This retrospective study analyzed the ultrasonographic features of IgG4-related kidney disease (IgG4-RKD) in patients diagnosed between January 2015 and December 2023. The studies involving humans were approved by the Institutional Review Board of Peking University First Hospital, Beijing, China. All procedures were conducted in accordance with institutional and national ethical standards. The requirement for written informed consent was waived due to the retrospective nature of the study.

We identified 15 patients with biopsy-confirmed IgG4-RKD from the medical records at Peking University First Hospital. Inclusion criteria were: (1) pathologically confirmed IgG4-RKD according to the 2011 and 2020 IgG4-RKD diagnostic criteria (12, 15); (2) availability of complete renal ultrasonographic examination data; and (3) complete clinical and laboratory data. Patients with concurrent kidney diseases that could confound ultrasonographic findings (such as diabetic nephropathy, lupus nephritis, or other primary glomerulonephritis) were excluded. Specifically for lupus nephritis, all patients were screened, and those positive for antinuclear antibodies (ANA) were confirmed to not have systemic lupus erythematosus based on negative anti-dsDNA antibody results and a failure to meet the 2012 Systemic Lupus International Collaborating Clinics classification criteria or the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus.

All patients underwent standardized renal ultrasonography using high-resolution ultrasound systems (GE Logiq 9, GE Logiq E9, Philips HDI 5000, Philips EPIQ 7, Aloka Prosound F75, Esaote Mylab90, Toshiba Aplio 500) with 1–5 MHz convex transducers. Although multiple ultrasound systems were used, all examinations followed standardized image acquisition protocols to minimize inter-device variability. Examinations were performed by experienced sonographers who were blinded to the patients’ clinical information. Both gray-scale and color Doppler imaging were performed in all patients. Gray-scale evaluation included kidney size measurements, parenchymal thickness assessment, echogenicity and corticomedullary differentiation evaluation, and documentation of focal lesions. Doppler evaluation with resistive index (RI) measurement in interlobar arteries was available in 66.7% (10/15) of patients.

Ultrasonographic images were retrospectively reviewed by two ultrasound radiologists (with 8 and 10 years of experience, respectively), who were blinded to clinical outcomes. Discrepancies were resolved by consensus. The following parameters were evaluated:

Renal size and morphology: Kidney length was categorized as enlarged (>12 cm), normal (9–12 cm), or small (<9 cm) (16).

Parenchymal characteristics: Parenchymal thickness, echogenicity (normal, increased, or heterogeneous), and corticomedullary differentiation (preserved or impaired).

Focal lesions: Presence of hypoechoic/anechoic areas or hyperechoic foci.

Associated findings: Presence of hydronephrosis, calculi, or simple cysts.

Hemodynamic parameters: Renal arterial resistive index (RI), with values >0.7 considered elevated (17).

The diagnosis for all patients was pathologically confirmed using formalin-fixed, paraffin-embedded tissue obtained from percutaneous core needle biopsies. No surgical nephrectomy specimens were included in this study.

For light microscopy, 3-μm sections were stained with Hematoxylin and Eosin, Periodic acid–Schiff, Masson’s trichrome, and Jones methenamine silver. For immunofluorescence, 3-μm cryostat sections were stained with polyclonal fluorescein isothiocyanate-conjugated antibodies to IgG, IgM, IgA, C3, C1q, and fibrinogen.

Immunohistochemical staining was performed on 3-μm paraffin-embedded sections. The staining was performed manually. After antigen retrieval by pronase digestion, the sections were blocked with peroxidase-blocking buffer (Zhongshan Golden Bridge, ZSGB-BIO, China) for 20 min at room temperature and 3% BSA for 30 min at 37 °C, and then incubated with polyclonal rabbit anti-human IgG (1:100 dilution, Dako, F0202) and IgG4 (1:500 dilution, Dako, A0136). Secondary antibodies were applied and detection was performed using a polymer-based detection system (Zhongshan Golden Bridge, ZSGB-BIO, China) with diaminobenzidine as the chromogen. Random visual fields were acquired on a DM2500 light macroscope (Leica, Wetzlar, Germany). The diagnostic criteria for IgG4-RKD on histopathology included the presence of >10 IgG4-positive plasma cells per high-power field (HPF) and a ratio of IgG4-positive to IgG-positive plasma cells >40%.

For electron microscopy, specimens were fixed in 2.5% glutaraldehyde, postfixed in 1% osmium tetroxide, and embedded in Epon 812 resin. Ultrathin sections were stained with uranyl acetate and lead citrate and examined by a transmission electron microscope (JEM-1400 flash, Jeol, Tokyo, Japan).

All statistical analyses were performed using SPSS software (version 26.0, IBM, Armonk, NY). Continuous variables were assessed for normality and presented as mean ± standard deviation (SD) for normally distributed data, or as median (range) for non-normally distributed data. For key laboratory parameters such as serum creatinine and IgG4, both metrics were reported to fully characterize their distribution. Categorical variables were presented as percentages. All percentages were calculated based on the number of patients with available data for each specific parameter.

Correlations between ultrasonographic features and clinical/laboratory parameters were analyzed using Fisher’s exact test for categorical variables and Student’s t-test or Mann–Whitney U test for continuous variables. Correlations between two continuous variables, such as sonographic measurements and laboratory parameters, were assessed using the Pearson or Spearman rank correlation coefficient. The concordance between specific sonographic features and histopathological findings was evaluated using cross-tabulation, and sensitivity was calculated to assess the ability of an ultrasound sign to detect a specific pathology within the patient cohort.

A two-tailed p-value of < 0.05 was considered statistically significant.

The study included 15 patients with biopsy-confirmed IgG4-RKD, comprising 13 males (86.7%) and 2 females (13.3%). The mean age at diagnosis was 63.7 ± 7.9 years (range: 48–80 years). The median duration of disease prior to diagnosis was 11 months (range: 1 week to 11 years). Among these patients, 33.3% (5/15) had a disease duration of 6 months or less, 40.0% (6/15) had a duration between 6 months and 2 years, and 26.7% (4/15) had a duration greater than 2 years.

The initial clinical manifestations that led to medical attention varied among patients. Elevated serum creatinine was detected incidentally in 60.0% (9/15) of patients during routine examinations or evaluations for other conditions. Symptomatic urinary abnormalities, including proteinuria and increased urinary foam, were the primary complaint in 20.0% (3/15) of patients. Additional presentations included poor appetite (13.3%, 2/15) and polyuria with weight loss (6.7%, 1/15).

Two patterns of disease onset were observed. In 26.7% (4/15) of patients, renal manifestations were the initial presentation of IgG4-related disease. In the majority of cases (73.3%, 11/15), renal involvement was diagnosed subsequently, following the identification of IgG4-related disease in other organs.

Multi-organ involvement was a common feature, with 60.0% (9/15) of patients having three or more organs affected. Specifically, 20.0% (3/15) had isolated renal disease, 20.0% (3/15) had two organs involved, and 46.7% (7/15) had extensive disease affecting five or more organs. Beyond the kidneys (100%), the most frequently involved organs were lymph nodes (60.0%), lungs (46.7%), pancreas (26.7%), and bile ducts (26.7%).

As shown in Table 1, laboratory evaluation revealed several key features. Impaired renal function was common, with 86.7% of patients presenting with elevated serum creatinine (median: 218.0 μmol/L).

The defining serological characteristic was markedly elevated serum IgG4, found in all patients (100%), with a mean of 2.54 ± 1.49 g/L (median: 2.80; range: 1.36–4.92 g/L). Hypocomplementemia was also common, with C3 and C4 levels reduced in 100 and 81.8% of tested patients, respectively. Other notable immunological and inflammatory markers included an elevated IgG4/IgG ratio (in 42.9% of those tested), ANA positivity (33.3%), elevated IgE (71.4%), and high levels of ESR and CRP.

Pathological analysis of renal biopsies demonstrated characteristic histopathological features of IgG4-RKD. Glomerular structures were predominantly preserved, with 66.7% (10/15) of biopsies showing no significant glomerular abnormalities, while ischemic sclerosis was seen in 13.3%. In contrast, widespread tubular changes were present in 86.7% (13/15) of biopsies, including tubular atrophy, degeneration, lysosomal accumulation in the tubular epithelium (53.3%), and microvilli detachment (33.3%). The most prominent changes were interstitial; a dense inflammatory cell infiltration was observed in 86.7% of biopsies, composed of lymphocytes (86.7%), plasma cells (80.0%), and fewer eosinophils (26.7%). Interstitial fibrosis, frequently displaying the characteristic “storiform” pattern, was identified in 73.3% of biopsies (Figure 1A). Immunohistochemical staining for IgG4 was performed on seven patients (46.7% of the cohort) (Figure 1B). All seven of these patients showed a dense infiltration of IgG4-positive plasma cells (>10/HPF). However, only three of these seven patients also met the criterion for an elevated IgG4/IgG ratio (>40%). Electron microscopy findings were supportive of the diagnosis, revealing interstitial infiltration by plasma cells and the characteristic finding of sparse, granular electron-dense deposits within the tubular basement membranes.

The ultrasonographic findings for the 15 patients are detailed in Table 2. The predominant pattern was bilateral renal involvement, observed in 93.3% (14/15) of patients, with the majority also having well-preserved renal contours (93.3%).

While the mean renal length was within the upper limits of normal at 11.8 ± 1.0 cm for the right kidney and 11.6 ± 0.9 cm for the left, further analysis revealed that 20.0% (3/15) of right kidneys and 33.3% (5/15) of left kidneys measured >12 cm in length. Overall, 40.0% of patients (6/15) had at least one enlarged kidney (>12 cm). No atrophic kidneys (<9 cm) were found in the cohort.

The most characteristic parenchymal abnormalities were increased echogenicity, present in 73.3% (11/15) of patients, and a heterogeneous echotexture, seen in 60.0% (9/15). Impaired corticomedullary differentiation was also common, observed in 60.0% of cases. Furthermore, multiple focal hypoechoic or anechoic areas were a notable finding in 46.7% (7/15) of patients, while punctate hyperechoic foci were identified in 33.3% (5/15).

Doppler analysis was available for 10 patients (66.7%), revealing a mean resistive index (RI) of 0.67 ± 0.08 (range: 0.56–0.81). An elevated RI (>0.7) was present in 40.0% (4/10) of these patients. The distribution of RI values was as follows: 20.0% were between 0.5–0.6, 40.0% between 0.61–0.7, 30.0% between 0.71–0.8, and 10.0% were >0.8.

Notably, one patient (6.7%) presented with a right renal focal mass-like lesion that was initially misdiagnosed as renal cell carcinoma, appearing as a heterogeneous, hypoechoic mass on grayscale imaging (Figure 2A) with only peripheral vascularity on color Doppler (Figure 2B). Other associated findings were also documented; hydronephrosis was absent in all cases, while renal calculi and simple cysts were detected in 20.0 and 26.7% of patients, respectively.

While individual ultrasonographic abnormalities were frequent, the combination of features provided a more consistent pattern in identifying patients with IgG4-RKD. The presence of at least two of the primary abnormalities (renal enlargement, increased/heterogeneous echogenicity, hypoechoic areas, or an elevated RI) was observed in a large majority of the cohort (86.7%). Furthermore, a combination of at least three of these key features was found in 53.3% of patients.

Specific combinations were also analyzed. A pattern of renal enlargement combined with increased echogenicity was present in 60.0% of patients, while a combination of heterogeneous echotexture and multiple hypoechoic areas was seen in 40.0%. The triad of renal enlargement, heterogeneous echogenicity, and an elevated RI was observed in 26.7% of patients.

Key ultrasonographic features showed high concordance with specific histopathological changes. Heterogeneous echogenicity was a sensitive indicator of underlying interstitial fibrosis (90.9% sensitivity, 84.6% concordance). The presence of multiple hypoechoic areas corresponded well with focal inflammatory infiltrates (83.3% sensitivity, 76.9% concordance). An elevated RI (>0.7) was suggestive of microvascular pathology (75.0% sensitivity, 70.0% concordance), while punctate hyperechoic foci were associated with calcifications or crystal deposits.

Twelve of the 15 patients were treated. Glucocorticoids were the primary treatment in all treated patients (100%, 12/12), predominantly as prednisone/prednisolone (91.7%, 11/12) with methylprednisolone used in one case (8.3%, 1/12). Most received glucocorticoid monotherapy (75.0%, 9/12), while some had combination therapy with immunosuppressants (16.7%, 2/12) or immunomodulators (8.3%, 1/12).

Treatment response was favorable in all followed patients (100%, 10/10), with significant improvement in 60.0% (6/10) and partial improvement in 40.0% (4/10). Serum creatinine decreased in all cases. Follow-up ultrasonography, performed at a median of 6 months (range: 3–12 months) after treatment initiation and available for 6 of the 10 treated patients, showed kidney size reduction in 83.3% (5/6) and improved echogenicity in 66.7% (4/6). Hypoechoic areas demonstrated the most rapid response, with resolution in 75.0% (3/4) of relevant cases.

Baseline ultrasonographic features correlated with treatment outcomes, with better functional recovery in patients showing milder initial echogenicity changes.