Plasma neutrophil gelatinase-associated lipocalin and kidney graft outcome

Abstract

Background: Plasma neutrophil gelatinase-associated lipocalin (pNGAL) has been investigated extensively in acute kidney injury. This study investigated its pathophysiological significance and utility as marker for graft failure and mortality in stable kidney transplant recipients (KTR).

Methods: Baseline pNGAL was measured in 698 KTR (58% male, age 53 ± 13 years, estimated glomerular filtration rate 52.4 ± 20.4 mL/min/1.73 m²) at median 5.4 (interquartile range 1.8-12.0) years after transplantation, enrolled in the prospective TransplantLines Food and Nutrition Biobank and Cohort Study.

Results: pNGAL concentrations were higher in males, younger patients, patients with a deceased-donor kidney and higher serum creatinine. Independent of these, pNGAL was positively associated with urinary protein excretion, systemic inflammation parameters and calcineurin inhibitor use. During median follow-up of 5.3 (4.5-6.0) years, death-censored graft failure rates were 3.9%, 7.3% and 25.0% across increasing tertiles of pNGAL (P_log-rank < 0.001). Cox-regression analyses showed no independent associations of pNGAL with mortality, but strong associations with graft failure (hazard ratio, per doubling 4.16; 95% confidence interval 3.03-5.71; P < 0.001), which remained independent of adjustment for confounders. These associations were present only in patients with pre-existent proteinuria and poor kidney function.

Conclusions: pNGAL is associated with parameters of kidney graft damage and with graft failure. The latter association is particularly present in KTR with pre-existent poor kidney function and proteinuria. Trial Registration: ClinicalTrials.gov NCT02811835.

Keywords: graft failure; inflammation; kidney transplant; mortality.

FIGURE 1:

Kaplan–Meier analyses for (A) death-censored graft survival and (B) patient survival across tertiles of pNGAL. P-values represent significance of differences between the groups, as assessed using log-rank tests.

FIGURE 2:

Graphical representation of the association between pNGAL and risk of death-censored graft failure, based on a multivariable Cox proportional hazards regression analyses. The model was adjusted for the full model of age, sex, time after transplantation, eGFR, log₂ 24-h urinary protein excretion, anti-HLA class II antibodies, pre-emptive transplantation, history of rejection, history of cardiovascular disease, log₂ leukocyte count and log₂ hs-CRP, and presented in relation to the histogram of pNGAL. The blue line represents the hazard ratio and the shaded blue area about the line the associated pointwise 95% CI.

FIGURE 3:

Forest plot for the association of pNGAL with death-censored graft failure in subgroups. The model was adjusted for the full model of age, sex, time after transplantation, eGFR, log₂ 24-h urinary protein excretion, anti-HLA class II antibodies, pre-emptive transplantation, history of rejection, history of cardiovascular disease, log₂ leukocyte count and log₂ hs-CRP.