Background/Purpose:

High mobility group box 1 protein (HMGB-1) had been implicated in the pathogenesis of SLE and potentially lupus nephritis (LN).  There is increased expression in the both the glomerulus and mesangium and is found to be increased in the serum of LN patients compared to controls. To further investigate what happens locally in the kidney, we analyzed the urine of active LN patients for HMGB-1.

Methods:

Urine from 61 Einstein Lupus Cohort patients was included in this study. 32 patients had active, biopsy-proven LN, (15 class III or IV, 7 mixed class III/IV+V , 10 class V; all had renal SLEDAI ≥4)  and 29 had inactive, non-LN SLE (general SLEDAI≤2). HMGB-1 was detected by western blot using a polyclonal antibody against it. Band intensities were measured with ImageJ software and HMGB-1 was normalized to albumin for each sample. Urine was then normalized to urine creatinine to account for the volume of each specimen.  All data was analyzed using STATA 10.1

Results:

Of the 61 patients, 90.2% are female and 9.8% are male.  47.5% are Hispanic, 45.9% are Black and 6.6% are of another race/ethnicity. The median age and disease duration were 39y and 7.5y respectively. Overall, LN patients have lower median serum albumin levels (3.6 v 4.1, p<0.001) and higher median protein to creatinine ratios (“uP/C”, 1.22 v 0.11, p<0.001), but there was no statistically significant difference in serum creatinine or GFR when compared to those with inactive SLE.

Median normalized urine HMGB-1 was significantly elevated in LN patients compared to inactive SLE (53.81 v 9.46, p<0.001). A difference in median levels was also seen between the classes.  There was a significant difference between proliferative and membranous disease (33.4 v 138.8, p=0.003) and there seemed to be increased levels between mixed and membranous disease (47.5 v 138.8, p=0.07). However there was no significant difference between proliferative and mixed LN (33.4 v 47.5, p=0.21)

uP/C was associated with urinary HMGB-1 (r=0.52, p<0.001), but across the classes this was true only for membranous disease (r=0.71, p=0.022, proliferative, p=0.63; mixed, p=0.34). This is despite the fact that median uP/C was highest in mixed disease as compared membranous and proliferative (2.82 v 1.75 v 0.70, p=0.06).

Conclusion:

This is the first study to look at urinary HMGB-1 levels in lupus nephritis. Levels are significantly higher in active LN patients compared to inactive SLE. Levels may be associated with class where the highest levels were seen in membranous disease. While this was correlated to uP/C in the membranous group, it was neither correlated in the mixed group, despite having higher levels of proteinuria, nor in the proliferative group, where there was also elevated urinary protein though not to the level of the other groups. Therefore it is possible that the same process that drives proteinuria in membranous disease is driving elevated HMGB-1 levels.