Hepatitis y riñon
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El documento resume las generalidades de los virus de la hepatitis B y C, incluyendo su genoma, transmisión, presentación aguda y crónica, y relación con enfermedad renal glomerular. Describe las manifestaciones clínicas de la hepatitis B y C, así como sus mecanismos patogénicos renales como la glomerulonefritis membranoproliferativa y membranosa. Finalmente, discute la relación entre la hepatitis y el trasplante renal.
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Hepatitis y riñon
- 1. Dra Silvana A. Ferrara Dra. María Lara Virus Hepatitis y Riñón
- 2. Agenda Virus de Hepatitis y Riñón Dra. Silvana A. Ferrara Generalidad del Virus GMN relacionadas Trasplante Renal
- 3. Enfermedad infectocontagiosa sistémica causada por varios virus que afectan principalmente el hígado. Produciendo inflamación y necrosis del los hepatocitos con alteraciones clínicas, bioquímicas e histológicas, que se superan con la erradicación del virus y el desarrollo de la inmunidad” Hepatitis Viral Definición
- 4. Generalidades Virus de Hepatitis B y C B C GENOMA ADN bicatenario ARN monocatenario TRANSMISION Parenteral Sexual Lactancia Parenteral Sexual NO lactancia AGUDA 50-75% 20% CRONICA 30 a 90%< 5 a 5-10% >5 60 a 85% FULMINANTE <2% < 0.2% INCUBACIÓN 30-180 d. Prom: 60d 15 d- 150d (7sem) VACUNA SI NO WHO
- 5. Hepatitis B y C: Clínica
- 7. Hepatitis B Generalidades • Ubicuo • 2400 millones crónicos en el mundo • 780 mil muertes al año 650mil por Cirrosis y HPC 130mil por Hepatitis Aguda • 90% de Adultos remisión espontanea • Cirrosis/HPC 20-30% de Adultos Crónicos • Familia: Hepadnaviridae • Genero: Orthohepadnavirus • ADN bicatenario • Genotipos A-G • Sobrevive hasta 7 días fuera • Tenofovir/Entecavir/Lamivudina/INT • No cura pero controla
- 8. Dienstag, Jules L. Hepatitis B Virus Infection N Engl J Med 2008 359: 1486-1500
- 9. Hepatitis B Interpretación de Pruebas Serológicas Control Center Disease
- 10. Hepatitis B Evolución Clínica
- 11. Hepatitis B Relación con ERC Predominancia en Niños Predominancia sexo Masculino 4:1 Asia y Africa Sub-Sahariana Artritis Reactiva/Vasculitis/Eritemas GMN asociada a Hepatitis crónica Semin Immunopathol (2007) 29:397–414 Poliarteritis Nodosa GMN Membranosa GMN Membranoproliferativa
- 12. Mecanismos de Patogenia Renal Semin Immunopathol (2007) 29:397–414
- 13. Panarteritis Nodosa Hepatitis B Criterios de clasificación del ACR (1990) • Pérdida de peso > 4 kg • Livedo reticularis • Dolor testicular • Mialgias, debilidad o dolor al tacto en MsInfs • Mononeuropatía o polineuropatía • Tensión arterial diastólica > 90 mm Hg • Nitrógeno ureico > 40 mg/dl o creatinina > 1,5 mg/dl • Presencia del virus de la hepatitis B • Arteriografía con aneurismas u oclusiones de arterias viscerales • Biopsia de arterias de pequeño o mediano calibre con infiltrado leucocitario 3 o más criterios. Especifidad 86,6% Sensibilidad 82%.
- 14. Tratamiento: • Plasmaféresis • interferón-α y la ribavirina • Esteroides periodos cortos en casos graves. Poliarteritis Nodosa Hepatitis B
- 15. GMN Membranosa Hepatitis B Función renal Normal Sindrome Nefrótico Microhematuria en 50% Hipertensión 10-20% Remisión espontánea sobre todo en niños 1/3 desarrollaran ERC G5 al cabo de 10 años masculino, >edad, HTA, persistencia de proteinuria , severidad de cambios crónicos biopsia Enzimas Hepáticas Normales o ligeramente elevadas.
- 16. GMN Membranosa Hepatitis B
- 17. GMN Membranosa Hepatitis B • Inmunosupresor no beneficioso • Esteroides: mayor replicación Viral • Antiviral – INT alfa – Lamivudina, Tenofovir, tebivudina, adefovir
- 18. Hepatitis C Generalidades • Familia: Flaviviridae • Genero: Hepacivirus • ARN Monocatenario • Infección Aguda Asintomática 80% • Remisión espontánea 15-50% • Infección crónica 85-50% • 15-20% llegará a Cirrosis/HPC • 150 millones afectados crónicamente • 500.000 muertes al año • Interferon pegilado/ribivirina • Alcance de Cura en 90% px Tratados
- 20. 70% 20 - 30% 1,4%/año 60 – 85% 15 – 40% 30% 10 años 20 años 30 años Hepatitis C Infección Crónica Resolución Normalización ALT Hepatitis Crónica Cirrosis Hepatocarcinoma Muerte Poterucha, J: Gastroenterology and Hepatology Part II. Mayo Clinic Internal Medicine Review, 8th. Edition. Informa Healthcare, 2008. p. 301. Hepatitis C Evolución Clínica
- 21. Manifestaciones extrahepáticas(38%) Hematológicas Criolobulinemia Linfomas Púrpura Trombocitopénica Cutáneas Porfiria Cutánea Tarda Liquen Plano Tejido conectivo Fibrosis Pulmonar Sind. Sjogren Ulceras corneales MoorenTiroiditis Poliarteritis nodosa Renales GN Membranoproliferativa GN Membranosa Otras Cacoub, P, Renou, C, Rosenthal, E, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Medicine (Baltimore) 2000; 79:47. Hepatitis C Manifestaciones Extra-hepáticas
- 22. Hepatitis C relación con ERC • Infección por VHC asociada a mayor progresión de ERC • Carga vírica: factor predictivo de progresión de ERC • Primeros síntomas: proteinuria + Hematuria microscópica • Control Nefrológico Anual en Px Infectados • Biopsia Renal ante hallazgos clínicos de GMN • Depósito de ARN viral y otras proteínas se correlaciona con mayor proteinuria • Interferon – Disminución de ARN viral – Disminución Proteinuria Crioglobulinemia GMN Membranoproliferativa GMN Membranosa Kidney International (2008) 73 (Suppl 109)
- 23. Mecanismos de Patogenia Renal
- 24. Manifestaciones Renales (GMN MP): Precedida por síntomas No Nefrológicos 55% Proteinuria+ Hematuria Macro + IR 25% Sind. Nefrítico 20% Sind. Nefrótico Crioglobulinemia mixta Sind. Raynaud Púrpura Palpable Artralgias/Artritis Neuropatía Periférica GMN MP tipo 1 o tipo 3 Hipocomplementemia (C1q, C3, C4) ALT elevada (70%) GMN Crioglobulinémica Hepatitis C Hepatitis Research and Treatment Volume 2010, Article ID 534327/Clin J Am Soc Nephrol 4: 207–220, 2009
- 25. GN MP Crioglobulinémica Hepatitis C
- 26. Tratamiento Sintomático Antiviral – Interferón alfa – Interferon Pegilado – Ribavirina • Tratamiento de dislipidemias • Inhibiciòn del Eje R-A-A Inmunosupresor • Plasmaféresis • Pulsos de esteroides • Ciclofosfamida • Rituximab GMN MP Crioglobulinémica Tratamiento
- 27. Engrosamiento de MBG por depósito subepiteliales Puede haber depósitos Subendoteliales e hipercelularidad mesangial Normocomplementemia No Factor Reumatoideo No Crioglobulinas Sind Nefrótico IF: IgG, C3, IgA, Full house Tratamiento: INT alfa GMN Membranosa Hepatitis C Hepatitis Research and Treatment Volume 2010, Article ID 534327/Clin J Am Soc Nephrol 4: 207–220, 2009
- 28. • El riesgo relativo de muerte con injerto funcionante y de pérdida de injerto es mayor en Sero+ Mayor proteinuria y progresión de ERC Riesgo de GMN de novo o recidiva • VHC no contraindica Trasplante Renal Administrar INF pretrasplante. • Recibir de Sero+ no empeora pronostico del injerto • Inmunosupresores: Mayor replicación viral – Mayor Lesión Hepática. Hepatitis C y Trasplante Renal Nefrología 2009;29(Sup. Ext. 5):17-21.
- 29. VHB se asiocia a Panarteritis y GNM Membranosa VHC se asocia a Crioglobulinemia y GNM Membranoproliferativa Asociación entre VHC Glomerulopatías del trasplante El tratamiento de elección son los antivirales, algunos casos precisan inmunosupresión. Conclusiones Hepatitis y Riñón
Notas del editor
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- Hepatitis B (Brenner Hepatitis B antigenemia has been associated with GN for more than 30 years. Hepatitis B has a worldwide distribution. In countries where the virus is endemic (sub-Saharan Africa, Southeast Asia, Eastern Europe), there is vertical transmission from mother to infant and horizontal transmission between siblings. Hepatitis B–associated nephropathy occurs in these children with a 4:1 male preponderance.1048-1050 In the United States and Western Europe, where hepatitis B is acquired by parenteral routes or sexually, the nephropathy affects mainly adults and has a different clinical course from the endemic form.1051-1053 However, hepatitis B–associated nephropathy is rare in hepatitis B carriers.1054 PAN has also been associated with hepatitis B.1055 Clinical Features Most patients present with proteinuria or the nephrotic syndrome. In endemic areas, there may not be a preceding history of hepatitis. The majority of patients have normal renal function at the time of presentation. There may be urinary erythrocytes, but the majority have a bland sediment. Liver disease may be absent (carrier state) or chronic and clinically mild. Serum aminotransferases may be normal or modestly elevated (100–200 IU/L). Liver biopsies in these patients often show chronic active hepatitis. Some patients ultimately develop cirrhosis in their biopsies. There is often a spontaneous resolution of the carrier state with resolution of renal abnormalities. Spontaneous resolution of HBV-associated nephropathy is particularly common in children from endemic areas. The probability of a spontaneous remission may be as high as 80% after 10 years.1056,1057
- La capa externa lipidica contiene las proteínas de superficie que determinan en Antígeno de superficie (HBsAg). En la parte interna esta la nucleocapside o core. El core contiene un DNA de doble cadena parcial circular y expresa en su superficie el antígeno core (HBcAg). El anticuerpo contra esta proteína puede ser del tipo IgM o IgG. Las subunidad proteica del core se denomina antígeno e (HBeAg), el anticuerpo correspondiente es el anti-Hbe.
- After entering hepatocytes by endocytosis, the partially double-stranded viral genomic DNA is transported into the nucleus, where it is converted to covalently closed circular DNA, which serves as a template for transcription of viral mRNAs, which in turn are used for viral replication through reverse transcription and the production of viral DNA polymerase and other viral proteins HBV is not directly cytopathic to hepatocytes. The host immune response, especially via virus-specific cytotoxic T lymphocytes, is the basis for hepatocellular damage as well as viral clearance. Neonatal exposure to HBV when the immune system is immature results in minimal acute hepatitis, but this is followed by chronic infection in 90% of subjects, and contributes to the bulk of chronic HBV carriers.
- The main pathogenic mechanism in HBV-related glomerular diseases is through the deposition of immune complexes in the glomerulus. The immune complexes are comprised of viral antigens and the antibodies that these antigens invoke from the host. Whether these immune complexes are formed in situ or are derived from circulating immune complexes being trapped in the glomerulus remains controversial. Various HBV antigens including hepatitis B surface antigen (HBsAg), hepatitis B early antigen (HBeAg), and hepatitis B core antigen (HBcAg) have been demonstrated in the glomeruli of patients with HBV-related glomerulonephritis, and the detection of covalently closed circular DNA in renal tissue has also been reported [5]. Immune deposition occurs predominantly in the subepithelial region but can also involve the mesangial and occasionally subendothelial areas, depending on the size of the antigens and immune complexes. It has been speculated that the low molecular weight of HBeAg (3×105 Da) might account for its ability to traverse the glomerular basement membrane and thus the formation of subepithelial immune deposits [6]. The observed association between remission of proteinuria and clearance of HBeAg also provides indirect evidence that the antigen is involved in pathogenesis. The immune complexes then activate complements and glomerular injury occurs via the formation of membrane attack complex and other downstream events such as the induction of proteases, oxidation injury, and disruption of cytoskeleton
- Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis (GN) or vasculitis in arterioles, capillaries, or venules. Any artery in the kidney can be affected by polyarteritis nodosa, from the main renal artery to the interlobular arteries, although the interlobar and arcuate arteries are affected most often.1 Nodular inflammatory lesions and aneurysms (pseudoaneurysms) can be observed grossly when medium-sized arteries are involved. Inflammation in small arteries can be observed only by microscopy Depósito de ICC HTA Hematuria Microscópica, poteinuria. Insuficiencia Renal
- The characteristic acute lesion is segmental transmural fibrinoid necrosis of arteries, usually accompanied by infiltrating leukocytes with leukocytoclasia (Fig. 24.16).3,69 The earliest lesions have numerous neutrophils, and later lesions have predominantly mononuclear leukocytes. Acute lesions may be complicated by thrombosis or hemorrhage. Older lesions develop fibrosis and endarterial remodeling. The aneurysms of necrotizing arteritis are not true aneurysms but rather are inflammatory pseudoaneurysms En estos casos se asocian desde el principio plasmaféresis y antivíricos. Los antivíricos más utilizados son el interferón-α y laribavirina, en monoterapia o combinados. El tratamiento convencional con esteroides y CYM estimularía la replicación vírica favoreciendo la cronificación de la hepatitis. Por lo tanto, si es necesario, deben pautarse sólo esteroides, y durante un periodo corto de tiempo para un control rápido de las manifestaciones vasculíticas más graves. La plasmaféresis ayuda a controlar la vasculitis sin que sea necesario mantener los esteroides.
- Most patients present with proteinuria or the nephrotic syndrome. In endemic areas, there may not be a preceding history of hepatitis. The majority of patients have normal renal function at the time of presentation. There may be urinary erythrocytes, but the majority have a bland sediment. Liver disease may be absent (carrier state) or chronic and clinically mild. Serum aminotransferases may be normal or modestly elevated (100–200 IU/L). Liver biopsies in these patients often show chronic active hepatitis. Some patients ultimately develop cirrhosis in their biopsies. There is often a spontaneous resolution of the carrier state with resolution of renal abnormalities. Spontaneous resolution of HBV-associated nephropathy is particularly common in children from endemic areas. The probability of a spontaneous remission may be as high as 80% after 10 years
- MGN, with thickened and rigid peripheral capillary walls but with patent capillary lumina. Mesangial abnormalities are more common in secondary membranous nephropathy H&E, ×400 Immunofluorescent staining and electron microscopy demonstrate granular IgG C3, and some IgM staining in the subepithelial region along the glomerular basement membrane accompanied by extensive effacement of the podocyte foot processes, and in some cases viral particles in various locations within the glomerulus.
- In children with a mild endemic form of hepatitis B–associated nephropathy, no treatment other than supportive care is advocated. In patients with progressive renal dysfunction, INF has been used with mixed results. Steroids do not significantly improve proteinuria and may potentially enhance viral replication.1068,1069 Nucleoside analogs, including lamivudine, telbivudine, adefovir, entecavir, and tenofovir, suppress HBV replication by inhibiting viral DNA polymerase and have demonstrated clinical utility in treating hepatitis B infection. Lamivudine was shown to reduce proteinuria and lead to a lesser incidence of ESRD in 10 patients with hepatitis B–associated nephropathy.1070 Preemptivelamivudine therapy in renal transplant recipients has shown improved survival compared with historical control participants.
- Circulating HCV particles can be associated with low- and very-low-density lipoproteins (LP). Virus binding to the cell surface and entry may involve the low density lipoprotein receptor (LDLR), glycosaminoglycans (GAG), scavenger receptor class B type I (SR-BI), the tetraspanin protein CD81 and claudin-1 (CLDN1). CLDN1 functions at a late stage of cell entry, possibly at tight junctions of polarized hepatocytes. Internalization depends on clathrin-mediated endocytosis. Acidification of the endosome induces HCV glycoprotein membrane fusion. Little is known about the uncoating process, which results in genome release into the cytosol. Virus binding and internalization (a); cytoplasmic release and uncoating (b); IRES-mediated translation and polyprotein processing (c); RNA replication (d); packaging and assembly (e); virion maturation and release (f). The topology of HCV structural and non-structural proteins at the endoplasmic reticulum membrane is shown schematically. HCV RNA replication occurs in a specific membrane alteration, the membranous web. Note that IRES-mediated translation and polyprotein processing, as well as membranous web formation and RNA replication, which are illustrated here as separate steps for simplicity, might occur in a tightly coupled fashion. IRES, internal ribosome entry site.
- Descritas hasta en un 38% de los pacientes
- The pathogenesis of HCV-related nephropathies is immune complex mediated. A clonal expansion of B cells secreting IgM rheumatoid factors has been seen with chronic HCV infection. It has been established that HCV infects B lymphocytes and stimulates the production of antibodies. The viral particle is composed of structural and nonstructural glycoproteins. The E2 structural glycoprotein is the site for binding of a polyclonal IgG in the presence of HCV RNA in the infected lymphocyte. In type II cryoglobulinemia, IgM κ monoclonal B cell-derived antibody (which acts as an anti-IgG rheumatoid factor) binds the Fc portion of the polyclonal IgG to produce cryoprecipitate. The major components of cryoprecipitate in HCV-infected individuals are IgM rheumatoid factors, polyclonal IgG anti-HCV antibodies, and HCV RNA.. HCV-specific proteins have been isolated from glomerular lesions.1078 The disappearance of viremia in response to INF (see below) is associated with a diminution of proteinuria;a relapse of viremia is accompanied by increasing proteinuria. A role for LDL receptors as a portal of entry for HCV Renal parenchyma expresses CD81 and SR-B1 receptors that allow HCV binding to the cell surface and endocytosis (14). Indeed, HCV RNA and related proteins have been found in mesangial cells, tubular epithelial cells, and endothelial cells of glomerular and tubular capillaries (15,16). The presence of HCV-related proteins in the mesangium was associated with higher proteinuria (16), possibly reflecting direct mesangial injury by HCV infection. A role in HCV-associated renal injury has been recently suggested for toll-like receptors (TLRs), primary proteins expressed on immune and nonimmune cells as key components of the innate immune system (17). TLRs recognize molecular patterns associated with microbial pathogens and induce an immune response (17). Renal biopsy findings of increased expression of TLR3 specifically in microdissected glomeruli of patients with HCV-related membranoproliferative glomerulonephritis (MPGN), but not non-HCV MPGN (18), suggest a link between TLR3 and HCV-related glomerular disease. TLR3 is expressed preferentially in the mesangial cell target of HCVrelated MPGN. However, while HCV is a single strain RNA virus, TLR3 recognizes double-strand RNA, and the implications of these findings in disease pathophysiology remain to be established. Much more is known about kidney injury due to systemic immune response to HCV infection that is mediated by cryoglobulins (a group of globulins with the common property of precipitating from cooled serum), HCV-antibody immune complexes,or amyloid deposition (14). Persistence of HCV leads to chronic overstimulation of B-lymphocytes and production of mixed cryoglobulins mainly composed of a polyclonal immunoglobulin (Ig), either IgG or IgM, bound to another Ig that actsas an anti-rheumatoid factor (RF) (19 –22). Cryoglobulins are deposited in the mesangium during their trafficking in the glomerulus. Their nephrotoxicity is attributed to particular affinity of the IgM--RF for cellular fibronectin in the mesangial matrix. Cryoglobulins can also be deposited in the glomerular capillaries as eosinophilic material that stains densely with antisera to IgM, C3, and fibrin by immunofluorescence (14). This is usually associated with histologic signs of vasculitis and downstream fibrinoid necrosis of the glomeruli. Cryoglobulins may also induce endothelitis via anti-endothelial antibody activity and complement activation leading to overexpression
- Purpura (70%), Artritis (50%) Neuropatìa (20%)
- Hipercelularidad Mesangial Difusa + Incremento de la matriz mesangial + Trombos hialinos: depósitos amorfos eosinofílicos Positivos a la tinción del Acido Peryódico de schiff (PAS+) Imagen de doble contorno. Metamina de plata Inmunofluorescencia: IgM, IgG, C3, y cadenas ligeras kappa y lambda sobre todo en trombos, Estos depósitos son granulares en las paredes capilares
- Ribavirina: Anemia Grave refractaria Interferon: resultados contradictorios. IFN- is a nonglycosylated serum protein produced by immune cells in response to foreign antigen exposure. IFN is filtered by the glomerulus and reabsorbed by the proximal tubular cells, where it undergoes proteolytic degradation. Thus, accumulation of IFN occurs in patients with renal dysfunction. Several forms of IFN are available for therapeutic use, such as -2a, -2b, -n1. The main side effects associated with IFN include influenza-like symptoms, hematologic abnormalities, depression, confusion, anorexia, diarrhea, dermatitis, alopecia, increased infection rate, uncontrolled hypertension, heart failure, and pericarditis (60). Pegylated IFN- (PEG-IFN) A long-acting IFN-, namely pegylated IFN or peginterferon, produced by the covalent attachment of polyethylene glycol to the IFN molecule, has been developed. Two PEG-IFN formulations are currently approved for treatment of HCV: alfa-2a (PEG-IFN alfa-2a) and alfa-2b (PEG-IFN alfa-2b). Given the increased half-life as compared with conventional IFN, PEG-IFN formulations could be administered weekly. PEG-IFN alfa-2a is metabolized in the liver and kidneys, while PEG-IFN alfa-2b is cleared only by the kidneys. These pharmacokinetic differences account for a slower onset of side effects with PEG-IFN alfa-2a than alfa-2b in the presence of renal dysfunction (128). Adverse events with PEG-IFN therapy are the same as those of IFN. Ribavirin (RBV) RBV is a member of the nucleoside antimetabolite drugs that interfere with duplication of HCV RNA. Bioavailability of oral RBV is increased by 70% in coadministration with a high-fat meal. The principal route of elimination for RBV and its metabolites is the kidney. In patients with GFR less than 30 ml/min the blood area under the curve of RBV is threefold higher than in those with normal renal function. Thus, daily dosage of RBV in patients with chronic kidney disease should be adapted to GFR value and predicted according to specific formulas (129,130). RBV is not removed by hemodialysis (131). The main side effect of RBV is hemolytic anemia related to the high concentration of the drug in red blood cells when the renal clearance is markedly reduced. Indeed, ribavirin is taken up by an active cell surface transporter and phosphorylated to ribavirin triphosphate. Erythrocytes are, however, unable to dephosphorylate or secrete ribavirin triphosphate. As a result, the latter accumulates within the cell and adenosine triphosphate depletion occurs, leading to cell membrane damage. Injured red cells are then removed from the circulation by spleen cells (3). RBV is teratogenic, thus requiring reliable methods of contraception during treatment.
- Minimizar uso de esteroides INT en post trasplante mayor riesgo de rechazo agudo