AKI: definitions, detection & pitfalls Jon Murray
Previous conventional definition Acute renal failure (ARF) An abrupt and sustained decline in renal excretory function due to a reduction in glomerular filtration rate (GFR) Inconsistent and imprecise definitions have hindered Detection and diagnosis Monitoring and outcome measurements Clinical Management Education and Research
An abrupt and sustained decline in renal excretory function due to a reduction in glomerular filtration rate (GFR) GFR and renal excretory function
Measurement of GFR and renal excretory function In clinical practice assessment of GFR is usually extrapolated from 1. Serum creatinine level 2. Urine output These two parameters used in conventional ARF definitions because 1. Readily available and inexpensive 2. Usually reflect changes to GFR though important caveats
100 AKI: Definition, detection & pitfalls GFR Creatinine (relatively in tandem in steady state [CKD]) Creatinine 1 mg /dl 88 mol/l 50 25 12.5 6.25 Creatinine 2 mg /dl 176 mol/l Creatinine 3 mg /dl 265 mol/l Creatinine 4 mg /dl 354 mol/l Creatinine 5 mg /dl 442 mol/l
AKI: Kidney damage underlying kidney dysfunction ( GFR) precedes creatinine or urine output PITFALL 1 Serum creatinine rise lags behind fall in GFR Acute Illness
GFR Creatinine (does not occur in tandem during AKI) Creatinine 1 mg /dl 88 mol/l No 100 reliable biomarkers of kidney damage Creatinine 2 mg /dl 176 mol/l Changes 50 to biomarkers of kidney function (serum creatinine / urine output) occur some time after kidney insult / damage Creatinine 3 mg /dl 265 mol/l 25 Poor correlation between true GFR and serum creatinine during AKI Creatinine 4 mg /dl 354 mol/l 12.5 egfr of no use during non-steady state of AKI 6.25 Creatinine 5 mg /dl 442 mol/l
PITFALL 2: GFR is not only the determinant of renal creatinine excretion Renal excretion of creatinine glomerular filtration PLUS tubular secretion
Tubular secretion of creatinine most relevant to Patients with CKD and early in course of AKI
Drugs blocking tubular secretion of creatinine Increase serum creatinine independent of GFR (especially in patients with CKD)
So how should do we interpret serum creatinine and urine output? Questions 1. What is normal serum creatinine? 2. What is a patient s baseline creatinine? 3. What represents a significant change in creatinine? 4. Over what timescale should creatinine change occur? 5. What is normal urine output? 6. Can AKI occur in the presence of normal urine output?
Serum Creatinine Measurements typical variables in the steady state Serum Creatinine (proximal tubule) Serum Creatinine
Estimated typical baseline serum creatinine (µmol/l) Effect of age and ethnicity Age (years) Black males Other males Black females Other females 20 24 133 115 106 88 25 29 133 106 97 88 30 39 124 106 97 80 40 54 115 97 88 80 55 65 115 97 88 71 >65 106 88 80 71
Serum Creatinine Measurements acute and chronic variables affecting creatinine measurement
So how should do we interpret serum creatinine and urine output? Questions 1. What is normal serum creatinine? 2. What is a patient s baseline creatinine? Baseline creatinine is considered as the usual creatinine for a patient prior to their current illness Requires interpreting previous results within clinical context Consistently establishing correct baseline is perhaps the major pitfall of any computer-based AKI detection system
So how should do we interpret serum creatinine and urine output? Questions 1. What is normal serum creatinine? 2. What is a patient s baseline creatinine? 3. What represents a significant change in creatinine? 4. Over what timescale should creatinine change occur? 5. What is normal urine output? 6. Can AKI occur in the presence of normal urine output? answers underlie change from ARF (one outcome & definition) to AKI (a syndrome with stages of severity)
Why the change from ARF to AKI? Recognised that following an acute insult to the kidney 1. GFR often occurs in stages leading to a spectrum of outcomes rather than just normal kidney function or kidney failure 2. Acute renal failure is only one of the possible outcomes 3. Recovery from kidney insult is variable (complete, partial or none) 4. Timescale of any recovery is variable Term ARF replaced by acute kidney injury (AKI)
A conceptual model of AKI Preceding stages of increased risk (yellow) Stage where damage occurs but function (GFR) preserved (pink) Stages where damage causes function +/- failure (red) AKI complications & death (purple)
Recognised that following an acute insult to the kidney Even small rises in serum creatinine are independently associated with increased mortality and hence are incorporated into AKI definitions Creatinine 26-35 44-80 88-168 >176 mol/l Unadjusted Age & gender adjusted n = 1564 885 246 105 Multivariable adjusted adjusted for age, gender, diagnosisrelated group, weight, CKD status, and ICD-9-CM codes for respiratory, gastrointestinal, malignant, & infectious diseases Although causality not fully established this and other studies indicate that Mortality associated with change in serum creatinine. Chertow et al. (2005). J Am Soc Nephrol patients 16: 3365 3370. do not just An die increase of their in SCr co-morbidities > 0.5 mg/dl was with associated AKI but with die a 6.5-fold from(95% AKI CI 5.0-8.5) increase in the odds of death, a 3.5-d increase Thomas in LOS, et & al. ~ (2015) $7500 Kidney excess Int:87 costs. (1):62-73
AKI: Definition, Detection & Pitfalls AKI Scoring Systems RIFLE: 3 levels of renal dysfunction & 2 clinical consequences that follow acute kidney insult Category Change in creatinine OR Change in urine output* Risk Injury Failure 25% fall in baseline GFR or 1.5x rise in baseline creatinine 50% fall in baseline GFR or 2x rise in baseline creatinine 75% fall in baseline GFR or 3x rise in baseline creatinine** <0.5ml/kg/hr for > 6 hours <0.5 ml/kg/hr for >12 hours <0.3ml/kg/hr for > 24 hours Or anuria for >12 hours Loss ESRD Persistent loss of kidney function > 4 weeks End-stage kidney disease > 3 months * Worst scoring criteria used to assign RIFLE score ** Or creatinine rise of > 44micromol/l if (new) total creatinine > 350 mol/l Bellomo et al. (2004) 2nd International Consensus Conference of Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004 Aug. 8(4):R204-12
AKI: Definition, Detection & Pitfalls AKI Scoring Systems AKIN criteria: Mehta et al (2007). Crit Care. 2007. 11(2):R31 Category Change in creatinine OR Change in urine output* 1 0.3 mg/dl ( 26.4 μmol/l) Or 1.5-2.0 fold increase from baseline <0.5ml/kg/hr for > 6 hours 2 > 2- to 3-fold increase from baseline <0.5 ml/kg/hr for >12 hours 3 > 3-fold from baseline Or SCr 4.0 mg/dl [ 354 μmol/l] with acute rise 0.5 mg/dl [44 μmol/l]) <0.3ml/kg/hr for > 24 hours Or anuria for >12 hours Differences between RIFLE and AKIN Staging systems for AKI RIFLE assesses SCr changes 7 days AKIN criteria assesses changes 48 hrs AKIN includes less severe injury in diagnostic criteria AKIN avoids using GFR as a marker in AKI no reliable method to measure true real-time GFR & estimated GFRs are unreliable in AKI. AKIN proposed criteria met only after volume status has been optimized and obstructions must be excluded when oliguria used for diagnosis.
AKI: Definition, Detection & Pitfalls AKI Scoring Systems KDIGO criteria (2012): Kidney International 2:1-138 AKI is defined as any of the following: Increase in SCr by 0.3 mg/dl ( 26.5 mol/l) within 48 hours; or Increase in SCr to 1.5 x baseline, known or presumed to have occurred prior 7 days; or Urine volume < 0.5 ml/kg/h for 6 hours. AKI is staged as Category Change in creatinine OR Change in urine output* 1 1.5 1.9 times baseline OR 0.3 mg/dl (26.5 mol/l) increase <0.5ml/kg/hr for > 6 hours 2 2.0 2.9 times baseline <0.5 ml/kg/hr for >12 hours 3 3.0 times baseline OR Increase in serum creatinine to 4.0 mg/dl (353.6 mol/l) OR Initiation of dialysis / CVVH <0.3ml/kg/hr for > 24 hours Or anuria for >12 hours
Summary 1. The term AKI reflects a heterogeneous syndrome that comprises a spectrum of renal and patient outcomes that can follow renal insults. 2. Changes in serum creatinine do not reliably reflect real time changes in GFR - especially in the non-steady state setting of AKI. 3. Renal insult occurs before serum creatinine begins to rise +/- urine output falls. Delay in creatinine rise after onset of renal insult contributes to delays in AKI recognition but no better AKI biomarker routinely available 4. Acute and chronic confounding factors can affect serum creatinine levels independent of changes to GFR 5. Small rises in serum creatinine are independently associated with increased mortality & are thus incorporated into KDIGO AKI diagnosis & staging
Practical Points 1. A seemingly unremarkable / normal serum creatinine (e.g. 115µmol/l) may not be normal and may represent a significant loss of GFR. 2. Look at historical blood results in clinical context to establish baseline creatinine, track changes & consider drugs, muscle mass & other variables affecting creatinine. 3. AKI is typically accompanied by consistent rises in serum creatinine, in the order of at least 26 to 44µmol/l (0.3 to 0.5mg/dL) per day. 4. Slower rates of serum creatinine rise, especially when inter-dispersed by periodic falls in creatinine are more suggestive of pre-renal disease - where fluctuations in serum creatinine largely reflect fluctuations in renal perfusion. 5. During established AKI, diminishing rises in serum creatinine during cases may signal onset of renal recovery especially if accompanied by rise in urine output.