Liver Disease Among Renal Transplant Recipients

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.

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

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

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.

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.

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.

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