Original Paper
Nephron 2000;85:207–214
Increased Excretions of ß2-Microglobulin,
IL-6, and IL-8 and Decreased Excretion of
Tamm-Horsfall Glycoprotein in Urine of Patients
with Active Lupus nephritis
Chang-Youh Tsai a Tsai-Hung Wu b Chia-Li Yu c Jia-Yu Lu a
Ying-Yang Tsai a
Sections of a Allergy, Immunology and Rheumatology, and b Nephrology, Department of Medicine,
Taipei Veterans General Hospital, National Yang-Ming University, Taipei, and c Department of Medicine,
National Taiwan University Hospital, Taipei, Taiwan
Key Words
Interleukin 6 W Interleukin 8 W Lupus nephritis W
ß2-Microglobulin W Renal tubular function W
Tamm-Horsfall glycoprotein
Abstract
Tubulointerstitial nephritis is a less frequently recog-
nized but important complication of systemic lupus ery-
thematosus. We have investigated the cytokine ß2-micro-
globulin (ß2M) and Tamm-Horsfall glycoprotein (THG)
excretions in the urine of systemic lupus erythematosus
patients to identify indices for evaluation of tubulointer-
stitial inflammation in lupus nephritis (LN). Daily urine
was collected from 15 patients with active LN, from 12
patients with inactive LN, and from 17 normal subjects.
The amounts of soluble interleukin (IL) 2 receptor, IL-6,
IL-8, ß2M, and THG in urine were measured. ß2M and
THG were regarded as indicators of proximal and distal
renal tubule function, respectively. The urinary excre-
tions of IL-6 and IL-8 were significantly higher in patients
with active LN than in those with inactive LN and in nor-
mal individuals. The excretion of soluble IL-2 receptor in
all three groups of subjects was not significantly differ-
ent. On the other hand, the excretion of ß2M in patients
© 2000 S. Karger AG, Basel
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0028–2766/00/0853–0207$17.50/0
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E-Mail karger@karger.ch Accessible online at:
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Accepted: November 18, 1999
with LN was significantly higher than that in normal indi-
viduals. The excretion of ß2M in patients with active or
inactive LN was not significantly different. The THG
excretion was lower in patients with active LN and tubu-
lointerstitial inflammation as compared with patients
with inactive LN or normal individuals. Six patients
underwent pulse cyclophosphamide therapy during the
course of experiments. Five of them showed a decrease
in IL-8 and IL-6 excretions in urine after the treatment.
The excretions of ß2M and THG in urine, in addition to
IL-6 and IL-8, can reflect the renal inflammatory activity
in patients with lupus tubulointerstitial nephritis as well
as in those having lupus glomerulonephritis.
Copyright © 2000 S. Karger AG, Basel
Introduction
Glomerulonephritis (GN) is a common complication
in patients with systemic lupus erythematosus (SLE). The
severity of the glomerular lesions may determine the prog-
nosis of the patients with SLE [1, 2]. Tubulointerstitial
involvement of the kidneys is another well-recognized but
less frequently emphasized abnormality in SLE [3–6].
The lesion occurs rarely in SLE without glomerular in-
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Chang-Youh Tsai, MD, PhD
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Section of Allergy, Immunology, and Rheumatology, Department of Medicine
Taipei Veterans General Hospital
No. 201, Sec 2, Shih-Pai Road
Taipei 112 (Taiwan)
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volvement [7, 8]. Clinically, renal biopsy is usually per-
formed for the diagnosis and therapeutic guidance for
lupus nephritis (LN). Results from renal biopsies have
indicated that LN often presents with transition from one
histologic class to another at successive follow-ups [1, 2,
9–11]. Consequently, serial renal biopsies are necessary to
evaluate the accurate activity of LN. However, perform-
ing sequential renal biopsies in SLE patients is neither
desirable nor practical. Some of the routine laboratory
parameters such as urinary sediments, serum level of
DNA-anti-DNA immune complexes, and complements
may be helpful in determining the activity of LN [12–14].
Nevertheless, the parameters are not always easy to obtain
because serial blood drawings are necessary for some of
these items. Besides, fluctuations of these parameters are
frequently reflecting overall renal inflammation including
glomerular as well as tubulointerstitial pathology. Deter-
mination of the amount of immune process related mole-
cules in urine would thus be an alternative way to evaluate
the severity of renal inflammation in LN. These mole-
cules include interleukin (IL) 1, IL-6, IL-8, tumor necrosis
factor alpha (TNF-·), transforming growth factor beta,
IL-2 receptor (IL-2R), TNF inhibitors, and type IV colla-
gen [15–22].
Tamm-Horsfall glycoprotein (THG), a 7 ! 107-dalton
macromolecule, is synthesized exclusively by epithelial
cells in thick ascending limb of the loop of Henle and early
distal convoluted tubule of the kidney [23, 24]. The
macromolecule is directly excreted in the urine [25] and
can be used as a specific marker for distal renal tubular
cells. ß2-Microglobulin (ß2M), a low molecular weight pro-
tein (11,818 daltons), forming the light chain of the major
histocompatibility complex class I molecule [26], is nor-
mally eliminated by glomerular filtration followed by
reabsorption and catabolism in the proximal renal tubular
cells [27]. The increased urinary excretion of ß2M has
been used to diagnose tubulointerstitial renal lesions [28].
In the present study, we measured the proinflammatory
cytokines or cytokine receptor such as IL-8, IL-6, soluble
IL-2R (sIL-2R), and renal tubule associated molecules,
THG and ß2M, in the urine of patients with LN in order
to understand further the pathophysiology of the disease.
Patients and Methods
Patients and Controls
Twenty-seven patients (female:male ratio 25:2) fulfilling four or
more of the 1982 American Rheumatism Association revised criteria
for the classification of SLE [29] were enrolled in the present investi-
gation. All of the patients had disease complicated by nephritis as
208 Nephron 2000;85:207–214
diagnosed by renal biopsy. The activity of LN at the time of study
was judged by the following indices: (1) the presence of proteinuria;
(2) abnormal urinary sediments; (3) increased serum titer of anti-
dsDNA; (4) decreased serum levels of complements, and (5) presence
of GN and tubulointerstitial changes including tubular dilatation or
atrophy, inflammatory cell infiltration, and/or interstitial fibrosis as
demonstrated by renal biopsy. Fifteen patients were classified as hav-
ing active LN, while 12 patients were classified as having inactive
LN. Findings of urinary sediments, serum titers of anti-dsDNA, cre-
atinine clearance rates, and histopathological classifications of these
patients are listed in table 1. Seventeen normal individuals served as
controls. Twenty-four-hour urine was collected from patients and
controls. After pooling and recording the volume of the urine, 5-ml
urine samples were stored at –20 ° C for enzyme-linked immunosor-
bent assay (ELISA).
ELISA for IL-6, IL-8, sIL-2R, and ß2M
ELISA kits for IL-6 and IL-8 were purchased from R & D Systems
(Minneapolis, Minn., USA), for sIL-2R from AMAC (Westbrook,
Me., USA), and for ß2M from T Cell Sciences (Cambridge, Mass.,
USA). The minimal detectable doses were 3.5 pg/ml for IL-6,
18.1 pg/ml for IL-8, 210 pg/ml for sIL-2R, and 0.25 Ìg/ml for ß2M.
The detailed procedures for the detection of these molecules were
described in individual instructions provided by the manufacturers.
Purification of THG from Pregnancy Urine
Urine was collected from normal pregnant women after the 6th
month of conception. The purification of THG was carried out as
described previously [30, 31]. Briefly, a batch volume of pregnancy
urine was made 0.58 M with NaCl and stirred for 30 min, centri-
fuged at 2,000 g for 10 min, and the supernatant discarded. The pre-
cipitate was dissolved in alkaline distilled water (pH 9.0, adjusted
with 1 M NaOH) and centrifuged to remove insoluble substances.
The supernatant was then made 0.58 M NaCl. The precipitate was
again dissolved in alkaline distilled water (pH 9.0) and left stirred
overnight at 4 ° C, centrifuged, and the precipitate discarded. The
solution was dialyzed extensively against distilled water at 4 ° C,
lyophilized, weighed, and dissolved in phosphate-buffered saline
(PBS; pH 9.0). This THG solution was used for standard curve titra-
tion in the ELISA of THG. The identification of THG including its
purity and molecular weight was made using 10% sodium dodecyl
sulfate-polyacrylamide gel electrophoresis.
ELISA for THG
Polystyrene microtiter plates (Corning Glass Works, Corning,
N.Y., USA) were incubated with 100 Ìl/well of sheep IgG antihuman
uromucoid antibodies (20 Ìg protein/ml; Biodesign International,
Kennbunk, Me., USA) in coating buffer (50 mM ) carbonate buffer,
pH 9.6) at 4 ° C for 24 h before washing three times with 0.05%
Tween 20 in 0.01 M PBS (pH 7.2). The wells were subsequently
coated with 0.2% bovine serum albumin in PBS (pH 7.2) at room
temperature for 4 h. After washing three times, to each well was add-
ed 100 Ìl of standard THG solutions (5, 25, 125, and 625 ng/ml) or
1:4 diluted (PBS) urine and incubated at 37 ° C for additional 2 h.
After washes, each well was filled with 100 Ìl of 1:4,000 diluted
horseradish peroxidase conjugated sheep antiuromucoid antobodies
(Biodesign International) and incubated at 37 ° C for 2 h. After three
times of washing, color was developed by reacting wells with 100 Ìl
of substrate solution (0.01 g o-phenylenediamine dihydrochloride in
19 ml of PBS and 1 ml of 0.3% H2O2). The mixture was incubated at
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 Table 1. Comparisons of renal pathology, urine sediment, serum level of anti-dsDNA, and creatinine in active and
inactive LN

Patient Renal pathology Urine sediment, cells high-power field Anti-dsDNA Creatinine
No. IU/ml clearance
classa ICIb TICc red white casts
ml/min
blood cells blood cells

Active LN
1 III + D/F 3–5 6–10 – 90 58
2 IV + D/F 1+ 11–20 granular 1–2 74 81
3 IV ++ D/F 6–10 1+ – 1300 60
4 IV +++ F 1+ 6–10 granular 0–2 1300 80
5 IV + F 1+ 8–10 – 220 5.5
6 IV + F 0–2 11–20 – 1300 113
7 III + D 10–12 1–3 – 105 33
8 IV +++ D 4+ 6–10 – 91 58.6
9 IV +++ F 0 1+ – 1300 27
10 IV ++ F 0–2 36–50 – 1300 26.2
11 IV ++ 10–12 2+ – 1300 47
12 IV ++ F 6–10 6–10 hyaline 0–2 1300 12
13 III + D 6–10 6–10 – 280 85
14 IV ++ F 1+ 3–5 – 1300 37
15 III ++ D 3–5 11–20 epithelial 6–10 290 34.9
Inactive LN
1 V + F 0–2 0–2 – 64 11
2 II – 0 3–5 – !30 30
3 II – D 0–2 0–2 – !30 56
4 II – 0–2 3–5 – !30 94
5 II – 0 3–5 – !30 10
6 II – 0–1 1–2 – !30 42
7 II + 0–2 3–5 – !30 33
8 II – 0–2 3–5 – !30 67
9 V ++ D 0–2 3–5 – 50 69.8
10 II – 0 0–2 – !30 52
11 II – 0 0 – !30 57
12 V + F 3–5 3–5 – !30 110

a According to the WHO classification for lupus nephritis.

b Interstitial cell infiltration: – = No significant cellular infiltration in interstitium; + = a few mononuclear cells; ++ =
scattered mononuclear cells and polymorphonuclear cells; +++ = heavy mononuclear as well as polymorphonuclear
cell infiltration.
c Tubulointerstitial change: D = Tubular dilatation/atrophy; F = interstitial fibrosis.

37 ° C for 20 min, and the reaction was stopped by adding 50 Ìl of Results

4 M H2SO4. The concentration was measured by a spectrophotome-
ter at OD492 nm.
Statisticals
The results are presented as mean values B SD. Differences
among groups were assessed by Kruskal-Wallis test for nonparamet-
ric analysis of variance or Wilcoxon rank sum test using SPSS com-
puter software. Significance was set at p ! 0.05.
Active and Inactive LN
Conspicuously abnormal urinary sediments (erythro-
cytes, white blood cells, or casts) were present in active
but not in inactive LN (table 1). The serum titer of anti-
dsDNA antibodies in the active LN group was much high-
er than in the inactive LN group. However, the creatinine
clearance rate was variable in either group (table 1). The

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Fig. 1. Comparison of daily protein excretions in urine in patients
with active and inactive LN. The mean value in each group is shown
by a horizontal line. The p value was calculated by the Wilcoxon rank
sum test.
daily amount of proteinuria in active LN was significantly
higher (p = 0.0025 as calculated by nonparametric
Wilcoxon rank sum test) than in inactive LN (fig. 1).
Daily Urinary Excretions of IL-6, IL-8, and sIL-2R
in Patients with Active and Inactive LN and in
Normal Subjects
IL-6, IL-8, and sIL-2R are frequently found at the site
of immune system-mediated inflammation. The amount
of the molecules can reflect the severity of the inflamma-
tory reaction. As shown in figures 2 and 3, the daily uri-
nary excretions of IL-6 and IL-8 were significantly higher
in patients with active LN than in those with inactive LN
(p = 0.034 with regard to IL-6; p = 0.0034 with regard to
IL-8) or in normal controls (p ! 0.001 with regard to both
IL-6 and IL-8; calculations by nonparametric Wilcoxon
rank sum test). The sIL-2R excretion in urine was not sig-
nificantly different among the three groups of subjects
(nonparametric Kruskal-Wallis analysis of variance by
rank), as shown in figure 4. The results have indicated
210 Nephron 2000;85:207–214
Fig. 2. Comparison of daily urinary IL-6 excretions in patients with
active and inactive LN and in normal subjects. The mean value in
each group is shown by a horizontal line. The p values were calcu-
lated by the Wilcoxon rank sum test.
that immunological and inflammatory reactions are
present in the kidneys of patients with LN and can be
reflected by the amount of IL-6 and IL-8 in the urine.
Daily Urinary Excretions of ß2M and THG in Patients
with Active and Inactive LN and in Normal Subjects
We measured the urinary excretions of ß2M and THG
as the indices for proximal and distal tubule functions,
respectively. As shown in table 2, the urinary ß2M excre-
tion in patients with active and inactive LN was much
higher than in normal controls. On the other hand, the
urinary excretion of THG in patients with active LN was
significantly lower than in normal subjects. Among 15
patients with active LN, there were 9 patients with in-
tense cellular infiltration in the interstitium (++ or +++;
table 1). The THG excretion in the urine of these patients
was significantly lower than that of the other 6 patients
without significant interstitial cell infiltration (989.28 B
66.38 vs. 1705.28 B 193.16 Ìg/day; p ! 0.01 as calculated
by nonparametric Wilcoxon rank sum test). Although, the
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Fig. 3. Comparison of daily urinary excretions of IL-8 in patients
with active and inactive LN and in normal subjects. The mean values
in patients with active and inactive LN are shown by a horizontal
line. The p values were calculated by the Wilcoxon rank sum test.
Fig. 4. Comparison of daily urinary excretions of sIL-2R in patients
with active and inactive LN and in normal subjects. The mean value
in each group is shown by a horizontal line. The global p value which
was statistically insignificant was calculated by the Kruskal-Wallis
test for nonparametric analysis of variance.

Table 2. Comparison of daily urinary

excretions of ß2M and THG in controls and Controls Inactive LN Active LN
patients with inactive and active LN (n = 17) (n = 12) (n = 15)

ß2M, Ìg/day 202.10B107.57 2,840.38B1,110.50 4,025.56B1,456.53

p ! 0.001a 1 0.05b ! 0.0001a
THG, Ìg/day 2,286.47B79.77 1,654.02B248.90 1,275.69B384.28
p 1 0.05a 1 0.05b ! 0.01a

a Compared with the controls; the p value was calculated by Kruskal-Wallis test with Dunn
procedure.
b Comparison between inactive and active LN; the p value was calculated by Kruskal-
Wallis test with Dunn procedure.

differentiation of proximal from distal tubular damage
could not be definitely performed on the basis of histo-
pathological observations, these results have suggested
that the impairment of renal tubular function exists more
or less in patients with LN in addition to GN.
Consecutive Determination of Daily Urinary
Excretions of IL-6 and IL-8 in Patients with Active LN
before and after Immunosuppressive Therapy
Because IL-8 is a potent amplifier of acute inflamma-
tion [32] and is rarely found in normal urine (as shown in

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Fig. 5. Daily urinary IL-8 excretion in 6 patients with active LN
before and after two courses of immunosuppressive treatment (cyclo-
phosphamide 0.5 g/m2 within 6 months). The excretion of IL-8 in the
urine decreased in 5 patients. However, the IL-8 excretion in urine
remained high in 1 patient who was treated ineffectively.
figure 3), we measured this molecule in urine as an indica-
tor for renal inflammation. Also, previous investigations
[17] have demonstrated the usefulness of urinary IL-6
measurement in LN. We determined the urinary IL-6 and
IL-8 excretions in 6 patients with active LN before and
after treatment with cyclophosphamide. As shown in fig-
ure 5, the daily urinary IL-8 excretion decreased after
treatment in 5 of the 6 patients. The decrease was also in
parallel with the decrease of anti-dsDNA antibodies and
fading out of urine sediments (data not shown). The only
patient who did not show a decrease in the excretion of
IL-8 was found to be refractory to the immunosuppressive
therapy because she subsequently developed neurological
symptoms that were likely to be relevant to lupus activity.
The urinary IL-6 excretion also showed a similar de-
crease, as the patient underwent immunosuppressive
treatment (data not shown). These results suggested that
the urinary excretion of IL-6 and/or IL-8 is a good indica-
tor of the severity of renal inflammation and can have
therapeutic implications in monitoring the disease activi-
ty in patients with LN.
212 Nephron 2000;85:207–214
Discussion
The normal urine contains small amounts of IL-1 and
many kinds of cytokine inhibitors including IL-1 inhibi-
tor, sIL-2R, and TNF-R [33–37]. In diseases of the kidney
and the urinary tract, IL-1, IL-6, IL-8, TNF-·, and trans-
forming growth factor beta can be detected in the urine
[15–19]. Apparently, these cytokines are derived from
local production of various types of cells participating in
inflammatory reactions in the renal parenchyma.
Glomerular hypercellularity during the acute phase of
glomerular diseases is caused predominantly by intra-
glomerular infiltration of polymorphonuclear neutrophils
and mononuclear cells. However, the precise mechanism
eliciting the infiltration of these cells remains to be solved.
Accumulating evidence has indicated the inflammatory
cytokines such as IL-1 [38], TNF-· [38, 39], and IL-6 [40]
may play important roles in the pathogenesis of glomeru-
lar diseases and are involved in the acute exacerbation of
proliferative GN [15]. Recently, many authors reported
an elevation of urinary IL-6 and IL-8 in active LN [17,
18]. IL-6 is one of the cytokines involved in the inflamma-
tory response as well as in the defense mechanisms of the
host [41]. Our results also showed that the urinary IL-6
excretion can be a good indicator for the activity of LN.
IL-8, a specific and potent neutrophil chemotactic cyto-
kine, acts as a driving force for neutrophil activation dur-
ing the acute inflammatory reaction [32]. Thereby, the
detection of these proinflammatory cytokines in the urine
might be useful for detecting and monitoring the inflam-
matory activity of LN. Histologically, LN is not confined
to the glomerular lesions. 38–66% of the kidney biopsy
specimens from SLE patients are found to have GN in
conjunction with tubulointerstitial involvement [3–6].
The extraglomerular deposition of immune complexes at
the tubular and interstitial sites is believed to mediate the
development of different degrees of renal tubule impair-
ment in SLE [3, 4, 7]. In the present study, several inter-
esting findings have been observed in those with active
LN with tubulointerstitial inflammation: (1) elevated uri-
nary excretion of IL-6 and IL-8, but not sIL-2R, in active
rather than in inactive LN; (2) increased urinary ß2M
excretion in patients with LN as compared with normal
individuals, and (3) decreased urinary THG excretion in
active LN with tubulointerstitial disease. These results
have suggested that both glomerular and tubular lesions
exist in LN and that the lesions are more prominent in
active nephritis. In addition, both proximal and distal
renal tubule functions are impaired in patients with LN,
and the impairment seems to be relevant to the severity of
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glomerular as well as tubulointerstitial inflammation in
the kidney.
Damage of distal renal tubules in LN has been rarely
reported in the literature. We have selected THG, a 7 !
107-dalton macromolecule, as the indicator molecule be-
cause the protein is synthesized exclusively by the epithe-
lial cells of the thick ascending limb of Henle’s loop and
the early distal convoluted tubule [23, 24]. The macromo-
lecule is directly excreted without catabolism in the urine.
Thus, a decrease in the excretion of THG may reflect
purely the abnormality of the distal renal tubules. Because
it is difficult to differentiate distal or proximal tubular
damage even by histopathological examination, THG
quantitation in urine may be a good alternative way for
evaluation of the distal tubular damage. Furthermore,
THG can bind to viruses [42, 43], bacteria [44], bacterial
extract [45], and extracellular matrix [46] and may modu-
late immunologic [31] as well as inflammatory reactions
[30]. Hence, the protein is regarded as an important con-
tributor to the defense mechanism in the urinary system.
The decreased urinary excretion of THG in active LN
with tubulointerstitial damage may represent two clinical
meanings: (1) it reflects the severity of distal renal tubular
dysfunction in SLE patients, and (2) it may represent a
possible etiopathologic factor rendering LN patients sus-
ceptible to urinary tract infections. More direct evidence
may be necessary to support these speculations.
It is believed that the urinary excretion of ß2M is deter-
mined primarily by proximal renal tubular cells. More
than 99.9% of the filtered ß2M is reabsorbed and catabo-
lized in the proximal convoluted tubule [27]. The in-
creased urinary excretion of ß2M in patients with SLE was
reported by Yeung et al. [5]. The present investigation
also confirmed this finding. In addition, the urinary ex-
cretion of ß2M is remarkable in patients with active LN.
In a previous report [20], we have demonstrated an
increased urinary excretion of sIL-2R in patients with
active LN. However, we could not find a similar differ-
ence among patients with active or inactive LN as well as
in normal subjects in the present study, although a ten-
dency of an increased urinary excretion of sIL-2R in
patients with LN was noted. One possible reason for this
discrepancy is that sIL-2R may be a more sensitive index
for lupus GN than for lupus interstitial nephritis because
involvement of humoral as well as cellular factors in these
two conditions is different. Another reason might be that
measuring procedures are different in these two studies.
In the previous sIL-2 study, we did not measure the
amount of sIL-2R in fresh urine. Rather, we measured
this molecule in partially purified urinary protein (5 mg/
ml). sIL-2R molecules might have been ‘refined’ or con-
centrated during these procedures. Conversely, in the
present study, we measured the total amount of sIL-2R in
24-hour urine regardless of protein concentration. So, sIL-
2R molecules were in ‘crude’ status which could lead to
difficulty for measurement. Despite these presumable
causes for discordance, there might be other reasons lead-
ing to the disagreement which deserve further investiga-
tions.
In conclusion, the measurements of daily urinary IL-6
and IL-8 excretions may be more practical methods for
monitoring the progression of LN as compared with serial
renal biopsies. ß2M and THG can be used as sensitive
indicators reflecting the proximal and distal renal tubular
damage in patients with SLE. In addition to glomerular
lesions, both proximal and distal tubular impairments are
present in patients with active LN.
Acknowledgments
This work was supported by grants from National Science Coun-
cil (NSC88-2331-B075-049), Taipei Veterans General Hospital
(VGH-305 and VGH-5), and Yen-Tjing Ling Medical Research
Foundation (CI-87-3).

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