RESUMO
BACKGROUND: Acute kidney injury (AKI) often manifests in patients with liver disease because of a prerenal cause and presents as acute tubular necrosis or hepatorenal syndrome. Distinguishing between these entities is important for prognosis and treatment. Some patients may develop AKI related to their underlying liver disease: for example, membranoproliferative glomerulonephritis or IgA nephropathy. Bile cast nephropathy is an often ignored differential diagnosis of AKI in the setting of obstructive jaundice. It is characterized by the presence of bile casts in renal tubules, which can possibly cause tubular injury through obstructive and direct toxic effects. Thus, AKI in patients with liver disease may have a structural component in addition to a functional one. METHODS: In this study, we describe 2 patients with severe hyperbilirubinemia who developed AKI and underwent a kidney biopsy that revealed bile casts in tubular lumens, consistent with bile cast nephropathy. RESULTS: One patient was treated aggressively for alcoholic hepatitis and required hemodialysis for AKI. The second patient was treated conservatively for drug-induced liver injury and did not require dialysis. Both patients saw a reduction in their bilirubin and creatinine toward baseline. CONCLUSION: Bile cast nephropathy is an important pathological entity that may account for the renal dysfunction in some patients with liver disease. It requires kidney biopsy for diagnosis and may often be overlooked given the scarcity of kidney biopsy in this particular clinical setting. The etiology is multifactorial, and it is often difficult to predict without the aid of a renal biopsy.
Assuntos
Injúria Renal Aguda/patologia , Bile/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/complicações , Hepatite Alcoólica/complicações , Hiperbilirrubinemia/patologia , Icterícia Obstrutiva/complicações , Túbulos Renais/patologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Injúria Renal Aguda/urina , Adulto , Idoso de 80 Anos ou mais , Combinação Amoxicilina e Clavulanato de Potássio/efeitos adversos , Bilirrubina/sangue , Bilirrubina/urina , Biópsia , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/urina , Creatinina/sangue , Quimioterapia Combinada , Hepatite Alcoólica/sangue , Hepatite Alcoólica/terapia , Hepatite Alcoólica/urina , Humanos , Hiperbilirrubinemia/sangue , Hiperbilirrubinemia/etiologia , Icterícia Obstrutiva/sangue , Icterícia Obstrutiva/patologia , Icterícia Obstrutiva/urina , Túbulos Renais/diagnóstico por imagem , Túbulos Renais/ultraestrutura , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Microscopia Eletrônica , Diálise Renal , Ultrassonografia , Inibidores de beta-Lactamases/efeitos adversosRESUMO
AIM: To examine renal expression of organic anion transporter 5 (Oat5) and sodium-dicarboxylate cotransporter 1 (NaDC1), and excretion of citrate in rats with acute extrahepatic cholestasis. METHODS: Obstructive jaundice was induced in rats by double ligation and division of the common bile duct (BDL group). Controls underwent sham operation that consisted of exposure, but not ligation, of the common bile duct (Sham group). Studies were performed 21 h after surgery. During this period, animals were maintained in metabolic cages in order to collect urine. The urinary volume was determined by gravimetry. The day of the experiment, blood samples were withdrawn and used to measure total and direct bilirubin as indicative parameters of hepatic function. Serum and urine samples were used for biochemical determinations. Immunoblotting for Oat5 and NaDC1 were performed in renal homogenates and brush border membranes from Sham and BDL rats. Immunohistochemistry studies were performed in kidneys from both experimental groups. Total RNA was extracted from rat renal tissue in order to perform reverse transcription polymerase chain reaction. Another set of experimental animals were used to evaluate medullar renal blood flow (mRBF) using fluorescent microspheres. RESULTS: Total and direct bilirubin levels were significantly higher in BDL animals, attesting to the adequacy of biliary obstruction. An important increase in mRBF was determined in BDL group (Sham: 0.53 ± 0.12 mL/min per 100 g body weight vs BDL: 1.58 ± 0.24 mL/min per 100 g body weight, P < 0.05). An increase in the urinary volume was observed in BDL animals. An important decrease in urinary levels of citrate was seen in BDL group. Besides, a decrease in urinary citrate excretion (Sham: 0.53 ± 0.11 g/g creatinine vs BDL: 0.07 ± 0.02 g/g creatinine, P < 0.05) and an increase in urinary excretion of H(+) (Sham: 0.082 ± 0.03 µmol/g creatinine vs BDL: 0.21 ± 0.04 µmol/g creatinine, P < 0.05) were observed in BDL animals. We found upregulations of both proteins Oat5 and NaDC1 in brush border membranes where they are functional. Immunohistochemistry technique corroborated these results for both proteins. No modifications were observed in Oat5 mRNA and in NaDC1 mRNA levels in kidney from BDL group as compared with Sham ones. CONCLUSION: Citrate excretion is decreased in BDL rats, at least in part, because of the higher NaDC1 expression. Using the outward gradient of citrate generated by NaDC1, Oat5 can reabsorb/eliminate different organic anions of pathophysiological importance.
Assuntos
Colestase Extra-Hepática/metabolismo , Transportadores de Ácidos Dicarboxílicos/metabolismo , Icterícia Obstrutiva/metabolismo , Rim/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismo , Animais , Bilirrubina/sangue , Biomarcadores/sangue , Biomarcadores/urina , Colestase Extra-Hepática/sangue , Colestase Extra-Hepática/genética , Colestase Extra-Hepática/urina , Ácido Cítrico/urina , Ducto Colédoco/cirurgia , Transportadores de Ácidos Dicarboxílicos/genética , Modelos Animais de Doenças , Icterícia Obstrutiva/sangue , Icterícia Obstrutiva/genética , Icterícia Obstrutiva/urina , Ligadura , Masculino , Transportadores de Ânions Orgânicos Dependentes de Sódio/genética , Ratos Wistar , Circulação Renal , Eliminação Renal , Simportadores/genética , Fatores de Tempo , Regulação para CimaRESUMO
A 56-year-old man with obstructive icterus due to pancreas cysts presented with acute kidney insufficiency and bilirubin casts in the urinary sediment as a sign of bilirubin-associated acute kidney injury.
Assuntos
Injúria Renal Aguda/diagnóstico , Icterícia Obstrutiva/diagnóstico , Injúria Renal Aguda/urina , Bilirrubina/urina , Diagnóstico Diferencial , Humanos , Icterícia Obstrutiva/urina , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND & AIMS: Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5beta-reductase. METHODS: The effect of bile acids on glucocorticoid metabolism was studied in vitro in hepatic subcellular fractions and hepatoma cells, allowing quantitation of the kinetics and transcript abundance of 5beta-reductase. Metabolism was subsequently examined in vivo in rats following dietary manipulation or bile duct ligation. Finally, glucocorticoid metabolism was assessed in humans with obstructive jaundice. RESULTS: In rat hepatic cytosol, chenodeoxycholic acid competitively inhibited 5beta-reductase (K(i) 9.19+/-0.40 microM) and reduced its transcript abundance (in H4iiE cells) and promoter activity (reporter system, HepG2 cells). In Wistar rats, dietary chenodeoxycholic acid (1% w/w chow) inhibited hepatic 5beta-reductase activity, reduced urinary excretion of 3alpha,5beta-tetrahydrocorticosterone and reduced adrenal weight. Conversely, a fat-free diet suppressed bile acid levels and increased hepatic 5beta-reductase activity, supplementation of the fat-free diet with CDCA reduced 5beta-reductase activity, and urinary 3alpha,5beta-reduced corticosterone. Cholestasis in rats suppressed hepatic 5beta-reductase activity and transcript abundance. In eight women with obstructive jaundice, relative urinary excretion of 3alpha,5beta-tetrahydrocortisol was significantly lower than in healthy controls. CONCLUSION: These data suggest a novel role for bile acids in inhibiting hepatic glucocorticoid clearance, of sufficient magnitude to suppress hypothalamic-pituitary-adrenal axis activity. Elevated hepatic bile acids may account for adrenal insufficiency in liver disease.
Assuntos
Ácidos e Sais Biliares/farmacologia , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , Icterícia Obstrutiva/tratamento farmacológico , Sistema Hipófise-Suprarrenal/fisiologia , 3-Hidroxiesteroide Desidrogenases/genética , Animais , Sequência de Bases , Ácidos e Sais Biliares/uso terapêutico , Ductos Biliares/fisiologia , Citosol/enzimologia , Feminino , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Icterícia Obstrutiva/metabolismo , Icterícia Obstrutiva/urina , Cinética , Ligadura , Fígado/enzimologia , Masculino , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ratos , Ratos Wistar , Tetra-Hidrocortisol/urina , Transcrição Gênica/efeitos dos fármacosRESUMO
BACKGROUND: Decreased serum uric acid levels resulting from renal urate wasting occasionally are reported in hospitalized patients because of isolated or generalized proximal tubular damage. There are limited recent findings with regard to the incidence and cause of hypouricemia in patients admitted to an internal medicine clinic. The aim of this study is to examine the prevalence of hypouricemia in individuals admitted to our inpatient hospital-based facility and identify underlying causes and pathogenetic mechanisms and any association of hypouricemia and uricosuria with other tubular defects. METHODS: A total of 7,250 serum urate measurements were available on patients' admission. Hypouricemia is defined as a serum urate level less than 2.5 mg/dL (149 micromo/L). In all hypouricemic cases, a detailed clinical and laboratory investigation was performed. RESULTS: Hypouricemia was found in 90 patients (1.24%). In all except one patient, hypouricemia was associated with inappropriate uricosuria (urate fractional excretion [FE] > 10%; range, 10.8% to 94%). There was an inverse correlation between serum uric acid level and its FE (r = -0.73; P < 0.0001). The most common causes of hypouricemia were obstructive jaundice of any cause (n = 18), solid or hematologic neoplasias (n = 17), diabetes mellitus (n = 12), drugs affecting urate homeostasis (n = 10), and intracranial diseases (n = 8). Seventeen patients with hypouricemia showed one or more other manifestations of proximal tubular damage, such as glucosuria, inappropriate phosphaturia leading to hypophosphatemia, and kaliuria resulting in hypokalemia. CONCLUSION: Hypouricemia caused by inappropriate uricosuria is not rare in patients admitted to an internal medicine clinic, is related to underlying diseases, and may be associated with other abnormalities of proximal tubular function.