Acute Kidney Injury: Marker or Mediator of Subsequent CKD?

Correspondence LETTERS TO THE EDITOR Neutrophil Gelatinase-Associated Lipocalin (NGAL), Neutrophils, and CKD: Which Comes First? To the Editor: We read with great interest the article by Bhavsar et al,1 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 al2 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.2 Because neutrophilia is an independent determinant of NGAL level4 and the current NGAL immunoassays cannot distinguish between isoforms produced by renal tubular epithelial cells and those released by neutrophils,3 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. Giuseppe Lippi, MD Gianfranco Cervellin, MD Azienda Ospedaliero-Universitaria di Parma Parma, Italy

Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interests.

References 1. Bhavsar NA, Köttgen A, Coresh J, Astor BC. 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(2):865867. 2. Tian N, Penman AD, Manning RD Jr, Flessner MF, Mawson AR. Association between circulating specific leukocyte types and incident chronic kidney disease: the Atherosclerosis Risk in Communities (ARIC) Study. J Am Soc Hypertens. 2012;6(2):100-108. 3. Lippi G, Cervellin G. Neutrophil gelatinase-associated lipocalin: a more specific assay is needed for diagnosing renal injury. Clin Chim Acta. 2012;413(13-14):1160-1161. 4. Lippi G, Salvagno GL, Banfi G. Serum but not urine concentration of neutrophil gelatinase-associated lipocalin is influenced by acute leukocyte variations. Leuk Lymphoma. 2012;53(8):16431645. © 2012 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2012.06.031

In Reply to ‘Neutrophil Gelatinase-Associated Lipocalin (NGAL), Neutrophils, and CKD: Which Comes First?’ We are grateful for the careful review and insightful comments of Drs Lippi and Cervellin1 regarding the potential limitations of NGAL 184

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). There was not a significant association between neutrophil count and incident CKD in our population (P ⱖ 0.15 in all models), and a nonsignificant trend persisted in the association between NGAL level and incident CKD after adjustment for neutrophil count (P ⫽ 0.1). We agree that future studies may want to explore additional pathways through which NGAL may be associated with incident CKD, including its relationship with neutrophil count and inflammation in general. Nrupen A. Bhavsar, PhD, MPH Josef Coresh, MD, PhD Johns Hopkins University Baltimore, Maryland Brad C. Astor, PhD, MPH University of Wisconsin Madison, Wisconsin

Acknowledgements The authors thank Dr Anna Köttgen, a coauthor of their original article, for her input. Financial Disclosure: The authors declare that they have no relevant financial interests.

References 1. Lippi G, Cervellin G. Neutrophil gelatinase-associated lipocalin (NGAL), neutrophils, and CKD: which comes first? Am J Kidney Dis. 2013;61(1):184. 2. Bhavsar NA, Köttgen A, Coresh J, Astor BC. 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(2):865-867. © 2012 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2012.10.008

Acute Kidney Injury: Marker or Mediator of Subsequent CKD? To the Editor: The elegant analysis by Jones et al1 indicates that complete recovery of kidney function after an episode of acute kidney injury (AKI) in patients with normal baseline serum creatinine levels is associated with increased risk of de novo chronic kidney disease (CKD). However, the data reported leave the reader with no answer to some crucial questions. Did the development of AKI identify a group of patients who failed a “stress test” for their kidneys, in other words, patients predestined to have CKD? Did the acute process damage the kidneys such that a substantial decrease in glomerular filtration rate toward stage 3 CKD would occur in the years after the event despite “complete recovery” of kidney function at discharge? Jones et al1 describe a number of limitations that may confound or bias their results. Notably, individuals with pre-existing stages 1 and 2 CKD (defined by urine damage markers) were included in their analyses. Additionally, functional AKI (decreased kidney perfusion) was not differentiated from structural AKI (acute tubular necrosis). The findings of Jones et al1 contrast with the results in our 10-year follow-up of 425 critically ill patients without Am J Kidney Dis. 2013;61(1):184-185

Correspondence baseline CKD who developed AKI requiring kidney replacement therapy. In our study, none of the 126 survivors who experienced complete kidney function recovery developed de novo CKD, but all 100 patients who experienced only partial recovery of kidney function at discharge did.2 We should recognize that the relationship among patient risk factors, the precipitation of AKI, the development of CKD, and long-term mortality is complex and that de novo CKD may develop in patients with virtually complete recovery by 2 alternate models. First, risk factors may predispose patients to not only AKI, but also to the development of CKD despite apparent complete recovery from AKI. Second, persistent structural and/or functional damage to the kidneys in patients with partial recovery from AKI may mediate the development of de novo CKD. Helmut Schiffl, MD, PhD Susanne M. Lang, MD, PhD Rainald Fischer, MD, PhD University of Munich Munich, Germany

Am J Kidney Dis. 2013;61(1):184-185

Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interest.

References 1. Jones J, Holmen J, De Graauw J, Jovanovich A, Thornton S, Chonchol M. Association of complete recovery from acute kidney injury with incident CKD stage 3 and all-cause mortality. Am J Kidney Dis. 2012;60(3):402-408. 2. Schiffl H, Lang SM, Fischer R. Long-term outcome of survivors of ICU acute kidney injury requiring renal replacement therapy: a ten year prospective cohort study. Clin Kidney J. 2012;5(4):297-302. Jones et al declined to respond. © 2012 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2012.05.028

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