Table of Contents KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease 93 Tables, figures, algorithms, and supplementary material 95 KDIGO executive committee 96 Reference keys 97 CKD nomenclature 98 Conversion factors 99 Abbreviations and acronyms 100 Notice 101 Foreword 102 Work Group membership 103 Abstract 104 Summary of recommendation statements 108 Chapter 1: Detection and evaluation of HCV in CKD 114 Chapter 2: Treatment of HCV infection in patients with CKD 121 Chapter 3: Preventing HCV transmission in hemodialysis units 130 Chapter 4: Management of HCV-infected patients before and after kidney transplantation 137 Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection 142 Methods for guideline development 151 Biographic and disclosure information 157 Acknowledgments 158 References The development and publication of this guideline were supported by KDIGO. The opinions or views expressed in this professional education supplement 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 in the supplement by the authors may reflect their clinical experience or may be derived from the professional literature or other clinical sources. Because of the differences between in vitro and in vivo systems and between laboratory animal models and clinical data in humans, in vitro and animal data may not necessarily correlate with clinical results. Tables 106 Table 1. Infection control practices (“hygienic precautions”) particularly relevant in preventing HCV transmission 122 Table 2. Recent reported HCV prevalence in hemodialysis patients 122 Table 3. Factors and lapses in infection control practices associated with transmission of HCV infection in dialysis units 125 Table 4. Hygienic precautions for hemodialysis (dialysis machines) 127 Table 5. Steps to initiate concurrently and undertake following identification of a new HCV infection in a hemodialysis patient 127 Table 6. Strategies to support adherence to infection control recommendations in hemodialysis centers 128 Table 7. Key hygienic precautions for hemodialysis staff 143 Table 8. Systematic review topics and screening criteria 144 Table 9. Hierarchy of outcomes 145 Table 10. Work products for the guideline 146 Table 11. Classification of study quality 146 Table 12. GRADE system for grading quality of evidence 146 Table 13. Final grade for overall quality of evidence 147 Table 14. Balance of benefits and harms 147 Table 15. KDIGO nomenclature and description for grading recommendations 147 Table 16. Determinants of strength of recommendation 148 Table 17. The Conference on Guideline Standardization (COGS) checklist for reporting clinical practice guidelines Figures 105 Figure 1. Recommended DAA treatment regimens for patients with CKD G4–G5D and kidney transplant recipients, by HCV genotype 144 Figure 2. Search yield Algorithms 118 Algorithm 1. Treatment scheme for CKD G1–G5D 119 Algorithm 2. Treatment scheme for kidney transplant recipients 132 Algorithm 3. Proposed strategy in an HCV-infected kidney transplant candidate Supplementary Material Appendix A. Search strategies Appendix B. Concurrence with Institute of Medicine standards for systematic reviews and for guidelines Table S1. Summary table: diagnostic testing for liver fibrosis (by biopsy) Table S2. Evidence profile: diagnostic testing for liver fibrosis (by biopsy) Table S3. Summary table: HCV infection as independent predictor of CKD progression Table S4. Evidence profile: HCV infection as independent predictor of CKD progression Table S5. Summary table: treatment with direct-acting antiviral regimens in chronic HCV-infected CKD patients Table S6. Evidence profile: treatment with direct-acting antiviral regimens in chronic HCV-infected CKD patients Table S7. Summary table: treatment with direct-acting antiviral regimens in kidney transplant recipients with chronic HCV infection Table S8. Evidence profile: treatment with direct-acting antiviral regimens in kidney transplant recipients with chronic HCV infection Table S9. Summary table: isolation of HCV patients receiving hemodialysis Table S10. Evidence profile: isolation of HCV patients receiving hemodialysis Table S11. Summary table: transplantation versus waitlist among patients with HCV infection Table S12. Evidence profile: transplantation versus waitlist among patients with HCV infection Table S13. Summary table: HCV infection as predictor of death among kidney transplant recipients Table S14. Evidence profile: HCV infection as predictor of death and graft loss among kidney transplant recipients Table S15. Summary table: clinical outcomes of HCV-positive kidney transplant recipients from HCV-positive donors Table S16. Summary table: induction and immunosuppression in kidney transplant recipients with HCV infection Table S17. Summary table: HCV treatment of HCV-associated glomerular disease Table S18. Evidence profile: HCV treatment of HCV-associated glomerular disease Supplementary material is linked to the online version of the article at www.kisupplements.org. KDIGO Executive Committee Garabed Eknoyan, MDNorbert Lameire, MD, PhDFounding KDIGO Co-Chairs Bertram L. Kasiske, MDImmediate Past Co-Chair David C. Wheeler, MD, FRCPKDIGO Co-Chair Wolfgang C. Winkelmayer, MD, MPH, ScDKDIGO Co-Chair Ali K. Abu-Alfa, MDGeoffrey A. Block, MDJürgen Floege, MDJohn S. Gill, MD, MSKunitoshi Iseki, MDZhi-Hong Liu, MD, PhDMagdalena Madero, MDZiad A. Massy, MD, PhD Ikechi G. Okpechi, MBBS, FWACP, PhDBrian J.G. Pereira, MBBS, MD, MBARukshana Shroff, MD, FRCPCH, PhDPaul E. Stevens, MB, FRCPMarcello A. Tonelli, MD, SM, FRCPCSuzanne Watnick, MDAngela C. Webster, MBBS, MM (Clin Epi), PhDChristina M. Wyatt, MD KDIGO Staff John Davis, Chief Executive OfficerDanielle Green, Executive DirectorMichael Cheung, Chief Scientific OfficerTanya Green, Communications DirectorMelissa Thompson, Implementation Director Reference keys Nomenclature and Description for Rating Guideline Recommendations Within each recommendation, the strength of recommendation is indicated as Level 1, Level 2, or not graded, and the quality of the supporting evidence is shown as A, B, C, or D. Gradea Implications Patients Clinicians Policy Level 1 “We recommend” Most people in your situation would want the recommended course of action, and only a small proportion would not. Most patients should receive the recommended course of action. The recommendation can be evaluated as a candidate for developing a policy or a performance measure. Level 2 “We suggest” The majority of people in your situation would want the recommended course of action, but many would not. Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences. The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined. a The additional category “not graded” is used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements. They should not be interpreted as being weaker recommendations than Level 1 or 2 recommendations. Grade Quality of evidence Meaning A High We are confident that the true effect lies close to the estimate of the effect. B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. C Low The true effect may be substantially different from the estimate of the effect. D Very low The estimate of effect is very uncertain, and often will be far from the truth. Current Chronic Kidney Disease (CKD) Nomenclature Used by KDIGO CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health. CKD is classified based on cause, GFR category (G1–G5), and albuminuria category (A1–A3), abbreviated as CGA. Prognosis of CKD by GFR and albuminuria category Conversion Factors of Conventional Units to SI Units Conventional unit Conversion factor SI unit Creatinine mg/dl 88.4 μmol/l Note: conventional unit × conversion factor = SI unit. Albuminuria Categories in CKD Category AER (mg/24 h) ACR (approximate equivalent) Terms (mg/mmol) (mg/g) A1 300 >30 >300 Severely increasedb ACR, albumin-to-creatinine ratio; AER, albumin excretion rate; CKD, chronic kidney disease. a Relative to young adult level. b Including nephrotic syndrome (albumin excretion usually > 2200 mg/24 h [ACR > 2200 mg/g; > 220 mg/mmol]). Interpretation of HCV Assays Anti-HCV HCV-NAT Interpretation Positive Positive Acute or chronic HCV infection depending on the clinical context Positive Negative Resolution of HCV infection (i.e., successfully treated or spontaneously cleared) Negative Positive Early acute HCV infection; chronic HCV in the setting of immunosuppressed state; false anti-HCV negative or false HCV-NAT positive Negative Negative Absence of HCV infection Anti-HCV, HCV antibody; HCV, hepatitis C virus; NAT, nucleic acid testing. Abbreviations and acronyms AASLD American Association for the Study of Liver Diseases ALT alanine aminotransferase Anti-HCV HCV antibody APRI aspartate aminotransferase–platelet ratio index ASN American Society of Nephrology AUC area under the curve BSI bloodstream infection CDC Centers for Disease Control and Prevention CI confidence interval CKD chronic kidney disease CKD G4 CKD G5 chronic kidney disease GFR category 4 chronic kidney disease GFR category 5 CKD-EPI Chronic Kidney Disease Epidemiology Collaboration CNI calcineurin inhibitor CPG clinical practice guideline CrCl creatinine clearance DAA direct-acting antiviral DOPPS Dialysis Outcomes and Practice Patterns Study EASL European Association for the Study of the Liver eGFR estimated glomerular filtration rate ERT evidence review team ESKD end-stage kidney disease FDA Food and Drug Administration GFR glomerular filtration rate GN glomerulonephritis GRADE Grading of Recommendations Assessment, Development and Evaluation GT genotype HAV hepatitis A virus HBcAb antibody to hepatitis B core antigen HBsAb antibody to hepatitis B surface antigen HBsAg hepatitis B surface antigen HBV hepatitis B virus HCC hepatocellular carcinoma HCV hepatitis C virus HIV human immunodeficiency virus HR hazard ratio IFN interferon IU international unit KDIGO Kidney Disease: Improving Global Outcomes MMF mycophenolate mofetil MN membranous nephropathy MPGN membranoproliferative glomerulonephritis NAT nucleic acid test(ing) NS5A nonstructural protein 5A NS5B nonstructural protein 5B OR odds ratio PrOD (3D regimen) paritaprevir/ritonavir/ombitasvir and dasabuvir RBV ribavirin RCT randomized controlled trial RR relative risk SVR (weeks) sustained virologic response (at stated weeks) US United States Notice Section I: Use of the Clinical Practice Guideline This Clinical Practice Guideline document is based upon literature searches last conducted in May 2017, supplemented with additional evidence through July 2018. It is designed to assist decision making. It is not intended to define a standard of care, and should not be interpreted as prescribing an exclusive course of management. Variations in practice will inevitably and appropriately occur when clinicians consider the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Health care professionals using these recommendations should decide how to apply them to their own clinical practice. Section II: Disclosure Kidney Disease: Improving Global Outcomes (KDIGO) makes every effort to avoid any actual or reasonably perceived conflicts of interest that may arise from an outside relationship or a personal, professional, or business interest of a member of the Work Group. All members of the Work Group are required to complete, sign, and submit a disclosure and attestation form showing all such relationships that might be perceived as or are actual conflicts of interest. This document is updated annually and information is adjusted accordingly. All reported information is published in its entirety at the end of this document in the Work Group members’ Biographic and Disclosure section, and is kept on file at KDIGO. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention. Copyright © 2018, KDIGO. Published by Elsevier on behalf of the International Society of Nephrology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Single copies may be made for personal use as allowed by national copyright laws. Special rates are available for educational institutions that wish to make photocopies for nonprofit educational use. No part of this publication may be reproduced, amended, or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without explicit permission in writing from KDIGO. Details on how to seek reprints, permission for reproduction or translation, and further information about KDIGO’s permissions policies can be obtained by contacting Danielle Green, Executive Director, at email@example.com. To the fullest extent of the law, neither KDIGO, Kidney International Supplements, nor the authors, contributors, or editors assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Foreword With the growing awareness that chronic kidney disease (CKD) is an international health problem, Kidney Disease: Improving Global Outcomes (KDIGO) was established in 2003 with its stated mission to “improve the care and outcomes of kidney disease patients worldwide through promoting coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines.” The high prevalence of hepatitis C virus (HCV) in the CKD population was recognized once diagnostic testing became available in the early 1990s, as was its transmission within dialysis units. A series of publications subsequently identified the adverse consequences of HCV infection in the CKD population as well as its detrimental effect on recipient and graft outcomes following kidney transplantation. Although screening of blood products for HCV reduced its acquisition by blood transfusion, the unique aspects of its epidemiology in the CKD population were apparent. Studies also established that transmission was frequent in dialysis patients and typically reflected insufficient attention to body fluid precautions. Also confounding the management of HCV in the CKD population was an absence of biochemical liver dysfunction in most HCV-infected hemodialysis patients, which contributed to the lack of recognition of its presence and clinical significance. An additional difficulty was the lack of effective and tolerable antiviral agents to treat HCV in patients with CKD because interferon, especially in combination with ribavirin, had considerable toxicity. Furthermore, interferon was implicated in graft dysfunction in kidney transplant recipients. KDIGO convened a group of experts in this area to develop guideline recommendations for the prevention, diagnosis, and management of HCV in CKD a decade ago, which resulted in the publication of the very first KDIGO guideline in 2008. Since then there have been major advances in HCV management, particularly in antiviral therapy. As a result, much of the hesitancy in advising therapy for HCV-infected patients with CKD and following kidney transplant has now disappeared. In addition, diagnostic testing has evolved in chronic liver disease to the extent that fibrosis can now be assessed with noninvasive techniques such as transient elastography. Because of these advances in diagnostics and therapeutics, it was deemed appropriate to undertake a comprehensive review and update of the KDIGO HCV guideline in patients with kidney disease. It has been KDIGO’s philosophy to provide recommendations based on the best available clinical evidence without direct consideration of costs, as they vary widely across countries. The recent Lancet Commission on Essential Medicines articulated the importance and challenges of providing access to safe, effective, and affordable essential medicines, including treatments for combating HCV. 1 In this vein, the World Health Organization has issued its first global report to offer practical steps to expand access for such treatments. 2 We thank Michel Jadoul, MD, and Paul Martin, MD, for leading this important initiative, and we are especially grateful to the Work Group members who provided their time and expertise to this endeavor. In addition, this Work Group was ably assisted by colleagues from the independent evidence review team led by Ethan Balk, MD, MPH, Craig Gordon, MD, MS, Amy Earley, BS, and Mengyang Di, MD, PhD, who made this guideline possible. In keeping with KDIGO’s policy for transparency and rigorous public review during the guideline development process, its scope and the draft guideline were both made available for open commenting. The feedback received was carefully considered by the Work Group members who critically reviewed the public input and revised the guideline as appropriate for the final publication. David C. Wheeler, MD, FRCP Wolfgang C. Winkelmayer, MD, ScD KDIGO Co-Chairs Work Group membership Work Group Co-chairs Michel Jadoul, MDCliniques Universitaires Saint LucUniversité Catholique de LouvainBrussels, Belgium Paul Martin, MDMiller School of MedicineUniversity of MiamiMiami, FL, USA Work Group Marina C. Berenguer, MDLa Fe University Hospital, IIS La FeUniversity of Valencia-CIBERehdValencia, Spain Bertram L. Kasiske, MD, FACPHennepin County Medical CenterMinneapolis, MN, USA Wahid Doss, MDNational Hepatology and Tropical Medicine Research InstituteCairo, Egypt Ching-Lung Lai, MD, FRCP, FRACP, FHKAM (Med), FHKCP, FAASLDUniversity of Hong KongHong Kong, China Fabrizio Fabrizi, MDMaggiore Hospital and IRCCS FoundationMilan, Italy José M. Morales, MD, PhDHospital Universitario 12 de OctubreMadrid, Spain Jacques Izopet, PharmD, PhDCentre de Physiopathologie de Toulouse PurpanToulouse, France Priti R. Patel, MD, MPHCenters for Disease Control and PreventionAtlanta, GA, USA Vivekanand Jha, MBBS, MD, DM, FRCP, FRCP (Edin), FAMSThe George Institute for Global HealthNew Delhi, India Stanislas Pol, MD, PhDHôpital CochinParis, France Nassim Kamar, MD, PhDCHU RangueilToulouse, France Marcelo O. Silva, MDHospital Universitario AustralPilar, Argentina Evidence Review Team Center for Evidence Synthesis in Health, Brown University School of Public Health Providence, RI, USA Ethan M. Balk, MD, MPH, Project Director, Evidence Review Team DirectorCraig E. Gordon, MD, MS, Assistant Project Director, Evidence Review Team Associate DirectorAmy Earley, BS, Research AssociateMengyang Di, MD, PhD, Physician Researcher Abstract The Kidney Disease: Improving Global Outcomes (KDIGO) 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease represents a complete update of the prior guideline published in 2008. This guideline is intended to assist the practitioner caring for patients with hepatitis C virus (HCV) and chronic kidney disease (CKD), including those who are on chronic dialysis therapy and individuals with a kidney transplant. Specifically, the topic areas for which new recommendations are issued include detection and evaluation of HCV in CKD; treatment of HCV infection in patients with CKD; management of HCV-infected patients before and after kidney transplantation; prevention of HCV transmission in hemodialysis units; and diagnosis and management of kidney diseases associated with HCV infection. Development of this guideline update followed an explicit process of evidence review and appraisal. Treatment approaches and guideline recommendations are based on systematic reviews of relevant studies, and appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Limitations of the evidence are discussed, with areas of future research also presented. Keywords: chronic kidney disease; cryoglobulinemia; dialysis; direct-acting antivirals; glomerular diseases; hemodialysis; hepatitis C virus; infection control; guideline; KDIGO; kidney transplantation; liver testing; nosocomial transmission; screening; systematic review CITATION In citing this document, the following format should be used: 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. Summary of recommendation statements Chapter 1: Detection and evaluation of HCV in CKD 1.1 Screening patients with CKD for HCV infection 1.1.1: We recommend screening all patients for HCV infection at the time of initial evaluation of CKD (1C). 22.214.171.124: We recommend using an immunoassay followed by nucleic acid testing (NAT) if immunoassay is positive (1A). 1.1.2: We recommend screening all patients for HCV infection upon initiation of in-center hemodialysis or upon transfer from another dialysis facility or modality (1A). 126.96.36.199: We recommend using NAT alone or an immunoassay followed by NAT if immunoassay is positive (1A). 1.1.3: We suggest screening all patients for HCV infection upon initiation of peritoneal dialysis or home hemodialysis (2D). 1.1.4: We recommend screening all patients for HCV infection at the time of evaluation for kidney transplantation (1A). 1.2 Follow-up HCV screening of in-center hemodialysis patients 1.2.1: We recommend screening for HCV infection with immunoassay or NAT in in-center hemodialysis patients every 6 months (1B). 188.8.131.52: Report any new HCV infection identified in a hemodialysis patient to the appropriate public health authority (Not Graded). 184.108.40.206: In units with a new HCV infection, we recommend that all patients be tested for HCV infection and the frequency of subsequent HCV testing be increased (1A). 220.127.116.11: We recommend that hemodialysis patients with resolved HCV infection undergo repeat testing every 6 months using NAT to detect possible re-infection (1B). 1.2.2: We suggest that patients have serum alanine aminotransferase (ALT) level checked upon initiation of in-center hemodialysis or upon transfer from another facility (2B). 18.104.22.168: We suggest that hemodialysis patients have ALT level checked monthly (2B). 1.3 Liver testing in patients with CKD and HCV infection 1.3.1: We recommend assessing HCV-infected patients with CKD for liver fibrosis (1A). 1.3.2: We recommend an initial noninvasive evaluation of liver fibrosis (1B). 1.3.3: When the cause of liver disease is uncertain or noninvasive testing results are discordant, consider liver biopsy (Not Graded). 1.3.4: We recommend assessment for portal hypertension in CKD patients with suspected advanced fibrosis (F3–4) (1A). 1.4 Other testing of patients with HCV infection 1.4.1: We recommend assessing all patients for kidney disease at the time of HCV infection diagnosis (1A). 22.214.171.124: Screen for kidney disease with urinalysis and estimated glomerular filtration rate (eGFR) (Not Graded). 1.4.2: If there is no evidence of kidney disease at initial evaluation, patients who remain NAT-positive should undergo repeat screening for kidney disease (Not Graded). 1.4.3: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be followed up regularly to assess progression of kidney disease (1A). 1.4.4: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be screened and, if appropriate, vaccinated against hepatitis A virus (HAV) and hepatitis B virus (HBV), and screened for human immunodeficiency virus (HIV) (1A). Chapter 2: Treatment of HCV infection in patients with CKD 2.1: We recommend that all CKD patients infected with HCV be evaluated for antiviral therapy (1A). 2.1.1: We recommend an interferon-free regimen (1A). 2.1.2: We recommend that the choice of specific regimen be based on HCV genotype (and subtype), viral load, prior treatment history, drug–drug interactions, glomerular filtration rate (GFR), stage of hepatic fibrosis, kidney and liver transplant candidacy, and comorbidities (1A). 2.1.3: Treat kidney transplant candidates in collaboration with the transplant center to optimize timing of therapy (Not Graded). 2.2: We recommend that patients with GFR ≥ 30 ml/min per 1.73 m 2 (CKD G1–G3b) be treated with any licensed direct-acting antiviral (DAA)-based regimen (1A). 2.3: Patients with GFR 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). Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection 5.1: We recommend that a kidney biopsy be performed in HCV-infected patients with clinical evidence of glomerular disease (Not Graded). 5.2: We recommend that patients with HCV-associated glomerular disease be treated for HCV (1A). 5.2.1: We recommend that patients with HCV-related glomerular disease showing stable kidney function and/or non-nephrotic proteinuria be treated initially with DAA (1C). 5.2.2: We recommend that patients with cryoglobulinemic flare, nephrotic syndrome, or rapidly progressive kidney failure be treated, in addition to DAA treatment, with immunosuppressive agents with or without plasma exchange (1C). 5.2.3: We recommend immunosuppressive therapy in patients with histologically active HCV-associated glomerular disease who do not respond to antiviral therapy, particularly those with cryoglobulinemic kidney disease (1B). 126.96.36.199: We recommend rituximab as the first-line immunosuppressive treatment (1C). Chapter 1: Detection and evaluation of HCV in CKD 1.1 Screening patients with CKD for HCV infection Patients receiving maintenance hemodialysis and subgroups of CKD patients not yet on dialysis are known to have a high prevalence of HCV infection. The reasons for testing CKD patients for HCV infection include early detection and treatment of HCV infection, diagnostic evaluation of the cause of CKD, identification of infection control lapses in hemodialysis centers, and guidance on decisions surrounding kidney transplantation care. 1.1.1: We recommend screening all patients for HCV infection at the time of initial evaluation of CKD (1C). 188.8.131.52: We recommend using an immunoassay followed by nucleic acid testing (NAT) if immunoassay is positive (1A). 1.1.2: We recommend screening all patients for HCV infection upon initiation of in-center hemodialysis or upon transfer from another dialysis facility or modality (1A). 184.108.40.206: We recommend using NAT alone or an immunoassay followed by NAT if immunoassay is positive (1A). 1.1.3: We suggest screening all patients for HCV infection upon initiation of peritoneal dialysis or home hemodialysis (2D). 1.1.4: We recommend screening all patients for HCV infection at the time of evaluation for kidney transplantation (1A). Rationale 1.1.1: We recommend screening all patients for HCV infection at the time of initial evaluation of CKD (1C). 220.127.116.11: We recommend using an immunoassay followed by nucleic acid testing (NAT) if immunoassay is positive (1A). Any CKD patient who has a risk factor for HCV infection should be tested. 4 Additionally, HCV testing is warranted for the evaluation of CKD because: (i) the prevalence of HCV infection may be higher in patients with CKD not yet on dialysis than in the general population;5, 6 (ii) HCV infection increases the risk of developing CKD; 7 and (iii) HCV infection can accelerate progression of CKD.8, 9, 10 Diagnosis of HCV infection relies on various assays.11, 12 Serological assays that detect HCV antibody (anti-HCV) are based on enzyme immunoassays or chemoluminescence immunoassays. Anti-HCV tests are unable to distinguish between resolved HCV infection and current HCV infection. Detection of HCV viremia relies on NAT technologies. Qualitative and quantitative HCV RNA methods are available and have similar limits of detection (10–20 international units [IU]/ml). HCV antigen tests that detect core antigen alone or in combination with other HCV proteins have the potential to be less costly than NAT, but their limit of detection is higher (equivalent to about 150–3000 IU/ml).11, 13, 14, 15 The most usual strategy for diagnosis of HCV infection consists of initial screening with an inexpensive serological assay and, if the assay is positive, subsequent NAT. However, in high prevalence settings or very high risk groups, immediate NAT is an appropriate alternative. 1.1.2: We recommend screening all patients for HCV infection upon initiation of in-center hemodialysis or upon transfer from another dialysis facility or modality (1A). 18.104.22.168: We recommend using NAT alone or an immunoassay followed by NAT if immunoassay is positive (1A). The prevalence of HCV infection in patients undergoing hemodialysis (CKD G5 on dialysis) is higher than in the general population16, 17 and has been associated with the number of years one has been on hemodialysis. Patient-to-patient transmission of HCV infection in outpatient hemodialysis centers has occurred repeatedly despite widespread knowledge of this risk and published guidelines for prevention. Identification of HCV transmission within a dialysis facility should prompt immediate reevaluation of infection control practices and determination of appropriate corrective action (see Chapter 3).18, 19, 20, 21, 22 The majority of persons with HCV infection are asymptomatic, making screening necessary to detect infection in high-risk populations, particularly in hemodialysis patients in whom signs or symptoms of acute HCV infection are rarely recognized. Screening of maintenance hemodialysis patients for HCV infection is recommended by the United States (US) Centers for Disease Control and Prevention (CDC) and also the US Preventive Services Task Force.23, 24 Goals of screening in this patient population include early detection of HCV infection, treatment of infection, and detection of dialysis-related transmission. HCV screening is indicated in patients starting in-center maintenance hemodialysis and also in patients who transfer from another dialysis facility or modality. In dialysis units with a high prevalence of HCV, initial testing with NAT should be considered. An anti-HCV–negative, HCV RNA–positive (i.e., NAT-positive) profile strongly suggests acute HCV infection. Samples collected to test for HCV by NAT should be drawn before dialysis, because hemodialysis sessions reduce viremia level, although the mechanism remains unclear. 25 1.1.3: We suggest screening all patients for HCV infection upon initiation of peritoneal dialysis or home hemodialysis (2D). HCV transmission has typically been described in the context of in-center hemodialysis. In this setting, blood contamination on the hands of staff members or of medications, supplies, and equipment can contribute to HCV transmission. The current risk of health care–related HCV infection among patients who receive peritoneal dialysis or home hemodialysis has not been quantified. Many of these patients will require in-center hemodialysis at some point during their care, and may be at risk of acquiring HCV infection during that time. Screening of peritoneal dialysis and home hemodialysis patients should be considered upon initiation of dialysis to document baseline HCV infection status. If these patients transiently receive in-center hemodialysis, they should undergo HCV infection screening as per the recommendations for in-center hemodialysis patients, with consideration of continued screening until 6 months after the completion of in-center hemodialysis (and transition to a different modality). 1.1.4: We recommend screening all patients for HCV infection at the time of evaluation for kidney transplantation (1A). Kidney transplantation candidates should be tested for HCV infection during evaluation for transplantation. Determination of HCV status in recipients is essential for optimal management and potentially for acceptance of kidneys from HCV-infected donors (see Chapter 4). 1.2 Follow-up HCV screening of in-center hemodialysis patients 1.2.1: We recommend screening for HCV infection with immunoassay or NAT in in-center hemodialysis patients every 6 months (1B). 22.214.171.124: Report any new HCV infection identified in a hemodialysis patient to the appropriate public health authority (Not Graded). 126.96.36.199: In units with a new HCV infection, we recommend that all patients be tested for HCV infection and the frequency of subsequent HCV testing be increased (1A). 188.8.131.52: We recommend that hemodialysis patients with resolved HCV infection undergo repeat testing every 6 months using NAT to detect possible re-infection (1B). 1.2.2: We suggest that patients have serum alanine aminotransferase (ALT) level checked upon initiation of in-center hemodialysis or upon transfer from another facility (2B). 184.108.40.206: We suggest that hemodialysis patients have ALT level checked monthly (2B). Rationale 1.2.1: We recommend screening for HCV infection with immunoassay or NAT in in-center hemodialysis patients every 6 months (1B). 220.127.116.11: Report any new HCV infection identified in a hemodialysis patient to the appropriate public health authority (Not Graded). 18.104.22.168: In units with a new HCV infection, we recommend that all patients be tested for HCV infection and the frequency of subsequent HCV testing be increased (1A). 22.214.171.124: We recommend that hemodialysis patients with resolved HCV infection undergo repeat testing every 6 months using NAT to detect possible re-infection (1B). Patients who are not infected with HCV should be screened for presence of new infection every 6 months. 23 This recommendation includes anti-HCV–negative patients and anti-HCV–positive, HCV RNA–negative patients screened initially by immunoassay, as well as HCV RNA–negative patients screened initially by NAT. Patients who are anti-HCV–positive and HCV RNA–negative (i.e., NAT-negative) have resolved infection but remain at risk for re-infection if exposed. 26 Therefore, these patients should also undergo repeat screening. For dialysis patients who are anti-HCV–positive and HCV NAT–negative, screening for HCV reinfection should be conducted every 6 months using NAT. The purpose of the repeat screening is to identify new infections (i.e., newly acquired infections) that could represent transmission within the dialysis center. The baseline HCV testing results should be reviewed for any patient who has a positive HCV screening test result to determine whether there was a change in infection status indicating a new infection, and results must be communicated to the patient. Any patient with a current infection, whether new or pre-existing, should be linked to HCV care and considered for antiviral therapy. Acute HCV infection in a hemodialysis patient should be reported to the appropriate public health authority. Reporting may be mandated by law, as in the US, where a documented negative HCV antibody or NAT laboratory test result followed within 12 months by a positive HCV test result (test conversion) must be reported to public health authorities. 27 Acute HCV infection in a hemodialysis patient should be investigated and considered health care–related until proven otherwise. 28 Behavioral risk factors, along with dialysis and nondialysis health care exposures, should be evaluated by public health authorities. Molecular sequencing of HCV RNA from other patients in the facility may help to identify a source.22, 29, 30, 31 Acute HCV infection should also prompt immediate evaluation of all other patients in the same facility to identify additional cases. The status of all patients should be reviewed at the time a new infection is identified, and all patients previously known to be uninfected should be retested for HCV infection. The frequency of repeat screening should also be increased for a limited time: for example, monthly testing for 3 months, followed by testing again in 3 months, and then resumption of screening every 6 months if no additional infections are identified.20, 23 This strategy can help to identify delayed seroconversions (from the same exposure period as the index case) or other cases resulting from recurrent breaches. Use of this strategy has led to the detection of additional new cases in several reported outbreaks.22, 32 For anti-HCV–positive patients with chronic HCV infection who become HCV NAT–negative with a sustained virologic response (SVR) to HCV therapy, initiate NAT screening 6 months after documentation of SVR. SVR is determined based on results of NAT testing ≥ 12 weeks after the conclusion of therapy. For patients with spontaneous resolution of acute HCV infection as documented by a negative test for HCV RNA at ≥ 6 months after the onset of acute infection, NAT screening should begin 6 months after documented resolution of infection. 1.2.2: We suggest that patients have serum alanine aminotransferase (ALT) level checked upon initiation of in-center hemodialysis or upon transfer from another facility (2B). 126.96.36.199: We suggest that hemodialysis patients have ALT level checked monthly (2B). A baseline serum ALT test, followed by monthly testing, in susceptible patients has been recommended to enable early detection of new HCV infection in hemodialysis patients. 23 Newly infected patients may have an increase in ALT levels prior to antibody conversion, which should prompt additional evaluation. If an unexplained elevation (i.e., to greater than upper-limit normal) of ALT occurs, the patient should be tested for HCV infection. The exact predictive value of ALT screening for detection of HCV infection has been assessed in a single study and found to be moderate. 33 However, ALT monitoring is an inexpensive way to ensure that hemodialysis patients are assessed for possible acquisition of infection between regular antibody or NAT screenings. Because few hemodialysis patients with a new HCV infection report symptoms or have symptoms documented in their dialysis medical records, ALT levels are also often used retrospectively to define the likely exposure period for patients who acquired infection. Thus, monthly ALT levels are valuable to help narrow the focus of an HCV case investigation to the most likely exposure and source. The value of monthly ALT testing in patients who have resolved HCV infection has not been studied. 1.3 Liver testing in patients with CKD and HCV infection 1.3.1: We recommend assessing HCV-infected patients with CKD for liver fibrosis (1A). 1.3.2: We recommend an initial noninvasive evaluation of liver fibrosis (1B). 1.3.3: When the cause of liver disease is uncertain or noninvasive testing results are discordant, consider liver biopsy (Not Graded). 1.3.4: We recommend assessment for portal hypertension in CKD patients with suspected advanced fibrosis (F3–4) (1A). Rationale Evaluation of liver fibrosis in HCV-infected patients with CKD In the prior Kidney Disease: Improving Global Outcomes (KDIGO) HCV guideline published in 2008, 34 liver biopsy had been considered the gold standard to assess liver fibrosis in patients with CKD, including candidates for transplantation and transplant recipients. The primary objective of liver biopsy in patients with advanced CKD had been to diagnose cirrhosis. Because of the risk of liver-related mortality after kidney transplantation, cirrhosis had been considered a contraindication to kidney transplantation alone and led to consideration of combined liver-kidney transplantation. Current evidence suggests that biochemical noninvasive markers (FibroTest/FibroMeter, aspartate aminotransferase–platelet ratio index [APRI], Forns, or FIB-4 index) and morphological evaluation (liver stiffness by elastography) may have comparable accuracy in evaluating liver fibrosis in patients with CKD G4–5 as in the general population. 35 Noninvasive methods, especially elastography, are sufficiently reliable to detect extensive fibrosis and/or cirrhosis (F3–F4)36, 37 though noninvasive tests other than elastography may be less accurate (Supplementary Tables S1 and S2). Furthermore, although serious complications of liver biopsy are uncommon, patients are often reluctant to consider it, and its validity may be diminished by sampling as well as interpretation errors. Liver biopsy use in HCV-infected patients generally has declined. Because SVR can now be anticipated in the vast majority of patients treated for HCV, the management of the HCV-infected kidney transplant candidate, even with cirrhosis, has evolved. SVR is associated with sustained and long-lasting suppression of necroinflammation and may even result in regression of cirrhosis, potentially resulting in decreased disease-related morbidity and improved survival. 38 Even in the absence of regression of cirrhosis, kidney transplantation alone is feasible in the absence of major complications of portal hypertension, just like in patients with hepatitis B virus (HBV)–related cirrhosis. 39 Thus, the role of liver biopsy in evaluation of liver fibrosis in HCV-infected patients with CKD G4–5 will evolve given the high SVR rates obtained with current DAA regimens. Defining the severity of cirrhosis involves assessment for clinically significant portal hypertension (hepatic-vein wedge-pressure gradient of ≥ 10 mm Hg). 40 Methods include upper endoscopy, noninvasive radiological evaluation, or direct portal pressure measurement. Based on the Baveno VI consensus, 41 portal hypertension is very unlikely (and hence an upper endoscopy can be avoided with > 90% reliability) in patients with compensated cirrhosis but elastography 150,000/mm3. Whether this approach is also valid for patients on hemodialysis remains unknown. In summary, all HCV-infected patients with kidney failure should undergo a noninvasive biochemical and/or morphological evaluation to stage fibrosis and determine the role of antiviral therapies (see Chapter 2) and to facilitate the choice of kidney or combined liver-kidney transplantation in cirrhotic patients. When results between biochemical and morphological evaluation are discordant or when liver comorbidities are suspected, liver biopsy is suggested. 42 1.4 Other testing of patients with HCV infection Although HCV infection predominantly causes liver disease, it is also associated with extrahepatic manifestations including kidney disease. 43 HCV has been shown to infect both hepatocytes and lymphocytes; thus, lymphoproliferative disorders such as lymphoma and mixed cryoglobulinemia are linked to HCV infection. 44 HCV has also been implicated in derangements of multiple organ systems including cardiovascular, endocrine, muscular, nervous, ocular, respiratory, skeletal, cutaneous, and urinary systems. In addition, HCV can have a deleterious impact on psychosocial status. 45 The relationship between HCV infection and CKD is complex. HCV infection and CKD are prevalent in the general population and associated in various ways: patients on chronic hemodialysis are at increased risk of acquiring HCV, and some types of kidney disease are precipitated by HCV infection. Conventional risk factors for CKD such as aging, diabetes, hypertension, and metabolic syndrome do not fully explain the current frequency of CKD in the adult general population of developed countries. In addition to these conventional risk factors, accumulating evidence in the last decade has implicated HCV infection as a cause of kidney disease. HCV co-infection has also been implicated as a risk factor for CKD in HIV-infected patients. 46 A meta-analysis 7 of observational studies47, 48, 49, 50, 51, 52, 53, 54, 55 demonstrated a relationship between anti-HCV–positive serologic status and an increased incidence of CKD in the adult general population, with an adjusted hazard ratio (HR) of 1.43 (95% confidence interval [CI]: 1.23–1.63). Based on current information, patients with HCV infection should be regarded as being at increased risk of CKD, regardless of the presence of conventional risk factors for kidney disease. 1.4.1: We recommend assessing all patients for kidney disease at the time of HCV infection diagnosis (1A). 188.8.131.52: Screen for kidney disease with urinalysis and estimated glomerular filtration rate (eGFR) (Not Graded). 1.4.2: If there is no evidence of kidney disease at initial evaluation, patients who remain NAT-positive should undergo repeat screening for kidney disease (Not Graded). 1.4.3: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be followed up regularly to assess progression of kidney disease (1A). 1.4.4: We recommend that all CKD patients with a history of HCV infection, whether NAT-positive or not, be screened and, if appropriate, vaccinated against hepatitis A virus (HAV) and hepatitis B virus (HBV), and screened for human immunodeficiency virus (HIV) (1A). Rationale 1.4.1: We recommend assessing all patients for kidney disease at the time of HCV infection diagnosis (1A). 184.108.40.206: Screen for kidney disease with urinalysis and estimated glomerular filtration rate (eGFR) (Not Graded). The prevalence of CKD, defined by a reduction in eGFR and/or increased urinary albumin excretion, 56 exceeds 10% in the adult general population, according to numerous population-based studies. The prevalence of low GFR alone is around 5% to 6% but increases sharply with older age. Testing for CKD appears logical in HCV-infected individuals, as many authors have suggested a potential role of HCV infection as a cause of CKD. However, epidemiologic supporting data regarding the prevalence of CKD in HCV-infected patients were until recently limited and used variable criteria for the definition of CKD; the demographic/clinical characteristics of the representative patient population were variable as well. According to 3 studies performed in the US,47, 52, 55 the unadjusted prevalence of low GFR ( 1.5 mg/dl [>133 μmol/l]) in one large study of anti-HCV-seropositive veterans from the US was 4.8%. 57 In another large cohort of HCV-positive, HIV-positive patients from North America, the unadjusted frequency of low GFR ( 90%) excreted in feces with minimal renal clearance ( 800,000 IU/ml), prolonging duration of therapy to 16 weeks and the use of RBV, if possible, to avoid a reduction in SVR12 (from 99% with RBV to 88% without in 1 study) is suggested. 96 In the RUBY II trial presented at the 2016 AASLD Annual Meeting, dialysis patients with HCV GT1a were treated with ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir, and those infected with GT4 were treated with the first 2 agents without dasabuvir. RBV was not included in the regimen. Of the 13 treated subjects, 12 achieved SVR (92%). The remaining patient who discontinued antiviral therapy elected to undergo kidney transplantation. 97 All components of the combination regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir (used in GT1 and without dasabuvir in GT4) are predominantly excreted in the feces, with 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). Rationale 4.4.1: We recommend that patients previously infected with HCV who achieved SVR before transplantation be tested by NAT 3 months after transplantation or if liver dysfunction occurs (1D). Kidney transplantation outcomes in patients with HCV without extensive fibrosis who are successfully treated before transplantation should be equivalent to those in uninfected transplant recipients. With achievement of SVR, viral relapse is unlikely, although kidney transplant recipients with unexplained hepatic dysfunction should undergo HCV and HBV testing. 4.4.2: Untreated HCV-positive kidney transplant recipients should have the same liver disease follow-up as HCV-positive non-transplant patients, as outlined in the American Association for the Study of Liver Diseases (AASLD) guidelines (Not Graded). Kidney transplantation in patients with active HCV infection may be complicated by liver disease and also by extrahepatic complications. 194 These patients exhibited a lower graft and patient survival and an increased risk of severe liver disease compared with HCV-negative recipients.34, 194, 223, 255 Therefore, patients with persistent HCV RNA because of lack of treatment before transplantation or due to failure of therapy before or after transplantation should be considered for liver disease reevaluation and re-treatment with DAAs. Preliminary publications of the use of DAAs in kidney transplant patients have exhibited SVR of almost 100% without important side effects.118, 119 More recently, a trial compared 12 and 24 weeks of sofosbuvir and ledipasvir in 114 kidney transplant recipients infected with HCV GTs 1 and 4 (96% GT1) with an eGFR of 40 ml/min per 1.73 m2 or greater (median eGFR: 56 ml/min per 1.73 m2). The therapy was very well tolerated, and SVR rates were close to 100% without differences between arms, suggesting that a 12-week regimen is also indicated in kidney transplant recipients. 116 4.4.3: HCV-infected kidney transplant recipients should be tested at least every 6 months for proteinuria (Not Graded). 220.127.116.11: We suggest that patients who develop new-onset proteinuria (either urine protein-to-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). HCV infection has been reported as a risk factor for the development of proteinuria in kidney transplant recipients. 256 Several glomerular lesions have been described after kidney transplantation in HCV RNA–positive patients including recurrent or de novo cryoglobulinemic or non-cryoglobulinemic MPGN, 257 membranous nephropathy (MN), 258 acute transplant glomerulopathy, 194 anti-cardiolipin related thrombotic microangiopathy, 259 and chronic transplant glomerulopathy. 260 MPGN and MN are the most frequent lesions related to HCV infection. The most common presentation is proteinuria with or without microhematuria, or nephrotic syndrome. The pathogenesis of MPGN and MN seems to be related to the deposition of immune complexes containing HCV RNA in the glomerulus. 34 After HCV NAT–positive patients have undergone kidney transplantation, clinicians should screen for proteinuria and microhematuria. In the case of urine protein-to-creatinine ratio > 1 g/g or 24-hour urine protein (protein excretion rate) greater than 1 g on 2 or more occasions, a graft biopsy is indicated. Pathological examination should include immunofluorescence and electron microscopy. In the case of suspected transplant glomerulopathy, electron microscopy is mandatory to make the differential diagnosis with HCV-related MPGN.194, 260 For HCV-related glomerular disease, DAA therapy is indicated.261, 262, 263, 264, 265, 266, 267, 268, 269, 270 In severe HCV-related cryoglobulinemic MPGN, in addition to antiviral therapy with DAAs, rituximab and, in severe cases, plasmapheresis should be considered. 194 This is discussed in detail in Chapter 5. Research recommendations • Prospective studies should assess the best timing for HCV treatment in kidney transplant candidates: before or after transplantation? • Studies should examine whether accepting a kidney from an HCV-positive donor would reduce the time on the waiting list. Further studies are required in different countries because the prevalence of HCV in donors is highly variable worldwide. • Future research should evaluate the impact of delaying HCV treatment on HCV-induced morbidity (e.g., liver disease) and patient survival in HCV-positive kidney transplant candidates who are not given DAA therapy in order to be grafted with a kidney from a positive donor. • Prospective larger studies under investigational protocols should be conducted to corroborate the encouraging preliminary results obtained using kidneys from HCV-positive donors for HCV-negative recipients treated with DAAs. Studies should also examine the cost-effectiveness of this policy with different DAA treatment strategies. • SVR should be assessed in a large cohort of HCV-positive patients who receive a kidney allograft from a positive donor and who are given DAA therapy after transplantation. In this setting, the optimal timing for starting DAA therapy should be determined. • In patients presenting with an HCV-associated kidney disease after transplant, the effect of DAAs on the kidney graft should be assessed in a large series. Chapter 5: Diagnosis and management of kidney diseases associated with HCV infection In addition to chronic liver disease, HCV infection also leads to extrahepatic manifestations including kidney disease and mixed cryoglobulinemia. 271 Although chronic HCV infection has been identified as an important cause of tubulo-interstitial injury in a large case-control study, 272 HCV-associated glomerular disease is the most frequent type of kidney disease associated with HCV. HCV-induced glomerular disease occurs frequently in the context of HCV-associated mixed cryoglobulinemia, a systemic vasculitis characterized by involvement of small and, less frequently, medium-size vessels.273, 274, 275, 276, 277 Mixed cryoglobulinemia represents 60% to 75% of all cryoglobulinemia cases and is observed in connective tissue diseases and infectious or lymphoproliferative disorders, all grouped under the term “secondary mixed cryoglobulinemia.” After its identification, HCV has been recognized as the cause of 80% to 90% of idiopathic mixed cryoglobulinemia.273, 276 In general, HCV is associated with type II mixed cryoglobulinemia (cryoglobulins consisting of polyclonal IgG and monoclonal IgM with rheumatoid factor activity), although it is also less frequently associated with type III mixed cryoglobulinemia (cryoglobulins consisting of polyclonal IgG and polyclonal IgM). In the absence of an identified etiology (currently 50% of patients at the time of diagnosis) and is often resistant to antihypertensive drugs; the severity of hypertension often mirrors the severity of kidney disease. 330 Around 10% of patients present oliguric kidney failure.330, 331 Type II mixed cryoglobulinemia is most common in the fourth or fifth decade of life, and usually is characterized by periods of extrarenal symptoms alternating with periods of quiescence. 332 The exacerbation of extrarenal symptoms often is associated with a flare-up of kidney disease, but can occur independently. Patients with cryoglobulinemic GN have a poor prognosis, mainly because of a high incidence of infections, end-stage liver disease, and cardiovascular diseases.330, 331 RCTs are lacking to help establish evidence-based recommendations to treat glomerular lesions associated with HCV infection. Until this information is available, the treatment of HCV-associated GN should probably be driven by the severity of proteinuria and kidney failure. Given that remission of hematuria, proteinuria, and improvement of GFR in patients with HCV-associated GN who obtained sustained HCV RNA clearance by DAAs has been reported,261, 262, 263, 264, 265, 266, 267, 268, 269, 270 antiviral therapy with DAA regimens should be considered the first-line choice in patients with non-nephrotic proteinuria and relatively stable kidney function (Supplementary Tables S17 and S18). In addition, anti-proteinuric agents such as angiotensin-converting enzyme inhibitors/angiotensin receptor blockers should be given. Treatment including diuretics and antihypertensive agents should be used to achieve target blood pressure recommended in patients with CKD. 5.2.2: We recommend that patients with cryoglobulinemic flare, nephrotic syndrome, or rapidly progressive kidney failure be treated, in addition to DAA treatment, with immunosuppressive agents with or without plasma exchange (1C). Immunosuppressive agents have been administered to patients with serious, life-threatening complications of mixed cryoglobulinemia, such as MPGN, severe neuropathy, or extensive skin disease. Cyclophosphamide has been selected to improve kidney disease by reducing stimulation of B lymphocytes and cryoglobulin synthesis; steroid pulses have been given to treat glomerular inflammation, and plasma exchange has been employed to remove circulating cryoglobulins from the plasma and consequently to reduce the deposition of immune complexes to the kidneys. In patients with nephrotic-range proteinuria and/or rapidly progressive kidney failure and/or acute flare of cryoglobulinemia, control of disease by immunosuppressive agents, with or without plasma exchange (3 liters of plasma thrice weekly for 2–3 weeks), should be considered before the initiation of DAA therapy. Potential regimens include rituximab (375 mg/m2 weekly for 4 weeks) with or without corticosteroids (see below), or cyclophosphamide (2 mg/kg/d for 2–4 months) plus methylprednisolone pulses 0.5 to 1 g/d for 3 days. According to the decision of the clinician, immunosuppressive regimen alone or combined therapy (immunosuppressive agents plus DAA therapy) is suggested as the initial approach. Until a few years ago, combined therapy with corticosteroids and immunosuppressive agents—for example, treatment using sequentially cyclophosphamide and azathioprine—has been used while awaiting the response, if any, to antiviral therapy. In one retrospective study, the clinical outcome of 105 patients with essential mixed cryoglobulinemia vasculitis and renal involvement was evaluated throughout a median follow-up of 72 months since kidney biopsy. 330 Positive anti-HCV serologic status was reported in 85% of patients. About 80% of patients underwent treatment with oral or pulse intravenous steroids and/or cytotoxic agents, whereas 67% were treated with plasma exchange. Despite this aggressive treatment, patient survival was 49% at 10 years after kidney biopsy, and only 14% of patients had long-term remission of kidney disease. 330 By multivariate analysis, age > 50 years, purpura, splenomegaly, cryocrit levels > 10%, C3 plasma levels 1.5 mg/dl (> 133 μmol/l) were independent risk factors for death or dialysis. 330 Other case reports have also documented improvement following the administration of a combination of steroids and antivirals (IFN and RBV) or of the 3D regimen combined with plasmapheresis, corticosteroids, and rituximab.333, 334 5.2.3: We recommend immunosuppressive therapy in patients with histologically active HCV-associated glomerular disease who do not respond to antiviral therapy, particularly those with cryoglobulinemic kidney disease (1B). 18.104.22.168: We recommend rituximab as the first-line immunosuppressive treatment (1C). Limited information exists on the use of DAAs in patients with HCV-associated glomerular disease. Nine patients with symptomatic mixed cryoglobulinemic disease (seven with MPGN) and HCV GT1 underwent triple antiviral therapy (pegylated IFN, RBV, and boceprevir [n = 2] or telaprevir [n = 5] or sofosbuvir [n = 2]).325, 335 All patients reached SVR, but serum cryoglobulins persisted in 3 patients; also, the benefits on renal signs were partial. MPGN remitted in 3 patients after further treatment with corticosteroids or corticosteroids plus rituximab. More recently, encouraging results have been obtained with IFN-free DAA regimens for HCV-related glomerular disease; a small group of 7 patients with symptomatic mixed cryoglobulinemia and GN (5 had a biopsy-proven MPGN and 2 were diagnosed clinically) underwent sofosbuvir-based regimens (6 with sofosbuvir and simeprevir and 1 with sofosbuvir and RBV). 265 Only 1 patient was receiving ongoing immunosuppression concurrent with antiviral therapy. All patients had an improvement in eGFR and a reduction in proteinuria, particularly in those whose onset of proteinuria was recent. Also, in all patients HCV RNA was undetectable by week 4 and remained undetectable while on treatment. SVR was reached in 6 of 7 patients. In another cohort of 44 consecutive patients with HCV-associated mixed cryoglobulinemia, 4 patients had renal involvement. 263 The treatment of HCV-associated mixed cryoglobulinemia with sofosbuvir-based DAA therapy appeared to be highly effective (SVR12, 100%) and safe with some improvement of kidney disease262, 263 These studies suggest that IFN-free therapies can give high viral and clinical responses in a difficult-to-treat condition such as HCV-associated mixed cryoglobulinemia with renal involvement. In fact, the SVR rates ranging between 83% and 100% are comparable to the SVR12 rates reported with similar regimens in other non-cryoglobulinemic real-world groups. However, it is clear that we need larger and controlled studies to confirm these results. Combining DAA therapy with rituximab and other immunosuppressants might be of value for cases with severe or obstinate manifestations of cryoglobulinemic vasculitis. Immunosuppressive therapies are suggested typically for patients with HCV-associated mixed cryoglobulinemia showing severe disease manifestations, such as progressive glomerular disease. In addition to conventional immunosuppressants, which target inflammation at the glomerular level, encouraging results have been obtained with rituximab, a human-mouse chimeric monoclonal antibody that binds to the B-cell surface antigen CD20 and selectively targets B cells.336, 337, 338, 339, 340, 341 Rituximab interferes with synthesis of cryoglobulins, monoclonal IgM, and renal deposition of immune complexes. An important pathogenetic feature of mixed cryoglobulinemia (including cryoglobulinemic GN) is chronic stimulation of B lymphocytes by HCV and widespread auto-antibody synthesis related to HCV-induced lowering of cell activation threshold. Two RCTs have demonstrated the superiority of rituximab monotherapy as compared with conventional immunosuppressive therapy (i.e., corticosteroids, azathioprine, cyclophosphamide, methotrexate, and plasma exchange) for the treatment of HCV-associated cryoglobulinemic vasculitis in patients for whom prior IFN therapy failed to induce disease remission, or in patients who were not eligible for IFN therapy. Admittedly, only a minority of the included patients showed renal involvement.339, 341 Rituximab was well tolerated and was effective in 71.4% to 83% of patients with HCV-associated cryoglobulinemic vasculitis. Frequent relapses may occur after rituximab when B cells re-emerge in the peripheral blood; in addition, repeated rituximab infusions may expose patients to opportunistic infections. In a recent prospective, single-center study, 16 patients with cryoglobulinemic nephropathy (diffuse MPGN and mixed cryoglobulinemia) received rituximab at a dose of 375 mg/m2, according to a “4 + 2” protocol (days 1, 8, 15, and 22 plus one dose 1 and 2 months later). 337 No other immunosuppressive drugs were used. Safety and efficacy of rituximab was evaluated over a long-term follow-up (mean: 72.5 months). A significant improvement of cryoglobulinemic GN was found, starting from the second month after rituximab (serum creatinine from 2.1 ± 1.7 mg/dl [186 ± 150 μmol/l] to 1.5 ± 1.6 mg/dl [133 ± 141 μmol/l], P 70 years, GFR 1) or sparse (only 1 study or total N 2 ( 5 ( 1. Adapted by permission from Uhlig K, Macleod A, Craig J, et al. 353 Grading the overall quality of evidence The quality of the overall body of evidence was then determined on the basis of the quality grades for all outcomes of interest, taking into account explicit judgments about the relative importance of each outcome. The resulting 4 final categories for the quality of overall evidence were A, B, C, or D (Table 13). Table 13 Final grade for overall quality of evidence Grade Quality of evidence Meaning A High We are confident that the true effect lies close to that of the estimate of the effect. B Moderate The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. C Low The true effect may be substantially different from the estimate of the effect. D Very low The estimate of effect is very uncertain, and often will be far from the truth. Assessment of the net health benefit across all important clinical outcomes The net health benefit was determined on the basis of the anticipated balance of benefits and harms across all clinically important outcomes (Table 14). The assessment of net benefit also involved the judgment of the Work Group and the ERT. Table 14 Balance of benefits and harms When there was evidence to determine the balance of medical benefits and harms of an intervention to a patient, conclusions were categorized as follows: • For statistically significant benefit or harm, report as “benefit (or harm) of intervention.” • For nonstatistically significant benefit or harm, report as “possible benefit (or harm) of intervention.” • In instances where studies are inconsistent, report as “possible benefit (or harm) of intervention.” • “No difference” can only be reported if a study is not imprecise. • “Insufficient evidence” is reported if imprecision is a factor. Developing the recommendations Draft recommendation statements were developed by the Work Group Co-Chairs and Work Group members with input from all Work Group members. The health benefits, side effects, and risks associated with each recommendation were considered when formulating the guideline, as well as information on patient preferences when available. Recommendation statements were revised in a multistep process during face-to-face meetings and by subsequent drafts by e-mail. Relevant recommendations from the AASLD and EASL guidelines on management of HCV were reviewed to maximize consistency between guidelines. The final draft was sent for external public review. Based on feedback, it was further revised by the Work Group Co-Chairs and members. All Work Group members provided feedback on initial and final drafts of the recommendation statements and guideline text and approved the final version of the guideline. Grading the strength of the recommendations The strength of a recommendation is graded as level 1 or level 2. Table 15 shows the KDIGO nomenclature for grading the strength of a recommendation and the implications of each level for patients, clinicians, and policy makers. Recommendations can be for or against doing something. Each recommendation includes an explicit link between the quality of the available evidence and the strength of that recommendation. However, Table 16 shows that the strength of a recommendation is determined not only by the quality of the evidence but also by other, often complex judgments regarding the size of the net medical benefit (potential risks vs. benefit), values, and preferences, and costs. Formal decision analyses including cost analysis were not conducted. Table 15 KDIGO nomenclature and description for grading recommendations Gradea Implications Patients Clinicians Policy Level 1 “We recommend” Most people in your situation would want the recommended course of action and only a small proportion would not. Most patients should receive the recommended course of action. The recommendation can be evaluated as a candidate for developing a policy or a performance measure.
Level 2 “We suggest” The majority of people in your situation would want the recommended course of action, but many would not. Different choices will be appropriate for different patients. Each patient needs help to arrive at a management decision consistent with her or his values and preferences. The recommendation is likely to require substantial debate and involvement of stakeholders before policy can be determined. KDIGO, Kidney Disease: Improving Global Outcomes. a The additional category “not graded” was used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding monitoring intervals, counseling, and referral to other clinical specialists. The ungraded recommendations are generally written as simple declarative statements. They should not be interpreted as being weaker recommendations than Level 1 or 2 recommendations. Table 16 Determinants of strength of recommendation Factor Comment Balance between desirable and undesirable effects The larger the difference between the desirable and undesirable effects, the more likely a strong recommendation is warranted. The narrower the gradient, the more likely a weak recommendation is warranted.
Quality of the evidence The higher the quality of evidence, the more likely a strong recommendation is warranted.
Values and preferences The more variability in values and preferences, or the more uncertainty in values and preferences, the more likely a weak recommendation is warranted. Values and preferences were obtained from the literature where possible or were assessed in the judgment of the Work Group where robust evidence was not identified.
Costs (resource allocation) The higher the costs of an intervention—that is, the more resources consumed—the less likely a strong recommendation is warranted. Ungraded statements This category was designed to allow the Work Group to issue general advice. Typically an ungraded statement meets the following criteria: it provides guidance based on common sense; it provides reminders of the obvious; and it is not sufficiently specific to allow for application of evidence to the issue and therefore it is not based on systematic evidence review. As such, ungraded statements may be considered to be relatively strong recommendations; they should not be interpreted as weak recommendations based on limited or poor evidence. Common examples include recommendations about frequency of testing, referral to specialists, and routine medical care. We strove to minimize the use of ungraded recommendations. This grading scheme, with 2 levels for the strength of a recommendation together with four levels of grading the quality of the evidence, as well as the option of an ungraded statement for general guidance, was adopted by the KDIGO Board in December 2008. The Work Group took on the primary role of writing the recommendations and rationale statements and retained final responsibility for the content of the guideline statements and the accompanying narrative. The ERT reviewed draft recommendations and grades for consistency with the conclusions of the evidence review. Format for guideline recommendations Each chapter contains 1 or more specific recommendations. Within each recommendation, the strength of recommendation is indicated as level 1 or level 2 and the quality of the supporting evidence is shown as A, B, C, or D. The recommendation statements and grades are followed by the rationale text summarizing the key points of the evidence base and the judgments supporting the recommendation. In relevant sections, considerations of the guideline statements in international settings and suggested audit criteria are also provided where applicable. Important key points and research recommendations suggesting future research to resolve current uncertainties are also outlined at the conclusion of each chapter. Limitations of approach Although the literature searches were intended to be comprehensive, they were not exhaustive. Medline, Embase, and Cochrane databases were searched, but other specialty or regional databases were not. Hand searches of journals were not performed, and review articles and textbook chapters were not systematically searched. Recent conference abstracts were screened from ASN and AASLD, but older conference abstracts and other conference meetings were not specifically screened. We relied on Work Group members to provide the ERT with conference abstracts from recent EASL meetings. However, any important studies known to domain experts that were missed by the electronic literature searches were added to retrieved articles and reviewed by the Work Group. Review of guideline development process The Conference on Guideline Standardization (COGS) checklist has been developed to assess the quality of the methodological process for systematic review and guideline development. 356 Table 17 shows the criteria that correspond to the COGS checklist and how each one is addressed in this guideline. Similarly, Supplementary Appendix B demonstrates the level of concurrence with which this guideline corresponds to the Institute of Medicine’s standards for systematic reviews and guidelines.348, 349 Table 17 The Conference on Guideline Standardization (COGS) checklist for reporting clinical practice guidelines Topic Description Discussed in 2018 KDIGO HCV in CKD CPG 1. Overview material Provide a structured abstract that includes the guideline’s release date, status (original, revised, updated), and print and electronic sources. See Abstract and Methods for Guideline Development.
2. Focus Describe the primary disease/condition and intervention/service/technology that the guideline addresses. Indicate any alternative preventative, diagnostic, or therapeutic interventions that were considered during development. Management of HCV in terms of treatment, monitoring, and prevention in adults with CKD, including both dialysis and transplant populations.
3. Goal Describe the goal that following the guideline is expected to achieve, including the rationale for development of a guideline on this topic. This CPG is intended to assist the practitioner caring for patients with CKD and HCV and to prevent transmission, resolve the infection, and prevent adverse outcomes such as deaths, graft loss, and progression to kidney failure while optimizing patients’ quality of life.
4. User/setting Describe the intended users of the guideline (e.g., provider types, patients) and the settings in which the guideline is intended to be used. Target audience is practicing nephrologists and other health care providers for adults with CKD and HCV infection.
5. Target population Describe the patient population eligible for guideline recommendations and list any exclusion criteria. Adults with CKD and HCV infection; CKD patients on dialysis therapy.
6. Developer Identify the organization(s) responsible for guideline development and the names/credentials/potential conflicts of interest of individuals involved in the guideline’s development. Organization: KDIGO.Names/credentials/potential conflicts of interest of individuals involved in the guideline’s development are disclosed in the Biographic and Disclosure Information.
7. Funding source/sponsor Identify the funding source/sponsor and describe its role in developing and/or reporting the guideline. Disclose potential conflict of interest. This guideline is funded by KDIGO.Financial disclosures of Work Group members are published in Biographic and Disclosure Information section of the guideline.
8. Evidence collection Describe the methods used to search the scientific literature, including the range of dates and databases searched, and criteria applied to filter the retrieved evidence. Topics were triaged either to (i) systematic review, (ii) systematic search followed by narrative summary, or (iii) narrative summary. For systematic reviews, we searched PubMed, Embase, Cochrane Central Registry for trials, and Cochrane database of systematic reviews. Screening criteria for this and other topics are outlined in the Methods for Guideline Development chapter. The search was updated through May 2017 and supplemented by articles identified by Work Group members through July 2018. We also searched for pertinent existing guidelines and systematic reviews.
9. Recommendation grading criteria Describe the criteria used to rate the quality of evidence that supports the recommendations and the system for describing the strength of the recommendations. Recommendation strength communicates the importance of adherence to a recommendation and is based on both the quality of the evidence and the magnitude of anticipated benefits and harms. Quality of individual studies was graded in a 3-tiered grading system (see Table 11). Quality of evidence and strength of recommendations were graded following the GRADE approach (Table 12, Table 13, Table 15). The Work Group could provide general guidance in the form of ungraded statements.
10. Method for synthesizing evidence Describe how evidence was used to create recommendations, e.g., evidence tables, meta-analysis, decision analysis. For systematic review topics, summary tables and evidence profiles were generated. For recommendations on interventions, the steps outlined by GRADE were followed. 11. Prerelease review Describe how the guideline developer reviewed and/or tested the guidelines prior to release. The guideline had undergone external public review in February 2017. Public review comments were compiled and fed back to the Work Group, which considered comments in its revision of the guideline.
12. Update plan State whether or not there is a plan to update the guideline and, if applicable, an expiration date for this version of the guideline. The requirement for an update will be assessed periodically from the publication date or earlier if important new evidence becomes available in the interim. Such evidence might, for example, lead to changes to the recommendations or may modify information provided on the balance between benefits and harms of a particular therapeutic intervention.
13. Definitions Define unfamiliar terms and those critical to correct application of the guideline that might be subject to misinterpretation. See Abbreviations and Acronyms.
14. Recommendations and rationale State the recommended action precisely and the specific circumstances under which to perform it. Justify each recommendation by describing the linkage between the recommendation and its supporting evidence. Indicate the quality of evidence and the recommendation strength, based on the criteria described in Topic 9. Each guideline chapter contains recommendations for the management of HCV in CKD patients. Each recommendation builds on a supporting rationale with evidence tables if available. The strength of the recommendation and the quality of evidence are provided in parenthesis within each recommendation.
15. Potential benefits and harms Describe anticipated benefits and potential risks associated with implementation of guideline recommendations. The benefits and harm for each comparison of interventions are provided in summary tables and summarized in evidence profiles. The estimated balance between potential benefits and harm was considered when formulating the recommendations.
16. Patient preferences Describe the role of patient preferences when a recommendation involves a substantial element of personal choice or values. Recommendations that are level 2, or “discretionary,” indicate a greater need to help each patient arrive at a management decision consistent with her or his values and preferences.
17. Algorithm Provide (when appropriate) a graphical description of the stages and decisions in clinical care described by the guideline. Algorithms were developed where applicable (see Chapters 2 and 4).
18. Implementation considerations Describe anticipated barriers to application of the recommendations. Provide reference to any auxiliary documents for providers or patients that are intended to facilitate implementation. Suggest review criteria for measuring changes in care when the guideline is implemented. These recommendations are global. Local versions of the guideline are anticipated to facilitate implementation and appropriate care. Review criteria were not suggested because implementation with prioritization and development of review criteria have to proceed locally. Most recommendations are discretionary, requiring substantial discussion among stakeholders before they can be adopted as review criteria. The decision whether to convert any recommendations to review criteria will vary globally. Research recommendations were also outlined to address current gaps in the evidence base. CKD, chronic kidney disease; CPG, clinical practice guideline; GRADE, Grading of Recommendations Assessment, Development and Evaluation; HCV, hepatitis C virus; KDIGO, Kidney Disease: Improving Global Outcomes. Biographic and disclosure information Michel Jadoul, MD (Work Group Co-Chair), received his MD degree in 1983 at the Université Catholique de Louvain (UCL), Brussels, Belgium. Dr. Jadoul trained in internal medicine and nephrology under the mentorship of Professor Charles van Ypersele de Strihou. He has served as chair at the Department of Nephrology of the Cliniques Universitaires Saint-Luc since 2003 and is currently full clinical professor at UCL. Dr. Jadoul’s clinical activities focus on the follow-up of hemodialysis and CKD patients, and his main research interests include β2-microglobulin amyloidosis, hepatitis C, and other complications (e.g., falls, bone fractures, sudden death) in hemodialysis patients, as well as cardiovascular complications after kidney transplantation and various causes of kidney disease (e.g., drug-induced). Dr. Jadoul has co-authored over 230 scientific papers, most of them published in major nephrology journals. He is currently serving as a theme editor of Nephrology Dialysis Transplantation, and he is also a country co-investigator for the Dialysis Outcomes and Practice Patterns Study (DOPPS) (2001–present). In 2008, he received the international distinguished medal from the US National Kidney Foundation. He was previously a member of the KDIGO Executive Committee (2010–2015) and the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Council (2013–2016). Presently, Dr. Jadoul is the KDIGO Co-Chair Elect. Consultant: Astellas, GlaxoSmithKline, Merck Sharp & Dohme, Vifor Fresenius Medical Care Renal Pharma Grant/research support: Alexion, Amgen, Janssen-Cilag, Merck Sharp & Dohme Otsuka, Roche Speaker: AbbVie, Amgen, Menarini, Merck Sharp & Dohme, Vifor Fresenius Medical Care Renal Pharma Travel: Amgen All monies paid to institution. Paul Martin, MD, FRCP, FRCPI (Work Group Co-Chair), is professor of medicine, Mandel Chair of Gastroenterology, and chief of the Division of Gastroenterology and Hepatology at the University of Miami, USA. He graduated from medical school at University College, Dublin, Ireland and trained in internal medicine and gastroenterology in Dublin and in Canada. He was a medical staff fellow in the Liver Unit of the National Institutes of Health, where he trained with Dr. Jay Hoofnagle. He is Editor-in-Chief of Liver Transplantation and co-editor of Handbook of Liver Disease. Dr. Martin was previously a councilor for the American Society of Transplantation and has had a long-standing interest in viral hepatitis and organ transplantation. He was the Sheila Sherlock Lecturer for the Internal Association for the Study of Liver Disease in 2004 and received the Charles Trey Award from the American Liver Foundation in 2001. Board member: AbbVie, Bayer, Bristol-Myers Squibb Grant/research support: AbbVie*, Bristol-Myers Squibb*, Gilead*, Merck* *Monies paid to institution. Marina C. Berenguer, MD, is a consultant hepatologist at La Fe University Hospital in Valencia, Spain, and professor of medicine at the University of Valencia. She was trained in medicine at the University of Valencia before completing a fellowship at the Veterans Affairs Medical Center / University of California, San Francisco, with Dr. Teresa Wright. Prof. Berenguer is well recognized for her important contributions to the field of post-transplantation HCV liver disease, where she has been involved in the creation of various consensus documents on viral hepatitis and liver disease. She is also an active committee member for several national and international hepatology and liver transplantation societies. Prof. Berenguer has also coordinated research within a national research network in hepato-gastroenterology (“Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas,” CIBER-ehd) since its creation in 2006. Prof. Berenguer previously served as associate editor for the Journal of Hepatology and Liver Transplantation until December 2014, and is now deputy editor for Transplantation. She has authored more than 300 publications in peer-reviewed journals as well as over 70 chapters in international and national textbooks. Consultant: AbbVie, Gilead, Merck Sharp & Dohme Grant/research support: Gilead* Speaker: AbbVie, Astellas, Gilead, Merck Sharp & Dohme, Novartis *Monies paid to institution. Wahid Doss, MD, is professor of hepatogastroenterolgy and endemic medicine at Cairo University, Egypt. Dr. Doss became the Head of the National Hepatology Institute, Cairo, from 2006 through 2015, and he is presently the Head of the National Committee for the Control of Viral Hepatitis since 2006. Together with his colleagues, he established and supervised one of the most comprehensive hepatitis treatment programs worldwide, which has received acclaim from local and international organizations including the World Health Organization. Dr. Doss is a founding member of the gastrointestinal endoscopy unit at Kasr El Aini Hospital, Cairo University, and maintains a special interest in therapeutic endoscopic procedures. A member of EASL, AASLD, and American Society for Gastrointestinal Endoscopy, he is also a founding member and current vice president of the Egyptian Liver Care Society. Dr. Doss declared no competing interests. Fabrizio Fabrizi, MD, is staff nephrologist and professor of medicine at Maggiore Policlinico Hospital and IRCCS Foundation, Milan, Italy. His research focus is aimed at the understanding of the epidemiology, natural history, and management of viral hepatitis (HBV and HCV) in the CKD population through laboratory work, clinical research studies, and clinical trials. He has received grants from the Italian Society of Nephrology and fellowships from the Society of Italian-American Nephrologists as support for his research projects. Dr. Fabrizi has actively participated in the development of numerous national and international guidelines regarding the management of viral hepatitis in CKD patients, including the inaugural 2008 KDIGO HCV guideline. He currently serves on the editorial board of the International Journal of Artificial Organs and the Journal of Nephrology, and has authored more than 250 publications in peer-reviewed journals such as Kidney International, the American Journal of Kidney Diseases, and the Clinical Journal of the American Society of Nephrology, among others. Board member: AbbVie, Merck Sharp & Dohme Consultant: AbbVie Jacques Izopet, PharmD, PhD, is professor of virology at Toulouse University and head of the Federative Institute of Biology at Toulouse University Hospital, France. He is also head of a research team in the Pathophysiology Center of Toulouse-Purpan – INSERM UMR 1043/CNRS 5282. His primary research area has centered on viral persistence, host response, and pathophysiology, with a particular focus on HIV tropism and hepatitis E virus infection in immunocompetent and immunocompromised patients. Dr. Izopet has published over 450 papers in international journals. Dr. Izopet declared no competing interests. Vivekanand Jha, MBBS, MD, DM, FRCP, FRCP (Edin) FAMS, is the executive director at The George Institute for Global Health India, professor of nephrology at University of Oxford, UK, and the president-elect of the International Society of Nephrology. Prof. Jha received his internal medicine and nephrology training at the Postgraduate Institute of Medical Education and Research (PGIMER) in Chandigarh, India, and a research fellowship at Harvard University. He was a professor of nephrology, led the Stem Cell Research Facility, and was head of the Department of Translational and Regenerative Medicine at PGIMER. Prof. Jha focuses on the study of emerging public health threats globally and in India, and in finding solutions using innovative methodologies appropriate for emerging countries. He currently spearheads research projects in more than 20 countries with a particular interest in the understanding of global burden of kidney diseases, the social- and disease-related drivers of diseases and their determinants of outcome. Prof. Jha is an expert in the effect of tropical ecology on kidney diseases and the impact of infections on patients with kidney diseases. He has served as a Work Group member on prior KDIGO guidelines including the management of patients with glomerulonephritis and the care of kidney transplant recipients. Consultant: NephroPlus* Grants/research support: Baxter Healthcare*, GlaxoSmithKline* Speaker: Baxter Healthcare* *Monies paid to institution. Nassim Kamar, MD, PhD, is a professor of nephrology at Toulouse University Hospital in Toulouse, France, and is the head of the Department of Nephrology and Organ Transplantation at Toulouse University Hospital. Dr. Kamar received his medical degree from Dijon University, France. Thereafter, he received internship at Toulouse University, France, where he graduated with a specialty in nephrology. Dr. Kamar received additional training in kidney replacement therapy and medical pedagogy. He also completed a 1-year postdoctoral fellowship in basic research at the Department of Nephrology, La Charité Hospital, Berlin, Germany. Dr. Kamar was awarded his PhD in 2006. Dr. Kamar’s interests include the studying of viral infection, particularly hepatitis E virus, HCV, and cytomegalovirus infections that develop after solid organ transplantation. He is also interested in immunosuppression after solid organ transplantation. Dr. Kamar has published over 450 papers in peer-reviewed journals and was a member of The Council of the International Transplant Infectious Disease Society. He has received numerous awards, including la Fondation du Rein (2008), the Grand Prix de Médecine from the Académie des Sciences, Inscriptions et Belles-Lettres de Toulouse (2009), and the Palme de Médecine des CHU (2015). Board member: Astellas, Merck Sharp & Dohme, Novartis, Shire Consultant: Novartis Speaker: AbbVie, Amgen, Astellas, Chiesi, Fresenius, Gilead, Merck Sharp & Dohme, Neovii, Novartis, Roche, Sanofi, Shire Bertram L. Kasiske, MD, FACP, obtained his undergraduate training at Michigan State University, East Lansing, MI, USA. He received his medical degree from the University of Iowa, Iowa City, IA, USA and completed an internal medicine residency and fellowship training in nephrology at Hennepin County Medical Center, an affiliate hospital of the University of Minnesota in Minneapolis, USA. Dr. Kasiske is former deputy director of the US Renal Data System, former Editor-in-Chief of the American Journal of Kidney Diseases, and former Co-Chair of Kidney Disease: Improving Global Outcomes (KDIGO). Currently he is director of nephrology at Hennepin County Medical Center and professor of medicine at the University of Minnesota. Dr. Kasiske is the principal investigator for a National Institutes of Health grant to study long-term effects of living kidney donation. He is also the director of the Scientific Registry of Transplant Recipients, which is a federal registry of solid organ transplants in the US. Speaker: Novartis Ching-Lung Lai, MD, FRCP, FRACP, FHKAM (Med), FHKCP, FAASLD, is the Simon K Y Lee Professor in Gastroenterology and the Chair Professor of Medicine and Hepatology at the Department of Medicine, University of Hong Kong, where he has been working since his graduation with honors from the university. For the last 4 decades he has been extensively involved in research on various aspects of HBV, including its molecular virology, natural history, treatment, and prevention. Prof. Lai is one of the lead investigators in the pivotal trials of various nucleos(t)ide analogues that have revolutionized the treatment of chronic hepatitis B. More recently he has been involved in studies for the treatment of chronic hepatitis C. Prof. Lai has published over 500 peer-reviewed papers and reviews in international journals. His publications have been widely cited, and he is one of top scientists in the field of chronic hepatitis B infection. Prof. Lai was also invited to give the Leon Schiff State-of-the-Art Lecture at the 2005 annual meeting of the American Association for the Study of Liver Diseases (AASLD), entitled “The natural history and treatment of chronic hepatitis B: consensus and controversies,” and he has co-edited a book entitled Hepatitis B Virus. Board member: Arrowhead Research Corporation* Speaker: AbbVie, Gilead Sciences Hong Kong Limited *Monies paid to institution. Jose M. Morales, MD, PhD, is professor of medicine and senior investigator of the Research Institute in the Hospital 12 de Octubre (Madrid, Spain), educational ambassador of the International Society of Nephrology, and associate editor of Clinical Transplantation. He was medical director of the Renal Transplant Program of the Hospital 12 de Octubre in Madrid (one of the largest hospitals in Spain), chief of the Renal Transplant Office, and chief of the Section of Nephrology/Renal Transplantation. Prof. Morales also served as the past president of the Madrid Transplantation Society and a council member of the Spanish Transplantation Society. In addition, he was a council member of ERA-EDTA (1998–2001) and a medical coordinator of Forum Renal from Spain. Prof. Morales has published over 300 articles in peer-reviewed journals, and he has served as reviewer in the main nephrology and transplantation journals. His principal areas of scientific interest include clinical nephrology/transplantation, and immunosuppression and HCV. Prof. Morales has also been a principal investigator for many important trials involving immunosuppressive agents such as tacrolimus, extended-release tacrolimus, rapamycin, mycophenolate mofetil, everolimus, and belatacept. He was a member of the expert group that developed the European Best Practice Guidelines of Renal Transplantation (2000–2002) and a prior member of the Work Group that developed the 2008 KDIGO CPG on HCV in CKD. Recently, Madrid was chosen to host the Transplantation Society Congress in July 2018, and Dr. Morales is president of the local committee and vice chair of the 27th International Congress of the Transplantation Society. Consultant: Merck Sharp & Dohme Speaker: Astellas, Merck Sharp & Dohme Priti R. Patel, MD, MPH, is a medical officer in the Division of Healthcare Quality Promotion at the US Centers for Disease Control and Prevention (CDC), where she leads CDC’s dialysis safety efforts. She is also adjunct assistant professor of family and preventive medicine at the Emory University School of Medicine. Dr. Patel earned a Master of Public Health degree from Columbia University and received her medical degree from Howard University College of Medicine (1999). She completed a residency in internal medicine at the University of Pennsylvania (2002) and residency in preventive medicine at CDC (2005). She received training as an officer in the Epidemic Intelligence Service (EIS) program assigned to CDC’s Division of Viral Hepatitis (2004). In her work at CDC, Dr. Patel has supervised numerous outbreak investigations in dialysis centers, has contributed to CDC guidance documents, and develops resources and strategies to help prevent infections among dialysis patients. Dr. Patel has authored more than 80 peer-reviewed publications, largely focused on health care–associated infection prevention and patient safety. She is the director of CDC’s Making Dialysis Safer for Patients Coalition and a member of the Nephrologists Transforming Dialysis Safety Project Committee. Dr. Patel declared no competing interests. Stanislas Pol, MD, PhD, is professor of hepatology and gastroenterology at Université Paris Descartes, Paris, France, and head of the liver department at Cochin Hospital, Paris, France. He completed hepatology and gastroenterology residency and chief residency at the Necker-Enfants Malades University, and a molecular enzymology fellowship in Henri Mondor Hospital. Dr. Pol completed his MD thesis on occult HBV infections in 1983 and his PhD thesis on the regulation of iso-enzymes of aspartate aminotransferase in liver disease in 1992. Dr. Pol’s current research interests involve studying the impact of immune deficiency, including HIV, on the natural history of viral hepatitis; the treatment of viral hepatitis; and the reversal of cirrhosis. He is a co-leader of a research INSERM unit (U1223 of Institut Pasteur) studying the immune pathology of HCV infection. Dr. Pol is the recipient of several research awards and fellowships and has published more than 350 primary and review articles in the field of liver diseases. He has previously chaired the coordinated action 24 (AC 24) of the French Agency for AIDS and Viral Hepatitis (ANRS: therapeutic trials in viral hepatitis), and he is presently the clinical head of the French ANRS HEPATHER cohort, which includes HBV and HCV patients. He is also the director of the Center of Translational Research of Institut Pasteur since 2015. Board member: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme Consultant: AbbVie, Gilead Speaker: AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck Sharp & Dohme Marcelo O. Silva, MD, is the head of hepatology and liver transplant units at Austral University Hospital in Pilar, Argentina. He earned his medical degree with honors from the University of Buenos Aires, and completed his post-graduate medical education in internal medicine and gastroenterology at the University of Buenos Aires Hospital. Dr. Silva obtained hepatology training with a research and clinical fellowship at the Center for Liver Diseases, University of Miami School of Medicine. Upon completion of his fellowship, Dr. Silva served as assistant professor of clinical medicine at the University of Miami, FL. He has extensive experience in clinical trials involving chronic hepatitis B and C. Dr. Silva has published more than 60 papers in peer-reviewed journals, contributed over 100 abstracts and presentations in scientific meetings, and authored several book chapters. He also developed the Latin American Liver Research Education and Awareness Network to promote research education and awareness of liver diseases in the region. In January 2014, he was appointed as a board member of the World Health Organization Viral Hepatitis Scientific and Technical Advisory Committee Committee. Board member: AbbVie, Bristol-Myers Squibb, Gilead, Merck Sharp & Dohme Grants/research support: AbbVie*, Bristol-Myers Squibb*, Gilead*, Merck Sharp & Dohme* Speaker: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme Development of educational presentations: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme Travel: AbbVie, Bristol-Myers Squibb, Gador KDIGO Co-Chairs David C. Wheeler, MD, FRCP, is professor of kidney medicine at University College London, UK, an honorary consultant nephrologist at the Royal Free London NHS Foundation Trust, and an honorary professorial fellow of the George Institute for Global Health. He is a clinician scientist with an interest in the complications of CKD, specifically those that increase the burden of cardiovascular disease and/or accelerate progression of kidney failure. He has participated in the design, roll-out, and monitoring of several large-scale clinical trials including the Study of Heart and Renal Protection (SHARP) and the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE). He currently sits on the steering committee of Canaglifozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) and is co-chief investigator of the Dapagliflozin in CKD (DAPA-CKD) study. He is clinical lead for Division 2 of the North Thames Clinical Research Network and heads a team of 10 clinical trial nurses and practitioners at the Centre for Nephrology, Royal Free Hospital in London. He has been involved in clinical practice guideline development for several organizations, most recently for KDIGO, of which he is currently Co-Chair. He is past president of the UK Renal Association and past chair of the UK Renal Registry. His other responsibilities include membership of the editorial board of the Journal of the American Society of Nephrology and of the Executive Committee of Standardised Outcomes in Nephrology (SONG). Consultant: Akebia, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daichii-Sankyo, GlaxoSmithKline, Janssen, Vifor Fresenius Medical Care Renal Pharma Grants/research support: AstraZeneca Speaker: Amgen, Vifor Fresenius Medical Care Renal Pharma Wolfgang C. Winkelmayer, MD, MPH, ScD, is the Gordon A. Cain Chair of Nephrology and professor of medicine at Baylor College of Medicine in Houston, TX, USA. Dr. Winkelmayer received his medical degree (1990) from the University of Vienna, Austria, and later earned a Master of Public Health in health care management (1999) and a Doctor of Science in health policy (2001) from Harvard University. He then spent 8 years on the faculty of Brigham and Women’s Hospital and Harvard Medical School, where he established himself as a prolific investigator and leader in the discipline of comparative-effectiveness research as it pertains to patients with kidney disease. From 2009 to 2014, he was the director of clinical research in the Division of Nephrology at Stanford University School of Medicine, Palo Alto, CA, USA. He assumed his current position as chief of nephrology at Baylor College of Medicine in September 2014. His main areas of research interest include comparative effectiveness and safety research of treatment strategies for anemia, as well as of various interventions for cardiovascular disease in patients with kidney disease. Dr. Winkelmayer is a member of the American Society of Clinical Investigation. His clinical passion lies in providing quality kidney care to the predominantly disadvantaged and un(der)insured population in the public safety net health system of Harris County, TX. Dr. Winkelmayer has authored over 300 peer-reviewed publications, and he has a particular interest in medical publishing. He currently serves as an associate editor for the Journal of the American Medical Association, was a co-editor of the American Journal of Kidney Disease from 2007 to 2016, and has been appointed to several other editorial boards of leading nephrology and epidemiology journals. He also volunteers his time toward important initiatives of the American Society of Nephrology (e.g., Public Policy Board).He joined KDIGO volunteer leadership as an executive committee member in 2015 and has served as its Co-Chair since 2016. Consultant: Akebia, Amgen, AstraZeneca, Bayer, Daichii-Sankyo, Relypsa, Vifor Fresenius Medical Care Renal Pharma Speaker: FibroGen Evidence review team Ethan M. Balk, MD, MPH, is associate director of the Center for Evidence Synthesis in Health and associate professor at Brown University School of Public Health in Providence, RI, USA. He is project director of the evidence review team and has collaborated on numerous KDIGO guidelines, and prior to that on Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines since 2000. As project director for this guideline, he played a role in providing methodological expertise in the guideline development process and assisted in the collection, evaluation, grading, and synthesis of evidence and the revisions of the final evidence report. Dr. Balk also provided methodological guidance and training of Work Group members regarding topic refinement, key question formulation, data extraction, study assessment, evidence grading, and recommendation formulation. His primary research interests are evidence-based medicine, systematic review, clinical practice guideline development, and critical literature appraisal. Dr. Balk declared no competing interests. Craig Gordon, MD, MS, is associate professor of medicine at Boston University Medical Center and training program director for the nephrology fellowship at Boston Medical Center, USA. Dr. Gordon graduated from New York University School of Medicine and received his master’s degree from the Tufts University Sackler School of Graduate Biomedical Sciences in Clinical Care Research. Dr. Gordon previously served as the assistant project director of the evidence review team for the 2008 KDIGO CPG on HCV in CKD. He served as the associate director of the evidence review team and assistant project director for the 2018 KDIGO CPG on HCV in CKD. Dr. Gordon provided methodologic expertise to the Work Group during the guideline development process and assisted in the collection, evaluation, grading, and synthesis of evidence for the guideline, as well providing guidance to Work Group members in the areas of topic refinement, key question formulation, data extraction, study assessment, evidence grading, and recommendation formulation. His primary research interests are in the management of HCV in patients with CKD, as well as evidence-based medicine and systematic review related to other areas of nephrology. Board member: AbbVie Consultant: Alexion Mengyang Di, MD, PhD, is currently a medical resident at Rhode Island Hospital, Alpert Medical School, Brown University, Providence, RI, USA. She was a member of the evidence review team as a postdoctoral research associate at the Center for Evidence Synthesis in Health, Brown University School of Public Health. Dr. Di obtained her medical degree from the Chinese Academy of Medical Sciences and Peking Union Medical College, and her PhD in epidemiology from the Chinese University of Hong Kong. She was a core member of the evidence review team and performed key functions including study selection, data extraction, data analysis, drafting of evidence tables, and critical literature appraisals. Her research interests include systematic review, meta-analysis, and decision analysis. Dr. Di declared no competing interests. Amy Earley, BS, is a research associate with the evidence review team from the Center for Evidence Synthesis in Health at Brown University in Providence, RI, USA. She is key in conducting the evidence review, which includes running searches, screening, data extraction, drafting of tables and methods sections, proofing of guideline drafts, and critical literature appraisal. She also holds an important role in coordinating the guideline development activities within the evidence review team, especially in the development of the evidence reports for all guidelines. In addition to her role with the evidence review team, Ms. Earley works as a senior research associate at Evidera, where she is a lead researcher and principal investigator on qualitative and quantitative meta-research projects (meta-analyses and indirect treatment comparisons). Ms. Earley declared no competing interests. Acknowledgments A special debt of gratitude is owed to the KDIGO Co-Chairs, David Wheeler and Wolfgang Winkelmayer, for their invaluable guidance throughout the development of this guideline. In particular, we thank Ethan Balk, Craig Gordon, and the ERT members for their substantial contribution to the rigorous assessment of the available evidence. We are also especially grateful to the Work Group members for their expertise throughout the entire process of literature review, data extraction, meeting participation, and the critical writing and editing of the statements and rationale, which made the publication of this guideline possible. The generous gift of their time and dedication is greatly appreciated. Finally, and on behalf of the Work Group, we gratefully acknowledge the careful assessment of the draft guideline by external reviewers. The Work Group considered all of the valuable comments made and, where appropriate, suggested changes were incorporated into the final publication. The following individuals provided feedback during the public review of the draft guideline: Saeed M.G. Al-Ghamdi; Alsayed Alnahal; Mona Alrukhaimi; Andrea Angioi; Mustafa Arici; Mariano Arriola; Suheir Assady; Peter Bárány; Rashad S. Barsoum; Donald L. Batisky; Mohammed Benyahia; Roy D. Bloom; Boris Bogov; Rafael Burgos-Calderon; Maria Buti; Jianghua Chen; Rolando Claure-Del Granado; Andrew J. Crannage; Ana Maria Cusumano; Nida Dincel; Ute Eisenberger; Mohamed E. Elrggal; Patrícia Ferreira Abreu; Hélène Fontaine; Rebeca García-Agudo; Alvaro Garcia Garcia; Osama Gheith; HaiAn Ha Phan; Karin Hagen; Mohammed Haji Rashid Hassan; William E. Haley; Qiang He; Scott D. Holmberg; Eero Honkanen; Lai Seong Hooi; Jean-Michel Hougardy; Chandra Mauli Jha; Dario Jimenez Acosta; Holly J. Kramer; John R. Lake; Maria-Carlota Londoño; José Antó Lopes; Cesar Loza; Gerson Marques Pereira Junior; Gerardo Mogni; Anne Moorman; Sameh Morgan; Eugen Mota; Ricardo Mouzo; Reem A. Mustafa; Judit Nagy; Mustafa Nazzal; Armando Luis Negri; Abdou Niang; Julio Pascual; Nikil Patel; Ioan Mihai Paţiu; Saime Paydas; Jim Pearce; Ligia Petrica; Pradeep Kumar Rai; Harun Rashid; Hector Rodriguez; A. Blythe Ryerson; Deepak Sharma; Catherine Staffeld-Coit; Ekamol Tantisattamo; Yusuke Tsukamoto; Nosratola D. Vaziri; J. Todd Weber; Andrzej Więcek; Mai-Szu Wu; Chul-Woo Yang; Bahaa M. Zayed Participation in the review does not necessarily constitute endorsement of the content of this report by the above individuals or the organizations or institutions they represent. Michel Jadoul, MD Paul Martin, MD Work Group Co-Chairs