Hepatitis C virus (HCV) infection is a very common comorbidity among patients with end-stage renal disease (ESRD). HCV prevalence among hemodialysis patients has been reported to be between 10% and 60% (1). Of these patients, the incidence of cirrhosis has been reported to be as high as 22% (2). This becomes an issue when considering such patients for kidney transplantation (KTx). In addition, the number of HCV-infected patients with ESRD on the kidney transplant waiting list in the United States is growing (3). There are concerns that recipients with advanced fibrosis may suffer decompensation of their liver disease. The use of immunosuppression after transplantation may also cause progression of viral replication and liver disease (4).
Evaluating HCV-infected patients with ESRD is complicated by the fact that liver function tests and clinical findings may be nonspecific because of the renal disease (1, 5). True portal hypertension and extent of liver disease may be difficult to assess without invasive testing such as liver biopsies and portal pressure measurements. A close working relationship between hepatology, nephrology, and surgery is essential.
There is a belief that these patients may be better served with a simultaneous liver-kidney transplantation, especially among those who have advanced fibrosis. However, this is controversial and has significant implications on national liver allocation because this may be unnecessary and reduces the number of available livers. Because of the implementation of the model for end-stage liver disease (MELD) scoring system for liver transplants, the number of simultaneous liver-kidney transplantation has increased by 300% (6).
The purpose of this study was to review our experience with HCV-infected patients with ESRD evaluated for KTx and determine the relationship of cirrhosis of the liver to outcomes after KTx alone.
Of 90 referred patients, only 66 patients were listed for KTx alone. Fifteen patients showed significant medical comorbidities. Nine patients showed significant cardiovascular disease (5 with coronary artery disease, 2 with severe congestive heart failure, and 2 with cerebrovascular disease); One patient showed severe sleep apnea and pulmonary hypertension. Three patients showed cachexia and poor overall physical condition, and two others demonstrated uncontrolled psychiatric disorders. Nine patients demonstrated significant social/financial issues that precluded transplantation. Two patients showed active substance abuse, and seven had no insurance coverage for transplantation. One patient was found to have decompensated liver disease, which necessitated a simultaneous liver-kidney transplantation. Two patients were removed from the waiting list, one because of worsening of nonliver medical comorbidities (36 months after listing) and another because of financial/insurance issues (32 months after listing). Sixty-four patients were then reviewed for this study.
The most common cause of ESRD was hypertension (30 patients, 46.88%), followed by diabetes (DM) (20 patients, 31.25%)(Table 1). Laboratory values and clinical findings reported were from the time of listing. The most common HCV genotype was 1A (38 patients, 59.4%). Two patients were hepatitis B core antibody positive as well (both from patients with ESRD but with no cirrhosis [NC group]). Twelve patients (18.75%) showed biopsy-proven cirrhosis. Mean follow-up period (SD) since listing for transplant was 45 (24) months.
Differences between listed HCV+ patients with ESRD and cirrhosis (C group) and NC group patients are shown in Table 2. All patients in C group were men and mostly African American (75%). Among all covariates, only the hepatic portal venous gradient (HPVG) was found to be significantly different between the groups: 5.6 (2.4) versus 3.8 (2) for C group and NC group, respectively (P=0.011). Twelve patients were treated for HCV liver disease (4 from C and 8 from NC). Only three (1 from C and 2 from NC) had a successful treatment with sustained virologic clearance. The calculated MELD score was not different between the groups because they were only weighted for renal failure. The total bilirubin and international normalized ratio (INR) values were normal because all these patients presented with compensated liver disease. The mean total bilirubin values (SD) were 0.5 (0.1) versus 0.4 (0.2) (P=0.9) and the mean INR was 1 (0.2) versus 1 (0.1) (P=0.95), for C group and NC group, respectively.
Thirty-seven patients underwent KTx alone (9 from C and 28 from NC)(Table 2). All patients received deceased donor kidneys. Twenty-seven received United Network for Organ Sharing–defined standard criteria donor kidneys (7 from C and 20 from NC), and the remaining 10 received extended criteria donor kidneys. The mean time on the waiting list was 24.1 months versus 19.8 months for C group and NC group, respectively (P=0.30). Only one transplanted patient (from NC) experienced successful HCV treatment. Twelve patients received HCV+ donor kidneys (1 from C and 11 from NC). Mean duration of follow-up after transplantation was 32 (20) months. All other demographic features were not different between the groups among the transplanted patients.
Overall 1- and 3-year patient survival rates after transplantation were 94.4% and 85.8%, respectively. Number of patients at risk at time 0, 1, and 3 years was 9, 8, and 5 in the C group and 28, 27, and 15 in the NC group, respectively. Figure 1 shows Kaplan-Meier curves estimating 1- and 3-year patient survival rates between the groups: 88.9% and 88.9% versus 96.3% and 77.9% for C group and NC group, respectively (P=0.76). One patient from C group versus 4 patients from NC group died. The reasons for patient deaths were cardiac arrests in 3 patients (1 from C and 2 from NC), metastatic renal carcinoma of native kidneys (1 from NC), and metastatic hepatocellular carcinoma (HCC) (1 from NC). All 5 patients died with functioning grafts. No patients developed liver failure after transplantation.
Overall 1- and 3-year graft survival rates were 88.1% and 79.3%. Figure 2 shows Kaplan-Meier curves estimating 1- and 3-year graft survival rates between the groups: 75% and 75% versus 92.1% and 75% for C group and NC group, respectively (P=0.72). The reasons for graft failure were recurrent kidney disease in one patient, chronic allograft nephropathy in two patients, and death with functioning grafts in five patients.
Table 3 shows analyses of factors associated with graft and patient survival. Only increasing recipient age and decreasing albumin levels were significantly associated with decreased patient and graft survival. The presence of cirrhosis was not found to be a significant variable affecting either graft or patient survival.
KTx of HCV+ patients remains a challenge because, in addition to their renal failure, the patients liver disease must be taken into account. The transplant team needs a multidisciplinary approach in this regard. There is a controversy about possible decompensation of liver disease, progression of HCV viral loads with this immunosuppression, or development of HCV transplant glomerulopathy. Zylberberg et al. (7) showed severe evolution of HCV liver disease in kidney recipients. However, in a 10-year study following 51 kidney transplant recipients positive for HCV with serial liver biopsies, Kamar et al. (8) showed that HCV infection was not harmful on liver histology in at least 50% of patients. In addition, that study and another by Roth et al. (9) actually showed regression of liver fibrosis in some patients after KTx. Good survival rates have been demonstrated for these patients, especially if they have minimal or well-controlled liver disease.
The issue of these patients undergoing transplantation in the setting of cirrhosis is more controversial. Previous recommendations have suggested that KTx alone should not be performed in a patient with a liver biopsy demonstrating advanced fibrosis (10–12). However, Campbell et al. (13) showed in a retrospective study of 58 HCV+ kidney transplant recipients that posttransplant survival was similar between patients with minimal and advanced fibrosis of their liver. However, one of the limitations of that study was that only two patients demonstrated cirrhosis (stage IV fibrosis). We believe that ours is the largest single-center study to date looking at kidney transplant recipients with cirrhosis specifically.
In these situations, a simultaneous liver-kidney transplantation may be advocated. There is paucity of data to evaluate this, however. This may be an inappropriate use of a liver allograft. With a calculated MELD score weighted for patients with renal insufficiency, a patient on dialysis automatically receives a score of 21, despite all other liver parameters being normal. And in certain parts of this country, this may be enough to receive a liver allograft (14). Among our patients, the represented MELD scores were all dependant on the renal failure; the INR and total bilirubin levels were normal in both groups. The incidence of simultaneous liver-kidney transplantation among transplant centers in the United States ranges from 0% to 43.7% of all liver transplantations (6). Our study suggests that simultaneous liver-kidney transplantation in a patient with well-compensated cirrhosis and ESRD may be a waste of liver allocation.
Appropriately assessing the extent of portal hypertension is paramount. Clinical evaluation of this may be difficult in a patient with ESRD because they may also have similar sequelae including ascites, uremic mental status changes, gastrointestinal bleeding, and coagulopathy. The use of a transjugular approach is a good way to accurately measure real pressure gradients, and HPVG measurements greater than 10 mm Hg predicting clinical decompensation is a good reference for the evaluation of these patients (15). Thus, any patient with HPVG greater than 10 mm Hg was not listed for KTx alone. In addition, the liver biopsy may be performed at the same time.
HCV+ patients with ESRD have been demonstrated to have higher viral loads than patients with no ESRD (1). Studies have shown that success rates for transplant patients may be better if HCV+ patients have successful treatments with sustained viral responses (16, 17). Our protocol is to attempt treatment of HCV liver disease before transplantation when possible. However, response rates among patients with ESRD is worse than those of patients no ESRD, and ribavarin regimens may be contraindicated. In a prospective controlled trial, however, Kokoglu et al. (18) showed a sustained viral response rate of 75% among HCV-infected patients with ESRD using pegylated interferon, so treatment should be attempted when feasible. In our cohort, only 18.7% of patients could undergo therapy before transplant, and only 25% of these were successful.
The use of HCV+ donor organs is widely practiced for both kidney and liver transplant recipients (19, 20). Our center uses this practice if the recipient is known to have genotype I. Studies have shown, however, that HCV genotype does not affect patient survival after kidney transplantation (21). Our center has also previously reported worse outcomes with HCV+ kidney donors older than 50 years (22), and thus, we only accept HCV donor kidneys from younger donors.
Although none of our patients developed liver decompensation after transplantation, we did note the one patient who developed aggressive metastatic HCC 16 months after transplantation. The risk of developing HCC in HCV+ patients is high, and this risk increases in the presence of cirrhosis (23). Renal insufficiency and immunosuppression may additionally increase this risk, but this risk has not been well quantified. Of note, our patient was not cirrhotic, and yearly screening ultrasonographies were performed on these patients.
This study has several limitations. This is a retrospective study with its inherent shortcomings. It may also be pointed out that our patient numbers are small, but the numbers of HCV+ patients with ESRD and cirrhosis undergoing KTx alone is a small number anywhere, and multicenter studies looking at similar data may be necessary to further evaluate these data. However, we believe that we addressed an important question for transplant physicians: in a compensated HCV+ patient with cirrhosis and ESRD with HPVG less than 10 mm Hg, a combined liver-kidney transplantation may be unnecessary; KTx alone may be performed safely.
MATERIALS AND METHODS
This was a retrospective study approved by the institutional review board at our institution.
Ninety HCV-infected patients with ESRD were referred for KTx to our center from January 2003 to December 2010. Our center’s protocol involves a comprehensive evaluation by our transplant surgery, nephrology, and hepatology team. Patients with evidence of decompensated liver disease, including variceal bleeds, portosystemic encephalopathy, ascites, and HCC, were ruled out for KTx alone. All other patients who passed initial medical/social/financial evaluation underwent transjugular liver biopsy and measurement of HPVG. Patients with HPVG less than 10 mm Hg were ruled out for KTx alone. All patients underwent screening imaging of their liver to evaluate for hepatocellular carcinoma.
If there were no medical/financial contraindications, treatment of HCV was initiated by our hepatology team in an attempt to eradicate the virus before KTx. All patients listed for KTx are evaluated by our hepatology team on a yearly basis to evaluate for progression of their liver disease. Patients who were listed for KTx alone were given the option of accepting a HCV+ donor kidney. Patients are told that this may increase their chances of receiving an allograft sooner. Kidneys from HCV+ donors older than 50 years were not accepted for transplant.
Patients in this study were divided into C group versus NC group, based on their biopsy. Liver fibrosis was graded between 0 and 4 (4 being cirrhotic) by a hepatopathologist using the Metavir scoring system. We analyzed patient demographics, waitlist characteristics, hepatic disease parameters, and use of HCV+ donors for transplant. Post-KTx outcomes, including 1- and 3-year patient and graft survival rates, were compared between the groups.
Continuous variables were analyzed using Student t test or the Wilcoxon-Mann-Whitney test. Categorical covariates were analyzed using chi-square or Fisher exact test.
Analysis of factors affecting patient and graft survival was performed using Cox proportional hazards models. Patient survival was calculated from time of transplant to death or last follow-up. Graft survival was calculated from time of transplant to return to chronic dialysis, death, or last follow-up. Graft survival was not censored for death with functioning graft. All analysis was performed using SAS version 9.2 (SAS Institute, Cary, NC), and P<0.05 was considered significant.
1. Sterling RK, Sanyal AJ, Luketic VA, et al.. Chronic hepatitis C
infection in patients with end stage renal disease: characterization of liver histology and viral load in patients awaiting renal transplantation. Am J Gastroenterol 1999; 94: 3576.
2. Morales JM, Campistol JM, Dominguez-Gill B. Hepatitis C
virus infection and kidney transplantation. Semin Nephrol 2002; 22: 365.
3. Wells JT, Lucey MR, Said A. Hepatitis C
in transplant recipients of solid organs, other than livers. Clin Liver Dis 2006; 10: 901.
4. Giordano HM, Franca AVC, Meirelles L, et al.. Chronic liver disease in kidney recipients with hepatitis C
infection. Clin Transpl 2003; 17: 195.
5. Martin P, Carter D, Fabrizi F, et al.. Histopathological features of hepatitis C
in renal transplant candidates. Transplantation 2000; 69: 1479.
6. Eason JD, Gonwa TA, Davis CL, et al.. Proceedings of consensus conference on simultaneous liver kidney transplantation (SLK). Am J Transplant 2008; 8: 2243.
7. Zylberberg H, Nalpas B, Carnot F, et al.. Severe evolution of chronic hepatitis C
in renal transplantation: a case control study. Nephrol Dial Transplant 2002; 17: 129.
8. Kamar N, Rostaing L, Selves J, et al.. Natural history of hepatitis C
virus–related fibrosis after renal transplantation. Am J Transplant 2005; 5: 1704.
9. Roth D, Reddy KR, Kupin W, et al.. Long-term impact of HCV on clinical outcomes and liver histology in kidney recipients. Am J Transplant 2004; A478: 289.
10. Fabrizi F, Poordad FF, Martin P. Hepatitis C
infection and the patient with end-stage renal disease. Hepatology 2002; 36: 3.
11. Kasiske BL, Cangro CB, Hariharan S, et al.. The evaluation of renal transplant candidates; clinical practice guidelines. Am J Transplant 2001; 2 (suppl 1): 5.
12. Mouquet C, Mathurin P, Sylla C, et al.. Hepatic cirrhosis
and kidney transplant
outcome. Transplant Proc 1997; 29: 2406.
13. Campbell MS, Constantinescu S, Furth EE, et al.. Effects of hepatitis C
–induced liver fibrosis on survival in kidney transplant
recipients. Dig Dis Sci 2007; 52: 2501.
14. Trotter JF, Osgood MJ. MELD scores of liver transplant recipients according to size of waiting list. JAMA 2004; 291: 1871.
15. Ripoll C, Groszmann R, Garcia-Tsao G, et al.. Portal hypertension collaborative group. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis
. Gastroenterology 2007; 133: 481.
16. Huraib S, Iqbal A, Tanimu D, Abdullah A. Sustained virological and histological response with pretransplant interferon therapy in renal transplant patients with chronic viral hepatitis C
. Am J Nephrol 2001; 21: 435.
17. Kim E, Ko HH, Yoshida EM. Treatment issues surrounding hepatitis C
in renal transplantation: a review. Ann Hepatol 2011; 10: 5.
18. Kokoglu OF, Ucmak H, Hosuglu S, et al.. Efficacy and tolerability of pegylated-interferon alpha-2a in hemodialysis patients with chronic hepatitis C
. J Gastroenterol Hepatol 2006; 21: 575.
19. Maluf DG, Archer KJ, Mas VR. Kidney grafts from HCV positive donors: advantages and disadvantages. Transplant Proc 2010; 42: 2346.
20. Morales JM, Campistol JM, Dominguez-Gil B, et al.. Long-term experience with kidney transplantation from hepatitis C
–positive donors into hepatitis C
–positive recipients. Am J Transplant 2010; 10: 2453.
21. Natov SN, Lau JY, Ruthazer R, et al.. Hepatitis C
virus genotype does not affect patient survival among renal transplant candidates. The New England Organ Bank Hepatitis C
Study Group. Kidney Int 1999; 56: 700.
22. Killackey MT, Fargen K, Islam T, et al.. Successful use of hepatitis C
positive kidneys for transplantation: caution on the use of older donors. Hepatology 2007; 46: 892A.
23. Lok AS, Seeff LB, Morgan TR, et al.. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C
–related advanced liver disease. Gastroenterology 2009; 136: 138.