Researchers at Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, have recently proposed a Renal Activity Index for Lupus (RAIL), incorporating traditional and novel urinary biomarkers (UBMs) to quantify lupus nephritis (LN) activity.1 The development of this scale, once further validated, will give clinicians the ability to verify LN activity without the need for an invasive kidney biopsy. These results were recently published in Arthritis Care & Research.
Prior research has shown that several UBMs appear to correlate with distinct histologic changes in LN, noting that levels of several markers change in response to disease activity status or in response to treatment.2 Thus, researchers aimed to select several of these UBMs, in conjunction with traditional measures of LN, to formulate a disease activity index that may accurately provide a quantification of histologic inflammation that is historically only provided with invasive biopsy.
Study participants included in data analysis of this cross-sectional study were all diagnosed with juvenile-onset systemic lupus erythematosus (SLE) who had kidney biopsy results as part of standard of care. At point of kidney biopsy, random urine samples were collected for UBM testing, and patients were then prospectively followed. Treatment for LN was given at time of urine collection and biopsy, according to the patient’s attending physician. Markers of LN progression including glomerular filtration rate (GFR), random urine protein to creatinine ratio, and serum creatinine were recorded.
High Yield Data Summary
- The Renal Activity Index for Lupus (RAIL) scale, utilizing urinary biomarkers of lupus nephritis (LN), was developed by researchers to noninvasively measure inflammation in LN
- Index accuracy appears to be minimally influenced by LN chronicity and concurrent use of medications, including those targeting the renin-angiotensin-aldosterone system
To further assess disease activity, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were also completed and served as measures of LN damage and clinical activity.
A single nephropathologist interpreted histological findings on kidney biopsies of all study participants in a blinded fashion, using the ISN/RPS classification. The National Institutes of Health Chronicity Index (NIH-CI) was scored to quantify LN damage as seen on kidney biopsy, while the National Institutes of Health activity index (NIH-AI) was used to quantify acute glomerular injury.
UBMs considered in this study included: neutrophil gelatinase–associated lipocalin (NGAL), monocyte chemotactic protein 1 (MCP-1), ceruloplasmin, adiponectin, hemopexin, kidney injury molecule 1 (KIM-1), alpha-1-acid glycoprotein (AAG), transforming growth factor β (TGFβ), hepcidin, lipocalin-like prostaglandin D synthase (L-PGDS), transferrin, vitamin D binding protein (VDBP), microalbumin, cystatin C, endothelial protein C receptor (EPCR), and liver-type fatty acid binding protein 1 (L-FABP).
Forty seven patients with LN were prospectively followed in the study, with a mean ± SD age of 15.7 ± 3.01 years, mean extrarenal SLEDAI score of 9.7 ± 8.20, and interval time between kidney biopsy and urine collection of 0 ± 3 days. SDI renal scores were positive in 32% of the patients. Resultant quality of biopsy specimens limited assignment of NIH-AI, TIAI, and NIH-CI scores to every sample, so these scores were only available for 41, 32, and 40 of the biopsies, respectively.
After analyzing levels of UBMs, researchers found that GAL, MCP-1, KIM-1, and L-PGDS were all elevated in urine samples of patients who had kidney biopsy evidence of endocapillary hypercellularity. The UBMs NGAL, KIM-1, and MCP-1 were also found in higher concentrations in the urine of patients with tubular cell flattening and necrosis on kidney biopsy. NGAL, but not MCP-1 or KIM-1, was elevated in patients with tubular cell pyknosis and epithelial cells in the tubular lumen on biopsy.
NGAL was moderately correlate with GFR, and the majority of UBMs were weakly correlated (Pearson’s correlation coefficient 0.2 ≤ r < 0.4) with the protein to creatinine ratio. UBM levels were differentially associated with each other. KIM-1 was the single best UBM for capturing LN-activity (NIH-AI) status (AUC 0.86 [95% CI 0.74–0.98]). GFR was a good predictor of LN-activity status.
Mean levels of L-FABP were significantly reduced in LN class 3, 4, or 5 as compared to LN class 2 (0.24 [95% confidence interval [95% CI 0.16–0.36] vs 0.97 [95% CI 0.26–3.62]; P=.05). “Taken together, urine L-FABP levels >1.0 decreased the likelihood of the presence of class 3, 4, or 5 LN by 30% (negative LR 0.2), while cystatin C levels >3.3 decreased the likelihood of LN class 3, 4, or 5 by about 23% (negative LR 0.29),” the authors stated.
Multiple logistic modeling was used in a stepwise manner to identify NGAL, ceruloplasmin, MCP-1, adiponectin, hemopexin, and KIM-1 as the most fit predictors of LN-activity, using both the NIH-AI and TIAI. These UBMs were subsequently included in the RAIL index. After data analyses, traditional measures of LN disease activity were not found to best predict biopsy-proven LN status.
[Proposed RAIL Score] = − 4.29 − 0.34 × NGAL − 0.06 × ceruloplasmin + 0.89 × MCP-1 + 0.18 × adiponectin − 0.65 × hemopexin + 0.62 × KIM-1
A RAIL score of ≥0.39 should correctly identify 90% of all cases with high LN-activity status, with a false positive rate controlled at 14%, according to study researchers1
Summary and Clinical Applicability
RAIL was developed by researchers utilizing urinary biomarkers of LN as a way noninvasively assess degrees of LN inflammation.
“If confirmed in ongoing experiments, the RAIL will allow for more effective and personalized monitoring of LN and its therapy,” the authors concluded.
Limitations and Disclosures
- Cutoff scores for the RAIL need to be determined for various patient subgroups
- Patients in this study received a variety of medication regimens, and as such these study findings will need to be confirmed in a larger cohort
Dr Brunner has received consulting fees, speaking fees, and/or honoraria from Biogen/Idec, Bristol-Myers Squibb, GlaxoSmithKline, and MedImmune/AstraZeneca. Dr Rovin has received consulting fees, speaking fees, and/or honoraria from Biogen/Idec, Bristol-Myers Squibb, Eli Lilly, Genentech, GlaxoSmithKline, MedImmune/AstraZeneca, and Questcor.
- Brunner HI, Bennett MR, Abulaban K, et al. Development of a novel renal activity index of lupus nephritis in children and young adults. Arthritis Care Res (Hoboken). 2016;68(7):1003-11.
- Brunner HI, Bennett MR, Mina R, Suzuki M, Petri M, Kiani AN, et al. Association of noninvasively measured renal protein biomarkers with histologic features of lupus nephritis. Arthritis Rheum 2012;64:2687–97.