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

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