Abstract
Aims
Renal vascular lesions are common in diabetic nephropathy (DN), but their association with echocardiographic indices related to diastolic function remains unclear. This study investigated the relationship between renal vascular lesion severity and echocardiographic indices in biopsy-confirmed DN.
Methods
This biopsy-based cross-sectional study included 360 patients with biopsy-confirmed DN and available echocardiographic data. Renal vascular lesions were evaluated using a composite score of arteriolar hyalinosis and arteriosclerosis, and patients were categorized into three severity groups (scores 0–1, 2–3, and 4). Echocardiographic indices included E/e′, e′, and left atrial diameter (LA). Multivariable linear regression models were used to assess the associations between renal vascular lesion severity and echocardiographic parameters. Sensitivity analyses were performed using continuous vascular lesion scores and additional covariate adjustment.
Results
Among 360 patients, 53, 253, and 54 were classified into the 0–1, 2–3, and 4 score groups, respectively. Compared with the 0–1 group, moderate and severe vascular lesions were associated with higher E/e′ (β = 1.814 and 2.910, respectively) and larger LA (β = 1.722 and 2.917, respectively) after multivariable adjustment. Continuous score analysis showed that each 1-point increase in vascular lesion score was associated with higher E/e′, larger LA, and lower e′. Associations with E/e′ and LA were generally consistent across sensitivity analyses, whereas the association with e′ was less stable.
Conclusions
In patients with biopsy-confirmed DN, greater renal vascular lesion severity was associated with higher E/e′ and larger LA, highlighting a potential link between renal vascular pathology and echocardiographic indices related to diastolic function.
Keywords: Diabetic nephropathy, renal vascular lesions, echocardiography, cardiac diastolic function, E/e′ ratio
Introduction
With the rising global burden of type 2 diabetes mellitus (T2DM), chronic diabetic complications have become an increasingly important contributor to morbidity and mortality worldwide [1]. Among these complications, diabetic nephropathy (DN), as one of the most important microvascular complications in patients with T2DM, is the primary cause of end-stage renal disease (ESRD) and is also associated with an increased risk of cardiovascular events and mortality among patients with T2DM [2].
DN is characterized by complex and multidimensional pathological alterations. In addition to the classic mesangial expansion, basement membrane thickening, and tubulointerstitial fibrosis, vascular lesions represent an important pathological component of DN and have been associated with renal disease progression and clinical outcomes [3]. Renal vascular lesions in DN are mainly characterized by arteriolar hyalinosis and arteriosclerosis, which may be accompanied by endothelial dysfunction, vascular wall thickening, luminal narrowing, and impaired renal microcirculation. These vascular abnormalities may contribute not only to impaired renal perfusion and progressive renal injury but also reflect broader systemic vascular involvement in patients with diabetes [4].
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with diabetic nephropathy (DN). Patients with DN have a substantially higher risk of cardiovascular events and death than diabetic patients without nephropathy, and many patients die from cardiovascular complications before progressing to end-stage kidney disease [5,6]. In patients with DN, multiple factors, including hemodynamic abnormalities, volume overload, electrolyte disturbances, and activation of the renin–angiotensin–aldosterone system (RAAS), may collectively contribute to adverse cardiac remodeling and functional impairment, highlighting the close interplay between renal and cardiovascular systems [7]. Therefore, early echocardiographic alterations and clarification of their relationship with renal pathological injury may provide clinically relevant insights for cardiovascular risk stratification and integrated disease management.
Echocardiography is a noninvasive, widely available, and repeatable method for evaluating cardiac structure and function. Among echocardiographic parameters, the ratio of early transmitral inflow velocity to early diastolic mitral annular velocity (E/e′) is commonly used to estimate left-ventricular filling pressure and is an important component of diastolic function assessment [8]. Early diastolic mitral annular velocity (e′) primarily reflects myocardial relaxation, whereas left atrial (LA) diameter provides information related to left atrial remodeling associated with chronic elevation of left-ventricular filling pressure [8]. In patients with T2DM and DN, echocardiographic abnormalities related to diastolic function are frequently observed [9,10]. However, most available evidence has relied on clinical indicators such as estimated glomerular filtration rate (eGFR), proteinuria, or chronic kidney disease (CKD) stage, whereas data directly linking pathologically defined renal vascular lesions with echocardiographic indices related to diastolic function in biopsy-confirmed DN remain limited.
Therefore, this study aimed to investigate the association between renal vascular lesion severity and echocardiographic indices related to diastolic function in patients with biopsy-confirmed DN. We hypothesized that more severe renal vascular lesions would be associated with higher E/e′, lower e′, and enlarged LA diameter, reflecting a potential association between renal vascular pathology and echocardiographic changes related to diastolic function.
Methods
Study design and participants
This was a retrospective observational cross-sectional study conducted at the Second Hospital of Hebei Medical University. Adult patients with diabetes who underwent native kidney biopsy between January 2015 and August 2025 were retrospectively screened. A total of 803 patients with diabetes underwent native kidney biopsy and were initially identified. Kidney biopsy was performed according to institutional protocols and established clinical indications [11], including rapid eGFR decline, abrupt increase in proteinuria, significant proteinuria without diabetic retinopathy (DR), or glomerular hematuria.
Patients were excluded according to the following criteria:
type 1 diabetes mellitus or other specific types of diabetes;
history of kidney transplantation, insufficient glomeruli for pathological evaluation, or coexistence of nondiabetic kidney disease;
known severe structural heart disease or rhythm disorders that could substantially affect echocardiographic assessment, including severe valvular heart disease, congenital heart disease, primary cardiomyopathy, atrial fibrillation, or other significant rhythm disorders interfering with Doppler measurements;
unavailable or non-retrievable echocardiographic records, or the absence of key echocardiographic parameters required for the present analysis, including E/e′, e′, or left atrial diameter (LA).
After applying inclusion and exclusion criteria, 360 patients with T2DM and biopsy-confirmed DN were included in the final analysis. The flow of patient selection is shown in Figure 1.
Figure 1.
Flow diagram of study participant selection.
Abbreviations: MN, membranous nephropathy; IgAN, IgA nephropathy; BNS, benign nephrosclerosis; MCD, minimal change disease; LN, lupus nephritis; ANCA-GN, antineutrophil cytoplasmic antibody–associated glomerulonephritis; FSGS, focal segmental glomerulosclerosis; MPGN, membranoproliferative glomerulonephritis; T2DM, type 2 diabetes mellitus.
This study was approved by the Ethics Committee of the Second Hospital of Hebei Medical University (Approval No. 2025-R642). All procedures were conducted in accordance with the principles of the Declaration of Helsinki. Given the retrospective nature of the study and the use of anonymized clinical data, the requirement for written informed consent was waived by the ethics committee. Data extraction and analysis were performed only after ethics approval had been obtained.
Clinical and laboratory data
We collected sex, age, height, weight, smoking status, systolic blood pressure (SBP), duration of diabetes, duration of hypertension, diabetic retinopathy (DR), and medication use, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), sodium–glucose cotransporter 2 inhibitors (SGLT2i), and diuretic therapy. Fasting venous blood samples were used to measure HbA1c, serum creatinine (Scr), hemoglobin, serum albumin, and lipid profile (TC, TG, LDL-C, HDL-C). Laboratory measurements were obtained during the same hospitalization as kidney biopsy.
Urinary protein excretion was quantified using 24-h urine collection and expressed as g/24 h. Measurements of 24-h urinary protein (24-h UP) were obtained from routine clinical records, and when more than one result was available, the value measured closest to the date of kidney biopsy was selected for analysis. eGFR was calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation [12]. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m2).
Echocardiographic assessment
Transthoracic echocardiography (TTE) was performed during the same hospitalization as kidney biopsy by experienced sonographers using commercially available ultrasound systems, including the Philips iE33 system and the Aloka ProSound F75 system (Hitachi Ltd., Tokyo, Japan). Although equipment changed during the study period, acquisition and measurement procedures remained consistent according to departmental standards. Doppler and tissue Doppler measurements, including septal and lateral e′, were obtained using standardized anatomical sites and measurement methods. Reports were retrospectively reviewed via the hospital electronic medical record system. The primary index of left ventricular filling pressure was the average E/e′, calculated as the mean of septal and lateral measurements. Secondary parameters included average e′, E/A ratio, LA, ejection fraction (EF), and left-ventricular mass index (LVMI), with LVMI calculated by the linear Devereux formula and indexed to body surface area [13].
Renal pathology assessment
Renal biopsy specimens were reviewed independently by two experienced renal pathologists who were unaware of the patients’ clinical information. Any disagreement in pathological assessment was resolved by joint reevaluation and consensus. Only biopsy specimens containing at least 10 glomeruli were considered adequate for pathological evaluation. All specimens were routinely processed for light microscopy (LM) and immunofluorescence (IF). Electron microscopy (EM) was additionally performed in cases with suspected early DN on LM or when the diagnosis could not be clearly established based on LM and IF findings. All cases suspected of class I DN underwent EM examination for accurate pathological classification. DN classes (I–IV) were determined according to the Renal Pathology Society classification [14].
The percentage of global glomerulosclerosis was calculated for each biopsy specimen. Tubulointerstitial lesions were evaluated using the interstitial fibrosis and tubular atrophy (IFTA) score (0–3). Renal vascular lesions were assessed using a composite score incorporating arteriolar hyalinosis and arteriosclerosis. The composite vascular lesion score ranged from 0 to 4. For analysis, patients were classified into three groups according to vascular lesion severity: mild vascular injury (score 0–1), moderate vascular injury (score 2–3), and severe vascular injury (score 4). These categories were defined according to the severity gradient of renal vascular lesions and were intended to represent increasing degrees of vascular injury. The predominance of patients in the moderate vascular injury group may reflect the characteristics of biopsy-based DN cohorts, as patients with very mild disease are less likely to undergo kidney biopsy, whereas those with advanced renal failure may also have limited indications for biopsy. Arteriolar hyalinosis and arteriosclerosis were graded according to the Renal Pathology Society (RPS) classification criteria [14]. The basic pathological criteria are summarized in Supplementary Table S1, and the representative images of renal vascular lesion severity are presented in Figure 2.
Figure 2.
Representative renal vascular lesions in biopsy-confirmed diabetic nephropathy.
(A) Arteriolar hyalinosis. (B) Arteriosclerosis with intimal thickening and luminal narrowing. (C) Severe arteriosclerosis with marked intimal thickening. Periodic acid–silver methenamine–Masson (PASM–Masson) stain; original magnification: A, ×400; B, ×100; C, ×400.
Statistical analysis
Continuous variables are presented as mean ± standard deviation or median (interquartile range), and categorical variables as counts (percentages). Comparisons among renal vascular lesion severity groups were performed using one-way ANOVA or Kruskal–Wallis tests for continuous variables, and chi-square or Fisher’s exact tests for categorical variables, as appropriate.
Trends in echocardiographic parameters across ordered renal vascular lesion severity groups were assessed by assigning ordinal values to the three groups and fitting linear regression models. Multivariable linear regression analyses were then performed to examine the associations between renal vascular lesion severity groups and echocardiographic parameters. The mild vascular injury group was used as the reference group. The primary outcome was E/e′, and the secondary outcomes included e′ and LA. Regression coefficients, standard errors, and 95% confidence intervals were reported. Additional analyses were performed using the same multivariable linear regression models to separately evaluate the associations of arteriolar hyalinosis and arteriosclerosis with echocardiographic parameters.
Sequential multivariable linear regression models were constructed. Model 1 was adjusted for age, sex, and BMI. Model 2 was further adjusted for duration of diabetes, hypertension status, SBP, HbA1c, and smoking status. Model 3 was additionally adjusted for ACEI/ARB use, SGLT2i use, TC, TG, HDL-C, and LDL-C. Three additional sensitivity models were constructed based on Model 3. Standardized β coefficients were additionally calculated from Model 3 after standardizing both the continuous vascular lesion score and each echocardiographic outcome to z scores, to facilitate comparison of effect sizes across outcomes. Model 4 additionally included eGFR and ln-transformed 24-h urinary protein; Model 5 additionally included serum albumin and hemoglobin; and Model 6 additionally included IFTA. Multicollinearity was evaluated using variance inflation factors (VIFs), with all VIFs below 5, indicating no substantial collinearity.
The assumptions of the linear regression models were assessed using residual-versus-fitted plots, normal Q–Q plots, scale-location plots, and influence diagnostics. Homoscedasticity was additionally evaluated using the Breusch–Pagan test. To further assess model robustness, the main analyses were repeated using HC3 heteroscedasticity-robust standard errors. Additional sensitivity analyses were conducted after excluding influential observations identified by Cook’s distance > 4/n, where n represents the sample size. Because the residual distribution of E/e′ showed some upper-tail deviation from normality, an additional sensitivity analysis was performed using log-transformed E/e′.
All statistical analyses were performed using R software, version 4.5.1. Two-sided p < 0.05 was considered statistically significant.
Results
Baseline characteristics
A total of 360 patients with biopsy-confirmed DN met the inclusion criteria for this study. Among them, 53 patients were classified into the mild vascular injury group, 253 into the moderate vascular injury group, and 54 into the severe vascular injury group. The baseline characteristics are summarized in Table 1. The overall median age was 54 years, and most patients were men (66.4%). Compared with the mild vascular injury group, patients with severe vascular lesions were older (56 [51, 65] vs. 47 [38, 54] years, p < 0.001), had a longer duration of diabetes (10.00 [3.00, 14.00] vs. 3.50 [1.00, 8.25] years, p = 0.004), and showed a higher prevalence of diabetic retinopathy (73.6% vs. 38.5%, p < 0.001). Duration of hypertension also differed significantly among the three vascular lesion groups (p = 0.008).
Table 1.
Baseline characteristics according to renal vascular lesion severity.
| Characteristics | All (n = 360) | 0–1 score (n = 53) |
2–3 score (n = 253) |
4 score (n = 54) |
P value |
|---|---|---|---|---|---|
| Age (years) | 54(45, 60) | 47 (38, 54) | 54 (46, 61) | 56 (51, 65) | <0.001 |
| Male, n (%) | 239 (66.4) | 41 (77.4) | 165 (65.2) | 33 (61.1) | 0.158 |
| BMI (kg/m²) | 25.0 (23.4, 27.7) | 24.84 (22.92, 29.38) | 25.15 (23.44, 27.34) | 24.52 (23.52, 27.41) | 0.563 |
| Duration of diabetes (years) | 7.0 (2.0, 12.0) | 3.50 (1.00, 8.25) | 7.00 (2.00, 12.00) | 10.00 (3.00, 14.00) | 0.004 |
| Duration of hypertension (years) | 3.0 (0.5, 10.0) | 1.00 (0.00, 3.00) | 3.00 (0.50, 10.00) | 3.00 (1.00, 10.00) | 0.008 |
| Hypertension, n (%) | 286 (79.4) | 37 (69.8) | 203 (80.2) | 46 (85.2) | 0.123 |
| SBP (mmHg) | 149 (131, 164) | 143 (126, 158) | 149 (131, 164) | 152 (137, 171) | 0.062 |
| DBP (mmHg) | 87 ± 13 | 88 ± 13 | 87 ± 14 | 85 ± 13 | 0.551 |
| Smoking, n (%) | 141 (39.5) | 23 (43.4) | 97 (38.6) | 21 (39.6) | 0.813 |
| HbA1c (%) | 7.4 (6.4, 8.9) | 7.2 (6.5, 8.0) | 7.3 (6.3, 8.9) | 7.8 (6.9, 9.3) | 0.137 |
| DR, n (%) | 219 (61.7) | 20 (38.5) | 160 (64.0) | 39 (73.6) | <0.001 |
| ACEI/ARB, n (%) | 159 (44.2) | 21 (39.6) | 117 (46.2) | 21 (38.9) | 0.473 |
| SGLT2i, n (%) | 118 (32.8) | 18 (34.0) | 89 (35.2) | 11 (20.4) | 0.107 |
| Scr (mg/dL) | 1.29 (0.93, 1.88) | 1.09 (0.79, 1.48) | 1.27 (0.95, 1.88) | 1.44 (1.12, 2.04) | 0.008 |
| eGFR (mL/min/1.73 m²) | 56.99 (36.93, 86.63) | 79.63 (51.18, 101.84) | 57.16 (36.85, 84.29) | 44.92 (34.06, 60.77) | <0.001 |
| Serum albumin (g/L) | 33.0 (27.7, 38.4) | 40.4 (31.0, 42.9) | 32.2 (27.2, 37.4) | 33.6 (29.8, 37.7) | <0.001 |
| Hemoglobin (g/L) | 115.0 (100.3, 129.0) | 128.0 (114, 146.5) | 114.0 (100, 127) | 111.0 (98.3, 123.8) | <0.001 |
| TC (mmol/L) | 4.59 (3.90, 5.53) | 4.88 (3.97, 5.66) | 4.55 (3.86, 5.51) | 4.67 (4.04, 5.48) | 0.540 |
| TG (mmol/L) | 1.74 (1.27, 2.42) | 2.06 (1.36, 2.69) | 1.67 (1.24, 2.34) | 1.94 (1.26, 2.98) | 0.045 |
| HDL-C (mmol/L) | 1.00 (0.87, 1.23) | 0.97 (0.88, 1.07) | 1.03 (0.86, 1.26) | 1.00 (0.88, 1.18) | 0.225 |
| LDL-C (mmol/L) | 3.01 (2.34, 3.83) | 3.04 (2.34, 3.88) | 3.00 (2.36, 3.76) | 2.99 (2.17, 3.84) | 0.996 |
| 24-h UP (g/24 h) | 3.19 (1.16, 5.97) | 1.18 (0.39, 4.37) | 3.33 (1.48, 6.20) | 3.84 (1.29, 6.61) | <0.001 |
| E/e′ | 11.60 (9.29, 14.80) | 9.30 (8.00, 11.62) | 12.00 (9.50, 14.79) | 13.00 (10.50, 18.00) | <0.001 |
| E/A | 0.80 (0.70, 0.90) | 0.80 (0.70, 1.20) | 0.80 (0.70, 0.90) | 0.73 (0.70, 0.89) | 0.160 |
| e′ (cm/s) | 6.00 (5.00, 7.00) | 6.00 (5.00, 8.00) | 6.00 (5.00, 7.00) | 6.00 (5.00, 6.00) | 0.025 |
| LA (mm) | 35.00 (33.00, 38.00) | 33.00 (31.00, 37.00) | 35.00 (33.00, 38.00) | 37.00 (35.00, 39.00) | 0.001 |
| EF (%) | 64.40 (62.00, 67.65) | 65.10 (62.00, 69.00) | 64.55 (61.98, 67.62) | 63.53 (62.00, 66.70) | 0.253 |
| LVMI (g/m²) | 93.67 (75.31, 112.73) | 83.87 (72.04, 110.92) | 91.31 (76.17, 111.03) | 103.04 (82.17, 121.35) | 0.104 |
| Glomerular lesion classification | <0.001 | ||||
| Class I/II DN, n (%) | 122 (33.9) | 35 (66.0) | 75 (29.6) | 12 (22.2) | |
| Class III/IV DN, n (%) | 238 (66.1) | 18 (34.0) | 178 (70.4) | 42 (77.8) | |
| Global glomerulosclerosis (%) | 21.25 (6.25, 37.60) | 10.00 (0.00, 21.40) | 22.00 (6.30, 38.50) | 28.90 (13.55, 47.00) | <0.001 |
| IFTA | 0.003 | ||||
| 0/1 | 152 (42.2) | 33 (62.3) | 102 (40.3) | 17 (31.5) | |
| 2/3 | 208 (57.8) | 20 (37.7) | 151 (59.7) | 37 (68.5) |
Notes: Data are presented as n (%), median (interquartile range), or mean ± standard deviation. P values represent overall comparisons across the three groups.
Abbreviations: BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; DR, diabetic retinopathy; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; SGLT2i, sodium–glucose cotransporter 2 inhibitor; eGFR, estimated glomerular filtration rate; TC, total cholesterol; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; 24-h UP, 24-h urinary protein; E/e′, ratio of early transmitral inflow velocity to early diastolic mitral annular velocity; e′, early diastolic mitral annular velocity; LA, left atrial diameter; E/A, ratio of early to late transmitral inflow velocity; EF, ejection fraction; LVMI, left-ventricular mass index; IFTA, interstitial fibrosis and tubular atrophy.
Across vascular lesion groups, kidney function progressively worsened, with lower eGFR (from 79.63 [51.18, 101.84] to 44.92 [34.06, 60.77] mL/min/1.73 m2, p < 0.001) and higher 24-h urinary protein excretion (from 1.18 [0.39, 4.37] to 3.84 [1.29, 6.61] g/24 h, p < 0.001) observed with increasing vascular lesion severity. In addition, patients with more severe vascular lesions had lower serum albumin levels (from 40.4 [31.0, 42.9] to 33.6 [29.8, 37.7] g/L, p < 0.001) and lower hemoglobin concentrations (from 128 [114, 146.5] to 111 [98.3, 123.8] g/L, p < 0.001).
Regarding echocardiographic parameters, E/e′ progressively increased across vascular lesion severity groups (9.30 [8.00, 11.62], 12.00 [9.50, 14.79], and 13.00 [10.50, 18.00], respectively; p < 0.001), and LA diameter also increased (33.00 [31.00, 37.00], 35.00 [33.00, 38.00], and 37.00 [35.00, 39.00] mm, respectively; p = 0.001). e′ showed a modest but statistically significant difference across groups (p = 0.025), whereas E/A, EF, and LVMI did not differ significantly across groups. The proportion of advanced RPS glomerular classes III–IV increased from 34.0% in the mild group to 77.8% in the severe group (p < 0.001). Global glomerulosclerosis was higher in the severe vascular injury group than in the mild group (28.90% vs. 10.00%, p < 0.001), and higher IFTA scores were more frequently observed with increasing vascular lesion severity (p = 0.003).
Trends in echocardiographic parameters across renal vascular lesion severity groups
The distributions of echocardiographic parameters across renal vascular lesion score groups are shown in Figure 3. E/e′ increased progressively with increasing vascular lesion severity (P for trend < 0.001). In contrast, e′ showed a decreasing trend across ordered vascular score groups (P for trend = 0.003). LA also increased progressively with greater vascular lesion severity (P for trend = 0.004).
Figure 3.
Distribution of echocardiographic parameters according to renal vascular lesion severity groups.
Boxplots showing (A) E/e′, (B) e′, and (C) left atrial diameter (LA) across renal vascular lesion score groups (0–1, 2–3, and 4). P values are for trend across ordered vascular lesion severity groups.
Associations between renal vascular lesion severity groups and echocardiographic parameters
Multivariable linear regression analyses were performed to examine the associations between renal vascular lesion severity groups and echocardiographic parameters (Table 2). In the fully adjusted model (Model 3), compared with the mild vascular injury group, both the moderate and severe vascular injury groups were associated with higher E/e′ (β = 1.814, 95% CI: 0.341 to 3.287 and β = 2.910, 95% CI: 0.969 to 4.851, respectively) and larger LA (β = 1.722, 95% CI: 0.338 to 3.107 and β = 2.917, 95% CI: 1.079 to 4.755, respectively). Lower e′ values were also observed in the moderate and severe vascular injury groups after adjustment (β = −1.891, 95% CI: −3.328 to −0.453 and β = −2.092, 95% CI: −3.985 to −0.199, respectively).
Table 2.
Multivariable linear regression analyses of associations between renal vascular lesion severity groups and echocardiographic parameters.
| Variable | Model 1 β (SE); 95% CI |
Model 2 β (SE); 95% CI |
Model 3 β (SE); 95% CI |
|---|---|---|---|
| E/e′ | |||
| Score 0/1 | reference | ||
| Score 2/3 | 1.850 (0.709) [0.455 to 3.245]** |
1.828 (0.726) [0.401 to 3.256]* |
1.814 (0.749) [0.341 to 3.287]* |
| Score 4 | 2.946 (0.922) [1.133 to 4.760]** |
2.886 (0.959) [0.999 to 4.774]** |
2.910 (0.986) [0.969 to 4.851]** |
| e′ (cm/s) | |||
| Score 0/1 | reference | ||
| Score 2/3 | −1.958 (0.672) [−3.280 to −0.636]** |
−1.899 (0.704) [−3.284 to −0.514]** |
−1.891 (0.731) [−3.328 to −0.453]** |
| Score 4 | −2.329 (0.873) [−4.045 to −0.613]** |
−2.156 (0.930) [−3.986 to −0.326]* |
−2.092 (0.962) [−3.985 to −0.199]* |
| LA (mm) | |||
| Score 0/1 | reference | ||
| Score 2/3 | 1.470 (0.683) [0.126 to 2.814]* |
1.441 (0.679) [0.105 to 2.776]* |
1.722 (0.704) [0.338 to 3.107]* |
| Score 4 | 2.684 (0.892) [0.931 to 4.438]** |
2.624 (0.905) [0.845 to 4.403]** |
2.917 (0.934) [1.079 to 4.755]** |
Notes: The 0–1 score group was used as the reference group.
Model 1 was adjusted for age, sex, and body mass index (BMI).
Model 2 was further adjusted for duration of diabetes, hypertension status (yes/no), systolic blood pressure (SBP), HbA1c, and smoking status.
Model 3 was additionally adjusted for ACEI/ARB use, SGLT2i use, and lipid profile (TC, TG, HDL-C, and LDL-C).
Unstandardized β represents the adjusted mean difference in echocardiographic parameters compared with the reference group.
Abbreviations: E/e′, ratio of early transmitral inflow velocity to early diastolic mitral annular velocity; e′, early diastolic mitral annular velocity; LA, left atrial diameter; CI, confidence interval; SE, standard error.
*p < 0.05; **p < 0.01.
To further evaluate the relationship of individual vascular lesions, additional analyses were performed by separately examining arteriolar hyalinosis and arteriosclerosis (Supplementary Table 2). After adjustment for the covariates included in Model 3, arteriosclerosis remained associated with higher E/e′ (β = 1.319, 95% CI: 0.501 to 2.136, p = 0.002) and lower e′ values (β = −0.928, 95% CI: −1.733 to −0.123, p = 0.024), whereas arteriolar hyalinosis showed no significant associations with E/e′ or e′. Neither arteriolar hyalinosis nor arteriosclerosis was significantly associated with LA after multivariable adjustment.
Associations between continuous renal vascular lesion score and echocardiographic parameters
To evaluate whether the observed associations remained consistent when renal vascular lesion severity was modeled continuously, the composite vascular lesion score was additionally analyzed as a continuous variable (Table 3). In the fully adjusted model, each 1-point increase in vascular lesion score was associated with higher E/e′ (β = 0.737, 95% CI: 0.223 to 1.251) and larger LA (β = 0.655, 95% CI: 0.168 to 1.143). Conversely, higher vascular lesion scores were associated with lower e′ values (β = −0.712, 95% CI: −1.214 to −0.211). The corresponding standardized β coefficients from Model 3 were 0.147 for E/e′, −0.157 for e′, and 0.140 for LA, indicating comparable effect sizes across the three echocardiographic parameters. These findings were generally consistent with the grouped analyses.
Table 3.
Multivariable linear regression analyses of associations between continuous renal vascular lesion score and echocardiographic parameters.
| Variable | Model 1 β (SE); 95% CI |
Model 2 β (SE); 95% CI |
Model 3 β (SE); 95% CI |
Model 3 Standardized β; (95% CI) |
|---|---|---|---|---|
| E/e′ | 0.738 (0.247) [0.252 to 1.224]** |
0.746 (0.256) [0.242 to 1.251]** |
0.737 (0.261) [0.223 to 1.251]** |
0.147 (0.036 to 0.258) |
| e′ (cm/s) | −0.776 (0.233) [−1.235 to −0.318]** |
−0.743 (0.248) [−1.232 to −0.255]** |
−0.712 (0.255) [−1.214 to −0.211]** |
−0.157 (−0.271 to −0.043) |
| LA (mm) | 0.582 (0.239) [0.111 to 1.052]* |
0.606 (0.242) [0.130 to 1.082]* |
0.655 (0.248) [0.168 to 1.143]** |
0.140 (0.036 to 0.244) |
Notes: Model 1 was adjusted for age, sex, and body mass index (BMI).
Model 2 was further adjusted for duration of diabetes, hypertension status (yes/no), systolic blood pressure (SBP), HbA1c, and smoking status.
Model 3 was additionally adjusted for ACEI/ARB use, SGLT2i use, and lipid profile (TC, TG, HDL-C, and LDL-C).
β represents the adjusted mean difference in echocardiographic parameters associated with each 1-point increase in renal vascular lesion score. Standardized β coefficients from Model 3 were additionally provided to allow comparison of relative effect sizes across outcomes.
Abbreviations: E/e′, ratio of early transmitral inflow velocity to early diastolic mitral annular velocity; e′, early diastolic mitral annular velocity; LA, left atrial diameter; CI, confidence interval; SE, standard error.
*p < 0.05; **p < 0.01.
Sensitivity analyses
To evaluate the potential influence of volume status-related treatment, we repeated the analyses after excluding patients receiving diuretic therapy (n = 33). After exclusion of these patients, the associations between vascular lesion severity and higher E/e′ (β = 1.533, 95% CI: 0.504–2.562; p = 0.004) and larger LA (β = 1.598, 95% CI: 0.612–2.584; p = 0.002) remained consistent with the primary analysis (Supplementary Table S3).
Additional sensitivity analyses were performed based on Model 3 by further adjusting for renal function, nutritional status, and renal pathological parameters (Supplementary Table S4). After additional adjustment for eGFR and ln-transformed 24-h urinary protein (Model 4), the association between severe vascular injury and higher E/e′ was attenuated and no longer statistically significant, whereas the association with larger LA remained statistically significant. After further adjustment for serum albumin and hemoglobin (Model 5), severe vascular injury remained significantly associated with higher E/e′ and larger LA, while both moderate and severe vascular injury groups were associated with lower e′ values compared with the mild vascular injury group. After additional adjustment for IFTA (Model 6), the associations of severe vascular injury with higher E/e′ and larger LA remained statistically significant, whereas the association with lower e′ was attenuated and no longer statistically significant in the severe vascular injury group.
Robustness analysis using HC3 heteroscedasticity-robust standard errors and exclusion of influential observations
To further evaluate model robustness, the primary analyses were repeated using HC3 heteroscedasticity-robust standard errors. Results remained generally consistent with the main findings. Compared with the mild vascular injury group, the severe vascular injury group remained associated with higher E/e′ (β = 2.910, p = 0.004) and larger LA (β = 2.917, p = 0.002), whereas the association with e′ remained inverse but was attenuated.
Additional analyses excluding influential observations identified by Cook’s D > 4/n yielded similar findings. Compared with the mild vascular injury group, the severe vascular injury group remained associated with higher E/e′ (β = 2.420, p = 0.003) and larger LA (β = 3.629, p < 0.001), whereas the association with e′ was no longer statistically significant. Overall, the robustness analyses supported stable associations of renal vascular lesion severity with higher E/e′ and larger LA.
Regression diagnostics showed no substantial evidence of nonlinearity or heteroscedasticity for the models of E/e′, e′, or LA. Although the E/e′ model showed some upper-tail deviation from residual normality, the findings remained consistent after log transformation of E/e′. In the log-transformed model, compared with the mild vascular injury group, both the moderate (β = 0.118, p = 0.037) and severe vascular injury groups (β = 0.197, p = 0.007) remained significantly associated with higher log-transformed E/e′.
Discussion
In this study of patients with T2DM and biopsy-confirmed DN, we investigated the association between renal vascular lesion severity and echocardiographic indices related to diastolic function. Using a semi-quantitative pathological vascular score, we found that greater renal vascular lesion severity was associated with higher E/e′ and larger LA diameter in the primary multivariable analyses. These findings remained generally consistent when vascular lesions were modeled as both categorical and continuous variables and were further supported by trend, sensitivity, and robustness analyses. In contrast, e′ showed an inverse but less consistent association across analytical approaches. Collectively, these findings suggest a potential link between renal vascular pathology and echocardiographic indices related to diastolic function in biopsy-confirmed DN.
However, the relationship between renal vascular lesions and echocardiographic alterations should be interpreted in the context of overall kidney disease severity. After additional adjustment for eGFR and ln-transformed 24-h urinary protein, the association between severe vascular lesions and higher E/e′ was attenuated and no longer statistically significant, suggesting that the association may be partly explained by overall kidney disease severity. Because eGFR and proteinuria may represent both markers of kidney disease severity and potential intermediate factors linking renal vascular injury with cardiovascular involvement, adjustment for these variables may also introduce potential overadjustment. In contrast, the association between severe vascular lesions and left atrial diameter remained statistically significant after additional adjustment, suggesting that this association may not be fully explained by eGFR and proteinuria alone.
The magnitude of these echocardiographic differences may also have clinical implications. Compared with patients with mild vascular lesions, those with severe vascular lesions exhibited an adjusted increase of approximately 2.9 in E/e′ and an increase of approximately 2.9 mm in LA. Although these differences should not be interpreted as indicating clinically defined diastolic dysfunction, they may be consistent with a greater burden of elevated left-ventricular filling pressure and left atrial remodeling in patients with more severe renal vascular involvement. Given the high cardiovascular risk profile of patients with DN, even the modest differences in echocardiographic indices related to diastolic function may be clinically relevant and warrant further investigation in longitudinal studies.
These findings should be considered within the broader context of cardiorenal interaction. Epidemiological data show that heart failure and CKD frequently coexist in patients with T2DM and are associated with increased mortality [15]. Cardiovascular disease and CKD are increasingly recognized as interconnected conditions driven by shared risk factors and overlapping pathophysiological pathways rather than a simple unidirectional process [16]. This relationship may also be viewed within the broader framework of hypertension-mediated and systemic vascular organ damage. In hypertensive populations, vascular abnormalities such as increased arterial stiffness and cardiac target-organ damage such as increased left ventricular mass frequently coexist, suggesting a shared pathophysiological background rather than isolated organ-specific injury [17]. In this context, renal vascular lesions and echocardiographic alterations observed in our cohort may be consistent with parallel manifestations of systemic vascular and hemodynamic injury. Notably, alterations related to diastolic function are commonly observed cardiac abnormalities in CKD and may resemble a heart failure with preserved ejection fraction (HFpEF) phenotype [18]. Supporting this concept, previous studies in patients with biopsy-confirmed DN have demonstrated that renal vascular injury is associated with a greater burden of cardiovascular structural abnormalities and adverse cardiovascular outcomes, independent of conventional clinical risk factors [19,20]. In our cohort, greater renal vascular lesion severity was associated with longer diabetes duration and more pronounced alterations in echocardiographic indices related to diastolic function, consistent with these prior observations. Taken together, these findings are consistent with the possibility that renal vascular lesions and cardiac abnormalities in DN may coexist within a broader pattern of systemic vascular involvement; however, shared upstream factors such as age, hypertension, diabetes duration, CKD severity, and systemic microvascular disease may also contribute to both.
The mechanisms underlying the association between renal vascular lesions and echocardiographic alterations related to diastolic function remain incompletely understood, but several interconnected pathways may provide a plausible explanation. In patients with DN, renal vascular lesions may represent more than localized kidney injury and reflect broader systemic vascular dysfunction, including increased arterial stiffness, microvascular impairment, endothelial dysfunction, chronic vascular inflammation, and activation of the RAAS [18,21]. According to Brownlee’s unifying hypothesis, hyperglycemia-induced mitochondrial reactive oxygen species (ROS) overproduction and accumulation of advanced glycation end products (AGEs) are considered upstream drivers linking metabolic stress to endothelial dysfunction, vascular remodeling, and myocardial structural remodeling, including fibrosis [22,23]. Concurrently, persistent low-grade inflammation and RAAS activation may further amplify oxidative stress and endothelial injury, contributing to processes involved in myocardial fibrosis and impaired ventricular compliance [24]. These structural and functional alterations may increase arterial stiffness and microvascular resistance, elevate left ventricular afterload, and subsequently contribute to myocardial hypertrophy, interstitial fibrosis, left atrial enlargement, and E/e′ elevation [25]. Notably, e′ primarily reflects active myocardial relaxation and is more susceptible to factors such as age, left-ventricular hypertrophy, blood pressure, and measurement variability, which may explain its relatively less stable association with renal vascular lesions [26]. Collectively, these pathways offer a hypothesis-generating framework for interpreting the observed association and require further investigation in longitudinal and mechanistic studies.
Beyond the conventional cardiorenal framework, our findings may also be interpreted within the emerging concept of cardiovascular–kidney–metabolic (CKM) syndrome, which emphasizes the interconnected progression of metabolic dysfunction, renal impairment, and cardiovascular abnormalities across disease stages [27]. Metabolic abnormalities may coexist with hypertension, vascular dysfunction, cardiac remodeling, and renal injury, reflecting interconnected processes contributing to target-organ damage. Previous studies in hypertensive populations have shown that metabolic phenotypes have been associated with multiple forms of hypertension-mediated organ damage, including increased left-ventricular mass, arterial stiffness, microvascular rarefaction, and albuminuria [28]. Within this framework, individuals with T2DM accompanied by renal injury and subclinical cardiovascular abnormalities may share features associated with more advanced CKM stages [29]. Although CKM staging was not formally evaluated in the present study, the observed association between biopsy-defined renal vascular lesions and echocardiographic indices related to diastolic function may be consistent with broader cardiovascular–renal–metabolic involvement in patients with DN, rather than indicating a direct causal relationship between renal vascular injury and cardiac abnormalities. These findings further underscore the potential value of integrating renal pathological information with cardiovascular assessment to improve understanding of disease burden beyond conventional biochemical indicators.
Unlike previous studies that relied primarily on biochemical indicators such as eGFR, proteinuria, and CKD stage to evaluate the relationship between DN and cardiac structure or echocardiographic indices related to diastolic function, our study used biopsy-defined renal vascular scores to characterize the pathological vascular involvement [30–32]. By integrating renal vascular pathology with echocardiographic assessment, our findings add pathological evidence to existing observations regarding cardiorenal interaction in patients with DN and suggest that biopsy-defined vascular lesions may provide complementary information beyond conventional clinical indicators of kidney disease severity. These findings support a more integrated renal–cardiac evaluation in patients with DN, particularly among those with severe renal vascular lesions. Importantly, our results should not be interpreted as supporting the use of renal vascular lesions to predict clinically defined diastolic dysfunction; rather, they underscore the potential value of greater attention to echocardiographic assessment, especially E/e′ and LA, in patients with more severe renal vascular lesions.
The present study has several strengths. The inclusion of biopsy-confirmed DN reduced diagnostic uncertainty and enabled direct evaluation of renal vascular pathology using an RPS-based semi-quantitative scoring system. In addition, multiple echocardiographic indices related to diastolic function, including E/e′, e′, and left atrial diameter, were evaluated. The consistency of findings across grouped and continuous vascular score analyses, trend tests, and robustness analyses further supports the stability of the observed associations. Nevertheless, several limitations should be considered. First, the cross-sectional design precludes the assessment of temporal relationships and does not allow causal inference. Second, the single-center design and biopsy-based inclusion criteria may introduce selection bias, as patients undergoing kidney biopsy often represent a selected subgroup with more severe or atypical disease manifestations, potentially limiting generalizability. In addition, the final analysis was restricted to patients with retrievable echocardiographic records and the required echocardiographic parameters. Because echocardiography was performed as part of routine clinical care and some examinations performed before admission or outside our institution were not retrievable from the hospital electronic medical record system, selection bias related to echocardiographic data availability cannot be completely excluded. Third, although multiple clinical covariates were adjusted for, residual confounding cannot be fully excluded. Volume status may influence echocardiographic parameters such as E/e′ and left atrial diameter. Although sensitivity analyses excluding patients receiving diuretics and additional adjustment for serum albumin and hemoglobin showed consistent results, standardized volume status assessments, including systematic edema evaluation and objective fluid overload measurements, were unavailable in this retrospective study. Furthermore, although patients with overt clinical heart failure are generally less likely to undergo kidney biopsy because of procedural considerations, and patients with severe structural heart disease or significant rhythm disorders were excluded in this study, detailed cardiovascular disease information, including coronary artery disease and prior myocardial infarction, was not systematically available. Therefore, residual confounding related to underlying cardiovascular disease burden cannot be completely excluded. Fourth, echocardiographic data were retrospectively extracted from routine clinical reports over an approximately 10-year period. Although acquisition and measurement procedures remained consistent according to departmental standards, changes in ultrasound equipment over time may have introduced some measurement variability, particularly for tissue Doppler parameters. Intraobserver and interobserver reproducibility data were not available. In addition, not all parameters recommended for guideline-based comprehensive assessment of left ventricular diastolic function, such as left atrial volume index and tricuspid regurgitation velocity, were available. Finally, renal pathological evaluation may be affected by sampling limitations and interobserver variability.
Conclusion
In patients with biopsy-confirmed DN, greater renal vascular lesion severity was associated with higher E/e′ and larger left atrial diameter. These findings suggest an association between renal vascular pathology and echocardiographic indices related to diastolic function and are consistent with broader cardiovascular–renal interactions in DN. The association with e′ was less consistent and requires further validation. However, causal inference cannot be established because of the cross-sectional design. Further longitudinal and mechanistic studies are warranted to clarify temporal relationships and the underlying pathophysiological mechanisms.
Supplementary Material
Glossary
Abbreviations
- DN
diabetic nephropathy
- T2DM
type 2 diabetes mellitus
- ESRD
end-stage renal disease
- CKD
chronic kidney disease
- CVD
cardiovascular disease
- TTE
transthoracic echocardiography
- BMI
body mass index
- SBP
systolic blood pressure
- DBP
diastolic blood pressure
- ACEI/ARB
angiotensin-converting enzyme inhibitors/angiotensin receptor blockers
- SGLT2i
sodium–glucose cotransporter 2 inhibitors
- Scr
serum creatinine
- DR
diabetic retinopathy
- eGFR
estimated glomerular filtration rate
- LM
light microscopy
- IF
immunofluorescence
- EM
electron microscopy
- IFTA
interstitial fibrosis and tubular atrophy
- IQR
interquartile range
- CI
confidence interval
- MN
membranous nephropathy
- IgAN
IgA nephropathy
- BNS
benign nephrosclerosis
- MCD
minimal change disease
- LN
lupus nephritis
- ANCA-GN
antineutrophil cytoplasmic antibody–associated glomerulonephritis
- FSGS
focal segmental glomerulosclerosis
- MPGN
membranoproliferative glomerulonephritis
- 24- h UP
24-hour urinary protein
- E/e′
ratio of early transmitral inflow velocity to early diastolic mitral annular velocity
- e′
early diastolic mitral annular velocity
- LA
left atrial diameter
- E/A
ratio of early to late transmitral inflow velocity
- EF
ejection fraction
- LVMI
left ventricular mass index
- RPS
Renal Pathology Society
- RAAS
renin–angiotensin–aldosterone system
- ROS
reactive oxygen species
- CKM
cardiovascular–kidney–metabolic
- AGEs
advanced glycation end products
- HFpEF
heart failure with preserved ejection fraction
Funding Statement
This work was supported by the Hebei Provincial Medical Science Research Project (No. 20220984).
Ethics approval and consent to participate
This study was approved by the Ethics Committee of the Second Hospital of Hebei Medical University (Approval No. 2025-R642) and conducted in accordance with the Declaration of Helsinki. The requirement for written informed consent was waived due to the retrospective design and use of anonymized clinical data.
Disclosure statement
The authors report no conflicts of interest in this work.
Availability of data and materials
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.