Liver Disease Among Renal Transplant Recipients

32

Liver Disease Among Renal Transplant Recipients ADNAN SAID, NASIA SAFDAR, and MICHAEL R. LUCEY

CHAPTER OUTLINE

Overview of Incidence and Clinicopathologic Associations Combined Liver and Kidney Diseases Polycystic Disease Drug-Induced Hepatotoxicity Specific Immunosuppressive Agents in Renal Transplantation and Hepatotoxicity Azathioprine Calcineurin Inhibitor-Induced Hepatotoxicity Sirolimus Mycophenolate Mofetil, Mycophenolic Acid Monoclonal Antibodies T Cell Costimulatory Inhibitor Hepatitis Viruses Associated with Renal Transplantation Hepatitis B Virus HBV Viral Structure and Proteins Tests for Detection of Hepatitis B Epidemiology of HBV Hepatitis B Infection in Patients Awaiting Renal Transplant on Dialysis Pretransplant Management of Hepatitis B-Positive Dialysis Patients Posttransplant Prognosis in Hepatitis B Recipients De Novo HBV Infection After Kidney Transplantation Antiviral Therapy of Chronic Hepatitis B in Renal Transplant Candidates/Recipients Specific Antiviral Agents for HBV Used in Renal Transplant Recipients Treatment of Fibrosing Cholestatic Hepatitis B in Renal Transplant Recipients Summary Hepatitis C Virus Viral Structure

Overview of Incidence and Clinicopathologic Associations Theoretically, the spectrum of liver disease in renal transplant recipients should mimic the spectrum of disease seen in society. It is axiomatic that renal transplant recipients are at risk for all the acute and chronic liver disorders seen in the nontransplant population. Surveys of the prevalence

HCV Species Clinical Manifestations of Hepatitis C Infection in Immunocompetent Hosts Incidence/Prevalence and Transmission of Hepatitis C in Renal Transplant Patients Allograft Transmission of HCV Effect of Pretransplant HCV on Posttransplant Outcomes HCV and Posttransplant Diabetes in the Renal Transplant Recipient HCV and Posttransplant Nephropathy Immunosuppressive Strategies in Renal Transplant Patients Infected with HCV Hepatitis C Antiviral Therapy Treatment of HCV in the Renal Transplant Candidate and Recipient Hepatitis E Nonalcoholic Fatty Liver Disease and Renal Transplant NAFLD Post Renal Transplant NAFLD and Outcomes in Renal Transplant Recipients Treatment of NAFLD Hepatocellular Carcinoma After Renal Transplantation Systemic Infections Resulting in Hepatitis and Liver Disease Liver Abscess Mycobacterial Infection Viral Infections Herpesviruses Cytomegalovirus Epstein–Barr Virus Herpes Simplex Virus Varicella-Zoster Virus Human Herpesvirus 6 and 7

of chronic liver injury in otherwise healthy subjects suggest that the burden of unrecognized liver disease in the apparently healthy community is high. A study by Ioannou et al.1 used the National Health and Nutrition Examination Survey (NHANES) conducted between 1999 and 2002 to assess the prevalence of elevated serum transaminase activities in a cohort of 6823 American adults. The prevalence of elevated alanine aminotransferase (ALT) was 8.9%, a result 539

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that is more than double that of previously available estimates in similar populations. Recently another NHANES study of American adolescents identified the presence of an elevated ALT, defined as a value above 30 U/mL, in 8.0% of the population.2 Risk factors for an elevated ALT included higher waist circumference, body mass index, fasting blood glucose, and fasting triglycerides. These studies indicate the potential hazards in estimating the likely prevalence of liver disease in a special population, such as recipients of renal transplantation in the absence of good data. The rise in nonalcoholic steatohepatitis, the advent of highly effective antiviral therapy to eradicate chronic hepatitis C virus (HCV) infection, and possible changing use of alcohol mean that a contemporary assessment of the spectrum of liver disease might be quite different from previous reports and in one country compared with another.3 Consequently, it should be noted that there have been no comprehensive attempts to characterize liver disease in renal transplant recipients since Allison et al.4 examined the prevalence and nature of chronic liver disease among 538 patients with functioning renal allografts managed in Scotland between 1980 and 1989. The authors reported that biochemical evidence of liver dysfunction was observed in 37 patients (7%), 19 (4%) of whom were seropositive for HCV. The work of Allison et  al. is most likely an underestimate given that it was undertaken just as HCV infection was discovered, and, as will be discussed later, HCV prevalence in renal transplant cohorts has been reported to be as high as 40%. In the subsequent sections of this chapter we will discuss in more detail some liver disorders that appear to occur in greater frequency in renal transplant recipients compared with the background population. In some circumstances, such as autosomal dominant polycystic disease, the liver and kidney disorder are part of the same underlying disease. In other patients in whom renal failure coexists with liver disease, the two conditions are acquired separately. Chronic infections with hepatotropic viruses (hepatitis B virus [HBV] and HCV) fall into this category. We will consider liver diatheses that are consequences of the inherent risks of the transplant process, including drug-related injury secondary to immunosuppressant medications or hepatic manifestations of opportunistic infections secondary to immunosuppression. Finally, the high prevalence of metabolic syndrome and obesity in the renal transplant population has led to the increasing recognition of nonalcoholic fatty liver disease (NAFLD) in the renal transplant population. Current knowledge about this common condition and its consequences and treatment are addressed. 

and liver polycystic disease and mutations in AD-PKD2 account for the majority of the remainder.5,6 Patients with mutations in PKD2 tend to have later onset of disease and approximately 16 years of increased life expectancy compared with patients who have mutations in PKD1, but otherwise the natural history is identical, regardless of whether PKD1 or PKD2 is the mutated gene. Renal cystic disease associated with autosomal dominant polycystic disease may develop renal failure that requires hemodialysis or renal transplantation. The severity of hepatic cystic disease correlates with both the severity of renal cystic disease and the degree of renal dysfunction. Hepatic cysts are lined with secretory biliary epithelium. The cysts are first noted after puberty and increase in prevalence with age.7 In addition, hepatic cyst prevalence is correlated with renal cyst volume.7 The lifetime risk for expression of hepatic cysts is equal in male and female holders of the genetic defect, but hepatic cysts tend to be larger and more numerous in women, possibly because of the influence of estrogen on hepatic cyst growth.8 Symptoms caused by hepatic cysts in adult-onset autosomal dominant polycystic disease are the result of a compartment disorder in which the abdominal cavity is unable to accommodate the cystic mass. Patients with massive hepatic cysts can experience abdominal pain, early satiety, or dyspnea (Fig. 32.1). These “bulk” symptoms may be so troubling as to warrant liver transplantation. In addition, uncommon complications, such as cyst rupture, infection, torsion, or hemorrhage, can occur.9 Hepatic function and portal hemodynamics are usually normal. Biliary obstruction, portal hypertension, ascites, variceal hemorrhage, and encephalopathy are rare features of autosomal dominant polycystic disease. There is no good medical therapy for the abdominal symptoms associated with autosomal dominant polycystic disease. Agents such as somatostatin and sirolimus have been tried without much success.5 For women with symptomatic cysts, stopping oral contraceptive or hormone replacement therapy should be considered, but data on efficacy are anecdotal. There are many procedures described to ameliorate the discomfort associated with

Combined Liver and Kidney Diseases POLYCYSTIC DISEASE Autosomal dominant polycystic disease is a condition arising from mutations in two distinct genes that result in the development of the renal and liver cysts. Mutations in ADPKD1 account for up to 90% adult-onset combined kidney

Fig. 32.1  The liver has innumerable cysts, ranging from small to large, in a patient with autosomal dominant polycystic liver/kidney disease.

32 • Liver Disease Among Renal Transplant Recipients

liver cysts. Cyst aspiration under sonographic guidance may provide temporary relief, but the cysts inevitably recur. Continuous or intermittent drainage through a permanent percutaneous catheter should be strongly discouraged because it runs the risk of converting a sterile cyst into a pyogenic abscess. Surgical approaches include open or laparoscopic cyst fenestration, hepatic resection, and liver transplantation. The results of liver transplantation for polycystic liver disease are mixed with a higher than expected incidence of posttransplant complications, including infections. Nevertheless, these patients have had improved access to liver transplant via approval of model for end-stage liver disease (MELD) exception scores. In an audit of United Network for Organ Sharing (UNOS) data from 2002 to 2015, 620 patients with polycystic liver disease were 5.7 times more likely to be transplanted than patients with chronic liver failure and patients with liver cancer.10 Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD-1 gene that encodes the protein fibrocystin.11 Congenital hepatic fibrosis (CHF), caused by ductal plate malformation of the developing biliary system, is invariably present in patients with ARPKD.12 Clinical presentation is related to age. Renal disease predominates in patients that present neonatally. Hepatic manifestations predominate in older children and adults, although overlap is common.12 The predominant manifestations of CHF are the development of portal hypertension, dilation of the intrahepatic bile ducts (also known as Caroli’s syndrome), and vascular anomalies. Variceal formation and hemorrhage, splenomegaly, and thrombocytopenia are common.12 Dilation of the intrahepatic bile ducts can result in recurrent bile stasis and cholangitis. Finally, anomalies of portal venous anatomy are frequent. Treatment for CHF is focused on prevention of variceal hemorrhage and promotion of adequate biliary drainage to prevent cholangitis.13 

DRUG-INDUCED HEPATOTOXICITY Drug-induced liver injury (DILI) can have a wide spectrum, ranging from asymptomatic elevations of liver enzymes to acute liver failure. With rare exceptions, the serum biochemical and liver histologic patterns are not diagnostic of drug-related injury. Rather, DILI is often diagnosed based upon a combination of temporal relationship to a particular drug use, exclusion of other pathology (such as viral hepatitis), and knowledge of the common pattern of liver test abnormalities associated with particular drugs.14–18 Improvement of liver tests with discontinuation of the offending medications offers further evidence of DILI, but improvement may take weeks. The severity of drug-related injury may be predicted by the degree of impairment of hepatic function. In particular the presence of jaundice in association with elevated aminotransferases (known as “Hy’s rule”) is often an ominous sign of significant hepatocellular injury and risk of progression to liver failure.14,15,18 In the two largest series to date, mortality or liver transplantation from idiosyncratic (excluding acetaminophen) drug reactions occurred in 11.7% and 15% of cases.14,15

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The mechanisms of drug injury are multiple as well. Toxic metabolites produced by detoxification of medications through the liver, most commonly via the cytochrome P-450 mechanisms, may contribute to dose-related hepatotoxicity such as seen with acetaminophen.16,19 Other medications may have immunologic mechanisms of injury that are not dose-related and considered idiosyncratic.16,18,19 Most patients present asymptomatically or with nonspecific symptoms. Occasionally, a hypersensitivity reaction of fever, lymphadenopathy, and leukocytosis, often with eosinophilia, may be seen.20,21 Liver test abnormalities are variable. The most common pattern is acute hepatocellular injury with elevations of aminotransferases greater than twofold normal with lesser elevations of alkaline phosphatase; however, cholestasis and bile duct loss (e.g., amoxillcin-clavulinic acid toxicity) and bland fibrosis (methotrexate) are also seen.14,15 In transplant patients the opportunities for drug-related hepatotoxicity abound because of the use of multiple medications, many of which are metabolized via the same pathways in the liver, thereby increasing the risk of accumulation of hepatotoxic metabolites. Common medication classes used in transplant that have been implicated in DILI include immunosuppressive medications,22–24 antibiotics,14,15 antihyperlipidemics,14,15 and drugs for hypertension and diabetes.14,15 In addition, numerous herbal and nonprescription agents have also been implicated in the development of DILI. Finally, more than one agent may be implicated as the etiology for DILI in a given patient.15 Table 32.1 shows some common medications that stimulate or block the cytochrome P-450 system within the liver and may influence the serum concentrations of other drugs and their metabolites. The main treatment for DILI is withdrawal of the offending drug. There are few therapies that have been shown to improve outcomes in clinical trial. Two exceptions are N-acetylcysteine for acetaminophen toxicity and l-carnitine for valproic acid toxicity.25,26 Corticosteroids are of unproven benefit. In cases that progress to liver failure, liver transplantation should be considered.26 

TABLE 32.1  Medications that Stimulate or Inhibit the Cytochrome P-450 System and Can Influence the Level of Other Medications (Such as Cyclosporine) MEDICATIONS THAT STIMULATE CYTOCHROME P-450 AND CAN DECREASE THE LEVEL OF CALCINEURIN INHIBITOR Trimethoprim-sulfamethoxazole Isoniazid Nafcillin Phenytoin Carbamazepine Omeprazole MEDICATIONS THAT INHIBIT CYTOCHROME P-450 AND CAN INCREASE THE LEVEL OF CALCINEURIN INHIBITOR Diltiazem Fluconazole Tetracycline Tacrolimus Sex hormones Metoclopramide

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Specific Immunosuppressive Agents in Renal Transplantation and Hepatotoxicity AZATHIOPRINE Azathioprine is an antimetabolite agent that inhibits purine synthesis. It is the prodrug of 6-mercatopurine (6-MP) and inhibits deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. A broad range of hepatotoxicity has been associated with the use of azathioprine in renal transplant recipients, although it is considered rare.22,27–31 The pathogenesis of azathioprine hepatotoxicity is multifactorial, resulting from endothelial damage,32 direct hepatotoxicity,33 and interlobular bile duct injury.34 In addition, serum levels of the 6-MP metabolite 6-methylmercaptopurine ribonucleotide have been associated with the development of hepatotoxicity.35 The most severe manifestation of azathioprine toxicity is sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease. The hallmark of SOS is obliteration and fibrosis of the central hepatic venule and sinusoidal congestion.30 SOS is manifested by jaundice, ascites, hepatomegaly, weight gain, and elevated liver enzymes (typically alkaline phosphatase with minimal increases in aminotransferases). In the first few months after kidney transplantation it can present with asymptomatic hyperbilirubinemia and elevated liver enzymes, but progresses to jaundice, hepatomegaly, and ascites after the first year.36 The diagnosis can be made clinically, but it is often difficult to make. In the hematopoietic stem cell population, SOS is diagnosed by two of the three criteria being met: serum bilirubin greater than 2 mg/dL, hepatomegaly or right upper quadrant pain, and sudden weight gain of 2% body weight.31 However, these criteria were established in the hematopoietic stem cell transplant population and not validated in solid-organ transplantation. Doppler ultrasound is useful for documenting ascites and hepatomegaly, and for ruling out biliary obstruction or infiltrative processes. Liver biopsy can be used to help make a diagnosis, as can measurement of the wedged hepatic venous portal gradient (HVPG).37,38 Poor outcomes are associated with higher bilirubin, degree of weight gain, aminotransferase elevation, and HVPG elevation.38 With cessation of azathioprine it rarely has been reported to regress.39 Specific therapy for SOS, including defibrotide, heparin, ursodeoxycholic acid, and prostaglandin E1, has produced mixed results.38 Transjugular intrahepatic portosystemic shunt and liver transplantation have been reported in small series and case reports, respectively.40 Other vascular diseases of the liver have also been attributed to azathioprine, including peliosis hepatis (dilated blood-filled cavities within the liver), presumably secondary to endothelial injury within the liver, leading to sinusoidal dilation. Nodular regenerative hyperplasia can be associated with peliosis. Veno-occlusive disease is rarely seen and by the time it appears, portal hypertension with complications of ascites and variceal hemorrhage are often present.41 Azathioprine-induced hepatitis has been reported more frequently in kidney transplant recipients with chronic viral hepatitis. In one study of 1035 transplant recipients,

21 fulfilled the criteria for azathioprine hepatitis with jaundice at presentation. Viral hepatitis markers (HCV, HBV, or both) were present in all 20 that were tested. The jaundice disappeared and liver enzymes normalized in all within 4 to 12 weeks of azathioprine discontinuation or dose reduction. Rechallenge with azathioprine was performed in four patients, with recurrence of jaundice in all cases.42,43 In some of these patients, histologic findings were more consistent with azathioprine toxicity than viral hepatitis with intrahepatic cholestasis, centrilobular hepatocellular necrosis, and vascular lesions. Most did have chronic liver disease secondary to viral hepatitis on histology (18 out of 21). Some have suggested that patients with viral hepatitis and associated chronic inflammation have reduced catabolism and higher levels of toxic azathioprine metabolites in the liver, with resultant increases in rates of fibrosis, cirrhosis, and hepatotoxicity.42,43 Other potential mechanisms include accelerated course of viral hepatitis because of the use of more potent immunosuppressive regimens (prednisone–azathioprine–cyclosporine) with improvements occurring as a result of withdrawal of immunosuppression. These theories are difficult to prove. Nevertheless, in transplanting patients with viral hepatitis it is a good policy to use minimal immunosuppression (single or dual regimens rather than triple regimens) to minimize acceleration of viral hepatitis-associated liver disease. 

CALCINEURIN INHIBITOR-INDUCED HEPATOTOXICITY Cyclosporine and tacrolimus are immunosuppressive medications that belong to the class of calcineurin inhibitors.44,45 Cyclosporine-induced hepatotoxicity is uncommon and the mechanisms of cyclosporine toxicity are incompletely understood. Cyclosporine is metabolized via the cytochrome P-450 system and interactions with medications that inhibit or stimulate this pathway can result in increased or decreased cyclosporine levels respectively, thereby increasing the risk for hepatotoxicity.46 Cyclosporine-induced decrease in bile flow can result from reduced bile acid secretion and is associated with risk of bile duct stones and sludge formation in 2% to 5% of transplant recipients.47 Rarely, increases in aminotransferases have occurred, mostly in the first 90 days, and these respond to a reduction in doses. Persistent elevations in aminotransferases are rare and occur in less than 5% to 10% of renal transplant recipients.48,49 Transient elevations of bilirubin or aminotransferases are more common, occur early (within the first 3 months posttransplantation), and are reversible with dose reductions or discontinuation.47 Among renal transplant recipients without preexisting liver disease, azathioprine-treated patients had a higher incidence of posttransplant chronic liver disease compared with cyclosporine-treated patients.50 Tacrolimus has a similar immunosuppressive mechanism of action to cyclosporine.45 In liver transplant recipients it is associated with fewer episodes of acute rejection, need for salvage immunosuppressive therapy, or ductopenic rejection than cyclosporine. The overall patient and graft survival rates are similar to those seen with cyclosporine.48 Similar to cyclosporine, tacrolimus levels were higher in HCV-positive renal transplant recipients, presumably secondary to impaired cytochrome P-450-related metabolism

32 • Liver Disease Among Renal Transplant Recipients

of tacrolimus.51 Unlike cyclosporine, tacrolimus is not associated with reductions in bile flow and choledocholithiasis. Also tacrolimus was associated with less hyperbilirubinemia (0.3%) compared with cyclosporine (3.3%) in renal transplant recipients in a large comparative trial.52 Elevations in aminotransferases are generally mild, even with supratherapeutic levels, and reversible with dose reduction.53 

SIROLIMUS Sirolimus (rapamycin) is an mammalian target of rapamycin (mTOR) inhibitor that is structurally related to tacrolimus. Sirolimus-induced hepatotoxicity is uncommon. Elevations of aminotransferases with nonspecific histologic changes have been reported.54,55 The liver test abnormalities have resolved with discontinuation of sirolimus. Sirolimus hepatotoxicity has been better described in liver transplant recipients. Of 10 patients treated with sirolimus, two had sinusoidal congestion and one had eosinophilia consistent with a drug-related allergic reaction. Increases in aminotransferases were mild and normalized in all patients by 1 month.24 Another study analyzed a cohort of 97 patients treated with sirolimus-based immunosuppression post liver transplant. Surprisingly, 61 patients discontinued treatment because of adverse effects, including 21 patients that discontinued treatment because of hepatotoxicity.56 Cyclosporine, but not tacrolimus, can interfere with sirolimus pharmacokinetics, and caution must be exercised when combining these agents. 

MYCOPHENOLATE MOFETIL, MYCOPHENOLIC ACID Mycophenolate mofetil is an ester of mycophenolic acid that is readily absorbed. It inhibits purine synthesis by noncompetitively inhibiting a key enzyme in the de novo purine pathway, inosine monophosphate dehydrogenase. Hepatotoxicity is exceedingly uncommon but has been reported in isolated cases.23 

MONOCLONAL ANTIBODIES Monoclonal antibodies are commonly used as induction immunosuppression in kidney transplantation. Use of alemtuzumab (Campath; anti-CD52 humanized antibody) has been shown to accelerate hepatic fibrosis in HCVinfected transplant recipients and should generally be avoided in solid-organ recipients with chronic viral hepatitis.57 Anti-CD3 antibodies are used less often now for salvage of refractory rejection but have rarely been associated with severe hepatitis and elevation of aminotransferases up to 20-fold.58 Cytokine-mediated reactions presumably can cause the occasional hepatotoxicity seen with anti-CD3 antibodies. The interleukin-2 receptor antibody basiliximab has only been reported to cause hepatotoxicity in case reports in children.59 

T CELL COSTIMULATORY INHIBITOR Belatacept is a fusion protein designed to inhibit T cell activation by blocking a costimulatory pathway. Belatacept binds CD80 and CD86 on antigen-presenting cells with

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high affinity, preventing T cell activation by blocking interaction of CD80/86 with CD28. To date, there have been no reports of hepatotoxicity related to belatacept. 

Hepatitis Viruses Associated With Renal Transplantation HEPATITIS B VIRUS HBV Viral Structure and Proteins Hepatitis B is a hepatotropic enveloped, partially doublestranded DNA virus that is a member of the hepadnavirus family.60 The core of the virus comprises an RNA-dependent DNA polymerase plus a partially double-stranded DNA. After entry into the hepatocyte, the HBV enters the nucleus and forms what is known as covalently closed circular DNA (cccDNA). This DNA is produced by repair of the gapped virion DNA and is the likely source of the transcripts used to produce the viral proteins. The genome of the HBV encodes four different genes. The C gene encodes core protein, the P gene encodes the hepatitis B polymerase, the S gene encodes three different polypeptides of the envelope (pre-S1, pre-S2, and S), and the X gene encodes proteins potentially involved in the transactivation of viral replication. The hepatitis B viral antigens consist of the hepatitis B core antigen (HBcAg) and a subunit of the core called the hepatitis B e antigen (HBeAg). The HBeAg is released in high concentrations in the plasma during viral replication and is an indirect marker of active viral replication. The envelope protein is referred to as the hepatitis B surface antigen (HBsAg) and is likely responsible for viral binding to the hepatocyte. HBsAg is released in excess in the serum in individuals with chronic hepatitis B infection. Its presence in individuals 6 months after exposure to HBV defines the presence of chronic hepatitis B infection. Presently, there are eight distinct genotypes of HBV. The prevalence of these distinct genotypes varies geographically. Although there is growing evidence that the HBV genotype may have implications for treatment success, seroconversion, severity of liver disease, and development of hepatocellular carcinoma (HCC), current management does not change with HBV genotype and thus is not routinely determined.61  Tests for Detection of Hepatitis B HBV can cause acute and chronic infections. Acute infection is associated with acute hepatitis characterized by inflammation and hepatocellular necrosis. The diagnosis rests on detecting HBsAg in the serum of a patient with clinical and laboratory evidence of acute hepatitis (Table 32.2). Patients with a silent, self-limiting infection are able to produce protective antibody (HBsAb) and ultimately clear the virus. These patients are negative for HBsAg but positive for HBsAb and HBcAb. Chronic HBV infection is accompanied by evidence of hepatocellular injury and inflammation and is associated with chronic hepatitis. The diagnosis is made by showing persistently elevated serum transaminases and HBsAg in the serum at least 6 months after exposure to HBV infection.61 

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TABLE 32.2  Commonly Used Tests for Detection of Hepatitis B Infection and Their Interpretation HBsAg

Anti-HBs

Anti-HBc

Interpretation

+ + – –

– – + +

– + + –

Early acute infection Acute or chronic infection Cleared HBV infection—immune Vaccine response—immune

HBc, hepatitis B core; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus.

Epidemiology of HBV Routes of Transmission. Hepatitis B is widespread worldwide with more than a billion individuals estimated to be carrying the virus. Areas of high incidence include China, Southeast Asia, and sub-Saharan Africa.62,63 Worldwide, more than 350 million people have chronic HBV infection, and in the US alone more than 1 million individuals are estimated to have chronic infection.63 HBV is transmitted via perinatal, parenteral, or sexual exposure; transmission via the fecal-oral route does not occur. In countries with a high prevalence of hepatitis B infection the route of transmission is mainly vertical, at childbirth or, to a lesser degree, horizontally among household contacts in the first decade of life. In countries with a lower prevalence of hepatitis B infection, the majority of infections occurs in adulthood, and they are transmitted sexually and to a lesser extent by intravenous drug use.63  Natural History of HBV Infection. Hepatitis B can result either in a self-limited acute infection or progress to chronic liver disease. Progression to chronic hepatitis B infection after acute infection depends on the age of exposure to the virus. The risk of developing chronic HBV infection is over 90% for vertically acquired virus. The risk of chronic HBV infection in young children (<5 years old) is 25% to 30%. Clinically symptomatic infection is rare in children. Conversely, transmission in adulthood is associated with clinically apparent hepatitis in over 30% of individuals (>90%).63 Acute infection in adults when clinically apparent is often associated with jaundice and elevated aminotransferases with liver histology revealing portal inflammation, interface hepatitis, and lobular inflammation. Eventually, often over several weeks, the jaundice resolves and aminotransferases are more modestly elevated. Eventually, over 80% of nonimmunosuppressed adults who develop acute hepatitis B will not progress to chronic infection (HBsAg-negative, HBsAb-positive, HBcAb-positive). However, in dialysis patients, exposure to acute HBV results in chronic infection in the majority of nonvaccinated individuals (80%), likely because of their immunocompromised state and inability to mount protective antibody and T cell responses.64 The natural history of chronic hepatitis B infection depends on the age at which infection occurs. After perinatally transmitted infection there is an immune-tolerant phase in which high levels of viral replication (with high serum HBV DNA levels) are accompanied by minimal injury on liver biopsy and normal serum liver enzymes. The immune-tolerant phase can last from the first up to the third decade of life, after which transition occurs to the immune clearance phase.63 In this phase immune activity against HBV is noted by elevated levels of liver enzymes

and decreasing HBV DNA. Immune clearance can fail and lead to recurrent phases of HBV replication accompanied by surges of serum HBV DNA and aminotransferases, which increase the risk of fibrosis progression toward cirrhosis and HCC. Some patients can further enter into the “inactive carrier state” with disappearance of the HBeAg from serum and development of anti-HBe antibodies. These patients have detectable HBsAg and may have low levels of HBV viremia, but aminotransferases are normal or nearnormal and there is little to no necroinflammation on liver biopsy. Even in the inactive carrier state, patients can revert to HBeAg positivity and develop evidence of chronic hepatitis. Therefore they require lifelong follow-up. In addition, some patients remain HBeAg-negative, but develop evidence of ongoing chronic hepatitis marked by HBV viremia, elevated aminotransferases, and ongoing necroinflammation on liver biopsy.65,66 Most of these patients are felt to have virus with a mutation in the precore or core promoter region of the viral genome. Serum HBsAg positivity is lost infrequently. The outcomes of chronic HBV infection vary from an inactive carrier state to cirrhosis and its attendant complications, such as variceal hemorrhage, ascites, and encephalopathy. Risk for liver disease progression is increased in older patients, patients with higher HBV DNA levels, in patients coinfected with human immunodeficiency virus (HIV), HCV, or HDV, and with concomitant toxin exposures such as alcohol, smoking, or aflatoxin.61 In addition, the risk of HCC is elevated in chronic HBV, even in the absence of cirrhosis. 

Hepatitis B Infection in Patients Awaiting Renal Transplant on Dialysis The incidence and prevalence of hepatitis B infection among patients awaiting renal transplantation have declined in recent decades, in large measure because of hepatitis B vaccination of patients on dialysis and improved infection control measures during dialysis. Before hepatitis B vaccination, 3% to 10% of patients on dialysis developed this disease,67,68 with even higher incidences reported from countries with a high prevalence of HBV infection. Presently, about 1% of patients on dialysis in the US are infected with HBV, with a higher prevalence seen in developing countries.69-71 HBV vaccination is important for the prevention of HBV transmission during hemodialysis. One case control study demonstrated a 70% reduction in risk of acquiring HBV among hemodialysis patients that underwent HBV vaccination.72 Universal vaccination of dialysis patients, although recommended, is not universally undertaken. One survey of 12 centers from 11 countries showed routine vaccination of nonimmune subjects in only 66.7% (8 of 12) of centers. Vaccination has a lower response rate in end-stage renal disease (ESRD) patients, with 50% to 60% of dialysis patients developing adequate titers of anti-HBs antibodies.73,74 Similarly, success of HBV vaccination correlates with glomerular filtration rate (GFR) and thus “earlier” vaccination is more successful.75 Despite lower rates of antiHBs development, there is some evidence that vaccination confers protective T cell responses and there are reduced rates of HBV infection even if anti-HBs antibodies are not detected in vaccinated dialysis patients.76

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There are several additional strategies to improve the success of HBV vaccination, including intramuscular injections, doubling of vaccine dose, giving additional booster doses, and prompt revaccination in nonresponders.77 In addition to the previous strategies, doubling the vaccine dose, giving an additional booster dose, and promptly repeating the HBV vaccination series in nonresponders can be considered. Nonresponse is defined as an antiHBs antibody titer less than 10 IU/L 1 to 2 months post series completion.78 Annual testing of anti-HBs titers should be undertaken with boosters given whenever the anti-HBs titer falls under 10 IU/L. Clinical and histologic outcomes in dialysis patients with HBV infection are generally similar to that seen in immunocompetent individuals. The majority of these individuals do not die of liver disease. In one study of dialysis patients in which 30% were infected with HBV, fewer than 5% died from liver disease. This may be as a result of the presence of other comorbidities (competing causes of mortality) in their patients such as cardiovascular disease or infections in addition to insufficient length of follow-up.79 The effect of antiviral therapy on the natural history of chronic HBV infection on hemodialysis patients has not been studied. 

Pretransplant Management of Hepatitis B-Positive Dialysis Patients Liver enzymes (aminotransferases) do not accurately reflect the stage of liver disease in patients with chronic viral hepatitis and ESRD. Patients with chronic HBV on dialysis should have imaging for assessment of liver fibrosis before renal transplantation. Newer imaging based on noninvasive measurements of fibrosis such as transient elastrography is more accurate in distinguishing minimal or no fibrosis from advanced fibrosis and cirrhosis than serum markers, although in hepatitis B these data are extrapolated mostly from nondialysis patients.80 Patients with fibroscan demonstrating elevated values of fibrosis (F2 or greater) should proceed to a liver biopsy. Patients with cirrhosis on the biopsy should be considered for a combined liver–kidney transplant when portal hypertension develops. Criteria for antiviral therapy in nontransplant patients include evidence of chronic necroinflammation of the liver, evidenced by an elevated ALT and aspartate aminotransferase (AST) in the setting of HBeAg positivity or in the setting of an elevated serum HBV DNA in HBeAg-negative patients.81 However, in patients undergoing renal transplantation there is increased risk of reactivation of viral replication and increased viral replication after transplantation with exposure to immunosuppressive agents. In addition, HBV-positive renal allograft recipients have worse outcomes in terms of liver disease and renal allograft function (discussed later). Therefore it is prudent to start antiviral therapy before renal transplantation for patients with evidence of active viral replication. This includes patients with positivity for HBsAg and/or any detectable viral load.  Posttransplant Prognosis in Hepatitis B Recipients Post–renal transplantation, hepatitis B-infected recipients are generally felt to have decreased survival compared with noninfected recipients, although this finding is controversial. In one study of 1250 renal allograft recipients, with a median follow-up of 125 months, cirrhosis occurred in 30%

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and renal allograft survival was reduced compared with recipients not infected with chronic hepatitis B.64 Overall mortality was not different between HBV-positive and HBV-negative recipients in this study. A study of 51 renal transplant recipients with chronic hepatitis B infection found reduced patient survival and a higher incidence of death caused by liver failure in the hepatitis B group (44%) compared with nonhepatitis-infected controls (0.6%). In multivariable analysis in the hepatitis B group the presence of hepatitis B antigen was not an independent predictor of death; patient age, serum creatinine, and proteinuria at 3 months after transplant were independent predictors of reduced patient survival.82 Other large studies have found significant reductions in long-term patient and graft survival in HBsAg-positive kidney transplant recipients compared with noninfected renal transplant recipients. In a cohort of 128 renal transplant recipients infected with HBV, the 10-year survival was 55% compared with 80% in non-HBV-infected renal transplant recipients.83 Age at transplant and presence of cirrhosis were independent prognostic factors for survival in this study. Another study found a significant difference in longterm survival between hepatitis B-positive recipients compared with recipients without chronic viral hepatitis66 with a relative risk (RR) of mortality of 2.36 for 42 HBsAg-positive recipients. Finally, a meta-analysis that included 6050 renal transplant recipients found increased mortality (RR of death with HBsAg positivity 2.49) associated with chronic hepatitis B infection and reduced graft survival (RR of graft loss 2.49).84 Differences in outcome between studies may result from small numbers in some studies, length of follow-up, heterogeneity of patient characteristics such as age at transplant, replicative state of hepatitis B, presence or absence of cirrhosis at time of transplant, and the confounding effect of antiviral therapy for hepatitis B. Studies with larger numbers, longer follow-up, and with matched case-control design and multivariate analysis have tended to show a reduction in patient and graft survival associated with chronic hepatitis B infection in renal transplant recipients. Several studies have documented the progression of fibrosis in HBsAg-positive kidney transplant recipients after transplant. In a study of 151 HBsAg-positive kidney transplant recipients, 28% had a histologic diagnosis of cirrhosis at a mean of 66 months posttransplant.64 HCV coinfection was the only identifiable risk factor for fibrosis progression. More recently, a cohort of 55 HBsAg-positive kidney transplant recipients underwent liver biopsy at a mean of 5 years after transplantation. On logistic regression, the only risk factor for the development of cirrhosis was the time interval between kidney transplant and liver biopsy.85 In rare cases viral replication may become uncontrolled in the setting of immunosuppression after renal transplantation. In this state the virus may become directly cytopathic and lead to a state of hepatocellular failure with profound cholestasis. The liver biopsy is characteristic with hepatocyte ballooning, cholestasis, and perisinusoidal fibrosis. This condition is called fibrosing cholestatic hepatitis, and was first described in liver transplant recipients infected with HBV.86 Once established, the prognosis is poor, even with antiviral therapy. Preemptive suppressive antiviral therapy is the judicious strategy to prevent this feared

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Kidney Transplantation: Principles and Practice

outcome. In rare cases the suppression of viral replication with long-term antiviral therapy has resulted in salvage of liver and graft function (discussed later). The natural history of chronic HBV infection in kidney transplant recipients in the era of antiviral therapy is less well studied. A recent, small study of 63 HBsAg-positive kidney transplant recipients revealed an improved 20-year mortality (83% vs. 34%, P = 0.006) in patients treated with antiviral therapy.87 

De Novo HBV Infection After Kidney Transplantation Development of de novo hepatitis B after renal transplantation can be associated with rapid viral replication and progression of liver disease.88 The hepatitis B serologic and virologic status of the donor and recipient are important risk factors that predict development of de novo hepatitis B infection after renal transplantation. The highest risk of de novo hepatitis exists in recipients who are nonimmune for hepatitis B (HBsAb-negative) and receive an organ from HBsAg/HBeAg-positive donors. The risk of transmission from an HBcAb-positive-only donor (HBsAg-negative, HBcAb-positive, negative serum HBV DNA donor) to a hepatitis B-negative recipient also exists, although it is reduced compared with that seen in liver transplant recipients.89,90 It is important to note that isolated HBcAb positivity could represent an early, acute HBV infection or possibly a longstanding, chronic infection with low-level HBV viremia. Determination of donor IgM HBcAb should be performed in patients with an isolated positive HBcAb. Positive titers for IgM suggest a recent infection and should be considered high risk for transmission of HBV to the recipient. HBV DNA should also be determined in the isolated HBcAb-positive donor with consideration of HBV prophylaxis for the recipient. The risk of de novo HBV infection is considerably reduced if the recipient is positive for HBsAb, although it is not completely eliminated. In one series where HBcAb-positiveonly donors were used for recipients with a prior history of hepatitis B or HBV vaccination, none developed clinically evident hepatitis B, although 27% did develop HBcAb and/ or HBsAb positivity after transplant.91 In a more recent study from Italy, 344 patients received anti-HBcAb-positive allografts and no recipient developed HBsAg positivity, including 62 patients that had not undergone HBV vaccination.90 Finally, a cohort of 46 patients that received an anti-HBcAb-positive donor kidney were followed for 36 months posttransplant. Anti-HBsAb-positive (immunized) recipients received no prophylaxis. Naïve patients received 1 year of lamivudine prophylaxis. No patients developed evidence of HBV viremia or development of HBsAg.92 HBV reactivation is a well-known complication of immunosuppressive therapy. Although rituximab is increasingly used for desensitization of ABO-incompatible or positive crossmatch kidney transplantation, the risk of HBV reactivation in HBsAg-negative/hepatitis B core antibody (anti-HBc)-positive kidney transplant patients receiving rituximab desensitization remains undetermined. In a study of 172 resolved HBV patients who underwent living donor kidney transplant 5 of 49 patients who received rituximab (10.2%) had HBV reactivation compared with 2 of 123 control patients who did not receive rituximab (1.2%). In

the rituximab group, two patients experienced HBV-related severe hepatitis, and one patient died as a result of hepatic failure. The median time from rituximab desensitization to HBV reactivation was 11 months (range, 5–22 months). By contrast, no patients in the control group experienced severe hepatitis. Rituximab desensitization (hazard ratio [HR], 9.18; 95% confidence interval [CI], 1.74–48.86; P  =  0.009) and hepatitis B surface antibody status (HR, 4.74; 95% CI, 1.05–21.23, P  =  0.04) were significant risk factors for HBV reactivation.93 Ultimately, prevention of de novo hepatitis B in renal transplant recipients is best achieved by universal vaccination of all dialysis patients. Alternatively, organs from HBsAg-positive donors can be offered only to recipients with preexisting HBV infection or those individuals who have been successfully vaccinated for HBV. Use of HBcAb-positive donors is often center-specific. If such organs are used, posttransplant usage of prophylaxis with antiviral medication or hepatitis B immune globulin should be considered, especially in patients without evidence of HBV immunity. 

Antiviral Therapy of Chronic Hepatitis B in Renal Transplant Candidates/Recipients Data regarding the optimal timing of antiviral therapy for HBV in renal transplant candidates are scarce (Table 32.3). The risks of liver disease progression and severe hepatitis B reactivation posttransplant have to be weighed against the risk of antiviral toxicity and viral resistance developing. However, with the development of the newer-generation antinucleos(t)ide analogs entecavir and tenofovir (see later), the risk of viral resistance is much lower than with lamivudine or adefovir. Data for antiviral therapy posttransplant have mostly been performed using lamivudine. In one trial, the efficacy of lamivudine in preventing viral replication after renal transplantation was compared in HBsAgpositive recipients using three strategies: (1) preemptive lamivudine therapy (HBV DNA-positive recipients, received lamivudine therapy 0–9 months before renal transplant, n = 7); (2) prophylactic lamivudine therapy (HBV DNAnegative, received lamivudine therapy before transplant, n = 3); and (3) salvage therapy (HBV DNA-positive, advanced hepatic dysfunction after transplant, received lamivudine after transplant after hepatic dysfunction, n = 6).94 HBV DNA disappeared in all recipients in all groups on therapy. The recurrence rate of HBV viremia was 10% (1 out of 10) in the preemptive and prophylactic group compared with 42% (11 out of 25) in a nonlamivudine-treated group. In the group treated for hepatic dysfunction HBV DNA disappeared in all 6 cases but recurred in 50% (3 out of 6) while on lamivudine. In another trial of lamivudine therapy, HBV DNA levels were measured and lamivudine was started before renal transplantation if the HBV DNA rose to more than 2.83 × 108 copies/mL alone or to >2.83 × 107 copies/mL with elevated AST/ALT from 1996 to 2000 (so-called de novo group).95 This strategy was compared with preemptive use of lamivudine for patients who had undergone transplantation before 1996 (when lamivudine became commercially available) and thus received therapy later after transplantation than the de novo group. Even though suppression of HBV DNA and normalization of aminotransferases were achieved in all patients, the survival of the de novo treated group was comparable to that of

TABLE 32.3  Selected Pretransplant and Posttransplant (Nonliver) Studies of Antiviral Therapy in HBV Patients

Study

Patient Population

Number in Study

PRETRANSPLANT Fontaine et al.266

Dialysis patients

5

Duarte et al.267

Dialysis patients

2

POSTTRANSPLANT Fontaine et al.266 Postrenal transplant patients 26 with HBV infection Hu et al., 2012107 Postrenal transplant patients 27 with HBV infection Fontaine et al.103 Han et al. 200194

Post kidney transplantation with lamivudine-resistant HBV Post kidney transplantation with HBV (HBsAg+)

11

HBV Antiviral Therapy

Duration of Therapy

HBV DNA Suppression

HBeAg Seroconversion to Anti-HBe

Lamivudine 10 mg daily in 3, 50 mg thrice weekly in 2 Interferon-alfa 3 mu thrice weekly

12 months (7–28)

5/5

1/5

2/5 (at months 7, 18 of lamivudine)

3 months

2/2

2/2

None

Lamivudine 100 mg/day Entecavir

16.5 months (4–31) 104 weeks

26/26 undetectable

6/26

8/26

100% undetectable after 104 weeks

0/27

Adefovir 10 mg/day

15 months (3–19)

Median change –5.6 log copies/mL (–2.2 to –7.7) On treatment Group 1: 6/6 On treatment Group 2: 11/11

3/5 HBeAg-positive seroconverted after 35 weeks 0/6 that were initially HBeAg+ Group 1: 0/6 Group 2: 0/11

Group 1: 3/6 Group 2: 1/10

Chan et al., 2004269 Post kidney transplantation with HBV (HBsAg+)

29

Lamivudine 100 mg/day

Fabrizi et al., 200496

184 (meta-analysis of 14 studies)

Lamivudine Variable 50–150 mg/ day Entecavir 0.5 Median 16.5 mg/day titrated months to 1.0 mg/day after 1 month

Chan et al. 200295

Post kidney transplantation with HBV (HBsAg+)

PuchhammerStockl et al., 200099

Post kidney transplantation with HBV (HBsAg+)

Thabut et al. 2004268

Post kidney transplantation with HBV (HBsAg+)

Post kidney transplantation with HBV (HBsAg+)

Kamar et al., 2008108 Posttransplantation with lamivudine or adefovir-­ resistant HBV (HBsAg+)

10 (8 kidney)

Period I: 36.3 ± 11.4 months Period II: 27.6 ± 14.5 months >12 months

26/26 undetectable

Not mentioned. 3/14 HBeAg+ patients became undetectable

11 (40.7%) became lamivudine-resistant at 9.5–24 months after starting treatment

HBV undetectable in 10/11 undetectable by PCR

Not reported

Lamivudine resistance in 5/11 from 9 to 15 months after starting lamivudine

Median duration 64.5 months (6–93)

11/11 undetectable on treatment

0 of 4 HBeAg+ patients

56.7 ± 12.5 months

29/29 undetectable on treatment initially

5/15 who were HBeAg +

91% HBV DNA undetectable

27% in 4 of 14 studies

Lamivudine resistance with virologic breakthrough in 8/14 patients from 9 to 24 months after starting lamivudine 14/29 (48%) developed lamivudine resistance (10–35 months after starting treatment) 18% in 8 of 14 studies

HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; mu, million units; PCR, polymerase chain reaction.

5/8 kidney recipients Not reported developed undetectable HBV DNA

Not reported

547

Group 1: Follow-up 15–60 months Group 2: Follow-up 9–30 months

Not detected

32 • Liver Disease Among Renal Transplant Recipients

Group 1: After developing Lamivudine recurrent hepatic dysfunction 100 mg/day after renal transplant (6) Group 2: Preemptive or prophylactic treatment for HBsAg-+ recipients beginning before renal transplantation (10) Period II: Post 1996. De novo Lamivudine preemptive therapy before renal 100 mg/day transplantation and continued after transplantation (11) Period I: pre-1996. Preemptive therapy after renal transplantation 11 Lamivudine 100 mg/day in 7, reduced dose in 4 per renal function 14 Lamivudine 100 mg/day

Virologic Breakthrough

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Kidney Transplantation: Principles and Practice

HBsAg-negative controls, whereas HBsAg-positive patients who were transplanted before 1996 and received preemptive therapy with rising HBV DNA after renal transplantation had a higher risk of overall (RR 9.7) and liver-related mortality (RR 68.0). More recently, a meta-analysis of 14 clinical trials using lamivudine in kidney transplant recipients demonstrated that HBV DNA clearance occurred in 91% and normalization of ALT occurred in 81% of treated patients.96 Antiviral therapy should thus be offered to all hepatitis B-positive (HBsAg-positive) kidney transplant recipients, including those on the waiting list. This recommendation applies even to surface antigen-positive patients with a negative HBV DNA. The optimal duration of therapy is yet to be determined and in an immunocompromised host may need to be indefinite. Cessation of antiviral therapy in the immunocompromised host is associated with an increased risk of flare-up of liver disease and, rarely, decompensated liver disease in both the transplant recipient and patients without organ transplantation.95,97 

Specific Antiviral Agents for HBV Used in Renal Transplant Recipients Lamivudine. The cytosine analog lamivudine has been the most extensively studied antiviral for HBV. A dose of 100 mg/day has been shown to be highly effective in suppression of HBV replication and normalization of aminotransferases in over 80% of individuals.96,98–100 Cessation of antiviral therapy has been associated with virologic and clinical relapse.100 The major drawback with lamivudine is the high rate of viral resistance. The risk of resistance increases with duration of lamivudine therapy. In a meta-analysis of 14 clinical trials (184 recipients) of lamivudine after renal transplantation, the majority of recipients had HBV DNA clearance (91%) and biochemical normalization (81%), and the risk of lamivudine resistance was 18%.98 Although HBeAg loss was higher with prolonged therapy, the resistance was also higher, thereby limiting its efficacy. Given the high risk of viral resistance, lamivudine is no longer preferred as firstline therapy for HBV.81  Adefovir. Adefovir dipivoxil, an oral prodrug of adefovir, is a nucleotide analog of adenosine monophosphate. Adefovir therapy has demonstrated efficacy in treatment-naïve and lamivudine-resistant patients with HBV.42,101,102 Standard adefovir dosage is 10 mg/day. The dose should be adjusted based on GFR. In patients with a renal transplant it has been used in small studies, mostly reported in lamivudineresistant recipients. In one study of 11 renal transplant recipients, there was a significant reduction in HBV DNA after initiation of adefovir with a median decline of 5.5 log in HBV DNA after 12 months of therapy. No virologic breakthrough was observed and no significant changes in creatinine occurred.103 Adefovir resistance is much less common than with lamivudine, even after prolonged therapy.104 If adefovir is used in patients with lamivudine resistance, lamivudine should continue to be administered and dual therapy continued indefinitely. The principal drawback to adefovir therapy is the risk of nephrotoxicity. In a recent study of 11 renal transplant recipients with chronic HBV, adefovir therapy

was associated with an increased serum creatinine and increased proteinuria at 2-year follow-up. In addition, there was evidence for proximal tubular dysfunction with adefovir usage.105 Given the risk of nephrotoxicity, adefovir should be used with caution in kidney transplant recipients.  Entecavir. Entecavir, an analog of 2′-deoxyguanosine, is a nucleoside analog with potent activity against HBV replication. In a randomized, controlled trial of HBeAg-positive nontransplant patients, 48 weeks’ treatment with entecavir, dosed at 0.5 mg/day, resulted in higher rates of histologic, virologic (undetectable HBV DNA), and biochemical (normalization of ALT) response compared with lamivudine 100 mg/day.106 In another study in renal transplant recipients, entecavir was compared with 3-TC. Of the 27 recipients, 18 (67%) were NUC-naïve patients, and 9 (33%) were 3TC-experienced without YMDD mutations. HBV DNA levels became undetectable in 70%, 74%, 96%, and 100% of patients after 12, 24, 52, and 104 weeks, respectively, of entecavir treatment without viral resistance. By comparison with the 19 3TC-treated patients, ETV-treated recipients presented higher rates of undetectable HBV DNA than 3TC-treated recipients (32%, 37%, 63%, and 63% at 12, 24, 52, and 104 weeks, respectively; P < 0.005). There was no change of GFR and no lactic acidosis or myopathy during treatment.107 In a study where 10 transplant recipients (8 kidney) with adefovir or lamivudine resistance were treated with entecavir, mean HBV DNA levels decreased and HBV DNA clearance was achieved in 50%.108 Unlike lamivudine, resistance to entecavir is low in treatment-naïve patients. In phase III trial data, viral breakthrough was only seen in 3.6% of treatment-naïve patients at 96 weeks of entecavir therapy.109 However, entecavir should be used with caution in patients with lamivudine resistance or viral breakthrough while on lamivudine therapy. In a study of nontransplant patients on 5 years of entecavir therapy for chronic HBV, entecavir resistance developed in 51% of patients with documented lamivudine resistance.110 Entecavir should be considered a first-line treatment for kidney transplant candidates and recipients with chronic HBV that have no concern for lamivudine resistance.  Tenofovir. Tenofovir disoproxil fumarate is a nucleotide analog originally approved for therapy against HIV. Tenofovir is structurally similar to adefovir, but less nephrotoxic, allowing for higher dosing and a more potent antiviral effect. In randomized, controlled trials of nontransplant patients with chronic HBV, tenofovir has been shown to be an effective antiviral against HBV. In a phase III trial of tenofovir versus adefovir in HBeAg-positive patients, after 48 weeks of therapy a greater proportion of tenofovir-treated patients achieved a negative HBV DNA (76% vs. 13%), ALT normalization (68% vs. 54%), and surface antigen loss (3% vs. 0%). Tenofovir resistance appears rare. In the original phase III clinical trials, no patients had genotypic evidence of mutations known to cause tenofovir resistance. Unlike entecavir, tenofovir is effective in the setting of lamivudine resistance. In a randomized trial of HIV/HBV-coinfected patients known to be lamivudine-resistant, both adefovir and tenofovir were found to be efficacious in decreasing

32 • Liver Disease Among Renal Transplant Recipients

HBV DNA at 48 weeks.42 Tenofovir should be used with caution in cases of known adefovir resistance. Data regarding tenofovir in transplant recipients are scarce. A recent study of seven transplant (3 kidney) patients with chronic HBV treated with tenofovir showed a decline in HBV DNA during treatment, with three patients achieving serum DNA clearance.111 Despite the lack of data in kidney transplant recipients, tenofovir should be considered a first-line agent for the treatment of chronic HBV in kidney transplant candidates and recipients.  Interferon. Use of interferon is associated with an unacceptably high risk of precipitating renal allograft rejection, sometimes irreversibly, despite salvage immunosuppressive therapy. Its use in the renal transplant recipient should thus be avoided given the availability of other antiviral agents for hepatitis B.112,113 

Treatment of Fibrosing Cholestatic Hepatitis B in Renal Transplant Recipients Fibrosing cholestatic HBV is a histologic and clinical variant of hepatitis B characterized by hepatocyte ballooning, cholestasis, minimal inflammation, periportal fibrosis, and massive viral replication (Fig. 32.2). It was first described in HBV-infected recipients of liver allografts but has also been subsequently described in other immunosuppressed states.114 Patients often develop rapidly progressive liver failure and spontaneous recovery is rare. Lamivudine has been reported to be useful in case reports, resulting in successful resolution of the severe acute hepatitis and hepatic failure associated with this condition.115 With appropriate antiviral therapy, fibrosing cholestatic HBV should occur extremely infrequently.  Summary In summary, chronic HBV infection in kidney transplant candidates and recipients has become less common in developed countries. This decrease in prevalence and incidence of new cases can be attributed to improved public health efforts, particularly infection control measures during hemodialysis, and widespread HBV immunization. All patients with chronic kidney disease (CKD) should be

Fig. 32.2 Perisinusoidal fibrosis and hepatocyte ballooning without inflammatory infiltration. Characteristic histologic appearance of fibrosing cholestatic hepatitis B.

549

immunized against HBV. HBV vaccination is more successful at higher GFR and therefore should ideally be administered well before the onset of hemodialysis. All patients who are candidates or who have undergone kidney transplantation and are positive for HBsAg should undergo a liver biopsy and be given antiviral therapy to decrease the risk of liver disease progress or severe HBV exacerbation after initiation of immunosuppression. Tenofovir and entecavir should be considered first-line antiviral therapy because of their potency, tolerability, and the low risk of resistance development. 

HEPATITIS C VIRUS Viral Structure The discoveries of hepatitis A virus (HAV) and HBV between the years of 1967 and 1973116 were a medical breakthrough; however, it left many unanswered questions. For the next 16 years, patients with non-A non-B hepatitis became increasingly recognized as having a form of chronic liver disease. In 1989 Choo et  al.117 published the first account of HCV, which was further described as a single-stranded, enveloped, positive-sense RNA virus. It is classified in the Flaviviridae family.  HCV Species HCV can be thought of as a spectrum of similar viruses. Seven HCV genotypes with several distinct subtypes have been identified throughout the world.118 Within a genotype or subtype, the genome of HCV is highly mutable because of the lack of efficient proofreading capabilities. As the virus replicates over time, selective pressures from the immune system and/or antiviral treatments cause the viral populations to evolve. These mutant versions of genotypes are called “quasispecies.” The heterogeneity of this virus is what allows it to evade immunologic detection and elimination thus far, preventing the development of a vaccine. Epidemiologic studies on the HCV genotypes have been performed demonstrating significant regional variation. Genotype 1 is found worldwide although it is by far the most common (60%–70% of isolates) in the US, Europe,119 Japan, and Taiwan. Although less common genotypes 2 and 3 are also found in these areas, genotypes 4, 5, and 6 are rarely encountered. Genotype 3 is predominant in India, the Far East, and Australia.120,121 Genotype 4 is present in North Africa and the Middle East, with a particularly high incidence in Egypt. Genotype 5 has been most frequently detected in South Africa, whereas genotype 6 has been rather isolated to Hong Kong.122 The significance of viral genotypes is not entirely clear, but important clinical differences have been shown. Amoroso et  al.123 followed patients with acute viral hepatitis and found that those infected with genotype 1 developed chronic infection at a significantly higher rate compared with those with genotypes 2 and 3.  Clinical Manifestations of Hepatitis C Infection in Immunocompetent Hosts In general, HCV is a chronic infection and its acute form often goes unrecognized. Of patients with acute HCV 20% to 30% have symptoms 2 to 12 weeks after exposure.124,125 The symptoms are generally mild and include lethargy,

550

Kidney Transplantation: Principles and Practice

nausea, vomiting, jaundice, and anorexia. Serum aminotransferases can range from 2- to 10-fold above normal. Rarely, acute HCV can lead to acute hepatic failure,126 although this is exceedingly uncommon. Diagnosis of acute HCV is made by testing for HCV RNA, which can be identified in serum a few days to weeks after exposure.126,127 Anti-HCV antibodies are typically not detected for weeks to months after exposure and may not develop in immunocompromised individuals or in patients on dialysis.128 Chronic HCV develops in about 85% of those who are exposed. In the majority of patients, the clinical course is remarkably nonspecific. Fatigue and nonspecific arthralgias are common complaints and typically improve with eradication of the virus.129 Studies have estimated 20% to 35% of patients will have progression of liver disease to cirrhosis over 20 to 30 years.130 A study by Cacoub et al.129 found that 38% of HCV patients presented with at least one clinical extrahepatic manifestation. The associated findings include hematologic disorders such as cryoglobulinemia, lymphoma, and porphyria cutanea tarda and other rashes. Dry eyes and mouth, pruritus, renal disease including membranoproliferative glomerulonephritis (MPGN), and diabetes are often present. 

Incidence/Prevalence and Transmission of Hepatitis C in Renal Transplant Patients It is estimated that 180 million people are infected with HCV worldwide, with 4 million people in the US thought to be HCV antibody carriers. Among those with anti-HCV antibodies, about 80% are viremic.131 The principal risk factors for HCV infection are transfusion of unscreened blood products and intravenous drug use. With the development of blood donor screening in the 1990s, transfusion-related HCV transmission is now exceedingly rare.132 Other risk factors for HCV transmission include nosocomial transmission, including via hemodialysis and occupational exposure. Transmission of HCV via hemodialysis and occupationally is less frequent with the use of improved universal precautions. Sexual transmission is felt to be rare. The prevalence of HCV in patients with CKD is higher than in the general population, particularly in patients on hemodialysis. HCV prevalence in hemodialysis units across seven countries was reported in the Dialysis Outcomes and Practice Patterns Study and showed a mean HCV prevalence of 13.5% with a range between the countries of 2.6% to 22.9%. HCV prevalence is higher in Japan, Italy, and Spain and lower in Germany and the United Kingdom. The US had a 14% HCV prevalence and a hemodialysis seroconversion rate of 2.5% per 100 patient years.133 However, in the US, there is high variability in the prevalence of chronic HCV among hemodialysis units based on location.134 Historically, blood products were the major contributor to infection in these patients. As mentioned previously, in the past decade this method of transmission has been virtually eliminated with reliable screening methods135,136 and decreased transfusion requirements directly related to the increased use of hematopoietic growth factors.135,137 Despite these improvements, studies show de novo infections do occur in dialysis units, though clearly identifiable risk factors have not been reproducibly demonstrated.138

Given the prevalence of chronic HCV among patients on hemodialysis, a significant number of patients on the renal transplant waiting list are infected with HCV. Accurate data regarding infection rates in this transplant-associated population are complicated by several factors, including the insidious and indolent nature of the disease in the setting of uremia,139 regional variations of the HCV genome, the use of nonstandardized diagnostic methods, and the absence of good prospective, well-powered studies. Risk factors for HCV among transplant candidates include length of time on hemodialysis, exposure to blood products before universal screening, and the prevalence of chronic HCV infection in the dialysis center. 

Allograft Transmission of HCV As transplant waiting lists soar to record levels, programs of all organ types are faced with decisions regarding the use of extended criteria (previously called marginal) donor organs, including those positive for HCV antibody. Historically, allocation of HCV-positive organs has been restricted to HCV-positive recipients. This recommendation is based on evidence that transplantation of HCV-positive organs into HCV-negative recipients is a risk factor for poorer outcomes in renal transplant patients.140 In contrast, outcome data regarding kidney transplantation from HCV antibody-positive donors to HCV-positive recipients are ­ mixed. Recipient wait time may be substantially reduced and there appears to be no effect on short-term mortality.141–143 Similarly, registry studies have shown that kidney transplantation from deceased anti-HCV antibody-positive donors has a survival advantage compared with staying on dialysis for HCV-positive recipients.140 Recently with the availability of potent and highly effective direct-acting antiviral agents for hepatitis C there has been interest in using organs from HCV-positive donors for HCV-negative recipients. In a pilot randomized controlled trial HCV-positive kidneys were transplanted in 10 HCVnegative recipients who were then given early posttransplant HCV antiviral therapy (preemptive treatment). All patients cleared the HCV with 12 weeks of therapy and had preserved renal allograft function and good liver function without significant adverse events.142,144 Currently, the Kidney Disease Improving Global Outcomes (KDIGO) practice guidelines recommend restricting the use of allografts from HCV-infected donors to HCV-infected recipients and this practice is still considered investigational.145,146  Effect of Pretransplant HCV on Posttransplant Outcomes Patient and Graft Survival. Some controversy exists regarding the effect of pretransplant HCV infection on the outcome of renal transplantation (Table 32.4). Initially, studies of short follow-up periods suggested that neither patient nor graft survival were altered posttransplant despite a logarithmic increase in HCV RNA levels.147–149 Orloff et al. reported the liver biopsy findings at 3 to 7 years after kidney transplantation in HCV-positive subjects. Of these 12% had chronic active hepatitis, 50% showed mild hepatitis, and 38% had normal histology. Furthermore, hepatitis C conferred no adverse effect on patient or graft survival.147 Lee et  al. also determined that HCV infection

32 • Liver Disease Among Renal Transplant Recipients

TABLE 32.4  Outcomes in HCV-Positive Recipients (Compared With HCV-Negative Recipients) Undergoing Renal Transplantation Type of Transplant

Outcome

Renal transplant recipients

Decreased long-term patient survival (follow-up >10 years) Decreased graft survival De novo or recurrent glomerulopathy Cirrhosis Posttransplant diabetes

HCV, hepatitis C virus.

did not reduce renal allograft or patient survival; however, they identified more liver disease and a greater prevalence of life-threatening sepsis in the HCV-infected recipient population.150 In contrast, studies with more lengthy follow-up after transplantation have found decreased patient and/or graft survival in HCV-positive renal transplant recipients.83,151–153 Periera et  al.206 compared the prevalence of posttransplantation liver disease and graft and patient survival in HCV-positive and HCV-negative kidney transplant recipients. Among recipients who were HCV-positive before transplantation, the RR was 5.0, 1.3, and 3.3 for posttransplantation liver disease, graft loss, and death, respectively. There was a significant increase in death caused by sepsis with an RR of 9.9.154 Similarly, Hanafusa et  al. found clinically significant hepatitis in 55% of HCV-positive kidney transplant recipients. They also found a significant decline in the 20-year survival in the HCV-positive patients compared with the HCV-negative cohort (64% vs. 88%).153 The most common reasons for increased mortality in HCV-positive renal transplant recipients are excess risk of diabetes, cardiovascular disease, systemic infections, and cancer.155 In a meta-analysis of observational studies after renal transplantation that included eight studies, the presence of HCV antibody was an independent risk factor for death and graft failure after renal transplant (RR for death 1.79, 95% CI 1.57–2.03) and for renal graft failure 1.56 (95% CI 1.35–1.80). HCC and liver cirrhosis were more frequent causes of mortality in HCV-positive than HCV-negative recipients.156 Despite the finding that graft and overall survival are probably decreased in kidney transplant recipients with chronic HCV infection, overall mortality has been shown to be improved with transplantation over long-term dialysis. HCV infection is associated with increased hospitalization, need for transfusions, and reduced quality of life in patients with ESRD.157 Dialysis patients with HCV have a 15% to 30% increased risk of mortality compared with patients without HCV on dialysis.158,159 HCV infection thus should not be considered a contraindication to consideration of kidney transplantation.160 Particularly with the availability of highly effective antiviral therapy for hepatitis C that can be used both in ESRD and after renal transplantation, posttransplant outcomes in HCV-positive recipients are expected to improve to those seen in non-HCV recipients.161

551

Assessment of fibrosis stage in the patient with ESRD can be done noninvasively using transient elastography-based techniques such as fibroscan. This modality is good at distinguishing minimal fibrosis from advanced fibrosis and cirrhosis and can obviate the need for staging liver biopsy in those with low fibrosis scores.162 Most studies regarding posttransplant HCV outcomes are directed to chronically infected recipients, usually subjects who acquired HCV during hemodialysis. However, the subset of solid-organ transplant recipients who become infected with HCV in the perioperative period have a markedly different course. Delladetsima et  al.163 followed 17 such patients by biochemical and histologic markers for a mean of 7 years. Six (35%) patients died a median of 6 years posttransplant because of: fibrosing cholestatic hepatitis, vanishing bile duct syndrome, cirrhosis, miliary tuberculosis, and myocardial infarction. Overall the yearly fibrosis progression rate was five times that of age-matched immunocompetent HCV-infected patients. These studies suggest that HCV acquired at the time of transplantation may have a particularly aggressive course. 

HCV and Posttransplant Diabetes in the Renal Transplant Recipient The association of diabetes mellitus and HCV has become increasingly apparent both in the immune-competent HCV population and particularly after solid-organ transplantation in HCV-infected patients. The overall incidence of posttransplant diabetes mellitus (PTDM) has been reported to vary from 10% to 54% and has shown similar long-term effects as diabetes mellitus types 1 and 2, with cardiac and renal dysfunction in a significant proportion.164 Yildiz et al. reported a case-controlled study of 43 renal transplant recipients with PTDM in which 72% were HCV-infected, compared with a prevalence of 37% in the recipients without PTDM (P = 0.002).165 This association was further observed by Bloom et  al.166 where PTDM occurred more frequently in HCV-positive than HCV-negative patients (39.4% vs. 9.8%; P = 0.0005). Their data further found that among the HCV-positive patients there was an eightfold increased incidence of PTDM in those treated with tacrolimus (58%) compared with cyclosporine (7.7%).  HCV and Posttransplant Nephropathy Posttransplant renal disease is common among HCV-positive recipients of any organ. Whereas the causes of renal injury after transplantation are multifactorial in nature, chronic allograft nephropathy among renal transplant recipients and nephrotoxicity resulting from calcineurin inhibitors are the most common etiologies.167 Kidney transplant recipients with chronic HCV infection are at risk of additional immune-mediated nephropathies, with MPGN being the most common, followed by membranous nephropathy, minimal change disease, and renal thrombotic microangiopathy. These may be recurrent or present de novo.168 MPGN has been reported in 45% of HCV-positive renal transplant recipients who underwent renal biopsy for worsening renal function. In the HCV-negative group, the incidence was only 5.9%. De novo disease was found in 18% of the MPGN patients and chronic renal allograft nephropathy was similar in both HCV-positive and negative recipients.169 

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Immunosuppressive Strategies in Renal Transplant Patients Infected With HCV No studies have been performed to determine optimal immunosuppressive regimens in renal transplant recipients infected with HCV. Viral replication is increased with the use of immunosuppressive agents, but the effect on patient survival, progression of liver disease, and graft function is unknown. As mentioned previously, studies have clearly demonstrated tacrolimus as an additive risk in HCV patients for the development of PTDM.170 In addition, as mentioned previously, in liver transplant recipients cyclosporine may have an anti-HCV effect and improve the probability of successful HCV treatment.171,172 However, there are no data regarding cyclosporine effects on HCV in kidney transplant recipients. Similarly, although corticosteroid boluses have been shown to increase HCV viral load dramatically and decrease time to HCV recurrence in liver transplant recipients,173,174 there are no data in kidney transplant recipients. Finally, although poor outcomes have been reported with antibody induction in HCV-positive liver transplant recipients, there are no data on kidney transplant recipients. In the absence of data, few recommendations can be made regarding immunosuppression strategy in HCVinfected kidney transplant recipients. Given the permissive effects of immunosuppression on HCV replication, a reasonable goal is to provide the minimum dose of immunosuppression to prevent rejection.  Hepatitis C Antiviral Therapy Eradication of HCV has several benefits (Table 32.5). HCV is associated with worse patient and graft survival and increased risk of PTDM and de novo glomerulopathy. Eradication of HCV pretransplant might mitigate some of these adverse outcomes.175–177 Posttransplant HCV treatment in kidney transplant recipients was historically limited because of the use of interferon in all regimens until 2011. Interferon-based therapy was long (48 weeks), poorly tolerated, with multiple side effects including severe constitutional symptoms, pancytopenia, and depression, and it had a poor response rate. Most importantly it carried the risk of precipitating renal transplant rejection and therefore was rarely used after renal transplantation.178,179 The standard of care for HCV treatment has evolved over the years from standard interferon monotherapy, to standard interferon plus the antiviral ribavirin, to pegylated interferon and ribavirin, to, most recently, the addition of direct-acting antiviral agents (DAAs). The first DAAs (telaprevir and boceprevir) had similar issues because they had to be used in interferon-containing regimens and thus carried all the side effects and risks of interferon.180 Since 2014, however, DAAs are available that are used without interferon. The new generation of DAA treatments work directly on HCV replication and have revolutionized HCV therapy. These agents are potent, highly effective in curing HCV infection, and well tolerated. They inhibit the HCV NS5B polymerase, the HCV NS5A protein, and the HCV NS3/4 protease, which are proteins integral for viral replication. These antiviral agents are available in all oral therapies and have virologic response

(sustained virologic response [SVR]) or cure rates in excess of 90% with treatment durations of 8 to 24 weeks.181 Specific antiviral treatments vary by genotype, presence or absence of cirrhosis, and according to GFR. Recently approved mediations include pangenotypic regimens that can be used in patients with CKD, patients on dialysis, and posttransplant.182 The specific regimen chosen is likely to be a moving target with rapid advances in HCV therapies. Up-to-date information can be obtained from the HCV treatment guidelines published by the American Association for the Study of Liver Diseases (AASLD) accessible at https://www.hcvguid elines.org/.182 

Treatment of HCV in the Renal Transplant Candidate and Recipient The optimal timing of HCV treatment with new DAAs is yet to be determined (see Table 32.5). Effective HCV therapy is available for patients on dialysis and if cure is achieved, relapse after renal transplant is unlikely. However, clearing HCV therapy on dialysis may deprive HCV-positive patients of the chance of receiving an organ from a HCV-positive donor with a shorter waiting time. Posttransplant treatment of HCV with DAAs can work rapidly, effectively, and safely and may be a better option rather than treating patients on the waiting list unless there is concern about worsening liver disease on the waiting list, usually in patients with advanced fibrosis or early cirrhosis. The exact timing of posttransplant treatment is not established but earlier treatment is preferred, because it can prevent HCV-related worsening of kidney function, liver disease, or other extrahepatic effects of hepatitis C. Treatment Before Renal Transplantation. Concerns with pretransplant treatment on dialysis include decreased options in patients with CKD. However recently therapies that are effective in ESRD have been approved. Grazoprevir/elbasvir has a cure rate (SVR) of 94% in stage 4 to 5 CKD (including dialysis) for patients with genotype 1 or 4 HCV infection.183 In another study the combination of glecaprevir/pibrentasvir had a SVR rate of 98% in patients with CKD and ESRD.184 Sofosbuvir-based regimens are effective and safe in patients even with decompensated cirrhosis. Although sofosbuvir is not approved for use if GFR is less than 30, there are numerous reports and cases of safety and tolerability when sofosbuvir is used in decompensated cirrhosis with GFR less than 30.185  Treatment After Renal Transplantation. Hepatitis C therapy with DAAs after renal transplant has been reported predominantly in real-world experiences from single-center and multicenter studies and in small clinical trials. The results demonstrate excellent SVR rates in excess of 95% and therapy that is well tolerated. Hepatitis C DAA treatment in kidney transplant recipients was analyzed in a real-world experience in 119 patients from 15 hospitals in Spain. HCV was caused by genotype 1b in 66.5%, genotype 1a in 13.4%, genotype 2 in 4.2%, and genotype 3 in 7.5%. DAA treatment included a polymerase

TABLE 32.5  Selected Pretransplant and Posttransplant (Nonliver) Studies of Antiviral Therapy in HCV Patients Study

Patient Population

N

Antiviral Therapy

Duration of Therapy

SVR

Side Effects/ Discontinuation The frequencies of adverse events were comparable between the immediate treatment and deferred treatment groups (76% vs. 84%), most adverse events were of mild or moderate intensity in both treatment groups. The most common adverse events (≥10% frequency) were headache, nausea, and fatigue and were comparable in the two groups. Adverse events that were reported in at least 10% of the patients were pruritus, fatigue, and nausea. Serious adverse events were reported in 24% of the patients. Four patients discontinued the trial treatment prematurely because of adverse events. Four patients experienced serious adverse events; all were considered unrelated to treatment. Ribavirin therapy was interrupted in 9 patients because of anemia Nine grade 1 adverse events possibly related to treatment were reported in 7 patients (anemia, headache). One grade-2 event of asthenia was reported. One grade-3 event (Streptococcus sp. sepsis) was reported and considered unrelated to treatment with SOF TIW and DCV

Outcome after Transplant

PRETRANSPLANT Roth D, et al., The Lancet 2015270

HCV genotype 1 with 235 stage 4–5 CKD including 76% on dialysis

Grazoprevir/elbasvir immediate and deferred treatment arms

12 weeks

99%

Gane E et al., NEJM 2017184

HCV genotype 1–5 with CKD and ESRD (85% on hemodialysis)

104

Glecaprevir/pibrentasvir

12 weeks

98%

Pockros et al., Gastroenterology 2016271

HCV genotype 1 patients with CKD stage 4 and 5

20

12 weeks

90%

Desnoyer et al., J Hepatol 2016272

HCV genotype 1 (n = 11) or 2 (1)

12

Ombitasvir coformulated with paritaprevir and ritonavir, administered with dasabuvir+ ribavirin for genotype 1a (13) Sofosbuvir, 400 mg once daily (n = 7) or 3 times a week (n = 5), after hemodialysis with either simeprevir, daclatasvir, ledipasvir, or ribavirin

12–24 weeks

83%

HAI at 1 year after transplant lower in group A (1.19 ) than group B (5.5).

Gentil et al., Transp Proc. 2016186

Kidney transplant recipi- 119 ents from 15 Spanish hospitals

Fernandez et al., J Hepatol 2017187

Kidney transplant recipi- 101 ents from Spanish registry

91% had sofosbuvir-based therapy, 12–24 weeks sofosbuvir with ledipasvir, or simeprevir or daclatasvir with or without ribavirin. PrOD in 9% 57% had sofosbuvir with ledipasvir, 12–24 weeks 17% sofosbuvir with daclatasvir. ribavirin adjuvant treatment in 41%

97.8%

Side effects tolerable, 3 patients discontinued treatment because of anemia, 1 because of tacrolimus neurotoxicity.

Renal function did not change.

98%

Side effects tolerable, grade 2–3 anemia in 33% receiving ribavirin and in 15% without ribavirin.

Renal function did not change. Patients with cirrhosis had higher incidence of renal dysfunction; 55% required immunosuppression adjustment. Continued

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POSTTRANSPLANT

553

554

TABLE 32.5  Selected Pretransplant and Posttransplant (Nonliver) Studies of Antiviral Therapy in HCV Patients—cont’d SVR

Side Effects/ Discontinuation

Outcome after Transplant

Sofosbuvir-based therapy in all. Combined with either simeprevir, ledipasvir, paired with ribavirin, or ribavirin alone

12 weeks

91%

11 patients with adverse events, 3 serious. 1 was related- cardiac arrhythmia (sofosbuvir + simeprevir)

Renal function did not change.

15

Sofosbuvir and ledipasvir

8–12 weeks

100%

Mild fatigue, nausea, headache, and ­hypertension in 5/15

25

Sofosbuvir plus ribavirin (n  =  3); sofosbuvir plus daclatasvir (n  =  4); sofosbuvir plus simeprevir, with (n  =  1) or without ribavirin (n  =  6); sofosbuvir plus ledipasvir, with (n  =  1) or without ribavirin (n  =  9); and sofosbuvir plus pegylatedinterferon plus ribavirin (n  =  1) Sofosbuvir-based therapies with ledipasvir, daclatasvir, simeprevir with or without ribavirin

12–24 weeks

100%

1 patient with anemia, otherwise well tolerated therapy

No change in renal allograft function; liver tests improved; 55% required increase in tacrolimus dosing. No change in renal graft function and no change in immunosuppressive levels.

Antiviral Therapy

Lin MV et al., PLoS ONE Renal transplant recipients with HCV 2016188 genotype 1 in 21/24 and genotype 2 in 3/24 Eisenberger et al., Renal transplant Transplantation recipients with HCV 2017189 genotype 1 or 4

24

Kamar et al., American J Transplant, 2016190

Renal transplant recipients with HCV genotype 1–4

Sawinski et al., Am J Transplant, 2016161

Renal transplant 20 recipients with HCV genotype 1 (85%) and genotype 2

Patient Population

12 weeks

Anemia in 2 patients, one r­ equired ­transfusion rejection

Renal graft function remained stable. Immunosuppression dose adjusted in 45%.

CKD, chronic kidney disease; ESRD, end-stage renal disease; HAI, hepatic activity index; HCV, hepatitis C virus; PrOD, paritaprevir/ritonavir/ombitasvir plus dasabuvir; SVR, sustained virologic response, defined as undetectable HCV RNA 12 weeks after the end of therapy.

Kidney Transplantation: Principles and Practice

Duration of Therapy

N

Study

32 • Liver Disease Among Renal Transplant Recipients

inhibitor in 108 (91%) patients, often in combination with the NS5a inhibitor ledipasvir in 65 cases, the NS3/4 protease inhibitor simeprevir in 17 cases, the NS5a inhibitor daclatasvir in 16 cases. In 20 patients ribavirin was used as a coadjuvant therapy. Nine cases were treated with 3-D therapy (ombitasvir-dasabuvir-paritaprevir-ritonavir combination). SVR was seen in 97.8% of cases. Side effects were generally limited and not attributable to DAA except in seven cases where treatment had to be interrupted because of anemia (three patients), neurotoxicity because of tacrolimus interaction with 3-D (one patient), and other (three patients). Renal function and proteinuria did not change.186 In the Hepa-C Spanish Registry, data were reported on 103 HCV-positive kidney transplant recipients treated with DAAs. These patients were treated at a median interval of 147 months after kidney transplant (range 1–561 months). The majority (83%) were genotype 1, and 81% had previously failed interferon therapy. Cirrhosis was present in 35%. The most commonly used DAA combinations were sofosbuvir/ledipasvir (n = 59, 57%) and sofosbuvir/daclatasvir (n = 18, 17%). Ribavirin was used in 41% of patients. The SVR rate after 12 weeks (SVR12) was 98%. Grade 2 or 3 anemia appeared in 14 (33%) of patients receiving ribavirin and in 9 (15%) without ribavirin (P = 0.03). There were three episodes of acute humoral graft rejection, no patient discontinued therapy because of adverse events, and 57 (55%) patients required immunosuppression dose adjustment. Overall, there were no significant differences in the mean level of serum creatinine, estimated GFR (eGFR), and proteinuria before and after treatment. Nonetheless, 17 (16%) patients experienced renal dysfunction (increase in serum creatinine >25%) during antiviral therapy, of whom 65% were cirrhotic.187 A retrospective chart review with prospective clinical follow-up of postkidney transplant patients treated with DAA therapies in three city hospitals was reported. Twenty-four kidney recipients with HCV infection received all-oral DAA therapy posttransplant. The majority had HCV genotype 1a infection (58%). All patients received full-dose sofosbuvir; it was paired with simeprevir (nine patients without and three patients with ribavirin), ledipasvir (seven patients without and one patient with ribavirin), or ribavirin alone (four patients). The overall SVR12 was 91% (21 out of 23 patients). Two treatment failures were successfully retreated with alternative DAA regimens and achieved SVR. Both initial failures occurred in patients with advanced fibrosis or cirrhosis, with genotype 1a infection, and prior HCV treatment failure.188 Fifteen renal allograft recipients with therapy-naïve HCV genotype 1a, 1b, or 4 were treated with the combination of sofosbuvir and ledipasvir without ribavirin for 8 or 12 weeks. Clinical data were retrospectively analyzed for viral kinetics and for renal and liver function parameters. One hundred percent of patients exhibited SVR at week 12 after the end of treatment. Clinical measures of liver function improved substantially for all patients. Adverse events were scarce and the drugs well tolerated; renal transplant function and proteinuria remained stable. Importantly, dose adjustments for tacrolimus were necessary for maintaining sufficient trough levels.189

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In a real-world experience, 25 kidney transplant patients were treated with DAAs. Ten had advanced liver fibrosis (F3 and F4 Metavir score) and the remaining 15 patients had mild liver fibrosis (F1/F2 Metavir score) and either HCVassociated extrahepatic manifestations or a history of graft loss caused by HCV-associated glomerulonephritis. Most patients (20 of 25) were infected with HCV genotype 1. Patients were given sofosbuvir plus ribavirin (n = 3); sofosbuvir plus daclatasvir (n = 4); sofosbuvir plus simeprevir, with (n = 1) or without ribavirin (n = 6); sofosbuvir plus ledipasvir, with (n = 1) or without ribavirin (n = 9); and sofosbuvir plus pegylated-interferon plus ribavirin (n = 1). Antiviral therapy was given for 12 (n = 19) or 24 weeks (n = 6). SVR at 12 weeks was 100%. Eight patients had impaired kidney function, but there were no acute rejection episodes and no graft losses. However, tacrolimus trough levels were significantly decreased after HCV clearance.190 Sawinski et al. reported on 20 HCV-positive patients with a kidney transplant and treated with a DAA-based therapy, without interferon alpha. Three of these patients also received ribavirin. Of the 20 patients, 88% were infected by genotype 1 and 50% had biopsy-proven advanced hepatic fibrosis. DAA therapy was initiated at a median of 888 days after kidney transplantation. All 20 patients achieved SVR at 12 weeks after completing therapy.161 In a randomized, phase 2, open-label study treatmentnaïve or -experienced kidney transplant recipients with chronic genotype 1 or 4 HCV infection with an eGFR of 40 mL/min or greater were randomly assigned 1:1 to receive ledipasvir (90 mg) and sofosbuvir (400 mg) for 12 or 24 weeks. Of all participants, 91% had genotype 1 infection and 15% had compensated cirrhosis. One hundred percent of patients (57 of 57) treated for 12 weeks (95% CI, 94%–100%) and 100% of those (57 of 57) treated for 24 weeks (95% CI, 94%–100%) achieved SVR. Serious adverse events were reported in 13 patients (11%). Of these, three events—syncope, pulmonary embolism, and serum creatinine increase—in three patients were determined to be treatment related. Treatment with ledipasvir/sofosbuvir for 12 or 24 weeks was well tolerated and seemed to have an acceptable safety profile among kidney transplant recipients with HCV genotype 1 or 4 infection, all of whom achieved SVR12.191 Although some of these DAAs do not interact with calcineurin inhibitors or mTOR inhibitors, some such as ledipasvir, simeprevir, or ombitasvir can interact with immunosuppressive agents, most commonly through their effect on cytochrome P-450. Also, as liver function improves with use of any effective DAA, hepatic metabolism of immunosuppressive agents may improve, reducing trough levels of antirejection agents. Vigilance of immunosuppression levels and renal function is required in monitoring. 

HEPATITIS E Hepatitis E virus (HEV) is a nonenveloped, single-strand RNA virus of the family Hepaviridae.192 HEV is considered endemic in developing countries and is spread via fecal-oral transmission, similarly to hepatitis A.193 In immunocompetent patients, HEV has a clinical course similar to HAV, manifested by an acute, sometimes icteric, self-limited illness without the potential for chronicity.

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However, in recent years, zoonotic transmission (frequently from a swine vector) of HEV in industrialized countries has become increasingly recognized. In France, anti-HEV antibodies are present in 16.6% of blood donors and 6% to 16% of renal transplant recipients.194 In addition, chronic hepatitis resulting from HEV infection has been reported in immunocompromised patients, including liver and kidney transplant recipients.195 Thus chronic HEV infection should be considered in kidney transplant recipients with unexplained liver test abnormalities. There is no effective vaccination available for HEV. Current recommendations for HEV prevention focus primarily on proper hygiene and consumption of properly cooked food. Bloodborne transmission of HEV is felt to be rare. There are no data on the natural history of HEV infection on kidney transplant recipients. Similarly, there are very limited data on treatment for chronic HEV. Pegylated interferon-α has been used in liver transplant recipients, but caution should be used in renal transplant recipients because of the known risk of allograft loss. Ribavirin has also been used in kidney transplant recipients with chronic HEV infection. Kamar et  al.196 published a series of six kidney transplant recipients with chronic HEV hepatitis treated with ribavirin at a dose of 600 to 800 mg/day. All patients achieved serum viral clearance at 3 months. Four patients achieved a durable response after cessation of ribavirin. Larger studies are needed to determine optimal dose and duration of ribavirin therapy for chronic HEV. 

Nonalcoholic Fatty Liver Disease and Renal Transplant NAFLD is the most prevalent chronic liver disease in the US, affecting 30% of the general adult population and up to 60% to 70% of diabetic and obese patients. NAFLD encompasses a histologic spectrum ranging from simple steatosis to the more progressive form, nonalcoholic steatohepatitis (NASH), which is often associated with fibrosis and can lead to cirrhosis. NAFLD is intimately linked to metabolic syndrome, in particular the closely linked epidemic of obesity, type 2 diabetes, hyperlipidemia, and hypertension.197 Metabolic syndrome and its components are associated with increased risk of CKD. Metabolic syndrome has been associated with azotemia, proteinuria, and glomerular injury. Given the close association of NAFLD with metabolic syndrome, it is not surprising that NAFLD is associated with CKD.198,199 However, there is significant evidence that NAFLD increases the incidence of CKD, in excess of that expected because of the associated metabolic risk factors such as diabetes and hypertension. In a meta-analysis of 20 studies, NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (HR 1.79, 95% CI 1.65–1.95) CKD. The more progressive form of NAFLD, NASH, was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced liver fibrosis was also associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than nonadvanced

fibrosis. These effects remained after adjustment for diabetes status.200 NAFLD itself may add to this renal dysfunction, possibly via associated chronic inflammation and oxidative stress.200 The role of inflammatory mediators, such as tumor necrosis factor (TNF) alpha, in NASH is of particular interest in the pathophysiology of CKD.198,201 Not only is the risk of CKD in patients with NAFLD increased, the incidence of simultaneous liver-kidney transplant (SLK) is increased in NAFLD compared with other causes of cirrhosis. In a UNOS database query of 38,533 liver transplants between 2002 to 2011 in the US, 5.6% received SLK with the proportions of SLKs being 8.7% in NAFLD; 5% in HCV, HBV, or liver cancer; and 6.2% in alcohol-induced or cholestatic cirrhosis. Furthermore, the incidence of SLK performed for NAFLD increased from 6.3% in 2002 to 2003 to 19.2% in 2010 to 2011.202

NAFLD POST RENAL TRANSPLANT Given the high prevalence and incidence of metabolic syndrome in renal transplant recipients, NAFLD is expected to be commensurately frequent. The diagnosis of NAFLD is traditionally made with liver biopsy, which is invasive and not acceptable to many patients. Imaging techniques such as ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) have also been used to make diagnosis of NAFLD after serologic exclusion of other chronic liver conditions but suffer from reduced sensitivity and specificity (ultrasound), and cost and limited availability (MRI). Consequently, few studies have systematically investigated the frequency of NAFLD post– renal transplant. Using a new technology (transient elastography, or TE) that utilizes noninvasive shear wave technology and liver attenuation (controlled attenuation parameter, or CAP) to diagnose liver steatosis and stiffness, Mikolasevic et  al. investigated the prevalence of NAFLD in renal transplant recipients. When including presence of any steatosis independent of fibrosis as inclusion of NAFLD, a prevalence of 57.5% was described in 73 renal transplant recipients followed for more than 1-year post transplant. In the study, the severity of hepatic steatosis was independently associated with increasing serum creatinine levels after transplant (correlation coefficient r = 0.66, P < 0.001). The liver fibrosis severity in NAFLD also correlated with worsening serum creatinine. Most importantly liver enzymes did not differ between those with and without NAFLD in the renal transplant population, suggesting that elevated liver enzymes are not an accurate way to detect NAFLD in this population. Longer prospective studies in larger cohorts of renal transplant recipients with biopsy-proven NAFLD are needed to confirm these findings and to determine whether improvement in NAFLD will prevent or delay the development and progression of CKD.203 

NAFLD AND OUTCOMES IN RENAL TRANSPLANT RECIPIENTS Although 5-year patient and liver graft survival were similar in NAFLD and non-NAFLD SLK patients, in an audit of UNOS data, the 5-year kidney graft outcome was worse for

32 • Liver Disease Among Renal Transplant Recipients

NAFLD versus other causes (70% vs. 79%, P = 0.002) after controlling for recipient characteristics.202 Cardiovascular diseases (CVDs) are the predominant cause of mortality in renal transplant recipients and are closely associated with the metabolic syndrome. Obesity, hypertension, diabetes, and dyslipidemia are significant concerns post–renal transplant in 20% to 70% of recipients. These same risk factors are also closely associated with NAFLD. In the general population the predominant cause of mortality in patients with NAFLD is CVD.204 Whether NAFLD is independently associated with CVD in renal transplant recipients was investigated in a large single-center study in the Netherlands. Of 602 renal transplant recipients over a 2-year period, 388 had metabolic syndrome. NAFLD was presumed based on indirect markers, primarily elevated liver enzymes, and was associated with the presence of metabolic syndrome. In regression analyses, both elevated gamma-glutamyltransferase (GGT) (HR 1.43(.21–1.69, P < 0.001) and alkaline phosphatase (HR = 1.34 (1.11–1.63), P = 0.003) were independently associated with mortality. Limitations of this study included that the definition of NAFLD as elevated liver enzymes is not necessarily sensitive or specific for NAFLD in the absence of either imaging or liver biopsy to confirm the diagnosis.205 In another single-center study, carotid atherosclerosis was assessed in 71 renal transplant recipients who had NAFLD diagnosed by TE. These individuals with NAFLD showed more carotid atherosclerosis than renal transplant recipients without NAFLD.206 Potential mechanisms whereby NAFLD is associated with CVD and mortality include increased oxidative stress and endothelial dysfunction seen in patients with NAFLD. Rajman et  al. reported the presence of small low-density lipoprotein (LDL) particles in uremic dyslipidemia, which is persistent after renal transplantation. These may play a pathogenic role in NAFLD development in renal transplant recipients, contribute to further insulin resistance, and promote atherosclerosis. Concentrations of plasminogen activator inhibitor-1 (PAI-1) are also elevated in patients with NAFLD, which is another risk factor for CVD.207–211 

TREATMENT OF NAFLD The mainstay of treatment of NASH is weight loss through a combination of exercise and diet. Treatment of the underlying metabolic diseases including diabetes, hypertension, and hyperlipidemia is integral in preventing exacerbation of the disease.212 Medical therapies for NAFLD include agents that can improve glycemic control, lipid metabolism, or those with antioxidant effects. Use of thiazolidinediones (TZDs) such as pioglitazone, which improve insulin resistance, have shown some benefit in randomized controlled trials and are associated with histologic improvements, and they can be used in the treatment of NAFLD. Vitamin E, which is an antioxidant, has shown histologic benefits in randomized controlled trials of NAFLD as well.213 Although many of these studies have a small cohort of patients and the histologic endpoints were not standardized, the AASLD has published guidelines recommending the use of vitamin E

557

and pioglitazone in nondiabetic adults with biopsy-proven NASH.214 Other treatments related to disordered cholesterol metabolism and insulin resistance including statins, fibrates, metformin, and glucagon-like peptide (GLP-1) analogs have shown improvement in liver enzymes and weight loss without changes in histologic staging of the disease. Although statins have not shown any benefit on NAFLD-related liver disease there has been reduction in CVD-related events in patients with NAFLD without any significant adverse effects on liver function.212 Guidelines recommend ACE inhibitors and angiotensin receptor blockers (ARBs) as preferred agents for diabetic kidney disease and nondiabetic kidney diseases with proteinuria. In these diseases, they lower blood pressure, reduce proteinuria, slow the progression of kidney disease, and likely reduce CVD risk by mechanisms in addition to lowering blood pressure. In these types of CKD, ACE inhibitors and ARBs are recommended even in the absence of hypertension.145 In patients with NAFLD who have CKD, renin-angiotensin blockade using ACE inhibitors and ARBs have demonstrated benefits in liver and kidney disease. Limited data from 223 patients in three randomized controlled trials in NAFLD suggests that ARBs attenuate steatosis, insulin resistance, and inflammatory markers independent of reduction in blood pressure.215 Telmisartan, which is an ARB with peroxisome proliferator activated receptor gamma regulating activity, was compared with the use of valsartan in the Fatty Liver Protection by Telmisartan (FANTASY Trial) and found to cause reduction in necroinflammation, NAFLD activity score, fibrosis stage in NASH, and microalbuminuria.216 

Hepatocellular Carcinoma After Renal Transplantation In the setting of immunosuppression loss of tumor surveillance can lead to higher risk for various malignancies. HCC is more common after renal transplantation (incidence 1.4%– 4%) than in the general population (incidence 0.005%– 0.015%).217–220 This risk is particularly true for renal transplant recipients infected with chronic HBV or HCV. In areas endemic for HBV, HCC is the most common tumor after renal transplantation (20%–45%).221,222 Recently, Hoffman et al.223 published data on the development of de novo HCC in transplant recipients. Using US registry data of more than 200,000 transplant recipients, the incidence of HCC in nonliver transplant recipients was 6.5 per 100,000 person-years. HBV and HCV infection were independently predictive of the development of de novo HCC. Estimated survival was worse than that expected for similar-stage tumors in nontransplanted populations.219,222 Because outcomes after HCC are poor, preventive measures are important, including: vaccination of renal transplant waiting list patients for HBV, antiviral therapy for HCV and HBV in the dialysis population, continued antiviral treatment for HBV in the renal transplant recipient, exclusion of patients with ESRD and cirrhosis from isolated kidney transplantation and in select cases consideration of these patients for combined liver transplantation.

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Renal transplant recipients infected with HBV/HCV and uncontrolled viral replication or with advanced fibrosis/ cirrhosis should be entered in an HCC surveillance protocol. Current AASLD guidelines recommend surveillance with ultrasound with or without alpha-fetoprotein every 6 months.224 

Systemic Infections Resulting in Hepatitis and Liver Disease A number of systemic infections have hepatitis as part of the clinical manifestation. Foremost among these are infections caused by herpesviruses, which are major pathogens in organ transplantation. Other infections primarily involving the liver are also reviewed.

LIVER ABSCESS Pyogenic liver abscess does not represent a specific liver disease but is a final common pathway of many pathologic processes. The incidence of pyogenic liver abscess ranges from 8 to 20 cases per 100,000 hospital admissions225; a population-based study reported 2.3 cases per 100,000 persons per year.226 A population-based study found no increased risk of pyogenic liver abscess in renal transplant recipients.226 Abscesses may be classified by presumed route of hepatic invasion: (1) biliary tree, (2) portal vein, (3) hepatic artery, (4) direct extension from contiguous focus of infection, and (5) penetrating trauma.225 Approximately 50% of pyogenic liver abscesses are cryptogenic.227 The microbiology of pyogenic liver abscess is variable and depends on the route of infection. Most infections are polymicrobial, with enteric facultative and anaerobic bacteria being the most common agents. Candida species should also be suspected as a pathogen in pyogenic abscesses, accounting for 22% of abscesses in one series.228 Although fever and constitutional symptoms are frequent, only 1 in 10 patients presents with the classic triad of fever, jaundice, and right upper quadrant tenderness. Although liver function tests are abnormal in most patients, the elevation is usually modest. Radiographic imaging using MRI, CT, or ultrasonography is essential to making the diagnosis. Microbiologic diagnosis rests on obtaining purulent material from the abscess cavity, which should be sent for Gram stain and culture. In general, treatment consists of antimicrobial therapy for 3 to 4 weeks and drainage of the abscess. Some investigators have reported success with treatment of small abscesses with antibiotic therapy alone; however, most patients will require some form of abscess drainage.229 Drainage may be achieved by percutaneous aspiration with or without placement of a drainage catheter. Generally, abscesses larger than 5 cm require placement of a catheter.230 Endoscopic drainage via endoscopic retrograde cholangiopancreatography has been reported to be successful in cases where the abscess communicates with the biliary tree.231 Finally, surgical drainage may be needed in cases with multifocal abscesses, heavily loculated abscesses, or unsuccessful percutaneous drainage. Amebiasis is a far less common cause of liver abscess in the US but one that must be considered in patients living in or traveling to countries where the prevalence of amebiasis

is high.232 There is a marked male predominance and amebic liver abscesses are usually solitary.233 Clinical signs and symptoms and liver test abnormalities do not help distinguish amebic from pyogenic liver abscesses. Serology for antibodies to Entamoeba histolytica is useful to determine current or past infection. After confirmation of an abscess on imaging, if amebic rather than pyogenic liver abscess is suspected, treatment with metronidazole for 10 days is necessary. Renal transplant recipients traveling to areas endemic for amebiasis should be counseled to avoid ingestion of potentially contaminated food and water, such as fresh produce that cannot be adequately cooked.234 Boiling water before use is essential to destroy the cysts of E. histolytica, which are not killed by low-dose iodine or chlorine tablets. 

MYCOBACTERIAL INFECTION Tuberculosis is an important cause of morbidity and mortality among renal transplant recipients. The risk of active tuberculosis is at least 50-fold higher in renal transplant recipients compared with nontransplant patients; most reactivation disease has been reported to occur in the first year after transplantation.235,236 Liver involvement with tuberculosis remains rare; when present, it is usually associated with pulmonary disease237 or gastrointestinal involvement. Three patterns of tuberculous liver involvement have been reported238: (1) diffuse involvement of the liver in association with tuberculosis at other body sites; (2) miliary involvement of the liver with no other known organ involvement (granulomatous hepatitis); and (3) focal lesion in the liver, either an abscess or a tuberculoma.239 Constitutional symptoms and fever are common but nonspecific. A modest degree of transaminase and alkaline phosphatase elevation is common. Imaging followed by tissue staining for acid-fast bacilli and culture for mycobacteria are required to confirm the diagnosis. 

VIRAL INFECTIONS Herpesviruses The herpesviruses include cytomegalovirus (CMV), Epstein– Barr virus (EBV), herpes simplex virus (HSV), human herpesvirus 6 and 7, and varicella-zoster virus (VZV). The herpesvirus family is responsible for considerable morbidity and mortality in transplant recipients. In particular, CMV remains a major health threat after solid-organ transplantation. All the herpesviruses have the ability to remain latent in tissues after acute infection. Liver involvement frequently is a part of the clinical presentation of herpesvirusrelated diseases.  Cytomegalovirus CMV is one of the most important pathogens in transplant recipients.234,240 Unlike the other herpesviruses, such as HSV and VZV, which remain latent in highly restricted areas of the body, once acquired, latent CMV can be found in multiple body sites. After transplantation, approximately 50% of transplant patients excrete CMV in body secretions (e.g., saliva and urine) at some point.240 In addition, over 60% of patients develop antigenemia within the first 100 days after transplantation.241

32 • Liver Disease Among Renal Transplant Recipients

Hepatitis is a major clinical manifestation of CMV disease. In the immunocompetent patient, the disease is usually mild and self-limiting, although rare cases of fulminant CMV hepatitis have been described.242 In the transplant recipient, CMV hepatitis is a more severe illness, usually with other organ involvement or disseminated disease, and is not uncommon. In a series of 97 renal transplant recipients with CMV disease, half had evidence of CMV hepatitis; the severity of hepatitis was greater in primary disease than in cases of reactivation.241 In an autopsy series of four immunocompromised patients with overwhelming CMV infection, Ten Napel et al. showed that liver cell damage was extensive but inflammatory infiltration was less prominent than in immunocompetent patients with CMV infection.243 Intracellular CMV inclusion bodies were found in the hepatocytes, vascular endothelium, and bile epithelium. Given the significant morbidity and mortality of CMV infection, including CMV hepatitis, in solid-organ transplant recipients, prevention and treatment of CMV infection posttransplant are of utmost importance. The diagnosis and treatment of CMV infection and strategies for CMV prophylaxis in kidney transplant recipients are covered in another chapter. 

Epstein–Barr Virus EBV, a member of the human gammaherpesvirus family, is a ubiquitous pathogen. More than 90% of the world’s population is infected.244 The virus is shed intermittently into saliva245 and is believed to be transmitted through close contact with oral secretions. EBV infection may present as primary or secondary infection (reactivation). Childhood disease is usually asymptomatic. Infection acquired in adolescence or young adulthood frequently causes the clinical syndrome of acute infectious mononucleosis, characterized by fever, pharyngitis, and lymphadenopathy in 75% of patients.246 A nonspecific hepatitis is common in acute infectious mononucleosis. Jaundice is apparent in 5% to 9% of patients. Liver function test abnormalities peak with acute illness and return to normal over 1 to 2 months. In instances where liver biopsies have been obtained, minimal swelling and vacuolization of hepatocytes can be seen accompanied by a lymphocytic or monocytic infiltrate in portal regions.247 EBV establishes latency248 and may reactivate later; the risk of reactivation is especially high in immunosuppressed patients. Primary infection with EBV after transplantation may manifest as a febrile illness with constitutional signs and symptoms. EBV has a central role in the pathogenesis of posttransplant lymphoproliferative disorder (PTLD),249 although not all PTLD is caused by EBV. The diagnosis and treatment of EBV and PTLD are discussed in Chapter 31.  Herpes Simplex Virus HSV is an alpha herpesvirus with a genome consisting of a linear, double-stranded DNA molecule.250 The two types of HSV, HSV-1 and HSV-2, have 50% sequence homology. In the US population, seroprevalence rates range from 56% to 60% for HSV-1 and from 15% to 18% for HSV-2. First episodes of HSV, or primary infection, are frequently accompanied by systemic signs and symptoms and have a longer

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duration of symptoms.251 The virus establishes latency in ganglia and may reactivate. Immunocompromised patients have been found to have more severe primary infections and more frequent reactivations.252 In renal transplant recipients, the incidence of HSV infection has been reported to be 30% to 50% in the absence of prophylaxis.253,254 The risk of HSV reactivation is highest in the first 3 months posttransplant because of the higher level of immunosuppression needed during this period. Oral acyclovir for prophylaxis against HSV has greatly reduced the incidence of HSV infection.253,254 Hepatitis with HSV has been well described in the general population and the renal transplant population. Kusne et al.255 reported a series of 12 cases of HSV hepatitis that developed a median of 18 days after solid-organ transplantation. The clinical features included fever, herpetic stomatitis, and abdominal pain, usually in association with disseminated disease. Clinical features associated with mortality included bacteremia, hypotension, disseminated intravascular coagulation, and gastrointestinal bleeding. HSV hepatitis was associated with 67% mortality in this patient population. Conclusive diagnosis of HSV hepatitis rests on demonstration of viral involvement of liver tissue. Histologically, hepatocytes have enlarged “ground-glass” nuclei with chromatin margination. Because of the high mortality associated with HSV hepatitis, transplant recipients who present with fever, progressive transaminase elevation, and abdominal symptoms with or without evidence of cutaneous herpes simplex infection should prompt consideration of HSV hepatitis and treatment with intravenous acyclovir. 

Varicella-Zoster Virus VZV is another herpesvirus that causes two distinct diseases—varicella and herpes zoster. Primary infection with VZV causes varicella in susceptible hosts. Children generally develop mild disease compared with adults or immunosuppressed patients. Whereas only 0.1% of varicella infections develop in this population, 25% of varicella-related deaths occur in this patient population.256 Hepatic involvement with varicella is uncommon but has been described in transplant recipients. A study assessing clinical features of liver transplant patients with varicella hepatitis showed that the most common presenting features were cutaneous vesicular lesions, fever, and acute abdominal or back pain. The rash may not be apparent at the time of hepatic involvement, however, and the diagnosis of varicella hepatitis may be delayed. In case reports, high-dose acyclovir (10 mg/kg every 8 hours) has been shown to treat varicella hepatitis successfully. Like all herpesviruses, VZV establishes latency and may subsequently reactivate.257 Reactivation of latent VZV typically results in a localized skin infection known as herpes zoster, or shingles.258 Disseminated zoster in transplant patients can be a severe, prolonged illness with hepatitis as a prominent manifestation. In a case series of four renal transplant recipients that developed primary (one patient) or reactivation VZV infection (three patients), all four had multiorgan involvement and three of the four developed hepatitis.258 In general, primary varicella infection is a more severe illness than reactivated disease. Fehr et al. reviewed all cases

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of herpes zoster in renal transplant recipients and found 34 reported cases, most of which were primary infections. Analysis of these cases showed that disseminated intravascular coagulation and hepatitis occurred in half of the cases and pneumonitis in 29% of patients. The overall mortality was 34%, although it appears to have decreased over time from 53% to 22%.258 Treatment of disseminated zoster in transplant patients should be undertaken promptly with high-dose acyclovir. 

Human Herpesvirus 6 and 7 Human herpesvirus 6 (HHV-6) and 7 (HHV-7) are ubiquitous lymphotropic herpesviruses and were initially isolated from patients with lymphoproliferative disorders.259 Seroprevalence surveys have found that HHV-6 infection occurs in the majority of children by age 3 years, and the prevalence in adults is greater than 90%. The major childhood clinical syndrome caused by HHV-6 primary infection is exanthem subitum. Infection in immune-competent adults is usually benign, presenting as fever with lymphadenopathy or an infectious mononucleosis-like syndrome. HHV-6 infection posttransplant has been frequently reported in kidney transplant recipients.260,261 Typically, HHV-6 reactivation is asymptomatic, even in kidney transplant patients. However, symptomatic and even fatal HHV-6 infections have been reported in the kidney transplant population. Hepatitis has been rarely reported in both the immune-competent and transplant populations.262–264 There are no controlled trials of antiviral therapy for HHV-6 or HHV-7 infection. According to the American Society of Transplantation’s Infectious Disease Community of Practice guidelines, IV ganciclovir or foscarnet is first-line therapy for active disease.265

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