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Maleic acid (MA) induces renal tubular cell dysfunction directed to acute kidney injury (AKI). AKI is an increasing global health burden due to its association with mortality and morbidity. However, targeted therapy for AKI is lacking. Previously, we determined mitochondrial-associated proteins are MA-induced AKI affinity proteins. We hypothesized that mitochondrial dysfunction in tubular epithelial cells plays a critical role in AKI. In vivo and in vitro systems have been used to test this hypothesis. For the in vivo model, C57BL/6 mice were intraperitoneally injected with 400 mg/kg body weight MA. For the in vitro model, HK-2 human proximal tubular epithelial cells were treated with 2 mM or 5 mM MA for 24 h. AKI can be induced by administration of MA. In the mice injected with MA, the levels of blood urea nitrogen (BUN) and creatinine in the sera were significantly increased (p < 0.005). From the pathological analysis, MA-induced AKI aggravated renal tubular injuries, increased kidney injury molecule-1 (KIM-1) expression and caused renal tubular cell apoptosis. At the cellular level, mitochondrial dysfunction was found with increasing mitochondrial reactive oxygen species (ROS) (p < 0.001), uncoupled mitochondrial respiration with decreasing electron transfer system activity (p < 0.001), and decreasing ATP production (p < 0.05). Under transmission electron microscope (TEM) examination, the cristae formation of mitochondria was defective in MA-induced AKI. To unveil the potential target in mitochondria, gene expression analysis revealed a significantly lower level of ATPase6 (p < 0.001). Renal mitochondrial protein levels of ATP subunits 5A1 and 5C1 (p < 0.05) were significantly decreased, as confirmed by protein analysis. Our study demonstrated that dysfunction of mitochondria resulting from altered expression of ATP synthase in renal tubular cells is associated with MA-induced AKI. This finding provides a potential novel target to develop new strategies for better prevention and treatment of MA-induced AKI.
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Lesión Renal Aguda , Apoptosis , Maleatos , Ratones Endogámicos C57BL , Mitocondrias , ATPasas de Translocación de Protón Mitocondriales , Animales , Humanos , Masculino , Ratones , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Apoptosis/efectos de los fármacos , Línea Celular , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Túbulos Renales Proximales/patología , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , ATPasas de Translocación de Protón Mitocondriales/metabolismo , ATPasas de Translocación de Protón Mitocondriales/genética , Especies Reactivas de Oxígeno/metabolismoRESUMEN
In autosomal dominant polycystic kidney disease (ADPKD) with germline mutations in a PKD1 or PKD2 gene, innumerable cysts develop from tubules, and renal function deteriorates. Second-hit somatic mutations and renal tubular epithelial (RTE) cell death are crucial features of cyst initiation and disease progression. Here, we use established RTE lines and primary ADPKD cells with disease-associated PKD1 mutations to investigate genomic instability and DNA damage responses. We found that ADPKD cells suffer severe chromosome breakage, aneuploidy, heightened susceptibility to DNA damage, and delayed checkpoint activation. Immunohistochemical analyses of human kidneys corroborated observations in cultured cells. DNA damage sensors (ATM/ATR) were activated but did not localize at nuclear sites of damaged DNA and did not properly activate downstream transducers (CHK1/CHK2). ADPKD cells also had the ability to transform, as they achieved high saturation density and formed colonies in soft agar. Our studies indicate that defective DNA damage repair pathways and the somatic mutagenesis they cause contribute fundamentally to the pathogenesis of ADPKD. Acquired mutations may alternatively confer proliferative advantages to the clonally expanded cell populations or lead to apoptosis. Further understanding of the molecular details of aberrant DNA damage responses in ADPKD is ongoing and holds promise for targeted therapies.
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Quistes , Riñón Poliquístico Autosómico Dominante , Humanos , Riñón Poliquístico Autosómico Dominante/genética , Canales Catiónicos TRPP/metabolismo , Mutación , Riñón/metabolismo , Quistes/metabolismo , Inestabilidad CromosómicaRESUMEN
Acute kidney injury (AKI) is increasing in prevalence and causes a global health burden. AKI is associated with significant mortality and can subsequently develop into chronic kidney disease (CKD). The kidney is one of the most energy-demanding organs in the human body and has a role in active solute transport, maintenance of electrochemical gradients, and regulation of fluid balance. Renal proximal tubular cells (PTCs) are the primary segment to reabsorb and secrete various solutes and take part in AKI initiation. Mitochondria, which are enriched in PTCs, are the main source of adenosine triphosphate (ATP) in cells as generated through oxidative phosphorylation. Mitochondrial dysfunction may result in reactive oxygen species (ROS) production, impaired biogenesis, oxidative stress multiplication, and ultimately leading to cell death. Even though mitochondrial damage and malfunction have been observed in both human kidney disease and animal models of AKI and CKD, the mechanism of mitochondrial signaling in PTC for AKI-to-CKD transition remains unknown. We review the recent findings of the development of AKI-to-CKD transition with a focus on mitochondrial disorders in PTCs. We propose that mitochondrial signaling is a key mechanism of the progression of AKI to CKD and potential targeting for treatment.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Animales , Humanos , Insuficiencia Renal Crónica/metabolismo , Lesión Renal Aguda/etiología , Lesión Renal Aguda/terapia , Lesión Renal Aguda/metabolismo , Riñón/metabolismo , Transducción de Señal , Estrés OxidativoRESUMEN
AIMS: To investigate whether metabolic syndrome (MetS) could predict renal outcome in patients with established chronic kidney disease (CKD). MATERIALS AND METHODS: We enroled 2500 patients with CKD stage 1-4 from the Integrated CKD care programme, Kaohsiung for delaying Dialysis (ICKD) prospective observational study. 66.9% and 49.2% patients had MetS and diabetes (DM), respectively. We accessed three clinical outcomes, including all-cause mortality, RRT, and 50% decline in estimated glomerular filtration rate events. RESULTS: The MetS score was positively associated with proteinuria, inflammation, and nutrition markers. In fully adjusted Cox regression, the hazard ratio (HR) (95% confidence interval) of MetS for composite renal outcome (renal replacement therapy, and 50% decline of renal function) in the DM and non-DM subgroups was 1.56 (1.15-2.12) and 1.31 (1.02-1.70), respectively, while that for all-cause mortality was 1.00 (0.71-1.40) and 1.27 (0.92-1.74). Blood pressure is the most important component of MetS for renal outcomes. In the 2 by 2 matrix, compared with the non-DM/non-MetS group, the DM/MetS group (HR: 1.62 (1.31-2.02)) and the non-DM/MetS group (HR: 1.33 (1.05-1.69)) had higher risks for composite renal outcome, whereas the DM/MetS group had higher risk for all-cause mortality (HR: 1.43 (1.09-1.88)). CONCLUSIONS: MetS could predict renal outcome in patients with CKD stage 1-4 independent of DM.
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Diabetes Mellitus , Fallo Renal Crónico , Síndrome Metabólico , Insuficiencia Renal Crónica , Humanos , Síndrome Metabólico/complicaciones , Síndrome Metabólico/epidemiología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Riñón/fisiología , Diabetes Mellitus/epidemiología , Tasa de Filtración Glomerular , Factores de RiesgoRESUMEN
BACKGROUND: Autosomal-dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary kidney disease and the fourth leading cause of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). Nevertheless, there is a paucity of epidemiological research examining the risk factors and survival on RRT for ADPKD. Thus, we aimed to investigate the cumulative effects of cardiometabolic comorbidities, including hypertension (HTN), type 2 diabetes mellitus (DM), and dyslipidemia (DLP) to clinical outcomes in ADPKD. METHODS: We identified 6,142 patients with ADPKD aged ≥ 20 years from 2000 to 2015 using a nationwide population-based database. HTN, DM, and DLP diagnoses before or at the time of ADPKD diagnosis and different combinations of the three diagnoses were used as the predictors for the outcomes. Survival analyses were used to estimate the adjusted mortality risk from cardiometabolic comorbidities and the risk for renal survival. RESULTS: Patients with ADPKD who developed ESRD had the higher all-cause mortality (HR, 5.14; [95% CI: 3.88-6.80]). Patients with all three of the diseases had a significantly higher risk of entering ESRD (HR:4.15, [95% CI:3.27-5.27]), followed by those with HTN and DM (HR:3.62, [95% CI:2.82-4.65]), HTN and DLP (HR:3.54, [95% CI:2.91-4.31]), and HTN alone (HR:3.10, [95% CI:2.62-3.66]) compared with those without any three cardiometabolic comorbidities. CONCLUSIONS: Our study discovered the cumulative effect of HTN, DM, and DLP on the risk of developing ESRD, which reinforces the urgency of proactive prevention of cardiometabolic comorbidities to improve renal outcomes and overall survival in ADPKD patients.
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Diabetes Mellitus Tipo 2 , Hipertensión , Fallo Renal Crónico , Riñón Poliquístico Autosómico Dominante , Humanos , Riñón Poliquístico Autosómico Dominante/epidemiología , Riñón Poliquístico Autosómico Dominante/terapia , Riñón Poliquístico Autosómico Dominante/diagnóstico , Estudios Retrospectivos , Diabetes Mellitus Tipo 2/complicaciones , Fallo Renal Crónico/terapia , Fallo Renal Crónico/tratamiento farmacológico , Hipertensión/epidemiología , Hipertensión/complicacionesRESUMEN
Kidney tubular dysfunction contributes to acute kidney injury and to the transition to chronic kidney disease. Although tubular mitochondria have been implicated in the pathophysiology of kidney failure, the mechanisms are not yet clear. Here, we demonstrated that ischemia-reperfusion injury induced acute translocation and activation of mitochondrial protein kinase B (also known as AKT1) in the kidney tubules. We hypothesized that mitochondrial AKT1 signaling protects against the development of acute kidney injury and subsequent chronic kidney disease. To test this prediction, we generated two novel kidney tubule-specific transgenic mouse strains with inducible expression of mitochondria-targeted dominant negative AKT1 or constitutively active AKT1, using a Cre-Lox strategy. Inhibition of mitochondrial AKT1 in mitochondria-targeted dominant negative AKT1 mice aggravated azotemia, tubular injuries, kidney fibrosis, glomerulosclerosis, and negatively impacted survival after ischemia-reperfusion injury. Conversely, enhancing tubular mitochondrial AKT1 signaling in mitochondria-targeted constitutively active AKT1 mice attenuated kidney injuries, protected kidney function, and significantly improved survival after ischemia-reperfusion injury (76.9% vs. 20.8%, respectively). Uncoupled mitochondrial respiration and increased oxidative stress was found in the kidney tubules when mitochondria AKT1 was inhibited, supporting the role of mitochondrial dysfunction in the pathophysiology of kidney failure. Thus, our studies suggest tubular mitochondrial AKT1 signaling could be a novel target to develop new strategies for better prevention and treatment of kidney injury.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Animales , Apoptosis , Riñón/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , Daño por Reperfusión/metabolismoRESUMEN
End-stage kidney disease (ESKD) presents a significant public health challenge, with hemodialysis (HD) remaining one of the most prevalent kidney replacement therapies. Ensuring the longevity and functionality of arteriovenous accesses is challenging for HD patients. Blood flow sound, which contains valuable information, has often been neglected in the past. However, machine learning offers a new approach, leveraging data non-invasively and learning autonomously to match the experience of healthcare professionas. This study aimed to devise a model for detecting arteriovenous grafts (AVGs) stenosis. A smartphone stethoscope was used to record the sound of AVG blood flow at the arterial and venous sides, with each recording lasting one minute. The sound recordings were transformed into mel spectrograms, and a 14-layer convolutional neural network (CNN) was employed to detect stenosis. The CNN comprised six convolution blocks with 3x3 kernel mapping, batch normalization, and rectified linear unit activation function. We applied contrastive learning to train the pre-training audio neural networks model with unlabeled data through self-supervised learning, followed by fine-tuning. In total, 27,406 dialysis session blood flow sounds were documented, including 180 stenosis blood flow sounds. Our proposed framework demonstrated a significant improvement (p<0.05) over training from scratch and a popular pre-trained audio neural networks (PANNs) model, achieving an accuracy of 0.9279, precision of 0.8462, and recall of 0.8077, compared to previous values of 0.8649, 0.7391, and 0.6538. This study illustrates how contrastive learning with unlabeled blood flow sound data can enhance convolutional neural networks for detecting AVG stenosis in HD patients.
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Redes Neurales de la Computación , Diálisis Renal , Humanos , Masculino , Femenino , Constricción Patológica , Persona de Mediana Edad , Fallo Renal Crónico/terapia , Fallo Renal Crónico/fisiopatología , Anciano , Derivación Arteriovenosa Quirúrgica , Aprendizaje Automático , Sonido , Oclusión de Injerto Vascular/fisiopatología , Oclusión de Injerto Vascular/etiologíaRESUMEN
Introduction: Hypervolemia is a prevalent comorbidity of chronic kidney disease (CKD) patients. Thiazide diuretics (THZ) are the most common treatment for volume overload and hypertension (HTN). This study examines the association between THZ usage and clinical outcomes among CKD patients in a nationwide cohort. Method: The total number of patients in the study was 24,312. After matching with one non-user randomly selected from the CKD population, we identified 8501 patients in the THZ and the comparison cohorts. Cox proportional hazards regression analysis was conducted to estimate the associations of THZ on the incidence of all-cause mortality, end-stage renal disease (ESRD), congestive heart failure (CHF), acute myocardial infarction (AMI), peripheral arterial occlusive disease (PAOD), and stroke. Results: The all-cause mortality rate was significantly lower in THZ users than in non-users (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.60- 0.71). The THZ usage was associated with a lower incidence of ESRD, AMI, PAOD, and stroke (P<0.05). In subgroup analysis, some significant clinical outcomes were related with CKD stages 3 and 4 (P<0.05); however, there were no clinical associations in CKD stage 5. In further THZ subtype analysis, there were clinical associations with fewer deaths, ESRD, AMI, and PAOD accompanying chlorthalidone treatment. Moreover, the indapamide prescription was linked to lower mortality, ESRD, AMI, and PAOD prevalence. However, there were significantly greater incidences of ESRD, CHF, and AMI in the metolazone users. Conclusion: THZ usage is associated with lower mortality and incidence of ESRD, AMI, PAOD, and stroke s in patients with CKD stages 3 and 4.
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Insuficiencia Cardíaca , Fallo Renal Crónico , Infarto del Miocardio , Insuficiencia Renal Crónica , Inhibidores de los Simportadores del Cloruro de Sodio , Accidente Cerebrovascular , Humanos , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/complicaciones , Masculino , Femenino , Anciano , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Persona de Mediana Edad , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/tratamiento farmacológico , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/complicaciones , Infarto del Miocardio/epidemiología , Accidente Cerebrovascular/epidemiología , Enfermedad Arterial Periférica/epidemiología , Incidencia , Modelos de Riesgos Proporcionales , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipertensión/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/mortalidad , Singapur/epidemiologíaRESUMEN
Gout is strongly associated with the incidence of atherosclerotic events, including stroke and myocardial infarction. Considering the increased prevalence of stroke in the population with gout, the aim of this study was to evaluate the effects of benzbromarone, a uricosuric agent, on the incidence of stroke in the population with gout. We used data from the Taiwanese National Health Insurance Registration Database (NHIRD). The benzbromarone user cohort included 15,143 patients; each patient was age- and sex-matched with one non-user randomly selected from the population with gout. Cox proportional hazard regression analysis was conducted to estimate the effects of benzbromarone on the incidence of stroke in the population with gout. The incidence of stroke was significantly lower in benzbromarone users than in benzbromarone non-users. The HR for the incidence of stroke was lower in male benzbromarone users than in non-users. An analysis of three age groups (<40, 40-59, and ≥60 years) indicated that the HRs in those aged 40-59 years and ≥60 years were significantly lower among benzbromarone users than non-users. In the population with gout, the incidence of stroke was lower in benzbromarone users than in benzbromarone non-users.
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Background: The management of the coexistence of heart disease and kidney disease is increasingly challenging for clinicians. Chronic kidney disease (CKD) is not only a prevalent comorbidity of patients with heart failure but has also been identified as a noteworthy risk factor for all-cause mortality and poor clinical outcomes. Digoxin is one of the commonest treatments for heart disease. There are few trials investigating the role of digoxin in patients with cardiorenal syndrome (CRS). This study aims to examine the association between digoxin usage and clinical outcomes in patients with CRS in a nationwide cohort. Method: We conducted a population-based study that included 705 digoxin users with CRS; each patient was age, sex, comorbidities, and medications matched with three non-users who were randomly selected from the CRS population. Cox proportional hazards regression analysis was conducted to estimate the effects of digoxin on the incidence of all-cause mortality, congestive heart failure (CHF) hospitalization, coronary artery disease (CAD) hospitalization, and end-stage renal disease (ESRD). Results: The all-cause mortality rate was significantly higher in digoxin users than in non-users (adjusted hazard ratio [aHR] = 1.26; 95% confidence interval [CI] = 1.09-1.46, p = 0.002). In a subgroup analysis, there was significantly high mortality in the 0.26-0.75 defined daily dose (DDD) subgroup of digoxin users (aHR = 1.49; 95% CI = 1.23-1.82, p<0.001). Thus, the p for trend was 0.013. With digoxin prescription, the CHF hospitalization was significantly higher [subdistribution HR (sHR) = 1.17; 95% CI = 1.05-1.30, p = 0.004], especially in the >0.75 DDD subgroup (sHR = 1.19; 95% CI = 1.01-1.41, p = 0.046; p for trend = 0.006). The digoxin usage lowered the coronary artery disease (CAD) hospitalization in the > 0.75 DDD subgroup (sHR = 0.79; 95% CI = 0.63-0.99, p = 0.048). In renal function progression, more patients with CRS entered ESRD with digoxin usage (sHR = 1.34; 95% CI = 1.16-1.54, p<0.001). There was a significantly greater incidence of ESRD in the < 0.26 DDD and 0.26-0.75 DDD subgroups of digoxin users (sHR = 1.32; 95% CI = 1.06-1.66, p = 0.015; sHR = 1.44; 95% CI = 1.18-1.75; p for trend<0.001). Conclusion: Digoxin should be prescribed with caution to patients with CRS.
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Síndrome Cardiorrenal , Enfermedad de la Arteria Coronaria , Insuficiencia Cardíaca , Fallo Renal Crónico , Humanos , Digoxina/efectos adversos , Síndrome Cardiorrenal/tratamiento farmacológico , Síndrome Cardiorrenal/epidemiología , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/epidemiología , Fallo Renal Crónico/epidemiología , Fallo Renal Crónico/tratamiento farmacológico , HospitalizaciónRESUMEN
OBJECTIVES: This study aimed to investigate the relationship between cardiovascular mortality in elderly Asians and decline in renal function. DESIGN: A retrospective cohort study. SETTING: Community-based health examination database from Taipei city. PARTICIPANTS: At the beginning, the database included 315 045 health check-up visits of 97 803 elderly persons aged ≥65 years old from 2005 to 2012. After excluding missing values and outliers, there were 64 732 elderly persons with at least two visits retained for further analyses. PRIMARY OUTCOME MEASURES: Kidney function indicators include estimated glomerular filtration rate (eGFR) and urine protein, and rapid decline in eGFR was defined as slope ≤ -5 mL/min/1.73 m2 per year. The endpoint outcome was defined as the cardiovascular deaths registered in the death registry encoded by the International Classification of Diseases. We applied a Cox proportional hazards model to analyse the association between renal function and cardiovascular mortality. RESULTS: In this study, we found 1264 elderly persons died from cardiovascular diseases, for whom the data included 4055 previous health check-up visits. We observed significant and independent associations of eGFR <60 mL/min/1.73 m2 (HR (95% CI) of 60>eGFR≥45 and eGFR<45 in males: 2.85 (1.33 to 6.09) and 3.98 (1.84 to 8.61); in females: 3.66 (1.32 to 10.15) and 6.77 (2.41 to 18.99)), positive proteinuria (HR (95% CI) of +/-, +,++ and +++, ++++ in males: 1.51 (1.29 to 1.78) and 2.31 (1.51 to 3.53); in females: 1.93 (1.54 to 2.42) and 4.23 (2.34 to 7.65)) and rapid decline in eGFR (HR (95% CI) in males: 3.24 (2.73 to 3.85); in females: 2.83 (2.20 to 3.64) with higher risk of cardiovascular mortality. The joint effect of increased concentration of urine protein and reduced eGFR was associated with a higher risk of cardiovascular mortality. CONCLUSIONS: Renal function and rapid decline in renal function are independent risk factors for cardiovascular mortality in the elderly.
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Enfermedades Cardiovasculares , Insuficiencia Renal Crónica , Anciano , Femenino , Tasa de Filtración Glomerular , Humanos , Riñón/fisiología , Masculino , Proteinuria , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Background: Heart rate variability (HRV) represents changes in the time between successive heart beats, and it has been used to assess the autonomic nervous system. Previous studies have reported autonomic dysfunction in diabetic patients undergoing hemodialysis (HD), however, no studies have evaluated the effects of age on changes in HRV in these patients. The aim of this study was to examine the effects of age on changes in HRV in diabetic HD patients. Methods: We enrolled 84 diabetic patients receiving maintenance HD. HRV was measured before and after HD to assess changes in HRV (ΔHRV). The patients were divided into two groups based on their age (65 years< or ≥65 years). Results: Compared to the patients aged <65 years, those aged ≥65 years had a higher high frequency (HF) % (p = 0.032) before HD. The patients aged <65 years had a significant increase in very low frequency, low frequency (LF), and HF after HD. The patients aged ≥65 years had a significant increase in LF, but a significant decrease in HF% after HD. There was a significant interaction between age and change of HF% (p = 0.023) after HD. After multivariate adjustments for clinical, biochemical data and medications, systolic blood pressure, total cholesterol, hemoglobin, and hemoglobin were associated with ΔLF, whereas cerebrovascular disease, systolic blood pressure, and fasting glucose were associated with ΔHF% in patients aged ≥65 years. Conclusion: Our study demonstrated significant changes in HRV after HD in diabetic patients. In the patients aged ≥65 years, LF was increased, whereas HF% was decreased significantly after HD. Among the HRV parameters, age had an interaction with the change of HF%.