DKD remains one of the most common and concerning complications of T2DM, posing significant challenges to patient management and quality of life [9, 10]. The findings of this study highlight the potential importance of UCr as an early biomarker for the detection and assessment of DKD risk. Our results demonstrate a significant association between UCr levels and the occurrence and severity of DKD, emphasizing its clinical relevance in routine diabetes care.

We observed a non-linear relationship between UCr levels and DKD, suggesting that UCr may serve as an early alert signal for renal dysfunction in patients with T2DM. Specifically, the likelihood of developing DKD seems to decrease when UCr levels are below the threshold of 17,421 µmol/L, indicating that UCr may reflect the compensatory function of the kidneys. However, when UCr levels exceed this threshold, there is a positive correlation with DKD progression, suggesting that increased creatinine excretion may indicate potential tubular dysfunction and renal stress. This finding is particularly important, as early intervention is crucial for slowing the progression of kidney damage and improving patient outcomes.

Butt et al. emphasized the importance of elevated creatinine levels as a marker of kidney disease progression in diabetic patients, as well as its association with other kidney function markers such as blood urea nitrogen and glomerular filtration rate [11]. Their research supports the significance of urinary creatinine levels as a critical indicator for diagnosing and monitoring DKD, aligning with the necessity for comprehensive metabolic assessments in the management of diabetic patients. Additionally, Zhou et al. explored the application of the urine C-peptide creatinine ratio in assessing β-cell function in T2DM patients under varying kidney function conditions [12]. Although this study did not specifically target DKD, it underscored the role of urinary creatinine in evaluating diabetes-related complications, highlighting the broader relevance of UCr levels in diabetes management.

Furthermore, the statistical association between UCr and DKD underscores its potential value as a screening tool. Given that UCr measurement is relatively simple and non-invasive, regular UCr assessments could enable healthcare providers to identify high-risk patients earlier. Early identification of patients who may benefit from interventions, such as diabetes control, lifestyle modifications, or pharmacotherapy, could mitigate or delay the onset of severe renal complications. While UACR and eGFR are established biomarkers for DKD, our findings highlight the potential complementary role of UCr in clinical practice. UACR primarily reflects glomerular filtration, while eGFR estimates overall kidney function. In contrast, our data suggest that UCr provides additional information, particularly reflecting tubular function, revealing a non-linear relationship with DKD incidence and progression not fully captured by UACR or eGFR alone. The identification of UCr inflection points may enhance early detection of DKD, enabling more timely interventions. A combined approach, using UCr in conjunction with UACR and eGFR, might lead to a more accurate risk stratification and more tailored management strategies. Future studies are needed to evaluate the clinical utility and cost-effectiveness of incorporating UCr into routine DKD monitoring.

The implications of this study extend to clinical management strategies for T2DM patients. Current guidelines typically emphasize the importance of monitoring kidney function through eGFR and the UALB/UCr [13, 14]. However, as more evidence supports the role of UCr, incorporating UCr assessment into existing monitoring protocols may be prudent [15, 16]. Doing so could enhance the sensitivity of early DKD detection, facilitating more timely and targeted therapeutic interventions. These thresholds suggest that regular monitoring of UCr levels in individuals with T2DM could facilitate earlier detection of those at higher risk of developing DKD. Patients whose UCr levels consistently exceed the identified thresholds might benefit from more frequent monitoring, earlier nephrology referral, and the proactive implementation of DKD preventative strategies, such as optimized glycemic control and blood pressure management. Furthermore, the observed non-linear relationship between UCr levels and DKD severity suggests that treatment strategies could potentially be tailored based on a patient’s UCr level relative to these thresholds. However, it is crucial to acknowledge that these findings require validation in larger, prospective studies before they can be confidently incorporated into routine clinical practice. Future research should focus on evaluating the predictive performance of these thresholds in diverse populations and determining the optimal strategies for their clinical application. In recent advancements in biomarker research, the role of urinary Smad1 has emerged as a promising indicator for predicting the onset of mesangial matrix expansion in diabetic nephropathy [17]. This study highlights the significance of urinary Smad1 as a novel biomarker that may serve as an early warning sign for changes in kidney structure associated with DKD.

Our multivariate model adjusted for age, gender, BMI, and hypertension, several unadjusted factors may influence the observed relationship. For instance, the use of ACE inhibitors or diuretics could impact urinary creatinine excretion and confound the association between UCr and DKD. Furthermore, longer duration of diabetes is known to increase DKD risk, and the presence of comorbidities such as cardiovascular disease could also influence kidney function. Although we did not fully adjust for these factors, we believe that our large sample size and rigorous methodology mitigate the potential for significant confounding bias. However, future research should consider more comprehensive data collection on medication use, diabetes duration, and the prevalence of various comorbidities to provide a more nuanced understanding.

In discussing the treatment and management strategies for DKD, it is important to highlight the renoprotective effects of SGLT2 inhibitors, incretin-related drugs such as GLP-1 receptor agonists, and mineralocorticoid receptor antagonists (MRA). These drugs have been demonstrated in several clinical studies to slow the progression of DKD. Firstly, GLP-1 receptor agonists have shown protective effects on the glomerular endothelium damaged by diabetes, although this effect might be inhibited by the activation of PKCβ [18]. Additionally, incretin-based therapy is widely recognized for its benefits in preventing vascular complications associated with diabetes [19]. Secondly, SGLT2 inhibitors not only alleviate renal burden by lowering blood glucose levels but also provide renal protection by reducing intraglomerular pressure and mitigating inflammatory pathways [20]. Moreover, MRAs such as finerenone have shown efficacy in improving renal outcomes in diabetic patients with low eGFR [21]. Overall, existing and emerging therapeutic strategies confer renal protection through various mechanisms, and an optimal combination of these medications might enhance therapeutic benefits for high-risk patients [22].

While this study provides important insights, further research is needed to validate the predictive value of UCr across different populations and stages of DKD. Longitudinal studies could offer greater understanding of the fluctuations in UCr levels as renal function changes, potentially revealing patterns that could enhance predictive capabilities. Additionally, exploring the biochemical mechanisms associated with UCr and DKD may provide valuable information for developing targeted therapies. We acknowledge the limitations inherent in a retrospective study design. The potential for unmeasured confounders and the possibility of selection bias are limitations that could affect the generalizability of our findings. To mitigate these limitations and strengthen the conclusions, we plan to conduct a prospective cohort study to validate our findings in an independent population. This prospective study will allow for more rigorous control of confounding variables and provide more robust evidence for the clinical utility of UCr in early DKD detection.

In conclusion, this study reinforces the position of UCr as a promising biomarker for the early detection and management of DKD in T2DM patients. As the medical community continues to seek more effective monitoring strategies and interventions to improve renal outcomes, UCr may play a pivotal role in clinical practice, enhancing the quality of patient care and health outcomes in the diabetic population. By prioritizing UCr assessment, clinicians may increase opportunities to preserve renal function and improve the quality of life for patients at risk for DKD.