Interferon-alpha facilitates renal transplantation in hemodialysis patients with chronic viral hepatitis

Interferon-Alpha Facilitates Renal Transplantation in Hemodialysis Patients With Chronic Viral Hepatitis

Ramon Duarte, MD, Sameer Huraib, MD, Riyad Said, MD, Abdullah Abdel-Khadir, MD, Stephen Sullivan, MD, Ahmed Chaballout, MD, Fayiz Sbeih, MD, and Tariq Mughal, MD

0 Interferon-alpha has not been used previously in hemodialysis patients with chronic hepatitis B and C. This uncontrolled report evaluates the biochemical and/or histologic profile resulting from the administration of interferon-alpha in seven hemodialysis patients, two with chronic hepatitis B and five with hepatitis C. Biochemical improvement was noted in all these patients. Histologic progression did not occur in the two cases in which such assessment was made, and five of them were subsequently transplanted without recurrence of disease. Q 7995 by the National Kidney Foundation, Inc.

INDEX WORDS: Interferon-alpha; hepatiiis B and C; hemodialysis; renal transplantation.

L ATENT INFECTION with the hepatitis B and C viruses has been associated with the

development of chronic liver disease and hepato- cellular carcinoma.’ While the prevalence of hepatitis B has remained relatively constant in hemodialysis patients, that of hepatitis C has been noted to increase.’ Part of this increment has been correlated to the length of time on dialysis, to the number of blood transfusions used to treat the anemia of renal disease prior to the widespread availability of erythropoietin, and to the earlier unavailability of serologic or viral markers of infection in donor blood.3 Even though chronic hepatitis C is associated with a higher rate of progression to cirrhosis as compared with hepatitis B,4” several reports have emphasized the pro- gressive nature of both chronic viral hepatitis in this population of patients with its apparent increased morbidity.46 Liver dysfunction similarly has been noted to progress following renal transplantation, particularly in patients with hepatitis B.7 This has led some investigators to recom- mend avoiding transplantation in patients who are chronically infected with either of these viruses.5S6 In addition, current renal transplantation screening criteria exclude patients with active hepatitis B- and C-associated liver dysfunction. On the other hand, there have been several re-

From the Departments of Medicine, Pathology, and Sur- gery. King Fahad National Guard Hospital, Saudi Arabia.

Received October 21. 1993; accepted in revised fotm Au- gust 15, 1994.

Address reprint requests to Ramon Duarte, MD, FACP, Hemodialysis Unit, Department of Medicine, King Fahad National Guard Hospital, PO Box 22490, Riyadh 11426, Saudi Arabia.

0 1995 by the National Kidney Foundation, Inc. 0272-6386/9X2501-0008$3.00/O

ports on the successful use of interferon-alpha (IFN) to treat chronic hepatitis in patients with normal renal function.7*8 In all those studies, patients with chronic renal failure or active renal disease were excluded; parenthetically, some investigators consider chronic renal failure to be a contraindication for IFN administration.’ Given the indisputably better quality of life offered by renal transplantation, it also will be desirable to extend the benefits of IFN to patients with end- stage renal disease to modify the course of liver disease and render them suitable for transplantation. Preliminary observations have established the safety and efficacy of IFN administration to hemodialysis patients. lo A more recent controlled study also attested to these findings.” The present uncontrolled report expands our experience with this treatment in seven hemodialysis patients. It also includes data for five of those patients who were successfully transplanted following such an intervention.

MATERIALS AND METHODS

The study was carried out at the Ring Fahad National Guard Hospital, Riyadh, Saudi Arabia, between late 1990 and 1993.

The hemodialysis unit at our hospital provides care for 66 outpatients. Of these, two patients are chronic carriers of the hepatitis B virus, giving a prevalence of 3%. On the other hand, 12 patients have been diagnosed as being chronic carriers of the hepatitis C virus, a prevalence of 30%. The current report includes two patients with chronic hepatitis B and five with hepatitis C for whom serial biochemical and baseline histologic features were ascertained. In all cases, other factors known to cause chronic hepatitis were excluded by careful drug history, absence of stigmata of Wilson’s disease, or l- antitrypsin deficiency, serologic testing for Brucella sp, cyto- megalovirus, herpes simplex, and Epstein-Barr viruses. The diagnosis of hepatitis C was established by testing for the antibody with a second-generation ELISA test; confirmation was carried out by a four-antigen recombinant immunoblot

40 American Journal of Kidney Diseases, Vol25, No 1 (January), 1995: pp 40-45

INTERFERON-ALPHA IN HEMODIALYSIS

assay (RIBA 4). Patients were eligible to receive IFN if the results of their liver function tests (LFTs) were abnormal for at least 6 months prior to the documentation of chronic liver disease by percutaneous liver biopsy.

Those patients whose LFTs normalized spontaneously during the baseline observation period were not considered for therapy. Informed consent was obtained from all patients. The histologic diagnosis of chronic persistent or active hepatitis was necessary for inclusion. We were unable to obtain viral titers in blood. All biopsy specimens were stained for iron to exclude hemosiderosis. Each patient received IFN in a dose ranging from 2.5 to 3 million units (MU) subcutane- ously (SC) three times per week following each dialysis ses- sion for a period of 3 months. Patients were monitored with weekly blood counts and biweekly LFTs to detect side effects. Those patients who had a relapse of abnormal LFTs following the first course of treatment received a second course of similar duration. Histologic follow-up was carried out in two patients (cases no. I and 5) after 12 and 36 months, respectively. Patients whose LFTs and/or histologic examina- tion showed improvement were subsequently cleared for renal transplantation provided there were no other contraindica- tions for it. Statistical analysis of differences in enzyme values was carried out by Student’s r-test for paired observations.

Case No. I

A 28-year-old woman who had received hemodialysis since 1988 was found to have a persistent elevation of liver enzymes and to be positive for antibodies to hepatitis C virus (anti-HCV). A liver biopsy done in January 1991 revealed chronic persistent hepatitis. In April 1991, the patient received IFN 3 MU SC after each hemodialysis for a period of 3 months, with normalization of the biochemical picture. She had a recurrence of abnormal LFTs in October 1991, for which she received a further 3-month course of IFN with eventual complete normalization of the liver enzymes. A repeat biopsy in January 1992 showed improvement in the histologic picture (Fig 1). The patient has been in biochemical remission since December 199 1.

41

Case No. 2

A 20-year-old man had been receiving hemodialysis since 1990 and was positive for anti-HCV with persistent high liver enzymes. A liver biopsy was performed in 1991 that showed chronic persistent hepatitis. The patient received a 3-month course of IFN 3 MU SC after each hemodialysis treatment. Following the therapy, the LFTs normalized completely until July 1993, when he received a living-related renal allograft. Following surgery the patient developed acute tubular necrosis and required antithymocyte globulin for 2 weeks. During this time no flare-up of liver disease was documented and his liver enzymes remain normal 6 months after transplantation.

Case No. 3

A 32-year-old man receiving dialysis was found to be positive for anti-HCV in October 1990. He had consistently high liver enzymes and a liver biopsy showing evidence of chronic persistent hepatitis. He was given IFN 5 MU SC in November 1990, followed by 3 MU SC postdialysis three times per week for a total treatment period of 3 months. All the patient’s liver enzymes normalized while he was receiving IFN, but the antibody to the C virus remained detectable. He subsequently received a living-related renal allograft and experienced no postoperative flare-up of hepatitis. Twelve months posttransplantation the patient’s LFIs remain normal.

Case No. 4

A 24-year-man receiving hemodialysis was found to have abnormal LFI results and a positive anti-HCV in December 1991. The patient underwent liver biopsy in July 1992, and the histologic picture revealed chronic persistent hepatitis. He was treated with IFN 3 MU SC after each hemodialysis for 3 months, following which that results of the LFfs normalized and remained normal until he received a cadaveric renal transplant in May 1993. The postoperative course was uneventful without flare-up of liver disease and his enzymes continue to be normal 11 months posttransplantation.

Fig 1. Photomicrograph of liver biopsy specimen before (A) and after (6) IFN therapy in patient no. 1. Note the almost complete disappearance of mononuclear cell infiltrates from the portal tract after treetment. (Hematoxyiin- eosin stain; magnification x250.)

42 DUARTE ET AL

Fig 2. Liver biopsy of patient no. 5 before (A) and after (6) IFN reveals marked reduction in the portal tract infiltration by mononuclear cells as well as resolution of piecemeal necrosis after treatment. (Hematoxylin-eosin stain; magnification x250.)

Case No. 5 A 14-year-old patient who had been receiving hemodialy-

sis since 1987 was transfusion dependent until February 1989, at which time he was subjected to splenectomy. Liver enzymes were persistently elevated throughout this period of time, and a liver biopsy in 1989 revealed chronic active hepatitis (Fig 2A). The patient was given IFN according to the protocol, following which the HBe antigen cleared, he developed antibody to the HBe antigen, and the liver enzymes normalized. A repeat biopsy done in September 1992 revealed evidence of chronic persistent hepatitis without piecemeal necrosis or cirrhosis (Fig 2B). The patient was suhse- quently transplanted with a cadaveric renal allograft without any reactivation of hepatitis. At follow-up 12 months postop- eratively, the patient remains immune to the HBe antigen and his LETS are normal.

Case No. 6 A 21-year-old Kuwaiti man who had been receiving hemo-

dialysis since 1988 was diagnosed to have chronic persistent hepatitis B with e antigenemia in October 1990 after repeated monthly LFLs displayed increases in aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase for the preceding 6 months. The patient was treated with IFN 5 MU SC three times per week for 1 week, followed by 3 MU SC after each hemodialysis treatment for 3 months. Following IFN therapy, all the patient’s liver enzymes normalized, the HBe antigen cleared, and the patient developed antibody to the HBe antigen. This improvement was maintained for a period of 9 months following treatment; after this time, the patient returned to Kuwait and was lost to follow-up.

Case No. 7 A 25-year-old Saudi man was found to have abnormal liver

function and positive anti-HCV in October 1992. A liver biopsy done in February 1993 revealed chronic persistent hepatitis. The patient was started on IFN 3 MU SC thrice weekly postdialysis for 3 months. Following such a course, the patient’s LETS normalized and the patient was trans-

planted in another country with a kidney from an unrelated living donor in June 1993. Following transplantation, he developed a perirenal hematoma that became infected and required drainage. The LFTs remained normal despite the fact that the patient experienced two episodes of rejection that required steroid therapy as well as OKT3 administration. At last follow-up, liver function remained normal; however, the patient developed recurrent focal segmental glomerulosclero- sis 2 months posttransplantation.

RESULTS

Table 1 shows that all patients with elevation of the liver enzymes for at least 6 months prior to biopsy had either chronic persistent5 or chronic active’ hepatitis. In some of these patients the liver enzyme abnormalities were present for a longer period of time and displayed some inter- mittent fluctuations, particularly in those patients who were carriers of the hepatitis C virus. Those fluctuations were only transient and never reached normal values.

After IFN treatment the liver enzyme profile displayed a gradual reduction in activity and fi- nally normalized in 6 to 8 weeks. Two patients (cases no. 1 and 5) required two courses of therapy. The follow-up observation period after treatment ranged from 6 to 24 months (mean, 13.8 months) (Table 2). Up to the time of this report or transplantation, there has been no reappear- ance of liver enzymes abnormalities in any patient. Follow-up liver biopsy studies were avail- able only in two patients after a time interval of 12 to 36 months (cases no. 1 and 5).

Even though no scoring system was used, histologic improvement consisting of disappearance

INTERFERON-ALPHA IN HEMODIALYSIS 43

Table 1. Clinical, Biochemical, and Histologic Characteristics of Hemodialysis Patients Before and After Interferon-Alpha

Patients NO.*

cause of ESRD Risk Factor

Histology Before/

After IFN Pre-IFN Enzyme& Post-IFN Enzymest: AST/ALT/LDH (U/L) AST/ALT/LDH (U/L) Transplantation

1 26/F Anti-HCV + CGN Multiple ET CPl-ltrlO 55ll23l200 14/37/204 NO infiltrate

2 20/M Anti-HCV + RN BT CPH 09/202/470 33/38/w Yes 3 32/M Anti-HCV + Unknown BT CPH 65/211/312 27/42/l 75 YeS 4 25/M Anti-HCV + CGN BT CPH 87/l 02/292 17/34/l 50 Yes 5 14/M Hep B Sag + MPGN BT CAH/CPH 154/226/364 30/25/l 70 YeS

E Ag + 6 21/M Hep B Sag f, CGN BT CAH 166/270/350 32/l 2/200 NO

EAa+ 7 25/M Anti-HCV + FSGS Transplant BT CPH 40/91/350 37/2#230 Yes

Mean -t SD = 96/166/ Mean k SD = 271301 350 + 4/10/6 162 + 3i7llO

AbbMatlons: ESRD, end-stage renal disease; CON, chronic glomerulonephritis; RN, reflux nephropathy; FSGS, focal segmental glm~~k&~is; MPGN, membrancprolifemtive glomerulonephritis; Anti-HCV, antibody to hepatits C virus; BT, blood transfusion; CPH, chronic penIstent hepariis (pati& no. 1 had fOllOWUp biopsy 12 months later): CAH, chronic active hepatiis (patient no. 5 had follow-up biopsy 36 months later); Hep B Sag, hepatitis B surfacze antigen; E Ag+, antigen; ABT, aepartate aminotransferase; ALT, alanine amlnotransferase; LDH, lactate dehydrcgenasa.

* Mean age = 23.5 (range, 14 to 32). t Liver enqme atilVfiieS are mean peak VSIUSS Of B-month ObseWatiOn period. Normal range 15 tO 37 for AST, 30 to 65 for ALT, and 100 to 230 for LDH. P

< 0.01 compared with baseline for AST, ALT, and LDH. $ Patients no. 1 and 5 had two ccwses of therapy.

of cellular infiltrates and no evidence of progression to chronic active hepatitis or cirrhosis was detected (Figs 1 and 2). The administration of IFN was not associated with any complications, except for a transient febrile reaction in patients no. 4 and 5. Both the leukocyte and platelet counts remained normal. There was no evidence of reactivation of hepatitis B during the administration of IFN, as reported in those studies in- volving patients with normal renal function.7*8

Five of the patients have subsequently been

transplanted without recurrence of liver enzyme abnormalities in the posttransplant follow-up period, which ranged from 6 to 12 months (Table 2). Three patients received a cadaver+ allograft (patients no. 3, 4, and 5), one received a living- related kidney (patient no. 2), and one received a living unrelated graft (patient no. 7). The interval between IFN therapy and renal transplantation ranged from 6 to 24 months (mean, 13.8 months). Throughout this period all patients remained in biochemical remission.

Table 2. Clinical and Biochemical Course of Five Patients Before and After Renal Transplantation

Patient No. Donor

Pretransplant Post-transplant Follow-up Follow-up

(mo) (mo)

Pretransplantt: AST/ALT/LDH Post-transplant?: AST/ALT/LDH

(U/L) (U/L)

2 LR 3 CAD 4 CAD 5 CAD 7 LNR

7 24

8 24

6 Mean =

13.8

6 12 11 12

6 Mean = 9.4

28/31/190 30/27/210 32/31/780 13/30/l 43 321247230 15/29/l 46 23/l 9/l 70 361311222 34/48/l 37 11/17/116

Mean 2 SD = 29.8/30.6/183 Mean + SD = 2lf26XVl67.4 2 5.2/6.1/l 0.2 k 314.2112.3

Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; LR, living- related donor; CAD, cadaver allograft; LNR, living non-related donor.

l Follow-up has now been extended to an additional 2 more months for each patient without change in peak enzyme values.

T Enzyme activities are peak values within the normal range. P = NS compared with pretransplant for AST, ALT, and LDH.

44 DUARTE ET AL

DISCUSSION

Our current experience indicates that the administration of IFN to patients with end-stage renal disease is both safe and effective in induc- ing biochemical remission. The observed effects were improvement in LFTs, and in two cases histologic progression did not occur. Such a response was similarly observed in trials of IFN in patients with normal renal function.6-8 It should be noted, however, that in those previous trials the liver abnormalities recurred at various inter- vals after stopping the administration of the drug.7V8 As opposed to those subjects with normal renal function, all our hemodialysis patients showed no recurrence of abnormalities in LFTs after interruption of therapy. Such a contradic- tory response cannot be explained on the basis of either higher or longer lasting blood levels in dialysis patients, since pharmacokinetic data have demonstrated that the half-life of IFN is not prolonged in patients with renal dysfunction.” More likely, since uremia depresses cell-medi- ated immunity, IFN could help restore such a function and enable better host control of viral replication in infected cells.13 Without having measured the titer of B-virus DNA or C-virus RNA in our patients prior to therapy, we cannot attribute such a response to inhibition of viral replication. However, when viral markers were monitored in nondialysis patients with hepatitis B or C who responded to therapy, pretreatment titer of these viruses were 10w,‘~-‘~ suggesting that the above mechanisms could be implicated. None of our patients with hepatitis B or C developed the transient “transaminitis” previously described after initiation of therapy.9.‘4 It is there- fore possible that a major component of IFN’s action(s) could be related to inhibition of colla- gen synthesis either directly or indirectly through a modulation of the host’s immune response.‘* In this regard, recent data suggest that downregulation of intercellular adhesion molecules in hepatocytes could represent the initial step in such a process.” Besides our preliminary report,” a recent controlled study has similarly documented the efficacy of IFN on the course of chronic hepatitis in hemodialysis patients, but no longitudinal follow-up of treated patients was carried out after renal transplantation. Despite the fact that the administration of IFN has been reported to cause

exacerbation of autoimmune thyroiditis and in- terstitial pneumonitis, we have not observed any such complications. Neither have we noted any flare-up of hepatitis following transplantation nor detected an increased number of rejection episodes. The latter could be attributed to the length of time elapsing between the therapy and renal transplantation. In conclusion, IFN is not only safe to be administered after hemodialysis, but might offer the potential of making renal transplantation a feasible option for chronically infected patients with hepatitis B and C. Whether chronic liver dysfunction will be apparent on longer follow-up of these patients cannot be ascertained from this limited and uncontrolled experience.

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INTERFERON-ALPHA IN HEMODIALYSIS 45

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Interferon-alpha facilitates renal transplantation in hemodialysis patients with chronic viral hepatitis

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