Клиникопатологические характеристики и результаты недиабетических реалистических заболеваний у пациентов с типом 2 Диабет: Ретроспективное кохартное исследование.

Introduction

Chronic kidney disease (CKD) is projected to become the fifth leading cause of death worldwide by 2,040, imposing a significant economic burden on global health [ 1 ]. Type 2 diabetes mellitus (T2D) is generally considered the primary cause of CKD [ 2 , 3 ], particularly diabetic nephropathy (DN), which accounts for up to 40% of end-stage renal disease (ESRD) cases [ 4 , 5 ]. However, recent advancements in the clinical diagnosis, treatment, and researches on diabetes and kidney injury have revealed that not all cases of kidney injury in individuals with T2D are attributable to DN. A substantial number of patients are diagnosed with nondiabetic renal disease (NDRD). Therefore, relying solely on clinical indicators to diagnose DN may lead to misdiagnosis, making renal biopsy crucial in distinguishing between DN and NDRD.

The global prevalence of NDRD ranges from 20 to 60% [ 6 – 10 ]. A national study conducted in China over 11 years, surveying 1604 T2D patients who underwent kidney biopsy, found that the proportions of DN, NDRD, and DN combined with NDRD were 44.7%, 49.1%, and 6.2%, respectively [ 9 ]. NDRD encompasses a wide range of diseases with diverse causes and pathophysiologies that can potentially affect the risk of ESRD and mortality to varying extents. Among Asians, membranous nephropathy (MN), IgA nephropathy (IgAN), and podocytopathies are reported as the three most common pathological diagnoses within the NDRD category [ 7 , 10 – 12 ]. Although several studies have compared the prognoses of DN and NDRD [ 7 , 11 , 13 ], research on the characteristics and prognosis of NDRD subtypes is limited. This knowledge gap highlights the need for further investigation of the specific features and outcomes of different NDRD subtypes in patients with T2D.

Therefore, we conducted a retrospective observational study of a cohort of T2D patients with kidney disease who had undergone a previous renal biopsy. The objectives of this study were (1) to explore and compare the clinicopathological characteristics of the top three NDRD subtypes (MN, IgAN, and podocytopathy) in patients with T2D at our clinical center and (2) to investigate specific predictors and renal outcomes among these patients. Our findings aimed to provide early warning indicators of disease prognosis and inform effective intervention strategies for patients with T2D and NDRD.

Methods

Study Populations

This retrospective cohort study was conducted at the Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. A total of 646 adult patients with T2D were enrolled, who underwent renal biopsy between January 1, 2008, and December 31, 2024. The cohort comprised 380 patients with DN (59%), 197 with NDRD (30%), and 69 with DN and NDRD (11%). We further analyzed a subset of 123 patients with the three most common NDRD subtypes, IgAN (T2D-IgAN, n = 52), MN (T2D-MN, n = 48), and podocytopathies (T2D-Podo, n = 23), including adult minimal change disease and focal segmental glomerulosclerosis (FSGS). Indications for renal biopsy in adult patients with T2D and renal injury included the need for further determination of the etiology of kidney injury or showing characteristics inconsistent with typical DN progression, such as sudden decline in renal function, overt proteinuria (3.5 g/24 h), and hematuria without diabetic retinopathy (DR) or neuropathy. Patients who had a history of kidney transplantation or dialysis, a follow-up time of <12 months, or incomplete clinical data were excluded from the study. Additionally, patients with secondary MN and IgAN due to conditions such as systemic lupus erythematosus, malignant tumors, hepatitis B viral infection, or drug-induced secondary nephropathy were excluded (online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000552662 ).

This retrospective study was reviewed and approved by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and was conducted in accordance with the Declaration of Helsinki. All the enrolled patients provided signed informed consent (No. 2022-KY-074(K)).

Data Collection

Demographic characteristics and laboratory data were collected from electronic medical records prior to renal biopsy. The collected information included: (1). patient demographics: age, sex, and duration of T2D; (2). medication history: use of oral hypoglycemic drugs (OHDs) and insulin; (3). clinical parameters: presence of hypertension and DR; (4). laboratory values: serum creatinine, proteinuria, estimated glomerular filtration rate (eGFR), hematuria, hemoglobin, glycosylated hemoglobin A1c (HbA1c), serum immunoglobulins (IgA, IgG, IgG4, IgM), and complement factors (C3, C4); (5). treatment history: use of renin-angiotensin system inhibitors (RASIs), steroids, and immunosuppressants. The eGFR was calculated using the CKD-EPI formula developed by the American Chronic Kidney Disease Epidemiology Collaborative Working Group [ 14 ]. T2D diagnosis was based on American Diabetes Association (ADA) criteria [ 15 ].

Renal Biopsy and Pathological Evaluation

All the patients included in this study underwent renal biopsy, and the samples were independently reviewed by two experienced pathologists. NDRD was diagnosed based on pathological characteristics observed by light microscopy, immunofluorescence, and electron microscopy. Sclerosis and crescent formation, interstitial fibrosis and tubular atrophy, interstitial inflammation, and glomerular antigen deposits for IgG, IgA, IgM, and C3 were descriptively recorded using semiquantitative scoring. Secondary MN and IgAN were clinically excluded in all patients with NDRD. The criteria for pathological characteristics as defined by the 2020 Renal Pathology Society (RPS) Consensus Guidelines.

Treatment Protocol

Treatment regimens were administered by 2 or more experienced nephrologists according to established guidelines and clinical experience [ 16 ]. The therapeutic protocol consisted of immunosuppressive regimens and supportive therapy. Immunosuppressive regimens included glucocorticoids, cyclophosphamide, rituximab, leflunomide, tacrolimus, and mycophenolate mofetil. Supportive therapies mainly include glycemic and lipid control, RASI, and diuretics. Regimens for T2D management include OHDs, insulin, and lifestyle interventions, such as diabetes self-management education and support, medical nutrition therapy, physical activity, smoking cessation counseling, and psychosocial care.

Atherosclerosis Assessment

Doppler ultrasound examinations (Siemens, 5–13 MHz linear array probe) were performed to detect atherosclerotic lesions, including atherosclerotic plaques and stenosis, in the carotid and lower limb arteries. Atherosclerotic plaques were defined according to the Mannheim consensus as local structural invasion of the artery cavity (≥0.5 mm) or 50% (thickness >1.5 mm. Plaques with low echogenicity in >50% of their areas were defined as unstable [ 17 ].

Follow-Up and Endpoints

The median follow-up duration was 80 months (interquartile range: 62–102). Renal endpoints were defined as doubling of the baseline serum creatinine level, ESRD, or death.

Statistical Analysis

Statistical analysis was performed using SPSS software (version 21.0; SPSS Inc., Chicago, IL, USA). Normally distributed data are presented as mean ± standard deviation, whereas skewed data are expressed as medians with interquartile ranges. Categorical data were reported as frequencies (%). The chi-square test was used to compare categorical variables. For continuous variables, comparisons between groups were performed using 1-way analysis of variance (ANOVA) for normally distributed data and the Kruskal-Wallis H test for non-normally distributed data. Cumulative renal survival was estimated using Kaplan-Meier survival curves and compared using the log-rank test. A multivariate Cox proportional hazards regression model was used to identify the factors significantly affecting renal outcomes in patients with NDRD. The model included the following covariates: age, sex, T2D duration, presence of DR, hypertension, MN, IgAN, podocytopathy, eGFR, 24-h proteinuria, serum albumin, TC, TG, glomerular sclerosis, C3 deposits, interstitial inflammation, IgG deposits, and IgA deposits. Statistical significance was set at p < 0.05.

Results

Clinical Characteristics and Laboratory Data of NDRD Patients

Among 197 T2D patients with NDRD, the top 3 subtypes were IgAN ( n = 59, 30.0%), MN ( n = 56, 28.0%), and podocytopathies ( n = 25, 13.0%). Mesangial proliferative glomerulonephritis (MsPGN) and hypertensive renal disease accounted for 8.0% and 4.8% of the cases, respectively. The pathological subtypes of NDRD are illustrated in Figure 1 . We then focused on the top 3 subtypes of NDRD patients for the subsequent data analysis. After excluding the patients with malignant tumors, incomplete clinical data, follow-up of less than 12 months, or those on renal dialysis (online suppl. Table S1), a total of 123 patients were included and divided into 3 groups: T2D-IgAN ( n = 52), T2D-MN ( n = 48) and T2D-Podo ( n = 23).

Distribution of renal disease in the NDRD group. IgAN, IgA nephropathy; MN, membranous nephropathy; Podo, Podocytopathies; MsPGN, mesangial proliferative glomerulonephritis; HTD, hypertensive renal disease; IN, interstitial nephritis; ANCN-RN, ANCA-related nephritis; HSPN, Henoch-Schönlein purpura nephritis; MAN, myeloma-associated nephropathy; LCN, light chain nephropathy; IgMN, IgM nephropathy; MPGN, membranous proliferative glomerulonephritis; HBV-AN, HBV-associated nephritis; TBN, thin basement nephropathy; LN, lupus nephritis; IgG4-RD, IgG4-related disease; CGN, crescentic glomerulonephritis.

Patients in the T2D-MN group were older and exhibited higher levels of proteinuria, total cholesterol, and serum IgG as well as lower serum albumin levels. Patients in the T2D-IgAN group exhibited higher serum IgA levels. Other baseline characteristics, including T2D duration, blood pressure, DR, creatinine, eGFR, hemoglobin, HbA1c, triglycerides, serum C3 and C4, and medication use (RASI, OHD, and insulin), did not differ significantly among the groups ( Table 1 ). Doppler ultrasonography revealed that T2D-MN patients had a higher prevalence of atherosclerotic plaques in both carotid and lower extremity arteries (LEAs) than the T2D-IgAN and T2D-podo groups (carotid: 39.6% vs. 13.5% vs. 17.4%, p = 0.007; lower extremity: 37.5% vs. 11.5% vs. 8.7%, p = 0.002) (online suppl. Table S2). The T2D-MN group also demonstrated a higher prevalence of unstable plaques. These findings suggest that T2D-MN patients presented with more severe clinical symptoms, laboratory abnormalities, and imaging findings.

Table 1. Baseline and pathological characteristics of the study population with different types of NDRD ​ T2D+IgAN ( N = 52) T2D+MN ( N = 48) T2D+Podo ( N = 23)
p value Demographic characteristics  Age, years 48.06±13.28 58.52±11.19 *† 47.52±12.68 0.001  Male, n (%) 27 (51.9%) 34 (70.8%) 14 (60.9%) 0.153  Duration of DM, years 2.00 (1.00–6.00) 4.50 (1.00–10.00) 2.00 (1.00–7.50) 0.199  Hypertension, n (%) 36 (69.2%) 30 (62.5%) 18 (73.9%) 0.592  DR, n (%) 5 (9.6%) 6 (12.5%) 2 (8.7%) 0.850 Laboratory data  Creatinine, uoml/L 75 (61–95) 75 (59–83) 69 (56–85) 0.429  eGFR, mL/min/1.73 m 2 87.32±26.23 94.52±26.72 99.76±37.59 0.189  Albumin, g/L 41.29±6.67 31.35±7.18 *† 40.65±8.64 <0.001  Cholesterol, mmol/L 5.29±1.37 6.87±2.71 *† 5.04±1.85 0.001  Triglyceride, mmol/L 2.59±1.96 2.89±2.31 2.98±1.16 0.684  Hemoglobin, g/L 136±17 137±16 138±21 0.875  HbA1c, % 6.80 (6.20–7.90) 6.80 (6.10–6.80) 7.00 (6.05–8.10) 0.842  Proteinuria, g/24h 1.09 (0.35–2.45) 5.20 (2.86–6.82) *† 1.70 (0.73–3.36) <0.001  Hematuria, n (%) 52 (100.0%) †‡ 43 (89.6%) 16 (69.6%) 0.001  Serum IgA 3.47±1.14 ‡† 2.44±1.33 2.95±1.29 0.001  Serum IgG 11.78±3.05 7.40±3.50 *† 12.07±3.91 <0.001  Serum IgG4 0.57 (0.26–0.84) 0.12 (0.01–0.47) *† 0.34 (0.25–0.55) 0.001  Serum IgM 1.09±0.70 0.89±0.38 1.21±0.67 0.088  Serum C3 1.22 (1.05–1.38) 1.12 (1.00–1.26) 1.24 (1.06–1.44) 0.065  Lower serum C3, n (%) 7 (14.0%) 9 (20.5%) 0 (0.0%) 0.262  Serum C4 0.25±0.09 0.25±0.08 0.29±0.08 0.194  Lower serum C4, n (%) 4 (8.0%) 1 (2.3%) 0 (0.0%) 0.150 Pathological characteristics, n (%)  Glomerular sclerosis ​ ​ ​ ​   Global sclerosis 9 (17.3) †‡ 2 (4.2) 1 (4.3) 0.036   Segmental sclerosis 5 (9.6) 1 (2.1) 4 (17.4) 0.549   Crescent 2 (3.8) 0 (0) 0 (0) 0.145  IFTA≥50% 21 (40.4) 10 (20.8) 7 (30.4) 0.107  Interstitial inflammation 44 (84.6) †‡ 25 (52.1) 17 (73.9) 0.002  Arteriosclerosis 22 (42.3) 19 (39.6) 8 (34.8) 0.827  IgM deposit 7 (13.5) 4 (8.3) 4 (17.3) 0.858  IgG deposit 4 (8.0) 48 (100) †* 1 (4.3) <0.001  IgA deposit 52 (100) †‡ 5 (10.4) 0 (0) <0.001  C3 deposit 14 (28.0) †‡ 8 (16.7) 2 (8.7) 0.043 Medications, n (%)  OHD 27 (51.9) 24 (50.0) 13 (56.5) 0.876  Use of insulin 16 (30.8) 17 (35.4) 9 (39.1) 0.759  RASI 42 (80.8) 41 (85.4) 20 (87.0) 0.427  Steroids+immunosuppressants 15 (29) 20 (42) 8 (35) 0.639 Common complications, n (%)  Osteoporosis 2 (4) 2 (4) 1 (4) 0.346  Thromboembolism 0 (0) 2 (4) 0 (0) 0.278  Infection 1 (2) 5 (10) 1 (4) 0.127  HCE 0 (0) 0 (0) 0 (0) 0  Hospitalizations 12 (23) 15 (31) 5 (21) 0.287 T2D, type 2 diabetes mellitus; Podo, Podocytopathies; IgAN, IgA nephropathy; MN, membranous nephropathy; eGFR, estimated glomerular filtration rate; HbA1c%, glycated hemoglobin; DR, diabetic retinopathy; IFTA, interstitial fibrosis and tubular atrophy; OHD, oral hypoglycemic drugs; RASI, renin-angiotensin aldosterone system inhibitors. HCE, hyperglycemic crisis episodes.
p < 0.05 was considered statistically significant.
‡ Podo vs. IgAN. *Podo vs. MN.
† IgAN vs. MN. ‡ *, †, p < 0.05.

Baseline and pathological characteristics of the study population with different types of NDRD

T2D, type 2 diabetes mellitus; Podo, Podocytopathies; IgAN, IgA nephropathy; MN, membranous nephropathy; eGFR, estimated glomerular filtration rate; HbA1c%, glycated hemoglobin; DR, diabetic retinopathy; IFTA, interstitial fibrosis and tubular atrophy; OHD, oral hypoglycemic drugs; RASI, renin-angiotensin aldosterone system inhibitors. HCE, hyperglycemic crisis episodes.

p < 0.05 was considered statistically significant.

‡ Podo vs. IgAN.

*Podo vs. MN.

† IgAN vs. MN.

‡ *, †, p < 0.05.

Pathological Characteristics in NDRD Patients

Next, we examined the renal pathological characteristics of the patients with NDRD using microscopic diagnosis and semiquantitative analysis ( Table 1 ). Representative histological images of the NDRD subtypes are shown in Figure 2 . T2D-IgAN patients exhibited a higher prevalence of glomerular injury compared to those in the T2D-MN and T2D-podo groups: 9 (17.3%) cases presented with global sclerosis, 5 (9.6%) cases with segmental sclerosis, and 2 (3.8%) cases with crescent formation. T2D-IgAN patients were more susceptible to pronounced renal interstitial inflammation (84.6% vs. 52.1% vs. 73.9%, p = 0.002). Notably, C3 deposition was observed in the glomeruli of all 3 NDRD subtypes, albeit in varying degrees and proportions: 28% in T2D-IgAN, 16.7% in T2D-MN, and 8.7% in T2D-podo. However, no statistically significant differences in interstitial fibrosis and tubular atrophy or IgM deposits were observed between the groups.

Histological figures of NDRD patients. Images of DM-IgAN, DM-MN, DM-Podo, and the first column images are seen on light microscopy with Hematoxylin and Eosin Staining. Original magnification, ×400. The middle column images are immunofluorescence with IgA, IgG, C3. The last column images are Electron Microscope. NDRD, nondiabetic renal disease; Podo, Podocytopathies; IgAN, IgA nephropathy; MN, membranous nephropathy; DM, diabetes mellitus.

Therapeutic Regimen and Complications of NDRD during Follow-Up

Analysis of the data from our study cohort revealed diverse therapeutic regimens among patients with NDRD. Most patients (84%) received RASI-based conservative and supportive treatment after confirmation of the diagnosis. Novel hypoglycemic drugs, including sodium-dependent glucose transporter 2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase 4 inhibitors, were administered to a small subset of patients with NDRD (12%) to improve renal outcomes. Immunosuppressive therapy comprising glucocorticoids alone or in combination with cyclophosphamide, tacrolimus, or leflunomide was administered to 43 (35%) patients. A small proportion of patients ( n = 5) received CD20 monoclonal antibody therapy such as rituximab. Notably, the use of steroids and/or immunosuppressants was higher in T2D-MN patients (42%) compared to the T2D-IgAN (29%) and T2D-podo (35%) groups (online suppl. Fig S2; online suppl. Table S3).

Several complications occurred during the follow-up period ( Table 1 ). Patients in the MN group exhibited a higher incidence of thromboembolism, pulmonary infections, and urinary tract infections. Additionally, 2 patients in the MN group experienced cardiovascular events and stroke.

Predictors and Comparison of Renal Survival in NDRD Patients

To evaluate the impact of different pathological subtypes on renal endpoints, we constructed Kaplan-Meier survival plots. During follow-up, 20 patients progressed to renal endpoints, defined as doubling of baseline serum creatinine levels, ESRD, or death. Although not statistically significant, the T2D-MN group exhibited the poorest renal outcomes (log-rank X 2 = 1.639, p = 0.441) ( Fig. 3 ). Multiple Cox proportional hazards models revealed that only eGFR (>60 mL/min/1.73 m 2 ; HR 0.296, 95% CI: 0.110–0.796, p = 0.016), C3 deposit (HR 3.021, 95% CI: 1.084–8.419, p = 0.034), and T2D duration exceeding 10 years (HR 4.168, 95% CI: 1.389–12.503, p = 0.011) remained independent predictors of renal endpoints ( Table 2 ). The Kaplan-Meier survival curves demonstrated that patients with glomerular C3 deposits had a high risk of renal endpoints among patients with NDRD (log-rank X 2 = 14.941, p < 0.001) ( Fig. 3 ).

Kaplan-Meier analysis for renal survival in NDRD patients. a Comparison of renal prognosis of the top 3 subtypes in NDRD patients. b Comparison of renal prognosis with or without glomerular C3 deposit in NDRD patients. Differences between the groups were compared using the log-rank test.

Table 2. Multivariate Cox proportional hazards models showing predictors for time to renal events ​ Univariate analysis Multivariate analysis HR (95% CI)
p value HR (95% CI)
p value IgAN vs. podocytopathy 0.772 (0.199–2.992) 0.708 0.660 (0.153–2.838) 0.576 MN vs. podocytopathy 1.434 (0.394–5.218) 0.585 1.578 (0.380–6.542) 0.530 Duration of T2D (>10 year) 5.760 (2.086–15.905) 0.001 4.168 (1.389–12.503) 0.011 eGFR (>60 mL/min/1.73 m 2 ) 0.226 (0.093–0.547) 0.001 0.296 (0.110–0.796) 0.016 C3 deposit 4.910 (2.013–11.979) 0.001 3.021 (1.084–8.419) 0.034 eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes mellitus. The following variables were incorporated as covariates: age, sex, duration of T2D, presence of diabetic retinopathy, hypertension, MN, IgAN, Podocytopathy, eGFR, 24-h proteinuria, serum albumin, TC, TG, glomerular sclerosis, C3 deposit, interstitial inflammation, IgG deposit, IgA deposit.

Multivariate Cox proportional hazards models showing predictors for time to renal events

eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes mellitus.

The following variables were incorporated as covariates: age, sex, duration of T2D, presence of diabetic retinopathy, hypertension, MN, IgAN, Podocytopathy, eGFR, 24-h proteinuria, serum albumin, TC, TG, glomerular sclerosis, C3 deposit, interstitial inflammation, IgG deposit, IgA deposit.

Discussion

NDRD encompasses various primary and secondary kidney conditions in patients with diabetes, which necessitates requiring distinct treatment approaches that is different from DN patients. Clinically, NDRD should be carefully identified in diabetic patients with renal injury when certain indicators are present: diabetes duration less than 5 years, annual eGFR decline exceeding 10 mL/min/1.73 m 2 , overt proteinuria, and hematuria without DR or neuropathy. However, relying solely on clinical and laboratory indicators could result in misdiagnosis in diabetic patients with kidney injury, renal pathology has become particularly important as a golden standard to differentiate various glomerulopathies and tubulopathies in diabetic patients, providing individualized treatment and minimize the side effect of nephrotic drugs on diabetes and its related complications. In this study, we found that IgAN, MN and podocytopathies were the most common NDRD pathological types which are consistent with the findings from previous studies [ 7 , 11 , 18 ]. Several studies have compared the prognoses of DN and NDRD, demonstrating poorer cardiovascular and renal outcomes in DN [ 7 , 11 , 13 ]. However, researches focusing on the comparison of characteristics and prognosis between NDRD subtypes remain limited.

MN is characterized by subepithelial glomerular immune complexes, which lead to glomerular basement membrane damage and typically present clinically as nephrotic syndrome, with a higher frequency of C3 deposition observed in the context of diabetes [ 19 ]. In our study, T2D patients with MN were older, presented more severe symptoms such as nephrotic proteinuria, hypoalbuminemia and dyslipidemia as compared with T2D-IgAN or T2D-podocytopathies. In addition, the T2D-MN group exhibited a higher risk of thromboembolism, cardiovascular events, and stroke. Previous findings have demonstrated that the coexistence of diabetes in patients with MN accelerates renal function deterioration and serves as an independent risk factor for renal outcomes [ 20 , 21 ]. In our study, we found T2D-MN patients showed poorer long-term renal outcomes as compared with T2D-IgAN or T2D-Podo patients, which is consistent with the findings of Chou et al. [ 22 ]. The possible reasons could be older age population, higher risk of thrombotic and cardiovascular complications and infections due to the immunosuppressants treatment.

IgAN is defined by dominant mesangial deposition of IgA-containing immune complexes, leading to mesangial hypercellularity and typically presenting with hematuria or/and varying degrees of proteinuria. In our cohort of T2D patients with biopsy-proven IgAN, microscopic hematuria was more common and serum IgA levels were higher compared to those with T2D-MN or T2D-podocytopathy. Importantly, our findings indicate that T2D-IgAN patients exhibit more complex and diverse pathological characteristics, including a higher incidence of glomerular sclerosis and interstitial inflammation, than those with T2D-MN or T2D-podo. Furthermore, it has been clinically observed that patients with IgAN superimposed on diabetes tend to present at an older age, with higher serum triglyceride levels, thicker glomerular basement membranes, and a greater risk of composite renal endpoint events, compared to their counterparts with IgAN alone.

Podocytopathies in adults, most commonly presenting as minimal change disease or FSGS, are defined by primary podocyte injury, resulting in disruption of the glomerular filtration barrier and manifesting clinically as proteinuria and hypoalbuminemia. However, not all podocytopathies present with massive proteinuria, and some manifest as asymptomatic proteinuria, with or without a reduced glomerular filtration rate [ 23 ]. Distinguishing between podocytopathies and DN in patients with diabetes is challenging. Key clues include the progressive increase in proteinuria or nephrotic syndrome in a short term, the duration of diabetes and its complications such as retinopathy and peripheral vascular disease should also be considered as clues for identification. Different from T2D-MN or T2D-IgAN, though the renal histological changes under light or fluorescence microscopy are mild in T2D-podo, pathological diagnosis by electron microscopy is important, characterized by increased fusion of podocyte foot processes accompanied by extensive microvilli formation.

Notably, we found C3 deposition was observed in the glomeruli of T2D patients with MN, IgAN and Podocytopathies, which was also an independent risk factor for renal endpoints in patients with NDRD. Studies have reported C3 as the predominant complement type in renal tissue, potentially serving as a prognostic biomarker for IgAN [ 24 , 25 ]. Extensive C3 accumulation in kidney tissues has been associated with worse kidney outcomes than mild accumulation in patients with MN [ 26 ]. C3 deposition is also an independent risk factor for poor renal outcomes in FSGS [ 27 ]. In the diabetic environment, chronic hyperglycemia and the accumulation of advanced glycation end-products (AGEs) promote complement activation mainly via the lectin pathway (MBL-dependent) and the alternative pathway (Bb-driven), resulting in uncontrolled C3 cleavage and glomerular deposition [ 28 ]. This C3 deposition, often independent of immunoglobulins, exacerbates local inflammation through the C3a/C5a-mediated recruitment of inflammatory cells and direct damage to podocytes and endothelial cells, thus accelerating the renal progression in NDRD patients. Thus, we speculate that abnormal complement C3 activation may exacerbate immune mechanisms under diabetic status, leading to extensive C3 deposition and aggravating kidney injury.

In our study cohort, the treatment strategies were based on a combination of pathological and clinical characteristics. Over 50% of T2D patients with NDRD received conservative therapy (RASI, antihypertensives, glycemic, and lipid control), but the remission rates for MN, IgAN, and podocytopathy groups were similar, being 74%, 74%, and 77%, respectively. Emerging evidence supports SGLT-2 inhibitors [ 29 – 33 ], sodium-dependent glucose transporters 2 (SGLT-2) inhibitors [ 29 , 33 ], GLP-1 receptor agonist [ 34 , 35 ], and mineralocorticoid receptor antagonists (MRA) [ 30 – 32 ] for CKD management, offering multi-organ protection. These treatments have demonstrated protective effects on multiple organs and have improved cardiac and renal outcomes, potentially offering promising therapeutic regimens for patients with NDRD. Recent developments in biological agents such as rituximab, targeted-release budesonide, belimumab, and complement inhibitors have proven to be first-line targeted therapies for glomerulopathies, including MN, podocytopathies, IgAN, and other secondary glomerulopathies [ 36 – 38 ]. These advancements offer promising strategies and potential benefits to patients with NDRD. Taken together, treatment of patients with NDRD is both comprehensive and challenging.

The incidence of diabetic kidney disease has increased alongside the increasing prevalence of diabetes, highlighting the importance of understanding the NDRD spectrum. Our study, the largest to date on NDRD subgroup analysis, surpasses previously published small sample studies [ 39 ]. Furthermore, this is the first study to conduct a cross-sectional analysis of NDRD subtypes and to thoroughly examine the pathological characteristics and prognosis of each NDRD subgroup. This study provides valuable insights into the management and treatment of NDRD. However, this study had some limitations. First, this study is subject to selection bias due to non-protocol-based renal biopsy indications. Biopsies were performed at clinician discretion, likely prioritizing patients with severe or atypical presentations. This may limit the generalizability of our findings to all type 2 diabetes patients with NDRD, particularly those with milder disease. However, our cohort represents a clinically relevant subset – patients who would typically undergo biopsy in real-world practice. Future studies with standardized biopsy criteria could further validate these results. Second, the criteria for renal biopsy were not protocol-based, potentially leading to an overrepresentation of patients with severe renal manifestations and an underrepresentation of those with milder disease. Third, some recent organ-protective therapeutic drugs or biological agents were not routinely applied to our early enrolled patients because of the timing of indication approval and medication initiation. The heterogeneity in immunosuppressive therapy across NDRD subtypes represents a potential confounding by indication, which could not be fully adjusted for in our model due to the interdependence between diagnosis and treatment initiation. We are currently expanding our follow-up cohort to explore the prospects of novel treatments for NDRD.

In conclusion, our study revealed that glomerular C3 deposits, eGFR <60 mL/min/1.73 m 2 and a history of diabetes for >10 years were independent risk factors for renal progression and poor outcomes in patients with NDRD. A combination of clinical factors and pathological characteristics is recommended to better predict the prognosis of patients with NDRD, which could help clinicians initiate early intervention and prevent complications. In conclusion, organ-protective drugs, novel immunosuppressants, and biologics with minimal glucocorticoid strategies may provide optimized treatment options for patients with NDRD in the future.

Acknowledgments

The authors thank the patients for participation in our study and the staff of the department of nephrology at Shanghai Jiao Tong University Affiliated Sixth People’s Hospital for assistance.

Statement of Ethics

All patients included in this study agreed and signatured informed consent (No. 2016-41). The study protocol was approved by the Ethics Committee of the Shanghai Jiao Tong University Affiliated Sixth People’s Hospital and was conducted in full accordance with the principles of the Declaration of Helsinki. All patients provided written informed consent.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This work was supported by the National Science and Technology Major Project [2024ZD0523400, 2024ZD0523404]; Key medical and industrial projects [YG2023ZD21]; National Key Research and Development Program of China [2023YFC2411800, 2023YFC2411802]; National Nature Science Foundation of China [82170727]; China International Medical Exchange Foundation [Z-2017-26-2202-2]. The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in the writing the manuscript.

Author Contributions

the study, Y.F., Q.J., and N.S.W. designed the research project. Q.J. reviewed the pathology diagnosis and characteristics. T.Z., Q.Y.L., Z.L., H.R.F., and Q.M.Z. performed the study, collected the clinical data, and worked on the follow-up of patients. T.Z. and Q.Y.L. analyzed the data and drafted the manuscript. Y.F. revised and approved the final version of the manuscript.

Funding Statement

This work was supported by the National Science and Technology Major Project [2024ZD0523400, 2024ZD0523404]; Key medical and industrial projects [YG2023ZD21]; National Key Research and Development Program of China [2023YFC2411800, 2023YFC2411802]; National Nature Science Foundation of China [82170727]; China International Medical Exchange Foundation [Z-2017-26-2202-2]. The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in the writing the manuscript.

Data Availability Statement

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request.

References

Associated Data

Supplementary Materials

Data Availability Statement

The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request.