Pulse Wave Amplitude Drops Index: A Biomarker of Cardiovascular Risk in Obstructive Sleep Apnea.

Rationale: It is currently unclear which patients with obstructive sleep apnea (OSA) are at increased cardiovascular risk. Objective: To investigate the value of pulse wave amplitude drops (PWADs), reflecting sympathetic activations and vasoreactivity, as a biomarker of cardiovascular risk in OSA. Methods: PWADs were derived from pulse oximetry-based photoplethysmography signals in three prospective cohorts: HypnoLaus (N = 1,941), the Pays-de-la-Loire Sleep Cohort (PLSC; N = 6,367), and "Impact of Sleep Apnea syndrome in the evolution of Acute Coronary syndrome. Effect of intervention with CPAP" (ISAACC) (N = 692). The PWAD index was the number of PWADs (>30%) per hour during sleep. All participants were divided into subgroups according to the presence or absence of OSA (defined as ⩾15 or more events per hour or <15/h, respectively, on the apnea-hypopnea index) and the median PWAD index. Primary outcome was the incidence of composite cardiovascular events. Measurements and Main Results: Using Cox models adjusted for cardiovascular risk factors (hazard ratio; HR [95% confidence interval]), patients with a low PWAD index and OSA had a higher incidence of cardiovascular events compared with the high-PWAD and OSA group and those without OSA in the HypnoLaus cohort (HR, 2.16 [1.07-4.34], P = 0.031; and 2.35 [1.12-4.93], P = 0.024) and in the PLSC (1.36 [1.13-1.63], P = 0.001; and 1.44 [1.06-1.94], P = 0.019), respectively. In the ISAACC cohort, the low-PWAD and OSA untreated group had a higher cardiovascular event recurrence rate than that of the no-OSA group (2.03 [1.08-3.81], P = 0.028). In the PLSC and HypnoLaus cohorts, every increase of 10 events per hour in the continuous PWAD index was negatively associated with incident cardiovascular events exclusively in patients with OSA (HR, 0.85 [0.73-0.99], P = 0.031; and HR, 0.91 [0.86-0.96], P < 0.001, respectively). This association was not significant in the no-OSA group and the ISAACC cohort. Conclusions: In patients with OSA, a low PWAD index reflecting poor autonomic and vascular reactivity was independently associated with a higher cardiovascular risk.

Mean Oxygen Saturation during Sleep Is Related to Specific Brain Atrophy Pattern.

OBJECTIVE: There is much controversy about the neurobiological mechanisms underlying the effects of sleep-disordered breathing on the brain. The aim of this study was to investigate the association between markers of sleep-related hypoxemia and brain anatomy. METHODS: We used data from a large-scale cohort from the general population (n = 775, 50.6% males, age range = 45-86 years, mean age = 60.3 ± 9.9) that underwent full polysomnography and brain magnetic resonance imaging to correlate respiratory variables with regional brain volume estimates. RESULTS: After adjusting for age, gender, and cardiovascular risk factors, only mean oxygen saturation during sleep was associated with bilateral volume of hippocampus (right: p = 0.001; left: p < 0.001), thalamus (right: p < 0.001; left: p < 0.001), putamen (right: p = 0.001; left: p = 0.001), and angular gyrus (right: p = 0.011; left: p = 0.001). We observed the same relationship in left hemispheric amygdala (p = 0.010), caudate (p = 0.008), inferior frontal gyrus (p = 0.004), and supramarginal gyrus (p = 0.003). The other respiratory variables-lowest oxygen saturation, percentage of sleep time with oxygen saturation < 90%, apnea-hypopnea index, and oxygen desaturation index-did not show any significant association with brain volumes. INTERPRETATION: Lower mean oxygen saturation during sleep was associated with atrophy of cortical and subcortical brain areas known for high sensitivity to oxygen supply. Their vulnerability to hypoxemia may contribute to behavioral phenotype and cognitive decline in patients with sleep-disordered breathing. ANN NEUROL 2020;87:921-930.

Risk factors of excessive daytime sleepiness in a prospective population-based cohort.

Although excessive daytime sleepiness is commonly evaluated in clinical and research settings using the Epworth Sleepiness Scale, few studies have assessed the factors associated with its incidence in the general population. We prospectively investigated the predictors of incident and persistent excessive daytime sleepiness in 2,751 subjects (46.1% men, mean age 56.0 ± 9.8 years) from the CoLaus-PsyCoLaus population-based cohort (Lausanne, Switzerland) over 5 years. Participants completed the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index, and underwent a full clinical evaluation at baseline and 5 years afterwards. Ambulatory polysomnography was performed at baseline in a sub-sample of 1,404 subjects. Among the 2,438 subjects without excessive daytime sleepiness (Epworth Sleepiness Scale ≤ 10) at baseline, the 5-year incidence of excessive daytime sleepiness was 5.1% (n = 124). Multivariate logistic regression revealed that male sex, depressive symptoms, reported poor sleep quality and moderate to severe obstructive sleep apnea were independent predictors of incident excessive daytime sleepiness, while older age, moderate coffee consumption, periodic leg movement during sleep and hypertension were independent protective factors. Stratified analysis according to sex and age showed some distinctive associations. Among the 313 patients with excessive daytime sleepiness at baseline, 137 (43.8%) had persistent excessive daytime sleepiness 5 years later. Our findings provide new insights into the predictors of incident excessive daytime sleepiness, but interventional studies are needed to understand the impact of treating these risk factors on the incidence of excessive daytime sleepiness.

Intrathecal morphine and sleep apnoea severity in patients undergoing hip arthroplasty: a randomised, controlled, triple-blinded trial.

BACKGROUND: Intrathecal morphine prolongs analgesia after surgery, but has been implicated in postoperative respiratory depression or apnoeic episodes. However, this has not been investigated in a prospective trial using respiratory polygraphy. This randomised controlled triple-blinded trial tested the hypothesis that intrathecal morphine increases sleep apnoea severity, measured using respiratory polygraphy. METHODS: Sixty subjects undergoing hip arthroplasty under spinal anaesthesia received either 15 mg isobaric bupivacaine 0.5% with 0.5 ml normal saline 0.9% (control group) or 15 mg isobaric bupivacaine 0.5% with 0.5 ml intrathecal morphine 100 µg (intrathecal morphine group). Respiratory polygraphy was performed before surgery and on the first and third postoperative nights. The primary outcome was the apnoea-hypopnoea index in the supine position (supine AHI) on the first postoperative night. Secondary outcomes included supine AHI on the third postoperative night, oxygen desaturation index (ODI), and ventilatory frequency during the first and third postoperative nights. RESULTS: On the first postoperative night, mean (95% confidence interval) values for supine AHI were 20.6 (13.9-27.3) and 21.2 (12.4-30.0) events h-1 in the control and intrathecal morphine groups, respectively (P=0.90). There were no significant between-group differences for any of the secondary outcomes, except for a significantly higher central and mixed apnoea index preoperatively and significantly lower mean SpO2 on the third postoperative night in the control group. CONCLUSIONS: Intrathecal morphine did not increase sleep apnoea severity when measured using respiratory polygraphy. Of note, all patients had an increased number of apnoeic episodes on the third postoperative night. CLINICAL TRIAL REGISTRATION: NCT02566226.

Chronic pain in narcolepsy type 1 and type 2 - an underestimated reality.

Narcolepsy is a rare sleep disorder classified in types 1 and 2. The co-morbidities of narcolepsy type 1, with hypocretin-1 deficiency, are established. Hypocretin-1 in the central and peripheral nervous systems regulates nociception and pain. However, the patients with narcolepsy type 2 have similar excessive daytime sleepiness and co-morbidities without elucidation. The objective of the study was to determine the frequency and the characteristic of chronic pain according to the type of narcolepsy. We also investigated the effect of the interaction between the nutritional status and the type of narcolepsy. It was a cross-sectional study using self-administered questionnaires. Patients with narcolepsy (33 type 1 and 33 type 2), from Universidade Federal de São Paulo, Brazil, matched by age and gender to 33 control subjects were included. Both types of narcolepsy presented a high frequency of chronic pain (84.84% type 1 versus 75.75% type 2), with indistinct pain characteristics between them. The odds ratio was 20.8 in type 1 and 11.6 in type 2, compared with controls. Obese individuals with narcolepsy type 1 and type 2 did not present a significant difference in pain intensity, compared with obese controls. Patients with narcolepsy type 1 and type 2 were associated with a high frequency of chronic pain. Chronic pain emerged as a co-morbidity never reported before in type 2. Depression possibly influences pain perception in these patients. Obesity might play a role in pain intensity in narcolepsy. The treatment of narcolepsy should take account of chronic pain, depression and obesity management.

REM-associated sleep apnoea: prevalence and clinical significance in the HypnoLaus cohort.

This study determined the prevalence of rapid eye movement (REM) related sleep-disordered breathing (REM-SDB) in the general population and investigated the associations of REM-SDB with hypertension, metabolic syndrome, diabetes and depression.Home polysomnography (PSG) recordings (n=2074) from the population-based HypnoLaus Sleep Cohort (48.3% men, 57±11 years old) were analysed. The apnoea-hypopnoea index was measured during REM and non-REM sleep (as REM-AHI and NREM-AHI, respectively). Regression models were used to explore the associations between REM-SDB and hypertension, diabetes, metabolic syndrome and depression in the entire cohort and in subgroups with NREM-AHI <10 events·h-1 and total AHI <10 events·h-1The prevalence of REM-AHI ≥20 events·h-1 was 40.8% in the entire cohort. An association between increasing REM-AHI and metabolic syndrome was found in the entire cohort and in both the NREM-AHI and AHI subgroups (p-trend=0.014, <0.0001 and 0.015, respectively). An association was also found between REM-AHI ≥20 events·h-1 and diabetes in both the NREM-AHI <10 events·h-1 (odds ratio (OR) 3.12 (95% CI 1.35-7.20)) and AHI <10 events·h-1 (OR 2.92 (95% CI 1.12-7.63)) subgroups. Systolic and diastolic blood pressure were positively associated with REM-AHI ≥20 events·h-1REM-SDB is highly prevalent in our middle-to-older age sample and is independently associated with metabolic syndrome and diabetes. These findings suggest that an increase in REM-AHI could be clinically relevant.

Obstructive sleep apnoea as a risk factor for incident metabolic syndrome: a joined Episono and HypnoLaus prospective cohorts study.

Cross-sectional studies have demonstrated that obstructive sleep apnoea (OSA) and metabolic syndrome (MetS) are often associated, but whether a temporal relationship exists is unknown. We aimed to investigate the effect of OSA on the risk of developing MetS in the general population.A prospective study was conducted combining two population-based samples: Episono (Brazil) and HypnoLaus (Switzerland). MetS was assessed according to unified criteria. Polysomnography (PSG) was performed at baseline and follow-up in Episono, and at baseline in HypnoLaus. OSA was defined according to the apnoea-hypopnoea index as mild (≥5- <15 events h-1) and moderate-to-severe (≥15 events·h-1). We included 1853 participants (mean±sd age 52±13 years, 56% female) without MetS at baseline.After mean±sd 6±1 years, 318 (17.2%) participants developed MetS. Moderate-to-severe OSA was independently associated with incident MetS (OR 2.58, 95% CI 1.61-4.11) and increased the number of MetS components from baseline to follow-up through mediation of the percentage of time with arterial oxygen saturation <90%. Subset analysis in Episono confirmed that the increase in this parameter between baseline and follow-up PSGs represented a risk factor for incident MetS (OR 1.42, 95% CI 1.04-1.95, for each 10% increase).OSA is independently associated with an increased risk of developing MetS through mediation of nocturnal hypoxaemia in the general population.

The relationship between sleep apnea, metabolic dysfunction and inflammation: The gender influence.

Obstructive sleep apnea (OSA) has been associated with increased risk of cardiovascular morbidity and mortality. Although inflammatory markers may mediate this association, it is unknown the influence of gender in this mechanism. Thus, we aimed to evaluate the interaction effects between OSA and gender on metabolic and inflammatory profile in a population sample. This study is part of EPISONO cohort, in which 1042 participants underwent polysomnography, answered questionnaires, and had their blood collected for analysis of fasting glucose, total cholesterol and fractions, leptin, ghrelin, liver transaminases, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and C-reactive protein. The results showed that men with OSA had higher leptin levels, shorter sleep latency and lower N3 sleep stage compared to men control (CTRL). They also presented higher apnea index and number of central apneas compared to both CTRL men and OSA women. In women, OSA was related to longer REM sleep latency, higher apnea-hypopnea index (AHI) during REM sleep and increased TNF-α levels compared to CTRL women. A multivariate model showed that male gender, ghrelin and total cholesterol were negatively associated with TNF-α, while IL-6, triglycerides and hypopnea index were positively associated (R2=0.21). Additionally, gender (men), body mass index, ghrelin, apnea index and smoking were positive predictors of leptin levels (R2=0.55). Of note, postmenopause was associated with changes observed in both TNF-α and AHI during REM sleep in women with OSA. Taken together, our study suggests that OSA consequences may differ between genders and this could indicate a need for different OSA management in women according to their reproductive life's stage.

Is the chronotype associated with obstructive sleep apnea?

PURPOSE: Chronotype and obstructive sleep apnea (OSA) appear to have a similar lifelong evolution, which could indicate a possible effect of morningness or eveningness in the apnea-hypopnea index (AHI). The present study aimed to examine the prevalence of chronotypes in a representative sample of São Paulo city residents and to investigate the effect of chronotypes on the severity of OSA. METHODS: We performed a cross-sectional analysis using the São Paulo Epidemiologic Sleep Study (EPISONO). All participants underwent a full-night polysomnography and completed the Morningness-eveningness, Epworth Sleepiness Scale, and UNIFESP Sleep questionnaires. Chronotypes were classified as morning-type, evening-type, and intermediate. RESULTS: Morning-type individuals represented 52.1% of the sample, followed by intermediate (39.5%), and evening-type (8.4%) individuals. After stratifying the sample by body mass index (BMI) (>26.8 kg/m(2)) and age (>42 years), we observed increased AHI values in morning- and evening-type individuals. CONCLUSION: We demonstrated, for the first time, an age- and BMI-related effect of morning- and evening-types in OSA severity, suggesting that the intermediate chronotype might play a role as a protective factor in older and overweight patients.

Fibromyalgia and sleep in animal models: a current overview and future directions.

Sleep disorders are highly prevalent in patients with fibromyalgia (FM). Many of the daytime symptoms, such as chronic pain and fatigue, may be related to the non-restorative sleep patterns associated with the disease. Pain influences the sleep process and sleep disturbances decrease the pain threshold in a reciprocal framework. Thus, understanding the link between sleep and FM has become an important research topic in basic science. Therefore, in the current review we connect these topics and provide some insights into the cyclic relationship between sleep and pain, which has been addressed mainly in animal models. Additionally, we highlight the urgent need for sleep studies in FM animal models, which might improve the knowledge base and accelerate advances in this field.

Changes in gene expression in the frontal cortex of rats with pilocarpine-induced status epilepticus after sleep deprivation.

Sleep and epilepsy present a bidirectional interaction. Sleep complaints are common in epilepsy, and sleep deprivation may provoke seizures. However, the mechanisms underlying this relationship are unknown. Thus, this study investigated the effects of paradoxical sleep deprivation (PSD24h) and total sleep deprivation (TSD6h) in the expression of genes related to reactive oxygen species and nitric oxide production in the frontal cortex of a rodent model of temporal lobe epilepsy (PILO). The data show that PILO rats had increased NOX-2 expression and decreased SOD expression, independent of sleep. Higher NOX-2 expression was observed only in PILO rats subjected to the control condition and TSD6h. Also, eNOS and DDAH1 were increased in the PILO group submitted to TSD6h. Moreover, CAT expression in the frontal cortex of PILO rats submitted to PSD24h was reduced compared to that of PILO rats that were not sleep-deprived. The molecular changes found in the frontal cortex of PILO rats following sleep deprivation suggest a mechanism via oxidative stress.

Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period.

Intermittent hypoxia (IH) is a frequent occurrence in sleep and respiratory disorders. Both human and murine studies show that IH may be implicated in metabolic dysfunction. Although the effects of nocturnal low-frequency intermittent hypoxia (IH(L)) have not been extensively examined, it would appear that IH(L) and high-frequency intermittent hypoxia (IH(H)) may elicit distinct metabolic adaptations. To this effect, C57BL/6J mice were randomly assigned to IH(H) (cycles of 90 s 6.4% O(2) and 90 s 21% O(2) during daylight), IH(L) (8% O(2) during daylight hours), or control (CTL) for 5 wk. At the end of exposures, some of the mice were subjected to a glucose tolerance test (GTT; after intraperitoneal injection of 2 mg glucose/g body wt), and others were subjected to an insulin tolerance test (ITT; 0.25 units Humulin/kg body wt), with plasma leptin and insulin levels being measured in fasting conditions. Skeletal muscles were harvested for GLUT4 and proliferator-activated receptor gamma coactivator 1-α (PGC1-α) expression. Both IH(H) and IH(L) displayed reduced body weight increases compared with CTL. CTL mice had higher basal glycemic levels, but GTT kinetics revealed marked differences between IH(L) and IH(H), with IH(L) manifesting the lowest insulin sensitivity compared with either IH(H) or CTL, and such findings were further confirmed by ITT. No differences emerged in PGC1-α expression across the three experimental groups. However, while cytosolic GLUT4 protein expression remained similar in IH(L), IH(H), and CTL, significant decreases in GLUT4 membrane fraction occurred in hypoxia and were most pronounced in IH(L)-exposed mice. Thus IH(H) and IH(L) elicit differential glucose homeostatic responses despite similar cumulative hypoxic profiles.

Impairment of sexual function in rats with epilepsy.

INTRODUCTION: Epilepsy is a chronic disease that affects men and women of all ages, with different levels of severity. Many individuals with epilepsy also suffer from impairments in sexual function. However, it is difficult to differentiate between the impact of the disease and the impact of antiepileptic drugs on sexual function in human subjects. AIMS: To evaluate sexual behavior in adult male rats submitted to chronic pilocarpine-induced epilepsy. METHODS: First, non-epileptic rats were exposed to nine training sessions to acquire sexual experience, and their baseline sexual performance was evaluated. Then, the same rats were given pilocarpine to induce status epilepticus followed by chronic epilepsy. Once the animals had developed spontaneous recurrent seizures, their sexual behavior was evaluated during three sessions. MAIN OUTCOME MEASURES: Examine changes in latencies to first mount, intromission, and ejaculation, and the total number of mounts, intromissions, and ejaculations. RESULTS: All outcome measures related to sexual motivation and sexual performance were markedly impaired during chronic epilepsy compared with the baseline and the control group. CONCLUSION: These findings will aid in understanding the interaction between sexual behavior and epilepsy, as well as encouraging further experimental studies in human patients with epilepsy suffering from sexual dysfunction.

Associations of indicators of sleep impairment and disorders with low muscle strength in middle-aged and older adults: The HypnoLaus cohort study.

OBJECTIVE: Investigate associations of objective and subjective indicators of sleep impairment and disorders with low muscle strength (LMS) in different age groups and genders using data from a population-based cohort study. METHODS: Polysomnographic and subjective sleep data from participants (aged 40-80 years) of the HypnoLaus study (Lausanne, Switzerland) were cross-sectionally analyzed. Indicators of sleep impairment and disorders were based on pre-defined cutoffs. LMS was defined according to the diagnosis of sarcopenia (grip strength <27 kg for men and <16 kg for women). Results obtained by multivariate logistic regression were controlled for confounders. RESULTS: 1902 participants (mean [SD] age, 57.4 [10.5] years; 968 [50.9 %] female) were enrolled. Objective short (<6.2 h) and long sleep durations (>8.5 h) were associated with LMS (OR = 1.74, 95 % CI = 1.07-2.82; OR = 6.66, 95 % CI = 3.45-12.87, respectively). Increased nighttime wakefulness >90 min and severe obstructive apnea (OSA) (AHI > 30) were associated with LMS (OR = 1.60, 95 % CI = 1.01-2.56; OR = 2.36, 95 % CI = 1.29-4.31, respectively). In adults aged over 60 years, these associations persisted, and reduced sleep efficiency was associated with LMS (aOR = 1.81, 95 % CI 1.05-3.13). Objective long sleep duration was associated with LMS in both genders and severe OSA predicted LMS among women (aOR = 2.64, 95 % CI 1.11-6.24). CONCLUSIONS: Markers of early sarcopenia are affected by long sleep duration from middle age onwards in both genders. Older adults are more susceptible to the effects of other indicators of inappropriate sleep duration and quality. The findings support a potential role of sarcopenia in age-related OSA. The intricate relationships between sleep and muscle health are potential targets of public health interventions and clinical research on preventive and therapeutic strategies against the increasing morbimortality observed with ageing.

A novel EEG marker predicts perceived sleepiness and poor sleep quality.

STUDY OBJECTIVES: To determine if a novel EEG-derived continuous index of sleep depth/alertness, the odds ratio product (ORP), predicts self-reported daytime sleepiness and poor sleep quality in two large population-based cohorts. METHODS: ORP values which range from 0 (deep sleep) to 2.5 (fully alert) were calculated in 3s intervals during awake periods (ORPwake) and NREM sleep (ORPNREM) determined from home sleep studies in the HypnoLaus (N = 2162: 1106 females, 1056 males) and men androgen inflammation lifestyle environment and stress (MAILES) cohorts (N = 754 males). Logistic regression was used to examine associations between ORPwake, ORPNREM, and traditional polysomnography measures (as comparators) with excessive sleepiness (Epworth sleepiness scale >10) and poor sleep quality (Pittsburgh sleep quality index >5) and insomnia symptoms. RESULTS: High ORPwake was associated with a ~30% increase in poor sleep quality in both HypnoLaus (odds ratio, OR, and 95% CI) 1.28 (1.09, 1.51), and MAILES 1.36 (1.10, 1.68). High ORPwake was also associated with a ~28% decrease in excessive daytime sleepiness in the MAILES dataset. ORPNREM was associated with a ~30% increase in poor sleep quality in HypnoLaus but not in MAILES. No consistent associations across cohorts were detected using traditional polysomnography markers. CONCLUSIONS: ORP, a novel EEG-derived metric, measured during wake periods predicts poor sleep quality in two independent cohorts. Consistent with insomnia symptomatology of poor perceived sleep in the absence of excessive daytime sleepiness, ORPwake may provide valuable objective mechanistic insight into physiological hyperarousal.

Association Between Sleep Microstructure and Incident Hypertension in a Population-Based Sample: The HypnoLaus Study.

Background Poor sleep quality is associated with increased incident hypertension. However, few studies have investigated the impact of objective sleep structure parameters on hypertension. This study investigated the association between sleep macrostructural and microstructural parameters and incident hypertension in a middle- to older-aged sample. Methods and Results Participants from the HypnoLaus population-based cohort without hypertension at baseline were included. Participants had at-home polysomnography at baseline, allowing assessment of sleep macrostructure (nonrapid eye movement sleep stages 1, 2, and 3; rapid eye movement sleep stages; and total sleep time) and microstructure including power spectral density of electroencephalogram in nonrapid eye movement sleep and spindles characteristics (density, duration, frequency, amplitude) in nonrapid eye movement sleep stage 2. Associations between sleep macrostructure and microstructure parameters at baseline and incident clinical hypertension over a mean follow-up of 5.2 years were assessed with multiple-adjusted logistic regression. A total of 1172 participants (42% men; age 55±10 years) were included. Of these, 198 (17%) developed hypertension. After adjustment for confounders, no sleep macrostructure features were associated with incident hypertension. However, low absolute delta and sigma power were significantly associated with incident hypertension where participants in the lowest quartile of delta and sigma had a 1.69-fold (95% CI, 1.00-2.89) and 1.72-fold (95% CI, 1.05-2.82) increased risk of incident hypertension, respectively, versus those in the highest quartile. Lower spindle density (odds ratio, 0.87; 95% CI, 0.76-0.99) and amplitude (odds ratio, 0.98; 95% CI, 0.95-1.00) were also associated with higher incident hypertension. Conclusions Sleep microstructure is associated with incident hypertension. Slow-wave activity and sleep spindles, 2 hallmarks of objective sleep continuity and quality, were inversely and consistently associated with incident hypertension. This supports the protective role of sleep continuity in the development of hypertension.

Genomic damage in the progression of chronic kidney disease in rats.

Patients with chronic renal failure exhibit massive oxidative genome damage and an elevated risk of cancer. Previous studies have demonstrated the relationship between DNA damage and carcinogenesis. The current study aimed to investigate whether the progression of chronic kidney disease induces genomic damage in an animal model. Adult Wistar rats were assigned to either the control or chronic kidney disease groups. The chronic kidney disease group was subdistributed into five groups with progressively longer durations of disease (30, 60, 90, 120 and 150 days). The results showed that chronic kidney disease induced genomic damage in the blood, liver and kidney cells during all periods evaluated, as indicated by the mean tail moment measured in the comet assay. In brain cells, no genetic damage was induced at early/intermediate disease durations; however, positive genotoxicity was found at 120 and 150 days. Blood pressure and pro-inflammatory cytokine levels (IL-1α, IL-1ß, IL-6 and TNFα) were increased after chronic kidney disease induction, while blood iron concentration was significantly reduced in these animals. The results suggest that chronic kidney disease progression contributes to DNA damage in blood, liver, kidney and brain and that such damage can be mediated by hypertension, an inflammatory status and iron deficiency. Additionally, the brain was sensitive to genotoxic insult after extended chronic kidney disease, suggesting a potentially important role of genetic damage in the neurological disorders of end-stage renal patients.