Hyo Jeong Kim

Key Points: Elevated growth differentiation factor-15 was associated with higher CKD risk, whereas Mendelian randomization suggested a possible protective association with kidney function. Proteomics identified TNF receptor signaling, extracellular matrix organization, and leukocyte chemotaxis as candidate pathways. Growth differentiation factor-15 may serve as a prognostic biomarker, while its possible protective role and underlying mechanisms require further study. Background: Growth differentiation factor-15 (GDF-15) has been implicated in adverse outcomes in cardiovascular disease and diabetes, highlighting its potential as a prognostic marker. However, its association with CKD development remains unclear. Therefore, we investigated the association between GDF-15 and incident CKD and explored potential causal mechanisms. Methods: We analyzed 31,965 UK Biobank participants without preexisting CKD. The primary outcome was incident CKD, defined by diagnostic codes or an eGFR 2 (eGFR-based CKD). Proteomics-based mediation and protein–protein interaction analyses identified potential mediators linking GDF-15 to CKD. A bidirectional 2-sample Mendelian randomization (MR) analysis using genome-wide association study summary statistics evaluated the potential causal relationship between GDF-15 and eGFR. Results: In multivariable cause-specific analyses, higher GDF-15 levels were significantly associated with increased CKD risk (hazard ratios: Q2, 1.05 [0.87 to 1.26]; Q3, 1.21 [1.01 to 1.45]; Q4, 1.87 [1.56 to 2.26] versus Q1; P for trend < 0.001). Similar results were observed for eGFR-based CKD. Mediation analysis identified candidate proteins potentially involved in TNF receptor signaling, extracellular matrix organization, and immune cell chemotaxis. MR analysis demonstrated a significant association between genetically predicted higher GDF-15 levels and higher eGFR (inverse-variance weighted coefficient, 0.003; 95% confidence interval, 0.001 to 0.004; P = 0.004). Conversely, higher genetically predicted eGFR was associated with lower GDF-15 levels (inverse-variance weighted coefficient, −1.238; 95% confidence interval, −1.591 to −0.886; P < 0.001). Conclusions: This study provides evidence supporting the role of GDF-15 as a prognostic biomarker for CKD and MR analyses provide suggestive evidence of a possible protective association of GDF-15 with kidney function. Further studies are needed to explore the mechanistic pathways and therapeutic implications of GDF-15 in kidney diseases.

Background/Objectives Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases involved in collagen cross-linking, has emerged as a key mediator of pathological extracellular matrix remodeling and tissue fibrosis. Dysregulated LOXL2 activity has been implicated in various fibrotic diseases; however, its role in fibrosis-driven chronic kidney injury, particularly in the context of calcineurin inhibitor-induced kidney toxicity, remains incompletely defined. Methods To investigate the contribution of LOXL2 inhibitor to cyclosporine A (CsA)-induced nephropathy, a well-established model of progressive tubulointerstitial fibrosis, male CD-1 mice were administered either saline or CsA (15 mg/kg/day, intraperitoneally) for 8 weeks. After 4 weeks of CsA exposure, CsA-treated mice were further divided into two groups and received either vehicle or a LOXL2 inhibitor (10 mg/kg/day, oral gavage) for an additional 4 weeks. Kidney function, albuminuria, histological fibrosis, inflammatory cell infiltration, and profibrotic gene expression were assessed. Results In a murine model of CsA-induced nephropathy, pharmacological inhibition of LOXL2 markedly improved kidney outcomes. LOXL2 inhibition significantly reduced albuminuria and ameliorated kidney dysfunction. In parallel, tubulointerstitial fibrosis was substantially attenuated, accompanied by reduced myofibroblast activation and extracellular matrix accumulation. These protective effects were associated with downregulation of profibrotic and inflammatory mediators and inhibition of TGF-β-related downstream signaling pathways activated by CsA. Conclusions The present preclinical findings suggest that Compound #765-mediated LOXL2 inhibition may offer a potential therapeutic benefit in CsA-induced fibrosis, though further validation is warranted.

Background: The impact of facility-level comorbidity burden on the prognosis of hemodialysis patients remains unclear. This study aimed to investigate the association between facility-level comorbidity burden and hemodialysis outcomes. Methods: We examined 15,481 participants receiving hemodialysis at primary clinics participating in the Periodic Hemodialysis Quality Assessment by Health Insurance Review and Assessment Service in Korea. Facility-level comorbidity burden, defined as the sum of the Charlson Comorbidity Index of all patients divided by the number of nurses in each hemodialysis center, was the primary predictor. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE). Results: During a median follow-up of 6.8 years, MACCE and all-cause mortality occurred in 9,797 (63.3%) and 8,513 participants (55.0%), respectively. Participants in the highest facility-level comorbidity burden had the highest incidence rates of both MACCE and all-cause mortality. Hazard ratios (HRs) of MACCE and all-cause mortality in the highest vs. the lowest quartile were 1.10 (95% confidence interval [CI], 1.03–1.18) and 1.14 (95% CI, 1.06–1.22), respectively. Applying the facility-level comorbidity burden as a continuous variable, each 10-unit increase in facility-level comorbidity burden was associated with a 4% and 8% higher risk of MACCE and all-cause mortality, respectively. These associations remained consistent across subgroups. Conclusion: Our findings revealed that the facility-level comorbidity burden in hemodialysis centers was associated with a higher hazard of poor outcomes in patients undergoing hemodialysis.

Triglyceride-glucose index (TyGi), a surrogate marker of metabolic dysfunction, has not been evaluated for kidney outcomes in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). We aimed to evaluate this association in individuals with MAFLD. Totally 868 patients with MAFLD from the Gangnam Severance Medical Cohort (2006-2021) were included. TyGi trajectories were defined using latent class mixture modeling based on their longitudinal changes: decreasing (n = 426) vs. increasing (n = 442). MAFLD was diagnosed based on hepatic steatosis and at least one of the following: overweight or obese, type 2 diabetes, or two or more metabolic abnormalities. Kidney outcomes included: sustained reduction in eGFR to <60 mL/min/1.73 m2 for those with baseline eGFR of ≥60 mL/min/1.73 m2, ≥30% decline from baseline for those with eGFR <60 mL/min/1.73 m2, or initiation of dialysis or kidney transplantation. Cause-specific Cox proportional hazard models assessed the association between TyGi trajectories and kidney outcomes. The participants' mean age was 52.3 ± 10.4 years and 504 (58.1%) were male. Over a median follow-up of 6.9 years (4.0- 10.0 years), 36 kidney outcome events occurred. The incidence rates were 4.02 and 9.06 per 1,000 person-years in the decreasing and increasing TyGi trajectory groups, respectively (p = 0.02). In a multivariable cause-specific Cox model, the increasing trajectory group had a significantly greater risk of kidney outcomes than the decreasing group (hazard ratio, 3.68; 95% confidence interval, 1.68- 8.05; p = 0.001). Subgroup analyses showed consistent findings. Increasing longitudinal TyGi levels are associated with a higher risk of adverse kidney outcomes in patients with MAFLD.

Koh HB, et al. Yonsei Med J. 2026 Jan;67(1):17-26. https://doi.org/10.3349/ymj.2025.0065

Key Points: Higher dietary inflammatory index was associated with incident CKD in adults with clinically normal kidney function. Association between dietary inflammatory index and incident CKD mediated by death receptor and TNF receptor-related pathways and plasma omega-3 fatty acids. Specific dietary patterns such as higher oily fish intake, lower consumption of sugar-rich foods, may be linked to lower inflammation-related kidney risk. Background: Although the association between diet-induced inflammation and the risk of cardiovascular disease or cancer has been previously reported, its contribution to CKD and the underlying biologic mechanisms remain unclear. This study aimed to elucidate the mechanistic role of the dietary inflammatory index (DII) in CKD through multiomics-based mediation analyses and to provide clinically relevant insight. Methods: This study included 158,722 UK Biobank participants without underlying CKD (median age 57 years; 53% female). The DII was assessed through a 24-hour dietary recall and categorized into quartiles. Incident CKD was identified using International Classification of Diseases-10 and Office of Population Censuses and Surveys Classification of Interventions and Procedures-4 codes. In a subcohort with creatinine follow-up, CKD was also defined as an eGFR 2 . Mediation analyses using proteomics and metabolomics data were conducted to explore potential mechanisms linking diet-induced inflammation to CKD. Individual food item analyses were performed to identify their association with CKD through diet-induced inflammation. Results: During a median of 11.2 years of follow-up, CKD occurred in 4382 patients. Cox regression revealed that the adjusted hazard ratios for incident CKD were higher in a stepwise fashion across higher DII quartiles (adjusted hazard ratio and 95% confidence interval: Q2, 1.08 [0.99 to 1.18]; Q3, 1.15 [1.05 to 1.26]; Q4, 1.17 [1.06 to 1.29]) relative to Q1 ( P -for-trend < 0.001). Similar results were observed with eGFR-defined CKD. Proteomics-based mediation analysis identified death receptor and TNF receptor-related proteins as mediators linking diet-induced inflammation to CKD. Metabolomics analysis highlighted omega-3 fatty acids, especially docosahexaenoic acid, as protective mediators. Oily fish intake was inversely associated with CKD risk, while sugar-rich and high-fat dairy consumption showed positive associations, partly through inflammatory pathways. Conclusions: The association between the DII and incident CKD risk may be partly mediated by alterations in circulating protein profiles involving TNF receptor superfamily-related pathways and plasma omega-3 fatty acids. Dietary counseling aimed at lowering the consumption of sugar-rich and high-fat dairy products may be beneficial.

Background: Sacubitril-valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction (HFrEF). However, its long-term protective effects on cardiac function with concurrent acute kidney injury (AKI) remain unclear. This study investigated the recovery of cardiac function relative to kidney function decline. Methods: A total of 512 patients with HFrEF who started sacubitril-valsartan or valsartan treatment were enrolled in cohort 1. Additionally, patients who experienced AKI and underwent follow-up transthoracic echocardiography were enrolled in cohort 2. In cohort 1, short- and long-term kidney outcomes were analyzed. For cohort 2, changes in cardiac function in relation to changes in kidney function after drug initiation were analyzed. Results: The mean age of the patients was 68.3 ± 15.1 years, and 57.4% of the patients were male. AKI occurred in 15.9% of the sacubitril-valsartan group and 12.5% of the valsartan group. After AKI, 78.4% of patients in the sacubitril-valsartan group and 71.4% of those in the valsartan group underwent recovery. Furthermore, cardiovascular outcomes in patients who developed AKI after drug initiation were analyzed in cohort 2. The sacubitril-valsartan group showed a greater improvement in cardiac function compared with the valsartan group (12.4% ± 15.4% vs. 1.4% ± 5.7%, p = 0.046). The ratio of deltas of cardiac and kidney function in the sacubitril-valsartan and valsartan groups were –1.76 ± 2.58 and –0.20 ± 0.58, respectively (p = 0.03).Conclusion: Patients with HFrEF treated with sacubitril-valsartan exhibited significant improvements in cardiovascular outcomes despite AKI.

BACKGROUND: Atrial fibrillation (AF) can lead to stroke, heart failure, and mortality and has a greater prevalence in dialysis patients than in the general population. Several studies have suggested that uremic toxins may contribute to the development of AF. However, the association between dialysis adequacy and incident AF has not been well established. METHODS: In this retrospective nationwide cohort study, we analyzed data from the Korean National Periodic Hemodialysis Quality Assessment from 2013 to 2015 of patients who received outpatient maintenance hemodialysis 3× a week. The main exposure was single pooled Kt/V (spKt/V), which is the dialysis adequacy index, and the primary outcome was the development of AF. For the primary analysis, patients were categorized into quartiles according to baseline spKt/V. The lowest quartile, representing the lowest adequacy, was used as the reference group. Fine-Gray subdistribution hazard models were used, treating all-cause mortality as a competing risk. RESULTS: Of 25 173 patients, the mean age was 60 (51–69) years, and 14 772 (58.7%) were men. During a median follow-up of 5.7 years, incident AF occurred in a total of 3883 (15.4%) patients. Participants with a higher spKt/V tended to have lower AF incidence. In survival analysis, a graded association was observed between the risk of incident AF and spKt/V quartiles: subdistribution hazard ratios and 95% CIs for the second, third, and the highest quartile compared with the lowest quartile were 0.90 (95% CI, 0.82–0.98), 0.84 (95% CI, 0.77–0.93), and 0.79 (95% CI, 0.72–0.88), respectively. CONCLUSIONS: This nationwide cohort study showed that a higher spKt/V is associated with a reduced risk of incident AF. These findings suggests that reducing uremic toxin burden through enhanced dialysis clearance may be associated with a lower risk of AF development in patients undergoing maintenance hemodialysis.

Background: Insomnia is a known risk factor for cardio-cerebrovascular disease in the general population; however, its effect on cardio-cerebrovascular outcomes in end-stage kidney disease patients is unclear. Therefore, this study aimed to investigate the association between cardio-cerebrovascular outcomes and insomnia in patients who initiated maintenance dialysis. Methods: This study used nationwide Korean health insurance claims data to analyze 79 420 patients who initiated maintenance dialysis from January 2009 to December 2017. Insomnia was defined using claim codes and sleep medication prescription data. Patients were categorized according to the presence of insomnia before and after dialysis initiation: (i) no insomnia, (ii) insomnia before dialysis only (improved insomnia), (iii) insomnia after dialysis only (developed insomnia) and (iv) insomnia in both periods (persistent insomnia). The primary and secondary outcomes were major adverse cardiac and cerebrovascular events (MACCE) and all-cause mortality, respectively. The outcome risks were estimated by Cox regression models with inverse probability of treatment weighting. Results: The mean age was 61.4 ± 13.4 years, and 39.7% were women. During the transition period from pre-dialysis to maintenance dialysis, 13.2% experienced insomnia. The insomnia groups showed significantly higher risks for MACCE [weighted hazard ratios (95% confidence intervals): developed insomnia, 1.26 (1.25–1.28); improved insomnia, 1.31 (1.29–1.33); persistent insomnia, 1.39 (1.37–1.41)] and higher all-cause mortality risks than the no insomnia group. The insomnia-related cardio-cerebrovascular disease risk elevation was more prominent in younger and male patients. Conclusions: Insomnia may increase cardio-cerebrovascular disease and all-cause mortality risk among end-stage kidney disease patients who initiate maintenance dialysis.