INTRODUCTION

Anti‑neutrophil cytoplasm antibody (ANCA)‑associated vasculitis (AAV) is a necrotizing vasculitis that primarily affects small blood vessels and is classically divided into three subtypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).^1,2Renal involvement in AAV is indeed a critical factor in determining disease outcomes,^3,4often leading to kidney failure and requiring specialized treatment approaches. Identifying specific ANCA markers, such as anti‑proteinase 3 (PR3) and anti‑myeloperoxidase (MPO) antibodies, plays an important role in distinguishing between these subtypes and guiding clinical management.^5,6While AAV with renal involvement is often studied in international cohorts, the clinical characteristics of Portuguese patients with AAV and associated kidney involvement might not be as well‑documented in the literature. Given the regional differences in patient presentation, genetic factors, and treatment responses, there may be an underrepresentation of this specific population’s outcomes and management approaches.^7-9This study aims to describe the demographic features, clinical presentation, treatment strategies, and outcomes of a large cohort of AAV patients with kidney involvement managed at our tertiary care center, Hospital de São João.

MATERIAL AND METHODS

Since December 2010, at Hospital de São João in Porto, the ambulatory care of patients with AAV and kidney involvement has been primarily overseen by a multidisciplinary team, comprising two Nephrologists, one Rheumatologist, and one Internal Medicine specialist. This descriptive cross‑sectional study identified eligible patients through electronic medical records from January 2010 to June 2023. Inclusion criteria required patients to be aged 18 years or older and have AAV with biopsy‑confirmed kidney involvement. Exclusion criteria included serological ANCA‑negative cases, eosinophilic granulomatosis with polyangiitis, and overlap syndromes. Data collection focused on demographic and clinical variables, kidney pathology findings, treatment regimens and patient outcomes. The data analysis was performed using SPSS Statistics 27® software.

RESULTS

At the beginning of the study, 80 patients with AAV were assessed for eligibility. As depicted in Fig. 1, 51 patients met the eligibility criteria and were included in the analysis.

Figure 1 Study flow diagram. 

General demographic aspects

A male predominance has been observed in our population, with almost two‑thirds of the cohort (n= 31, 61%). At disease presentation, the median age was 66 (IQR, 56‑74) years old, and 77% (n= 39) of patients had at least one major comorbidity (hypertension, diabetes, dyslipidemia or overweight/obesity). A previous chronic kidney disease (CKD) diagnosis had been established in 18% (n= 9) of patients before AAV presentation. The median glomerular filtration rate by the CKD‑EPI equation was 45 (IQR 35‑53) mL/min/1.73 m² in that particular population.

Disease presentation and diagnosis

Only two patients with vasculitic lesions on kidney histology presented with preserved renal function despite microscopic hematuria and proteinuria. Most of our patients (96%, n= 49) had rapidly progressive glomerulonephritis (RPGN) as the renal manifestation of the vasculitic process. The median serum creatinine at disease presentation was 4.2 (IQR, 2.5‑5.7) mg/dL and 29% (n=15) of patients required hemodialysis. According to ANCA specificity, 78% (n= 40) of patients presented a positive test for anti‑myeloperoxidase and 22% (n= 11) for anti‑proteinase 3 antibodies. Extrarenal manifestations were frequently reported, with involvement of the upper and lower respiratory tract in 43% (n= 22) of cases, the nervous system in 6% (n= 3), the musculoskeletal system in 4% (n= 2), and the eyes in 2% (n= 1). The median diagnosis delay was 30 (IQR, 14‑87) days from the onset of the disease to diagnosis, with the majority of delays attributed to delays in referral.

Kidney pathology

According to Berden et al histopathologic classification,¹⁰ our patients were classified as having a ‘crescentic class’, ‘mixed class’, ‘sclerotic class’ and ‘focal class’ presentation in 26 (51%), 15 (29.4%), 5 (9.8%) and 5 (9.8%) cases, respectively. Correlating histologic activity with renal function at diagnosis, our population was categorized as: low, intermediate or high risk of developing end‑stage renal disease (ESRD) in 6 (13.3%), 21 (46.6%) and 18 (40%) cases, respectively, according to renal risk score (RRS) developed by Brix et al.¹¹ Notably, among the evaluated parameters, only the RRS demonstrated a statistically significant correlation with kidney survival (p = 0.003).

Implemented treatment regimens

Concerning “induction” therapy of AAV and according to CYCLOPS study,¹² cyclophosphamide i.v. plus glucocorticoids composed the most used treatment plan, in 44 patients (86%). Rituximab (1 g at weeks 0 and 2) plus glucocorticoids¹³ were preferred in five cases (10%), all introduced after 2020 (Fig. 2). In one case (2%) a combination of rituximab (1 g at 0 and 2 weeks) with i.v. cyclophosphamide¹⁴ was used. In one case (2%) no immunosuppressive therapy was initiated due to the presence of massive irreversible lesions documented on kidney biopsy and given the absence of extrarenal manifestations. The median cumulative cyclophosphamide dose was 6 g (IQR, 3.25‑8.25). Plasma exchange was performed in 12 cases (24%), nine with alveolar hemorrhage, and all before 2020 (Fig. 2). The median number of sessions per patient was seven. For “maintenance” therapy, azathioprine (AZA) was the standard immunosuppression regimen used in 32 patients (63%). Mycophenolate mofetil (MMF) was used in one case (2%) due to gastrointestinal intolerance to AZA. Maintenance with rituximab was started after 2019 in six cases (12%). The median cumulative dose was 2.5 g (IQR, 2-4). Before the implementation of current guidelines, rituximab was typically selected in cases of azathioprine allergy or intolerance, or in patients with a history of re- lapse. Glucocorticoid tapering regimens obeyed to the British Society of Rheumatology until 2020 after which a quicker tapering schedule was implemented according to the PEXIVAS study.¹⁵ Representing a median time of 46 (IQR 18 - 100) months on remission maintenance treatment, 31 patients (61%) were under glucocorticoids on the date of the last evaluation (or death or hemodialysis initiation when applicable) with a median daily prednisone dose of 5 mg (IQR 2.5- 5).

Figure 2 Distribution of “induction” therapy protocols and the implementation of plasma exchange therapies over time in our center. 

Outcomes

Of the 15 patients who required hemodialysis at disease presentation, six (40%) presented renal recovery (n= 3 MPO, n= 3 PR3). Nevertheless, during a median follow‑up of 39 (IQR, 7‑84) months, 20 patients (39%) progressed to end‑stage kidney disease, 10 patients (20%) died with preserved renal function and 21 patients (41%) survived with preserved renal function. Relapses occurred in 10 patients (20%), with the respiratory tract being the most frequently involved system (n= 6, 60%). Infection and death affected, respectively, 18 (35%) and 17 patients (33%) during the follow‑up period. In patients with a reported cause of death, infectious diseases were the leading cause (29%) followed by cancer (24%) and cardiovascular disease (6%). The median time from AAV diagnosis until death was 67 months (minimum 2 months; maximum 151 months). Table 1 summarizes the main aspects of the demographic and clinical characteristics of our population.

Table 1 Demographic and clinical characteristics of our population with AAV, according to serologic classification. 

ANCA‑MPO: anti‑neutrophil cytoplasm antibodies against myeloperoxidase; ANCA‑PR3: anti‑neutrophil cytoplasm antibodies against proteinase‑3; IQR: interquartile range; CKD: chronic kidney disease. * Censored to death.

DISCUSSION

In a country where epidemiological data on AAV is scarce and needed for a better uniformization of management among clinicians,¹⁶ this is the largest series of patients with biopsy‑proven renal AAV reported from Portugal. In line with other Southern European populations,^17,18our reported mean age at onset of disease was the 6th decade of life, males were the most affected gender and a clear predominance of ANCA‑MPO was observed. The majority of patients (77%) had at least one major comorbidity and a significant proportion of patients (18%) had been previously diagnosed with CKD, raising awareness for the high level of suspicion required for the diagnosis of AAV even in comorbid populations. Consistent with other recent literature,¹⁷ our reported ‘diagnosis delay’ of 1 month follows the idea that time to diagnosis after the occurrence of the first vasculitis‑related symptoms is getting shorter in the last decades. Nevertheless, 25% of our patients still have a period between clinical presentation and kidney histopathological confirmation longer than three months. This highlights the importance of not delaying the initiation of immunosuppressive therapy when a clinical presentation is consistent with small‑vessel vasculitis and is accompanied by positive ANCA serology, particularly in specialized centers dealing with rapidly deteriorating patients.¹⁹ Kidney biopsy remains crucial for diagnosis confirmation and provides relevant prognostic information.¹⁹ In our population, the MPO subgroup, compared to the PR3 subgroup, exhibited a higher incidence of the mixed class based on the histopathologic classification by Berden et al,^¹⁰ along with a greater proportion of patients classified as high risk for developing ESRD according to the Renal Risk Score proposed by Brix et al.^¹¹ This aligns with the observation that the PR3 subgroup experienced a higher rate of renal function recovery after dialysis initiation and better preservation of kidney function during follow‑up. Notably, in our cohort, the RRS was the only available tool for predicting kidney survival.²⁰ Regarding induction treatment protocol, our department’s practice began to change around 2020s. After gaining an on‑label indication for AAV,¹³ rituximab has become available as a biosimilar, which simplified its prescription. As such, in the past years, we have experienced a progressive switch from cyclophosphamide to rituximab as the first‑line drug for the treatment of AAV, especially in older and frail patients. Based on the findings of recent randomized controlled trials,^13,14,22we believe that larger and more rigorous studies will be crucial in supporting the broader adoption of treatment regimens designed to minimize drug-related toxicity. In accordance with the best available evidence, our department has progressively implemented protocols involving more rapid glucocorticoid tapering over the years.¹⁵ The PEXIVAS study^¹⁵ has guided our clinical approach to the use of plasmapheresis in AAV. Nonetheless, accumulating evidence supports considering plasma exchange in patients who present with dialysis‑dependent kidney injury or rapidly progressive renal dysfunction. If it is true that since the 1960s a dramatic improvement in AAV therapeutic arms and prognosis was observed with oral cyclophosphamide and glucocorticoid,²¹ nowadays we still notice a 39% progression to end‑stage kidney disease during a median follow‑up of 39 months in our population. Mortality reaches 33%, mostly due to infectious or unknown causes, and the infection rate gets 35% of our patients. This reality, combined with the limited evidence supporting the use of rituximab in patients with significantly reduced or rapidly declining glomerular filtration rates,¹⁴ highlights the need for a more tailored approach for the Portuguese population.¹⁶ In summary, this study is a modest but important cohort of Portuguese patients with renal AAV. Despite some limitations, like the descriptive and retrospective design of the study, recruitment from the same geographical zone (North of Portugal), and absence of information about cumulative dose of glucocorticoids, we believe this paper offers an important representation of the epidemiology, diagnosis, treatment regimens, and outcomes of ANCA‑positive vasculitis patients with kidney involvement in Portugal. Fortunately, in recent years, multicenter initiatives and national registries have been established by the Immunonephrology Working Group of the Portuguese Society of Nephrology. These efforts aim to provide a more comprehensive understanding of small‑vessel vasculitis within our country.