinary Cys C showed insignificant correlation with chronicity indices with lowest sensitivity and specificity. The statistically significantly high levels of serum and urinary ET-1 and AAG were related to specific histologic findings in LN with significant positive correlations with SLEDAI and chronicity indices in renal biopsy and highest sensitivity and specificity. Notably, these plasma biomarkers were increased linearly as renal function declined whereas urinary ET-1 and AAG rose exponentially. Thus, urinary ET-1 and AAG may be considered as a useful measure of renal inflammatory disease activity while measured renal function is still normal. Nevertheless, urinary and serum B2M exhibit a statistically insignificantly positive correlations and serum GAL-3 show insignificantly statistically negative correlations with SLEDAI and chronicity indices with lowest specificity and sensitivity reflecting the difficulty of being these biomarkers were useful markers for assessing activity and detection of early disease flares in patients with LN. Conventional clinical parameters such as creatinine clearance, proteinuria, urine sediments, anti-dsDNA, and complement levels are not sensitive or specific enough for detecting ongoing disease activity in the LNs and early relapse of nephritis. Conclusions: In this study biomarkers namely; Endothelin -1(ET-1) and α_1-acid glycoprotein (AAG) found to be associated with specific tissue changes observed in conjunction with LN activity and chronicity. The preliminary results suggest that these biomarkers may be part of a panel that in combination may eventually be able to predict histology without the need of an invasive biopsy. Currently, however we try to discover if these promising biomarkers actually alter patient outcomes and improve the lives of the patients with this life-threatening disease complication of SLE