The purpose of this study was to examine the effect of pretransplant interferon administration on the occurrence of post-transplant de novo glomerulonephritis in hepatitis C virus (HCV)-positive renal allografts. From December 1992 to December 2000, 78 HCV-positive patients received a renal allograft in our unit. Fifteen out of 78 received pretransplant interferon for 1 year. Hepatitis C virus was investigated by serology and qualitative polymerase chain reaction (PCR). Hepatitis C virus-related de novo glomerulonephritis (membranoproliferative or membranous) was suggested by proteinuria (>1.5 g/24 h) and/or microhematuria and always diagnosed by renal biopsy. Of 15 HCV-positive recipients who received pretransplant interferon, 10 (67%) became HCV-RNA negative at the time of transplantation and only one out of the 15 (6.7%) developed de novo glomerulonephritis (this patient was HCV-RNA positive at transplantation). Among non-interferon-treated allograft recipients, 28.7% had negative HCV-RNA and 12 out of 63 (19%) developed de novo glomerulonephritis (9, membranoproliferative; 3 membranous), all 12 having positive HCV-RNA at transplantation (p < 0.0001). In conclusion, pretransplant interferon may reduce the occurrence of post-transplant HCV-related de novo glomerulonephritis. Our results suggest that the indication for pretransplant interferon should be extended to treat all HCV-RNA positive candidates for renal transplantation.
Hepatitis C virus (HCV) infection complicates clinical outcome in liver and renal allografts (1). Besides its important contribution to chronic liver disease, HCV infection is also a relevant cause of de novo immune-mediated glomerulonephritis in both kidney and liver transplantation (2,3). In a previous work we demonstrated that de novo type I membranoproliferative glomerulonephritis (MPGN) is mediated by a very low level of nephritogenic type II cryoglobulins containing HCV-RNA (4). Recently, we showed that the development of de novo membranous (MNG) and especially MPGN in renal allografts is strongly associated with pretransplant HCV-positive serology, and we emphasized that these glomerular lesions induce an accelerated loss of the graft (5). As yet, there is no effective and safe therapy for HCV-related glomerular lesions in the transplant setting. Low ribavirin doses may be effective in treating HCV-induced nephrotic syndrome in liver transplantation (6). However, ribavirin-based therapy can induce hemolytic anemia, especially when there is a low glomerular filtration rate, the glomerular disease rapidly recurs after the treatment has been withdrawn and ribavirin exerts its beneficial effect without decreasing HCV-RNA (6). On the other hand, interferon administration can induce graft dysfunction or rejection (7). Bearing in mind the above-mentioned treatment limitations in renal allografts, antiviral treatment of HCV-infected renal transplant candidates with interferon (IFN)-α, prior to transplantation, is strongly recommended as it seems to be beneficial for the post-transplant course of liver disease (8).
We hypothesize that interferon treatment in HCV-positive patients on the waiting list for transplantation may also prevent post-transplant HCV-related glomerulonephritis. Therefore, the purpose of this study was to examine whether pretransplant interferon-α administration modifies the occurrence of post-transplant de novo glomerulonephritis in HCV-positive renal allografts.
Materials and Methods
In 1991, our center initiated a prospective, nonrandomized study to treat chronic hepatitis C with interferon in kidney transplant candidates undergoing dialysis. The study protocol was approved by the Hospital of Bellvitge Review and Ethics Committee, and all patients gave informed consent. Interferon therapy was indicated based on viral, biochemical and histological criteria, as previously described (9). Briefly, dialysis candidates for renal transplantation with chronic HCV hepatitis (high ALT levels for at least 6 months) were identified. In the absence of exclusion criteria for interferon treatment (liver cirrhosis, hepatitis B virus coinfection, heart failure, active alcohol abuse or illicit drugs, psychiatric disorder, epilepsy, pregnancy), a liver biopsy was performed to assess chronic hepatitis and to exclude cirrhosis. Treatment consisted of lymphoblastoid α-nl interferon (GSK, Tres Cantos, Madrid). Doses were as follows: 3 million units (MU) administered s.c. after hemodialysis sessions 3 times a week for 6 months, followed by 1.5 MU for another 6 months. Afterwards, patients were put on the waiting list. Serum HCV-RNA was determined by qualitative assay (Amplicor, Roche Diagnostic Systems, IN, USA) and tested at baseline, at the end of treatment, and every 6 weeks thereafter. The study period described here began when the first interferon-treated patient was transplanted. So, from December 1992 to December 2000, 82 serological HCV-positive patients received a renal allograft from a serological HCV-negative donor in our transplant program. These cases were divided in two groups: the IFN-treated group (patients received pretransplant interferon) and the non-IFN-treated group. All cases were followed in our center. De novo glomerulonephritis was suggested by proteinuria (>1.5 g/24 h) and microhematuria, but always confirmed by renal biopsy, as described (5). HCV-related de novo glomerulonephritis was defined as the presence of membranous (MGN) or membranoproliferative (MPGN) glomerulonephritis on the graft, if such glomerular diseases were not primary causes of chronic renal failure. Groups were compared using the Chi-square test for categorical variables, the t-test or anova for normally distributed data and the Mann–Whitney U-test or Kruskall–Wallis test for non-normally distributed variables. Graft survival was studied using Kaplan–Meier survival analysis, and differences between the groups were established using the log-rank test. Numerical results were expressed as mean ± SD. A two-tailed p-value of less than 0.05 was considered to be significant.
Of the 82 renal transplants, 3 never functioned and 1 suffered renal vein thrombosis immediately after surgery (none of them had received interferon) and thus they were excluded from the study. Of the remaining 78 patients, 15 received pretransplant interferon to treat chronic hepatitis C infection. This treatment produced sustained negative HCV-RNA in 10 of the 15 patients and alanine aminotransferase (ALT) normalization in all 15 patients. Baseline characteristics and the follow-up period were similar in non-IFN-treated patients and IFN-treated patients, and the ratio of positive HCV-RNA patients was higher in the non-IFN-treated group, as expected (Table 1). All 78 patients had normal transaminases at transplantation.
Table 1. Baseline characteristics of HCV-positive patients who received pretransplant interferon (IFN-treated) and those who did not (non-IFN-treated). All 78 patients had normal transaminases at transplantation
In the non-IFN-treated group there were nine cases in which HCV-RNA was not determined. Abbreviations are: ESRD, end-stage renal disease; GN, glomerulonephritis; KT, kidney transplant; PRA, panel reactive anti-HLA antibodies; ALG/ATG, induction therapy with antilymphocyte antibodies; CIT, cold ischemia time; DGF, delayed graft function; AR, acute rejection episodes.
Of the 63 HCV-positive recipients who did not receive interferon, HCV-RNA was not available in nine cases, was positive (noIFN/RNA positive) in 39 and was negative (noIFN/RNA negative) in 15. Thus, these nine cases for whom HCV-RNA was not available were excluded from subsequent analysis. The pathological diagnosis in the noIFN/RNA negative group was chronic allograft nephropathy (CAN) in three cases, whereas in the noIFN/RNA positive group there were nine cases of de novo MPGN, three cases of MGN and 11 cases of CAN.
Of the 15 IFN-treated patients, ten were HCV-RNA negative at the time of transplantation (IFN-responder group) and five were HCV-RNA positive (IFN-nonresponder group). Renal histology in the IFN-responder group showed two cases of CAN and one case of recurrence of IgA nephropathy. In the IFN-nonresponder group, there was one case of CAN and one case of de novo MGN.
Thus, as summarized in Table 2, in HCV-positive renal allografts de novo MPGN and MGN occurred only when HCV-RNA was positive. Baseline characteristics were similar in all groups. All patients received cyclosporin-based immunosuppression, and there were no differences concerning induction therapy with antilymphocyte antibodies or mofetil mycophenolate (MMF) and steroid withdrawal.
Table 2. Baseline characteristics and evaluation of the occurrence of de novo glomerulonephritis (GN) in HCV-positive patients treated with pretransplant interferon (IFN) or not treated with pretransplant interferon (noIFN), classified according to whether they were pretransplant HCV-RNA positive (HCV-RNA+, nonresponder) or HCV-RNA negative (HCV-RNA−, responder)
The nine cases with HCV-RNA not available were excluded. For abbreviations, see Table1.
p=0.02 vs. noIFN-HCV-RNA negative; p =0.04 vs. IFN-responder.
We analyzed whether IFN and HCV-RNA influenced graft outcome (Figure 1). Using the log-rank test method, groups associated with poor graft survival were IFN-nonresponder (p = 0.005) and noIFN/RNA positive (p = 0.05). There were 4/5 graft losses in the IFN-nonresponder group (2 due to death, 1 due to CAN, 1 due to de novo MGN); 2/10 in the IFN-responder group (1 due to acute vascular rejection, 1 due to death); 3/15 in the noIFN/RNA negative group (1 due to death, 2 due to CAN); and 20/39 in the noIFN/RNA positive group (4 due to death, 7 due to de novo MPGN, 2 due to de novo MGN and 7 due to CAN). Patient survival was similar in all groups. Causes of death were one gastric carcinoma and one acute myocardial infarction in the IFN-nonresponder group; one acute myocardial infarction in the IFN-responder group; one pulmonary cancer in the noIFN/RNA negative group; and one lymphoma, one sepsis, one sudden death and one stroke in the noIFN/RNA positive group. The clinical outcome of IFN-treated patients is shown in more detail in Table 3.
Table 3. Clinical evolution of patients treated with pretransplant interferon
Pathology and graft loss
a Denotes last control follow-up year and analytical parameters in dead patients. For remaining patients current analytical parameters are reported.Abbreviations: sCrea, serum creatinine; HD, hemodialysis; AVR, acute vascular rejection; CAN, chronic allograft nephropathy MGN, membranous glomerulonephritis; AMI, acute myocardial infarction.
There are several published studies regarding treatment of HCV infection with antiviral agents in the post-transplant period (10). The aim of most of these was to avoid the progression of chronic liver disease. However, in the transplant setting, interferon-α is poorly tolerated and its risk of renal failure or rejection is greater than 50%. Some success in using ribavirin to treat HCV-associated nephrotic syndrome after liver transplantation (6) was reported, but ribavirin exerted this effect without decreasing HCV-RNA. Hence, at present there is no effective and safe therapy to treat HCV infection and HCV-related glomerulonephritis after renal transplantation. Therefore, authors agree that the best way to prevent the progression of chronic liver disease is to treat HCV-candidates for renal transplantation on dialysis before transplantation (2,10). The administration of interferon in dialysis patients is much more effective than in the general population. Sustained HCV-RNA negative response in immunocompetent patients is 15–20%, whereas in dialysis it is higher than 50% after 12 months of treatment, as we have observed (9). It is not clear why, but it is probably because interferon accumulates in dialysis patients, and consequently drug exposure is higher (11). The clinical use of interferon in uremic patients causes similar adverse events to those found in the general population, but the proposed schedule of 3 times a week for 12 months is well tolerated, as described above (9).
Current policies for indicating interferon therapy in uremic candidates for renal transplantation are always based on liver histology (9,10). Thus, in the absence of chronic hepatitis, HCV-RNA-positive carriers are not treated. This fact is important as there is no relationship between the progression of liver disease and the development of de novo glomerulonephritis (5). In this report we have shown that only positive HCV-RNA carriers developed de novo glomerulonephritis. Pre-transplant interferon induced serum HCV-RNA clearance in 2/3 of the patients, suggesting that interferon prevented de novo glomerulonephritis due to its antiviral effect.
In conclusion, pretransplant interferon may reduce the occurrence of post-transplant de novo glomerulonephritis in HCV-infected candidates for renal transplantation by the clearance of serum HCV-RNA. Our results suggest that the indication for pretransplant interferon-α should be extended to treat all HCV-RNA-positive candidates for renal transplantation.
This work was presented orally at the American Transplant Congress, Washington, DC, 2002. The authors thank Dr Marta Carrera for performing the pathology assessment of renal biopsies.