□ CASE REPORT □
Changes in the Urinary Excretion of β2-Microglobulin
(β2MG) and N-acety-β-D-glucosaminidase (NAG)
during Treatment for Lupus Nephritis
Takahiro Masuda1, Tetsu Akimoto
1, Yasuhiro Ando
1, Yoshihiko Ueda2, Wako Yumura1and Eiji Kusano
1, Takahisa Kobayashi1, Daishi Meguro
Tubulointerstitial involvement in the kidneys is frequently found but it is a less emphasized feature of lu-
pus nephritis (LN). Recent studies have shown increases in the urinary excretion of β2-microglobulin (β2
MG) and N-acetyl-beta-D-glucosaminidase (NAG), which are considered to indicate the presence of tubu-
lointerstitial damage, particularly in cases of LN. However, the changes in these urinary parameters during
the clinical course of LN have not yet been fully clarified. In this report, we describe the changes in the uri-
nary excretion of β2MG and NAG during immunosuppressive treatment combined with double filtration plas-
mapheresis in a case of LN.
Key words: β2-microglobulin, N-acety-beta-D-glucosaminidase, lupus nephritis, tubulointerstitial nephritis,
double filtration plasmapheresis
Systemic lupus erythematosus (SLE) is a chronic autoim-
mune disease with multiple organ involvement. Renal mani-
festation, i.e., lupus nephritis (LN), is one of the most im-
portant organ deficiencies in SLE (1). The formation of im-
mune complexes within the glomeruli seems to be a central
event in the pathophysiology of LN. Tubulointerstitial in-
volvement is another well recognized but less frequently
emphasized abnormality in LN (2, 3). Several proteins other
than albumin excreted in the urine such as β2-microglobulin
(β2MG) and N-acetyl-beta-D-glucosaminidase (NAG) are
considered useful parameters for the evaluation of renal tu-
bulointerstitial lesions (2, 4, 5).
We herein describe a case of LN associated with the ele-
vation of β2MG and NAG. A renal biopsy revealed the
presence of tubulointerstitial damage, and the urinary excre-
tion of these molecules decreased along with an improve-
ment of proteinuria. To our knowledge, this is the first re-
port demonstrating the changes of these molecules during
treatment for LN.
A 47-year-old man was admitted to our hospital in March
2003 with the chief complaint of progressive swelling of his
legs. One year before admission, he developed a skin rash in
a sun-exposed area and had been suffering from intermittent
polyarthritis. He had no apparent past history of kidney dis-
ease. On admission, he looked well and also appeared alert
and oriented. Laboratory findings on admission are listed in
Table 1. Based on the revised American Rheumatic Associa-
tion criteria for SLE (6), he was diagnosed to have SLE
with serum antinuclear antibodies (ANA), anti-Smith anti-
body (αSmab), and clinical pictures, including photosensi-
tivity, intermittent polyarthritis, and nephrotic syndrome.
The renal biopsy revealed segmental endocapillary prolifera-
tion associated with mesangial alterations (Fig. 1 Panel A)
and interstitial infiltration of inflammatory cells (Fig. 1
Panel B). In addition to mesangial proliferation, subepithe-
lial and subendothelial deposits were also confirmed by
１Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke and
cal University Koshigaya Hospital, Koshigaya
Received for publication July 23, 2007; Accepted for publication November 2, 2007
Correspondence to Dr. Tetsu Akimoto, firstname.lastname@example.org
２Department of Pathology, Dokkyo Medi-
F i g u r e 1 . A : T h e r e n a l b i o p s y s p e c i me n i n t h i s c a s e s h o w i n g e n d o c a p i l l a r y h y p e r c e l l u l a r i t y , c a p i l -
l a r y d o u b l e c o n t o u r s , w i r e l o o p l e s i o n . B : I n f i l t r a t i o n o f n u me r o u s i n f l a mma t o r y c e l l s w a s s e e n i n
t h e i n t e r s t i t i u m ( a r r o w ) . A t r o p h i c c h a n g e s o f t u b u l e s w e r e a l s o d e mo n s t r a t e d . P e r i o d i c - a c i d S c h i f f
( P A S ) s t a i n . C : Me s a n g i a l p r o l i f e r a t i o n , s u b e p i t h e l i a l ( a r r o w h e a d ) a n d s u b e n d o t h e l i a l d e p o s i t s ( a r -
r o w ) w e r e s e e n b y e l e c t r o n mi c r o s c o p y o f r e n a l b i o p s y s p e c i me n ( × 1 8 , 0 0 0 ) . T h e s c a l e b a r i s i n d i -
c a t e d i n e a c h p a n e l ( A , B ) .
T a b l e 1 . L a b o r a t o r y D a t a o n A d o mi s s i o n
electron microscopy (Fig. 1 Panel C). As a result, we made
a final diagnosis of diffuse proliferative LN Class IV-S (A/
C) + V based on the classification criteria of the Interna-
tional Society of Nephrology/ Renal Pathology Society
(ISN/RPS) 2003 (7).
From the 21st hospital day, intravenous methylpredniso-
lone (mPSL), 1,000 mg, was given daily for three days, fol-
lowed by 40 mg prednisolone (PSL) per day orally. As
shown in Fig. 2, the initial decrease in the daily urine pro-
tein was temporal and hypoalbuminemia persisted. Then, we
decided to give him an intravenous pulse dose of cyclophos-
phamide (0.5 g/m2body surface area). Since his nephrotic
state persisted, we applied therapeutic apheresis. Double fil-
tration plasmapheresis (DFPP), which filtered 3 L of plasma
with 25 g of supplemental albumin, was performed on the
67th, 70th, 76th, and 83rd hospital days. In each DFPP ses-
sion, an ethylene-vinylalcohol membrane plasma fractionator
with an average pore size of 0.025 μm and effective surface
area of 1.7 m2(EC-40W; Asahi Medical Co., Tokyo, Japan)
was used together with a hollow fiber polyethylene mem-
brane plasma separator with an average pore size of 0.3 μm
and an effective surface area of 0.8 m2(OP-08; Asahi Medi-
cal Co., Tokyo, Japan). After the initiation of DFPP, the uri-
nary protein excretion gradually decreased and an improve-
ment in hypoproteinemia was also seen. The urinary excre-
tion of β2MG, NAG decreased along with an improvement
in the serological abnormalities (Fig. 2). Along with the re-
mission of nephrotic syndrome, PSL was gradually tapered
to 5 mg per day.
Tubulointerstitial changes in renal tissue have been found
in conjunction with glomerular disease in from 38% to 66%
of renal biopsy specimens from patients with LN (2, 3). The
extraglomerular deposits of immune complexes are thought
to mediate the development of various degrees of damage
within the tubulointerstitium (8). The pathological and clini-
cal scenario of tubulointerstitial damage can also occur in
combination with disease of diverse etiology, including in-
fectious, drug-related, metabolic, obstructive, habitual, toxic
mechanisms and other collagen diseases such as Sjögren
syndrome (9). However, there is no available information
suggesting such a possibility in this case. On the other hand,
the nephrotic range of proteinuria observed in the present
case might play a role in the observed interstitial damage
since it is considered that high urinary protein content may
elicit proinflammatory and profibrotic effects that could con-
tribute to tubulointerstitial damage and loss of renal function
An increased amount of urinary β2MG, which is synthe-
sized by most nucleated cells and is filtered freely in the
glomerular basement membrane, has also been considered to
reflect the renal inflammatory activity in patients with LN
(2). In addition, an increased activity of NAG has been con-
sidered to be an early indicator of tubular epithelial damage
and therefore determination of the urinary NAG activity may
be a useful supplement to a routine biochemical analysis of
urine in cases of LN (5). However, the longitudinal changes
in the urinary excretion of these molecules during the treat-
ment of LN still remain to be elucidated.
F i g u r e 2 . H o s p i t a l c o u r s e o f t h i s c a s e . A f t e r t h e i n i t i a t i o n o f
D F P P , u r i n a r y p r o t e i n e x c r e t i o n g r a d u a l l y d e c r e a s e d a n d a n
i mp r o v e me n t i n h y p o p r o t e i n e mi a w a s s e e n . T h e u r i n a r y e x ?
c r e t i o n l e v e l s o f β 2 MG a n d N A G w e r e 1 0 , 7 4 6 μ g / l a n d 3 4 . 3
U / g C r , a n d d e c r e a s e d t o 1 5 6 μ g / l a n d 1 1 . 6 U / g C r , r e s p e c t i v e ?
l y , a l o n g w i t h a n i mp r o v e me n t i n s e r o l o g i c a l p a r a me t e r s o f
l u p u s .
The present report clearly demonstrated for the first time
that the urinary excretion of β2MG and NAG decreased
along with an improvement of proteinuria during the treat-
ment. These observations suggest the prompt recovery of the
tubulointerstitial damage probably induced by the high uri-
nary protein. Therefore, the monitoring of these urinary pro-
teins seems to be useful for evaluating the effect of treat-
ment of LN as well as the disease activity within the inter-
stitium. Alternatively, the latent relationship between the
changes in the urinary excretion of β2MG and NAG and the
subsequent outcome of LN needs to be elucidated, since re-
cent studies suggest that not only glomerulopathy but also
tubulointerstitial lesions play a role in making an accurate
prognosis of many forms of glomerular disease, including
LN (2, 3, 11, 12).
Non-specific immunosuppression by corticosteroids and
cytotoxic agents remains the gold standard treatment for LN
(13), and no clear advantage has been demonstrated by per-
forming therapeutic apheresis as a routine treatment for LN.
However, there are still several anecdotal reports suggesting
a beneficial effect of apheresis as an adjunct to conventional
immunosuppressive treatment for removing immune com-
plexes, autoantibodies, inflammatory cytokines, and other
unrecognized mediators in cases of LN (1, 14). In the pre-
sent case, we initially treated with corticosteroid, however,
the elevation of ANA and αSmab persisted, and the decrease
in the urine protein was temporary even after the administra-
tion of cyclophosphamide. We therefore decided to apply
therapeutic apheresis as an adjunct treatment with expecta-
tion of removal of several putative humoral factors that
might play a major role in LN.
The choice of the mode of apheresis could be an impor-
tant determinant of the beneficial and adverse effects of
apheresis. Indeed, there is a potential risk for transmission
of disease especially when fresh frozen plasma is used as re-
placement fluid (15). Conversely, it is reported that the treat-
ments in which albumin is administered as volume replace-
ment fluid are associated with fewer adverse reactions when
compared to those using fresh frozen plasma (1). We there-
fore chose DFPP as an adjunct treatment for lupus nephritis
in our case. It may be difficult to evaluate the impact of
DFPP exclusively in our present cases since it was used in
combination with immunosuppressive treatments. However,
the rapid improvement in the clinical parameters after DFPP,
i.e., a further decrease in the urinary protein levels along
with an improvement in the symptoms of hypoproteinemia,
suggests that DFPP may have facilitated the recovery of
above described renal injuries.
1. Mistry-Burchardi N, Schönermarck U, Samtleben W. Apheresis in
lupus nephritis. Ther Apher 5: 161-170, 2001.
2. Tsai CY, Wu TH, Yu CL, Lu JY, Tsai YY. Increased excretion of
β2-microglobulin, IL-6, and IL-8 and decreased excretion of
Tamm-Horsfall glycoprotein in urine of patients with active lupus
nephritis. Nephron 85: 207-214, 2000.
3. O’Dell JR, Hays RC, Guggenheim SJ, Steigerwald JC. Tubu-
lointerstitial renal disease in systemic lupus erythematosus. Arch
Intern Med 145: 1996-1999, 1985.
4. Hayashi M, Ueda Y, Hoshimoto K, et al. Changes in urinary ex-
cretion of six biochemical parameters in normotensive pregnancy
and preeclampsia. Am J Kidney Dis 39: 392-340, 2002.
5. Erdener D, Aksu K, Bicer I, Deganavsargil E, Kutay FZ. Urinary
N-acetyl-β-D-glucosaminidase (NAG) in lupus nephritis and rheu-
matoid arthritis. J Clin Lab Anal 19: 172-176, 2005.
6. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for
the classification of systemic lupus erythematosus. Arthritis
Rheum 25: 1271-1277, 1982.
7. Weening JJ, D’Agati VD, Schwartz MM, et al. International Soci-
ety of Nephrology Working Group on the Classification of Lupus
Nephritis; Renal Pathology Society Working Group on the Classi-
fication of Lupus Nephritis. The classification of glomerulonephri-
tis in systemic lupus erythematosus revisited. Kidney Int 65: 521-
530, 2004 (erratum in: Kidney Int 65: 1132, 2004).
8. Brentjens JR, Sepulveda M, Baliah T, et al. Interstitial immune
complex nephritis in patients with systemic lupus erythematosus.
Kidney Int 7: 342-350, 1975.
9. Toto RD. Acute tubulointerstitial nephritis. Am J Med Sci 299:
10. Kuusniemi AM, Lapatto R, Holmberg C, Karikoski R, Rapola J,
Jalanko H. Kidneys with heavy proteinuria show fibrosis, inflam-
mation, and oxidative stress, but no tubular phenotypic change.
Kidney Int 68: 121-132, 2005.
11. Hill GS, Delahousse M, Nochy D, Mander C, Bariety J. Protein-
uria and tubulointerstitial lesions in lupus nephritis. Kidney Int 60:
12. Singh AK, Ucci A, Madias NE. Predominant tubulointerstitial lu-
pus nephritis. Am J Kidney Dis 27: 273-278, 1996.
13. Houssiau FA. Management of lupus nephritis: An update. J Am
Soc Nephrol 15: 2694-2704, 2004.
DOI: 10.2169/internalmedicine.47.0464 Download full-text
14. Madore F, Lazarus JM, Brady HR. Therapeutic plasma exchange
in renal disease:J Am Soc Nephrol 7: 367-386, 1997.
15. Laskus T, Cianciara J, Slusarczyk J. Follow-up study of an out-
break of non-A and non-B hepatitis in plasmapheresis unit. Liver
10: 49-53, 1990.
Ⓒ 2008 The Japanese Society of Internal Medicine