Autonomic Nervous System Dysfunction in Peritoneal Dialysis Patients: An Underrecognized Cardiovascular Risk Factor?

BACKGROUND: In patients with end-stage kidney disease (ESKD) receiving peritoneal dialysis (PD), cardiovascular events represent the predominant cause of morbidity and mortality, with cardiac arrhythmias and sudden death being the leading causes of death in this population. Autonomic nervous system (ANS) dysfunction is listed among the non-traditional risk factors accounting for the observed high cardiovascular burden, with a plethora of complex and not yet fully understood pathophysiologic mechanisms being involved. SUMMARY: In recent years, preliminary studies have investigated and confirmed the presence of ANS dysfunction in PD patients, while relevant results from cohort studies have linked ANS dysfunction with adverse clinical outcomes in these patients. In light of these findings, ANS dysfunction has been recently receiving wider consideration as an independent cardiovascular risk factor in PD patients. The aim of this review was to describe the mechanisms involved in the pathogenesis of ANS dysfunction in ESKD and particularly PD patients and to summarize the existing studies evaluating ANS dysfunction in PD patients. KEY MESSAGES: ANS dysfunction in PD patients is related to multiple complex mechanisms that impair the balance between SNS/PNS, and this disruption represents a crucial intermediator of cardiovascular morbidity and mortality in this population.

Heart rate variability at rest and in response to stress: Comparative study between hemodialysis and peritoneal dialysis patients.

Cardiac arrhythmias and sudden death are the leading causes of mortality in end-stage kidney disease (ESKD). Autonomic nervous system (ANS) dysfunction contributes to this arrhythmogenic background. This study compared heart rate variability (HRV) indices between hemodialysis (HD) and peritoneal dialysis (PD) patients, both at rest and in response to mental and physical stimulation maneuvers. Thirty-four HD and 34 PD patients matched for age, sex, and dialysis vintage, and 17 age- and sex-matched controls were studied. ANS function was examined by linear and non-linear HRV indices. Heart rate was recorded continuously (Finometer-PRO) at rest and during ANS maneuvers (orthostatic, mental-arithmetic, sit-to-stand, handgrip exercise tests). At rest, no significant differences between HD and PD were observed in HRV (root mean square of successive differences [RMSSD]: HD = 57.1 ± 81.1 vs PD = 69.6 ± 113.4 ms; P = 0.792), except for detrended fluctuation analysis (DFA-α1) (HD = 0.87 ± 0.40 vs PD = 0.70 ± 0.20; P = 0.047). DFA-α1 was significantly lower in PD than controls (1.00 ± 0.33; P < 0.05). All HRV indices during the mental-arithmetic test (RMSSD: HD = 128.2 ± 346.0 vs PD = 87.5 ± 150.0 ms; P = 0.893) and the physical stress tests were similar between HD and PD. The standard deviation along the line-of-identity (SD2)/the standard deviation perpendicular to the line-of-identity (SD1) ratio during mental-arithmetic was marginally lower in HD and significantly lower in PD than controls (PD = 1.31 ± 0.47 vs controls = 1.79 ± 0.64; P < 0.05). Both dialysis groups presented similar patterns in HRV responses during orthostatic and handgrip exercise tests. After the sit-to-stand, RMSSD, SD1, SD2, and DFA-α2 were higher compared to rest only in HD (RMSSD = 57.1 ± 81.1 vs 126.7 ± 185.7 ms; P = 0.028), suggesting a greater difficulty of HD patients in recovering normal ANS function in response to physical stress. In conclusion, HRV indices at rest and after mental and physical stimulation did not differ between HD and PD; however, the ANS responses following the sit-to-stand test were more impaired in HD. These findings suggest that ANS dysfunction is not largely affected by dialysis modality, but small differences in normal ANS recovery may exist.

Cerebral oxygenation during exercise deteriorates with advancing chronic kidney disease.

BACKGROUND: Cognitive impairment and exercise intolerance are common in chronic kidney disease (CKD). Cerebral perfusion and oxygenation play a major role in both cognitive function and exercise execution. This study aimed to examine cerebral oxygenation during a mild physical stress in patients at different CKD stages and controls without CKD. METHODS: Ninety participants (18 per CKD stage 2, 3a, 3b and 4 and 18 controls) underwent a 3-min intermittent handgrip exercise at 35% of their maximal voluntary contraction. During exercise, cerebral oxygenation [oxyhaemoglobin (O2Hb), deoxyhaemoglobin (HHb) and total haemoglobin (tHb)] was assessed by near-infrared spectroscopy. Indices of microvascular (muscle hyperaemic response) and macrovascular function (carotid intima-media thickness and pulse wave velocity (PWV)) and cognitive and physical activity status were also evaluated. RESULTS: No differences in age, sex and body mass index were detected among groups. The mini-mental state examination score was significantly reduced with advancing CKD stages (controls: 29.2 ± 1.2, stage 2: 28.7 ± 1.0, stage 3a: 27.8 ± 1.9, stage 3b: 28.0 ± 1.8, stage 4: 27.6 ± 1.5; P = .019). Similar trends were observed for physical activity levels and handgrip strength. The average response in cerebral oxygenation (O2Hb) during exercise was lower with advancing CKD stages (controls: 2.50 ± 1.54, stage 2: 1.30 ± 1.05, stage 3a: 1.24 ± 0.93, stage 3b: 1.11 ± 0.89, stage 4: 0.97 ± 0.80 µmol/l; P < .001). The average tHb response (index of regional blood volume) showed a similar decreasing trend (P = .003); no differences in HHb among groups were detected. In univariate linear analysis, older age, lower estimated glomerular filtration rate (eGFR), Hb, microvascular hyperaemic response and increased PWV were associated with poor O2Hb response during exercise. In the multiple model, eGFR was the only parameter independently associated with the O2Hb response. CONCLUSIONS: Brain activation during a mild physical task appears to decrease with advancing CKD as suggested by the smaller increase in cerebral oxygenation. This may contribute to impaired cognitive function and reduced exercise tolerance with advancing CKD.

Muscle Oxygenation and Microvascular Reactivity Across Different Stages of CKD: A Near-Infrared Spectroscopy Study.

RATIONALE & OBJECTIVE: Previous studies in chronic kidney disease (CKD) showed that vascular dysfunction in different circulatory beds progressively deteriorates with worsening CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with different stages of CKD versus controls. STUDY DESIGN: Observational controlled study. SETTING & PARTICIPANTS: 90 participants (18 per CKD stage 2, 3a, 3b, and 4, as well as 18 controls). PREDICTOR: CKD stage. OUTCOME: The primary outcome was muscle oxygenation at rest. Secondary outcomes were muscle oxygenation during occlusion-reperfusion and exercise, and muscle microvascular reactivity (hyperemic response). ANALYTICAL APPROACH: Continuous measurement of muscle oxygenation [tissue saturation index (TSI)] using near-infrared spectroscopy at rest, during occlusion-reperfusion, and during a 3-minute handgrip exercise (at 35% of maximal voluntary contraction). Aortic pulse wave velocity and carotid intima-media thickness were also recorded. RESULTS: Resting muscle oxygenation did not differ across the study groups (controls: 64.3% ± 2.9%; CKD stage 2: 63.8% ± 4.2%; CKD stage 3a: 64.1% ± 4.1%; CKD stage 3b: 62.3% ± 3.3%; CKD stage 4: 62.7% ± 4.3%; P=0.6). During occlusion, no significant differences among groups were detected in the TSI occlusion magnitude and TSI occlusion slope. However, during reperfusion the maximum TSI value was significantly lower in groups of patients with more advanced CKD stages compared with controls, as was the hyperemic response (controls: 11.2%±3.7%; CKD stage 2: 8.3%±4.6%; CKD stage 3: 7.8%±5.5%; CKD stage 3b: 7.3%±4.4%; CKD stage 4: 7.2%±3.3%; P=0.04). During the handgrip exercise, the average decline in TSI was marginally lower in patients with CKD than controls, but no significant differences were detected across CKD stages. LIMITATIONS: Moderate sample size, cross-sectional evaluation. CONCLUSIONS: Although no differences were observed in muscle oxygenation at rest or during occlusion, the microvascular hyperemic response during reperfusion was significantly impaired in CKD and was most prominent in more advanced CKD stages. This impaired ability of microvasculature to respond to stimuli may be a crucial component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance. PLAIN-LANGUAGE SUMMARY: Previous studies in chronic kidney disease (CKD) have shown that vascular dysfunction in different circulatory beds progressively deteriorates with CKD severity. This study evaluated muscle oxygenation and microvascular reactivity at rest, during an occlusion-reperfusion maneuver, and during exercise in patients with nondialysis CKD versus controls, as well as across different CKD stages. It showed that the microvascular hyperemic response after an arterial occlusion was significantly impaired in CKD and was worst in patients with more advanced CKD. No significant differences were detected in skeletal muscle oxygenation or muscle oxidative capacity at rest or during the handgrip exercise when comparing patients with CKD with controls or comparing across CKD stages. The impaired ability of microvasculature to respond to stimuli may be a component of the adverse vascular profile of patients with CKD and may contribute to exercise intolerance.

Hemodialysis Effects on Autonomic Function: Results of Linear and Nonlinear Analysis of Heart Rate Variability at Rest and in Response to Physical and Mental Stress Tests.

INTRODUCTION: Cardiac arrhythmias are the most common cause of death in hemodialysis. Autonomic dysfunction plays a central role in this arrhythmogenic background. Previous studies on hemodialysis-related changes in heart rate variability (HRV) give contradictory results. This study investigated HRV indices both at rest and in response to physical and mental stimulation maneuvers at multiple time-points around and during the hemodialysis procedure. METHODS: Autonomic function was assessed by linear and nonlinear HRV indices at predialysis, during dialysis (3 equal time-periods), postdialysis, and on the nondialysis day in 36 hemodialysis patients. Continuous measurement of beat-by-beat heart rate was recorded with Finometer-PRO (The Netherlands) at rest and after orthostatic, sit-to-stand, handgrip, and mental-arithmetic test. RESULTS: The RMSSD, SD1, and SD2 indices significantly increased during dialysis (early-HD, mid-HD, late-HD periods) compared with the predialysis levels (p < 0.05) and returned to baseline postdialysis (RMSSD: 54.39 ± 83.73 vs. 137.98 ± 109.53* vs. 119.85 ± 97.34* vs. 144.47 ± 88.74* vs. 85.82 ± 121.43msec, *p < 0.05 vs. predialysis and postdialysis). No differences were detected in the above indices between the predialysis and nondialysis day. However, postdialysis, the HRV responses to orthostatic and sit-to-stand tests were more exaggerated than in the predialysis measurements (p < 0.05). The HRV responses both at resting and physical tests in the nondialysis day were similar to the predialysis levels. HRV indices in the mental arithmetic test during hemodialysis were much higher than at the nondialysis day (RMSSD: 77.05 [180.41] versus 19.75 [105.47] msec; p = 0.031). CONCLUSIONS: Hemodialysis causes marked changes in the autonomic function. Resting HRV indices return to baseline postdialysis, but HRV responses to physical stress remain exaggerated and return to baseline on the nondialysis day. Detecting patients with significant autonomic dysfunction may help towards reduction of arrhythmia risk through individualized approaches.

A patient with dialysis-dependent acute kidney injury due to hantavirus complicated with SARS-CoV-2 infection.

In this case, we report a 64-year-old man presenting with anorexia, nausea and vomiting, mild abdominal pain, and oligoanuria for a few hours. His previous medical history included diabetes, hypertension, and chronic kidney disease (CKD) stage 3. Upon arrival, laboratory results revealed stage III acute kidney injury (AKI) with hyperkalemia requiring dialysis treatment. During hospitalization, both pre-renal and post-renal causes of AKI were excluded, and a careful diagnostic evaluation, including kidney biopsy and serology testing, revealed acute interstitial nephritis and positive IgM for hantavirus. The patient was started on steroid treatment, which led to complete recovery of kidney function over 3 months. Moreover, during his hospitalization, the patient was also diagnosed with SARS-CoV-2 infection, possibly due to intra-hospital transmission and was hospitalized at the COVID-19 Department for 14 days, eventually with no further complications. Hantavirus nephropathy should be at the differential diagnosis of AKI, even in the absence of typical symptoms. Steroid treatment may be helpful in reversal of kidney injury.

Cardiac geometry, function, and remodeling patterns in patients under maintenance hemodialysis and peritoneal dialysis treatment.

Cardiovascular disease is the leading cause of mortality in patients with end-stage-kidney disease. Evidence on the possible echocardiographic differences between hemodialysis and peritoneal dialysis (PD) is scarce. This study aimed to evaluate differences in left (LA) and right atrial (RA), left (LV) and right ventricular (RV) geometry, systolic and diastolic function in hemodialysis, and PD patients. Thirty-eight hemodialysis and 38 PD patients were matched for age, sex, and dialysis vintage. Two-dimensional and tissue-Doppler echocardiography, and lung ultrasound were performed during an interdialytic day in hemodialysis and before a programmed follow-up visit in PD patients. Vena cava diameter (11.09 ± 4.53 vs. 14.91 ± 4.30 mm; p < 0.001) was significantly lower in hemodialysis patients. Indices of LA, RA, LV, and RV dimensions were similar between the two groups. LVMi (116.91 [38.56] vs. 122.83 [52.33] g/m2 ; p = 0.767) was similar, but relative wall thickness was marginally (0.40 [0.14] vs. 0.45 [0.15] cm; p = 0.055) lower in hemodialysis patients. LV hypertrophy prevalence was similar between groups (73.7% vs. 71.1%; p = 0.798), but hemodialysis patients presented eccentric and PD patients concentric LVH. Regarding ventricular systolic function, stroke volume (p = 0.030) and cardiac output (p = 0.036) were higher in hemodialysis, while RV systolic pressure (RVSP) (20.37 [22.54] vs. 27.68 [14.32] mm Hg; p = 0.009) was higher in PD. No significant differences were evidenced in diastolic function indices and lung water excess between the two groups. A moderate association was noted between ultrasound B-lines score and LA volume index (r = 0.465, p < 0.001), RVSP (r = 0.431, p < 0.001), and E/e' ratio (r = 0.304, p = 0.009). Hemodialysis and PD patients present largely similar echocardiographic indices reflecting cardiac geometry, systolic, and diastolic function, but different patterns of abnormal LV remodeling.

Associations of serum sclerostin and Dickkopf-related protein-1 proteins with future cardiovascular events and mortality in haemodialysis patients: a prospective cohort study.

BACKGROUND: Sclerostin and Dickkopf-related protein-1 (Dkk-1) proteins are inhibitors of the canonical Wnt/ß-catenin bone pathway. Sclerostin but not Dkk-1 is associated with increased arterial stiffness. This study examined the prognostic significance of sclerostin and Dkk-1 levels for cardiovascular outcomes and mortality in haemodialysis (HD) patients. METHODS: Serum sclerostin and Dkk-1 levels were measured with enzyme-linked immunosorbent assay in 80 HD patients that were followed-up for a median of 45 months. Factors that could interfere with the association of sclerostin and Dkk-1 with outcomes [including carotid-femoral pulse wave velocity (PWV), parathyroid hormone (PTH), calcium-phosphate product and others] were assessed at baseline. The primary endpoint was a combination of all-cause death, non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, hospitalization for decompensated heart failure and new-onset atrial fibrillation. Secondary endpoints included cardiovascular and all-cause mortality. RESULTS: Cumulative freedom from the primary endpoint was significantly lower for higher tertiles of sclerostin (77.8, 69.2 and 40.7%; Tertiles 1-3, respectively; log-rank P = 0.004). The risk for the primary outcome gradually increased for higher sclerostin tertiles [Tertile 3: hazard ratio (HR) = 3.847, 95% confidence interval (CI) 1.502-9.851]. No significant association was evident between sclerostin and all-cause mortality, whereas higher sclerostin levels presented a trend towards higher risk for cardiovascular mortality. Dkk-1 levels exhibited no association with the risk of the primary or secondary endpoints. In stepwise Cox regression modelled analysis, sclerostin levels were associated with the primary outcome, independently of PTH, calcium-phosphate product, serum albumin, C-reactive protein and PWV levels (HR = 2.921, 95% CI 1.401-6.090; P = 0.004). CONCLUSIONS: High sclerostin levels are associated with lower cumulative freedom and higher risk for a composite endpoint of cardiovascular events and mortality. Dkk-1 exhibited no association with the future risk of adverse outcomes.

Serum Copeptin, NLPR3, and suPAR Levels among Patients with Autosomal-Dominant Polycystic Kidney Disease with and without Impaired Renal Function.

BACKGROUND: The pathophysiology of renal disease progression in autosomal-dominant polycystic kidney disease (ADPKD) involves not only cystogenesis but also endothelial dysfunction, leading to the activation of inflammatory and fibrotic pathways. This study evaluated the levels of biomarkers related to osmoregulation, immune system activation, and tubular injury in ADPKD patients with impaired or preserved renal function. METHODS: This study included 26 ADPKD patients with modestly impaired renal function (estimated glomerular filtration rate [eGFR] 45-70 mL/min/1.73 m2; Group A), 26 age- and sex-matched ADPKD patients with relatively preserved renal function (eGFR >70 mL/min/1.73 m2; Group B), and 26 age- and sex-matched controls (Group C). Serum levels of copeptin, the inflammasome nucleotide-binding and oligomerization domain-like receptors pyrin domain-containing protein 3 (NLRP3), and soluble urokinase-type plasminogen activator receptor (suPAR) were measured with ELISA techniques. RESULTS: Patients in Group A had higher levels of copeptin (median [interquartile range]: 50.44 [334.85] pg/mL), NLRP3 (5.86 [3.89] ng/mL), and suPAR (390.05 [476.53] pg/mL) compared to patients in Group B (32.38 [58.33], p = 0.042; 2.42 [1.96], p < 0.001; and 313.78 [178.85], p = 0.035, respectively) and Group C (6.75 [6.43]; 1.09 [0.56]; and 198.30 [28.53], respectively; p < 0.001 for all comparisons). Levels of all studied markers were also significantly higher in Group B patients compared to controls (p < 0.001), despite having similar eGFR. In patients with ADPKD, all studied biomarkers were correlated positively with asymmetric-dimethylarginine (ADMA) and endocan levels, and negatively with eGFR. ADMA and endocan levels were the only parameters independently associated with increased copeptin levels. CONCLUSIONS: This study showed that ADPKD patients with impaired and preserved renal function had higher copeptin, NLRP3, and suPAR levels than controls. Such findings support that cystogenesis and inflammation are associated with endothelial dysfunction, even in the early stages of ADKPD.

Benefits and risks of frequent or longer haemodialysis: weighing the evidence.

Although the ability of individuals with end-stage renal disease to maintain body homoeostasis is equally impaired during all weekdays, conventional haemodialysis (HD) treatment is scheduled thrice weekly, containing two short and one long interdialytic interval. This intermittent nature of HD and the consequent fluctuations in volume, metabolic parameters and electrolytes have long been hypothesized to predispose to complications. Large observational studies link the first weekday with an increased risk of cardiovascular morbidity and mortality. Several schemes of frequent and/or longer, home or in-centre HD have been introduced, aiming to alleviate the above risks by both increasing total dialysis duration and reducing the duration of interdialytic intervals. Observational studies in this field have non-uniform results, showing that enhanced frequency in home (but not in-centre) HD is associated with reduced mortality. Evidence from the randomized Daily and Nocturnal Trials of the Frequent HD Network suggest the opposite, showing mortality benefits with in-centre daily but not with home nocturnal dialysis. Secondary analyses of these trials indicate that daily and nocturnal schedules do not have equal effects on intermediate outcomes. Alternative schemes, such as thrice weekly in-centre nocturnal HD or every-other-day HD, seem to also offer improvements in several intermediate endpoints, but need further testing with randomized trials. This review summarizes the effects of frequent and/or longer HD methods on hard and intermediate outcomes, attempting to provide a balanced overview of the field.

Chronic Therapy with Sucroferric Oxyhydroxide Does Not Affect Iron and Anemia Markers in Dialysis Patients.

INTRODUCTION: Sucroferric oxyhydroxide (SOH) is an iron-based phosphate binder (PB), and its use has been widely expanded since its initial approval in 2014. Based on the existing data, however, it remains yet unclear whether its long-term administration is followed by iron overload in dialysis patients. The purpose of this observational study was to evaluate the longstanding effects of SOH on the anemia and iron indices in patients on dialysis. METHODS: A total of 110 patients from 3 dialysis centers were included in the study; 49 were under chronic treatment with SOH (cohort A), while 61 were either receiving other PB or no treatment for hyperphosphatemia (cohort B). We initially compared the hematologic profile of patients in 2 cohorts (phase I), and subsequently, we evaluated modifications of the above parameters in the SOH treated patients over a period of 6 months (phase II). RESULTS: There were no statistically significant differences between 2 cohorts in terms of hemoglobin (Hb; 11.4 ± 1.3 vs. 11.6 ± 0.9 g/dL, p = 0.375), ferritin (473 ± 230 vs. 436 ± 235 ng/mL, p = 0.419) and transferrin saturation (TSAT;26.6 ± 13.2 vs. 26.5 ± 10.6%, p = 0.675), serum phosphate concentration (4.57 ± 1.05 vs. 4.3 ± 0.96 mg/dL, p = ns), and intact PTH (286 ± 313 vs. 239 ± 296 pg/mL, p = ns). Marginally, but significantly higher calcium levels were found in cohort A compared to cohort B (9.18 ± 0.58 vs. 8.9 ± 0.51 mg/dL, respectively, p = 0.008). In phase II, no significant changes were observed in hematological parameters after a 6-month treatment with SOH (Hb: from 11.5 ± 1.1 to 11.4 ± 1.3 g/dL, p = 0.4, serum ferritin levels: from 475 ± 264 to 473 ± 230 ng/mL, p = 0.951, TSAT: from 26.5 ± 16.7 to 26.6 ± 13.2%, p = 0.933). There were also no significant changes in the administration of iron supplements or erythropoietin dose during this period. CONCLUSIONS: SOH is an effective PB, and its long-term use is not complicated by iron overload.

Weak within-individual association of blood pressure and pulse wave velocity in hemodialysis is related to adverse outcomes.

OBJECTIVES: Hemodialysis patients have premature arterial stiffness, and the relationship between pulse wave velocity (PWV) and blood pressure (BP) may be different than in other hypertensives. Previous studies in such patients showed that when BP decrease is accompanied by PWV decrease the survival is improved. This study examines the prognostic role of the mean BP (MBP)-PWV association for cardiovascular outcomes and all-cause mortality in hemodialysis. METHODS: A total of 242 hemodialysis patients underwent 48-h ambulatory BP monitoring with Mobil-O-Graph-NG and were followed for 33.17 ±â€Š19.68 months. The within-individual MBP-PWV association (MBP, dependent and PWV independent variable) was evaluated using the ß-coefficient value from simple linear regression analysis for each patient. The primary end-point was first occurrence of all-cause death, nonfatal myocardial infarction or nonfatal stroke. Secondary end-points were all-cause mortality, cardiovascular mortality and a combination of cardiovascular events. RESULTS: Higher quartiles of ß-coefficients (indicating strong within-individual association of MBP with PWV) were related to greater cumulative freedom from the primary end-point (50.8, 60.0, 70.0 and 80.3% for quartiles 1-4, respectively; log-rank P = 0.001), better overall survival (60.7, 61.7, 73.3, 86.9%; log-rank P = 0.002) and better cardiovascular survival (78.7, 75.0, 81.7, 91.8% for quartiles 1-4; log-rank P = 0.044). The future risks of the primary end-point, all-cause and cardiovascular mortality and the combined outcome were progressively increasing with lower quartiles of ß-coefficients, indicating patients with weak MBP-PWV association (hazard ratios for all-cause mortality 3.395; 95% confidence interval: 1.524-7.563, P = 0.003 for quartile 1 vs. quartile 4). CONCLUSION: Weaker within-individual MBP-PWV association, based on ABPM recordings, is associated with higher risk of death and cardiovascular events in hemodialysis. These findings support that arterial stiffness insensitive to BP changes is the underlying factor for adverse outcomes in these individuals.

Soluble Klotho is associated with mortality and cardiovascular events in hemodialysis.

BACKGROUND: Klotho is a transmembrane protein acting as a co-receptor for FGF-23 and thus exerts clinical actions on mineral metabolism. The association of secreted Klotho with outcomes in CKD patients is unclear. This study examined the relation between plasma Klotho and cardiovascular events in dialysis patients, accounting for common and CKD-MBD related risk factors, arterial stiffness and atherosclerotic burden. METHODS: Seventy-nine chronic hemodialysis patients were observed for a median follow-up of 5.5 years. Klotho levels as well as carotid-femoral pulse wave velocity (cfPWV) and common carotid intima-media thickness (ccIMT) measurements were performed at baseline. The primary end-point was first occurrence of all-cause death, non-fatal myocardial infarction or non-fatal stroke. Secondary end-points were: (i) all-cause mortality; (ii) cardiovascular mortality; (iii) a combination of cardiovascular death, non-fatal MI, non-fatal stroke, resuscitation after cardiac arrest, coronary revascularization, heart failure hospitalization and atrial fibrillation. RESULTS: Cumulative freedom from the primary endpoint was 31% for the low-Klotho group (≤745 pg/ml) and 53% for the high-Klotho group (logrank p = 0.017); HR: 2.137, 95%CI 1.124-4.065. Cumulative survival was insignificantly lower (44% vs 56%, p = 0.107), but cumulative cardiovascular survival (63% vs 88%, p = 0.029) and cumulative freedom from the cardiovascular composite outcome (18% vs 45%, p = 0.009) were significantly lower in the low-Klotho group. In modelled Cox-regression analysis the association of low Klotho with the primary endpoint remained significant after stepwise adjustment for cFGF3, PTH, Ca x P product, established risk factors (age, dialysis vintage, diabetes, hypertension, smoking, history of cardiovascular disease) as well as cfPWV and ccIMT [Model 6: HR:2.759, 95%CI 1.223-6.224, p = 0.014]. CONCLUSIONS: Low Klotho is associated with cardiovascular events in hemodialysis patients, independently from factors associated with mineral-bone disease, common risk factors and intermediate outcomes, such as cfPWV and ccIMT.