Sepsis induced Acute Kidney Injury

1. Sepsis induced Acute Kidney Injury Pathophysiology and Epidemiology Joseph A Carcillo MD Center for Critical Care Nephrology Children’s Hospital of Pittsburgh and University of Pittsburgh School of Medicine

2. My Disclosures I hold a US patent on use of Type IV PDEI to prevent and treat sepsis induced renal injury I am the taskforce chair of the ACCM guidelines for hemodynamic support of newborn and pediatric septic shock I am a member of the Center of Critical Care Nephrology at the University of Pittsburgh

3. Overview • Magnitude of problem – associated effects • S-AKI: Pathophysiology • Can we pick up potential cases before they hit hard ? : Early recognition and prevention of AKI • Prevention of damage if AKI occurs

4. Early acute kidney injury and sepsis: a multi-centre evaluation Sean M Bagshawet al for the ANZICS Database Management Committee • Total ICU patients - 120,123 • Patients with sepsis - 33,375 (27.8%). • Patients with septic AKI - 14,039 (42.1%) • Stratification by RIFLE • Risk Category - 38.5% • Injury Category - 38.8% Failure Category-22.7%

6. Sepsis Prevalence, Outcomes, and Therapies (SPROUT) study • SPROUT study :prospective, cross-sectional study of the point prevalence, therapies, and outcomes for pediatric patients with severe sepsis admitted to a PICU • Study population :7,000 children across 128 sites in 26 countries OUTCOMES: Paediatric severe sepsis : accounts >8% of all critically ill children. A typical 16-bed PICU is likely to be treating at least one critically ill child for severe sepsis at any given time. PICU and hospital mortality rates were 24% and 25%, respectively Weiss, Fitzgerald, Pappachan, et al.: Am J RespirCrit Care Med Vol 191, Iss 10, pp 1147–1157, May 15, 2015

7. Sepsis Prevalence, Outcomes, and Therapies (SPROUT) study Acute Kidney Injury in Pediatric Severe Sepsis: An Independent Risk Factor for Death and New Disability Crit Care Med. 2016 Aug 10. AIM : Global prevalence of paediatric septic AKI Association of septic AKI with mortality or composite outcome of new disability No acute kidney injury or stage 1 acute kidney injury (“no/mild acute kidney injury”) vs Stage 2 or 3 acute kidney injury (“severe acute kidney injury”). Primary outcome - Composite of death or new moderate disability at discharge defined as a Pediatric Overall Performance Category score of 3 or higher and increased by 1 from baseline. Julie C. Fitzgerald, Rajit K. Basu, Akash Deep, for the Sepsis PRevalence, OUtcomes, and Therapies Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators Network

8. Patients with no AKI versus those with stage 2/3 AKI 493 patients enrolled in the SPROUT study with severe sepsis had AKI 21% had severe AKI

9. Sepsis Prevalence, Outcomes, and Therapies (SPROUT) study Acute Kidney Injury in Pediatric Severe Sepsis: An Independent Risk Factor for Death and New Disability Crit Care Med. 2016 Aug 10. Patient Outcomes Julie C. Fitzgerald, Rajit K. Basu, Akash Deep, for the Sepsis PRevalence, OUtcomes, and Therapies Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators Network

10. What is AKI? Kellum 2016 Current Opinion in Critical Care

23. Sepsis reduced : • Medullary perfusion - average of 1289 to 628 blood perfusion units • Medullary oxygenation from 32 to 16 mm Hg • Urinary oxygenation - from 36 to 24 mm Hg • Restoring blood pressure with norepinephrine further reduced : • Medullary perfusion - to 331 blood perfusion units Medullary oxygenation - 8 mm Hg • Urinary oxygenation - 18 mm Hg. • Cortical perfusion and oxygenation were preserved

24. Conclusions : • Crucial role of intra-renal blood flow mal-distribution in the process of SAKI • Despite large increases in global RBF and renal oxygen delivery, significant hypoperfusion and hypoxia were detected at the medullary but not at the cortical level • This hemodynamic and oxygenation “mismatch” between cortex and medulla occurred before AKI became evident and thus may be a key determinant in initiating SAKI - sepsis-induced nitric oxide synthase–mediated deficit in intra-renal autoregulatory capacity, rendering the renal medulla more susceptible to a hypoxic insult. • Resuscitation of blood pressure with norepinephrine exacerbates medullary hypoxia. • What happens after 6 hours ????? • Medullary oxygenation recovered after 6 hours of norepinephrine • Other indices and subsequent development of AKI was not clear • -

25. Factors predisposing to IAH/ACS : • Sepsis • Large-volume fluid resuscitation • Poly-transfusion • Mechanical ventilation • high intra-thoracic pressures • Acidosis Compliance  CVP PcwP Heart PeeP Diaphragm IAP • IAH • CMP • ITP • PPH Abdomen Compression of renal vasculature--- AKI

26. Photomicrograph of a renal biopsy specimen shows renal medulla, which is composed mainly of renal tubules. Features suggesting acute tubular necrosis are the patchy or diffuse denudation of the renal tubular cells with loss of brush border (blue arrows); flattening of the renal tubular cells due to tubular dilation (orange arrows); intratubular cast formation (yellow arrows); and sloughing of cells, which is responsible for the formation of granular casts (red arrow). Finally, intratubular obstruction due to the denuded epithelium and cellular debris is evident (green arrow); note that the denuded tubular epithelial cells clump together because of rearrangement of intercellular adhesion molecules

29. Sepsis and AKI pathophysiological interaction in SA-AKI. Reprinted with permission from Romanovsky et al.92

30. Sepsis AKI in Children Post-mortem Fig. 1 Representative histological pictures from some of the enrolled cases. a Section shows glomerulus with mesangial proliferation and blood less glomerulus with fibrinous deposits in the glomerular capillary lumen. Hematoxylin and Eosin stain, ×40. b Sections shows glomerulus with occlusion of fibrin thrombi in glomerular capillaries (thrombotic microangiopathy, highlighted by the arrow heads) with evidence of segmental endocapillary proliferation (arrow). Hematoxylin and Eosin stain, ×40. c Section shows tubules showing evidence of acute tubular necrosis, exemplified by the loss of epithelial nuclei (arrow head) and glomerulus showing evidence of thrombotic microangiopathy (arrow). Hematoxylin and Eosin stain, ×40 • Ramachandran Rameshkumar Email author, SriramKrishnamurthy,RajeshNachiappa Ganesh, Subramanian Mahadevan,ParameswaranNarayanan,PonnarmeniSatheesh,Puneet Jain Clinical and Experimental Nephrology; 2016

31. 10 days in rodents but 6 weeks to 3 months In humans

36. Table I. Pediatric version of the Risk of renal dysfunction; Injury to kidney; Failure of kidney function; Loss of kidney function, ESRD (pRIFLE) classification • eCCL, estimated creatinine clearance. • Pediatric modified RIFLE classification system as per Akcan-Arikan et al6 and reported mortality rate in terms of aORs and AKI by RIFLE.17

39. Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray • Rajit K Basu1, • Stephen W Standage1, • Natalie Z Cvijanovich2, • Geoffrey L Allen3, • Neal J Thomas4, • Robert J Freishtat5, • Nick Anas6, • Keith Meyer7, • Paul A Checchia8, • Richard Lin9, • Thomas P Shanley10, • Michael T Bigham11, • Derek S Wheeler1, • Prasad Devarajan1, • Stuart L Goldstein1 and • Hector R Wong1Email author • Critical Care201115:R273 Figure 1 Results of the leave-one-out cross-validation procedure involving 21 gene probes. The procedure was based on a Support Vector Machines algorithm and was targeted at prediction of 'SSAKI' and 'no SSAKI' classes. Performance calculations provided as the percentage with 95% confidence intervals (CIs). LR, likelihood ratio; NPV, negative predictive value; PPV, positive predictive value; SSAKI, sepsis-shock-associated acute kidney injury.

40. Cell Cycle Arrest In Response To Cell Stress • An Alarm Signal Of Impending Cell Damage Nephrocheck

41. Sepsis Surgery Kashani et al. Critical Care 2013, 17:R25

42. Prevalence of Acute Kidney Injury, According to Stage, during the First Week of ICU Admission. Kaddourah A et al. N Engl J Med 2017;376:11-20 Kaddourah A et al. N Engl J Med 2017;376:11-20.

43. Kaplan–Meier Survival Curves According to Maximum Stage of Acute Kidney Injury (AKImax). Kaddourah A et al. N Engl J Med 2017;376:11-20.

44. Akash Deep, et al King’s College , London • Fluid-refractory septic shock between September 2010 and February 2014 • Non-invasive ultrasound cardiac output monitoring (USCOM) used - cardiac index (CI), stroke volume index (SVI), systemic vascular resistance index (SVRI) • Central venous pressure (CVP), central venous oxygen saturation(ScvO2), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP). • Hospital acquired and community acquired septic shock. • Diagnosis and staging of AKI was made using Kidney Disease Improving Global Outcomes criteria (KDIGO). • Correlation between various haemodynamic variables and development of AKI was sought.

45. TABLE – 3 Hemodynamic parameters measured during the first 24 hours of admission to PICU

46. Prediction model using lactate, diastolic blood pressure, SVRI and CVP Deep et al, London

47. Sepsis Associated AKI • Not solely due to hypo-perfusion • Mounting evidence suggests it is multifactorial (particularly inflammation): • ischemia-reperfusion damage • direct inflammatory injury • endothelial cell and microcirculatory dysfunction • micorvascular thrombosis • apoptotic changes