Evidence-based protocol for diagnosis and treatment of hepatorenal syndrome is independently associated with lower mortality.

BACKGROUND: Hepatorenal syndrome (HRS) is the deadliest complication of cirrhosis. The purpose of this study is to analyze if the use of a protocol for HRS is associated with higher survival in these patients. METHODS: An evidence-based protocol for the diagnosis and treatment of HRS was instituted in 2013. Data from medical records from 2010 to 2016 were obtained by searching the hospital database for patients who received terlipressin, in the three years before and after the institution of the protocol. Data were reviewed to confirm the diagnosis of HRS and multiple variables were collected. Liver-specific scores were calculated and a stepwise Cox regression approach was used for univariate and multivariate analysis. RESULTS: The study included 46 patients, 20 from the pre-protocol period and 26 from the post-protocol period. Respectively, mortality at 30 days, 90 days and 365 days was 75%, 75% and 90% for the pre-protocol period, and 61%, 69% and 80% for the post-protocol period. In the multivariate analysis, an aspartate aminotransferase (AST) of <40U/L, the pre-protocol period and higher Child-Turcotte-Pugh scores were associated with higher 30-day and 90-day mortality. The total mean dose of terlipressin and human albumin used per patient was reduced from 27mg to 22mg and from 236g to 144g, respectively, after the institution of the protocol. This was not associated with higher mortality. CONCLUSION: The use of an evidence-based protocol for the treatment of HRS translated into a higher survival. The authors suggest that the use of evidence-based protocols for the diagnosis and treatment of HRS could reduce cost and mortality in tertiary hospitals.

Deoxyribonuclease partially ameliorates thioacetamide-induced hepatorenal injury.

Several recent studies have shown that liver injury is associated with the release of DNA from hepatocytes. This DNA stimulates innate immunity and induces sterile inflammation, exacerbating liver damage. Similar mechanisms have been described for acute renal injury. Deoxyribonuclease degrades cell-free DNA and can potentially prevent some of the induced tissue damage. This study analyzed the effects of thioacetamide-induced hepatorenal injury on plasma DNA in rats. Plasma DNA of both nuclear and mitochondrial origin was higher in thioacetamide-treated animals. Administration of deoxyribonuclease resulted in a mild, nonsignificant decrease in total plasma DNA and plasma DNA of mitochondrial origin but not of nuclear origin. This was accompanied by a decrease in bilirubin, creatinine, and blood urea nitrogen as markers of renal function. In conclusion, the study confirmed the hepatotoxic and nephrotoxic effect of thioacetamide. The associated increase in cell-free DNA seems to be involved in hepatorenal pathogenesis because treatment with deoxyribonuclease resulted in a partial prevention of hepatorenal injury. Further experiments will focus on the effects of long-term treatment with deoxyribonuclease in other clinically more relevant models. Clinical studies should test endogenous deoxyribonuclease activity as a potential risk determinant for kidney or liver failure.NEW & NOTEWORTHY Thioacetamide-induced hepatorenal injury resulted in higher plasma cell-free DNA. Deoxyribonuclease decreased average cell-free DNA of mitochondrial origin but not nuclear origin. Deoxyribonuclease partially prevented hepatorenal injury in rats.

Neutrophil gelatinase-associated lipocalin in prediction of mortality in patients with hepatorenal syndrome: a prospective observational study.

BACKGROUND & AIMS: Hepatorenal syndrome (HRS) is a severe complication of cirrhosis which is characterized by renal dysfunction and associated with poor survival. Neutrophil gelatinase-associated lipocalin (NGAL) is a troponin-like biomarker for human acute kidney injury. We aimed to investigate levels of plasma and urine NGAL in HRS and predictive ability of these markers for all-cause mortality, in HRS, stable cirrhosis and control subjects. METHODS: A total of 64 patients with cirrhosis (8 patients with type 1 HRS, 22 with type 2 HRS, and 34 without HRS) and 23 control subjects were included in the study. Blood and urine samples were measured with Human NGAL sandwich ELISA. Patients were followed up prospectively. RESULTS: Patients with type 1 and type 2 HRS had significantly higher plasma and urine NGAL levels compared with stable cirrhosis and control subjects. Cox regression analysis showed that plasma NGAL and MELD-Na scores were independent predictors of mortality. ROC-curve analysis showed that the plot of the plasma NGAL, urine NGAL, MELD-Na and Child-Turcot-Pugh score could predict all-cause mortality in cirrhotic patients' area under the curve (AUC 0.819, 0.686, 0.807 and 0.795 respectively). CONCLUSIONS: NGAL could predict mortality in patients with HRS independent of other commonly used risk factors.

Marked enzymuria after bone marrow transplantation: a correlate of veno-occlusive disease-induced "hepatorenal syndrome".

During the first month after bone marrow transplantation, approximately 15% of patients develop acute renal failure (ARF). This usually occurs in the setting of hepatic veno-occlusive disease (VOD). Prior clinical data have suggested that this form of ARF has a hemodynamic basis, analogous to the hepatorenal syndrome (HRS). If so, then proximal tubular injury would not be expected. To directly test this hypothesis, enzymuria (N-acetyl-beta-D-glucosaminidase [NAG]) was quantitated in the following groups of patients within the first 35 days after BMT: (1) VOD+ARF (serum creatinine level > 1.5 mg/dL; N = 10); (2) VOD with relatively normal renal function (serum creatinine level < 1.5 mg/dL; N = 11); and (3) patients without hepatic or renal complications (BMT controls; N = 12). For comparison, NAG was also quantitated in the following groups of non-BMT patients: (1) toxic/ischemic acute tubular necrosis (ATN) (N = 10); (2) jaundice without azotemia (N = 5); and (3) HRS (N = 6). Urine samples from eight healthy subjects established normal NAG concentrations (2.5 +/- 0.5 microU/mg urinary creatinine; mean +/- SE). All non-BMT patients with ATN had markedly elevated NAG levels (61 +/- 12; P < 0.001), validating the test as a marker of tubular damage. NAG concentrations were significantly elevated in all of the control BMT patients (24 +/- 3; P < 0.01), and the presence of VOD was associated with further striking increments (approximately 50 times normal). However, the degree of enzymuria was virtually identical for VOD patients with (125 +/- 27) and without (122 +/- 17) ARF. Jaundice in a non-BMT setting was associated with only mild NAG elevations (11 +/- 2). However, striking enzymuria was noted in all HRS patients (61 +/- 20), equaling the levels seen with ATN. The following conclusions were derived: (1) subclinical tubular injury, as defined by enzymuria, appears to be ubiquitous after BMT; (2) VOD dramatically increases the extent of enzymuria; (3) the degree of enzymuria in VOD patients is not correlated with renal dysfunction, implying that the associated ARF has a large hemodynamic component; and (4) HRS and ATN manifest comparable degrees of enzymuria, suggesting that substantial tubular damage exists in both of these forms of ARF.

Effect of blood purification on the kidney function of the jaundiced rat.

This paper is aimed at evaluating the effect of blood purification on the mitochondrial functions of the kidney in jaundiced rats. At 1, 2, or 3 weeks after bile duct ligation and dissection, obstructive jaundiced rats were utilized for experiment. Cross circulation in 1 ml/min between jaundiced rats and normal rats was performed for 1 or 3 h. Immediately and 24 h after cross circulation, the rats were killed and mitochondrial respiratory functions of the kidney were assessed by measuring oxygen consumption. Mitochondrial function, especially ATP synthesis, showed significant improvement in jaundiced rat with 2 or 3 weeks of biliary obstruction. Cross circulation for 3 h was more effective than that for 1 h. These data suggest that the renal energy production can be increased significantly in obstructive jaundice by blood purification treatment.

Immunohistochemical distribution of renal prostaglandin endoperoxide synthase and prostacyclin synthase: diminished endoperoxide synthase in the hepatorenal syndrome.

To evaluate possible causes of the diminished prostaglandin production in advanced hepatorenal syndrome, prostaglandin endoperoxide synthase and prostacyclin synthase were localized and semiquantitated by immunofluorescence in postmortem, biopsy and nephrectomy renal tissues. In normal kidneys, antiprostacyclin synthase serum caused intense staining in peritubular capillaries, in the adjacent renal interstitial cells and in glomerular mesangial regions. Antiprostaglandin endoperoxide synthase serum caused staining of collecting duct epithelial cells, cells of the thin ascending limb and possibly glomerular mesangial cells. Prostacyclin synthase-positive staining was graded 5+ (scale of 0+ to 5+) in all kidney samples. Medullary collecting tubule prostaglandin endoperoxide synthase-positive staining was graded 4+ or 5+ in kidney samples from patients with acute tubular necrosis or acute tubulointerstitial nephritis and from patients with liver failure without the hepatorenal syndrome. However, prostaglandin endoperoxide synthase-positive staining was markedly diminished or absent (average 1+) in patients with the hepatorenal syndrome. These data suggest that loss of the medullary prostaglandin endoperoxide synthase is the cause of diminished urinary prostaglandin E2 excretion in the hepatorenal syndrome.

Multiple peroxisomal enzymatic deficiency disorders. A comparative biochemical and morphologic study of Zellweger cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy.

Biologic, morphologic, and biochemical investigations performed in 2 patients demonstrate multiple peroxisomal deficiencies in the cerebrohepatorenal syndrome of Zellweger (CHRS) and neonatal adrenoleukodystrophy (NALD). Very long chain fatty acids, abnormal bile acids, including bile acid precursors (di- and trihydroxycoprostanoic acids), and C29-dicarboxylic acid accumulated in plasma in both patients. Generalized hyperaminoaciduria was also present. Peroxisomes could not be detected in CHRS liver and kidney; however, in the NALD patient, small and sparse cytoplasmic bodies resembling altered peroxisomes were found in hepatocytes. Hepatocellular and Kupffer cell lysosomes were engorged with ferritin and contained clefts and trilaminar structures believed to represent very long chain fatty acids. Enzymatic deficiencies reflected the peroxisomal defects. Hepatic glycolate oxidase and palmitoyl-CoA oxidase activities were deficient. No particle-bound catalase was found in cultured fibroblasts, and ether glycerolipid (plasmalogen) biosynthesis was markedly reduced. Administration of phenobarbital and clofibrate, an agent that induces peroxisomal proliferation and enzymatic activities, to the NALD patient did not bring about any changes in plasma metabolites, liver peroxisome population, or oxidizing activities.