1. The Ins and Outs of Acute Kidney Injury: pathophysiology, clinical relevance and new concepts Ayla R. Preston, DVM, MS Practice Limited to Emergency and Critical Care

2. 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

3. 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

4. Pathophysiology Decreased renal function in AKI is multifactorial and complex at the cellular level ▫Decreased intrarenal blood flow ▫Cellular damage

5. Pathophysiology Four phases of AKI ▫Initiation ▫Extension ▫Maintenance ▫Recovery

6. 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

7. 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.

8. 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

9. 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

10. Risk factors for AKI Hetastarch ▫Growing evidence to support this in people Fluid overload Hypotension Infarction Ischemia Renal toxic drugs ▫Aminoglycosides ▫NSAIDs Infectious diseases

11. Poor prognostic indicators (dogs) Creatinine > 10 mg/dL Hypocalcemia Hyperphosphatemia Anemia Decreased urine output Lack of improvement/worsening of azotemia Pancreatitis Sepsis

12. Poor prognostic indicators (cats) Significantly lower levels of: ▫PCV ▫WBC ▫Albumin ▫LDH ▫Blood glucose ▫Body temperature Older patients

13. 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)

14. 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 hr Injury 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

15. 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

16. Stage 1 Creatinine increase from 150-199% from baseline Or creatinine increase of 0.3 mg/dL from baseline Stage 2 Creatinine increase from 200-299% from baseline Stage 3 Creatinine increase >300% from baseline Or absolute creatinine value > 4 mg/dL

17. 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

18. 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

19. Important point Small increases in SCr are clinically relevant even when absolute values are within reference intervals

20. New concepts Dogs appear to share similar cellular mechanisms of AKI when looking histopathologically Hydroxyethyl starches and AKI ▫Significant concern in human medicine

21. 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

22. 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?

23. 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)

24. 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

25. Histopathologic evaluation Assessing for the presence of apoptosis in the study and control dogs

26. 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

27. 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

28. 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

29. 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)

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

37. Proposed mechanisms of injury Osmotic nephrosis ▫Talked about most commonly Tubular plugging due to viscous urine Inflammation of the renal interstitium

39. 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

40. 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

41. How common is AKI 2 0 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

43. 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

44. Ayla R. Preston, DVM, MS, Practice Limited to ECC Small Animal Emergency and Critical Care Four Seasons Veterinary Specialists 970-800-1106 (w) draylab@gmail.com Questions?