Neutrophil Gelatinase-Associated Lipocalin (NGAL), Neutrophils, and CKD: Which Comes First?

We read with great interest the article by Bhavsar et al,1Bhavsar N.A. Köttgen A. Coresh J. Astor B.C. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) as predictors of incident CKD stage 3: the Atherosclerosis Risk in Communities (ARIC) Study.Am J Kidney Dis. 2012; 60: 865-867Abstract Full Text Full Text PDF Scopus (83) Google Scholar who concluded that higher levels of neutrophil gelatinase-associated lipocalin (NGAL), but not kidney injury molecule 1 (KIM-1), were associated with incident chronic kidney disease (CKD) stage 3 at follow-up. Although both molecules are upregulated substantially in the kidney after ischemic damage and thereby may serve as reliable biomarkers of kidney injury, NGAL also is produced by a kaleidoscope of extrarenal sources, especially neutrophils. It is noteworthy that in the same Atherosclerosis Risk in Communities (ARIC) Study, Tian et al2Tian N. Penman A.D. Manning Jr, R.D. Flessner M.F. Mawson A.R. Association between circulating specific leukocyte types and incident chronic kidney disease: the Atherosclerosis Risk in Communities (ARIC) Study.J Am Soc Hypertens. 2012; 6: 100-108Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar recently observed that increased neutrophil count was associated significantly with a greater incidence of CKD. In particular, a 10% increase in neutrophils was associated with hazard ratio (HR) of 2.0 (95% confidence interval [CI], 1.5-2.7), an association that was greater (HR, 2.2; 95% CI, 1.6-2.9) after adjusting for baseline kidney function, age, sex, and race.2Tian N. Penman A.D. Manning Jr, R.D. Flessner M.F. Mawson A.R. Association between circulating specific leukocyte types and incident chronic kidney disease: the Atherosclerosis Risk in Communities (ARIC) Study.J Am Soc Hypertens. 2012; 6: 100-108Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Because neutrophilia is an independent determinant of NGAL level4Lippi G. Salvagno G.L. Banfi G. Serum but not urine concentration of neutrophil gelatinase-associated lipocalin is influenced by acute leukocyte variations.Leuk Lymphoma. 2012; 53: 1643-1645Crossref PubMed Scopus (18) Google Scholar and the current NGAL immunoassays cannot distinguish between isoforms produced by renal tubular epithelial cells and those released by neutrophils,3Lippi G. Cervellin G. Neutrophil gelatinase-associated lipocalin: a more specific assay is needed for diagnosing renal injury.Clin Chim Acta. 2012; 413: 1160-1161Crossref PubMed Scopus (22) Google Scholar it is challenging at this point to establish whether NGAL or increased neutrophils might be causal in the pathogenesis of CKD. Further studies are needed to clarify this issue. We read with great interest the article by Bhavsar et al,1Bhavsar N.A. Köttgen A. Coresh J. Astor B.C. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) as predictors of incident CKD stage 3: the Atherosclerosis Risk in Communities (ARIC) Study.Am J Kidney Dis. 2012; 60: 865-867Abstract Full Text Full Text PDF Scopus (83) Google Scholar who concluded that higher levels of neutrophil gelatinase-associated lipocalin (NGAL), but not kidney injury molecule 1 (KIM-1), were associated with incident chronic kidney disease (CKD) stage 3 at follow-up. Although both molecules are upregulated substantially in the kidney after ischemic damage and thereby may serve as reliable biomarkers of kidney injury, NGAL also is produced by a kaleidoscope of extrarenal sources, especially neutrophils. It is noteworthy that in the same Atherosclerosis Risk in Communities (ARIC) Study, Tian et al2Tian N. Penman A.D. Manning Jr, R.D. Flessner M.F. Mawson A.R. Association between circulating specific leukocyte types and incident chronic kidney disease: the Atherosclerosis Risk in Communities (ARIC) Study.J Am Soc Hypertens. 2012; 6: 100-108Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar recently observed that increased neutrophil count was associated significantly with a greater incidence of CKD. In particular, a 10% increase in neutrophils was associated with hazard ratio (HR) of 2.0 (95% confidence interval [CI], 1.5-2.7), an association that was greater (HR, 2.2; 95% CI, 1.6-2.9) after adjusting for baseline kidney function, age, sex, and race.2Tian N. Penman A.D. Manning Jr, R.D. Flessner M.F. Mawson A.R. Association between circulating specific leukocyte types and incident chronic kidney disease: the Atherosclerosis Risk in Communities (ARIC) Study.J Am Soc Hypertens. 2012; 6: 100-108Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Because neutrophilia is an independent determinant of NGAL level4Lippi G. Salvagno G.L. Banfi G. Serum but not urine concentration of neutrophil gelatinase-associated lipocalin is influenced by acute leukocyte variations.Leuk Lymphoma. 2012; 53: 1643-1645Crossref PubMed Scopus (18) Google Scholar and the current NGAL immunoassays cannot distinguish between isoforms produced by renal tubular epithelial cells and those released by neutrophils,3Lippi G. Cervellin G. Neutrophil gelatinase-associated lipocalin: a more specific assay is needed for diagnosing renal injury.Clin Chim Acta. 2012; 413: 1160-1161Crossref PubMed Scopus (22) Google Scholar it is challenging at this point to establish whether NGAL or increased neutrophils might be causal in the pathogenesis of CKD. Further studies are needed to clarify this issue. Financial Disclosure: The authors declare that they have no relevant financial interests. Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM-1) as Predictors of Incident CKD Stage 3: The Atherosclerosis Risk in Communities (ARIC) StudyAmerican Journal of Kidney DiseasesVol. 60Issue 2PreviewIdentifying individuals at risk of chronic kidney disease (CKD) is critical for timely treatment initiation to slow progression of the disease. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are known biomarkers of acute kidney injury, but it is unknown whether these markers are associated with incident CKD stage 3 in the general population. Full-Text PDF In Reply to ‘Neutrophil Gelatinase-Associated Lipocalin (NGAL), Neutrophils, and CKD: Which Comes First?’American Journal of Kidney DiseasesVol. 61Issue 1PreviewWe are grateful for the careful review and insightful comments of Drs Lippi and Cervellin1 regarding the potential limitations of NGAL as a biomarker of kidney disease. In our study,2 the ability to address the issue of whether NGAL concentration predicts incident chronic kidney disease (CKD) independent of neutrophil count is limited because they were not measured at the same study visit. Using neutrophil counts from study visits 6 or 9 years earlier than the visit at which NGAL was measured, we found that NGAL level and neutrophil count were correlated only weakly (r < 0.07 for all). Full-Text PDF