Risk of death and liver cirrhosis in anti-HCV-positive long-term haemodialysis patients

Mario Espinosa, Alejandro Martin-Malo, Maria Antonia Alvarez de Lara and Pedro Aljama

Servicio de Nefrologia, Hospital Universitario Reina Sofia, Cordoba, Spain



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Hepatitis C virus (HCV) infection is the most common cause of chronic liver disease in haemodialysis patients. The aim of this study was to assess the impact of HCV infection on patient survival in a cohort of long-term haemodialysis patients and to evaluate the percentage of anti-HCV-positive patients that evolve to liver cirrhosis.

Methods. In 1992, 175 patients who had been on intermittent haemodialysis therapy for at least 6 months were included in the study (57 anti-HCV-positive and 118 anti-HCV-negative patients). Evaluation of patient outcome included date and cause of death, kidney transplantation, and the diagnosis of liver cirrhosis. Patient survival was estimated by the Kaplan–Meier method and compared by the log-rank test. The Cox proportional hazards model was used to estimate the risk of death among dialysis patients who were anti-HCV positive. Other prognostic variables studied included age, gender, diabetes mellitus as cause of end-stage renal disease (ESRD), history of previous transplant, transplantation during follow-up, and time on haemodialysis treatment. The diagnosis of liver cirrhosis was made based on clinical and/or histological criteria.

Results. Eight-year patient survival in anti-HCV-positive subjects was lower (32%) than in anti-HCV-negative patients (52%) (log-rank, P=0.03). Four variables were found to be independent prognostic factors in patient survival: age (relative risk (RR) 1.04); diabetes as cause of ESRD (RR 3.6); transplantation during follow-up (RR 0.66) and presence of HCV antibodies (RR 1.62). The causes of death did not differ significantly between groups, except that four anti-HCV-positive patients died from liver disease. Ten (17.5%) of the 57 anti-HCV-positive patients were diagnosed to have liver cirrhosis at a median of 10 years after renal replacement therapy initiation and a median of 7 years after the first ALT level increase.

Conclusion. In conclusion, our study shows an increased risk of death among long-term haemodialysis patients infected with HCV compared with non-infected patients. This might be partly explained by the high proportion of these patients that evolve to liver cirrhosis.

Keywords: cirrhosis; death; haemodialysis; hepatitis C virus; survival



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Hepatitis C virus (HCV) infection is the most common cause of chronic liver disease among haemodialysis (HD) patients and renal transplantation recipients. However, the long-term complications of this infection in these patients have not been elucidated. The impact of HCV infection on patient survival after kidney transplantation remains controversial. Most studies evaluating the impact of HCV on graft and patient survival do not show a significant difference between anti-HCV-positive and -negative patients [15]. However, recent reports [610] have shown a deleterious effect on long-term graft and patient survival among kidney transplant recipients. These contradictory results may be attributed to many factors, the most important of which is in all likelihood the time of evolution of chronic liver disease. Chronic hepatitis-associated mortality is mainly a result of the development of liver fibrosis and, subsequently, cirrhosis. Therefore, a long-term follow-up is probably needed to demonstrate a deleterious effect on survival in HCV-infected patients. In HD patients this controversy does not exist, maybe due to a lack of information. Only two recent reports have shown a relationship between HCV infection and poor survival [6,11]. Furthermore, no data exists concerning the percentage of anti-HCV-positive HD patients who evolve to liver cirrhosis. This information is crucial because if HD patients with HCV infection are at an increased risk of death or liver cirrhosis, this would justify the huge effort needed to identify, prevent and treat this infection.

The aims of the present study were: (i) to assess the impact of HCV infection on patient survival in a cohort of long-term HD patients; and (ii) to determine the percentage of anti-HCV-positive patients who evolve to liver cirrhosis.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
The present study was undertaken using a prospective cohort design. All patients undergoing regular haemodialysis in the area of Cordoba (Spain) on January 1992 (n=214) were initially included in the study. Patients attended either a central hospital dialysis unit or one of the four outlying dialysis units. Conventional haemodialysis techniques were performed, for 3–5 h per treatment three times a week. Bicarbonate dialysis was used for all patients. Dialysis prescriptions were individually adjusted to achieve a target Kt/V of >=1.2. Medication included phosphate binders, iron, multivitamins, anti-hypertensive drugs and calcitriol.

Patients who had undergone haemodialysis for<6 months (n=28) were excluded from the study, as well as eight who were anti-HCV-negative at enrollment and who suffered from acute hepatitis in the follow-up, and three HBeAg-positive patients (one of them anti-HCV positive). Eight patients classified as HBsAg ‘healthy’ carriers (HBsAg positive, and HBeAg and HBV-DNA negative) were included in the study. These eight patients were enrolled because in a large survey of HBsAg carriers, only a few non-uraemic [12,13] and uraemic [14,15] patients were found to have serious liver disease with excellent long-term survival.

Clinical information registered at the time of enrollment included age, gender, time on haemodialysis, diabetes as a cause of end-stage renal disease (ESRD), previous transplant, and anti-HCV status. Patients were followed up until death or the end of the study, on 31 December 1999. The causes of death during the 8-year follow-up period were classified as cardiovascular, liver, malignancies, infections, unknown and other miscellaneous diseases.

Diagnosis of liver cirrhosis was made by clinical criteria (ascites, jaundice, bleeding oesophageal varices, hepatic encephalopathy, prolonged prothrombin time and albumin <3 g/dl) in five subjects and by histological criteria in another five anti-HCV-positive patients. In four of these patients, the liver biopsy was indicated because they presented high ALT levels. In the other patient, who had normal ALT levels, the liver biopsy specimen was obtained during a surgical procedure. None of the patients included in this study admitted to being an alcohol abuser. Liver histology was evaluated according to established histological criteria. Chronic active hepatitis (CAH) was characterized by piecemeal necrosis and parenchymal inflammation. The degree of fibrosis was graded as follows: 0, no fibrosis; 1, portal fibrosis; 3, bridging fibrosis; or 4, cirrhosis. Case records of the patients with liver cirrhosis were analysed in a retrospective manner to determine the probable date of acute hepatitis. These occurred before 1990, when enzyme immunoassays to detect anti-HCV were unavailable in nine patients. Acute hepatitis was diagnosed when the first increase in transaminase levels was observed, requiring previous monthly determinations of ALT under the ‘normal’ limit (<27 IU/l). Our preliminary studies [16] have shown that in our dialysis unit, 27 IU/l is the upper limit (mean+2 SD) of ALT for HD patients without liver disease. ALT levels were determined in all HD patients every month, thus making it relatively uncomplicated to determine the probable date of acute hepatitis. The ALT value used for calculation purposes was, for each anti-HCV-positive patient, the mean value for the 12 monthly tests obtained in the last year of the follow-up. Patients were considered to have high ALT levels if the mean annual ALT level was >27 IU/l.

Anti-HCV-positive patients were deemed viremic if at least one polymerase chain reaction (PCR) test was positive, and non-viremic when all PCR results were negative. These definitions were used because if there is no contamination, false-positive PCR results are unlikely. By contrast, false-negative PCR results may occur due to the fluctuating pattern of viremia or a low virus level in the blood of HD patients.

Laboratory methods
Complete blood biochemistry, HBsAg and anti-HCV tests were performed in all patients on a monthly basis during the period of study. HBeAg and HBV-DNA tests were performed at 6-month intervals on HBsAg-positive patients. HBsAg was radioimmunoassay tested (Abbott Laboratories). Anti-HCV was assayed in all patients occasionally from 1990 to 1991 by first generation. Before the patients were enrolled in the study in January 1992, the anti-HCV was determined monthly in all HD patients by second-generation ELISA (Abbott Laboratories). In 1995, this assay was changed by the Imx HCV assay (Abbott Laboratories).

Baseline, a second-generation immunoblot assay (RIBA HCV 2.0 SIA; Chiron Corporation) was performed on all anti-HCV-positive HD patients to confirm the ELISA result. HCV-RNA was determined annually from 1996 in all anti-HCV-positive patients by PCR, using the Amplicor diagnostic system (Hoffman-LaRoche). Anti-HCV was used as a disease marker because it is an uncomplicated test, and was performed monthly on all HD patients. However, PCR studies (which were not performed on all patients) do have certain technical limitations.

Statistical analysis
The chi-square test was used to compare qualitative values, and the student's test was used to compare quantitative variables. Results are expressed as mean±standard deviation. All statistical tests are two-tailed. A P value of <0.05 is considered statistically significant.

Two analyses were performed to evaluate the impact of HCV infection on survival; the Kaplan–Meier analysis and the Cox proportional hazards analysis. The Cox proportional hazards model was used to estimate the adjusted relative risk of each parameter with regard to survival. The prognostic variables studied included anti-HCV-positive, age, male gender, diabetes mellitus as cause of ESRD, history of previous transplant, time on haemodialysis in 1992, and transplantation during the follow-up period. Transplantation during the follow-up was treated as a time-dependent covariate. For each risk factor, its effect was assessed as an effect modifier or confounder. Once potential confounders were shown to have no association with death, they were omitted from the final model. Variables were selected by backward elimination using likelihood ratio tests. For categorical variables, the RR was equal to eB, where B is the regression coefficient for that variable. Both age and time on haemodialysis in 1992 were analysed as continuous variables increasing per year. Eight-year patient survival was estimated by the Kaplan–Meier method and compared by log-rank test. When analysing patient survival, a switch to peritoneal dialysis was regarded as censored information. Patients did not contribute to the part of the survival curve during the interval between onset of renal replacement therapy and enrollment in the study in 1992. The survival curve was therefore truncated on the left and censored on the right. Calculations were performed using SPSS statistical software (SPSS, Chicago, IL, USA).



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
One-hundred-and-seventy-five patients were included in the final study group, 57 of whom (32.5%) were anti-HCV positive. During the 8-year follow-up, 81 patients (46.2%) died and 42 patients (24%) underwent kidney transplantation (nine anti-HCV-positive patients and 33 anti-HCV-negative patients; P=0.07). No patient was transferred to a dialysis unit outside Cordoba, and only one patient switched to peritoneal dialysis. Clinical characteristics of the anti-HCV-positive and -negative patients are shown in Table 1Go. It should be stressed that anti-HCV-positive patients underwent haemodialysis treatment for a longer period than those without HCV infection (8.4±4.5 vs 4.0±2.8 years, P<0.0001). HCV-RNA was performed during the follow-up in 45 of the 57 (79%) anti-HCV-positive HD patients, and 34 (75.6%) were considered viremic. In 33 of the 57 (57.9%) anti-HCV-positive patients, the mean ALT in the last year of follow-up was >27 IU/l.


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Table 1. Clinical characteristics at baseline and causes of death among anti-HCV-positive and -negative HD patients

 
Analysis of the baseline covariants (Table 2Go) showed that age, diabetes as cause of ESRD and anti-HCV-positive status were significantly associated with increased mortality. Table 3Go shows the Cox proportional hazards model. Four variables were found to be an independent prognostic value in patient survival: age (RR 1.04), diabetes (RR 3.6), presence of HCV antibodies (RR 1.62), and transplantation during the follow-up period (RR 0.66). Gender, time on haemodialysis and history of previous transplant were not significant predictors of mortality. Figure 1Go shows survival among anti-HCV-negative and -positive patients. Eight-year patient survival was 32% for anti-HCV-positive patients against 52% for anti-HCV-negative patients (log-rank test, P=0.03).


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Table 2. Clinical characteristics among patients that died in the follow-up

 

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Table 3. Results of the multivariate Cox proportional hazard analysis

 


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Fig. 1. Patient survival in anti-HCV-positive (dotted line) and -negative (solid line) patients. Shown is the actuarial survival from 1992 until death (n=81) or December 1999, whichever occurred first. By the log-rank test, P=0.03.

 
The causes of death during the follow-up period are shown in Table 4Go. They did not differ significantly between both groups. It should be noted, however, that four anti-HCV-positive patients died from liver disease.


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Table 4. Clinical characteristics of anti-HCV-positive patients according to liver cirrhosis

 
Ten (17.5%) of the 57 anti-HCV-positive patients (one of them HBsAg-positive) were diagnosed of liver cirrhosis with a median of 10 years (range 4–16 years) after initiating renal replacement therapy. The probable date of acute hepatitis was known in nine of them. These nine patients were diagnosed with liver cirrhosis for a median of 7 years (range 3.6–15 years) after the first ALT level increase. Table 4Go shows the clinical and biochemical characteristics of the anti-HCV-positive patients with liver cirrhosis. Five (50%) of the 10 anti-HCV-positive patients with liver cirrhosis were diagnosed by liver biopsy (three patients had cirrhosis associated with CAH and two had inactive cirrhosis). This finding was unexpected as these five patients showed no clinical liver cirrhosis criteria. Prothrombin time, albumin and bilirubin were also normal. It is interesting to note that one of these patients with liver cirrhosis also showed normal ALT levels (<27 IU/l) in the last year and was diagnosed during a surgical procedure. In one patient, the evolution to liver cirrhosis was particularly rapid. This patient suffered acute hepatitis C 1 month after presenting with retroperitoneal haematoma, which was treated with blood transfusions and surgery. The seroncoversion of anti-HCV and the detection of HCV-RNA in serum confirmed the diagnosis of acute hepatitis C. HBsAg, DNA-HBV and anti-HIV were negative. A liver histology obtained 8 months after the acute hepatitis episode showed a CAH with bridging necrosis; a laparoscopy performed 1 year later showed cirrhosis of the liver. The patient developed decompensated cirrhosis and died as a result 3 years after the acute episode. In the other five patients, the diagnosis of liver cirrhosis was made by clinical and biochemical criteria. All these patients with liver cirrhosis died in the follow-up (four liver disease, two malignancy, one sepsis and three other causes). All three HBeAg-positive patients (one of them anti-HCV positive) excluded from the present study were also diagnosed with liver cirrhosis during the follow-up period and died from liver disease.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This study demonstrates that in long-term HD patients, the presence of anti-HCV was associated with a higher risk of death and that 17.5% of these patients evolved to liver cirrhosis 10 years after initiation of renal replacement therapy.

It is reasonable to think that HCV infection increases the risk of death among HD patients, whether or not long-term complications (mainly cirrhosis and carcinoma) are present. The interval between the initial presentation of post-transfusion NANB in retrospective studies and the onset of chronic hepatitis, cirrhosis and hepatocelular carcinoma is 10, 21 and 29 years, respectively, in non-uraemic patients [17,18]. This long-term follow-up is difficult to obtain in HD patients. It must be taken into account that HD patients have an annual death rate of 16.1% [19], and an overall cumulative probability of survival at 10 years of 54% [20] might be considered excellent. Time on haemodialysis can be used as an approximate estimation of the evolution of HCV infection, as most anti-HCV-positive patients acquire the infection during haemodialysis therapy. Furthermore, at least before the use of erythropoietin, patients were at greater risk of acquiring this infection at the beginning of renal replacement therapy, when more blood transfusions were needed. Mean time on haemodialysis in the anti-HCV-positive patients in our study before enrollment was 8.4 years, and the follow-up time was 8 years. Liver disease evolution was probably long, with a high probability of developing end-stage liver disease. Indeed, cirrhosis was present in 17.5% of the anti-HCV-positive patients at a median 10 years after initiation of renal replacement therapy and a median 7 years after the first ALT level increase. To our knowledge this is the first time that this evolution has been quantified. This finding is in accordance with histological studies in which 5.8–9.5% of anti-HCV-positive patients had liver cirrhosis [2123]. Moreover, considering that progression of liver disease to cirrhosis is silent, that biochemical data on cirrhosis are only present in the advanced stages of liver cirrhosis, and even that ALT levels can be ‘normal’ because these values in HD patients are lower than in non-uraemic patients, some cases of cirrhosis can remain undiagnosed if a liver biopsy is not performed. This evolution to cirrhosis is difficult to compare with that described in non-uraemic patients. Moreover, the natural history of chronic HCV infection in non-uraemic patients has not been fully defined [24]. Prospective studies of transfusion-associated non-A, non-B hepatitis in non-uraemic patients showed that 8–14 years after acute hepatitis, 8–24% of the patients had histologically defined cirrhosis. We have observed a rapid progression to liver cirrhosis, which is in contrast to the general population. Although the diagnosis of liver cirrhosis could be anticipated in HD patients due to the strict medical controls that are carried out, it is reasonable to think that immune dysfunctions associated with uraemia would justify this evolution. In this regard it has been reported that HCV infection in immunocompromised patients has a severe and rapidly progressive course [25]. Other factors that might promote progression of HCV-related chronic liver disease are viral dose at the time of infection and viral genotype. Some authors conclude that a more severe disease is associated with genotype 1b, although the data are contradictory [24]. Although the amount of virus involved in haemodialysis-acquired HCV transmission is presumably far less than that associated with transfusion, its role in predicting cirrhosis is unknown. Other prospective studies with more patients, taking into consideration the exact date of acute hepatitis and all these factors, are needed to answer this question.

Our analysis showed that patients with HCV infection have an increased risk of death (RR 1.62) compared with those not infected. In a group of patients referred for kidney transplantation, Pereira et al. showed that the relative risk of death was 1.41 for anti-HCV-positive patients compared with anti-HCV-negative subjects [6]. Stehman-Breen et al. were the first to compare the risk of death of chronic dialysis patients infected with HCV with those not infected, showing the relative risk of death to be 1.78 [11]. Time on haemodialysis did not increase the risk of death during the follow-up, as has been shown in other studies [26,27]. Diabetic patients fared worse than non-diabetic patients, as has been reported previously [28,29]. Age was also a significant risk factor for the survival of dialysis patients, as has been found in other studies [19,28].

The finding of a deleterious impact of HCV on survival in HD patients is at variance with outcomes in studies on non-uraemic patients with post-transfusion NANBH. Seeff et al. [30] showed that after an average follow-up of 18 years, mortality among patients with post-transfusion NANBH was similar to two control groups of patients. This less favorable evolution in anti-HCV-positive HD patients might be explained by immune dysfunctions associated with uraemia and chronic liver disease. Patients with advanced liver disease and cirrhosis have multiple immunological defects [31] which, exacerbated by the immune uraemia dysfunction [32,33], would increase the risk of lethal infections and cancer. In this regard, Pereira et al. [6] reported that anti-HCV-positive patients referred for kidney transplantation are 2.4 times more likely to die as a result of liver disease or infection. In our study, liver disease was the cause of death in four patients (11.8%), and anti-HCV-positive patients with liver cirrhosis were more likely to die as a result of liver disease or malignancy than anti-HCV-positive patients without liver cirrhosis.

In conclusion, our study found an increased risk of death among long-term HD patients infected with HCV compared with non-infected patients. This would be explained by the high proportion of these patients that evolve to liver cirrhosis.



   Acknowledgments
 
The authors wish to thank Dr Vicente Barrio for statistical assistance with the manuscript.



   Notes
 
Correspondence and offprint requests to: Dr Mario Espinosa, Servicio de Nefrologia, Hospital Universitario Reina Sofia, Avda Menendez Pidal s/n, E-14004 Cordoba, Spain. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 24. 1.00
Revision received 2. 3.01.