Effective therapies to manage antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis have transformed a fatal disease into a relapsing-remitting disease. Predictors of relapses, identified in numerous studies, include ear, nose, and throat involvement; proteinase 3 (PR3)-ANCA positivity; granulomatosis with polyangiitis as the disease phenotype; preserved kidney function; prior relapse; and the use of maintenance agents other than rituximab (1).
Analyses of patients recruited into the earlier European Vasculitis Society trials, who were followed for over 5 years, indicated that the occurrence of a renal relapse significantly predicted the risk of kidney failure with a subhazard ratio of almost 9 (2). This finding clearly underlines the importance to avoid disease relapses, and especially renal relapses, to limit the loss of nephrons and thus reduce the risk of kidney failure. A candidate biomarker should ideally associate with disease activity and should become detectable or increase in the months before a relapse occurs. Furthermore, it needs to distinguish risk of disease activity of ANCA-glomerulonephritis (GN) from potential differential diagnoses, such as acute kidney injury (AKI) due to infectious complications or drug-induced AKI. In addition, a candidate biomarker would ideally be easily measurable, and its predictive capacity should be confirmed by independent research groups.
Urinary soluble CD163 (sCD163) has emerged as a promising biomarker, with the ability to distinguish between active disease and remission, active ANCA-GN and other glomerular diseases, and AKI and different causes and to predict renal relapse. At a diagnostic cutoff of 253 ng/mmol, a 2021 study by Moran et al. (3) reported an area under the curve of 0.95, with a sensitivity of 96.8% and a specificity of 86.8% to detect renal relapse. In a more recent study by Sonnemann et al. (4), flow cytometry assessment of urinary T cells of 95 patients, of whom 52 had active ANCA-GN, revealed that CD3+, CD4+, and regulatory T cell counts were significantly higher during phases of active renal disease compared with urine samples obtained during remission. Detection of CD3+ T cells and regulatory T cells outperformed other experimental markers such as urinary sCD163, monocyte chemoattractant protein 1, and complement C5a in the urine, whereas a dipstick analysis showed a more robust diagnostic performance. In a follow-up study—the prospective PRE-FLARED (Urinary T Lymphocytes Predict Renal Flares in Patients With Inactive ANCA-Associated Glomerulonephritis) study—the authors investigated whether urinary T lymphocyte assessment would predict renal flares within 6 months of assessment. For this purpose, 102 patients in remission were recruited. Patients with a subsequent renal relapse (n = 10; 9.8%) had higher detectable urinary CD4+ lymphocytes (811 cells per 100 mL of urine) compared with those with a stable remission (38 cells per 100 mL of urine) by using a cutoff of over 490 CD4+ T cells, a sensitivity of 60%, and a specificity of 97.8%, with an area under the curve of 0.88. Measurement of CD4+ T cells predicted renal relapse more accurately as widely available biomarkers, such as ANCA titers, proteinuria/albuminuria, and hematuria. The addition of PR3-ANCA to urinary CD4+ T lymphocytes yielded better diagnostic accuracy (5).
The findings of PRE-FLARED are highly relevant, and urinary CD4+ T cell analysis might further help to identify patients at risk of subsequent disease relapses. This would have direct implications on management of patients with ANCA-GN, as the analysis might identify a subset of patients who will require longer-term maintenance therapies. In the therapy of ANCA-GN, the ultimate goal must be avoidance of renal relapses, given their impact on kidney failure risk. Independent confirmation of measurement of urinary T lymphocytes to predict relapses and eventually a clinical trial with the aim to stratify patients according to their levels of CD4+ T cells in the urine are required to further personalize treatment approaches in ANCA-GN (Figure).
ANCA-GN: From pathophysiology to clinical implications
Citation: Kidney News 16, 7
Footnotes
References
- 1.↑
Kronbichler A, et al. Diagnosis and management of ANCA-associated vasculitis. Lancet 2024; 403:683–698. doi: 10.1016/S0140-6736(23)01736-1
- 2.↑
Wester Trejo MAC, et al. Renal relapse in antineutrophil cytoplasmic autoantibody-associated vasculitis: Unpredictable, but predictive of renal outcome. Rheumatology (Oxford) 2019; 58:103–109. doi: 10.1093/rheumatology/key260
- 3.↑
Moran SM, et al.; Nephrotic Syndrome Study Network (NEPTUNE). The clinical application of urine soluble CD163 in ANCA-associated vasculitis. J Am Soc Nephrol 2021; 32:2920–2932. doi: 10.1681/ASN.2021030382
- 4.↑
Sonnemann J, et al. Urinary T cells identify renal antineutrophil cytoplasmic antibody-associated vasculitis and predict prognosis: A proof of concept study. Kidney Int Rep 2023; 8:871–883. doi: 10.1016/j.ekir.2023.01.013
- 5.↑
Prskalo L, et al. Urinary CD4+ T cells predict renal relapse in ANCA-associated vasculitis. J Am Soc Nephrol 2024; 35:483–494. doi: 10.1681/ASN.0000000000000311
