Justin M. Belcher

Association of AKI With mortality and complications in hospitalized patients with cirrhosis

Acute kidney injury (AKI) is a common and devastating complication in patients with cirrhosis. However, the definitions of AKI employed in studies involving patients with cirrhosis have not been standardized, lack sensitivity, and are often limited to narrow clinical settings. We conducted a multicenter, prospective observational cohort study of patients with cirrhosis and AKI, drawn from multiple hospital wards, utilizing the modern acute kidney injury network (AKIN) definition and assessed the association between AKI severity and progression with in‐hospital mortality. Of the 192 patients who were enrolled and included in the study, 85 (44%) progressed to a higher AKIN stage after initially fulfilling AKI criteria. Patients achieved a peak severity of AKIN stage 1, 26%, stage 2, 24%, and stage 3, 49%. The incidence of mortality, general medical events (bacteremia, pneumonia, urinary tract infection), and cirrhosis‐specific complications (ascites, encephalopathy, spontaneous bacterial peritonitis) increased with severity of AKI. Progression was significantly more common and peak AKI stage higher in nonsurvivors than survivors (P < 0.0001). After adjusting for baseline renal function, demographics, and critical hospital‐ and cirrhosis‐associated variables, progression of AKI was independently associated with mortality (adjusted odds ratio = 3.8, 95% confidence interval 1.3‐11.1). Conclusion: AKI, as defined by AKIN criteria, in patients with cirrhosis is frequently progressive and severe and is independently associated with mortality in a stage‐dependent fashion. Methods for earlier diagnosis of AKI and its progression may result in improved outcomes by facilitating targeted and timely treatment of AKI. (HEPATOLOGY 2013)

Kidney Biomarkers and Differential Diagnosis of Patients With Cirrhosis and Acute Kidney Injury

Acute kidney injury (AKI) is common in patients with cirrhosis and associated with significant mortality. The most common etiologies of AKI in this setting are prerenal azotemia (PRA), acute tubular necrosis (ATN), and hepatorenal syndrome (HRS). Accurately distinguishing the etiology of AKI is critical, as treatments differ markedly. However, establishing an accurate differential diagnosis is extremely challenging. Urinary biomarkers of kidney injury distinguish structural from functional causes of AKI and may facilitate more accurate and rapid diagnoses. We conducted a multicenter, prospective cohort study of patients with cirrhosis and AKI assessing multiple biomarkers for differential diagnosis of clinically adjudicated AKI. Patients (n = 36) whose creatinine returned to within 25% of their baseline within 48 hours were diagnosed with PRA. In addition, 76 patients with progressive AKI were diagnosed by way of blinded retrospective adjudication. Of these progressors, 39 (53%) patients were diagnosed with ATN, 19 (26%) with PRA, and 16 (22%) with HRS. Median values for 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 differed between etiologies and were significantly higher in patients adjudicated with ATN. The fractional excretion of sodium (FENa) was lowest in patients with HRS, 0.10%, but did not differ between those with PRA, 0.27%, or ATN, 0.31%, P = 0.54. The likelihood of being diagnosed with ATN increased step‐wise with the number of biomarkers above optimal diagnostic cutoffs. Conclusion: Urinary biomarkers of kidney injury are elevated in patients with cirrhosis and AKI due to ATN. Incorporating biomarkers into clinical decision making has the potential to more accurately guide treatment by establishing which patients have structural injury underlying their AKI. Further research is required to document biomarkers specific to HRS. (Hepatology 2014;60:622–632)

Clinical Applications of Biomarkers for Acute Kidney Injury

Research into novel therapies for acute kidney injury (AKI) has been hampered by reliance on a diagnosis predicated on changes in serum creatinine level. As a marker for changing kidney function rather than frank kidney injury, creatinine level lacks sensitivity and specificity for the diagnosis of AKI and shows significant lag time before increasing after injury. It has been unclear whether the failure to translate promising results from animal studies in AKI into successful human trials has been caused by lack of therapeutic efficacy or inappropriately delayed application of the intervention. Multiple novel biomarkers with the potential to revolutionize the timing and accuracy of the diagnosis of AKI currently are under investigation. We have chosen to use one of these biomarkers, interleukin 18 (IL-18), to show the ways in which biomarkers at present can supplement the conventional management of AKI. IL-18 is well suited for this analysis because it is both a mediator of and marker for AKI. We describe 2 cases in which reliance on serum creatinine level for the diagnosis of AKI led to diagnostic and management uncertainty. In the context of these cases, we discuss how IL-18 and other biomarkers can facilitate earlier detection, enhance the differential diagnosis, and allow more prescient prognosis. Additionally, we describe the potential role for biomarkers in prospective trial design and discuss the utility of biomarkers in facilitating adequate powering of trials through more accurate characterization of cases and controls.

Acute Kidney Injury in Patients With Cirrhosis: Perils and Promise

A 62-year-old man with cirrhosis secondary to hepatitis C and chronic alcohol abuse was admitted to the intensive care unit with hematemesis and mental status changes. Physical examination showed ascites and stigmata of chronic liver disease. Blood pressure was noted as 87/42 mm Hg and laboratory studies showed a serum creatinine level of 0.8 mg/dL, an estimated glomerular filtration rate of 84 mL/min/1.73 m(2) calculated using the Modification of Diet in Renal Disease Study equation, a serum sodium level of 123 mEq/L, a total serum bilirubin level of 4.3 mg/dL, and an international normalization ratio of 1.6. The patient was resuscitated with packed red blood cells and fresh-frozen plasma and bleeding was controlled. However, on the third day of admission, creatinine level increased to 1.5 mg/dL. Examination of urine sediment showed 1 to 5 bilirubin-stained granular casts per high-powered field and a few renal tubular epithelial cells. The urine sodium level was 21 mEq/L and the fractional excretion of sodium was 0.43%.

Urinary Biomarkers and Progression of AKI in Patients with Cirrhosis

BACKGROUND AND OBJECTIVES AKI is a common and severe complication in patients with cirrhosis. AKI progression was previously shown to correlate with in-hospital mortality. Therefore, accurately predicting which patients are at highest risk for AKI progression may allow more rapid and targeted treatment. Urinary biomarkers of structural kidney injury associate with AKI progression and mortality in multiple settings of AKI but their prognostic performance in patients with liver cirrhosis is not well known. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A multicenter, prospective cohort study was conducted at four tertiary care United States medical centers between 2009 and 2011. The study comprised patients with cirrhosis and AKI defined by the AKI Network criteria evaluating structural (neutrophil gelatinase-associated lipocalin, IL-18, kidney injury molecule-1 [KIM-1], liver-type fatty acid-binding protein [L-FABP], and albuminuria) and functional (fractional excretion of sodium [FENa]) urinary biomarkers as predictors of AKI progression and in-hospital mortality. RESULTS Of 188 patients in the study, 44 (23%) experienced AKI progression alone and 39 (21%) suffered both progression and death during their hospitalization. Neutrophil gelatinase-associated lipocalin, IL-18, KIM-1, L-FABP, and albuminuria were significantly higher in patients with AKI progression and death. These biomarkers were independently associated with this outcome after adjusting for key clinical variables including model of end stage liver disease score, IL-18 (relative risk [RR], 4.09; 95% confidence interval [95% CI], 1.56 to 10.70), KIM-1 (RR, 3.13; 95% CI, 1.20 to 8.17), L-FABP (RR, 3.43; 95% CI, 1.54 to 7.64), and albuminuria (RR, 2.07; 95% CI, 1.05-4.10) per log change. No biomarkers were independently associated with progression without mortality. FENa demonstrated no association with worsening of AKI. When added to a robust clinical model, only IL-18 independently improved risk stratification on a net reclassification index. CONCLUSIONS Multiple structural biomarkers of kidney injury, but not FENa, are independently associated with progression of AKI and mortality in patients with cirrhosis. Injury marker levels were similar between those without progression and those with progression alone.

Early trends in cystatin C and outcomes in patients with cirrhosis and acute kidney injury.

Background. Acute kidney injury (AKI) is a common and severe complication in patients with cirrhosis. Progression of AKI to a higher stage associates with increased mortality. Intervening early in AKI when renal dysfunction is worsening may improve outcomes. However, serum creatinine correlates poorly with glomerular filtration in patients with cirrhosis and fluctuations may mask progression early in the course of AKI. Cystatin C, a low-molecular-weight cysteine proteinase inhibitor, is a potentially more accurate marker of glomerular filtration. Methods. We conducted a prospective multicenter study in patients with cirrhosis comparing changes in cystatin and creatinine immediately following onset of AKI as predictors of a composite endpoint of dialysis or mortality. Results. Of 106 patients, 37 (35%) met the endpoint. Cystatin demonstrated less variability between samples than creatinine. Patients were stratified into four groups reflecting changes in creatinine and cystatin: both unchanged or decreased 38 (36%) (Scr−/CysC−); only cystatin increased 25 (24%) (Scr−/CysC+); only creatinine increased 15 (14%) (Scr+/CysC−); and both increased 28 (26%) (Scr+/CysC+). With Scr−/CysC− as the reference, in both instances where cystatin rose, Scr−/CysC+ and Scr+/CysC+, the primary outcome was significantly more frequent in multivariate analysis, P = 0.02 and 0.03, respectively. However, when only creatinine rose, outcomes were similar to the reference group. Conclusions. Changes in cystatin levels early in AKI are more closely associated with eventual dialysis or mortality than creatinine and may allow more rapid identification of patients at risk for adverse outcomes.

Urine Interleukin 18 and Lipocalin 2 Are Biomarkers of Acute Tubular Necrosis in Patients With Cirrhosis: A Systematic Review and Meta-analysis

BACKGROUND & AIMS Acute kidney injury (AKI) is a common complication in patients with cirrhosis that increases mortality. The most common causes of AKI in these patients are prerenal azotemia, acute tubular necrosis (ATN), and hepatorenal syndrome; it is important to determine the etiology of AKI to select the proper treatment and predict patient outcome. Urine biomarkers could be used to differentiate between patients with ATN and functional causes of AKI. We performed a systematic review and meta‐analysis of published studies to determine whether urine levels of interleukin (IL)18 and lipocalin 2 or neutrophil gelatinase‐associated lipocalin (NGAL) are associated with the development of ATN in patients with cirrhosis. METHODS We searched MEDLINE, Scopus, ISI Web of Knowledge, and conference abstracts through December 31, 2015, for studies that assessed urine biomarkers for detection of acute kidney injury in patients with cirrhosis or reported an association between urine biomarkers and all‐cause mortality in these patients. We included only biomarkers assessed in 3 or more independent studies, searching for terms that included urine biomarkers, cirrhosis, NGAL, and IL18. We calculated the pooled sensitivities and specificities for detection and calculated the area under the receiver operating characteristic curve (AUC) values using a bivariate logistic mixed‐effects model. We used the χ2 test to assess heterogeneity among studies. RESULTS We analyzed data from 8 prospective studies, comprising 1129 patients with cirrhosis. We found urine levels of the markers discriminated between patients with ATN and other types of kidney impairments, with AUC values of 0.88 for IL18 (95% confidence interval [CI], 0.79–0.97) and 0.89 for NGAL (95% CI, 0.84–0.94). Urine levels of IL18 identified patients who would die in the hospital or within 90 days (short‐term mortality) with an AUC value of 0.76 (95% CI, 0.68–0.85); NGAL identified these patients with the same AUC (0.76; 95% CI, 0.71–0.82). CONCLUSIONS In a systematic review and meta‐analysis, we found that urine levels of IL18 and NGAL from patients with cirrhosis discriminate between those with ATN and other types of kidney impairments, with AUC values of 0.88 and 0.89, respectively. Urine levels of IL18 and NGAL identified patients with short‐term mortality with an AUC value of 0.76. These biomarkers might be used to determine prognosis and select treatments for patients with cirrhosis.

Is It Time to Evolve Past the Prerenal Azotemia versus Acute Tubular Necrosis Classification

For more than 70 years, the cornerstone for the diagnosis and management of acute kidney injury (AKI) has been the paradigm wherein its etiologies have been broken down into categories of prerenal, intrinsic, and postrenal disease ([1][1]). With postrenal obstruction usually readily apparent, the

Acute Kidney Injury in Liver Disease: Role of Biomarkers

Acute kidney injury (AKI) is a common complication in patients with advanced cirrhosis and is associated with significant mortality. The most common etiologies of AKI in this setting are prerenal azotemia, acute tubular necrosis, and hepatorenal syndrome. Despite the overall poor outcomes of patients with cirrhosis and AKI, potentially efficacious therapies exist but must be tailored to the specific AKI etiology. Unfortunately, determining the etiology of AKI in the setting of cirrhosis is notoriously difficult. Many of the standard diagnostic tools, such as urine microscopy and the fractional excretion of sodium, have traditionally been ineffective. Novel biomarkers of kidney tubular injury may be able to assist with differential diagnosis and the appropriate targeting of treatments by distinguishing structural from functional causes of AKI. In recent studies, both urinary neutrophil gelatinase-associated lipocalin and interleukin-18 have shown the ability to distinguish hepatorenal syndrome from prerenal azotemia and acute tubular necrosis. In addition, multiple biomarkers, including neutrophil gelatinase-associated lipocalin and interleukin-18, have demonstrated the ability to independently predict both progression of AKI and mortality. Critically, recent research also indicated that commonly available tests, fractional excretion of sodium and proteinuria, may also be able to distinguish etiologies of AKI in cirrhosis, but diagnostic cutoffs must be re-conceptualized specifically to this unique AKI setting.

Development of a Targeted Urine Proteome Assay for kidney diseases

Since human urine is the most readily available biofluid whose proteome changes in response to disease, it is a logical sample for identifying protein biomarkers for kidney diseases.