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\title{A Rare Case: IgG4-Related Chronic Inflammatory Disease with Kidney
Involvement}



\author[1]{Fatos Mete}%
\author[2]{Tuba Mengeneci}%
\author[1]{Emre Albayrak}%
\author[1]{Yavuz AYAR}%
\author[1]{Melike Nalbant}%
\author[3]{ilknur özdeniz mutlucan}%
\author[4]{Zeliha Fusun Baba}%
\affil[1]{Bursa City Hospital}%
\affil[2]{1}%
\affil[3]{Ministry of Health Bursa City Hospital}%
\affil[4]{Acibadem İnternational Hospital}%


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  \date{May 06, 2024}


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\textbf{A Rare Case: IgG4-Related Chronic Inflammatory Disease with
Kidney Involvement}

Fatos METE\selectlanguage{ngerman}¹, Tuba MENGENECI¹, Emre ALBAYRAK¹, Yavuz
AYAR\textsuperscript{2}, Melike NALBANT\textsuperscript{3}, Ilknur
MUTLUCAN\textsuperscript{4}, Zeliha Fusun BABA\textsuperscript{5}

\textsuperscript{1}Bursa City Hospital, Department of Internal Medicine,
Bursa, Turkey

\textsuperscript{2}Bursa City Hospital, Department of Internal Medicine,
Division of Nephrology, Bursa, Turkey

\textsuperscript{3}Bursa City Hospital, Department of Medical Pathology,
Bursa, Turkey

\textsuperscript{4}Bursa City Hospital, Department of Radiology, Bursa,
Turkey

\textsuperscript{5}Ac\selectlanguage{polish}ı\selectlanguage{english}badem International Hospital, Department of
Medical Pathology, Istanbul, Turkey

\textbf{INTRODUCTION}

IgG4-related disease (IgG4-RD) is an immune-mediated chronic
inflammatory disease that progresses to fibrosis. It is a multisystemic
disease with involvement of secretory glands and kidney etc. It usually
has a subacute course and is frequently observed in middle-aged and
older male population. The pathogenesis of IgG4-RD is still unclear but
elevated IgG4 levels and the good response of IgG4-RD patients to
treatment with rituximab (B-cell depletion treatment), suggest a role of
the humoral immune system in the pathogenesis of IgG4-RD Glucocorticoids
and rituximab used in the treatment of the disease. Early diagnosis,
treatment and follow-up are important for prognosis and recurrence of
the disease (1-4) (Table 1). In our case, we evaluated a patient who had
arthritis, pain, itching, tearing, redness, and referred to our clinic
with impairment in renal function tests from an external center.

\textbf{Case Presentation}

A 52 years old male patient with a history of allergic rhinitis and not
using any medication before evaluated. Serum urea 102.1mg/dl
(12.84-42.8mg/dl), creatinine 4.66mg/dl (0.70-1.20mg/dl), eGFR 13
ml/min/1.73m2 (60-120 ml/min/1.73m2), serum albumin 30.4 gr/l (35-52
gr/l), blood eosinophil 1.23 10\^{}3/\selectlanguage{greek}µ\selectlanguage{english}l (0.03 - 0.59 10\^{}3/\selectlanguage{greek}µ\selectlanguage{english}l),
C-reactive protein 69.8 mg/l (0-5 mg/l), 1+proteinuria in complete
urinalysis, 1527.5 mg/day proteinuria in 24-hour urine, C3c 0.38 g/l
(0.9-1.8 g/l), C4 \textless{}0.02 (0.1-0.4 g/l), serum amyloid A 50.70
mg/dl (5.7-8.2 mg/dl), IgG 37.83g /l (7-16g/l), \selectlanguage{greek}α\selectlanguage{english}1 globulin 6\%
(2.9-4.9\%), \selectlanguage{greek}β\selectlanguage{english}1 globulin 3.2\% (4.7-7.2), \selectlanguage{greek}β\selectlanguage{english}2 globulin\% in protein
electrophoresis 7.8 (3.2-6.5), \selectlanguage{greek}γ \selectlanguage{english}globulin 39.4\% (11.1-18.8) were
detected in laboratuary assessment. The patient's liver and thyroid
function tests and pancreatic enzymes were normal. There was no growth
in the blood and urine cultures. Rheumatoid factor and autoantibody
tests were negative in his examinations in our clinic. Contrast-enhanced
abdominal computed tomography of the patient revealed an inflamed
appearance in the adipose tissue in the left pararectal region, loss of
corticomedullary separation and hypodense patchy areas in both kidneys
detected (Figure 1 and 2). Contrast nephropathy, tubulointerstitial
nephritis(TIN) or vasculitis considered in the differential diagnosis.

In the needle biopsy samples taken from the left pararectal region of
the patient, mononuclear inflammatory cells infiltration rich with
eosinophil leukocytes and plasma cells observed in fibrolipomatous
tissues showing fibrosis. More than 10 IgG4-expressing plasma cells
counted in 1 high magnification field in plasma cells that showed CD68
negative and CD138 positive staining. These histopathological findings
found to be significant in terms of IgG4-RD.

The patient had normal kidney size and proteinuria over 1.5 g/day.
Kidney biopsy performed. No endocapillary or extracapillary
proliferative or necrotizing lesions observed in the biopsy. Intense
fibrocollagenous connective tissue increase in the interstitium, and
tubular atrophy, coarsening and wrinkling of the tubular basement
membranes noted. Mononuclear cell infiltration rich with plasma cells
observed. In the IgG4 staining, it was seen that the plasma cells
stained positively in 16-20/ one large magnification. No significant
vasculopathy, arteriolar concentric sclerosis or hyalinosis detected in
the arteries.

Considering IgG4-related tubulointerstitial nephritis, 250mg/day
intravenous prednisolone started for 3 days, followed by maintenance
0.5mg/kg/day oral prednisolone. Angiotensin converting enzyme and proton
pump inhibitor, calcium+vitamin D was given. At the first follow-up
after 15 days, the patient stated that his current complaints regressed
dramatically. Laboratuary values found as serum urea 95.7mg/dl
(12.84-42.8mg/dl), creatinine 1.96mg/dl (0.70-1.20mg/dl), and 24-hour
urine protein 238.5mg/day (0-140mg/dl). The patient's follow-up and
treatment continue in our unit.

\selectlanguage{polish}\textbf{DISCUSSİON}\selectlanguage{english}

IgG4-RD is a fibroinflammatory disease involving almost all organs.
Patients may be asymptomatic or have severe symptoms. Clinical diagnosis
of the disease may be difficult or the findings may be confused with
other diseases. The American College of Rheumatology/European League
Against Rheumatism IgG4-RD determined classification criteria (4). The
disease progresses with tissue and organ involvement, IgG4 level is
usually high, it can also be found normal. IgG4-RD can lead to fibrosis
and can cause to organ failure Tissue biopsy is important to support the
diagnosis (1, 5). While the disease is first described as associated
with autoimmune pancreatitis, it can affect organs such as the thyroid,
salivary gland, biliary tract, and kidney etc (6, 7).

The kidney is involved in approximately 20\% of patient with IgG4-RD.
The most common kidney disease is TIN. Retroperitoneal fibrosis can
cause to obstructive acute renal injury (ARI). Rarely, IgG4-RKD can
represent as a glomerular disease, especially as membranous nephropathy
(MN) (8).

IgG4-related TIN, has been identified as a part of systemic IgG4-RD. On
biopsy, TIN shows an IgG4 + plasma cell-rich infiltrate, and may show
tubulointerstitial immune complex deposits. Saeki et al evaluated 23
patients with renal parenchymal injury, and more than 60\% of them had
TIN. Light microscopy demonstrated dense cell infiltration with fibrosis
and tubular atrophy. The infiltrate was predominantly composed of plasma
cells and lympho-cytes, and also eosinophils in some patients (8-10).
IgG4-RD with TIN cases presented with hypertension, elevated serum
creatinine and IgG4, proteinuria and eosinophilia have been reported
(11, 12).

CT is the primary imaging modality used to examine patients with
suspected IgG4-RD. Multiple low-density lesions on enhanced CT are the
most common radiologic finding in IgG4-related TIN, but diffuse
bilateral renal swelling may be observed when severe renal failure is a
contraindication for the administration of contrast medium. Kidney
abnormalities on CT imaging have been observed in nearly 70 \% of
patients with IgG4- RD (13-16).

In a study, 9 patients described with IgG4-RD MN. All patients showed
MGN on biopsy, presented with proteinuria (mean 8.3 g/day), and most had
elevated serum creatinine (mean 2.2 mg/dl). All biopsies showed a
pattern of MGN with subepithelial deposits in a membranous pattern seen
by immunofluorescence (IF), electron microscopy, or light microscopy,
including immunoperoxidase staining for IgG4. In another study about
IgG4-RD MN, interstitial IgG4+ plasma cell infiltration (\textgreater{}
10/hpf ), and IgG4-positive plasma cells account for more than 40\% of
IgG+ plasma cells detected in immunohistochemistry staining (14, 15,
17).

The efficacy of glucocorticoids and rituximab (RTX) in the treatment of
IgG4-RD has been demonstrated. IgG4-related disease usually responds to
high-dose glucocorticoids, with an average dose of 40mg/day, which is
subsequently tapered. In a study, partial and complete response observed
in all patients after glucocorticoid and RTX treatment. International
consensus recommends a much more gradual tapering of the dose, over a
period of 3--6 months. With this dosing scheme, the rate of relapses was
23\% (2, 18, 19). Good response to RTX has been obtained in IgG4-related
disease. In another study, RTX was used as induction therapy at a dose
of 1000 mg on days 1 and 15, without simultaneous corticosteroids (26
patients) or with a gradual reduction of the dose of the latter during
the first 2 months (4 patients). Using a responder index to measure
IgG4-RD activity, 97\% of the individuals had an activity response at 6
months, with 47\% incomplete remission, and 40\% maintaining that
response at 12 month (20). In a French study, patients who received
rituximab treatment 375 mg/m\textsuperscript{2} once a week (4 doses)
and 1000 mg on the 1st and 15th days were evaluated, the response to the
treatment was 93.5\%. The relapse rate was 41.9\% (after mean 19.0 \selectlanguage{ngerman}±11.5
months) and relapse after retreatment was 27.2\% (21).

In our study, we evaluated a 52-year-old patient who presented with
proteinuria and acute kidney injury. The diagnosis of IgG4-RD were made
according to American College of Rheumatology/European League Against
Rheumatism classification criteria for IgG4-related disease in our case
(4) {[}Hypocomplementemia (6 points), IgG4 levels (4 points), IgG4
staining level in biopsy (14 points) and radiological kidney involvement
(10 points), total 34 points{]} (Table 1). The patient's clinical course
was stable and proteinuria regressed after steroid treatment. The
complete urinalysis, protein, erythrocyte and leukocyte were negative.
In his control after 60 days, serum urea decreased to 53.1 mg/dL and
creatinine to 1.71 mg/dL. Glucocorticoid dose reduced to 15 mg/day.

In conclusion, renal involvement in IgG4-related disease is rare. Early
diagnosis and treatment and management of the disease are important for
survival and progression of the disease.

\textbf{REFERENCES}

1. Kurowecki D, Patlas MN, Haider EA, Alabousi A. Cross-sectional
pictorial review of IgG4-related disease. Br J Radiol.
2019;92(1103):20190448.

2. Karim AF, Bansie RD, Rombach SM et al. The treatment outcomes in
IgG4-related disease. Neth J Med. 2018;76(6):275-85.

3. Wallace ZS, Perugino C, Matza M et al. Immunoglobulin G4-related
Disease. Clin Chest Med. 2019;40(3):583-597.

4. Wallace ZS, Naden RP, Chari S, Choi HK, Della-Torre E, Dicaire JF,
Hart PA et al. The 2019 American College of Rheumatology/European League
Against Rheumatism classification criteria for IgG4-related disease. Ann
Rheum Dis. 2020;79(1):77-87.

5. Bhattad PB, Joseph DL, Peterson E. IgG4-Related Disease Manifesting
as Hypocomplementemic Tubulointerstitial Nephritis: A Rare Case Report
and Literature Review. J Investig Med High Impact Case Rep. Jan-Dec
2020;8:2324709620952213.

6. Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, Yamamoto M,
Takahashi H et al. Proposal for a new clinical entity, IgG4-positive
multiorgan lymphoproliferative syndrome: analysis of 64 cases of
IgG4-related disorders. Ann Rheum Dis. 2009;68(8):1310-5.

7. Vasaitis L. IgG4-related disease: A relatively new concept for
clinicians. Eur J Intern Med. 2016;27:1-9.

8. Saeki T, Nishi S, Imai N, Ito T, Yamazaki H, Kawano M, Yamamoto M et
al. Clinicopathological characteristics of patients with IgG4-related
tubulointerstitial nephritis Kidney Int. 2010;78(10):1016-23.

9. Boffa JJ, Esteve E, Buob D. Renal involvement in IgG4-related
disease. Presse Med. 2020;49(1):104017.

10. Cornell LD. IgG4-related tubulointerstitial nephritis. Kidney Int.
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11. Watson SJW, Jenkins DAS, Bellamy COS. Nephropathy in IgG4-related
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12. Yoneda K, Murata K, Katayama K, Ishikawa E, Fuke H, Yamamoto N, Ito
K et al. Tubulointerstitial nephritis associated with IgG4-related
autoimmune disease Am J Kidney Dis. 2007;50(3):455-62.

13. Quattrocchio G, Roccatello D. IgG4-related nephropathy. J Nephrol.
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14. Alexander MP, Larsen CP, Gibson IW, Nasr SH, Sethi S, Fidler ME,
Raissian Y et al. Membranous glomerulonephritis is a manifestation of
IgG4-related disease. Kidney Int. 2013;83(3):455-62.

15. Stone JH, Brito-Zerón P, Bosch X, Ramos-Casals M. Diagnostic
Approach to the Complexity of IgG4-Related Disease. Mayo Clin Proc.
2015;90(7):927-39.

16. Zhang S, Yang Q. Imaging findings of IgG4-related kidney disease
without extrarenal organ involvement: A case report. Medicine
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17. Zhang NN, Wang YY, Kong LX, Zou WZ, Dong B. IgG4-related kidney
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manifestation: report of one case and literature review. BMC Nephrol.
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18. Ardila-Suarez O, Abril A, Gómez-Puerta JA. IgG4-related disease: A
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19. Wallace ZS, Deshpande V, Mattoo H, Mahajan VS, Kulikova M, Pillai S,
Stone JH. IgG4-Related Disease: Clinical and Laboratory Features in One
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20. Carruthers MN, Topazian MD, Khosroshahi A, Witzig TE, Wallace ZS,
Hart PA, Deshpande V et al. Rituximab for IgG4-related disease: a
prospective, open-label trial. Ann Rheum Dis. 2015;74(6):1171-7.

21. Ebbo M, Grados A, Samson M, Groh M, Loundou A, Rigolet A, Terrier B
et al. Long-term efficacy and safety of rituximab in IgG4-related
disease: Data from a French nationwide study of thirty-three patients.
PLoS One. 2017;12(9):e0183844.

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