Does Sleep Apnea Damage the Kidneys?

Sleep apnea (SA) is increasingly recognized as a global health concern, with potential adverse effects in a variety of systems, including cardiovascular complications, diabetes mellitus, and chronic obstructive pulmonary disease.^1–3 In patients with SA, intermittent hypoxemia induces inflammation and subsequent endothelial injury, increased sympathetic activity, and hyper-tension.^4–9 In addition, excessive daytime somnolence, neuro-cognitive impairment, and increased accidents due to increased sleepiness are the most obvious health consequences of SA.^10,11

Similar to SA, aging of the population and the obesity epidemic contribute to the growing numbers of patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD).

Chronic kidney disease has an estimated prevalence of 8% to 16% among adults worldwide. It may lead to premature death from cardiovascular disease and infections or may progress to ESRD. It is estimated that nearly two million people will require renal replacement therapy by the year 2030.¹² Taiwan has the highest prevalence of ESRD in the world. Many previous studies have shown an association between sleep-related breathing disorders such as SA and both CKD and protein-uria.^13–30 Furthermore, some small studies have demonstrated improvement in kidney function with the use of continuous positive airway pressure devices.^18,19 However, many of these studies were limited by small sample sizes, cross-sectional study designs, inappropriate comparison groups, and insufficient adjustment for potential confounders. Therefore, the report by Lee and colleagues in this issue of SLEEP presents a valuable addition to the literature, confirming that sleep apnea is an independent risk factor for chronic kidney disease in Taiwan.³¹

Lee et al. conducted a large, retrospective cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan to test the extent that sleep apnea was associated with chronic kidney disease and end-stage renal disease. They analyzed 4,674 adults with newly diagnosed sleep apnea from 2000 to 2010, frequency matched to 23,370 adults without SA (non-SA) based on gender, age, and year of receiving medical service. Sleep apnea patients had significantly higher rates of comorbid conditions known to influence chronic kidney disease at baseline. Kaplan-Meier survival curves demonstrated significantly lower CKD and ESRD free survival rates in SA compared to the matched non-SA group. Using the Cox proportional hazards model, they found that patients with SA had a nearly 2-fold increase in the incidence of CKD and ESRD, even after adjustment for confounders. The risk for CKD in SA patients was present in both genders, whereas the risk for ESRD in SA patients was absent in men but present in women.³¹ Taking into account that death is a competing risk factor for CKD, the competing-risk regression model generally confirmed these findings. Interestingly, although some differences were apparent between genders with the competing-risk regression model, it did not find a statistically significant risk for ESRD due to SA in the total cohort or in men, but did in women (HR 2.32, 95% CI 1.03–5.25, P < 0.05).

The study by Lee et al. has several strengths not found in previous published studies.^13–30 They not only adjusted for well-known risk factors for CKD, such as hypertension and diabetes mellitus, but also many other conditions associated with CKD.^32–38 In addition, they adjusted for important socioeconomic factors that may have confounded the relationship between SA and CKD, including geographic locations, enrollee categories, income, and urbanization level. The statistical approach strengthened the findings by reporting not only traditional Cox regression models, but also sensitivity analysis in which another hypothetical unmeasured confounding factor with a similar risk effect as CKD could be added to the model. The use of the competing-risk regression model also strengthened the results by accounting for death as a competing risk for CKD and ESRD.

This large observational study³¹ using administrative claims data also has several limitations. First, the absence of data on different stages of CKD using different ICD-9-CM codes makes it impossible to differentiate risk for different levels of CKD severity. Relating sleep apnea to increased severity of CKD would have provided stronger evidence for the relationship between SA and CKD. Second, the lack of demographic information on body mass index (BMI), medication history, and smoking status, all important determinants of CKD, is a limitation. However, as Lee et al. point out, they attempted to adjust for other factors such as gout and diseases of the musculoskeletal system and connective tissue, both of which are highly associated with nonsteroidal anti-inflammatory drug use; chronic obstructive pulmonary disease, which is highly associated with smoking; and obesity (instead of BMI). Third, the relationship between CKD and ESRD may have been due to differences in ascertainment between the sleep apnea and non-sleep apnea groups. For example, health care providers attentive enough to screen and diagnose patients with SA may also pay attention to testing for other chronic health conditions with shared risk factors such as CKD. Yet, the observed relationship between SA and ESRD diminishes one's concern that the association between SA and kidney disease is due to ascertainment. The presence of ESRD could be expected to be observed similarly across providers and advanced health systems since this diagnosis is related to either dialysis or death. Lastly, since Taiwan has substantially higher rates of CKD and ESRD than those found in most of the world, the observations from this study may not extend to other countries. However, the epidemic of ESRD makes these findings relating SA to CKD of major public health importance in Taiwan, and potentially globally, if the biological pathways could be determined.

The study of Lee et al. extends findings from previous studies showing significant associations between sleep apnea and chronic kidney disease. The gender differences found in the competing-risk regression model suggest that SA confers increased risk for CKD in both genders, as well as ESRD in women but not men. Given these findings, it seems prudent to consider screening for CKD in patients with SA with regular laboratory measurements of kidney function (creatinine and estimated glomerular filtration rate) as well as random urine albumin/creatinine ratios to screen for proteinuria, as other studies have linked SA with proteinuria.^24–26 By identifying CKD early, steps may be taken to prevent progression of CKD to ESRD in the high-risk SA population. Such measures may include intensification of blood pressure control, proteinuria-reducing medications, smoking cessation, lifestyle modifications, and potentially therapies focused at treating SA. In addition, the findings from this large observational study linking sleep apnea to chronic kidney disease suggest that further studies are needed to determine whether such interventions delay progression of the latter and improve survival.

CITATION

Liang K, Unruh M. Does sleep apnea damage the kidneys? SLEEP 2015;38(2):167–169.

DISCLOSURE STATEMENT

The authors have indicated no financial conflicts of interest.