Neutrophil Gelatinase-associated Lipocalin as a Cardiovascular Biomarker
Type 4 CRS defines the impact CKD has on the heart-kidney interaction, best highlighted by those patients with CKD (stages 1–5) and acute coronary syndromes (ACS) or congestive cardiac failure. Across the spectrum of prospective and retrospective studies of both CKD and ESRD, the incidence of ischaemic heart disease is high, while also associating a poor prognosis for those with CKD who have acute ischaemic events. The reasons for this are multifactorial, relating not only to dysregulated vascular calcification, endothelial dysfunction, and circulating inflammatory mediators, but also to more conservative therapeutic strategies compared to those with no evidence of CKD or AKI. In a prospective series of 4,758 patients with diabetes mellitus and ACS, outcomes were assessed and compared with the subgroup of patients with CKD (34.8 %). Striking differences were apparent between the groups, with only 15.7–35.7 % of the CKD group receiving beta-adrenergic antagonists, and 21.1–27.7 % receiving angiotensin- converting inhibitors. For those with severe CKD, 82 % of patients were treated with medical therapy alone, with 14 % undergoing PCI, and only 3.9 % proceeding to surgical revascularisation. Within the CKD group, those who received PCI had significantly better survival rates (59.0 versus 44.3 months, p<0.0001).29
Simultaneous cardiorenal dysfunction due to systemic illness, such as sepsis or diabetes, comprises type 5 CRS. In the Sepsis occurrence in acutely ill patients (SOAP) study by Vincent et al., examining critically ill patients in European intensive care units, positive fluid balance in patients with sepsis was one of the main predictors of mortality.30 In patients with severe sepsis, cardiovascular organ failure occurred in 62.6 % of patients, with 42.3 % mortality. The role of specific biomarkers in this setting is less well defined, with cardiac troponins and BNP showing some association with adverse outcomes in acute ‘secondary’ cardiorenal syndrome.
Neutrophil Gelatinase-associated Lipocalin as a Biomarker for Progression of Chronic Kidney Disease
The role of NGAL as a risk marker for progression of CKD has been demonstrated in several recent studies, showing inverse and independent relationships to eGFR, as well as showing an association with adverse outcomes. Furthermore, this relationship exists regardless of the primary cause of CKD, underscoring the increasingly appreciated important role that injured renal tubules play in the final common pathway of progression towards ESRD. In 96 patients with CKD of mixed aetiology (such as diabetic nephropathy, biopsy-confirmed glomerulonephritis, and autosomal polycystic kidney disease), significant inverse correlations were seen with both sNGAL and uNGAL, when compared to eGFR (uNGAL R= –0.41, p<0.0001, sNGAL R= –0.44, p<0.0001), as seen in Figure 1.15
In direct comparison for predicting
progression of CKD, uNGAL was superior to eGFR (AUC 0.78 versus 0.64). Using multivariate analysis, both sNGAL and uNGAL also predicted increased risk of CKD progression, independent of both eGFR and advancing age.31
Ding et al.33
Figure 2: Correlation Between Neutrophil Gelatinase-associated Lipocalin Levels and N-terminal-pro Brain Natriuretic Brain Peptide in Patients with Chronic Systolic Heart Failure
10,000
Controls CHF
1000 100 10 1 0,1 10 100 1000 NT-proBNP (pg/mL)
CHF = chronic heart failure; NT-proBNP = N-terminal-pro brain natriuretic brain peptide; NGAL = neutrophil gelatinase-associated lipocalin. © American Society of Nephrology. Figure reproduced with permission.
Figure 3: Serum Levels of Neutrophil Gelatinase-associated Lipocalin in Healthy Controls
140 120 100 80 60 40 20 0
Controls * * * * # * * * r = 0.26, P = 0.007 10,000
NYHA II
NYHA III
NYHA IIV
Serum levels of neutrophil gelatinase-associated lipocalin in healthy controls (n = 20) and 150 patients with chronic heart failure in New York Heart Association class II (n = 40), III (n = 71), and IV (n = 39). *p<0.05. ***p<0.001 versus controls. #p<0.05 versus NYHA III or NYHA IV. Data are mean ± SEM.
© Oxford University Press. Figure reproduced with permission.
urinary N-acetyl-glucosaminidase (NAG) were still within normal levels. Thus, there is increasing evidence that NGAL is a potentially useful marker of CKD, reflecting ongoing tubular inflammation and injury.
Neutrophil Gelatinase-associated Lipocalin in Atherosclerosis
In patients with autosomal dominant polycystic kidney disease, sNGAL and uNGAL similarly correlated with severity of CKD.32
examined a cohort of 70 patients with IgA nephropathy (IGAN), showing a clear correlation between uNGAL levels and the degree of tubulointerstitial disease, as demonstrated by histopathologic findings from renal biopsies (tubular atrophy, interstitial fibrosis, and inflammatory cell infiltrates). Importantly, uNGAL was also raised up to three times higher than in the controls, in patients with earlier stages of disease (Lee Grade II IGAN), where more traditional markers such as
INTERVENTIONAL CARDIOLOGY
Beyond the renal tubular epithelium and the neutrophil, NGAL has also been shown to play a role in modulating matrix metalloproteinase-9 (MMP-9), itself associated with both large and small vessel atherosclerosis and plaque stability.34,35
Galis et al.36
showed that MMP-9, a member of the endopeptidase family, plays a key role in proteolytic activity in the plaque, thus contributing to collagen degradation, plaque instability and risk of rupture. Furthermore, high levels of serum MMP-9 are independently associated with adverse cardiovascular outcomes.37
Using a rat
carotid injury model, Bu et al. were able to demonstrate induction of intimal smooth muscle cell NGAL expression by an acute vascular inflammatory regulator (NF-κB) in response to angioplastic injury, as well as providing data to suggest that NGAL is also up-regulated in
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NGAL (µg/mL)
NGAL (µg/gCr
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