EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Introduction: Hyperuricemia caused by pegylated-interferon-α2a and ribavirin therapy has been rarely reported. We report a case of severe hyperuricemia and urate nephropathy in a liver transplant recipient with recurrent hepatitis C, which required discontinuation of therapy, rasburicase, and hemo-dialysis.

Case Report: A 64-year-old female liver transplant recipient was begun on treatment of fibrosis cholestatic hepatitis with pegylated-interferon-α2a and ribavirin therapy. She received a one-time dose of pegylated-interferon-α2a 135 mcg subcutaneously, and ribavirin was initiated. Within 24 hours of treatment initiation, she developed an acute kidney injury with serum creatinine increased from a baseline 132.6 μmol/L (1.5 mg/dL) to 459.7 μmol/L (5.2 mg/dL) within 72 hours. Ultrasound and computed tomography of the kidneys were normal with no stones and urinalysis showed no crystals. Her ribavirin dosage was adjusted based on her changing renal function. Within 72 hours after treatment initiation, her serum uric acid level was 1392 μmol/L (23.4 mg/dL), for which she received rasburicase 3 mg intravenously. Ribavirin was discontinued at this time. The next day, her serum uric acid level and remained elevated at 1166 μmol/L (19.6 mg/dL) and she received a second dose of rasburicase 7.5 mg and hemodialysis. Her serum uric acid level decreased to 131 μmol/L (2.2 mg/dL) and remained within normal limits; however, she continued to require intermittent hemodialysis until she died from complications of sepsis 38 days after admission. After discontinuation, she was not rechallenged with pegylated-interferon-α2a /and ribavirin.

Conclusions: A liver transplant recipient with recurrent hepatitis C developed severe hyperuricemia and urate nephropathy shortly after receiving pegylated-interferon-α2a and ribavirin therapy. The patient’s hyperuricemia was managed with rasbu-ricase and hemodialysis. This rare but potentially serious adverse reaction can limit the use of these agents in patients with recurrence of life threatening hepatitis C after liver transplant.

Key words : Uric acid, Hepatitis C, Fibrosing cholestatic hepatitis

Hepatitis C virus (HCV) is a leading cause of end-stage liver disease and an indication for orthotopic liver transplants worldwide.¹ Hepatitis C virus recurrence is universal after transplant and recurrent cirrhosis is associated with poor graft outcomes and death.¹

Liver biopsy is the established criterion standard for diagnosing HCV recurrence; however, the ideal treatment for HCV recurrence in transplant recipients has not been elucidated. Combination antiviral therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV), with or without novel direct-acting antivirals, has been used with the goal of viral eradication to prevent hepatitis, cirrhosis, and hepatocellular carcinoma. Combination therapy with PEG-IFN/RBV is more effective than PEG-IFN monotherapy, but a sustained viral response is achieved in only 30% to 50% of cases after transplant.² The addition of telaprevir or boceprevir to PEG-IFN/RBV has demonstrated viral suppression in 67% and 45% of patients at 24 weeks.³

Despite the potential benefit of PEG-IFN/RBV treatment, poor tolerability remains a concern. Adverse effects of the combination therapy include anemia, neuropsychiatric effects, fatigue, and hyperuricemia.^2,4 Hyperuricemia associated with PEG-IFN/RBV occurs in up to 24% of patients.⁴ A transient, dose-dependent hemolytic anemia is a known adverse effect of RBV, which typically increases uric acid levels by 10%.⁴ Although the mechanism of PEG-IFN/RBV-associated hyperuricemia is not completely understood, it is theorized that phosphatized RBV accumulates in erythrocytes, which inhibits inosine-5’-monophosphate dehydrogenase and ATP, causing hemolysis and uric acid production, with IFN possibly worsening underlying factors, which induce hyperuricemia.⁴

We report the first case of severe hyperuricemia after treatment with PEG-IFN/RBV in a liver transplant recipient with HCV precipitating urate nephropathy requiring treatment with hemodialysis and rasburicase.

A 64-year-old white female orthotopic liver transplant recipient presented 3 months posttransplant with jaundice, scleral icterus, an increase in total bilirubin from 10.3 μmol/L (0.6 mg/dL) to 130 μmol/L (7.6 mg/dL), HCV RNA > 69 million IU/mL, and creatinine of 83.9 μmol/L (1.1 mg/dL). Ultrasound of the liver was normal with no thrombus and a small amount of ascites. Liver biopsy revealed early fibrosing cholestatic hepatitis with no rejection. Current medications included amlodipine, metoprolol, esomeprazole, sulfamethoxazole/trimethoprim, val-ganciclovir, magnesium oxide, prednisone, mycophenolate mofetil, and tacrolimus. Prednisone and mycophenolate were discontinued upon admission and combination PEG-IFN/RBV HCV therapy was planned. If this combination was well tolerated, telaprevir was scheduled to begin the following day with tacrolimus held and redosed while on telaprevir.

On day 3 of admission, the patient received IFN-α2a 135 mcg subcutaneously (PEGASYS; Hoffman-La Roche Inc., Nutley, NJ, USA) and RBV 200 mg orally twice daily (Sandoz Inc., Princeton, NJ, USA). On day 4, the patient developed acute kidney injury. Her creatinine steadily increased, peaking at 396.5 μmol/L (5.2 mg/dL) on day 7 (Figure 1). On days 5 and 6, because of declining renal function she received a reduced dose of RBV (200 mg orally once daily) and treatment was discontinued after day 6. Tacrolimus levels were within the therapeutic range and no nephrotoxic drugs were given. Ultrasound and noncontrast computed tomography of the kidneys were normal showing no stones (Figures 2A and 2B). Urinalysis revealed no crystals.

On day 6, the patient’s serum uric acid level was 1225 μmol/L (20.6 mg/dL), repeated and reported as 1392 μmol/L (23.4 mg/dL) (Figure 1). Rasburicase (Sanofi Inc., Bridgewater, NJ, USA) 3 mg was given intravenously. On day 7, the uric acid level decreased to 1166 μmol/L (19.6 mg/dL) and a second intravenous dose of rasburicase (7.5 mg) was administered. At this time, the patient’s hyperkalemia was refractory to medical therapy necessitating hemodialysis. After a second hemodialysis treatment on day 8, her uric acid level decreased to 131 μmol/L (2.2 mg/dL) and remained within normal limits for the remainder of her hospital stay; however, she continued to require intermittent hemodialysis. Of note, the patient developed urosepsis from Enterococcus faecium on day 6, which was treated with intravenous vancomycin. Her white blood count was 3800 cells/mm3 at that time. On day 9 the patient was leukopenic with an absolute neutrophil count of 840 cells/mm3, which declined to a nadir of 648 cells/mm3 on day 11. Her neutrophil count recovered by day 14 after 4 doses of granulocyte colony stimulating factor. Additionally, she developed Clostridium difficile-associated diarrhea on day 18, which was treated with oral vancomycin. At 38 days after admission, the patient died at the hospice with complications from sepsis, refusing further therapy.

Serum uric acid levels are affected by the rate of purine synthesis, certain diseases, diet, and medication. Increased uric acid production can result from leukemias, lymphomas, solid-organ tumors treated with chemotherapeutic agents, radiation therapies, tumor lysis syndrome, and hemolytic anemias.^5,6 Elevated levels of uric acid may be seen in gout and nephrolithiasis.⁵ Hyperuricemia may be exacerbated by hypovolemia with or without renal failure and diuretic use. Intake of purines, including meats, seafood, sorbitol, sucrose, lactate, methyl-xanthines, and beer, also increases uric acid levels.⁵ Drugs known to cause hyperuricemia include cyclosporine, ethambutol, pyrazinamide, and aspirin.⁵ Cyclosporine, which increases proximal tubule absorption, decreases secretion of uric acid from the renal tubules and caused hyperuricemia in 30% to 85% of transplant recipients.⁵ Tacrolimus also has been implicated.⁷

Elevated uric acid levels are associated with metabolic syndrome, glucose intolerance, dyslipi-demia, hypertension, and kidney disease.⁵ Untreated elevated serum uric acid levels can result in nephrolithiasis and crystallization of uric acid in the renal tubules leading to a spectrum of kidney complications from mild acute kidney injury to severe renal dysfunction requiring dialysis. Hyperuricemia is also a risk factor for steatosis, nonalcoholic fatty liver disease, liver disease progression, and poorly sustained HCV response to PEG-IFN/RBV.⁸

Uric acid production starts with the purine bases adenine and guanine produced in the metabolism of nucleic acids, which creates hypoxanthine and subsequently forms xanthine via xanthine oxidase.⁶ Xanthine oxidase breaks down xanthine to uric acid. Approximately 30% of uric acid is eliminated from the body via the biliary and gastrointestinal tract with the remaining 70% excreted by the kidneys.⁶ High serum uric acid levels causing renal failure may not precipitate crystals in the urine, and renal failure can decrease excretion of uric acid leading to hyperuricemia.⁶

Treatment modalities focus on blocking further production, breaking down excess, and clearing high levels of uric acid from the body. Rasburicase, a recombinant urate oxidase enzyme, breaks down uric acid to allantoin, which is highly soluble and easily excreted in the urine.⁹ Adverse events of rasburicase are rash, fever, nausea, vomiting, constipation, abdominal pain, anaphylaxis, methemoglobinemia, hemolysis, and sepsis.⁹ Rasburicase is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency. It does not interact with the cytochrome P450 system or tacrolimus or cyclosporine metabolism.⁹ Allopurinol prevents further formation of uric acid via inactivation of xanthine oxidase but does not dissolve existing uric acid and is contraindicated in patients on azathioprine.⁵ Hemodialysis, another treatment modality for the removal of serum uric acid, can remove approximately 1 gram of uric acid per session with high flux dialyzers.¹⁰

To date, there has only been one case report of uric acid nephrolithiasis after liver transplant and one case of multiple uric acid stones after combination HCV therapy in a nontransplant patient.^4,7 Hwang and Goldfarb in 2004 reported a liver transplant recipient diagnosed with a 3-mm uric acid stone, uric acid 303 μmol/L (5.1 mg/dL), and serum creatinine 150.3 μmol/L (1.7 mg/dL) who was on tacrolimus immunosuppression 1 year after transplant.⁷ The patient was treated with potassium citrate and the stone passed spontaneously with no recurrence. In 2001, Fontana reported multiple uric acid nephrolithiasis in a nontransplant HCV patient receiving PEG-IFN/RBV therapy with a peak serum uric acid level of 571 μmol/L (9.6 mg/dL), the result of hemolytic anemia secondary to RBV which was discontinued.⁴ Therapy with PEG-IFN was continued for 12 months and HCV RNA became undetectable and hyperuricemia and nephrolithiasis resolved.

Our patient developed severe hyperuricemia and acute urate nephropathy shortly after administration of PEG-IFN-α2a and RBV. Using a validated adverse reaction probability scale, it is "probable" that our patient’s hyperuricemia was induced by RBV.¹¹ However, tacrolimus, combination PEG-IFN, and renal failure also contributed to high serum uric acid. Our patient’s hyperuricemia was rapidly corrected with hemodialysis, rasburicase, and discontinuation of RBV.

Despite the recent approval of novel antiviral agents, and the pending approval of several more, ribavirin may still be included in modern treatment regimens for recurrent HCV infections after liver transplant. Sofosbuvir and ribavirin combination with or without interferon has been used successfully in cases of fibrosing cholestatic hepatitis C after transplant.^12-14 An interferon and ribavirin-free regimen using a combination of sofosbuvir and daclatasvir also has been used at least in one case.¹⁵ However, at the time this manuscript was accepted, guidelines continue to include ribabivirin in regimens for the treatment of HCV recurrence after liver transplantation (www.hcvguidelines.org).

We present a case of PEG-IFN-α2a and RBV-induced hyperuricemia with urate nephropathy necessitating hemodialysis and rasburicase treatment in a patient with HCV recurrence postliver transplant. While optimal management of HCV recurrence in liver transplant recipients is not well established, antiviral therapy with PEG-IFN/RBV, with or without novel direct-acting antivirals, may be attempted. Clinicians caring for such patients should be aware of the possibility of hyperuricemia and urate nephropathy associated with PEG-IFN/RBV use.

Volume: 13 Issue: 6 December 2015

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