Cardiorenal syndrome (CRS) represents a complex bidirectional interaction between cardiac and renal dysfunction, where acute or chronic dysfunction in one organ induces secondary dysfunction in the other (1). Among the various subtypes, type 4 CRS—where chronic kidney disease contributes to cardiac dysfunction—is particularly prevalent in patients with diabetes mellitus, a population inherently at high risk due to microvascular and macrovascular complications (2,3). Early identification and monitoring of CRS in diabetic individuals is crucial, as this syndrome is associated with increased hospitalization, poor quality of life, and a significantly elevated risk of cardiovascular mortality (4,5).

Diabetes mellitus contributes to renal dysfunction through glomerular hyperfiltration and diabetic nephropathy, and simultaneously increases the risk of heart failure via mechanisms such as left ventricular hypertrophy, myocardial fibrosis, and autonomic neuropathy (6,7). The progression to CRS in this population is often insidious and underdiagnosed in its early stages, necessitating improved screening tools and diagnostic strategies (8).

Biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cystatin C have emerged as valuable indicators of cardiac and renal stress, respectively. NT-proBNP is a well-established marker of myocardial wall stress and is widely used for the diagnosis and prognosis of heart failure (9). Cystatin C, an endogenous marker of glomerular filtration rate (GFR), is considered more sensitive than creatinine in detecting early renal impairment, especially in diabetic populations (10). When combined, these markers may enhance diagnostic accuracy and risk stratification in CRS (11).

Echocardiography remains a cornerstone of non-invasive cardiac assessment, allowing real-time visualization of left ventricular function, diastolic dysfunction, and structural changes that are often early indicators of CRS in diabetic patients (12,13). However, routine echocardiographic monitoring is often underutilized in asymptomatic diabetic patients, despite evidence showing that early detection of subclinical cardiac dysfunction can prevent progression to overt heart failure (14).

Given the growing burden of diabetes worldwide and the rising incidence of CRS, there is a need for longitudinal studies to evaluate the predictive value of combined biomarker and echocardiographic surveillance in this high-risk group. The present study was designed to assess the development and progression of CRS in patients with type 2 diabetes over an 18-month period using serial measurements of NT-proBNP, cystatin C, and echocardiographic parameters.

Study Design and Population

This was a prospective longitudinal study conducted at a tertiary care hospital over an 18-month period. The study enrolled 120 adult patients (aged 40–70 years) diagnosed with type 2 diabetes mellitus for at least five years. Patients were selected from the outpatient endocrinology and cardiology departments. Inclusion criteria required stable glycemic control (HbA1c ≤ 9%) and an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m² at baseline. Exclusion criteria included a history of myocardial infarction, valvular heart disease, atrial fibrillation, congenital heart disease, or end-stage renal disease requiring dialysis.

Clinical and Laboratory Assessments

Baseline evaluations included a detailed medical history, physical examination, and laboratory testing. Blood samples were collected to measure fasting glucose, HbA1c, serum creatinine, cystatin C, and NT-proBNP. Serum creatinine was used to calculate eGFR using the CKD-EPI formula. NT-proBNP was measured using a high-sensitivity electrochemiluminescence immunoassay. Cystatin C levels were determined through nephelometric analysis.

Patients were followed at 9-month and 18-month intervals for repeat testing of biomarkers. All biochemical tests were performed in the same laboratory to ensure consistency.

Echocardiographic Evaluation

Transthoracic echocardiography was performed by an experienced cardiologist blinded to the biomarker data. Standard two-dimensional, M-mode, and Doppler studies were conducted using a GE Vivid™ E95 system. Left ventricular ejection fraction (LVEF) was calculated using the biplane Simpson method. Diastolic function was assessed using mitral inflow patterns (E/A ratio), tissue Doppler imaging (E/e′), and left atrial volume index. Additional measurements included left ventricular mass and relative wall thickness.

Definition of Cardiorenal Syndrome

Cardiorenal syndrome was defined as the development of new or worsening renal dysfunction (≥25% decline in eGFR or rise in cystatin C ≥20%) in conjunction with newly diagnosed or worsening cardiac dysfunction (LVEF decline ≥10% or development of diastolic dysfunction). Patients meeting both renal and cardiac deterioration criteria were classified as CRS-positive.

Statistical Analysis

Data were entered and analyzed using SPSS version 26.0. Continuous variables were expressed as mean ± standard deviation. Changes in biomarker and echocardiographic values over time were assessed using repeated-measures ANOVA. Categorical variables were analyzed using Chi-square tests. Kaplan-Meier survival analysis was used to estimate the cumulative incidence of CRS, and log-rank tests were applied to compare survival curves. A p-value <0.05 was considered statistically significant.

Baseline Characteristics

Out of 120 participants enrolled, 108 (90%) completed all three follow-up visits over the 18-month study period. The mean age of the cohort was 58.4 ± 7.2 years, with a male predominance (61.1%). The baseline clinical and laboratory characteristics of the study population are presented in Table 1.

Table 1: Baseline Characteristics of Study Participants (n = 108)

Changes in Biomarkers Over Time

A significant rise in NT-proBNP and cystatin C levels was noted over the 18-month period among participants who developed cardiorenal syndrome. Mean NT-proBNP increased from 186 ± 45 pg/mL at baseline to 325 ± 62 pg/mL at 18 months (p < 0.001), while cystatin C rose from 1.08 ± 0.14 mg/L to 1.36 ± 0.18 mg/L (p = 0.002). These changes are summarized in Table 2.

Table 2: Biomarker Trends Over Time in CRS Group (n = 35)

Echocardiographic Findings

Among CRS-positive patients (n = 35), a significant decline in LVEF and worsening of diastolic function were observed. LVEF declined from 58.2% ± 4.1% to 52.3% ± 5.7% (p < 0.001), and the proportion of patients with Grade II or higher diastolic dysfunction increased from 12% at baseline to 46% at 18 months. These changes are detailed in Table 3.

Table 3: Echocardiographic Changes in CRS Group (n = 35)

Incidence and Predictors of CRS

Over the study period, 35 out of 108 patients (32.4%) developed CRS. Kaplan-Meier analysis revealed a significantly higher incidence of CRS in participants with baseline NT-proBNP levels >250 pg/mL (log-rank p = 0.002). The incidence of CRS by biomarker quartiles is shown in Table 4.

Table 4: Incidence of Cardiorenal Syndrome by NT-proBNP Quartiles

This longitudinal study investigated the development of cardiorenal syndrome (CRS) in type 2 diabetic patients using serial measurements of NT-proBNP, cystatin C, and echocardiographic parameters. Over an 18-month period, approximately one-third of patients developed CRS, with significant elevations in NT-proBNP and cystatin C levels preceding clinical deterioration. These findings underscore the importance of early and repeated screening to identify high-risk individuals before irreversible organ damage occurs.

Diabetic individuals are inherently predisposed to both renal and cardiac dysfunction due to chronic hyperglycemia, systemic inflammation, endothelial injury, and microvascular complications (1,2). The bidirectional impact of heart and kidney dysfunction in this population often leads to accelerated disease progression, culminating in CRS (3). Our findings align with previous reports indicating that diabetes is a major contributor to both type 2 (chronic cardiac dysfunction leading to renal impairment) and type 4 (chronic kidney disease leading to cardiac dysfunction) CRS (4,5).

The significant rise in NT-proBNP levels observed in our study among CRS-positive patients corroborates earlier studies that have demonstrated its strong predictive value for cardiovascular events and mortality in both diabetic and renal populations (6,7). NT-proBNP reflects ventricular wall stress and can be elevated before overt clinical symptoms of heart failure become apparent, making it a sensitive early marker (8). Similarly, cystatin C has been shown to outperform creatinine in detecting early kidney dysfunction and has been linked with adverse cardiovascular outcomes (9,10).

Echocardiographic deterioration in our CRS cohort, particularly in terms of reduced left ventricular ejection fraction (LVEF) and increased diastolic dysfunction, suggests that cardiac structural and functional changes parallel biomarker trends. These observations support recommendations that diabetic patients undergo periodic echocardiographic surveillance, especially when biomarker levels begin to rise (11,12).

The Kaplan-Meier analysis highlighted that baseline NT-proBNP levels above 250 pg/mL were strongly associated with a higher incidence of CRS, consistent with previous findings from the CHARM and PARADIGM-HF trials where elevated natriuretic peptides were linked to worsening cardiorenal outcomes (13). This reinforces the role of NT-proBNP not only as a diagnostic but also as a prognostic tool in diabetes-associated CRS.

An important strength of this study is its longitudinal design, which allowed dynamic monitoring of pathophysiological changes rather than relying on single time-point measurements. The combination of biomarker trends and echocardiographic parameters enhances diagnostic accuracy and allows better risk stratification, aligning with the recommendations for integrative monitoring in high-risk populations (14).

However, there are limitations to consider. The study was single-center and relatively small in sample size, which may limit generalizability. Additionally, although biomarkers were sensitive in predicting CRS, their levels can be influenced by other comorbidities such as infections, pulmonary hypertension, or anemia (15). Future studies should include larger, multicenter cohorts and explore interventions that might reverse or delay CRS progression in diabetic individuals.

This study highlights the clinical utility of NT-proBNP, cystatin C, and echocardiography in identifying diabetic patients at risk for cardiorenal syndrome. Routine monitoring of these parameters can facilitate earlier diagnosis and timely interventions, potentially improving long-term outcomes in this vulnerable population.

This longitudinal study emphasizes the significant risk of cardiorenal syndrome in patients with type 2 diabetes mellitus. Elevated levels of NT-proBNP and cystatin C, along with echocardiographic evidence of declining cardiac function, serve as early predictors of CRS. Regular and combined biomarker testing with echocardiographic monitoring can facilitate earlier detection, risk stratification, and timely intervention, potentially improving long-term outcomes in diabetic patients.

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