Guideline 4: Management of HCV-infected patients before and after kidney transplantation

Kidney International (2008) 73 (Suppl 109), S53-S68; doi:10.1038/ki.2008.87

Guideline 4.1: Evaluation and management of kidney transplant candidates regarding HCV infection

INTRODUCTION
HCV infection is present in a higher proportion of patients with CKD Stage 5 than in the general population. As a consequence, many of these patients present for consideration of kidney transplantation with either previously undiagnosed disease or never having had a thorough evaluation of their liver disease. In some studies, almost 25% of these patients already have significant fibrosis or cirrhosis on liver biopsy. The impact of HCV infection on the candidacy and post-transplant outcomes of the viremic patient with CKD Stage 5 remains a challenging clinical issue.

4.1.1 All kidney transplant candidates should be evaluated for HCV infection (see Algorithm 2). (Strong)

In low-prevalence settings, initial testing with EIA and follow-up of positive EIA with NAT should be considered. (Moderate)

In high-prevalence settings, initial testing with NAT should be considered. (Moderate)

4.1.2 HCV infection should not be considered a contraindication for kidney transplantation. (Moderate)

4.1.3 It is suggested that HCV-infected kidney transplant candidates undergo a liver biopsy before transplantation. (Weak)

4.1.4 It is suggested that HCV-infected patients with cirrhosis confirmed by liver biopsy, but clinically compensated liver disease, be considered for kidney transplantation only in an investigational setting. (Weak)

4.1.5 It is suggested that HCV-infected kidney transplant candidates be considered for treatment with standard IFN before transplantation (see Algorithm 2). (Weak)

4.1.6 It is suggested that patients on a kidney transplant waiting list be evaluated for HCV infection (see Algorithm 3). (Weak)

For patients who have never been tested for HCV, it is suggested that testing be performed with EIA in lowprevalence settings (with follow-up of positive results by NAT) and NAT in high-prevalence settings (see Guideline 1.1.1). (Weak)

It is suggested that HCV-infected patients not previously known to be viremic be placed on-hold status, pending full evaluation of the severity of their liver disease. (Weak)

It is suggested that patients who had received antiviral treatment before listing and had SVR have testing with NAT repeated at least annually (see Guideline 2.3.2) (Weak); if NAT becomes positive, it is suggested that the patient be put on-hold status and have full evaluation of their liver disease. (Weak)

It is suggested that HCV-infected patients who had prior evaluation with liver biopsy, but either failed or refused antiviral treatment, have repeat liver biopsy every 3-5 years while on the transplant waiting list, depending on their histologic stage. (Weak)

BACKGROUND
Compared to remaining on dialysis, kidney transplantation confers a survival advantage to HCV-infected patients. Kidney transplantation should therefore be considered the treatment of choice for patients with CKD Stage 5 and HCV infection.^110,253,254 The prevalence of HCV infection among kidney transplant recipients ranges from 7 to 40%, with wide geographic and demographic variation.^{40,110,159,255} HCV infection is associated with both hepatic and extrahepatic complications. To date, the major focus has been on the hepatic complications of HCV. Several cross-sectional studies have indicated that approximately 25% of HCV-infected patients being evaluated for kidney transplantation have significant liver fibrosis (bridging fibrosis or cirrhosis). Unfortunately, post-transplant outcomes in these studies are not known.^177,256-260 One study that provided some information on pretransplant liver injury indicated that the presence of cirrhosis before kidney transplantation was an independent predictor of poor long-term survival.¹¹⁸

The evaluation and pretransplant management of HCVinfected kidney transplant candidates require consideration of the following issues: screening for HCV infection; impact of HCV infection on transplant outcomes; determination of the severity of liver disease; treatment of HCV infection with IFN; safety of transplanting patients under treatment with IFN; ongoing care after treatment with IFN; and selection of patients for transplantation based on liver histology.

RATIONALE
4.1.1 All kidney transplant candidates should be evaluated for HCV infection (see Algorithm 2). (Strong)

In low-prevalence settings, initial testing with EIA and follow-up of positive EIA with NAT should be considered. (Moderate)

In high-prevalence settings, initial testing with NAT should be considered. (Moderate)

It is recommended that all potential kidney transplant recipients should be evaluated for HCV infection. As detailed in Guideline 1.1.2, EIA is adequate to rule out HCV infection in low-prevalence areas when the test is negative; however, a positive EIA would require NAT for confirmation. In higher prevalence areas, initial testing for HCV should be with NAT. It has been well established that the presence of HCV infection influences post-transplant outcomes. In addition, HCV infection has been unequivocally demonstrated to be transmitted by transplantation. As kidneys from HCVinfected donors are occasionally used for transplantation (see Guideline 4.2), it is essential that the HCV status of the recipient be known to optimize the allocation process.

HCV Infection and outcome after kidney transplantation
Although HCV-infected patients fare better with a kidney transplant than on maintenance dialysis (Table 22), there is good evidence that HCV-infected kidney transplant recipients have worse patient and allograft survival after transplantation when compared to uninfected kidney transplant recipients (Table 23).^{114,115,118,159,261-264} The increased mortality after kidney transplantation in this population has, in part, been attributed to progressive liver disease after transplantation. ^118,159,264 However, extrahepatic post-transplant complications of HCV infection, such as NODAT,^{127,128,132,265,266,267,268} post-transplant GN,^{122,123,125,269-271} and sepsis,²⁶⁴ are additional complications that contribute to the inferior outcomes observed in these patients. In light of the clinically significant impact that HCV infection has on kidney transplant outcomes, it is recommended that kidney transplant candidates who are HCVinfected should be informed and counseled about the associated hepatic and extrahepatic risks, the need for additional diagnostic studies and therapeutic interventions before and after transplantation, and possible delay in transplantation.

Recipient HCV viremia and impact on donor kidney allocation (also see guideline 4.2)
The HCV status of a transplant candidate directly impacts donor selection. There is good evidence that HCV can be transmitted from infected donors to recipients by organ transplantation.^272-274 This may occur as a new infection in a previously uninfected recipient or superinfection with a different genotype in an HCV-infected recipient.²⁷⁵ As such, it is preferable to transplant kidneys from HCV-infected donors to recipients who are viremic. The present logistics dictate that deceased donors are only screened with EIA for evidence of HCV antibodies. However, a positive anti-HCV test in donors does not distinguish active viremia from antibody acquired after previously cleared infection. Blanket policies excluding the use of HCV antibody-positive donors have the potential to therefore result in the unnecessary discarding of kidneys from seropositive individuals, who in reality may have no detectable viremia. Moreover, available data indicate that the transplantation of kidneys from HCVinfected donors to HCV-infected candidates is associated with improved survival compared to the remaining waitlisted and dialysis-dependent candidates (Table 24).²⁷⁶

4.1.2. HCV infection should not be considered a contraindication for kidney transplantation (Moderate).

Studies in kidney transplant recipients demonstrate that post-transplant immunosuppressive therapy has a permissive effect on viral replication.^272,277,278 This has the potential to accelerate liver injury after transplantation. Despite this, it is recommended that HCV infection should not be considered a contraindication to transplantation for the following reasons:

Three retrospective studies of HCV-infected patients have demonstrated that survival is improved with transplantation compared to the remaining wait-listed on dialysis in HCV-infected patients with kidney failure (Table 22).^110,253,254 Compared to maintenance hemodialysis, no published studies have shown a lack of survival benefit from transplantation in this patient population. This survival advantage in favor of transplantation over dialysis is the basis for considering transplantation as the treatment of choice for patients with CKD Stage 5 and HCV infection.

Liver disease does not progress in many patients after kidney transplantation. Clinical and histologic progression of chronic liver disease is generally slow when and if it does occur. Whereas progressive liver disease does impact patient outcomes, it usually occurs over many years and thereby affects long-term survival. In single center studies of HCV-infected transplant recipients, the reported increased rates of death due to liver disease occurred in the second and third decade after kidney transplantation. ^{114,115,118,120,159,262-264} However, many of these studies are retrospective and examined outcomes in patients in whom a diagnosis of HCV infection was made only after transplantation. This could have resulted in underrecognition of more advanced cases of liver disease at the time of transplantation, accounting for increased rates of decompensated liver disease in the reported cohorts. In contrast, there are a few recent single-center reports where sequential post-transplant liver biopsies have shown that in as many as 80% of the patients, hepatic injury does not progress after kidney transplantation.^279,280

It is absolutely essential that these considerations are explained and discussed with potential recipients before a joint decision is made to proceed with transplantation.

Although the evidence supporting this guideline recommendation is limited and the quality is graded as 'weak,' the majority of the Work Group felt that this statement be upgraded to 'moderate' strength based on four criteria: (i) there are three retrospective studies showing a survival benefit of transplantation over dialysis for HCV-infected CKD Stage 5 patients; (ii) there are no published studies demonstrating a worse outcome with transplantation compared to dialysis for these patients; (iii) it is extremely unlikely that an RCT comparing transplantation to dialysis for long-term treatment of HCV-infected CKD Stage 5 patients will ever be performed; and (iv) the practice of transplantation over dialysis has evolved into the universal standard of care for CKD Stage 5 patients with HCV infection.

4.1.3. It is suggested that HCV-infected kidney transplant candidates undergo a liver biopsy before transplantation. (Weak).

Because of the poor sensitivity of HCV antibody testing in patients with kidney failure,⁴¹ a decision to perform a liver biopsy should be based on the presence of a positive NAT. In the absence of supportive or contrary data, it was the judgment of the Work Group that all persistently viremic HCV-infected kidney transplant candidates should undergo pretransplant liver biopsy. A liver biopsy performed before kidney transplantation is necessary to determine the severity of hepatic injury and thereby to assess the prognosis and management of the patient both before and after transplantation (see Algorithms 2 and 3). This recommendation is contrary to the AASLD guideline that recommends liver biopsy for patients with genotypes 1 and 4, but considers it unnecessary for patients infected with genotypes 2 and 3 (https://www.aasld.org/eweb).

The rationale for a liver biopsy is based on the following evidence:

Liver injury markers (for example, ALT) do not reliably reflect the histologic severity of disease in this population.²⁸¹

Single-center retrospective cross-sectional studies have reported that up to 25% of HCV-infected patients being evaluated for kidney transplantation have bridging fibrosis or cirrhosis on biopsy.^177,256-260

There are no definitive studies that have examined whether the histologic stage of the pretransplant biopsy predicts post-transplant liver disease and outcome. However, the presence of cirrhosis on pretransplant liver biopsy has been reported to be associated with a 10-year survival of only 26%.¹¹⁸

Several studies have shown that 19-64% of HCV-infected kidney transplant recipients have post-transplant liver disease compared with only 1-30% of patients without evidence of HCV infection.^{114,115,118,120,159,262-264} A study from the New England Organ Bank has shown that the RR of post-transplantation liver disease was 5.0 for kidney transplant recipients with anti-HCV antibodies.²⁶⁴ Most of these investigations are retrospective and examined outcomes in patients in whom a pretransplant liver biopsy was not performed. This may have resulted in underrecognition of more advanced liver disease at the time of transplantation, accounting for increased rates of decompensated liver disease in the reported populations.

Studies with no pretransplant biopsy, but with sequential post-transplant liver biopsies, have demonstrated that liver histology may progress in about 20% of patients.^280,282

Liver biopsy before kidney transplantation should be used as a means to guide antiviral therapy (also see treatment Guidelines 2.1.3 and 2.1.4). A high-quality liver biopsy of at least 2 cm in length and containing 45 portal zones is required for adequate Metavir/Ishak scoring.^283-285

It is recognized that evaluation of liver injury is an evolving field and that noninvasive tests (for example, Fibroscans) are emerging. The utility of noninvasive studies for assessing liver injury in HCV-infected CKD patients is not currently known.

4.1.4. It is suggested that HCV-infected patients with cirrhosis confirmed by liver biopsy, but clinically compensated liver disease, be considered for kidney transplantation only in an investigational setting. (Weak).

The presence of compensated liver cirrhosis before kidney transplantation has the potential to increase the risk of recipient mortality in terms of operative procedure, marginal posttrans plant reserve and nutritional state, and increased susceptibility to post-transplant infectious and metabolic complications ,as well as evolution to decompensated liver disease and the subsequent need for a liver transplant. As such, it is recommended that HCV-infected kidney transplant candidates with liver cirrhosis on biopsy only be considered for kidney transplantation under investigational protocol. This is based on the fact that there are very limited outcome data regarding transplantation of a kidney alone in HCV-infected recipients with pre-existing compensated cirrhosis of the liver. A retrospective study reported that patients with liver cirrhosis before kidney transplant had a 10-year rate of survival of only 26%.¹¹⁸ Also, there are no data available to determine whether patients with early cirrhosis on liver biopsy yet well-compensated clinical disease do better if they are transplanted or remain on dialysis. A trial of IFN therapy can be considered for such patients, although regression of fibrosis was demonstrated only in 7.8% of non-CKD patients and in three of four dialysis patients, numbers that are too small to draw any conclusions.¹⁵⁶

HCV-infected patients with evidence of decompensated liver disease should be evaluated for simultaneous liverkidney transplantation. Transplantation of a kidney alone in this situation is not recommended.

4.1.5. It is suggested that HCV-infected kidney transplant candidates be considered for treatment with standard IFN before transplantation (see Algorithm 2). (Weak).

Although there is good evidence that HCV-infected kidney transplant recipients have worse patient and allograft survival after transplantation when compared to their uninfected counterparts,^{114,115,118,159,261-264} the evidence that treatment with IFN before transplantation improves outcomes is very poor. The recommendation in this guideline is therefore the judgment of the Work Group.

After kidney transplantation, both hepatic and extrahepatic HCV-related complications have been demonstrated to contribute to the inferior patient and kidney allograft outcomes observed in this patient population. The rationale underlying this guideline is that in HCV-infected kidney transplant candidates, the achievement of a sustained virologic response before transplantation will be durable and reduce the risk of both hepatic and extrahepatic manifestations associated with viremia after transplantation. The evidence supporting this recommendation is as follows:

Uncontrolled trials have demonstrated that administration of nonpegylated IFN therapy to dialysis patients with HCV infection achieves SVR in about 40% of cases.^{134,135,138,139,141-143,198-202,286,287}

Uncontrolled studies in kidney transplant candidates with HCV infection have shown that SVR achieved before transplantation is sustained in 80-90% of recipients after transplantation.^{134,138,166,201-203} Although no information was given in any of these reports regarding liver biopsy after transplantation, there was no clinical evidence of progressive liver disease.

A few retrospective studies have demonstrated that achieving SVR with IFN therapy in kidney transplant candidates was associated with no cases of NODAT.^203,288

In liver transplant recipients with recurrent HCV infection, insulin resistance has been reported to increase in concert with viral replication,²⁸⁹ whereas achievement of SVR with IFN has been associated with resolution of NODAT.²⁹⁰

Available data in nondiabetic, non-CKD, and HCVinfected subjects demonstrate improved glucose tolerance and enhanced insulin sensitivity after 4 months of IFN therapy.²⁹¹

In a controlled trial of pretransplant antiviral therapy in CKD Stage 5 patients with HCV infection, patients in whom SVR was achieved before transplantation had a significantly lower incidence of HCV-related GN after transplantation compared to persistently viremic patients.¹⁵⁵

In a relatively large retrospective study of HCV-infected kidney transplant recipients, the absence of IFN therapy before kidney transplantation was associated with a significantly increased risk for chronic allograft nephropathy.²⁹²

It is not known whether the potential benefits of treatment with IFN in an effort to achieve SVR are outweighed by the downside of needing to be on inactive status on the waiting list during the course of therapy, thereby missing a potential opportunity to be transplanted. To mitigate this possibility, it is recommended that if an early virologic response is not obtained within 12 weeks of initiating IFN, the treatment can be discontinued. This recommendation is based on studies indicating that the chance of achieving SVR in this population is o10% in the absence of an early viral response at 12 weeks^139,141 (see Guideline 2).

Moreover, it is recommended that patients should not receive a kidney transplant while they are still receiving IFN. The evidence for this recommendation is limited to several small case series and case reports which indicate that IFN may cause acute kidney injury in 40-100% of kidney transplant recipients.^{157,158,160,293-299} The majority of IFN-induced acute kidney injury appears to be predominantly related to its immunomodulatory properties, leading to increased rates of both cell- and antibody-mediated rejection. Furthermore, the clearance of IFN is delayed in the setting of dialysis, and the risk exists of exposing the transplanted kidney to IFN before the drug has been fully cleared from the system.

The optimal time to wait between completion of standard IFN therapy and proceeding with transplantation in kidney transplant candidates with HCV infection is unknown. A 28-day wait is recommended after terminating or completing standard IFN therapy before proceeding with transplantation, based on avoiding exposure of the transplanted kidney to IFN, as most of the IFN is cleared by the kidneys and its halflife is prolonged in dialysis patients.^{178,287,296,300,301} As it will not be known whether the patient has achieved SVR until 6 months after the completion of therapy, it is recommended that these patients only receive a kidney from an HCVnegative donor during this period of time. The delayed drug clearance in dialyzed patients, who achieve a higher area under the curve with each dose, also accounts for the high treatment discontinuation rates in this population because of adverse effects induced by this therapy.^{134,139,142,198,286,287} A single case report suggests that accumulation and bioavailability of IFN may be even greater in the setting of peritoneal dialysis.²⁹⁶ Consequently, transplantation of a kidney before IFN was adequately cleared from the circulation and before its immunomodulatory effects subside could potentially increase the risk of allograft dysfunction due to rejection in the early post-transplant period.

It is also recommended that although patients with HCV infection are being treated with IFN, they should continue to accumulate time on the waiting list toward eventual transplantation.

4.1.6 It is suggested that patients on a kidney transplant waiting list be evaluated for HCV infection (see Algorithm 3). (Weak).

For patients who have never been tested for HCV, it is suggested that testing be performed with EIA in lowprevalence settings (with follow-up of positive results by NAT) and NAT in high-prevalence settings (see Guideline 1.1.1). (Weak)

It is suggested that HCV-infected patients not previously known to be viremic be placed on-hold status, pending full evaluation of the severity of their liver disease. (Weak)

It is suggested that patients who had received antiviral treatment before listing and had SVR have testing with NAT repeated at least annually (see Guideline 2.3.2) (Weak); if NAT becomes positive, it is suggested that the patient be put on-hold status and have full evaluation of their liver disease. (Weak)

It is suggested that HCV-infected patients who had prior evaluation with liver biopsy, but either failed or refused antiviral treatment, have repeat liver biopsy every 3-5 years while on the transplant waiting list, depending on their histologic stage. (Weak)

Kidneys for transplantation are scarce, and transplantation is a serious and expensive procedure. As such, it is recommended that all patients on the waiting list with an unknown HCV status be tested for HCV infection before transplantation. Patients found to have a positive NAT test result should be placed on-hold status and referred to a hepatologist for evaluation and possible treatment. This recommendation is based on the evidence that SVRs can be obtained after treatment using IFN-based regimens and remain durable after transplantation.²⁰³ For patients in whom SVR was previously obtained, it is important to perform a NAT annually while on the list to confirm durability of the SVR. Patients who relapse should be placed on hold and referred to a hepatologist for evaluation. Although no data exist on treatment of relapsers with kidney failure, there are data from the general population indicating that these patients can be successfully retreated using a longer course of therapy.

For persistently viremic patients who either failed to achieve SVR or refused IFN therapy, annual re-evaluation should include an assessment of the clinical stability of the liver disease by a hepatologist. Furthermore, it is the judgment of the Work Group that a repeat liver biopsy be performed every 3 years in patients whose baseline liver biopsy (obtained before transplant) showed Metavir Stage 3 and every 5 years for those whose liver biopsy was Metavir Stage 1 or 2. There are no good data to support this recommendation, although it has been demonstrated that liver disease can progress in patients on dialysis.¹¹⁰ With waiting times in some centers now exceeding 5 years, it is entirely possible that liver injury might worsen in the interval between listing and transplantation.

The rationale underlying these recommendations is mainly expert judgment based on the following data:

Waiting times for deceased donor kidney transplants have continued to lengthen. The median waiting time for deceased donor kidney transplantation in the United States is currently 3-4 years. Moreover, there is a 6-8% per year risk of mortality of CKD Stage 5 patients awaiting kidney transplantation.³⁰² In the context of these lengthening waiting times, it is imperative that listed patients continue to be monitored before receiving a kidney transplant to ensure medical suitability for transplantation.

Most allocation policies currently dictate that wait-listed patients be medically cleared for transplantation on a continued basis until they are actually transplanted.³⁰³ It is recommended that medical clearance follow the above recommendations.

A strong epidemiologic link between diabetes and HCV infection is now well established.^304,305 One large retrospective study demonstrated that HCV-infected patients who remained on the waiting list had a greater risk of mortality than those being transplanted and that this risk escalated with time.²⁵³ The major mortality determinant in this study was the presence of diabetes as a comorbid condition, although progressive liver disease did occur in some cases as well. The co-existence of HCV and diabetes in patients on the kidney transplant waiting list therefore identifies a subgroup at high risk for mortality.

Liver disease may progress in patients on dialysis while on the waiting list.^67,110

LIMITATIONS

There are very few randomized, prospective, or longitudinal studies that address the evaluation and management of HCV-infected kidney transplant candidates.

Many of the published studies include small numbers of patients.

Most outcome studies are retrospective and included several studies where a diagnosis of HCV infection was made only after transplantation.

Studies do not always distinguish between patients being evaluated for kidney transplantation alone vs simultaneous liver-kidney transplantation.

RESEARCH RECOMMENDATIONS

Prospective observational studies are needed to evaluate the natural history of HCV infection after kidney transplantation and to include a histologic, clinical, and biochemical assessment of liver injury both before and after exposure to chronic maintenance immunosuppression.

RCTs are required in HCV-infected kidney transplant candidates examining the effectiveness of pretransplant IFN-based therapy on post-transplant outcomes, including patient and graft survival, progressive liver disease, NODAT, and glomerulopathy.

Prospective studies are needed in HCV-infected CKD Stage 5 patients with well-compensated cirrhosis, comparing the safety and effectiveness of kidney transplant alone to remaining on maintenance dialysis.

Prospective assessment is needed to assess the utility of repeat liver biopsy in HCV-infected kidney transplant candidates who remain on the waiting list.

Observational outcome studies should be conducted to examine HCV-infected CKD Stage 5 patients coinfected with HIV or HBV.

The effect of specific immunosuppressive agents on hepatic and extrahepatic post-transplant complications should be studied.

Guideline 4.2: Use of kidneys from HCV-infected donors
INTRODUCTION
It has been clearly demonstrated that HCV can be transmitted by kidney transplantation. In this context, it is imperative to know the HCV status of both the organ donor and recipient.

4.2.1 All kidney donors should be tested for HCV infection. (Strong)

Testing with both EIA and NAT (if NAT is available) is suggested. (Weak)

4.2.2 It is suggested that transplantation of kidneys from donors infected with HCV be restricted to recipients with positive NAT. (Weak)

BACKGROUND
HCV infection may be transmitted by transplantation from infected donors to uninfected recipients.^273,306,307 For this reason, organ procurement organizations routinely screen all potential donors for evidence of HCV infection. The current standard of practice is to screen all donors for HCVantibody. However, antibody testing does not distinguish between donors who are viremic from those who have immunity following a previous infection (see Guideline 1). As such, the current standard of testing does not allow identification of viremic donors who are potentially infectious as opposed to those who are not. The prevalence of HCV infection among deceased donors worldwide ranges from 1 to 11%^.306Variable transmission rates (25-73%) of HCV have been reported. This variability is likely related to several factors, including: (i) incomplete follow-up and testing of recipients after transplantation; (ii) variation in prevalence rates of viremia among different donor populations who are tested only with EIA, where anti-HCV positivity may reflect immunity to prior infection rather than active infection (see Guideline 1); and (iii) the use of pulsatile perfusion for procured donor kidneys, where the perfusate is associated with reduction in HCV RNA levels.³⁰⁸ Recipient outcomes after the transmission of HCV by an infected kidney show that 73% develop HCV viremia, 50% become anti-HCVpositive, and 35% develop abnormal ALT/AST levels.³⁰⁷

The use of kidneys from anti-HCV-positive donors requires a balanced evaluation of the risks of HCV transmission compared to the benefits of being transplanted instead of remaining on dialysis. In all such cases, the recipient should be informed and participate in decisionmaking. It is also important to inform recipients of any information on the HCV status of the donor that becomes available after transplantation.

RATIONALE
4.2.1 All kidney donors should be tested for HCV infection. (Strong)

Testing with both EIA and NAT (if NAT is available) is suggested. (Weak)

Antibody testing does not distinguish donors who have active viremia from those who have acquired immunity after a previous infection (see Guideline 1). As such, kidney donors are best screened for HCV infection using NAT, which is the optimal way to distinguish between donors who may or may not be potentially infectious. This important variation from current practice directly impacts many current donor and recipient allocation policies. The basis for this recommended change in practice is supported by the following evidence:

HCV can be transmitted from infected donors to uninfected recipients.²⁷³

Recipients of kidneys from HCV-infected donors have an increased risk of liver disease.^{127,273,309,310}

Some, but not all, studies indicate that recipients of kidneys from HCV-infected donors have a greater risk of mortality compared to recipients of kidneys from uninfected donors.^307,311 The increased mortality may be related to higher rates of both liver disease and susceptibility to NODAT in recipients of kidneys from infected donors.¹²⁷

Where NAT is not available or results cannot be obtained expeditiously, third-generation EIA testing should be used as an alternative (see Guideline 1). The performance of the third-generation EIA in the general population is excellent and should be utilized in settings where NAT testing is not available. However, not all anti-HCV-positive donors are viremic, so discarding kidneys from EIA-positive donors will result in the loss of kidneys that could otherwise be used.

The data on the transmission of HCV from living kidney donors are weak. Living donors should be tested for HCV infection using NAT. Those donors who are HCV-infected should not be considered because of the potential risk, although not well studied, of transmitting HCV infection to the recipient. In addition, as HCV has been associated with several glomerulopathies (see Guideline 5), the HCV-infected donor is at increased risk of developing extrahepatic viral manifestations, such as immune complex disease of the native kidneys, as well as diabetes mellitus.

4.2.2. It is suggested that transplantation of kidneys from donors infected with HCV be restricted to recipients with positive NAT. (Weak).

Uninfected recipients of kidneys from HCV-infected donors have increased rates of liver disease and diabetes after transplantation.^{127,273,309,310} There is good evidence that HCV infection can be transmitted via transplantation and that acquisition of the virus has the potential to lead to the development of post-transplant liver disease.^{127,273,309,310} A study of Medicare beneficiaries in the United States Renal Data System (USRDS) registry indicates that the transmission of HCV infection via transplantation was associated with an increased risk of NODAT and a reduction in recipient life expectancy.¹²⁷ To avoid these potential but major complications in uninfected recipients, it is suggested that kidneys from HCV-infected donors should not be used in potential recipients without HCV viremia. However, kidneys from donors infected with HCV can be used in potential recipients with evidence of active HCV viremia at the time of transplantation. This recommendation is based on the following observations:

Studies have shown that the use of kidneys from HCVinfected donors in recipients already infected with HCV may shorten waiting times and neither affect short-term survival nor invariably lead to progressive liver disease (Table 24).^272,312-314 In contrast, a registry analysis demonstrated that recipients of kidneys from HCVinfected donors was associated with a higher rate of mortality, regardless of the anti-HCV antibody status of the recipient.³¹¹ This study, although large, is limited by the absence of information regarding recipient baseline liver histology or comorbidity, or the reason underlying the decision to use an HCV-infected donor kidney in a given situation.

Large registry analysis indicates that the use of kidneys from anti-HCV-positive deceased donors in HCV-infected recipients is associated with superior patient survival compared to remaining on dialysis (Table 24).²⁷⁶

The risks and effects of superinfection with an HCV genotype from the donor that is different from the genotype of the potential HCV-infected recipient are unknown. A new genotype superinfection through transplantation has been reported in two single-center investigations.^275,315 Although one of the studies reported that elevated transaminase levels did occur,²⁷⁵ the other found no impact on patient or graft survival.³¹⁵

The use of pulsatile pump perfusion may reduce the viral load in the donor kidney and has the potential to reduce viral transmission from HCV-infected organs.^274,308 Wherever possible, this technique for preserving the procured kidney is recommended in situations where the donor is known to be HCV-infected.

As always, potential recipients of kidneys from HCVinfected donors must be fully informed of the involved risks and benefits and participate in the decision to proceed with treatment.
LIMITATIONS

There are few randomized, prospective, or longitudinal studies that address the safety of using kidneys from HCV-infected deceased donors.

Many of the published studies include small numbers of patients.

Most outcome studies are retrospective.

Registry studies have been based on antibody testing in donors, which does not distinguish between donors who have active viremia from those who have acquired immunity after a previous infection.

Registry analyses cannot provide information on the baseline liver histology or comorbidity.

In many of the studies, the reason underlying the decision to use an HCV-infected donor kidney is not given.

RESEARCH RECOMMENDATIONS

Randomized trials are needed to examine the role of pulsatile perfusion in reducing the rates of viral transmission by the transplantation of HCV-infected deceased donor organs.

Prospective studies are needed to longitudinally evaluate the rate of superinfection and its clinical impact after transplantation of a kidney from an HCVinfected deceased donor to an HCV-infected recipient.Such studies should include virologic (for example, genotype and viral load) and histologic (for example, serial liver biopsy) assessment, as well as clinical and biochemical markers of liver injury.

Prospective observational studies are required to examine the effect of kidneys from HCV-infected deceased donors on hepatic and extrahepatic posttransplant recipient outcomes.

Guideline 4.3: Use of maintenance immunosuppressive regimens

INTRODUCTION
The most appropriate immunosuppressive protocol for the HCV-infected recipient has not been determined. In this context, all currently available agents can be used for induction and maintenance therapy.

4.3 All conventional current maintenance immunosuppressive regimens can be considered for use in HCV-infected kidney transplant recipients. (Weak)

RATIONALE
By virtue of their mechanisms of action, immunosuppressive therapies have the potential to have a permissive effect on HCV kinetics after transplantation. This may result in differing effects of the various immunosuppressive agents on viral replication, progressive liver disease, extrahepatic manifestations, and patient and graft outcomes after kidney transplantation in HCV-infected recipients. In addition, diminished drug clearance in the setting of hepatic dysfunction may affect blood levels of commonly used immunosuppressive agents that are metabolized in the liver, such as cyclosporin and tacrolimus. At the present time, there are relatively few studies that examine the impact of immunosuppression on HCV-related outcomes in kidney transplant patients. Although there are studies in liver transplant recipients, the data from these studies cannot be readily extrapolated to the kidney transplant population. Effective immunosuppressive treatment of HCV-infected kidney transplant recipients, therefore, requires consideration of the safety and efficacy of current agents balanced against their potential adverse effects.

Available evidence indicates that all conventional, current maintenance immunosuppressive agents can be used in kidney transplant patients infected with HCV. Viral replication is increased after transplantation in the setting of chronic immunosuppression use, although it is not clear whether or how this impacts liver disease, or patient, or graft survival in kidney transplant recipients.^277,278,316 For example, studies in HCV-infected liver transplant recipients suggest that treatment with corticosteroid boluses for acute rejection may result in up to a 100-fold increase in HCV RNA concentrations, increased frequency of acute hepatitis, and decreased time to recurrence of disease.^317,318 However, this has not been established in kidney transplant patients with HCV infection. As far as mycophenolic acid-based therapies in HCV-infected transplant recipients are concerned, there is growing evidence for the rationale of using this adjunctive agent to spare exposure to the potential toxicities of calcineurin inhibitors and steroids, although specific data are limited in this regard. Studies in HCV-infected nontransplant patients suggest that mycophenolic acid therapies may have an inhibitory effect on viral replication, but this has not been established in transplant recipients.³¹⁹ On the other hand, there is no convincing evidence of a specific deleterious effect of mycophenolic acid therapy on either graft or patient outcomes in kidney transplant recipients with HCV infection. ^320,321 In fact, a retrospective registry analysis indicates that mycophenolate mofetil was associated with favorable outcomes, even after adjustment for all possible confounding factors.³²⁰ Trials in liver transplant patients have confirmed the potential clinical outcome benefit associated with mycophenolate mofetil. Regarding calcineurin inhibitors, emerging evidence from retrospective studies suggests that cyclosporin, but not tacrolimus, may inhibit HCV viral replication. However, this remains to be validated in kidney transplant patients. Also, the available studies suggest that tacrolimus is more diabetogenic than cyclosporin in most transplant recipients (see Guideline 4.4.3). Among HCVinfected kidney transplant recipients, the risk of NODAT appears to be especially high in patients being treated with tacrolimus. For patients developing hyperglycemia in the setting of tacrolimus use, conversion to a cyclosporin-based regimen should be considered.

Among antibody therapies commonly used for induction or for treating acute rejection, unfavorable outcomes have been frequently reported in the literature concerning liver transplant patients with HCV infection. In contrast, preliminary registry data of 3706 patients from the United States indicate that antibody induction is associated with improved patient and graft outcomes in HCV-infected kidney transplant recipients.³²²

There are limited data on the use of sirolimus in HCVinfected kidney transplant recipients. This is another area in which more information would be needed before specific recommendations could be made.

On the basis of the available-although sparse-evidence, and even though most immunosuppressive agents increase viral replication, these therapies can all be used in kidney transplant patients with HCV infection. The following recommendations are made for consideration in the management of these patients:

All currently available maintenance immunosuppressive therapies can be used in kidney transplant recipients with HCV infection.

Selection of specific immunosuppressive agents should be tailored to the needs of each individual patient, balancing the potential impact on HCV-related hepatic and extrahepatic complications vs the risk of rejection.

Maintenance immunosuppression should consist of the lowest possible doses of all of the therapies that will provide effective antirejection coverage.

Patients should be carefully monitored for posttransplant complications and liver disease as described in Guideline 4.4.

At the present time, it is not clear that the impact of immunosuppression on outcomes in liver transplant patients with HCV infection can automatically be extrapolated to HCV-infected kidney transplant recipients as well. Further investigation will be required in this area.

LIMITATIONS

There are few randomized, prospective, or longitudinal studies that examine immunosuppression use in HCV-infected kidney transplant recipients.

Most outcome studies are retrospective.

Many of the published studies include small numbers of patients.

Registry analyses do not provide sufficient or adequate information on baseline liver histology or patient comorbidity.

Very few studies have examined viral replication after kidney transplantation.

It is unknown whether the impact of immunosuppression in HCV-infected liver transplant recipients can be extrapolated to kidney transplant recipients.

RESEARCH RECOMMENDATIONS

Prospective randomized trials are required comparing the calcineurin inhibitors, cyclosporine A, and tacrolimus in HCV-infected kidney transplant recipients in terms of efficacy, patient and graft outcomes, and impact on viral kinetics, as well as other HCV-related complications, for example, NODAT or glomerulopathy.

Prospective studies are needed to examine the impact of antibody induction therapy on virologic, histologic, clinical, and biochemical markers in HCV-infected kidney transplant recipients.

A prospective study should be conducted to examine the effect of sirolimus and everolimus on viral replication in HCV-infected kidney transplant recipients.

Guideline 4.4: Management of HCV-related complications in kidney transplant recipients
INTRODUCTION
HCV-infected kidney transplant recipients are at increased risk of several complications in the post-transplant period. Worsening liver disease, in addition to several extrahepatic clinical events such as NODAT and glomerular disease of the allograft, has been reported. In this context, close follow-up of the HCV-infected kidney transplant recipient is mandatory.

4.4.1 It is suggested that HCV-infected kidney transplant recipients more than 6 months after transplant have their liver disease evaluated at least annually. (Weak)

4.4.2 For HCV-infected kidney transplant recipients in whom the benefits of antiviral treatment clearly outweigh the risks (see Guidelines 2.1.5 and 2.2.4), monotherapy with standard IFN is suggested. (Weak)

4.4.3 It is suggested that HCV-infected kidney transplant recipients be screened for the development of hyperglycemia after transplantation. (Weak)

4.4.4 It is suggested that HCV-infected kidney transplant recipients be tested at least every 3-6 months for proteinuria. (Weak)

It is suggested that patients who develop new onset proteinuria (either urine protein/creatinine ratio 41 or 24-h urine protein greater than 1 g on two or more occasions) have an allograft biopsy with immunofluorescence and electron microscopy included in the analysis. (Weak)

4.4.5 Because of the risk of rejection, it is suggested that kidney transplant recipients with HCV-associated glomerulopathy not receive IFN-based therapy, unless it is determined that the benefits of therapy outweigh the risks of treatment. (Weak)

BACKGROUND
Although HCV-infected patients fare better with kidney transplant than with maintenance dialysis, there is good evidence that HCV-infected kidney transplant recipients have worse patient and allograft survival after transplantation compared to their uninfected counterparts. Initial reports indicated that patient survival in the short term (within 5 years after transplant) did not differ between kidney transplant recipients with or without HCV infection.^323-328 However, recent studies with longer term follow-up have demonstrated that HCV infection is associated with a detrimental effect on patient outcomes. ^{114,115,117,118,120,159,261-264,320,329,330} The increased mortality after kidney transplantation in this population has, in part, been attributed principally to progressive liver disease after transplantation,^118,159,264 but extrahepatic complications of HCV infection are also common and collectively contribute to the inferior outcomes observed in this patient population.

Efforts to improve post-transplant outcomes of HCVinfected kidney transplant recipients require the early detection, prevention, and treatment of complications related to chronic HCV infection. These include ongoing monitoring of liver function; selective and cautious use of IFN in the post-transplant setting; prevention, detection, and treatment of extrahepatic complications of NODAT and post-transplant glomerulopathy.
RATIONALE
4.4.1. It is suggested that HCV-infected kidney transplant recipients more than 6 months after transplant have their liver disease evaluated at least annually. (Weak).
HCV infection generally has an indolent course and the progression of liver disease is gradual.20 Nevertheless, all HCV-infected kidney transplant recipients should have their ALT/AST levels monitored on an ongoing basis after transplantation, based on the following evidence:

Many studies, although all retrospective, have demonstrated that HCV-infected kidney transplant recipients have an increased risk of mortality from liver disease after transplantation.^118,159,264 Hepatic complications are primarily related to liver injury, manifested by ALTelevations or progressive chronic liver injury.^{114,115,117,118,159,262-264} In a recent meta-analysis that evaluated the natural history of HCV infection in kidney transplant recipients, mortality due to liver disease (cirrhosis or hepatocellular carcinoma) was increased in HCV-infected patients in six of the eight studies included in the analysis, with a summary estimate for the RR of death of 1.79.⁸⁰ Overall, the rates of liver disease-related deaths ranged from 2.6 to 40% in HCV-infected patients and from 0 to 37% in uninfected patients. The available studies are subject to some important limitations. First, some investigations examined outcomes in kidney transplant recipients in whom a diagnosis of HCV hepatitis was made only after transplantation; second, the majority of studies did not provide adequate detail regarding virology and also did not incorporate liver histology before kidney transplantation. These shortcomings may have resulted in underrecognition of advanced liver disease present at the time of transplantation, leading to increased rates of decompensated liver disease among HCV-infected kidney transplant recipients. Recent publications have provided additional, albeit somewhat conflicting, post-transplant histologic information through the use of sequential liver biopsies in HCV-infected recipients.^279,280,282 Once again, none of these studies included pretransplant liver biopsies. In the first of these retrospective but case-controlled studies, both liver histologic activity and fibrosis were reported to progress more rapidly in the transplant recipients than those observed among immunocompetent patients without kidney disease.²⁸² In sharp contrast, the second study reported that rates of liver disease progression were lower in transplant recipients than in infected individuals with normal kidney function.²⁷⁹ The most recent study was a prospective cohort analysis, where up to four sequential post-kidney transplant liver biopsies were performed over a 10-year follow-up period.²⁸⁰ This analysis confirmed that the progression of liver disease was gradual and that histologic progression occurred in about 40% of patients, while the majority either had stable histology (40%) or regression (20%). On the basis of the foregoing evidence, it is concluded that kidney transplant recipients with HCV infection are at increased risk for progressive hepatic injury after kidney transplantation, but progressive liver disease is slow and does not occur in all patients.

Immunosuppression may increase HCV viral replication after transplantation²⁷⁸and occasionally results in accelerated liver injury.¹¹⁰ Cases of fibrosing cholestatic hepatitis have been reported in kidney transplant patients with HCV infection,^189,331 but are not common.

In light of the heightened predisposition to liver-related morbidity and its impact on mortality, coupled with reported cases of fibrosing cholestatic hepatitis, it is recommended that regular, ongoing post-transplant monitoring of HCV-infected kidney transplant recipients be performed, including followup with a hepatologist in the event of clinically worsening liver disease. The following specific recommendations are proposed for managing HCV infection-related liver disease in HCV-infected kidney transplant recipients:

Liver enzymes should be checked every month for the first 6 months of the post-transplant period and every 3 months thereafter.

The detection of clinically worsening liver enzymes should prompt early referral for hepatologic evaluation
.
Annual liver ultrasound and a-fetoprotein level to screen for hepatocellular carcinoma should be considered in patients with cirrhosis on liver biopsy.

Except in special situations, IFN therapy should be avoided after kidney transplantation (see Guideline 4.4.2).

There is no reason to perform liver biopsies in the post-transplant period, unless: (i) there is evidence of worsening liver disease; or (ii) as part of an investigational protocol.

4.4.2. For HCV-infected kidney transplant recipients in whom the benefits of antiviral treatment clearly outweigh the risks (see Guidelines 2.1.5 and 2.2.4), monotherapy with standard IFN is suggested. (Weak).

IFN is effective for viral eradication in HCV-infected patients, especially when combined with ribavirin (see Guideline 2). Induction of SVR with IFN in the pretransplant setting frequently persists after kidney transplantation and can be associated with a reduction in HCV-related complications (see Guideline 4.1). However, the administration of IFN after kidney transplantation can be deleterious to the allograft and should generally be avoided in kidney transplant recipients unless there is indication of worsening hepatic injury on biopsy or clinically decompensating liver disease. This suggestion is supported by evidence of kidney graft dysfunction during IFN therapy in at least 12 published, although uncontrolled retrospective or observational studies (Guideline 2, Tables 12-14).^{2-4,142,160,161,163,165,290,293,295,297,298,332,333} Reported rates of kidney graft dysfunction range from 9 to 100%, with most episodes occurring between 0.3 and 8 months after initiation of therapy. In several cases, graft dysfunction limited the benefit of IFN and was followed by graft loss. Most kidney graft dysfunction was related to increased rates of acute rejection associated with the use of this immunostimulatory agent. In nontransplant patients, IFN has also been associated with the exacerbation of cryoglobulinemia³³⁴ as well as acute renal failure³³⁵ and glomerulopathy^.336

On the other hand, patients with worsening liver disease (for example, fibrosing cholestatic hepatitis) are at increased risk for a subsequent liver transplant or even death. In these patients, IFN-based therapy may be potentially lifesaving and should be administered despite the risk of kidney graft dysfunction. In the studies cited above, HCV viral clearance was achieved 0-50% of the time. In a recent meta-analysis, the summary estimate for SVR was 18%.²⁹⁴ To this end, there is one report of two patients who developed fibrosing cholestatic hepatitis after kidney transplantation, where IFN successfully reversed the acute hepatic insult.¹⁸⁹ There is also one case series of 11 patients where administration of very low-dose IFN (1x10⁶U thrice weekly) achieved SVR in three of the patients, a partial response in another three, and only one patient experienced acute graft dysfunction. Another single case report suggests that SVR was obtained in a kidney transplant recipient with the use of IFNß.³³⁷

On the basis of the above evidence, the following recommendations are made:

IFN is contraindicated in kidney transplant recipients for the treatment of extrahepatic complications of HCV infection.

IFN should only be used in the setting of clinically and histologically worsening liver disease, where the potential benefits of treatment (in terms of eradicating virus and attenuating liver injury or preventing liver failure) outweigh the substantial risks of kidney allograft injury and graft loss due to the therapy.

4.4.3. It is suggested that HCV-infected kidney transplant recipients be screened for the development of hyperglycemia after transplantation. (Weak).

The frequency of HCV infection is increased among diabetic patients in the general population.^338,339 In addition, HCV infection has been strongly associated with new-onset diabetes mellitus, both in the general population and in transplant recipients. In NHANES III, HCV infection was associated with a 3.7-fold increased risk of type 2 diabetes mellitus,³⁰⁵ and others have reported a higher prevalence of impaired fasting glucose among HCV-infected patients compared to uninfected patients.³⁰⁴

The overall reported rates of new-onset diabetes mellitus after solid organ transplantation range from 2 to 53%.³⁴⁰ The wide range stems, in part, from a previous lack of uniform criteria for defining NODAT. Definitions have ranged from the de novo requirement for insulin or oral hypoglycemic agents to various target glucose levels not necessarily consistent with American Diabetes Association (ADA) guidelines. Subject to these limitations, several retrospective cohort studies and one registry analysis indicate that the rates of NODAT among HCV-infected kidney transplant recipients range between 10 and 65%, with a three- to fivefold increased risk of NODAT among HCV-infected kidney transplant recipients.^{127,128,132,265,266,341} At least two of these studies suggest that the risk of NODAT in HCV-infected recipients was especially exaggerated in patients being treated with tacrolimus, as opposed to cyclosporine-based maintenance immunosuppression.^128,341 A similar increased risk of NODAT has been made in liver transplant recipients with HCV infection.^289,290,342As with uninfected kidney transplant recipients, NODAT typically occurs in HCV-infected patients within the first 3 months after transplantation.^127,128

The adverse effects of NODAT on morbidity, mortality, and graft survival after transplantation are well established in kidney transplant recipients.^127,266 However, outcome data in the subset of HCV-infected patients with NODAT are sparse. One analysis of Medicare beneficiaries in the USRDS registry noted that among HCV-infected kidney transplant recipients, the development of NODAT was associated with a significant reduction in lifespan.¹²⁷ In another study of HCV-infected liver transplant recipients, there was a significantly higher cumulative mortality rate of 56% among patients with NODAT compared to 14% in the nondiabetic cohort.²⁹⁰

The available data provide convincing evidence of a relationship between HCV infection and an increased risk of NODAT after kidney transplantation. Although less well supported from the available evidence, it appears that HCVinfected recipients with NODAT have a higher risk of mortality than their nondiabetic counterparts. Also, many studies have demonstrated that, considered separately, both HCV infection and NODAT^266,343 independently predict a higher risk of mortality in kidney transplant patients. As early detection of NODAT in HCV-infected transplant recipients is desirable to initiate therapy, the following recommendations are made:

Nondiabetic HCV-infected kidney transplant candidates should have an oral glucose tolerance test during evaluation for a kidney transplant to screen for preexisting diabetes mellitus. Fasting blood sugars should be obtained weekly during the first 3 months of the post-transplant period, then every other week for months 4-6, and then monthly for months 6-12. After the first post-transplant year, fasting blood glucose and/or glycosylated hemoglobin should be measured at least annually. This is in keeping with the guidelines of the American Society of Transplantation for outpatient surveillance of kidney transplant recipients.³⁴⁴

The diagnosis of hyperglycemia should be in keeping with current ADA criteria of a fasting blood glucose >125 mg per 100 ml (6.9mmol l^-1) on two separate occasions.³⁴⁵

The use of immunosuppressive drugs that are associated with diabetogenic side effects should be balanced to optimize antirejection efficacy while simultaneously minimizing the risk of hyperglycemia.

Patients with evidence of hyperglycemia as defined by the ADA criteria should be referred to a diabetologist for further evaluation and management.

Whether the use of oral glucose tolerance tests or more frequent glucose monitoring in HCV-positive kidney transplant recipients will lead to earlier diagnosis and treatment of NODAT remains to be determined.
4.4.4 It is suggested that HCV-infected kidney transplant recipients be tested at least every 3-6 months for proteinuria. (Weak).

It is suggested that patients who develop new onset proteinuria (either urine protein/creatinine ratio >1 or 24-h urine protein greater than 1 g on two or more occasions) have an allograft biopsy with immunofluorescence and electron microscopy included in the analysis. (Weak)

4.4.5 Because of the risk of rejection, it is suggested that kidney transplant recipients with HCV-associated glomerulopathy not receive IFN-based therapy, unless it is determined that the benefits of therapy outweigh the risks of treatment. (Weak).

HCV infection has been implicated in the pathogenesis of glomerular disease in both native and transplanted kidneys.³⁴⁶ Among kidney transplant recipients, the prevalence of proteinuria is increased in those with HCV infection compared to uninfected patients.¹²² HCV-infected kidney transplant recipients have an increased risk of posttransplant glomerulopathy, leading to graft dysfunction and loss. Because kidney transplant recipients with HCV infection are predisposed to post-transplant glomerulopathy, a proactive approach to detecting evidence of glomerular injury is specifically recommended:

Baseline urine protein-to-creatinine ratio and urinalysis should be obtained within the first 2 weeks after transplantation, or as soon as a stable level of kidney function is achieved. Thereafter, patients should be screened for proteinuria at least every 3–6 months for the first post-transplant year and then twice per year thereafter. These recommendations are in keeping with the guidelines published by the American Society of Transplantation.³⁴⁴

MPGN is commonly observed in kidney allograft biopsies from HCV-infected patients with proteinuria and may be associated with both chronic allograft nephropathy and either de novo disease or posttransplant recurrence of the native kidney lesion.³⁴⁶ Distinguishing the cause of MPGN is important as it may influence subsequent therapy. The presence of immune complex deposition favors a diagnosis of MPGN and may result in accelerated graft loss.¹²²

A biopsy of the kidney allograft should be performed in HCV-infected kidney transplant recipients who are found to have proteinuria (urine protein-to-creatinine ratio >1.0, or 24-h urine protein >1.0 g on two occasions) or microscopic hematuria without other causes identified.

Kidney biopsy should be studied with light microscopy, immunofluorescence techniques, and electron microscopy.

Specific glomerular changes characteristic of cryglobulinemic MPGN may indicate the need to consider specific therapy (see Guideline 5).

Distinguishing the cause of MPGN is important as it may influence subsequent therapy. The presence of immune complex deposition favors a diagnosis of MPGN and may result in accelerated graft loss.¹²²

A biopsy of the kidney allograft should be performed in HCV-infected kidney transplant recipients who are found to have proteinuria (urine protein-to-creatinine ratio 41.0, or 24-h urine protein 41.0 g on two occasions) or microscopic hematuria without other causes identified.

Kidney biopsy should be studied with light microscopy, immunofluorescence techniques, and electron microscopy.

Specific glomerular changes characteristic of cryglobulinemic MPGN may indicate the need to consider specific therapy (see Guideline 5).

IFN-based therapies may be effective in treating HCV-related glomerulopathy in native kidney disease (see Guideline 5.3). However, IFN use in kidney transplant recipients is associated with an increased risk of rejection (see Guideline 4.4.2). The RR of kidney allograft loss from progressive HCV-associated glomerulopathy vs that from IFN-induced rejection is unknown. Emerging data suggest that the administration of IFN to HCV-infected patients before transplantation may prevent post-transplant GN (discussed in Guideline 4.1.5). The limited available data indicate that antiviral therapies such as ribavirin can be antiproteinuric in kidney transplant recipients.¹⁸⁷ Nonspecific antiproteinuric measures, such as blockade of the renin-angiotensin- aldosterone system with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB), may be useful adjuncts. Although these agents have been extensively investigated in native kidney disease, studies in kidney transplant patients are relatively sparse in general and nonexistent in HCV-infected recipients in particular. However, the available data from native kidney disease studies can be extrapolated to the kidney transplant population. Support for this judgment comes from studies in kidney transplant patients showing that treatment with ACEI/ARB reduces proteinuria³⁴⁷ and slows progressive chronic allograft dysfunction and failure.^348,349 The following recommendations are made on the basis of the above information and the limited number of studies thatspecifically address optimal therapy of HCV-related posttransplant glomerulopathy:

Because of the increased risk of allograft dysfunction, it is suggested that treatment with IFN-based therapy generally be avoided in kidney recipients with HCVassociated glomerulopathy. Any decision to use IFN should be individualized, weighing the potential benefit of treatment vs the risk of rejection. If a decision to treat is made, there are limited data on the use of pegylated IFN and ribavirin in this setting; however, in patients with estimated GFR >50 ml per min per 1.73m², combination therapy with IFN and ribavirin can be considered.

Ribavirin can reduce proteinuria in HCV-associated glomerulopathy, although its impact on kidney function is unknown and it does not lead to viral clearance.

Strong consideration should be given to treat HCVinfected kidney transplant candidates in the pretransplant period, as achievement of a pretransplant SVR is frequently durable and appears to be associated with a reduced risk of post-transplant glomerulopathy (see Guideline 4.1.5).

Antiproteinuric therapy with agents that block the renin-angiotensin-aldosterone system should be used as tolerated. Careful monitoring of kidney function, serum potassium, and hemoglobin during ACEI/ARB therapy is essential, particularly if recipients have impaired kidney function.

General treatment principles for CKD management should be followed, including target levels of proteinuria, blood pressure, and lipids, as described in guidelines by KDOQI and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
LIMITATIONS

There are no prospective studies examining the natural history of liver disease progression in HCV-infected kidney transplant recipients, especially in terms of pretransplant liver histology.

There is a lack of prospective studies evaluating extrahepatic HCV-related complications in kidney transplant recipients.

Most published studies include small numbers of patients.

Registry studies are short on detailed and patientspecific data.

All outcome studies are retrospective.

It is not known whether practice standards used for the nontransplant population or for liver transplant recipients with HCV infection can be applied to HCV-infected kidney transplant recipients.

RESEARCH RECOMMENDATIONS

Prospective studies are needed to evaluate the natural history of HCV infection in kidney transplant recipients in terms of progressive liver disease as well as extrahepatic complications.

Studies are needed to determine the mechanism of NODAT in HCV-infected transplant recipients as well as possible therapies that may mitigate or prevent this complication.

Prospective randomized trials of IFN or other emerging antiviral therapies administered to HCVinfected kidney candidates before transplantation are needed to examine the effects on hepatic and extrahepatic complications of HCV developing after transplantation.

Prospective trials are needed to examine the efficacy of anti-CD20 in post-transplant GN and its effect on viral replication.

Mission Statement:

Guideline 4: Management of HCV-infected patients before and after kidney transplantation