Introduction
Immunoglobulin G4 (IgG4)-related disease (RD) was first reported as Japanese patients with sclerosing pancreatitis in 2001 [1]. Currently, IgG4-RD is considered a systemic disorder based on several reports. It is a unique immune-mediated disease that can occur in each organ and lead to permanent organ dysfunction and death if left untreated [2,3]. Moreover, it is characterized by elevated serum IgG4 concentration, lymphoproliferative infiltration enriched with IgG4-positive plasma cells in affected tissues, and distinct storiform fibrosis in affected organs [3–6]. The kidney and retroperitoneum have been reported frequently involved organs in IgG4-RD, and renal involvement can manifest as renal parenchymal and pelvic lesions or as urinary tract obstruction from retroperitoneal fibrosis [7–9]. The comprehensive terms for renal and retroperitoneal involvement of IgG4-RD were IgG4-related kidney disease (IgG4-RKD) and IgG4-related retroperitoneal fibrosis (IgG4-RPF), respectively [9]. The global incidences of IgG4-RKD and IgG4-RPF remain unknown. To date, most studies include case reports, those with a small cohort, and epidemiological research. Most epidemiological studies have been reported in North America, Europe, China, and Japan [10–21]. The current study aimed to demonstrate the clinical features and outcomes of IgG4-RKD and IgG4-RPF compared to other organs involvement.
Methods
Study population
The current study was approved by the Institutional Review Board (IRB) of the Catholic University of Korea (No. KC20RASI6074), and it was performed in accordance with the Declaration of Helsinki. Informed consent was waived from IRB due to the retrospective design. This retrospective observational study included patients diagnosed with IgG4-RD using the comprehensive diagnostic criteria (CDC) [7] from January 2009 to July 2019 at Seoul St. Mary’s Hospital, Yeouido St. Mary’s Hospital, and Uijeongbu St. Mary’s Hospital. Data were collected from the patient’s electronic medical records.
Diagnosis of immunoglobulin G4-related kidney disease and retroperitoneal fibrosis
Patients were diagnosed with IgG4-RD according to the CDC and/or other specific criteria for each organ, such as the presence of type 1 autoimmune pancreatitis, IgG4-RKD, IgG4-related Mikulicz disease (IgG4-related sialadenitis and dacryoadenitis), and IgG4-related sclerosing cholangitis [7]. The CDC comprises three parts, which are as follows: (a) clinical or radiological features showing diffuse/localized swelling or masses in single or multiple organs; (b) serological examination showing elevated serum IgG4 concentrations (≥135 mg/dL); (c) histopathological findings including marked lymphoplasmacytic infiltrate with fibrosis and infiltrate of IgG4-positive plasma cells with an IgG4+/IgG+ plasma cell ratio of >40% and IgG4+ plasma cell/high power field of >10. In addition, patients were classified into three disease grades based on the number of fulfilled criteria: (1) those who fulfilled all three criteria were diagnosed with ‘definite IgG4-RD,’ (2) those who fulfilled the clinical and histopathological criteria but without elevated serum IgG4 concentrations were diagnosed with ‘probable IgG4-RD,’ and (3) those who fulfilled the clinical and serological criteria but without histopathological features were diagnosed with ‘possible IgG4-RD.’ Renal involvement was defined as the presence of two or more of the following features: (a) presence of some kidney damage, as manifested by abnormal urinalysis including proteinuria and hematuria or decreased kidney function; (b) abnormal radiologic findings on enhanced computed tomography (CT): (i) multiple low-density lesions, and/or (ii) diffuse kidney enlargement, and/or (iii) hypovascular solitary mass, and/or (iv) hypertrophic lesion of renal pelvic wall without irregularity of the renal pelvic surface, or renal uptake on 18F-fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) scan; (c) a renal biopsy result consistent with the IgG4-RD CDC criteria [7], or another organ biopsy result with renal radiologic lesions. Retroperitoneal involvement was defined as the presence of at least one of the following features: (a) an RPF biopsy result consistent with the IgG4-RD CDC criteria [7]; (b) another organ biopsy result consistent with the IgG4-RD CDC criteria [7] and concurrently observed radiologic lesions of RPF: (i) circumferential or anterolateral soft tissue involving from renal to iliac arteries, and/or (ii) retroperitoneal mass or fat stranding, and/or (iii) diffuse thickening of the abdominal aortic wall. Patients were divided into three groups as follows: (a) the RKD group included patients with renal involvement and/or another organ site including RPF; (b) the RPF group included patients with retroperitoneal involvement and/or another organ site other than kidney; (c) the Others group included patients without both renal and retroperitoneal involvement. The flowchart for the enrollment of patients is illustrated in Fig. 1.
Evaluation of clinical features
We collected data on age at diagnosis, sex, follow-up duration, comorbidities (hypertension, diabetes melliuts, autoimmune disease, and malignancy), number of organs involved, type of imaging study, whether or not biopsy, IgG4-RD disease grade (definite/probable/possible), and treatment strategies and duration. Information on clinical characteristics was collected from the patient’s electronic medical records. Organ involvement was defined as the presence of lesions confirmed via imaging studies or characteristic pathological findings of IgG4-RD on biopsy. Multiple organ involvement was defined as two or more affected organs. We analyzed data regarding complete blood counts, blood chemistry, erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (hs-CRP), serum complement component 3 (C3), complement component 4 (C4), serum IgG, IgG4, anti-nuclear antibody, anti-double strand DNA antibody, anti-Sjögren–syndrome–related antigen A autoantibody, anti-Sjögren-syndrome-related antigen B autoantibody, anti-mitochondrial antibody, anti-centromere antibody, and urine protein-to-creatinine ratio at the time of diagnosis. Renal function was assessed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) [22]. To confirm whether organs were affected, all patients underwent at least one imaging study at the time of diagnosis: CT scan, magnetic resonance imaging, and 18F-FDG PET/CT scan.
Evaluation of treatment response and outcomes
The standard guideline for the evaluation of treatment response has not yet been established. The treatment response classification was defined by referring to the treatment response classification methods in previous studies [21,23,24]. The changes in clinical characteristics or radiologic findings were identified 3 months after treatment initiation, and then treatment responses were classified as follows:
(1) Complete response: The complete disappearances of both organs involvement on follow-up imaging studies and the clinical symptoms were observed.
(2) Partial response: The clinical symptoms improved, and organ involvement was regressed by more than 50% on follow-up imaging studies.
(3) Stable disease: The clinical symptoms still remained, and organ involvement was regressed to less than 50% on follow-up imaging studies.
(4) Progression: New clinical symptoms or organ involvement was identified, or previous clinical symptoms and organ involvement worsened.
Finally, complete remission or relapse depending on the status after the end of treatment within the follow-up period was evaluated as the final clinical outcome of disease. Complete remission was defined as a state with resolution of both clinical symptoms and organ involvement on the imaging studies for more than 6 months after treatment initiation. Relapse was defined as the recurrence of clinical symptoms or organ involvement or the occurrence of new organ involvement at any time after completion of treatment.
Statistical analysis
Continuous variables (including demographic and clinical characteristics) with a normal distribution were presented as mean ± standard deviation and those with a non-normal distribution as median and interquartile range (IQR). Categorical variables were expressed as frequency and percentage. The Pearson chi-square test was performed to compare different groups and categorical variables. Meanwhile, the Fisher exact test was used if the assumptions required for parametric testing were not met. For multiple comparisons of the three groups, we used a one-way analysis of variance followed by Bonferroni post hoc correction for continuous variables. Univariate and multivariate logistic regression analyses logistic regression analyses were performed to determine independent associations with renal or retroperitoneal involvement. The results were reported as odds ratios (ORs) with 95% confidence intervals (95% CIs). The p-values less than 0.05 were considered statistically significant. All statistical analyses were performed using IBM SPSS version 24.0 (IBM Corp.).
Results
Basic demographics and clinical characteristics of entire patients
In total, 94 patients were diagnosed with IgG4-RD, and the number of newly diagnosed patients in our cohort increased every year from one patient in 2009 to 23 patients in 2018 (Fig. 2). The basic demographic and clinical characteristics of all patients are presented in Table 1. The mean age at diagnosis of IgG4-RD was 54.8 ± 14.2 years, and the median follow-up duration was 32.9 months (IQR, 14.9–55.4 months). In total, 58 of 94 patients (61.7%) were male. Three patients (3.2%) had autoimmune diseases prior to IgG4-RD. One patient had systemic lupus erythematosus, and two patients had Sjögren syndrome. Five (5.3%) had been diagnosed with malignant diseases such as thyroid cancer (n = 1), breast cancer (n = 1), prostate cancer (n = 1), gastric cancer (n = 1), and craniopharyngioma (n = 1) before being diagnosed with IgG4-RD. Among them, four had no evidence of recurrence of the underlying malignant diseases at the time of IgG4-RD diagnosis. Only one patient with prostate cancer was treated with hormone therapy. Fifty-six patients (59.6%) with IgG4-RD experienced involvement of two or more organs. Patients presented with various symptoms based on the organs involved. Flank pain (n = 13, 13.8%) was the most common symptom, followed by abdominal pain (n = 12, 12.8%) and eyelid swelling (n = 12, 12.8%). Four patients (4.3%) complained of only fever. Five patients (5.3%) were incidentally found to have elevated serum creatinine levels without symptoms on medical examination. Further, 10 patients (10.6%) were incidentally diagnosed via imaging studies on medical examination. In total, 74 patients (78.7%) underwent biopsy of the involved organs. After biopsy, 44 patients (46.8%) were diagnosed with definite IgG4-RD. The median of serum IgG4 levels was 352 mg/dL (IQR, 124.9–942.3 mg/dL), and 62 patients (66.0%) had above 135 mg/dL in serum IgG4 levels. The patients with elevated serum ESR and serum hs-CRP were 40 patients (42.6%) and 42 patients (44.7%), respectively. Ten patients (10.6%) had hypocomplementemia with at least one decrease in C3 or C4. The distribution and proportion of involved organs are shown in Supplementary Table 1 (available online).
Differences in clinical features according to renal or retroperitoneal involvement
In total, 13 (13.8%) and 22 patients (23.4%) were classified into the RKD and the RPF group, respectively. The differences in clinical features among the three groups are presented in Table 1. Patients in the RKD (62.2 ± 10.8 years) and the RPF groups (60.1 ± 15.2 years) were statistically significantly older than those in the Others group (51.1 ± 13.3 years) (p = 0.004 and p = 0.02, respectively). The proportion of males in the RPF group was statistically significantly higher than that in the Others group (86.4% vs. 49.2%; p = 0.002). The prevalence of underlying diseases and the multiple-to-single organ involvement ratio were similar among the three groups. Symptoms related to the affected site were more common in the Others group compared to the RKD and the RPF groups (p = 0.03 and p = 0.03, respectively).
Based on the laboratory findings, renal function in the RKD (median serum creatinine, 1.45 mg/dL and mean CKD-EPI eGFR, 56.8 mL/min/1.73 m2) and the RPF groups (median serum creatinine, 1.03 mg/dL and mean CKD-EPI eGFR, 70.6 mL/min/1.73 m2) was statistically significantly worse than those in the Others group (median serum creatinine, 0.82 mg/dL and mean CKD-EPI eGFR, 94.3 mL/min/1.73 m2) (serum creatinine, p < 0.001 and CKD-EPI eGFR, p = 0.001). Eosinophilia was statistically significantly more common in the RKD group (38.5%) compared to the RPF (9.1%) or the Others groups (8.5%) (p = 0.01). Hypocomplementemia was statistically significantly more common in the RKD group compared to the Others groups (57.1% vs. 8.5%; p = 0.006). The mean of serum IgG levels and the proportion of elevated serum IgG4 levels were no differences with statistically significant among the three groups.
In the RKD group, all patients underwent histologic examination. Eleven of 13 patients (84.6%) underwent kidney biopsies, and two patients (15.4%) underwent biopsies for other affected organs, such as the lacrimal gland and bile duct. The final diagnosis of all renal tissue was tubulointerstitial nephritis (TIN). In the RPF group, 17 patients (77.3%) underwent histologic examination. Ten of them (45.5%) underwent biopsies for RPF lesions, and seven patients (31.8%) underwent for other affected organs.
Logistic regression analysis of the factors associated with IgG4-RKD and IgG4-RPF is presented in Table 2. In multivariate analysis, deteriorated renal function at the time of diagnosis and hypocomplementemia were associated with renal involvement (OR, 0.95 [95% CI, 0.91–0.98] and OR, 14.04 [95% CI, 1.38–142.95]; p = 0.002 and p = 0.03, respectively). The factors associated with retroperitoneal involvement were older at the time of diagnosis, male and higher serum IgG4 levels at the time of diagnosis (OR, 1.05 [95% CI, 1.00–1.11]; OR, 6.11 [95% CI, 1.41–26.61]; and OR, 1.00 [95% CI, 1.00–1.00]; p = 0.04, p = 0.02, and p = 0.03, respectively).
Comparison of treatment and clinical outcomes among the three groups
Differences in treatment strategies and responses among the three groups are presented in Table 3. The treatment durations of the RKD and the RPF groups were statistically significantly longer than that of the Others group (p = 0.04 and p = 0.01, respectively). The most common treatment was glucocorticoids (GCs) monotherapy for overall patients (n = 50, 53.2%) and for each group. In addition, GCs were administered in combination with other immunosuppressive agents (n = 18) or surgical resection (n = 9). Hence, 75 patients (79.8%) received GCs-based therapy in overall patients. In overall patients, the median initial GCs dose was 45 mg/day (as prednisolone), and the median maintenance dose was 5 mg/day (as prednisolone). There was no statistically significant difference among the three groups. The proportion of treatment strategies was similar among the three groups. In overall patients, nine patients (9.6%) had only regular followed-up without treatment. One of them was in the RKD group, and the other was in the Others group. Forty-six patients (48.9%) initially achieved a complete response to treatment. Two patients experienced disease progression in spite of treatment in the Others group. There was no statistically significant difference in initial response to treatment among the three groups. A comparison of the final outcome among the three groups is shown in Fig. 3. Thirty-nine patients (41.5%) achieved complete remission. There was no statistically significant difference among the three groups (p = 0.74). The relapse rate of the RKD group (30.8%, n = 4) was higher than those of the RPF (18.2%, n = 4) and the Others groups (16.9%, n = 10), but there was no statistically significant difference among the three groups (p = 0.74). In the RKD group, 11 patients (84.6%) who had initially complete or partial response to treatment had improvement in mean CKD-EPI eGFR from 55.4 mL/min/1.73 m2 to 64.7 mL/min/1.73 m2, and there were no patients undergoing renal replacement therapy for end-stage renal disease after completion of initial treatment. There were no deaths among the entire patients during the follow-up period.
Discussion
There were 94 cases of IgG4-RD during the 9.5-year study period. There were only one to five new cases per year within the first 6 years, and then it increased to more than 10 cases per year within the last 4 years. This finding showed that the diagnosis of IgG4-RD made by clinicians is increasing, and more cases of IgG4-RD may be reported in Korea.
This study is the first report to compare the clinical features of IgG4-RKD, IgG4-RPF, and IgG4-RD involving other organs in Korea. The clinical features of entire patients in our study were similar to those of previous studies reported from other countries in terms of sex, age, and organs involved [13–16,25]. The initial clinical symptoms varied depending on the site and severity of organ involvement. Fifteen patients (16.0%) were asymptomatic at the time of diagnosis, particularly in the RKD and RPF groups. Patients with kidney or retroperitoneum involvement showed decreased renal function at diagnosis compared to patients with other organs involvement. Uremic symptoms and signs such as nausea, vomiting, fatigue, anorexia, edema, and oliguria were expected to appear due to renal dysfunction. Uremic symptoms commonly tend to occur once creatinine clearance decreases below 10 to 20 mL/min [26]. However, because the number of patients in that finding was only two patients in the RKD group and only three patients in the RPF group, most patients with renal or retroperitoneal involvement were asymptomatic or diagnosed incidentally.
Despite the characteristic findings of IgG4-RD being evident in histological examinations, 34% of the patients did not meet the criteria based on serum IgG4 levels. In previous studies, an elevation of serum IgG4 levels has been reported to occur in approximately 55% to 97% of cases, indicating a relatively broad range of positivity [10,27]. Although useful for initial screening, there is a need for determining a cutoff value of serum IgG4, and a growing recognition of the necessity for new biomarkers. Recently, novel serological and cellular biomarkers, such as serum IgG2, serum IgG4:IgG RNA ratio, CD4 and/or CD8, and signaling lymphocytic activation molecule family member 7, have been proposed [27]. However, since the studies on these novel markers are still limited to a single or a small number of studies, further researches are needed.
A significantly higher proportion of hypocomplementemia was observed in the RKD group. Hypocomplementemia is known to be an important laboratory finding, especially in IgG4-RKD [4,12,28]. As known, hypocomplementemia is associated with the activity of the classical complement pathway, and serum IgG4 does not bind to complement component 1q, thereby not activating the classical complement pathway [5]. Several reports have described that patients with renal involvement exhibit high levels of serum circulating immune complexes and immune-complex deposition in the basement membranes of the renal tubules, suggesting an immune-complex mechanism [18,21]. Subtypes such as IgG1 or IgG3 are likely associated with the formation of immune complexes resulting in hypocomplementemia. In IgG4-RKD, other IgG subtypes such as IgG1, IgG2, and IgG3 are often elevated despite normal levels of serum IgG4 with hypocomplementemia [27]. Therefore, it is hypothesized that these subtypes and hypocomplementemia might become indicators of renal involvement, and it can be assumed there is a possibility of a pathophysiological mechanism unique to renal involvement that is distinct from other organ involvement.
In terms of renal histopathological findings, all patients had TIN. All glomerular and tubulointerstitial diseases including TIN, membranous nephropathy, immunoglobulin A nephropathy, mesangial proliferative and membranous proliferative glomerulonephritis can be noted in histopathological findings, and TIN is known as the most common finding [9,29].
The treatment duration was longer in the RKD and RPF groups compared to the Others group. The standard guidelines of treatment have not yet been established, but in general, several expert groups recommended that some patients with multi-organ disease, elevation of serum IgG4, peripheral eosinophilia, and organ dysfunction should be considered for maintenance treatment after induction treatment [27]. In the RKD and RPF groups, organ dysfunction with decreased renal function or eosinophilia was observed at the time of diagnosis. In some patients, immunosuppressive agents such as azathioprine, methotrexate, cyclosporine, tacrolimus, and mycophenolate mofetil were administered either as monotherapy or in combination therapy with GCs. A meta-analysis of 15 observational, uncontrolled, non-randomized clinical trials reported that patients treated with immunosuppressive agents and GCs in combination therapy had a higher remission rate than those given GCs monotherapy or immunosuppressive agents monotherapy [30]. Further studies are needed to demonstrate the efficacy of immunosuppressant monotherapy as GCs-sparing treatment in induction of remission. The proportions of patients who responded to the initial treatment (sum of complete response and partial response) were 84.6% for the RKD group, 95.5% for the RPF group, and 81.4% for the Others group, with no statistical differences among the groups. These treatment response rates were similar to previous studies [12,13,17,18]. There has been still no research on the differences in treatment response and treatment duration according to invaded organs. The proportion of patients who achieved complete remission and finished medical therapy was 38.5% for the RKD group, 45.5% for the RPF group, and 40.7% for the Others group. The proportion did not reach half in any of the groups. Even if there was an initial response to treatment, evidence of relapse or progression was observed during the process of discontinuing or reducing the medication, necessitating the maintenance of low-dose steroids. This is consistent with similar findings from previous studies [4,10,13,31]. With ongoing research into the diverse pathophysiology of IgG4-RD, there have been proposals for new drug therapies [27].
Our study had several limitations. First, this was a retrospective observational study. Second, the diagnosis and treatment strategy for IgG4-RD were inconsistent as physicians from different departments diagnosed disease, because IgG4-RD is a systemic disorder. As mentioned earlier, it is likely due to the lack of a universal consensus on treatment and regimen. However, there are international guidelines for diagnosis or generally recommended treatments that can provide medical evidence to physicians. Third, because the follow-up duration was short and there was a lack of standard tool for the assessment of disease outcomes, some data for assessment of treatment response and outcomes were missing. Despite these limitations, the biopsy rate was not low, with a rate of 78.7%, and all patients underwent imaging studies for IgG4-RD diagnosis.
In conclusion, our study demonstrated that renal and retroperitoneal involvement in IgG4-RD presented clinical features that distinguish it from other organs involvement, such as incidental diagnosis, hypocomplementemia, eosinophilia, and the need for a longer duration of maintenance treatment. These points may be helpful in diagnosing and management of IgG4-RKD or IgG4-RPF. However, uncertainty and questions regarding clinical differences according to the invaded organs, diagnosis, treatment, and long-term outcomes still remain. Further analyses and researches will be needed to establish a universal consensus for the various subsets of IgG4-RD.
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