Complications of Cirrhosis
Complications of Cirrhosis
Hepatorenal syndrome (HRS) is an extremely problematic complication of CLD, and (type 1) HRS portends a poor prognosis. An interesting randomized, double-blind, placebo-controlled multicenter clinical trial evaluated the predictors of response to terlipressin and albumin in HRS type 1. HRS reversal was seen in 34% (19/56) vs. 13% (7/56) of patients treated with terlipressin or placebo, respectively (P = 0.002). When therapy was not considered, serum creatinine (SCr) became the only significant predictor of HRS reversal (P = 0.029). The likelihood of HRS reversal in either treatment arm was greatest in those with SCr below 3.0 mg/dl (50% response rate with terlipressin vs. 33% in placebo), less so in those with SCr of 3.0–5.0mg/dl (31% response rate with terlipressin vs. 9% in placebo), and least in those with SCr above 5.0mg/dl (11% response rate with terlipressin vs. 0% in placebo). On univariate analysis, predictors of overall survival were alcoholic hepatitis, SCr and MELD score. On multivariate analysis, baseline SCr was also predictive of survival (P<0.001), with a 50% increase in risk of mortality for every mg/dl increase in creatinine. Even though the only variable predictive of HRS reversal was baseline SCr, if SCr had not decreased by day 4, patients did not subsequently respond to therapy. Baseline SCr, Child-Pugh score, and presence of alcoholic hepatitis were predictive of survival at 180 days. Although patients responding to terlipressin will show a sustained improvement in mean arterial pressure (MAP) during therapy, the change in MAP immediately following the administration of terlipressin is not predictive of a response. One might consider the use of terlipressin with albumin in HRS type 1 if SCr is less than 5 mg/dl; however, once the SCr exceeds 7 mg/dl, or if the SCr does not decrease by day 4, the likelihood of response with terlipressin is negligible and the utility of using it can be questioned. Unfortunately, terlipressin continues to be unavailable in the US at this time.
Another RCT examined whether pentoxifylline might prevent HRS in cirrhotics with ascites; this study compared pentoxifylline 400mg p.o. t.i.d. (group A) to placebo (group B) for 6 months. Those in group A had an improvement in creatinine clearance at 1 (P = 0.001) and 3 months (P = 0.001) without any significant changes in SCr over a 1, 3, and 6-month period. Also, there was an improvement in sodium and MAP at 1, 3 and 6 months (P = 0.01). Those in group B had an increase in SCr at 1 month (P = 0.007), 3 months (P = 0.001), and 6 months (P = 0.001) with a decline in serumsodium at 1 month (P = 0.02) and 6 months (P = 0.002). Overall 21% of patients developed HRS [2 patients in group A (6%) and 10 patients in group B (32%); P = 0.01] with 75% of patients responding to terlipressin and albumin. There was no difference found between the cause of cirrhosis and occurrence of HRS; however, patients who developed HRS had higher TNF-a (P = 0.01), lower MAP (P = 0.01), and lower serum sodium levels (P = 0.003), according to baseline characteristics. Hence pentoxifylline can be considered in preventing HRS in patients with cirrhosis and ascites at risk for HRS if creatinine clearance is between 41 and 80 ml/min.
An interesting study characterized the types of renal dysfunction in 152 cirrhotics admitted with SCr of at least 1.5 mg/dl; 70% of patients had acute kidney injury (AKI), 17% had chronic kidney disease (CKD) with associated AKI, and 13% had CKD alone. The cause of renal dysfunction was further characterized as prerenal azotemia, intrinsic renal disease, HRS type 1, HRS type 2, and postrenal disease; of which 56, 33, 9, 0, and 2% of the cohort were represented, respectively. The overall mortality for the cohort was 31%, the highest of which was found in type 1 HRS overall (11/14 or 79%), with 8/11 (73%) presenting with AKI only, and 3/3 (100%) presenting with AKI þ CKD. The mortality figure for type 1 HRS is typical and is consistent with a robust patient cohort. It was interesting that the authors were unable to identify any patients meeting diagnostic criteria for type 2 HRS as defined according to the International Ascites Club criteria, suggesting that the diagnostic criteria for this form of HRS may need re-evaluation, or more interestingly, that HRS type 2 may not represent a unique functional kidney disorder.
Hepatorenal Syndrome
Hepatorenal syndrome (HRS) is an extremely problematic complication of CLD, and (type 1) HRS portends a poor prognosis. An interesting randomized, double-blind, placebo-controlled multicenter clinical trial evaluated the predictors of response to terlipressin and albumin in HRS type 1. HRS reversal was seen in 34% (19/56) vs. 13% (7/56) of patients treated with terlipressin or placebo, respectively (P = 0.002). When therapy was not considered, serum creatinine (SCr) became the only significant predictor of HRS reversal (P = 0.029). The likelihood of HRS reversal in either treatment arm was greatest in those with SCr below 3.0 mg/dl (50% response rate with terlipressin vs. 33% in placebo), less so in those with SCr of 3.0–5.0mg/dl (31% response rate with terlipressin vs. 9% in placebo), and least in those with SCr above 5.0mg/dl (11% response rate with terlipressin vs. 0% in placebo). On univariate analysis, predictors of overall survival were alcoholic hepatitis, SCr and MELD score. On multivariate analysis, baseline SCr was also predictive of survival (P<0.001), with a 50% increase in risk of mortality for every mg/dl increase in creatinine. Even though the only variable predictive of HRS reversal was baseline SCr, if SCr had not decreased by day 4, patients did not subsequently respond to therapy. Baseline SCr, Child-Pugh score, and presence of alcoholic hepatitis were predictive of survival at 180 days. Although patients responding to terlipressin will show a sustained improvement in mean arterial pressure (MAP) during therapy, the change in MAP immediately following the administration of terlipressin is not predictive of a response. One might consider the use of terlipressin with albumin in HRS type 1 if SCr is less than 5 mg/dl; however, once the SCr exceeds 7 mg/dl, or if the SCr does not decrease by day 4, the likelihood of response with terlipressin is negligible and the utility of using it can be questioned. Unfortunately, terlipressin continues to be unavailable in the US at this time.
Another RCT examined whether pentoxifylline might prevent HRS in cirrhotics with ascites; this study compared pentoxifylline 400mg p.o. t.i.d. (group A) to placebo (group B) for 6 months. Those in group A had an improvement in creatinine clearance at 1 (P = 0.001) and 3 months (P = 0.001) without any significant changes in SCr over a 1, 3, and 6-month period. Also, there was an improvement in sodium and MAP at 1, 3 and 6 months (P = 0.01). Those in group B had an increase in SCr at 1 month (P = 0.007), 3 months (P = 0.001), and 6 months (P = 0.001) with a decline in serumsodium at 1 month (P = 0.02) and 6 months (P = 0.002). Overall 21% of patients developed HRS [2 patients in group A (6%) and 10 patients in group B (32%); P = 0.01] with 75% of patients responding to terlipressin and albumin. There was no difference found between the cause of cirrhosis and occurrence of HRS; however, patients who developed HRS had higher TNF-a (P = 0.01), lower MAP (P = 0.01), and lower serum sodium levels (P = 0.003), according to baseline characteristics. Hence pentoxifylline can be considered in preventing HRS in patients with cirrhosis and ascites at risk for HRS if creatinine clearance is between 41 and 80 ml/min.
An interesting study characterized the types of renal dysfunction in 152 cirrhotics admitted with SCr of at least 1.5 mg/dl; 70% of patients had acute kidney injury (AKI), 17% had chronic kidney disease (CKD) with associated AKI, and 13% had CKD alone. The cause of renal dysfunction was further characterized as prerenal azotemia, intrinsic renal disease, HRS type 1, HRS type 2, and postrenal disease; of which 56, 33, 9, 0, and 2% of the cohort were represented, respectively. The overall mortality for the cohort was 31%, the highest of which was found in type 1 HRS overall (11/14 or 79%), with 8/11 (73%) presenting with AKI only, and 3/3 (100%) presenting with AKI þ CKD. The mortality figure for type 1 HRS is typical and is consistent with a robust patient cohort. It was interesting that the authors were unable to identify any patients meeting diagnostic criteria for type 2 HRS as defined according to the International Ascites Club criteria, suggesting that the diagnostic criteria for this form of HRS may need re-evaluation, or more interestingly, that HRS type 2 may not represent a unique functional kidney disorder.
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