Peter McCullough, Early Identification and Assessment of Acute and Chronic Kidney Disease
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This document discusses early identification and assessment of acute and chronic kidney disease. It provides information on acute kidney injury (AKI), including definitions, biomarkers, pathophysiology, and clinical evidence. Neutrophil gelatinase-associated lipocalin (NGAL) is discussed as a promising early biomarker for detecting AKI, with studies showing it can predict AKI hours earlier than serum creatinine. The document also reviews evidence on using NGAL to detect AKI in various clinical settings like cardiac surgery, sepsis, and kidney transplantation. A case study is presented on a high-risk cardiac surgery patient where NGAL measurements could help guide management.
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Peter McCullough, Early Identification and Assessment of Acute and Chronic Kidney Disease
- 1. Early Identification and Assessment of Acute and Chronic Kidney Disease 1 Peter A. McCullough, MD, MPH FACC, FACP, FAHA, FCCP, FNKF Baylor University Medical Center, Dallas, TX e-mail: peteramccullough@gmail.com
- 2. 2 Outline •What is acute kidney injury (AKI)? • Biomarkers for kidney disease • Physiology and pathophysiology • Clinical evidence • Case study • Conclusions
- 3. 3 Acute Kidney Injury (AKI) • AKI, formerly known as acute renal failure, is common – Definition of AKI is subjective and leads to difficulties in detection and diagnosis • Abrupt decrease in kidney function that leads to accumulation of nitrogenous wastes, such as blood urea nitrogen and creatinine • Revised nomenclature of AKI describes conditions that include both structural damage and dysfunction Devarajan P. J Am Soc Nephrol. 2006;17:1503-1520. Ricci Z, Ronco C. Crit Care. 2008;12:230-236.
- 4. Tubular Recovery and Renal Reserve in AKI ~30% of In-hospital AKI results in permanent loss in eGFR (~5% ESRD) ~70% must have had tubular recovery or compensation by the remaining nephrons Adapted fromThadhani et al., N Engl J Med 1996
- 5. 5 Contributing Factors to Acute Renal Failure 48% 34% 27% 26% 19% 6% 3% 12% 50 40 30 20 10 0 Major Surgery Cardiogenic Shock Septic Shock Hypovolemia Drug-induced Hepatorenal Syndrome Obstructive Uropathy Other % of Patients Uchino S, et al. JAMA. 2005;294:813-818.
- 6. 6 Age-Adjusted Hospitalization Rates for Kidney Disease by Type of Kidney Failure (1980-2005) Rate of hospitalization from ARF increased from 1.8 per 10,000 population in 1980 to 36.5 in 2005 MMWR Morb Mortal Wkly Rep. 2008;57:309-312.
- 7. 7 Mortality in Acute Kidney Injury No AKI AKI 75% 50% 25% 0% Mortality Star RA, Kidney Int 54:1817-1831, 1998. 7% 34%
- 8. Definition of Acute Kidney Injury (KDIGO)
- 9. Clinical Actions for Acute Kidney Injury
- 10. History of Urine in Western Medicine • Ancient Babylonian and Sumerian physicians first inscribed their evaluations of urine into clay tablets as early as 4,000 B.C. Figure: People showing for a diagnose a sample of their urine to the physician Constantine the African. Yoquinto, My Health Daily News, Aug 15 2011
- 11. Evolution in Cardiac and Renal Diagnostics Time 1950’s 1960’s 1970’s 1980’s 1990’s 2000 AMI WBC count LDH, SGOT, SGPT CPK CK-MB Troponin -T Troponin - I AKI Change in serum creatinine No Change Change in serum creatinine The renal testing arena is in need of the introduction of novel, early and more sensitive and specific biomarkers Conger JD, Am J Kidney Dis 26:565-576, 1995. Star RA, Kidney Int 54:1817-1831, 1998.
- 12. Creatinine is Not An Ideal Biomarker 120 Surgery, MI, sepsis 100 80 60 40 20 6 7 0 5 3 4 2 1 12 Adapted from Moran SM, Myers BD. Kidney International. 1985;27:928- 937 GFR (mL/min) Serum Creatinine (SCr) (mg/dL) 0 Reversal of ischemia 0 7 14 21 28 Time, days
- 13. 13 Vaidya, et al. Ann Rev Pharmacol Toxicol. 2008;48:463-493. Spectrum of Kidney Injury Unmet need SCr detection
- 14. New Biomarkers for Detecting AKI Post Injury in Various Clinical Situations Biomarker Sample Source Cardiopulmonary Bypass (CPB) Contrast Nephropathy Sepsis or ICU Kidney Transplant (tx) Cystatin C Plasma 12 hrs post-CPB 8 hrs postcontrast 48 hrs before AKI Variable IL-18 Urine 4-6 hrs post-CPB Not tested 48 hrs before AKI 12-24 hrs post-tx KIM-1 Urine 12-24 hrs post- CPB Not tested Not tested Not tested NGAL Urine/ Plasma 2 hrs post-CPB 2-4 hrs postcontrast 48 hrs before AKI 12-24 hrs post- tx (urine only) L-FABP Urine NephroChe Adapted from Parikh CR, Devarajan P. Crit Care Med. 2008;36(suppl):S159-S165. 12 hours
- 15. 15 Neutrophil Gelatinase Associated Lipocalin (NGAL), Lipocalin-2, Siderocalin: Physiology and Clinical Relevance • Member of the lipocalin superfamily • Normally expressed at very low levels in kidney, lungs, heart, stomach, and colon • Increased after injury • Increased after ischemia – One of the most highly induced proteins in kidney after ischemic or nephrotoxic AKI in animal models – Highly up-regulated in the distal convoluted tubule during injury/ischemia, leading to a marked increase of NGAL in the urine • Protective role – Murine models of renal ischemia-reperfusion showed amelioration of morphologic and functional injury when treated with NGAL • Early diagnostic biomarker for AKI Devarajan P. Nephrol Dial Transplant. 2008;23:3737-3743. Parikh CR, Devarajan P. Crit Care Med. 2008;36(suppl):S159-S165. Mishra J, et al. J Am Soc Nephrol. 2004;15:3073-3082.
- 16. 16 Ischemic Kidneys Synthesize Renal NGAL mRNA Adapted from Schmidt-Ott KM, et al. J Am Soc Nephrol. 2007;18:407-413. mRNA Levels, fold change Hours Post-Ischemia *P≤.05 NGAL FGF2 (basic fibroblast growth factor) HF (hypoxia-inducible factor) BMP7 (bone morphogenic protein 7) * * 0 10 20 30 40 50 * * 1000 100 10 1 0.1 0.01 * * * * * * * * * * * *
- 17. NGAL Siderophore Labile Iron ·O - 2 Haber Weiss Fe3+ Fe2+ O 2 H OH - 2O + + OH · H 2O 2 Fenton Ferric Iron = Fe 3 + ; Ferrous iron= Fe 2 + ; hydrogen peroxide = H 2 O2 ; Hydroxyl radical = OH . ;Hydroxide anion = OH - ; oxygen = O 2 ; superoxide anion = . O 2 - ACS AKI Oxidative Stress Reactions
- 19. 19 Analysis of Urine and Serum NGAL After Cardiopulmonary Bypass Urine NGAL Serum NGAL Serum Creatinine Rise 0 2 4 6 8 12 24 36 48 60 72 84 96 108 120 Time after cardiopulmonary bypass (h) 225 200 175 150 125 100 75 50 25 0 Serum NGAL (ÎĽg/L) NGAL increased 2 hours after cardiopulmonary bypass Adapted from Mishra J, et al. Lancet. 2005;365:1231-1238. N = 71 Time after cardiopulmonary bypass (h) 225 200 175 150 125 100 75 50 25 0 Urine NGAL (ÎĽg/L) 0 2 4 6 8 1122 12 222444 24 333666 36 48 444888 60 666000 777222 72 84 888444 999666 96 108 111000888 112200 120 Acute renal failure (n=20) Without acute renal failure (n=51) Serum Creatinine Rise 00 22 44 66 88 111222 222444 333666 444888 666000 777222 888444 999666 111000888 112200
- 20. 20 Urine NGAL Levels Post-Cardiopulmonary Bypass 15-fold increase in urine NGAL at 2 hours after CPB and 25-fold increase at 4 hours after CPB in children 1200 1000 800 600 400 200 0 0 2 4 6 8 12 24 36 48 72 No AKI AKI Hours after cardiopulmonary bypass NGAL (ng/ml) Bennett M, et al. Clin J Am Soc Nephrol. 2008;3:665-673. N = 196 * * * * * * * * *P <0.05 comparing patients with or without AKI
- 21. 21 Urine and Plasma NGAL Is Predictive of AKI After Cardiopulmonary Bypass • Sensitivity and specificity – Urine NGAL: 92.7% and 77.8% – Plasma NGAL: 80% and 66.7% Adapted from Tuladhar SM, et al. J Cardiovasc Pharmacol. 2009. 100 80 60 40 20 0 2 hours after surgery 0 20 40 60 80 100 Specificity, % Sensitivity, % Urine NGAL (AUC = 0.96) Plasma NGAL (AUC = 0.85)
- 22. 22 Use of NGAL in Patients at Risk for Cardiac Surgery-Associated AKI Conditions Causing High Risk for Cardiac Surgery–Associated AKI Preoperative estimated GFR <60 mL/min/1.73 m2 Preoperative LVEF<35% Emergency surgery Cardiogenic shock Acute MI in the week preceding surgery Left main coronary artery disease Receiving diuretic or inotropic therapy for decompensated HF CPB time >3 h The authors recommended that serial testing of NGAL should be conducted in patients with these clinical conditions GFR, Estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; SCr, serum creatinine; CPB, cardiopulmonary bypass Cruz DN, et al. J Thorac Cardiovasc Surg. 2010;139:1101-1106.
- 23. 23 NGAL for the Diagnosis of AKI in the Emergency Department NGAL Serum Creatinine Nickolas TL, et al. Ann Intern Med. 2008;148:810-819. 1500 1250 g ÎĽg/1000 NGAL, 750 Urine 500 250 Kidney Function N = 635 0 * * * * * * AKI Prerenal Azotemia CKD Normal 20.00 18.00 16.00 14.00 12.00 10.00 8.00 6.00 4.00 2.00 0.00 * * * ** *** * AKI Prerenal Azotemia CKD Normal Kidney Function Presenting Serum Creatinine, mg/dL
- 24. 24 Meta-Analysis: Accuracy of NGAL in AKI • Meta-analysis of 19 diagnostic studies (2538 patients) • NGAL was a valuable and early predictor of AKI, both overall and across a diverse range of clinical settings • The cutoff NGAL value for optimum sensitivity and specificity across all settings was >100 ng/mL • A more consistent cutoff value of >150 ng/mL was identified when using standardized platforms Diagnostic and Prognostic Accuracy of NGAL Setting Specificity AUC-ROC Diagnostic Odds Ratio AKI across settings 85.1 0.815 18.6 AKI after cardiac surgery 75.1 0.775 13.1 AKI in critically ill patients 75.5 0.728 10.0 AKI after contrast infusion 96.3 0.894 92.0 AKI prediction using serum NGAL 86.6 0.775 17.9 AKI prediction using urine NGAL 84.3 0.837 18.6 Haase M, et al. Am J Kidney Dis. 2009;54:1012-1024.
- 25. 25 NGAL for Prediction of Chronic Kidney Disease Progression Both serum and urine NGAL predicted CKD progression independently of other potential confounders like estimated GFR or age Serum NGAL associated with a 2% risk of progression Urine NGAL associated with a 3% risk of progression Bolignano D, et al. Clin J Am Soc Nephrol. 2009;4:337-344. N = 96
- 26. 26 Urine NGAL as a Marker for Chronic Heart Failure Urine NGAL levels were highly elevated in patients with chronic heart failure (CHF) Damman K, et al. Eur J Heart Fail. 2008;10:997-1000. N = 110
- 27. 27 Urine NGAL as a Predictive Biomarker for Delayed Graft Function Following Kidney Transplantation * †‡ ‡ ‡ †Time After Transplantation Urine NGAL (ng/mL) Delayed Graft Function Slow Graft Function Immediate Graft Function Hall IE, et al. J Am Soc Nephrol. 2010;21:189-197. N = 91 POD indicates postoperative day * P<.05, †P<.01, ‡ P<.001
- 28. 28 Case Study 1: 73-Year-Old Male • 73-year-old male is to undergo cardiac surgery with cardiopulmonary bypass (CPB) • The planned procedure is a 3-vessel “re-do” CABG and mitral valve replacement • Patient has a history of CHF (LVEF 25%, ischemic cardiomyopathy, prior CABG), Diabetes Mellitus, and CKD (serum creatinine 1.9mg/dL)
- 29. 29 Case Study 1: 73-Year-Old Male (Cont’d) • Operative course: complicated by difficulty weaning from CPB, and postoperative hypotension requiring placement of an intra-aortic balloon pump – CPB duration 180 minutes • Serum creatinine measurements shown at right 1.9 1.7 1.8 1.9 2 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 Preoperative Postoperative 3 Hours 6 Hours Serum Creatinine (mg/dL) Time After Surgery
- 30. 30 Case Study 1: 73-Year-Old Male (Cont’d) • The patient has decreased urine output on ICU arrival and does not respond to fluid administration • Patient given furosemide, again with no response • He requires transfusion of blood products, and is developing metabolic acidosis – Serum creatinine 1.9 mg/dL • What is your next approach for this patient?
- 31. 31 Case Study 1: 73-Year-Old Male (Cont’d) • Now, if urinary NGAL levels were also determined in addition to serum creatinine… • Urine NGAL measurements shown at right • Do the NGAL measurements affect your treatment approach? – Do you continue to monitor serum creatinine and NGAL for a longer time period or do you start renal replacement therapy immediately? Serum Creatinine 2 2000 dL) mg/1.5 (creatinine 1 Serum 0.5 0 Preoperative Postoperative 3 Hours 6 Hours 1800 1600 1400 1200 1000 800 600 400 200 0 Urine NGAL (ng/mL) Urine NGAL Time After Surgery
- 32. L-Type Fatty Acid Binding Protein 32
- 33. 33 Kidney International (2010) 77, 708–714; doi:10.1038/ki.2009.422; published online 25 November 2009 Diagnostic performance of urinary liver-type fatty acid-binding protein (L-FABP) for the identification of established acute kidney injury (AKI) in hospitalized patients. Receiver operating characteristic curve for AKI versus hospitalized controls (intensive care unit controls and precatheterization controls). Area under the curve (AUC) was 0.93 (95% CI 0.88–0.97) using a cutoff of 47.1 ng per mg Cr; sensitivity was 83% (95% CI 73–90%), and specificity was 90% (95% CI 77–97%). CI, confidence intervals; Cr, creatinine
- 34. 34 Kidney International (2010) 77, 708–714; doi:10.1038/ki.2009.422; published online 25 November 2009 Comparison of urinary liver-type fatty acid-binding protein (L-FABP) levels in patients with established acute kidney injury (AKI) by clinical outcome. Box and whisker plots of normalized urinary L-FABP levels in patients meeting the composite end point of death/renal replacement therapy (RRT) and those who survived without RRT. Cr, creatinine.
- 35. 35 Kidney International (2010) 77, 708–714; doi:10.1038/ki.2009.422; published online 25 November 2009 Comparison of urinary liver-type fatty acid-binding protein (L-FABP) levels in patients with acute kidney injury (AKI) by cause.Box and whisker plots of normalized urinary L-FABP levels in patients with established AKI caused by acute tubular necrosis (ATN), sepsis, nephrotoxin exposure, contrast-induced nephropathy, and other underlying disease. Cr, creatinine.
- 36. NephroCheck: (TIMP-2 x IGFBP-7 Product in Spot Urine) 36
- 37. 37
- 38. New Spectrum of AKI based on Combination of Functional and Damage Biomarkers NO DAMAGE DAMAGE PRESENT Based on Serum Creatinine NO FUNCTIONAL CHANGE NNoo ffuunnccttiioonnaall cchhaannggeess oorr ddaammaaggee DDaammaaggee wwiitthhoouutt lloossss ooff ffuunnccttiioonn DDaammaaggee wwiitthh lloossss ooff ffuunnccttiioonn LLoossss ooff ffuunnccttiioonn wwiitthhoouutt ddaammaaggee FUNCTIONAL CHANGE Based on NGAL
- 39. New Criteria for AKI Diagnosis and Staging Using Biomarkers Based on Serum Creatinine and Urine Output Based on NGAL
- 40. • Filtration • Protein catabolism • Sodium/water balance • Electrolyte balance • Blood pressure control • Hormone production – 1,25 OH-Vit D – Erythropoietin • Enzyme production – Renin • Drug excretion • ?Vascular integrity – Systemic – Pulmonary – Cerebral – Local renal McCullough PA, Braunwald’s Text of Cardiovascular Disease, 8th Ed, 2007
- 41. 41
- 42. 42
- 43. Microalbuminuria and eGFR as CKD Screening Tests by Age KEEP, N=40,013; NHANES, N=10,486 McCullough PA, et al, Am J Kid Dis, Vol 51, No4, Suppl 2, April, 2008
- 44. Microalbuminuria as a CKD Progression and CVD Risk Marker Systemic Vasculature Injured Endothelium Renal Vasculature Clinical and Subclinical Atherosclerosis Cardiovascular Risk Factors: Age Diabetes Hypertension Smoking Absent nocturnal BP dipping Salt sensitivity Left ventricular hypertrophy Dyslipidemia Central obesity Insulin resistance Elevated CRP Sympathetic dysfunction Hyperuricemia Microalbuminuria Figure 2. Microalbuminuria, manifestation of diffuse endothelial cell injury; BP, blood pressure; CRP, C-reactive protein. Toto RD. J Clin Hypertens. 2004;6(Suppl 3):2-7.
- 45. 45
- 46. 46 Anemia in CKD: Evaluate Screen and Evaluate When eGFR < 60 ml/min
- 47. 47 Nature Reviews Nephrology 6, 699- 710 (December 2010)
- 48. 48 Conclusions • Rates of hospitalization with kidney disease are increasing • There is a need for an early, reliable, and accurate predictor of AKI for early intervention • Urine NGAL, L-FABP, and NephroCheck are the early commericalized markers worldwide • The eGFR and spot urine albumin:creatinine ratio are standard assessments for CKD – CKD-Mineral and bone disease calls for reflexive testing – CKD-Anemia also calls for reflexive testing • Future studies of advanced markers will likely enhance our understanding of AKI/CKD and identify new treatment targets
Editor's Notes
- Overview Today’s presentation will review the unmet clinical needs for rapid and accurate diagnosis and assessment of acute kidney injury and highlight substantial data for neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker that can offer considerable value in this area. Acute kidney injury is an under-diagnosed condition in which the severity is associated with its outcome. In order to mitigate the potential problems of kidney dysfunction, timely intervention is important, and early detection is key to early intervention. Various definitions for AKI have been utilized, without consensus on how best to assess kidney function, what markers best reflect kidney function, and what values can discriminate normal from abnormal kidney function. This presentation will review the definition of and prevalence of acute kidney injury; the role of biomarkers in kidney disease; the physiology and pathophysiology of NGAL; and the clinical evidence for the use of NGAL as a biomarker for acute kidney injury. We will also review 2 case studies before the conclusion of the program.
- Acute Kidney Injury (AKI) Kidney dysfunction is an under-recognized problem in which the severity is associated with the outcome. Acute kidney injury (AKI), formerly known as acute renal failure (ARF), is the abrupt decrease in kidney function that leads to accumulation of nitrogenous wastes, such as blood urea nitrogen and creatinine. Although the epidemiology of AKI was unclear in the past given the lack of a precise definition, the new AKI nomenclature, as defined by the RIFLE criteria, emphasizes the fact that AKI exists along a continuum; the greater the severity of injury, the more likely it is that the overall outcome will be unfavorable. The prior definition of ARF focused on patients with severe and established renal failure (function), but the reclassification also includes those who are receiving dialysis and those who have a specific clinical syndrome, describing conditions that encompass both structural damage and dysfunction. References Devarajan P. J Am Soc Nephrol. 2006;17:1503-1520. Ricci Z, Ronco C. Crit Care. 2008;12:230-236.
- Contributing Factors to Acute Renal Failure In almost half of the patients, acute renal failure (ARF) was associated with septic shock (48%). Major surgery (34%), cardiogenic shock (27%), and hypovolemia (26%) were also contributors to acute renal failure. At the time of the study, there was no established definition for acute kidney injury, which imposed problems for collecting information on epidemiology. Patients in this study were considered to have severe ARF, with the criteria for ARF being oliguria defined as urine output of less than 200 mL in 12 hours and/or marked azotemia defined as blood urea nitrogen level higher than 84 mg/dL. Patients were included in study from 54 hospitals in 23 countries. Reference Uchino S, et al. JAMA. 2005;294:813-818.
- Age-Adjusted Hospitalization Rates for Kidney Disease by Type of Kidney Failure (1980-2005) The rate of hospitalization for kidney disease increased from 1980-2005 primarily due to hospitalizations with diagnoses of acute renal failure. The National Hospital Discharge Survey (NHDS) was conducted annually by the CDC for the period of 1980-2005. Data were taken from medical records from a sample of approximately 500 nonfederal short-stay hospitals (&lt;30 days) in the 50 states and the District of Columbia. The report indicated that numbers and rates of kidney disease hospital discharge diagnoses have increased since the early 1990s and a shift has occurred in the type of kidney disease accounting for most of these hospitalizations, from chronic kidney disease to acute renal failure. The age-adjusted rate per 10,000 population for hospitalization for ARF increased from 1.8 in 1980 to 36.5 in 2005. In 1980, 7.3% of all kidney disease hospitalizations were for acute renal failure (ARF), 35.0% were for chronic kidney failure (CKF), and 56.0% were for other kidney disease diagnoses. However, in 2005, 60.0% of these hospitalizations were for ARF, 24.3% were for CKF, and 9.3% were for other kidney disease diagnoses. These data show a large increase in kidney disease hospitalizations for ARF. Reference MMWR Morb Mortal Wkly Rep. 2008;57:309-312.
- Mortality in Acute Renal Failure Acute renal failure is a serious illness associated with a high risk of mortality. The development of even mild, acute renal failure (ARF) increases morbidity. The mortality rate in patients without renal failure was 7% compared with 34% in patients who developed acute renal failure in a population undergoing contrast nephropathy. Reference Star RA, Kidney Int 54:1817-1831, 1998.
- The Fascinating History of Urine Tests Luke Yoquinto, MyHealthNewsDaily Contributor Date: 15 August 2011 Time: 02:03 PM ET http://www.livescience.com/35819-history-urine-tests.html
- Evolution in Renal Diagnostics The evolution of diagnostic markers in acute myocardial infarction has yielded sensitive, early markers, such as the troponins. The lack of early markers for AKI akin to troponins in acute myocardial infarction is evident in the use of serum creatinine to diagnose AKI. Serum creatinine lags behind renal injury and is a poor marker for AKI. Early assessment of biomarkers may provide an opportunity to diagnose and treat early in AKI.
- Creatinine is Not An Ideal Biomarker Plasma creatinine is influenced by many non-renal events that regulate creatinine generation, volume of distribution, and creatinine excretion, making it a less-than-ideal biomarker of renal function because these events can be altered during acute renal failure. Creatinine is cleared from plasma into urine not only by glomerular filtration but also by tubular secretion. A sudden fall in GFR to a constant low level causes a slow increase in plasma creatinine; the rate of the rise depends on the new GFR, on the rate of creatinine generation, and on the volume of distribution of creatinine. A new steady state is reached when the creatinine generation equals creatinine clearance. The opposite occurs during recovery from acute renal failure. Thus, serum creatinine will typically increase several days after a sharp decline in glomerular filtration. Reference Moran SM, Myers BD. Kidney International. 1985;27:928-37.
- Spectrum of Kidney Injury Biomarkers need to detect AKI at an earlier time point than the typically delayed rise in serum creatinine so that a rapid diagnosis can be made and interventions can be applied in a timely manner. A reduction in the GFR causes an increase in serum creatinine. The increase in serum creatinine occurs after possible kidney injury has already occurred. Creatinine is not an ideal biomarker for diagnosing AKI because it is a marker of GFR not kidney injury. There can be up to a 48 hour delay after kidney injury occurs before serum creatinine level rises and during this delay, damage to the kidney has already occurred. This delay in diagnosis prevents timely treatment of the patient suffering with AKI. Reference Vaidya, et al. Ann Rev Pharmacol Toxicol. 2008;48:463-493.
- New Biomarkers for AKI in Various Clinical Situations In addition to serum creatinine, there are several emerging biomarkers that offer promise for AKI. Of the potential biomarkers for AKI in various clinical situations, NGAL is one of the earliest biomarkers for AKI in various clinical settings. In the table shown in the slide, “48 hrs before AKI” indicates that the marker is elevated 48 hours before a significant rise in serum creatinine, which was used as the standard for AKI. Abbreviations: IL-18, interleukin-18; KIM-1, kidney injury molecule 1. Reference Parikh CR, Devarajan P. Crit Care Med. 2008;36(suppl):S159-S165.
- NGAL Physiology and Clinical Relevance Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a member of the lipocalin superfamily. It is a 25 kDa protein covalently bound to gelatinase from neutrophils. It is normally expressed at low levels in several tissues; however, it’s expression is dramatically increased after injury to kidney epithelial cells. NGAL is thought to help protect the kidney after acute injury and may serve as an excellent biomarker for AKI. References Devarajan P. Nephrol Dial Transplant. 2008;23:3737-3743. Parikh CR, Devarajan P. Crit Care Med. 2008;36(suppl):S159-S165. Mishra J, et al. J Am Soc Nephrol. 2004;15:3073-3082.
- Ischemic Kidneys Synthesize Renal NGAL mRNA Ischemic kidneys synthesize NGAL for at least 50 h after reperfusion. An approximately 1000-fold increase in NGAL message (measured by real-time reverse transcriptase–PCR) occurs in response to renal ischemia. Compared with the smaller degrees of modulation of genes that are relevant to acute renal injury, such as hypoxia-inducible factor (HIF), FGF2, and bone morphogenic protein 7 (BMP7), the mRNA levels of NGAL are much more abundant. *P≤0.05 significantly modulated from time zero. Reference Schmidt-Ott KM, et al. J Am Soc Nephrol. 2007;18:407-413.
- Analysis of Urine and Serum NGAL After Cardiopulmonary Bypass Diagnosis of AKI in children undergoing cardiopulmonary bypass (CPB) with serum creatinine occurred 1-3 days after CPB, but urine and serum NGAL levels increased 2 hours after CPB in those patients with AKI. The mean urine (left) and serum (right) NGAL concentrations at various time points show a robust increase in both serum and urine NGAL at 2 hours after CPB in patients with AKI. Urine NGAL peaked very early after cardiopulmonary bypass and was sustained throughout the duration of the study. Patients without AKI, in contrast, had consistently low concentrations of NGAL. When urine NGAL was normalized for serum creatinine excretions, the overall pattern remained consistent, with urine NGAL peaking very early and having a lesser but sustained increase throughout the study. Serum NGAL concentrations, as well, peaked early after CPB, followed by a gradual reduction over the duration of the study, with a lower peak concentration than urine NGAL. Background information: Serial urine and plasma NGAL measurements were analyzed in 71 children who underwent cardiopulmonary bypass surgery. The primary outcome was acute renal failure defined as a 50% increase in serum creatinine from baseline. Reference Mishra J, et al. Lancet. 2005;365:1231-1238.
- Urine NGAL Levels Post-Cardiopulmonary Bypass Urine NGAL measurements were obtained from children (N = 196) undergoing cardiopulmonary bypass (CPB) at different time points to see whether NGAL could predict AKI after CPB. AKI was defined as a ≥50% increase in serum creatinine. NGAL analysis was performed using the ARCHITECT® NGAL assay at various time points post-CPB. Subjects who subsequently developed AKI showed a robust 15-fold increase in urine NGAL within 2 hours and a 25-fold increase at 4 and 6 hours post-CPB compared with patients who did not develop AKI. A statistically significant urine NGAL increase was apparent up to 48 hours after CPB (P &lt;0.05). Serum creatinine increases, in contrast, were delayed by 2 to 3 days after CPB. Background information: This study was performed in children who had no comorbid conditions, such as advanced age, atherosclerotic disease, and diabetes, which makes them the ideal group for biomarker studies. Reference Bennett M, et al. Clin J Am Soc Nephrol. 2008;3:665-673.
- Urine and Plasma NGAL Is Predictive of AKI After Cardiopulmonary Bypass In the same study, the differences between NGAL in AKI versus no AKI patients for plasma and serum were statistically significant. The area under the ROC curve for plasma NGAL was 0.85 (95% CI 0.73-0.97) 2 hours after CPB and 0.96 for the urine NGAL/creatinine ratio. A sensitivity of 92.7% and specificity of 77.8% was obtained for urine NGAL/mmol creatinine, and a sensitivity of 80% and specificity of 90% was obtained for plasma NGAL. The AUC for urine NGAL was superior to plasma NGAL. Reference Tuladhar SM, et al. J Cardiovasc Pharmacol. 2009.
- Use of NGAL in Patients at Risk for Cardiac Surgery-Associated AKI A recent article analyzed the use of biomarkers for assessing AKI in patients undergoing cardiac surgery-associated AKI. The authors indicate that lack of early biomarkers for AKI has prevented timely interventions to mitigate the effects of AKI. Because serum creatinine is not a timely marker of AKI, it cannot be used to institute potentially effective therapies to treat AKI in patients during phases when the injury is still potentially reversible. The authors identified specific clinical conditions that represent high risk for cardiac surgery-associated AKI (as shown on the slide) and they recommend that serial testing of NGAL should be conducted in patients with these conditions. The authors concluded that NGAL measurement in patients at risk for cardiac surgery-associated AKI can facilitate its early diagnosis and allow clinicians to implement therapeutic adjustments that have the potential to reverse renal cellular damage and minimize further kidney injury. Reference Cruz DN, et al. J Thorac Cardiovasc Surg. 2010;139:1101-1106.
- NGAL for the Diagnosis of AKI in the Emergency Department The objective of this study was to test the sensitivity and specificity of a single measurement of urine NGAL and other urine proteins, to detect AKI in a spectrum of patients. In this prospective cohort study, urine and blood samples were collected from 635 patients presenting to the emergency department for hospital admission. These patients had normal kidney function or acute kidney injury, prerenal azotemia, or chronic kidney disease. Patient samples were assessed for levels of NGAL, creatinine, N-acetyl-β-D-glucosaminidase, α1-microglobulin, α1-acid glycoprotein. The results indicated that NGAL was highly specific and sensitive for acute kidney injury. Moreover, in multiple logistic regression, urine NGAL level was highly predictive of clinical outcomes, including nephrology consultation, dialysis, and admission to the intensive care unit (odds ratio, 24.71 [CI, 7.69 to 79.42]). The investigators concluded that a single measurement of urine NGAL helps to distinguish acute injury from normal function, prerenal azotemia, and CKD and predicts poor inpatient outcomes. Background information: Patients with acute kidney injury had a significantly elevated mean urine NGAL level compared with the other kidney function groups (416 μg/g creatinine [SD, 387]; P = 0.001). At a cutoff value of 130 μg/g creatinine, sensitivity and specificity of NGAL for detecting acute injury were 0.900 (95% CI, 0.73 to 0.98) and 0.995 (CI, 0.990 to 1.00), respectively, and positive and negative likelihood ratios were 181.5 (CI, 58.33 to 564.71) and 0.10 (CI, 0.03 to 0.29); these values were superior to those for N-acetyl-β-D-glucosaminidase, α1-microglobulin, α1-acid glycoprotein, fractional excretion of sodium, and serum creatinine. Reference Nickolas TL, et al. Ann Intern Med. 2008;148:810-819.
- Meta-Analysis: Accuracy of NGAL in AKI Due to varying definitions of AKI, different clinical settings, and variation in timings of NGAL measurement, the utility of NGAL as a biomarker and a standardized cutoff value had not been established. The aim of this meta-analysis was to determine the early diagnostic and prognostic accuracy of NGAL levels for acute kidney injury (AKI) and estimate a clear cutoff NGAL value for early AKI detection. Haase et al performed a systematic review and meta-analysis of 19 diagnostic studies (2538 patients) to estimate the diagnostic and prognostic accuracy of NGAL for early detection of AKI. The study shows that NGAL is a valuable and early predictor of AKI, both overall and across a diverse range of clinical settings. The predictive value of NGAL in adults was useful; however, it was lower and showed greater variation compared with the value of NGAL in children. Further investigations evaluating comorbidities and pathophysiological characteristics of AKI need to be carried out. The cutoff NGAL value for optimum sensitivity and specificity to predict AKI across all settings was above 100 ng/mL and varies by indication. In adults, the cutoff value was higher (170 ng/mL) compared with children (100-135 ng/mL). A more consistent cutoff value of &gt;150 ng/mL was identified when using standardized platforms, compared with the variability seen in cutoff values derived from research-based NGAL assay. NGAL levels had prognostic value for clinical outcomes, such as initiation of RRT and mortality. Reference Haase M, et al. Am J Kidney Dis. 2009;54:1012-1024.
- NGAL for Prediction of Chronic Kidney Disease Progression Serum and urine NGAL levels were assessed in a cohort of 96 patients affected by nonterminal chronic kidney disease (CKD) of various etiology in order to determine whether NGAL could predict the progression of CKD. Progression of CKD was assessed as doubling of baseline serum creatinine and/or onset of endstage renal disease (ESRD) and Kaplan-Meier survival curves were generated of renal endpoint in patients with serum NGAL levels above and below the cutoff level of 435 mg/mL (left) and with urine NGAL levels above and below the cutoff level of 231 ng/mL (right). Patients with elevated NGAL showed a significantly faster progression to endpoint. Reference Bolignano D, et al. Clin J Am Soc Nephrol. 2009;4:337-344.
- Urine NGAL as a Marker for Chronic Heart Failure Patients with chronic heart failure (CHF) frequently have renal dysfunction (as measured by decreased glomerular filtration rate; GFR). It is common for CHF patients to have elevated urinary albumin excretion (UAE) levels even if GFR is only mildly impaired. Patients with CHF were assessed for GFR, UAE, and urine NGAL levels to establish the relationship between NGAL and GFR and NGAL and UAE in this population. Urine NGAL levels were highly elevated in patients with CHF (n = 90) compared with healthy controls (n = 20). NGAL levels were significantly related to the estimated GFR, serum creatinine, and UAE levels. The box plots for NGAL and UAE levels display median (horizontal bars), interquartile ranges (lower and upper limits of boxes), and 5th and 95th percentiles (error bars). Reference Damman K, et al. Eur J Heart Fail. 2008;10:997-1000.
- Urine NGAL as a Predictive Biomarker for Delayed Graft Function Following Kidney Transplantation This study was a prospective, multicenter, observational cohort study of deceased-donor kidney transplant patients to evaluate urine NGAL as a biomarker for predicting dialysis within 1 week of transplant and subsequent graft recovery. Graft recovery was classified as delayed graft function (DGF)*, slow graft function (SGF), or immediate graft function (IGF). Of the 91 patients in the cohort, 34 had DGF, 33 had SGF, and 24 had IGF. Median NGAL levels were statistically different among these three groups at all time points. ROC curve analysis suggested that the ability of NGAL to predict dialysis within 1 wk was moderately accurate when measured on the first postoperative day, whereas the fall in serum creatinine (SCr) was not predictive. In multivariate analysis, elevated levels of NGAL predicted the need for dialysis after adjusting for recipient and donor age, cold ischemia time, urine output, and SCr. NGAL quintiles also predicted graft recovery up to 3 months later. In summary, urine NGAL is an early, noninvasive, accurate predictor of both the need for dialysis within the first week of kidney transplantation and 3-month recovery of graft function. *DGF was defined by at least one dialysis session within 7 days of transplant. In those who did not require dialysis, SGF was defined as a creatinine reduction ratio (difference between SCr at 0 hours and the SCr on day 7 divided by SCr at 0 hours) &lt;0.7, and IGF was defined as a ratio ≥0.7. Reference Hall IE, et al. J Am Soc Nephrol. 2010;21:189-197.
- Case Study 1: 73-Year-Old Male This patient has several risk factors for AKI, including preoperative factors (his age, CHF, DM, CKD) and operative factors (combination of “re-do” CABG plus valve replacement; use and duration of CPB).
- Case Study 1: 73-Year-Old Male (Cont’d) In addition to preoperative and operative risk factors, this patient has and additional postoperative risk factor for AKI: postoperative hypotension requiring intraaortic balloon pump placement. His serum creatinine levels are abnormal at baseline and decrease slightly after CPB. There is a slight increase in serum creatinine at 6 hours, but not a significant change from baseline. The patient had complications from the CPB and the long duration of CPB is another risk factor for AKI. Serum creatinine measurements do not show a significant change, but a slight increase is present at 6 hours after surgery.
- Case Study 1: 73-Year-Old Male (Cont’d) Patient is given a diuretic and requires a blood transfusion. The creatinine is not increased. How do you approach this patient?
- Case Study 1: 73-Year-Old Male (Cont’d) What do the NGAL measurements add to this case? Urinary NGAL drastically increases post-CPB and remains high for 6 hours. Do these measurements provide additive information? At this point, do you treat them for AKI? Compared with the creatinine values, the NGAL measurements help to define the problem sooner.
- Fig 2: New spectrum of AKI based on combination of functional and damage biomarkers As illustrated in this figure the combination of functional and damage biomarkers allows the clinician to differentiate a normal state of kidney function from abnormal to diagnose AKI. The current criteria for diagnosis include the lower two quadrants. This new spectrum enables the recognition of four subgroups of patients according to their AKI state. Patients negative for functional and kidney damage markers are considered to have no AKI (upper left quadrant). The ability to detect a state of damage alone (right upper quadrant) allows an expanded criteria for diagnosis of AKI. This may represent a “subclinical “state in which loss of function might develop several days after detection of kidney damage or not at all, however maybe associated with impaired outcomes. The bottom left quadrant indicates a dynamic change in renal filtration of serum creatinine but without detectable kidney damage that may be physiologic such as seen in patients with dehydration. The right lower quadrant represents patients with functional and damage criteria of AKI associated with the worst prognosis. It is expected that the process is dynamic and patients will move from one phase to another during the course of their illness. Currently there is limited information on what thresholds will be applicable for each of the damage biomarkers for the best diagnostic and staging criteria based on damage criteria alone. This will need to be defined in future studies.
- Fig 3: New criteria for AKI diagnosis are displayed. In order to diagnose AKI selecting the worst criterion (function [RIFLE/AKIN] or damage) is recommended. In the appropriate clinical setting, this new damage biomarker criterion will enhance the ability of RIFLE/AKIN to define AKI. There are currently insufficient injury biomarker data to support staging of AKI, however, AKI stages basing on renal function changes are suggested to remain. The semi-quantitative trend for increasing biomarker severity associated with increasing kidney damage is suggested by the literature and is displayed by darkening background color as well as the symbols: +/++/+++. *Adapted from RIFLE/AKIN criteria. AKIN= acute kidney injury Network; sCrea=serum creatinine; UO=urine output; RRT=renal replacement therapy.