Association of Chronic Insomnia With Mortality and Adverse Renal Outcomes

Objective: To examine whether chronic insomnia is associated with an increased risk of adverse renal outcomes and all‐cause mortality. Patients and Methods: We examined associations of chronic insomnia (defined as the presence of both International Classification of Diseases, Ninth Revision codes 307.42, 307.49, and 780.52 and long‐term use of insomnia medications) with adverse renal outcomes (end‐stage renal disease, incidence of estimated glomerular filtration rate [eGFR] ≤45 mL/min per 1.73 m2, and eGFR slopes <−3.0 mL/min per 1.73 m2 per year) and all‐cause mortality in a national cohort of 1,639,090 US veterans by using Cox proportional hazards and logistic regression models with multivariable adjustments. Results: A total of 36,741 patients (2.24%) had chronic insomnia; 32,985 (89.8%) were male and 28,090 (76.5%) were white, with a mean baseline eGFR of 84.1±16.4 mL/min per 1.73 m2. Chronic insomnia was associated with a significantly higher risk of eGFR 45 mL/min per 1.73 m2 or less (multivariable‐adjusted hazard ratio [HR], 1.39; 95% CI, 1.34‐1.44; P<.001), and rapid loss of kidney function (odds ratio, 1.07; 95% CI, 1.03‐1.12; P=.002), but not end‐stage renal disease (HR, 1.25; 95% CI, 0.81‐1.93; P=.32). Chronic insomnia was not associated with a higher risk of all‐cause mortality (HR, 1.00; 95% CI, 0.97‐1.03; P=.99). Conclusion: Chronic insomnia is associated with a higher risk of development and progression of chronic kidney disease, but not ESRD. Further studies are needed to establish the underlying mechanisms of action and to determine whether treatment of insomnia could be beneficial to prevent deteriorating kidney function.


S
leep is a necessary function in our daily life that is essential for biological rejuvenation and organ recovery. 1Sleep disorders can result in mental or physical dysfunction.Insomnia is one of the most common sleep disorders, affecting as many as one-third of the world's population. 2 Chronic insomnia is usually defined as persistent difficulty in initiating sleep, maintaining sleep, or waking up earlier than desired for several months, although the diagnosis of insomnia was revised many times in the Diagnostic and Statistical Manual of Mental Disorders 3 and International Classification of Sleep Disorders (ICSD-3). 4In addition to its social and psychological effects such as fatigue, 5 deficient performance, 6,7 and decreased memory and attention, 8,9 chronic insomnia causes overactivation of the hypothalamic-pituitary-adrenal axis and the sympathoadrenal system 10,11 and is associated with an increased incidence of cardio-and cerebrovascular diseases 12,13 and metabolic abnormalities. 14,15n spite of calls to devote more attention to the adverse effects of sleep disorders, 16,17 to our knowledge no study has examined the effect of chronic insomnia on renal outcomes, such as incidence of chronic kidney disease (CKD) or rate of kidney function deterioration.We hypothesized that chronic insomnia could be associated with adverse renal outcomes.To test this hypothesis, we examined the association of chronic insomnia in a large nationally representative cohort of US veterans with a normal baseline estimated glomerular filtration rate (eGFR).

Cohort Definition
This study used data from a historical cohort study (Racial and Cardiovascular Risk Anomalies in Chronic Kidney Disease [RCAV]) For editorial comment, see page 1540 examining risk factors and outcomes of incident CKD, which has been previously described. 18,19Briefly, our parent cohort consisted of patients who received care at any US Department of Veterans Affairs (VA) facility from October 1, 2004, through September 30, 2006, with measurement of at least 1 serum creatinine value, and had an eGFR of greater than 60 mL/min per 1.73 m 2 during this time period.Patients were entered into the RCAV cohort on the date of the first eGFR assessment of greater than 60 mL/min per 1.73 m 2 .The algorithm for our present analytical cohort definition is shown in Figure 1.To select only patients with primary chronic insomnia, we used the insomnia research diagnostic criteria suggested by Edinger et al 20 in 2004 and in ICSD-3. 4hronic insomnia was defined as the presence of International Classification of Diseases, Ninth Revision (ICD-9) codes 307.42, 307.49, and 780.52 and long-term use of insomnia medications (defined as the pharmacy dispensation records of a benzodiazepine, Z-drugs [nonbenzodiazepine drug], or ramelteon for at least 3 months and with a medication refill overdue period of <90 days).After we excluded patients with preexisting insomnia and other sleep disorders (sleep apnea, circadian rhythm sleep disorder, hypersomnia, parasomnia,  23 We used the respective means of all eGFR, BMI, and blood pressure recordings within 180 days of the new cohort entry date as baseline values for these variables. For patients without any BMI or blood pressure measured during this time period, we used the last available measurement preceding the baseline date.Information on race was cross-referenced with data obtained from Medicare through the VA Medicare Data Merge Initiative. 24Data on medication exposure were collected from VA pharmacy dispensing records. 25Information on allcause mortality was obtained from the VA Vital Status Files that contain dates of death up to July 26, 2013, from all available sources in the VA system.Information on end-stage renal disease (ESRD) was obtained from the United States Renal Data System up to September 13, 2011.Information on mental health encounters was based on VA mental health clinical service codes and frequency rank (Supplemental Table 2, available online at http://www.mayoclinicproceedings.org).Chronic pain scale was defined as a score of greater higher than 5 on the pain scale in at least 3 outpatient encounters.

Statistical Analyses
Descriptive analyses were performed using mean AE SD, median (IQR), and proportion (percentage), as appropriate.Because of the large size of the cohort, all patient characteristics were statistically significantly different (P<.001) between patients with and without chronic insomnia, and hence we regarded them as considerable differences only if they were biologically meaningful.Event rates and the corresponding 95% CIs were calculated using the patient-year (PY) approach for mortality, incident eGFR less than 45 mL/min per 1.73 m 2 , and ESRD.Cox proportional hazards regression models with adjustment for potential confounders were used for examining the association of chronic insomnia with all-cause mortality, ESRD, and incidence of eGFR 45 mL/min per 1.73 m 2 or less.The association of insomnia with rapid kidney function decline (defined as eGFR slopes <À3.0 mL/min per 1.73 m 2 per year) 26 was examined using logistic regression models.Patients were followed from the date of cohort entry until death or were censored at the date of the last health care encounter documented in the VA Vital Status Files or on July 26, 2013.For ESRD analyses, follow-up lasted until the first event date, death, last encounter, or September 13, 2011.The eGFR slopes of the insomnia group were estimated using a linear mixed effects model with random intercept and slope based on all available serum creatinine levels after the date of insomnia diagnosis.The slopes of the control group were estimated using all available serum creatinine levels from the date of cohort entry to the end of follow-up.
The effect of potential confounders on outcomes was analyzed by sequential multivariable adjustments including baseline age (model 1), baseline eGFR, sex, race (model 2), BMI, baseline blood pressure (model 3), chronic pain, comorbid conditions (cardiovascular disease, cerebrovascular disease, hypertension, congestive heart failure, malignant neoplasm, liver disease, chronic lung disease, peripheral artery disease, peptic ulcer, human immunodeficiency virus, diabetes, and the Deyo-modified Charlson comorbidity index 27 ), mental health encounters, and use of antihypertensive drugs from baseline until the end of follow-up (model 4).A propensity scoreematched cohort was created using a 1:1 nearest-neighbor matching without replacement after calculating the propensity scores for the likelihood of presence vs absence of chronic insomnia by using logistic regression models involving all of the abovementioned variables.Differences between variables were examined by calculating standardized differences, and values less than 0.1 were considered acceptable for matching.We performed subgroup analyses to examine effect modification by prespecified demographic and comorbid characteristics.
Data were mainly missing on race (147,874 patients; 9.0%) and income (111,288 patients; 6.8%); 11.7% (191,138)  Patients with chronic insomnia were younger, but there were no major differences in comorbidities between the 2 groups, except that more patients with chronic insomnia had chronic pain, received mental health services, and received antihypertensive therapy.

Mortality
Over a median follow-up period of 4.76 years (IQR, 0.003-6.81years), 11.19% of cohort died (mortality rate, 25.5 cases per 1000 PY; 95% CI, 25.4-25.6cases per 1000 PY), with 3730 deaths in the insomnia group (23.2 cases per 1000 PY; 95% CI, 22.5-24.0cases per 1000 PY) and 179,765 deaths in the control group (25.6 cases per 1000 PY; 95% CI, 25.5-25.7 cases per 1000 PY).Compared with control patients, patients with chronic insomnia did not have a higher risk of all-cause mortality after multivariable adjustments (multivariableadjusted hazard ratio for all-cause mortality associated with chronic insomnia, 1.00; 95% CI, 0.97-1.03;P¼.99) (Supplemental Table 3).The results were similar after adjustment for socioeconomic status (Supplemental Table 5, available online at http://www.mayoclinicproceedings.org).The association between chronic insomnia and mortality was consistent in propensity scoreematched analyses.In subgroup analyses, several patient characteristics modified the association between chronic insomnia and mortality, with insomnia being associated with lower mortality in older patients and patients with preexisting coronary artery disease and with higher mortality in patients with higher BMI (Supplemental Figure 4, available online at http://www.mayoclinicproceedings.org).

DISCUSSION
In this large cohort of US veterans, we examined the association of chronic insomnia with allcause mortality, incidence of eGFR 45 mL/min per 1.73 m 2 or less, ESRD, and rapid loss of kidney function.Chronic insomnia was associated with a higher risk of incidence of eGFR 45 mL/ min per 1.73 m 2 or less and rapid loss of kidney function, even after accounting for measured confounders.The association of insomnia with  The P values for between-group differences in each listed variable are <.001.
incident ESRD was not statistically significant, but the number of ESRD events were very small.To our knowledge, only a few previous studies have examined the association of sleep disorders with renal outcomes and none of them studied the effect of strictly defined chronic insomnia on renal end points. 28horter sleep duration was found to be associated with faster renal function decline 16 in the American Nurses' Health Study, but the study was based on self-reported insomnia symptoms.Similarly, a Japanese study found that sleeping for a shorter duration did not increase the risk of CKD overall but it increased the risk significantly in shift workers. 29Another observational study based on the Taiwan National Health Insurance Database also reported that nonapnea sleep disorders (including most types of sleep disorders, not just chronic insomnia) were associated with a higher risk of CKD 17 and a higher incidence of acute kidney injury. 30Our study is the first to examine the association between primary chronic insomnia and adverse renal outcomes.
However, the lack of increased risk of mortality reported in our study supports the results from previous studies, which described an association between sleep disorders and a higher risk of cardio-and cerebrovascular events 31 or mortality. 32A meta-analysis from 15 studies performed in European countries and in the United States reported that difficulty in initiating sleep, maintaining sleep, or having nonrestorative sleep was associated with a higher risk of cardio-and cerebrovascular events. 12However, the significant association between sleep disorders and mortality or cardio-and cerebrovascular disease incidence was highly correlated with sleep duration. 33Both shorter and longer sleep durations were associated with a higher risk of clinical events compared with a sleep duration of 7 to 9 hours.The different results for the association between chronic insomnia and allcause mortality in our cohort may be due to differences in patient populations and differences in available data used to adjust for potential confounding.
The mechanisms of action that could explain the association between chronic insomnia and CKD incidence and progression are complex.Insomnia could have an indirect effect on kidney function by causing or worsening the metabolic syndrome or by worsening hypertension and diabetes.Insomnia symptoms have been associated with worse metabolic abnormalities in several previous studies, [34][35][36] although some studies indicated that only certain types of insomnias (eg, difficulty in maintaining sleep 37 ) had marked effects on the metabolic syndrome whereas other types of insomnia symptoms, such as early morning awakening, 36 displayed no significant association.
In addition, chronic insomnia is highly correlated with chronic stress because stress could be both a cause and a consequence of insomnia.Chronic insomnia results in overactivation of the hypothalamicpituitary-adrenal axis and the sympathoadrenal system, 10 which is supported by our finding that patients with chronic insomnia had a higher prevalence of mental disorders and chronic pain.The resulting elevated glucocorticoid and epinephrine/ norepinephrine levels could cause disorders in glucose metabolism 38 or other endocrine systems, 39 which may result in worsening obesity 40 and diabetes 41,42 or cardiovascular tension, 43 which could be manifested as tachycardia or hypertension.Consequently, either diabetes or hypertension could damage the kidney and lead to worsening kidney function.
Our study has limitations that need to be acknowledged.Our cohort was defined using ICD-9 codes and medication use, and hence we could not determine sleep duration and the type of insomnia.We also could not verify whether patients with chronic insomnia underwent polysomnography to determine which sleep stage was abnormal.We examined male US veterans managed in the VA health care system, and hence our cohort may not be representative of the general population.We adjusted for known confounders, but we cannot rule out the effect of unmeasured confounders.We were unable to account for the presence or severity of proteinuria because of its extensive missingness.We used a stringent definition for chronic insomnia, which resulted in the exclusion of a large number of individuals who did not fit the predefined criteria.Because medication use was part of our criteria, it is possible that the detected associations were a result of the applied medications, and not insomnia per se. 44To differentiate medication effects from those of insomnia, one would need an assessment of the effectiveness of medication regimens in relieving insomnia, which would require prospective assessments.We did not have information on cause-specific deaths and hence we are unable to confirm whether most deaths were related to cardio-or cerebrovascular events.Consequently, it is possible that the lack of an association between chronic insomnia and all-cause mortality was due to a preponderance of deaths with mechanisms that cannot be attributed to insomniarelated physiological changes.

CONCLUSION
Chronic insomnia is significantly associated with a higher risk of incident eGFR 45 mL/ min per 1.73 m 2 or less and rapid loss of kidney function.Randomized controlled trials are warranted to investigate the clinical effects of various interventions used to treat chronic insomnia on these outcomes.
22hort definition: Algorithm used to define the study cohort.eGFR¼estimated glomerular filtration rate.wascalculatedusing the Chronic Kidney Disease Epidemiology Collaboration equation22on the basis of the serum creatinine levels extracted from VA Corporate Data Warehouse LabChem data files.
21using ICD-9 diagnosis and procedure codes and Current Procedural Terminology codes.Patients' demographic characteristics, socioeconomic status (marital status and income), chronic pain, BMI, and blood pressure were obtained from the VA Corporate Data Warehouse.The estimated glomerular filtration rate of patients have 1 missing value, but only 4.4% (71,339) of patients have missing values for more than 1 variable.Eighty-four percent of patients had complete information available for the final multivariable model (model 4).Because of the relatively low proportion of missingness in the main multivariable model, missing data were not imputed.Adjustment for socioeconomic characteristics was performed only in sensitivity analyses because of the relatively higher proportion of missingness for income data.Statistical analyses were performed using Stata/MP version 14 (StataCorp LLC).The study was approved by the institutional review boards of the Memphis VA Medical Center and the Long Beach VA Medical Center.RESULTS Overall, 93.4% (1,530,823) of patients were male and 70.0%(1,147,936) were white.The mean baseline age of patients in the chronic insomnia group vs those in the control group was 58.9AE13.8years vs 63.3AE13.4years, and the mean estimated GFR was 84.1AE16.4mL/min per 1.73 m 2 vs 81.0AE16.4mL/min per 1.73 m 2 .The baseline characteristics are summarized in the Table.

TABLE . Baseline
Characteristics of the Chronic Insomnia Group vs Control Group a,b,c