Background: There is ongoing debate on the correlation between chronic kidney disease (CKD) and insulin resistance (IR)-related indices. Our objective was to explore the prognostic ability of IR-related indexes for the prevalence of CKD, as well as the mortality from all causes and cardiovascular disease (CVD) in CKD patients. Methods: The data used in this study came from the National Health and Nutrition Examination Survey (NHANES). Binary logistic regression analysis, Cox proportional hazards model, and restricted cubic spline (RCS) were used to analyze the relationship between IR-related indexes, including metabolic score of IR (METS-IR), homeostatic model assessment for IR (HOMA-IR), triglyceride glucose index (TyG), triglyceride glucose-waist-to-height ratio (TyG-WHtR), triglyceride glucose-body mass index (TyG-BMI), with CKD and its all-cause mortality and CVD mortality. Subgroup analysis was performed to test the stability of the results. Finally, the predictive power of IR-related indexes for CKD was tested by the receiver operating characteristic (ROC) curve. Results: Among the recruited 10,660 participants, 15.42% were CKD patients. All IR-related indexes were found to be nonlinearly correlated to the prevalence of CKD in the study. When the TyG index was higher than 9.05, it was positively associated with CKD (OR: 1.77, 95% CI 1.44–2.18). Moreover, increased TyG-WHtR level was correlated with a greater prevalence of CKD when it was higher than 4.3 (OR: 1.31, 95% CI 1.19–1.45). Other IR-related indexes (METS-IR, HOMA-IR, and TyG-BMI) showed fewer notable correlations with CKD. The association of IR-related indexes and the prevalence of CKD remained consistent in most subgroups (P for interactions > 0.05). TyG-WHtR was also the predictor of all-cause mortality in CKD patients (HR: 1.34, 95% CI 1.14–1.58), while other IR-related indexes were not correlated with the all-cause mortality or CVD mortality in CKD patients (P > 0.05). Otherwise, ROC curves showed that TyG-WHtR had more robust diagnostic efficacy than other IR-related indexes (METS-IR, HOMA-IR, TyG, and TyG-BMI) in predicting CKD (area under the curve: 0.630, 95% CI 0.615–0.644). Conclusions: IR-related biomarkers (METS-IR, HOMA-IR, TyG, and TyG-BMI) were positively correlated with the prevalence of CKD. Moreover, TyG-WHtR enhanced CKD and its all-cause mortality prediction. In patients with elevated levels of IR-related indexes, the early detection and intervention of IR may reduce the occurrence of CKD and the prognosis of CKD patients.

Acute kidney injury (AKI) is an important cause of chronic kidney disease (CKD), but the underlying mechanisms are unclear. Animal models are tools for studying the AKI-CKD progression. Kidney ischemia-reperfusion injury (IRI) models, especially the unilateral IRI (uIRI) model with delayed contralateral kidney resection, are commonly used to induce fibrotic progression to CKD after AKI. However, in previous studies, we found that details of the operation had a significant impact on the long-term outcomes of the kidney in this uIRI model. In this study, we investigated the effects of resection timing of the contralateral intact kidney, core body temperatures during ischemia, and time length of kidney ischemia on kidney function, histological injury and kidney fibrosis after AKI, using a mouse uIRI model with delayed contralateral nephrectomy. The results showed that all these parameters significantly affected the AKI-CKD transition. The post-AKI fibrosis worsened and the survival rate declined with a longer interval between contralateral nephrectomy and uIRI, higher ischemic body temperature, or longer ischemic duration when the other two variables were fixed. In conclusion, in the uIRI model with delayed contralateral nephrectomy, kidney fibrosis after AKI is influenced by many factors. Strictly controlling the experimental conditions is very important for the stability and consistency of the model.

Fibrosis is characterized by progressively excessive deposition of matrix components and may lead to organ failure. Transforming growth factor-β (TGF-β) is a key cytokine involved in tissue repair and fibrosis. TGF-β's profibrotic signaling pathways converge at activation of β-catenin. β-Catenin is an important transcription cofactor whose function depends on its binding partner. Promoting β-catenin binding to forkhead box protein O (Foxo) via inhibition of its binding to T-cell factor (TCF) reduces kidney fibrosis in experimental murine models. Herein, we investigated whether β-catenin/Foxo diverts TGF-β signaling from profibrotic to physiological epithelial healing. In an in vitro model of wound healing (scratch assay), and in an in vivo model of kidney injury, unilateral renal ischemia reperfusion, TGF-β treatment in combination with either ICG-001 or iCRT3 (β-catenin/TCF inhibitors) increased β-catenin/Foxo interaction, increased scratch closure by increased cell proliferation and migration, reduced the TGF-β-induced mesenchymal differentiation, and healed the ischemia reperfusion injury with less fibrosis. In addition, administration of ICG-001 or iCRT3 reduced the contractile activity induced by TGF-β in C1.1 cells. Together, our results indicate that redirection of β-catenin binding from TCF to Foxo promotes β-catenin/Foxo-mediated epithelial repair. Targeting β-catenin/Foxo may rebuild normal structure of injured kidney.

Even after recovery of kidney function following AKI, progression to CKD may still occur, characterized by a reduction in peritubular capillaries (PTC) and subsequent kidney fibrosis. Reactive oxygen species (ROS) from uncoupled eNOS are suspected to damage endothelial cells and cause PTC rarefaction observed in AKI-CKD. Intermedin (IMD) inhibits eNOS uncoupling by activating AMPK, but its impact on AKI-CKD transition remains unclear. We utilized IMD-deficient (IMD^-/-) mice to explore its effects on AKI-CKD transition, PTC density, endothelial damage, and kidney ROS in a kidney ischemia/reperfusion injury (IRI) model. To elucidate its protective mechanism for PTCs, we subsequently investigated the effects of IMD on endothelial cells and ROS using a hypoxia/reoxygenation (HR) model with human umbilical vein endothelial cells (HUVECs). Finally, we investigated the influence of IMD on AMPK/GTPCH-I/BH4/eNOS to explore its mechanism in alleviating oxidative stress. Compared with IMD^+/+ littermate sham controls, PTC density was significantly reduced in IMD^-/- sham mice, with significantly increased oxidative stress. Post-AKI, both IMD^+/+ and IMD^-/- mice demonstrated substantial declines in kidney function and histology, along with significant fibrosis, PTC reduction, and heightened oxidative stress. Moreover, the severity of kidney damage in IMD^-/- mice following AKI was considerably more pronounced than in IMD^+/+ mice. HR significantly induced eNOS uncoupling and oxidative stress in HUVECs. Treatment with IMD effectively inhibited eNOS uncoupling and ROS production, achieving levels comparable to the antioxidant N-acetylcysteine. The inhibitory effect of IMD on eNOS uncoupling was abrogated when L-NAME was introduced after HR. HR significantly impaired AMPK activation, which could be reversed by IMD. Additional experiments with inhibitors of GTPCH-I and AMPK, and exogenous BH4, confirmed that IMD protects endothelial cells by activating AMPK/GTPCH-I/BH4, thereby inhibiting eNOS uncoupling and ROS production. We concluded that IMD inhibits AKI-CKD transition by protecting endothelial cells of PTC via AMPK/GTPCH-I/BH4/eNOS pathway.

Type 3 cardiorenal syndrome (CRS type 3) triggers acute cardiac injury from acute kidney injury (AKI), raising mortality in AKI patients. We aimed to identify risk factors for CRS type 3 and develop a predictive nomogram. In this retrospective study, 805 AKI patients admitted at the Department of Nephrology, Second Hospital of Shanxi Medical University from 1 January 2017, to 31 December 2021, were categorized into a study cohort (406 patients from 2017.1.1-2021.6.30, with 63 CRS type 3 cases) and a validation cohort (126 patients from 1 July 2021 to 31 Dec 2021, with 22 CRS type 3 cases). Risk factors for CRS type 3, identified by logistic regression, informed the construction of a predictive nomogram. Its performance and accuracy were evaluated by the area under the curve (AUC), calibration curve and decision curve analysis, with further validation through a validation cohort. The nomogram included 6 risk factors: age (OR = 1.03; 95%CI = 1.009-1.052; p = 0.006), cardiovascular disease (CVD) history (OR = 2.802; 95%CI = 1.193-6.582; p = 0.018), mean artery pressure (MAP) (OR = 1.033; 95%CI = 1.012-1.054; p = 0.002), hemoglobin (OR = 0.973; 95%CI = 0.96--0.987; p < 0.001), homocysteine (OR = 1.05; 95%CI = 1.03-1.069; p < 0.001), AKI stage [(stage 1: reference), (stage 2: OR = 5.427; 95%CI = 1.781-16.534; p = 0.003), (stage 3: OR = 5.554; 95%CI = 2.234-13.805; p < 0.001)]. The nomogram exhibited excellent predictive performance with an AUC of 0.907 in the study cohort and 0.892 in the validation cohort. Calibration and decision curve analyses upheld its accuracy and clinical utility. We developed a nomogram predicting CRS type 3 in AKI patients, incorporating 6 risk factors: age, CVD history, MAP, hemoglobin, homocysteine, and AKI stage, enhancing early risk identification and patient management.