Case Conference

A case of IgG4-related kidney disease

Basic Data
• 魏 O 木 71 y/o M
• BW/BH: 77.2kg/159cm
• Underlying disease
Type-2 diabetes mellitus
Hypertension
Dyslipidemia
Benign prostate hypertrophy
Medication T.O.C.C & Social & Family

• Atorvastatin • No cigarette smoking, alcohol drinking or

• Aspirin betel nut use
• Pentoxifylline • Occupation: retired truck driver
• Losartan • Family: no contributory, no known
kidney disease history
• Empagliflozin(Jardiance)
• Basal-bolus Insulin(Apidra + Toujeo)
• Harnalidge
• Followed diabetes mellitus at our hospital since 2014, Cr: 1.5-2.5 mg/dL
• 2020 September, transferred to LMD

2023/08/17
•Fast deteriorating of renal function
eGFR: 77.32 on 2022/09/27  9.9 on 2023/07/26

2023/09/01 Nephrology OPD

•No significant foamy urine
•Fair urine output with no significant edema
•Fair appetite with no uremic symptoms
•Well control of DM(HbA1c: 6.5%)
•No recent change of current medication use
Lab data

WBC Hb Plt RBC MCV Neu Lym Mono Eos Baso

10.11 15.2 132 5.32 86.3 65.5 14.4 5.6 12.9 1.6

BUN Cr eGFR GOT GPT Na K Ca TP Alb

80.3 7.08 8.20 31 40 136 4.2 8.4 10.2 3.5
Lab data
Urine analysis
pH Protein Blood Nitrite Gravity R.B.C. W.B.C. Epi Bac Colour Glu
5.0 1+ 2+ - 1.000 3-5 0-5 0-5 - L. Y. +/-

Cast Crystal Dysmorphic RBC Urine B-J protein

Not found Not found None Negative

U protein U creatine UPCR

50.3 mg/dL 64.3 mg/dL 782mg/g
Urine immunofixation
albumin α-1 Globulin α-2 Globulin β-Globulin γ-Globulin Biclonal IgG λ and free κ chain
22.7% 9.1% 2.0% 10.0% 56.20%
Serum immunofixation
albumin α-1 Globulin α-2 Globulin β-Globulin γ-Globulin
Monoclonal IgG λ chain
3.4gm% 0.3gm% 0.7gm% 0.7gm% 5.0gm%
Lab data
ANA Anti-ds-DNA Anti-Ro/La Ab Anti-SSB/La Ab Anti-GBM Ab p-ANCA C-ANCA
Negative Negative Negative Negative Negative Negative Negative

IgG IgA IgM IgG-4 cryoglobulin

4827 137 153 2949.2 Negative

C3 C4 HBsAg Anti-HBs HCVAb

82 29 Negative Negative Negative

Free κ Free λ β2-microglobulin

345.0 mg/L 426.0 mg/dL 15.01 mg/dL
Renal sonography
•Right kidney 10.4 cm,
parenchymal thickness 1.92 cm
•Left kidney 10.54 cm,
parenchymal thickness 1.88 cm
•Echogenicity of renal parenchyma: Gr. I-II
2023/10/17 Renal biopsy
Pathology result:
•Lymphoplasmacytic and eosinophil-rich inflammatory infiltrates with irregular
fibrosis, IgG4/IgG > 40%
 Compatible with IgG4-related tubulointerstitial nephritis
•Segmental thickening of GBM(>700 nm), subendothelial widening with fluffy
material, may indicate developing DM nephropathy
 Start corticosteroid
OPD survey
IgG4 Related Kidney
Disease
IgG4 related disease
1960s Multifocal idiopathic fibrosclerosis

• Lymphoplasmacytic sclerosing pancreatitis (LPSP)(1991)

1990s
• Autoimmune related pancreatitis(AIP)

• Numerous IgG4-positive plasma cell infiltrates in both the pancreatic

2003
and extra-pancreatic lesions of type 1 AIP
 IgG4-related systemic disease

2010s • First general consensus on IgG4-related disease(2010)

• ACR/EULAR classification criteria for IgG4-related disease(2019)

Saeki, T., & Kawano, M. (2014). IgG4-related kidney disease. Kidney international, 85(2), 251–257. https://doi.org/10.1038/ki.2013.393
IgG4 related kidney disease

2004 • Case of acute tubulointerstitial nephritis associated with AIP

• Affects approximately 30% of patients with IgG4-related disease

2010s
• First diagnostic criteria proposed on 2011(Kawano, M., Saeki, T. et al. JSN)
• Revise diagnosis criteria in 2020

Saeki, T., & Kawano, M. (2014). IgG4-related kidney disease. Kidney international, 85(2), 251–257. https://doi.org/10.1038/ki.2013.393
Saeki T, Kawano M, Nagasawa T, et al. Validation of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD) 2011, and
proposal of a new 2020 version [published correction appears in Clin Exp Nephrol. 2021 Apr;25(4):443-444]. Clin Exp Nephrol.
2021;25(2):99-109. doi:10.1007/s10157-020-01993-7
IgG4 related kidney disease
• Retroperitoneal fibrosis
• Tubulo-interstitial nephritis (TIN)
• Membranous nephropathy (MN)

Peyronel, F., & Vaglio, A. (2023). IgG4-Related Kidney Disease. Clinical journal of the American
Society of Nephrology : CJASN, 18(8), 994–996. https://doi.org/10.2215/CJN.0000000000000235
 IgG4-related tubulo-interstitial nephritis

Clinical Features
•The most common manifestation of IgG4-related disease with kidney
involvement, 15%–24.6% of all IgG4-related disease
•Older mean age: 60s
•M: F: about 3:1
•Variable degree of kidney dysfunction with subnephrotic range
proteinuria

Zhang NN, Wang YY, Kong LX, Zou WZ, Dong B. IgG4-related kidney disease (IgG4-RKD) with
membranous nephropathy as its initial manifestation: report of one case and literature review.
BMC Nephrol. 2019;20(1):263. Published 2019 Jul 16. doi:10.1186/s12882-019-1419-6
Kawano M, Saeki T, Nakashima H, et al. Proposal for diagnostic criteria for IgG4-
related kidney disease. Clin Exp Nephrol. 2011;15(5):615-626. doi:10.1007/s10157-
011-0521-2
Kawano M, Saeki T, Nakashima H. IgG4-related kidney disease and retroperitoneal
fibrosis: An update. Mod Rheumatol. 2019;29(2):231-239.
IgG4-related tubulo-interstitial nephritis
Serological features
•High serum IgG4 level ( > 90%)
Higher serum IgG4 concentrations (>5 g/L)  more severe kidney disease
•Hypergammaglobulinemia (51%)
•Hypocomplementemia (54%)
•High serum IgE level (70%)
•Eosinophilia (33%–48%)
Saeki T, Kawano M. IgG4-related kidney disease [published correction appears in Kidney Int.
2014 Jun;85(6):1472]. Kidney Int. 2014;85(2):251-257. doi:10.1038/ki.2013.393

Kawano M, Saeki T, Nakashima H. IgG4-related kidney disease and retroperitoneal

fibrosis: An update. Mod Rheumatol. 2019;29(2):231-239.
doi:10.1080/14397595.2018.1554321
Zhang NN, Wang YY, Kong LX, Zou WZ, Dong B. IgG4-related kidney disease (IgG4-RKD) with
membranous nephropathy as its initial manifestation: report of one case and literature review.
BMC Nephrol. 2019;20(1):263. Published 2019 Jul 16. doi:10.1186/s12882-019-1419-6
 IgG4-related tubulo-interstitial nephritis
• Characteristic radiologic features: bilateral nodular or wedge-shaped lesions with
low contrast enhancement on CT and MRI T2-weighted

A. Multiple low-density lesions in the bilateral kidneys

B. Diffuse patchy involvement of the bilateral kidneys
C. Rim-like lesion of the kidney Kawano, M., Saeki, T., & Nakashima, H. (2019). IgG4-related kidney
D. Renal pelvis thickening with smooth intraluminal surface disease and retroperitoneal fibrosis: An update. Modern
rheumatology, 29(2), 231–239.
IgG4-related tubulo-interstitial nephritis

Typical histopathologic features

•Diffuse inflammatory infiltrate rich in plasma cells and eosinophils
•Presence of IgG4-positive plasma cells within the tubulo-interstitium
•Storiform fibrosis
•Severe tubular atrophy

Kawano, M., Saeki, T., & Nakashima, H. (2019). IgG4-related kidney disease and retroperitoneal fibrosis:
An update. Modern rheumatology, 29(2), 231–239. https://doi.org/10.1080/14397595.2018.1554321
A. Copious plasma cell infiltrates in the interstitium (CD138 immunostaining)
B. Many IgG4-positive plasma cell infiltrates with germinal center in the subcapsular
interstitium (IgG4 immunostaining)
Kawano, M., Saeki, T., & Nakashima, H. (2019). IgG4-related kidney disease and retroperitoneal fibrosis:
An update. Modern rheumatology, 29(2), 231–239. https://doi.org/10.1080/14397595.2018.1554321
C. Storiform fibrosis (periodic acid-methenamine-silver staining)
D. Many eosinophil infiltrates in the interstitium (hematoxylin and eosin staining)
Kawano, M., Saeki, T., & Nakashima, H. (2019). IgG4-related kidney disease and retroperitoneal fibrosis:
An update. Modern rheumatology, 29(2), 231–239. https://doi.org/10.1080/14397595.2018.1554321
• Elevated serum IgG4 level
• Image findings
• Kidney injury
• Histological findings
• Other extra-renal organ manifestation
• Excluded other possible disease
Treatment
• Corticosteroid
Prednisolone 0.6(0.35-1.0)mg/kgBW/day for 2-4 weeks
Taper to 2.5-10mg QD in 2-3 months
Well response in > 90% of patients
• B-cell depletion therapy  Rituximab
More in second line use, but some use as first line treatment with well
response
• Other DMARDs  no validate evidence now

Saeki, T., Kawano, M., Mizushima, I., Yamamoto, M., Wada, Y., Nakashima, H., Homma, N., Tsubata, Y.,
Takahashi, H., Ito, T., Yamazaki, H., Saito, T., & Narita, I. (2013). The clinical course of patients with
IgG4-related kidney disease. Kidney international, 84(4), 826–833.
Treatment
• Relapse rate: 20%
• Higher relapse rate:
Complement consumption
More organs involved
If ANCA related
Early tapering or discontinuing corticosteroid use
• First-line therapy with rituximab  lower relapse rate

Saeki, T., Kawano, M., Mizushima, I., Yamamoto, M., Wada, Y., Nakashima, H., Homma, N., Tsubata, Y.,
Takahashi, H., Ito, T., Yamazaki, H., Saito, T., & Narita, I. (2013). The clinical course of patients with
IgG4-related kidney disease. Kidney international, 84(4), 826–833.
Take home message
• Unexplained impairment of kidney function, tubular proteinuria
• Hypergammaglobulinemia, elevated serum IgG4, and reduced serum
complement(C3 and/or C4) levels
Reference
• Saeki, T., & Kawano, M. (2014). IgG4-related kidney disease. Kidney international, 85(2), 251–257.
https://doi.org/10.1038/ki.2013.393
• Kawano M, Saeki T, Nakashima H, et al. Proposal for diagnostic criteria for IgG4-related kidney disease. Clin Exp Nephrol.
2011;15(5):615-626. doi:10.1007/s10157-011-0521-2
• Engelsgjerd, J. S., & LaGrange, C. A. (2022). Retroperitoneal Fibrosis. In StatPearls. StatPearls Publishing.
• Peyronel, F., & Vaglio, A. (2023). IgG4-Related Kidney Disease. Clinical journal of the American Society of Nephrology :
CJASN, 18(8), 994–996. https://doi.org/10.2215/CJN.0000000000000235
• Kawano, M., Saeki, T., & Nakashima, H. (2019). IgG4-related kidney disease and retroperitoneal fibrosis: An
update. Modern rheumatology, 29(2), 231–239. https://doi.org/10.1080/14397595.2018.1554321
• Chaba, A., Devresse, A., Audard, V., Boffa, J. J., Karras, A., Cartery, C., Deltombe, C., Chemouny, J., Contamin, C., Courivaud,
C., Duquennoy, S., Garcia, H., Joly, D., Goumri, N., Hanouna, G., Halimi, J. M., Plaisier, E., Hamidou, M., Landron, C.,
Launay, D., … Zaidan, M. (2023). Clinical and Prognostic Factors in Patients with IgG4-Related Kidney Disease. Clinical
journal of the American Society of Nephrology : CJASN, 18(8), 1031–1040. https://doi.org/10.2215/CJN.0000000000000193
• Saeki, T., Kawano, M., Mizushima, I., Yamamoto, M., Wada, Y., Nakashima, H., Homma, N., Tsubata, Y., Takahashi, H., Ito,
T., Yamazaki, H., Saito, T., & Narita, I. (2013). The clinical course of patients with IgG4-related kidney disease. Kidney
international, 84(4), 826–833. https://doi.org/10.1038/ki.2013.191
Reference
• Saeki T, Kawano M, Nagasawa T, et al. Validation of the diagnostic criteria for IgG4-related kidney disease (IgG4-RKD)
2011, and proposal of a new 2020 version [published correction appears in Clin Exp Nephrol. 2021 Apr;25(4):443-444]. Clin
Exp Nephrol. 2021;25(2):99-109. doi:10.1007/s10157-020-01993-7
• Kawano M, Saeki T, Nakashima H. IgG4-related kidney disease and retroperitoneal fibrosis: An update. Mod Rheumatol.
2019;29(2):231-239. doi:10.1080/14397595.2018.1554321
• Zhang NN, Wang YY, Kong LX, Zou WZ, Dong B. IgG4-related kidney disease (IgG4-RKD) with membranous nephropathy as
its initial manifestation: report of one case and literature review. BMC Nephrol. 2019;20(1):263. Published 2019 Jul 16.
doi:10.1186/s12882-019-1419-6