Do Children With Acute Kidney Injury Require Long-term Evaluation for CKD?

Abstract

Related Article, p. 523Acute kidney injury (AKI) affects a growing number of children and is associated with high morbidity and mortality. The incidence of AKI in children differs according to the population described. Approximately 10% of all children admitted to a pediatric intensive care unit develop AKI,1Schneider J. Khemani R. Grushkin C. Bart R. Serum creatinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit.Crit Care Med. 2010; 38: 933-939Crossref PubMed Scopus (239) Google Scholar which doubles if only those admitted for longer than 12 hours are considered.2Alkandari O. Eddington K.A. Hyder A. et al.Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study.Crit Care. 2011; 15: R146Crossref PubMed Scopus (230) Google Scholar Critically ill children on mechanical ventilation and receiving vasopressive/inotropic medications have an 82% incidence of AKI.3Akcan-Arikan A. Zappitelli M. Loftis L.L. Washburn K.K. Jefferson L.S. Goldstein S.L. Modified RIFLE criteria in critically ill children with acute kidney injury.Kidney Int. 2007; 71: 1028-1035Crossref PubMed Scopus (927) Google Scholar Neonates with perinatal asphyxia, those with birth weight <1,500 g,4Koralkar R. Ambalavanan N. Levitan E.B. McGwin G. Goldstein S. Askenazi D. Acute kidney injury reduces survival in very low birth weight infant.Pediatr Res. 2011; 69: 354-358Crossref PubMed Scopus (221) Google Scholar and those who receive extracorporeal membrane oxygenation5Askenazi D.J. Ambalavanan N. Hamilton K. et al.Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation.Pediatr Crit Care Med. 2011; 12: e1-e6Crossref PubMed Scopus (123) Google Scholar also have high rates of AKI. Mortality in neonates and children with AKI is higher than for those without AKI even after controlling for potential confounders.2Alkandari O. Eddington K.A. Hyder A. et al.Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study.Crit Care. 2011; 15: R146Crossref PubMed Scopus (230) Google Scholar, 3Akcan-Arikan A. Zappitelli M. Loftis L.L. Washburn K.K. Jefferson L.S. Goldstein S.L. Modified RIFLE criteria in critically ill children with acute kidney injury.Kidney Int. 2007; 71: 1028-1035Crossref PubMed Scopus (927) Google Scholar, 5Askenazi D.J. Ambalavanan N. Hamilton K. et al.Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation.Pediatr Crit Care Med. 2011; 12: e1-e6Crossref PubMed Scopus (123) Google Scholar It previously was assumed that those who survive an episode of AKI would recover kidney function without long-term sequelae. However, during the last decade, epidemiologic data from critically ill children6Askenazi D.J. Feig D.I. Graham N.M. Hui-Stickle S. Goldstein S.L. 3-5 Year longitudinal follow-up of pediatric patients after acute renal failure.Kidney Int. 2006; 69: 184-189Crossref PubMed Scopus (330) Google Scholar and adults7Weiss A.S. Sandmaier B.M. Storer B. Storb R. McSweeney P.A. Parikh C.R. Chronic kidney disease following non-myeloablative hematopoietic cell transplantation.Am J Transplant. 2006; 6: 89-94Crossref PubMed Scopus (83) Google Scholar, 8Wald R. Quinn R.R. Luo J. et al.University of Toronto Acute Kidney Injury Research GroupChronic dialysis and death among survivors of acute kidney injury requiring dialysis.JAMA. 2009; 302: 1179-1185Crossref PubMed Scopus (546) Google Scholar, 9Newsome B.B. Warnock D.G. McClellan W.M. et al.Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction.Arch Intern Med. 2008; 168: 609-616Crossref PubMed Scopus (248) Google Scholar, 10Lo L.J. Go A.S. Chertow G.M. et al.Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.Kidney Int. 2009; 76: 893-899Crossref PubMed Scopus (441) Google Scholar, 11Lafrance J.P. Djurdjev O. Levin A. Incidence and outcomes of acute kidney injury in a referred chronic kidney disease cohort.Nephrol Dial Transplant. 2010; 25: 2203-2209Crossref PubMed Scopus (74) Google Scholar, 12James M.T. Hemmelgarn B.R. Wiebe N. et al.Alberta Kidney Disease NetworkGlomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study.Lancet. 2010; 376: 2096-2103Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 13James M.T. Ghali W.A. Tonelli M. et al.Acute kidney injury following coronary angiography is associated with a long-term decline in kidney function.Kidney Int. 2010; 78: 803-809Crossref PubMed Scopus (179) Google Scholar, 14Ishani A. Xue J.L. Himmelfarb J. et al.Acute kidney injury increases risk of ESRD among elderly.J Am Soc Nephrol. 2009; 20: 223-228Crossref PubMed Scopus (873) Google Scholar, 15Ishani A. Nelson D. Clothier B. et al.The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death.Arch Intern Med. 2011; 171: 226-233Crossref PubMed Scopus (281) Google Scholar, 16Hsu C.Y. Chertow G.M. McCulloch C.E. Fan D. Ordoñez J.D. Go A.S. Nonrecovery of kidney function and death after acute on chronic renal failure.Clin J Am Soc Nephrol. 2009; 4: 891-898Crossref PubMed Scopus (311) Google Scholar, 17Choi A.I. Li Y. Parikh C. Volberding P.A. Shlipak M.G. Long-term clinical consequences of acute kidney injury in the HIV-infected.Kidney Int. 2010; 78: 478-485Crossref PubMed Scopus (108) Google Scholar, 18Ando M. Ohashi K. Akiyama H. et al.Chronic kidney disease in long-term survivors of myeloablative allogeneic haematopoietic cell transplantation: prevalence and risk factors.Nephrol Dial Transplant. 2010; 25: 278-282Crossref PubMed Scopus (68) Google Scholar, 19Amdur R.L. Chawla L.S. Amodeo S. Kimmel P.L. Palant C.E. Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.Kidney Int. 2009; 76: 1089-1097Crossref PubMed Scopus (235) Google Scholar with AKI suggest that survivors are at risk of developing chronic kidney disease (CKD).A recent meta-analysis showed that adults with AKI are at a 9-fold increased risk of developing CKD, a 3-fold increased risk of developing end-stage kidney disease, and a 2-fold increased long-term mortality risk compared with patients without AKI.20Coca S.G. Singanamala S. Parikh C.R. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis.Kidney Int. 2011; ([published online ahead of print November 23, 2011])https://doi.org/10.1038/ki.2011.379Crossref PubMed Scopus (1329) Google Scholar Despite these strong associations, several limitations in these studies limit our ability to decisively conclude that AKI causes CKD. First, although control for known confounders has been attempted, sample size limits the ability to test for multiple confounders, interactions among variables have not been explored, and unmeasured variables cannot be accounted for. Second, these studies are limited by selection bias because individuals with AKI often have comorbid conditions that predispose to CKD, and those with CKD are more likely to develop AKI.21Singh P. Rifkin D.E. Blantz R.C. Chronic kidney disease: an inherent risk factor for acute kidney injury?.Clin J Am Soc Nephrol. 2010; 5: 1690-1695Crossref PubMed Scopus (70) Google Scholar Long-term follow-up studies of children with AKI help mitigate these limitations because children are less likely to have CKD before AKI occurs and usually do not have the typical comorbid conditions (eg, diabetes mellitus and hypertension) associated with CKD.In this month's issue of the American Journal of Kidney Diseases, Mammen et al22Mammen C. Al Abbas A. Skippen P. et al.Long-term risk of CKD in children surviving episodes of acute kidney injury in the intensive care unit: a prospective cohort study.Am J Kidney Dis. 2012; 59: 523-530Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar report results of the largest long-term follow-up study of AKI in children conducted to date, which included 126 critically ill children with AKI and no pre-existing CKD. For the mentioned reasons, this cohort provides a unique opportunity to examine the association between AKI and the subsequent development of CKD. At 1-3 years of follow-up, 13 of 126 (10%) children developed CKD (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 or persistent albuminuria). In addition, 59 of 126 (47%) patients were considered at risk of CKD (defined as eGFR of 60-90 mL/min/1.73 m2, hyperfiltration [eGFR >150 mL/min/1.73 m2], or hypertension). The authors were diligent in their evaluation of kidney-related parameters whereby they repeated abnormal urinalyses (on first-morning voids) and performed ambulatory blood pressure monitoring to confirm the presence of hypertension.The major limitation of the study is inherent to the loss of follow-up whereby only a subset of hospital survivors (126 of 299 [42%] children) had subsequent evaluations. There were minimal differences between the 2 groups, including a lower proportion of stage 1 AKI (35% vs 50%), lower nadir hemoglobin level (9.2 vs 9.9 g/dL), and higher peak mean airway pressure (16.2 vs 13 cm H2O) in children who were included in the cohort compared with those lost to follow-up. Although not described in the report, many children who have AKI die within a few years after hospital discharge.6Askenazi D.J. Feig D.I. Graham N.M. Hui-Stickle S. Goldstein S.L. 3-5 Year longitudinal follow-up of pediatric patients after acute renal failure.Kidney Int. 2006; 69: 184-189Crossref PubMed Scopus (330) Google Scholar A previous follow-up study of children with AKI found that at least 18% of hospital survivors died several years after the index hospitalization. Whether these patients had CKD and whether CKD had a direct impact on long-term mortality are unknown.This epidemiologic study is supported by animal models showing that AKI has long-term kidney consequences. After ischemia-reperfusion injury, there is substantial damage to tubular and endothelial cells,23Sutton T.A. Mang H.E. Campos S.B. Sandoval R.M. Yoder M.C. Molitoris B.A. Injury of the renal microvascular endothelium alters barrier function after ischemia.Am J Physiol Renal Physiol. 2003; 285: F191-F198Crossref PubMed Scopus (259) Google Scholar leading to vascular injury and dropout as well as tubulointerstitial fibrosis.24Basile D.P. Donohoe D. Roethe K. Osborn J.L. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function.Am J Physiol Renal Physiol. 2001; 281: F887-F899PubMed Google Scholar The vascular dropout after AKI results in endothelial cell damage, endothelial cell differentiation, and impaired regenerative capacity, which might contribute to progressive CKD.25Basile D.P. Friedrich J.L. Spahic J. et al.Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury.Am J Physiol Renal Physiol. 2011; 300: F721-F733Crossref PubMed Scopus (221) Google ScholarWhat is unclear is an understanding of which patients are at the highest risk of developing CKD. Certain causes of AKI or disease severity might pose different risks. Novel biomarkers of kidney injury measured at different times in the course of AKI might help risk-stratify those who will progress to CKD. In 2009, Ko et al26Ko G.J. Grigoryev D.N. Linfert D. et al.Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition.Am J Physiol Renal Physiol. 2010; 298: F1472-F1483Crossref PubMed Scopus (149) Google Scholar analyzed the transcriptome in the repair stage of the mouse ischemia-reperfusion AKI model. Their findings suggest that kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, 2 of the most promising biomarkers for the early detection of AKI, also might be useful markers for identifying sustained kidney injury and progression to CKD after episodes of AKI. In addition, these authors found changes in expression levels of hypertension-related regulatory genes, which could reveal the underlying mechanisms responsible for persistent kidney and vascular injury after AKI.Although animal AKI models do not mirror human studies, these types of data along with human epidemiologic studies provide evidence that children with AKI are at risk of CKD. Therefore, after AKI, it is the opinion of the author that children should be monitored and treated for CKD-related problems. Our current practice is to follow up children with AKI within 1 month of hospital discharge, quarterly for 2 visits, and then annually for 2 years. If CKD or hypertension develops, treatment and additional monitoring are required. After several years of follow-up, if CKD or hypertension does not develop, patients and their primary care providers are advised to periodically monitor blood pressure and urinalysis for markers of kidney damage as potential early indicators of CKD.Despite the growing evidence showing a strong association between AKI and CKD, further work is required to better understand the relationship between AKI and CKD in children. Several questions remain unanswered and should be pursued. First, there is a need to identify clinical factors (eg, comorbid conditions and causes and severity of AKI) and potential biomarker profiles during the various stages of AKI that can help stratify patients at risk of developing CKD. Second, well-designed clinical trials are needed to show that a therapy aimed at preventing AKI or attenuating its severity might decrease the future development of CKD. Such studies could not only provide evidence that AKI leads to CKD, but also offer life-altering interventions to halt the progression of CKD and reduce medical expenditures after AKI. Related Article, p. 523 Related Article, p. 523 Related Article, p. 523 Acute kidney injury (AKI) affects a growing number of children and is associated with high morbidity and mortality. The incidence of AKI in children differs according to the population described. Approximately 10% of all children admitted to a pediatric intensive care unit develop AKI,1Schneider J. Khemani R. Grushkin C. Bart R. Serum creatinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit.Crit Care Med. 2010; 38: 933-939Crossref PubMed Scopus (239) Google Scholar which doubles if only those admitted for longer than 12 hours are considered.2Alkandari O. Eddington K.A. Hyder A. et al.Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study.Crit Care. 2011; 15: R146Crossref PubMed Scopus (230) Google Scholar Critically ill children on mechanical ventilation and receiving vasopressive/inotropic medications have an 82% incidence of AKI.3Akcan-Arikan A. Zappitelli M. Loftis L.L. Washburn K.K. Jefferson L.S. Goldstein S.L. Modified RIFLE criteria in critically ill children with acute kidney injury.Kidney Int. 2007; 71: 1028-1035Crossref PubMed Scopus (927) Google Scholar Neonates with perinatal asphyxia, those with birth weight <1,500 g,4Koralkar R. Ambalavanan N. Levitan E.B. McGwin G. Goldstein S. Askenazi D. Acute kidney injury reduces survival in very low birth weight infant.Pediatr Res. 2011; 69: 354-358Crossref PubMed Scopus (221) Google Scholar and those who receive extracorporeal membrane oxygenation5Askenazi D.J. Ambalavanan N. Hamilton K. et al.Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation.Pediatr Crit Care Med. 2011; 12: e1-e6Crossref PubMed Scopus (123) Google Scholar also have high rates of AKI. Mortality in neonates and children with AKI is higher than for those without AKI even after controlling for potential confounders.2Alkandari O. Eddington K.A. Hyder A. et al.Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study.Crit Care. 2011; 15: R146Crossref PubMed Scopus (230) Google Scholar, 3Akcan-Arikan A. Zappitelli M. Loftis L.L. Washburn K.K. Jefferson L.S. Goldstein S.L. Modified RIFLE criteria in critically ill children with acute kidney injury.Kidney Int. 2007; 71: 1028-1035Crossref PubMed Scopus (927) Google Scholar, 5Askenazi D.J. Ambalavanan N. Hamilton K. et al.Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation.Pediatr Crit Care Med. 2011; 12: e1-e6Crossref PubMed Scopus (123) Google Scholar It previously was assumed that those who survive an episode of AKI would recover kidney function without long-term sequelae. However, during the last decade, epidemiologic data from critically ill children6Askenazi D.J. Feig D.I. Graham N.M. Hui-Stickle S. Goldstein S.L. 3-5 Year longitudinal follow-up of pediatric patients after acute renal failure.Kidney Int. 2006; 69: 184-189Crossref PubMed Scopus (330) Google Scholar and adults7Weiss A.S. Sandmaier B.M. Storer B. Storb R. McSweeney P.A. Parikh C.R. Chronic kidney disease following non-myeloablative hematopoietic cell transplantation.Am J Transplant. 2006; 6: 89-94Crossref PubMed Scopus (83) Google Scholar, 8Wald R. Quinn R.R. Luo J. et al.University of Toronto Acute Kidney Injury Research GroupChronic dialysis and death among survivors of acute kidney injury requiring dialysis.JAMA. 2009; 302: 1179-1185Crossref PubMed Scopus (546) Google Scholar, 9Newsome B.B. Warnock D.G. McClellan W.M. et al.Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction.Arch Intern Med. 2008; 168: 609-616Crossref PubMed Scopus (248) Google Scholar, 10Lo L.J. Go A.S. Chertow G.M. et al.Dialysis-requiring acute renal failure increases the risk of progressive chronic kidney disease.Kidney Int. 2009; 76: 893-899Crossref PubMed Scopus (441) Google Scholar, 11Lafrance J.P. Djurdjev O. Levin A. Incidence and outcomes of acute kidney injury in a referred chronic kidney disease cohort.Nephrol Dial Transplant. 2010; 25: 2203-2209Crossref PubMed Scopus (74) Google Scholar, 12James M.T. Hemmelgarn B.R. Wiebe N. et al.Alberta Kidney Disease NetworkGlomerular filtration rate, proteinuria, and the incidence and consequences of acute kidney injury: a cohort study.Lancet. 2010; 376: 2096-2103Abstract Full Text Full Text PDF PubMed Scopus (233) Google Scholar, 13James M.T. Ghali W.A. Tonelli M. et al.Acute kidney injury following coronary angiography is associated with a long-term decline in kidney function.Kidney Int. 2010; 78: 803-809Crossref PubMed Scopus (179) Google Scholar, 14Ishani A. Xue J.L. Himmelfarb J. et al.Acute kidney injury increases risk of ESRD among elderly.J Am Soc Nephrol. 2009; 20: 223-228Crossref PubMed Scopus (873) Google Scholar, 15Ishani A. Nelson D. Clothier B. et al.The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death.Arch Intern Med. 2011; 171: 226-233Crossref PubMed Scopus (281) Google Scholar, 16Hsu C.Y. Chertow G.M. McCulloch C.E. Fan D. Ordoñez J.D. Go A.S. Nonrecovery of kidney function and death after acute on chronic renal failure.Clin J Am Soc Nephrol. 2009; 4: 891-898Crossref PubMed Scopus (311) Google Scholar, 17Choi A.I. Li Y. Parikh C. Volberding P.A. Shlipak M.G. Long-term clinical consequences of acute kidney injury in the HIV-infected.Kidney Int. 2010; 78: 478-485Crossref PubMed Scopus (108) Google Scholar, 18Ando M. Ohashi K. Akiyama H. et al.Chronic kidney disease in long-term survivors of myeloablative allogeneic haematopoietic cell transplantation: prevalence and risk factors.Nephrol Dial Transplant. 2010; 25: 278-282Crossref PubMed Scopus (68) Google Scholar, 19Amdur R.L. Chawla L.S. Amodeo S. Kimmel P.L. Palant C.E. Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.Kidney Int. 2009; 76: 1089-1097Crossref PubMed Scopus (235) Google Scholar with AKI suggest that survivors are at risk of developing chronic kidney disease (CKD). A recent meta-analysis showed that adults with AKI are at a 9-fold increased risk of developing CKD, a 3-fold increased risk of developing end-stage kidney disease, and a 2-fold increased long-term mortality risk compared with patients without AKI.20Coca S.G. Singanamala S. Parikh C.R. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis.Kidney Int. 2011; ([published online ahead of print November 23, 2011])https://doi.org/10.1038/ki.2011.379Crossref PubMed Scopus (1329) Google Scholar Despite these strong associations, several limitations in these studies limit our ability to decisively conclude that AKI causes CKD. First, although control for known confounders has been attempted, sample size limits the ability to test for multiple confounders, interactions among variables have not been explored, and unmeasured variables cannot be accounted for. Second, these studies are limited by selection bias because individuals with AKI often have comorbid conditions that predispose to CKD, and those with CKD are more likely to develop AKI.21Singh P. Rifkin D.E. Blantz R.C. Chronic kidney disease: an inherent risk factor for acute kidney injury?.Clin J Am Soc Nephrol. 2010; 5: 1690-1695Crossref PubMed Scopus (70) Google Scholar Long-term follow-up studies of children with AKI help mitigate these limitations because children are less likely to have CKD before AKI occurs and usually do not have the typical comorbid conditions (eg, diabetes mellitus and hypertension) associated with CKD. In this month's issue of the American Journal of Kidney Diseases, Mammen et al22Mammen C. Al Abbas A. Skippen P. et al.Long-term risk of CKD in children surviving episodes of acute kidney injury in the intensive care unit: a prospective cohort study.Am J Kidney Dis. 2012; 59: 523-530Abstract Full Text Full Text PDF PubMed Scopus (369) Google Scholar report results of the largest long-term follow-up study of AKI in children conducted to date, which included 126 critically ill children with AKI and no pre-existing CKD. For the mentioned reasons, this cohort provides a unique opportunity to examine the association between AKI and the subsequent development of CKD. At 1-3 years of follow-up, 13 of 126 (10%) children developed CKD (defined as estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 or persistent albuminuria). In addition, 59 of 126 (47%) patients were considered at risk of CKD (defined as eGFR of 60-90 mL/min/1.73 m2, hyperfiltration [eGFR >150 mL/min/1.73 m2], or hypertension). The authors were diligent in their evaluation of kidney-related parameters whereby they repeated abnormal urinalyses (on first-morning voids) and performed ambulatory blood pressure monitoring to confirm the presence of hypertension. The major limitation of the study is inherent to the loss of follow-up whereby only a subset of hospital survivors (126 of 299 [42%] children) had subsequent evaluations. There were minimal differences between the 2 groups, including a lower proportion of stage 1 AKI (35% vs 50%), lower nadir hemoglobin level (9.2 vs 9.9 g/dL), and higher peak mean airway pressure (16.2 vs 13 cm H2O) in children who were included in the cohort compared with those lost to follow-up. Although not described in the report, many children who have AKI die within a few years after hospital discharge.6Askenazi D.J. Feig D.I. Graham N.M. Hui-Stickle S. Goldstein S.L. 3-5 Year longitudinal follow-up of pediatric patients after acute renal failure.Kidney Int. 2006; 69: 184-189Crossref PubMed Scopus (330) Google Scholar A previous follow-up study of children with AKI found that at least 18% of hospital survivors died several years after the index hospitalization. Whether these patients had CKD and whether CKD had a direct impact on long-term mortality are unknown. This epidemiologic study is supported by animal models showing that AKI has long-term kidney consequences. After ischemia-reperfusion injury, there is substantial damage to tubular and endothelial cells,23Sutton T.A. Mang H.E. Campos S.B. Sandoval R.M. Yoder M.C. Molitoris B.A. Injury of the renal microvascular endothelium alters barrier function after ischemia.Am J Physiol Renal Physiol. 2003; 285: F191-F198Crossref PubMed Scopus (259) Google Scholar leading to vascular injury and dropout as well as tubulointerstitial fibrosis.24Basile D.P. Donohoe D. Roethe K. Osborn J.L. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function.Am J Physiol Renal Physiol. 2001; 281: F887-F899PubMed Google Scholar The vascular dropout after AKI results in endothelial cell damage, endothelial cell differentiation, and impaired regenerative capacity, which might contribute to progressive CKD.25Basile D.P. Friedrich J.L. Spahic J. et al.Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury.Am J Physiol Renal Physiol. 2011; 300: F721-F733Crossref PubMed Scopus (221) Google Scholar What is unclear is an understanding of which patients are at the highest risk of developing CKD. Certain causes of AKI or disease severity might pose different risks. Novel biomarkers of kidney injury measured at different times in the course of AKI might help risk-stratify those who will progress to CKD. In 2009, Ko et al26Ko G.J. Grigoryev D.N. Linfert D. et al.Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition.Am J Physiol Renal Physiol. 2010; 298: F1472-F1483Crossref PubMed Scopus (149) Google Scholar analyzed the transcriptome in the repair stage of the mouse ischemia-reperfusion AKI model. Their findings suggest that kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, 2 of the most promising biomarkers for the early detection of AKI, also might be useful markers for identifying sustained kidney injury and progression to CKD after episodes of AKI. In addition, these authors found changes in expression levels of hypertension-related regulatory genes, which could reveal the underlying mechanisms responsible for persistent kidney and vascular injury after AKI. Although animal AKI models do not mirror human studies, these types of data along with human epidemiologic studies provide evidence that children with AKI are at risk of CKD. Therefore, after AKI, it is the opinion of the author that children should be monitored and treated for CKD-related problems. Our current practice is to follow up children with AKI within 1 month of hospital discharge, quarterly for 2 visits, and then annually for 2 years. If CKD or hypertension develops, treatment and additional monitoring are required. After several years of follow-up, if CKD or hypertension does not develop, patients and their primary care providers are advised to periodically monitor blood pressure and urinalysis for markers of kidney damage as potential early indicators of CKD. Despite the growing evidence showing a strong association between AKI and CKD, further work is required to better understand the relationship between AKI and CKD in children. Several questions remain unanswered and should be pursued. First, there is a need to identify clinical factors (eg, comorbid conditions and causes and severity of AKI) and potential biomarker profiles during the various stages of AKI that can help stratify patients at risk of developing CKD. Second, well-designed clinical trials are needed to show that a therapy aimed at preventing AKI or attenuating its severity might decrease the future development of CKD. Such studies could not only provide evidence that AKI leads to CKD, but also offer life-altering interventions to halt the progression of CKD and reduce medical expenditures after AKI. Financial Disclosure: The author declares that he has no relevant financial interests. Long-term Risk of CKD in Children Surviving Episodes of Acute Kidney Injury in the Intensive Care Unit: A Prospective Cohort StudyAmerican Journal of Kidney DiseasesVol. 59Issue 4PreviewThe development of standardized acute kidney injury (AKI) definitions has allowed for a better understanding of AKI epidemiology, but the long-term renal outcomes of AKI in the pediatric critical care setting have not been well established. This study was designed to: (1) determine the incidence of chronic kidney disease (CKD) in children 1-3 years after an episode of AKI at a tertiary-care pediatric intensive care unit (ICU), (2) identify the proportion of patients at risk of CKD, and (3) compare ICU admission characteristics in those with and without CKD. Full-Text PDF