Immunoglobulin G4 (IgG4)-related disease is a systemic, fibro-inflammatory disorder with pseudotumoral lesions, IgG4-positive lymphoplasmacytic infiltrates, and tissue fibrosis that can be seen within any organ (1). Serum IgG and IgG4 levels are typically elevated, but normal levels do not rule out the diagnosis. Kidney involvement occurs in 30% of cases, presenting as tubulointerstitial nephritis, glomerular lesions (e.g., membranous nephropathy), and macroscopic kidney abnormalities (bilateral kidney hypertrophy, pseudotumors, and hypermetabolic kidney lesions on 18-F-fluorodeoxyglucose-positron emission tomography-computed tomography [18-FDG-PET-CT]).
A retrospective, observational cohort study by Anis Chaba et al. (2) analyzed 101 adult patients from 35 European sites with IgG4-related kidney disease from January 1997 through December 2019. Patients were categorized into two groups: 1) kidney involvement without an alternative diagnosis and 2) established IgG4-related disease with kidney failure, proteinuria, and/or kidney lesions on imaging. Exclusions were retroperitoneal fibrosis and incomplete follow-up. Data on clinical, biological, imaging, and histopathological features; treatment; and outcomes were collected.
Kidney involvement was seen in 60% of patients, and 86% had systemic involvement at diagnosis. Extrarenal features included lymphadenopathies (57%), autoimmune pancreatitis (42%), sialadenitis (36%), lung involvement (28%), and cholangitis (25%). Laboratory findings revealed hypergammaglobulinemia, elevated IgG4 levels (94%), and decreased complement (C) levels (45%).
Among the patients, 51% had acute kidney injury (AKI), 23% had AKI-on-chronic kidney disease (CKD), and 14% had isolated CKD. Median serum creatinine (sCr) was 2.4 mg/dL (interquartile range [IQR], 1.6–3.6) with a corresponding estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m² (IQR, 17–43). Primary urinalysis findings were often without active sediment; however, hematuria and leukocyturia were noted in 27% and 16%, respectively. The median urinary protein-to-creatinine ratio was 600 mg/g (IQR, 200–1100), with >1000 mg/g in 31% of cases, primarily indicating glomerular involvement. CT scan abnormalities were found in 61% of patients, including bilateral kidney hypertrophy, pseudotumor, and low-density areas. An 18-FDG-PET CT scan was performed in 63% of patients, revealing hypermetabolic kidney lesions in 38% and extrarenal lesions in 74%.
Kidney biopsies were conducted in 82% of patients, showing tubulointerstitial involvement in all cases and additional glomerular lesions, most commonly membranous nephropathy, in 16% of cases. Tubulointerstitial lymphoplasmacytic infiltrates and predominant IgG4(+) plasma cells were observed. Dense fibrosis (>50% kidney tissue) was described in 42% of cases, whereas the storiform pattern was rare.
Corticosteroid (CS) therapy was administered to 90% of patients (mean dose, 0.8 ± 0.3 mg/kg/day), and 18 patients (18%) received rituximab as initial therapy (77% received 1 g at days 1 and 15, around two cycles). No specifications were made on which patients received chosen therapies. After a median follow-up of 24 months, 35% of patients experienced relapse, with a median relapse time of 12 months. Multivariable analysis showed that muti-organ involvement and low C3/C4 levels were associated with a higher relapse risk, whereas rituximab was associated with a lower risk. This effect persisted after weighting and propensity score analysis.
Patients who received rituximab first had lower relapse rates (22% vs. 37%) and similar kidney outcomes with lower rates of complications such as death (6% vs. 15%) and infections (17% vs. 25%). At the last follow-up, 71% of patients had CKD, with a median eGFR of 45 mL/min/1.73 m², and 32% had an eGFR ≤30 mL/min/1.73 m². Progression to end stage kidney disease occurred in 12% of patients, and 13% died. Factors associated with severe CKD were age, peak sCr, prolonged CS duration (>12 months), and cholangitis. Logistic regression analysis identified age, peak sCr, and serum IgG4 levels ≥5 g/L as independent predictors of severe CKD. Serum IgG4 levels at diagnosis and the state of interstitial fibrosis and tubular atrophy on kidney biopsy were related to eGFR at the last follow-up.
This retrospective analysis highlights IgG4-related kidney disease primarily affecting middle-aged males and presenting as tubulointerstitial nephritis with glomerular involvement in approximately 25% of cases. CSs are commonly used but carry a relapse risk, especially in patients with CKD. Rituximab shows promise as a first-line treatment to reduce relapse rates. Close monitoring is essential for individuals with organ involvement and elevated IgG4 levels, as these conditions are associated with poorer outcomes. Given the 23 years examined within this retrospective study, it is difficult to compare cases, particularly with advancements in biomarkers and therapeutics. Further controlled trials are needed to confirm these findings.
Chaba A, et al. Clinical and prognostic factors in patients with IgG4-related kidney disease. Clin J Am Soc Nephrol 2023; 18: 1031–1040. doi: 10.2215/CJN.0000000000000193