Title: Assessing the utility and cost-effectiveness of anti-PLA2R for diagnosing patients with membranous nephropathy in clinical practice: a systematic review and evidence synthesis study
Funder: Department of Health and Social Care

Abstract: Introduction Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, with a significant burden on healthcare systems worldwide. In the majority of patients MN is an autoimmune disease (known as primary MN), which is associated with the autoantibody to the M-type phospholipase A2 receptor (PLA2R). There is now increasing evidence for the sensitivity and specificity of the anti-PLA2R antibody test as a tool to distinguish between primary and secondary MN (i.e. MN secondary to other diseases such as cancer), and to guide immunosuppression treatment decisions. There are currently no nationally standardised guidelines for the investigation and management of MN, and international guidelines are based on expert consensus due to the disparate nature of the evidence available and lack of prospective randomly controlled trials (RCTs) in this area. Renal biopsy remains the gold standard method of diagnosis, meaning patients are routinely subjected to an invasive procedure that comes with inherent risks (notably bleeding and infection) and high cost. Aims This study aims to investigate the utility and cost-effectiveness of the anti-PLA2R test for diagnosing patients with primary MN. The specific objectives are to: Review the evidence on the diagnostic accuracy, clinical utility and cost-effectiveness of the anti-PLA2R test. Create an economic model to either justify or disapprove the notion of solely relying on serum anti-PLA2R ELISA for diagnosing primary MN compared to standard practice of renal biopsy for all. We aim to balance the financial burden on the NHS system and patient safety and health outcomes using that model. Consult nephrologists and patients on their experiences of diagnosing/ being diagnosed with MN, and identify any perceived barriers to the broader use of the biomarker in standard care practice. Methodology The project aims will be answered via three corresponding work packages (WP). In WP1, a systematic review will be conducted to collate evidence on the diagnostic accuracy, clinical utility and cost-effectiveness of the anti-PLA2R test for guiding the diagnosis of primary MN. In WP2, a de novo model-based economic evaluation will be undertaken to assess if anti-PLA2R-guided renal biopsy is a cost-effective strategy for patients with suspected MN, compared to standard care (biopsy for all). In WP3, clinician and patient consultations will be conducted to ascertain patient and clinician opinions on the suggested use of the test, and identify potential barriers to implementing the anti-PLA2R test as a part of standard care. Outcomes By systematically evaluating the clinical and cost-effectiveness of the anti-PLA2R test, this project has the potential to improve patient health outcomes and provide significant cost savings to the healthcare service. If the test is found to be clinically and economically effective, the results will be used to develop clinical guidelines for diagnosing MN, drawing on existing affiliations with national and international clinical networks. Where a definitive answer as to the clinical- and cost-effectiveness of anti-PLA2R is not possible due to remaining uncertainties in the evidence base, the findings will be used to identify future research requirements.

Lay abstract: Membranous nephropathy is one of the main causes of kidney disease in adults worldwide. Most patients get better with treatment but about a third will not and will need dialysis or a kidney transplant. The most common cause of membranous nephropathy is an autoimmune disease, where the body s immune system attacks the kidney. This is called primary membranous nephropathy . It may also result from damage caused by other illnesses, such as cancer. In these cases, the disease is called secondary membranous nephropathy . At the moment, a kidney biopsy is used to find out if patients have the disease. This involves removing a small part of the kidney, which can be painful, may cause bleeding, and can lead to delays in diagnosis and treatment. In the last 10 years, the part of the immune system that damages the kidney in primary disease (called the anti-PLA2R antibody) has been discovered. A simple blood test can now be used to detect this antibody, and this could be used to identify the disease. This blood test could save many people from having unnecessary, painful and costly biopsies, and may also help them get treated more quickly. In this project we will gather the results from international studies that have already taken place, to find out how good the blood test is at identifying patients with primary membranous nephropathy. We will then build a computer model to capture all the costs and health effects involved with using the test, compared to having a biopsy. This model will help to show if the test is of benefit and whether it is good value for money for the NHS. We will also ask patients and their doctors about using the test in practice. We will present our findings to national and international committees and experts. If the antibody test is found to be clinically useful and provides value for money to the NHS, then we will use the results to create safe and useful clinical guidelines for using the test. Based on this, we would use the blood test instead of a biopsy to treat people more quickly and avoid side effects. This could also save the NHS a large amount of money every year, by reducing unnecessary operations and treatment delays. Our project team includes members from Manchester with clinical expertise in diagnosing membranous nephropathy, and members from Leeds with expertise in economic modelling and test evaluations. With this expert team, the results of this study could be used to benefit patients and save costs for the NHS, and healthcare systems worldwide.

Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: RENAL AND UROGENITAL