Background
Antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis is a systemic autoimmune disease characterized by pauci-immune-type necrotizing small-vessel vasculitis; vessels in the kidney, skin, respiratory tract, gastrointestinal tract, and peripheral nerves are often involved. Patients with ANCA-associated renal vasculitis may present with a variety of clinical manifestations, such as fatigue, fever, and weight loss [
1]. Although routine laboratory tests are generally nonspecific for ANCA-associated renal vasculitis, common laboratory findings in ANCA-associated renal vasculitis include leukocytosis, thrombocytosis, normochromic and normocytic anaemia, and the elevation of acute-phase inflammatory proteins. For example, a previous study reported that anaemia was seen in 73% of patients with granulomatosis with polyangiitis (GPA) and the mean haemoglobin was 11.1 g/dL (range, 5.0–15.1 g/dL) before treatment initiation [
2]. In another study, 14/36 (39%) of GPA patients with remission status presented with anaemia, and the mean haemoglobin was 13.0 ± 2.1 g/dl [
3]. Thus, anaemia is known to be a common complication of patients with ANCA-associated renal vasculitis.
Anaemia has also been reported as a complication in other autoimmune inflammatory diseases, such as rheumatoid arthritis [
4], inflammatory bowel disease [
5,
6] and systemic lupus erythematosus (SLE) [
7]. Anaemia that occurs as a complication in these diseases is generally known as anaemia of chronic disease (ACD; also called anaemia of inflammation) [
8]. The mechanisms of ACD are thought to be hepcidin-induced changes in iron metabolism, inadequate response of erythropoiesis, and shortening of the erythrocyte lifespan. A number of serious conditions are associated with ACD, including infections, malignancies, autoimmune diseases, chronic rejection after transplantation, and chronic kidney disease (CKD). ACD is automatically presumed to be complicated with ANCA-associated renal vasculitis, and the causes of anaemia with ANCA-associated renal vasculitis are expected to be multifactorial. These causes can include renal dysfunction, alveolar haemorrhage, malnutrition, the use of immunosuppressive drugs, frequent in-hospital phlebotomies and iron deficiency. However, the associations among these factors and the severity of anaemia in patients with ANCA-associated renal vasculitis have not been elucidated in detail. Moreover, almost all previous studies of anaemia in association with other autoimmune inflammatory diseases excluded patients with renal dysfunction. Therefore, the pathogenesis and severity of anaemia in patients with ANCA-associated renal vasculitis may differ from those of anaemia in patients with other autoimmune inflammatory diseases.
In general, anaemia in elderly patients is closely associated with various poor outcomes such as hospitalization and mortality [
9]. In patients with heart failure, anaemia is associated with increased mortality [
10]. Additionally, in patients with CKD, several studies have demonstrated that anaemia is closely related to mortality and the progression of renal failure [
11,
12]. Therefore, the combination of severe anaemia and ANCA-associated renal vasculitis may lead to poor renal prognosis and shortened lifespan.
In the present study, we aimed to investigate the prevalence and pathogenesis of anaemia in patients with ANCA-associated renal vasculitis. We also evaluated the pathological findings and the impact of anaemia on the renal and life prognoses of the patients.
Discussion
In the present study, we focused on the physiological impact of anaemia in cases of ANCA-associated renal vasculitis. All ANCA-associated renal vasculitis patients in this cohort were found to have anaemia, and the causes of anaemia in our patients were expected to be multifactorial, with renal anaemia being the predominant type. Also, the severity of anaemia was closely associated with renal function, but not with the iron-related or inflammation-related findings. Moreover, anaemia severity was a factor affecting the renal and life prognoses of ANCA-associated renal vasculitis patients.
Before discussing our findings, we should first consider the previous studies on anaemia in patients with other autoimmune inflammatory diseases. The previous studies reported that the prevalence of anaemia was 33–59% in patients with rheumatoid arthritis [
4], 20–68% in those with inflammatory bowel disease [
5] and 38% in those with SLE [
7]. According to these studies, the causes of anaemia were multifactorial, and the main cause was ACD. In comparison, we found that anaemia was more frequent in patients with ANCA-associated renal vasculitis, and the causes of anaemia with ANCA-associated renal vasculitis were multifactorial, just as for anaemia with other autoimmune inflammatory diseases. However, the most prevalent cause was renal anaemia, not ACD. More than 90% of our patients had renal anaemia, while approximately half of the patients had ACD. A possible reason for the high prevalence of anaemia in our patients with ANCA-associated renal vasculitis may have been the interaction between renal anaemia and ACD. As described above, renal dysfunction is an important cause of ACD [
8]. By contrast, inflammation is an essential cause of renal anaemia [
22]. Both renal anaemia and ACD are mediated through the effects of inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumour necrosis factor-alpha. Therefore, in this study, we suspected that hepcidin played a key role in the interaction between renal anaemia and ACD. Hepcidin is an acute-phase protein, which is mainly produced in the liver and secreted into the circulation. Hepcidin is the main regulator of iron metabolism, and its production is regulated by changes in the body’s iron stores, inflammation, erythropoietic activity, and hypoxia [
23]. It has been reported that the hepcidin level is increased in CKD patients, possibly due to increased production and/or reduced renal clearance [
24,
25]. Hepcidin is also an acute-phase reactant induced by inflammation. We therefore expected the hepcidin concentration to be increased in our patients with ANCA-associated renal vasculitis due to both renal dysfunction and inflammation. However, in this cohort, the hepcidin-25 concentration was not significantly related to anaemia severity, renal dysfunction, or other inflammatory findings. In patients with ANCA-associated renal vasculitis, there may be a more complex relationship among various factors that influence hepcidin levels, including iron, inflammation, reduced renal clearance, and anaemia severity [
26]. Additionally, the measurement of the serum hepcidin-25 concentration was performed in only a limited number of patients.
Next, we addressed the reason for the high prevalence of renal anaemia and the influence of renal anaemia on the severity of anaemia in our patients with ANCA-associated renal vasculitis. McClellan et al. [
15] reported that the prevalence of anaemia increased as the level of kidney function decreased. For example, the percentage of patients with haemoglobin ≤12 g/dL increased from 26.7% to 75.5% as the glomerular filtration rate decreased from ≥ 60 mL/min/1.73 m
2 to < 15 mL/min/1.73 m
2. In our cohort, all patients had renal involvement, and the median eGFR was 15.3 mL/min/1.73 m
2. Therefore, advanced renal dysfunction with ANCA-associated renal vasculitis corresponded to a high prevalence of renal anaemia and anaemia severity. We also performed a review of the literature to examine how renal anaemia affects anaemia severity in patients with ANCA-associated vasculitis (Table
3). Several previous studies have reported an association between renal dysfunction and anaemia severity. However, anaemia severity was relatively mild in the studies that included patients without renal involvement—that is, in patients with preserved renal function [
2,
3,
27]. On the other hand, anaemia severity was relatively advanced in the ANCA-associated renal vasculitis cohorts [
28‐
30]. Moreover, there may be a tendency for the severity of anaemia to progress as the level of kidney function decreases. As a result, we can conclude that the causes of anaemia with ANCA-associated renal vasculitis are multifactorial, and that while renal anaemia is easily missed, it is the most frequent and influential cause of anaemia in patients with ANCA-associated renal vasculitis.
Table 3
Association of renal dysfunction and anaemia severity in patients with ANCA-associated vasculitis
| GPA (remission status) | 36 | 58 ± 15 | 42% had pauci-immune crescentic glomerulonephritis | (eGFR 40.6 ± 21.4 ml/min/1.73 m2) | 13.0 ± 2.1 |
| GPA | 158 | 41 (range, 9–78) | 77 | not available | 11.1 (range, 5.0–15.1) |
| ANCA-associated vasculitis | 535 | 61 (49–69) | not available | 2.3 (1.1–5.6) | 9.8 (8.6–11.5) |
| ANCA-associated vasculitis | 81 | 61 (50–68) | 100 | 3.6 (2.3–6.0) | 9.8 (8.8–11.7) |
| ANCA-associated vasculitis | 75 | 60 (53–68) | 100 | 5.0 (3.4–7.9) | 8.5 (7.5–9.8) |
| ANCA-associated vasculitis | 123 | 62 ± 12 | 100 | 5.0 ± 3.8 | 8.3 ± 2.1 |
The present study | ANCA-associated renal vasculitis | 45 | 71 ± 7.8 | 100 | 3.2 (range, 1.0–11.7) | 7.5 ± 1.3 |
Next, we investigated the mechanism of renal anaemia in ANCA-associated renal vasculitis patients. Our study of the histopathological findings demonstrated that renal interstitial damage is associated with anaemia severity. Some recent studies investigated the association between anaemia and biopsy-proven interstitial lesions of diabetic nephropathy [
19], or between anaemia and post-transplant nephropathy [
20]. Based on the findings of these previous studies and our present investigation, it is possible to propose several mechanisms by which interstitial damage could influence anaemia. One such mechanism is a reduction in the production of erythropoietin resulting from a decrease in erythropoietin-producing cells due to interstitial damage. Recent basic science studies have suggested that renal interstitial fibroblasts produce erythropoietin in response to hypoxia or anaemia [
31]. Therefore, the progression of interstitial damage could lead to the development of anaemia, resulting in erythropoietin deficiency. However, in this study, there was no significant relationship between the area of interstitial damage and the serum erythropoietin concentration. Nonetheless, this discrepancy may be attributable to study limitations. That is, we measured the serum erythropoietin concentration only in a limited number of patients. In addition, we could not perform renal biopsies in all patients.
Whether anaemia with ANCA-associated renal vasculitis influences the renal and life prognoses must also be addressed. As described above, several studies have demonstrated that anaemia is a risk factor for shortened lifespan and/or increased renal dysfunction [
11,
12]. Similarly, the present data demonstrated that anaemia severity was associated with life prognosis in our patients with ANCA-associated renal vasculitis. On the other hand, eGFR was also significantly different between the groups at the time of minimum eGFR, and the lower haemoglobin group tended to have a lower eGFR. Therefore, our results underscore that the severity of anaemia has an impact on renal and life prognoses. In general, the administration of ESAs is beneficial in patients with renal anaemia [
32,
33], and the use of ESAs may be a treatment option for patients with ACD [
8]. Unfortunately, although renal anaemia was diagnosed in 35 patients in this cohort, ESAs were used in only 16 of the 35 (46%). There is a possibility that the treatment for anaemia itself would lead to an improvement in the prognosis of patients with ANCA-associated renal vasculitis. In the future, therefore, it will be important to investigate the efficacy of earlier treatment initiation for anaemia, the optimal timing of anaemia intervention and the effectiveness of ESAs therapy.
Finally, our study has several limitations. First, this study was a retrospective investigation of a small cohort at a single centre, and our results therefore cannot be generalized without further investigation. Second, when our patients with ANCA-associated renal vasculitis had both renal anaemia and ACD, it was difficult to clearly distinguish between them. Third, as described above, we could not analyse patients with ANCA-associated vasculitis without renal involvement. Despite these limitations, the present study provided the first investigation of the pathogenesis of anaemia with ANCA-associated renal vasculitis and the impact of anaemia on prognosis. It is hoped that our findings will inspire additional research in a larger cohort.