[Paradigm shift in understanding Acute kidney injury in patients with chronic liver disease: From pathophysiology to defining disease entities]. / Paradigmenwechsel im Verständnis der akuten Nierenschädigung bei chronischer Leberinsuffizienz: Von der Pathophysiologie zur Definition von Krankheitsentitäten.

The hepatorenal syndrome (HRS) is only a part of the wide spectrum of renal injury in patients with end-stage liver cirrhosis. Besides that, the advanced liver disease itself, or its underlying causes, as well as comorbidities, like diabetes mellitus, adiposity and arterial hypertension, can directly cause parenchymal renal insults (bile acid nephropathy, ischemic tubular injury, diabetic/hypertensive nephropathy, hepatitis B- and C-associated glomerulonephritis etc.). This kind of kidney injury is collectively described as non-hepatorenal syndrome AKI (non-HRS AKI. Beyond that, accumulating evidence highlights the role of systemic inflammation as an important common factor in the pathogenesis of decompensated liver cirrhosis, acute in chronic liver failure (ACLF) and renal dysfunction.In this review, we discuss recent data about definition, classification and pathophysiology of HRS, HRS-AKI and Non-HRS-AKI and exploit in this regard the diagnostic and prognostic potential of respective newer serum and urine markers.

A Treat-to-Target Concept to Guide the Medical Management of Hepatorenal Syndrome.

BACKGROUND: The principle of treating-to-target has been successfully applied to many diseases with significant improvement in patient care and as a useful guidance for healthcare providers. Appreciation of the central role for arterial vasodilatation in the pathogenesis of hepatorenal syndrome (HRS) has led to routine use of vasoconstrictors in combination with albumin in patients with HRS. An appropriate target to guide such therapy, however, has not yet been established. AIMS: The purpose of the current study was to identify a suitable target that can predict clinical outcome and guide the medical management of type 1 HRS, a condition associated with very poor prognosis. METHODS: A total of 85 patients with type 1 HRS who received a combination therapy of vasoconstrictors and albumin were enrolled. A potential therapeutic target was identified by univariate and multivariate logistic regression analyses. The treat-to-target concept to guide the management of HRS was then tested via a retrospective cohort study. RESULTS: A change in mean arterial pressure (MAP) during treatment was identified as a sole independent predictor for patient survival. Compared with mild or no increase in MAP, achievement in a marked increase in MAP of more than 10 mmHg in these patients was associated with better overall survival and transplant-free survival. Increased MAP to higher than 15 mmHg did not result in further improvement in clinical outcome. CONCLUSIONS: A treat-to-target concept by the use of a specific goal of MAP is feasible and may potentially guide the medical management of type 1 HRS.

Effect of various drugs used in conservative therapy of hepatorenal syndrome: a retrospective drug utilization study.

OBJECTIVES: To analyze the impact of various drugs used in conservative therapy on renal failure and mortality in hepatorenal syndrome (HRS) at a tertiary care teaching hospital. MATERIALS AND METHODS: Retrospective review of hospital admission records was conducted for case records with HRS as diagnosis. Demographic and clinical data and drug utilization pattern were collected in a pre-designed patient information sheet. Impact of various drugs especially hepatoprotector antioxidant, silymarin, on survival benefits in terms of number of patients alive, change in mean arterial pressure (MAP) and change in serum creatinine at the end of treatment period were estimated by univariate and followed by multivariate analysis. RESULTS: Of the total 89 case records, 31 met the eligibility criteria and were included in the analysis. On multivariate analysis, a significant correlation between use of intravenous fluids (IVFs) and survival benefits was observed (P < 0.05); wherein patients treated with IVFs had an increase in log odds of survival by 2.42 (95% CI = 1.06 to 121.13) as compared to patient not treated with IVF. However, MAP was not affected by any of the treatment modalities. While change in serum creatinine level was not significantly (P = 0.06, regression correlation = -0.3) correlated with duration of treatment with IVFs. CONCLUSION: Use of IVFs may be associated with better short-term survival benefits and favor HRS reversal. Use of silymarin as hepatoprotector antioxidant has no beneficial effects on HRS reversal or survival benefits.

Impact of hepatorenal syndrome and liver transplantation.

PURPOSE OF REVIEW: Hepatorenal syndrome (HRS) is an extremely detrimental complication of cirrhosis, with dismal survival in untreated patients. Continued advances in understanding the pathophysiology of HRS have improved HRS recognition and facilitated development of effective treatment strategies. In this article, we review current concepts in HRS pathophysiology, guidelines for HRS diagnosis, effective treatment options presently available, and controversies surrounding liver versus liver-kidney transplant in transplant candidates. RECENT FINDINGS: Published diagnostic criteria for HRS have improved early recognition and intervention in HRS. Increasing data support vasoconstrictor therapy for HRS reversal. Several randomized controlled trials clearly demonstrate efficacy of terlipressin therapy in HRS reversal; although comparable studies are lacking with norepinephrine, preliminary findings suggest that this regime may be the preferred alternative when terlipressin is unavailable for use. In transplant candidates without response to vasoconstrictor therapies, mounting evidence supports simultaneous liver-kidney transplantation if prolonged pretransplant dialysis is required. SUMMARY: Prompt identification and therapy initiation in transplant candidates with HRS may improve transplantation rates and posttransplantation outcomes. Future studies identifying optimal vasoconstrictor regimens, alternative therapies, and factors predictive of response to therapy are needed. The appropriate use of simultaneous liver-kidney transplants in patients with HRS remains controversial and requires further analysis by the transplant community.

Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome.

UNLABELLED: Renal vasoconstriction is a key factor in the development of hepatorenal syndrome (HRS) and may be secondary to increased activities of endothelin-1, a potent renal vasoconstrictor. To assess the effects of tezosentan, a nonselective endothelin receptor antagonist, on renal function in patients with type 2 HRS, six male patients, 56.3 +/- 2.5 years old, with cirrhosis and type 2 HRS were treated with tezosentan; ascending doses of 0.3, 1.0, and 3.0 mg/hour, each for 24 hours, were used for the initial 2 patients, but a constant dose of 0.3 mg/hour for up to 7 days was used for the remaining 4 patients. The glomerular filtration rate, renal plasma flow, 24-hour urinary volume, mean arterial pressure (MAP), heart rate, tezosentan levels, and vasoactive hormones were measured daily. Albumin was given as required. The study was stopped early because of concerns about the safety of tezosentan in type 2 HRS. Five patients discontinued the study early; one stopped within 4 hours because of systemic hypotension (MAP < 70 mm Hg), and 4 patients stopped at approximately 4 days because of concerns about worsening renal function (serum creatinine increased from 180 +/- 21 to 222 +/- 58 micromol/L, P > 0.05) and decreasing urine volume (P = 0.03) but without a significant change in MAP. The plasma tezosentan concentrations were 79 +/- 34 ng/mL at a steady state during infusion at 0.3 mg/hour. The plasma endothelin-1 concentrations increased from 2.7 +/- 0.3 pg/mL at the baseline to 19.1 +/- 7.3 pg/mL (P < 0.05). CONCLUSION: An endothelin receptor blockade potentially can cause a deterioration in renal function in patients with cirrhosis and type 2 HRS. Caution should be taken in future studies using endothelin receptor antagonists in these patients.

Recent advances in the management of hepato-renal syndrome (HRS).

Hepato-renal syndrome (HRS) is a functional renal failure complicating end-stage liver disease. HRS is characterized by marked arterial vasodilation (mainly of the splanchnic bed) and severe renal vasoconstriction. HRS is classified into 2 types: type I HRS shows a rapid and progressive decline in renal function with a very poor prognosis (median survival of about 2 weeks); HRS type 2 has a more stable renal failure, with a median survival of about 6 months. The management of HRS is still a big challenge. The definitive therapy for HRS is liver transplantation (LT); however, the survival rate of HRS patients is poor, and important organ shortage exists. Various approaches have been used for HRS treatment including vasoconstrictor therapy. Recent evidence has shown that vasoconstrictor agents are effective and serve as a bridge to LT; the rationale for vasoconstrictors is to counteract the splanchnic arterial vasodilation and increase the effective arterial blood volume. Thus, renal perfusion and glomerular filtration rates improve. Terlipressin, a V1 vasopressin agonist, has been used frequently. A recent meta-analysis of clinical trials showed that the pooled rate of patients who reversed HRS after terlipressin therapy was 0.52 (95% CI, 0.42; 0.61; P = 0.0001, /2 = 24.6%). The pooled Odds Ratio (OR) for mortality rate in HRS patients who were not responders to terlipressin versus responders was 5.746 (95% CI, 1.5; 21.9; P = 0.0005). Prospective, controlled clinical trials are in progress to address the impact of vasoconstrictor use on survival in HRS patients. Alternative therapies such as transjugular intrahepatic portosystemic shunts (TIPS) and extracorporeal albumin dialysis (ECAD) have given encouraging results but experience is extremely limited.

Polyethylene glycol-modified bilirubin oxidase improves hepatic energy charge and urinary prostaglandin levels in rats with obstructive jaundice.

BACKGROUNDS/AIMS: No study has so far been conducted to clarify whether the presence of hyperbilirubinemia is detrimental to liver and renal functions. In the present study, the effects of polyethylene glycol-modified bilirubin oxidase (PEG-BOX) therapy on liver and renal function tests, hepatic energy charge and urinary prostaglandin levels were evaluated in a rat model of obstructive jaundice. METHODS: Sprague-Dawley rats were used in the experimental model of obstructive jaundice. PEG-BOX or an equivalent amount of PEG alone was intravenously injected into the animals and sampling of blood and urine, and liver harvesting were done sequentially after bile duct ligation. RESULTS: Conventional liver function tests showed no difference between PEG-BOX and control groups. However, bilirubin concentrations in the peripheral blood and liver tissue specimens markedly decreased, and the hepatic energy charge significantly increased in the PEG-BOX group as compared to controls. The blood concentration of bile acid was lower, but its urinary excretion was higher in the PEG-BOX group than in the control group. In vitro incubation of PEG-BOX with serum from rats with obstructive jaundice decreased the concentration of bilirubin but not that of bile acid. The urinary levels of prostaglandin E2 and the thromboxane B2/6-keto-prostaglandin Fla ratio were significantly lower in the PEG-BOX group than in the control group. CONCLUSIONS: The systemic reduction of bilirubin concentration may contribute to normalization of the urinary levels of prostaglandins and thromboxane B2, to decrease in serum bile acid levels, and to improvement of the hepatic energy charge in obstructive jaundice. These findings suggest that preoperative improvement of jaundice may be beneficial to patients with obstructive jaundice.