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Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine logoLink to Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine
. 2019 Feb 15;15(2):207–213. doi: 10.5664/jcsm.7618

Elevated Serum Markers of Acute Kidney Injury in Patients With Obstructive Sleep Apnea

Li-Pang Chuang 1,2, Shih-Wei Lin 1, Li-Ang Lee 2,3, Chih-Hsiang Chang 4, Hung-yu Huang 1, Han-Chung Hu 1,6, Kuo-Chin Kao 1,6, Meng-Jer Hsieh 5,6, Cheng-Ta Yang 1,2, Hsueh-Yu Li 2,3, Ning-Hung Chen 1,6,✉
PMCID: PMC6374082  PMID: 30736871

Abstract

Study Objectives:

Previous research revealed a positive correlation between endothelial cell injury (indicated by albuminuria) and obstructive sleep apnea (OSA). However, little else has been revealed about acute kidney injury (AKI) in patients with OSA.

Methods:

This prospective study recruited consecutive patients undergoing overnight polysomnography for evaluation of sleep apnea. Patients in whom any major disease or recent infection had been previously diagnosed were excluded. Ultimately, data from 75 patients with apnea-hypopnea indices of 5 or more were analyzed. Baseline values for the urinary albumin-creatinine ratio (UACR), serum levels for three markers of AKI (cystatin C, neutrophil gelatinase-associated lipocalin [NGAL], interleukin-18 [IL-18]), and polysomnography data were recorded and analyzed. Patients then were followed for 6 months of continuous positive airway pressure (CPAP) treatment.

Results:

At baseline, UACRs were greater in patients with more severe OSA (P = .005, r = .329). All three serum markers of AKI (cystatin C, NGAL, and IL-18) studied were positively correlated with OSA severity, and two (cystatin C and IL-18) were positively correlated with the frequency of oxygen desaturation during sleep. However, none of the AKI markers had positive correlations with UACR. After 6 months of CPAP treatment, UACR and IL-18 were decreased significantly in patients with good adherence.

Conclusions:

Albuminuria and levels of three serum markers of AKI (cystatin C, NGAL, IL-18) were positively correlated with OSA severity, and good adherence with CPAP treatment decreased albuminuria and interleukin-18 levels. These results may provide additional tools for assessing early renal injury in patients with OSA.

Citation:

Chuang LP, Lin SW, Lee LA, Chang CH, Huang HY, Hu HC, Kao KC, Hsieh MJ, Yang CT, Li HY, Chen NH. Elevated serum markers of acute kidney injury in patients with obstructive sleep apnea. J Clin Sleep Med. 2019;15(2):207–213.

Keywords: albuminuria, cystatin c, interleukin-18, neutrophil gelatinase-associated lipocalin, obstructive sleep apnea

BRIEF SUMMARY

Current Knowledge/Study Rationale: Previous research demonstrated a positive correlation between albuminuria and the severity of obstructive sleep apnea. However, little else has been revealed about acute kidney injury in patients with obstructive sleep apnea.

Study Impact: We recruited 75 consecutive patients with obstructive sleep apnea and found that baseline levels of albuminuria and serum markers of acute kidney injury (cystatin C, neutrophil gelatinase-associated lipocalin, and interleukin-18), had positive correlations with the severity of obstructive sleep apnea. After 6 months of continuous positive airway pressure treatment, albuminuria and interleukin-18 were decreased significantly in patients with good adherence.

INTRODUCTION

Obstructive sleep apnea (OSA) has a prevalence of 2% to 4% in the general population.1 Recent studies have addressed the cardiovascular consequences of OSA, such as hypertension, ischemic heart disease or stroke, and neurocognitive deficits.2 Endothelial injury due to intermittent hypoxia may play a key role in systemic vascular damage, which leads to cardiovascular and neurocognitive diseases. Albumin-uria, indicated by an elevated urinary albumin-creatinine ratio (UACR), is a sensitive indicator of endothelial injury, and previous research showed that elevated UCAR was associated with increased cardiovascular risk for patients with diabetes mellitus (DM) or hypertension, and for the general population.3–6

Chronic kidney injury, such as end-stage renal disease and proteinuria, are closely associated with OSA.7 Moreover, lowering albuminuria is associated with better health outcomes, and is a target for treatment of patients with chronic kidney disease, with or without hypertension or diabetes.3,4 Our group previously demonstrated an increased UACR in patients with OSA without DM or hypertension,8 and that treatment of OSA by continuous positive airway pressure (CPAP) can reverse proteinuria in patients with OSA.9

Microalbuminuria is a sensitive biomarker of systemic endothelial injury. Recent studies have examined acute kidney injury (AKI) in patients with OSA. For example, a study of renal biopsies of patients with morbid obesity and OSA showed glomerulomegaly and focal segmental sclerosis, presumably from increased glomerular filtration and blood flow.10 Cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) are the most commonly studied biomarkers during ischemic changes of the proximal tubules.11 Changes in levels of these markers provide an earlier sign of AKI than does serum creatinine (SCr) elevation.

Measurements of individual AKI markers in patients with OSA have been reported previously, but to our knowledge there has been no comprehensive study in these patients to evaluate their use to assess AKI.12–17 The current study examines the use of three serum markers of AKI—cystatin C, NGAL, and IL-18—to evaluate the effects of CPAP treatment of patients with OSA.

METHODS

Study Population

The study protocol was approved by the Research and Ethics Committee of the Chang Gung Memorial Hospital (CGMH) in Taiwan (CGMH IRB no.97-0231C, no.98-2149B, and no.99-0940C). Each patient provided informed consent before participating. This study was funded by the National Institute of Science (MOST 104-2314-B-182A-119-MY3 and MOST 106-2314-B-182A-073) and Chang Gung Memorial Hospital (CMRPG3D1011 and CMRPG391231-3).

Adults age 20 years or older who visited our sleep clinics because of snoring and sleepiness between 2008 and 2012 were invited on presentation to enroll in the study. Medical records were reviewed for baseline data. Patients were excluded for a previous diagnosis of OSA, DM (defined as use of a DM medication, fasting glucose of at least 126 mg/dL, or glycated hemoglobin (HbA1C) of at least 6.5% at baseline screening18), abnormal renal function (defined as SCr higher than 1.4 mg/ dL), liver cirrhosis, chronic obstructive pulmonary disease, hematologic disease, autoimmune disease, cancer, heart failure, or recent infection. Patients taking angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), or diuretics were also excluded.

Polysomnography

All patients underwent standard in-laboratory overnight polysomnography (PSG) (Embla N7000, Medcare, Reykjavik, Iceland) performed using conventional methods. The variables recorded were as follows: four channels of the electroencephalogram (C3/A2, C4/A1, O1/A2, O2/A1); bilateral electro-oculogram; chin, left, and right anterior tibial electro-myogram; electrocardiogram; airflow (measured by pressure sensors and thermistors); chest and abdominal wall movement (measured by inductive respiratory plethysmographic bands); snoring (measured by a neck microphone); and arterial oxygen saturation (SpO2) (measured by pulse oximetry). Video recording was used to assess the behavior of all participants while sleeping. All measurements were collected on a computerized sleep system (Somnologica Studio 3.0, Med-care, Reykjavik, Iceland). Apnea was defined as a cessation of airflow for at least 10 seconds. Hypopnea was defined as an abnormal respiratory event with at least 30% reduction of airflow (relative to baseline) for at least 10 seconds, with at least 4% oxygen desaturation and/or arousal. The apnea-hypopnea index (AHI) is the number of events of apnea plus hypopnea per hour of total sleep time. All patients with an AHI of 5 or more were invited to participate further in the study. The oxygen desaturation index (ODI) is the number of times per hour during sleep that the blood oxygen level dropped by 4% or more from baseline.

CPAP Use and Adherence Evaluation

Participating patients with moderate or severe OSA used CPAP during 6 consecutive months of follow-up evaluation. Adherence with CPAP treatment was determined by downloading data directly from the CPAP machine's recorder. The adherence rate was defined as the number of nights during which CPAP was used for at least 4 hours divided by the total number of follow-up days.

Specimen Sampling and Enzyme-Linked Immunosorbent Assay

Morning blood and urine samples were collected from all study participants. Peripheral venous blood (20 mL) was sampled at 6:00 am on the morning after PSG and at the end of the follow-up period, with the patient in the supine position and before eating. Samples were collected in heparin rinse tubes, and centrifuged (3000 rpm × 20 minutes) within 30 minutes of collection. The levels of cystatin C, NGAL, and IL-18 were determined by enzyme-linked immunosorbent assay kits (R&D System, Inc., Minneapolis, Minnesota, United States). Briefly, a microplate was first coated with 100 μL per well of the diluted capture antibody overnight at room temperature. After washing, the microplate was blocked with 300 μL of a reagent diluent for 1 hour. Standards and samples were diluted in the reagent diluent, added to the microplate, and incubated for 2 hours. After washing, 100 μL of detection antibody was added, and incubated for 2 hours. After washing, 100 μL of streptavidin horseradish peroxidase was added, and incubated for 20 minutes. Then, 100 μL of substrate solution was added, and incubated for 20 minutes. The reaction was stopped by adding 50 μL of the stop solution. The concentration of each marker was determined by absorbance at 450 nm, using a microplate reader.

Statistical Analysis

The t test was used to compare mean values of two groups, and one-way analysis of variance to compare differences among more than two groups. Correlations of AKI markers, UACR, and parameters of PSG were determined by linear regression. All values are expressed as mean ± standard error of the mean. All analyses were two-tailed, and a value of P < .05 was considered statistically significant. Statistical analyses were performed using Statistical Package for Social Sciences 20.0 for Windows (SPSS Inc., Chicago, Illinois, United States).

RESULTS

A total of 172 consecutive adult outpatients who received initial diagnoses of OSA and agreed to use CPAP continuously were enrolled in the study. Excluded were 70 individuals due to elevated fasting blood sugar or HbA1C, and 27 individuals were lost to follow-up. Thus, the final study cohort consisted of 75 patients with OSA (Table 1). We divided these patients into four groups according to the severity of OSA, as indicated by the number of respiratory events per hour of sleep (AHI). These four groups had no significant differences in age, fasting glucose, HbA1C, SCr, cholesterol, or triglycerides. However, the four groups had significant differences in body mass index (BMI) and AHI.

Table 1.

Baseline characteristics and polysomnography parameters of enrolled patients.

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Analysis of UACR (an indicator of early endothelial injury) revealed a positive association with baseline AHI (Figure 1). More specifically, UACR was higher in groups with higher AHI scores, and there was positive correlation between AHI score and UACR among all patients (P = .005, r = .329).

Figure 1. Relationship of UACR with AHI at baseline.

Figure 1

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(A) When patients were placed into four groups according to AHI, UACR increased as AHI increased. (B) There was positive correlation between AHI and UACR (P = .005, r = .329). AHI = apnea-hypopnea index, UACR = urinary albumin-creatinine ratio.

Figure 2 shows that there were positive correlations of AHI with plasma cystatin C (P < .001, r = .529), NGAL (P = .038, r = .240), and serum IL-18 (P < .001, r = .702) levels.

Figure 2. Relationship of serum markers of acute kidney injury with AHI at baseline.

Figure 2

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There were positive correlations of AHI with (A) plasma cystatin C, (B) serum NGAL, and (C) IL-18. AHI = apnea-hypopnea index, IL-18 = interleukin-18, NGAL = neutrophil gelatinase-associated lipocalin.

The ODI indicates the frequency of intermittent hypoxia and is an integral characteristic of OSA. Figure 3 shows that there were positive correlations of ODI with levels of cystatin C (P = .001, r = .383) and IL-18 (P < .001, r = .573), but not NGAL (P = .45).

Figure 3. Relationship of serum markers of acute kidney injury with ODI.

Figure 3

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There were positive correlations of the ODI with (A) serum cystatin C and (C) serum IL-18, but not with (B) serum NGAL. IL-18 = interleukin-18, NGAL = neutrophil gelatinase-associated lipocalin, ODI = oxygen desaturation index.

Possible correlations of the three serum markers of AKI with endothelial injury and PSG parameters (Table 2) were assessed. UACR had no significant correlation with any of the AKI markers studied. However, the AHI correlated significantly with cystatin C (P < .001), NGAL (P < .05), and Il-18 (P < .001). In addition, the ODI correlated with cystatin C (P < .05) and IL-18 (P < .001), but not with NGAL levels.

Table 2.

R values from linear regression of serum markers of acute kidney injury with PSG parameters and albuminuria.

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Among the 75 study patients, 55 with moderate to severe OSA were followed during 6 consecutive months of CPAP treatment. A CPAP adherence rate higher than 70% was recorded for 21 patients, who were defined as the “good adherence” group. No significant differences in demographic parameters were found between the poor and good adherence groups (Table 3). However, for the good adherence group, UACR decreased significantly after 6 months of CPAP treatment. Additionally, of the AKI markers studied, IL-18 was found to be decreased significantly in the good CPAP adherence group (Table 3).

Table 3.

Demographic data and change in acute kidney injury markers stratified by CPAP adherence.

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DISCUSSION

It is important to identify individuals with kidney damage before there is detectable change in renal function, so that treatment can begin early. Our previous study of patients with OSA demonstrated that albuminuria is associated with AHI, and that albuminuria can be reversed by CPAP treatment.9 Such treatments are especially important in cases of AKI, which is clinically quiescent and irreversible after progression to a terminal stage.19 Other than the well-known presentation of endothelial injury with microalbuminuria, there is little known about the effect of OSA on AKI. An abrupt change in SCr, the most common indicator of AKI, correlates strongly with poor outcomes in multiple clinical settings.20 SCr is a standard indicator of kidney injury: however, SCr alone cannot meaningfully identify different types of AKI, the time of onset, rate of progression, or recovery. This has hindered the successful implementation of promising therapeutics.21

Recent study reports have proposed the use of several novel plasma and urine biomarkers to characterize the cause and course of AKI. Some of the more promising biomarkers are uri-nary or plasma NGAL, IL-18, and cystatin C.22–24 Recent data suggest that some of these new biomarkers represent important parameters of acute tubular necrosis, and are reliable predictors of the development and prognosis of AKI.25 In addition, monitoring these markers may help with early diagnosis and tracking of disease progression or recovery, not only in patients with various forms of AKI and other renal diseases, but also in patients with cardiorenal syndrome, heart failure, cardio-pulmonary bypass, and cardiothoracic surgical interventions.26

Cystatin C is mainly used as a biomarker of kidney function. The serum level of cystatin C is a more precise indicator of kidney function (as indicated by the glomerular filtration rate) than is SCr.27,28 There is some evidence that cystatin C can be used to predict the risk of the development of chronic kidney disease, in that it signals a state of preclinical kidney dysfunction.29 Cystatin C seems to have a stronger correlation with long-term outcome than does glomerular filtration rate, so cystatin C might also be linked to mortality factors independent of kidney function.30 Among patients with OSA, an increased level of cystatin C indicates clinically latent renal dysfunction,12 and treatment with a CPAP ventilator reduces the serum level of cystatin C in patients with OSA.13

NGAL has a role in innate immunity, in that it sequesters iron and therefore limits bacterial growth.31 NGAL expression occurs in neutrophils, and also at low levels in the kidney, prostate, and epithelia of the respiratory and alimentary tracts.32 Clinicians also use NGAL as a biomarker of kidney injury. In the case of AKI, there are high levels of NGAL in the blood and urine within 2 hours of renal injury.33 NGAL is a more precise and sensitive biomarker of AKI than is SCr. In fact, the increased urinary excretion of NGAL is due to tubular alterations that occur before any kidney damage can be detected by other methods. Therefore, monitoring NGAL levels can shorten delays in the diagnosis and treatment of AKI.34 For patients with OSA, the level of urinary NGAL was reported to be proportional to the severity of OSA and intermittent hypoxia14: however, a more recent paper reported no differences of uri-nary NGAL among patients with OSA.17

IL-18 is a cytokine in the IL-1 superfamily that is produced by macrophages and other cells.35 IL-18 mediates ischemic proximal tubular injury in mice and proinflammatory responses. Following ischemic injury, proximal tubules produce IL-18, which is then activated by caspase 1 and excreted into the urine.36 Urinary IL-18 is a useful biomarker of AKI, with moderate predictive value in all clinical settings.37 Serum IL-18 is an inflammatory marker in patients with OSA,15 and treatment with adenotonsillectomy can reduce serum IL-18 levels in children with OSA.16 The current study demonstrates for the first time a significant decrease in serum IL-18 levels in patients with OSA with good CPAP adherence.

The current study and several previous studies indicate a significant positive correlation between albuminuria and OSA severity.8,38,39 Microalbuminuria, indicated by an elevated UACR, is a sensitive indicator of endothelial injury and a risk factor for cardiovascular disease in patients with diabetes or hypertension, and in the general population.3–6,40 Cardiovascular complications are the major adverse effects of OSA. Because UACR correlates positively with OSA severity and negatively with CPAP adherence, it is not only a marker for cardiovascular risk, but is also a sensitive marker for treatment efficacy. The results presented here also demonstrate no significant correlation between albuminuria and the three tested AKI markers. Albuminuria is a well-known clinical biomarker for glomerular injury, and NGAL is also a marker of tubular injury.41 Thus, these markers might be useful for assessing the onset or extent of glomerular and tubular injury in patients with OSA.

Although OSA is obviously a chronic disorder, nighttime events such as intermittent hypoxia may have acute effects that contribute to this disease. According to the published paper by Tamaki et al., just 1 night of hypoxic stress can activate the invasiveness of monocytes in patients with OSA.42 Additionally, our previously published reports of studies assessing serum MMP-9 expression in patients with OSA revealed the same phenomenon; 1 night of hypoxia events can increase MMP-9 expression after sleep.43 It seems that some aspects of OSA-related injury occur on a nightly basis. However, during the events-free daytime, some injury may recover to a certain extent, depending on the severity of the injury itself and the host reparative ability.44 Thus, studies of patients with OSA using different measurement time points, such as before or after sleep, may yield different results for some injury markers.

There are several limitations of the current study that could potentially bias the results. The sample size was relatively small. However, we still found significant correlations of all three AKI markers with severity of OSA. Another limitation is that we did not specifically exclude patients with hypertension, and this could have biased the results. However, we did exclude patients who took ACEIs, ARBs, or diuretics, drugs that can affect the levels of AKI markers.34 Body weight was one of the confounding factors in the previous studies of albuminuria, but recent research indicated that body weight has no significant association with NGAL levels, so the body weight factor can be ignored in the current study.45 Finally, the relatively small number of patients assessed after CPAP use, especially in the mild (AHI 5 to 15) OSA group, and the lack of a non-CPAP control group, are other limitations of the current study.

In summary, the current study demonstrated that the serum levels of three AKI markers—cystatin C, NGAL, and IL-18— had positive correlations with the severity of OSA, and also confirmed the previously reported correlation of OSA severity with albuminuria. Our findings suggest that, in addition to endothelial injury, as assessed by albuminuria, multiple causes of AKI should be considered as consequences of OSA. Clinical measurement of AKI markers, such as cystatin C, NGAL, and IL-18, may provide improved screening for early renal injury in patients with OSA.

DISCLOSURE STATEMENT

Work for this study was performed at Sleep Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan. All authors have seen and approved the manuscript. This study was funded by Ministry of Science and Technology (MOST 104-2314-B-182A-119-MY3 and MOST 106-2314-B-182A-073) and Chang Gung Memorial Hospital (CMRPG3F0071, CMRPG3G0421 and CORPG3F0861). The funders had no role in performing the study or in preparation of the manuscript. The authors report no conflicts of interest.

ABBREVIATIONS

ACEI

angiotensin-converting enzyme inhibitor

AHI

apnea-hypopnea index

AKI

acute kidney injury

ARB

angiotensin II receptor blocker

BMI

body mass index

CPAP

continuous positive airway pressure

DM

diabetes mellitus

HbA1C

glycated hemoglobin

IL-18

interleukin-18

NAGL

neutrophil gelatinase-associated lipocalin

ODI

oxygen desaturation index

OSA

obstructive sleep apnea

PSG

polysomnography

SCr

serum creatinine

UACR

urinary albumin-creatinine ratio

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