The Ins and Outs of Acute Kidney Injury: pathophysiology, clinical relevance and new concepts

Ayla R. Preston, DVM, MSPractice Limited to Emergency and Critical Care

Background•Clinical problem in the critically ill•Acute kidney injury (AKI) defined

▫Acute reduction in function that may only be reflected by small increases in serum creatinine

•Mortality of AKI▫Human medicine

~50%▫Veterinary medicine

~60% in dogs ~64% in cats

Background• Why not acute renal failure (ARF)?

▫ARF = rapid, sustained decrease in renal function▫Not very specific▫Diagnose ARF when patient is azotemic

• Why AKI?▫First termed by the Acute Kidney Injury Network

(AKIN)▫Incorporates entire spectrum of ARF▫Identifies minor changes in renal function

(important)▫Has prognostic indications

Pathophysiology•Decreased renal function in AKI is

multifactorial and complex at the cellular level ▫Decreased intrarenal blood flow▫Cellular damage

Pathophysiology•Four phases of AKI

▫Initiation▫Extension▫Maintenance▫Recovery

Pathophysiology•Initiation phase

▫When pathologic damage is initiated▫May not have abnormal laboratory values▫Pre-renal causes

Shock, hypotension, dehydration▫Renal causes

Ischemia, infarction, toxins, infectious diseases, drugs , HES, acute pancreatitis, MODS

▫Post-renal causes Urolithiasis, urethral obstruction, uroabdomen

Pathophysiology•Extension

▫Downstream effects of the initial event (propagation)

▫Laboratory abnormalities may not be evident

▫Mechanisms can be complex and depend upon underlying etiology Ischemia, inflammation, oxidative damage,

tubular dysfunction, cellular hypoxia, etc.

Pathophysiology•Maintenance

▫May last for days to weeks▫Characterized by:

Azotemia Uremia Combination Variable urine production

▫Nephron dysfunction may continue from mechanisms described in the extension phase

Pathophysiology •Recovery

▫Renal tubules can undergo repair▫Azotemia improves▫May or may not have complete return of

“pre-injury” renal function▫Patients generally very polyuric during this

phase of AKI

Risk factors for AKI•Hetastarch

▫Growing evidence to support this in people •Fluid overload•Hypotension•Infarction•Ischemia•Renal toxic drugs

▫Aminoglycosides▫NSAIDs

•Infectious diseases

Poor prognostic indicators (dogs)•Creatinine > 10 mg/dL•Hypocalcemia•Hyperphosphatemia•Anemia•Decreased urine output•Lack of improvement/worsening of

azotemia•Pancreatitis•Sepsis

Poor prognostic indicators (cats)•Significantly lower levels of:

▫PCV▫WBC▫Albumin▫LDH ▫Blood glucose▫Body temperature

•Older patients

Diagnosis of AKI•Risk, Injury, Failure, Loss, End-stage

renal disease (RIFLE)•Acute Kidney Injury Network (AKIN)•Veterinary Acute Kidney Injury Staging

System (VAKI)•International Renal Interest Society

(IRIS)

• Increase in SCr x 1.5 • GFR decrease > 25%• UO < 0.5 ml/kg/hr x 6 hr

Risk• Increase in SCr x 2.0• GFR decrease > 50%• UO < 0.5 ml/kg/hr x 12

hrInjury

• Increase in SCr x 3.0• GFR decrease > 75%• UO < 0.3 ml/kg/hr x 24

hr or anuria x 12 hr

Failure

• Persistent ARF = complete loss of renal function x 4 weeks

Loss

• End-stage renal disease

ESRD

Three stages

Two outcomes

RIFLE in the clinic setting •Severe dog fight presents to Urgent Care

▫Stabilized, maintained on intravenous fluid therapy

▫Baseline serum creatinine (SCr) = 0.5 mg/dL

▫SCr 48-hours later = 1.0 mg/dL Don’t over look this change! Yes, SCr is in the normal reference range,

however…▫Injury category

Stage 1• Creatinine increase from 150-199% from

baseline• Or creatinine increase of 0.3 mg/dL from

baselineStage 2• Creatinine increase from 200-299% from

baseline

Stage 3• Creatinine increase >300% from baseline• Or absolute creatinine value > 4 mg/dL

VAKI in the clinic setting •Hit by car, polytrauma

▫Hypotensive/hypoxemic upon presentation▫Stabilized in the ICU, hospital stay of 4

days▫Baseline SCr = 0.6 mg/dL ▫Highest SCr value = 0.9 mg/dL

Stage 1

Clinical relevance •AKI staging in dogs

▫Modified RIFLE criteria Mortality of dogs in the Injury/Failure category

was significantly higher than those in the Risk category

▫Modified AKIN criteria (VAKI) Dogs meeting AKI criteria were less likely to

survive to discharge▫AKI staging criteria-Cowgill system

Relationship exists between levels of AKI and mortality at 30 and 90 days

Important point•Small increases in SCr are clinically

relevant even when absolute values are within reference intervals

New concepts •Dogs appear to share similar cellular

mechanisms of AKI when looking histopathologically

•Hydroxyethyl starches and AKI▫Significant concern in human medicine

Why might histopathology matter?• Modification of patient therapy

▫Discontinue potentially harmful medications▫Cognizant fluid administration (type, amount)▫Adjustment to anesthesia protocols▫Other potential renal protective therapies▫Initiation of extracorporeal therapies▫Novel interventional therapy

• Owner education▫Prognosis▫Financial investment

Important findings in people •Apoptosis may be

an important factor in AKI secondary to septic shock in people

•Does apoptosis happen in dogs with AKI?

Retrospective study ▫Acute

pancreatitis▫Sepsis▫Septic peritonitis▫Multiple organ

dysfunction syndrome (MODS)

▫Trauma

▫Hemoabdomen▫Disseminated

intravascular coagulation (DIC)

▫Non-renal neoplasia

▫Gastric dilitation volvulus (GDV)

Medical records search (2002-2010)

Increase in SCr during hospitalization Study population

No increase or <1.5 x in SCr during hospitalization Control population

Hospitalization in ICU for at least 48-hours

Normal SCr upon admission

> 2 SCr

Exclusion criteria: -Previous renal disease-Azotemic upon hospital admission-Post-renal causes of azotemia

Histopathologic evaluation•Assessing for the presence of apoptosis in

the study and control dogs

Results •HA-AKI dogs exhibited more severe

histopathologic changes compared to dogs that did not have significant increases in SCr, as evident by increased numbers of apoptotic bodies and TUNEL positive nuclei

Potential application? •Understanding cellular mechanisms for

development of AKI may provide insight into the prevention and treatment of this important organ complication in critical illness

•Special staining may improve our scientific understanding of the underlying apoptotic pathways

Use of HES and AKI-what’s the evidence? •Information available is limited to human

medicine•Important information to be aware of •Early trials investigating HES solutions

▫Lancet 2001 (first trial) Frequency of AKI, oliguria, peak SCr were

significantly higher in HES group HES use was an independent factor for AKI

Early trials investigating HES•Based on results from Lancet 2001,

additional studies performed (variable results)▫SOAP study: HES use associated with

higher need for RRT Same finding not present after multivariable

analysis▫CRYCO study: artificial colloids associated

with AKI in a dose-dependent manner▫VISEP study: trial stopped for safety

reasons (high rates of AKI and RRT)

Recent trials investigating HES •Three recent trials looking at HES 130/0.4

▫Theoretically a safer option because of lower MW and MS

▫CRYSTMAS study: no difference between AKIN and RIFLE criteria or mortality up to 90 days Well designed, but deemed underpowered

▫6S trial: HES group had higher need for RRT and had increased mortality at 90 days

▫CHEST trial: higher incidence of AKI in crystalloid group, higher need for RRT in HES group

Meta-analyses comparing HES and crystalloids•Cochrane Reviews

▫2011 34 studies Relative risk (RR) for AKI = 1.5 RR for RRT = 1.38 Increased risk of AKI should be considered

when weighing risk:benefit of HES for resuscitation

Meta-analyses comparing HES and crystalloids•Cochrane Reviews

▫2013 42 studies RR for AKI = 1.59 RR for RRT = 1.31 Conclusion: current evidence suggests that

all HES products increase the risk of AKI and RRT in all patient populations

Meta-analyses comparing HES and crystalloids•JAMA Systematic Review and Meta-

analysis▫2012

38 trials RR for death = 1.07 RR for RRT = 1.32 Conclusion: clinical use of HES for acute

volume resuscitation is not warranted due to serious safety concerns

Experimental studies •Porcine kidney perfusion model

▫Compared 10% HES 200/0.5, 6% HES 130/0.42 and LRS

▫HES decreased urine output and chloride clearance

▫Increased beta-NAG (tubular injury biomarker)

▫Osmotic nephrosis▫Macrophage infiltration, interstitial cell

proliferation

Experimental studies •Rat models of sepsis

▫One study compared 6% HES 130/0.4 and 0.9% NaCL HES resulted in increased serum NGAL

(renal injury biomarker) Increased kidney injury scores based on

histopathologic analysis

Experimental studies •Rat models of sepsis

▫Another study compared two formulations of 6% HES 130/0.42 vs crystalloid No independent effect of HES on

inflammatory mediator expression in the kidney

No independent effect of HES on urine/serum NGAL concentrations

Proposed mechanisms of injury•Osmotic nephrosis

▫Talked about most commonly •Tubular plugging due to viscous urine•Inflammation of the renal interstitium

Osmotic nephrosis•Does not always result in proximal tubular

dysfunction•Can develop and disappear without

clinical signs•AUS findings

▫Non-specific•Urinalysis

▫Tubular proteinuria ▫Vacuolated tubular cells

Osmotic nephrosis•Autopsy results in people

▫Large, pale kidneys•Histopathology

▫Focal or diffuse “clear-cell” transformation of proximal tubular renal epithelial cells

▫Tiny vesicles under apical cell membrane▫Fine vacuolization of the cytoplasm

How common is AKI 20 to HES in VM?•We don’t know (yet)•Some argue AKI secondary to HES

doesn’t happen in veterinary medicine•Keep in mind the size of human trials

▫Large veterinary trials will likely be indicated to truly evaluate for AKI secondary to colloid use

•While dogs do have more alpha-amylase in their plasma, we are not certain this protects them against complications from HES use

Take home points•AKI is an important disease process in

critically ill patients•Complex physiology•Small changes in SCr should not be overlooked• Beginning to understand what may be

happening at the cellular level•While not yet documented in dogs, the effects

of HES and AKI in human patients/experimental models should be considered

Ayla R. Preston, DVM, MS, Practice Limited to ECC

Small Animal Emergency and Critical Care Four Seasons Veterinary Specialists970-800-1106 (w) draylab@gmail.com

Questions?