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 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. 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 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. 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. Consequently, it should be noted that there have been no comprehensive attempts to characterize liver disease in renal transplant recipients since Allison et al. 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.
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 AD-PKD1 account for up to 90% adult-onset combined kidney and liver polycystic disease and mutations in AD-PKD2 account for the majority of the remainder. 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. In addition, hepatic cyst prevalence is correlated with renal cyst volume. 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.
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. 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. 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 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.
Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD-1 gene that encodes the protein fibrocystin. Congenital hepatic fibrosis (CHF), caused by ductal plate malformation of the developing biliary system, is invariably present in patients with ARPKD. 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. 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. 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.
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. 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. 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.
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. Other medications may have immunologic mechanisms of injury that are not dose-related and considered idiosyncratic. Most patients present asymptomatically or with nonspecific symptoms. Occasionally, a hypersensitivity reaction of fever, lymphadenopathy, and leukocytosis, often with eosinophilia, may be seen. 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.
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, antibiotics, antihyperlipidemics, and drugs for hypertension and diabetes. 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. 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.
| 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 |
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. Corticosteroids are of unproven benefit. In cases that progress to liver failure, liver transplantation should be considered.
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. The pathogenesis of azathioprine hepatotoxicity is multifactorial, resulting from endothelial damage, direct hepatotoxicity, and interlobular bile duct injury. In addition, serum levels of the 6-MP metabolite 6-methylmercaptopurine ribonucleotide have been associated with the development of hepatotoxicity.
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. 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. 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. 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). Poor outcomes are associated with higher bilirubin, degree of weight gain, aminotransferase elevation, and HVPG elevation. With cessation of azathioprine it rarely has been reported to regress. Specific therapy for SOS, including defibrotide, heparin, ursodeoxycholic acid, and prostaglandin E 1 , has produced mixed results. Transjugular intrahepatic portosystemic shunt and liver transplantation have been reported in small series and case reports, respectively. 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.
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. 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. 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. 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. 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. 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. 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. 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.
Tacrolimus has a similar immunosuppressive mechanism of action to cyclosporine. 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.
Similar to cyclosporine, tacrolimus levels were higher in HCV-positive renal transplant recipients, presumably secondary to impaired cytochrome P-450-related metabolism of tacrolimus. 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. Elevations in aminotransferases are generally mild, even with supratherapeutic levels, and reversible with dose reduction.
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. 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. 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. 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.
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 HCV-infected transplant recipients and should generally be avoided in solid-organ recipients with chronic viral hepatitis. 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. 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.
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 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 double-stranded DNA virus that is a member of the hepadnavirus family. 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.
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.
| HBsAg | Anti-HBs | Anti-HBc | Interpretation |
|---|---|---|---|
| + | – | – | Early acute infection |
| + | – | + | Acute or chronic infection |
| – | + | + | Cleared HBV infection—immune |
| – | + | – | Vaccine response—immune |
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.
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. 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. 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.
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%). 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.
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. 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 near-normal 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. 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. 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, 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.
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. 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. Similarly, success of HBV vaccination correlates with glomerular filtration rate (GFR) and thus “earlier” vaccination is more successful. Despite lower rates of anti-HBs 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.
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. 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. 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. 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. 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. 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% and renal allograft survival was reduced compared with recipients not infected with chronic hepatitis B. 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.
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. Age at transplant and presence of cirrhosis were independent prognostic factors for survival in this study. Another study found a significant difference in long-term survival between hepatitis B-positive recipients compared with recipients without chronic viral hepatitis 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).
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. 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.
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. Once established, the prognosis is poor, even with antiviral therapy. Preemptive suppressive antiviral therapy is the judicious strategy to prevent this feared 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.
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. 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. 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-positive-only 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. 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. 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.
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.
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 HBsAg-positive 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 DNA-negative, 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). 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 × 10 8 copies/mL alone or to >2.83 × 10 7 copies/mL with elevated AST/ALT from 1996 to 2000 (so-called de novo group). 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 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.
| Study | Patient Population | Number in Study | HBV Antiviral Therapy | Duration of Therapy | HBV DNA Suppression | HBeAg Seroconversion to Anti-HBe | Virologic Breakthrough |
|---|---|---|---|---|---|---|---|
| Pretransplant | |||||||
| Fontaine et al. | Dialysis patients | 5 | Lamivudine 10 mg daily in 3, 50 mg thrice weekly in 2 | 12 months (7–28) | 5/5 | 1/5 | 2/5 (at months 7, 18 of lamivudine) |
| Duarte et al. | Dialysis patients | 2 | Interferon-alfa 3 mu thrice weekly | 3 months | 2/2 | 2/2 | None |
| Posttransplant | |||||||
| Fontaine et al. | Postrenal transplant patients with HBV infection | 26 | Lamivudine 100 mg/day | 16.5 months (4–31) | 26/26 undetectable | 6/26 | 8/26 |
| Hu et al., 2012 | Postrenal transplant patients with HBV infection | 27 | Entecavir | 104 weeks | 100% undetectable after 104 weeks | 3/5 HBeAg-positive seroconverted after 35 weeks | 0/27 |
| Fontaine et al. | Post kidney transplantation with lamivudine-resistant HBV | 11 | Adefovir 10 mg/day | 15 months (3–19) | Median change –5.6 log copies/mL (–2.2 to –7.7) | 0/6 that were initially HBeAg+ | Not detected |
| Han et al. 2001 | Post kidney transplantation with HBV (HBsAg+) | Group 1: After developing recurrent hepatic dysfunction after renal transplant (6) Group 2: Preemptive or prophylactic treatment for HBsAg-+ recipients beginning before renal transplantation (10) | Lamivudine 100 mg/day | Group 1: Follow-up 15–60 months Group 2: Follow-up 9–30 months | On treatment Group 1: 6/6 On treatment Group 2: 11/11 | Group 1: 0/6 Group 2: 0/11 | Group 1: 3/6 Group 2: 1/10 |
| Chan et al. 2002 | Post kidney transplantation with HBV (HBsAg+) | Period II: Post 1996. De novo preemptive therapy before renal transplantation and continued after transplantation (11) Period I: pre-1996. Preemptive therapy after renal transplantation | Lamivudine 100 mg/day | Period I: 36.3 ± 11.4 months Period II: 27.6 ± 14.5 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 |
| Puchhammer-Stockl et al., 2000 | Post kidney transplantation with HBV (HBsAg+) | 11 | Lamivudine 100 mg/day in 7, reduced dose in 4 per renal function | >12 months | HBV undetectable in 10/11 undetectable by PCR | Not reported | Lamivudine resistance in 5/11 from 9 to 15 months after starting lamivudine |
| Thabut et al. 2004 | Post kidney transplantation with HBV (HBsAg+) | 14 | Lamivudine 100 mg/day | Median duration 64.5 months (6–93) | 11/11 undetectable on treatment | 0 of 4 HBeAg+ patients | Lamivudine resistance with virologic breakthrough in 8/14 patients from 9 to 24 months after starting lamivudine |
| Chan et al., 2004 | Post kidney transplantation with HBV (HBsAg+) | 29 | Lamivudine 100 mg/day | 56.7 ± 12.5 months | 29/29 undetectable on treatment initially | 5/15 who were HBeAg + | 14/29 (48%) developed lamivudine resistance (10–35 months after starting treatment) |
| Fabrizi et al., 2004 | Post kidney transplantation with HBV (HBsAg+) | 184 (meta-analysis of 14 studies) | Lamivudine 50–150 mg/day | Variable | 91% HBV DNA undetectable | 27% in 4 of 14 studies | 18% in 8 of 14 studies |
| Kamar et al., 2008 | Posttransplantation with lamivudine or adefovir-resistant HBV (HBsAg+) | 10 (8 kidney) | Entecavir 0.5 mg/day titrated to 1.0 mg/day after 1 month | Median 16.5 months | 5/8 kidney recipients developed undetectable HBV DNA | Not reported | Not reported |
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.
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. Cessation of antiviral therapy has been associated with virologic and clinical relapse.
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%. 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 first-line therapy for HBV.
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. 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 lamivudine-resistant 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. Adefovir resistance is much less common than with lamivudine, even after prolonged therapy. 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. 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.
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.
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%.
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. 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.
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 HBV DNA at 48 weeks. 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. 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.
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. 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. 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 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 1973 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. 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. 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, 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. 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.
The significance of viral genotypes is not entirely clear, but important clinical differences have been shown. Amoroso et al. 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. The symptoms are generally mild and include lethargy, 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, 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. 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.
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. Studies have estimated 20% to 35% of patients will have progression of liver disease to cirrhosis over 20 to 30 years. A study by Cacoub et al. 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. 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. 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. However, in the US, there is high variability in the prevalence of chronic HCV among hemodialysis units based on location. 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 methods and decreased transfusion requirements directly related to the increased use of hematopoietic growth factors. Despite these improvements, studies show de novo infections do occur in dialysis units, though clearly identifiable risk factors have not been reproducibly demonstrated.
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, 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. 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. 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. 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 HCV-negative 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.
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.
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. 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. Lee et al. also determined that HCV infection 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.
| 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 |
In contrast, studies with more lengthy follow-up after transplantation have found decreased patient and/or graft survival in HCV-positive renal transplant recipients. Periera et al. 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. 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%).
The most common reasons for increased mortality in HCV-positive renal transplant recipients are excess risk of diabetes, cardiovascular disease, systemic infections, and cancer.
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.
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. Dialysis patients with HCV have a 15% to 30% increased risk of mortality compared with patients without HCV on dialysis.
HCV infection thus should not be considered a contraindication to consideration of kidney transplantation. 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.
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.
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. 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. 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). This association was further observed by Bloom et al. 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 eight-fold 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.
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. 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.
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. In addition, as mentioned previously, in liver transplant recipients cyclosporine may have an anti-HCV effect and improve the probability of successful HCV treatment. 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, 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 HCV-infected 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.
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