Executive Summary Of The KDIGO 2022 Clinical Practice Guideline For The Prevention, Diagnosis, Evaluation, And Treatment Of Hepatitis C in Chronic Kidney Disease Ⅱ
Sep 19, 2023
Chapter 4: Management of HCV-infected patients before and after kidney transplantation
If left untreated, HCV infection decreases patient survival and allograft survival following kidney transplantation. However, for patients with CKD G5 or G5D and HCV infection, survival is still improved by kidney transplantation compared to remaining on chronic dialysis. DAA therapy has also been shown to be effective and well-tolerated in kidney transplant recipients.
4.1: Evaluation and management of kidney transplant candidates regarding HCV infection
4.1.1: We recommend kidney transplantation as the best therapeutic option for patients with CKD G5 irrespective of the presence of HCV infection (1A).
4.1.2: We suggest that all kidney transplant candidates with HCV be evaluated for severity of liver disease and presence of portal hypertension prior to acceptance for kidney transplantation (2D).
4.1.2.1: We recommend that patients with HCV, compensated cirrhosis, and no portal hypertension undergo isolated kidney transplantation and that patients with decompensated cirrhosis or clinically significant portal hypertension (i.e., hepatic venous pressure gradient ‡10 mm Hg or evidence of portal hypertension on imaging or exam) undergo a simultaneous liver–kidney transplantation (1B). Treatment of those with mild-to-moderate portal hypertension should be determined on a case-by-case basis.
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4.1.2.2: We recommend referring patients with HCV and decompensated cirrhosis for combined liver–kidney transplantation (1B).
4.1.3: Timing of HCV treatment in relation to kidney transplantation (before vs. after) should be based on donor type (living vs. deceased donor), wait-list times by donor type, center-specific policies governing the use of kidneys from HCV-infected deceased donors, and severity of liver fibrosis (Not Graded).
4.1.3.1: We recommend that all kidney transplant candidates with HCV be considered for DAA therapy, either before or after transplantation (1A).
4.1.3.2: We suggest that HCV-infected kidney transplant candidates with a living kidney donor be considered for treatment before or shortly after transplantation depending on the anticipated timing of transplantation (2B).
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Management of HCV-infected kidney transplant candidates. An approach to the evaluation and management of HCV-infected kidney transplant candidates is presented in Figure 2. First, patients who are anti-HCV antibody–positive require confirmation of viremia (HCV RNA), and evaluation of the severity of liver disease and extent of fibrosis, typically by noninvasive means, is also needed as outlined in Chapter 1. If cirrhosis is suspected based on clinical findings or after assessment of liver fibrosis, additional evaluation is needed to determine if clinically significant portal hypertension is present. A wedged hepatic venous pressure gradient $10 mm Hg is consistent with significant portal hypertension. Patients with clinical evidence of decompensated cirrhosis (esophageal varices or other clinical findings, such as ascites or hepatic encephalopathy, among others) or significant portal hypertension should be evaluated for simultaneous liver–kidney transplant even if they have achieved SVR( (Figure 2). In HCV-infected patients with compensated cirrhosis without portal hypertension or in those without evidence of cirrhosis, kidney transplantation alone is recommended as DAA therapy can prevent the progression of liver disease (Figure 2). DAA therapy should be administered to all HCV-infected kidney transplant candidates, either before or after transplantation.
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Timing of antiviral therapy. Factors guiding the timing of HCV treatment (before vs. after kidney transplantation) include donor type (living vs. deceased donor), anticipated waiting list time by donor type, severity of hepatic fibrosis, and willingness of the patient and program to accept an organ from an HCV-infected donor. In a patient with compensated cirrhosis or no cirrhosis whose waiting period for transplant is likely to be greater than 24 weeks, DAA therapy can be administered prior to transplant to allow treatment of 12 weeks duration with confirmation of SVR 12 weeks after its completion (Figure 2). HCV-infected kidney transplant candidates with an identified living kidney donor can be treated for HCV before or shortly after transplantation depending on the anticipated timing of transplantation.
Figure 2 | Proposed management strategy in a hepatitis C virus (HCV)-infected kidney transplant candidate. *Clinically significant portal hypertension is defined as hepatic venous pressure gradient $10 mm Hg or evidence of portal hypertension on imaging or exam, e.g., ascites, esophageal varices, collaterals on imaging. F0, no scarring or fibrosis; SKLT, simultaneous kidney–living transplantation.
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4.2: Use of kidneys from HCV-infected donors
4.2.1: We recommend that all kidney donors be screened for HCV infection with both immunoassay and nucleic acid testing (NAT) (if NAT is available) (1A).
4.2.2: After assessment of liver fibrosis, HCV-infected potential living kidney donors who do not have cirrhosis should undergo HCV treatment before donation if the recipient is HCV-uninfected; they can be accepted for donation if they achieve sustained virologic response (SVR) and remain otherwise eligible to be a donor (Not Graded).
4.2.3: We recommend that kidneys from HCV-infected donors be considered regardless of the HCV status of potential kidney transplant recipients (1C).
4.2.4: When transplanting kidneys from HCV-infected donors into HCV-uninfected recipients, transplant centers must ensure that patients receive education and are engaged in discussion with sufficient information to provide informed consent. Patients should be informed of the risks and benefits of transplantation with an HCV-infected kidney, including the need for DAA treatment (Not Graded).
4.2.5: When transplanting kidneys from HCV-infected donors into HCV-uninfected recipients, transplant centers should confirm the availability of DAAs for initiation in the early post-transplant period (Not Graded).
The use of kidneys from HCV-infected living and deceased donors expands the donor pool, and their use should be encouraged. Previously, kidneys from HCV-infected deceased donors were offered only to HCV-infected recipients, which reduced waiting times for transplantation without a negative impact on patient survival. In this setting, DAA therapy should be administered post-transplant to prevent the progression of liver disease and other extrahepatic complications of HCV.
Deceased donor transplantation from HCV-infected donors to uninfected recipients. More recently, kidneys from HCV-infected donors have been transplanted into HCV-uninfected recipients. For these patients, DAA therapy administered at the time of transplant or early thereafter is safe and effective to prevent complications of HCV infection in the recipient. Despite differing DAA regimens and timing of initiation, DAA treatment for 4–8 weeks has been associated with excellent rates of viral clearance (SVR12) as well as excellent allograft function and survival, with excellent patient survival rates at 1 year following transplant. Very short treatment duration (<8 days) has been more frequently associated with viral relapse; thus, a full 12-week treatment course is often required. Therapy should be started promptly post-transplant to avoid severe acute HCV infection.
HCV and living kidney donation. Potential living kidney donors should undergo HCV testing using immunoassay as well as nucleic acid testing (NAT). If a potential living kidney donor is HCV-NAT–positive, an evaluation for the severity of liver disease and fibrosis should be undertaken and the donation should be deferred until after successful DAA therapy in the donor and SVR are confirmed. Living donation can then proceed if the evaluation of the donor excludes extensive hepatic fibrosis.
4.3: Use of maintenance immunosuppressive regimens
4.3.1: We recommend that kidney transplant recipients being treated with DAAs be evaluated for the need for dose adjustments of concomitant immunosuppressants (1C).
HCV viral load increases following kidney transplantation due to therapeutic immunosuppression, although this does not prevent successful DAA therapy. Drug–drug interactions are an important issue to consider when DAA regimens are used in kidney transplant recipients due to shared cytochrome P450 metabolism leading to substrate competition. This issue is particularly relevant in kidney transplant recipients treated with calcineurin and mTOR inhibitors. The Hepatitis Drug Interactions website is a useful resource for potential drug–drug interactions (http://www.hep-druginteractions.org).
4.4: Management of HCV-related complications in kidney transplant recipients
4.4.1: We suggest that patients previously infected with HCV who achieved SVR before transplantation undergo testing by NAT 3 months after transplantation or if liver dysfunction occurs (2D).
4.4.2: Kidney transplant recipients with cirrhosis should have the same liver disease follow-up as non-transplant patients, as outlined in the American Association for the Study of Liver Diseases (AASLD) guidelines (Not Graded).
4.4.3: HCV-infected kidney transplant recipients should be tested at least every 6 months for proteinuria (Not Graded). 4.4.3.1: We suggest that patients who develop new-onset proteinuria (either urine protein-creatinine ratio > 1 g/g or 24-hour urine protein > 1 g on 2 or more occasions) have an allograft biopsy with immunofluorescence and electron microscopy included in the analysis (2D). 4.4.4: We recommend treatment with a DAA regimen in patients with post-transplant HCV-associated glomerulonephritis (1D).
Successful antiviral therapy prevents the progression of liver disease and allograft injury due to HCV infection. SVR is durable but if there is evidence of hepatic dysfunction, HCV reinfection, and HBV reactivation or acquisition should be excluded. As in any cirrhotic patient, regular surveillance for hepatocellular carcinoma and other complications of HCV and liver disease is recommended following kidney transplantation of HCV-infected patients, as outlined in the AASLD and EASL guidelines. Following transplantation, patients with prior HCV infection should be monitored for proteinuria, microscopic hematuria, and decreased GFR. HCV-related allograft injury is suggested by abnormalities in these parameters in HCV viremic recipients and should prompt allograft biopsy including immunofluorescence and electron microscopy. Evidence of post-transplant HCV-associated glomerulonephritis is an additional indication for DAA therapy.
CHAPTER 5: DIAGNOSIS AND MANAGEMENT OF KIDNEY DISEASES ASSOCIATED WITH HCV INFECTION
5.1: HCV-infected patients with a typical presentation of immune-complex proliferative glomerulonephritis can be managed without a confirmatory kidney biopsy. However, a biopsy may be indicated in certain clinical circumstances (Figure 3) (Not Graded).
Figure 3 | Indications for biopsy in patients with hepatitis C virus (HCV) and severe glomerulonephritis. The algorithm above assumes that a patient with HCV and chronic kidney disease is already receiving direct-acting antiviral (DAA) treatment. Systemic signs of cryoglobulinemia include skin lesions such as purpura, arthralgias, and weakness. eGFR, estimated glomerular filtration rate; RPGN, rapidly progressive GN; SVR, sustained virologic response.
5.2: We recommend that patients with HCV-associated glomerulonephritis receive antiviral therapy (1A).
5.2.1: We recommend that patients with HCV-associated glomerulonephritis, stable kidney function, and without nephrotic syndrome be treated with DAAs prior to other treatments (1C).
5.2.2: We recommend that patients with cryoglobulinemic flare or rapidly progressive glomerulonephritis be treated with both DAAs and immunosuppressive agents with or without plasma exchange (1C).
5.2.2.1: The decision whether to use immunosuppressive agents in patients with nephrotic syndrome should be individualized (Not Graded).
5.2.3: We recommend immunosuppressive therapy in patients with histologically active HCV-associated glomerulonephritis who do not respond to antiviral therapy, particularly those with cryoglobulinemic kidney disease (1B).
5.2.3.1: We recommend rituximab as the first-line immunosuppressive treatment (1C).
Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection
Immune-complex glomerulonephritis is a common extrahepatic manifestation of HCV infection. This can occur with or without evidence of mixed cryoglobulinemic vasculitis.
In an HCV-infected patient with a typical presentation of immune-complex glomerulonephritis (Figure 3) and stable GFR, DAA therapy can be initiated without performing a kidney biopsy. In the event that GFR or proteinuria worsens following treatment, or if immunosuppressive therapy is being considered, a kidney biopsy should be performed. Patients with atypical presentations, and those with evidence of rapidly progressive glomerulonephritis or severe nephrotic syndrome, should undergo kidney biopsy.
In patients with progressive decline in GFR due to active glomerulonephritis or a cryoglobulinemic flare, concomitant immunosuppressive therapy should be administered. If successful treatment with DAA does not result in an improvement in glomerulonephritis, immunosuppressive therapy is recommended. If nephrotic syndrome is present, treatment should be individualized based on various factors, including severity of kidney dysfunction and degree of nephrotic syndrome. When immunosuppressive treatment is indicated, rituximab is generally used as the first-line agent.
Table 1 | Summary of key messages from KDIGO 2022 HCV Guideline Update
DAAs are highly effective and well-tolerated for the treatment of HCV in patients across all CKD stages, including those undergoing dialysis therapy and kidney transplant recipients, with no need for dose adjustment Pangenotypic DAA regimens, including sofosbuvir-based regimens, and genotype-specific regimens are safe and effective for advanced CKD (CKD G4-G5ND or G5D) and for kidney transplant recipients, and can be selected based on local practices and availability of specific DAAs
If pan-genotypic regimens are not available, genotypes should be ascertained prior to DAA treatment
Protease inhibitors (“-previous” such as simeprevir, paritaprevir, and grazoprevir) are contraindicated in patients with Child-Pugh B and C cirrhosis
Particular care with DAA agents should be exercised in kidney transplant recipients given the potential drug–drug interactions with immunosuppressive agents such as calcineurin and mTOR inhibitors. Readers should consult http://www.hep-druginteractions.org
Because of concerns about HBV reactivation during/after DAA treatment, testing for HBV serological markers (i.e., hepatitis B surface antigen [HBsAg], total core antibody [anti-HBc], and antibody to HBV surface antigen [anti-HBs]) should be performed prior to HCV treatment with DAA therapy If HBsAg is present, the patient should undergo assessment for HBV therapy. If HBsAg is absent but markers of prior HBV infection (HBcAb-positive with or without HBsAb) are detected, HBV reactivation should be excluded with HBV DNA testing if levels of liver function tests rise during DAA therapy Kidney transplant candidates with HCV should be evaluated for severity of liver disease and presence of portal hypertension prior to acceptance for kidney transplantation. Results from this assessment will help guide the decision of kidney transplantation alone versus simultaneous kidney–liver transplantation
DAA therapy should be administered to all HCV-infected kidney transplant candidates, either before or after transplantation
Timing of DAA treatment for kidney transplantation candidates (before vs. after transplantation) should be based on donor type (living vs. deceased donor), wait-list times by donor type, center-specific policies governing the use of kidneys from HCV-positive deceased donors, and severity of liver fibrosis
All living kidney donors should be screened for HCV infection with immunoassay and NAT if seropositive Kidneys from HCV-infected donors can be offered to potential recipients regardless of HCV status, provided that national or regional laws and regulations allow this practice
Conclusion
The efficacy and safety of DAA have profoundly changed the landscape of HCV management in patients with CKD and necessitated an update to the KDIGO 2018 guideline on HCV in CKD. The key messages related to HCV in CKD are outlined in Table 1. The most significant new developments are reviewed below. First, the finding of the safety and efficacy of sofosbuvir in patients with CKD G4-G5 and G5D adds an additional pan-genotypic agent to the DAA armamentarium and one that can be utilized in patients with cirrhosis. Second, the field of deceased donor kidney transplantation from HCV-viremic individuals to uninfected recipients has made major advances since the publication of the 2018 guideline, with future studies expected to refine the timing and duration of treatment and provide additional information on long-term clinical outcomes associated with this practice. Finally, the role of DAAs and immunosuppressive agents for HCV-associated immunecomplex glomerulonephritis continues to evolve with an increasingly clear message about which patients require kidney biopsy before therapy, which can be treated with DAA alone, and which require immunosuppressive treatment, primarily with rituximab.
DISCLOSURE
PM declared having received consultancy fees from AbbVie and Gilead; grant support from AbbVie* and Gilead*; and fees for the development of educational presentations from SC Liver Research Consortium. MCB declared having received consultancy fees from AbbVie, Deep Genomics, Intercept, Natera, and Orphalan; grant support from Gilead and Intercept; and speaker honoraria from AbbVie, Astellas, Chiesi, Deep Genomics, Gilead, Intercept, Novartis, and Orphalan. AB declared having received consultancy fees from AstraZeneca* and Chemocentryx*; having served on advisory boards at AstraZeneca* and Bayer*; and having received speaker honoraria from AbbVie, MSD/Merck, and Vifor. DSG declared having received grant support from Abbvie and Gilead*; fees for the development of educational presentations from Pfizer; and having provided expert testimony for White and Williams. JJ declared having received grant support from Bristol Myers Squibb* and Gilead*; and speaker honorarium from Gilead. NK declared having served as a board member and having received consultancy fees from Astellas, AstraZeneca, Biotest, Chiesi, CSL Behring, ExeViR, GSK, Hansa, MSD, Novartis, Sandoz, Sanofi, and Takeda. MGP declared having served as a board member for Gilead; having received consultancy fees from Gilead and Myralis; and speaker honoraria from Gilead. SP declared having received consultancy fees and speaker honoraria from AbbVie, Biotest, Gilead, Janssen, LFB, MSD, Shinogi, and ViiV Healthcare; and grant support from Bristol Myers Squibb, Gilead, MSD, and Roche. MES declared having received consultancy fees from Bioporto, Gilead, Mallinckrodt, and Travere; and grant support from AbbVie*, Angion*, EMD Serono*, Gilead*, and Merck*. CEG declared having received consultancy fees from Alexion, Gilead, and Otsuka; grant support from Alexion, Palladio Biosciences, and Reata; and speaker honoraria from Alexion. MJ declared having received consultancy fees from Astellas*, AstraZeneca*, Bayer*, Boehringer Ingelheim*, Fresenius Medical Care Asia Pacific*, Mundipharma*, and Vifor Fresenius Medical Care*; grant support from Amgen* and AstraZeneca*; and speaker honoraria from Astellas*, AstraZeneca*, Mundipharma*, and Vifor Fresenius Medical Care*. All the other authors declared no competing interests.
ACKNOWLEDGMENTS
The development and publication of this guideline were supported by KDIGO. The opinions or views expressed in this summary are those of the authors and do not necessarily reflect the opinions or recommendations of the International Society of Nephrology or Elsevier. Dosages, indications, and methods of use for products that are referred to by the authors may reflect their clinical experience or may be derived from the professional literature or other clinical sources.
REFERENCES
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2. Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2018 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl. 2018;8:91–165.
3. Kidney Disease: Improving Global Outcomes (KDIGO) Hepatitis C Work Group. KDIGO 2022 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int. 2022;102(6S):S129–S205.
4. European Association for the Study of the Liver (EASL). EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–398.
5. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–1599.
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