In this study, we collaborated with 12 university and 8 related hospitals to collect clinical data on 144 RPF patients. The study was a retrospective investigation aimed at fact-finding; therefore, statistical analysis was problematic due to missing values (data) as well as differences among hospitals in diagnostic and treatment strategies, and evaluation of outcomes. However, recent real RPF treatment data in the Kyushu-Okinawa area was available, allowing this fact-finding study to include the largest number of Japanese patients to date.
Diagnosis of RPF was based on imaging studies performed by attending physicians in each hospital with or without pathological diagnosis. The primary diagnostic finding for inclusion was presence of fibrotic tissue in retroperitoneal lesion. Presence of ureteral obstruction or inflammation were not required for inclusion. Coexistence of malignancy in different lesions was included. Patient history of radiation and surgical intervention in retroperitoneal area were included as secondary RPF. No patients had apparent systemic infectious disease. According to our criteria, 15 patients were classified as secondary RPF, and 129 patients were diagnosed with iRPF. However, prompt establishment of exact global diagnostic criteria is strongly recommended.
In our study, mean age at diagnosis was slightly higher than that published in previous reports2–7. Although this was not a population-based study, male predominance was apparent with a male-to-female ratio of 5.1: 1.0. The result was higher than that found in the literature2–7. As a risk factor, a significant association between RPF and smoking has been reported. In this case-control study, the risk was higher (odds ratio of 3.21) in current smokers and former smokers (odds ratio of 2.93) compared with individuals with no history of smoking 10. Indeed, a high incidence (59.6%) of smoking history was observed in our study, and the result is consistent with previous reports. RPF has been reported to include chronic periaortitis, perianeurysmal fibrosis and inflammatory abdominal aortic aneurysm, which suggests a meaningful correlation between arteriosclerotic disease and RPF2–6. Compared with previous studies, the incidence of arteriosclerotic disease as a comorbidity was high (32.8%), and the incidence of autoimmune disease was similar (14.3%) in the current study2–6. In addition, results of 17 patients administered aspirin and beta-adrenergic blocker may correlate with arteriosclerotic disease.
Outcome of iRPF in reduction of size and/or urinary tract improvement was evaluated for a total of 126 patients in this study. As a result, glucocorticoid therapy achieved a favorable response rate (84%), and ureteral stent was removed in 53.4% of the patients. The response rate was slightly higher than previous reports2–6. The results indicate the apparent efficacy of glucocorticoid, and that glucocorticoid therapy is a standard first-line treatment for iRPF. As the next step, standardization of treatment protocol is necessary. In the literature, the recommended treatment strategy is an initial dose of 0.6-1mg/kg/day of prednisolone for 2-4 weeks, with the dosage gradually tapered to 2.5-5mg/day over a period of greater than 6 months2. Tanaka et al. suggested the convenience of treatment initiated with 0.6mg/kg/day of prednisolone for 4weeks, and then a 10% reduction in dosage every 2 weeks for IgG4-related disease (IgG4RD)5. Indeed, median initial dose was 30mg for 26.5 days in the current study, and a total of 46% of the patients started with 30mg/day of prednisolone. The results of our study were similar to the protocol for IgG4RD, and the efficacy seemed to be acceptable. No significant differences were noted between responder group and non-responder group in treatment dose and period in both initial and maintenance phase. However, the maintenance treatment period in non-responder group seemed to be longer than in responder group, which suggests unnecessarily prolonged treatment. A prospective study analyzing both efficacy and safety would be helpful in establishing a standard protocol for iRPF.
Recently, the majority of idiopathic RPF has been classified as IgG4RD, and greater than half of idiopathic RPF patients were reported to have been diagnosed with IgG4RD by histological examination4. However, the exact pathophysiology is controversial due to the fact that fundamental IgG4RD is a systemic disease, whereas RPF occurs in a limited area of the retroperitoneum. Frequency of concurrent RPF in IgG4RD has been reported as 3-19%11, and approximately 60% of RPF is reported to be associated with IgG4RD12. However, no systematic analysis of a large cohort to evaluate the association with IgG4RD has been conducted. In the current study, only 7 cases were diagnosed as IgG4RD by pathological analysis; however, a total of 69 patients were analyzed for serum IgG4 concentration, and elevation (cut-off value of <125mg/dL) was observed in 43 patients (62.3%). Interestingly, patients with high serum IgG4 concentration showed a favorable response to glucocorticoid therapy. In spite of the limitation of our study, statistical significance was observed. Although the exact number of potentially overlapped IgG4RD could not be evaluated, serum IgG4 concentration may be a candidate as a predictive biomarker of glucocorticoid therapy. In this study, acceptable AUC (0.793) was observed, and cut-off value was calculated as 67.6 mg/dL. However, the values of sensitivity and specificity (0.85 and 0.636) might not be sufficient as cut-off levels. Further prospective examination is recommended to clarify our result.
A tendency of high serum IgG and low sIL-2R concentration was also observed in the favorable response group; however, no statistical significance was observed (Figure 2b-c). Serum sIL2-R was examined to rule out malignant lymphoma. As a result, increased serum level was observed in 74.5%; however, the degree of increase was not significant compared with that of malignant lymphoma13. RPF is also associated with inflammation. In addition, infiltration of both B cells (and/or IgG4-positive plasma cell) and T cells has also been confirmed pathologically. Therefore, the phenomenon may not be a disease-specific result; however, our investigation revealed that this is the first time that elevated serum sIL2-R level has been described in RPF.
As mentioned above, limitations of our study are its being a retrospective investigation, which created obstacles to accurate statistical analysis due to missing values (data), and differences among hospitals in diagnostic and treatment strategies as well as evaluation of outcomes.