Prognostic Biomarkers For Acute Kidney Injury In Liver Cirrhosis

In 2015 the International Club of Ascites redefined AKI in cirrhosis as an increase in serum creatinine (sCr) of 26.5 µmol/L as even small increases in sCr are clinically relevant and associated with poorer outcomes. The investigators recently conducted a ward-based study of 105 cirrhotic patients admitted to the Royal Infirmary of Edinburgh (RIE) Liver Unit over a 3-month period and showed that 40% of patients developed AKI, and incidence of AKI increased with severity of cirrhosis. Increased AKI stage was associated with incrementally longer hospital stay, at an extra cost to the NHS of ~£400/day (data.gov.uk), and a greater mortality. Indeed, the mortality rate for cirrhotic patients without AKI was 6%, compared to 18%, 35% and 50% in patients with AKI stage 1, 2 and 3 respectively.

sCr is a suboptimal marker of renal dysfunction in advanced cirrhosis. Despite a normal sCr, patients may already have significant renal dysfunction, thus rendering sCr a late marker of AKI. Moreover, recurrent mild episodes of AKI, where sCr may not exceed normal laboratory limits, can lead to a gradual deterioration in baseline renal function, increased susceptibility to further acute insults and higher mortality. There is an urgent unmet need for a superior, more sensitive biomarker (a renal equivalent of troponin I (TnI)) to better identify cirrhotic patients who are most at risk of developing AKI, to aid earlier recognition of kidney impairment and allow rapid and targeted treatment. This is especially important because pre-transplant renal dysfunction in patients with cirrhosis is associated with increased morbidity and mortality after liver transplantation.

The urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP) and albumin, are significantly higher in cirrhotic patients with acute tubular necrosis (ATN), compared with pre-renal AKI and hepatorenal syndrome (HRS). Additionally, L-FABP is a marker of renal hypoxia and has been identified as a promising marker for early diagnosis of AKI, and for predicting dialysis requirement and in-hospital mortality. In view of the progressive renal vasoconstriction that occurs as cirrhosis advances, L-FABP may be a potentially relevant marker, although increased hepatic release may render it non-specific in the context of acute liver injury.

Plasma KIM-1 is a biomarker that is specific and sensitive for both acute and chronic kidney injury. KIM-1 is a transmembrane glycoprotein that is upregulated in proximal tubular cells during AKI. Work from our Group showed that early measurement of plasma KIM-1 was a more sensitive predictor of patient outcome than sCr in AKI after paracetamol-induced acute liver injury. Furthermore, in a cohort of patients with type-1 diabetes, normal sCr and normo/microalbuminuria, an elevated plasma KIM-1 level was strongly associated with risk of early progressive renal decline. However, plasma KIM-1 has never been evaluated in patients with chronic liver disease.

HYPOTHESES

1. Plasma KIM-1 will be higher in patients with cirrhosis who go on to develop AKI and serve as an earlier predictive marker when compared with sCr.
2. Plasma KIM-1 will be more effective at early identification of AKI than other candidate AKI biomarkers (fractional excretion of sodium (FeNa), protein to creatinine ratio (PCR), urinary L-FABP and urinary KIM-1).

Protocol

Blood and urine samples will be collected on admission and day 2, to assess initial trends (in a similar way to TnI). Measurements will be repeated on day 7 (or at discharge if <7 days) as a potential indicator of unresolved AKI. Final follow-up samples will be taken 30 days after discharge. Plasma will be prepared from whole blood samples according to an established SOP and stored along with urine specimens (using a linked anonymised format) at -800 d.c. in the RIE Clinical Research Facility (RIE CRF). KIM-1 will be measured by microsphere-based Luminex technology, as previously described for human plasma. Urinary L-FABP will be measured by ELISA. Outcome data up to 30 days will be collected from TRAK and case note reviews.