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Chronic hepatitis in end-stage renal disease: Comparison of HBsAg-negative and HBsAg-positive patients
Kidney International, Vol. 28 (1985), pp. 959—967
Chronic hepatitis in end-stage renal disease: Comparison of HBsAg-negative and HBsAg-positive patients PATRICK S. PARFREY, DOMINQUE FARGE, R.D. CLARKE FORBES, RAYMOND DANDAVINO, SCOTT KENICK, and RONALD D. GUTTMANN Transplant Service, Division of Nephrology and Gastroenterology, Department of Pathology, Royal Victoria Hospital, McGill University, Montreal, and Division of Nephrology, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, and Division of Nephrology, The Health Sciences Centre, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
Chronic hepatitis in end-stage renal disease: Comparison of HBsAgnegative and HBsAG-positive patients. To determine the outcome of chronic hepatitis in ESRD we studied all 358 renal transplant recipients and 295 hemodialysis patients treated for > 1 year since 1970. The
AgHBs nCgatifs ont progresse vers une hepatite chronique active sur la biopsie hepatique, contre 71% (15/21) chez les patients AgHBs positifs.
Chez les malades ayant eu des biopsies rCpCtCes, une stabilité histologique a etC observCe chez 66% (4/6) des patients AgHB5 nCgatifs, mais seulement chez 18% (13/16) des patients AgHB5 positifs, avec une
incidence of chronic hepatitis (elevated SGOT for> 1 year) was 15% (N = 54) in transplanted and 3.4% (N = 10) in dialysis patients. Forty-eight
durCe de surveillance identique. Aucun patient dialysC n'est mort de maladie hCpatique. Nous concluons que I'hCpatite chronique survient plus frequemment chez les patients transplantCs que dialyses, et que l'hCpatite chronique sans AgHB5 a un devenir cinique et histologique meilleur que celui de l'hepatite chronique avec AgHBs chez les patients
percent (26) of transplanted and 50% (5) of dialysis patients were HB5Ag positive. In the transplanted group, the clinical outcome of chronic hepatitis was significantly better in HB5Ag-negative compared to HBsAg-positive patients; 11% died, none from liver disease, and 32% remitted after a mean follow-up from start of liver disease of 77.3 8.2 months, whereas in the HB5Ag-positive group 54% (14) died, nine from liver disease, and one remitted after a follow-up of 90.2 8.9 months.
transpiantCs.
Adverse prognostic factors (age, duration of diabetes, and heart dis-
ease) present before ESRD treatment began were similar in both groups, as was duration of follow-up. Only 14% (2/14) of HBsAgnegative patients progressed to chronic active hepatitis on liver biopsy
compared to 71% (15/21) of HBsAg-positive patients. Histological
stability in those with serial biopsies occurred in 66% (4/6) of HBsAgnegative patients, but in only 18% (13/16) of HBsAg-positive patients with a similar duration of follow-up. No dialysis patients died from liver disease. We conclude that chronic hepatitis occurs more frequently in transplanted than dialyzed patients, and that HBsAg-negative chronic hepatitis has a more benign, clinical, and histological outcome than chronic HB5Ag-positive hepatitis in renal transplant recipients.
Hépatite chronique au cours de l'insuffisance rénale terminale: comparaison des patients AgHB5 negatifs et AgHBs positifs. Pour
determiner l'Cvolution de l'hepatite chronique au cours de l'IRC terminale nous avons Ctudié l'ensemble des 358 transplantés et 295 hémodialysés traités depuis plus d'un an a partir de 1970. L'incidence de l'hCpatite chronique (SOOT élevées depuis plus d'un an) a etC de 15% (N = 54) chez les transplantes et de 3,4% (N = 10) chez les dialyses. 48% (26) des transplantCs et 50% (5) des dialyses Ctaient AgHBs positifs. Dans le groupe transplantes, l'évolution de l'hepatite chronique a etC significativement meilleure chez les patients AgHBs nCgatifs que chez ceux AgHBs positifs: 11% sont dCcCdCs, aucuns de
maladie hCpatique, et 32% ont guCri après une durCe moyenne de surveillance de 77,3
8,2 mois après le debut de Ia maladie hépatique.
Dans le groupe AgHBs positifs, 54% (14) sont dCcCdCs, 9 de leur maladie hepatique, et un a gueri apres un suivi de 90,2 8,9 mois. Les
Over the last ten years, data has accumulated to suggest that chronic liver disease in renal transplant recipients is responsible for considerable morbidity and mortality [1—101. The incidence
of chronic hepatitis in renal transplant patients has been estimated to be 6 to 16% [1—3] and is usually due to either hepatitis
B virus (HBV) infection or non-A, non-B disease. Recent prospective histological studies demonstrated that in the immu-
nosuppressed renal transplant patient, HBV infection often resulted in the development of chronic active hepatitis, which may lead to cirrhosis and death from hepatoma and hepatic failure [11—13]. The natural course of HBV disease in renal transplant recipients may be progressive and distinct from that in dialysis patients [12, 13]. Non-A, non-B hepatitis is now the most frequent cause of transfusion-related hepatitis [14]. It has a propensity to chronicity in patients without renal disease [15—17]. Among transplant patients, progressive liver disease due to non-A, non-B hepatitis has been reported to occur in about 50% of cases [3], although it may be morphologically more benign than in HBV disease [18]. In patients with long-functioning renal allografts, hepatic failure was the leading cause of death, often associated with extrahepatic sepsis [4]. Actual survival of patients with chronic hepatitis was significantly higher when compared to
facteurs de mauvais pronostic (age, durCe du diabète et maladie cardiaque) presents avant Ic traitement de l'insuffisance rCnale those without chronic hepatitis [4]. A recent editorial [10] chronique dtaient identiques dans les deux groupes, de méme que Ia emphasized the lack of studies available to establish the impact durée de Ia surveillance. 14% (2/14) seulement parmi les patients of transplantation on the course of chronic HBV liver disease. Similar studies are lacking in patients with non-B hepatitis and Received for publication January 18, 1985, and in revised form June 10, 1985
© 1985 by the International Society of Nephrology
are necessary because current policy demands that most patients receive blood transfusions before transplantation. This policy may increase short-term allograft survival, but at the expense of long-term patient survival. 959
Parfrey et a!
960
The purposes of the present study were: (1) to ascertain the incidence and causes of chronic hepatitis in patients treated for end-stage renal disease (ESRD) in two hospitals in Montreal, the Royal Victoria Hospital and Maisonneuve-Rosemont Hospital, since routine HBsAg testing became available; (2) to determine the clinical and histological progression of chronic hepatitis in patients treated for ESRD; (3) to study the cause of death in ESRD patients with chronic hepatitis; and (4) to assess
Chronic hemodialysis group Ten of 295 patients with ESRD treated by dialysis for more than 1 year developed chronic hepatitis. This group consisted of six male and four female patients whose mean age was 39 years 4 SE. Two patients had undergone one renal transplant during the period of follow-up and one patient received two transplants, all of which failed within 3 months. While on dialysis, none of these patients received immunosuppressive agents. The whether the outcome of chronic hepatitis was different in underlying renal diseases were: chronic glomerulonephritis (N patients who were HBsAg negative compared to those who = 5), tuberculosis (N = 1), chronic pyelonephritis/reflux were HBsAg positive. nephropathy (N = 2) and interstitial nephritis (N = 2).
Clinical data The records of all 64 patients treated for ESRD in both study groups were reviewed to document clinical signs and problems related to chronic liver disease. Each living patient was evalu-
Methods
Patients We studied all patients who were treated for ESRD for longer than 1 year and who received their first definitive treatment for chronic renal failure (dialysis or kidney transplant) at the Royal Victoria Hospital and Maisonneuve-Rosemont Hospital from
ated at his or her last follow-up visit for the presence of
jaundice, encephalopathy, flapping tremor, abnormal liver size, splenomegaly, and ascites. Age, presence of diabetes mellitus, occurrence of congestive heart failure, or myocardial infarction January, 1970, to June, 1983. During that period, 358 had before treatment for ESRD began and other serious co-morbid
transplants that functioned for longer than 1 year and 295 illnesses which might have an adverse effect on long-term patients were maintained on dialysis for longer than 1 year. prognosis were recorded. The cause of death was assessed by From these groups, we studied every patient who developed the primary physician. chronic hepatitis, defined as elevated serum glumatic Immunosuppressant dosage (azathioprine, steroids, cyclosporine) were recorded every 6 months from time of entry in the
oxaloacetic transaminase levels for at least 1 year.
study to last follow-up. Exposure to liver toxins, alcohol use, and drug schedules were reviewed in all patients. Three transplant patients were assessed by their personal physicians as alcohol abusers (daily alcohol intake > 6 glasses beer/spirits per
Renal transplant group
Between 1970 and 1983, 54 of 358 patients who had a day). Hepatotoxicity caused by drugs was excluded in all
functioning renal allograft for at least 1 year developed chronic
although one transplant recipient received cyclospohepatitis. This group consisted of 38 male patients and 16 patients, rime A and a second one isoniazid. female patients whose mean age was 36.4 1.4 SE years. All underwent hemodialysis prior to transplantation. The mean Laboratory data 1.4 months (range 1 to 84 duration of dialysis was 13.2 Serum glumatic oxaloacetic transaminase (SGOT) and serum months). All patients but one were treated with a conventional immunosuppressive regimen consisting of high-dose prednisone glumatic pyruvic transaminase (SGPT), alkaline phosphatase, immediately following transplantation, tapering to a mainte- total bilirubin, and HBsAg were recorded before treatment for nance dose of 15 mg/day 1 year after transplantation. ESRD began and then every 6 months during time of follow-up. Azathioprine maintenance dose was usually 100 to 125 mg/day. SGOT were recorded monthly (if performed) for the year prior Patients who developed evidence of acute rejection during to the last liver biopsy. When no biopsy was available (because follow-up were usually treated intravenously with methyl prednisone (750 mg) or high oral prednisone cyclophosphamide
patients had remitted, were dead, or refused the biopsy)
monthly SGOT were recorded for the year prior to last fol-
(400 mg). One patient did not receive azathioprine, but low-up or death.
SGOT, SGPT, and alkaline phosphatase were measured by cyclosporine, according to the Canadian Multicentre Study autoanalyzer. HBsAg was detected by radioimmunoassay, but Protocol [19]. Azathioprine was stopped in six patients and
reduced below 100 mg/day for more than 1 year in an additional the sensitivity for HBsAg detection improved over the 14 years 11 patients. Azathioprine was stopped in one patient because of of the study.
a skin epithelioma, in 15 transplant recipients following the
onset of chronic liver disease, in two patients when they returned to dialysis, and in one patient because of a very good graft function with low immunosuppression dosage. The underlying renal diseases were: primary glomerulonephritis (N = 30), secondary glomerulonephritis (N = 2), obstruction/chronic pyelonephritis (N = 7), diabetes mellitus (N = 4), polycystic
kidney disease (N =
3),
medullary cystic disease (N =
1),
congenital hypoplasialsolitary kidney (N = 2), cystinosis (N = 1), malignant hypertension (N = 2), gout (N = 1) and analgesic nephropathy (N 1).
Definitions Chronic hepatitis was defined as a mean SGOT or SGPT level greater than 40 units/liter for at least 1 year and still elevated 1
year after first high level was observed. We chose this SGOT level because many transplant patients with chronic HBV liver disease have aggressive liver disease with SGOT levels less than twice normal [12] and because SGOT activity is often decreased in azotemic patients [20, 21]. Hepatitis B liver disease denoted the presence of circulating HBsAg.
961
Chronic hepatitis in ESRD patients
Non-B liver disease was defined as the presence of elevated enzymes level (> 40 .dliter) for at least 1 year in the absence of circulating HBsAg or the development of infiltrative disease
Table 1. Demography of HBsAg-positive and negative renal transplant recipients with chronic hepatitis
diagnosed on liver biopsy or observed in another organ, or other known hepatotoxic agents. Remission was indicated when liver enzymes were normal for at least 1 year following hepatitis.
Sex, FIM Mean age at time of transplant, years Time on dialysis before transplantation, months Time of follow-up after transplantation, months
Histological assessment of liver biopsy specimens Patients who were alive at time of the study (1983—4) and in whom transaminase levels had been raised for the previous 12 Time of follow-up after months (mean SGOT > 40 dliter) underwent liver biopsies. chronic liver disease developed, months Previous liver biopsy or autopsy specimens were obtained. Sixteen of the 54 patients with chronic hepatitis had partici- Number of patients a Standard error pated in a prospective histological study of HBsAg-positive
HBsAgpositive
HBsAgnegative
Total
8/18
8/20
16/38
34.7
2.1k
37.6
1.9
36.4
1.4
10.4
3.1
15.7
3.0
13.2
1.4
103.8
9.2
95.2
9.5
98.1
6.3
90.2
8.9
77.3
8.2
83.5
6.0
26
28
54
liver disease in renal transplant recipients which we have
reported previously [12, 131. All biopsy specimens were embed-
ded in parafin, sectioned, and stained with hematoxylin and eosin, periodic acid Schiff, Masson trichrome, and Perl's prussian blue. Both the degree of inflammatory cell infiltration and fibrosis in the liver were graded blind to the clinical state on a scale of 1 to 3. This system was applied separately to each perivenular, lobular, portal, periportal, and septal area on the biopsy. The total inflammatory and total fibrosis scores per biopsy were then calculated [12, 221. Based on these and the
Results
Incidence and causes of chronic hepatitis in ESRD Incidence: Sixty-four patients had elevated liver enzymes for at least 1 year. The incidence of chronic hepatitis in the renal
transplant recipients treated for at least 1 year was 15% (54/358). In the hemodialysis patients treated for more than one year, it was 3.4% (10/295), which was significantly lower than in the transplant group (x 2 = 25.2, P < 0.005). The incidence of
overall morphological appearance, a histological diagnosis was made according to one of eight distinct entities as follows: (1) chronic hepatitis has decreased in renal transplant recipients normal; (2) virus only (V): histologic evidence of HBV within during recent years, the incidence being 20% from 1970—1975, hepatocytes, "ground glass" cells, in otherwise normal biopsy; 12% from 1975—1980, and 10% from 1980—1983. (3) reactive hepatitis (H): hepatocyte necrosis with Causes: The etiology of chronic hepatitis in patients treated
reticuloendothelial proliferation, sometimes with leucocytic for ESRD was divided into two categories according to the and histiocytic infiltration; (4) chronic persistent hepatitis results of HBsAg screening. Forty-eight percent (26/54) of renal (CPH): significant portal mononuclear cell infiltration, absent or transplant recipients with chronic hepatitis were HBsAg posiminimal piecemeal necrosis, insignificant fibrosis, and retention tive, as were 50% (5/10) of hemodialysis patients. Demographic
of normal lobular architecture; (5) chronic active hepatitis data for HBsAg-positive and negative renal transplant recipi(CAH): portal and periportal inflammation with piecemeal ents with chronic hepatitis is shown in Table 1. necrosis, varying degrees of lobular hepatitis and portal fibrosis, often with lobular extention and bridging; (6) cirrhosis (C) with diffuse hepatic fibrosis and nodular regeneration; (7)
hepatocellular carcinoma or hepatoma (K); and (8) other abnormalities.
In the results, categories 2 to 4 (V, H, and CPH) are called Group I (non-aggressive liver disease) and categories 5 to 7 (CAH, C, and K) are called Group II (aggressive liver disease). Ninety-two biopsy specimens were assessed, obtained from
34 of the 64 patients. In the transplant groups 22 of the 54 patients had serial biopsies (the number varying from 2 to 7) and
an additional ten patients had one biopsy. Liver biopsy specimens were not available in 22 patients because they were dead (N = 2), liver disease had remitted (N = 8), they refused biopsy (N = 11) or had a medical contraindication (N = 1). In the chronic hemodialysis group, three biopsy specimens were available in two patients. One patient had one liver biopsy within the first 16 months of starting treatment and the second was carried out after clinical manifestations of chronic liver disease had occurred. One other hemodialysis patient underwent one liver biopsy. In the remaining patients, no biopsy was available because three of them had biological remission, two were dead without autopsy and three were alive but refused biopsy.
HBsAg-positive transplant patients with chronic hepatitis Figure 1 illustrates the time at which chronic hepatitis was initially detected (using liver enzyme determination), the duration of chronic hepatitis during time of follow-up, the time post transplant at which HBsAg was first detected, the duration of the chronic carrier state, and the results of liver biopsies. Hepatitis B serology. Seven patients were HBsAg positive prior to transplantation, four were found to be positive at time of transplant, ten within six months post transplantation, and five more than 6 months after transplantation (Fig. 1). All of these patients had serial HBsAg tests during time of follow-up and none of the 26 converted to negative.
The duration of HBsAg-carner state before hepatitis appeared varied between 0 and 208 months. Four patients had HBsAg first detected after liver enzymes rose (range, 29 to 74 months after enzyme elevation). The other 22 patients who were found to be HBsAg positive before or at time of enzyme elevation had a mean chronic carrier state of 25.0 9.7 months. Clinical sequelae. Fourteen of the 26 patients died, nine of whom (64%) died from liver disease (Table 2). Among the nine patients who died with liver disease, one had chronic persistent
hepatitis, two chronic active hepatitis, five cirrhosis, and one
Parfrey et
962
1
Table 2. Causes of death in HBsAg-positive and negative transplant patients with chronic hepatitis
t
C V
t
A
t LD
U,
A
fYr
C a)
0 CT3
.1 LID
t
I
v
2 2
3
Total
14/26
Total
3/28
HBsAg-negative pneumonia metastatic cancer myocardial infarction
rtLD C ,ILD
JP A
3
Group II. Other causes sepsis brain sarcoma cardiac disease
t LD
Hr AA C
I
No. of patients
HBsAg-positive Group I. End-stage liver disease hepatic failure sepsis + hepatic failure gastrointestinal hemorrhage hepatoma bronchopleural fistula + ascites
PA A
I
al
.tLD
from liver disease; t, death from other causes; _r1_, SGOT > 40 Jliter; —, time on transplant, ---, back to dialysis, — - —,lost from follow-up; N, normal liver; V, virus only; H, reactive hepatitis; P,
liver disease. The second patient remitted and did not undergo biopsy. Morphological outcome. Nineteen patients had histological assessment at most recent follow-up, 14 of whom had developed chronic active hepatitis or cirrhosis (Group II histology). Morphological progression. Histological deterioration was defined as greater than one grade change in total fibrosis score, and it was observed in 12 of 16 (75%) patients who had serial biopsies. A change from Group I benign histology to Group II aggressive histology occurred in ten of the 15 patients (67%). Eight of the 12 patients who progressed died from liver disease. Only one patient out of 16 had histological improvement after 72 months of follow-up, regressing from CPH to virus only. No patients ever regressed from Group II to Group I. The mean follow-up from start of chronic liver disease to last biopsy was 69.7 29.4 months for the four-patients who remained stable and 87.4 12.8 for the 12 who had histological deterioration. Risk of cirrhosis and hepatic failure. Twenty-one patients free from cirrhosis at the time they were found to be HBsAg positive were followed for a total of 159 years (mean/patient, 7.57 years). Eight of the 21 subsequently developed cirrhosis, making the risk of developing cirrhosis 5.0% per patient year. The risk of developing aggressive liver disease (Group II) was 9.4% per patient year. Fifteen of 21 patients developed chronic
chronic persistent hepatitis; F, fibrosis only; A, chronic active hepatitis;
active hepatitis or cirrhosis after a mean follow-up of 7.57
v
c
t V
VV
A
t
A
t __ V C
V
t
t LID
t
LID
C I
12
I 36
I
60
I 84
t 108
132
156
Post transplantation, months
Fig. 1. Clinical, biochemical, and histological evolution of HBsAgpositive chronic hepatitis in renal transplant recipients. Symbols are: f , time of detection of HBsAg; •, patient refused biopsy; tLD, death
C, cirrhosis; K, hepatoma; ®, remission: SGOT normal for> 1 year.
hepatoma. The mean duration of chronic hepatitis was 84.5 13.7 months (21 to 161 months). Clinical signs of chronic liver disease were not observed in patients within the group with benign histology (Group I). One patient with chronic persistent hepatitis died from sepsis and hepatic failure. However, autopsy revealed acute hepatitis with underlying chronic persistent hepatitis. Biochemical remission occurred in one of the 26 patients while transplanted. Two patients went back to dialysis having had a functioning transplant for more than 1 year. One patient had already progressed to cirrhosis and eventually died from
years. The risk of death from liver disease was 4.1% per patient year, specifically, 9 of 26 patients died from liver disease after a mean follow-up of 8.3 years. Assessment of adverse prognostic factors which were present before treatment for ESRD began revealed that nine of the 26
patients had an episode of congestive heart failure before starting treatment for ESRD, one had had a myocardial infarct and three had diabetes mellitus. HBsAg-negative transplant recipients with chronic hepatitis Figure 2 shows the duration of follow-up, evolution of chronic hepatitis, results of liver biopsies, and clinical outcome in all HBsAg-negative transplant patients with chronic hepatitis.
963
Chronic hepatitis in ESRD patients
Table 3. Comparison of the clinical and histological sequelae in HB5Ag-positive and negative renal transplant recipients Outcome
FF
Remission (biochemical) Died Died from liver disease Resulted in chronic active hepatitis or cirrhosis on biopsy Remained histologically stable on serial biopsies
J jL I I
F'
A
a-
®
6.6 8.3
< 0.05 < 0.05
9/26
9/28 3/28 0/28
11.6
< 0.005
15/21
2/14
10.6
< 0.005
3/16
4/6
—
—
123 months of chronic hepatitis. Five patients developed
patients evolved from Group I to Group II after a mean follow-up of 72.5 months (± 20.7), following start of liver disease. Only one patient had an increase in fibrosis score of greater than 1. Risk of cirrhosis and hepatic failure. The risk of dying from hepatic failure was zero after a mean follow-up from start of chronic hepatitis of 76.6 months. The risk of developing endstage liver disease was 0.6. One of the 28 patients developed
_r N
J
N
-J
1
®
portal hypertension after a mean follow-up from start of chronic
Il:le F
1/26 14/26
P
chronic persistent hepatitis after a mean duration of hepatitis before last biopsy of 31.8 6.6 months, and two developed CAH after a mean duration of chronic hepatitis of 46.5 10.5 months. Only six patients had serial biopsies. None of the six
__J
12
HBsAgnegative
formed in 14 of the 28 patients. Six of the 14 patients showed normal liver biopsy, having had chronic hepatitis for 53.3 24 months. One patient had non-specific reactive hepatitis after
St
_EL__
HBsAgpositive
I 36
hepatitis of 6.3 years. Two of the 14 patients who had at least one biopsy developed CAH during a mean follow-up from start of chronic hepatitis of 5 years. The risk of developing aggressive disease (Group II) was 3.5% per patient year following start of liver disease. Seven of the 28 patients had congestive heart failure before
®
I
60
84
I 108
—
132
156
treatment for ESRD began, none had had myocardial infarction, and one had diabetes mellitus.
Post transplantation, months
Fig. 2. Clinical, biochemical, and histological evolution of HB5Ag-
negative chronic hepatitis in renal transplant recipients, Symbols shown in Fig. 1.
Comparison of chronic hepatitis sequelae in HBsAg-positive and negative transplanted patients (Table 3)
Clinical sequelae. The overall mortality rate in transplant patients with chronic hepatitis was significantly higher in the Clinical sequelae. Three of 28 patients died, none of them HBsAg-positive patients (54%), compared to HBsAg-negative from hepatic failure (Table 2). One of the three patients had transplant recipients (11%). remission of chronic hepatitis before dying, one had persistent No HBsAg-negative transplant patients died from liver diselevated enzymes but no autopsy was obtained, one died in ease and 32% underwent spontaneous remission, compared to another city and no histological data was available. None of 35% mortality rate from liver failure in HBsAg-positive patients them had any clinical signs of liver disease. Among the 25 living and 4% remission during period of transplantation. The time of patients with chronic hepatitis, eight had remitted at last follow-up after chronic hepatitis started was similar for both follow-up. Thus, remission from chronic hepatitis had occurred groups, being 90.2 8.9 months in the HBsAg-positive group in 32% of patients with chronic non-B hepatitis. The 17 remain-
and 77.3
8.2 in the HBsAg-negative group. Adverse prognos-
ing transplanted patients with persistent HBsAg-negative tic factors present before treatment for ESRD were similar in chronic hepatitis have been followed for 65 8.7 months since start of liver disease, one of whom has developed splenomegaly and osephageal varicies when followed for 96 months. One patient went back to hemodialysis and remitted after 36 months on dialysis. Morphological outcome. At least one liver biopsy was per-
HBsAg-positive and HBsAg-negative patients. The mean age at time of transplant in the former group was 35 2 and in the
latter group it was 38
2 years. There was no significant
difference between the two groups comparing the incidence of congestive heart failure, myocardial infarction, and diabetes mellitus before treatment for ESRD began.
964
Parfrey et at
Morphological sequelae. Only two of the 14 HBsAg-negative patients who had liver biopsies developed chronic active hepatitis after a mean duration of hepatitis of 50 months, compared to 15 of 21 HBsAg-positive patients (x2 = 10.6, P < 0.005). The histological progression of chronic liver disease when assessed
[12, 13]. Therefore, we have entered patients in our study who persistently have had liver enzymes above the upper limit of normal for at least 1 year. In our study, the overall incidence of chronic hepatitis among ESRD patients was 9.8%, but there was a much higher inci-
by serial biopsies appeared less aggressive in patients with HBsAg-negative hepatitis, compared to the HBsAg-positive patients. Sixty-six percent of the non-B patients remained histologically stable (mean follow-up of 60 24 months alter
dence in transplant patients (15%) compared to patients on dialysis (3.4%). In other studies, the incidence of chronic hepatitis was estimated to be between 6 and 16% in renal
transplant recipients [1—3] and 5 to 28% in hemodialysis patients chronic hepatitis started), compared to only 19% in the HBsAg- [22, 24, 25]. Since our criteria for entry in the study were positive group (follow-up 70 29 months after chronic hepatitis identical in both transplant and dialysis groups, three different started). There was no statistical difference in both groups explanations could explain our findings. First, SOOT measurebetween the mean duration of follow-up after chronic hepatitis ments may have been bad indices of chronic hepatitis in started. patients on dialysis and may have led to an underestimation of
Patients on chronic hemodialysis with chronic hepatitis
Ten patients treated by dialysis for more than 1 year had
viral-induced liver disease in that group of patients because decreased serum SGOT activity has been reported in the serum
of uremic patients [20, 211. Second, the diminished im-
munoresponsiveness in transplant patients who receive immunosuppressive therapy may have put them at increased risk chronic hepatitis started, and two had HBsAg first detected of reactivation of viral replication [6] and of stimulating hischronic hepatitis, half of whom were HBsAg positive. HBsAg-positive. Three patients were HBsAg positive before
alter chronic hepatitis started (7 and 17 months after). One out of five patients reverted to an HBsAg-negative state within 30 months. The four others remained positive during the entire follow-up period. Only one patient had serial liver biopsies. He evolved from virus only to cirrhosis within 92 months. One of the five patients
tologic progression. It has also been reported that patients with normal liver function at time of transplant who subsequently developed active liver disease had abnormal liver biopsies at time of transplantation [11]. Thus, the infection occurred during dialysis, but did not progress to give clinical or biological signs until immunosuppression was prescribed. Immunosuppression
died from cardiac arrhythmias. No patient has died from of HBsAg-positive patients without ESRD who had chronic chronic liver disease. One patient has had remission of chronic hepatitis, and the other three patients have refused biopsy. HBsAg-negative. Five patients had HBsAg negative chronic hepatitis. All but one patient (80%) with non-B hepatitis remitted, compared to only one HBsAg-positive patient (20%). One patient died from sudden death and no patient developed signs of cirrhosis. The single patient whose chronic hepatitis had not remitted at time of the study refused biopsy. A single biopsy was available in one patient and it showed reactive hepatitis. Discussion
This study demonstrates that in patients with end-stage renal disease, chronic hepatitis: (1) occurs less frequently in patients on dialysis compared to transplant patients, (2) has a marked tendency to morphological progression in HBsAg-positive renal transplant patients, associated with an increase in mortality rate due to liver disease, and (3) has a significantly better clinical and
histological outcome in transplant patients with chronic HBsAg-negative hepatitis compared to those who are HBsAg positive. Incidence of chronic hepatitis. The usual definition of chronic hepatitis used in patients without renal disease is the persis-
active hepatitis has also been associated with deleterious effects [27, 28]. Finally, the data may have resulted from selection bias. Preferential treatment with transplantation was often given to HBsAg-positive dialysis patients in the early 1970s. One reason for this was that it was thought that immunosuppression could prevent progression of aggressive disease [22]. Another reason
was that dialysis doctors wanted to decrease the risk of cross infection between HB5Ag-positive and negative patients and, therefore, advised HBsAg-positive transplant patients to undergo transplantation. Hepatitis B-positive hepatitis. In our study, HB virus was responsible for about one-half the cases of chronic hepatitis in both dialysis and transplant groups. In transplant patients, considerable controversy remains concerning their respective evolutions [10, 14]. It appears from prospective histologic studies that HBV liver disease tends to progress to aggressive liver disease in renal transplant recipients [11—13]. HBsAgpositive patients treated with hemodialysis have also been reported to progress to chronic active hepatitis [29]. However, detailed review of the literature reveals the lack of long-term follow-up study in ESRD patients with chronic hepatitis and of any comparison between the outcome of HBsAg-positive and
tence of a serum glutamate pyruvate transaminase level or negative chronic liver disease in dialysis or in transplant glutamatic oxaloacetic transaminase level greater than twice the patients. upper limit of laboratory normal for longer than 6 months [23]. In the general population, persistent HBs antigenemia for However, decreased SGOT activity occurs in dialysis patients more than 6 months occurs in about 10% after acute hepatitis, [20, 211. Consequently, SOOT level above the upper limit of the one-half of whom remain carriers for longer than 2 years. In assay in dialysis patients is probably clinically important and persistent carriers, clinical and histological evidence of chronic may represent high levels of liver disease activity. Further- hepatitis may develop [301. However, only a small proportion
more, in transplant patients with hepatitis B disease, the develop chronic active hepatitis [31, 32]. Progression of liver relationship between serum liver enzyme levels and the activity
disease is usually insidious in the absence of cirrhosis [33—351. of liver disease is poor; patients with active inflammation on The natural history of HBY disease in patients without ESRD is liver biopsy often having SOOT levels less than twice normal shown in Figure 3A. The outcome in transplanted patients is
Chronic hepatitis in ESRD patients
965
A Usual outcomes in HBV infection
B Outcomes of HBV in transplant recipients
Chronic carrier
normal liver
Fig. 3. A. Usual clinical and histological outcomes of acute hepatitis B infection in patients without end-stage renal fialure. (From [31] and a slide of Dienstag, DL, personal communication.) B Outcomes in HBV infection in renal transplant recipients (from [12, 13] and this study.)
markedly different (Fig. 3B). In the current study, none of the HBsAg-positive transplanted patients with chronic hepatitis converted to negative and only one of the dialysis patients did so. A very high proportion (7 1%) of HBsAg-positive renal transplant recipients progressed to chronic active hepatitis, and only 18% of those with serial liver biopsies remained histolog-
ically stable. This progression was associated with a high mortality rate from liver disease. This is consistent with the report from Belgium of a fivefold increased mortality due to hepatic failure in HBsAg-positive patients who became infected in the late 60s and 70s [91 and with our prospective clinical and histologic studies in HBsAg-positive transplant patients [12, 13].
HBsAg-negative hepatitis. In this study, renal transplant recipients with HBsAg-negative hepatitis had a much less aggressive course when compared with HBsAg-positive pa-
HBsAg-positive patients, and mortality was significantly less than that of HBsAg-positive patients. This difference in mortality was not the result of selection bias. Adverse prognostic factors before treatment for ESRD began, such as age, diabetes mellitus, and heart disease [36], were similar in both HBsAgpositive and negative groups. Although fewer serial biopsy specimens were obtained, the overall histologic outcome of chronic non-B hepatitis was less aggressive compared to the HBsAg-positive patients and consistent with the clinical outcome. Only two of the 14 patients (14%) with liver biopsies developed aggressive disease, and 66% of those with serial biopsies remained histologically stable. The duration of follow-up from start of chronic hepatitis was similar to that in the HBsAg-positive chronic hepatitis patients. Figure 4, upper panel, shows the result of chronic non-A, non-B hepatitis in patients without end-stage renal failure. In
tients. Biochemical remission occurred spontaneously in 32% of HBsAg-negative patients, compared to zero remission in these patients, the histological outcome of chronic non-A,
Farfrey et al
966
study, the rate of biochemical remission was higher in HBsAg-
HB,Ag-negative chronic hepatitis in patients without ESRD (35% of acute hepatitis)
55% CPH
Remission
40% CAR
negative compared to HBsAg-positive patients with chronic hepatitis, but death from chronic liver disease did not occur in either group. In view of the frequency of chronic hepatitis in ESRD patients and in view of the policy to give pretranspiant blood transfusions to most potential renal transplant recipients, much larger, multi-center studies to investigate both clinical and morphological outcomes are required to confirm our findings and to determine the exact long-term risk of both RB sAgpositive and negative chronic hepatitis in patients with ESRD.
5%
Cirrhosis
Death
liver disease
HB,Ag-negative chronic hepatitis in renal transplant recipients
I 30% Remission
I 30%
Normal
liver
30% CPH
Reprint requests to Dr. P.S. Parfrey, Division of Nephrology, The Wealth Sciences Centre, St. John's, Newfoundland, Canada
References CAH
i/o
i/o
Cirrhosis
Death liver disease
Fig. 4. Clinical and morphological outcomes of chronic non-A, non-B hepatitis in patients without ESRD (upper panel) (from [31]) and in renal transplant recipients (lower panel).
1. ANURAS S, Pnos J, BONNEY WW, FORKER EL, COLVILLE DS,
Coiut RJ: Liver disease in renal transplant recipients. Arch Intern Med 137:42—48, 1977
2. SOPKO J, ANURA5 S: Liver disease in renal transplant recipients. Am J Med 64:139—146, 1978 3. WARE AJ, LUBY JP, HOLLINGER B, EIGENBRODT EH, CUTHBERT JA, ATKIN CR, SHOREY J, HULL AR, COMBES D: Etiology of liver
disease in renal transplant patients. Ann Intern Med 91:364—371, 1979
non-B hepatitis was 40% developed chronic active hepatitis and 5% cirrhosis when followed for 1 to 3 years [31]. In our study,
4. WEIR MR, KIRKMAN RL, STROM TB, TILNEY NL: Liver disease in
recipients of long functioning renal allografts (abstract). Kidney mt
the outcome in renal transplant recipients was as good, if not better: 5% developed chronic active hepatitis and 5% cirrhosis when followed for 1 to 11 years (Fig. 4, lower panel). Thus, in contrast to HBV disease, it appears that chronic non-B hepatitis in renal transplant recipients has no adverse effect on longevity. One defect of our paper is that data on blood transfusions in
25:352, 1984 5. SHIDEMAN J, NAJARIAN JS, SIMMONS RL, KJELLSTRAND CM: Long-term survival and complications more than 10 years following
the period prior to the development of hepatitis was not
7. BERNE TV, CHATTERJEE SN, Ciio JR, PAYNE JE: Hepatic dysfunction in recipients of renal allografts. Surg Gynecol Obstet
collected. Given the present policy for giving transfusions prior
to transplantation and the likelihood that nontranspianted patients will receive fewer transfusions, such information should be obtained in future studies, especially since the risk of late liver death should be included as a factor when assessing the value of pretransplant transfusions. However, non-A, non-B hepatitis is now the most frequent cause of transfusion-related hepatitis [14] and our paper suggests that chronic non-B hepatitis has a better prognosis than chronic HBV hepatitis in renal transplant recipients. Another paper [37], evolved from the present study, examines the effect of azathioprine reduction on liver disease progression and on graft function. It concludes that late prolonged reduction of azathioprine does not slow the progression of liver disease in renal transplant recipients with either HBsAg-positive or negative chronic hepatitis, nor does it predispose to graft failure. However, reduction of immunosuppression early in the course of hepatitis B disease may be necessary to prevent adverse long-term sequelae in HBsAg hepatitis. In summary, we conclude that chronic hepatitis occurs more frequently in transplant than dialysis patients and is caused by HBV in about one-half the patients. The clinical, biochemical, and morphological course of HBsAg-negative chronic hepatitis is significantly more benign than that of HBsAg-positive renal transplant recipients with chronic hepatitis. A high late mortality due to chronic liver disease occurred in HBsAg-positive patients, which was not observed in HBsAg-negative patients. Although small numbers of hemodialysis patients entered the
renal transplantation, in Uremia. Pathobiology of Patients Treated for 10 Years or More, edited by GIORDANO C, FRIEDMAN EA, Milan, Wichtig Editore, 1981, pp 143—152 6. WElL R, SCHROKER GPJ, WEST JC, STARZL TE: A 14-year experience with kidney transplantation. World J Surg 1:145—150, 1977 141:171—175, 1975
8. WELLER JM, HAINE5 RF, CAMPBELL DA, MOORE FE: Character-
ization of patients with renal transplants functioning for 10 or more years, in Uremia. Pathobiology of Patients Treated for 10 Years or More, edited by GIORDANO C, FRIEDMAN EA, Milan, Wichtig Editore, 1981, pp 175—179 9. PIRSON Y, ALEXANDRE GPJ, VAN YPERSELE DE STRIHOU C: Long-term effects of HB antigenemia on patient survival after renal transplantation. N EngI J Med 296:194-196, 1977 10. STROM TB: Hepatitis B, transfusions and renal transplantation five years later. NEnglJMed3O7:1141—1142, 1982 11. DEGOS F, DEGOTT C, BEDROSSIAN J, CAMILERI JP, BARBANEL C,
DUBOUST A, RUEFF D, BENHAMON JP, KREIS H: Is renal trans-
plantation involved in post-transplantation liver disease? Transplantation 29:100—102, 1980 12. PARFREY PS, FORBES RDC, HUTCHINSON TA, BEAUDOIN JG, DAUPHINEE WD, HOLLOMBY DJ, GUTTMANN RD: The clinical and
pathological course of hepatitis B liver disease in renal transplant recipients. Transplantation, 37:461—466, 1984 13. PARFREY PS, FORBES RDC, HUTCHINSON TA, KENICK 5, FARGE
D, DAUPHINEE WD, SEELY JF, GUTTMANN RD: The impact of
renal transplantation on the course of hepatitis B liver disease. Transplantation 39:610—615, 1985 14. DIENSTAG JL: Non-A, non-B hepatitis I—Recognition, epidemiology, and clinical features. Gastroenterology 85:439—462, 1980 15. KORETZ RL, STONE 0, GITNIcK GL: The long-term course of non-A, non-B post-transfusion hepatitis. Gastroenterology 79:893—898, 1980 16. BERMAN M, ALTER HJ, I5HAK KG, PURCELL RH, JONES EA: The
chronic sequaelae of non-A, non-B hepatitis. Ann Intern Med 91:1—6, 1979
17. REALDI G, ALBERT! A, RUGGE M, RIGOLI AM, TRMOLADA F,
SCHIVAZAPPA L, RAOUL A: Long-term follow-up of acute and
967
Chronic hepatitis in ESRD patients chronic non-A, non-B post-transfusion hepatitis: Evidence of progression to liver cirrhosis. Gut 23:270—275, 1982 18. PARFREY PS, FORBES RDC, HUTCHINSON TA, BEAUDOIN JG, DAUPHINEE WD, GUTTMANN RD: The prevalence and progression
of liver disease in renal transplant recipients: a histological study. Transplant Proc 16:1103—1105, 1984
28. WELLER IVD, BASSENDINE M, MURRAY A, CRAXI A, THOMAS HC, SHERLOCK 5: The effects of prednisone/azathioprine in chronic hepatitis B viral infection. Gut 23:650—655, 1982 29. JUNGERS P, NARET C, DEGOTT C, YENI, T, BACH JF: Histological
and immunological survey of chronic active hepatitis in 650 hemodialyzed patients, in Transplantation and Clinical Immunology, edited by TOURAINE JL, TRAEGER J, BETUEL H, vol 10,
19. CANADIAN MULTICENTER TRANSPLANT STUDY GROUP. A random-
ized clinical trial of cyclosporin in cadaveric renal transplant. N Engi J Med 309:809—815, 1983 20. COHEN GA, GOFFINET JA, DONABEDIN RK, CONN HO: Observa-
tions on decreased glutamic oxaloacetic transaminase (SGOT activity) in azotemic patients. Ann Intern Med 84:275—280, 1976 21. WARNOCK LG, STONE WJ, WAGNER C: Decreased aspartate aminotransferase (SGOT) activity in serum of uremic patients. Clin Chem 20:1213—1216, 1974 22. PARFREY PS, PARADINAS FJ, O'DRIscoLL JB, CURTIS JR, GOWER
PE:
Chronic liver
disease in hemodialysis patients. Proc Eur Dial
Transplant Assoc 19:153—158, 1982 23. SHERLOCK 5: Disease of the Liver (6th ed), Oxford, Blackwell, 1981 24. KNODELL RG, CONRAD ME, ISHAK KG: Development of chronic
liver disease after acute non-A, non-B post-transfusion hepatitis. Gastroenterology 72:902—909, 1977 25. GALBRAITH RM, P0RTMAN B, EDDLESTON ALWF, WILLIAMS R,
GOWER PE:
Chronic
liver disease developing after outbreak of
HsAg-negative hepatitis in hemodialysis unit. Lancet 11:886—889, 1975
26. NAGINGTON 5, COSSART YE, COHEN BJ: Reactivation of hepatitis
B after transplantation operations. Lancet 1:558—560, 1977 27, LAM KC, LAL CL, NG RP, TREPO C, Wu PC: Deleterious effect of prednisone in HB5Ag-positive chronic active hepatitis. N Engl J Med 304:380—386, 1981
Amsterdam, Excerpta Medica, 1979, pp 38—43
30. REDEKER AG: Viral hepatitis—Clinical aspects. Am J Med Sci 270:9—16, 1975
31. DEINHARDT F, DEINHARDT J:
Viral
Hepatitis, Laboratory and
Clinical Science, New York, Marcel Dekker, 1983 32. NIELSEN JO, DIETRICHSON 0, ELLING P, CHRISTOFFERSEN P: Incidence
and meaning of persistence of Australia antigen in
patients with acute viral hepatitis. Lancet 2:1388—1393, 1972 33. DUDLEY FJ, SCHEUER PJ, SHERLOCK 5: Natural history of hepatitis
associated antigen positive chronic liver disease. Lancet 2:1338—1343, 1972
34. VIOLA LA, BARRISON IG, COLEMAN JC, PARADINAS FJ, FLUKER JL, EVAN BA, MURRAY-LYON IM: Natural history of liver disease in chronic hepatitis B surface antigen carriers. Lancet 2:1156-1159, 1981 35.
BECKER MD, SCHEUER PJ, BATISTA A, SHERLOCK S: Prognosis of
chronic persistent hepatitis. Lancet 1:52—56, 1970 36. HUTCHINSON T, DUNCAN T, MACGIBBON B: Predicting survival in
adults with endstage renal disease—An age equivalence index. Ann Intern Med 96:417—423, 1982 37. FARGE D, PARFREY PS, FORBES RDC, DANDAVINO R, GUTTMANN
RD: Reduction of azathioprine in renal transplant recipients with chronic hepatitis, Transplantation in press
Chronic hepatitis in end-stage renal disease: Comparison of HBsAg-negative and HBsAg-positive patients PATRICK S. PARFREY, DOMINQUE FARGE, R.D. CLARKE FORBES, RAYMOND DANDAVINO, SCOTT KENICK, and RONALD D. GUTTMANN Transplant Service, Division of Nephrology and Gastroenterology, Department of Pathology, Royal Victoria Hospital, McGill University, Montreal, and Division of Nephrology, Maisonneuve-Rosemont Hospital, University of Montreal, Montreal, and Division of Nephrology, The Health Sciences Centre, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
Chronic hepatitis in end-stage renal disease: Comparison of HBsAgnegative and HBsAG-positive patients. To determine the outcome of chronic hepatitis in ESRD we studied all 358 renal transplant recipients and 295 hemodialysis patients treated for > 1 year since 1970. The
AgHBs nCgatifs ont progresse vers une hepatite chronique active sur la biopsie hepatique, contre 71% (15/21) chez les patients AgHBs positifs.
Chez les malades ayant eu des biopsies rCpCtCes, une stabilité histologique a etC observCe chez 66% (4/6) des patients AgHB5 nCgatifs, mais seulement chez 18% (13/16) des patients AgHB5 positifs, avec une
incidence of chronic hepatitis (elevated SGOT for> 1 year) was 15% (N = 54) in transplanted and 3.4% (N = 10) in dialysis patients. Forty-eight
durCe de surveillance identique. Aucun patient dialysC n'est mort de maladie hCpatique. Nous concluons que I'hCpatite chronique survient plus frequemment chez les patients transplantCs que dialyses, et que l'hCpatite chronique sans AgHB5 a un devenir cinique et histologique meilleur que celui de l'hepatite chronique avec AgHBs chez les patients
percent (26) of transplanted and 50% (5) of dialysis patients were HB5Ag positive. In the transplanted group, the clinical outcome of chronic hepatitis was significantly better in HB5Ag-negative compared to HBsAg-positive patients; 11% died, none from liver disease, and 32% remitted after a mean follow-up from start of liver disease of 77.3 8.2 months, whereas in the HB5Ag-positive group 54% (14) died, nine from liver disease, and one remitted after a follow-up of 90.2 8.9 months.
transpiantCs.
Adverse prognostic factors (age, duration of diabetes, and heart dis-
ease) present before ESRD treatment began were similar in both groups, as was duration of follow-up. Only 14% (2/14) of HBsAgnegative patients progressed to chronic active hepatitis on liver biopsy
compared to 71% (15/21) of HBsAg-positive patients. Histological
stability in those with serial biopsies occurred in 66% (4/6) of HBsAgnegative patients, but in only 18% (13/16) of HBsAg-positive patients with a similar duration of follow-up. No dialysis patients died from liver disease. We conclude that chronic hepatitis occurs more frequently in transplanted than dialyzed patients, and that HBsAg-negative chronic hepatitis has a more benign, clinical, and histological outcome than chronic HB5Ag-positive hepatitis in renal transplant recipients.
Hépatite chronique au cours de l'insuffisance rénale terminale: comparaison des patients AgHB5 negatifs et AgHBs positifs. Pour
determiner l'Cvolution de l'hepatite chronique au cours de l'IRC terminale nous avons Ctudié l'ensemble des 358 transplantés et 295 hémodialysés traités depuis plus d'un an a partir de 1970. L'incidence de l'hCpatite chronique (SOOT élevées depuis plus d'un an) a etC de 15% (N = 54) chez les transplantes et de 3,4% (N = 10) chez les dialyses. 48% (26) des transplantCs et 50% (5) des dialyses Ctaient AgHBs positifs. Dans le groupe transplantes, l'évolution de l'hepatite chronique a etC significativement meilleure chez les patients AgHBs nCgatifs que chez ceux AgHBs positifs: 11% sont dCcCdCs, aucuns de
maladie hCpatique, et 32% ont guCri après une durCe moyenne de surveillance de 77,3
8,2 mois après le debut de Ia maladie hépatique.
Dans le groupe AgHBs positifs, 54% (14) sont dCcCdCs, 9 de leur maladie hepatique, et un a gueri apres un suivi de 90,2 8,9 mois. Les
Over the last ten years, data has accumulated to suggest that chronic liver disease in renal transplant recipients is responsible for considerable morbidity and mortality [1—101. The incidence
of chronic hepatitis in renal transplant patients has been estimated to be 6 to 16% [1—3] and is usually due to either hepatitis
B virus (HBV) infection or non-A, non-B disease. Recent prospective histological studies demonstrated that in the immu-
nosuppressed renal transplant patient, HBV infection often resulted in the development of chronic active hepatitis, which may lead to cirrhosis and death from hepatoma and hepatic failure [11—13]. The natural course of HBV disease in renal transplant recipients may be progressive and distinct from that in dialysis patients [12, 13]. Non-A, non-B hepatitis is now the most frequent cause of transfusion-related hepatitis [14]. It has a propensity to chronicity in patients without renal disease [15—17]. Among transplant patients, progressive liver disease due to non-A, non-B hepatitis has been reported to occur in about 50% of cases [3], although it may be morphologically more benign than in HBV disease [18]. In patients with long-functioning renal allografts, hepatic failure was the leading cause of death, often associated with extrahepatic sepsis [4]. Actual survival of patients with chronic hepatitis was significantly higher when compared to
facteurs de mauvais pronostic (age, durCe du diabète et maladie cardiaque) presents avant Ic traitement de l'insuffisance rCnale those without chronic hepatitis [4]. A recent editorial [10] chronique dtaient identiques dans les deux groupes, de méme que Ia emphasized the lack of studies available to establish the impact durée de Ia surveillance. 14% (2/14) seulement parmi les patients of transplantation on the course of chronic HBV liver disease. Similar studies are lacking in patients with non-B hepatitis and Received for publication January 18, 1985, and in revised form June 10, 1985
© 1985 by the International Society of Nephrology
are necessary because current policy demands that most patients receive blood transfusions before transplantation. This policy may increase short-term allograft survival, but at the expense of long-term patient survival. 959
Parfrey et a!
960
The purposes of the present study were: (1) to ascertain the incidence and causes of chronic hepatitis in patients treated for end-stage renal disease (ESRD) in two hospitals in Montreal, the Royal Victoria Hospital and Maisonneuve-Rosemont Hospital, since routine HBsAg testing became available; (2) to determine the clinical and histological progression of chronic hepatitis in patients treated for ESRD; (3) to study the cause of death in ESRD patients with chronic hepatitis; and (4) to assess
Chronic hemodialysis group Ten of 295 patients with ESRD treated by dialysis for more than 1 year developed chronic hepatitis. This group consisted of six male and four female patients whose mean age was 39 years 4 SE. Two patients had undergone one renal transplant during the period of follow-up and one patient received two transplants, all of which failed within 3 months. While on dialysis, none of these patients received immunosuppressive agents. The whether the outcome of chronic hepatitis was different in underlying renal diseases were: chronic glomerulonephritis (N patients who were HBsAg negative compared to those who = 5), tuberculosis (N = 1), chronic pyelonephritis/reflux were HBsAg positive. nephropathy (N = 2) and interstitial nephritis (N = 2).
Clinical data The records of all 64 patients treated for ESRD in both study groups were reviewed to document clinical signs and problems related to chronic liver disease. Each living patient was evalu-
Methods
Patients We studied all patients who were treated for ESRD for longer than 1 year and who received their first definitive treatment for chronic renal failure (dialysis or kidney transplant) at the Royal Victoria Hospital and Maisonneuve-Rosemont Hospital from
ated at his or her last follow-up visit for the presence of
jaundice, encephalopathy, flapping tremor, abnormal liver size, splenomegaly, and ascites. Age, presence of diabetes mellitus, occurrence of congestive heart failure, or myocardial infarction January, 1970, to June, 1983. During that period, 358 had before treatment for ESRD began and other serious co-morbid
transplants that functioned for longer than 1 year and 295 illnesses which might have an adverse effect on long-term patients were maintained on dialysis for longer than 1 year. prognosis were recorded. The cause of death was assessed by From these groups, we studied every patient who developed the primary physician. chronic hepatitis, defined as elevated serum glumatic Immunosuppressant dosage (azathioprine, steroids, cyclosporine) were recorded every 6 months from time of entry in the
oxaloacetic transaminase levels for at least 1 year.
study to last follow-up. Exposure to liver toxins, alcohol use, and drug schedules were reviewed in all patients. Three transplant patients were assessed by their personal physicians as alcohol abusers (daily alcohol intake > 6 glasses beer/spirits per
Renal transplant group
Between 1970 and 1983, 54 of 358 patients who had a day). Hepatotoxicity caused by drugs was excluded in all
functioning renal allograft for at least 1 year developed chronic
although one transplant recipient received cyclospohepatitis. This group consisted of 38 male patients and 16 patients, rime A and a second one isoniazid. female patients whose mean age was 36.4 1.4 SE years. All underwent hemodialysis prior to transplantation. The mean Laboratory data 1.4 months (range 1 to 84 duration of dialysis was 13.2 Serum glumatic oxaloacetic transaminase (SGOT) and serum months). All patients but one were treated with a conventional immunosuppressive regimen consisting of high-dose prednisone glumatic pyruvic transaminase (SGPT), alkaline phosphatase, immediately following transplantation, tapering to a mainte- total bilirubin, and HBsAg were recorded before treatment for nance dose of 15 mg/day 1 year after transplantation. ESRD began and then every 6 months during time of follow-up. Azathioprine maintenance dose was usually 100 to 125 mg/day. SGOT were recorded monthly (if performed) for the year prior Patients who developed evidence of acute rejection during to the last liver biopsy. When no biopsy was available (because follow-up were usually treated intravenously with methyl prednisone (750 mg) or high oral prednisone cyclophosphamide
patients had remitted, were dead, or refused the biopsy)
monthly SGOT were recorded for the year prior to last fol-
(400 mg). One patient did not receive azathioprine, but low-up or death.
SGOT, SGPT, and alkaline phosphatase were measured by cyclosporine, according to the Canadian Multicentre Study autoanalyzer. HBsAg was detected by radioimmunoassay, but Protocol [19]. Azathioprine was stopped in six patients and
reduced below 100 mg/day for more than 1 year in an additional the sensitivity for HBsAg detection improved over the 14 years 11 patients. Azathioprine was stopped in one patient because of of the study.
a skin epithelioma, in 15 transplant recipients following the
onset of chronic liver disease, in two patients when they returned to dialysis, and in one patient because of a very good graft function with low immunosuppression dosage. The underlying renal diseases were: primary glomerulonephritis (N = 30), secondary glomerulonephritis (N = 2), obstruction/chronic pyelonephritis (N = 7), diabetes mellitus (N = 4), polycystic
kidney disease (N =
3),
medullary cystic disease (N =
1),
congenital hypoplasialsolitary kidney (N = 2), cystinosis (N = 1), malignant hypertension (N = 2), gout (N = 1) and analgesic nephropathy (N 1).
Definitions Chronic hepatitis was defined as a mean SGOT or SGPT level greater than 40 units/liter for at least 1 year and still elevated 1
year after first high level was observed. We chose this SGOT level because many transplant patients with chronic HBV liver disease have aggressive liver disease with SGOT levels less than twice normal [12] and because SGOT activity is often decreased in azotemic patients [20, 21]. Hepatitis B liver disease denoted the presence of circulating HBsAg.
961
Chronic hepatitis in ESRD patients
Non-B liver disease was defined as the presence of elevated enzymes level (> 40 .dliter) for at least 1 year in the absence of circulating HBsAg or the development of infiltrative disease
Table 1. Demography of HBsAg-positive and negative renal transplant recipients with chronic hepatitis
diagnosed on liver biopsy or observed in another organ, or other known hepatotoxic agents. Remission was indicated when liver enzymes were normal for at least 1 year following hepatitis.
Sex, FIM Mean age at time of transplant, years Time on dialysis before transplantation, months Time of follow-up after transplantation, months
Histological assessment of liver biopsy specimens Patients who were alive at time of the study (1983—4) and in whom transaminase levels had been raised for the previous 12 Time of follow-up after months (mean SGOT > 40 dliter) underwent liver biopsies. chronic liver disease developed, months Previous liver biopsy or autopsy specimens were obtained. Sixteen of the 54 patients with chronic hepatitis had partici- Number of patients a Standard error pated in a prospective histological study of HBsAg-positive
HBsAgpositive
HBsAgnegative
Total
8/18
8/20
16/38
34.7
2.1k
37.6
1.9
36.4
1.4
10.4
3.1
15.7
3.0
13.2
1.4
103.8
9.2
95.2
9.5
98.1
6.3
90.2
8.9
77.3
8.2
83.5
6.0
26
28
54
liver disease in renal transplant recipients which we have
reported previously [12, 131. All biopsy specimens were embed-
ded in parafin, sectioned, and stained with hematoxylin and eosin, periodic acid Schiff, Masson trichrome, and Perl's prussian blue. Both the degree of inflammatory cell infiltration and fibrosis in the liver were graded blind to the clinical state on a scale of 1 to 3. This system was applied separately to each perivenular, lobular, portal, periportal, and septal area on the biopsy. The total inflammatory and total fibrosis scores per biopsy were then calculated [12, 221. Based on these and the
Results
Incidence and causes of chronic hepatitis in ESRD Incidence: Sixty-four patients had elevated liver enzymes for at least 1 year. The incidence of chronic hepatitis in the renal
transplant recipients treated for at least 1 year was 15% (54/358). In the hemodialysis patients treated for more than one year, it was 3.4% (10/295), which was significantly lower than in the transplant group (x 2 = 25.2, P < 0.005). The incidence of
overall morphological appearance, a histological diagnosis was made according to one of eight distinct entities as follows: (1) chronic hepatitis has decreased in renal transplant recipients normal; (2) virus only (V): histologic evidence of HBV within during recent years, the incidence being 20% from 1970—1975, hepatocytes, "ground glass" cells, in otherwise normal biopsy; 12% from 1975—1980, and 10% from 1980—1983. (3) reactive hepatitis (H): hepatocyte necrosis with Causes: The etiology of chronic hepatitis in patients treated
reticuloendothelial proliferation, sometimes with leucocytic for ESRD was divided into two categories according to the and histiocytic infiltration; (4) chronic persistent hepatitis results of HBsAg screening. Forty-eight percent (26/54) of renal (CPH): significant portal mononuclear cell infiltration, absent or transplant recipients with chronic hepatitis were HBsAg posiminimal piecemeal necrosis, insignificant fibrosis, and retention tive, as were 50% (5/10) of hemodialysis patients. Demographic
of normal lobular architecture; (5) chronic active hepatitis data for HBsAg-positive and negative renal transplant recipi(CAH): portal and periportal inflammation with piecemeal ents with chronic hepatitis is shown in Table 1. necrosis, varying degrees of lobular hepatitis and portal fibrosis, often with lobular extention and bridging; (6) cirrhosis (C) with diffuse hepatic fibrosis and nodular regeneration; (7)
hepatocellular carcinoma or hepatoma (K); and (8) other abnormalities.
In the results, categories 2 to 4 (V, H, and CPH) are called Group I (non-aggressive liver disease) and categories 5 to 7 (CAH, C, and K) are called Group II (aggressive liver disease). Ninety-two biopsy specimens were assessed, obtained from
34 of the 64 patients. In the transplant groups 22 of the 54 patients had serial biopsies (the number varying from 2 to 7) and
an additional ten patients had one biopsy. Liver biopsy specimens were not available in 22 patients because they were dead (N = 2), liver disease had remitted (N = 8), they refused biopsy (N = 11) or had a medical contraindication (N = 1). In the chronic hemodialysis group, three biopsy specimens were available in two patients. One patient had one liver biopsy within the first 16 months of starting treatment and the second was carried out after clinical manifestations of chronic liver disease had occurred. One other hemodialysis patient underwent one liver biopsy. In the remaining patients, no biopsy was available because three of them had biological remission, two were dead without autopsy and three were alive but refused biopsy.
HBsAg-positive transplant patients with chronic hepatitis Figure 1 illustrates the time at which chronic hepatitis was initially detected (using liver enzyme determination), the duration of chronic hepatitis during time of follow-up, the time post transplant at which HBsAg was first detected, the duration of the chronic carrier state, and the results of liver biopsies. Hepatitis B serology. Seven patients were HBsAg positive prior to transplantation, four were found to be positive at time of transplant, ten within six months post transplantation, and five more than 6 months after transplantation (Fig. 1). All of these patients had serial HBsAg tests during time of follow-up and none of the 26 converted to negative.
The duration of HBsAg-carner state before hepatitis appeared varied between 0 and 208 months. Four patients had HBsAg first detected after liver enzymes rose (range, 29 to 74 months after enzyme elevation). The other 22 patients who were found to be HBsAg positive before or at time of enzyme elevation had a mean chronic carrier state of 25.0 9.7 months. Clinical sequelae. Fourteen of the 26 patients died, nine of whom (64%) died from liver disease (Table 2). Among the nine patients who died with liver disease, one had chronic persistent
hepatitis, two chronic active hepatitis, five cirrhosis, and one
Parfrey et
962
1
Table 2. Causes of death in HBsAg-positive and negative transplant patients with chronic hepatitis
t
C V
t
A
t LD
U,
A
fYr
C a)
0 CT3
.1 LID
t
I
v
2 2
3
Total
14/26
Total
3/28
HBsAg-negative pneumonia metastatic cancer myocardial infarction
rtLD C ,ILD
JP A
3
Group II. Other causes sepsis brain sarcoma cardiac disease
t LD
Hr AA C
I
No. of patients
HBsAg-positive Group I. End-stage liver disease hepatic failure sepsis + hepatic failure gastrointestinal hemorrhage hepatoma bronchopleural fistula + ascites
PA A
I
al
.tLD
from liver disease; t, death from other causes; _r1_, SGOT > 40 Jliter; —, time on transplant, ---, back to dialysis, — - —,lost from follow-up; N, normal liver; V, virus only; H, reactive hepatitis; P,
liver disease. The second patient remitted and did not undergo biopsy. Morphological outcome. Nineteen patients had histological assessment at most recent follow-up, 14 of whom had developed chronic active hepatitis or cirrhosis (Group II histology). Morphological progression. Histological deterioration was defined as greater than one grade change in total fibrosis score, and it was observed in 12 of 16 (75%) patients who had serial biopsies. A change from Group I benign histology to Group II aggressive histology occurred in ten of the 15 patients (67%). Eight of the 12 patients who progressed died from liver disease. Only one patient out of 16 had histological improvement after 72 months of follow-up, regressing from CPH to virus only. No patients ever regressed from Group II to Group I. The mean follow-up from start of chronic liver disease to last biopsy was 69.7 29.4 months for the four-patients who remained stable and 87.4 12.8 for the 12 who had histological deterioration. Risk of cirrhosis and hepatic failure. Twenty-one patients free from cirrhosis at the time they were found to be HBsAg positive were followed for a total of 159 years (mean/patient, 7.57 years). Eight of the 21 subsequently developed cirrhosis, making the risk of developing cirrhosis 5.0% per patient year. The risk of developing aggressive liver disease (Group II) was 9.4% per patient year. Fifteen of 21 patients developed chronic
chronic persistent hepatitis; F, fibrosis only; A, chronic active hepatitis;
active hepatitis or cirrhosis after a mean follow-up of 7.57
v
c
t V
VV
A
t
A
t __ V C
V
t
t LID
t
LID
C I
12
I 36
I
60
I 84
t 108
132
156
Post transplantation, months
Fig. 1. Clinical, biochemical, and histological evolution of HBsAgpositive chronic hepatitis in renal transplant recipients. Symbols are: f , time of detection of HBsAg; •, patient refused biopsy; tLD, death
C, cirrhosis; K, hepatoma; ®, remission: SGOT normal for> 1 year.
hepatoma. The mean duration of chronic hepatitis was 84.5 13.7 months (21 to 161 months). Clinical signs of chronic liver disease were not observed in patients within the group with benign histology (Group I). One patient with chronic persistent hepatitis died from sepsis and hepatic failure. However, autopsy revealed acute hepatitis with underlying chronic persistent hepatitis. Biochemical remission occurred in one of the 26 patients while transplanted. Two patients went back to dialysis having had a functioning transplant for more than 1 year. One patient had already progressed to cirrhosis and eventually died from
years. The risk of death from liver disease was 4.1% per patient year, specifically, 9 of 26 patients died from liver disease after a mean follow-up of 8.3 years. Assessment of adverse prognostic factors which were present before treatment for ESRD began revealed that nine of the 26
patients had an episode of congestive heart failure before starting treatment for ESRD, one had had a myocardial infarct and three had diabetes mellitus. HBsAg-negative transplant recipients with chronic hepatitis Figure 2 shows the duration of follow-up, evolution of chronic hepatitis, results of liver biopsies, and clinical outcome in all HBsAg-negative transplant patients with chronic hepatitis.
963
Chronic hepatitis in ESRD patients
Table 3. Comparison of the clinical and histological sequelae in HB5Ag-positive and negative renal transplant recipients Outcome
FF
Remission (biochemical) Died Died from liver disease Resulted in chronic active hepatitis or cirrhosis on biopsy Remained histologically stable on serial biopsies
J jL I I
F'
A
a-
®
6.6 8.3
< 0.05 < 0.05
9/26
9/28 3/28 0/28
11.6
< 0.005
15/21
2/14
10.6
< 0.005
3/16
4/6
—
—
123 months of chronic hepatitis. Five patients developed
patients evolved from Group I to Group II after a mean follow-up of 72.5 months (± 20.7), following start of liver disease. Only one patient had an increase in fibrosis score of greater than 1. Risk of cirrhosis and hepatic failure. The risk of dying from hepatic failure was zero after a mean follow-up from start of chronic hepatitis of 76.6 months. The risk of developing endstage liver disease was 0.6. One of the 28 patients developed
_r N
J
N
-J
1
®
portal hypertension after a mean follow-up from start of chronic
Il:le F
1/26 14/26
P
chronic persistent hepatitis after a mean duration of hepatitis before last biopsy of 31.8 6.6 months, and two developed CAH after a mean duration of chronic hepatitis of 46.5 10.5 months. Only six patients had serial biopsies. None of the six
__J
12
HBsAgnegative
formed in 14 of the 28 patients. Six of the 14 patients showed normal liver biopsy, having had chronic hepatitis for 53.3 24 months. One patient had non-specific reactive hepatitis after
St
_EL__
HBsAgpositive
I 36
hepatitis of 6.3 years. Two of the 14 patients who had at least one biopsy developed CAH during a mean follow-up from start of chronic hepatitis of 5 years. The risk of developing aggressive disease (Group II) was 3.5% per patient year following start of liver disease. Seven of the 28 patients had congestive heart failure before
®
I
60
84
I 108
—
132
156
treatment for ESRD began, none had had myocardial infarction, and one had diabetes mellitus.
Post transplantation, months
Fig. 2. Clinical, biochemical, and histological evolution of HB5Ag-
negative chronic hepatitis in renal transplant recipients, Symbols shown in Fig. 1.
Comparison of chronic hepatitis sequelae in HBsAg-positive and negative transplanted patients (Table 3)
Clinical sequelae. The overall mortality rate in transplant patients with chronic hepatitis was significantly higher in the Clinical sequelae. Three of 28 patients died, none of them HBsAg-positive patients (54%), compared to HBsAg-negative from hepatic failure (Table 2). One of the three patients had transplant recipients (11%). remission of chronic hepatitis before dying, one had persistent No HBsAg-negative transplant patients died from liver diselevated enzymes but no autopsy was obtained, one died in ease and 32% underwent spontaneous remission, compared to another city and no histological data was available. None of 35% mortality rate from liver failure in HBsAg-positive patients them had any clinical signs of liver disease. Among the 25 living and 4% remission during period of transplantation. The time of patients with chronic hepatitis, eight had remitted at last follow-up after chronic hepatitis started was similar for both follow-up. Thus, remission from chronic hepatitis had occurred groups, being 90.2 8.9 months in the HBsAg-positive group in 32% of patients with chronic non-B hepatitis. The 17 remain-
and 77.3
8.2 in the HBsAg-negative group. Adverse prognos-
ing transplanted patients with persistent HBsAg-negative tic factors present before treatment for ESRD were similar in chronic hepatitis have been followed for 65 8.7 months since start of liver disease, one of whom has developed splenomegaly and osephageal varicies when followed for 96 months. One patient went back to hemodialysis and remitted after 36 months on dialysis. Morphological outcome. At least one liver biopsy was per-
HBsAg-positive and HBsAg-negative patients. The mean age at time of transplant in the former group was 35 2 and in the
latter group it was 38
2 years. There was no significant
difference between the two groups comparing the incidence of congestive heart failure, myocardial infarction, and diabetes mellitus before treatment for ESRD began.
964
Parfrey et at
Morphological sequelae. Only two of the 14 HBsAg-negative patients who had liver biopsies developed chronic active hepatitis after a mean duration of hepatitis of 50 months, compared to 15 of 21 HBsAg-positive patients (x2 = 10.6, P < 0.005). The histological progression of chronic liver disease when assessed
[12, 13]. Therefore, we have entered patients in our study who persistently have had liver enzymes above the upper limit of normal for at least 1 year. In our study, the overall incidence of chronic hepatitis among ESRD patients was 9.8%, but there was a much higher inci-
by serial biopsies appeared less aggressive in patients with HBsAg-negative hepatitis, compared to the HBsAg-positive patients. Sixty-six percent of the non-B patients remained histologically stable (mean follow-up of 60 24 months alter
dence in transplant patients (15%) compared to patients on dialysis (3.4%). In other studies, the incidence of chronic hepatitis was estimated to be between 6 and 16% in renal
transplant recipients [1—3] and 5 to 28% in hemodialysis patients chronic hepatitis started), compared to only 19% in the HBsAg- [22, 24, 25]. Since our criteria for entry in the study were positive group (follow-up 70 29 months after chronic hepatitis identical in both transplant and dialysis groups, three different started). There was no statistical difference in both groups explanations could explain our findings. First, SOOT measurebetween the mean duration of follow-up after chronic hepatitis ments may have been bad indices of chronic hepatitis in started. patients on dialysis and may have led to an underestimation of
Patients on chronic hemodialysis with chronic hepatitis
Ten patients treated by dialysis for more than 1 year had
viral-induced liver disease in that group of patients because decreased serum SGOT activity has been reported in the serum
of uremic patients [20, 211. Second, the diminished im-
munoresponsiveness in transplant patients who receive immunosuppressive therapy may have put them at increased risk chronic hepatitis started, and two had HBsAg first detected of reactivation of viral replication [6] and of stimulating hischronic hepatitis, half of whom were HBsAg positive. HBsAg-positive. Three patients were HBsAg positive before
alter chronic hepatitis started (7 and 17 months after). One out of five patients reverted to an HBsAg-negative state within 30 months. The four others remained positive during the entire follow-up period. Only one patient had serial liver biopsies. He evolved from virus only to cirrhosis within 92 months. One of the five patients
tologic progression. It has also been reported that patients with normal liver function at time of transplant who subsequently developed active liver disease had abnormal liver biopsies at time of transplantation [11]. Thus, the infection occurred during dialysis, but did not progress to give clinical or biological signs until immunosuppression was prescribed. Immunosuppression
died from cardiac arrhythmias. No patient has died from of HBsAg-positive patients without ESRD who had chronic chronic liver disease. One patient has had remission of chronic hepatitis, and the other three patients have refused biopsy. HBsAg-negative. Five patients had HBsAg negative chronic hepatitis. All but one patient (80%) with non-B hepatitis remitted, compared to only one HBsAg-positive patient (20%). One patient died from sudden death and no patient developed signs of cirrhosis. The single patient whose chronic hepatitis had not remitted at time of the study refused biopsy. A single biopsy was available in one patient and it showed reactive hepatitis. Discussion
This study demonstrates that in patients with end-stage renal disease, chronic hepatitis: (1) occurs less frequently in patients on dialysis compared to transplant patients, (2) has a marked tendency to morphological progression in HBsAg-positive renal transplant patients, associated with an increase in mortality rate due to liver disease, and (3) has a significantly better clinical and
histological outcome in transplant patients with chronic HBsAg-negative hepatitis compared to those who are HBsAg positive. Incidence of chronic hepatitis. The usual definition of chronic hepatitis used in patients without renal disease is the persis-
active hepatitis has also been associated with deleterious effects [27, 28]. Finally, the data may have resulted from selection bias. Preferential treatment with transplantation was often given to HBsAg-positive dialysis patients in the early 1970s. One reason for this was that it was thought that immunosuppression could prevent progression of aggressive disease [22]. Another reason
was that dialysis doctors wanted to decrease the risk of cross infection between HB5Ag-positive and negative patients and, therefore, advised HBsAg-positive transplant patients to undergo transplantation. Hepatitis B-positive hepatitis. In our study, HB virus was responsible for about one-half the cases of chronic hepatitis in both dialysis and transplant groups. In transplant patients, considerable controversy remains concerning their respective evolutions [10, 14]. It appears from prospective histologic studies that HBV liver disease tends to progress to aggressive liver disease in renal transplant recipients [11—13]. HBsAgpositive patients treated with hemodialysis have also been reported to progress to chronic active hepatitis [29]. However, detailed review of the literature reveals the lack of long-term follow-up study in ESRD patients with chronic hepatitis and of any comparison between the outcome of HBsAg-positive and
tence of a serum glutamate pyruvate transaminase level or negative chronic liver disease in dialysis or in transplant glutamatic oxaloacetic transaminase level greater than twice the patients. upper limit of laboratory normal for longer than 6 months [23]. In the general population, persistent HBs antigenemia for However, decreased SGOT activity occurs in dialysis patients more than 6 months occurs in about 10% after acute hepatitis, [20, 211. Consequently, SOOT level above the upper limit of the one-half of whom remain carriers for longer than 2 years. In assay in dialysis patients is probably clinically important and persistent carriers, clinical and histological evidence of chronic may represent high levels of liver disease activity. Further- hepatitis may develop [301. However, only a small proportion
more, in transplant patients with hepatitis B disease, the develop chronic active hepatitis [31, 32]. Progression of liver relationship between serum liver enzyme levels and the activity
disease is usually insidious in the absence of cirrhosis [33—351. of liver disease is poor; patients with active inflammation on The natural history of HBY disease in patients without ESRD is liver biopsy often having SOOT levels less than twice normal shown in Figure 3A. The outcome in transplanted patients is
Chronic hepatitis in ESRD patients
965
A Usual outcomes in HBV infection
B Outcomes of HBV in transplant recipients
Chronic carrier
normal liver
Fig. 3. A. Usual clinical and histological outcomes of acute hepatitis B infection in patients without end-stage renal fialure. (From [31] and a slide of Dienstag, DL, personal communication.) B Outcomes in HBV infection in renal transplant recipients (from [12, 13] and this study.)
markedly different (Fig. 3B). In the current study, none of the HBsAg-positive transplanted patients with chronic hepatitis converted to negative and only one of the dialysis patients did so. A very high proportion (7 1%) of HBsAg-positive renal transplant recipients progressed to chronic active hepatitis, and only 18% of those with serial liver biopsies remained histolog-
ically stable. This progression was associated with a high mortality rate from liver disease. This is consistent with the report from Belgium of a fivefold increased mortality due to hepatic failure in HBsAg-positive patients who became infected in the late 60s and 70s [91 and with our prospective clinical and histologic studies in HBsAg-positive transplant patients [12, 13].
HBsAg-negative hepatitis. In this study, renal transplant recipients with HBsAg-negative hepatitis had a much less aggressive course when compared with HBsAg-positive pa-
HBsAg-positive patients, and mortality was significantly less than that of HBsAg-positive patients. This difference in mortality was not the result of selection bias. Adverse prognostic factors before treatment for ESRD began, such as age, diabetes mellitus, and heart disease [36], were similar in both HBsAgpositive and negative groups. Although fewer serial biopsy specimens were obtained, the overall histologic outcome of chronic non-B hepatitis was less aggressive compared to the HBsAg-positive patients and consistent with the clinical outcome. Only two of the 14 patients (14%) with liver biopsies developed aggressive disease, and 66% of those with serial biopsies remained histologically stable. The duration of follow-up from start of chronic hepatitis was similar to that in the HBsAg-positive chronic hepatitis patients. Figure 4, upper panel, shows the result of chronic non-A, non-B hepatitis in patients without end-stage renal failure. In
tients. Biochemical remission occurred spontaneously in 32% of HBsAg-negative patients, compared to zero remission in these patients, the histological outcome of chronic non-A,
Farfrey et al
966
study, the rate of biochemical remission was higher in HBsAg-
HB,Ag-negative chronic hepatitis in patients without ESRD (35% of acute hepatitis)
55% CPH
Remission
40% CAR
negative compared to HBsAg-positive patients with chronic hepatitis, but death from chronic liver disease did not occur in either group. In view of the frequency of chronic hepatitis in ESRD patients and in view of the policy to give pretranspiant blood transfusions to most potential renal transplant recipients, much larger, multi-center studies to investigate both clinical and morphological outcomes are required to confirm our findings and to determine the exact long-term risk of both RB sAgpositive and negative chronic hepatitis in patients with ESRD.
5%
Cirrhosis
Death
liver disease
HB,Ag-negative chronic hepatitis in renal transplant recipients
I 30% Remission
I 30%
Normal
liver
30% CPH
Reprint requests to Dr. P.S. Parfrey, Division of Nephrology, The Wealth Sciences Centre, St. John's, Newfoundland, Canada
References CAH
i/o
i/o
Cirrhosis
Death liver disease
Fig. 4. Clinical and morphological outcomes of chronic non-A, non-B hepatitis in patients without ESRD (upper panel) (from [31]) and in renal transplant recipients (lower panel).
1. ANURAS S, Pnos J, BONNEY WW, FORKER EL, COLVILLE DS,
Coiut RJ: Liver disease in renal transplant recipients. Arch Intern Med 137:42—48, 1977
2. SOPKO J, ANURA5 S: Liver disease in renal transplant recipients. Am J Med 64:139—146, 1978 3. WARE AJ, LUBY JP, HOLLINGER B, EIGENBRODT EH, CUTHBERT JA, ATKIN CR, SHOREY J, HULL AR, COMBES D: Etiology of liver
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non-B hepatitis was 40% developed chronic active hepatitis and 5% cirrhosis when followed for 1 to 3 years [31]. In our study,
4. WEIR MR, KIRKMAN RL, STROM TB, TILNEY NL: Liver disease in
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the outcome in renal transplant recipients was as good, if not better: 5% developed chronic active hepatitis and 5% cirrhosis when followed for 1 to 11 years (Fig. 4, lower panel). Thus, in contrast to HBV disease, it appears that chronic non-B hepatitis in renal transplant recipients has no adverse effect on longevity. One defect of our paper is that data on blood transfusions in
25:352, 1984 5. SHIDEMAN J, NAJARIAN JS, SIMMONS RL, KJELLSTRAND CM: Long-term survival and complications more than 10 years following
the period prior to the development of hepatitis was not
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collected. Given the present policy for giving transfusions prior
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D, DAUPHINEE WD, SEELY JF, GUTTMANN RD: The impact of
renal transplantation on the course of hepatitis B liver disease. Transplantation 39:610—615, 1985 14. DIENSTAG JL: Non-A, non-B hepatitis I—Recognition, epidemiology, and clinical features. Gastroenterology 85:439—462, 1980 15. KORETZ RL, STONE 0, GITNIcK GL: The long-term course of non-A, non-B post-transfusion hepatitis. Gastroenterology 79:893—898, 1980 16. BERMAN M, ALTER HJ, I5HAK KG, PURCELL RH, JONES EA: The
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