Human Pathology: Case Reports 13 (2018) 27–32

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Human Pathology: Case Reports

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Case Report

Lupus nephritis with massive subendothelial deposits in a patient with T

autoimmune hepatitis-related cirrhosis
⁎
Natsuki Shimaa, , Keiichi Sumidaa, Hiroki Mizunoa, Toshiharu Uenoa, Masahiro Kawadaa,
Akinari Sekinea, Masayuki Yamanouchia, Rikako Hiramatsua, Noriko Hayamia, Eiko Hasegawaa,
Tatsuya Suwabea, Junichi Hoshinoa,d, Naoki Sawaa, Kenmei Takaichia,d, Kenichi Ohashib,c,
Takeshi Fujiib, Yoshifumi Ubaraa,d
a
Nephrology Center, Toranomon Hospital, Kanagawa, Japan
b
Department of Pathology, Toranomon Hospital, Tokyo, Japan
c
Department of Pathology, Yokohama City University Hospital Graduate School of Medicine, Graduate School of Medicine, Kanagawa, Japan
d
Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan

A R T I C LE I N FO A B S T R A C T

Keywords: A 72-year-old Japanese woman with a history of autoimmune hepatitis-associated liver cirrhosis and porto-
Lupus nephritis systemic shunt was admitted to our hospital for evaluation of renal dysfunction, nephrotic range proteinuria, a
Systemic lupus erythematosus high titer of anti-double-stranded DNA antibody, and hypocomplementemia. Renal biopsy showed massive
Autoimmune hepatitis-associated liver cirrhosis subendothelial deposits (wire loop lesions), and class IV-G (A/C) lupus nephritis was diagnosed.
Portosystemic shunt
Immunosuppressants, such as steroids (including intravenous methylprednisolone pulse therapy) and myco-
Wire loop lesion
phenolate mofetil, could not prevent renal dysfunction. It was assumed that circulating immune deposits pro-
duced in the gastrointestinal tract entered the systemic circulation from the portal vein via the portosystemic
shunt without hepatic clearance, resulting in massive subendothelial and mesangial accumulation compared to
lupus nephritis patients without a shunt and causing renal injury.

1. Introduction
Systemic lupus erythematosus (SLE) is a chronic inflammatory dis-
ease that affects the kidneys in about 50% of patients, with renal in-
volvement being called lupus nephritis (LN). In SLE patients, LN is a
major determinant of morbidity and mortality, and it progresses to end-
stage renal disease (ESRD) despite potent immunosuppressive therapy
[1]. Various factors contribute to development of chronic kidney dis-
ease/ESRD following acute or subacute renal injury in SLE patients,
including inflammation, activation of intrinsic renal cells, cellular stress
and hypoxia, metabolic abnormalities, aberrant tissue repair, and tissue
fibrosis [2]. In patients with LN, deposits of immune complexes are well
known to be more abundant compared to patients with other types of
proliferative glomerulonephritis such as IgA nephropathy. Although
“wire loop” lesions due to deposition of immune complexes are sug-
gestive of LN, the meaning of these structures remains unknown.
We encountered a patient with LN and massive subendothelial
deposits that were far more extensive than in other patients with LN.
The possible pathogenesis of these massive deposits is discussed in re-
lation to this patient's portosystemic shunt and liver cirrhosis.
2. Case report
A 72-year-old Japanese woman was referred to our hospital for
evaluation of rapidly progressive renal dysfunction and nephrotic range
proteinuria. Liver dysfunction was first detected at the age of 60 years.
A definite diagnosis of autoimmune hepatitis (AIH) was made according
to the revised scoring system of the International Autoimmune
Hepatitis Group [score of 16: female (+2), AST ratio (+2), IgG level
(+1), antinuclear antibody (+3), viral markers (+3), drug (+1), al-
cohol (+2) and autoimmune disease (+2)] [3]. Ultrasonography and
contrast-enhanced computed tomography (CT) demonstrated liver cir-
rhosis with a portosystemic shunt including dilatation of paraumbilical
veins. Esophageal varices were treated by endoscopic variceal ligation.

Abbreviations: IC, immune complexes; EDD, electron-dense deposits; SLE, systemic lupus erythematosus; LN, lupus nephritis; ESRD, end-stage renal disease; MPGN, membranoproli-
ferative glomerulonephritis; eGFR, estimated glomerular filtration rate; LM, light microscopy; IF, immunofluorescence; anti-ds-DNA, anti-double-stranded DNA; ITIM, immunoreceptor
tyrosine based inhibitory motif; ISN/RPS, International Society of Nephrology/Renal Pathology Society; RPGN, rapidly progressive glomerulonephritis
⁎
Corresponding author at: Nephrology Center, Toranomon Hospital, Kajigaya 1-3-1, Takatsu-ku, Kawasaki, Kanagawa 213-8587, Japan.
E-mail address: shimanatsuki@jichi.ac.jp (N. Shima).

https://doi.org/10.1016/j.ehpc.2018.04.001
Received 28 January 2018; Received in revised form 24 March 2018; Accepted 3 April 2018
2214-3300/ © 2018 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
N. Shima et al. Human Pathology: Case Reports 13 (2018) 27–32

Table 1
Laboratory data on admission.
Onset Normal range Onset Normal range

White blood cell (/μL) 3800 3200–7900 IgG (mg/dL) 1314 870–1700
Red blood cell (×106/μL) 2.99 3.7–5.7 IgA (mg/dL) 361 110–410
Hemoglobin (g/dL) 9.6 11.3–15.0 IgM (mg/dL) 87.7 35–220
Platelet (×104/μL) 13.9 15.5–35.0 C-reactive protein (mg/dL) 0.3 0.0–0.3
Prothrombin time (%) 83.1 ≧75 C3 (mg/dL) 25 86–160
Activated partial thromboplastin time (sec) 39.1 27.0–40.0 C4 (mg/dL) 2 17–45
Total protein (g/dL) 5.0 6.9–8.4 CH50 (U/mL) 7 30–50
Albumin (g/dL) 2.2 3.9–5.2 C1q (μg/mL) 14.9 ≦3.0
Aspartate aminotransferase (IU/L) 29 13–33 Rheumatoid factor (IU/mL) 27 0–15
Alanine aminotransferase (IU/L) 14 6–27 Antinuclear antibody ×640 < 40
Alkaline phosphatase (IU/L) 181 117–350 Anti-double strand DNA antibody (IU/mL) 3140 < 12
Lactate dehydrogenase (IU/L) 201 119–229 Anti-Sm antibody Negative Negative
γ-Glutamyl transpeptidase (IU/L) 68 9–109 Anti-RNP antibody Negative Negative
Total bilirubin (mg/dL) 0.7 0.3–1.1 Anti-SS-A antibody 16 Negative
Cholinesterase (IU/L) 160 220–495 Anti-smooth muscle antibody Negative Negative
NH3 (μg/dL) 79 6–51 Anti-liver/kidney microsome type 1 antibody Negative Negative
Urea nitrogen (mg/dL) 62 8–21 Anti-mitochondrial M2 antibody (U/mL) 2.9 < 7.0
Creatinine (mg/dL) 1.47 0.46–0.78 Hepatitis B virus DNA Negative Negative
Uric acid (mg/dL) 8.7 2.5–7.0 Hepatitis C virus RNA Negative Negative
eGFR (mL/min/1.73 m2) 27.6 ≧90 Urinary RBC sediment (/HPF) 11–30 <1
Na (mmol/L) 141 139–146 Urinary protein (g/day) 6.52 < 0.15
K (mmol/L) 4.8 3.7–4.8
Cl (mmol/L) 113 101–109

PAS
PAS

PAM Masson PAM Masson

Fig. 1. Microscopy of a renal biopsy specimen. a: Extracapillary and endocapillary glomerulonephritis is noted. In glomeruli with few or no proliferative changes, the
peripheral intracapillary spaces are markedly widened and filled with homogenous and rigid material (arrow) on PAM-Masson staining, forming so-called “wire loop”
lesions. b: Immunofluorescence (IF) shows prominent deposits of IgG, IgA, IgM, C3, and C1q (full house) within the glomerular basement membrane and the
mesangial region. c: On electron microscopy (EM), massive subendothelial electron-dense deposits (EDD) are noted, but there are no microfibrillary structures
showing a fingerprint pattern (inset).

Thereafter, she was stable without immunosuppressant therapy. Six
months before admission, her creatinine was 0.68 mg/dL and her esti-
mated glomerular filtration rate (eGFR) was 64.1 mL/min/1.73 m2, but
creatinine began to increase subsequently and anasarca became severe.
On admission, she had a height of 153.5 cm and weight of 63.9 kg
(weight gain of 7.6 kg in 1 month), with a blood pressure of 133/
54 mmHg, heart rate of 78/min, and temperature of 37.2 °C. There was
severe edema of the legs, and oral ulceration was detected. However,
there were no other skin lesions, and no joint pain or neurologic
symptoms. Laboratory findings were as follows (Table 1): white blood
cell count, 3800/μL; red blood cell count, 2.99 × 106/μL; hemoglobin,
9.6 g/dL; platelet count, 139 × 103/μL; total protein, 5.0 g/dL; al-
bumin, 2.2 g/dL; serum urea nitrogen, 62 mg/dL; serum creatinine,
1.47 mg/dL; eGFR, 27.6 mL/min/1.73 m2, and CRP was 0.3 mg/dL.
Immunological studies were positive for speckled and homogenous
antinuclear antibody. In addition, anti-double-stranded DNA (anti-ds-
DNA) antibody was 3140 IU/mL (normal: > 12) and anti-SS-A (Ro)
antibodies were positive at a titer of 1:16. However, anti-U1 ribonu-
cleoprotein antibody and anti-Smith antibody were negative. Anti-
phospholipid antibody was also negative, including anti-cardiolipin

28
N. Shima et al. Human Pathology: Case Reports 13 (2018) 27–32

Fig. 1. (continued)

29
N. Shima et al.
1c
Fig. 1. (continued)
2a
Fig. 2. Histological examination at autopsy. a. Preserved glomeruli show chronic inactive lesions with scarring, including fibrous crescents or segmental sclerosis, but
there is no active endocapillary or extracapillary glomerulonephritis. b. IF shows disappearance of the full house pattern (IgG, IgA, IgM, C3, and C1q). c. EM reveals
disappearance of subendothelial wire loop lesions (large arrow), though small intramembranous EDDS (small arrow) are still seen.
(beta2 glycoprotein) antibody and lupus anticoagulant. Anti-smooth
muscle antibody and anti-liver/kidney microsome type 1 antibody were
negative. CH50 was 7 U/mL (normal: > 30 U/mL), C3 was 25 mg/dL
(normal: 86–160), and C4 was 2 mg/dL (normal: 17–45). Total urinary
protein excretion was 6.52 g/day, and the sediment contained 11–30
erythrocytes per high-power field. Unenhanced CT scans showed liver
cirrhosis with massive ascites and bilateral pleural effusions.
3. Renal biopsy findings
Light microscopic (LM) examination of a renal biopsy specimen
revealed global sclerosis in 4 out of 24 glomeruli, with over 50% of the
glomeruli being affected. Eight glomeruli showed cellular or fi-
brocellular crescents with necrotic changes. Endocapillary glomer-
ulonephritis was prominent with karyorrhexis and hyaline thrombi. In
the glomeruli with few or no proliferative changes, the peripheral in-
tracapillary spaces showed marked enlargement and were filled with
homogenous and rigid material on PAM-Masson staining, representing
so-called “wire loop” lesions (Fig. 1a). There was no evidence of sub-
epithelial spike formation. Chronic inactive lesions with adhesions were
seen in some areas. Tubular atrophy and tubulointerstitial fibrosis oc-
cupied approximately 50% of the total renal cortex. Moderate hyaline
sclerosis was detected in the arterioles, and interlobular arteries showed
also mild to moderate sclerotic change, but the finding of vasculitis was
not noted. Immunofluorescence (IF) showed prominent deposits of IgG,
30
Human Pathology: Case Reports 13 (2018) 27–32
IgA, IgM, C3, and C1q (so-called “full house”) within the glomerular
basement membrane and the mesangium (Fig. 1b). Analysis of IgG
subclasses demonstrated a similar level of positivity for IgG1, IgG2,
IgG3, and IgG4. C4 was negative. Electron microscopy (EM) revealed
massive subendothelial electron-dense deposits (EDD), but micro-
fibrillary structures showing a fingerprint pattern were not detected
(Fig. 1c). Small EDDs were also noted in the subepithelial region. From
these findings, class IV-G (A/C) LN was diagnosed according to the
classification of the International Society of Nephrology/Renal Pa-
thology Society (ISN/RPS) [4].
3.1. Clinical course
She fulfilled 5 items of the 1997 American College of Rheumatology
(ACR) criteria for the classification of SLE [oral ulceration, renal dis-
order, leukopenia, positive anti-ds-DNA and antinuclear antibody], and
was diagnosed as having SLE. She received intravenous methylpredni-
solone pulse therapy (1000 mg/day for three days), followed by oral
prednisolone at 40 mg/day. Anti-ds-DNA antibody decreased and hy-
pocomplementemia subsided, but her renal function deteriorated ra-
pidly and hemodialysis was required. She also developed disturbance of
consciousness. Mycophenolate mofetil was added at a dose of 1000 mg/
day, along with plasma exchange and rituximab (375 mg/m2).
However, her renal function and disturbance of consciousness did not
improve. She died of multiple organ failure about 3.5 months after
admission.
4. Autopsy findings
Autopsy was done at 10 h after death. The liver showed advanced
cirrhosis. Light microscopy of the kidney showed that sclerotic region in
glomeruli, moderate to severe tubular atrophy, and fibrosis of tubu-
lointerstitium occupied approximately 50% of total renal cortical re-
gion. The preserved glomeruli collapsed and featured chronic inactive
lesions with scarring, including fibrous crescents or segmental sclerosis,
but there was no active endocapillary or extracapillary glomerulone-
phritis (Fig. 2). IF revealed disappearance of the full house pattern,
including IgG, IgA, IgM, C3, and C1q. In addition, EM showed dis-
appearance of subendothelial wire loop lesions, though small in-
tramembranous EDDs were still present. Class III (c) LN showing post-
treatment changes was diagnosed according to the ISN/RPS classifica-
tion, but we believe that ischemic change related to collapsed glomeruli
could be more critical to renal function than the glomerular changes.
N. Shima et al.
2b
Fig. 2. (continued)
5. Discussion
Acute or subacute renal failure can occur for various reasons in
patients with LN, which is a major determinant of morbidity and
mortality in SLE. The risk of progression to ESRD is higher in certain
subsets of LN, e.g., the risk may be as high as 44% over 15 years in
patients with class IV LN [1,5]. In a retrospective study of 101 patients
who had biopsy-proven severe LN with rapidly progressive glomer-
ulonephritis (RPGN), clinicopathological data and long-term outcomes
were compared with another 200 randomly enrolled patients who had
severe LN without RPGN. Multivariate analysis revealed that serum
creatinine and the extent of crescentic change were the most important
risk factors for ESRD in severe LN associated with RPGN (p < 0.001)
[6]. In the present patient, class IV LN itself was a risk factor for ESRD.
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Human Pathology: Case Reports 13 (2018) 27–32
Cellular or fibrocellular crescents affecting one third of the glomeruli
may also have made a contribution.
In addition, she had massive subendothelial immune complex (IC)
deposits, which may have developed secondary to liver cirrhosis. It was
recently reported that the ITIM-bearing IgG Fc receptor (FcγRIIb),
which is highly expressed by liver sinusoidal endothelial cells, is re-
sponsible for removing small ICs from the blood and minimizes pa-
thologic deposition of inflammatory complexes by maintaining low
circulating concentrations [7]. Therefore, liver dysfunction could have
led to an increase of circulating ICs in this patient, resulting in sub-
endothelial deposition. In our patient, serum C1q was 14.9 μg/mL
(normal < 3.0) and anti-ds-DNA antibody was 3,140 U/mL
(normal < 12). The marked elevation of C1q and anti-ds-DNA anti-
body could suggest a high level of circulating ICs.
N. Shima et al.
2c
Fig. 2. (continued)
Hepatic clearance of circulating ICs is also important in diseases
associated with portal vein shunts. Two cases of membranoproliferative
glomerulonephritis (MPGN) after creation of a transjugular intrahepatic
portosystemic shunt have been reported. It is plausible that the porto-
hepatic communication created by the shunt induced MPGN via de-
position of ICs that were not processed in the liver [8]. MPGN asso-
ciated with a congenital portosystemic shunt has also been reported.
Proteinuria resolved after shunt ratio reduction by percutaneous
transhepatic portal vein embolization, following which renal function
and histopathological findings improved without immunosuppressive
therapy [9]. Furthermore, Takada et al. reported that two patients with
alcoholic cirrhosis who had massive subendothelial deposits had a close
relation with portal systemic shunt. Both the massive deposits and renal
disease were improved by steroid therapy in these patients [10]. These
reports indicate that IgA produced in the gastrointestinal tract can enter
the systemic circulation from the portal vein via a portosystemic shunt,
to create mesangial and subendothelial deposits, resulting in the de-
velopment of IgA nephropathy. Particularly massive deposition of ICs
may occur in patients with liver cirrhosis due to impaired hepatic
clearance of IgA after it has entered the systemic circulation.
LN is more severe in younger age, but less severe in older adults.
When severe LN is developed in older patient, any risk factor should be
considered. We believe that coexistence of liver cirrhosis and porto-
systemic shunt might contribute to massive subendothelial deposition
of our LN patient via the above mechanism.
In conclusion, we evaluated a 72-year-old woman with a history of
liver cirrhosis, who developed nephrotic range proteinuria with rapidly
progressive renal failure. Renal biopsy showed massive subendothelial
deposits and class IV-G (A/C) LN was diagnosed. In LN patients with
liver cirrhosis and a portosystemic shunt, both previous reports [8–10]
and this case indicate that ICs produced in the gastrointestinal tract
32
Human Pathology: Case Reports 13 (2018) 27–32
may enter the systemic circulation from the portal circulation via the
shunt without being removed by the liver, resulting in massive de-
position in the glomerular capillaries compared to patients without a
portosystemic shunt, though whether her immune complex can be
produced in her gastrointestinal tract remains uncertain.
Disclosures
The authors declare no competing financial interests.
The authors also declare that they have no conflicts of interest.
Consent from relatives was obtained to publish the case report.
Acknowledgment
This study was funded by the Okinaka Memorial Institute for
Medical Research.
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