Diagnosis and Management of AKI in Patients With Cirrhosis
Diagnosis and Management of AKI in Patients With Cirrhosis
AKI is defined as an acute significant reduction in the glomerular filtration rate (GFR). sCr remains the most practical biomarker of renal function in patients with ARF (with or without cirrhosis). However, sCr as a biomarker of renal function has many limitations in clinical practice since it is influenced by bodyweight, race, age, and gender. The use of sCr in patients with cirrhosis is also affected by: (1) decreased formation of creatinine from creatine in muscles, secondary to muscle wasting; (2) increased renal tubular secretion of creatinine; (3) the increased volume of distribution in cirrhosis that may dilute sCr; (4) interference with assays for sCr by elevated bilirubin. As a consequence, measurement of sCr in patients with cirrhosis overestimates GFR or kidney function. Therefore, the use of a fixed threshold of sCr at 1.5 mg/dL (133 μmol/L) to define AKI in cirrhosis is problematic, because of two crucial problems. The first is that an sCr value of 1.5 mg/dL (133 μmol/L) often signifies that GFR is markedly decreased (to ~30 mL/min); secondly, the fixed threshold does not take into account the dynamic changes in sCr that occur in the preceding days or weeks, which are needed to distinguish between acute and chronic kidney injury. Since the use of a single value of sCr is not sufficient to diagnose AKI, a dynamic definition referring to an acute increase of sCr to ≥50% from baseline to a final value ≥1.5 mg/dL (133 μmol/L) has been used in several clinical studies in patients with cirrhosis (Table 1). AKI, as defined by these criteria, was a strong predictor of in-hospital mortality in patients with cirrhosis.
In recent years, diagnostic criteria have been proposed for the diagnosis of ARF in non-cirrhotic patients, now termed AKI. In particular, two separate bodies developed and published two consensus definitions of AKI: the Acute Dialysis Quality Initiative group for the Risk, Injury, Failure, Loss of Renal Function and End-Stage Renal Disease (RIFLE) criteria; and the Acute Kidney Injury Network (AKIN) group for the AKIN criteria (Table 1). More recently, a panel of experts has suggested combining part of the AKIN criteria (increase of sCr of 0.3 mg/dL (26.5 μmol/L) within 48 h or by ≥50% from baseline together with a reduction in urine output to <0.5 mL/kg/h for >6 h) with part of the RIFLE criteria (increase of sCr ≥50% within 1 week or a reduction in GFR by >25% together with a reduction in urine output to <0.5 mL/kg/h for >6 h), thus leading to the proposal of the Kidney Disease Improving Global Outcome (KDIGO) criteria (Table 1). However, the use of a reduction of urine output in patients with cirrhosis and ascites as a diagnostic criterion is a problem, since these patients are frequently oliguric with avid sodium retention and yet may maintain a relatively normal GFR. Conversely, these patients may have an increased urine output because of diuretic treatment. Thus, urine collection is often inaccurate in clinical practice and the use of kinetic changes in sCr becomes the crux of the definition for the diagnosis of AKI in cirrhosis.
The main differences between these new criteria over the conventional criteria in patients with cirrhosis are the following: (1) an absolute increase in sCr is considered; (2) the threshold of sCr ≥1.5 mg/dL (133 μmol/L) is abandoned; and (3) a staging system of AKI, based on a change in sCr over a slightly longer time frame, arbitrarily set at 1 week to enable assessment for progression of stage (modified from AKIN staging) as well as a regression of stage (Table 1). AKIN criteria have been shown to be a good predictor of mortality in large cohorts of hospitalised cirrhotic patients, including those in intensive care units and the critically ill. More recently, AKI as diagnosed with AKIN criteria has been shown to be associated with increased mortality in patients with cirrhosis who were hospitalised in regular wards in an AKIN stage-dependent fashion. Further, the progression of AKI through stages (eg, from stage 1 to 2 or stage 2 to 3) was strongly correlated with an increased mortality in these patients. Nevertheless, a comparison of the prognostic accuracy of the conventional criteria and the new criteria in patients with cirrhosis was considered crucial for the development of a new algorithm for the management of AKI and was proposed by the ICA in 2011.
However, the cut-off value of 1.5 mg/dL (133 μmol/L) still has important resonance with many clinicians. Two prospective studies have recently shown that a cut-off value of sCr of 1.5 mg/dL (133 μmol/L) is useful to predict progression of AKI and consequently the prognosis in patients with cirrhosis. Thus, an sCr ≥1.5 mg/dL (133 μmol/L) was the only predictive factor for progression of the initial AKI stage (AKI stage at the first fulfilment of AKIN criteria) to a higher AKI stage during hospitalisation (peak AKI stage). Thereafter, it was also shown that the cut-off value of sCr ≥1.5 mg/dL (133 μmol/L) was important when patients with peak AKI stage 1 were considered. In fact, patients with AKI stage 1 could be divided into two groups: those whose peak sCr did not exceed 1.5 mg/dL (stage 1-A), whose short term mortality might be similar to those without AKI and in whom regression might occur more frequently; and those whose peak sCr exceeded 1.5 mg/dL (stage 1-B), whose short term mortality was higher than those without AKI. Patients with AKI stage 2 and 3 have the highest mortality. However, whether these observations can be generalised to all hospitalised patients with cirrhosis should be assessed in future studies. In fact, as far as the impact of peak AKI stage 1 on in-hospital mortality, it has recently been observed that in patients who developed AKI as a consequence of a bacterial infection, those with stage 1 AKI and a final sCr ≤1.5 mg/dL (133 μmol/L) had a higher short term mortality compared to those without AKI. In addition, regarding regression of AKI stage, it has recently been observed (in non-hospitalised patients) that despite resolution of most AKI episodes in patients with advanced cirrhosis, a gradual and significant increase in sCr and a gradual reduction in mean arterial pressure were observed during follow-up, associated with a significant reduction in mid-term survival compared with non-AKI patients. Indeed, the main lesson learnt from the application of AKIN criteria is that even a small increase in sCr should be identified as early as possible for potential early interventions.
Diagnostic Criteria of AKI and Their Application in Patients With Cirrhosis
AKI is defined as an acute significant reduction in the glomerular filtration rate (GFR). sCr remains the most practical biomarker of renal function in patients with ARF (with or without cirrhosis). However, sCr as a biomarker of renal function has many limitations in clinical practice since it is influenced by bodyweight, race, age, and gender. The use of sCr in patients with cirrhosis is also affected by: (1) decreased formation of creatinine from creatine in muscles, secondary to muscle wasting; (2) increased renal tubular secretion of creatinine; (3) the increased volume of distribution in cirrhosis that may dilute sCr; (4) interference with assays for sCr by elevated bilirubin. As a consequence, measurement of sCr in patients with cirrhosis overestimates GFR or kidney function. Therefore, the use of a fixed threshold of sCr at 1.5 mg/dL (133 μmol/L) to define AKI in cirrhosis is problematic, because of two crucial problems. The first is that an sCr value of 1.5 mg/dL (133 μmol/L) often signifies that GFR is markedly decreased (to ~30 mL/min); secondly, the fixed threshold does not take into account the dynamic changes in sCr that occur in the preceding days or weeks, which are needed to distinguish between acute and chronic kidney injury. Since the use of a single value of sCr is not sufficient to diagnose AKI, a dynamic definition referring to an acute increase of sCr to ≥50% from baseline to a final value ≥1.5 mg/dL (133 μmol/L) has been used in several clinical studies in patients with cirrhosis (Table 1). AKI, as defined by these criteria, was a strong predictor of in-hospital mortality in patients with cirrhosis.
In recent years, diagnostic criteria have been proposed for the diagnosis of ARF in non-cirrhotic patients, now termed AKI. In particular, two separate bodies developed and published two consensus definitions of AKI: the Acute Dialysis Quality Initiative group for the Risk, Injury, Failure, Loss of Renal Function and End-Stage Renal Disease (RIFLE) criteria; and the Acute Kidney Injury Network (AKIN) group for the AKIN criteria (Table 1). More recently, a panel of experts has suggested combining part of the AKIN criteria (increase of sCr of 0.3 mg/dL (26.5 μmol/L) within 48 h or by ≥50% from baseline together with a reduction in urine output to <0.5 mL/kg/h for >6 h) with part of the RIFLE criteria (increase of sCr ≥50% within 1 week or a reduction in GFR by >25% together with a reduction in urine output to <0.5 mL/kg/h for >6 h), thus leading to the proposal of the Kidney Disease Improving Global Outcome (KDIGO) criteria (Table 1). However, the use of a reduction of urine output in patients with cirrhosis and ascites as a diagnostic criterion is a problem, since these patients are frequently oliguric with avid sodium retention and yet may maintain a relatively normal GFR. Conversely, these patients may have an increased urine output because of diuretic treatment. Thus, urine collection is often inaccurate in clinical practice and the use of kinetic changes in sCr becomes the crux of the definition for the diagnosis of AKI in cirrhosis.
The main differences between these new criteria over the conventional criteria in patients with cirrhosis are the following: (1) an absolute increase in sCr is considered; (2) the threshold of sCr ≥1.5 mg/dL (133 μmol/L) is abandoned; and (3) a staging system of AKI, based on a change in sCr over a slightly longer time frame, arbitrarily set at 1 week to enable assessment for progression of stage (modified from AKIN staging) as well as a regression of stage (Table 1). AKIN criteria have been shown to be a good predictor of mortality in large cohorts of hospitalised cirrhotic patients, including those in intensive care units and the critically ill. More recently, AKI as diagnosed with AKIN criteria has been shown to be associated with increased mortality in patients with cirrhosis who were hospitalised in regular wards in an AKIN stage-dependent fashion. Further, the progression of AKI through stages (eg, from stage 1 to 2 or stage 2 to 3) was strongly correlated with an increased mortality in these patients. Nevertheless, a comparison of the prognostic accuracy of the conventional criteria and the new criteria in patients with cirrhosis was considered crucial for the development of a new algorithm for the management of AKI and was proposed by the ICA in 2011.
However, the cut-off value of 1.5 mg/dL (133 μmol/L) still has important resonance with many clinicians. Two prospective studies have recently shown that a cut-off value of sCr of 1.5 mg/dL (133 μmol/L) is useful to predict progression of AKI and consequently the prognosis in patients with cirrhosis. Thus, an sCr ≥1.5 mg/dL (133 μmol/L) was the only predictive factor for progression of the initial AKI stage (AKI stage at the first fulfilment of AKIN criteria) to a higher AKI stage during hospitalisation (peak AKI stage). Thereafter, it was also shown that the cut-off value of sCr ≥1.5 mg/dL (133 μmol/L) was important when patients with peak AKI stage 1 were considered. In fact, patients with AKI stage 1 could be divided into two groups: those whose peak sCr did not exceed 1.5 mg/dL (stage 1-A), whose short term mortality might be similar to those without AKI and in whom regression might occur more frequently; and those whose peak sCr exceeded 1.5 mg/dL (stage 1-B), whose short term mortality was higher than those without AKI. Patients with AKI stage 2 and 3 have the highest mortality. However, whether these observations can be generalised to all hospitalised patients with cirrhosis should be assessed in future studies. In fact, as far as the impact of peak AKI stage 1 on in-hospital mortality, it has recently been observed that in patients who developed AKI as a consequence of a bacterial infection, those with stage 1 AKI and a final sCr ≤1.5 mg/dL (133 μmol/L) had a higher short term mortality compared to those without AKI. In addition, regarding regression of AKI stage, it has recently been observed (in non-hospitalised patients) that despite resolution of most AKI episodes in patients with advanced cirrhosis, a gradual and significant increase in sCr and a gradual reduction in mean arterial pressure were observed during follow-up, associated with a significant reduction in mid-term survival compared with non-AKI patients. Indeed, the main lesson learnt from the application of AKIN criteria is that even a small increase in sCr should be identified as early as possible for potential early interventions.
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