Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) hepatitis C guidelines: a European Renal Best Practice (ERBP) position statement

Recently the Kidney Disease Improving Global Outcomes (KDIGO) initiative published ‘the first product of what has been an unprecedented undertaking of the renal community’ [ 1 ]: the first set of global nephrological guidelines devoted to prevention, diagnosis and treatment in hepatitis C [ 1 ]. Previously, the KDIGO Board had defined non-duplication of existing guidelines and priority to topics of worldwide interest as its primary goals. Ultimately, a major infectious disease hepatitis C (HCV) was considered as the first topic to be dealt with because ‘(i) of the larger number of available studies on the subject; (ii) HCV is an infection that can detrimentally affect patients throughout the spectrum of chronic kidney disease (CKD) and can itself cause kidney disease; and (iii) HCV is a problem of worldwide cli- nical relevance in developed and developing countries’ [ 2 ]. A group of experts was commissioned to develop a rigorous and consistent approach for the development and grading of the evidence considered for, and recommendations established by KDIGO guidelines, based on the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach (table 1) [ 3 ]. This approach was followed by the interdisciplinary, international and independent Work Group charged with developing the guideline. The guidelines were subjected to a three-step review process. Initially, the KDIGO Board reviewed all questions to be addressed (in December 2005). In the second phase, a first draft of the final guidelines was reviewed by the Board and representatives of Caring for Australians with Renal Impairment (CARI), United Kingdom Renal Association (UK-RA), Canadian Society of Nephrology (CSN), Kidney Disease Outcomes Quality Initiative (KDOQI) and European Best Practice Guidelines (EBPG) (in December 2006). Finally, the draft guidelines were submitted for public review and comment by any interested individual or party. All comments received by the Work Group were considered, discussed and, if relevant, included in the final document. It is thus clear that prominent European experts were also actively participating in this process of global guideline elaboration. Most recently, European Renal Association–European Dialysis and Transplantation Association (ERA-EDTA) analysed its 10-year-long history of commitment to producing guidelines in nephrology in light of the new perspectives offered by recent KDIGO, UK National Institute for Health and Clinical Excellence (NICE), KDOQI and CARI documents and the clear trends in (i) selecting therapies based on the most objective evidence available and (ii) financial policies based on performance indicators. Originally, it was thought that KDIGO would cover the whole guideline spectrum, producing new and updated nephrology guidelines on any theme considered suitable. In 2006, the KDIGO Board of Directors decided, however, to concentrate on selected topics only. This left a new opening for existing guideline bodies as more room was created for a more active participation of European as well as of other more local guideline initiatives. ERA-EDTA joined the KDIGO project of producing global guidelines from the very beginning, the general philosophy of KDIGO being to globalize the evidence and to localize the implementation. Nevertheless, the collaboration with KDIGO should be continued without neglecting our own European identity. A new ERA-EDTA initiative, European Renal Best Practice (ERBP), was established to cover all aspects related to European nephrological guidelines [ 4 ], replacing the previous European Best Practice Guidelines (EBPG), aiming at (i) producing new guidelines in areas not covered by other initiatives, (ii) endorsing and fine-tuning guidelines produced by other bodies to European conditions and (iii) highlighting still controversial areas where consensus-driven expert advice might be useful for daily practice. The current document addresses the second of these aims—namely endorsing and fine-tuning guidelines produced by other bodies to European conditions. An ad hoc Work Group was commissioned by the ERBP Advisory Board to recommend endorsement of the hepatitis C KDIGO guidelines, with possible comments, amendments or caveats applying to the local European conditions, if needed. An important point to be answered was why it is appropriate to adapt guidelines for regional circumstances. Epidemiology, dialysis practice and reimbursement are significantly different across the world. With the notable exception of parts from Eastern Europe, hepatitis C incidence and prevalence are low. A capitation system with a fixed price per dialysis is more widely present; strict protocols are required on a large scale by state or private operators, based on an optimum compromise between evidence-derived efficiency and costs. Significant new evidence has emerged in the area of hepatitis C treatment, after the publishing of KDIGO guidelines (see below). Thus, evidence was reviewed from the particular perspective of European experience and current nephrology practice. In the following publication, if appropriate, statements approved by the ERBP Work Group will be given in general and as per guideline. The same GRADE approach as applied by KDIGO was maintained. Table 1 summarizes the interpretation of the guidance statements used in the KDIGO hepatitis C guidelines as this differs from the GRADE approach [ 3 ]. There are three levels of recommendation, ‘strong’, ‘moderate’ and ‘weak’, based on the strength of the underlying evidence. Each statement uses specific wording and formatting according to the strength of the recommendation. As in many cases in nephrology, there are few randomized controlled trials evaluating this specific area; therefore, the majority of statements are weak recommendations. In agreement with the introductory background laid down by the KDIGO co-chairs, the ERBP Work Group underlines the fact that ‘statements specified as “Weak” refer to consensus-based recommendations where the evidence is low, very low, or absent, with the expectation that consideration would be given to follow the suggested judgment-based recommendation on an individual basis’. The decision to follow any guideline statement, dependent on the level of its supporting evidence, must be made individually for each patient. 1.1.1 It is suggested that CKD patients be tested for HCV. (Weak) 1.1.2 Testing for HCV should be performed in patients on maintenance haemodialysis (CKD stage 5D) and kidney transplant candidates. (Strong) 1.2.1 Patients on haemodialysis should be tested when they first start haemodialysis or when they transfer from another haemodialysis facility. (Strong) In haemodialysis units with a low prevalence of HCV, initial testing with EIA (if positive, followed by NAT) should be considered (see Algorithm 1). (Moderate) In haemodialysis units with a high prevalence of HCV, initial testing with NAT should be considered (see Algorithm 1). (Moderate) 1.2.2 For patients on haemodialysis who test negative for HCV, retesting every 6–12 months with EIA should be considered. (Moderate) 1.2.3 Testing for HCV with NAT should be performed for haemodialysis patients with unexplained abnormal aminotransferase(s) levels. (Strong) 1.2.4 If a new HCV infection in a haemodialysis unit is suspected to be nosocomial, testing with NAT should be performed in all patients who may have been exposed. (Strong) Repeat testing with NAT is suggested within 2–12 weeks in initially NAT-negative patients. (Weak) The following issue was identified by the ERBP Work Group. In the 2002 EBPG-HD, the enzyme immunoassay (EIA) test was advised for screening and the recombinant immunoblot assay (RIBA) test for confirmation [ 5 ]. Nucleic acid testing (NAT) was only considered for patients with consistently positive ALT who are HCV negative. Hence, as compared to EBPG 2002, KDIGO 2008 broadens the candidate population to be tested by NAT. Detection of HCV RNA by PCR assay is acknowledged by the ERBP Work Group to be the best strategy because of false negative results in patients tested by EIA. A significant proportion of false negatives with EIA are seen also in a European setting [ 6 ]. Furthermore, a window period during incubation is seen when EIA is used. It is thus recognized that PCR is excellent but expensive while ELISA is cheaper but less accurate. There is a potential conflict of interest between ‘treating as well as possible’ and ‘doing as much as possible’ with the same amount of funds, particularly in a bundled reimbursement system. Units with the highest prevalence of HCV are usually located in regions where dialysis reimbursement is low. However, ERBP considered it difficult to set a limit discriminating high versus low HCV, in order to establish cut-off values to distinguish between EIA and NAT—as preferred choice for primary testing. In addition, such figures may differ from region to region. The ERBP Work Group considers that every nephrologist should decide in function of this knowledge and that no strong recommendation can be issued. The ERBP Work Group considers that it is up to the medical and managing team of the unit to find a balance between ‘individual patient best practice’ and ‘health organizational point of view best practice’ when setting the HCV retesting frequency ceiling for a particular HD centre. Further European research is encouraged. 2.1.1 It is suggested that CKD patients with HCV infection be evaluated for antiviral treatment. (Weak) 2.1.2 It is suggested that the decision to treat be based on the potential benefits and risks of therapy, including life expectancy, candidacy for kidney transplantation and comorbidities. (Weak) 2.1.3 It is suggested that in CKD patients—except kidney transplant recipients—who develop an acute HCV infection, a waiting period beyond 12 weeks to observe spontaneous clearance (by NAT) is not justified, and that antiviral treatment should be started. (Weak) 2.1.4 It is suggested that HCV-infected patients accepted for kidney transplantation be treated (see Guideline 4). (Weak) 2.1.5 It is suggested that treatment of HCV-infected kidney transplant recipients be considered only when the benefits of treatment clearly the of to (Weak) It is suggested that antiviral be considered for patients with (see Guideline (Weak) The following issue was identified by the ERBP Work Group. the treatment of transplant on the potential conflict of interest is between and for being of the fact that the of transplantation is that of dialysis in However, only a few studies analysed the that HCV-infected patients who on dialysis less well patients who are and only are available [ ]. The on transplant dialysis patients with is by large studies from that the is with HCV without HCV after the of the and the of are to in the group [ ]. is significantly more in HCV-infected kidney transplant recipients and the for [ ]. from the there is a of HCV and an for after transplantation in the patients [ ]. studies have compared HCV patients who have the with and no HCV and a significantly for in the treated [ ]. Finally, with a negative HCV RNA to the is with [ ]. The ERBP Work Group with the to to clear HCV in transplant by appropriate treatment. The issue of HCV treatment in the transplant population will be discussed in with Guideline The decision to treat patients not on the transplant is more All should or and a of disease and comorbidities. A is preferred with the exception for most cases of 2 or the was suggested as a to in with renal it has been in CKD patients. the for considered in haemodialysis patients is still as values are in general in these patients compared to the and well as stage of are important in the decision to if the patient is has on and the of the primary kidney disease is not HCV the of might be If the patient in is with HCV 1 with a high is to clear the are with for treatment [ ]. is with in particular in CKD The prevalence of and patient to be in [ ]. The ERBP Work Group considers that treatment should be considered for without major and that the decision to treat should be discussed with the particularly if patients are with For HCV-infected patients with CKD 1 and antiviral treatment and is as in the general (Weak) It is suggested that be according to patient (Weak) For HCV-infected patients with CKD 4 and 5 not on with with to the level of kidney function is (Weak) For HCV-infected patients with CKD stage on maintenance with that is for a of 2 is (Weak) For HCV-infected kidney transplant recipients in the benefits of antiviral treatment clearly the risks (see Guideline with is (Weak) The following were identified by the ERBP Work Group. There are only a few published studies in CKD The ERBP group also reviewed published by the of or not available for review and in the KDIGO practice guidelines, most of being and Thus, the on in dialysis patients are a number of trials with would be more for its as it is compared with three for recent studies a of in CKD ERBP considers that it is difficult to recommend in CKD it will most be in the In the KDIGO guidelines, there was a that had not been to with to and in CKD However, recent from have used with The [ with and in HD patients results with a and However, it is important to that the of the patients without significant also the on decision to treat have had an on treatment A very recent randomized compared and in HD patients [ a versus and a with versus by In to these positive a recent all cases from the to of HD patients treated with in a high prevalence of and of the incidence of was to and incidence of was Furthermore, compared with published a low and an were not supporting the of [ ]. The on of in the dialysis population has been by [ ]. other recent studies have the related to in CKD patients [ ]. results in the medical up to this point and of versus in dialysis are related also to the of patient during antiviral of patients is with and antiviral treatment. The ERBP Work Group considers that antiviral treatment with of patients and rigorous during treatment should be encouraged. be a treatment in dialysis patients in or in collaboration with such A rigorous of treatment of and is of the of antiviral of difficult cases with should be to only at where levels can be controlled [ ]. In the of the ERBP Work related to KDIGO Table in with and may be considered as the preferred in CKD but this should only be in defined as HCV RNA clearance 6 months after of antiviral treatment, is suggested for to antiviral treatment. (Weak) If is it is suggested that testing with NAT be performed to that the patient (Weak) For patients on maintenance testing with NAT every 6 months is (Weak) All patients with HCV infection, of treatment or treatment should be followed for comorbidities. (Strong) Patients who have evidence of or should have every 6 (Strong) for patients without is (Weak) The ERBP Work Group with the recommendations and in Guideline of HCV-infected patients is not as an to strict for of (Weak) The of dialysis for HCV-infected patients is not (Moderate) is it is suggested that the of HCV-infected patients can be there is and strict (Weak) It is suggested to of in performance of haemodialysis (Weak) The following were identified by the ERBP Work Group. the KDIGO hepatitis C also cover CKD and no recommendations are for The ERBP Work Group considers that the practice related to the of hepatitis C in patients in be The 2002 EBPG that in to are the most treatment of patients in areas with is in units with a high prevalence of HCV infection [ 5 ]. that in by the KDIGO guidelines [ 1 are the KDIGO that ‘the of HCV patients is not as an to strict infection for of and the of dialysis for HCV patients is not However, the ERBP Work Group underlines that there is no only versus these to in a where the of the infection is The ERBP Work Group considers that of should be the of of positive patients be considered, but only if this practice not have a negative on the and of in the unit as a might be only considered as an in with a high HCV prevalence for setting a ceiling as for HCV All kidney transplant should be evaluated for HCV infection (see Algorithm (Strong) In initial testing with EIA and of positive EIA with NAT should be considered. (Moderate) In initial testing with NAT should be considered. (Moderate) HCV infection should not be considered a for kidney (Moderate) It is suggested that HCV-infected kidney transplant a (Weak) It is suggested that HCV-infected patients with by but be considered for kidney transplantation only in an (Weak) It is suggested that HCV-infected kidney transplant be considered for treatment with transplantation (see Algorithm (Weak) It is suggested that patients on a kidney transplant waiting be evaluated for HCV infection (see Algorithm (Weak) For patients who have been tested for HCV, it is suggested that testing be performed with EIA in of positive results by NAT) and NAT in (see Guideline (Weak) It is suggested that HCV-infected patients not to be be on of the of (Weak) It is suggested that patients who had received antiviral treatment and had have testing with NAT at (see Guideline if NAT positive, it is suggested that the patient be on and have of (Weak) It is suggested that HCV-infected patients who had with but or antiviral treatment, have a every while on the transplant waiting on (Weak) All kidney should be tested for HCV (Strong) Testing with EIA and NAT (if NAT is is (Weak) It is suggested that transplantation of from with HCV be to recipients with positive NAT. (Weak) All current maintenance can be considered for in HCV-infected kidney transplant (Weak) It is suggested that HCV-infected kidney transplant recipients more 6 months after transplant have disease evaluated at (Weak) For HCV-infected kidney transplant recipients in the benefits of antiviral treatment clearly the risks (see Guidelines 2.1.5 and with is (Weak) It is suggested that HCV-infected kidney transplant recipients be for the development of after (Weak) It is suggested that HCV-infected kidney transplant recipients be tested at every months for (Weak) It is suggested that patients who develop new or on or more have an with and included in the (Weak) of the of it is suggested that kidney transplant recipients with not therapy, it is that the benefits of the risks of treatment. (Weak) The following were identified by the ERBP Work Group. The issue of can be as HCV-infected patients as well as any stage 5 CKD patient [ after transplantation on HCV patients in the and patient as well as incidence of and patients. with studies that HCV clearance during HD in possible in and in of [ ], the for to HCV However, should that this strategy may be with such as high and possible to treatment per is from in the dialysis and patients on the waiting for that may between 6 months to (in the of a patient with a 1 The ERBP Work Group considers it of the that confirmation from that patients still to waiting and that after of or therapy, patients be to an active on the waiting The ERBP Work Group that patients be the and of therapy, and that they should be given the to in the decision of being treated or not with This was also the of the KDIGO Finally, the strategy and and may not be appropriate for with the prevalence of HCV is The ERBP Work Group with the research recommendation for randomized controlled trials to the of the would of HCV-infected dialysis patients for a transplant with during the patient has an on the transplant waiting All participating patients should a as at would be when after many should be patient and The second point that is all HCV-infected kidney transplant should a This issue is a of in the general and at a is only for patients with 1 and 4 in order to [ ]. As the to is to and a that has been in of HCV-infected dialysis patients [ ], the ERBP Work Group with the to a in all transplant candidates. The strategy for for HCV-infected transplant who to dialysis with a is not discussed in the KDIGO It is to that the strategy for patients to dialysis with a the in with or no versus and of because of the of on this important issue [ ]. the in to kidney function and with only while may be with significant and [ ]. In addition, may an in might be for the [ ]. the other the with continued may the of such as infection, chronic with and disease [ ]. any guidance on this issue would be only and has been to therapy, and has the potential to on of the [ ]. the incidence of acute is not the studies that such an is not the the by by in this specific of patients the of an to the clear can be given to this The ERBP Work Group that be well of these the frequency of acute is not it a of Guideline it is suggested that HCV-infected patients be tested at for and to possible kidney (Weak) Guideline it is suggested that a kidney be performed in HCV-infected patients with evidence of (Weak) Guideline it is suggested that for patients with particularly antiviral treatment as per Guideline be considered. (Weak) It is suggested that be considered for patients with kidney (Weak) The ERBP Work Group with the in Guideline ERBP considers that the following research areas are particularly in the European the current trends in HCV in CKD in the limit between and for HCV in order to the optimum testing the optimum retesting strategy for HD of in CKD patients and its versus Evaluation of the of therapy, patients because of treatment with versus and when an available without antiviral the current experience from treatment and in patients. Evaluation of therapies for HCV, as this is with new in and and used in with and in many cases ERA-EDTA is strong in the following of of guidelines at its own general and of guidelines on All these aspects should be and ERA-EDTA is weak in the following of guidelines at other general of guidelines at specific of guidelines at in the as of the most and All these aspects can be A guideline will be included at the joined ERA-EDTA and in and will be throughout to throughout the of and is and will be A to the guidelines on the of ERA-EDTA will be a from the are in with European National It is suggested that HCV testing as for HD be performed in patients who are transplant acute of and are to be to It is suggested that for dialysis who are on the waiting for transplantation or from where the hepatitis C prevalence is best to patients to start on dialysis or to the of infection during if a patient is not a candidate for or should not be advised to or HD to other patients from hepatitis C Furthermore, the to start patients on or HD to by of from the HD unit not the of haemodialysis units to the as in the KDIGO of HCV is the to or HCV can in the for at The of has been in [ ]. on the general of infection the following should be when and other all of with should be in addition, should be performed and after as All should be made to of to the should be a a when The of to used for of or for a or a should be All with during the should be with a is in a system can be used to the to the to the For if the is in a larger it is suggested that should be to the to a final of from and should be in a and clearly identified The should be and by by a and are of the ERBP Advisory of the ERBP Advisory Board are and the and are of and were of the process of the KDIGO hepatitis C A for the of in the and with KDIGO and ERBP This document has been approved by the Advisory Board of ERBP and by the ERA-EDTA of interest statement related by and Global nephrology a first in the