**1. Introduction**

The prevalence of obesity has been rising regardless of age, sex, and race for the past few decades [1] and is a growing public healthcare concern worldwide [2–4]. Obesity has been implicated in the development of several chronic comorbidities, including type 2 diabetes mellitus, hypertension, cardiovascular disease, stroke, dyslipidemia, obstructive sleep apnea, fatty liver and biliary disease, osteoarthritis, and malignancies, leading to increased cardiovascular and all-cause mortality [5–7]. Obesity is also associated with a significantly increased risk of chronic kidney disease (CKD) progression and development of end-stage renal disease (ESRD) [8,9].

The renal e ffects of obesity include both structural and functional adaptations. Excessive body weight is related to intrarenal hemodynamic parameters, namely increased renal blood flow and hyperfiltration. Pathologically, this promotes low glomerular density with glomerulomegaly and thickening of the glomerular basement membrane (GBM) [10–12]. These glomerular changes are defined as obesity-related glomerulopathy, a secondary form of focal segmental glomerulosclerosis (FSGS) [13]. Clinically, obesity-related glomerulopathy presents with subnephrotic or nephrotic-range proteinuria without other features of nephrotic syndrome and rapid loss of kidney function [14,15]. In addition to obesity-related glomerulopathy, obesity may be a risk factor for progression of IgA nephropathy (IgAN) [16–21]. Most studies demonstrated that excessive BMI, especially a BMI greater than 25 kg/m2, was a risk factor for renal disease progression in IgAN patients [16,17]. On the other hand, BMI was not an independent predictor for IgAN progression in some reports [18,22]. Furthermore, recent research showed that underweight, rather than obesity, was an independent risk factor for progression to ESRD, which might be associated with malnutrition status [21]. Therefore, it is di fficult to conclude the overall e ffect of BMI on progression of IgAN with the existing evidence. This may be due to the complex pathophysiological association among obesity, metabolic abnormalities, and renal outcomes.

To date, there are few studies regarding the e ffect of obesity on histopathological changes in IgAN. Therefore, we conducted a multi-center cohort study using a kidney biopsy registry to elucidate the complex association between obesity and the clinicopathological characteristics of IgAN in Korea. We focused on the impact of obesity on histopathologic and clinical severity at the time of kidney biopsy in IgAN.

#### **2. Materials and Methods**

#### *2.1. Study Design and Data Source*

This was a cross-sectional study of a multi-center cohort that included patients older than 18 who underwent kidney biopsy at eight university hospitals a ffiliated with the College of Medicine Catholic University of Korea between January 2015 and November 2019. This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of the College of Medicine, Catholic University of Korea (XC19OEDI0025). Written informed consent was obtained from patients at the time of biopsy.

We retrospectively collected records from patients with primary IgAN. We excluded 20 out of 557 patients diagnosed with IgAN whose histologic descriptive form was not in accordance with others. A total of 537 patients were finally enrolled in the present study. Patients with Henoch-Schonlein purpura nephritis were ineligible. Patients were divided into three groups according to body mass index (BMI). BMI was calculated as (weight in kilograms)/(height in meters)2. Subjects were categorized according to the Asia-Pacific obesity classification as follows: underweight (<18.5 kg/m2), normal weight/overweight (18.5–24.9 kg/m2), and obese (≥25 kg/m2) [23]. The BMI cut-o ffs in the World Health Organization (WHO) classification have categorized BMI 25–29.9 as overweight and ≥30 kg/m<sup>2</sup> as obese [24]. The Asia-Pacific classification of BMI has a lower cut-o ff for overweight and obese categories compared to the WHO classification. Because the Korean Society for the Study of Obesity defined obesity as BMI ≥ 25 kg/m<sup>2</sup> according to the Asia-Pacific obesity classification [25], we used a

cut-o ff point for BMI of 25 kg/m<sup>2</sup> in the present study. A flow diagram for patient selection is presented in Figure S1 (Supplementary Materials).

#### *2.2. Data Collection and Definitions*

Using the database from the Kidney Biopsy Registry of Catholic Medical Center, all patients were admitted for kidney biopsy and we collected the following data at the time of kidney biopsy. Baseline demographics and clinical data ([including age, sex, height, weight, BMI, co-morbidities, systolic blood pressure (SBP), diastolic blood pressure (DBP), laboratory data, and treatment characteristics) were collected. Blood chemistry data included hemoglobin, high sensitivity-C-reactive protein (hs-CRP), fasting glucose, creatinine, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), uric acid, total cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), serum complement 3 (C3), complement 4 (C4), and serum IgA levels. Proteinuria was assessed by 24 h urine collection. The estimated glomerular filtration rate (eGFR) was calculated from the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [26]. The degree of urinary red blood cells (RBC) sediment was scored in five phases, as follows: <3 RBCs/high power field (HPF), 0; 3–5 RBCs/HPF, 1; 5–9 RBCs/HPF, 2; 10–19 RBCs/HPF, 3; and more than 19 RBCs/HPF, 4. We also assessed treatment plans after the diagnosis of IgAN, including use of anti-hypertensive medications, diuretics, lipid-lowering drugs, and immunosuppressive medications.

## *2.3. Histopathologic Parameters*

All kidney tissue specimens were obtained by percutaneous needle biopsy. Pathologic slides were reviewed by expert renal pathologists in each center. On light microscopy, the total number of glomeruli and the percentage of glomerulosclerosis and crescents were assessed quantitatively. Renal histologic findings were scored according to the histologic grading system from our university as follows. The severity of mesangial matrix expansion (MME), mesangial cell proliferation, endocapillary proliferation, interstitial fibrosis (IF), tubular atrophy (TA), arterial intimal hyalinosis, and fibrous vessel wall thickening were semi-quantitatively graded from 0 to 4 as follows: grade 0, absent; grade 1, trace (<20%); grade 2, mild (20%–40%); grade 3, moderate (40%–70%); and grade 4, severe (≥70%). Renal biopsy findings were also assessed according to the Oxford classification (MEST score) [27] or the WHO classification (class I to VI) [28]. On immunofluorescence microscopy, the severity of mesangial deposition of IgA, C3, and C4d were graded as 0 (absent), +1 (trace), +2 (mild), +3 (moderate), and +4 (marked).

## *2.4. Statistical Analysis*

Continuous data were expressed as mean ± standard deviation and were compared using one-way ANOVA followed by Sche ffe's post-hoc comparisons (parametric) or Kruskal–Wallis test (non-parametric) as appropriate. Categorical data were expressed as numbers (percentage) and compared using the chi-squared test. Spearman correlation coe fficients were calculated for correlations between BMI and clinical/laboratory variables. Linear regression analyses were performed to evaluate the association between BMI and histopathologic parameters and the associations between eGFR and 24 h proteinuria and clinicopathological parameters. Logistic regression analyses were performed to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for high grades of MME, IF, and TA, and positive mesangial deposition of C3 and IgA according to the BMI groups. High-grade MME, IF, and TA were defined as grades 2–4, and positive mesangial C3 and IgA deposition was defined as scores ≥ +2. A *p* value of <0.05 was considered statistically significant. The statistical analyses were performed using SPSS version 20.0 software (SPSS, Inc., Chicago, IL, USA).
