Mechanisms and Management in Acute Kidney Injury Paul Stevens Kent Kidney Care Centre

Father and Son

Chapter 55: Ischuria Printed for Payne & Foss, Pall Mall, London

What I’m Not Going to Talk About Vasopressors Dopamine agonists Natriuretic peptides Adenosine agonists N-acetylcysteine Loop diuretics and osmotic diuretics Prophylactic dialysis/HF

What I Am Going to Talk About Conceptual models Definition(s) Why does it matter? What’s important? Adding insult to injury UK AKI consensus Could this happen in your hospital? Avoiding AKI

Pathogenesis

Renal Perfusion Parenchymal Structures Urine output Induce  GFR Pre-renal Parenchymatous (intrinsic) Post-renal Sudden causes affecting AKI Called

Acute Kidney Injury Postrenal AKI Intrinsic AKI Prerenal AKI Acute interstitial nephritis Acute tubular necrosis Acute GN Acute vascular syndromes Intratubular obstruction

Glomerular Haemodynamics – Renal Hypoperfusion Hypoperfusion (uncompensated) Decreased afferent blood flow Decreased efferent blood flow Decreased GFR Hypoperfusion (compensated by PGE2 & AII) Preserved GFR Vasodilatation Prostaglandins Vasoconstriction Angiotensin II

Acute Kidney Injury Conceptual Model DeathDeath ComplicationsComplications NormalNormal Increased risk Kidney failure DamageDamage  GFR Antecedents Intermediate Stage AKI Outcomes Markers such as NGAL, KIM-1 and IL-18 are surrogates Damage GFR Mehta et al. Critical Care 2007;11:R31 Stages defined by creatinine and UOP are surrogates

Acute Kidney Injury Defined as any of the Following: “That’s a new term the nephrologists came up with, they’re still working on a definition for it” Definitions…

RIFLE Criteria for AKI GFR criteriaUOP criteria Risk  SCr x1.5 or GFR  >25% UOP <.5ml/kg/h for 6 hrs High sensitivity Injury  SCr x2 or GFR  >50% UOP <.5ml/kg/h for 12 hrs Failure  SCr x3 or GFR  >75% UOP <.5ml/kg/h for 24 hrs or anuria for 12 hrs High specificity Loss Persistent ARF = complete loss of kidney function > 4 weeks ESRF ESRF > 3 months Bellomo et al. Crit Care 2004;8:R204-R212

Acute Kidney Injury Network Criteria StageCreatinine CriteriaUOP Criteria 1 ↑SCr ≥ 26.4 μmol/L or ↑SCr ≥ % 6 hr 2 ↑SCr > % 12 hr 3 ↑ SCr >300% or SCr ≥354 μmol/L + acute ↑ ≥44 μmol/L in ≤24hr or RRT initiated < 0.3 mL/kg/hr for 24 hr or anuria for 12 hr Mehta et al. Crit Care 2007;11:R31 48 hour time constraint

KDIGO AKI Definition Acute kidney injury/impairment (AKI) is defined as any of the following: –Increase in SCr by >0.3 mg/dl (>26.4 µmol/L) within 48 hours, or –Increase in SCr by >1.5-fold above baseline which is known or presumed to have occurred within 7 days, or –Urine volume <0.5 ml/kg/h for 6 hours. KDIGO AKI GL. Kidney inter., Suppl. 2012; 2: 1–138

KDIGO AKI Staging StageSerum creatinineUrine output 1 ≥ times baseline (7 days) OR 26.5 µmol/L increase (48 hrs) < 0.5 ml/kg/hr for 6-12 hrs 2≥ times baseline < 0.5 ml/kg/hr for ≥12hrs 3 ≥ 3.0 times baseline OR increase in creatinine to ≥ 354 µmol/L OR Renal replacement therapy < 0.3 ml/kg/hr for ≥24hrs OR Anuria for ≥ 12hrs KDIGO AKI Guideline. Kidney inter., Suppl. 2012; 2: 1–138

Why Does It Matter? AKI is commoner than many realise Mortality from AKI remains high AKI doubles hospital length of stay AKI predicts subsequent mortality and CKD AKI is costly

What’s Important? Baseline risksClinical conditionsDrugs Advanced ageSepsisContrast media DiabetesHypotension/ShockAntibiotics CKDVolume depletionChemotherapy Heart failureRhabdomyolysisNSAIDs Liver failureCardiac/vasc surgACEI/ARB Male genderNon-renal solid organ Tx Race/geneticMechanical ventilation Low albumin Abdominal compartment syndrome Arterial disease ADQI 4 th Consensus Conference

Key Assessments: All Patients All 3 Key Assessments 2 of 3 Key Assessments 1 of 3 Key Assessments No Key Assessments Stevens et al, QJ Med 2001;94:

Factors Associated with Stage 3 AKI Stevens et al, QJ Med 2001;94: Volume depletion &/or hypotension ObstructionSepsisDrug related N = 288 of which 163 community acquired and 125 hospital acquired

NCEPOD Key Findings Only 50% of AKI care considered good Poor assessment of risk factors Delay in recognition of AKI post-admission in 43% Poor recognition of acute illness, hypovolaemia and sepsis 33% of patients had inadequate investigations 29% had inadequacies in clinical management Complications missed (13%), avoidable (17%) or badly managed (22%)

UK AKI Consensus 2012: Biomarkers, e-Alerts & Fluids Authors/members of Consensus Panel: Feehally J (Co-Chair); Gilmore I (Co-Chair); Barasi S; Bosomworth M; Christie B; Davies A; Dhesi J; Dowdle R; Gibbins C; Gonzalez I; Harding S; Lamont D; Murphy G; Ostermann M; Parr J; Stevens PE

UK AKI Consensus: Apple Pie Stuff Improved training and education Early recognition of AKI All non-elective admissions require –assessment of risk factors for AKI –assessment of volume status –urinalysis –medicines review, ACEi/ARB, NSAID should be withheld pending senior review within 12 hours –baseline SCr and electrolytes repeated within 24 h Agreed nephrology referral criteria management-of-acute-kidney-injury-nov-2012.pdf

UK AKI Consensus: Specifics Fluid therapy should be guided by repeated evaluation of volume status. A balanced salt solution should be the usual fluid for volume replacement Identification of AKI in both primary and secondary care should be facilitated through introduction of e-alert systems It is premature to recommend the use of novel biomarkers of AKI in current clinical practice

Fluid Prescribing: Lessons Not Learned NCEPOD Extremes of Age (1999) –Fluid management in the elderly is often poor; it should be accorded the same status as drug prescription Scottish Audit of Surgical Mortality (2009) –Fluid balance in the surgical patient remains problematic, often managed by relatively junior staff and continuing education and use of appropriate guidance is to be encouraged NICE IV fluid therapy in adults in hospital (2013) –Errors in prescribing, leading to insufficient or excessive provision of IV fluids or electrolytes, are common and have adverse effects on patient morbidity and mortality

AKI and Volume Loading Korean War –Incidence of dialysis requiring AKI 1:200 Vietnam War –Incidence of dialysis requiring AKI 1:600

Colloids –Albumin –Gelatins –Starches Or Crystalloids –0.9% saline –Dextrose –Balanced solutions

Abnormal Saline THE ABUSE OF NORMAL SALT SOLUTION Evans GH. JAMA 1911;LVII(27): “under certain circumstances saline solutions are productive of great harm to the tissues of the body, and are even capable of producing death” ELECTROLYTE SOLUTION APPROXIMATING PLASMA CONCENTRATIONS Fox CL, Winfield JM, Slobody LB, Swindler CM, Lattimer JK. JAMA 1952;148(10): “retention of chloride exceeded the retention of sodium in all experiments with sodium chloride solutions and emphasize the disadvantage of using chloride in replacement solutions in concentrations that are greater than the normal concentration of chloride in plasma”

Crystalloid Solution Characteristics Solution Electrolyte Content (mmol/l) Osmolality (mOsm/kg) pH 0.9% NaClNa + 154Cl Dextrose (4%) Saline (0.18%) Na + 31Cl % DextroseNil Hartmann’s solution Na K + 5 Ca 2+ 2 Cl HCO † Plasma- lyte®148 Na K + 5 Mg Cl - 98 HCO *

Saline vs. Hartmans in Healthy Subjects Double blind crossover study in 10 healthy male volunteers 2 L of 0.9% saline or Hartmann's solution infused over 60 min Subjects not allowed to eat or drink Body weight and blood tests hourly for 6 h Subjects voided their bladders as the need arose and, in all cases, at the end of 6 h No significant difference in baseline parameters prior to infusions Reid et al. Clinical Science 2003;104:17–24

56% of the infused saline was retained, compared with 30% of the Hartmann's solution time to micturition less after Hartmann's than after saline (median: 70 cf. 185 min; p = 0.008) Reid et al. Clinical Science 2003;104:17–24

Saline vs. Plasmalyte® in Healthy Subjects Randomized, double-blind, cross-over study of 2 L of 0.9% saline or Plasma-lyte®148 solution infused over 60 min in 12 male volunteers MRI measurements at t = 90 min to assess renal cortical tissue perfusion and renal artery blood flow velocity Chowdhury et al. Ann Surg 2012;256:18–24

0.9% saline cf. Plasmalyte in Abdominal Surgery Observational study of adult patients undergoing major open abdominal surgery –0.9% saline (30,994 patients) or a balanced crystalloid solution (926 patients) Outcomes –in-hospital mortality 5.6% (saline) vs. 2.9% (balanced) –≥1 major complications 33.7% (saline) vs. 23% (balanced) Treatment with balanced fluid was associated with less –infection (P = 0.006) –renal failure requiring dialysis (P < 0.001) –blood transfusion (P < 0.001) –electrolyte (P = 0.046) and acid-base disturbance (P < 0.001), and intervention (P = 0.02) Shaw et al. Ann Surg 2012;255:821–829

From: Association Between a Chloride-Liberal vs Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults Yunos NM et al. JAMA. 2012;308(15): doi: /jama Chloride rich (0.9% saline, 4% succinylated gelatin solution, or 4% albumin solution) versus chloride poor (Hartmann’s, Plasma-Lyte 148 or chloride-poor 20% albumin) Chloride administration decreased by mmol (from 694 to 496 mmol/patient) from control to intervention periods

Fluid Balance Lesson for Surgeons “The body is not analogous to a tank into which water can be forced until it finally bursts out through the kidneys” Lattimer JK: A Plan for the Management of Anuria. J. Urology, 54: , 1945

AKI and Volume Responsiveness Adapted from Himmelfarb et al Clin J Am Soc Nephrol 2008:3;

Acute Kidney Injury and Sepsis AKI occurs in –19% culture positive in moderate sepsis –23% culture positive in severe sepsis –51% culture positive in septic shock 70% mortality in sepsis and AKI combined Rangel-Frausto et al. JAMA 1995;273: Schrier & Wang NEJM 2004;351:159-69

Assessment and Monitoring: Physiological Observations Initial assessment should include at least: –heart rate –respiratory rate –systolic blood pressure –level of consciousness –oxygen saturation –temperature. Acutely ill patients in hospital: NICE clinical guideline 50

AKI in East Kent: Initial Assessments All AKI n=288 Sepsis & AKI n=74 Respiratory rate29%38% Oxygen status30%49% Blood culture42%66% MSU57%73% CRP18%31% Stevens et al, QJ Med 2001;94:

Assessment Can Be Influenced

Could This Happen in Your Hospital? 37 year old man, depressed 1 litre of Brandy, 24 paracetamol, 12 Nurofen plus at c hrs Vomited, fell asleep against a radiator and woke up the following morning Left leg was uncomfortable on waking and swollen

Presented to A&E a.m. seen by Orthopaedic SHO, admitted, NBM in case of theatre, Voltarol analgesia Muddy brown urine (once) Reviewed at hrs –Tachycardic, lying BP of 130/80 –Unable to move his left leg, left KJ & AJ were absent –Medical SHO called Could This Happen in Your Hospital?

Treated with Parvolex, bloods sent Results –Na 138, K 5.2, Urea 19.1, Creatinine 280, Alb 40, AST Clotting was normal, FBC showed WCC 20.9 (19.3N), Hb 17.8, Plt 247. Paracetamol and aspirin levels were below toxic levels Medical registrar reviewed him at and noted severe oedema in the left thigh, sensory and motor loss in the left leg and muscle fasciculation Could This Happen in Your Hospital?

Avoiding Acute Kidney Injury 1.Recognise and assess the patient at risk 2.Avoid nephrotoxic agents 3.Maintain effective circulatory volume 4.Recognise and treat hypoxia 5.Treat infection, avoid nosocomial infection 6.Pharmacological manipulation to maintain RBF, perfusion pressure and GFR

Per Ardua Ad Urinam Acknowledgements: Air Commodore David Rainford Dr Chris Farmer Jean Irving Helen Hobbs Toby Wheeler Dr Hannah Kilbride Dr Michael Bedford