Protocol for a Systematic review of the application of the Kidney Failure Risk Equation and Oxford classification in estimating prognosis in IgA Nephropathy

Protocol for a Systematic review of the application of the Kidney Failure Risk Equation and Oxford classification in estimating prognosis in IgA Nephropathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Protocol for a Systematic review of the application of the Kidney Failure Risk Equation and Oxford classification in estimating prognosis in IgA Nephropathy Michael Toal, Ruth Fergie, Michael Quinn, Christopher Hill, Ciaran O'Neill, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3252590/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 May, 2024 Read the published version in Systematic Reviews → Version 1 posted 5 You are reading this latest preprint version Abstract Background IgA Nephropathy (IgAN) is a common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Outcomes are highly variable and predicting risk of disease progression at an individual level is challenging. Accurate risk stratification is important to identify individuals who are most likely to benefit from treatment. The Kidney Failure Risk Equation (KFRE) has been extensively validated in CKD populations and predicts the risk of ESRD at two and five years using non-invasive tests, however it’s predictive performance in IgAN is unknown. The Oxford Classification (OC) describes pathological features demonstrated on renal biopsy that are associated with adverse clinical outcomes that may also inform prognosis. The objective of this systematic review is to compare the KFRE with the OC in determining prognosis in IgAN. Methods A systematic review will be conducted and reported in line with PRISMA guidelines (PRISMA-P checklist attached as supplement). Inclusion criteria will be cohort studies that apply the KFRE or OC to determine the risk of CKD progression or ESRD in individuals with IgAN. Multiple databases will be searched in duplicate to identify relevant studies, which will be screened first by title, then by abstract and then by full text analysis. Results will be collated for comparison. Risk of bias and confidence assessments will be conducted independently by two reviewers, with a third reviewer available if required. Discussion Identifying individuals at the highest risk of progression to ESRD is challenging in IgAN, due to the heterogeneity of clinical outcomes. Risk prediction tools have been developed to guide clinicians; however it is imperative that these aids are accurate and reproducible. The OC is based on observations made by specialist renal pathologists and may be open to observer bias, therefore the utility of prediction models incorporating this classification may be diminished, particularly as in the future novel biomarkers may be incorporated into clinical practice. Systematic Review registration: Prospero no. CRD42022364569 IgA Nephropathy Glomerulonephritis Renal biopsy Prognostic assessment Prognosis Risk assessment Prediction tool Kidney failure risk equation Oxford classification BACKGROUND IgA Nephropathy (IgAN) was first described by Hinglais and Berger in 1968 and is the most common form of primary glomerulonephritis worldwide( 1 ). The disease course of IgAN is heterogeneous with up to 30–50% of affected individuals progressing to end-stage renal disease (ESRD) within five to ten years, whilst others have stable disease without significant progression over decades( 2 – 4 ). Identifying individuals at the highest risk for progression to ESRD is challenging and the 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines highlighted risk stratification as a high priority for research in IgAN ( 5 ). The understanding of the pathophysiology of IgAN is constantly evolving and there are multiple therapeutic trials ongoing to find novel agents to stabilise patients at the highest risk of progression to ESRD ( 6 , 7 ). Previous therapeutic trials in IgAN have been limited by recruitment of individuals at lower risk of progression to ESRD. Timely risk stratification to identify persons most likely to progress to ESRD will allow for more targeted clinical trials in the future ( 8 , 9 ). The Kidney Failure Risk Equation (KFRE) (Table.1) was developed from a Canadian cohort and validated in a multi-national cohort of over 700,000 patients ( 10 ). This equation, using either four or eight variables, has demonstrated excellent discrimination and can accurately predict the risk of kidney failure at a two- or five-year horizon for all forms of chronic kidney disease (CKD). The IgAN Risk Prediction (IRP) tool was developed specifically for IgAN and incorporates the Oxford classification (OC) into the risk evaluation (Table 1.) ( 11 ). OC is a histopathological scoring system developed to facilitate estimations of prognosis by classifying the degree of pathological abnormalities demonstrated on renal biopsy examination and is specific to IgAN ( 12 ). A renal biopsy is a crucial investigation in nephrology which facilitates the diagnosis of kidney diseases, estimation of prognosis and guides treatment ( 13 ). It is however an invasive procedure, with a significant risk of bleeding, requiring intervention in around 1 in 200 procedures in some case series ( 14 , 15 ). Whilst both the KFRE and IRP have been externally validated, there is limited evidence to determine which method provides optimal prognostic assessment, therefore it is unknown if a renal biopsy improves the accuracy of this estimation. Affected individuals will often have multiple blood and urine tests over a follow-up period, however an invasive renal biopsy is seldom repeated. The OC will therefore provide a snapshot of disease activity, but does not capture the nuances and dynamic changes in disease trajectory, which can be routinely tracked with blood and urine tests. If the OC did not provide superior predictive accuracy compared to clinical features alone, the international community may reconsider the utility of the OC in renal biopsy reports of IgAN. Table 1. Parameters required for each prognostic algorithm *Proteinuria expressed as urinary albumin:creatinine ratio in KFRE and grams/day in IRP. **Obtained by renal biopsy. KFRE: Kidney failure risk equation, OC: Oxford classification, IRP: IgAN Risk Prediction tool, eGFR: estimated glomerular filtration rate (ml/min/1.73m 2 ) , MAP : mean arterial pressure (mmHg), M: mesangial hypercellularity score, E: endocapillary hypercellularity score, S: segmental sclerosis score, T: tubular atrophy/interstitial fibrosis score, C: crescents score, RASB: renin-angiotensin system blockers Objectives The research question for this review is: Does the Kidney Failure Risk Equation provide more accurate prediction of disease progression and kidney failure than the Oxford Classification (MEST-C score) in patients with IgAN? METHODS Eligibility criteria Studies that will be considered for inclusion in the review will be those which investigate a population or sub-group of patients diagnosed with IgAN on native renal biopsy and compare the prognostic accuracy of the Kidney Failure Risk Equation (KFRE) with an alternative prediction tool which incorporates the OC of histopathological assessment. The inclusion criteria for study outcomes will include progression of disease as defined by a reduction in estimated glomerular filtration rate (eGFR), rise in serum creatinine or kidney failure events as defined by an eGFR below 15 ml/min/1.73m 2 or use of renal replacement therapies (kidney transplantation or dialysis). The KFRE was first published in 2011, therefore studies from 2011 onwards will be considered for inclusion. Research subjects must be humans only. Eligibility criteria will not be limited to the English language and translation services will be used where appropriate. Publications will not be limited to journal articles and appropriate grey-literature will be considered eligible. Information sources The following databases will be searched: Medline, EMBASE, Scopus, PubMed, Web of Science and Google (including Google Scholar). Search strategy The following search strategy will be applied: 1. “IgA Nephropathy” OR “Immunoglobulin A Nephropathy” OR “Glomerulonephritis, IGA” OR “Berger’s disease” 2. “Kidney Failure Risk Equation” OR “KFRE” 3. “Oxford” OR “MEST” OR “MEST-C” 4. “Disease progression” OR “Prognostic Assessment” OR “Risk Assessment” 5. 1 AND 2 AND 3 AND 4 Study records Study records will be imported into reference management software (Rayyan™) which will remove duplicates and maintain a library of eligible studies. Screening of studies will be performed independently by the corresponding author (MT) and a second reviewer (RF). Any disagreements regarding suitability of studies will be discussed amongst the two reviewers and a third reviewer (APM), if necessary. Studies will initially be screened by title, then by abstract, then by reviewing the full-text article. Data will be extracted using a standardised form for collating study data. The study authors will be contacted by MT if crucial data is missing in the eligible studies that prohibits analysis. Data Items The review will be limited to patients with a diagnosis of IgAN, proven by a native renal biopsy. Patients with all other diagnoses based on renal biopsy will not be included, nor will patients with other forms of renal diseases, not diagnosed by renal biopsy. Any international cohort or sub-group will be considered eligible. Measurements of proteinuria will be converted into standardised units of albumin: creatinine ratio where required( 16 ). Outcomes and prioritisation Studies that include measurements of discrimination and calibration such as the area under the curve (AUC) of the receiver-operating curve or Harrell’s C-statistic will be included. Studies that compare predicted outcomes with observed outcomes will also be eligible for inclusion. Excluded studies will be those which do not report either of the aforementioned outcomes and are limited to other parameters such as relative risk and hazard ratios without a direct measure of classification. Follow up time of the cohort equal to or beyond two years from renal biopsy will be considered to be appropriate for inclusion in the analysis. Risk of bias in individual studies Risk of bias will be assessed in any study meeting the inclusion criteria using PROBAST ( P rediction model R isk O f B ias AS sessment T ool) ( 17 ). This tool was designed specifically for studies of prognostic assessment, as many different prediction methods can be available for single disease entities. It comprises of twenty signalling questions across four domains: participants, predictors, outcomes and analysis. For each domain, the reviewer is required to determine a risk of bias and a level of concern regarding the study’s applicability to the review question. Two independent reviewers (MT and RF) will use PROBAST to assess risk of bias, with APM acting as a third reviewer if required. Data Synthesis Data from eligible studies will be collated for meta-analysis if possible. The number of participants in each cohort study will be described and their geographical location will be included. The baseline characteristics of all participants will be described in terms of age, gender and measurements of kidney function such as eGFR, serum creatinine and proteinuria. The long-term outcomes of each cohort will also be described- specifically detailing incidence of ESRD. The prognostic accuracy of tools under investigation will be described using Harrell’s c-index, a derivation from the AUC. These results will be collated into graphical form for comparison. Heterogeneity in studies will be assessed using the I 2 method. A subgroup analysis will investigate prognostic accuracy for studies which included other outcome measures such as a decline in eGFR over time of 30%, 40% or 50%. Meta-bias The risk of publication bias will be examined by evaluation of individual patient data provided by studies. If this is not adequately described in a paper, the authors will be contacted in order to ensure there is transparency of results without selective reporting. A funnel plot will be employed to investigate the risk of publication bias by demonstration of asymmetry, with a p < 0.10 considered to be significant( 18 ). Reviewer selection bias will be addressed by two independent reviewers performing an identical search strategy, with a third reviewer available to resolve any inconclusive results. Confidence in cumulative evidence The certainty in the evidence presented will be analysed using the GRADE approach. This assessment analyses the quality of five domains: risk of bias, inconsistency, imprecision, indirectness and publication bias ( 19 ). This system will be applied to each described outcome, detailing the authors’ confidence in each conclusion. Recommendations will be given for future studies to address the current gaps in the literature. DISCUSSION The burden of CKD is increasing globally and is projected to become the 5th most common cause of years of life lost by 2040 ( 20 ). IgAN is a common cause of CKD which has been observed to progress to ESRD in up to 50% of cases within 5 years follow-up in a UK cohort study ( 4 ). The increased risk of mortality has also been observed specifically in an IgAN cohort study, with progression to ESRD associated with a threefold increase in mortality within the follow-up period (median: 13.6 years) ( 21 ). There are numerous available risk prediction tools for kidney disease, however the KFRE and OC were selected for this review as they have been extensively validated and incorporated into UK and international guidelines ( 5 , 22 ). The OC has been adopted internationally since its conception in 2009, however the reported prognostic value of each component of the MEST-C score varies in the literature and poor reproducibility between reporting pathologists has been identified as a significant limitation ( 23 – 25 ). The KFRE is based on age, sex, location and automated laboratory values, therefore it may have increased reproducibility, but its application in IgAN has not been investigated in detail. As the understanding of the pathophysiology in IgAN continues to improve, therapeutic targets are likely to become more readily available to manage individuals at higher risk of progression ( 26 ). Several biomarkers have been identified in IgAN for diagnosis and prognostic assessment, however these have not yet come into clinical practice ( 27 , 28 ). In membranous nephropathy, the highly specific anti-phospholipase A2 receptor antibody test has the potential to mitigate the requirement for renal biopsy and exposing individuals to the hazards associated ( 29 ). If such a biomarker for IgAN became integrated into clinical practice, diagnostic and prognostic approaches may need to adapt towards more non-invasive methods. The outcomes associated with IgAN are heterogeneous, therefore identifying high risk individuals who require close monitoring and treatment is challenging. This review is intended to assist clinicians in selecting the most accurate tool to provide effective and tailored treatment to individuals affected by IgAN. Abbreviations AUC Area under the curve CKD Chronic kidney disease eGFR Estimated glomerular filtration rate ESRD End-stage renal disease GRADE Grades of Recommendation, Assessment, Development and Evaluation Working Group KDIGO Kidney disease improving global outcomes KFRE Kidney failure risk equation IgAN Immunoglobulin A Nephropathy IRP IgAN Risk Prediction tool MEST-C Mesangial hypercellularity, Endocapillary hypercellularity, Segmental sclerosis, Tubular atrophy/interstitial fibrosis, Crescents PROBAST Prediction model Risk of Bias Assessment tool OC Oxford classification RRT Renal replacement therapies Declarations Ethics approval and consent to participate: not applicable Consent for publication: all authors have consented to this publication Availability of data and materials: not applicable Competing interests: none to declare Funding: MT is supported by a clinical fellowship award from the Northern Ireland Kidney Research Fund. This organisation did not have any involvement in developing the research protocol. Authors Contributions Concept, first reviewer and original manuscript: MT Second reviewer: RF Guarantor of review: APM Supervision and corrections: MQ, CH, CON, APM Acknowledgements: The authors would like to thank university librarians Richard Fallis and Angela Thompson for their assistance in devising the search strategy. References Rodrigues JC, Haas M, Reich HN. IgA nephropathy. Clin J Am Soc Nephrol. 2017;12(4):677–86. Coppo R, D’Arrigo G, Tripepi G, Russo ML, Roberts ISD, Bellur S, et al. Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update. Nephrol Dial Transplant. 2020 Jun 1;35(6):1002–9. Knoop T, Vikse BE, Mwakimonga A, Leh S, Bjørneklett R. Long-term outcome in 145 patients with assumed benign immunoglobulin A nephropathy. Nephrol Dial Transplant. 2017 Nov 1;32(11):1841–50. Pitcher D, Braddon F, Hendry B, Mercer A, Osmaston K, Saleem MA, et al. Long-Term Outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023 Jun 1;18(6):727–38. Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int [Internet]. 2021 Oct;100(4):S1–276. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0085253821005627 Cheung CK, Rajasekaran A, Barratt J, Rizk D v. An Update on the Current State of Management and Clinical Trials for IgA Nephropathy. J Clin Med. 2021 Jun 4;10(11):2493. Gentile M, Sanchez-Russo L, Riella L V, Verlato A, Manrique J, Granata S, et al. Immune abnormalities in IgA nephropathy. Clin Kidney J. 2023 Jun 30;16(7):1059–79. Rauen T, Wied S, Fitzner C, Eitner F, Sommerer C, Zeier M, et al. After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy. Kidney Int. 2020 Oct;98(4):1044–52. Lv J, Zhang H, Perkovic V. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy. JAMA. 2017;318(5):432–42. Tangri N, Grams ME, Levey AS, Coresh J, Appel LJ, Astor BC, et al. Multinational assessment of accuracy of equations for predicting risk of kidney failure a meta-analysis. JAMA. 2016 Jan 12;315(2):164–74. Barbour SJ, Coppo R, Zhang H, Liu ZH, Suzuki Y, Matsuzaki K, et al. Evaluating a New International Risk-Prediction Tool in IgA Nephropathy. JAMA Intern Med. 2019 Jul 1;179(7). Roberts ISD, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, et al. The Oxford classification of IgA nephropathy: Pathology definitions, correlations, and reproducibility. Kidney Int. 2009 Sep;76(5):546–56. Rottenstreich A. Bleeding Risk Assessment and the Role of Primary Hemostasis Screening in Patients Undergoing Kidney Biopsy. Isr Med Assoc J. 2018;20(August):499–503. Charu V, O’Shaughnessy MM, Chertow GM, Kambham N. Percutaneous Kidney Biopsy and the Utilization of Blood Transfusion and Renal Angiography Among Hospitalized Adults. Kidney Int Rep. 2019 Oct 1;4(10):1435–45. Bandari J, Fuller TW, Turner II RM, D’Agostino LA. Renal biopsy for medical renal disease: indications and contraindications. Can J Urol. 2016;23(1):8121–6. Sumida K, Nadkarni GN, Grams ME, Sang Y, Ballew SH, Coresh J, et al. Conversion of urine protein–creatinine ratio or urine dipstick protein to urine albumin–creatinine ratio for use in chronic kidney disease screening and prognosis: An individual participant–based meta-analysis. Ann Intern Med. 2020 Sep 15;173(6):426–35. Moons KGM, Wolff RF, Riley RD, Whiting PF, Westwood M, Collins GS, et al. PROBAST: A tool to assess risk of bias and applicability of prediction model studies: Explanation and elaboration. Ann Intern Med. 2019 Jan 1;170(1):W1–33. Ahmed I, Sutton AJ, Riley RD. Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: A database survey. BMJ . 2012 Jan 3;344(7762). Iorio A, Spencer FA, Falavigna M, Alba C, Lang E, Burnand B, et al. Use of GRADE for assessment of evidence about prognosis: Rating confidence in estimates of event rates in broad categories of patients. BMJ. 2015 Mar 16;350(h870). Foreman KJ, Marquez N, Dolgert A, Fukutaki K, Fullman N, McGaughey M, et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016–40 for 195 countries and territories. Lancet. 2018 Nov 10;392(10159):2052–90. Jarrick S, Lundberg S, Welander A, Carrero JJ, Höijer J, Bottai M, et al. Mortality in IgA nephropathy: A nationwide population-based cohort study. J Am Soc Nephrol. 2019 May 1;30(5):866–76. Chronic kidney disease: assessment and management NICE guideline [Internet]. 2021. Available from: www.nice.org.uk/guidance/ng203 Cattran DC, Coppo R, Cook HT, Feehally J, Roberts ISD, Troyanov S, et al. The Oxford classification of IgA nephropathy: Rationale, clinicopathological correlations, and classification. Kidney Int. 2009 Sep;76(5):534–45. Coppo R, Troyanov S, Bellur S, Cattran D, Cook HT, Feehally J, et al. Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments. Kidney Int. 2014 Jan 1;86(4):828–36. Howie AJ, Lalayiannis A. Systematic Review of the Oxford Classification of IgA Nephropathy: Reproducibility and Prognostic Value. Kidney360. 2023;June 26(Online ahead of print.). Boyd JK, Cheung CK, Molyneux K, Feehally J, Barratt J. An update on the pathogenesis and treatment of IgA nephropathy. Kidney Int. 2012 May;81(9):833–43. Coppo R. Biomarkers and targeted new therapies for IgA nephropathy. Pediatr Nephrol. 2017 May;32(5):725–31. Chen P, Yu G, Zhang X, Xie X, Wang J, Shi S, et al. Plasma galactose-deficient IgA1 and C3 and CKD progression in IgA nephropathy. Clin J Am Soc Nephrol. 2019 Oct 7;14(10):1458–65. Beck LH, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-Type Phospholipase A 2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy. N Engl J Med. 2009;1(2):11–21. Supplementary Files PRISMAPchecklistcompleted.docx Cite Share Download PDF Status: Published Journal Publication published 04 May, 2024 Read the published version in Systematic Reviews → Version 1 posted Editorial decision: Major revision 25 Jan, 2024 Reviewers agreed at journal 04 Jan, 2024 Reviewers invited by journal 04 Jan, 2024 Editor assigned by journal 16 Nov, 2023 First submitted to journal 10 Aug, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3252590","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":265367355,"identity":"a9977d5c-a029-43a2-8951-d752aae398d2","order_by":0,"name":"Michael Toal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYLCCBwYScgwMPBCOBEHlbECcUGBhTKqWDxWJDURr0Z3ffPBDgoFEet+N3AMMP2oYEmc2ENBidowtWQKoJXfmjbwExp5jDImzCdlidozHAKxlw40cAwbeBobEeURoMf4BcpgBUAvjXyK1mIFsSQBpYQbZQoTD0tIsgFoMZ555l3BY5piEMWHvHz58+MaHP3XyfMdzDz58U2MjO+MAIWvg4AAYEY5IVC2jYBSMglEwCrACANkRQCONR61DAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-1690-9206","institution":"Queen's University Belfast","correspondingAuthor":true,"prefix":"","firstName":"Michael","middleName":"","lastName":"Toal","suffix":""},{"id":265367356,"identity":"4f92d8d6-f2aa-402a-8a99-0b3f5d18c5d8","order_by":1,"name":"Ruth Fergie","email":"","orcid":"","institution":"Queen's University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Ruth","middleName":"","lastName":"Fergie","suffix":""},{"id":265367357,"identity":"1e956b20-9c41-407e-ba90-3c6169b8f7ec","order_by":2,"name":"Michael Quinn","email":"","orcid":"","institution":"Queen's University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Quinn","suffix":""},{"id":265367358,"identity":"bf0c25c6-6b54-471a-bb42-b605242595b6","order_by":3,"name":"Christopher Hill","email":"","orcid":"","institution":"Belfast City Hospital Health and Social Services Trust: HCS Belfast Health and Social Care Trust","correspondingAuthor":false,"prefix":"","firstName":"Christopher","middleName":"","lastName":"Hill","suffix":""},{"id":265367359,"identity":"6be48016-d902-480c-931c-bf0f2247ce8d","order_by":4,"name":"Ciaran O'Neill","email":"","orcid":"","institution":"Queen's University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Ciaran","middleName":"","lastName":"O'Neill","suffix":""},{"id":265367360,"identity":"96c3ed64-3bbf-430e-bb5d-ebc2321b85cd","order_by":5,"name":"Alexander P Maxwell","email":"","orcid":"","institution":"Queen's University Belfast","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"P","lastName":"Maxwell","suffix":""}],"badges":[],"createdAt":"2023-08-10 14:14:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3252590/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3252590/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13643-024-02543-y","type":"published","date":"2024-05-04T19:57:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":56042830,"identity":"14c80364-5b26-4979-ae60-e70c34b51698","added_by":"auto","created_at":"2024-05-07 20:07:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":359500,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3252590/v1/30f2af50-cb20-484c-a4b2-3a34bc776f80.pdf"},{"id":49303969,"identity":"3cee6ff7-ead6-47cc-9ebb-49bb686a8c85","added_by":"auto","created_at":"2024-01-08 10:45:23","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":35058,"visible":true,"origin":"","legend":"","description":"","filename":"PRISMAPchecklistcompleted.docx","url":"https://assets-eu.researchsquare.com/files/rs-3252590/v1/0faf549a1f5665fd57205920.docx"}],"financialInterests":"","formattedTitle":"Protocol for a Systematic review of the application of the Kidney Failure Risk Equation and Oxford classification in estimating prognosis in IgA Nephropathy","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eIgA Nephropathy (IgAN) was first described by Hinglais and Berger in 1968 and is the most common form of primary glomerulonephritis worldwide(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The disease course of IgAN is heterogeneous with up to 30\u0026ndash;50% of affected individuals progressing to end-stage renal disease (ESRD) within five to ten years, whilst others have stable disease without significant progression over decades(\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Identifying individuals at the highest risk for progression to ESRD is challenging and the 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines highlighted risk stratification as a high priority for research in IgAN (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). The understanding of the pathophysiology of IgAN is constantly evolving and there are multiple therapeutic trials ongoing to find novel agents to stabilise patients at the highest risk of progression to ESRD (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Previous therapeutic trials in IgAN have been limited by recruitment of individuals at lower risk of progression to ESRD. Timely risk stratification to identify persons most likely to progress to ESRD will allow for more targeted clinical trials in the future (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe Kidney Failure Risk Equation (KFRE) (Table.1) was developed from a Canadian cohort and validated in a multi-national cohort of over 700,000 patients (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). This equation, using either four or eight variables, has demonstrated excellent discrimination and can accurately predict the risk of kidney failure at a two- or five-year horizon for all forms of chronic kidney disease (CKD). The IgAN Risk Prediction (IRP) tool was developed specifically for IgAN and incorporates the Oxford classification (OC) into the risk evaluation (Table\u0026nbsp;1.) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). OC is a histopathological scoring system developed to facilitate estimations of prognosis by classifying the degree of pathological abnormalities demonstrated on renal biopsy examination and is specific to IgAN (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). A renal biopsy is a crucial investigation in nephrology which facilitates the diagnosis of kidney diseases, estimation of prognosis and guides treatment (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). It is however an invasive procedure, with a significant risk of bleeding, requiring intervention in around 1 in 200 procedures in some case series (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Whilst both the KFRE and IRP have been externally validated, there is limited evidence to determine which method provides optimal prognostic assessment, therefore it is unknown if a renal biopsy improves the accuracy of this estimation. Affected individuals will often have multiple blood and urine tests over a follow-up period, however an invasive renal biopsy is seldom repeated. The OC will therefore provide a snapshot of disease activity, but does not capture the nuances and dynamic changes in disease trajectory, which can be routinely tracked with blood and urine tests. If the OC did not provide superior predictive accuracy compared to clinical features alone, the international community may reconsider the utility of the OC in renal biopsy reports of IgAN.\u003c/p\u003e \u003cp\u003e\u003cimg 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\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 1. Parameters required for each prognostic algorithm\u003c/p\u003e\n\u003cp\u003e*Proteinuria expressed as urinary albumin:creatinine ratio in KFRE and grams/day in IRP. **Obtained by renal biopsy. \u0026nbsp;KFRE: Kidney failure risk equation, OC: Oxford classification, IRP: IgAN Risk Prediction tool, eGFR: estimated glomerular filtration rate (ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e) , MAP : mean arterial pressure (mmHg), M: mesangial hypercellularity score, E: endocapillary hypercellularity score, S: segmental sclerosis score, T: tubular atrophy/interstitial fibrosis score, C: crescents score, RASB: renin-angiotensin system blockers\u003c/p\u003e \u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eThe research question for this review is: Does the Kidney Failure Risk Equation provide more accurate prediction of disease progression and kidney failure than the Oxford Classification (MEST-C score) in patients with IgAN?\u003c/p\u003e \u003c/div\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cp\u003eStudies that will be considered for inclusion in the review will be those which investigate a population or sub-group of patients diagnosed with IgAN on native renal biopsy and compare the prognostic accuracy of the Kidney Failure Risk Equation (KFRE) with an alternative prediction tool which incorporates the OC of histopathological assessment. The inclusion criteria for study outcomes will include progression of disease as defined by a reduction in estimated glomerular filtration rate (eGFR), rise in serum creatinine or kidney failure events as defined by an eGFR below 15 ml/min/1.73m\u003csup\u003e2\u003c/sup\u003e or use of renal replacement therapies (kidney transplantation or dialysis). The KFRE was first published in 2011, therefore studies from 2011 onwards will be considered for inclusion. Research subjects must be humans only. Eligibility criteria will not be limited to the English language and translation services will be used where appropriate. Publications will not be limited to journal articles and appropriate grey-literature will be considered eligible.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInformation sources\u003c/h2\u003e \u003cp\u003eThe following databases will be searched: Medline, EMBASE, Scopus, PubMed, Web of Science and Google (including Google Scholar).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eThe following search strategy will be applied:\u003c/p\u003e\u003cp\u003e1. \u0026ldquo;IgA Nephropathy\u0026rdquo; OR \u0026ldquo;Immunoglobulin A Nephropathy\u0026rdquo; OR \u0026ldquo;Glomerulonephritis, IGA\u0026rdquo; OR \u0026ldquo;Berger\u0026rsquo;s disease\u0026rdquo;\u003c/p\u003e \u003cp\u003e2. \u0026ldquo;Kidney Failure Risk Equation\u0026rdquo; OR \u0026ldquo;KFRE\u0026rdquo;\u003c/p\u003e \u003cp\u003e3. \u0026ldquo;Oxford\u0026rdquo; OR \u0026ldquo;MEST\u0026rdquo; OR \u0026ldquo;MEST-C\u0026rdquo;\u003c/p\u003e \u003cp\u003e4. \u0026ldquo;Disease progression\u0026rdquo; OR \u0026ldquo;Prognostic Assessment\u0026rdquo; OR \u0026ldquo;Risk Assessment\u0026rdquo;\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003cp\u003e5. 1 AND 2 AND 3 AND 4\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003eStudy records\u003c/h2\u003e \u003cp\u003eStudy records will be imported into reference management software (Rayyan\u0026trade;) which will remove duplicates and maintain a library of eligible studies. Screening of studies will be performed independently by the corresponding author (MT) and a second reviewer (RF). Any disagreements regarding suitability of studies will be discussed amongst the two reviewers and a third reviewer (APM), if necessary. Studies will initially be screened by title, then by abstract, then by reviewing the full-text article.\u003c/p\u003e \u003cp\u003eData will be extracted using a standardised form for collating study data. The study authors will be contacted by MT if crucial data is missing in the eligible studies that prohibits analysis.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eData Items\u003c/h2\u003e \u003cp\u003eThe review will be limited to patients with a diagnosis of IgAN, proven by a native renal biopsy. Patients with all other diagnoses based on renal biopsy will not be included, nor will patients with other forms of renal diseases, not diagnosed by renal biopsy. Any international cohort or sub-group will be considered eligible. Measurements of proteinuria will be converted into standardised units of albumin: creatinine ratio where required(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes and prioritisation\u003c/h2\u003e \u003cp\u003eStudies that include measurements of discrimination and calibration such as the area under the curve (AUC) of the receiver-operating curve or Harrell\u0026rsquo;s C-statistic will be included. Studies that compare predicted outcomes with observed outcomes will also be eligible for inclusion. Excluded studies will be those which do not report either of the aforementioned outcomes and are limited to other parameters such as relative risk and hazard ratios without a direct measure of classification. Follow up time of the cohort equal to or beyond two years from renal biopsy will be considered to be appropriate for inclusion in the analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias in individual studies\u003c/h2\u003e \u003cp\u003eRisk of bias will be assessed in any study meeting the inclusion criteria using \u003cb\u003ePROBAST\u003c/b\u003e (\u003cb\u003eP\u003c/b\u003erediction model \u003cb\u003eR\u003c/b\u003eisk \u003cb\u003eO\u003c/b\u003ef \u003cb\u003eB\u003c/b\u003eias \u003cb\u003eAS\u003c/b\u003esessment \u003cb\u003eT\u003c/b\u003eool) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). This tool was designed specifically for studies of prognostic assessment, as many different prediction methods can be available for single disease entities. It comprises of twenty signalling questions across four domains: participants, predictors, outcomes and analysis. For each domain, the reviewer is required to determine a risk of bias and a level of concern regarding the study\u0026rsquo;s applicability to the review question. Two independent reviewers (MT and RF) will use PROBAST to assess risk of bias, with APM acting as a third reviewer if required.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eData Synthesis\u003c/h2\u003e \u003cp\u003eData from eligible studies will be collated for meta-analysis if possible. The number of participants in each cohort study will be described and their geographical location will be included. The baseline characteristics of all participants will be described in terms of age, gender and measurements of kidney function such as eGFR, serum creatinine and proteinuria. The long-term outcomes of each cohort will also be described- specifically detailing incidence of ESRD. The prognostic accuracy of tools under investigation will be described using Harrell\u0026rsquo;s c-index, a derivation from the AUC. These results will be collated into graphical form for comparison. Heterogeneity in studies will be assessed using the I\u003csup\u003e2\u003c/sup\u003e method. A subgroup analysis will investigate prognostic accuracy for studies which included other outcome measures such as a decline in eGFR over time of 30%, 40% or 50%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eMeta-bias\u003c/h2\u003e \u003cp\u003eThe risk of publication bias will be examined by evaluation of individual patient data provided by studies. If this is not adequately described in a paper, the authors will be contacted in order to ensure there is transparency of results without selective reporting. A funnel plot will be employed to investigate the risk of publication bias by demonstration of asymmetry, with a p\u0026thinsp;\u0026lt;\u0026thinsp;0.10 considered to be significant(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Reviewer selection bias will be addressed by two independent reviewers performing an identical search strategy, with a third reviewer available to resolve any inconclusive results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eConfidence in cumulative evidence\u003c/h2\u003e \u003cp\u003eThe certainty in the evidence presented will be analysed using the GRADE approach. This assessment analyses the quality of five domains: risk of bias, inconsistency, imprecision, indirectness and publication bias (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). This system will be applied to each described outcome, detailing the authors\u0026rsquo; confidence in each conclusion. Recommendations will be given for future studies to address the current gaps in the literature.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe burden of CKD is increasing globally and is projected to become the 5th most common cause of years of life lost by 2040 (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). IgAN is a common cause of CKD which has been observed to progress to ESRD in up to 50% of cases within 5 years follow-up in a UK cohort study (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The increased risk of mortality has also been observed specifically in an IgAN cohort study, with progression to ESRD associated with a threefold increase in mortality within the follow-up period (median: 13.6 years) (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). There are numerous available risk prediction tools for kidney disease, however the KFRE and OC were selected for this review as they have been extensively validated and incorporated into UK and international guidelines (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe OC has been adopted internationally since its conception in 2009, however the reported prognostic value of each component of the MEST-C score varies in the literature and poor reproducibility between reporting pathologists has been identified as a significant limitation (\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). The KFRE is based on age, sex, location and automated laboratory values, therefore it may have increased reproducibility, but its application in IgAN has not been investigated in detail.\u003c/p\u003e \u003cp\u003eAs the understanding of the pathophysiology in IgAN continues to improve, therapeutic targets are likely to become more readily available to manage individuals at higher risk of progression (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Several biomarkers have been identified in IgAN for diagnosis and prognostic assessment, however these have not yet come into clinical practice (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In membranous nephropathy, the highly specific anti-phospholipase A2 receptor antibody test has the potential to mitigate the requirement for renal biopsy and exposing individuals to the hazards associated (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). If such a biomarker for IgAN became integrated into clinical practice, diagnostic and prognostic approaches may need to adapt towards more non-invasive methods.\u003c/p\u003e \u003cp\u003eThe outcomes associated with IgAN are heterogeneous, therefore identifying high risk individuals who require close monitoring and treatment is challenging. This review is intended to assist clinicians in selecting the most accurate tool to provide effective and tailored treatment to individuals affected by IgAN.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eArea under the curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCKD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eeGFR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEstimated glomerular filtration rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eESRD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEnd-stage renal disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGRADE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGrades of Recommendation, Assessment, Development and Evaluation Working Group\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eKDIGO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eKidney disease improving global outcomes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eKFRE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eKidney failure risk equation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIgAN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eImmunoglobulin A Nephropathy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIgAN Risk Prediction tool\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMEST-C\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMesangial hypercellularity, Endocapillary hypercellularity, Segmental sclerosis, Tubular atrophy/interstitial fibrosis, Crescents\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePROBAST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePrediction model Risk of Bias Assessment tool\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOxford classification\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRenal replacement therapies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: not applicable\u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication: all authors have consented to this publication\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: not applicable\u003c/p\u003e\n\u003cp\u003eCompeting interests: none to declare\u003c/p\u003e\n\u003cp\u003eFunding:\u0026nbsp;MT is supported by a clinical fellowship award from the Northern Ireland Kidney Research Fund. This organisation did not have any involvement in developing the research protocol.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors Contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConcept, first reviewer and original manuscript: MT\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSecond reviewer: RF\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eGuarantor of review: APM\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSupervision and corrections: \u0026nbsp;MQ, CH, CON, APM\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAcknowledgements: The authors would like to thank university librarians Richard Fallis and Angela Thompson for their assistance in devising the search strategy.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRodrigues JC, Haas M, Reich HN. IgA nephropathy. Clin J Am Soc Nephrol. 2017;12(4):677\u0026ndash;86. \u003c/li\u003e\n\u003cli\u003eCoppo R, D\u0026rsquo;Arrigo G, Tripepi G, Russo ML, Roberts ISD, Bellur S, et al. Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update. Nephrol Dial Transplant. 2020 Jun 1;35(6):1002\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eKnoop T, Vikse BE, Mwakimonga A, Leh S, Bj\u0026oslash;rneklett R. Long-term outcome in 145 patients with assumed benign immunoglobulin A nephropathy. Nephrol Dial Transplant. 2017 Nov 1;32(11):1841\u0026ndash;50. \u003c/li\u003e\n\u003cli\u003ePitcher D, Braddon F, Hendry B, Mercer A, Osmaston K, Saleem MA, et al. Long-Term Outcomes in IgA Nephropathy. Clin J Am Soc Nephrol. 2023 Jun 1;18(6):727\u0026ndash;38. \u003c/li\u003e\n\u003cli\u003eRovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int [Internet]. 2021 Oct;100(4):S1\u0026ndash;276. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0085253821005627\u003c/li\u003e\n\u003cli\u003eCheung CK, Rajasekaran A, Barratt J, Rizk D v. An Update on the Current State of Management and Clinical Trials for IgA Nephropathy. J Clin Med. 2021 Jun 4;10(11):2493. \u003c/li\u003e\n\u003cli\u003eGentile M, Sanchez-Russo L, Riella L V, Verlato A, Manrique J, Granata S, et al. Immune abnormalities in IgA nephropathy. Clin Kidney J. 2023 Jun 30;16(7):1059\u0026ndash;79. \u003c/li\u003e\n\u003cli\u003eRauen T, Wied S, Fitzner C, Eitner F, Sommerer C, Zeier M, et al. After ten years of follow-up, no difference between supportive care plus immunosuppression and supportive care alone in IgA nephropathy. Kidney Int. 2020 Oct;98(4):1044\u0026ndash;52. \u003c/li\u003e\n\u003cli\u003eLv J, Zhang H, Perkovic V. Effect of Oral Methylprednisolone on Clinical Outcomes in Patients With IgA Nephropathy. JAMA. 2017;318(5):432\u0026ndash;42. \u003c/li\u003e\n\u003cli\u003eTangri N, Grams ME, Levey AS, Coresh J, Appel LJ, Astor BC, et al. Multinational assessment of accuracy of equations for predicting risk of kidney failure a meta-analysis. JAMA. 2016 Jan 12;315(2):164\u0026ndash;74. \u003c/li\u003e\n\u003cli\u003eBarbour SJ, Coppo R, Zhang H, Liu ZH, Suzuki Y, Matsuzaki K, et al. Evaluating a New International Risk-Prediction Tool in IgA Nephropathy. JAMA Intern Med. 2019 Jul 1;179(7). \u003c/li\u003e\n\u003cli\u003eRoberts ISD, Cook HT, Troyanov S, Alpers CE, Amore A, Barratt J, et al. The Oxford classification of IgA nephropathy: Pathology definitions, correlations, and reproducibility. Kidney Int. 2009 Sep;76(5):546\u0026ndash;56. \u003c/li\u003e\n\u003cli\u003eRottenstreich A. Bleeding Risk Assessment and the Role of Primary Hemostasis Screening in Patients Undergoing Kidney Biopsy. Isr Med Assoc J. 2018;20(August):499\u0026ndash;503. \u003c/li\u003e\n\u003cli\u003eCharu V, O\u0026rsquo;Shaughnessy MM, Chertow GM, Kambham N. Percutaneous Kidney Biopsy and the Utilization of Blood Transfusion and Renal Angiography Among Hospitalized Adults. Kidney Int Rep. 2019 Oct 1;4(10):1435\u0026ndash;45. \u003c/li\u003e\n\u003cli\u003eBandari J, Fuller TW, Turner II RM, D\u0026rsquo;Agostino LA. Renal biopsy for medical renal disease: indications and contraindications. Can J Urol. 2016;23(1):8121\u0026ndash;6. \u003c/li\u003e\n\u003cli\u003eSumida K, Nadkarni GN, Grams ME, Sang Y, Ballew SH, Coresh J, et al. Conversion of urine protein\u0026ndash;creatinine ratio or urine dipstick protein to urine albumin\u0026ndash;creatinine ratio for use in chronic kidney disease screening and prognosis: An individual participant\u0026ndash;based meta-analysis. Ann Intern Med. 2020 Sep 15;173(6):426\u0026ndash;35. \u003c/li\u003e\n\u003cli\u003eMoons KGM, Wolff RF, Riley RD, Whiting PF, Westwood M, Collins GS, et al. PROBAST: A tool to assess risk of bias and applicability of prediction model studies: Explanation and elaboration. Ann Intern Med. 2019 Jan 1;170(1):W1\u0026ndash;33. \u003c/li\u003e\n\u003cli\u003eAhmed I, Sutton AJ, Riley RD. Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: A database survey. BMJ . 2012 Jan 3;344(7762). \u003c/li\u003e\n\u003cli\u003eIorio A, Spencer FA, Falavigna M, Alba C, Lang E, Burnand B, et al. Use of GRADE for assessment of evidence about prognosis: Rating confidence in estimates of event rates in broad categories of patients. BMJ. 2015 Mar 16;350(h870). \u003c/li\u003e\n\u003cli\u003eForeman KJ, Marquez N, Dolgert A, Fukutaki K, Fullman N, McGaughey M, et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016\u0026ndash;40 for 195 countries and territories. Lancet. 2018 Nov 10;392(10159):2052\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eJarrick S, Lundberg S, Welander A, Carrero JJ, H\u0026ouml;ijer J, Bottai M, et al. Mortality in IgA nephropathy: A nationwide population-based cohort study. J Am Soc Nephrol. 2019 May 1;30(5):866\u0026ndash;76. \u003c/li\u003e\n\u003cli\u003eChronic kidney disease: assessment and management NICE guideline [Internet]. 2021. Available from: www.nice.org.uk/guidance/ng203\u003c/li\u003e\n\u003cli\u003eCattran DC, Coppo R, Cook HT, Feehally J, Roberts ISD, Troyanov S, et al. The Oxford classification of IgA nephropathy: Rationale, clinicopathological correlations, and classification. Kidney Int. 2009 Sep;76(5):534\u0026ndash;45. \u003c/li\u003e\n\u003cli\u003eCoppo R, Troyanov S, Bellur S, Cattran D, Cook HT, Feehally J, et al. Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments. Kidney Int. 2014 Jan 1;86(4):828\u0026ndash;36. \u003c/li\u003e\n\u003cli\u003eHowie AJ, Lalayiannis A. Systematic Review of the Oxford Classification of IgA Nephropathy: Reproducibility and Prognostic Value. Kidney360. 2023;June 26(Online ahead of print.). \u003c/li\u003e\n\u003cli\u003eBoyd JK, Cheung CK, Molyneux K, Feehally J, Barratt J. An update on the pathogenesis and treatment of IgA nephropathy. Kidney Int. 2012 May;81(9):833\u0026ndash;43. \u003c/li\u003e\n\u003cli\u003eCoppo R. Biomarkers and targeted new therapies for IgA nephropathy. Pediatr Nephrol. 2017 May;32(5):725\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eChen P, Yu G, Zhang X, Xie X, Wang J, Shi S, et al. Plasma galactose-deficient IgA1 and C3 and CKD progression in IgA nephropathy. Clin J Am Soc Nephrol. 2019 Oct 7;14(10):1458\u0026ndash;65. \u003c/li\u003e\n\u003cli\u003eBeck LH, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-Type Phospholipase A 2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy. N Engl J Med. 2009;1(2):11\u0026ndash;21. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"IgA Nephropathy, Glomerulonephritis, Renal biopsy, Prognostic assessment, Prognosis, Risk assessment, Prediction tool, Kidney failure risk equation, Oxford classification","lastPublishedDoi":"10.21203/rs.3.rs-3252590/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3252590/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIgA Nephropathy (IgAN) is a common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Outcomes are highly variable and predicting risk of disease progression at an individual level is challenging. Accurate risk stratification is important to identify individuals who are most likely to benefit from treatment. The Kidney Failure Risk Equation (KFRE) has been extensively validated in CKD populations and predicts the risk of ESRD at two and five years using non-invasive tests, however it\u0026rsquo;s predictive performance in IgAN is unknown. The Oxford Classification (OC) describes pathological features demonstrated on renal biopsy that are associated with adverse clinical outcomes that may also inform prognosis. The objective of this systematic review is to compare the KFRE with the OC in determining prognosis in IgAN.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA systematic review will be conducted and reported in line with PRISMA guidelines (PRISMA-P checklist attached as supplement). Inclusion criteria will be cohort studies that apply the KFRE or OC to determine the risk of CKD progression or ESRD in individuals with IgAN. Multiple databases will be searched in duplicate to identify relevant studies, which will be screened first by title, then by abstract and then by full text analysis. Results will be collated for comparison. Risk of bias and confidence assessments will be conducted independently by two reviewers, with a third reviewer available if required.\u003c/p\u003e\u003cp\u003e\u003cb\u003eDiscussion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eIdentifying individuals at the highest risk of progression to ESRD is challenging in IgAN, due to the heterogeneity of clinical outcomes. Risk prediction tools have been developed to guide clinicians; however it is imperative that these aids are accurate and reproducible. The OC is based on observations made by specialist renal pathologists and may be open to observer bias, therefore the utility of prediction models incorporating this classification may be diminished, particularly as in the future novel biomarkers may be incorporated into clinical practice.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSystematic Review registration:\u003c/b\u003e\u003c/p\u003e \u003cp\u003eProspero no. CRD42022364569\u003c/p\u003e","manuscriptTitle":"Protocol for a Systematic review of the application of the Kidney Failure Risk Equation and Oxford classification in estimating prognosis in IgA Nephropathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-08 10:45:18","doi":"10.21203/rs.3.rs-3252590/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2024-01-25T21:03:33+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-01-04T13:14:02+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-04T11:10:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-11-16T13:56:20+00:00","index":"","fulltext":""},{"type":"submitted","content":"Systematic Reviews","date":"2023-08-10T10:13:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4bc962ce-3b99-40e4-a083-bfb5b11a1913","owner":[],"postedDate":"January 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-07T20:01:35+00:00","versionOfRecord":{"articleIdentity":"rs-3252590","link":"https://doi.org/10.1186/s13643-024-02543-y","journal":{"identity":"systematic-reviews","isVorOnly":false,"title":"Systematic Reviews"},"publishedOn":"2024-05-04 19:57:21","publishedOnDateReadable":"May 4th, 2024"},"versionCreatedAt":"2024-01-08 10:45:18","video":"","vorDoi":"10.1186/s13643-024-02543-y","vorDoiUrl":"https://doi.org/10.1186/s13643-024-02543-y","workflowStages":[]},"version":"v1","identity":"rs-3252590","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3252590","identity":"rs-3252590","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}