PURPOSE:Due to chronic toxicity, tacrolimus-sparing is an important issue in kidney transplant recipients (KTRs). Several studies have shown that bisphosphonate use is associated with favorable graft outcomes in KTRs. We investigated whether the association between tacrolimus trough levels (TTLs) and graft outcomes differed according to bisphosphonate use in KTRs. MATERIALS AND METHODS:We conducted a retrospective study encompassing 1441 KTRs who were administered tacrolimus-based immunosuppressants. The primary exposure was a time-dependent cross-product of TTLs (low TTLs vs. normal-high TTLs with a reference of 6 ng/mL) and bisphosphonate use. Two primary outcomes were evaluated: overall graft loss (death or conversion to kidney replacement) and an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m². RESULTS:During the median follow-up of 6.1 (3.4-9.7) years, overall graft loss occurred in 157 (10.9%) patients. Cox regression revealed that normal-high TTLs without bisphosphonate use were associated with a reduced risk of overall graft loss [adjusted hazard ratio (aHR), 0.65; 95% confidence interval (CI), 0.45-0.95] compared to low TTLs without bisphosphonate use. The use of bisphosphonate in conjunction with normal-high TTLs correlated with an even lower risk of overall graft loss (aHR, 0.25; 95% CI, 0.08-0.80) compared with low TTLs without bisphosphonate use. In patients with low TTLs, bisphosphonate use was associated with a reduced risk of overall graft loss compared with non-use (aHR, 0.20; 95% CI, 0.09-0.43). Similar trends were observed in the eGFR outcome. CONCLUSION:The use of bisphosphonate was associated with favorable graft outcomes, even with low TTLs. Incorporating bisphosphonate into a conventional immunosuppressant regimen may potentially reduce tacrolimus requirement.

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:Anemia is a common complication in patients with non-dialysis chronic kidney disease managed with erythropoiesis- stimulating agents. Although biweekly darbepoetin alfa administration is standard practice, extended-interval dosing may improve convenience and adherence and reduce hemoglobin overshoot risk. Methods:This prospective, single-arm, phase 4 study evaluated the non-inferiority, safety, and clinical feasibility of switching from biweekly to once-every-4-week darbepoetin alfa administration in patients with non-dialysis chronic kidney disease. Participants initially received biweekly dosing for 12 weeks (run-in), followed by once-every-4-week dosing for 12 weeks (evaluation). The primary outcome was the absolute change in hemoglobin during each period. Secondary outcomes included response frequency, rate within the target range (hemoglobin >10.0 to ≤11.0 g/dL), and incidence of hemoglobin >11.0 g/dL. Results:Forty patients completed the study. The absolute change in hemoglobin during once-every-4-week dosing (evaluation) was non-inferior to that observed during biweekly dosing (run-in) (mean difference, -0.140 g/dL; 95% confidence interval, -0.434 to 0.154; non-inferiority p = 0.03). The proportion of patients maintaining hemoglobin ≥10.0 g/dL at the end of the once-every-4-week dosing period was 75.0%, with the hemoglobin >11.0 g/dL incidence significantly decreasing from 35.0% to 15.0% (p = 0.02). Generalized estimating equations and post-hoc analyses confirmed significant temporal changes in overshooting patterns, with a stable within-target hemoglobin response. Conclusion:Once-every-4-week darbepoetin alfa administration is non-inferior to biweekly dosing for hemoglobin control in patients with non-dialysis chronic kidney disease and reduces the risk of hemoglobin overshooting. This supports the clinical utility of once-every- 4-week dosing following current anemia management guidelines.

Background: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. Methods: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. Results: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. Conclusion:Increasing longitudinal TyGi levels are associated with a higher risk of adverse kidney outcomes in patients with MAFLD.

Statins act as antifibrotic agents but their mechanism is unclear. Therefore, we aimed to evaluate the antifibrotic effects of rosuvastatin in a chronic kidney fibrosis model in vivo and transforming growth factor-β1 (TGF-β1)-stimulated Madin-Darby canine kidney (MDCK) cells in vitro. Mice with unilateral ischemic reperfusion injury and contralateral nephrectomy (uIRIx) were administered vehicle or rosuvastatin (10 mg/kg/day by oral gavage) for four weeks and kidney fibrosis markers were analyzed. Moreover, control and homeobox protein Hox-A13 (HOXA13) knocked-down MDCK cells were stimulated with TGF-β1 (5 ng/ml) and then treated with rosuvastatin. The uIRIx mice developed severe tubulointerstitial fibrosis with increased α-smooth muscle actin (α-SMA), collagen I and uterine sensitization-associated gene-1 (USAG-1) expression, but rosuvastatin therapy attenuated these expression and improved fibrosis. Rosuvastatin also reduced Smad3 phosphorylation and increased Smad1/5/9 phosphorylation, both associated with bone morphogenetic protein-7 (BMP-7) signaling. TGF-β1-stimulated MDCK cells exhibited increased α-SMA, fibronectin, vimentin, and collagen 1 expression, which rosuvastatin reversed. In addition, TGF-β1-stimulated MDCK cells demonstrated increased USAG-1 expression without changes in BMP-7 expression. Gene knockdown using HOXA13 siRNA suggested rosuvastatin decreased USAG-1 expression by increasing HOXA13 expression. Our results demonstrate that rosuvastatin inhibits kidney fibrosis by activating BMP-7 signaling via upregulation of HOXA13 and downregulation of USAG-1.

Sarcopenia, characterized by progressive loss of muscle mass and function, is a prevalent complication in hemodialysis (HD) patients, significantly impacting morbidity and quality of life. Uremic toxics, oxidative stress as well as systemic inflammation contribute to muscle degradation. Short-term treatment with medium cut-off (MCO) dialyzers have demonstrated potential in increasing muscle while maintain fat tissue in maintenance HD patients, This study aimed to investigate long-term effects of MCO dialyzer in muscle mass and serum albumin in maintenance HD patients. We performed a randomized prospective study with 77 HD patients, divided into MCO dialyzer group (MCO, n = 39) and high-flux dialyzer group (HF, n = 38) (31 males, mean age 64.8 ± 12.2 years) from dialysis units of Gangnam Severance hospital and Yongin Severance hospital, Korea. Measurements of body weight, height, bioelectrical impedance analysis (BIA), and various biochemical parameters were taken at baseline and 12 months. Both group showed a slight decline in albumin levels, with a slightly greater drop in MCO group, but the difference was not statistically significant (−0.10 vs −0.19, p-value 0.065). Beta2-microglobulin levels increased in the HF group but slightly decreased in the MCO group (2.59 vs −0.51, p-value 0.025). The appendicular skeletal mass index (ASMI) that reflects skeletal muscle mass amount remained stable in the MCO group but declined in the HF group (−0.81 vs 0.27, p-value 0.049]. Kappa and Lambda free light chain level decreased in both group but were reduced greater in MCO group than in HF group at 12 months(−17.96 vs −74.89, p-value 0.008; −29.01 vs −54.23, p value <0.001). Long-term use of MCO dialyzer may improve muscle mass by reducing toxic middle molecules. These findings suggest that the potential role of MCO dialyzers in preventing sarcopenia in maintenance HD patients. Further large-scale studies are needed to confirm these benefits.

Background: G2/M cell cycle arrest of proximal tubular epithelial cells following acute kidney injury results in maladaptive repair and promotes chronic kidney disease. We investigated whether erythropoiesis-stimulating agents (ESA) regulate G2/M arrest and mitigate kidney fibrosis. Methods: Human kidney 2 (HK-2) cells were stimulated with TGF-β or paclitaxel, treated with darbepoetin alfa (DARB) at 0.5 ug/mL or 5 ug/mL, and cell cycles were analyzed using flow cytometry. In vivo experiments involved intraperitoneal administration of DARB (0.5 or 5 ug/kg) to the unilateral ureteral obstruction (UUO) mouse model on post-operative days three and seven. Kidney fibrosis and cell cycle regulatory proteins were analyzed using immunohistochemistry, RT-PCR, and immunoblotting. The effect of DARB on kidney fibrosis was compared with that of a p53 inhibitor. Results: In HK-2 cells treated with TGF-β or paclitaxel, G2/M cell cycle regulatory proteins were upregulated; however, this effect was reversed by DARB treatment. Immunostaining for p53 and Ki-67 indicated that the proliferative and fibrotic activities observed in TGF-β-treated HK-2 cells were mitigated by DARB treatment. Histological analysis of UUO mice using F4/80 staining and TUNEL assay showed that DARB treatment reduced inflammatory cell infiltration and apoptotic cell accumulation. Additionally, fibrotic changes assessed by Masson’s trichrome, Sirius red, and PAS staining confirmed the antifibrotic effects of DARB treatment in UUO mice, independent of changes in hemoglobin levels, suggesting a mechanism distinct from its hematopoietic effects. DARB reduced fibrosis-related markers by suppressing G2/M cell cycle regulatory markers and inhibited the JNK and p38-MAPK signaling pathways, which play key roles in kidney fibrosis in TGF-β-treated HK-2 cells and UUO mice. Finally, DARB treatment demonstrated an anti-fibrotic effect in HK-2 cells stimulated with TGF-β or paclitaxel, comparable to that of a p53 inhibitor. Conclusions: DARB treatment decreased G2/M cell phase arrest and attenuated kidney fibrosis, suggesting a new renoprotective mechanism for ESA.

Background:Lysyl oxidase-like 2 (LOXL2) has been implicated in tissue fibrosis; however, its role in diabetic podocyte injury remains unclear. This study aimed to investigate the contribution of LOXL2 to fibrotic signaling in podocytes under high-glucose conditions and identify its downstream molecular pathways. Methods:LOXL2 expression was examined in the glomeruli of patients with diabetes using immunofluorescence staining. Human podocytes were cultured under normal or high-glucose conditions, and LOXL2 was silenced using short hairpin RNA. The gene and protein expression of fibrotic markers, autophagy-related proteins, and key signaling molecules were assessed using quantitative real-time polymerase chain reaction and western blotting. Results:LOXL2 expression was markedly elevated in the glomeruli of patients with diabetes, particularly in podocytes. In vitro, high-glucose levels significantly upregulated LOXL2 and TGF-β messenger RNA expression in podocytes. LOXL2 knockdown suppressed TGF-β expression and reduced the protein levels of collagen I and α-smooth muscle actin. Furthermore, the phosphorylation of Smad2 and expression of Smad4 decreased in LOXL2-deficient cells, indicating that LOXL2 promotes fibrosis via the transforming growth factor-beta (TGF-β)/Smad pathway. In contrast, the LOXL2 knockdown did not significantly affect the expression of autophagy markers (p62, Beclin-1, and LC3A/B) or activation of the p38 MAPK pathway. Conclusion:LOXL2 is upregulated in diabetic podocytes and contributes to hyperglycemia-induced fibrosis by activating the TGF-β/Smad signaling pathway. These findings suggest that LOXL2 may serve as a potential therapeutic target for preventing or attenuating podocyte injury in patients with diabetic nephropathy.

BACKGROUND:The effects of atherogenic indices on kidney function remain unclear. This study evaluated the association between atherogenic indices and risk of chronic kidney disease (CKD) in adults with metabolic derangements. METHODS:A total of 4,176 participants from the Gangnam Severance Medical Cohort (2006-2021), which consisted of participants who had at least one disease related to metabolic derangements including diabetes mellitus, fatty liver, and hypertension were enrolled and atherogenic indices (lipid ratios including atherogenic index of plasma [AIP]) were assessed. The study endpoint was a composite kidney outcome (estimated glomerular filtration rate [eGFR] of <60 mL/min/1.73 m2 in at least two measurements in participants with baseline eGFR of ≥60 mL/min/1.73 m2; ≥30% decrease in eGFR from baseline in participants with baseline eGFR of <60 mL/min/1.73 m2; or the initiation of dialysis or kidney transplantation). RESULTS:During a median follow-up of 6.0 years (interquartile range, 2.5-11.0 years), 1,266 composite kidney outcomes (30.3%) occurred. The highest quartile of AIP showed a higher risk of composite kidney outcome than the lowest quartile (hazard ratio [HR], 1.31; 95% confidence interval [CI], 1.12-1.54). This association was consistent when the AIP was treated as a continuous variable (HR per 1.0 increase, 1.51; 95% CI, 1.21-1.88). However, other atherogenic indices did not show significant associations with composite kidney outcome. Adding AIP to the traditional risk model to predict composite kidney outcomes significantly improved the C-index, net reclassification index, and integrated discrimination improvement. The association between high AIP and an increased risk of composite kidney outcome was consistent regardless of subgroup. CONCLUSION:High AIP was associated with an increased risk of CKD in adults with metabolic derangements.

Statins act as antifibrotic agents but their mechanism is unclear. Therefore, we aimed to evaluate the antifibrotic effects of rosuvastatin in a chronic kidney fibrosis model in vivo and transforming growth factor-β1 (TGF-β1)-stimulated Madin-Darby canine kidney (MDCK) cells in vitro. Mice with unilateral ischemic reperfusion injury and contralateral nephrectomy (uIRIx) were administered vehicle or rosuvastatin (10 mg/kg/day by oral gavage) for four weeks and kidney fibrosis markers were analyzed. Moreover, control and homeobox protein Hox-A13 (HOXA13) knocked-down MDCK cells were stimulated with TGF-β1 (5 ng/ml) and then treated with rosuvastatin. The uIRIx mice developed severe tubulointerstitial fibrosis with increased α-smooth muscle actin (α-SMA), collagen I and uterine sensitization-associated gene-1 (USAG-1) expression, but rosuvastatin therapy attenuated these expression and improved fibrosis. Rosuvastatin also reduced Smad3 phosphorylation and increased Smad1/5/9 phosphorylation, both associated with bone morphogenic protein-7 (BMP-7) signaling. TGF-β1-stimulated MDCK cells exhibited increased α-SMA, fibronectin, vimentin, and collagen 1 expression, which rosuvastatin reversed. In addition, TGF-β1-stimulated MDCK cells demonstrated increased USAG-1 expression without changes in BMP-7 expression. Gene knockdown using HOXA13 siRNA suggested rosuvastatin decreased USAG-1 expression by increasing HOXA13 expression. Our results demonstrate that rosuvastatin inhibits kidney fibrosis by activating BMP-7 signaling via upregulation of HOXA13 and downregulation of USAG-1.

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.

Abstract Background and Aims Lysyl oxidase-like 2 (LOXL2), an amine oxidase, contributes to fibrotic scarring in the tissue by facilitating collagen cross-linking. Recent data demonstrated upregulation of lysyl oxidase and LOXL2 in the fibrotic kidneys after administration of cylosporine A (CsA). Thus, inhibition of LOXL2 may render therapeutic effects against CsA-induced nephropathy by ameliorating tubulointerstitial fibrosis. Method Low salt fed CD-1 mice were administered saline or CsA (15 mg/kg/day, intraperitoneally) for 8 weeks. At 4 weeks, CsA-treated animals were divided into 2 groups respectively and treated with: (1) vehicle, (2) LOXL2 inhibitor (10 mg/kg/day, gavage feeding) for another 4 weeks up to 8 weeks. We explored the reduction of tubulointerstitial fibrosis as well as albuminuria with administration of LOXL2 inhibitor in CsA nephropathy mouse model. Results CsA administration significantly increased the levels of serum creatinine (10.0 ± 1.2 vs. 28.4 ± 4.3, p = 0.02), tubular injury scores (0.1 ± 0.2 vs. 3.6 ± 1.3, p = 0.03), tubulointerstitial fibrosis (Sirius red positive area, 14 ± 6% vs. 204 ± 43%, p = 0.01), F4/80 positive inflammatory cell infiltration in mouse kidney (2 ± 1 vs. 21 ± 4, p = 0.001). These changes were associated with upregulated mRNA expression of LOXL2, TGF-β1, and monocyte chemoattractant protein-1 (MCP-1). Administration of LOXL2 inhibitor significantly suppressed the expression of alpha-SMA and collagen 1A, intrarenal F4/80 positive inflammatory cell infiltrations (21 ± 4 vs. 14 ± 2, p = 0.001) and improved tubular injury scores (3.6 ± 1.3 vs. 1.6 ± 1.1, p = 0.02). Moreover, LOXL2 inhibitor effectively reduced albuminuria excretion (46 ± 4 vs. 22 ± 6, p = 0.02). Conclusion Our results suggest that LOXL2 inhibitor treatment can attenuate CsA nephropathy progression and LOXL2 may be a potential therapeutic target in CsA nephropathy.

AbstractBackgroundThe association between the adiponectin‐to‐leptin ratio (A/L ratio) and the risk of incident chronic kidney disease (CKD) is poorly understood. This study aimed to investigate the association between A/L ratio and the risk of incident CKD and to examine whether such a relationship varied according to sex and body composition.MethodsIn this prospective community‐based cohort, participants with normal kidney function were analysed (N = 5192). The association between the A/L ratio at baseline and the risk of incident CKD, defined as two or more occasions with an estimated glomerular filtration rate of <60 mL/min/m2 or proteinuria of ≥1+ on a dipstick test during the follow‐up period, was evaluated using multivariable Cox proportional hazards analyses. Subgroup analyses were conducted based on sex, body mass index (BMI) and the presence of sarcopenia.ResultsThe participants' mean age was 57.2 ± 8.3 years, and 53.2% were women. The A/L ratio was higher in men compared with women (1.5 [0.8–3.2] and 0.5 [0.3–0.9] μg/ng, P < 0.001). During a median follow‐up of 9.8 [9.5–10.0] years, 417 incident CKD events occurred (8.7 per 1000 person‐years). Men in the highest quartile of A/L ratio had a lower risk of incident CKD (adjusted hazard ratio [aHR], 0.57; 95% confidence interval [CI], 0.33–0.99) than those in the lowest quartile. Additionally, a 1.0 increase in A/L ratio was associated with a 12% decreased risk of incident CKD in men (aHR, 0.88; 95% CI, 0.80–0.97). However, no significant association was observed in women. In subgroup analysis stratified by BMI and the presence of sarcopenia, the association between a high A/L ratio and a reduced risk of incident CKD was consistent in men with a BMI < 23.0 kg/m2 and those with sarcopenia. However, no significant association was observed between men with a BMI ≥ 23.0 kg/m2 and those without sarcopenia.ConclusionsA high A/L ratio is an independent marker of a reduced risk of incident CKD in men, especially in those with a BMI < 23.0 kg/m2 and sarcopenia.

Rationale & Objective The association of long-term cumulative blood pressure (BP) loads with the risk of incident chronic kidney disease (CKD) remains a matter of debate. This study aimed to investigate this association among healthy Korean adults with normal kidney function. Study Design Prospective cohort study. Setting & Participants We analyzed 5,221 participants without CKD in the Korean Genome and Epidemiology Study. Cumulative systolic and diastolic BP (SBP and DBP) loads were calculated as the ratios of the areas under the curve (AUC) for SBP ≥120 mmHg or ≥80 mmHg for DBP divided by the AUC for all SBP or DBP measurements during the exposure period. These AUCs were categorized into four groups: group 0 (reference), cumulative BP load of 0 and groups 1-3, tertiles of cumulative BP loads. Outcome Primary endpoint was incident CKD defined as a composite of an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2 or proteinuria greater than 1+ on dipstick examination for at least two consecutive measurements ≥90 days apart. Analytical Approach Multivariable Cox proportional hazards regression to estimate the independent association of cumulative BP loads with incident CKD. Results Higher cumulative SBP and DBP loads were associated with an increased risk of incident CKD (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.12-1.35 for SBP and HR 1.14, 95% CI 1.04-1.26 for DBP loads for each 1.0 unit greater load). Compared to SBP group 0, groups 2 and 3 were associated with 1.94- and 1.89-fold greater risk of incident CKD. Compared to DBP group 0, groups 2 and 3 were associated with 1.42- and 1.54-fold greater risks. These associations of high cumulative BP loads with an increased risk of incident CKD remained consistent even in subgroups not taking antihypertensive agents or without prior hypertension diagnosis. Limitations The assessment of CKD outcomes relied on eGFR and spot urine tests. Conclusions These findings highlight the association between high cumulative SBP and DBP loads and the occurrence of CKD, even in individuals with normal BP levels.