Among the HCV-related extrahepatic manifestations, cryoglobulinemic vasculitis represents a severe condition often complicated by renal involvement (30). According to the type of immunoglobulins (Igs) involved, cryoglobulins (CGs) have been classified into type I, type II, and type III (35). Type I CG is frequently seen in monoclonal gammopathies like multiple myeloma or Waldenstrom’s macroglobulinemia. Types II and III CGs are a mix of both polyclonal IgG and monoclonal IgM with RF activity. Type II CG is mainly found secondary to infections such as HCV, hepatitis B virus (HBV), and human immunodeficiency virus. Type III CG is frequently associated with connective tissue diseases and rarely found in HCV-related MPGN. Mixed cryoglobulins (MCs) are the typical consequence of HCV infection and are often associated with MPGN. Types II and III MCs are generally present. A polyclonal IgG binds to another immunoglobulin, which acts as an antiglobulin and as an anti-IgG RF. HCV is known to be the cause of 80% of MCs. The pathophysiological mechanism of HCV-related GN probably involves E2-CD81 interaction. The E2 protein of HCV interacts with the CD81 that is the cellular receptor for HCV and is required for the infection of hepatocytes (36). Type I MPGN is the most frequent GN associated with chronic HCV infection. The pathogenesis of MPGN is due to glomerular deposition of immune complexes often containing MCs; however, glomerular deposition of immune complexes in HCV-MPGN may be observed even in the absence of MCs (37). The immune complex deposits in the mesangium and subendothelium activate the complement system and mononuclear cells, which alter glomerular permeability and cause subsequent cell damage through the release of proteases and oxidants (38). Overall, the prevalence of MPGN is higher in HCV patients with MCs. HCV-RNA has been observed in 80% of patients with cryoglobulinemia-associated MPGN, but only in 25% of MPGN patients without cryoglobulinemia (38). MPGN may be associated with HCV infection independently of circulating MCs. In such cases, the immunecomplexes containing HCV are responsible for the GN. Viral nonstructural protein 3 (NS3) may be present in the deposits with a linear or granular pattern along the capillary walls and the mesangium (33).

Several cases of membranous nephropathy (MN) have been described in HCV-infected patients (39, 40). The findings are similar to those observed in the classic idiopathic MN due to phospholipase A2 receptor (PLA2R). Complement level in the serum is normal and both CGs and RF are absent. Yamabe et al. (40) found that 8% of MN patients were HCV-positive compared to less than 1% of patients with different forms of GN with the exclusion of MPGN.

Diffuse proliferative GN with paramesangial dense IgM and C3 deposits may be occasionally observed in HCV-positive patients (41). The association of IgA nephropathy with HCV infection has been reported (42–44). Some of these reports describe a successful treatment with interferon alpha (IFNα). Several studies have highlighted the association between HCV and focal segmental glomerulosclerosis (FSGS) (45, 46). Shah et al. (46) reported that treatment with pegylated IFNα resulted in a sustained virologic response (SVR), with a clinical remission lasting more than 5 years. Six cases of fibrillary immunotactoid glomerulopathies associated with HCV infection have been described (47–49). The best described are six cases by Markowitz et al. (47). They describe four cases of fibrillary GN and two cases of immunotactoid glomerulopathy associated with HCV infection. The renal biopsy showed a membranoproliferative pattern, but electron microscopy revealed fibrils of 16–28 nm diameter in fibrillary GN and 35–45 nm in immunotactoid glomerulopathy. Both fibrillary GN and immunotactoid glomerulopathy are similar to cryoglobulinemic GN, suggesting a common pathogenetic mechanism of organized glomerular deposits. In a review article, Johnson et al. (50) observed that patients affected by MPGN in association with HCV infection often have tubulointerstitial inflammation and scarring. More recently, in another study (51), tubulointerstitial changes were frequently observed in HCV-infected patients, and the viral antigens and HCV-RNA were detected in the tubulointerstitium of these patients.

HCV is an enveloped virus with single stranded RNA and a genome composed of structural and nonstructural proteins (Figure 2) (6). Seven genotypes have been identified and divided into subtypes and strains (70). The genotypes are differentially distributed worldwide and the efficacy of DAA drugs may vary according to the HCV genotype. In the past, interferon-based regimen constituted the standard of care treatment. The first drug used was the recombinant alpha interferon (IFNα) in combination with ribavirin. Initially, IFNα was used as monotherapy, but the efficacy in terms of SVR was poor, the treatment was expensive, and several side effects were reported. In addition, when used in transplant patients, it could generate severe acute rejection (71). On the other hand, when used in combination with ribavirin, the treatment leads to dose-dependent hemolytic anemia (72). Fabrizi et al. (73) performed a meta-analysis and concluded that the efficacy and safety of IFN-based therapies are unsatisfactory with low efficacy and high rate of side effects, particularly when used in transplant patients. This treatment was the standard of care until 1998. Later, the introduction of pegylated-IFNα increased the SVR and it became the standard of care until 2011.

The knowledge of the mechanism of action of HCV and the viral proteins involved in its replication allowed for the development of specific drugs for direct antiviral (DAA) treatment. The first generation of DAA was represented by boceprevir and telaprevir, which inhibit the NS3/4A protease activity. However, these drugs frequently induced viral resistance and therefore are combined with pegIFN and ribavirin. There are four classes of DAA agents based on their mechanisms of action (Table 3).

The first class includes the protease inhibitors (PIs) acting on NS3/4A. These drugs block a viral enzyme (protease) that enables the HCV to survive and replicate in host cells. The best-known drugs of this class are simeprevir and paritaprevir acting on genotypes 1 and 4, and grazoprevir acting on genotypes 1, 3, and 4. These drugs are usually used in combination to achieve a stable SVR (74). The second class comprises nucleoside and nucleotide NS5B polymerase inhibitors that inhibit intrahepatic replication. The main drug belonging to this class is sofosbuvir. Sofosbuvir acts against genotypes 1–4 and was recently approved for use in combination with other DAAs. In particular, sofosbuvir has been studied in the HCV-TARGET study (75). As an increased rate of adverse events was observed in patients with renal failure, the current guidelines of the American Association for the Study of Liver Disease (AASLD) recommend that sofosbuvir should be used only in patients with an estimated glomerular filtration rate (eGFR) higher than 30 mL/min (74). The third class includes the NS5A inhibitors that block the virus protein NS5A, which is required for replication and various stages of infection. Several drugs belong to this class, which include ombitasvir (acting against genotypes 1 and 4), pibrentasvir (a pangenotype drug), daclatasvir (acting on genotype 3), elbasvir (acting on genotypes 1 and 4), ledipasvir (acting on genotype 1), and velpatasvir (a pan-genotype drug). A combination of ombitasvir/paritaprevir-ritonavir and dasabuvir is often used and represents the 3D regimen, marketed as Viekira Pak. This combination has been studied in the RUBY-I trial in CKD patients (76) obtaining a SVR without side effects. The fourth class of drugs includes dasabuvir, a non-nucleoside NS5B polymerase inhibitor that stops HCV from reproducing by inserting itself into the virus so that other pieces of the HCV cannot attach to it. All the currently recommended regimens include at least two agents of different classes. The most common combination is a NS5A inhibitor with a polymerase inhibitor or a protease inhibitor. For resistant populations, the addition of ribavirin is recommended (77).

In the days of interferon therapy, peg-IFN or ribavirin (RBV) in combination with rituximab (RTX) was found to be more effective than peg-IFN or RBV alone in the treatment of HCV-associated MC (78, 79). Although the discovery of new DAAs has revolutionized the therapeutic approach, data on their efficacy in patients with HCV-associated cryoglobulinemic vasculitis and GN are disappointing, probably due to the inability of the drugs to suppress the immune-mediated process (80). RTX, in combination with DAA drugs, seems to have some impact on HCV-related cryoglobulinemic vasculitis. However, with the new generation of DAAs, the percentage of patients needing to receive concomitant immunosuppression is decreasing. Forty-three percent of patients treated with first-generation protease inhibitors required RTX or steroids, compared to 17% of patients treated with sofosbuvir (79, 81). In more recent studies on sofosbuvir-based therapy, only 4.5% of patients required RTX (82, 83). In severe forms of cryovasculitis, it is necessary to use immunosuppression as a rescue therapy during treatment with DAAs (84), and complete remission of MC in response to combination therapy with DAA and RTX has been reported (85). All these findings have been incorporated in the recently published KDIGO guidelines (86). Accordingly, the recommendation is that patients with HCV-related glomerular disease should be initially treated with DAA. For those patients who have flares or rapidly progressive kidney failure, in addition to DAA, immunosuppression should be used with or without plasma exchange. In the case of lack of response to DAA therapy, RTX treatment is recommended.

HCV infection is associated with a higher incidence of decreased eGFR, increased risk of CKD progression, and mortality. In a meta-analysis that included 890,560 patients, seropositive patients against HCV had a 70% increased risk of reduced eGFR (87) and in the REVEAL study, HCV-positive patients had a lower eGFR and an increased risk of ESRD (47, 88). These data were confirmed by another study performed on US veterans (89). In this study, HCV positivity was associated with a deterioration of kidney function and the development of ESRD. Also, the NHANES III study confirmed a significantly higher microalbuminuria in HCV-positive patients (90). In addition to specific renal diseases, cardiovascular disease and diabetes mellitus account for the rapid evolution of CKD in HCV patients (31). The discovery of DAA agents represented a relevant step in the evolution of HCV treatment by allowing to treat CKD patients independently of the existence of an HCV-related specific nephropathy. The aim of HCV treatment is to reach a stable SVR over time as documented by HCV serology and nucleic acid testing (NAT), 3 months after the end of treatment (91).

Most of the DAA studies in the general population included patients with normal renal function and randomized controlled trials (RCTs) for CKD included patients with stages 4 and 5. As patients with CKD stages 1–3 are not considered a priority (87), data for these patients derive from post-marketing or real-world studies (92). In the TRIO Network, the combination of elbasvir and grazoprevir (EBR/GZR) obtained a stable SVR, and about 50% were CKD stages 1–3 patients (93). The same combination was equally effective in a different study (94). The HCV TARGET database (73) did not find any difference in SVR rates comparing different CKD stages. This study as well as a study by Sise et al. (95) analyzed a sofosbuvir-based regimen. In this study, a sofosbuvir-based regimen reached a stable SVR independently of the CKD stage. To date, the use of sofosbuvir is only recommended for patients with an eGFR >30/mL/min, and investigations on the use of sofosbuvir in patients with ESRD are underway. Based on pharmacokinetic studies, sofosbuvir may accumulate in ESRD patients reaching an area under the curve (AUC) increase of 171%. Reports on safety of sofosbuvir in patients with ESRD are still sparse, and the available data are based on few studies with limited number of patients (96–98).

The use of DAAs in patients with CKD stages 4 and 5 (< 30/mL/min) is confirmed by several studies and RCTs. In the C-SURFER study (99), a combination of grazoprevir and elbasvir achieved a stable SVR in ESRD patients affected by HCV genotype 1. This combination therapy was approved by the FDA in 2016. A retrospective analysis of this combination therapy confirmed its safety and efficacy (100). This is currently the recommended treatment for ESRD patients affected by genotype 1 or 4 (Table 4) (6). In August 2017, the FDA approved the pan-genotypic combination of glecaprevir (NS3/4 protease inhibitor) and pibrentasvir (NS5A inhibitor). The EXPEDITION-4 RCT investigated this combination (101). The combination therapy administered to ESRD patients affected by genotypes 1–6 resulted in a stable SVR in 98% of patients, with few adverse events. The results of EXPEDITION-4 are encouraging but need confirmatory studies because of the small numbers of patients affected by genotypes 5 and 6. Even though DAA therapy is expensive, recent studies documented that grazoprevir/elbasvir is cost-effective in the United States (102) and France (103).

The recently published KDIGO guidelines (104) are in line with these studies and recommend a combination of grazoprevir/elbasvir for HCV patients with CKD stages 4 and 5 (Table 5) (104). A relevant question is: “how and when a dialysis patient should be treated?” This is discussed by Davis et al. (105). RNA-positive patients with an active infection should undergo a complete evaluation of liver disease. If they are affected by a severe decompensate cirrhosis, they should be listed for a combined liver–kidney transplant; otherwise, they can remain on dialysis and get treated for HCV. If the liver evaluation shows only a mild activity with mild fibrosis, then the patients are transplant candidates, and there are two options. First, patients who are transplant candidates and have living donors should be treated immediately for HCV infection and transplanted if found negative. Second, patients who do not have living donors could be listed for HCV-positive cadaver donor if the transplant center accepts this activity or should wait for a cadaver donor and treat HCV while on dialysis and waiting (Figure 3). However, dialysis patients who are not transplant candidates should also receive treatment for HCV infection. We have already highlighted that HCV dialysis patients are affected by multiple hepatic and extrahepatic adverse events. Early data suggest a benefit with the new DAAs. The treatment cost does not justify withdrawing treatment for these patients, even if they are not transplant candidates (106).

The optimal timing to treat kidney transplant candidates is a matter of debate. On one hand, treatment before transplantation decreases early posttransplant complications related to HCV infection. On the other hand, postponing treatment opens the possibility of transplanting a kidney from an HCV-positive donor, which means there is a shorter waiting time. Whether or not to treat HCV dialysis patients before transplantation is a concern that should be based on several considerations, such as the extent of liver damage, availability of living donors, and extrahepatic manifestations of HCV. Patients with early cirrhosis without portal hypertension are considered for kidney-alone transplantation and the decision to treat with DAAs prior to transplantation also relies on other factors such as the availability of a living donor (107). In this scenario, it is better to treat before transplant if the transplant itself is not imminent. Based on several studies, it could be said that the delay of transplantation should be individualized according to specific conditions (108, 109). Extrahepatic manifestations of HCV include mixed cryoglobulinemic syndrome (MCS) and lymphoproliferative disorders. Patients with active HCV-associated MCS should undergo treatment before transplantation in order to avoid further complications (107). A regression of lymphoproliferative disorders related to HCV has been documented in 75% of patients (110). These patients too should be treated before transplantation.

The advent of DAAs made it possible to transplant HCV-positive kidneys into HCV-positive recipients. Before the advent of DAAs, a large study documented the long-term survival of patients transplanted with HCV-positive kidney (111). In the era of DAA therapy, several studies have documented that transplantation of an HCV-positive kidney into an HCV-positive recipient, and treatment with DAA post-transplant, had excellent outcomes, with stable SVR rates (112, 113). In addition, DAAs have allowed the transplantation of HCV-infected kidneys into HCV-uninfected recipients. In addition to individual reports, two main studies examined this strategy. In the THINKER trial, patients were enrolled and treated a few days after transplantation with elbasvir and grazoprevir. Recipients became positive after transplantation, but an SVR was obtained in all the patients at 3 months (114). In the EXPANDER-1 trial, eight patients were transplanted in the same way. DAA therapy obtained an SVR in 3 months (115).

Colombo et al. (116) performed a phase 2 RCT to evaluate the safety and efficacy of the combination of ledipasvir and sofosbuvir in 114 renal transplant patients with HCV genotype 1 or 4. SVR was obtained in all the patients with an excellent renal outcome. Saxena et al. (117) reported the efficacy of DAA therapy in 443 patients who received either kidney transplant or liver transplant, or combined liver–kidney transplant. The majority of patients were treated with sofosbuvir/ledipasvir with or without RBV. DAA therapy was effective and safe in both kidney and liver transplantation. Reau et al. (118) in the MAGELLAN 2 study investigated the safety and efficacy of glecaprevir and pibrentasvir in liver or kidney transplant patients. SVR was achieved in 99% of patients, with a 100% kidney and graft survival. The 2017 AASLD (119) published the guidelines for kidney transplant patients, and the KDIGO guidelines recall what has been described above on the management of HCV-infected patients before and after kidney transplantation (Table 5) (120). One important concern with the new DAAs in kidney transplant patients is the drug interactions with the immunosuppressive agents. Cyclosporine, tacrolimus, and sirolimus are metabolized in the liver by the cytochrome 450. As a result, for most DAAs, a substrate competition may occur, influencing their elimination. A careful dosage of DAAs and immunosuppressive agents is therefore recommended (120).