Clinical Impacts of Urinary Neutrophil Gelatinase-Associated Lipocalin in Patients With Chronic Kidney Disease Undergoing Percutaneous Coronary Intervention

Yuta Ozaki; Yusuke Uemura; Akihito Tanaka; Shogo Yamaguchi; Takashi Okajima; Takayuki Mitsuda; Shinji Ishikawa; Kenji Takemoto; Toyoaki Murohara; Masato Watarai

doi:10.1253/circj.CJ-24-0060

Abstract

Background: Chronic kidney disease (CKD) is associated with poor prognosis in patients undergoing percutaneous coronary intervention (PCI). Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for renal injury. However, the association between urinary NGAL concentrations and renal and cardiovascular events in patients with CKD undergoing PCI has not been elucidated. This study investigated the clinical impact of urinary NGAL concentrations on renal and cardiovascular outcomes in patients with non-dialysis CKD undergoing PCI.

Methods and Results: We enrolled 124 patients with non-dialysis CKD (estimated glomerular filtration rate <60 mL/min/1.73 m²) undergoing elective PCI. Patients were divided into low and high NGAL groups based on the median urinary NGAL concentration measured the day before PCI. Patients were monitored for renal and cardiovascular events during the 2-year follow-up period. Kaplan-Meier analyses showed that the incidence of renal and cardiovascular events was higher in the high than low NGAL group (log-rank P<0.001 and P=0.032, respectively). Multivariate Cox proportional hazards analyses revealed that urinary NGAL was an independent risk factor for renal (hazard ratio [HR] 4.790; 95% confidence interval [CI] 1.537–14.924; P=0.007) and cardiovascular (HR 2.938; 95% CI 1.034–8.347; P=0.043) events.

Conclusions: Urinary NGAL could be a novel and informative biomarker for predicting subsequent renal and cardiovascular events in patients with CKD undergoing elective PCI.

Contemporary percutaneous coronary intervention (PCI), including new-generation drug-eluting stents, intracoronary imaging guidance, and subsequent optimal medical therapy, have improved long-term outcomes in patients with coronary artery disease.¹^–³ However, the presence and severity of chronic kidney disease (CKD) are strong predictors of poor renal and cardiovascular outcomes.⁴^,⁵ The number of patients with CKD is globally increasing due to the growing number of patients with advanced age, hypertension, and diabetes.⁶ Therefore, the discovery of a useful predictor for patients with CKD who are at a high risk of adverse events would be clinically valuable. Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein released from renal tubular cells in response to various damaging stimuli.⁷ Due to its rapid release after injury, urinary NGAL is considered a biomarker of acute kidney injury.⁸ However, elevated NGAL concentrations before damage have been reported to reflect a higher burden of renal tubular injury, leading to a rapid decline in renal function.⁹^,¹⁰ Recent studies have demonstrated the expression of NGAL in cardiomyocytes and atherosclerotic plaques, and its putative role in the pathology of cardiovascular disease has been highlighted.¹¹^,¹² However, whether urinary NGAL concentrations predict CKD progression and cardiovascular events in patients with stable coronary artery disease undergoing PCI has not been elucidated. Japanese public health insurance allows the measurement of urinary NGAL once at the time of diagnosis and thereafter 3 times through treatment for acute kidney injury. The aim of this study was to examine the clinical impact of urinary NGAL concentrations on renal and cardiovascular outcomes in patients with non-dialysis CKD undergoing elective PCI.

Methods

This was a single-center retrospective cohort study. We reviewed 354 consecutive patients with CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m²) undergoing PCI at Anjo Kosei Hospital between October 2017 and September 2019. The exclusion criteria were age <18 years, undergoing dialysis, PCI for acute coronary syndrome, and lack of urinary NGAL data.

Because of the study’s retrospective nature, the requirement for written informed consent to participate was replaced with an opt-out method. This study was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the local institutional ethics committee (Approval no. R23-070).

Medical records were reviewed to document medical history, medications, and comorbidities. Diabetes was determined based on either a physician’s diagnosis, treatment with antidiabetic medications, or fasting blood glucose ≥126 mg/dL, random blood glucose ≥200 mg/dL, or HbA1c ≥6.5%. Hypertension was defined as the regular use of antihypertensive medications to control blood pressure or a blood pressure reading of ≥140/90 mmHg on at least 2 consecutive measurements. A history of heart failure was defined as previous hospitalization for heart failure diagnosed using the Framingham criteria.¹³

Urinary NGAL was measured the day before and 4 h after the procedure using chemiluminescent immunoassay technology on an ARCHITECT analyzer (Abbott Laboratories, Abbott Park, IL, USA). Spontaneously voided urine samples were collected and immediately processed. As described previously,¹⁴ urinary NGAL values were normalized by urinary creatinine (μg/gCr) to adjust for the potential effects of differences in urinary concentration and hydration status in single-spot urine samples. The upper reference limit of urinary NGAL in this measurement system is 21.7 μg/gCr. Other biochemical markers were measured using a LABOSPECT 008 autoanalyzer (Hitachi Co., Tokyo, Japan). eGFR was calculated using the Japanese equation for serum creatinine level, age, and sex.¹⁵

All patients received intravenous 0.9% saline hydration (1.0 mL/min at least 8 h before the procedure until 12 h after the operation). PCI was performed using standard interventional techniques.² All procedures, including the approach site, the use of stents and other interventional devices, and subsequent therapeutic management, were left to the discretion of each operator. Monomeric, non-ionic, and low osmolality iomeprol (Iomeron 350; Bracco, Tokyo, Japan) was used as the contrast medium.

Patients were followed up for 2 years. All patients underwent regular follow-up (typically every 3 months) during outpatient clinical visits. The primary endpoint was the incidence of renal events, determined as a composite of a reduction 30% in eGFR, end-stage renal disease (defined as the need for dialysis or kidney transplantation), and renal death.¹⁶ Another endpoint was the incidence of major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, unplanned revascularization for de novo lesions, and non-fatal cerebral infarction.

We also examined the incidence of contrast-induced acute kidney injury, defined as a 25.0% increase in baseline creatinine or an absolute increase of 0.5 mg/dL within 48 h after the procedure, according to the Kidney Disease Improving Global Outcomes classification.¹⁷ Post-procedure serum creatinine concentrations were typically evaluated in the morning after PCI.

Data are expressed as percentages for categorical variables and as the mean±SD or median with interquartile range (IQR) for normally and non-normally distributed continuous variables, respectively. The χ² test was used to compare categorical variables between groups. Unpaired Student’s t-test was used to compare continuous variables with a normal distribution, and the Mann-Whitney U test was used to compare non-normally distributed continuous variables. Correlations between baseline urinary NGAL concentrations and eGFR or the urinary albumin-to-creatinine ratio (UACR) were analyzed using Spearman’s rank test. The event-free rate was determined using Kaplan-Meier analysis with the log-rank test. A Cox proportional hazards model was used to determine independent predictors of the time-to-event incidence of clinical events and hazard ratios (HRs) with 95% confidence intervals (CIs). We used 3 models in the multivariate analyses of renal and cardiovascular events:

• Model 1, adjusted for diabetes, eGFR, UACR, and urinary NGAL

• Model 2, adjusted for all variables in Model 1 plus age and sex

• Model 3, adjusted for all variables in Model 2 plus: (1) for renal events, a history of heart failure, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, the use of mineralocorticoid receptor antagonists, and the use of sodium-glucose cotransporter 2 inhibitors; or (2), for cardiovascular events, hypertension, a history of myocardial infarction, and the use of statins.

The risk factors established in previous reports were selected as covariates.¹⁸^–²⁰ For the Cox proportional analysis, urinary NGAL and UACR values were log₁₀ transformed to improve the normality of data distribution. Correlations between changes in urinary NGAL concentrations and percentage changes in serum creatinine concentrations after PCI were analyzed using a linear regression model with Spearman’s correlation test.

Statistical significance was set at P<0.05 in two-tailed tests in all analyses. All statistical analyses were conducted using IBM SPSS version 28.0.

Results

Of the 354 eligible patients, 68 patients undergoing hemodialysis, 114 patients who underwent PCI for acute coronary syndrome, and 48 patients without urinary NGAL data were excluded. Thus, 124 patients with a diagnosis of stable coronary artery disease who underwent elective PCI were included in the present study (Figure 1).

Figure 1.

Flowchart of the study population. Patients included in the study were divided into low and high neutrophil gelatinase-associated lipocalin (NGAL) groups based on the median urinary NGAL concentration measured the day before percutaneous coronary intervention (PCI). CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate.

Figure 2 shows the distribution of urinary NGAL concentrations at baseline and 4 h after the procedure. Patients were divided into 2 groups according to whether urinary NGAL concentrations at baseline were above (high NGAL) or below (low NGAL) the median concentration for the entire cohort (18.7 μg/gCr). Patients’ baseline characteristics are presented in Table 1. The high NGAL group had a higher prevalence of diabetes, lower eGFR, and higher UACR values than the low NGAL group. Urinary NGAL concentrations at baseline were negatively correlated with eGFR (ρ=−0.265; P=0.003) and positively correlated with UACR (ρ=0.480; P<0.001). Among the medications administered on admission, mineralocorticoid receptor antagonists were used more frequently in the high NGAL group. The volume of contrast medium per eGFR was comparable between the 2 groups (Table 1).

Figure 2.

Distribution of urinary neutrophil gelatinase-associated lipocalin (NGAL) normalized by creatinine (Cre) at baseline and after percutaneous coronary intervention (PCI). IQR, interquartile range.

Table 1.

Baseline Characteristics of All Patients and Those in the Low and High Neutrophil Gelatinase-Associated Lipocalin Groups

	All patients (n=124)	Low NGAL (n=62)	High NGAL (n=62)	P value
Age (years)	75.0 [69.8–80.0]	75.0 [71.0–80.0]	75.5 [67.3–80.0]	0.598
Male sex	93 (75.0)	51 (82.2)	42 (67.7)	0.062
Body mass index (kg/m²)	23.7 [21.5–26.8]	24.9 [22.8–27.1]	22.8 [21.1–25.9]	0.005
Diabetes	72 (58.1)	27 (43.5)	45 (72.6)	0.001
Hypertension	110 (88.7)	54 (87.1)	56 (90.3)	0.570
History of heart failure	35 (28.2)	13 (21.0)	22 (35.5)	0.107
History of MI	39 (31.5)	18 (29.0)	21 (33.9)	0.697
Albumin (g/dL)	3.9±0.4	4.0±0.8	3.7±0.8	<0.001
Hemoglobin (g/dL)	12.8±1.8	13.2±1.9	12.3±1.6	0.007
Creatinine (mg/dL)	1.16 [1.03–1.45]	1.13 [1.03–1.33]	1.21 [1.03–1.58]	0.147
eGFR (mL/min/1.73 m²)	46.4 [35.2–52.9]	48.2 [39.8–54.5]	40.9 [31.9–50.3]	0.013
eGFR <30 mL/min/1.73 m²	17 (13.7)	5 (8.1)	12 (19.4)	0.207
eGFR ≥30 to 45 mL/min/1.73 m²	40 (32.3)	19 (30.6)	21 (33.9)
eGFR ≥45 mL/min/1.73 m²	67 (54.0)	38 (61.3)	29 (46.8)
UACR (mg/gCr)	32.1 [9.7–216.8]	11.6 [7.3–52.7]	160.9 [22.4–708.2]	<0.001
Urinary NGAL (μg/gCr)
At baseline	18.7 [10.1–45.5]	10.0 [6.8–13.6]	47.6 [28.1–184.5]	<0.001
4 h after PCI	15.9 [10.7–54.6]	11.4 [8.4–14.7]	46.3 [20.8–144.8]	<0.001
Baseline medications
ACEi/ARBs	71 (57.3)	34 (54.8)	37 (59.7)	0.586
Any diuretic agents	61 (49.2)	30 (48.4)	31 (50.0)	0.857
MRAs	25 (20.2)	8 (12.9)	17 (27.4)	0.044
Statins	108 (87.1)	54 (87.1)	54 (87.1)	1.000
SGLT2 inhibitors	20 (16.1)	6 (9.7)	14 (22.6)	0.051
Multivessel disease	69 (55.6)	38 (61.3)	31 (50.0)	0.206
Contrast medium (mL)	50 (35–55)	50 (35–55)	43 (31–50)	0.196
Contrast volume/eGFR ratio	1.05 [0.87–1.42]	1.04 [0.76–1.30]	1.04 [0.86–1.44]	0.539
IVUS use	124 (100.0)	62 (100.0)	62 (100.0)	NA
Mechanical support	0 (0.0)	0 (0.0)	0 (0.0)	NA

Unless indicated otherwise, data are presented as median [interquartile range] or n (%). ACEi, angiotensin-converting enzyme inhibitor; ARBs, angiotensin receptor blockers; Cr, creatinine; eGFR, estimated glomerular filtration rate; IVUS, intravascular ultrasound; MI, myocardial infarction; MRAs, mineralocorticoid receptor antagonist; NA, not applicable; NGAL, neutrophil gelatinase-associated lipocalin; SGLT2, sodium-glucose cotransporter 2; UACR, urinary albumin to creatinine ratio.

The median duration of follow-up was 2.0 years (IQR 1.0–2.0 years). Forty patients were lost to follow-up. Details of the clinical events are presented in Table 2. Renal events occurred in 15 (24.2%) patients in the high NGAL group and in 1 (1.6%) patient in the low NGAL group (Table 2). Kaplan-Meier analysis revealed that the incidence of renal events was higher in the high than low NGAL group (log-rank P<0.001; Figure 3A). Univariate and multivariate Cox proportional hazard analyses were performed to identify independent risk factors for the cumulative incidence of renal events in patients with CKD undergoing PCI. In multivariate Cox regression models, urinary NGAL at baseline was an independent predictor of renal events, even after adjusting for eGFR and UACR (HR 4.790; 95% CI 1.537–14.924; P=0.007; Table 3).

Table 2.

Details of Clinical Events in the Low and High Neutrophil Gelatinase-Associated Lipocalin Groups

	Low NGAL (n=62)	High NGAL (n=62)
Renal events	1 (1.6)	15 (24.2)
eGFR reduction by 30%	1 (1.6)	13 (21.0)
End-stage renal disease	0 (0.0)	4 (6.5)
Renal death	0 (0.0)	0 (0.0)
MACCEs	3 (4.8)	11 (17.7)
Cardiovascular death	1 (1.6)	4 (6.5)
Non-fatal myocardial infarction	1 (1.6)	1 (1.6)
Unplanned revascularization for de novo lesion	2 (3.2)	7 (11.3)
Non-fatal cerebral infarction	0 (0.0)	0 (0.0)

Data are presented as n (%). MACCEs, major adverse cardiac and cerebrovascular events. Other abbreviations as in Table 1.

Figure 3.

Kaplan-Meier event-free rates for (A) renal events and (B) major cardiac and cerebrovascular events (MACCE) over 2 years. NGAL, neutrophil gelatinase-associated lipocalin.

Table 3.

Predictors of Renal Events Based on Cox Regression Analyses

Variables	Univariable analysis		Multivariate analysis
	Univariable analysis		Model 1		Model 2		Model 3
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Diabetes	1.110 (0.345–2.519)	0.901	0.586 (0.203–1.698)	0.325	0.505 (0.164–1.555)	0.234	0.280 (0.072–1.090)	0.066
eGFR	0.932 (0.896–0.970)	0.001	0.952 (0.910–0.997)	0.036	0.953 (0.911–0.998)	0.041	0.966 (0.915–1.020)	0.211
Log₁₀ UACR	2.608 (1.469–4.630)	0.001	1.270 (0.595–2.712)	0.537	1.417 (0.655–3.065)	0.376	2.117 (0.766–5.854)	0.148
log₁₀ urinary NGAL	4.401 (2.194–8.830)	<0.001	3.721 (1.562–8.866)	0.003	3.635 (1.480–8.931)	0.005	4.790 (1.537–14.924)	0.007

Model 1 was adjusted for diabetes, estimated glomerular filtration rate (eGFR), log-transformed urinary albumin-to-creatinine ratio (UACR), and log-transformed urinary neutrophil gelatinase-associated lipocalin (NGAL). Model 2 was adjusted for all variables in Model 1 plus age and sex. Model 3 was adjusted for all variables in Model 2 plus a history of heart failure and the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoid receptor antagonist, and use of sodium-glucose cotransporter 2 inhibitors. CI, confidence interval; HR, hazard ratio.

MACCE occurred in 11 (17.7%) patients in the high NGAL group and in 3 (4.8%) patients in the low NGAL group (Table 2). Kaplan-Meier analysis showed that the incidence of MACCE was higher in the high than low NGAL group (log-rank P=0.032; (Figure 3B). In the Cox regression analysis, urinary NGAL was an independent predictor of MACCE (HR 2.938; 95% CI 1.034–8.347; P=0.043; Table 4).

Table 4.

Predictors of Major Cardiac and Cerebrovascular Events Based on Cox Regression Analyses

Variables	Univariable analysis		Multivariate analysis
	Univariable analysis		Model 1		Model 2		Model 3
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
Diabetes	0.933 (0.323–2.688)	0.897	0.890 (0.286–2.770)	0.840	0.840 (0.267–2.646)	0.766	0.943 (0.280–3.165)	0.924
eGFR	0.957 (0.918–0.998)	0.038	0.953 (0.911–0.998)	0.041	0.957 (0.914–1.003)	0.067	0.949 (0.903–0.998)	0.043
Log₁₀ UACR	1.186 (0.662–2.123)	0.567	0.619 (0.286–1.342)	0.225	0.623 (0.281–1.379)	0.243	0.722 (0.303–1.721)	0.463
log₁₀ urinary NGAL	2.305 (1.073–4.951)	0.032	2.760 (1.080–7.052)	0.034	2.672 (1.007–7.085)	0.048	2.938 (1.034–8.347)	0.043

Model 1 was adjusted for diabetes, eGFR, log-transformed UACR, and log-transformed urinary NGAL. Model 2 was adjusted for all variables in Model 1 plus age and sex. Model 3 was adjusted for all variables in Model 2 plus a history of hypertension, a history of myocardial infarction, and statin use. Abbreviations as in Table 3.

Despite an increase in urinary NGAL concentrations 4 h after PCI in 51.2% of patients, there was no significant change in median NGAL concentrations across the total cohort (P=0.901). Changes in urinary NGAL concentrations were not associated with renal or cardiovascular events in univariate Cox regression analyses (HR 0.229 [95% CI 0.045–1.174; P=0.077] and HR 0.928 [95% CI 0.149–5.788; P=0.936], respectively).

No patient in either group developed contrast-induced acute kidney injury. Regression analysis also demonstrated that changes in urinary NGAL concentrations were not correlated with percentage changes in serum creatinine concentrations within 48 h after the procedure (ρ=−0.086, P=0.342).

Discussion

The present study is the first to demonstrate that the urinary NGAL concentration at baseline is an independent predictor of renal and cardiovascular events in patients with CKD undergoing elective PCI. We also revealed that changes in urinary NGAL concentrations after PCI were not significant and did not predict renal and cardiovascular outcomes in this cohort.

The subsequent progression of renal decline in patients with CKD undergoing PCI is an important clinical issue. Urinary albumin concentrations and eGFR at baseline are well-known predictors of renal function deterioration.¹⁸ However, these predictive abilities are sometimes insufficient in daily practice.²¹^,²² Recently, urinary NGAL has been highlighted for its potential role in the pathogenesis of CKD progression and as a biomarker for the early detection of acute kidney injury.⁸^,²³^,²⁴ Urinary albumin and eGFR represent the severity of glomerular lesions and the loss of functional nephrons, and elevated urinary NGAL concentrations reflect persistent tubular injury. Tubulointerstitial damage is a powerful predictor of CKD progression regardless of the primary cause.²⁵^,²⁶ Our data validate the predictive value of urinary NGAL concentrations for renal outcomes in patients with CKD and stable coronary artery disease undergoing elective PCI.

This study also indicates that urinary NGAL concentrations are associated with the incidence of MACCE in patients with CKD undergoing elective PCI. Although NGAL is highly expressed in tubular cells in response to renal injury, its increased expression has been observed in atherosclerotic plaques.²⁷ NGAL enhances the action of matrix metalloproteinase-9 and causes degradation of the extracellular matrix, leading to plaque instability.²⁸ Urinary NGAL predicts cardiovascular events in patients with CKD and peripheral artery disease.²⁹^,³⁰ In patients with coronary artery disease, plasma or serum NGAL concentrations are associated with severity, plaque vulnerability, and a higher incidence of cardiovascular events.³¹ We demonstrated that urinary NGAL concentrations could also stratify cardiovascular risk in patients with CKD and coronary artery disease.

Other biomarkers have also been reported to predict prognosis in patients with CKD.³²^–³⁴ Plasma B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) concentrations are associated with renal and cardiovascular prognosis in patients with CKD.³²^,³³ Because BNP and NT-proBNP are secreted by cardiomyocytes in response to increased transmural tension and neurohormonal stimulation, a cardiac involvement in terms of cardiorenal syndrome is suggested as the mechanism.³² Liver-type fatty-acid binding protein (L-FABP) is a soluble protein expressed in proximal tubular cells and its expression is upregulated by various stresses, such as urinary protein overload and tubular ischemia.³⁵ Urinary L-FABP correlates with the degree of tubulointerstitial damage and is associated with renal prognosis in patients with CKD.³⁴^,³⁶ The correlations and mutual influences of these biomarkers with urinary NGAL in patients with CKD undergoing PCI remain unknown and require further investigation.

In the present study, urinary NGAL concentrations did not increase significantly after PCI. Similarly, none of the patients developed contrast-induced acute kidney injury. This could be due to intravascular ultrasound-guided PCI, perioperative fluid replacement in all cases, and a low contrast volume.³⁷^,³⁸ These results suggest that measuring urinary NGAL concentrations after PCI may be less meaningful in contemporary PCI. However, our data indicate that urinary NGAL could provide valuable prognostic information, even in contemporary PCI, with a low frequency of acute renal injury.

Whether the elevated urinary NGAL concentration is a therapeutic target remains unclear. Sodium-glucose cotransporter 2 inhibitors and non-steroidal mineralocorticoid receptor antagonists exert protective effects on the kidneys and cardiovascular systems by modulating proinflammatory, metabolic, and osteogenic factors in animals.³⁹^,⁴⁰ Clinical trials of these agents or studies focusing on patients with CKD and high urinary NGAL concentrations are needed in the future.

The present study has several limitations. First, this was a single-center retrospective study with a small sample size. Second, despite performing multivariate analysis on several models, there may still be unadjusted confounding factors that could affect the association between urinary NGAL concentrations and clinical events. Third, patients’ baseline characteristics were observed only before PCI, and longitudinal data were not systematically collected during follow-up.

In conclusion, baseline urinary NGAL concentrations are associated with renal and cardiovascular events in patients with CKD without dialysis undergoing elective PCI. Measuring urinary NGAL concentrations could provide useful information for managing patients with CKD in the era of contemporary PCI. The significance of intervention for patients with elevated urinary NGAL concentrations needs to be clarified by future studies.

Acknowledgments

The authors are grateful to the medical staff of Anjo Kosei Hospital for their help collecting urine and blood samples.

Sources of Funding

This study did not receive any specific funding.

Disclosures

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. T. Murohara is a member of the Circulation Journal Team.

IRB Information

This study was approved by the Anjo Kosei Hospital Ethics Committee (Approval no. R23-070).

Data Availability

The deidentified participant data will not be shared.

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