Hepatitis C in Renal Transplantation
Dr S.J.Acharya M.D.,D.N.B. Acharya Dialysis Centre and Kidney Hospital Dhantoli , Nagpur shibu_acharya@yahoo.co.in
Case presentation
MB , 52 years old , non diabetic and non hypertensive male detected to be in end stage renal disease in 1989 . Following a period of about 3 months on hemodialysis , he was transplanted . His brother was a full house match and was accepted as a donor after satisfactory evaluation. At the time of transplantation , liver functions were normal and hepatitis viral markers were all negative . During transplant surgery he received one unit of blood transfusion . He was put on triple immunosuppressants namely prednisolone , azathioprine and cyclosporine . He developed post transplant diabetes for which he was on insulin .
During follow up he was found to have elevated SGPT ( 62 IU ) and bilirubin (2.2 mg/dl) . Azathioprine was reduced to 1 mg/kg daily and omitted after 3 months . Antibody to Hepatitis C antigen was detected . Hepatitis C RNA PCR was positive. He was followed over the period of 17 years . He maintained his kidney functions to normal , was non hypertensive throughout , did not have proteinuria , had not had a single episode of rejection. ECG was normal. His blood sugar levels were well under control and lipid profile was in acceptable range . LFT showed bilirubin of 2.2 mg /dl , direct 1.8 mg/dl , SGPT was 72 units . His liver functions remained same throughout this period . After 17 years of transplant he had mild chest discomfort in the early hours and before any medical help could be given , he succumbed . The terminal event was presumed to be acute coronary syndrome . He never had any cardiac symptoms earlier . Except for post transplant DM , he had no other risk factor for coronary artery disease like smoking ,hypertension , dyslipidemia or family history . His yearly ECG were also normal .
Discussion
Mr MB , 52 years old male patient had acquired hepatitis C presumably following a blood transfusion during the procedure of transplant surgery . This was reflected by the presence of antibody to hepatitis C and also positive RNA PCR test . Though clinically silent , he had evidence of hepatitis in the form of raised bilirubin and SGPT level . There are certain issues that need to be highlighted in this patient .
Hepatitis C virus (HCV) is highly prevalent among patients with end stage renal disease (ESRD) affecting as much as 10-20% of patients on hemodialysis. This is significantly higher than in the general population and as a result, a considerable number of patients referred for transplant evaluation are infected with hepatitis C with a prevalence ranging from 12-40%. In fact, HCV infection has now emerged as the leading cause of chronic liver disease in renal transplant patients.1, 2
Pre-transplant hepatitis C infection is associated with an increased risk of developing post transplant liver disease. 20% to 60% of patients have sustained elevations in serum transaminases, and in a majority of patients, there is a sustained viremic state. There is however no correlation between the degree of transaminitis, viral titers and extent of liver disease so that in most cases, a liver biopsy is required to fully assess the extent of the disease as well as to establish prognosis.3
Approximately 30% of patients with chronic HCV infection show persistently normal alanine aminotransferase (PNALT) levels. The majority of these patients have some degree of histological liver damage.4
One elevated ALT in the pretransplant period predicts the presence of hepatitis C for 55 % . ALT levels are persistently normal in up to 30 % of RNA positive patients . About 10 % of patients lose anti-HCV after renal transplantation but remain HCV-RNA positive .
Our patient was put on triple drug immunosuppressant to begin with and after 3 months azathioprine was omitted in view of raised SGPT and bilirubin level . Azathioprine is considered to be more hepatotoxic especially in presence of already existing liver dysfunction and hepatitis C virus. In transplanted patients with liver dysfunction, the use of azathioprine should be avoided since it is associated with more severe lesions . Mycophenolate mofetil tended to delay recurrent disease (50+/-35 versus 35+/-35 weeks, P=0.5) with significantly lower levels of aminotransferases (P<0.05). Furthermore, patients under MMF revealed less severe allograft fibrosis at disease recurrence .5
Though our patient had developed hepatitis as evident with the rise in SGPT and bilirubin , this remained stable all through 17 long years in spite of immunosuppressants though the virus is known to behave more aggressively in immunosuppressed individuals. The genome study for hepatitis C virus was not done . Atleast 6 genotyps of hepatitis C virus has been described .6 Possibly it was a less aggressive virus . He was closely followed up during his life time of 17 years post transplant during the period of which his kidney functions remained stable .He was on prednisolone and cyclosporine all these 17 years .
Mr MB had developed post transplant diabetes which is known complication of drugs like cyclosporine and prednisolone and was put on insulin. It is known that those who harbour hep C virus are more prone to develop PTDM . PTDM occurred more frequently in HCV+ than HCV- patients (39.4% versus 9.8%; P = 0.0005). 4,5,6, 7. Hepatitis C is a predictor of poorer renal survival in diabetic patients. 6,7
However not all patients with Hep C are lucky to maintain a stable liver function post transplant , 20% develop cirrhosis liver and death due to hepatic failure occur in 4 % .
Our patient succumbed to an unexpected coronary event .Coronary artery disease ( CAD ) another known complication in transplanted patients . In a Scandinavian study of 1347 grafts over 5 years , death from ischemic heart disease accounted for 53% of deaths with functioning graft . CAD is often associated with dyslipidemia .However our patient did not have dyslipidemia . In another study , HCV seropositivity was found to be associated with the presence of CAD with an odds ratio of 3.2 (95% confidence interval (CI) 1.1 to 9.2, p < 0.05)8
Mortality of HCV-positive renal-transplant patients is higher than that of HCV-negative ones. Liver disease and sepsis seem to be the main causes of death. Perreira et al reported a 1.41 relative risk of death from all causes and a 2.39 relative risk of death due to liver disease or infection among HCV positive recipients compared to HCV negative recipients 12. Similarly, Hanufasa et al have shown a decline in survival rate post transplantation among HCV positive recipients compared to HCV negative patients (63.9% vs. 87.9%) 13. This poor survival rate was mainly due to liver disease but was apparent only after the second decade post transplantation.
Graft survival is another area of concern among HCV positive transplant patients. Whether HCV infection confers an independent risk for acute rejection is a controversial issue. Correll et al reported a significantly lower rate of acute rejection in HCV positive patients which was ascribed to a reduction in naive T helper cells in HCV positive patients 14,15. In most other studies including more recent series, there seems to be a trend towards lower graft survival especially after a sustained follow up of greater than 5 years suggesting that the deleterious effects of HCV on patient and graft survival occur after an extended follow up.
Experience with the use of IFN in renal transplant has been disappointing mainly due to its limited efficacy in sustaining virologic response as well as an unacceptably high risk of rejection and graft loss (25-37%). There are several case reports on interferon-induced acute rejection .11 Up to 37 % may develop this complication . Low dose may be better tolerated but confers little chances of a sustained response . The sustained viral response to interferon monotherapy ranges from 16-64 %; data on combination treatment are available only in preliminary form . Experience with the use of interferon alpha as an anti-CMV agent following renal transplantation was complicated by a high incidence of steroid-resistant rejection and graft loss. An early attempt by Chan et al.3 to treat chronic hepatitis C in a transplant recipient with stable renal function met with virologic success, but the graft was lost 9 months after therapy . Another single case report of interferon use in a patient with combined HBV and HCV disease did not precipitate graft rejection, cleared HBV and led to a non-sustained virologic response for HCV . The largest series to date involves 16 patients, 37% of whom developed acute or subacute renal failure with IFN. Of these six patients , 3 developed irreversible renal failure with diffuse interstitial edema leading to interstitial fibrosis . Based on these limited data, routine use of interferon for the therapy of HCV after renal transplantation should not be recommended . 3
Because therapy for hepatitis C is limited, management of HCV positive renal transplant recipients poses a challenge. HCV positive transplant patients should be followed closely for virologic, biochemical and clinical evidences of active hepatitis. HCV serologies and RNA levels should be monitored at least twice a year or more frequently if clinically indicated. A liver biopsy should be considered in patients with chemical or virological evidence of active hepatitis and information from this should guide the modulation of immunosuppression. Whenever possible, immunosuppression should be kept at a minimum to decrease the risk of infection. In patients with rapidly declining liver function, a liver biopsy should be performed as soon as possible and therapy with interferon may be considered with provisions for active surveillance for allograft rejection.
Patient in the given case was followed over the period of 17 years . He maintained his kidney functions to normal , was non hypertensive throughout , did not have proteinuria , had not had a single episode of rejection . Patient did not receive any anti-viral therapy . To date, there is no efficient treatment of HCV infection after renal transplantation. Consequently, it is mandatory to treat by alpha-interferon all HCV-positive/RNA-positive dialysis patients waiting for renal transplantation.
After renal transplantation, there may be more frequent and more severe chronic rejection in anti-HCV positive recipients .
Graft survival is also lower in HCV-positive renal-transplant patients. This seems to be due in part to the occurrence of de novo glomerulopathy. Membranoproliferative glomerulonephritis in the graft has been ascribed to hepatitis C . Our patient did not have proteinuria or microscopic hematuria indicating absence of de novo glomerular disease in transplanted kidney.
In the short-term, there is no increased hepatic mortality in HCV infected transplanted patients but about 20 % develop unapparent cirrhosis over a period of four years and early death due to cirrhosis can occur . In one of the largest studies from Hannover, among 1241 renal transplants, 13 % had hepatitis C; only 4.3 % developed liver failure and there were no hepatic deaths . In contrast, in a recent study from Japan with high prevalence of HCV, there was a marked increase in hepatic mortality in the second decade after kidney transplantation: 20 year survival was decreased to 63.9 % in HCV-positive patients compared to 87.9 % in the control group . In the U.S., there was a 12 % mortality in a follow-up of 6 years in HBs-negative patients, most of whom presumably had hepatitis C . A more recent study from the US found patients with hepatitis to have higher mortality albeit mostly from non hepatic causes, in particular diabetes and coronary heart disease .12
in a study of 103 patients, there was an increased risk of liver disease (RR 5.0), death (RR 3.3) and sepsis (RR 9.9) . In a recent study from France on 499 hepatitis-B-negative patients followed for 80 months , there was increased mortality in anti-HCV positive patients (13.4 vs. 4.9 %; p<0.002). Most of this increased mortality was due to liver disease (5.4 vs. 0.3 %; p<0.0001). 12
As in hepatitis C in general, the level of transaminases does not predict the severity of histological lesions and a liver biopsy is therefore recommended . In a recent study, 36 % of patients had chronic active hepatitis and 5 % cirrhosis in a biopsy taken on average 38 months after transplantation . The presence of advanced chronic hepatitis or hemosiderosis predicts a great likelihood of hepatic death regardless of etiology of the underlying disease .
The survival rate of the graft was significantly less in the HCV+ cases: 90.6, 68.3 and 51.0% at respectively 1, 5 and 10 years, compared with 91.5, 84.7 and 66.5% in HCV- patients (P<0.01). The patient survival rate was: 96.4, 87.0, and 71.9% in the HCV+ patients at 1, 5, and 10 years, compared with 98.2, 96.0 and 90.0% in the HCV- cases respectively (P<0.01). The differences remained the same in stratified studies according to time spent in dialysis or pre/post-transplant evolution of HCV antibodies, even when immunologically high-risk patients were excluded. In multivariant analysis, the presence of HCV antibodies acted as a independent prognostic factor for the survival of the kidney and the patient: 3.0 (1.8–5.0) and 3.1 (1.2–7.8) odds-ratio (95% of the confidence interval), respectively. The main cause of death among HCV+ patients was cardiovascular; there was no apparent increase in mortality rate due to infections or chronic liver disease. The loss of organs was mainly due to chronic nephropathy or death with a functioning kidney17.
In a study by Narula et all , mean patient and graft survival duration in the anti-HCV negative group was longer (55 months [95% CI,range 51-58 months ]) than in the anti-HCV positive group (50 months [95% CI,range 43-58 months]) (p<0.05) 18
Summary
Though hepatitis C is associated with problems related to chronic active hepatitis , cirrhosis of liver, hepatic failure , chronic rejection , occurrence of de novo membrano-proliferative glomerulonephritis , these complications are not universal as is demonstrated by the present case . In fact many of these patients will do well in spite of lower dose of immunosuppressants . Presence of hepatitis C should not be a deterrent to transplantation .
References
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2 K. C. Abbott, K. L. Lentine, J. R. Bucci, L. Y. Agodoa, J. M. Koff, K. C. Holtzmuller, and M. A. Schnitzler :Impact of Diabetes and Hepatitis after Kidney Transplantation on Patients Who Are Affected by Hepatitis C VirusJ. Am. Soc. Nephrol., December 1, 2004; 15(12): 3166 - 3174.
3 Chan TM, Lok ASF, Cheng IKP, et al. (1993). A prospective study of hepatitis C virus infection among renal transplant recipients. Gastroenterology 104:862-8.
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