The Challenge of Assessing Remission and Relapse in ANCA Kidney Disease

ANCA vasculitides are aggressive and destructive multiorgan disorders. ANCA are diagnostic biomarkers of significant sensitivity and specificity, and their routine use in clinical practice has eased diagnosing the disease group.¹ Immunosuppression protects from organ and life-threatening ANCA disease, but continued immunosuppression has its short-term and long-term side effects and complications. We therefore aim to minimize vasculitis damage using as little treatment as possible to preserve patient well-being and organ function. The current challenges are to determine when inflammation has truly and completely resolved and to identify the return of inflammation at the earliest to avoid unnecessary scarring.

Advances in modern diagnostics will allow us to reform our definitions of disease activity and remission in the future. In clinical practice, the kidney biopsy remains the gold standard for diagnosing a kidney relapse in ANCA vasculitis. A kidney biopsy captures routinely 15–30 glomeruli and is sufficient to diagnose a new disease most of the time.² Clinicians aim to diagnose a relapse as early as possible, and rebiopsies of monitored patients have therefore the risk of providing a sampling error in focal disease; a rebiopsy might miss active lesions and demonstrate fibrosed lesions of previous activity only. Clinicians therefore might treat patients for early relapse in clinical scenarios of high suspicion, e.g., rising ANCA titer combined with returned hematoproteinuria despite negative tissue findings. The escalation of immunosuppression is therefore often preferred to define relapse in vasculitis research. Service provisions struggling with capacities, the risks of adverse events of an invasive biopsy, and its risk of sampling errors have also resulted in fewer rebiopsies in ANCA vasculitis. An urgent unmet need is a liquid biopsy, serum, and/or urine biomarkers that reliably identify active disease at the earliest possible time point.

A classic urinary biomarker for active disease in ANCA vasculitis is the microscopic hematuria. In a new patient, we often ascribe this to an active disease without histologic confirmation. Persistent hematuria has repeatedly been debated as a sign of scarring instead of active inflammation. In 2018, Rhee et al. demonstrated that an increase in microscopic hematuria was associated with a future relapse in ANCA kidney disease, but the median time to event was 22 months.³ The authors also found an association between persistent hematuria and subsequent nephritis relapse. Last year, Benichou et al. confirmed persistent hematuria at the end of induction treatment was independently associated with kidney relapse.⁴ We have to acknowledge that we still miss a measure of true immunologic remission in clinical practice. The rise of serum creatinine and the histologic confirmation of active disease demonstrate the belatedness of our clinical practice reacting when irreversible destruction has already appeared and kidney function is lost.

In this issue of JASN, Prskalo et al. provide evidence that a certain measure of urinary CD4⁺ T cells is associated with disease activity.⁵ The authors propose that the urinary lymphocyte count outperforms other urinary diagnostics, such as microscopic hematuria. In the prospective multicenter PRE-FLARED study, urinary CD4⁺ T cells were associated with an early return of intrarenal inflammation requiring an escalation of treatment soon after completing induction immunosuppression. Lymphocytes in the urine at the time of diagnosis did not predict outcomes beyond 6 months, but a high level of urinary CD4⁺ T cells seemed to predict the need for intensified immunosuppressive treatment beyond the standard therapy. This suggests that urinary T cells mirror the aggression and organization of kidney inflammation in ANCA vasculitis. A future perspective might be that urinary T cells will assist in guiding the intensity of immunosuppressive therapy. I am hesitant to declare urinary T cells a marker for disease relapse as increased urinary T cells seem to rather indicate an ongoing occult disease activity which we miss with our current diagnostics. This novel concept might assist our ability to differentiate remission and active disease in the future.

Novel diagnostics incorporating multiomics and artificial intelligence promise to advance our diagnostic abilities and change the way we stratify diseases, predict outcomes, and ultimately guide therapy (Figure 1).⁶ Clinicopathologic scores will be enhanced by deep learning programs.⁷ Omics studies will systematically capture and assess the molecular dimension at the genome, epigenome, transcriptome, proteome, and metabolome levels. Although comprehensive at each layer, each omics study will check one dimension. Integrating genomics and epigenomics, transcriptomics, proteomics, and metabolomics data will provide multilayer results redefining disease phenotypes and determining new treatment targets. ANCA vasculitides are rare diseases but convey significant morbidity and mortality. Therefore, omics findings from other more common kidney diseases require utility checks in ANCA vasculitides as many glomerular disorders share common inflammatory pathways. Genomic phenotypes identified in other kidney diseases might influence the severity of ANCA kidney vasculitis and the response to treatment. Transcriptomic and proteomic studies will reveal further biomarker candidates informing pathobiology and supporting a causal effect.^8,9 Urinary soluble CD163 is associated with glomerular inflammation and has already been shown to determine vasculitic flares in ANCA kidney disease. An usCD163 assay has been proposed with a diagnostic reference range for active disease.¹⁰

Figure 1.

Future perspective of multiomic-supported diagnostics facilitating prediction modeling of disease behavior in ANCA vasculitides.

In the discovery phase of biomarkers, urinary CD4⁺ T cells will now be required to pass the verification and validation phases before we can investigate them for clinical utility. A reliable cut-off will need to be determined at the time of diagnosis that heralds an escalation above standard treatment. Ideally, patients will be stratified into certain risk groups per laboratory, and histologic findings of modern omics-supported diagnostics and the amount of justifiable immunosuppression will need to be identified. This will hopefully enable interventional trials to move to an umbrella modus investigating drugs on different risk groups in the disease. The infectious complication remains the major cause of death in the first year after diagnosis, and we should therefore not forget that a low urinary CD4⁺ T-cell count was found in most patients and the majority of patients achieved remission. A most important aim is to determine how much less immunosuppression would have sufficed to achieve this result.

Ultimately, the incorporation of modern diagnostics will enable us to refine our definitions of remission and relapse, predict disease behavior, and ensure true remission with personalized treatment. However, our mandate is to predict patients' risk as accurately as possible, and many current measures are imperfect proxy for the information we would like to have. We will therefore give our best estimate while we await the next studies combining serial urinary erythrocyte and CD4⁺ T-cell counts, CD163, and protein–creatinine ratio levels for prediction modeling.

Disclosures

S.R. Brix reports employment with Manchester Royal Infirmary and Manchester University NHS Foundation Trust; research funding from Kidneys for Life and Wellcome Trust, University of Manchester; honoraria from Vifor; advisory or leadership role for Vifor and as Chair of the Scientific Monitoring Committee of the United Kingdom and Ireland Vasculitis Society; and speakers bureau for Vifor.

Funding

None.

Author Contributions

Writing – original draft: Silke R. Brix.