Adiponectin, an adipokine secreted by adipocytes, exerts favorable effects in the milieu of diabetes and metabolic syndrome through its anti-inflammatory, antifibrotic, and antioxidant effects. It mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor (PPAR)-α expression through adiponectin receptor (AdipoR)1 and AdipoR2, respectively, which in turn activate PPAR gamma coactivator 1 alpha (PGC-1α), increase the phosphorylation of acyl CoA oxidase, and upregulate the uncoupling proteins involved in energy consumption. Moreover, adiponectin potently stimulates ceramidase activity associated with its two receptors and enhances ceramide catabolism and the formation of its anti-apoptotic metabolite, sphingosine 1 phosphate (S1P), independently of AMPK. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular diseases, and increased adiponectin expression in the state of albuminuria suggest a protective and compensatory role for adiponectin in mitigating further renal injury during the development of overt diabetic kidney disease (DKD). We propose AdipoRon, an orally active synthetic adiponectin receptor agonist as a promising drug for restoration of DKD without inducing systemic adverse effects. Its renoprotective role against lipotoxicity and oxidative stress by enhancing the AMPK/PPARα pathway and ceramidase activity through AdipoRs is revealed here.

Adiponectin has multiple functions including insulin sensitization, anti-inflammation and antiatherogenesis in various organs. Adiponectin activates 5′-adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR)α via the adiponectin receptor (AdipoR) 1 and 2, which are critical for regulating lipids and glucose homeostasis and for controlling oxidative stress. We investigated whether resveratrol can inhibit renal damage in type 2 diabetic db/db mice and the underlying mechanisms of its effects. Four groups of male C57 BLKS/J db/m and db/db mice and human glomerular endothelial cells (HGECs) were used. Resveratrol was administered to diabetic and nondiabetic mice by oral gavage for 12 weeks starting at 8 weeks of age. In db/db mice, resveratrol increased serum adiponectin levels and decreased albuminuria, glomerular matrix expansion, inflammation and apoptosis in the glomerulus. Resveratrol increased the phosphorylation of AMPK and silent information regulator T1 (SIRT1), and decreased phosphorylation of downstream effectors class O forkhead box (FoxO)1 and FoxO3a via increasing AdipoR1 and AdipoR2 in the renal cortex. Furthermore, resveratrol increased expression of PPARγ coactivator (PGC)-1α, estrogen-related receptor-1α, and phosphorylated acetyl-CoA carboxylase and decreased sterol regulatory element-binding protein 1. This effect lowered the content of nonesterified fatty acid and triacylglycerol in the kidneys, decreasing apoptosis, oxidative stress and activating endothelial nitric oxide synthase. Resveratrol prevented cultured HGECs from undergoing high-glucose-induced oxidative stress and apoptosis by activating the AMPK–SIRT1–PGC–1α axis and PPARα through increases in AdipoR1 and AdipoR2 expression. These results suggest that resveratrol prevents diabetic nephropathy by ameliorating lipotoxicity, oxidative stress, apoptosis and endothelial dysfunction via increasing AdipoR1 and AdipoR2 expression.

Lymphangiogenesis occurs in response to renal injury and is correlated with interstitial fibrosis. Diabetes- and high-fat diet (HFD)-induced intrarenal lipotoxicity and their relationships with lymphangiogenesis are not established. We used PPARα agonist, fenofibrate, to unravel the linkage between lipotoxicity and lymphangiogenesis. Eight-week-old male C57BLKS/J db/db mice and HFD Spontaneously hypertensive rats (SHRs) were fed fenofibrate for 12 weeks. HK-2 and RAW264.7 cells were used to investigate their lymphangiogenic capacity in relation to lipotoxicity. Fenofibrate improved intrarenal lipotoxicity by increasing expression of PPARα and phosphorylation of AMPK. Lymphatic proliferation was attenuated; expression of lymphatic endothelial hyaluronan receptor-1 (LYVE-1), podoplanin, vascular endothelial growth factor-C (VEGF-C), and vascular endothelial growth factor receptor-3 (VEGFR-3) was decreased. In parallel, extent of tubulointerstitial fibrosis, apoptosis and inflammatory cell infiltration was reduced. In HK2 cells, palmitate- and high glucose-induced over expression of lymphatic makers was diminished by fenofibrate via activation of PPARα-AMPK-pACC signaling. Enhanced expression of M1 phenotype in RAW264.7 cells correlated with increased lymphatic growth. A causal relationship between lipotoxicity and lymphatic proliferation with a cellular link to macrophage activation can be speculated; pro-inflammatory M1 type macrophage is involved in the development of lymphangiogenesis through stimulation of VEGF-C and by its transdifferentiation into lymphatic endothelial cells.

Background: A vascular access blood flow (Qa) to cardiac output (CO) ratio greater than 0.3 increases the risk of high-output heart failure (HOHF). This study analyzed the characteristics and risk factors associated with a high Qa/CO ratio and effective CO (COef) in these patients over one year. Methods: This prospective study enrolled 142 hemodialysis (HD) patients, divided by the Qa/CO ratio. Baseline and one-year hemodynamics were measured: volume by bioimpedance, CO by echocardiography, Qa and brachial flow by transonic and ultrasound. Risk factors for HOHF were analyzed using receiver operating characteristic (ROC) curves and multivariable regression. Results: The study population was 66% male, mean age of 65, with 71% using arteriovenous fistulae (AVF) for vascular access. In the high Qa/CO group, cases of younger ages (62 vs. 67 years, p = 0.040) with upper arm access (73.1% vs. 32.8%, p < 0.001) were more prevalent, and diastolic blood pressure (DBP) was higher (76.8 ± 15.1 vs. 66.7 ± 14.4 mmHg, p = 0.002). Independent risk factors for high Qa/CO were elevated DBP (odds ratio [OR]: 1.080; 95% confidence interval [CI]: 1.028–1.134), upper arm access (OR: 8.113; 95% CI: 1.842–35.741), low resistive index (RI) (OR: 0.000; 95% CI: 0.000–0.417), and COef (OR: 0.164; 95% CI: 0.065–0.416). After one year, the high Qa/CO group showed significant increases in CO and COef (4.82 ± 1.25 L/min vs. 6.16 ± 2.05 L/min, p = 0.007, and 2.84 ± 0.95 L/min to 4.40 ± 1.89 L/min, p = 0.001, respectively). A baseline Qa cutoff value of 1.4 L/min demonstrated high diagnostic efficacy in identifying the high Qa/CO group. Conclusions: High Qa/CO ratios increase overt HOHF risk due to cardiac strain. This study reveals AV access-driven cardiac adaptations in patients with high Qa/CO and low COef, emphasizing the necessity for ongoing clinical and hemodynamic monitoring.

Background: The new Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations without a race coefficient have gained recognition across the United States. We aimed to test whether these new equations performed well in Korean patients with chronic kidney disease (CKD). Methods: This study included 2,149 patients with CKD G1–G5 without kidney replacement therapy from the Korean Cohort Study for Outcome in Patients with CKD (KNOW-CKD). The estimated glomerular filtration rate (eGFR) was calculated using the new CKD-EPI equations with serum creatinine and cystatin C. The primary outcome was 5-year risk of kidney failure with replacement therapy (KFRT). Results: When we adopted the new creatinine equation [eGFRcr (NEW)], 81 patients (23.1%) with CKD G3a based on the current creatinine equation (eGFRcr) were reclassified as CKD G2. Accordingly, the number of patients with eGFR of <60 mL/min/1.73 m2 decreased from 1,393 (64.8%) to 1,312 (61.1%). The time-dependent area under the receiver operating characteristic curve for 5-year KFRT risk was comparable between the eGFRcr (NEW) (0.941; 95% confidence interval [CI], 0.922–0.960) and eGFRcr (0.941; 95% CI, 0.922–0.961). The eGFRcr (NEW) showed slightly better discrimination and reclassification than the eGFRcr. However, the new creatinine and cystatin C equation [eGFRcr-cys (NEW)] performed similarly to the current creatinine and cystatin C equation. Furthermore, eGFRcr-cys (NEW) did not show better performance for KFRT risk than eGFRcr (NEW). Conclusion: Both the current and the new CKD-EPI equations showed excellent predictive performance for 5-year KFRT risk in Korean patients with CKD. These new equations need to be further tested for other clinical outcomes in Koreans.

Background: The 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine-based estimated glomerular filtration rate (eGFRcr) equation contains a race component that is not based on biology and may cause a bias in results. Therefore, the 2021 eGFRcr and creatinine-cystatin C–based eGFR (eGFRcr-cysC) equations were developed with no consideration of race. This study compared the cardiovascular event (CVE) and all-cause mortality and CVE combined predictability among the three eGFR equations in Korean chronic kidney disease (CKD) patients. Methods: This study included 2,207 patients from the KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease. Receiver operating characteristic (ROC) and net reclassification improvement (NRI) index were used to compare the predictability of the study outcomes according to the 2009 eGFRcr, 2021 eGFRcr, and 2021 eGFRcr-cysC equations. Results: The overall prevalence of CVE and all-cause mortality were 9% and 7%, respectively. There was no difference in area under the curve of ROC for CVE and mortality and CVE combined among all three equations. Compared to the 2009 eGFRcr, both the 2021 eGFRcr (NRI, 0.013; 95% confidence interval [CI], – 0.002 to 0.028) and the eGFRcr-cysC (NRI, –0.001; 95% CI, –0.031 to 0.029) equations did not show improved CVE predictability. Similar findings were observed for mortality and CVE combined predictability with both the 2021 eGFRcr (NRI, –0.019; 95% CI, –0.039–0.000) and the eGFRcr-cysC (NRI, –0.002; 95% CI, –0.023 to 0.018). Conclusion: The 2009 eGFRcr equation was not inferior to either the 2021 eGFRcr or eGFRcr-cysC equation in predicting CVE and the composite of mortality and CVE in Korean CKD patients.