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John A. Kellum, MD, MCCM Professor of Critical Care Medicine, Medicine,
Bioengineering and Clinical & Translational Science
Vice Chair for Research
Director, Center for Critical Care Nephrology University of Pittsburgh
Endophenotypes and AKI
Disclosures Consulting: • Adrenomed • AM Pharma • Astellas • Astute Medical • Atox Bio • Baxter • Bioporto • Cheetah Medical • Cytosorbents • Davita • Eliaz Pharma • Elsevier • Grifols • Hepa Wash
•Grant support: • Astellas • Astute Medical • Atox Bio • Baxter • Bioporto • RenalSense • TES Pharma
• Intellectual Property: • Astute Medical • Cytosorbents • PhotoPhage
• Mallinckrodt • Medibeacon • MedScape • Mitobridge • Novartis • NxStage • Oncogna • PhotoPhage • Potrero • Singulex • Sphingotech • Spectral Diagnostics • Sulfateq • TES Pharma
Updated Jan 2019
Endophenotype •…ability to differentiate between potential diagnoses
that present with similar symptoms.
•Genetic epidemiology • Separate behavioral symptoms into more stable phenotypes with a
clear genetic connection. • The concept to explain the geographic distribution of grasshoppers.
1966
•Psychiatric genetics • Bridge the gap between high-level symptom presentation and low-
level genetic variability, such as single nucleotide polymorphisms. • Examples: bipolar disorder and schizophrenia
•Other conditions • ADHD, addiction, Alzheimer's disease, obesity and cystic fibrosis
What is AKI? –AKI Syndromes
• Sepsis-associated AKI
•Nephrotoxic AKI
• Cardiorenal Syndrome
•Hepatorenal Syndrome
•Cardiac Surgery-associated AKI
•Glomerulonephritis
•Obstructive AKI
•Abdominal Compartment Syndrome
What is AKI?
Kellum 2016 Current Opinion in Critical Care
Sepsis and AKI
• Sepsis is the most common etiology of AKI • Approximately 50% of AKI is due to sepsis
• Sepsis causes more severe AKI • Stage 3 occurs in < 5% of CT surgery patients • Stage 3 occurs in > 20% of sepsis patients
•Outcomes from S-AKI are heterogenous • 1 in 3 patients recovery rapidly from S-AKI • 1 in 4 never recover • Reasons for this heterogeneity are unclear
Hoste et al. Intensive Care Med. 2015;41(8):1411-1423. Uchino et al. JAMA. 2005;294(7):813-813. Kellum et al. Am J Resp Crit Care Med. 2016;193(3):281-287.
Fibrosis after functional recovery with CLP in Mice
AKI virtually subclinical by 24h
Yet a pro-fibrotic phenotype emerges as early as 14d
Wen X et al. Under Review
Sepsis
Sepsis: Kidney
Normal
24hrs after sepsis
Gomez et al. SHOCK, Vol. 41, No. 1, pp. 3Y11, 2014
Augusto et al. ICM 2013;38:1826
35% with sepsis-AKI
1 in 3 of sepsis patients
Most Thrombocytopenia not due to DIC
Plts DIC TTP 90-day Mort
<50 37% 7.0% 65%
50-99 6.7% 6.7% 53%
100+ 0% 0% 27%
Pathogenesis of DIC
aHUS
Known genetic defects
Treatment
In-Patient and Out-Patient Encounters 14.6 Million Patients
Sepsis-AKI + Plts <50,000 Mortality: 67.7-68.8%
Conclusions
• Sepsis-associated AKI is common and severe thrombocytopenia (plts <50%) occurs in 20-25%
•DIC appears to explain <50% of cases and TTP <7% of cases.
•Genetic defects known to be causally related to aHUS were found in 3 of 6 patients tested (from a cohort of 1341 patients).
• Specific therapies (Eculizimab) are available
Follow @CCCNPitt ccm.pitt.edu/center-critical-care-nephrology