Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease

Abstract

Background and objectives: Chronic kidney disease (CKD) has recently assumed epidemic proportion, becoming a troubling emerging cause of morbidity, especially if it progresses to terminal stage (ESRD). The authors aimed to evaluate whether neutrophil gelatinase-associated lipocalin (NGAL), a novel specific biomarker of acute kidney injury, could predict the progression of CKD.

Design, setting, participants, & measurements: Serum and urinary NGAL levels, together with a series of putative progression factors, were evaluated in a cohort of 96 patients (mean age: 57 +/- 16 years) affected by nonterminal CKD (eGFR > or =15 ml/min/1.73 m(2)) of various etiology. Progression of CKD, assessed as doubling of baseline serum creatinine and/or onset of ESRD, was evaluated during follow-up.

Results: At baseline, both serum and urinary NGAL were inversely, independently, and closely related to eGFR. After a median follow-up of 18.5 mo (range 1.01 to 20), 31 patients (32%) reached the composite endpoint. At baseline, these patients were significantly older and showed increased serum creatinine, calcium-phosphate product, C-reactive protein, fibrinogen, daily proteinuria, and NGAL levels, whereas eGFR values were significantly lower. Univariate followed by multivariate Cox proportional hazard regression analysis showed that urinary NGAL and sNGAL predicted CKD progression independently of other potential confounders, including eGFR and age.

Conclusion: In patients with CKD, NGAL closely reflects the entity of renal impairment and represents a strong and independent risk marker for progression of CKD.

Figure 1.

Univariate baseline statistical correlations (Pearson coefficient) of estimated GFR (MDRD formula). Significant correlations was evidenced with serum neutrophil gelatinase-associated lipocalin sNGAL (A), urinary NGAL (uNGAL) (B), systolic blood pressure (C), hemoglobin (D), fibrinogen (E), and calcium-phosphate product (F). sNGAL and uNGAL were found to be the best eGFR correlates among all these variables.

Figure 2.

Linear decline of 1/creatinine (mg/dl) in patients who have experienced a progression in CKD during the follow-up period.

Figure 3.

Receiver operating characteristics curves of eGFR, serum neutrophil gelatinase-associated lipocalin (sNGAL), and urinary NGAL (uNGAL) considering progression of CKD as status variable. The area under the curve for eGFR, sNGAL, and uNGAL was 0.64 (95% CI, 0.53 to 0.73), 0.70 (95% CI, 0.60 to 0.79), and 0.78 (95% CI, 0.68 to 0.85) respectively. Both sNGAL and uNGAL areas were significantly different than that of eGFR (P = 0.03). On the contrary, the difference between the two NGAL areas was nonsignificant (P = 0.25). Black squares represent the best cut-off values to predict the progression of CKD. For sNGAL this value was found to be 435 ng/ml, with a sensitivity of 83.9 (95% CI, 66.3 to 94.5) and a specificity of 53.8 (95% CI, 41.0 to 66.3), whereas for uNGAL it was 231 ng/ml with a sensitivity of 80.6 (95% CI, 62.5 to 92.5) and a specificity of 73.8 (95% CI, 61.5 to 84.0).

Figure 4.

Kaplan-Meier survival curves of renal end-point in patients with serum neutrophil gelatinase-associated lipocalin (sNGAL) levels above and below the optimal receiver operating characteristics cut-off level of 435 ng/ml. Patients with sNGAL >435 ng/ml showed a significantly faster progression to endpoint (P = 0.002, log-rank test), with a hazard ratio of 3.37 (95% CI, 1.86 to 7.62). The number of nonprogressor subjects still in the study at specific time points is reported.

Figure 5.

Kaplan-Meier survival curves of renal end-point in patients with urinary neutrophil gelatinase-associated lipocalin (uNGAL) levels above and below the optimal ROC cut-off level of 231 ng/ml. Patients with uNGAL >231 ng/ml showed a significantly faster progression to endpoint (P < 0.0001, log-rank test), with a hazard ratio of 7.45 (95% CI, 3.58 to 15.53). The number of nonprogressor subjects still in the study at specific time points is reported.