**2. Natural history of HCV infection, morbidity and mortality in transplant**

HCV RNA can be detected in the blood after 1-3 weeks of first exposure. In majority of the HCV acute infection cases the patients are asymptomatic, however the disease can have a fulminant

© 2013 Amir et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

course. The natural history of Hepatitis C infection is quite variable with disease spectrum varyingfrommildtoseverehepatitis,hepaticcirrhosis,andhepatocellularcarcinoma.In60-85% ofthese cases,HCVRNAcanbedetectedfor6monthsorlonger.10-15%ofthese chronicpatients progress to develop liver cirrhosis (National Institute of Health [NIH], 2002). The virus is very slow to progress with almost no signs or symptoms in the first few years or decade. The most reliable tool to examine the progression of HCV liver damage is histologic evaluation of liver biopsy. The activity of liver disease can fluctuate, however, once there is fibrosis the damage is considered to be irreversible and progressive. Poynard, in 2001, reported that the average time of HCV infection to progress to liver cirrhosis is about 30 years, ranging from 13 years (for men who drank and were infected after the age of 40 years) to 42 years (for women who did not drink and were infected before the age of 40) (Poynard et al., 2001).

is significantly associated with improved survival as opposed to remaining on dialysis on transplant wait list (Abbott et al., 2004; Periera et al., 1998; Knoll et al., 1997; Maluf et al., 2007). Findings suggest that detrimental effect of transplantation in association with HCV infection does not outweigh its long term benefits on survival in end stage renal disease (ESRD) patients on dialysis and therefore anti-HCV positivity should not be considered as an absolute

Hepatitis C Infection in Kidney Transplantion

http://dx.doi.org/10.5772/55648

235

**Figure 1.** Kaplan-Meier estimate of the cumulative probability of patient survival. Reprinted from Transplantation Pro‐ ceedings, 38, 1890-1894 (2006), Pedroso S et al., Impact of Hepatitis C Virus on Renal Transplantation: Association

**Figure 2.** Kaplan-Meier estimate of the cumulative probability of graft survival.Reprinted from Transplantation Pro‐ ceedings, 38, 1890-1894 (2006), Pedroso S et al., Impact of Hepatitis C Virus on Renal Transplantation: Association

The increased morbidity and mortality in HCV infection is not only related to liver disease but also extrahepatic complications (Kidney disease: improving global outcome [KDIGO], 2008). HCV infection can predispose to the development of pre and posttransplant diabetes. A 2005 meta-analysis of 2502 patients noted a fourfold increase in the development of New Onset Diabetes mellitus after Transplantation (NODAT) among HCV infected patients when compared to the non-infected group (Gursoy et al., 2000; Abbott et al., 2004). It is suggested

with Poor Survival. With permission from Elsevier through Copyright Clearance Center

with Poor Survival. With permission from Elsevier through Copyright Clearance Center

contraindication for renal transplantation (Natov & Periera, 2012; Knoll et al, 1997).

HCV infection has been associated independently with increased mortality in Hemodialysis patients as shown by several studies including Dialysis Outcomes and Practice Patterns (DOPPS) conducted over three continents (Goodkin et al., 2003; Fibrizi, 2004, 2007).

Transplant recipients from HCV positive donors have a higher rate of fulminant or severe hepatitis and liver disease in general. The literature shows some controversy in results presented by various studies regarding survival. The overall survival and specifically of the allograft survival for HCV infected kidney transplant recipients are much worse than noninfected renal transplant recipients (Figures 1 & 2) (Pedroso et al., 2006). Several studies have shown that although recipients of organs from HCV infected donors have higher rates of liver disease, there is no solid evidence of decreased overall survival rate (Periera, 1991, 1995; Mendez et al., 1995). On the other hand, there are some other studies that show contrary results with recipients of organs from HCV infected donors to have significantly higher morbidity mainly due to liver disease and reduced overall survival with limited life expectancy (Pirsch et al., 1995). The presence of liver damage depending on the severity as determined by biopsy is a strong predictor of liver failure and death post-transplantation. Despite the ongoing controversy, majority of the data shows increased morbidity due to higher rate of liver disease. However, there is no consensus on lack of adverse effect on survival by initial studies that mostly represented comparatively small number of cases and short period of followup. Fabrizi and colleagues pooled these single studies in a meta-analysis and showed that anti HCV positive status is an independent and significant risk factor for death and graft failure after kidney transplantation with estimated relative risk of 1.79 and 1.56 respectively. In a recent study, Scott and colleagues also showed prevalence of HCV infection in renal transplant recipients to be 1.8% and reported the patient survival to be 77% and 90% at 5 years and 50% and 79% at 10 years for HCV antibody positive and HCV antibody negative groups. The most common causes of death in HCV positive kidney transplant recipients were cardiovascular disease, malignancy, and liver failure (Scott et al., 2010). In addition to increased mortality, Zylberberg et al found a significantly increased yearly progression rate of liver inflammation and fibrosis in HCV infected renal transplant recipients than immunocompetent group (Zylberberg et al., 2002). Alric and colleagues, on the contrary, showed the annual progression of liver fibrosis to be significantly lower in renal transplant recipients than patients with HCV and normal renal function (Alric et al., 2002). Reasons for the above mentioned difference is not clear. There is strong evidence that transplantation with kidney from HCV infected donor is significantly associated with improved survival as opposed to remaining on dialysis on transplant wait list (Abbott et al., 2004; Periera et al., 1998; Knoll et al., 1997; Maluf et al., 2007). Findings suggest that detrimental effect of transplantation in association with HCV infection does not outweigh its long term benefits on survival in end stage renal disease (ESRD) patients on dialysis and therefore anti-HCV positivity should not be considered as an absolute contraindication for renal transplantation (Natov & Periera, 2012; Knoll et al, 1997).

course. The natural history of Hepatitis C infection is quite variable with disease spectrum varyingfrommildtoseverehepatitis,hepaticcirrhosis,andhepatocellularcarcinoma.In60-85% ofthese cases,HCVRNAcanbedetectedfor6monthsorlonger.10-15%ofthese chronicpatients progress to develop liver cirrhosis (National Institute of Health [NIH], 2002). The virus is very slow to progress with almost no signs or symptoms in the first few years or decade. The most reliable tool to examine the progression of HCV liver damage is histologic evaluation of liver biopsy. The activity of liver disease can fluctuate, however, once there is fibrosis the damage is considered to be irreversible and progressive. Poynard, in 2001, reported that the average time of HCV infection to progress to liver cirrhosis is about 30 years, ranging from 13 years (for men who drank and were infected after the age of 40 years) to 42 years (for women who did not drink

HCV infection has been associated independently with increased mortality in Hemodialysis patients as shown by several studies including Dialysis Outcomes and Practice Patterns

Transplant recipients from HCV positive donors have a higher rate of fulminant or severe hepatitis and liver disease in general. The literature shows some controversy in results presented by various studies regarding survival. The overall survival and specifically of the allograft survival for HCV infected kidney transplant recipients are much worse than noninfected renal transplant recipients (Figures 1 & 2) (Pedroso et al., 2006). Several studies have shown that although recipients of organs from HCV infected donors have higher rates of liver disease, there is no solid evidence of decreased overall survival rate (Periera, 1991, 1995; Mendez et al., 1995). On the other hand, there are some other studies that show contrary results with recipients of organs from HCV infected donors to have significantly higher morbidity mainly due to liver disease and reduced overall survival with limited life expectancy (Pirsch et al., 1995). The presence of liver damage depending on the severity as determined by biopsy is a strong predictor of liver failure and death post-transplantation. Despite the ongoing controversy, majority of the data shows increased morbidity due to higher rate of liver disease. However, there is no consensus on lack of adverse effect on survival by initial studies that mostly represented comparatively small number of cases and short period of followup. Fabrizi and colleagues pooled these single studies in a meta-analysis and showed that anti HCV positive status is an independent and significant risk factor for death and graft failure after kidney transplantation with estimated relative risk of 1.79 and 1.56 respectively. In a recent study, Scott and colleagues also showed prevalence of HCV infection in renal transplant recipients to be 1.8% and reported the patient survival to be 77% and 90% at 5 years and 50% and 79% at 10 years for HCV antibody positive and HCV antibody negative groups. The most common causes of death in HCV positive kidney transplant recipients were cardiovascular disease, malignancy, and liver failure (Scott et al., 2010). In addition to increased mortality, Zylberberg et al found a significantly increased yearly progression rate of liver inflammation and fibrosis in HCV infected renal transplant recipients than immunocompetent group (Zylberberg et al., 2002). Alric and colleagues, on the contrary, showed the annual progression of liver fibrosis to be significantly lower in renal transplant recipients than patients with HCV and normal renal function (Alric et al., 2002). Reasons for the above mentioned difference is not clear. There is strong evidence that transplantation with kidney from HCV infected donor

(DOPPS) conducted over three continents (Goodkin et al., 2003; Fibrizi, 2004, 2007).

and were infected before the age of 40) (Poynard et al., 2001).

234 Current Issues and Future Direction in Kidney Transplantation

**Figure 1.** Kaplan-Meier estimate of the cumulative probability of patient survival. Reprinted from Transplantation Pro‐ ceedings, 38, 1890-1894 (2006), Pedroso S et al., Impact of Hepatitis C Virus on Renal Transplantation: Association with Poor Survival. With permission from Elsevier through Copyright Clearance Center

**Figure 2.** Kaplan-Meier estimate of the cumulative probability of graft survival.Reprinted from Transplantation Pro‐ ceedings, 38, 1890-1894 (2006), Pedroso S et al., Impact of Hepatitis C Virus on Renal Transplantation: Association with Poor Survival. With permission from Elsevier through Copyright Clearance Center

The increased morbidity and mortality in HCV infection is not only related to liver disease but also extrahepatic complications (Kidney disease: improving global outcome [KDIGO], 2008). HCV infection can predispose to the development of pre and posttransplant diabetes. A 2005 meta-analysis of 2502 patients noted a fourfold increase in the development of New Onset Diabetes mellitus after Transplantation (NODAT) among HCV infected patients when compared to the non-infected group (Gursoy et al., 2000; Abbott et al., 2004). It is suggested that HCV infection might be associated with increased insulin resistance contributing to development of NODAT.

potential organs for transplant (Natov & Periera, 2012). A large collaborative study was performed in United States that looked at the positive and negative predictive values of antibody screening tests. Eight organ procurement organizations representing different geographical regions studied 3078 cadaver organ donors. Using first generation enzyme linked immunosorbent assay ELISA1 anti-HCV test, the prevalence was found to be 5.1% (1.5-16.7%). Using the second generation ELISA2, the prevalence was 4.2%, with positive predictive value of 55% and negative predictive value of 100%. Some investigators have suggested the use of third generation ELISA3 tests to screen cadavers for HCV that be‐ cause of its improved specificity showed only 3.7% prevalence. On the other hand, the prevalence of HCV RNA (ribonuclease acid) detection by Polymerase chain reaction (PCR) was only 2.4%. Although discarding all ELISA2 positive organs would eliminate transmis‐ sion of HCV, there will be waste of 1.8% that will be discarded based on ELISA2 positivity while they are HCV RNA negative. However, it is currently not practical to test cadavers for HCV RNA status prior to organ procurement (Challine et al., 2004). The current practice in major centers is still to screen organ donors for antibodies against HCV. The serum amino‐ transferase levels are usually normal in uremic patients, and therefore are not considered reliable in determining disease activity and severity of fibrosis in this group. For clinically suspicious patients with elevated serum aminotransferase levels but negative antibody test, an HCV RNA assay with a detection limit of less than 50 IU/mL is recommended to rule out

Hepatitis C Infection in Kidney Transplantion

http://dx.doi.org/10.5772/55648

237

There is limited data on the impact of different HCV genotypes on survival after transplanta‐ tion. Data reported by New England Organ Bank had relatively small number of patients and

Liver biopsy remains the gold standard for assessment of liver damage and fibrosis. Several scoring systems are used for assessment of hepatic fibrosis that use various criteria such as activity index and special stains for collagen deposition. Examples of these scoring systems include hepatic activity index (HAI), Knodell score and the Matavir system. Patients with HCV infection can have evidence of histologic liver disease in the absence of elevated transaminases and abnormal liver function tests. Therefore there may be merit in performing liver biopsy on all anti-HCV positive patients on transplant wait list. In patients with histologic evidence of liver disease, the decision to proceed or not with transplantation should be made with extreme caution as post-transplant immunosuppression may exacerbate liver disease (Zylerberg et al.,

**4. Clinical outcome with impact of HCV status before transplantation, and**

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

HCV genotype distribution to reach a conclusion (Natov et al., 1999).

**use of allografts from HCV positive donors**

infection (Pawlotsky, 2002).

2002).

HCV has been associated with renal disease in both native and transplanted kidneys. It is in fact reported to be more associated with glomerular disease in renal transplants than native kidneys. This association is suggested to be secondary to immunosuppressive therapy leading to increased HCV RNA titres (Periera et al., 1995; Burstein & Rodby, 1993). In renal transplant recipients, HCV infection has been implicated in pathogenesis of acute glomerulopathy, de novo immune complex glomerulonephritis in allograft, and chronic allograft nephropathy (CAN) (Cosio et al., 1996; Roth et al., 1995; Ozdemir et al., 2006; Morales et al., 1997; Mahmoud et al., 2005). De novo membranoproliferative glomerulonephritis (MPGN), and de novo membranous glomerulonephritis (MGN), with or without mixed cryoglobulinemia are the most frequent glomerular patterns of injury seen in association with HCV infection in renal allografts. In 2001, one study reported the prevalence of de novo MPGN and MGN to be 45.4% and 18.2% in HCV positive transplant recipients as compared to 5.7% and 7.7% in HCV negative recipients (Cruzado et al., 2001). Subsequently, another study in 2006 reported the prevalence of de novo GN to be 34% in HCV infected recipients and only 6.6% in HCV negative recipients (Ozdemir et al., 2005). In general higher prevalence of autoimmune GN was associated with poor graft outcome, and even worse than de novo GN in HCV negative patients (Carbone et al., 2011).

Proteinuria is a common manifestation of kidney disease in HCV infected patients and renal biopsy is used to establish the diagnosis of glomerular injury, however currently it is impos‐ sible to determine HCV as the cause of glomerular damage based solely on morphologic assessment of renal biopsy. (Natov & Periera, 2012).

In 2005, Mahmoud et al reported a higher rate of CAN in HCV infected patients who did not receive interferon (IFN) therapy prior to renal transplant. Recent data also shows increased rate of graft failure due to CAN in HCV positive recipients than HCV negative (Scott et al., 2010). The Spanish Chronic Allograft Nephropathy Group analyzed 4304 renal transplant recipients with 587 of them being HCV positive over a period of 1990 to 2002. The study reported HCV infection to be associated with early proteinuria, lower renal function, de novo GN, chronic rejection, graft loss, and lower survival than HCV negative recipients (Morales et al., 2010). Another implication of HCV infection is its association with development of early graft dysfunction due to acute glomerular lesion. Examples of such lesions include acute transplant glomerulopathy, and de novo renal thrombotic microangiopathy (Cosio et al., 1996, Baid et al., 1995). Acute transplant glomerulopathy is mostly considered to be an atypical variant of acute cellular rejection and is also present more commonly in HCV positive recipients (Cosio et al., 1996a, 1996b).
