Impact of obesity on renal function in elderly Korean adults: a national population-based cohort study.

Background: Obesity is a well-known risk factor for chronic kidney disease and its progression. However, the impact of obesity on the renal function of the elderly population is uncertain. We investigated the association between obesity and renal outcomes in the elderly. Methods: We analyzed 130,504 participants from the Korean National Health Insurance Service-Senior cohort. Obesity was classified according to body mass index (BMI), sex-specific waist circumference (WC), and the presence of metabolic syndrome. The primary outcome was renal function decline, defined as a decline in the estimated glomerular filtration rate (eGFR) of at least 50% from baseline or new-onset end-stage renal disease. Results: During a follow-up period of 559,531.1 person-years (median, 4.3 years), 2,486 participants (19.0%; incidence rate of 4.44 per 1,000 person-years) showed renal function decline. A multivariate Cox proportional hazards model revealed that BMI/WC was not associated with renal function decline. However, the group with metabolic syndrome had a significantly increased risk of renal function decline compared to the group without metabolic syndrome (adjusted hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.13-1.36). Compared with the non-metabolic syndrome group, the adjusted HRs (95% CI) for participants with one through five components were 0.96 (0.84-1.11), 1.10 (0.96-1.27), 1.24 (1.06-1.45), 1.37 (1.12-1.66), and 1.99 (1.42-2.79), respectively (p for trend < 0.001). Conclusion: In elderly Korean adults, metabolic syndrome and the number of its components were associated with a higher risk of renal function decline, but BMI or WC was not significant.

Association between dementia diagnosis at dialysis initiation and mortality in older patients with end-stage kidney disease in South Korea.

Background: The prevalence of dementia is 2- to 7-fold higher among patients with end-stage kidney disease (ESKD) than among the general population; however, its clinical implications in this population remain unclear. Therefore, this study aimed to determine whether comorbid dementia increases mortality among older patients with ESKD undergoing newly initiated hemodialysis. Methods: We analyzed data from the Korean Society of Geriatric Nephrology retrospective cohort, which included 2,736 older ESKD patients (≥70 years old) who started hemodialysis between 2010 and 2017. Kaplan-Meier survival and Cox regression analyses were used to examine all-cause mortality between the patients with and without dementia in this cohort. Results: Of the 2,406 included patients, 8.3% had dementia at the initiation of dialysis; these patients were older (79.6 ± 6.0 years) than patients without dementia (77.7 ± 5.5 years) and included more women (male:female, 89:111). Pre-ESKD diagnosis of dementia was associated with an increased risk of overall mortality (hazard ratio, 1.503; p < 0.001), and this association remained consistent after multivariate adjustment (hazard ratio, 1.268; p = 0.009). In subgroup analysis, prevalent dementia was associated with mortality following dialysis initiation in female patients, those aged <85 years, those with no history of cerebrovascular accidents or severe behavioral disorders, those not residing in nursing facilities, and those with no or short-term hospitalization. Conclusion: A pre-ESKD diagnosis of dementia is associated with mortality following dialysis initiation in older Korean population. In older patients with ESKD, cognitive assessment at dialysis initiation is necessary.

Importance of dialysis specialists in early mortality in elderly hemodialysis patients: a multicenter retrospective cohort study.

The early mortality rate in elderly patients undergoing hemodialysis is more than twice that in young patients, requiring more specialized healthcare. We investigated whether the number of professional dialysis specialists affected early mortality in elderly patients undergoing hemodialysis. This multicenter retrospective cohort study analyzed data from 1860 patients aged ≥ 70 years who started hemodialysis between January 2010 and December 2017. Study regions included Seoul, Gyeonggi-do, Gangwon-do, Daejeon/Chungcheong-do, Daegu/Gyeongsangbuk-do, and Busan/Ulsan/Gyeongsangnam-do. The number of patients undergoing hemodialysis per dialysis specialist was calculated using registered data from each hemodialysis center. Early mortality was defined as death within 6 months of hemodialysis initiation. Gangwon-do (28.3%) and Seoul (14.5%) showed the highest and lowest early mortality rate, respectively. Similarly, Gangwon-do (64.6) and Seoul (43.9) had the highest and lowest number of patients per dialysis specialist, respectively. Relatively consistent results were observed for the regional rankings of early mortality rate and number of patients per dialysis specialist. Multivariate Cox regression analysis-adjusted for previously known significant risk factors-revealed that the number of patients per dialysis specialist was an independent risk factor for early mortality (hazard ratio: 1.031, p < 0.001). This study underscores the growing need for dialysis specialists for elderly hemodialysis patients in Korea.

Effect of low-density lipoprotein level and mortality in older incident statin-naïve hemodialysis patients.

BACKGROUND: This study aimed to analyze low-density lipoprotein cholesterol (LDL-C) levels and their relationship with mortality in order to identify the appropriate lipid profile for older Korean hemodialysis patients. METHODS: We enrolled a total of 2,732 incident hemodialysis patients aged > 70 years from a retrospective cohort of the Korean Society of Geriatric Nephrology from 2010 Jan to 2017 Dec, which included 17 academic hospitals in South Korea. Of these patients, 1,709 were statin-naïve, and 1,014 were analyzed after excluding those with missing LDL-C level data. We used multivariate Cox regression analysis to select risk factors from 20 clinical variables among the LDL-C groups. RESULTS: The mean age of the entire patient population was 78 years, with no significant differences in age between quartiles Q1 to Q4. However, the proportion of males decreased as the quartiles progressed towards Q4 (p < 0.001). The multivariate Cox regression analysis, which included all participants, showed that low LDL-C levels were associated with all-cause mortality. In the final model, compared to Q1, the hazard ratios (95% confidence interval) were 0.77 (0.620-0.972; p = 0.027), 0.85 (0.676-1.069; p = 0.166), and 0.65 (0.519-0.824; p < 0.001) for Q2, Q3, and Q4, respectively, after adjusting for covariates, such as conventional and age-specific risk factors. The final model demonstrated that all-cause mortality increased as LDL-C levels decreased, as confirmed by a restrictive cubic spline plot. CONCLUSIONS: In older hemodialysis patients who had not previously received dyslipidemia treatment, elevated LDL-C levels were not associated with increased all-cause mortality. Intriguingly, lower LDL-C levels appear to be associated with an unfavorable effect on all-cause mortality among high-risk hemodialysis patients.

Shared decision-making intervention regarding dialysis modality in patients with CKD stage 5.

BACKGROUND: Patients with kidney failure must make complicated decisions about the dialysis modalities used either at home or in-hospital. Different options have varying levels of impact on patients' physical and psychological conditions and their social life. The purpose of this study was to evaluate the implementation of an intervention designed to achieve shared decision making (SDM) in patients' options for dialysis. METHODS: SDM was performed after consent was written for stage 5 chronic kidney disease patients before dialysis, and 435 cases were performed in 408 patients from December 16, 2019 to June 30, 2021. Among these, 101 patients were compared by SDM measurement scale, patient satisfaction, disease recognition scale survey, and dialysis method. RESULTS: The average age of participants was 56 years, with a gender composition of 55 males (54.5%) and 46 females (45.5%). Following SDM, the final dialysis methods decided upon by patients and clinicians were peritoneal dialysis (67 patients, 66.3%), hemodialysis (22 patients, 21.8%), and kidney transplantation (1 patient, 1.0%). CONCLUSIONS: Among participating patients, SDM was effective when used to decide on dialysis treatment, and patients were satisfied with the dialysis method decision process. On the disease awareness scale, those who participated in this project had relatively high positive and low negative perceptions, so it can be concluded that SDM was relatively effective. The implementation of SDM was helpful in selecting patients' best dialysis methods, and SDM scale results were higher in the peritoneal dialysis group than in the hemodialysis group.

Comparison of the association intensity of creatinine and cystatin C with hyperphosphatemia and hyperparathyroidism in patients with chronic kidney disease.

Herein, we compared the association intensity of estimated glomerular filtration rate (eGFR) equations using creatinine (Cr) or cystatin C (CysC) with hyperphosphatemia and secondary hyperparathyroidism occurrence, which reflect the physiological changes occurring during chronic kidney disease (CKD) progression. This study included 639 patients treated between January 2019 and February 2022. The patients were divided into low- and high-difference groups based on the median value of the difference between the Cr-based eGFR (eGFRCr) and CysC-based eGFR (eGFRCysC). Sociodemographic and laboratory factors underlying a high difference between eGFRCr and eGFRCysC were analyzed. The association intensity of eGFRCr, eGFRCysC and both Cr- and CysC-based eGFR (eGFRCr-CysC) was compared using the area under the receiver operating characteristic curve (AuROC) values for hyperphosphatemia and hyperparathyroidism occurrence in the overall cohort and the low- and high-difference groups. Age > 70 years and CKD grade 3 based on eGFRCr were significant factors affecting the high differences. eGFRCysC and eGFRCr-CysC showed higher AuROC values than that of eGFRCr, especially in the high-difference group and in patients with CKD grade 3. Our results show that CysC should be evaluated in patients with significant factors, including age > 70 years and CKD grade 3, to accurately assess kidney function to better determine the physiological changes in CKD progression and predict prognosis accurately.

Association between physical activity and risk of renal function decline and mortality in community-dwelling older adults: a nationwide population-based cohort study.

BACKGROUND: Physical activity (PA) is an important risk factor associated with health outcomes. However, the relationship between PA and kidney function decline in older adults remains unclear. We examined the influence of PA on kidney function decline and mortality in community-dwelling older adults. METHODS: Adults aged ≥ 65 years with an estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m2 who had available health checkup data from 2009 to 2010 were included. The cohort was followed annually through December 2015 for anthropometric, sociodemographic, and medical information including outcomes and biennially for laboratory information from the health checkup. We divided these patients into three groups according to self-reported PA (Inactive group: no leisure-time PA, Active group: vigorous activity for at least 80 min/week or a sum of moderate-intensity activity and walking for at least 300 min/week, Low-active group: level of PA between the definitions of the other two groups). Associations between the intensity of PA and death, cardiovascular death, and ≥ 50% eGFR decline were investigated. RESULTS: Among 102,353 subjects, 32,984 (32.23%), 54,267 (53.02%), and 15,102 (14.75%) were classified into the inactive, low-active, and active groups, respectively. The active group was younger, contained a higher proportion of men, and had higher frequencies of hypertension, diabetes mellitus, drinking, and smoking than the other groups. The active group had significantly lower incidence rates of mortality, cardiovascular mortality, and kidney function decline than the other groups (all p < 0.001). The active group also showed lower all-cause (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.70-0.82) and cardiovascular mortality (HR, 0.64; 95% CI, 0.53-0.78) and protection against ≥ 50% eGFR decline (HR, 0.81; 95% CI, 0.68-0.97) compared with the inactive group in the fully adjusted Cox proportional hazards regression model. CONCLUSIONS: High PA was an independent modifiable lifestyle factor for reducing mortality and protecting against declines in kidney function in older adults.

Combined impact of the inter and intra-patient variability of tacrolimus blood level on allograft outcomes in kidney transplantation.

Introduction: Tacrolimus (TAC) has been widely used as an immunosuppressant after kidney transplantation (KT); however, the combined effects of intra-patient variability (IPV) and inter-patient variability of TAC-trough level (C0) in blood remain controversial. This study aimed to determine the combined impact of TAC-IPV and TAC inter-patient variability on allograft outcomes of KT. Methods: In total, 1,080 immunologically low-risk patients who were not sensitized to donor human leukocyte antigen (HLA) were enrolled. TAC-IPV was calculated using the time-weighted coefficient variation (TWCV) of TAC-C0, and values > 30% were classified as high IPV. Concentration-to-dose ratio (CDR) was used for calculating TAC inter-patient variability, and CDR < 1.05 ng•mg/mL was classified as rapid metabolizers (RM). TWCV was calculated based on TAC-C0 up to 1 year after KT, and CDR was calculated based on TAC-C0 up to 3 months after KT. Patients were classified into four groups according to TWCV and CDR: low IPV/non-rapid metabolizer (NRM), high IPV/NRM, low IPV/RM, and high IPV/RM. Subgroup analysis was performed for pre-transplant panel reactive antibody (PRA)-positive and -negative patients (presence or absence of non-donor-specific HLA-antibodies). Allograft outcomes, including deathcensored graft loss (DCGL) and biopsy-proven allograft rejection (BPAR), were compared. Results: The incidences of DCGL, BPAR, and overall graft loss were the highest in the high-IPV/RM group. In addition, a high IPV/RM was identified as an independent risk factor for DCGL. The hazard ratio of high IPV/RM for DCGL and the incidence of active antibody-mediated rejection were considerably increased in the PRA-positive subgroup. Discussion: High IPV combined with RM (inter-patient variability) was closely related to adverse allograft outcomes, and hence, more attention must be given to pre-transplant PRA-positive patients.

A Multi-Center, Prospective Observational Study to Investigate the Safety, Compliance, and Efficacy of Omethyl QTlet Soft Capsule.

Omega-3 fatty acids have been shown to be effective in lowering triglyceride (TG) levels; however, tolerability issues arise due to the large size of the pills. The purpose of this study was to examine the safety, compliance, and efficacy of Omethyl QTlet soft capsules (OQCs). This multi-center, prospective, observational study evaluated the safety, compliance, and efficacy of OQCs. Patients with hypertriglyceridemia with a history of omega-3 fatty acid intake were enrolled in this study and were prescribed OQCs (2 g−4 g/day) for eight weeks. All adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events (SAEs) were recorded for safety evaluation. Adherence to treatment was assessed using questionnaires, and efficacy was assessed by changes in lipid and lipoprotein levels after eight weeks from baseline. The convenience of taking medication was analyzed for 580 patients, and the efficacy test was performed for 563 patients. The AE and ADR rates were 8.2% and 5.7%, respectively. There were only two SAEs. Of the patients, 55.8% responded that the OQC improved medication convenience, and mean changes in TG, total cholesterol, LDL-C, and non-HDL-C from baseline to eight weeks were −37.88 mg/dL, −11.56 mg/dL, −5.55 mg/dL, and −10.87 mg/dL, respectively (p-values < 0.001). In patients who had previously taken omega-3 fatty acids, OQCs showed safety and efficacy in lowering TG, and it was confirmed that compliance with medicine also improved compared to omega-3 fatty acids.

Acute kidney injury due to intravenous detergent poisoning: A case report.

BACKGROUND: Detergent poisoning mostly occurs through oral ingestion (> 85%), ocular exposure (< 15%), or dermal exposure (< 8%). Reports of detergent poisoning through an intravenous injection are extremely rare. In addition, there are very few cases of renal toxicity directly caused by detergents. Here, we report a unique case of acute kidney injury caused by detergent poisoning through an accidental intravenous injection. CASE SUMMARY: A 61-year-old man was intravenously injected with 20 mL of detergent by another patient in the same room of a local hospital. The surfactant and calcium carbonate accounted for the largest proportion of the detergent. The patient complained of vascular pain, chest discomfort, and nausea, and was transferred to our institution. After hospitalization, the patient's serum creatinine level increased to 5.42 mg/dL, and his daily urine output decreased to approximately 300 mL. Renal biopsy findings noted that the glomeruli were relatively intact; however, diffuse acute tubular injury was observed. Generalized edema was also noted, and the patient underwent a total of four hemodiafiltration sessions. Afterward, the patient's urine output gradually increased whereas the serum creatinine level decreased. The patient was discharged in a stable status without any sequelae. CONCLUSION: Detergents appear to directly cause renal tubular injury by systemic absorption. In treating a patient with detergent poisoning, physicians should be aware that the renal function may also deteriorate. In addition, timely renal replacement therapy may help improve the patient's prognosis.

Ceria-Zirconia nanoparticles reduce intracellular globotriaosylceramide accumulation and attenuate kidney injury by enhancing the autophagy flux in cellular and animal models of Fabry disease.

BACKGROUND: Fabry disease (FD) is a lysosome storage disease (LSD) characterized by significantly reduced intracellular autophagy function. This contributes to the progression of intracellular pathologic signaling and can lead to organ injury. Phospholipid-polyethyleneglycol-capped Ceria-Zirconia antioxidant nanoparticles (PEG-CZNPs) have been reported to enhance autophagy flux. We analyzed whether they suppress globotriaosylceramide (Gb3) accumulation by enhancing autophagy flux and thereby attenuate kidney injury in both cellular and animal models of FD. RESULTS: Gb3 was significantly increased in cultured human renal proximal tubular epithelial cells (HK-2) and human podocytes following the siRNA silencing of α galactosidase A (α-GLA). PEG-CZNPs effectively reduced the intracellular accumulation of Gb3 in both cell models of FD and improved both intracellular inflammation and apoptosis in the HK-2 cell model of FD. Moreover these particles attenuated pro fibrotic cytokines in the human podocyte model of FD. This effect was revealed through an improvement of the intracellular autophagy flux function and a reduction in reactive oxygen species (ROS). An FD animal model was generated in which 4-week-old male B6;129-Glatm1Kul/J mice were treated for 8 weeks with 10 mg/kg of PEG-CZNPs (twice weekly via intraperitoneal injection). Gb3 levels were reduced in the kidney tissues of these animals, and their podocyte characteristics and autophagy flux functions were preserved. CONCLUSIONS: PEG-CZNPs alleviate FD associated kidney injury by enhancing autophagy function and thus provide a foundation for the development of new drugs to treat of storage disease.

Effect of shared decision-making education on physicians' perceptions and practices of end-of-life care in Korea.

BACKGROUND: Evidence of the ethical appropriateness and clinical benefits of shared decision-making (SDM) are accumulating. This study aimed to not only identify physicians' perspectives on SDM, and practices related to end-of-life care in particular, but also to gauge the effect of SDM education on physicians in Korea. METHODS: A 14-item questionnaire survey using a modified Delphi process was delivered to nephrologists and internal medicine trainees at 17 university hospitals. RESULTS: A total of 309 physicians completed the survey. Although respondents reported that 69.9% of their practical decisions were made using SDM, 59.9% reported that it is not being applied appropriately. Only 12.3% of respondents had received education on SDM as part of their training. The main obstacles to appropriate SDM were identified as lack of time (46.0%), educational materials and tools (29.4%), and education on SDM (24.3%). Although only a few respondents had received training on SDM, the proportion of those who thought they were using SDM appropriately in actual practice was high; the proportion of those who chose lack of time and education as factors that hindered the proper application of SDM was low. CONCLUSION: The majority of respondents believed that SDM was not being implemented properly in Korea, despite its use in actual practice. To improve the effectiveness of SDM in the Korean medical system, appropriate training programs and supplemental policies that guarantee sufficient application time are required.

Ceria-Zirconia Antioxidant Nanoparticles Attenuate Hypoxia-Induced Acute Kidney Injury by Restoring Autophagy Flux and Alleviating Mitochondrial Damage.

Oxidative stress is one of the principal causes of hypoxia-induced kidney injury. The ceria nanoparticle (CNP) is known to exhibit free radical scavenger and catalytic activities. When zirconia is attached to CNPs (CZNPs), the ceria atom tends to remain in a Ce3+ form and its efficacy as a free radical scavenger thus increases. We determined the effectiveness of CNP and CZNP antioxidant activities against hypoxia-induced acute kidney injury (AKI) and observed that these nanoparticles suppress the apoptosis of hypoxic HK-2 cells by restoring autophagy flux and alleviating mitochondrial damage. In vivo experiments revealed that CZNPs effectively attenuate hypoxia-induced AKI by preserving renal structures and glomerulus function. These nanoparticles can successfully diffuse into HK-2 cells and effectively counteract reactive oxygen species (ROS) to block hypoxia-induced AKI. This suggests that these particles represent a novel approach to controlling this condition.

Effects of 6 Months of Dapagliflozin Treatment on Metabolic Profile and Endothelial Cell Dysfunction for Obese Type 2 Diabetes Mellitus Patients without Atherosclerotic Cardiovascular Disease.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of cardiovascular death in individuals with type 2 diabetes mellitus (T2DM) and cardiovascular disease, but the effect of these inhibitors on early cardiovascular disease remains unknown. This study evaluated the effect of dapagliflozin on the metabolic profiles and endothelial cell function in obese patients with T2DM without established cardiovascular disease. METHODS: We enrolled 140 patients with a mean age, weight, and body mass index (BMI) of 47 years, 83 kg, and 30.3 kg/m2, respectively. Dapagliflozin (10 mg daily for 6 months) was administered to obese patients with T2DM without established cardiovascular disease. Participants' weight, BMI, body fat mass (BFM), muscle mass, glycosylated hemoglobin (HbA1c), lipid profile, waist to hip ratio (WHR), and pulse wave velocity (PWV) were measured at baseline and after 6 months. RESULTS: Participants experienced statistically significant reductions in their HbA1c, fasting plasma glucose, low-density lipoprotein cholesterol, total cholesterol, body weight, BMI, WHR, BFM, and aortic PWV, without a significant change in their muscle mass, extracellular fluid, or intracellular volume. Statistically significant reductions in aortic PWV were associated with a decrease in BFM, visceral fat, WHR, and homeostatic model assessment of insulin resistance. CONCLUSION: Dapagliflozin may be beneficial in preventing early cardiovascular disease in obese patients with T2DM without established cardiovascular disease.

Author Correction: Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity.

Crosstalk between liver and skeletal muscle is vital for glucose homeostasis. Hepatokines, liver-derived proteins that play an important role in regulating muscle metabolism, are important to this communication. Here we identify apolipoprotein J (ApoJ) as a novel hepatokine targeting muscle glucose metabolism and insulin sensitivity through a low-density lipoprotein receptor-related protein-2 (LRP2)-dependent mechanism, coupled with the insulin receptor (IR) signaling cascade. In muscle, LRP2 is necessary for insulin-dependent IR internalization, an initial trigger for insulin signaling, that is crucial in regulating downstream signaling and glucose uptake. Of physiologic significance, deletion of hepatic ApoJ or muscle LRP2 causes insulin resistance and glucose intolerance. In patients with polycystic ovary syndrome and insulin resistance, pioglitazone-induced improvement of insulin action is associated with an increase in muscle ApoJ and LRP2 expression. Thus, the ApoJ-LRP2 axis is a novel endocrine circuit that is central to the maintenance of normal glucose homeostasis and insulin sensitivity.

Bioelectrical Impedance Analysis Is Not Sufficient for Determining Water Deficit in Hypernatremic Patients.

BACKGROUND Hypernatremia is associated with poor outcomes in critically ill patients, and an accurate assessment of water volume is important to determine appropriate fluid hydration. Bioelectrical impedance analysis (BIA) is a new, noninvasive, and relatively easy method for measuring hydration status. This study aimed to investigate whether bioelectrical impedance measurements of body water could reduce the frequency of blood sampling for fluid replacement in patients with hypernatremia. MATERIAL AND METHODS Fifty-one hospitalized patients were studied with hypernatremia, defined as a serum sodium ≥150 mmol/L determined by laboratory testing. Laboratory and BIA measurements were compared, and water deficiency was calculated with a conventional formula (sodium-corrected Watson formula) and measured by BIA. RESULTS The value of the absolute fluid overload (AFO) equivalent to the overhydration (OH) value, determined using BIA, did not accurately represent water deficit in patients with hypernatremia (r=0.137, P=0.347). Although the total body water (TBW) measured by BIA showed a significant correlation with that determined by the conventional formula (r=0.861, P<0.001), there was a proportional bias (r=0.617, P<0.001). The intracellular water (ICW) measured by BIA underestimated the TBW level calculated by the conventional formula by about 14.06±4.0 L in the Bland-Altman analysis. CONCLUSIONS It is not currently possible to replace blood testing with BIA for assessing volume status in hypernatremic patients. However, ICW value measured by BIA might represent plasma sodium level more accurately than extracellular water (ECW) or TBW value in patients with hypernatremia.

NADPH oxidase 4 mediates TGF-ß1/Smad signaling pathway induced acute kidney injury in hypoxia.

Hypoxia is an important cause of acute kidney injury (AKI) in various conditions because kidneys are one of the most susceptible organs to hypoxia. In this study, we investigated whether nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase 4 (Nox4) plays a role in hypoxia induced AKI in a cellular and animal model. Expression of Nox4 in cultured human renal proximal tubular epithelial cells (HK-2) was significantly increased by hypoxic stimulation. TGF-ß1 was endogenously secreted by hypoxic HK-2 cells. SB4315432 (a TGF-ß1 receptor I inhibitor) significantly inhibited Nox4 expression in HK-2 cells through the Smad-dependent cell signaling pathway. Silencing of Nox4 using Nox4 siRNA and pharmacologic inhibition with GKT137831 (a specific Nox1/4 inhibitor) reduced the production of ROS and attenuated the apoptotic pathway. In addition, knockdown of Nox4 increased cell survival in hypoxic HK-2 cells and pretreatment with GKT137831 reproduce these results. This study demonstrates that hypoxia induces HK-2 cell apoptosis through a signaling pathway involving TGF-ß1 via Smad pathway induction of Nox4-dependent ROS generation. In an ischemia/reperfusion rat model, pretreatment of GKT137831 attenuated ischemia/reperfusion induced acute kidney injury as indicated by preserved kidney function, attenuated renal structural damage and reduced apoptotic cells. Therapies targeting Nox4 may be effective against hypoxia-induced AKI.