The association of obstructive sleep apnea and renal outcomes—a systematic review and meta-analysis

According to data from the National Health and Nutrition Examination Survey, the latest report from the United States Renal Data System indicated that chronic kidney disease (CKD) is more common than diabetes mellitus (DM) in the United States, an estimated 13.6% of adults having CKD as compared with 12.3% with DM [1]. Thus, CKD has become a serious public health issue, as it is not only debilitating to individuals, leading to severe complications, but is also a great burden on society, with a large associated cost [2]. Therefore, identifying and disrupting factors that contribute to CKD is not only beneficial to the health of individuals, but can also reduce the cost of treating the disease and its complications.

Obstructive sleep apnea (OSA) could be a potential risk factor for CKD. In the late 1980s, Sklar et al. initially found that OSA could be significantly associated with high-grade proteinuria [3]; they then confirmed these results in a larger cohort [4]. Subsequently, Canales et al. [5] further established that the degree of microalbuminuria is correlated with the severity of OSA. Moreover, Iseki et al. [6] reported that a Japanese population diagnosed with OSA had a higher chance of decreased renal function, as predicted from the estimated glomerular filtration rate (eGFR). Despite these reports suggesting a relationship between OSA and the development of CKD, other conflicting reports have presented evidence against the existence of a connection of OSA with proteinuria [7], albuminuria [8] and the eGFR [5, 9]. Thus, the associations of OSA with diverse renal outcomes should be clarified.

Recently, Leong et al. [10] conducted a meta-analysis that focused on patients with DM, and presented moderate evidence to show that OSA is associated with CKD. However, it should be noted that patients with DM are prone to suffering from nephropathy [2, 11], and the results may not be able to be generalized to other populations. Furthermore, previous studies [10, 12] did not elucidate a relationship between the severity of OSA and the degree of renal function change, which may be worthy of discussion. In order to clarify the uncertainties mentioned above, this meta-analysis study aimed to provide a more comprehensive overview of the relationship between OSA and renal function.

Our study followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [13] during all stages, including design, execution and reporting, when feasible. The present study was registered in the PROPERO database (CRD42015023791).

A flow diagram of the search for relevant trials is presented in Fig. 1. In total, 1240 studies were initially identified (Pubmed = 568, Web of Science = 640, CENTRAL = 32). After removal of duplicate articles (n = 415) and irrelevant articles (n = 788), 37 articles were selected for full-text review. A further 19 articles were excluded following detailed review, of which 3 were review articles, which we reviewed to find potential relevant articles [10, 12, 18]. The remaining 16 were excluded for the following reasons: 1 focused on central apnea [19], 6 did not have a clear definition of nephropathy [20‐25], 3 may have contained biased data (e.g., 1 related to creatinine clearance, i.e., over 200 ml/min [26], 2 had fewer than 10 subgroup participants [27, 28]), 3 had missing data [6, 7, 29], and 1 focused only on the OSA population without a control group [30]. Finally, 18 studies [5, 8, 9, 31‐45] that included 7090 patients were incorporated in our meta-analysis.

Our results indicated that OSA is not only significantly associated with poorer renal function in patients with DM, but also in patients without DM. In addition, we consolidated the significance of OSA in poorer renal function by reporting on different study designs, renal outcomes (eGFR or albuminuria/proteinuria) and OSA severities.

A recent meta-analysis by Leong [10] demonstrated that OSA is associated with poorer renal function in the diabetic population. However, the nature of diabetic patients leaves them more prone to suffering from nephropathy [2, 11], and therefore it could be suspected that this association may not apply to populations without DM. However, in our analysis, we not only confirmed that OSA is significantly associated with poorer renal function in diabetic patients, but also found that this relationship may also apply to non-diabetic patients. Thus, healthcare providers should be aware of the symptoms of OSA in clinical practice.

Possible mechanisms of the interaction between OSA and renal function change have been proposed. Turek et al. [12] pointed out that a specific feature of OSA is intermittent hypoxia followed by reoxygenation, stimulating the formation of reactive oxygen species, which promote inflammation and systemic endothelial dysfunction. During the hypoxia period, the rise in sympathetic tone and activation of the renin-angiotensin system cause the systematic and intraglomerular pressure to rise [46]. Therefore, it is plausible that the risk of CKD increases in parallel with an increased hypoxia duration and greater frequency, as confirmed in the meta-analysis examining the relationship of OSA severity with renal outcome. Of note, our results showing that there is an increased risk of CKD even in patients with mild OSA may be of particular importance, as there has been disagreement regarding treatment for patients with mild OSA [47, 48]. Thus, our result may present a different perspective on the clinical management of patients with OSA.

Despite our results suggesting a close relationship between OSA and poorer renal function, and implying that medical therapy that alleviates OSA could slow the development of CKD, clear evidence is still lacking. In a subgroup population with moderate-to-severe OSA, Tahrani et al. [37] demonstrated that participants adherent to continuous positive airway pressure (CPAP) therapy exhibited a slower decline in renal function as compared with CPAP non-adherent patients (−7.7% vs. -10%). In a retrospective study, Puckrin et al. [49] reported that participants who underwent CPAP therapy more often had lesser renal function decline and proteinuria. Despite these reports indicating a promising utility of CPAP for renal function protection in OSA patients, the results are limited by the small number of participants (< 50) [37, 49], a lack of statistical significance [37], and potential confounders in a retrospective study design [49]. In addition, these reports also truthfully reflect the limitations of CPAP in clinical practice, as most patients under OSA management have been found to be non-adherent (>60%) to CPAP [37, 49]. In the context that none of these reports showed any renal benefit of CPAP in mild OSA patients [37], further investigation may be necessary to ascertain the benefits of OSA management in CKD patients.

One of the purposes of this meta-analysis was to resolve discrepancies between some studies concerning the association between OSA and CKD. In a report based on 507 community-dwelling elderly men, Canales et al. showed that the severity of albuminuria increased with increasing severity of OSA, but the eGFR did not decrease with increasing severity of OSA [5]. Likewise, in a study that included 132 patients with untreated hypertension, Tsioufis et al. found that patients with OSA exhibited a higher degree of albuminuria, but there was no difference in renal function as estimated from the eGFR [9]. These reports may confuse the association between OSA and CKD. However, it should be noted again that albuminuria is an early indicator of renal damage, and a longer duration may be needed in order to observe a change in the eGFR. In addition, these results may be hampered by the limitations of the cross-sectional design, in terms of not being able to provide a clear chain of consequence between OSA and CKD. In contrast to these two studies, in a prospective cohort study based on 224 type 2 DM (T2DM) patients, Tahrani et al. [37] not only showed that in patients with OSA, the prevalence of diabetic nephropathy at baseline was significantly higher, but also clearly indicated that T2DM patients with OSA exhibited a greater eGFR decline at the end of the 2.5-year follow-up period. Taking these results together with the results of our meta-analysis, we concluded that OSA is significantly associated with poorer renal function, whether defined by albuminuria/proteinuria or the eGFR.

There were several limitations in our study. First, among the 18 eligible studies, only 2 cohort studies discussed the impact of OSA on renal function change [36, 37]. Of note, only one study was of a prospective design [37], the other being retrospective in nature [36]. Owing to study results potentially being biased by the nature of the study design, our results should be interpreted with caution. Second, it has been reported that there is an approximate 40% variation in the measurement of albuminuria [50], and significant inconsistency exists among various eGFR formulas [51]. Thus, our results may be biased by the renal function measurements obtained in these studies. Third, to maximize the information available, we artificially transformed the renal outcomes reported in some studies into odds ratios, which may have overinflated the results. Also, in most of included studies, unadjusted analyses were performed, and residual confounders remained. Thus, our results should be interpreted carefully. Fourth, our results may also be biased by the different diagnostic tools used to define OSA; they also may not apply to young adults, as most of the included study populations were aged over 50. Despite these limitations, our study is of merit in terms of showing a consistent and clear association between OSA and CKD from different perspectives. In addition, compared with other articles [10], our results were based on more sophisticated evidence in terms of not including potentially biased reports (e.g., including meeting abstracts [52, 53], studies with an unclear renal outcome definition, etc. [21]). Based on the above discussion, our results may provide additional information relevant to clinical practice.

In conclusion, our results indicated that OSA was significantly related to poorer renal function, suggesting that diagnosis of OSA should not be overlooked in clinical practice. Larger prospective studies may be necessary in order to compare renal outcomes with/without medical intervention to provide more persuasive data regarding the causality between OSA and renal function, particularly in patients with mild OSA.