Renal Disease Associated With Hepatitis C Infection After Kidney and Liver Transplantation1

Over the last decade, it has become evident that hepatitis C infection is associated with glomerular disease in native kidneys, with or without mixed cryoglobulinemia. Recent reports indicate that similar extrahepatic syndromes associated with hepatitis C can also occur after organ transplantation. This review will focus on our current understanding of hepatitis C-associated renal disease and mixed cryoglobulinemia, with particular emphasis on the recent recognition of these syndromes after kidney and liver transplantation (Table 1). The impact of hepatitis C on mortality and morbidity (e.g., liver disease, co-infections, etc.) after kidney and liver transplantation, or the issues of donor/recipient selection have been recently reviewed by others, and therefore will not be discussed here (1, 2).Table 1: Renal disease and mixed cryoglobulinemia associated with hepatitis C infectionHepatitis C Infection, Mixed Cryoglobulinemia, and Renal Disease in the Nontransplant Setting Since 1990, chronic hepatitis C virus (HCV) infection has been implicated in the pathogenesis of various extrahepatic syndromes. Of these, “essential mixed cryoglobulinemia” was the first in which chronic HCV infection was demonstrated (3–5). Subsequently, membranoproliferative glomerulonephritis (MPGN), a Sjogren’s-like syndrome, porphyria cutanea tarda, and chronic corneal ulcerations have also been reported to be associated with chronic HCV infection (6–8). Mixed cryoglobulinemia is a multisystem disorder with clinical manifestations including vasculitis with purpura, leg ulcers, arthralgias and/or arthritis, peripheral neuropathy, and glomerulonephritis in about half of the patients (7, 8). Mixed cryoglobulinemia is usually classified among the benign lymphoproliferative disorders, but an association with low-grade B-cell non-Hodgkin’s lymphoma has been recently reported (9, 10). The diagnosis of mixed cryoglobulinemia is based on the detection of cryoglobulins in serum (11). Cryoglobulins are classified as monoclonal (type I) if the cryoprecipitate contains an antibody with a single immunologic phenotype or mixed (type II and III) if there is a mixture of immunoglobulins (12). Type I cryoglobulinemia is mostly found in patients with lymphoproliferative diseases. Mixed cryoglobulins of type II consist of a monoclonal immunoglobulin, most often an IgM, which is associated with its antigen, e.g., polyclonal IgG. The monoclonal immunoglobulin generally has rheumatoid factor activity, that is antibody activity against the Fc portion of autologous IgG. Mixed cryoglobulins of type III constitute a mixture of polyclonal immunoglobulins belonging to different isotypes. In most cases of mixed cryoglobulinemia, hypocomplementemia (low C3, C4, CH50) is present (11). More than 80% of patients with type II and III mixed cryoglobulinemia have chronic HCV infection, with or without chronic active hepatitis, indicating a pathogenic role for HCV in the development of this syndrome (13). On the other hand, the prevalence of mixed cryoglobulinemia among the unselected HCV-infected patients has been reported to vary between 5% and 50% (14, 15). The discovery of an association between HCV infection and mixed cryoglobulinemia has made the term “essential mixed cryoglobulinemia” obsolete, and this syndrome is now referred as “HCV-associated mixed cryoglobulinemia” (7, 16–18). HCV infection has been linked to distinct histologic patterns of immune complex glomerulonephritis. The membranoproliferative type of glomerulonephritis (MPGN) is the most common pattern encountered (19, 20). Less frequently, HCV infection has been reported in association with membranous nephropathy (21), and recently, a possible relationship between HCV infection and fibrillary glomerulonephritis has been suggested (22, 23). It is important to emphasize that most patients with HCV-associated MPGN have mixed cryoglobulins in serum (type II or III), suggesting that the cryoglobulins play an essential role in the development of the renal disease (7, 11). The pathogenesis of HCV-associated glomerular disease likely involves the in situ formation or deposition of immune complexes (cryoglobulins) within the glomeruli. Support for this hypothesis is provided by the recent demonstration of HCV antigens in kidney deposits of patients with HCV-associated MPGN (24). After Kidney Transplantation HCV infection is an important public health problem in end-stage renal failure and, therefore, in the kidney transplant population. Several studies have shown that the prevalence of anti-HCV antibody among patients on dialysis is consistently higher than in the general population, ranging from 5% to 50% depending on the assays used and the patient population studied (2). As a result, the presence of HCV infection is not uncommonly detected in a subset of patients being evaluated for kidney transplantation. Furthermore, it has been demonstrated that HCV infection can be transmitted by organs from HCV-positive donors (2). The long-term clinical impact of HCV infection in renal allograft recipients is still under study, but accumulating evidence indicates that these patients are at higher risk of liver disease as well as death as a result of sepsis (1, 2, 25, 26). Membranoproliferative glomerulonephritis with or without mixed cryoglobulinemia. As previously described in native kidneys, the association of HCV infection with MPGN, de novo or recurrent, with or without cryoglobulinemia, has now been extensively documented in recipients of kidney transplants. In 1995, Roth et al. (27) first reported de novo MPGN in five HCV-infected renal transplant recipients. All five patients presented with nephrotic-range proteinuria. Two patients had developed proteinuria within 3 months after transplant, and three within 5–10 years. No circulating cryoglobulins were detected; however, the allograft biopsies from two patients contained immune complexes with a substructure suggestive of cryoglobulins. In 1996, Cruzado et al. (28) described six additional recipients with de novo MPGN who presented with proteinuria greater than 1.5 g/day, microhematuria, and impaired renal function, at an average of 53 months (range: 20–118 months) after transplantation. All patients fulfilled chronic hepatitis criteria on the basis of persistent elevation of transaminases. In contrast to the previous series, low concentrations of type II mixed cryoglobulins in serum with low C4 were observed in all patients. HCV RNA was detected in all six patients both in serum and cryoprecipitates, and the HCV RNA concentration was higher in cryoprecipitates than in serum samples, suggesting a pathogenic role of HCV in the formation of cryoglobulins. The same year, Hammoud et al. (29) reported 15 additional cases of type I MPGN from a cohort of 399 renal transplant recipients. Thirteen of these patients had de novo MPGN, and 2 had recurrent MPGN. Eight of these 15 recipients were positive for HCV. Among the patients with HCV-associated MPGN, two had circulating cryoglobulins, and three had hypocomplementemia. Progression to end-stage renal failure and graft loss occurred in five of eight HCV-positive and in three of seven HCV-negative patients. Recurrent MPGN in association with HCV infection has also been described in another case report (30). This patient presented 2 years after transplantation with nephrotic syndrome and hypocomplementemia despite negative cryoglobulins. From all these studies, it appears that, when MPGN in association with HCV infection occurs after renal transplantation, cryoglobulin detection and characterization can be difficult, possibly because of the ongoing immunosuppressive therapy that may reduce the cryoglobulin levels and/or alter the antigen-antibody ratio. Nevertheless, the presence of an elevated rheumatoid factor in serum, hypocomplementemia, and/or a renal biopsy demonstrating cryoglobulin-like deposits all suggest that low levels of circulating cryoglobulins may be present, but are often not detectable by currently utilized assays. We have recently reported type II mixed cryoglobulinemia developing 10 years after kidney transplantation in association with fibrosing cholestatic hepatitis, a fulminant form of hepatitis C (31). In this allograft recipient, cryoglobulinemia was manifested by vasculitis with lacunar infarcts in the brain and cutaneous pretibial ulcers without any evidence of overt renal disease. The cryocrit was 1% with undetectable C4 but markedly elevated rheumatoid factor. This case report illustrates that circulating cryoglobulins in HCV-infected recipients can rarely cause severe systemic vasculitis in the absence of significant disease in the renal allograft. Membranous nephropathy. Although MPGN is the most common lesion described in renal allograft recipients with HCV infection, membranous nephropathy has also been reported recently (32). In this study, a significantly higher prevalence of membranous nephropathy was found in HCV-positive than in HCV-negative patients (3.6% vs. 0.36%). All 15 HCV-infected recipients reported had positive HCV-RNA before and after transplantation, and presented with proteinuria and microscopic hematuria but stable renal function 4–56 months after transplantation. Membranous nephropathy was considered de novo in ten cases, recurrent in two, and undetermined in the remaining three cases. Seven patients presented with mild liver function abnormalities. All of these patients had normal complement levels, negative cryoglobulins, and non-elevated rheumatoid factor measurements. Nevertheless, during an average follow-up of 2 years, 12/15 (80%) patients developed progressive renal failure with persistent proteinuria and 8/15 (54%) patients returned to dialysis (32). In contrast, another study reported 16/415 renal transplant recipients presenting with membranous nephropathy; however, no significant association between HCV infection and membranous nephropathy was found (29). Therefore, the role of HCV in membranous nephropathy remains to be clarified after renal transplantation as de novo membranous nephropathy may also be the result of chronic alloimmune mechanisms of rejection, not associated with HCV infection (33). Acute transplant glomerulopathy. A condition unique to renal allografts, acute transplant glomerulopathy or acute allograft glomerulopathy, is believed to represent an unusual variant of acute allograft rejection that is observed 1–4 months after transplant in about 2–4% of all allograft biopsies (33). The salient pathological features are glomerular hypercellularity, injury or enlargement of endothelial cells, glomerular infiltration by mononuclear cells, and webs of periodic acid-Schiff-positive material. Acute transplant glomerulopathy was first described in association with cytomegalovirus infection (34), but more recently, an association with HCV infection also has been suggested (35). Cosio et al. reported an increased prevalence of acute transplant glomerulopathy both in HCV-positive patients and in HCV-negative recipients who received kidneys from HCV-positive donors. In most patients, acute transplant glomerulopathy was diagnosed within 1 month of transplantation, and renal allograft survival was significantly worse in this group of patients. It was proposed that the association of HCV infection with acute transplant glomerulopathy may be the result of activation of glomerular endothelial cells by HCV, and not the presence of cryoglobulins because pretransplant C3 levels and rheumatoid factor levels (used as surrogate markers for cryoglobulins) were normal in all patients (35). These new findings suggest that different viruses (cytomegalovirus and HCV) may be associated with the syndrome of acute transplant glomerulopathy, possibly through similar pathogenic mechanisms. Acute renal thrombotic microangiopathy. We have recently observed acute renal thrombotic microangiopathy (RTMA) associated with anticardiolipin antibodies in HCV-positive renal transplant recipients (36). Interestingly, thrombotic microangiopathy had been previously reported in native kidneys in two HCV-infected patients (37). In our series, among 18 HCV-positive recipients, 5 patients presented with biopsy-proven RTMA occurring 5–120 days after transplantation. All 5 patients had elevated anticardiolipin antibody levels (IgG or IgM), as compared to only 1 of 13 patients without RTMA (P <0.05). These patients also demonstrated an increased incidence of thrombotic complications before and after transplantation, including recurrent vascular access thrombosis, renal allograft artery thrombosis, and pulmonary embolism. In our study, rheumatoid factor and C4 levels were normal in pretransplant sera, suggesting that significant levels of circulating cryoglobulins were not present before transplantation (36). The precise underlying mechanism linking HCV to RTMA remains to be elucidated; one possibility is exaggerated endothelial cell activation by anticardiolipin antibodies, particularly in the presence of calcineurin inhibitors. In support of these observations, we have also observed RTMA/hemolytic uremic syndrome with high titers of anticardiolipin antibodies in the native kidneys of two patients with chronic HCV infection (38). Chronic transplant glomerulopathy (CTG). CTG, another complication of renal transplantation, is usually considered to be a glomerular manifestation of chronic rejection (33). Interestingly, the pathologic features of CTG, e.g., glomerular basement membrane duplication and mesangial proliferation, are reminiscent of MPGN, although immune complexes are typically not a major feature of CTG. However, immune complexes may be scant or absent after transplantation, thus rendering a clear distinction between CTG and MPGN difficult in most cases. CTG is clinically manifested by low-grade to nephrotic-range proteinuria, and has a poor prognosis; progressive decline in allograft function with eventual graft loss occurs in 60–70% of the affected patients (39, 40). In 1995, Gallay et al. (41) first suggested a possible association between HCV infection and CTG in two renal allograft recipients at 3 and 7 years after transplantation (41). Both patients had nephrotic-range proteinuria, a rising serum creatinine, HCV viremia with mildly impaired liver function tests, hypocomplementemia, and elevated rheumatoid factor. These authors speculated that some patients diagnosed with CTG may actually have HCV-associated MPGN. Subsequently, Cosio et al. (42) also reported an increased prevalence (33%) of HCV infection in 27 renal allograft recipients with CTG. In this study, however, the clinicopathologic differences were not analyzed, as immuno- fluorescence and electron microscopy findings were available only in a minority of cases. Consistent with these observations, we have also recently reported a significantly increased prevalence (36%) of HCV infection in renal transplant recipients with “CTG/de novo MPGN” (43). In view of the similarities between CTG and MPGN, we grouped together CTG and de novo MPGN as “CTG/de novo MPGN” and used patients with chronic cyclosporine toxicity as controls. The pathologic findings of CTG/de novo MPGN associated with HCV differed from those in HCV-negative patients by an increased prevalence of glomerular immune complexes and subendothelial electron-dense deposits. However, no differences could be distinguished by light microscopy. From these observations, it appears that screening for HCV infection is warranted in all recipients with CTG/de novo MPGN, as this may have implications for therapy. Allograft rejection. The impact that HCV infection may have on renal allograft rejection remains controversial. In the early 1980s, it was recognized that renal recipients with non-A non-B hepatitis (now identified as most often a result of HCV) were more prone to develop life-threatening infections, mostly extrahepatic sepsis, compared to recipients without chronic hepatitis (44). This observation suggested that HCV may have immunomodulatory properties resulting in an increased susceptibility to opportunistic infections. Increased incidence of infections in HCV-infected renal recipients has been subsequently confirmed by others (1, 2, 25, 26, 45). Consistent with these observations, some groups have found a decreased incidence or reduced severity of acute rejection in HCV-positive renal transplant recipients. These authors have suggested that less intensive immunosuppression protocols may be required in HCV-positive recipients (46, 47). Other studies, however, have not found a reduced incidence of acute rejection in HCV-infected renal recipients (36, 45, 48). In fact, an increased prevalence of allograft rejection was found in one study (35). Thus, the relationship between acute allograft rejection and HCV infection remains a matter of controversy, and larger, prospective studies will be required to clarify this important issue. In summary, it appears that the HCV-infected renal transplant recipient may be prone to develop a spectrum of renal manifestations associated directly or indirectly with the viral infection, and more work is needed to identify the mechanisms implicated and the potential strategies to prevent some of these specific renal syndromes after renal transplantation. After Liver Transplantation Hepatitis C is a major cause of end-stage liver failure, accounting for approximately 25–30% of all liver transplants currently performed (49). After liver transplantation, recurrence of HCV infection is common, and can range from an asymptomatic carrier state to chronic active hepatitis or cirrhosis. It has been established that more than 95% of HCV-positive recipients have persistent viremia using sensitive reverse transcriptase-polymerase chain reaction assays, and about 50–80% develop recurrent graft hepatitis within the first 2 years after transplantation (49–53). In recent studies that quantitated HCV RNA levels, a in viremia titers and was observed after transplantation, which a by progressive 1 after transplantation The increased HCV viremia was likely a result of the of immunosuppressive which antibodies, calcineurin and The of the different immunosuppressive to the in viremia after liver transplantation has not been studied In one study, which compared the of and cyclosporine in hepatitis liver transplant recipients, no differences in the recurrence of hepatitis or in the of viremia were found between the two calcineurin Although all immunosuppressive may HCV early after transplantation, used for immunosuppression may be a as suggested by an in serum HCV RNA levels in patients a of therapy important is the increased viremia and recurrence of HCV graft hepatitis after liver transplantation may or glomerular disease and/or cryoglobulinemia, which may be present in a subset of HCV-infected patients who present for liver transplantation. On the other hand, it could also be speculated that the and immunosuppressive properties of used in these patients may prevent clinical of immune complex disease. In recent years, a of reports of HCV-associated glomerular disease with nephrotic syndrome and of HCV-associated mixed cryoglobulinemia after liver transplantation have suggested that the in HCV viremia has the potential to renal disease and/or cryoglobulinemia These extrahepatic complications were in a case report of an HCV-infected liver transplant recipient who developed a nephrotic syndrome 3 months after transplantation cryoglobulins with an elevated rheumatoid factor and mildly C4 were present, and the renal biopsy demonstrated MPGN without cryoglobulin deposits. A report described three HCV-infected liver recipients who developed biopsy-proven glomerulonephritis after transplantation The clinical features were proteinuria, microscopic and mild to renal in association with a in HCV viremia and MPGN on renal biopsy in all three cases. patient also developed of vasculitis and was found to have type II mixed cryoglobulinemia. was used in these cases with Other similar of cryoglobulinemia presenting after liver transplantation in HCV-positive patients with or without renal have been reported a study compared renal disease in HCV-positive vs. HCV-negative liver transplant recipients A significantly greater of HCV-infected patients had of within 2 years after liver transplantation compared with HCV-negative patients vs. MPGN was only in the HCV-positive However, in this study, possible between proteinuria and viremia or cryoglobulinemia were not Nevertheless, this study the association between HCV infection and renal disease after liver transplantation. We have also a case of type III MPGN MPGN with membranous in the native kidneys of a liver transplant recipient with hepatitis indicating that features of MPGN and membranous nephropathy can in a patient 1 month after liver transplantation, this patient developed a severe nephrotic syndrome that a in recently, in a report of renal biopsies performed for of nephrotic syndrome and/or rising after liver transplantation, HCV was available in patients It was found that HCV-positive patients had immune complex glomerulonephritis or vs. only (MPGN) of HCV-negative patients. Although all the studies the association between mixed cryoglobulinemia and/or MPGN and HCV infection after liver transplantation, the prevalence and clinical of these complications have not been well in this patient population. We have recently studied the prevalence of mixed cryoglobulinemia in clinically stable HCV-infected liver transplant recipients at our patients in the HCV-positive group had mixed cryoglobulinemia present at the of and rheumatoid factor was significantly elevated in association with mixed cryoglobulinemia. In three of the patients with mixed cryoglobulinemia, manifestations of active vasculitis were present Thus, in an but unselected group of HCV-positive liver transplant recipients, it is to that we found a prevalence of mixed cryoglobulins. This prevalence appears to be similar to that reported in patients with chronic HCV infection The current understanding of the association between HCV infection, mixed cryoglobulinemia, and glomerular disease has the of for of patients with these In studies performed in patients with mixed cryoglobulinemia and glomerulonephritis in the with has been shown to reduce HCV viremia and cryoglobulin levels, proteinuria, and renal function (19, Of a clinical and with of HCV RNA from the serum during indicating that the of its However, of clinical and was common after of has also been used to mixed cryoglobulinemia and without in cases In cases not to with therapy may be This is suggested by a recent case report of HCV-associated severe glomerulonephritis in native kidneys, which to however, a long-term was after and therapy disease after kidney and liver transplantation. The of in HCV-infected renal transplant recipients remains as it has been associated with acute allograft rejection, through increased cell of antigens and of It is that an incidence of acute rejection from to has been reported that allograft function of kidney transplant recipients be In to acute rejection, acute renal after therapy can also be the result of other as acute with or without In some of chronic hepatitis by HCV after renal transplantation has been with without renal has also been used to HCV-associated glomerulonephritis after renal transplantation in two HCV-positive renal recipients who developed features of MPGN and both patients were with at the with in renal function in one (41). In other studies of HCV-associated de novo MPGN or membranous nephropathy after renal transplantation, were not described without have been used in five patients with membranous nephropathy with in two (32). After liver transplantation, has been used in cases to cryoglobulinemia with or without glomerular In contrast to its in renal transplant recipients, the of after liver transplantation not to a significant risk of acute rejection has also been shown recently to be for HCV-associated glomerulonephritis in native kidneys In recipients with nephrotic syndrome, proteinuria decreased significantly during without any significant in It was suggested that may be through mechanisms other than in viral by an immunomodulatory and strategies are required to transplant recipients with chronic HCV infection in view of the of therapy. In the potential of therapy to be against the risk of allograft rejection, in renal transplant recipients. and will be the to renal disease after kidney and liver transplantation remains to be studied in the in to these it is possible that immunosuppression in HCV-infected transplant recipients may have the potential of viremia after transplantation, which could result in decreased complications of HCV As high of used may be an important factor in viral and, therefore, it can be speculated that protocols may be for HCV-infected recipients.