Markers Reflect Kidney Changes in Lupus

By*Nancy Walsh, Staff Writer, MedPage Today
Published: August 02, 2012

Reviewed*by*Zalman S. Agus, MD; Emeritus Professor, Perelman School
of Medicine at the University of Pennsylvania

Histologic features seen on kidney biopsy are currently used as the
standard for the diagnosis of lupus nephritis and are typically used to
guide treatment.

Note that this study suggests that specific urinary biomarkers are
associated with specific tissue changes observed in conjunction with
lupus nephritis activity and chronicity, and may be helpful in the
noninvasive measurement of activity, chronicity, and the presence of
membranous disease.

Combinations of urinary biomarkers reflect the renal tissue changes
occurring in lupus nephritis and ultimately may be useful for
noninvasive disease assessment, researchers suggested.

Four markers together accurately predicted a renal biopsy activity score
of 7 or higher with a sensitivity of 72%, a specificity of 66%, and an
area under the receiver operating characteristic curve (AUC) of 0.85
(95% CI 0.69 to 1), according to Hermine Brunner, MD, of Cincinnati
Children's Hospital, and colleagues.

In addition, three of the markers predicted a biopsy chronicity index
score of 4 or higher, with a sensitivity of 73%, a specificity of 67%,
and an AUC of 0.83 (95% CI 0.67 to 0.93), the researchers reported in
the August Arthritis & Rheumatism.

Those scores are considered cutoffs for poor outcomes, they noted.

Current practice requires kidney biopsy for the diagnosis of lupus
nephritis and for following the effects of treatment.

This is because conventional measures of kidney function such as
proteinuria and glomerular filtration rate are "too inaccurate to
reliably discriminate between the acute inflammatory changes that are
amenable to immunosuppressive therapy and the chronic degenerative
changes that will not improve despite control of [systemic lupus
erythematosus] activity," they explained.

Brunner and colleagues previously identified a group of biomarkers that
correlated well with clinical measures of renal disease, such as the
Systemic Lupus Disease Activity Index–renal domain, but whether these
markers, with or without the traditional measures of kidney function,
also reflected the histologic processes involved has not yet been

So they explored the possible correlations among these factors in 76
patients whose median age was 23 and who had active inflammation and
degeneration on renal biopsy as evidenced by features such as mesangial
and capillary proliferation, cellular crescents, and glomerular

Most of the patients were female, and the majority were receiving
glucocorticoids and other immunosuppressives.

The urinary biomarkers measured included alpha1-acid glycoprotein (AAG),
transferrin (TF), ceruloplasmin (CP), neutrophil gelatinase-associated
lipocalin (NGAL), and monocyte chemotactic protein 1 (MCP-1).

Traditional measures of kidney function included glomerular filtration
rate (GFR), protein-to-creatinine (P:C) ratio, and levels of C3, C4, and
serum creatinine.

On univariate analysis, the researchers evaluated the accuracy, as shown
by the AUC, for each of the biomarkers in identifying biopsy activity
index scores, biopsy chronicity index scores, and the presence of class
V membranous lupus nephritis.

They found good to excellent accuracy (AUC 0.71 or higher) for
predicting high biopsy activity scores for AAG, TF, CP, MCP-1, and P:C
ratio, and excellent accuracy (AUC 0.81 or higher) for glomerular
filtration rate and serum creatinine in predicting high biopsy
chronicity scores.

On multivariate analysis, the combination of markers that predicted the
high biopsy activity score was MCP-1, CP, AAG, and P:C ratio, while the
combination that predicted the high chronicity score was NGAL, MCP-1,
and glomerular filtration rate.

For class V membranous nephritis, the predictors were MCP-1, AAG, TF,
C4, and glomerular filtration rate, with a sensitivity of 75%, a
specificity of 48%, and an AUC of 0.75 (95% CI 0.62 to 0.86).

In discussing the individual biomarkers, the researcher noted that:
MCP-1 is a recognized predictor of lupus nephritis flare and has been
shown in animal studies to influence proteinuria and survival.

The AAG marker is most often linked with histologic findings such as
crescents and mesangial proliferation and is elevated in other
inflammatory diseases of the kidney, functioning as a regulator of the
glomerular capillary wall.

Capillary and mesangial proliferation have been associated with
increases in TF and also in CP, a protein involved in tissue remodeling
after injury to the renal tubules.

Together, these markers "yielded excellent diagnostic abilities" in
lupus nephritis, suggesting that "accurate longitudinal noninvasive
assessment of [lupus nephritis] activity and chronicity is feasible,"
Brunner and colleagues observed.

However, "the presented analyses also suggest that additional markers
are needed to provide the highly accurate (AUC>0.9) diagnostic tests
that are urgently needed by clinicians to help guide [lupus nephritis]
therapy," they wrote.

The authors have been supported by the Alliance for Lupus Research, the
Cincinnati Children's Hospital, the National Institutes of Health, the
Hopkins Lupus Cohort, the National Center for Research Resources, and
the Department of Defense.

Two of the authors are co-inventors on patents for lupus nephritis
biomarker panels, and one has received fees from Abbott and Alere.

Primary source: Arthritis & Rheumatism
Source reference:
Brunner H, et al "Association of noninvasively measured renal protein
biomarkers with histologic features of lupus nephritis" Arthritis Rheum
2012; 64: 2687-2697.

Donna G.

1) Rejoice always, Pray continually, Give thanks in all circumstances,
For this is God's will for you in Christ Jesus. ( I Thessalonians
5:16-18 NIV )

2) ANGELS EXIST, but some times, since they don't all have wings, we
call them FRIENDS......

3) Just because you're in pain, doesn't mean you have to be one!