Liver Disease in Kidney Transplant Recipients Alan Gunderson, Adnan Said PII: DOI: Reference:
S0955-470X(14)00058-5 doi: 10.1016/j.trre.2014.08.002 YTRRE 355
To appear in:
Transplantation Reviews
Please cite this article as: Gunderson Alan, Said Adnan, Liver Disease in Kidney Transplant Recipients, Transplantation Reviews (2014), doi: 10.1016/j.trre.2014.08.002
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Liver Disease in Kidney Transplant Recipients
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Alan Gunderson, MD and Adnan Said, MD, MS
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Affiliation for both: Department of Medicine, Division of Gastroenterology and Hepatology, University of Wisconsin , School of Medicine and Public Health, Wm. S Middleton VA Medical center, Madison , WI 53705
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Word count: 3943 Abstract: 181 References: 86
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Tables 2, Figures 2
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Address for Correspondence: Adnan Said Division of Gastroenterology and Hepatology Department of Medicine University of Wisconsin, School of Medicine and Public Health Chief, Gastroenterology and Hepatology Medical director, liver transplant Wm. S. Middleton VAMC 4223 MFCB, 1685 Highland Ave Madison, WI 53705 Tel: 608-263-43034 Fax: 608-265-5677 Email:
[email protected] Keywords: Kidney transplantation, liver disease, hepatitis, polycystic liver, hepatitis C None of the authors have any financial or other conflicts of interest to report.
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Abstract
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Kidney transplant recipients can develop acute and chronic liver disease from a
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variety of conditions. Chronic viral hepatitis from hepatitis C is seen in increased frequency in hemodialysis patients. Genetic conditions, such as polycystic kidney
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disease, which lead to the need for kidney transplantation are also associated with
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liver diseases including congenital hepatic fibrosis and polycystic liver disease.
Other conditions that can induce liver disease in this immune-suppressed
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population include a multitude of viral infections, as well as other systemic
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infections that can involve the liver. Drug induced liver injury is also seen in
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increased rates due to the use of poly-pharmacy, the effect of immune-suppression on drug metabolizing pathways in the liver and the potential of drug to drug
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interactions.
Post transplant metabolic syndrome is also increased in kidney transplant recipients and this can lead to development of non-alcoholic fatty liver disease.
A knowledge of the presentation of these liver diseases is essential in diagnosing the cause of liver disease as well as informing the diagnostic workup. Specific therapies for the various conditions will also be discussed in this review.
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Introduction Kidney transplant recipients have added risk of acute and chronic liver disease.
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There is risk for viral hepatitis in hemodialysis populations, concomitant liver
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disease in inherited liver-kidney syndromes, and hepatotoxicity due to the effects of
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multiple medications (table 1).
There is sparse data describing liver disease within this population. Clinical
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presentation can range from asymptomatic elevations in liver enzymes to imaging
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abnormalities, development of severe hepatitis, cirrhosis, and occasionally associated liver tumors. The most comprehensive analysis of kidney transplant
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recipients by Allison et al found 7% had an abnormal ALT (alanine aminotransferase) and 4% were confirmed to have Hepatitis C virus (HCV)
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infection.1 More recent analyses have found that HCV alone might have prevalence
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of 40% in some renal transplant cohorts.2,3 Our goal is to describe relevant causes of liver dysfunction within the kidney transplant population and describe current
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approaches to the diagnosis and management.
Chronic Viral Hepatitis Chronic viral hepatitides are the most prevalent causes of chronic liver disease worldwide. The prevalence and incidence of chronic hepatitis C (HCV) is increased in hemodialysis patients. In kidney transplant patients, viral hepatitis is cause for significant concern, since regimens of immunosuppression enhance the ability of hepatitis B and C to evade the host immune system and replicate freely.
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Hepatitis C
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Epidemiology of hepatitis C
Overall 160 million people worldwide and 4 million in the US are estimated to have
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chronic HCV. There are distinct subspecies of hepatitis C (HCV), the frequencies of
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which vary around the world.4 Genotype 1 is most common in the United States, Europe and Japan. Genotype 3 predominates in India, the Far East, and Australia,
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Genotype 4 in Egypt, North Africa, and the Middle East. Finally, Genotype 5 has been most frequently found in South Africa and Genotype 6 in Hong Kong.5 The clinical
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importance of the Genotypes is that they respond differently to treatment.
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Genotypes 2, 3, and 5 respond better to interferon-based therapies than other
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genotypes.6-8 There have been a multitude of new antiviral treatments in
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development and some recently approved regimens that do not require interferon.
The main mode of transmission of HCV is inoculation through contact with blood or infected body fluids. This mainly occurs in the context of contaminated needles in intravenous drug use, intranasal cocaine use, and in those who received blood products prior to widespread testing for HCV became available (in the US before 1992). Although infection control practices in dialysis center have reduced the risk of transmission there is still a surprisingly high incidence of HCV transmission in patients on chronic hemodialysis. In one analysis, dialysis centers in the United States had a 14% prevalence of HCV and an anti-HCV antibody seroconversion rate
ACCEPTED MANUSCRIPT 5 of 2.5% per 100 patient years.2 The risk of HCV transmission in renal transplant candidates is affected by length of time on hemodialysis, exposure to blood products
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prior to the advent of universal screening methods, and prevalence of HCV within
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the dialysis center.3,9
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Screening for HCV is recommended for all persons at higher risk of infection
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(history of any of the exposures noted above) including annually for those on
Clinical course of hepatitis C
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chronic hemodialysis using serum PCR for HCV RNA.10
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Nearly 70 to 85% of those exposed to hepatitis C infection become chronically
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infected. Over the course of 20-30 years, 20-35% will progress to cirrhosis.11,12 In
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chronic infection, liver enzymes can range from 2-10 fold above the upper limit of normal but can be completely normal in upto a third of patients. The diagnosis is
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made by confirming the presence of HCV RNA, which can be detected within days to weeks after exposure .13,14 Anti-HCV antibodies can generally be detected weeks to months after exposure, but may not develop in immunocompromised patients including those on dialysis.
Impact of hepatitis C in Kidney Transplantation The long-term prognosis of kidney transplant recipients with chronic HCV is worse than those without HCV. One such study illustrated that the relative risk for post-
ACCEPTED MANUSCRIPT 6 transplant liver disease is 5.0, graft loss was 1.3, and death was 3.3 with the risk of death from sepsis being 9.9 in comparison to those without chronic HCV.15
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In a meta-analysis of 8 studies, HCV was associated with increased rates of graft loss
was increased post transplant as causes of mortality.
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and mortality in kidney recipients. Hepatic cirrhosis and hepatocellular carcinoma
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Although HCV acquired peri-operatively is rare, compared to chronic HCV infection
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acquired prior to transplantation, when it does occur the outcomes seem to be worse. In a small study of 17 recipients who were infected peri-operatively, liver
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disease occurred rapidly with 35% mortality within 6 years of kidney transplant due to cirrhosis as well as a rapid form of severe and fatal hepatitis known as
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fibrosing cholestatic hepatitis C.16
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Extra-hepatic manifestations of HCV can be damaging to the renal allograft and include immune-mediated nephropathies such as membranoproliferative
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glomerulonephritis (MPGN) and cryoglobulinemia as well as direct viral mediated glomerulonephritis. Cacoub et al found 38% of all HCV patients have at least one such manifestation.17 Notably, in chronic HCV patients post-transplant diabetes has been shown to be twice as common18,19 and post-transplant nephropathy eight times more common than in non-HCV infected patients.20 This also has adverse impact on cardiovascular risk. The risk is further potentiated by the use of diabetogenic immunesuppression, with tacrolimus having a higher risk of this than cyclosporine.18
ACCEPTED MANUSCRIPT 7 Although post transplant outcomes in HCV infected recipients are worse than nonHCV recipients, the HCV positive recipients still have a survival advantage compared
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to remaining on long term dialysis. Thus HCV is not a contra-indication to renal
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transplantation. Rather efforts to risk stratify by assessing the degree of liver
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mainstays in management of these candidates.
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disease and attempting antiviral therapy prior to kidney transplantation are
Given that organ demand far exceeds supply, extended criteria donors have been
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used for limited indications. Thus organs from HCV antibody positive donors can be offered to recipients with chronic hepatitis C infection.21,22 Use of extended criteria
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organs can substantially reduce the transplant waiting time, with no difference in
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short term mortality to those who received organs under conventional donor
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criteria.23-25 Additionally, there is a survival advantage to extended criteria organs
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over continued dialysis in patients with chronic HCV.26-28
Treatment of hepatitis C Immune-suppression strategies: There is little controlled data to suggest serious differences in immune-suppression strategies in kidney transplant recipients with HCV.29,30 In liver transplant recipients, steroid boluses have been shown to have a deleterious effect with higher rates of severe HCV recurrence. Minimization of immunosuppression is a common sense strategy to maintain a balance between preventing rejection and allowing permissive replication of HCV.
ACCEPTED MANUSCRIPT 8 Antiviral treatment: The goals of pre-transplant therapy are to eliminate the virus and to decrease the incidence of extrahepatic manifestations of HCV such as
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diabetes and de novo glomerulonephropathy post-transplant thus leading to
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improved patient and graft survival. Conventionally treatment should be undertaken before kidney transplantation, since after transplant there is a reduced
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chance of success in the presence of higher viral loads and immune-suppression.
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Furthermore interferon, which is up to this point the backbone of antiviral regimens, has a high risk of precipitating allograft rejection or renal failure.31
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Newer antiviral regimens, which do not include interferon, offer great hope for post-
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transplant efficacy and safety in this population.
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The standard of antiviral treatment regimens are still based upon Pegylated
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Interferon and Ribavirin with sustained virologic response rates similar to that of the general population (16-68%).32 Treatment courses are difficult to tolerate and
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generally are required for 24-48 weeks with addition of an HCV protease inhibitor required for Genotype 1, such as Telaprevir or Boceprevir.33-36 With the recent approval of Sofosbuvir, a direct acting polymerase inhibitor for HCV treatment, this paradigm might shift to 12-week courses of therapy that will for in many individuals still include interferon and Ribavirin. Other combinations of direct acting antiviral agents including second-generation protease inhibitors as well as nucleotide and non-nucleotide inhibitors are in clinical trials (in the nontransplant population thus far)with encouraging data for interferon free , all oral therapy regimens. Efficacy of these regimens is much improved (over 90%
ACCEPTED MANUSCRIPT 9 sustained virologic response or viral clearance) as is safety with shorter courses of therapy (Table 2). Important considerations include interactions between protease
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data for efficacy in the renal transplant population thus far.
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inhibitors and immune-suppression after renal transplant and lack of published
Epidemiology of hepatitis B
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Hepatitis B
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It is estimated that over 350 million people have chronic HBV infection with the most endemic areas being China, South-East Asia, and sub-Saharan Africa;37,38 an
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estimated 1 million within the US have chronic HBV infection. Worldwide, the most
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common mode of transmission is vertical transmission in the perinatal period or sexual contact among adults. A much smaller proportion are infected due to intravenous drug use. Dialysis patients are at risk of developing chronic infection after exposure due to their relative immunocompromised state.39 The risks of chronic infection are development of cirrhosis and hepatocellular carcinoma. Fortunately, vaccination against HBV can prevent infection. In dialysis patients, the efficacy of vaccination is diminished but still reduces the risk of acquiring HBV by 70%.40,.41,42
ACCEPTED MANUSCRIPT 10 Impact of hepatitis B in Kidney Transplantation Patients with chronic HBV on hemodialysis should undergo assessment for
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cirrhosis. There is significant heterogeneity among the quality and rigor of studies
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evaluating chronic HBV in renal transplant patients. Despite this there is some
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consensus that renal allograft recipients with chronic HBV have significantly reduced survival—most of which is related to liver failure, reduced kidney allograft
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survival, and increased rate of liver fibrosis post-transplant.32,43-45
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Development of new HBV infection after kidney transplantation is possible from donor-derived transmission. The highest risk for transmission occurs when the
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donor is HBsAg positive, and that risk increases when HBeAg is also detected,
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indicative of a high donor serum viral load. The risk from donors that are only
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HBcAb positive (negative HBsAg and HBV DNA) is lower but possible due to either transmission of HBV in peripheral blood mononuclear cells or because the donor
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has a new HBV infection in the “window period” before HBsAg is detected. The risk for de novo HBV infection is markedly influenced by the presence of HBsAb in the recipient, which marks immunity either from previous vaccination or previous clearance of HBV after exposure. The highest risk donor organs should be offered only to “immune” recipients where HBsAb is clearly detected and require anti-viral prophylaxis. In recipients without immunity to HBV, donor organs with HBcAb can be used if anti-viral prophylaxis is used.37
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Treatment of hepatitis B
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Treatment is considered in non-transplant patients who have HBeAg positivity and/or elevated HBV DNA and signs of necroinflammatory injury with elevated AST
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and ALT.46 In kidney transplantation, immunosuppression allows for increased viral replication and in rare cases hepatocellular failure with profound cholestasis
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can develop— a condition labeled fibrosing cholestatic hepatitis. To prevent this
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severe complication, antiviral treatment is recommended for all renal transplant recipients with detectable HBsAg and should continue for an indefinite period of
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time, since cessation of therapy in immunocompromised hosts can lead to flare of
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hepatitis B or decompensated liver disease.47,48
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The first-line anti-viral therapy should be one of the newer nucleos(t)ide analogues: Entecavir or Tenofovir are preferred for therapy due to their higher potency and
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lower rates of resistance in comparison with their predecessors Lamivudine or Adefovir. Even so, the majority of post-transplant studies have been conducted with Lamivudine, which in one trial significantly decreased overall and liver-related mortality;47 a meta-analysis of 14 Lamivudine trials found HBV DNA clearance in 91% and normalization of ALT in 81% of treated patients.49 Previous HBV anti-viral treatment history is important in antiviral agent selection, since prior Lamivudine therapy increases the risk for Entecavir resistance50 and prior Adefovir treatment increases the risk of Tenofovir resistance due to structural
ACCEPTED MANUSCRIPT 12 similarities between Entecavir and Lamivudine and between Adefovir and
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Tenofovir.
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Hepatitis E
Hepatitis E is a RNA virus that is transmitted feco-orally. The virus can be
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transmitted through contaminated food or water or by person to person in endemic
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areas.51 In non-endemic areas the mode of transmission is often zoonotic and
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spread is by domesticated swine.52
In the immunecompetent host the virus can cause a hepatitis that is self –limited
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and similar to hepatitis A. In kidney transplant recipients, hepatitis E infection has
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been reported to be a cause of chronic hepatitis.53
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Although Hepatitis E antibody tests are widely available they cannot be used to confirm the diagnosis. Even in industrialized countries the prevalence of HEV antibodies has been reported to be as high as 16%. Confirmation requires serum or stool HEV RNA PCR.
Treatment for chronic HEV in the kidney transplant recipient starts with reduction of immunosuppression. Ribavirin has been used in kidney transplant recipients in small series for upto after 3 months of treatment.53 Prevention includes avoiding
ACCEPTED MANUSCRIPT 13 contaminated food or water and cooking food thoroughly. There is no effective
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vaccine available yet.
Autosomal Dominant Polycystic Disease
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Polycystic Disease
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One of two known mutations can give rise to autosomal dominant polycystic kidney and liver disease: AD-PKD1 and AD-PKD2. The clinical course of either mutation is
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similar, however the former accounts for roughly 90% of combined kidney and liver
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polycystic disease, while the latter tends to have a later onset of disease and relatively longer life expectancy.54,55 The severity of cystic liver disease correlates
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with kidney cyst volume and renal function.56 Liver cysts increase in prevalence
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with age,56 and tend to be larger and more numerous in women (figure 1)—likely from the effects of estrogen.57 Pregnancy and hormonal therapy can lead to increased cysts.
Most hepatic cystic disease is asymptomatic but symptoms if they occur are generally related to cyst size with abdominal pain, early satiety, and dyspnea. Uncommon, but worrisome finding include: cyst hemorrhage, rupture, torsion, or infection.58 It is rare to develop consequences of portal hypertension or biliary obstruction, both of which if they occur are due to physical disruption by cysts rather than due to liver failure or cirrhosis. Medical therapy is generally relegated
ACCEPTED MANUSCRIPT 14 to attempts at stopping any hormone replacement therapy or oral contraceptives in women. Large symptomatic cysts are treated with by ultrasound-guided drainage
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liver transplantation for recalcitrant abdominal symptoms.
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and sclerosis, occasionally surgical fenestration and rarely partial hepatectomy or
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Autosomal Recessive Polycystic Disease
A mutation in the gene encoding fibrocystin protein59 is the culprit of autosomal
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recessive polycystic kidney disease (ARPKD). Associated ductal plate
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malformations in the developing liver result in the lesions of congenital hepatic fibrosis (CHF), which can manifest as portal hypertension with variceal hemorrhage,
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and hypersplenism. Other associated anomalies include dilation of intrahepatic bile ducts (intrahepatic choledochoceles of Caroli’s disease) with risks of cholangitis and
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cholangiocarcinoma and portal vascular anomalies.60
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Liver failure and cirrhosis is rare with these conditions. The clinical presentation of ARPKD relates to age, where kidney disease predominates in neonates, but hepatic
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manifestations dominate in those presenting as adults. From the prospective of the liver, treatment is directed to the consequence of portal hypertension and biliary stasis and cholangitis.61 Endoscopic therapies such as band ligation as well as portosystemic shunts, either transjugular (Transjugular portosystemic intrahepatic shunts) or surgical (splenorenal shunts) have been utilized with good results for prophylaxis of variceal hemorrhage.54,58 Occasionally for Caroli’s disease with recurrent cholangitis, liver or liver-kidney transplantation (if there is associated end-stage renal disease due to ARPKD) has been performed with good results.54
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Drug-Induced Liver Injury The number of medications that might incite drug-induced liver injury (DILI) is
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myriad. The National Library of Medicine has formulated a site dedicated to drugspecific information (livertox.nih.gov) for DILI.62 Implicating a drug as cause of liver
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injury is difficult, since there may not be a clear temporal relationship between abnormal liver enzymes and medication administration. Liver enzymes often
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must be excluded (i.e. viral hepatitis).
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improve with discontinuation of the culprit drug, and other confounding causes
The severity of DILI varies widely but can lead to liver transplantation or death in
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11.7-15% of cases of idiosyncratic drug reactions.63,64 The severity can be estimated by “Hy’s Law” which is a marker of poor prognosis if three criteria are satisfied:
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aminotranferases > 3 x ULN, total bilirubin > 2 x ULN without a similar rise in
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alkaline phosphatase, and no other reason found to explain the rise in aminotransferases or bilirubin apart from DILI.
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Drugs commonly implicated include antifungal, antibiotic, anticonvulsive, immunosuppressive, diabetic, and lipid-lowering agents. Drug-drug interactions are of particular importance in the transplant patient who is on multiple medications. Apart from directly hepatotoxic agents like Acetaminophen, where N-acteylcysteine is an effective therapy,65 treatment is relegated to withdrawal of the offending agent and supportive cares.
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Systemic Infections Systemic infections may result in hepatic manifestations. The most commonly liver
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infections implicated in post kidney transplant recipients include liver abscesses and systemic infections due to one of the family of herpesviruses: cytomegalovirus
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(CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella-zoster
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virus (VZV). Cytomegalovirus
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In immunocompetent patients, CMV is typically a self-limited and mild disease. However, in the transplant population it is a significant source of morbidity and
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60% of recipients have detectable CMV antigen within 100 days post transplant.66
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Due to antiviral prophylaxis after transplantation, the disease is often delayed beyond the first 6 to 12 months when the antiviral prophylaxis is typically stopped.
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CMV hepatitis generally occurs along with disseminated disease or during other
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organ involvement. Roughly half of recipients with systemic CMV have hepatitis, which is typically worse in primary infection than reactivation.67 The diagnosis is made when evidence of viremia is found by detectable CMV in blood and liver biopsy finds CMV inclusions (figure 2). Treatment and prophylaxis of CMV are accomplished with oral or intravenous antivirals (ganciclovir and valganciclovir ), which often are required for weeks or months. Epstein-Barr Virus EBV is ubiquitous in all populations by adulthood.68 After infection EBV leads to a latent infection, which can be reactivated, particularly in the immunosuppressed. In
ACCEPTED MANUSCRIPT 17 transplant patients acute infection may manifest similarly as in the general population, but it is also central to the development of post transplant
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lymphoproliferative disorder (PTLD),69 which carries a significant risk of mortality.
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The mainstay of therapy is reduction in immune-suppression. Antiviral treatment (acyclovir or valacyclovir) is generally reserved for cases where a significant viral
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load is detected although data to suggest post transplant efficacy is lacking.
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Herpes Simplex Virus
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HSV is a DNA virus with seroprevalence of HSV-1 roughly 60% and HSV-2 roughly 15% in the general US population., In the transplant population reactivation can
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occur because the virus establishes latency in ganglia.70 In immunocompromised patients primary infections are more severe and reactivations occur more often.71
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Kidney transplant recipients have an incidence of initial infection of 30-50%
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without Acyclovir antiviral prophylaxis.72,73 The risk of HSV reactivation is related to the level of immunosuppression, as such it is highest within the first 3 months
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following transplant.
HSV Hepatitis has been characterized in a post transplant population.74 It is associated with disseminated disease and in one series was found to develop a median 18 days following transplant with clinical features of fever, herpetic stomatitis, and abdominal pain. In that population a 67% mortality was associated with concomitant bacteremia, hypotension, DIC, or gastrointestinal bleeding. Due to the mortal risk, intravenous acyclovir therapy is generally started in any transplant recipient with fever, progressively abnormal transaminases, and abdominal pain
ACCEPTED MANUSCRIPT 18 even in the absence of cutaneous manifestations. The diagnosis is generally made by liver biopsy with features of enlarged “ground-glass” and chromatin margination
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within nuclei. Varicella-Zoster Virus
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Varicella develops mild disease mainly consisting of small blisters in children (chicken pox) but is more severe in adults and immunocompromised patients.
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Hepatitis resulting from varicella is uncommon in transplant recipients and when
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present it commonly accompanies symptoms of fever, cutaneous vesicles, and abdominal or back pain. Treatment is accomplished with high-dose intravenous
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acyclovir (10 mg/kg every 8 hours).
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Herpes zoster, the reactivation of latent VZV, results in cutaneous lesions (shingles).
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In disseminated disease, the course can be long and with hepatitis often as a prominent feature. In a case series of renal transplant recipients it was found that
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reactivated disease tends to be less severe than initial infection.75 Herpes zoster with concomitant DIC was found in 50% and pneumonitis in 29% of cases, it carried an overall mortality of 34% in this population. Treatment again is accomplished with high-dose acyclovir. Liver Abscess Pyogenic liver abscesses are relatively infrequent, accounting for 8-20 per 100,000 hospital admissions.41 The majority are polymicrobial with enteric bacteria, but up to 22% may be from Candida species.76 Immunosuppressed kidney recipients
ACCEPTED MANUSCRIPT 19 traveling outside of the US are at particular risk for amebic abscess as the result of Entamoeba histolytica contamination of foods washed with fresh water. E.
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histolytica cysts can only be destroyed by boiling water, not iodine tablets or UV
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light. Presentation is classically with right upper fever, quadrant pain, and jaundice. Liver chemistries tend to be only modestly abnormal, and abscesses are detected by
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imaging. Most often, treatment consists of guided percutaneous drainage and anti-
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infectives directed at the isolate of the fluid aspirate’s gram stain and culture. In some cases surgical drainage or resection is required when there are multifocal
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abscesses or when abscesses are loculated.76
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Mycobacteria
The rate of active tuberculosis is 50 fold higher in kidney transplant recipients than
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the general population, with the bulk of disease attributed to reactivation of disease
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within the first year after transplant.77,78 When the liver is involved it generally is concurrent with pulmonary or gastrointestinal disease. Presentation is often with
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constitutional symptoms such as fever, and modestly abnormal liver chemistries in a hepatocellular or infiltrative pattern. Imaging and tissue sampling for with acid fast staining and mycobacterial culture make the diagnosis.
ACCEPTED MANUSCRIPT 20 Liver diseases seen at a similar frequency in kidney transplant and non-
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transplant patients.
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In the general US population, non-alcoholic fatty liver disease (NAFLD) is a prevalent and increasing cause of chronic liver disease. By some estimates it is the
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commonest cause of chronic liver disease in the US. It is closely associated with the
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epidemic of obesity and diabetes and is the hepatic manifestation of the metabolic
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syndrome.
In transplant recipients the use of chronic immune-suppression including steroids
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and calcineurin inhibitors are linked to risk of diabetes, hypertension and
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transplantation.79
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hyperlipidemia and metabolic syndrome is common after kidney and liver
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NAFLD is often seen either prior to transplantation or arising de-novo after transplantation with the data being more robust in liver transplant recipients.80 Although in kidney transplant recipients the same can be surmised,81 thus far the evidence is still lacking regarding the incidence of NAFLD in this population.
NAFLD is often noted incidentally on imaging of the liver, presenting as steatosis on ultrasound, CT or MRI of the abdomen. Often liver enzymes can be elevated (in over two-third of individuals) and in a minority of individuals, NAFLD can lead to cirrhosis.
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Therapy includes treatment of obesity and its causes as well as the individual
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diseases that constitute the metabolic syndrome. Weight loss through exercise and
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dietary discretion is the best therapy. Control of diabetes and insulin resistance as well as hyperlipidemia and hypertension are also important in the management of
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NAFLD. Reduction of immune-suppression if feasible is an important strategy to
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minimize these metabolic side effects.
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Other causes of chronic liver disease should also be considered in kidney transplant recipients. These are not reported with any increased incidence in kidney transplant
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recipients. Thus autoimmune conditions (such as autoimmune hepatitis and
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primary biliary cirrhosis), primary sclerosing cholangitis, metabolic conditions such
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as alcohol induced liver disease and genetic conditions such as hemochromatosis, alpha1antitryspin deficiency and Wilson disease can all present with a wide
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spectrum of liver disease, ranging from asymptomatic elevation of liver enzymes to decompensated cirrhosis. Appropriate evaluation requires an index of suspicion, knowledge of diagnostic criteria, and exclusion of other diseases noted above.
ACCEPTED MANUSCRIPT 22 References 1.
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Figure 1. Multiple hepatic cysts in a patient with autosomal dominant polycystic and liver disease
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Figure 2.
This high power photomicrograph shows the characteristic nuclear and
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cytoplasmic inclusions typically seen with cytomegalovirus. In the left side of the photomicrograph note the enlarged or cytomegalic cell containing both nuclear and cytoplasmic
inclusions.
The
cytoplasmic
inclusions
are
usually
small
and
basophilic(arrowhead). The nuclear inclusions are usually much larger, eosinophilic and show a halo or clear space between the inclusion in the nuclear membrane (arrow).
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Table 1. Causes of Liver Disease in Renal Transplant Recipients Infections o Hepatotrophic Viral Hepatitis B Hepatitis C Hepatitis E o Non-hepatotrophic Viral Cytomegalovirus Epstein-Barr virus Herpes simplex virus Varicella-Zoster virus o Bacterial Hepatic abscess (polymicrobial) Mycobacteria Inherited o ADPKD o ARPKD o Alpha-1 antitrypsin deficiency o Hemochromatosis o Wilson disease Drug-Induced Liver Injury o Hepatocellular pattern Acetaminophen Allopurinol Amiodarone Fluoxetine INH NSAIDs Rifampin HMG-CoA reductase inhibitors Tetracyclines o Mixed pattern Amitriptyline Azathioprine Clindamycin Nitrofurantoin Phenytoin TMP/SMX Verapamil o Cholestatic pattern Amox/Clav Anabolic steroids OCPs Erythromycins
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Metabolic o NAFLD o Alcoholic liver disease Autoimmune o Autoimmune hepatitis o Primary biliary cirrhosis
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Terbinafine Tricyclic antidepressants
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Table 2. Hepatitis C Treatment Regimens Population
Duration of therapy
ABT-450/r ABT-267 ABT-333 Ribavirin *
Genotype 1 Nontransplant
12 weeks
Sofosbuvir Ledipasvir *
Genotype 1 NonTransplant
12 weeks
Sofosbuvir Peg-IFNα-2a Ribavirin
Genotype 1 Genotype 2&3 NonTransplant
12 weeks 24 weeks
90% 82 67%
Peg-IFNα-2a Ribavirin
Genotype 1& 4 Renal Transplant
24-48 weeks
37.5%83
Peg-IFNα-2a
Genotype 1 Hemodialysis
48 weeks
64%84
Genotype 1b, 2, & 3 Hemodialysis
48 weeks
25%85
Genotype 1, Genotype 2+3 Hemodialysis
48 weeks 24 weeks
94%86 100%
Peg-IFNα-2a Ribavirin
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Peg-IFNα-2a
* - This regimen is not yet FDA approved SVR= Sustained Virologic Response
SVR at 12 or 24 weeks >92%
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Anti-Viral Medication
>93%