RESUMO
Acute kidney injury (AKI) is a relatively common condition in patients with advanced liver disease and which is associated with increased mortality. It mainly affects patients with decompensated cirrhosis, particularly those with advanced portal hypertension and ascites. The dual organ involvement may have different forms. The contributing pathogenetic mechanisms are common and predict a dismal prognosis. Early diagnosis and interventions involving specialists (in particular, hepatologists and nephrologists) are essential to improve outcomes.
Assuntos
Injúria Renal Aguda , Síndrome Hepatorrenal , Humanos , Síndrome Hepatorrenal/diagnóstico , Síndrome Hepatorrenal/patologia , Cirrose Hepática/complicações , Injúria Renal Aguda/complicações , Injúria Renal Aguda/diagnóstico , Prognóstico , Ascite/complicações , Ascite/terapia , RimRESUMO
BACKGROUND: Hepatorenal syndrome type 1 (HRS-1), a form of acute kidney injury (AKI) in cirrhosis, has a median survival of days to weeks if untreated. The impact of reduction in AKI stage on overall survival in cirrhosis, independent of HRS reversal, is unclear. METHODS: The Randomized, placEbo-controlled, double-blind study to confirm the reVERSal of HRS-1 with terlipressin study assessed terlipressin versus placebo, both with albumin, as treatment for HRS-1 for ≤14 days. Renal dysfunction severity was categorized by AKI stage at enrollment. Baseline patient characteristics were evaluated as predictors of AKI improvement using a multivariate model; the association between AKI stage reduction and 90-day survival was assessed using linear regression. RESULTS: A total of 184 patients (terlipressin: n = 91; placebo: n = 93) with similar numbers in AKI Stages 1-3 (terlipressin/placebo, Stage 1: n = 25/26; Stage 2: n = 35/33; Stage 3: n = 31/34) were included. Predictors of AKI improvement were absence of alcoholic hepatitis, baseline serum creatinine and male gender. Overall survival was not significantly different across AKI stages (range 53-65%). In patients with no AKI worsening, 90-day survival was consistently better when AKI improved independent of HRS reversal, regardless of the initial AKI stage, with patients with Stage 1 at initial diagnosis achieving the greatest clinical benefit. A significant association was observed between AKI reduction and overall 90-day survival (P = 0.0022). CONCLUSIONS: A reduction in AKI stage, independent of HRS reversal, was sufficient to improve overall survival in patients with HRS-1. The goal for HRS-1 treatment should be less stringent than absolute HRS reversal.
Assuntos
Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/patologia , Síndrome Hepatorrenal/mortalidade , Terlipressina/uso terapêutico , Vasoconstritores/uso terapêutico , Injúria Renal Aguda/prevenção & controle , Idoso , Método Duplo-Cego , Feminino , Síndrome Hepatorrenal/tratamento farmacológico , Síndrome Hepatorrenal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
Hepatitis E virus (HEV) infection is a major cause of morbidity in endemic areas. Its consequences among chronic hepatitis B (CHB) patients have been under-reported. The aim of this study was to assess the impact of superinfective HEV infection (acute and past) on virological and clinical features of patients with CHB infection. Clinical, biochemical, virological and immunological data of 153 CHB patients including 98 with hepatitis B virus (HBV) monoinfection and 55 with HBV-HEV superinfection with both HEV and HBV infection was retrospectively investigated and analyzed in this study conducted in Wuhan, China. An overall anti-HEV IgG seroprevalence was found to be 35.9% in CHB patients. HBV-HEV superinfection patients showed significantly higher rate of complications (ascites, hepato-renal syndrome & encephalopathy) (all with P=0.04), cirrhosis (P<0.001) and acute-on-chronic liver failure (P<0.001) than HBV monoinfection patients. They also displayed elevated ALTs (P<0.001) and total serum bilirubin (P<0.001) with diminished albumin (P<0.001) and HBV viral load (P<0.001). Cytokines assay revealed increased expression of IL-6 (P=0.02), IL-10 (P=0.009) and TNF-α (P=0.003) in HBV-HEV superinfection patients compared to HBV monoinfection patients. Our study demonstrated that HEV superinfection in CHB patients was associated with progressive clinical manifestation, which is likely due to the enhanced expression of cytokines related with hepatocytes necrosis. HEV was also associated with repressed HBV replication, but the underlying mechanism requires further investigation.
Assuntos
Insuficiência Hepática Crônica Agudizada/virologia , Ascite/virologia , Encefalopatia Hepática/virologia , Hepatite B Crônica/virologia , Hepatite E/virologia , Síndrome Hepatorrenal/virologia , Cirrose Hepática/virologia , Superinfecção/virologia , Insuficiência Hepática Crônica Agudizada/complicações , Insuficiência Hepática Crônica Agudizada/imunologia , Insuficiência Hepática Crônica Agudizada/patologia , Adulto , Idoso , Alanina Transaminase/sangue , Alanina Transaminase/imunologia , Ascite/complicações , Ascite/imunologia , Ascite/patologia , Bilirrubina/sangue , Bilirrubina/imunologia , China , Feminino , Encefalopatia Hepática/complicações , Encefalopatia Hepática/imunologia , Encefalopatia Hepática/patologia , Anticorpos Anti-Hepatite/sangue , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/complicações , Hepatite B Crônica/imunologia , Hepatite B Crônica/patologia , Hepatite E/complicações , Hepatite E/imunologia , Hepatite E/patologia , Vírus da Hepatite E/imunologia , Vírus da Hepatite E/patogenicidade , Hepatócitos/imunologia , Hepatócitos/patologia , Hepatócitos/virologia , Síndrome Hepatorrenal/complicações , Síndrome Hepatorrenal/imunologia , Síndrome Hepatorrenal/patologia , Humanos , Imunoglobulina G/sangue , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Fígado/imunologia , Fígado/patologia , Fígado/virologia , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Superinfecção/complicaçõesRESUMO
Background: Patients with hepatorenal syndrome carry a high short-term mortality. Early diagnosis and treatment are essential for patients' outcome. Nevertheless diagnosis of HRS remains difficult. First-line therapy terlipressin is often associated with severe complications. Biomarkers become more on focus for an early diagnosis. Objective: The aim of this study was to test the diagnostic accuracy of urinary [TIMP-2]·[IGFBP7] for HRS patients and prognostic value for therapy responding patients. Material and methods: NephroCheck® measures urinary concentrations of TIMP-2 and IGFBP-7, both indicating stress of renal cells and associated with induction of cell cycle arrest. 22 HRS patients and 30 patients with normal kidney function were included. [TIMP-2]·[IGFBP7] was measured using NephroCheck®. HRS patients receiving terlipressin were also examined. Results: [TIMP-2]·[IGFBP7] values did not differ significantly (1.3 ± 2.09 vs. 1.03 ± 1.03; p = 0.55). Furthermore, there was no significant difference of [TIMP-2]·[IGFBP7] regarding response of terlipressin (1.32 ± 2.39 vs. 0.81 ± 1.05; p = 0.56). Low [TIMP-2]·[IGFBP7] values were significantly associated with higher mortality (p = 0.01). Conclusions: The results of this study suggest that [TIMP-2]·[IGFBP7] is not suitable for diagnostic of HRS and prediction of therapy response, but there might be evidence for prognostic value of [TIMP-2]·[IGFBP7] in regard to mortality of liver cirrhosis patients.
Assuntos
Pontos de Checagem do Ciclo Celular , Síndrome Hepatorrenal/diagnóstico , Síndrome Hepatorrenal/mortalidade , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/urina , Inibidor Tecidual de Metaloproteinase-2/urina , Biomarcadores/urina , Diagnóstico Precoce , Feminino , Síndrome Hepatorrenal/patologia , Síndrome Hepatorrenal/urina , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Background: Hepatorenal syndrome (HRS) is associated with a poor prognosis. In HRS type 1, loss of renal function is rapidly progressive, while HRS type 2 is characterised by chronic ascites and more moderately elevated renal parameters. While treatment with terlipressin/albumin is well established in type 1, its effectiveness in chronic HRS is less clear. Objective: The aim of this study was to evaluate the effectiveness of terlipressin/albumin treatment in patients with HRS type 2. Methods: All patients with a first episode of HRS between April 2013 and February 2016 were included in this observational study. Relevant clinical and laboratory parameters were recorded and patients were followed. Results: A total of 106 patients with HRS were included. With terlipressin therapy reversal of HRS types 1 and 2 was achieved in 48% and 46% of patients (p = 0.84) with relapse rates of 8% vs 50% (p = 0.001). Overall survival (OS) and survival free of liver transplantation (LTx) were similar in HRS types 1 and 2 (p = 0.69; p = 0.64). In multivariate analysis response to treatment was independently associated with better OS in HRS type 2, in addition to established risk factors such as lower Model for End-Stage Liver Disease score, absence of hepatic encephalopathy and eligibility for LTx. Conclusion: A terlipressin treatment course seems to be justified in selected patients with HRS type 2, especially in countries and settings with long transplant waiting lists. In addition treatment response might also help to identify HRS type 2 patients with a more favourable outcome.
Assuntos
Albuminas/uso terapêutico , Síndrome Hepatorrenal/tratamento farmacológico , Cirrose Hepática/complicações , Terlipressina/uso terapêutico , Vasoconstritores/uso terapêutico , Idoso , Quimioterapia Combinada/métodos , Feminino , Seguimentos , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/mortalidade , Síndrome Hepatorrenal/patologia , Humanos , Estimativa de Kaplan-Meier , Cirrose Hepática/mortalidade , Cirrose Hepática/cirurgia , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão/métodos , Resultado do TratamentoRESUMO
BACKGROUND: Hepatorenal syndrome (HRS) occurs in decompensated liver disease and carries high mortality. Vasoconstrictors are the drug of choice. Terlipressin is widely used and is expensive. In this study, we compared noradrenaline and terlipressin in the management of type 1 HRS. METHODS: Sixty consecutive patients with type 1 HRS were managed with noradrenaline (Group A, n = 30) or terlipressin (Group B, n = 30) with albumin in a randomized controlled trial at a tertiary center. RESULTS: Reversal of type 1 HRS was achieved in 16 (53%) patients in group A and 17 (57%) in group B. There was statistically insignificant difference between the two groups in decreasing serum creatinine and increasing urine output (p > 0.05). On univariate analysis, Child-Turcotte-Pugh (CTP) score, serum sodium, serum urea, serum albumin, prothrombin time, International normalized ratio (INR), serum alanine aminotransferase (ALT), ascitic fluid protein, and history of bleeding were associated with response to treatment (noradrenaline/terlipressin). However, on multivariate analysis, only baseline CTP score, serum urea, serum albumin, and prothrombin time were independent predictors of response. All patients who responded were discharged alive with no mortality within 30 days. CONCLUSIONS: There is no difference in outcome of patients with type 1 HRS treated with noradrenaline or terlipressin. Thus, noradrenaline, which is cheaper, can be used instead of terlipressin (Clinical Trials Registry-India [CTRI] No. CTRI/2011/09/002032).
Assuntos
Síndrome Hepatorrenal/tratamento farmacológico , Norepinefrina/uso terapêutico , Terlipressina/uso terapêutico , Vasoconstritores/uso terapêutico , Adulto , Idoso , Albuminas/uso terapêutico , Creatinina/sangue , Feminino , Síndrome Hepatorrenal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
AIM: To detect the expression of type I inositol 1,4,5-trisphosphate receptor (IP3RI) in the kidney of rats with hepatorenal syndrome (HRS). METHODS: One hundred and twenty-five Sprague-Dawley rats were randomly divided into four groups to receive an intravenous injection of D-galactosamine (D-GalN) plus lipopolysaccharide (LPS; group G/L, n = 50), D-GalN alone (group G, n = 25), LPS alone (group L, n = 25), and normal saline (group NS, n = 25), respectively. At 3, 6, 9, 12, and 24 h after injection, blood, liver, and kidney samples were collected. Hematoxylin-eosin staining of liver tissue was performed to assess hepatocyte necrosis. Electron microscopy was used to observe ultrastructural changes in the kidney. Western blot analysis and real-time PCR were performed to detect the expression of IP3RI protein and mRNA in the kidney, respectively. RESULTS: Hepatocyte necrosis was aggravated gradually, which was most significant at 12 h after treatment with D-galactosamine/lipopolysaccharide, and was characterized by massive hepatocyte necrosis. At the same time, serum levels of biochemical indicators including liver and kidney function indexes were all significantly changed. The structure of the renal glomerulus and tubules was normal at all time points. Western blot analysis indicated that IP3RI protein expression began to rise at 3 h (P < 0.05) and peaked at 12 h (P < 0.01). Real-time PCR demonstrated that IP3RI mRNA expression began to rise at 3 h (P < 0.05) and peaked at 9 h (P < 0.01). CONCLUSION: IP3RI protein expression is increased in the kidney of HRS rats, and may be regulated at the transcriptional level.
Assuntos
Síndrome Hepatorrenal/patologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Rim/patologia , Animais , Modelos Animais de Doenças , Galactosamina/toxicidade , Hepatócitos/patologia , Síndrome Hepatorrenal/induzido quimicamente , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Rim/irrigação sanguínea , Rim/citologia , Rim/ultraestrutura , Lipopolissacarídeos/toxicidade , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Microscopia Eletrônica , Músculo Liso Vascular/citologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/ultraestrutura , Necrose , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Organismos Livres de Patógenos EspecíficosRESUMO
Acute kidney injury (AKI) is common in patients with liver cirrhosis, occurring in 13-20% of patients hospitalized with decompensated cirrhosis, and is significantly associated with the prognosis. The development and progression of AKI is an independent predictive factor for mortality in these patients. If AKI develops, the renal function declines progressively even if AKI is improved later, the patients have a poorer prognosis compared to those who have not developed AKI. In addition, in patients without appropriate treatment or no improvement with the initial treatment, AKI often progress to hepatorenal syndrome (HRS), which is associated with significant morbidity and mortality. Therefore, early detection and appropriate management for the development of AKI is very important in these patients. Recently, there have been significant revisions in the diagnostic criteria and treatment of AKI and HRS; this manuscript reviews these changes.
Assuntos
Injúria Renal Aguda/diagnóstico , Síndrome Hepatorrenal/diagnóstico , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Creatinina/sangue , Síndrome Hepatorrenal/patologia , Síndrome Hepatorrenal/terapia , Humanos , Cirrose Hepática/complicações , Transplante de Fígado , Albumina Sérica/uso terapêutico , Índice de Gravidade de Doença , Vasoconstritores/uso terapêuticoRESUMO
Continuous intake of alcohol leads to liver cirrhosis because of imbalance of oxidative stress/antioxidative defense and chronic 'sterile inflammation'. Hepatorenal syndrome (HRS) is the most severe complication of liver cirrhosis. The aim of our study was to assess: (1) the oxidative stress/antioxidative defense markers such as malondialdehyde (MDA), oxidative glutathione (GSH) and glutathione S-transferase (GST), (2) inflammation [C-reactive protein (CRP)], and (3) nitrate/nitrite levels (NOx) and its substrate L-arginine level. The study enrolled three groups: a group with cirrhosis and HRS (48 patients), a group with cirrhosis without HRS (32 patients), and a control group (40 healthy blood donors). All the patients with cirrhosis and HRS had type II HRS. MDA concentration was significantly higher in the groups with cirrhosis with and without HRS. Significant positive correlation was documented between the MDA level and de Ritis coefficient (AST/ALT), a marker of liver damage severity; between MDA and inflammation (CRP); between MDA and NOx concentration in the groups with cirrhosis with and without HRS. The correlation between MDA and creatinine level was significant in the group with HRS. The levels of GSH and GST were significantly lower in the groups with cirrhosis with and without HRS. The results of the study revealed that an increase in MDA and NOx concentration, along with decreased values of antioxidative defense and L-arginine, may indicate that liver damage can have an influence on progression to renal failure.
Assuntos
Síndrome Hepatorrenal/patologia , Inflamação/patologia , Cirrose Hepática Alcoólica/patologia , Fígado/patologia , Adulto , Idoso , Arginina/sangue , Biomarcadores/sangue , Feminino , Glutationa/sangue , Glutationa Transferase/sangue , Síndrome Hepatorrenal/sangue , Síndrome Hepatorrenal/etiologia , Humanos , Inflamação/sangue , Inflamação/etiologia , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática Alcoólica/complicações , Masculino , Pessoa de Meia-Idade , Nitratos/sangue , Nitritos/sangue , Estresse Oxidativo , Estudos RetrospectivosRESUMO
Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end-stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile duct ligation (BDL)-induced hepatic and renal injury in mice in vivo by using biochemical assays, real-time polymerase chain reaction (PCR), Western blot, mass spectrometry, histology, and electron microscopy. BDL resulted in time-dependent hepatic injury and hyperammonemia which were paralleled by tubular dilation and tubulointerstitial nephritis with marked upregulation of lipocalin-2, kidney injury molecule 1 (KIM-1) and osteopontin. Renal injury was associated with dramatically impaired microvascular flow and decreased endothelial nitric oxide synthase (eNOS) activity. Gene expression analyses signified proximal tubular epithelial injury, tissue hypoxia, inflammation, and activation of the fibrotic gene program. Marked changes in renal arginine metabolism (upregulation of arginase-2 and downregulation of argininosuccinate synthase 1), resulted in decreased circulating arginine levels. Arginase-2 knockout mice were partially protected from BDL-induced renal injury and had less impairment in microvascular function. In human-cultured proximal tubular epithelial cells hyperammonemia per se induced upregulation of arginase-2 and markers of tubular cell injury. CONCLUSION: We propose that hyperammonemia may contribute to impaired renal arginine metabolism, leading to decreased eNOS activity, impaired microcirculation, tubular cell death, tubulointerstitial nephritis and fibrosis. Genetic deletion of arginase-2 partially restores microcirculation and thereby alleviates tubular injury. We also demonstrate that BDL in mice is an excellent, clinically relevant model to study the renal consequences of HRS. (Hepatology 2018; 00:000-000).
Assuntos
Injúria Renal Aguda/metabolismo , Arginina/metabolismo , Síndrome Hepatorrenal/patologia , Túbulos Renais/patologia , Óxido Nítrico Sintase/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/fisiopatologia , Animais , Biomarcadores/metabolismo , Biópsia por Agulha , Modelos Animais de Doenças , Progressão da Doença , Síndrome Hepatorrenal/mortalidade , Síndrome Hepatorrenal/fisiopatologia , Humanos , Imuno-Histoquímica , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Distribuição Aleatória , Medição de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Taxa de SobrevidaRESUMO
Hepatorenal syndrome (HRS) continues to be one of the major complications of decompensated cirrhosis, leading to death in the absence of liver transplantation. Challenges in precisely evaluating renal function in the patient with cirrhosis remain because of the limitations of serum creatinine (Cr) alone in estimating glomerular filtration rate (GFR); current GFR estimating models appear to underestimate renal dysfunction. Newer models incorporating renal biomarkers, such as the Cr-Cystatin C GFR Equation for Cirrhosis appear to estimate measured GFR more accurately. A major change in the diagnostic criteria for HRS based on dynamic serial changes in serum Cr that regard HRS type 1 as a special form of acute kidney injury promises the possibility of earlier identification of renal dysfunction in patients with cirrhosis. The diagnostic criteria of HRS still include the exclusion of other causes of kidney injury. Renal biomarkers have been disappointing in assisting with the differentiation of HRS from prerenal azotemia and other kidney disorders. Serum metabolomic profiling may be a more powerful tool to assess renal dysfunction, although the practical clinical significance of this remains unclear. As a result of the difficulties of assessing renal function in cirrhosis and the varying HRS diagnostic criteria and the rigor with which they are applied, the precise incidence and prevalence of HRS is unknown, but it is likely that HRS occurs more commonly than expected. The pathophysiology of HRS is rooted firmly in the setting of progressive reduction in renal blood flow as a result of portal hypertension and splanchnic vasodilation. Progressive marked renal cortical ischemia in patients with cirrhosis parallels the evolution of diuretic-sensitive ascites to diuretic-refractory ascites and HRS, a recognized continuum of renal dysfunction in cirrhosis. Alterations in nitrous oxide production, both increased and decreased, may play a major role in the pathophysiology of this evolution. The inflammatory cascade, triggered by bacterial translocation and endotoxemia, increasingly recognized as important in the manifestation of acute-on-chronic liver failure, also may play a significant role in the pathophysiology of HRS. The mainstay of treatment remains vasopressor therapy with albumin in an attempt to reverse splanchnic vasodilation and improve renal blood flow. Several meta-analyses have confirmed the value of vasopressors, chiefly terlipressin and noradrenaline, in improving renal function and reversing HRS type 1. Other interventions such as renal replacement therapy, transjugular intrahepatic portosystemic shunt, and artificial liver support systems have a very limited role in improving outcomes in HRS. Liver transplantation remains the definitive treatment for HRS. The frequency of simultaneous liver-kidney transplantation has increased dramatically in the Model for End-stage Liver Disease era, with changes in organ allocation policies. This has resulted in a more urgent need to predict native kidney recovery from HRS after liver transplantation alone, to avoid unnecessary simultaneous liver-kidney transplantation.
Assuntos
Testes Diagnósticos de Rotina/métodos , Síndrome Hepatorrenal/diagnóstico , Síndrome Hepatorrenal/patologia , Testes de Função Renal/métodos , Tratamento Farmacológico/métodos , Síndrome Hepatorrenal/fisiopatologia , Síndrome Hepatorrenal/terapia , Humanos , Cirrose Hepática/complicações , Transplante de Fígado , Metabolômica/métodos , Procedimentos Cirúrgicos OperatóriosAssuntos
Doença Hepática Terminal/cirurgia , Síndrome Hepatorrenal/cirurgia , Falência Hepática Aguda/cirurgia , Transplante de Fígado/estatística & dados numéricos , Doadores Vivos/estatística & dados numéricos , Listas de Espera/mortalidade , Adulto , Fatores Etários , Criança , Doença Hepática Terminal/mortalidade , Doença Hepática Terminal/patologia , Síndrome Hepatorrenal/patologia , Humanos , Fígado/patologia , Fígado/cirurgia , Falência Hepática Aguda/patologia , Transplante de Fígado/métodos , Índice de Gravidade de Doença , Transplantados/estatística & dados numéricos , Resultado do TratamentoRESUMO
Meckel syndrome (MKS) is an inherited autosomal recessive hepatorenal fibrocystic syndrome, caused by mutations in TMEM67, characterized by occipital encephalocoele, renal cysts, hepatic fibrosis, and polydactyly. Here we describe an ovine model of MKS, with kidney and liver abnormalities, without polydactyly or occipital encephalocoele. Homozygous missense p.(Ile681Asn; Ile687Ser) mutations identified in ovine TMEM67 were pathogenic in zebrafish phenotype rescue assays. Meckelin protein was expressed in affected and unaffected kidney epithelial cells by immunoblotting, and in primary cilia of lamb kidney cyst epithelial cells by immunofluorescence. In contrast to primary cilia of relatively consistent length and morphology in unaffected kidney cells, those of affected cyst-lining cells displayed a range of short and extremely long cilia, as well as abnormal morphologies, such as bulbous regions along the axoneme. Putative cilia fragments were also consistently located within the cyst luminal contents. The abnormal ciliary phenotype was further confirmed in cultured interstitial fibroblasts from affected kidneys. These primary cilia dysmorphologies and length control defects were significantly greater in affected cells compared to unaffected controls. In conclusion, we describe abnormalities involving primary cilia length and morphology in the first reported example of a large animal model of MKS, in which we have identified TMEM67 mutations.
Assuntos
Anormalidades Múltiplas/genética , Síndrome de Dandy-Walker/genética , Síndrome Hepatorrenal/genética , Proteínas de Membrana/genética , Mutação/genética , Cisto Pancreático/genética , Anormalidades Múltiplas/patologia , Substituição de Aminoácidos , Animais , Sequência de Bases , Cromossomos de Mamíferos/genética , Cílios/patologia , Síndrome de Dandy-Walker/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Loci Gênicos , Complexo de Golgi/metabolismo , Síndrome Hepatorrenal/patologia , Homozigoto , Rim/patologia , Proteínas de Membrana/química , Mutação de Sentido Incorreto/genética , Cisto Pancreático/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ovinos , Peixe-ZebraRESUMO
Renal failure commonly occurs in patients affected by cirrhosis, especially when there is ascites. It is typically secondary to intercurrent events that can further compromise blood flow in conditions of relatively decreased renal perfusion. Hepatorenal syndrome (HRS) is a particular and common type of kidney failure that affects patients with liver cirrhosis or, less frequently, with fulminant hepatic failure. The syndrome is characterized by splanchnic vasodilation and renal vasoconstriction. The classification of HRS identifies 2 categories of kidney failure, known as type 1 and type 2 HRS, that occur in patients with either cirrhosis or fulminant hepatic failure.
Assuntos
Injúria Renal Aguda/fisiopatologia , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/patologia , Humanos , Cirrose Hepática/complicações , Falência Hepática Aguda/complicações , Circulação Renal , VasoconstriçãoRESUMO
BACKGROUND: The manufacture and sale of natural products constitute a multi-billion dollar industry. Nearly a third of the American population admit to using some form of complementary or alternative medicine, with many using them in addition to prescription medications. Most patients fail to inform their healthcare providers of their natural product use and physicians rarely inquire. Annually, thousands of natural product-induced adverse events are reported to Poison Control Centers nationwide. Natural product manufacturers are not responsible for proving safety and efficacy, as the FDA does not regulate them. However, concerns exist surrounding the safety of natural products. SUMMARY: This review provides details on natural products that have been associated with renal dysfunction. We have focused on products that have been associated with direct renal injury, immune-mediated nephrotoxicity, nephrolithiasis, rhabdomyolysis with acute renal injury, hepatorenal syndrome, and common adulterants or contaminants that are associated with renal dysfunction. KEY MESSAGES: The potential for natural products to cause renal dysfunction is justifiable. It is imperative that natural product use be monitored closely in all patients. Healthcare practitioners must play an active role in identifying patients using natural products and provide appropriate patient education.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Produtos Biológicos/efeitos adversos , Síndrome Hepatorrenal/induzido quimicamente , Nefrolitíase/induzido quimicamente , Insuficiência Renal Crônica/induzido quimicamente , Rabdomiólise/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/patologia , Conhecimentos, Atitudes e Prática em Saúde , Síndrome Hepatorrenal/diagnóstico , Síndrome Hepatorrenal/patologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Nefrolitíase/diagnóstico , Nefrolitíase/patologia , Controle de Qualidade , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/patologia , Rabdomiólise/diagnóstico , Rabdomiólise/patologiaRESUMO
BACKGROUND: The efficacy of vasoconstrictors in hepatorenal syndrome (HRS) is variable. We hypothesized that the effectiveness of vasoconstrictor therapy in improving kidney function ultimately relates to the magnitude of the achieved mean arterial pressure (MAP) increase. METHODS: A retrospective study was conducted to identify cirrhotic individuals treated with vasoconstrictors for acute kidney injury (AKI) presumably caused by HRS to examine the relationship between change in MAP and change in serum creatinine (sCr) using multivariate mixed linear regression. RESULTS: Among 73 patients treated with midodrine/octreotide, change in MAP inversely correlated with change in sCr (p = 0.0005). The quartile with the greatest increase in MAP (+15.9 to +29.4 mm Hg) was associated with a subsequent absolute decrease in sCr. The strength of the correlation increased when the analysis was restricted to those who met the HRS criteria (n = 27, p = 0.002), where the third (+5.3 to +15.6 mm Hg) and fourth (+15.9 to +20.9 mm Hg) quartiles of MAP change were associated with a decrease in sCr. A similar but stronger correlation was found among 14 patients treated with norepinephrine either after failing midodrine/octreotide (n = 10) or de novo (n = 4; p = 0.002), where a rise in MAP of +19.2 to 25 mm Hg was associated with a larger reduction in sCr. Associations remained significant after adjustment for baseline parameters. CONCLUSIONS: The magnitude of MAP rise during HRS therapy with midodrine/octreotide or norepinephrine correlated with a reduction in sCr concentration. Our results suggest that achieving a pre-specified target of MAP increase might improve renal outcomes in hepatorenal AKI.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Pressão Arterial , Síndrome Hepatorrenal/tratamento farmacológico , Vasoconstritores/uso terapêutico , Injúria Renal Aguda/complicações , Injúria Renal Aguda/patologia , Idoso , Creatinina/sangue , Doença Hepática Terminal/patologia , Feminino , Síndrome Hepatorrenal/etiologia , Síndrome Hepatorrenal/patologia , Humanos , Testes de Função Renal , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Midodrina/uso terapêutico , Norepinefrina/uso terapêutico , Octreotida/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
AIM: To develop a practical and reproducible rat model of hepatorenal syndrome for further study of the pathophysiology of human hepatorenal syndrome. METHODS: Sprague-Dawley rats were intravenously injected with D-galactosamine and lipopolysaccharide (LPS) via the tail vein to induce fulminant hepatic failure to develop a model of hepatorenal syndrome. Liver and kidney function tests and plasma cytokine levels were measured after D-galactosamine/LPS administration, and hepatic and renal pathology was studied. Glomerular filtration rate was detected in conscious rats using micro-osmotic pump technology with fluorescein isothiocyanate-labelled inulin as a surrogate marker. RESULTS: Serum levels of biochemical indicators including liver and kidney function indexes and cytokines all significantly changed, especially at 12 h after D-galactosamine/LPS administration [alanine aminotransferase, 3389.5 ± 499.5 IU/L; blood urea nitrogen, 13.9 ± 1.3 mmol/L; Cr, 78.1 ± 2.9 µmol/L; K(+), 6.1 ± 0.5 mmol/L; Na(+), 130.9 ± 1.9 mmol/L; Cl(-), 90.2 ± 1.9 mmol/L; tumor necrosis factor-α, 1699.6 ± 599.1 pg/mL; endothelin-1, 95.9 ± 25.9 pg/mL; P < 0.05 compared with normal saline control group]. Hepatocyte necrosis was aggravated gradually, which was most significant at 12 h after treatment with D-galactosamine/LPS, and was characterized by massive hepatocyte necrosis, while the structures of glomeruli, proximal and distal tubules were normal. Glomerular filtration rate was significantly decreased to 30%-35% of the control group at 12 h after D-galactosamine/LPS administration [Glomerular filtration rate (GFR)1, 0.79 ± 0.11 mL/min; GFR2, 3.58 ± 0.49 mL/min·kgBW(-1); GFR3, 0.39 ± 0.99 mL/min·gKW(-1)]. The decreasing timing of GFR was consistent with that of the presence of hepatocyte necrosis and liver and kidney dysfunction. CONCLUSION: The joint use of D-galactosamine and LPS can induce liver and kidney dysfunction and decline of glomerular filtration rate in rats which is a successful rat model of hepatorenal syndrome.
Assuntos
Galactosamina , Síndrome Hepatorrenal/induzido quimicamente , Rim/fisiopatologia , Lipopolissacarídeos , Fígado/fisiopatologia , Animais , Citocinas/sangue , Modelos Animais de Doenças , Taxa de Filtração Glomerular , Síndrome Hepatorrenal/sangue , Síndrome Hepatorrenal/patologia , Síndrome Hepatorrenal/fisiopatologia , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Necrose , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Hepatorenal cell populations were studied in patients with HCV and HBV infection markers and renal dysfunction. Pronounced mosaicism of ultrastructural changes in hepatocytes was associated with polymorphic cytopathic effects caused by RNA-genome hepatitis C virus and DNA-genome hepatitis B virus. The destructive component of the tubular compartment predominated in renal biopsy specimens from patients, with subsequent degeneration of the tubular epithelium associated with progressive interstitial fi brosis. Immunohistochemical studies detected HCV NS3Ag and HBcAg structural marker in the tubular epitheliocytes. An appreciable part of the structural and functional changes in the liver in patients with HCV and HBV infections was caused by the therapeutic complex, including programmed hemoperfusion.
Assuntos
Biomarcadores/metabolismo , Hepatite B/metabolismo , Hepatite C/metabolismo , Hepatócitos/ultraestrutura , Síndrome Hepatorrenal/patologia , Rim/ultraestrutura , Adolescente , Adulto , Feminino , Humanos , Imuno-Histoquímica , Masculino , Microscopia Eletrônica , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Hepatorenal syndrome is one of the serious complications of cirrhosis and closely associated with the increasing intra-abdominal pressure (IAP). The study aims to explore the potential mechanism of intra-abdominal hypertension in the development of hepatorenal syndrome in mouse models. METHODS: Eighty male mice were randomly divided into model group (subcutaneous injection of carbon tetrachloride) and control group (subcutaneous injection of olive oil). After 12 weeks, parts of the mice were sacrificed and liver histopathology was detected. Then, albumin (30 g/L) and normal saline were separately injected into the peritoneal cavity of mice to induce the different IAP levels (0, 5, 10 and 20cmH2O). Blood urea nitrogen, serum creatinine and renal histopathology were examined 24 hours later. RESULTS: Blood urea nitrogen and serum creatinine levels were statistically significant high in the group of IAP= 10 and 20cmH2O as compared with the IAP= 0cmH2O. From results of renal histopathology, the constrictive renal tubular lumen and inflammatory infiltration in the interstitial were observed in groups of IAP= 5 and 10cmH2O. Besides, the formed casts and hyperemia in the renal interstitial could be detected in group of IAP= 20cmH2O. The cellular swelling and edema of renal tubular epithelial cells were found in model group simultaneously. CONCLUSIONS: Our study suggested that intra-abdominal hypertension was a significant pathological mechanism and a potential independent risk factor of hepatorenal syndrome.
Assuntos
Síndrome Hepatorrenal/etiologia , Hipertensão Intra-Abdominal/complicações , Albuminas , Animais , Biomarcadores/sangue , Nitrogênio da Ureia Sanguínea , Tetracloreto de Carbono , Creatinina/sangue , Síndrome Hepatorrenal/sangue , Síndrome Hepatorrenal/patologia , Hipertensão Intra-Abdominal/sangue , Hipertensão Intra-Abdominal/induzido quimicamente , Hipertensão Intra-Abdominal/patologia , Rim/patologia , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/complicações , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pressão , Fatores de Risco , Cloreto de SódioRESUMO
Cholemic nephrosis represents a spectrum of renal injury from proximal tubulopathy to intrarenal bile cast formation found in patients with severe liver dysfunction. However, the contribution of this diagnosis has been largely forgotten in the modern literature. To more precisely define this, we conducted a clinicopathologic study of 44 subjects (41 autopsies and 3 renal biopsies) from jaundiced patients at the University of Chicago. Of these, 24 patients had bile casts with involvement of distal nephron segments in 18 mild cases and extension to proximal tubules for 6 severe cases. Eleven of 13 patients with hepatorenal syndrome and all 10 with cirrhosis (due to alcoholism) had tubular bile casts. These casts significantly correlated with higher serum total and direct bilirubin levels, and a trend toward higher serum creatinine, AST, and ALT levels. Bile casts may contribute to the kidney injury of severely jaundiced patients by direct bile and bilirubin toxicity, and tubular obstruction. Both mechanisms are analogous to the injury by myeloma or myoglobin casts. Accounting for the presence of renal bile casts provides a more complete representation of the renal injury that can occur in this unique clinical setting. Thus, bile cast nephropathy is an appropriate term for the severe form of injury observed in the spectrum of cholemic nephrosis. Additional studies are needed to establish the significance of this parameter for patient management in different clinical settings.