SHOULD HEPATITIS C VIRUS INFECTION AFTER RENAL TRANSPLANTATION BE CONSIDERED AS A NEW SURROGATE MARKER FOR LATE GRAFT LOSS? |
José M. Morales, Madrid, Spain
|
Chair:
Alex M. Davison, Ancrum, United Kingdom
|
Gerhard Opelz, Heidelberg, Germany |
|
Prof Josè M. Morales
Renal Transplant Unit, Nephrology Department Hospital 12 de Octubre Madrid, Spain |
Slide 1
Thank you Alex. Dear Colleagues and friends. First of all I would like to thank the council for your kind invitation to participate in this session. Well, this session is about hepatitis C after renal transplantation, if hepatitis C could be a new surrogate marker for graft loss. First of all I would like to show you that hepatitis C is the principal liver disease after renal transplantation and since 1989 we know that hepatitis C worsens liver disease along time. Hepatitis C decreases the incidence of acute rejection, increases the incidence of infection. Hepatitis C induces glomerulonephritis before and after renal transplantation and also hepatitis C is important in the pathogenesis of post transplant diabetes mellitus. I believe these 3 points are well known, have been published in several times. Today I would like to discuss with you the influence of graft on patient survival.
Slide 2
As you know, Doctor Hariharan published in Kidney International 2002 a classic paper. The risk factor for late graft loss. As you can see donor race, donor black, cadaver transplantation, recipient black, prior transplantation, diabetes, acute rejection. The new concept introduced by Doctor Hariharan was that serum creatinine or delta serum creatinine was a predictor factor of the long-term follow up.
Slide 3
With hepatitis C what happened in the first 10 years? You can see this slide with the collaborative study in Spain among the Hospital Clinic Barcelona and Hospital 12 Octobre in Madrid showing that patient hepatitis C, in renal hepatitis C positive patients, donor negative, donor positive, receptor positive and negative to negative is an important number of patients and you can see that at 10 years there is not a statistical difference in patient survival between this possibility even donor positive, recipient positive.
Slide 4
This is in the first ten years but you can know this excellent paper published by Christoph Legendre from Paris and Doctor Legendre saw that at the beginning of transplantation in the first 10 years it is possible to not have a difference in patient survival but in the long-term follow up patient survival was lower, statistically lower in HCV positive patients.
Slide 5
But in our experience in Spain published in NDT in 1988 including nearly 500 patients, you can see that patient survival was statistically significantly lower compared with negative-negative but I believe this is acceptable, 70% at 10 years.
Slide 6
In the recent metanalyses published by Fabrizi in the Medical Journal of Transplantation you will see all these patients included, you can see that the relative risk is high in these patients with Hepatitis C concerning mortality.
Slide 7
Ok. But these are logical concepts, this is not a surprise. The surprise could be in this way. You can see that this experience in Spain again 1990-1998--- transplanted that the graft survival was statistically lower than negative-negative event hepatitis B positive.
Slide 8
In the metanalysis of Fabrizi published recently, you can see that again relative risk is cleverly elevated in hepatitis C positive patients. So in that hepatitis C is an independent risk factor for graft loss.
Slide 9
The question is why can hepatitis C influence graft survival? It is well known that hepatitis C induces proteinuria and this is a very nice paper from France published in 1998 that in pre-transplant HCV infection patients with HCV infection present more frequently proteinuria and in these patients who present proteinuria the long-term follow up is statistically lower than patients with proteinuria.
Slide 10
This proteinuria in most of the cases is due to glomerulonephritis induced by hepatitis C, for example, these are cryoglobulinemic, membranoproliferative glomerulonephritis associated with HCV infection that were first published by Doctor Cruzado from Barcelona in the American Journal of Transplantation.
Slide 11
Also we described that another lesion is possible membranous glomerulonephritis associated with hepatitis C virus infection in a similar way to patients without transplantation.
Slide 12
In this study concerning or revising all renal biopsies HCV positive or HCV negative you can see that de novo membranoproliferative glomerulonephritis and de novo membranoglomerulonephritis are associated with hepatitis C virus infection comparing with Hepatitis C negative. In a clinical setting most of the membranoproliferative glomerulonephritis that everyday we see in the clinical practice, most of them are related with hepatitis C virus infection.
Slide 13
But recently two papers have been published in order to demonstrate the implication of hepatitis C in the glomerular relation. This is a paper from Bari. Hepatitis C virus RNA and core protein in kidney glomerular and tubular structures isolated by laser capture microdissection.
Slide 14
And you can see that in patients with membranoproliferative glomerulonephritis or membranoglomerulonephritis, you can see that the preceding glomeruli, 80% in glomeruli and HCV RNA genomic sequence and also HCV core protein in the glomeruli and also in the tubules has an important new point. Therefore, this study emphasised that it is possible to detect the implications of HCV infection on the glomerular relation.
Slide 15
Another one is from Germany a novel role of Toll-like receptor 3 in hepatitis C –Associated glomerulonephritis and in patients with, HCV positive patients with glomerular relation, with membranoproliferative glomerulonephritis.
Slide 16
So an increase of Toll-receptor 3 mRNA expression and pro-inflammatory cytokines, indicating that probably this is an excuse to induce a glomerular lesion in patients with hepatitis C virus infection.
Slide 17
But the problem is glomerulonephritis after renal transplantation the incidence is low but the question is are there other mechanisms? You can see that in the Spanish study published in 2003 about late renal allograft failure between 1990 and 1998: a changing scenario, you can see that Hepatitis C positive was an independent risk factor for graft survival, independent risk factor for graft survival probably independent of the glomerular lesion.
Slide 18
In this way, you can see that it is delta serum creatinine we can observe that the increase of delta 3 months-1 year HCV positive, HCV negative is statistically significant and proteinuria is more frequent 1 year in HCV positive patients than HCV negative and the delta or proteinuria is also significantly increased in hepatitis C positive patients versus hepatitis C negative patients.
Slide 19
Again in protocol biopsies Doctor Moreso published that subclinical rejection associated with chronic allograft nephropathy in protocol biopsy as a risk factor for late allograft loss. Again hepatitis C positive is an independent risk factor in order to explain long-term graft loss.
Slide 20
Also in this study in Spain in almost 4000 people long-term results improved in spite of donor age and the number of mismatch HLA. You can obtain patients 1990, 1994, 1998 and the half-life increased in 1998 and these long-term results improved in spite of the increase of donor age and the number of mismatched HLA. Doctor Seron and colleagues, we explained this in order to decrement, a dramatic decrement of acute rejection, the new immunosuppressive drug, mainly MMF in this 1998 and one important point was the decrease of the prevalence of HCV infection after renal transplantation. Another one was a problematic to demonstrate that perhaps a statin could have a role.
Slide 21
The most important point is that the dramatic decrease of HCV infection in the patient who received the kidney in Spain 1990, 30% of the patients present HCV positive antibodies, HCV positive and this decrease to 10% in 1998 and in 1998 this dramatic decrease could favour the improvement of the results in the long-term follow up.
Slide 22
It’s important to know that in spite of this renal transplantation is the best therapy for patients with HCV positive infection in dialysis because as Doctor Bloom has demonstrated that patients transplanted or patients in the waiting list, you can see that patients transplanted the patient survival, the cumulative patient survival, patient transplantation are significantly high survival than patients in the waiting list because the mortality in the patient waiting list is increased.
Slide 23
And it’s important in this point that this mortality in the waiting list is influenced by the presence or not of diabetes in patients with HCV positive patients. Therefore, the best therapy for these HCV positive patients on dialysis is renal transplantation.
Slide 24
Therefore, the next question could be, how to prevent or to minimise the effect of HCV at renal transplantation? We have several points and I believe it is important to know this one. To treat with Interferon alpha patients with active chronic hepatitis virus RNA and also another important concept is to treat patients HCV RNA patients to avoid morbidity after renal transplantation. This is an important point.
Slide 25
This is an article that Doctor Campistol and myself published in JASN 2000 and you can see that patient HCV RNA negative with normal renal function should be immediately included in the waiting list. Patients with liver failure or cirrhosis should be considered for double liver and kidney transplantation and the problem is that most of the patients present HCV RNA it is necessary to perform a liver biopsy.
Slide 26
And if there is chronic hepatitis it is possible to treat with Interferon and you can see the other sequence. It is well known that in this metanalysis that Interferon is more effective in dialysis than in the normal population but more side effects, you can see that 30% of the patients should be drop out because of the important side effects and 40% treatment failure. Only 30% are experimented and sustained by viral response.
Slide 27
Recently Spanish Guidelines for Viral Infections have been published including Interferon. Interferon with 6 moles and then it is possible to introduce interferon and ribavirin if RNA is positive.
Slide 28
I would like to emphasise in this concept it is possible to treat with interferon in other situations irrespective of hepatitis chronic liver disease. It is necessary to study case by case. It’s necessary to consider original disease mainly if membranoproliferative GN and this is very important the treatment with Interferon could decrease the incidence of recurrent GN associated with HCV infection. In this way Doctor Cruzado published in the American Journal of Transplantation that the previous treatment with interferon decreases the incidence of post transplant GN and another possibility is to treat this patient with Interferon in order to decrease the incidence of Post transplant diabetes because of the higher risk of cardiovascular death.
Slide 29
Finally, we proposed with Doctor Campistol that HCV positive patients must be followed closely to detect deterioration of liver and renal function, infection, proteinuria, diabetes. It’s important to give a non-aggressive immunosuppression and monitor liver function. It’s necessary to be alert for severe and opportunistic infection. It’s very important also to test for proteinuria and microhematuria at each visit. Alert for post-transplant diabetes, alert for cardiovascular risk. I believe that in the next year alert for tumour in this patient in the long-term follow-up.
Slide 30
In this slide of Hariharan it is possible to demonstrate perhaps with more data that probably HCV infection could include an unusual renal marker for long-term renal transplant outcomes.
Slide 31
Finally, I would like to invite you to go to Madrid to visit the 24th National Congress of the Transplantation Society. Thank you very much for your attention.