Retrospective Cohort Evaluation of Renal Involvement in Non-HIV Castleman Disease Patients from a Single Academic Center in Beijing, China

Retrospective Cohort Evaluation of Renal Involvement in Non-HIV Castleman Disease Patients from a Single Academic Center in Beijing, China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Retrospective Cohort Evaluation of Renal Involvement in Non-HIV Castleman Disease Patients from a Single Academic Center in Beijing, China Hongtao Ling, Lihong Wang, Wei Wang, Xiaoying Yang, Wenqiong Wang, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8030031/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Jan, 2026 Read the published version in Annals of Hematology → Version 1 posted 9 You are reading this latest preprint version Abstract Castleman disease (CD), a rare and clinically heterogeneous condition, frequently involves renal impairment, though this relationship remains poorly characterized. This large cohort study of 183 patients (116 unicentric [UCD], 67 multicentric [MCD]) investigated renal involvement (RI). RI occurred in 6.03% (7/116) of UCD and 55.22% (37/67) of MCD patients. In UCD-RI, 4 underwent renal biopsy, revealing varied pathological results, and 1 underwent total left nephroureterectomy. In MCD-RI, common manifestations included edema, nephrotic syndrome, and acute renal failure. Thrombotic microangiopathy (TMA) was the most frequent renal pathology (9/19 biopsies). Acute renal failure often responded well to treatment, with 60% (9/15) achieving complete recovery. The 5-year renal survival rate in the MCD-RI group was 88.9%, not significantly different from UCD-RI (P = 0.45). Furthermore, the 5-year overall survival in the CD-RI group was 81.9%, showing no statistically significant difference from CD patients without renal involvement (P = 0.11). This study confirms that RI is more common in MCD, with TMA as a key pathological feature, and demonstrates that renal involvement does not negatively impact overall survival. Castleman disease renal involvement clinical characteristics renal pathology Figures Figure 1 Figure 2 Figure 3 1. Introduction Castleman disease (CD) is a rare lymphoproliferative disorder first described in 1956 [ 1 ] . Its position within the disease spectrum remains unclear, spanning hematology, oncology, rheumatology, and virology [ 2 ] . Clinically, CD is classified into unicentric (UCD) and multicentric (MCD) forms. As early as 2012, our hospital reported an initial cohort of CD patients with renal involvement, identifying thrombotic microangiopathy (TMA) as a common pathological feature [ 3 ] . This study describes a larger cohort from the same center in North China, focusing on renal involvement and prognosis in 183 CD patients. It is now widely accepted internationally that UCD and MCD are distinct entities, both in terms of clinical course and underlying pathogenesis [ 4 ][ 5 ] . Therefore, we have categorized renal involvement in Castleman disease into UCD and MCD groups, and will analyze and compare various clinical indicators and prognosis within each group. 2. Methods 2.1 Study Design and Participants This real-world, retrospective study enrolled patients diagnosed with CD at Peking University First Hospital between April 1, 2007, and April 30, 2025. The study was approved by the hospital's Ethics Committee, and all study procedures followed the ethical standards of the Declaration of Helsinki. Patients were rigorously screened according to the 2025 Chinese Castleman Disease Network (CCDN) guidelines [ 6 ] , excluding other diseases causing Castleman-like lymphadenopathy. All cases were diagnosed by experienced pathologists and confirmed based on their imaging studies (including CT, PET/CT) to determine the areas of lymph node involvement. Demographic, clinical, and laboratory data were collected retrospectively. We followed up with all patients via telephone and text message until July 2025. For lost-to-follow-up cases, we used the last visit date obtained from the Peking University First Hospital outpatient and inpatient medical record system as a substitute for the follow-up date. 2.2 Measurements and Definitions Castleman disease with renal involvement (CD-RI) was defined by the presence of at least one of the following: (1) hematuria, > 3 red blood cells per high-power field (HPF); (2) proteinuria, urinary protein > 150 mg/day; or (3) renal dysfunction, estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m². Other definitions in this study included: anemia defined as hemoglobin < 100 g/L, thrombocytopenia defined as platelets 15 mm/h for males and > 20 mm/h for females, elevated serum creatinine defined as > 133 µmol/L, hypoalbuminemia defined as plasma albumin 10 mg/L, elevated serum IgG defined as > 17 g/L, elevated interleukin-6 (IL-6) defined as > 6.4 pg/ml, and elevated vascular endothelial growth factor (VEGF) defined as > 142 pg/ml. Overall survival (OS) was defined as the time interval from the date of CD diagnosis to death from any cause or the last follow-up date. Renal survival rate was defined as the proportion of patients who maintained survival without dependence on hemodialysis or peritoneal dialysis. 2.3 Renal pathology Renal biopsy specimens were examined by direct immunofluorescence, light microscopy (LM), and electron microscopy (EM) techniques. Specimens were fixed in 4.5% buffered formaldehyde for LM, and part of the sample was fixed in 2.5% paraformaldehyde for EM. Consecutive serial 3-µm sections were used for histological staining. The following staining techniques were used: hematoxylin and eosin, periodic acid–Schiff, silver methenamine, and Masson's trichrome. EM was performed according to standard procedures. After being embedded in epon, ultrathin sections were mounted on metal grids and stained with uranyl acetate before being viewed in a transmission electron microscope (JEM-1230; JEOL, Tokyo, Japan). Amyloidosis was diagnosed with the aid of Congo red staining. The pathological diagnoses of all renal biopsies were reviewed and confirmed by two experienced pathologists. 2.4 Statistical Analysis Data were analyzed using SPSS 26.0 (IBM, Armonk, NY, USA) and R 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria). In descriptive statistics, categorical variables were presented as frequencies (percentages), and continuous variables as medians (interquartile range, IQR); percentages were calculated after excluding missing values. Group comparisons employed stratified analysis methods: unordered categorical variables used Fisher's exact test when cell expected frequencies were 0.05 for normal distribution), were analyzed using independent samples t-test for normally distributed data and the Mann-Whitney U test (for two groups) for non-normally distributed data. In survival analysis, Kaplan-Meier method was used to construct survival curves, and differences between groups were assessed by the Log-rank test. A P-value < 0.05 was considered statistically significant. 3. Results Of the 221 initially screened patients with Castleman-like features, 31 were excluded (SLE, POEMS, FDCS, lymphoma), and 7 were further excluded (missing data, diabetic nephropathy). The final cohort comprised 183 CD patients, classified as UCD (n = 116) and MCD (n = 67). Applying the CD-RI criteria, 7 were UCD with Renal Involvement (UCD-RI) and 37 were MCD with Renal Involvement (MCD-RI). Notably, we did not identify any HHV8-MCD patients in this cohort. (Fig. 1 ) 3.1 UCD-RI Among the 7 UCD-RI patients, 3 presented initially with symptoms such as edema and proteinuria and went directly to the Nephrology department, 1 patient presented to Respiratory Medicine, and 3 patients went directly to Surgery. The median age of the 7 patients was 34 years (range: 25–69), with a male-to-female ratio of 3:4. Regarding pathological type, 5 patients (71.4%) were diagnosed with the hyaline vascular (HV) type, and 2 (28.6%) with the plasma cell (PC) type. There were no statistically significant differences between the renal involvement and non-renal involvement groups in terms of gender ratio, age at diagnosis, time from onset to diagnosis, or pathological type. Among the 7 UCD-RI patients, 3 (42.9%) presented with at least one of the following: fever, fatigue, decreased appetite, and/or weight loss. Two patients (28.6%) had ascites and/or pleural effusion; no patients had pericardial effusion, hepatomegaly, or splenomegaly. Regarding renal manifestations, 5 patients (71.4%) presented clinically with hematuria, 3 (42.9%) with nephrotic syndrome, 1 (14.3%) with acute renal failure, and 1 (14.3%) with hydronephrosis of the left kidney due to compression by a mass in the left renal pelvis and ureter. Likely due to the small number of patients in the UCD-RI group, there were no statistically significant differences in anemia, thrombocytopenia, or serum creatinine. For elevated CRP, hsCRP, ESR, IL-6, and IgG, there was considerable missing data, most severely for VEGF, where no patient in the UCD-RI group had VEGF tested, and only 3 in the UCD-non-RI group did. In these aspects, there were no statistically significant differences between the two groups. (Table 1 ) Table 1 Laboratory parameters of UCD-RI patients UCD-RI UCD-non-RI P value (n = 7) (n = 109) Anemia, n(%) 1/7 (14.3%) 6/109 (5.5%) 0.361 Thrombocytopenia, n(%) 1/7 (14.3%) 1/109 (0.9%) 0.118 Hypoalbuminemia, n(%) 4/7 (57.1%) 31/106 (29.2%) 0.2 Scr, µmol/L 76.43(66-89.18) 66.35(58.4-79.75) 0.077 Elevated Scr 0/7 0/108 Elevated CRP, n(%) 2/3 (66.7%) 9/16 (56.3%) 1 Elevated hsCRP, n(%) 2/4 (50%) 15/38 (39.5%) 1 Elevated ESR, n(%) 3/5 (60%) 21/42 (50%) 1 Elevated IL-6, n(%) 1/3 (33.3%) 4/7 (57.1%) 1 Elevated VEGF, n(%) 0/0 3/3 (100%) Elevated IgG, n(%) 1/4 (25%) 4/22 (18.2%) 1 Four of the 7 patients underwent renal biopsy, revealing varied pathologies: TMA, focal segmental glomerulosclerosis (perihilar variant), membranous nephropathy, and ischemic kidney injury. (Fig. 2 ) The patient with the left renal pelvis and ureteral mass underwent left nephroureterectomy; pathology confirmed HV-type CD involving the renal tissue. 3.2 MCD-RI There were 37 MCD-RI cases. Among them, 22 patients presented initially with urinary system symptoms and went directly to Nephrology, 11 patients presented to Hematology, 2 to Gastroenterology, 1 to Respiratory Medicine, and 1 to Infectious Diseases. Compared to MCD-non-RI patients, there were no significant differences in gender ratio (59.5% vs. 46.7%, P = 0.296) or median age at diagnosis (52 years vs. 45 years, P = 0.233). The proportion of the mixed (Mix) pathological type was significantly higher in the MCD-RI group (43.2%) than in the MCD-non-RI group (13.3%) (P = 0.029). Regarding clinical subtypes, all iMCD-TAFRO cases exhibited renal involvement and were classified in the MCD-RI group, while all asymptomatic MCD (aMCD) cases were classified in the MCD-non-RI group; the difference between the two groups was statistically significant (P < 0.001). (Supplement Table 1 ) There were no significant statistical differences between MCD-RI and MCD-non-RI in the prevalence of fever (P = 0.176), night sweats (P = 0.684), or weight loss (P = 0.867). The proportions of patients with fatigue (73%) and decreased appetite (64.9%) were significantly higher in the MCD-RI group than in the MCD-non-RI group, with statistically significant differences (P < 0.001). The proportions of patients with pleural effusion (56.8%) and ascites (64.9%) in the MCD-RI group were higher than those in the MCD-non-RI group (pleural effusion 6.67%, ascites 3.33%), with statistically significant differences (P < 0.001). There were no significant differences between the two groups in hepatomegaly (P = 0.281), splenomegaly (P = 0.090), or rash (P = 0.650). (Supplement Table 2 ) Analysis of urinary symptom patterns(Supplement Fig. 1 ) revealed that isolated edema and the combination of edema with hematuria were the most common patterns (9/37 each). No cases presented with isolated oliguria. Four patients in the MCD-RI group had no specific urinary symptoms and were found to have elevated serum creatinine only during physical examination; these are not shown in the figure. The incidence rates of anemia, thrombocytopenia, and hypoalbuminemia were significantly higher in MCD-RI patients than in those without renal involvement (P < 0.05). For elevated CRP, ESR, IL-6, VEGF, and IgG, there was considerable missing data. A significant difference was observed only for elevated ESR (P = 0.016); there were no other statistically significant differences between the CD-RI and CD-non-RI groups for the remaining parameters. (Table 2 ) Table 2 Laboratory parameters of MCD-RI patients MCD-RI MCD-non-RI P value (n = 37) (n = 30) Anemia, n(%) 22/37 (59.5%) 8/30 (26.7%) 0.013 Thrombocytopenia, n(%) 11/37 (29.7%) 1/30 (3.3%) 0.005 Hypoalbuminemia, n(%) 34/37 (91.9%) 14/30 (46.7%) <0.001 Scr, µmol/L 146.06(107.95-246.35) 64.85(55.78–80.25) 133umol/L 23/37 (62.2%) 0 <0.001 eGFR<60, n(%) 30/37(81.1%) 0 <0.001 Positive occult blood in urine, n(%) 21/37(56.8%) 0 <0.001 Positive urine protein, n(%) 33/37(89.2%) 0 <0.001 Elevated CRP, n(%) 16/23 (69.6%) 7/15 (46.7%) 0.158 Elevated hsCRP, n(%) 13/20 (65%) 9/18 (50%) 0.35 Elevated ESR, n(%) 29/34 (85.3%) 13/23 (56.5%) 0.016 Elevated IL-6, n(%) 11/14 (78.6%) 8/11 (72.7%) 1 Elevated VEGF, n(%) 8/13 (61.5%) 1/5 (20%) 0.294 Elevated IgG, n(%) 15/33 (45.5%) 11/23 (47.8%) 0.861 Among the 37 MCD-RI patients, 14 had nephrotic syndrome, 14 had acute renal failure, 13 had chronic renal insufficiency, and 1 had rapidly progressive glomerulonephritis (RPGN). Seven patients required emergent renal replacement therapy, and 3 progressed to end-stage renal disease (ESRD). At initial treatment, 15 patients had an eGFR < 30 ml/min/1.73m², 15 had an eGFR between 30–60 ml/min/1.73m², and the remaining 7 had an eGFR greater than 60 ml/min/1.73m². Nineteen patients underwent renal biopsy. Among them, 9 patients had renal pathology showing TMA, with features of endothelial swelling, subendothelial space widening with double contour, or subendothelial accumulation of protein and debris. (Fig. 2 ) Other findings included 3 cases of IgG4-related disease, 3 cases of IgA nephropathy, 1 case of chronic tubulointerstitial nephritis (CTIN), 1 case of membranous nephropathy, 1 case of subacute tubulointerstitial nephritis, and 1 case of membranous nephropathy combined with type 2 crescentic glomerulonephritis. Both patients positive for anti-glomerular basement membrane (GBM) antibodies presented with RPGN; one did not undergo renal biopsy, and the other had pathology of membranous nephropathy combined with type 2 crescentic glomerulonephritis. Both patients positive for anti-neutrophil cytoplasmic antibodies (ANCA) underwent renal biopsy; one showed pathology of mild mesangial proliferative IgA nephropathy and presented with acute renal failure, and the other showed TMA without acute renal failure. Additionally, one patient presented with acute renal failure, and a Congo red stain of an abdominal wall fat biopsy showed amyloid deposition, but no renal biopsy was performed. 3.3 Clinical follow-up All UCD-RI patients underwent surgical resection. Three patients received glucocorticoid therapy, and two of them received glucocorticoids combined with cyclophosphamide. Among MCD-RI patients, 15 received lymphoma-like treatment regimens, 8 received myeloma-like regimens, 7 received glucocorticoids alone, 2 received glucocorticoids combined with cyclophosphamide, 1 received azathioprine combined with glucocorticoids, 3 were transferred to other hospitals for treatment, and 1 refused treatment. Among the 15 patients receiving lymphoma-like regimens, 4 received CHOP-like (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, and 11 received R-CHOP-like (rituximab plus CHOP) chemotherapy. Among the 8 patients receiving myeloma-like regimens, 1 received BCD (bortezomib, cyclophosphamide, dexamethasone) chemotherapy, and 7 received PD (pomalidomide, dexamethasone) or RD (lenalidomide, dexamethasone) regimens; one of these patients also received siltuximab. Fourteen of the 44 patients with renal involvement were lost to follow-up. The remaining 30 patients had a median follow-up time of 61 months (IQR: 20.5-107.75 months). Among the 15 patients with acute renal failure, 9 were considered recovered, 3 lacked post-treatment data, 3 progressed to ESRD, and 1 underwent kidney transplantation. Among the other 29 patients (Note: likely refers to the remaining CD-RI patients excluding the 15 with ARF, or total CD-RI follow-up group; context suggests possible slight inconsistency in total number referenced), 10 recovered completely with normalized renal function, 3 had partial recovery, 3 had persistent proteinuria, 8 lacked post-treatment data, and 5 showed no remission of renal dysfunction. Nine patients (9/30, 30.0%) with renal involvement and 14 patients (14/92, 15.2%) without renal involvement died during the follow-up period. One patient (1/9, 11.1%) in the renal involvement group died from renal failure; other causes of death included pancreatic cancer, infection, respiratory failure, etc. The 5-year renal survival rate in the MCD-RI group was 88.9% (Fig. 3 a), showing no statistically significant difference compared to the UCD-RI group (P = 0.45). The 5-year overall survival (OS) rate in the CD-RI group was 81.9% (Fig. 3 b, 95% CI, 120.38-170.97), which was not statistically significantly different from the CD-non-RI group (P = 0.11). 4. Discussion In this study, we characterized renal involvement in 183 Chinese patients with CD. Among them, 44 patients (24.0%) exhibited renal manifestations, including 7 with UCD and 37 with MCD, all of whom had been ruled out for common renal diseases (e.g., hypertension, diabetes, etc.). The most frequent clinical presentation was edema, while acute renal failure, nephrotic syndrome, and chronic renal insufficiency represented the predominant renal involvement patterns. Thrombotic microangiopathy-like lesions emerged as the most common pathological feature. Most patients recovered from acute renal failure. Notably, renal involvement did not affect overall survival during follow-up. It was previously believed that unicentric Castleman disease (UCD) rarely involved organ damage, except for potentially presenting with MCD-like systemic inflammatory reactions. This study included seven UCD patients with renal impairment, none of whom exhibited systemic inflammatory reactions. Their inflammatory markers—including ESR, CRP, hsCRP, and IL-6—showed no statistically significant differences compared to the UCD-non-RI group. Renal biopsy was performed in four of these patients, and the pathological findings varied considerably. One particularly notable case was asymptomatic and was only found to have left hydronephrosis caused by compression from a left ureteral mass on CT imaging, which is consistent with previous case reports of renal sinus Castleman disease [ 7 ] . Unlike those reports, however, pathological analysis in our case confirmed actual involvement of renal tissue, a feature shared with another reported case of renal pelvic Castleman disease [ 8 ] . Due to the rarity of Castleman disease and its atypical renal manifestations, the possibility of underdiagnosis or misdiagnosis remains substantial. In recent years, it has become increasingly clear that even HHV-8-negative MCD is not a homogeneous entity [ 9 ] . Renal involvement has been reported in 25%–54% of CD cases, which is consistent with the findings of our study (24.0%). Small vessel damage characterized by thrombotic microangiopathy (TMA) is a typical feature of renal involvement in HIV-negative MCD [ 3 ][ 10 ] . In this study, the MCD-RI group exhibited a higher prevalence of anemia, hypoalbuminemia, and elevated ESR compared to the MCD-non-RI group, which may be attributed to renal anemia and proteinuria. The higher incidence of thrombocytopenia is likely related to the inclusion of TAFRO subtype patients, all of whom presented with renal involvement. Notably, most patients in both the MCD-RI and MCD-non-RI groups showed varying degrees of elevated IL-6, suggesting a correlation between MCD pathogenesis and IL-6, consistent with previous studies [ 11 ][ 12 ] . The proportion of elevated VEGF levels was higher in the MCD-RI group (61.5%) than in the MCD-non-RI group (20%), implying a potential association between renal involvement and VEGF, though the difference was not statistically significant due to the small sample size. Flahault et al. linked renal TMA manifestations to preeclampsia (related to soluble Flt1, which blocks VEGF signaling) and renal lesions during anti-VEGF antibody therapy [ 13 ] . El Karoui et al. observed reduced glomerular VEGF expression only in some patients with renal TMA and found that loss of glomerular VEGF expression was associated with elevated plasma CRP levels [ 10 ] . Renal TMA with endothelial swelling has also been described in patients treated with VEGF antibodies or sirolimus. Decreased glomerular VEGF leads to loss of fenestrations essential for glomerular filtration barrier permeability, resulting in microvascular damage and TMA [ 14 ] . The study by Sun et al. confirmed that plasma VEGF levels were significantly elevated in CD patients with TMA compared to those without TMA, suggesting that elevated plasma VEGF may be associated with TMA rather than CD itself [ 15 ] . Regarding renal involvement and prognosis, although no statistically significant difference was observed between the CD-RI group and the CD-non-RI group (P = 0.11), this may be attributed to the relatively high number of lost-to-follow-up cases (33 patients) and an insufficient overall sample size, necessitating further expansion of the cohort for validation. Additionally, this study specifically introduced the concept of renal survival and found no significant difference in renal survival between the UCD and MCD subgroups (P = 0.45). Further comprehensive analysis incorporating other factors is required to draw more definitive conclusions. Only one patient presented with acute renal failure at onset, received treatment with corticosteroids combined with cyclophosphamide, and ultimately died due to renal failure. This finding contrasts with the conclusions reported by Zhang et al. in 2016 [ 5 ] . The discrepancy may be attributed to the following factors: i) Differences in inclusion criteria—our study classified patients with proteinuria into the CD-RI group even when renal function was normal; ii) Recent advances in treatment modalities may have contributed to improved patient outcomes. This study has several limitations. As a single-center investigation describing baseline characteristics and renal manifestations of CD, our findings may be subject to selection bias since our institution serves as a nephrology referral center with patients predominantly from North China. Additionally, the extended study period introduced confounding factors, including mortality from pancreatic cancer and other solid tumors, as well as COVID-19 and other infectious diseases during follow-up. Declarations Ethics approval and consent to participate The Ethics Committee of Peking University First Hospital approved this study (no. 2021[323]). Signed written consent was obtained from all patients. Consent for publication All patients approved the publication of this manuscript. Funding Information: This work was supported by Beijing Natural Science Foundation (7232175 and 7252135). Conflict of interest: The authors declare no competing financial interests. Author Contribution YD and LW conceptualized the research project. HL, Xiaoying Yang, Wenqiong Wang, SX, YZ and SG collected and analyzed the data. Wei Wang, YD, LW, WX, ZL, HL, and Xiaodi Yang managed patients and provided clinical data. HL wrote the original draft. YD, Xiaojuan Yu, and LW reviewed the manuscript. All authors have full access to all the data in the study and are ultimately responsible for the decision to submit for publication. Acknowledgement The authors would like to thank the Department of Pathology and the Renal Pathology Electron Microscopy Laboratory at Peking University First Hospital for providing the lymph node and renal pathology images. Data Availability The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. References Castleman B, Iverson L, Menendez VP. Localized mediastinal lymphnode hyperplasia resembling thymoma. Cancer. 1956;9(4):822-30. https://doi.org/10.1002/1097-0142(195607/08)9:43.0.co;2-4 Fajgenbaum DC, Uldrick TS, Bagg A, Frank D, Wu D, Srkalovic G, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-57. https://doi.org/10.1182/blood-2016-10-746933 Xu D, Lv J, Dong Y, Wang S, Su T, Zhou F, et al. Renal involvement in a large cohort of Chinese patients with Castleman disease. Nephrol Dial Transplant. 2012;27 Suppl 3:iii119-25. https://doi.org/10.1093/ndt/gfr245 Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020;135(16):1353-64. https://doi.org/10.1182/blood.2019000931 Zhang L, Li Z, Cao X, Feng J, Zhong D, Wang S, et al. Clinical spectrum and survival analysis of 145 cases of HIV-negative Castleman's disease: renal function is an important prognostic factor. Sci Rep. 2016;6:23831. https://doi.org/10.1038/srep23831 The guidelines for the diagnosis and treatment of Castleman disease in China (2025)]. Zhonghua Xue Ye Xue Za Zhi. 2025;46(3):216-22. https://doi.org/10.3760/cma.j.cn121090-20250101-00001 Zhang E, Li Y, Lang N. Case report: Castleman's disease involving the renal sinus resembling renal cell carcinoma. Front Surg. 2022;9:1001350. https://doi.org/10.3389/fsurg.2022.1001350 Fu D, Yang B, Yang M, Xu Z, Cheng W, Liu Z, et al. Misdiagnosis of renal pelvic unicentric Castleman disease: a case report. Front Surg. 2023;10:1225890. https://doi.org/10.3389/fsurg.2023.1225890 Hoffmann C, Hentrich M, Tiemann M, Rosenwald A, Weber F, Willenbacher W, et al. Recent Advances in Castleman Disease. Oncol Res Treat. 2022;45(11):693-704. https://doi.org/10.1159/000526640 El Karoui K, Vuiblet V, Dion D, Izzedine H, Guitard J, Frimat L, et al. Renal involvement in Castleman disease. Nephrol Dial Transplant. 2011;26(2):599-609. https://doi.org/10.1093/ndt/gfq427 Lang E, van Rhee F. Idiopathic multicentric Castleman disease: An update in diagnosis and treatment advances. Blood Rev. 2024;64:101161. https://doi.org/10.1016/j.blre.2023.101161 Alonzi T, Gorgoni B, Screpanti I, Gulino A, Poli V. Interleukin-6 and CAAT/enhancer binding protein beta-deficient mice act as tools to dissect the IL-6 signalling pathway and IL-6 regulation. Immunobiology. 1997;198(1-3):144-56. https://doi.org/10.1016/s0171-2985(97)80035-6 Flahault A, Vignon M, Rabant M, Hummel A, Noël LH, Canioni D, et al. Case report and literature review: Glomerular and neurologic thrombotic microangiopathy as a primary manifestation of multicentric castleman disease. Medicine (Baltimore). 2016;95(41):e5047. https://doi.org/10.1097/md.0000000000005047 Ozeki T, Tsuji M, Yamamoto J, Shigematsu C, Maruyama S. Thrombotic microangiopathy on kidney biopsy in a patient with TAFRO syndrome. CEN Case Rep. 2018;7(2):243-7. https://doi.org/10.1007/s13730-018-0338-x Sun PP, Yu XJ, Wang SX, Zhou XJ, Qu L, Zhang F, et al. Association of vascular endothelial growth factor and renal thrombotic microangiopathy-like lesions in patients with Castleman's disease. Nephrology (Carlton). 2020;25(2):125-34. https://doi.org/10.1111/nep.13630 Additional Declarations No competing interests reported. Supplementary Files Supplement.xlsx Cite Share Download PDF Status: Published Journal Publication published 15 Jan, 2026 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 30 Nov, 2025 Reviews received at journal 29 Nov, 2025 Reviews received at journal 16 Nov, 2025 Reviewers agreed at journal 11 Nov, 2025 Reviewers agreed at journal 11 Nov, 2025 Reviewers invited by journal 11 Nov, 2025 Editor assigned by journal 11 Nov, 2025 Submission checks completed at journal 11 Nov, 2025 First submitted to journal 04 Nov, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8030031","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":545750216,"identity":"3c8fc685-2cc4-49f1-a009-2222d592f51c","order_by":0,"name":"Hongtao Ling","email":"","orcid":"","institution":"Peking University First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hongtao","middleName":"","lastName":"Ling","suffix":""},{"id":545750217,"identity":"7f34935c-0ab3-4198-9fd9-8f7269c92825","order_by":1,"name":"Lihong Wang","email":"","orcid":"","institution":"Peking University First 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Huihui","middleName":"","lastName":"Liu","suffix":""},{"id":545750227,"identity":"1297f760-c5fd-4b5b-971d-065f36e3c4b4","order_by":11,"name":"Xiaodi Yang","email":"","orcid":"","institution":"Peking University First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaodi","middleName":"","lastName":"Yang","suffix":""},{"id":545750228,"identity":"68a299a2-404d-4144-826f-d49a4c178bb9","order_by":12,"name":"Xiaojuan Yu","email":"","orcid":"","institution":"Peking University First Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaojuan","middleName":"","lastName":"Yu","suffix":""},{"id":545750229,"identity":"8dd52beb-9fa7-4075-ac03-ba3feaa4144d","order_by":13,"name":"Yujun Dong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYDCCAyCiAkwygwjGBuK0nCFZC2MbKVr4jvcefs077449fwPvYWMeBhvZDQeYnz3Ap0XyzLk0a95tzxJnHOBLTuZhSDPecIDN3ACfFoMbOWbGvNsOJxgw8Bgf5mE4nLjhAA+bBGEtcw7bQ7X8J0qL8WPehsOMG4BagA47QFiL5JkzZoxzjh1OnHGYL9lwjkGy8czDbGZ4tfAd7zH+8KbmsD1/e+9hiTcVdrJ9x5uf4dUCBGxSPCCKGUSCgoqZgHqQko8/wDQPYaWjYBSMglEwMgEAmHNJwV7Ppb0AAAAASUVORK5CYII=","orcid":"","institution":"Peking University First Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yujun","middleName":"","lastName":"Dong","suffix":""}],"badges":[],"createdAt":"2025-11-04 14:38:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8030031/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8030031/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-026-06739-1","type":"published","date":"2026-01-15T16:30:32+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":96492908,"identity":"6b494b73-a668-46b4-b663-71313f141bc8","added_by":"auto","created_at":"2025-11-21 18:12:53","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1475310,"visible":true,"origin":"","legend":"","description":"","filename":"RetrospectiveCohortEvaluationofRenalInvolvementinNonHIVCastlemanDiseasePatientsfromaSingleAcademicCenterinBeijingChina.docx","url":"https://assets-eu.researchsquare.com/files/rs-8030031/v1/c23cebd9e8a4c56496d331fa.docx"},{"id":96492906,"identity":"7ef0ff87-46d4-43e7-824a-a9cee72d9a2c","added_by":"auto","created_at":"2025-11-21 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18:12:53","extension":"html","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":79037,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8030031/v1/f10c6a06303d7b3cf3bdbbfd.html"},{"id":96492905,"identity":"f0f94753-c1a5-44e0-94a4-57c129751167","added_by":"auto","created_at":"2025-11-21 18:12:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":60374,"visible":true,"origin":"","legend":"\u003cp\u003ePatient selection and classification flowchart.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8030031/v1/8f8125590639371e4ec14bcf.png"},{"id":96604266,"identity":"6fea3aaa-e2de-471b-a04d-4012cd977772","added_by":"auto","created_at":"2025-11-24 09:13:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1322915,"visible":true,"origin":"","legend":"\u003cp\u003epresents lymph node and renal pathology from two patients. a-d (Patient 1): Hyaline vascular (HV) lymph node and membranous nephropathy. (a) Hematoxylin and eosin (HE) ×20: Onion-skin appearance. (b) PASM+Masson ×400: Subepithelial immune deposits. (c) Electron microscopy (EM) \u0026amp; (d) immunofluorescence electron microscopy: Subepithelial/intramembranous electron-dense deposits. e-h (Patient 2): Mixed-type lymph node and thrombotic microangiopathy (TMA). (e) HE ×20: Onion-skin appearance. (f) CD138 ×20: Sheets of plasma cells. (g) PASM+Masson ×400: Segmental double contours. (h) EM: No electron-dense deposits.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8030031/v1/b4837a1ff31b3f51d5b75bb9.png"},{"id":96492910,"identity":"bf4f4eac-062c-424d-93c9-156043c78f92","added_by":"auto","created_at":"2025-11-21 18:12:53","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":78277,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup overall survival analysis. A Renal survival analysis based on clinical subtypes; B overall survival analysis of CD patients based on with/without renal involvement.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8030031/v1/8b94873c62feffe0e7a2124b.png"},{"id":100617631,"identity":"8f4f90d2-c2da-4172-b667-c842bdfc6353","added_by":"auto","created_at":"2026-01-19 17:54:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2182403,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8030031/v1/6d09dc8b-149d-4cc6-96e5-bb7fb576840b.pdf"},{"id":96604424,"identity":"a1213b66-2552-44b1-a0d2-bb9b4b6899d3","added_by":"auto","created_at":"2025-11-24 09:13:54","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":80036,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-8030031/v1/803bd35b08c773aee571022f.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Retrospective Cohort Evaluation of Renal Involvement in Non-HIV Castleman Disease Patients from a Single Academic Center in Beijing, China","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCastleman disease (CD) is a rare lymphoproliferative disorder first described in 1956\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Its position within the disease spectrum remains unclear, spanning hematology, oncology, rheumatology, and virology\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Clinically, CD is classified into unicentric (UCD) and multicentric (MCD) forms. As early as 2012, our hospital reported an initial cohort of CD patients with renal involvement, identifying thrombotic microangiopathy (TMA) as a common pathological feature\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. This study describes a larger cohort from the same center in North China, focusing on renal involvement and prognosis in 183 CD patients. It is now widely accepted internationally that UCD and MCD are distinct entities, both in terms of clinical course and underlying pathogenesis\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e][\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Therefore, we have categorized renal involvement in Castleman disease into UCD and MCD groups, and will analyze and compare various clinical indicators and prognosis within each group.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003ch2\u003e2.1 Study Design and Participants\u003c/h2\u003e\u003cp\u003eThis real-world, retrospective study enrolled patients diagnosed with CD at Peking University First Hospital between April 1, 2007, and April 30, 2025. The study was approved by the hospital's Ethics Committee, and all study procedures followed the ethical standards of the Declaration of Helsinki. Patients were rigorously screened according to the 2025 Chinese Castleman Disease Network (CCDN) guidelines\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, excluding other diseases causing Castleman-like lymphadenopathy. All cases were diagnosed by experienced pathologists and confirmed based on their imaging studies (including CT, PET/CT) to determine the areas of lymph node involvement. Demographic, clinical, and laboratory data were collected retrospectively. We followed up with all patients via telephone and text message until July 2025. For lost-to-follow-up cases, we used the last visit date obtained from the Peking University First Hospital outpatient and inpatient medical record system as a substitute for the follow-up date.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Measurements and Definitions\u003c/h2\u003e\u003cp\u003eCastleman disease with renal involvement (CD-RI) was defined by the presence of at least one of the following: (1) hematuria, \u0026gt;\u0026thinsp;3 red blood cells per high-power field (HPF); (2) proteinuria, urinary protein\u0026thinsp;\u0026gt;\u0026thinsp;150 mg/day; or (3) renal dysfunction, estimated glomerular filtration rate (eGFR)\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min/1.73m\u0026sup2;. Other definitions in this study included: anemia defined as hemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;100 g/L, thrombocytopenia defined as platelets\u0026thinsp;\u0026lt;\u0026thinsp;100 \u0026times; 10⁹/L\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e, elevated erythrocyte sedimentation rate (ESR) defined as \u0026gt;\u0026thinsp;15 mm/h for males and \u0026gt;\u0026thinsp;20 mm/h for females, elevated serum creatinine defined as \u0026gt;\u0026thinsp;133 \u0026micro;mol/L, hypoalbuminemia defined as plasma albumin\u0026thinsp;\u0026lt;\u0026thinsp;35 g/L, elevated C-reactive protein (CRP) defined as \u0026gt;\u0026thinsp;10 mg/L, elevated serum IgG defined as \u0026gt;\u0026thinsp;17 g/L, elevated interleukin-6 (IL-6) defined as \u0026gt;\u0026thinsp;6.4 pg/ml, and elevated vascular endothelial growth factor (VEGF) defined as \u0026gt;\u0026thinsp;142 pg/ml. Overall survival (OS) was defined as the time interval from the date of CD diagnosis to death from any cause or the last follow-up date. Renal survival rate was defined as the proportion of patients who maintained survival without dependence on hemodialysis or peritoneal dialysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Renal pathology\u003c/h2\u003e\u003cp\u003eRenal biopsy specimens were examined by direct immunofluorescence, light microscopy (LM), and electron microscopy (EM) techniques. Specimens were fixed in 4.5% buffered formaldehyde for LM, and part of the sample was fixed in 2.5% paraformaldehyde for EM. Consecutive serial 3-\u0026micro;m sections were used for histological staining. The following staining techniques were used: hematoxylin and eosin, periodic acid\u0026ndash;Schiff, silver methenamine, and Masson's trichrome. EM was performed according to standard procedures. After being embedded in epon, ultrathin sections were mounted on metal grids and stained with uranyl acetate before being viewed in a transmission electron microscope (JEM-1230; JEOL, Tokyo, Japan). Amyloidosis was diagnosed with the aid of Congo red staining. The pathological diagnoses of all renal biopsies were reviewed and confirmed by two experienced pathologists.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Statistical Analysis\u003c/h2\u003e\u003cp\u003eData were analyzed using SPSS 26.0 (IBM, Armonk, NY, USA) and R 4.5.1 (R Foundation for Statistical Computing, Vienna, Austria). In descriptive statistics, categorical variables were presented as frequencies (percentages), and continuous variables as medians (interquartile range, IQR); percentages were calculated after excluding missing values. Group comparisons employed stratified analysis methods: unordered categorical variables used Fisher's exact test when cell expected frequencies were \u0026lt;\u0026thinsp;5, and Pearson's chi-square test when \u0026ge;\u0026thinsp;5; ordered categorical variables used the Wilcoxon signed-rank test; continuous variables, after Shapiro normality test (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05 for normal distribution), were analyzed using independent samples t-test for normally distributed data and the Mann-Whitney U test (for two groups) for non-normally distributed data. In survival analysis, Kaplan-Meier method was used to construct survival curves, and differences between groups were assessed by the Log-rank test. A P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eOf the 221 initially screened patients with Castleman-like features, 31 were excluded (SLE, POEMS, FDCS, lymphoma), and 7 were further excluded (missing data, diabetic nephropathy). The final cohort comprised 183 CD patients, classified as UCD (n\u0026thinsp;=\u0026thinsp;116) and MCD (n\u0026thinsp;=\u0026thinsp;67). Applying the CD-RI criteria, 7 were UCD with Renal Involvement (UCD-RI) and 37 were MCD with Renal Involvement (MCD-RI). Notably, we did not identify any HHV8-MCD patients in this cohort. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.1 UCD-RI\u003c/h2\u003e\u003cp\u003eAmong the 7 UCD-RI patients, 3 presented initially with symptoms such as edema and proteinuria and went directly to the Nephrology department, 1 patient presented to Respiratory Medicine, and 3 patients went directly to Surgery. The median age of the 7 patients was 34 years (range: 25\u0026ndash;69), with a male-to-female ratio of 3:4. Regarding pathological type, 5 patients (71.4%) were diagnosed with the hyaline vascular (HV) type, and 2 (28.6%) with the plasma cell (PC) type. There were no statistically significant differences between the renal involvement and non-renal involvement groups in terms of gender ratio, age at diagnosis, time from onset to diagnosis, or pathological type.\u003c/p\u003e\u003cp\u003eAmong the 7 UCD-RI patients, 3 (42.9%) presented with at least one of the following: fever, fatigue, decreased appetite, and/or weight loss. Two patients (28.6%) had ascites and/or pleural effusion; no patients had pericardial effusion, hepatomegaly, or splenomegaly. Regarding renal manifestations, 5 patients (71.4%) presented clinically with hematuria, 3 (42.9%) with nephrotic syndrome, 1 (14.3%) with acute renal failure, and 1 (14.3%) with hydronephrosis of the left kidney due to compression by a mass in the left renal pelvis and ureter.\u003c/p\u003e\u003cp\u003eLikely due to the small number of patients in the UCD-RI group, there were no statistically significant differences in anemia, thrombocytopenia, or serum creatinine. For elevated CRP, hsCRP, ESR, IL-6, and IgG, there was considerable missing data, most severely for VEGF, where no patient in the UCD-RI group had VEGF tested, and only 3 in the UCD-non-RI group did. In these aspects, there were no statistically significant differences between the two groups. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLaboratory parameters of UCD-RI patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUCD-RI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUCD-non-RI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;7)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;109)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnemia, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1/7 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6/109 (5.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.361\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThrombocytopenia, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1/7 (14.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/109 (0.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.118\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypoalbuminemia, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4/7 (57.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31/106 (29.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScr, \u0026micro;mol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e76.43(66-89.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e66.35(58.4-79.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.077\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated Scr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0/7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0/108\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated CRP, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2/3 (66.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9/16 (56.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated hsCRP, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2/4 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15/38 (39.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated ESR, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3/5 (60%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21/42 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated IL-6, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1/3 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4/7 (57.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated VEGF, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0/0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3/3 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated IgG, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1/4 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4/22 (18.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFour of the 7 patients underwent renal biopsy, revealing varied pathologies: TMA, focal segmental glomerulosclerosis (perihilar variant), membranous nephropathy, and ischemic kidney injury. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) The patient with the left renal pelvis and ureteral mass underwent left nephroureterectomy; pathology confirmed HV-type CD involving the renal tissue.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.2 MCD-RI\u003c/h2\u003e\u003cp\u003eThere were 37 MCD-RI cases. Among them, 22 patients presented initially with urinary system symptoms and went directly to Nephrology, 11 patients presented to Hematology, 2 to Gastroenterology, 1 to Respiratory Medicine, and 1 to Infectious Diseases. Compared to MCD-non-RI patients, there were no significant differences in gender ratio (59.5% vs. 46.7%, P\u0026thinsp;=\u0026thinsp;0.296) or median age at diagnosis (52 years vs. 45 years, P\u0026thinsp;=\u0026thinsp;0.233). The proportion of the mixed (Mix) pathological type was significantly higher in the MCD-RI group (43.2%) than in the MCD-non-RI group (13.3%) (P\u0026thinsp;=\u0026thinsp;0.029). Regarding clinical subtypes, all iMCD-TAFRO cases exhibited renal involvement and were classified in the MCD-RI group, while all asymptomatic MCD (aMCD) cases were classified in the MCD-non-RI group; the difference between the two groups was statistically significant (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). (Supplement Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eThere were no significant statistical differences between MCD-RI and MCD-non-RI in the prevalence of fever (P\u0026thinsp;=\u0026thinsp;0.176), night sweats (P\u0026thinsp;=\u0026thinsp;0.684), or weight loss (P\u0026thinsp;=\u0026thinsp;0.867). The proportions of patients with fatigue (73%) and decreased appetite (64.9%) were significantly higher in the MCD-RI group than in the MCD-non-RI group, with statistically significant differences (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The proportions of patients with pleural effusion (56.8%) and ascites (64.9%) in the MCD-RI group were higher than those in the MCD-non-RI group (pleural effusion 6.67%, ascites 3.33%), with statistically significant differences (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). There were no significant differences between the two groups in hepatomegaly (P\u0026thinsp;=\u0026thinsp;0.281), splenomegaly (P\u0026thinsp;=\u0026thinsp;0.090), or rash (P\u0026thinsp;=\u0026thinsp;0.650). (Supplement Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003cp\u003eAnalysis of urinary symptom patterns(Supplement Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) revealed that isolated edema and the combination of edema with hematuria were the most common patterns (9/37 each). No cases presented with isolated oliguria. Four patients in the MCD-RI group had no specific urinary symptoms and were found to have elevated serum creatinine only during physical examination; these are not shown in the figure.\u003c/p\u003e\u003cp\u003eThe incidence rates of anemia, thrombocytopenia, and hypoalbuminemia were significantly higher in MCD-RI patients than in those without renal involvement (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). For elevated CRP, ESR, IL-6, VEGF, and IgG, there was considerable missing data. A significant difference was observed only for elevated ESR (P\u0026thinsp;=\u0026thinsp;0.016); there were no other statistically significant differences between the CD-RI and CD-non-RI groups for the remaining parameters. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLaboratory parameters of MCD-RI patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMCD-RI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMCD-non-RI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eP value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnemia, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22/37 (59.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8/30 (26.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.013\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThrombocytopenia, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11/37 (29.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/30 (3.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypoalbuminemia, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34/37 (91.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14/30 (46.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScr, \u0026micro;mol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e146.06(107.95-246.35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e64.85(55.78\u0026ndash;80.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScr\u0026gt;133umol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23/37 (62.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eeGFR\u0026lt;60, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30/37(81.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive occult blood in urine, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21/37(56.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePositive urine protein, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33/37(89.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated CRP, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16/23 (69.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7/15 (46.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.158\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated hsCRP, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13/20 (65%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9/18 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated ESR, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29/34 (85.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13/23 (56.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.016\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated IL-6, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11/14 (78.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8/11 (72.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated VEGF, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8/13 (61.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1/5 (20%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.294\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eElevated IgG, n(%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15/33 (45.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11/23 (47.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.861\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAmong the 37 MCD-RI patients, 14 had nephrotic syndrome, 14 had acute renal failure, 13 had chronic renal insufficiency, and 1 had rapidly progressive glomerulonephritis (RPGN). Seven patients required emergent renal replacement therapy, and 3 progressed to end-stage renal disease (ESRD). At initial treatment, 15 patients had an eGFR\u0026thinsp;\u0026lt;\u0026thinsp;30 ml/min/1.73m\u0026sup2;, 15 had an eGFR between 30\u0026ndash;60 ml/min/1.73m\u0026sup2;, and the remaining 7 had an eGFR greater than 60 ml/min/1.73m\u0026sup2;.\u003c/p\u003e\u003cp\u003eNineteen patients underwent renal biopsy. Among them, 9 patients had renal pathology showing TMA, with features of endothelial swelling, subendothelial space widening with double contour, or subendothelial accumulation of protein and debris. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) Other findings included 3 cases of IgG4-related disease, 3 cases of IgA nephropathy, 1 case of chronic tubulointerstitial nephritis (CTIN), 1 case of membranous nephropathy, 1 case of subacute tubulointerstitial nephritis, and 1 case of membranous nephropathy combined with type 2 crescentic glomerulonephritis. Both patients positive for anti-glomerular basement membrane (GBM) antibodies presented with RPGN; one did not undergo renal biopsy, and the other had pathology of membranous nephropathy combined with type 2 crescentic glomerulonephritis. Both patients positive for anti-neutrophil cytoplasmic antibodies (ANCA) underwent renal biopsy; one showed pathology of mild mesangial proliferative IgA nephropathy and presented with acute renal failure, and the other showed TMA without acute renal failure. Additionally, one patient presented with acute renal failure, and a Congo red stain of an abdominal wall fat biopsy showed amyloid deposition, but no renal biopsy was performed.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Clinical follow-up\u003c/h2\u003e\u003cp\u003eAll UCD-RI patients underwent surgical resection. Three patients received glucocorticoid therapy, and two of them received glucocorticoids combined with cyclophosphamide. Among MCD-RI patients, 15 received lymphoma-like treatment regimens, 8 received myeloma-like regimens, 7 received glucocorticoids alone, 2 received glucocorticoids combined with cyclophosphamide, 1 received azathioprine combined with glucocorticoids, 3 were transferred to other hospitals for treatment, and 1 refused treatment. Among the 15 patients receiving lymphoma-like regimens, 4 received CHOP-like (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, and 11 received R-CHOP-like (rituximab plus CHOP) chemotherapy. Among the 8 patients receiving myeloma-like regimens, 1 received BCD (bortezomib, cyclophosphamide, dexamethasone) chemotherapy, and 7 received PD (pomalidomide, dexamethasone) or RD (lenalidomide, dexamethasone) regimens; one of these patients also received siltuximab.\u003c/p\u003e\u003cp\u003eFourteen of the 44 patients with renal involvement were lost to follow-up. The remaining 30 patients had a median follow-up time of 61 months (IQR: 20.5-107.75 months). Among the 15 patients with acute renal failure, 9 were considered recovered, 3 lacked post-treatment data, 3 progressed to ESRD, and 1 underwent kidney transplantation. Among the other 29 patients (Note: likely refers to the remaining CD-RI patients excluding the 15 with ARF, or total CD-RI follow-up group; context suggests possible slight inconsistency in total number referenced), 10 recovered completely with normalized renal function, 3 had partial recovery, 3 had persistent proteinuria, 8 lacked post-treatment data, and 5 showed no remission of renal dysfunction.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eNine patients (9/30, 30.0%) with renal involvement and 14 patients (14/92, 15.2%) without renal involvement died during the follow-up period. One patient (1/9, 11.1%) in the renal involvement group died from renal failure; other causes of death included pancreatic cancer, infection, respiratory failure, etc. The 5-year renal survival rate in the MCD-RI group was 88.9% (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea), showing no statistically significant difference compared to the UCD-RI group (P\u0026thinsp;=\u0026thinsp;0.45). The 5-year overall survival (OS) rate in the CD-RI group was 81.9% (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb, 95% CI, 120.38-170.97), which was not statistically significantly different from the CD-non-RI group (P\u0026thinsp;=\u0026thinsp;0.11).\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn this study, we characterized renal involvement in 183 Chinese patients with CD. Among them, 44 patients (24.0%) exhibited renal manifestations, including 7 with UCD and 37 with MCD, all of whom had been ruled out for common renal diseases (e.g., hypertension, diabetes, etc.). The most frequent clinical presentation was edema, while acute renal failure, nephrotic syndrome, and chronic renal insufficiency represented the predominant renal involvement patterns. Thrombotic microangiopathy-like lesions emerged as the most common pathological feature. Most patients recovered from acute renal failure. Notably, renal involvement did not affect overall survival during follow-up.\u003c/p\u003e\u003cp\u003eIt was previously believed that unicentric Castleman disease (UCD) rarely involved organ damage, except for potentially presenting with MCD-like systemic inflammatory reactions. This study included seven UCD patients with renal impairment, none of whom exhibited systemic inflammatory reactions. Their inflammatory markers\u0026mdash;including ESR, CRP, hsCRP, and IL-6\u0026mdash;showed no statistically significant differences compared to the UCD-non-RI group. Renal biopsy was performed in four of these patients, and the pathological findings varied considerably. One particularly notable case was asymptomatic and was only found to have left hydronephrosis caused by compression from a left ureteral mass on CT imaging, which is consistent with previous case reports of renal sinus Castleman disease \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Unlike those reports, however, pathological analysis in our case confirmed actual involvement of renal tissue, a feature shared with another reported case of renal pelvic Castleman disease \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Due to the rarity of Castleman disease and its atypical renal manifestations, the possibility of underdiagnosis or misdiagnosis remains substantial.\u003c/p\u003e\u003cp\u003eIn recent years, it has become increasingly clear that even HHV-8-negative MCD is not a homogeneous entity\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Renal involvement has been reported in 25%\u0026ndash;54% of CD cases, which is consistent with the findings of our study (24.0%). Small vessel damage characterized by thrombotic microangiopathy (TMA) is a typical feature of renal involvement in HIV-negative MCD \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e][\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. In this study, the MCD-RI group exhibited a higher prevalence of anemia, hypoalbuminemia, and elevated ESR compared to the MCD-non-RI group, which may be attributed to renal anemia and proteinuria. The higher incidence of thrombocytopenia is likely related to the inclusion of TAFRO subtype patients, all of whom presented with renal involvement. Notably, most patients in both the MCD-RI and MCD-non-RI groups showed varying degrees of elevated IL-6, suggesting a correlation between MCD pathogenesis and IL-6, consistent with previous studies \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e][\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. The proportion of elevated VEGF levels was higher in the MCD-RI group (61.5%) than in the MCD-non-RI group (20%), implying a potential association between renal involvement and VEGF, though the difference was not statistically significant due to the small sample size. Flahault et al. linked renal TMA manifestations to preeclampsia (related to soluble Flt1, which blocks VEGF signaling) and renal lesions during anti-VEGF antibody therapy \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. El Karoui et al. observed reduced glomerular VEGF expression only in some patients with renal TMA and found that loss of glomerular VEGF expression was associated with elevated plasma CRP levels\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Renal TMA with endothelial swelling has also been described in patients treated with VEGF antibodies or sirolimus. Decreased glomerular VEGF leads to loss of fenestrations essential for glomerular filtration barrier permeability, resulting in microvascular damage and TMA \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. The study by Sun et al. confirmed that plasma VEGF levels were significantly elevated in CD patients with TMA compared to those without TMA, suggesting that elevated plasma VEGF may be associated with TMA rather than CD itself \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eRegarding renal involvement and prognosis, although no statistically significant difference was observed between the CD-RI group and the CD-non-RI group (P\u0026thinsp;=\u0026thinsp;0.11), this may be attributed to the relatively high number of lost-to-follow-up cases (33 patients) and an insufficient overall sample size, necessitating further expansion of the cohort for validation. Additionally, this study specifically introduced the concept of renal survival and found no significant difference in renal survival between the UCD and MCD subgroups (P\u0026thinsp;=\u0026thinsp;0.45). Further comprehensive analysis incorporating other factors is required to draw more definitive conclusions. Only one patient presented with acute renal failure at onset, received treatment with corticosteroids combined with cyclophosphamide, and ultimately died due to renal failure. This finding contrasts with the conclusions reported by Zhang et al. in 2016 \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. The discrepancy may be attributed to the following factors: i) Differences in inclusion criteria\u0026mdash;our study classified patients with proteinuria into the CD-RI group even when renal function was normal; ii) Recent advances in treatment modalities may have contributed to improved patient outcomes.\u003c/p\u003e\u003cp\u003eThis study has several limitations. As a single-center investigation describing baseline characteristics and renal manifestations of CD, our findings may be subject to selection bias since our institution serves as a nephrology referral center with patients predominantly from North China. Additionally, the extended study period introduced confounding factors, including mortality from pancreatic cancer and other solid tumors, as well as COVID-19 and other infectious diseases during follow-up.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\u003cp\u003e The Ethics Committee of Peking University First Hospital approved this study (no. 2021[323]). Signed written consent was obtained from all patients.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003eAll patients approved the publication of this manuscript.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding Information:\u003c/h2\u003e\u003cp\u003eThis work was supported by Beijing Natural Science Foundation (7232175 and 7252135).\u003c/p\u003e\u003cp\u003eConflict of interest: The authors declare no competing financial interests.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eYD and LW conceptualized the research project. HL, Xiaoying Yang, Wenqiong Wang, SX, YZ and SG collected and analyzed the data. Wei Wang, YD, LW, WX, ZL, HL, and Xiaodi Yang managed patients and provided clinical data. HL wrote the original draft. YD, Xiaojuan Yu, and LW reviewed the manuscript. All authors have full access to all the data in the study and are ultimately responsible for the decision to submit for publication.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors would like to thank the Department of Pathology and the Renal Pathology Electron Microscopy Laboratory at Peking University First Hospital for providing the lymph node and renal pathology images.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCastleman B, Iverson L, Menendez VP. Localized mediastinal lymphnode hyperplasia resembling thymoma. Cancer. 1956;9(4):822-30. \u0026nbsp; https://doi.org/10.1002/1097-0142(195607/08)9:4\u0026lt;822::aid-cncr2820090430\u0026gt;3.0.co;2-4\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eFajgenbaum DC, Uldrick TS, Bagg A, Frank D, Wu D, Srkalovic G, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-57. \u0026nbsp;https://doi.org/10.1182/blood-2016-10-746933\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eXu D, Lv J, Dong Y, Wang S, Su T, Zhou F, et al. Renal involvement in a large cohort of Chinese patients with Castleman disease. Nephrol Dial Transplant. 2012;27 Suppl 3:iii119-25. https://doi.org/10.1093/ndt/gfr245\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020;135(16):1353-64. https://doi.org/10.1182/blood.2019000931\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eZhang L, Li Z, Cao X, Feng J, Zhong D, Wang S, et al. Clinical spectrum and survival analysis of 145 cases of HIV-negative Castleman\u0026apos;s disease: renal function is an important prognostic factor. Sci Rep. 2016;6:23831. https://doi.org/10.1038/srep23831\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe guidelines for the diagnosis and treatment of Castleman disease in China (2025)]. Zhonghua Xue Ye Xue Za Zhi. 2025;46(3):216-22. https://doi.org/10.3760/cma.j.cn121090-20250101-00001\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eZhang E, Li Y, Lang N. Case report: Castleman\u0026apos;s disease involving the renal sinus resembling renal cell carcinoma. Front Surg. 2022;9:1001350. https://doi.org/10.3389/fsurg.2022.1001350\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eFu D, Yang B, Yang M, Xu Z, Cheng W, Liu Z, et al. Misdiagnosis of renal pelvic unicentric Castleman disease: a case report. Front Surg. 2023;10:1225890. https://doi.org/10.3389/fsurg.2023.1225890\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHoffmann C, Hentrich M, Tiemann M, Rosenwald A, Weber F, Willenbacher W, et al. Recent Advances in Castleman Disease. Oncol Res Treat. 2022;45(11):693-704. https://doi.org/10.1159/000526640\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eEl Karoui K, Vuiblet V, Dion D, Izzedine H, Guitard J, Frimat L, et al. Renal involvement in Castleman disease. Nephrol Dial Transplant. 2011;26(2):599-609. https://doi.org/10.1093/ndt/gfq427\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLang E, van Rhee F. Idiopathic multicentric Castleman disease: An update in diagnosis and treatment advances. Blood Rev. 2024;64:101161. https://doi.org/10.1016/j.blre.2023.101161\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAlonzi T, Gorgoni B, Screpanti I, Gulino A, Poli V. Interleukin-6 and CAAT/enhancer binding protein beta-deficient mice act as tools to dissect the IL-6 signalling pathway and IL-6 regulation. Immunobiology. 1997;198(1-3):144-56. https://doi.org/10.1016/s0171-2985(97)80035-6\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eFlahault A, Vignon M, Rabant M, Hummel A, No\u0026euml;l LH, Canioni D, et al. Case report and literature review: Glomerular and neurologic thrombotic microangiopathy as a primary manifestation of multicentric castleman disease. Medicine (Baltimore). 2016;95(41):e5047. https://doi.org/10.1097/md.0000000000005047\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eOzeki T, Tsuji M, Yamamoto J, Shigematsu C, Maruyama S. Thrombotic microangiopathy on kidney biopsy in a patient with TAFRO syndrome. CEN Case Rep. 2018;7(2):243-7. https://doi.org/10.1007/s13730-018-0338-x\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSun PP, Yu XJ, Wang SX, Zhou XJ, Qu L, Zhang F, et al. Association of vascular endothelial growth factor and renal thrombotic microangiopathy-like lesions in patients with Castleman\u0026apos;s disease. Nephrology (Carlton). 2020;25(2):125-34. https://doi.org/10.1111/nep.13630\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Castleman disease, renal involvement, clinical characteristics, renal pathology","lastPublishedDoi":"10.21203/rs.3.rs-8030031/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8030031/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCastleman disease (CD), a rare and clinically heterogeneous condition, frequently involves renal impairment, though this relationship remains poorly characterized. This large cohort study of 183 patients (116 unicentric [UCD], 67 multicentric [MCD]) investigated renal involvement (RI). RI occurred in 6.03% (7/116) of UCD and 55.22% (37/67) of MCD patients. In UCD-RI, 4 underwent renal biopsy, revealing varied pathological results, and 1 underwent total left nephroureterectomy. In MCD-RI, common manifestations included edema, nephrotic syndrome, and acute renal failure. Thrombotic microangiopathy (TMA) was the most frequent renal pathology (9/19 biopsies). Acute renal failure often responded well to treatment, with 60% (9/15) achieving complete recovery. The 5-year renal survival rate in the MCD-RI group was 88.9%, not significantly different from UCD-RI (P\u0026thinsp;=\u0026thinsp;0.45). Furthermore, the 5-year overall survival in the CD-RI group was 81.9%, showing no statistically significant difference from CD patients without renal involvement (P\u0026thinsp;=\u0026thinsp;0.11). This study confirms that RI is more common in MCD, with TMA as a key pathological feature, and demonstrates that renal involvement does not negatively impact overall survival.\u003c/p\u003e","manuscriptTitle":"Retrospective Cohort Evaluation of Renal Involvement in Non-HIV Castleman Disease Patients from a Single Academic Center in Beijing, China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-21 18:12:48","doi":"10.21203/rs.3.rs-8030031/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-30T06:19:16+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-29T23:53:43+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-16T10:36:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"159265158193811959900541609050181752851","date":"2025-11-11T22:58:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"61968343978949301221136468865798685461","date":"2025-11-11T21:01:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-11T14:42:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-11T10:48:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-11T10:48:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-11-04T14:34:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5746c776-b13f-4958-a808-c5786ce46211","owner":[],"postedDate":"November 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-19T17:25:24+00:00","versionOfRecord":{"articleIdentity":"rs-8030031","link":"https://doi.org/10.1007/s00277-026-06739-1","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2026-01-15 16:30:32","publishedOnDateReadable":"January 15th, 2026"},"versionCreatedAt":"2025-11-21 18:12:48","video":"","vorDoi":"10.1007/s00277-026-06739-1","vorDoiUrl":"https://doi.org/10.1007/s00277-026-06739-1","workflowStages":[]},"version":"v1","identity":"rs-8030031","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8030031","identity":"rs-8030031","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}