Clinical background

The disease and treatment burden

IgAN is the most common primary glomerulonephritis (GN) and frequent cause of renal failure worldwide (1). Therapeutic efforts to minimize progression and end-stage renal disease (dialysis) are urgently warranted but pharmaceutical immunosuppression employed in IgAN, the core therapeutic approach in inflammatory diseases, has become a highly controversial issue. This is reflected by the results of 2 randomized clinical trials (RCTs) that investigated the outcome in IgAN under the use of high-dose steroids and/or alternative IS substances (2, 3). While benefits of therapy are acknowledged, caution is exercised due to the risk of severe adverse events (AE) of therapy, and missing predictive parameters that might indicate a beneficial risk/harm ratio. It is important to mention that RCTs did not use histological parameters of IgAN to adjust for the opportunity of therapy benefits. In general, prognosis in GN is related to the ratio between acuity (of inflammation) and the presence of established fibrosis and scarring which cannot be reversed by IS therapy (4, 5). Clinical-pathological registries do show benefits when therapy is based on histological scores (6, 7) including the presence of glomerular crescents (8). However, a clinical significant crescent number threshold is under debate. Therefore, histological scores of IgAN use descriptive systems of crescent glomerular involvement, presence of inflammation and scarring (6, 7). Further, kidney biopsy is prone to sampling error, and multiple repeat biopsies are not feasible due to bleeding risks associated with this invasive procedure. These facts further underline the need for non-invasive biomarkers guiding personalized intervention in IgAN.

Personalised Medicine dimension of PersTIgAN

We propose the investigation of the value of urine proteome analysis in guiding personalized intervention in IgAN. Knowledge on disease specific proteomic changes, which can be detected in urine in a non-invasive way, enables early detection of disease (when irreversible structural damage has not occurred yet) and is expected to enable intervention in a personalized way (9). In addition, urine allows for multiple sampling, enabling non-invasive assessment of disease progression, but also of response to treatment. Proteomics can be used to (i) establish the diagnosis of IgAN, (ii) grade severity of inflammation, scarring and acuity (as a biological integral of these parameters), and (iii) evaluate therapeutic effects. The alternative, invasive repeated kidney biopsies, implies a frequently non-acceptable risk of complications. Of note: urine proteome data can be very well linked to changes observed in the tissue(10).

This personalized approach in therapy should enable targeting the already demonstrated therapeutic benefits of IS while avoiding undesired effects of therapy especially in those patients who will likely not respond to this treatment. For such discrimination regarding prognosis and expected therapy response in IgAN no marker or other guidance is currently available.

Unmet medical and patient need and the potential health impact

The outlined IgAN risk and therapy response classifier is intended to answer a major unmet clinical need in IgAN: to whom to apply individualized IS therapy on the basis of highly evident risk classification and therapy response prediction. Currently no tools reliably predict response to therapy in IgAN. This underlines an unmet clinical need for personalized strategies that will improve the management of IgAN patients. The early non-invasive stratification of patients to the right drug will enable timely personalised pharmacological interventions to reduce risk factors and promote a better quality of life. With this study we aim to assess if urinary proteomics/peptidomics can guide personalized intervention in IgAN patients. Accurate early identification and patient stratification for the best possible treatment of IgAN patients is expected to reduce the risk of end stage renal disease and mortality, hence reduce the burden associated with the management of IgAN patients on the limited health care resources. A recent publication indicated that urinary proteomics-guided routine in vitro diagnostics (IVD) will be cost-effective in patients with diabetic nephropathy (11), similar results were obtained when investigating the benefit of personalized intervention in IgAN, yet based on theoretical performance characteristics


References:  1. B. A. Julian, J. Novak, Curr. Opin. Nephrol. Hypertens. 13, 171 (2004).  2. T. Rauen et al., N. Engl. J. Med. 373, 2225 (2015).  3. J. Lv et al., JAMA 318, 432 (2017).  4. A. Bohle, S. kensen-Haen, G. H. von, Am. J. Nephrol. 7, 421 (1987).  5. R. A. Risdon, J. C. Sloper, H. E. De Wardener, Lancet 2, 363 (1968).  6. S. S. Bellur et al., Kidney Int. 91, 235 (2017).  7. S. H. Kang et al., Nephrol. Dial. Transplant. 27, 252 (2012).  8. S. J. Barbour et al., Kidney Int. 89, 167 (2016).  9. H. Mischak, Nephrol Dial Transplant 30, 532 (2015).  10. M. Krochmal et al., Sci. Rep. 7, 15160 (2017).  11. E. Critselis, A. Vlahou, V. Stel, R. L. Morton, Nephrol. Dial. Transplant. 33, 441 (2018).