Discussion
Our study showed that the average eGDR was significantly higher in the non-CKD group than in the CKD group, suggesting reduced insulin sensitivity in individuals with CKD. A follow-up study further identified a significant association between decreased insulin sensitivity and new-onset CKD, which was particularly pronounced in individuals without diabetes and those with higher baPWV. Mediation analysis indicated that diabetes, elevated blood pressure and AS mediated the relationship between eGDR and new-onset CKD.
IR can occur in both the early7 and uremic9 stages of CKD, and our data indicate that patients with CKD exhibit higher IR levels than those without CKD. Since this study was conducted in people who underwent health screening, most of the patients diagnosed with CKD were in the microalbuminuria stage, and relatively few individuals were in CKD stages 3–5. Therefore, no correlation analysis based on CKD stages was performed in this study. Common risk factors for IR in patients with CKD include obesity, reduced physical activity, sarcopenia, HTN, and dysregulated glucose and lipid metabolism.18 19 Skeletal muscles are the main sites of IR in patients with CKD.20 21 The muscles in patients with CKD become increasingly weak as the disease progresses, which may lead to IR by reducing the ability of the muscles to metabolize glucose. IR may disrupt muscle protein homeostasis, decreasing muscle mass and function.22 23 Moreover, patients with CKD exhibit several unique metabolic abnormalities such as accumulation of uremic toxins, metabolic acidosis, and vitamin D deficiency.19 From a molecular perspective, endothelial dysfunction, oxidative stress, inflammatory responses, activation of the renin–angiotensin–aldosterone system, muscle mitochondrial dysfunction, and metabolomic changes are all closely associated with IR.8 24
The hyperinsulinemic–euglycemic clamp technique (HECT) is the gold standard for evaluating IR. However, its complex operation and time-consuming nature make it difficult to implement on a large scale. Simplified insulin sensitivity indices developed based on FBG, insulin levels, and intravenous glucose tolerance tests tend to underestimate the degree of IR compared with HECT.25 26 Additionally, fasting insulin measurement is not a routine test for non-diabetic patients, and some antidiabetic medications may interfere with insulin measurements.27 The eGDR, calculated using WC, HbA1c, and HTN, makes it more suitable for clinical applications. Importantly, the eGDR demonstrates similar accuracy to the HECT clamp in assessing IR status. Studies indicate that IR exists prior to the onset of HTN and glucose/lipid metabolism disorders.28 29 IR shares common risk factors with CKD, including obesity, physical inactivity, sarcopenia, HTN, glucose/lipid metabolism disorders, and poor dietary habits. Accurate and convenient assessment of IR levels facilitates early identification of risk factors for CKD.
The relationship between IR and new-onset CKD has been previously demonstrated. The Uppsala Longitudinal Study of Adult Men Study suggested a negative correlation between IR and the occurrence of renal dysfunction, with a stronger correlation in individuals with normal FBG levels.6 A Swedish cohort study enrolling 22 146 patients with type 1 DM, with an average follow-up period of 4.8 years, showed that the incidence of CKD was 6.5% in those with an eGDR≥8 mg/(kg/min) and 46.6% in those with an eGDR<4 mg/(kg/min), indicating a significant increase in CKD incidence with increasing IR.11 In this study, diabetes-stratified subgroup analyses indicated a stronger link between IR and new-onset CKD in patients without DM compared with those with DM. These results suggest that IR contributes to CKD development independent of its impact on glucose metabolism. As confirmed in our previous research using the HECT, IR is caused by a variety of metabolic diseases and is not solely due to disturbances in glucose metabolism.30
In our previous study, we identified a non-linear relationship between homeostatic model assessment for IR and UACR with a saturation point.31 Similar findings were observed in studies exploring the relationship between IR and pre-diabetes and HTN in patients with abnormal glucose metabolism and non-alcoholic fatty liver disease.32–34 In this study, we assessed the linear and non-linear relationships between eGDR and CKD in both cross-sectional and cohort studies using the RCS. The results indicated that the non-linear relationship in the cross-sectional study was statistically significant, whereas the p value for non-linearity in the cohort study was not statistically significant. However, regardless of the study design, the overall trend showed that the CKD risk decreased with increasing eGDR. This was confirmed by logistic and Cox regression models and the subgroup analysis in both studies. However, the cause of this phenomenon remains unclear. Some researchers have attributed it to differences in participant selection and covariates. However, this explanation is not convincing. Additionally, the formulas used to assess IR in these studies were different. Another study applied multiple IR assessment formulas to explore the relationship between IR and CKD, indicating that the RCS curves of different formulas exhibit certain differences; however, this study was cross-sectional and did not use the eGDR formula.35 Overall, based on a literature review and our findings, we speculate that when IR reaches or exceeds a certain threshold, its detrimental effects do not disappear but rather saturate. This suggests that early intervention for IR may be beneficial for patients. Therefore, clinical practice requires a comprehensive analysis of the effect of IR levels on patients.
We revealed that the relationship between eGDR and new-onset CKD is influenced by glucose metabolism and blood pressure and partially mediated by baPWV. The American Heart Association defines cardiovascular–kidney–metabolic (CKM) syndrome as adverse interactions between cardiovascular disease, kidney disease, and metabolic disorders.36 Thus, IR may serve as a bridge to CKM syndrome. With an increase in IR levels, the proportion of patients with CKM syndrome stage 3 (including very high-risk CKD or subclinical cardiovascular disease) also increases.37 Atherosclerosis is associated with various metabolic diseases, including HTN, diabetes, hyperlipidemia, and obesity, with IR being a central aspect of these metabolic disorders.38 39 A decline in eGFR is not significantly correlated with new-onset atherosclerosis; instead, renal function decline is a consequence of atherosclerosis.40 Elevated IR levels correlate with a higher risk of AS (baPWV>1800 cm/s), microalbuminuria, and CKD.41 Hyperglycemia activates the advanced glycation end-products pathway, leading to endothelial injury, oxidative stress, and inflammatory responses, thereby accelerating atherosclerosis and glomerulosclerosis.42 43 IR stimulates the renin–angiotensin–aldosterone system, leading to water and sodium retention, elevated blood pressure, and intraglomerular HTN.44 45 Prolonged HTN exacerbates cardiac afterload and glomerular hyperfiltration, forming a vicious cycle of cardiac-kidney interactive damage. Renal blood flow, characterized by high perfusion and low resistance, makes the kidneys susceptible to damage from pulsatile pressure and flow.46 Atherosclerosis reduces the ability of vascular walls to buffer against pressure, leading to high-velocity arterial blood flow that affects the fragile microvascular system of kidneys, resulting in endothelial dysfunction and oxidative stress, ultimately causing microvascular ischemia and renal impairment.47 48 Treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been shown to improve atherosclerosis and slow the progression of CKD.46 49
Our results confirmed the association between IR and incident CKD and introduced a novel finding that baPWV mediates this relationship. Nonetheless, this study has some limitations. The HECT is recognized as the definitive method for assessing IR. Previous studies have established a strong correlation between eGDR and GDR measured using the HECT13; however, this claim has not been validated in the current population. Additionally, in large-sample clinical studies, the feasibility of the HECT is relatively low. However, because each simplified IR index has limitations, a combined assessment of multiple IR indices may improve the scientific rigor and accuracy of the research. At last, the study cohort was sourced from the PLA General Hospital Health Check Center, which may have led to a selection bias. Collecting nationwide data from various regions and conducting multicenter studies may yield more representative results.
In conclusion, this retrospective cohort study demonstrated an association between the IR index eGDR and the incidence of CKD, with a higher eGDR linked to a reduced risk of new-onset CKD. Furthermore, mediation analysis revealed that blood glucose, blood pressure, and AS mediated this relationship. These findings emphasize the need to manage IR and metabolic comorbidities to prevent CKD onset.
Leave a Reply