**4. Clinical outcome with impact of HCV status before transplantation, and use of allografts from HCV positive donors**

HCV has multiple distinct variants that are classified into six major types based on the viral genome sequence analysis. Each type consists of subtypes named in order of discovery such as a,b, c and so on, the subtypes may include individual isolates. Repeated infection or superinfection may occur in the same patient by the same or a different strain as HCV does not provide immunity. Thus transplant recipients that are positive for HCV RNA may have the viral genotype of the donor, same genotype as present pretransplant or both individual genotypes. The impact of superinfection is not clear, however there is some evidence that HCV infection by one or multiple strains does not impact the survival negatively, at least in the short term (Natov et al., 1999; Natov & Periera, 2012; Ali et al., 1998).

The use of renal allografts from HCV positive donors to be transplanted in HCV infected recipients may offer some advantage (Figure 3) (Abbott et al., 2003). This approach is consistent with 2008 Kidney Disease: Improving Global Outcomes (KDIGO) Guideline recommendations (KDIGO, 2008). A survey was performed in United States on 245 transplant centers with response obtained from 147 centers. The data showed that 49% of these centers use HCV seropositive donors (Batiuk et al., 2002). Patients who are HCV positive before transplant have a significantly higher risk of developing posttransplant liver disease, mainly chronic hepatitis and its sequelae. An unusual serious form of liver involvement termed fibrosing cholestatic hepatitis has been reported in such patients. it is characterized by severe cholestasis, extensive fibrosis, and rapidly progressive liver failure, and is most likely related to acute infection under maximum immunosuppression (Toth et al., 1998; Delladetsima et al., 2006). Kidney transplant in HCV positive patients is associated with a 1.8-30.3 fold increase in serum viral titer most likely due to increased viral proliferation secondary to immunosuppressive therapy. However, this increase in viral titer may not be associated with increased risk of posttransplant liver disease, neither does it have any association with transaminase pattern or histologic severity of liver injury (Natov & Periera, 2012; Periera et al., 1995; Rpth et al., 1996).

**Figure 4.** Kaplan-Meier plot of patient survival after renal transplantation, limited to patients who received a kidney positive for hepatitis C (DHCV+; n = 873) stratified by recipients who received mycophenolate mofetil (MMF) or those who did not (no MMF). Reprinted from J Am Soc Nephol, 14, 2908-2918 (2003), Abbott K et al., Hepatitis C and Renal Transplantation in the Era of Modern Immunosuppression. With permission through Copyright Clearance Center

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Although there is solid data that shows increased risk of developing liver disease in HCV positive patients, there are conflicting reports and data regarding impact on survival. Some studies failed to show any difference in overall survival in transplant recipients that were HCV positive or negative. Other studies of pretransplant HCV positive recipients reported increased mortality rate mainly due to liver disease and sepsis with a 3.3 fold increased risk of death and 9.9 fold higher risk of mortality due to sepsis (Natov & Periera, 2012; Periera et al., 1995; Legendre et al., 1998). A 2005 meta-analysis on eight clinical trials involving a cohort of 6365 patients showed an increased relative risk of death in HCV positive patients (1.79) mainly due to liver cirrhosis and cancer. In addition the relative risk of allograft failure was 1.56 (Fabrizi

Studies conducted in the 80s and 90s showed 35% of recipients who received allografts from HCV positive donors developed posttransplant liver disease, 50% became anti HCV positive after transplant, and 73% developed HCV viremia (Natov, 2002; Periera et al., 1994). The wide variation in the rate of transmission could be related to different prevalence among donors, difference in organ preservation and failure to test recipients in some centers. A large registry analysis in 2002 showed increased mortality in recipients of allografts from HCV positive donors regardless of the HCV status of the recipient (Bucci et al., 2002). Using the data from the Organ Procurement and Transplantation Network (OPTN), Maluf reported approximately 300 days shortening of wait time for HCV positive recipients receiving allografts from HCV positive donors compared with HCV negative recipients however there was significantly decreased graft and patient overall survival (Maluf et al., 2010). A larger analysis of the same data from OPTN was performed recently by Northup and colleagues in 2010 that included 19496 HCV positive recipients and 934 HCV positive donors. It showed the adjusted hazard ratio for death to be similar for HCV positive recipients of HCV positive donors and HCV positive recipients of HCV negative donors. The worst survival was seen in HCV negative

recipients who received allografts from HCV positive donors (Northup et al., 2010).

et al., 2005).

**Figure 3.** Kaplan-Meier plot of patient survival after renal transplantation, limited to patients who received a kidney positive for hepatitis C (DHCV+; n = 873) stratified by recipients who were HCV+ and HCV−. Reprinted from J Am Soc Nephol, 14, 2908-2918 (2003), Abbott K et al., Hepatitis C and Renal Transplantation in the Era of Modern Immuno‐ suppression. With permission through Copyright Clearance Center

Mycophenolate mofetil and antithymocyte globulin are reported to increase HCV viremia while cyclosporine was found to have a suppressive effect on HCV replicon RNA level and HCV protein expression in cultured human hepatocytes (Figure 4)(Abbott et al., 2003; Rostaing et al., 2000; Geith, 2011; Misiani et al., 1994).

not provide immunity. Thus transplant recipients that are positive for HCV RNA may have the viral genotype of the donor, same genotype as present pretransplant or both individual genotypes. The impact of superinfection is not clear, however there is some evidence that HCV infection by one or multiple strains does not impact the survival negatively, at least in the short

The use of renal allografts from HCV positive donors to be transplanted in HCV infected recipients may offer some advantage (Figure 3) (Abbott et al., 2003). This approach is consistent with 2008 Kidney Disease: Improving Global Outcomes (KDIGO) Guideline recommendations (KDIGO, 2008). A survey was performed in United States on 245 transplant centers with response obtained from 147 centers. The data showed that 49% of these centers use HCV seropositive donors (Batiuk et al., 2002). Patients who are HCV positive before transplant have a significantly higher risk of developing posttransplant liver disease, mainly chronic hepatitis and its sequelae. An unusual serious form of liver involvement termed fibrosing cholestatic hepatitis has been reported in such patients. it is characterized by severe cholestasis, extensive fibrosis, and rapidly progressive liver failure, and is most likely related to acute infection under maximum immunosuppression (Toth et al., 1998; Delladetsima et al., 2006). Kidney transplant in HCV positive patients is associated with a 1.8-30.3 fold increase in serum viral titer most likely due to increased viral proliferation secondary to immunosuppressive therapy. However, this increase in viral titer may not be associated with increased risk of posttransplant liver disease, neither does it have any association with transaminase pattern or histologic severity

term (Natov et al., 1999; Natov & Periera, 2012; Ali et al., 1998).

238 Current Issues and Future Direction in Kidney Transplantation

of liver injury (Natov & Periera, 2012; Periera et al., 1995; Rpth et al., 1996).

**Figure 3.** Kaplan-Meier plot of patient survival after renal transplantation, limited to patients who received a kidney positive for hepatitis C (DHCV+; n = 873) stratified by recipients who were HCV+ and HCV−. Reprinted from J Am Soc Nephol, 14, 2908-2918 (2003), Abbott K et al., Hepatitis C and Renal Transplantation in the Era of Modern Immuno‐

Mycophenolate mofetil and antithymocyte globulin are reported to increase HCV viremia while cyclosporine was found to have a suppressive effect on HCV replicon RNA level and HCV protein expression in cultured human hepatocytes (Figure 4)(Abbott et al., 2003; Rostaing

suppression. With permission through Copyright Clearance Center

et al., 2000; Geith, 2011; Misiani et al., 1994).

**Figure 4.** Kaplan-Meier plot of patient survival after renal transplantation, limited to patients who received a kidney positive for hepatitis C (DHCV+; n = 873) stratified by recipients who received mycophenolate mofetil (MMF) or those who did not (no MMF). Reprinted from J Am Soc Nephol, 14, 2908-2918 (2003), Abbott K et al., Hepatitis C and Renal Transplantation in the Era of Modern Immunosuppression. With permission through Copyright Clearance Center

Although there is solid data that shows increased risk of developing liver disease in HCV positive patients, there are conflicting reports and data regarding impact on survival. Some studies failed to show any difference in overall survival in transplant recipients that were HCV positive or negative. Other studies of pretransplant HCV positive recipients reported increased mortality rate mainly due to liver disease and sepsis with a 3.3 fold increased risk of death and 9.9 fold higher risk of mortality due to sepsis (Natov & Periera, 2012; Periera et al., 1995; Legendre et al., 1998). A 2005 meta-analysis on eight clinical trials involving a cohort of 6365 patients showed an increased relative risk of death in HCV positive patients (1.79) mainly due to liver cirrhosis and cancer. In addition the relative risk of allograft failure was 1.56 (Fabrizi et al., 2005).

Studies conducted in the 80s and 90s showed 35% of recipients who received allografts from HCV positive donors developed posttransplant liver disease, 50% became anti HCV positive after transplant, and 73% developed HCV viremia (Natov, 2002; Periera et al., 1994). The wide variation in the rate of transmission could be related to different prevalence among donors, difference in organ preservation and failure to test recipients in some centers. A large registry analysis in 2002 showed increased mortality in recipients of allografts from HCV positive donors regardless of the HCV status of the recipient (Bucci et al., 2002). Using the data from the Organ Procurement and Transplantation Network (OPTN), Maluf reported approximately 300 days shortening of wait time for HCV positive recipients receiving allografts from HCV positive donors compared with HCV negative recipients however there was significantly decreased graft and patient overall survival (Maluf et al., 2010). A larger analysis of the same data from OPTN was performed recently by Northup and colleagues in 2010 that included 19496 HCV positive recipients and 934 HCV positive donors. It showed the adjusted hazard ratio for death to be similar for HCV positive recipients of HCV positive donors and HCV positive recipients of HCV negative donors. The worst survival was seen in HCV negative recipients who received allografts from HCV positive donors (Northup et al., 2010).

In regards to superinfection, HCV genotype 1 is the most common genotype of HCV seen in Western countries and is notorious to be less responsive to antiviral therapy including Pegylated IFN and Ribavirin. Some authorities suggest that genotyping should be done routinely and genotype 1 renal allografts should not be used in recipients with other genotypes. However data is limited regarding this strategy (Carbone et al., 2011).

2008 KDIGO guidelines recommend monotherapy with standard IFN only to be considered in HCV positive kidney transplant recipients (Terraut & Adey, 2007; Kim et al., 2011; Carbone et al., 2011; Natov & Periera, 2012. Data on efficacy of Ribavirin treatment alone after transplant is limited. Combination therapy is the most likely regimen to achieve a sustained virologic response (SVR), however Ribavirin dosage must be adjusted based on the renal function to

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Large scale, multicenter clinical trials are needed to determine the optimal treatment approach in these populations. New therapies may offer specific advantages and show decreased

In addition SVR to antiviral therapy in patients with HCV associated renal disease has been associated with improvement in renal histology with reduced inflammation and immune deposits. Recently, five HCV positive renal transplant patients who developed type III cryoglobulinemic MPGN were successfully treated by Rituximab (anti-CD 20) chimeric

Transplantation after adequate antiviral therapy followed by minimal immunosuppression can be a good option. Recently, Shah and colleagues evaluated graft function and graft as well as patient survival in retrospective analyses of 132 HCV-positive renal transplant patients who received tolerance induction protocol (TIP) with minimal immunosuppression and compared them with 79 controls transplanted using standard triple immunosuppression drugs. TIP consisted of 1 donor-specific transfusion, peripheral blood stem cell infusion, portal infusion of bone marrow, and target-specific irradiation. In the TIP group patient survival at 1, 5, and 10 years was 92.4%, 70.4%, and 63.7%, respectively, versus 75.6%, 71.7%, and 55.7% in the control group. The graft survival was 92.9%, 81.5%, and 79.1% versus 91.7%, 75.7%, and 67.7%, respectively. Rejection episodes were less frequent in the former group. Abnormal liver enzymes were seen in 22% patients in the TIP group versus 31% of the control group (Shah et

HCV infection is relatively common among patients with ESRD on dialysis and kidney transplant recipients. It is a major cause of morbidity and mortality among this group. When indicated, treatment with IFN and antiviral therapy should be commenced prior to kidney transplantation. The optimal treatment of transplant patients with HCV infection is not known. IFN is not recommended posttransplant because of potential risk of rejection. However there are some life threatening HCV related complications that would compel the use of IFN in a renal transplant recipient. In conclusion, Ribavirin is contraindicated in dialysis patients and alternative drugs are needed to enhance antiviral effects of IFN. For renal transplant recipients, Ribavirin can be used in combination with IFN in patients with restored renal function, however the risk of acute rejection with IFN therapy remains a serious concern. Alternative drugs are also needed with better safety and efficacy for treatment of HCV posttransplant. Despite the ongoing dilemma HCV positive renal transplant recipients have a better survival

incidence of treatment-related side effects than the currently available drugs.

minimize the complication of anemia.

monoclonal antibody (Basse et al., 2005, 2006).

al., 2011).

**6. Conclusion**
