Hypocomplementemia is related to elevated serum levels of IgG subclasses other than IgG4 in IgG4-related kidney disease

Fujisawa, Yuhei; Mizushima, Ichiro; Yamada, Kazunori; Yamamoto, Motohisa; Saeki, Takako; Matsui, Shoko; Tsuge, Shunsuke; Hara, Satoshi; Ito, Kiyoaki; Fujii, Hiroshi; Takahashi, Hiroki; Nomura, Hideki; Kawa, Shigeyuki; Kawano, Mitsuhiro

doi:10.1080/14397595.2019.1709942

Cited by 12 publications

(9 citation statements)

References 19 publications

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“…We then turned our attention to the serum concentrations of IgG subtypes in patients with type 1 AIP/IgG4-RD. In line with the previous reports 4 , 9 , 27 – 29 , serum levels of IgG4 were much higher in type 1 AIP/IgG4-RD patients than in CP patients and HCs. In fact, IgG4 serum levels were at least three times higher in around 50% (11/21) of patients with type 1 AIP/IgG4-RD, as compared to its upper limits.…”

Section: Resultssupporting

confidence: 92%

Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease

Minaga

Watanabe

Hara

et al. 2020

Sci Rep

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IgG4-related disease (IgG4-RD) is a multi-organ autoimmune disease characterized by elevated serum IgG4 concentration. Although serum IgG4 concentration is widely used as a biomarker for IgG4-RD and type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of IgG4-RD, a significant number of patients have normal serum IgG4 levels, even in the active phase of the disease. Recently, we reported that the development of experimental AIP and human type 1 AIP is associated with increased expression of IFN-α and IL-33 in the pancreas. In this study, we assessed the utility of serum IFN-α and IL-33 levels as biomarkers for type 1 AIP and IgG4-RD. Serum IFN-α and IL-33 concentrations in patients who met the diagnostic criteria for definite type 1 AIP and/or IgG4-RD were significantly higher than in those with chronic pancreatitis or in healthy controls. Strong correlations between serum IFN-α, IL-33, and IgG4 concentrations were observed. Diagnostic performance of serum IFN-α and IL-33 concentrations as markers of type 1 AIP and/or IgG4-RD was comparable to that of serum IgG4 concentration, as calculated by the receiver operating characteristic curve analysis. Induction of remission by prednisolone treatment markedly decreased the serum concentration of these cytokines. We conclude that serum IFN-α and IL-33 concentrations can be useful as biomarkers for type 1 AIP and IgG4-RD.

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Section: Resultssupporting

confidence: 92%

Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease

Minaga

Watanabe

Hara

et al. 2020

Sci Rep

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“…Low C3 and C4 levels accounted for 69 and 50% of all the patients, respectively. Previous studies with biopsy-proven IgG4-RKD showed that C3 levels were negatively correlated with the renal deposition of C1q, storiform fibrosis, interstitial fibrosis, the number of IgG4-positive plasma cells (42), and deposition of non-IgG4 immunoglobulins in the TBM (43). This was similar to our results that high C3 and IgG3 levels were significantly correlated to the severity of the tubulointerstitial chronic injury.…”

Section: Discussionsupporting

confidence: 91%

Clinicopathological Patterns and Predictors of the Functional Restoration of Immunoglobulin G4-Related Kidney Disease: A Chinese Single-Center Cohort Study

Wang

Yang

2021

Front. Med.

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Background: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immunoreactivity-based fibro-inflammatory disease. Immunoglobulin G4-related kidney disease (IgG4-RKD) is a frequently overlooked diagnosis. This study aimed to describe IgG4-RKD and examine the factors relevant to the renal outcomes of IgG4-RD.Methods: We studied a prospective IgG4-RKD cohort between January 2012 and December 2020 with close follow-up. Clinicopathologic data at kidney biopsy were collected and analyzed. We aimed to explore independent risk factors for long-term renal outcome and disease relapse. Patients with an eGFR<45 ml/min per 1.73m2 at 12 months were defined as having poor outcomes.Results: The included 42 patients with IgG4-RKD had a mean age of 58.5 ± 8.7 years (male-to-female ratio = 5:1). The IgG4-RD responder index (RI) was 12.2 ± 3.3. A total of 66.7% of the patients presented with acute on kidney disease or acute on chronic kidney disease. Eight patients (19.0%) showed nephrotic-range proteinuria, and nine (21.4%) had high-titer IgG4-autoantibodies, including antineutrophil cytoplasmic antibody and anti-phospholipase A2 receptor. A kidney biopsy was conducted in 40 patients. Thirty-seven (90.0%) patients were diagnosed with IgG4-related tubulointerstitial nephritis, and 19 (47.5%) of them had concurrent glomerular diseases (membranous nephropathy [MN], n = 3; crescentic glomerulonephritis [CrGN], n = 11; diabetic kidney disease, n = 3; and both MN and CrGN, n = 2). IgG4-RD RI had a close relationship with serum C3 (R = −0.509, P = 0.001), C4 (R = −0.314, P = 0.049) levels, and peripheral blood eosinophil count (PBEC; R = 0.377, P = 0.024), factors that were not included in RI scores. Correlation analysis disclosed that IgG4-RD RI (R = 0.422, P = 0.007), organs involved (R = 0.452, P = 0.003), and C3 (R = −0.487, R = 0.002) were correlated with the percentage decrease of serum creatinine at 1 month. However, multivariate regression analysis failed to identify any clinicopathological parameters that could predict short-term renal restoration and IgG4-RKD relapse. Ten out of 29 variables, of most importance, were identified by the least absolute shrinkage and selection operator (LASSO) regression analysis. By multivariate logistic regression a higher serum IgG4 (OR = 0.671, P = 0.010), IgG1 (OR = 1.396, P = 0.049), IgG3 (OR = 19.154, P = 0.039), and erythrocyte sedimentation rate (ESR; OR = 1.042, P = 0.032) were found to be independent factors for poor long-term outcome. Conventional immunosuppressive medications and/or rituximab were prescribed, and in 83.3% of the patients, the kidney function improved. Repeat kidney biopsies confirmed the remission of interstitial inflammation in two patients under immunosuppressive therapy. However, the disease relapse rate was as high as 31.0%.Conclusions: We strongly recommend a kidney biopsy in active IgG4-RD, especially when there is proteinuria and renal dysfunction, because concurrent glomerular involvement and active interstitial inflammation should be assessed. A higher serum IgG1, IgG3, and ESR were independent factors for the poor long-term renal outcome; however, elevated IgG4 predicted a good renal prognosis, and appropriate and timely immunosuppressive therapy can help achieve a better prognosis.

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“…This finding suggests that although IgG4 may have contributed little to complement activation, IgG1 played a prominent role by forming an IgG1-type immune complex via the classical pathway (14). Similarly, hypocomplementemia in IgG4-related kidney disease is related to the elevation of IgG subclasses other than IgG4, including IgG1 (15). These studies suggest that not IgG4 but other types of IgG result in hypocomplementemia.…”

Section: Discussionmentioning

confidence: 89%

“…Similarly, hypocomplementemia in IgG4-related kidney disease is related to the elevation of IgG subclasses other than IgG4, including IgG1 ( 15 ). These studies suggest that not IgG4 but other types of IgG result in hypocomplementemia.…”

Section: Discussionmentioning

confidence: 99%

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Clinical Characteristics of Patients With IgG4-Related Disease Complicated by Hypocomplementemia

et al. 2022

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BackgroundA proportion of patients with immunogloblin G (IgG) 4-related disease (IgG4-RD) have hypocomplementemia. We aimed to identify characteristics of such patients.MethodsWe analyzed the demographic and clinical data and complement levels of 85 patients with IgG4-RD. We defined hypocomplementemia as serum C3 and/or C4 levels below the lower limit of normal at diagnosis. We also compared the characteristics of patients with and without IgG4-RD.ResultsThirty-two (38%) patients had hypocomplementemia at diagnosis. Patients with hypocomplementemia had more lymph node (p < 0.01), lung (p < 0.01), and kidney (p = 0.02) involvement and a higher IgG4-RD responder index than those without (p = 0.05). Additionally, patients with hypocomplementemia had significantly higher IgG (p < 0.01), IgG4 (p < 0.01), and soluble interleukin 2-receptor (sIL-2R) (p < 0.01) levels and total IgG minus IgG4 (p < 0.01). C3 and C4 levels negatively correlated with IgG, IgG4, and sIL-2R levels, total IgG minus IgG4, and number of IgG4-RD responder index: a measure of the disease activity in IgG4-RD. Patients with hypocomplementemia at diagnosis had a significantly higher frequency of relapse (p = 0.024), as determined using the log-rank test. A multivariate logistic regression analysis showed the presence of hypocomplementemia was independently associated with relapse (OR, 6.842; 95% confidence interval [95%CI], 1.684–27.79; p = 0.007).ConclusionsPatients with IgG4-RD with hypocomplementemia have a more active clinical phenotype, suggesting contributions of the complement system in the pathophysiology of IgG4-RD.

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Hypocomplementemia is related to elevated serum levels of IgG subclasses other than IgG4 in IgG4-related kidney disease

Cited by 12 publications

References 19 publications

Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease

Identification of serum IFN-α and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease

Clinicopathological Patterns and Predictors of the Functional Restoration of Immunoglobulin G4-Related Kidney Disease: A Chinese Single-Center Cohort Study

Clinical Characteristics of Patients With IgG4-Related Disease Complicated by Hypocomplementemia

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