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Published ahead of print on November 19, 2008
J Am Soc Nephrol 19: 2248-2250, 2008
© 2008 American Society of Nephrology
doi: 10.1681/ASN.2008101051
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Editorials

Occult Hepatitis C Virus Infection in Hemodialysis

Fabrizio Fabrizi*,{dagger} and Paul Martin{dagger}

* Division of Nephrology and Dialysis, Maggiore Hospital, Istituto Ricerca e Cura a Carattere Scientifico Foundation, Milano, Italy; and {dagger} Center for Liver Diseases, School of Medicine, University of Miami, Miami, Florida

Correspondence: Dr. Fabrizio Fabrizi, Divisione Nefrologica, Ospedale Maggiore, Pad. Croff, Via Commenda 15, 20122, Milano, Italy. Phone: 39-2-55034553; Fax: 39-2-55034550; E-mail: fabrizi{at}policlinico.mi.it


   Introduction
Top
 Introduction
DISCLOSURES
 REFERENCES
 
Nosocomial transmission in dialysis units maintains a higher prevalence of hepatitis C virus (HCV) infection in patients on maintenance dialysis than in the general population.1,2 HCV infection has a detrimental effect on survival in patients on maintenance dialysis3 and after renal transplantation. In a recent meta-analysis of observational studies,3 incorporating 11,589 unique patients on maintenance dialysis, the summary estimate for adjusted relative risk for all-cause mortality was 1.34 (95% confidence interval 1.13 to 1.59). The excess risk for death in HCV-positive patients was partially attributed to chronic liver disease with its attendant complications, particularly hepatocellular carcinoma and liver cirrhosis.

Routine serologic testing for anti-HCV antibody (twice a year) and periodic testing for alanine aminotransferase and {gamma}-glutamyl transpeptidase were suggested for detection of transmission of HCV within hemodialysis (HD) units.4 In the presence of elevated levels of liver enzymes, dialysis patients are usually tested for the major hepatitis viruses (hepatitis B virus [HBV] and HCV) with the differential diagnosis in this population including drugs hepatotoxicity, steatohepatitis, iron overload from repeated blood transfusions with ineffective erythropoiesis, and congestive heart failure. Three percent of patients on maintenance dialysis have elevated liver enzymes with unclear cause.5

A newly described entity that needs to be considered in this circumstance is so-called "occult HCV infection," which refers to detection of HCV viremia (HCV RNA) in hepatocytes or peripheral blood mononuclear cells in the absence in serum of conventional serologic or virologic evidence of infection. Support for existence of this entity comes from the observation that HCV, although a hepatotropic virus, also can replicate at extrahepatic sites, including peripheral blood mononuclear cells.6 One report7 described occult HCV infection in patients with intact renal function and chronic liver disease of unknown cause, 57% of whom had HCV RNA in their liver.

Information about occult HCV infection in patients on maintenance dialysis is limited.8–10 Barril et al.9 in this issue of JASN detected genomic HCV RNA in the PBMC from 45% (49 of 109) of long-term HD patients who had unexplained abnormalities in liver chemistries and were repeatedly anti-HCV antibody and serum HCV RNA negative. Antigenomic HCV RNA was found in 26 (53%) of 49 patients detected by strand-specific real-time PCR. These patients were followed up for a mean of 23.8 ± 24.5 mo; mortality was significantly and independently associated with age and occult HCV infection (odds ratio 3.84; 95% confidence interval 1.29 to 11.43; P = 0.015), according to their logistic regression model.

This is the first description of the epidemiology and potential significance of occult HCV infection in patients on maintenance HD; however, there are some caveats, including the relatively small number of patients studied and the seemingly striking association between occult HCV and mortality in these dialysis patients. This link between occult HCV and mortality (odds ratio 3.84) was much stronger than that observed between "classic" hepatitis C and survival in dialysis populations (adjusted relative risk 1.34).3 It is difficult to explain these conflicting results, because a comparative study11 of nonuremic patients suggested occult HCV is a mild disease with less liver damage than "classic" chronic hepatitis C, and the percentage of HCV-infected hepatocytes seems significantly lower in patients with "occult" HCV. No liver biopsy information on occult HCV in dialysis patients was provided. Furthermore, occult HCV infection in dialysis patients has been studied only in patients with biochemical signs of liver disease of unknown cause, but it needs to be established in HD populations without biochemical dysfunction, which is often absent in HD populations. Typical HCV-related liver disease in patients with uremia is characterized by spuriously low aminotransferases even in the presence of active infection. Other authors have reported occult HCV infection after spontaneous12 or treatment-induced13 clearance of serum HCV RNA.

The clinical consequences of occult HCV infection include the risk for HCV transmission from patients with occult HCV within HD units. Although from a theoretical point of view we cannot exclude nosocomial spread of occult HCV among HD patients, the low incidence of de novo HCV in patients undergoing maintenance HD in the developed world is due to screening of blood donors for anti-HCV antibody and the implementation of infection control precautions. A Belgian multicenter study showed a seroconversion reduction from 1.4 to 0.0% in annual incidence of anti-HCV antibody by full implementation of infection control procedures to prevent transmission of blood-borne pathogens, including HCV.14 If occult HCV infection does transmit HCV within dialysis units, then it seems that current measures to control spread of HCV, although they do not incorporate routine PCR or nucleic acid technology, should be adequate; however, given previous experience with transmission of HBV infection in renal transplant recipients from donors with HBV serologies indicative only of previous infection, more information is needed about occult HCV in this setting. HBV is transmitted from hepatitis B surface antigen–negative/anti–hepatitis B core antigen antibody–positive kidney donors with the incidence of de novo hepatitis B antigen seropositivity after renal transplantation ranging between 0.0 and 5.2%.15 Further information is needed to define the risk, if any, for HCV transmission from donors with occult HCV to uninfected recipients. Another theoretical concern is reactivation of HCV after renal transplantation in recipients with occult HCV because immunosuppressive therapy enhances HCV replication in organ transplant recipients.

In conclusion, preliminary data suggest a high frequency of occult HCV infection in dialysis patients with elevated liver enzymes who are anti-HCV antibody and HCV RNA negative. Further studies are needed to assess the clinical consequences of occult HCV infection in dialysis patients and renal transplant recipients.


   DISCLOSURES
Top
 Introduction
 DISCLOSURES
REFERENCES
 
None.


   Acknowledgments
 
This work was supported in part by the grant "Project Glomerulonephritis" in memory of Pippo Neglia.


   Footnotes
 
Published online ahead of print. Publication date available at www.jasn.org.

See related article, "Occult Hepatitis C Virus Infection among Hemodialysis Patients," on pages 2288–2292.


   REFERENCES
Top
 Introduction
 DISCLOSURES
 REFERENCES
 

  1. Fabrizi F, Lunghi G, Ganeshan V, Martin P, Messa P: Hepatitis C virus infection and the dialysis patient. Semin Dial 20 : 416 –422, 2007[CrossRef][Medline]
  2. Finelli L, Miller JT, Tokars JI, Alter MJ, Arduino MJ: National surveillance of dialysis-associated diseases in the United States, 2002. Semin Dial 18 : 52 –61, 2005[CrossRef][Medline]
  3. Fabrizi F, Takkouche B, Lunghi G, Dixit V, Messa P, Martin P: The impact of hepatitis C virus infection on survival in dialysis patients: Meta-analysis of observational studies. J Viral Hepat 14 : 697 –703, 2007[Medline]
  4. Centers for Disease Control and Prevention: Recommendations for preventing transmission of infections among chronic haemodialysis patients. MMWR Recomm Rep 50 : 1 –43, 2001[Medline]
  5. Kidney Disease: Improving Global Outcomes. KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of Hepatitis C in chronic kidney disease. Kidney Int 73 [Suppl 109]: S1 –S99, 2008
  6. Blackhard JT, Kemmer N, Sherman KE: Extrahepatic replication of HCV: Insights into clinical manifestations and biological consequences. Hepatology 44 : 15 –22, 2006[CrossRef][Medline]
  7. Castillo I, Pardo M, Bartolomè J, Ortiz-Movilla N, Rodriguez-Inigo E, De Lucas S, Salas C, Jimenez-Heffernan JA, Prez-Mota A, Graus J, Lopez-Alcorocho JM, Carreno V: Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver function tests is unknown. J Infect Dis 189 : 7 –14, 2004[Medline]
  8. Oesterreicher C, Hammer J, Koch U, Pfeffel F, Sunder-Plassmann G, Petermann D, Muller C: HBV and HCV genome in peripheral blood mononuclear cells in patients undergoing chronic hemodialysis. Kidney Int 48 : 1967 –1971, 1995[Medline]
  9. Barril G, Castillo I, Arenas MD, Espinosa M, Garcia-Valdecasas J, Garcia-Fernández N, González-Parra E, Alcazar JM, Sánchez C, Diez-Baylón JC, Martinez P, Bartolomé J, Carreño V: Occult hepatitis C virus infection among hemodialysis patients. J Am Soc Nephrol 19 : 2288 –2292, 2008[Abstract/Free Full Text]
  10. Thongsawat S, Maneekarn N, Kuniholm MH, Pantip C, Thungsuputi A, Lumlertkul D, Bannachak D, Nelson KE: Occult hepatitis C virus infection during an outbreak in a hemodialysis unit in Thailand. J Med Virol 80 : 808 –815, 2008[CrossRef][Medline]
  11. Pardo M, Lopez-Alcorocho JM, Rodriguez-Inigo E, Castillo I, Carreno V: Comparative study between occult hepatitis C virus infection and chronic hepatitis C. J Viral Hepat 14 : 36 –40, 2007[CrossRef][Medline]
  12. Pham TN, MacParland SA, Mulrooney PM, Cooksley H, Naoumov NV, Michalak TI: Hepatitis C virus persistence after spontaneous or treatment induced resolution of hepatitis C. J Virol 78 : 5867 –5874, 2004[Abstract/Free Full Text]
  13. Radkowski M, Gallegos-Orozco JF, Jablonska J, Colby TV, Walewska-Zielecka B, Kubicka J, Wilkinson J, Adair D, Rakela J, Laskus T: Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology 41 : 106 –114, 2005[CrossRef][Medline]
  14. Jadoul M, Cornu C, van Ypersele de Strihou C: Universal precautions prevent hepatitis C virus transmission: A 54 month follow-up of the Belgian Multicenter Study. The Universitaires Cliniques St-Luc (UCL) Collaborative Group. Kidney Int 53 : 1022 –1025, 1998[CrossRef][Medline]
  15. Fabrizi F, Bunnapradist S, Martin P: Transplanting kidneys from donors with prior hepatitis B infection: One response to the organ shortage. J Nephrol 15 : 605 –613, 2002[Medline]

Related Article

Occult Hepatitis C Virus Infection among Hemodialysis Patients
Guillermina Barril, Inmaculada Castillo, María Dolores Arenas, Mario Espinosa, Juan Garcia-Valdecasas, Nuria Garcia-Fernández, Emilio González-Parra, José María Alcazar, Carmen Sánchez, José Carlos Diez-Baylón, Pilar Martinez, Javier Bartolomé, and Vicente Carreño
J. Am. Soc. Nephrol. 2008 19: 2288-2292. [Abstract] [Full Text] [PDF]




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