Abstract
Introduction
ANCA-associated vasculitis is a rare autoimmune disease, and is particularly serious when the kidneys are involved. In addition to immunosuppressants, plasma exchanges are used to treat severe forms of vasculitis. The international guidelines recommend kidney biopsies for their diagnostic and prognostic roles. The Berden, ARRS (ANCA Renal Risk Score), and AKRiS (ANCA Kidney Risk Score) classifications show that certain histological lesions, such as interstitial fibrosis, tubular atrophy, and the percentage of normal glomeruli negatively impact kidney prognosis. The aim of this study was to evaluate the renal response of patients with severe forms of ANCA-associated vasculitis undergoing kidney biopsy and plasma exchanges, to identify the histological determinants favorable to kidney recovery.
Method
This was a retrospective multicenter study of 34 patients with ANCA-associated vasculitis with severe kidney involvement who were receiving plasma exchanges. The primary endpoint was death, the need for dialysis, or persistent kidney dysfunction (eGFR < 30 ml/min/1.73 m² for 3 months) at one year.
Results
Among the 34 patients (56% men), 19 (55%) met the primary endpoint. The 15 patients with an eGFR > 30 ml/min/1.73 m² at one year were younger (60 vs. 70 years), mostly male (73% vs. 42%), and had higher CRP levels (107 vs. 32 mg/l). Histologically, this group had more normal glomeruli (25% vs. 11%), less glomerulosclerosis (15% vs. 22%), and more cellular and partial crescents.
Conclusion
Patients treated by therapeutic plasmapheresis with a better kidney prognosis at 1-year had more normal glomeruli, less glomerulosclerosis and was associated with higher CRP. These results could support the systematic use of kidney biopsies for severe forms of ANCA-associated vasculitis, to better adapt treatments.
Keywords: Acute kidney injury, ANCA-associated vasculitis, Plasmapheresis, Kidney biopsy, Histological prognosis
Introduction
ANCA-associated vasculitis (AAV) is a rare autoimmune disease which may involve all the organs [1]. The diagnosis of kidney involvement is based on the presence of rapidly progressive glomerulonephritis, with the presence of plasma ANCA and extracapillary proliferation without immune complex deposits on kidney biopsy [2]. Prognosis is poor in the event of kidney involvement [3].
The current treatment for severe forms of AAV consists of Corticosteroid therapy and/or Avacopan [4] associated with cyclophosphamide and/or Rituximab [5]. These treatments are not devoid of risk, with a cumulative incidence of 16% of severe infections [6]. Therapeutic plasma exchange (TPE) has been widely proposed, with controversial efficacy in the scientific literature [7, 8]. Indeed, scientific societies do not formally recommend using therapeutic plasmapheresis. However, they do suggest considering its use if serum creatinine is > 300 µmol/l [9] or > 500 µmol/l [10, 11] based on the MEPEX study and the PEXIVAS subgroup analyses which showed a tendency to favor TPE for severe AKI requiring dialysis or not. Due to the great variability in the severity of initial kidney involvement, it is crucial to adapt induction treatment on a case-by-case basis, particularly regarding TPE, whose effectiveness remains controversial.
Kidney histology is one proposition for therapeutic adaptation as it is recommended by the European [12] and international [11] guidelines for diagnosis when there are no contraindications. The Berden classification [13], the ARRS [14] and the AKRiS [15] are scores that demonstrate the prognostic values of certain histological lesions, such as interstitial fibrosis, tubular atrophy, and the percentage of normal glomeruli. However, other lesions discovered on kidney biopsies may be associated with a poor kidney prognosis. For example, the presence of cellular crescents leads to a better prognosis than fibrous crescents [16], and the presence of vascular fibrinoid necrosis is associated with a poorer prognosis [17]. These prognostic scores allow personalized medicine but, so far, no therapeutic impact studies have ever been reported, although one recent retrospective study by Nezam et al. proposed a new score, the GFEV score, to help with making the decision to start TPE [18]. Moreover, there is still an ongoing debate as to which prognostic tools to use to justify the choice and indication for immunosuppressive treatment, particularly regarding histological kidney lesions [19]. Indeed, studies diverge on this point, notably due to the inclusion of patients with heterogeneous AAV at presentation, and the various therapeutic management schemes used, including therapeutic plasmapheresis.
In this context, we studied the determinants on kidney function at 1 year, including histological kidney lesions in patients presenting with severe AKI secondary to AAV, who received immunosuppressive therapy and therapeutic plasmapheresis.
Materials and methods
Population and inclusion criteria
This retrospective study included all patients recorded on the kidney biopsy registries of the pathology departments, managed in the nephrology departments of one tertiary hospital and one general hospital between January 2008 and December 2020.
Adult patients (> 18 years) with pauci-immune extracapillary glomerulonephritis associated with microscopic polyangiitis, granulomatosis with polyangiitis, or renal-limited vasculitis (RLV), presenting with severe acute kidney injury (Stage 3 AKI according to KDIGO), who had undergone a kidney biopsy within a maximum of two weeks after admission and were treated by therapeutic plasmapheresis, were included. In addition, all patients had corticosteroid boli, then oral treatment, alone or in combination with cyclophosphamide (500 mg x 6 over 3 months) or rituximab (375 mg/m² x 4 weekly) at the physician’s discretion.
The exclusion criteria included all patients whose final diagnosis was not AAV, those who had not received plasma exchange or had had fewer than 3 TPE sessions, and “double-positive” patients presenting with positive anti-GBM antibodies. All patients without TPE or with fewer than 3 TPE sessions were excluded in order to see the evolution of all patients treated by this technique according to their histological lesion and with sufficient quantities of TPE according to Sallee et al. [20]. The aim was to make a descriptive, exploratory study of this population.
Data collection
Sociodemographic, clinical, and biological characteristics collected included: age, gender, history of chronic kidney disease (eGFR < 60 ml/min/1.73 m² for more than 3 months). Clinical manifestations and the Birmingham Vasculitis Score (BVAS) were also identified.
Kidney parameters collected included: serum creatinine, the need for dialysis in the acute phase, proteinuria, and microscopic hematuria. ANCA type (anti-MPO or anti-PR3) and ANCA titer were recorded in UI/ml (ELISA/FEIA), along with hemoglobin, C-Reactive Protein (CRP), and presence of hypereosinophilia (used as a marker of the Th2 cytokine pathway).
Regarding therapeutics, the number of apheresis sessions and induction treatment (cyclophosphamide, rituximab, or corticosteroid pulses alone) were collected. Vital status and kidney function were evaluated one year after biopsy.
Histopathological evaluation
Histological parameters with recognized prognostic values were collected: percentages of normal glomeruli, sclerotic glomeruli, and non-sclerotic crescents, as well as interstitial fibrosis and tubular atrophy, necessary for the Berden classification [13], Brix score (ARRS) [14], modified Brix score (AKRiS) [15], and GFEV score [18].
Other specific histological criteria potentially linked to kidney prognosis were included, such as crescent type (cellular, fibro-cellular, or fibrous), their circumferential or segmental nature, Bowman’s capsule rupture, glomerular or arteriolar fibrinoid necrosis, and C3 and IgG deposits.
Other general lesions were studied: focal segmental glomerulosclerosis (FSGS), acute tubular necrosis (ATN), and interstitial inflammation. Glomerular lesions were analyzed as a percentage of abnormal glomeruli, and tubulo-interstitial lesions according to a semi-quantitative score (< 25%; 25–50%; >50%).
We included all kidney biopsies with over 5 glomeruli, considered as acceptable, and kidney biopsies with 10 glomeruli or more were considered as optimal.
Data were collected by a pathologist blinded to the clinical diagnosis and evolution, who viewed the biopsies and centralized them using a standardized form.
Primary endpoint and statistical analysis
The primary endpoint was a composite criterion: the need for dialysis at one year, the persistence of severe chronic kidney disease (eGFR < 30 ml/min/1.73 m²) or death with persistent kidney dysfunction according to the previous outcome at one year.
Patient characteristics were compared according to the presence or not of kidney endpoint at 1 year.
Statistical analysis
Quantitative variables with a non-Gaussian distribution were presented with their medians and interquartile ranges. Qualitative variables were expressed as numbers and percentages. A Fisher test was used to compare qualitative variables and a Mann-Whitney U test to compare quantitative variables.
A difference was considered statistically significant if p < 0.05. Analyses were performed with SAS version 9.3.
Results
A total of 34 patients who met the inclusion criteria were retrospectively included from 2 hospitals between January 2008 and December 2020 (Fig. 1: flow chart).
Fig. 1.
Flow chart. PLEX = Plasma Exchange, AAV = ANCA-Associated Vasculitis, eGFR = estimated glomerular filtration rate, GBM = Glomerular Basement Membrane
Among these, 56% were men with a median age of 67 years (Table 1), including 11 (32.4%) who presented an intra-alveolar hemorrhage (IAH), and the median BVAS score was 5.0 [4.0–9.0]. The blood test found median creatinine at 555 µmol/l [436.3–892.3], ANCA titers at 114.50 UI/l [49.8–189] (50% MPO, 47.1% PR3 and 2.9% without ANCA) and median CRP at 59.0 mg/l [12.8–130.3]. Urinalysis found proteinuria at 1.68 g/g [1.21– 2.80] and hematuria in 31 (91.2%) patients. Twenty-two patients (64.7%) required renal replacement therapy (RRT) at diagnosis and the median TPE session was 7 [6–10]. Nineteen patients (56%) reached the primary endpoint (Group 1 with less favorable kidney outcome vs. Group 2 with better kidney outcome). If we compare the two groups according to the primary endpoint, no statistical difference in socio-demographic characteristics can be observed. Extra-renal involvement was distributed relatively homogeneously between the two groups. However, pulmonary forms, including IAH, affected 7 (47%) patients in Group 2 compared to only 4 (21%) in Group 1, with no significant difference. The median BVAS score was 5.5 IQR [4–8] in the group with a less favorable kidney response (Group 1) vs. 4.0 [4–11] in Group 2. Regarding biological parameters, the group with a better kidney outcome (Group 2) had a higher median CRP (107 mg/l [53–154] vs. 32 mg/l [6.65–78.0], p-value of 0.03). The other parameters were not statistically significant.
Table 1.
Socio-demographic, clinical and biological data according to the occurrence of death, dialysis or persistence of severe kidney dysfunction (eGFR < 30 ml/min/1.73m2) at 1 year. Group 1: positive primary endpoint. Group 2: negative primary endpoint
| Group 1 (n = 19) | Group 2 (n = 15) | p-value | ||
|---|---|---|---|---|
| Socio-demographic parameters | ||||
| Age (years), median [IQR] | 67 [55 – 75] | 70.0 [64 – 80] | 60.0 [53 – 67] | 0.07 |
| Men, n (%) | 19 (55.9%) | 8 (42.1%) | 11 (73.3%) | 0.09 |
| CKD, n (%) | 7 (20.6%) | 4 (21.1%) | 3 (20.0%) | 1 |
| Past vasculitis, n (%) | 1 (2.9%) | 0 (0.0%) | 1 (6.7%) | |
| Clinical parameters | ||||
| Pulmonary involvement including IAH, n (%) | 11 (32.4%) | 4 (21.1%) | 7 (46.7%) | 0.15 |
| Cutaneous-articular involvement, n (%) | 12 (35.3%) | 7 (36.8%) | 5 (33.3%) | 0.62 |
| Other involvement, n (%) | 5 (10.7%) | 3 (15.8%) | 2 (13.3%) | 1 |
| ENT, n (%) | 2 (5.9%) | 1 (5.3%) | 1 (6.7%) | |
| Cardiac, n (%) | 1 (2.9%) | 1 (5.3%) | 0 (0.0%) | |
| Gastroenterological, n (%) | 3 (8.8%) | 2 (10.5%) | 1 (6.7%) | |
| Neurological, n (%) | 1 (2.9%) | 1 (5.3%) | 0 (0.0%) | |
| BVAS Score, median [IQR] | 5.0 [4.0 – 9.0] | 5.5 [4 – 8] | 4.0 [4 – 11] | 0.89 |
| Biological parameters | ||||
| Creatinine (mmol/l), median [IQR] | 554.5 [436.3 – 892.3] | 488 [438 – 853] | 630 [478 – 918] | 0.37 |
| Proteinuria (g/g), median [IQR] | 1.68 [1.21– 2.80] | 1.65 [1.4 – 3.1] | 1.70 [0.75 – 2.25] | 0.64 |
| Hematuria, n (%) | 31 (91.2%) | 17 (89.5%) | 14 (93.3%) | 1 |
| ANCA | ||||
| Positive, n (%) | 33 (97.1%) | 18 (94.7%) | 15 (100%) | 0.28 |
| Anti-MPO Ab, n (%) | 17 (50.0%) | 10 (52.6%) | 7 (46.7%) | 1 |
| Anti-PR3 Ab, n (%) | 16 (47.1%) | 8 (42.1%) | 8 (53.3%) | 0.73 |
| Negative, n (%) | 1 (2.9%) | 1 (5.3%) | 0 (0%) | |
| ANCA Titers (UI/l), median [IQR] | 114.50 [49.8 – 189] | 81.5 [33.2 – 123.8] | 147 [71.3 – 323] | 0.07 |
| Anti-MPO Ab (UI/l), median [IQR] | 124.5 [67 - 189] | 114.5 [42.3 – 125.3] | 156 [100 – 480] | 0.73 |
| Anti-PR3 Ab (UI/l), median [IQR] | 84.0 [48 – 320] | 56 [33.3 – 87.8] | 137 [70 – 322] | 0.52 |
| CRP (mg/l), median [IQR] | 59.0 [12.8 – 130.3] | 32.0 [6.65 – 78.0] | 107 [53 – 154] | 0.03* |
| Hemoglobin (g/dl), median [IQR] | 9.1 [8.1 – 10.2] | 9.7 [7.9 – 10.2] | 9.0 [8.2 – 9.8] | 0.66 |
| Hypereosinophilia, n (%) | 8 (23.5%) | 4 (21.1%) | 4 (26.7%) | 1 |
| Therapeutic parameters | ||||
| Early RRT, n (%) | 22 (64.7%) | 13 (68.4%) | 9 (60.0%) | 0.72 |
| Induction treatment | ||||
| Cyclophosphamide, n (%) | 16 (47.1%) | 9 (47.4%) | 7 (46.7%) | 1 |
| Rituximab, n (%) | 12 (35.3%) | 7 (36.8%) | 5 (33.3%) | 1 |
| Corticosteroids alone, n (%) | 6 (17.6%) | 3 (15.8%) | 3 (20.0%) | |
| Number of TPE, n [IQR] | 7 [6 – 10] | 7 [5.5 – 9.5] | 7 [7 – 9.5] | 0.27 |
IQR = Inter Quartile Range, CKD = Chronic Kidney Disease, IAH = Intra-Alveolar Hemorrhages, ENT = Ear Nose and Throat, BVAS = Birmingham Vasculitis Score, ANCA = Anti-Neutrophil Cytoplasmic antigen, MPO = Myeloperoxidase, PR3 = Proteinase 3, CRP = C-reactive protein, RRT = Renal replacement therapy, TPE = Therapeutic Plasma Exchange
The data on therapeutic management were homogeneous between the 2 groups in terms of the number of apheresis sessions with a median of 7 for both groups, with an IQR [5.5–9.5] for Group 1 and an IQR [7–9.5] for Group 2 (p-value 0.27). The percentage of patients in Group 1 requiring hemodialysis in the acute phase was 68% (13 patients) and 60% (9 patients) in Group 2 with a p-value of 0.72. The induction treatment received was also similar: cyclophosphamide was used in 47% of patients in both Groups 1 and 2 (9 and 7 patients, respectively), and rituximab in 37% of Group 1 (7 patients) and 33% of Group 2 (5 patients). Three patients (16%) in Group 1 and 3 patients (20%) in Group 2 had induction with corticosteroids alone.
The histological parameters of the two groups (Table 2) found a median number of glomeruli of 19 [11.5–30] in Group 1 and 14 [13–17] in Group 2 (5 patients [15%] with 5–10 glomeruli and all others ≥ 10). The median percentage of normal glomeruli was significantly higher in the group with a better kidney response (25%, IQR [18.4–37.1] vs. 12%, IQR [6.5–20.5], p = 0.02). Among the abnormal glomeruli, Group 1 had a higher median percentage of glomerulosclerosis (22% [11.8–27.5] vs. 15% [0–28.4], p = 0.06), fibro-cellular crescents (22.2% IQR [4.46–40.4] vs. 9.1% IQR [0–36.2], p = 0.56), fibrous crescents (5.6% IQR [0–23.1] vs. 0% [0.0–13.0], p = 0.54), and circumferential crescents (42.9% IQR [20.2–64.0] vs. 36.4% IQR [29.7–58.9], p = 0.85), compared to Group 2. Glomerular fibrinoid necrosis was more common in Group 2 (12 patients [80%]) vs. 13 patients ([68.4%], p = 0.22), just as focal segmental glomerulosclerosis (4 patients [27%]) vs. 2 patients [10%], p = 0.19). The presence of glomerular C3 and IgG deposits was evenly distributed between the two groups. Arteriolar fibrinoid necrosis was present in 3 patients (15.8%) in Group 1 and 1 (6.7%) in Group 2 (p = 0.61). In the tubulo-interstitial compartment, the presence of more than 25% acute tubular necrosis and interstitial fibrosis was distributed homogeneously between Groups 1 and 2, respectively (p = 1 for both parameters). Tubular atrophy of more than 25% was 37% in Group 1 and 20% in Group 2 (p = 0.45). Interstitial inflammation of more than 25% was found in 53% of patients in Group 1 and 40% in Group 2 (p = 0.51). Regarding the Berden classification, the class primarily represented was the crescentic class, with 73.7% of patients in Group 1 and 73.3% of patients in Group 2. Notably, none of the patients with a good kidney response were in the scerotic class. The median ARRS was higher in Group 1 (score of 7) than in Group 2 (score of 3, with a p-value of 0.06). The AKRiS was homogeneously distributed between the 2 groups, sharing the same 1st and 3rd quartiles of 11 and 18 respectively (p = 0.74). The GFEV score was also evenly distributed between the 2 groups (p = 0.73).
Table 2.
Histological data according to the occurrence of death, dialysis or persistence of severe kidney dysfunction (eGFR < 30 ml/min/1.73m2) at 1 year. Group 1: positive primary endpoint. Group 2: negative primary endpoint
| Study Population (n = 34) | Group 1 (n = 19) | Group 2 (n = 15) | p-value | ||
|---|---|---|---|---|---|
| Glomerular lesions | |||||
|
Total glomerular number, median [IQR] |
16.5 [13.0–25.5] | 19 [11.5–30] | 14 [13–17] | 0.24 | |
|
Normal glomeruli, n [IQR] median of percentage [IQR] |
3.0 [2–5] 18.3 [8.9–33.3] |
2 [1–4.5] 11.6 [6.5–20.5] |
4 [3–6.5] 25 [18.4–37.1] |
0.02* | |
|
Abnormal glomeruli, n [IQR] median of percentage [IQR] |
13.5 [8–20.5] 81.7 [66.7–91.1] |
18 [8–26] 88.4 [79.5–93.5] |
11 [7.5–15] 75 [62.9–81.7] |
0.02* | |
| Lesions from abnormal glomeruli | |||||
|
Glomerulosclerosis, n [IQR] median of percentage [IQR] |
2.0 [1–5] 19.1 [7.3–33.3] |
4 [1–5] 22.2 [11.8–27.5] |
1 [0–4] 15.4 [0–28.4] |
0.06 | |
|
Extra-capillary hypercellularity, n [IQR] median of percentage [IQR] |
10.5 [6–14] 80.9 [66.7–99.1] |
11 [6.5–15.5] 76.2 [66.7–92.7] |
9 [6–12.5] 84.6 [71.6–100] |
0.34 | |
|
Cellular, n [IQR] median of percentage [IQR] |
5.5 [2.5–8] 39.3 [16.1–76.7] |
5 [2–7.5] 27.8 [12.7–59.3] |
6 [4–7.5] 50 [31.0–81.8] |
0.23 | |
|
Fibrocellular, n [IQR] median of percentage [IQR] |
2.5 [0–5] 12.1 [0–40.7] |
3 [1–5] 22.2 [4.46–40.4] |
1 [0–5] 9.1 [0–36.2] |
0.56 | |
|
Fibrous, n [IQR] median of percentage [IQR] |
0.5 [0–2] 2.8 [0–16.5] |
1 [0–4] 5.6 [0–23.1] |
0 [0–1.5] 0.0 (0.0–13.0] |
0.44 | |
|
circumferential crescent, n [IQR] median of percentage [IQR] |
5.0 [3–10] 41.4 [25.2–62.3] |
5 [3.5–11] 42.9 [20.2–64.0] |
5 [2.5–8] 36.4 [29.7–58.9] |
0.85 | |
|
segmental crescent, n [IQR] median of percentage [IQR] |
4.5 [1.5–7] 30.5 [14.9–45.5] |
5 [1.5–7] 26.3 [13.4–39.1] |
3 [1.5–6.5] 33.3 [26.6–47.7] |
0.34 | |
|
BC rupture, n [IQR] median of percentage [IQR] |
1 [0–3] 4.8 [0–13.5] |
1 [0–3] 4.8 [ 0–13.4] |
0 [0–1] 0.0 [0–12.2] |
||
| Lesion from overall glomeruli | |||||
| Fibrinoid necrosis, n (%) | 25 (73.5%) | 13 (68.4%) | 12 (80.0%) | 0.22 | |
| FSGS, n (%) | 6 (17.6%) | 2.0 (10.5%) | 4 (26.7%) | 0.19 | |
| Vascular lesions | |||||
|
Arteriolar fibrinoid necrosis, n (%) |
4 (11.8%) | 3 (15.8%) | 1 (6.7%) | 0.61 | |
| Immunofluorescence ( N = 30) | |||||
| C3 deposits, n (%) | Present | 13.0 (43.3%) | 7 (43.8%) | 6 (42.9%) | 0.96 |
| IgG deposits, n (%) | Present | 5.0 (16.7%) | 3 (18.8%) | 2 (14.3%) | 1.00 |
| Tubulointerstitial lesions | |||||
| Interstitial Fibrosis, n (%) | < 25% | 24 (70.6%) | 13 (68.4%) | 11 (73.3%) | 1.00 |
| > 25% | 10 (29.4%) | 6 (31.6%) | 6 (40.0%) | ||
| Tubular Atrophy, n (%) | < 25% | 24 (70.6%) | 12 (63.2%) | 12 (80.0%) | 0.45 |
| > 25% | 10 (29.4%) | 7 (36.8%) | 3 (20.0%) | ||
| Interstitial Inflammation, n (%) | < 25% | 18 (52.9%) | 9 (47.4%) | 9 (60.0%) | 0.51 |
| > 25% | 16 (47.1%) | 10 (52.6%) | 6 (40.0%) | ||
| Acute Tubular Necrosis, n (%) | < 25% | 19 (55.9%) | 11 (57.9%) | 8 (53.3%) | 1.00 |
| > 25% | 15 (44.1%) | 8 (42.1%) | 7 (46.7%) | ||
| Histoprognostic scores | |||||
| Berden classification | |||||
| Focal class, n (%) | 3 (8.8%) | 1 (5.3%) | 2 (13.3%) | 0.39 | |
| Crescentic class, n (%) | 25 (73.5%) | 14 (73.7%) | 11 (73.3%) | ||
| Mixed, n (%) | 4 (11.8%) | 2 (10.5%) | 2 (13.3%) | ||
| Sclerotic, n (%) | 2 (5.9%) | 2 (10.5%) | 0 (0.0%) | ||
| ARRS score, median [IQR] | 7 [3–7] | 7 [5–9] | 3 [3–7] | 0.06 | |
| Low, n (%) | 1 (2.9%) | 1 (5.2%) | 0 (0%) | 0.27 | |
| Medium, n (%) | 25 (73.6%) | 12 (63.2%) | 13 (86.7%) | ||
| High, n (%) | 8 (23.5%) | 6 (31.6%) | 2 (13.3%) | ||
| AKRiS score, median [IQR] | 12.5 [11–18] | 14 [11–18] | 11 [11–18] | 0.74 | |
| Low, n (%) | 2 (5.9%) | 1 (5.2%) | 1 (6.7%) | 0.47 | |
| Medium, n (%) | 15 (44.1%) | 7 (36.8%) | 8 (53.3%) | ||
| High, n (%) | 14 (41.2%) | 10 (52.6%) | 4 (26.7%) | ||
| Very High, n (%) | 3 (8.8%) | 1 (5.2%) | 2 (13.3%) | ||
| GFEV Score, median [IQR] | 13.0 [5–15.8] | 12 [3.5–15.5] | 14 [5.0–15.5] | 0.61 | |
| Score > 7 | 21 (61.8%) | 11 (57.9%) | 10 (66.7%) | 0.73 | |
IQR = Inter Quartile Range, BC = Bowman’s Capsule, FSGS = Focal Segmental Glomerulosclerosis
Discussion
Our study identified patients with severe kidney involvement treated with therapeutic plasmapheresis in two distinct profiles, despite the predominance of cellular crescents in both groups. There was no statistical difference in socio-demographic or clinical parameters between the two groups defined by kidney outcome at 1 year. The group with the better kidney outcome at 1 year had a higher CRP at diagnosis. For the histological parameter, there was a significant statistical association between normal or abnormal glomeruli and kidney outcome at 1 year.
Our population showed a very high number of patients with a crescentic class in accordance with our selection criteria. Looking at other histological parameters, there was no statistical difference, but the small sample sizes of the groups and the low statistical power of the study are debatable.
If we compare our data with the literature, predominance of cellular crescents was also noticed in the MEPEX study with the same severity at inclusion, with 90% of total crescents [7]. We also found that the percentage of normal glomeruli was a major, well-described prognostic factor [14, 15, 16], particularly in the recent study by the Mayo Clinic [21]. It is also one of the key criteria in Berden’s histopathological classification [13]. Conversely, the higher the prevalence of glomerulosclerosis in the biopsy sample, the worse the kidney prognosis. Zauner et al. [22] showed that global glomerulosclerosis over 33% had a specificity of 100% for predicting end-stage renal disease (ESRD) or death at 24 months. In Neumann’s study [23], patients with less glomerulosclerosis had better kidney recovery. These findings corroborate our observations.
In our study, we examined the circumferential or partial nature of crescents. Few studies have distinguished segmental crescents from circumferential crescents. Unlu et al. [24] divided their cohort of 141 patients with pauci-immune necrotizing glomerulonephritis into 3 groups, according to the extent of extracapillary proliferation: ≥ 50% segmental extracapillary proliferation, ≥ 50% circumferential extracapillary proliferation (the “full moon” group), or neither. The “full moon” group had a greater risk of requiring dialysis during follow-up. The results of our study follow this trend, although they are not statistically significant. We hypothesize that these glomeruli retain residual filtration, thus favoring better recovery after induction treatment.
Conclusions in the literature regarding other lesions present during ANCA GN flare-ups, not included in the usual histoprognostic scores, such as fibrinoid necrosis or rupture of Bowman’s capsule, are divergent. Hauer et al. demonstrated that fibrinoid necrosis was one of the histological features most strongly associated with better kidney function at 18 months [25]. In our study, Group 2 patients more often presented glomerular fibrinoid necrosis (80% vs. 68%). Aasarod et al. [26] found no correlation between the initial kidney function and the number of glomeruli with Bowman’s capsule rupture. Similarly, we did not observe any difference in our cohort, although this type of lesion was rare.
Regarding the tubulointerstitial compartment, interstitial inflammation is well-documented for its link with kidney function at the time of biopsy [16, 25], but the data on its correlation with prognosis remain contradictory. In a study by Lim, moderate to severe interstitial inflammation was identified as a prognostic factor for ESRD [27]. In our cohort, we also observed a higher proportion of patients with over 25% interstitial inflammation in Group 1 (53% vs. 40%), but this difference was not statistically significant.
Interstitial fibrosis and tubular atrophy (IFTA) are usually evaluated together and considered as a single histological parameter [28]. Many studies have confirmed the association between the extent of IFTA and the evolution of kidney function in patients with ANCA GN [25, 22, 24]. In our cohort, a greater proportion of over 25% tubular atrophy was also found in the poor kidney outcome group (37% vs. 20%), whereas there was no difference regarding interstitial fibrosis. This observation correlates with the numerous sclerotic glomeruli responsible for downstream nephron destruction in the group with poor kidney outcome, but with interstitial fibrosis that has not had time to develop due to the pathology’s sub-acute nature.
Finally, in the vascular compartment, it should be noted that, as in the study by Boudhabhay et al. [17], due to our study’s small sample size, we were unable to find a difference between our groups regarding the presence of vasculitis but we noted a tendency for it to be more present in the poor prognosis group.
Several studies have compared the prognostic ability of different classifications to evaluate ESRD-free survival in their cohorts [29, 30]. AKRiS proved to be the most accurate classification for predicting progression to ESRD [15]. In our study, only the ARRS [14] also appeared to be higher in the group with a poorer kidney response, but without statistical significance (median of 7 vs. 3 with a p-value of 0.06). None of the patients in the group with good kidney outcome belonged to Berden’s sclerotic class. GFEV score was high in the two groups with no difference in score association between them.
Our study has several strengths. First, it was a multicenter study in which the kidney biopsies were interpreted by simultaneous double reading, blinded to the patient’s outcome. In agreement with the data in the literature, we found various determinants. The homogeneity of our population at the severe stage of AKI on the same immunosuppressive treatment limited an indication bias.
Nevertheless, the study does have several limitations. First, this was a retrospective observational study with a small number of patients, exposing it to a selection bias with an information bias. Certain data, such as previous symptoms, kidney function and ANCA kinetics were missing. Finally, the population selected must call into question the generalization of results to all patients with an achievable kidney biopsy.
Our results on severe kidney AAV have encouraged us to integrate kidney histology into therapeutics to offer personalized medicine. Some authors have demonstrated the importance and greater accuracy of therapeutic responses when they add histology [18, 31]. In addition to CRP, which has demonstrated its interest in other studies with other biomarkers such as flare- ups [32] and kidney involvement [33], the percentage of normal glomeruli is more associated with a favorable prognosis at 1 year. Depending on the type of extra-renal involvement, kidney-targeted immunosuppression may be adapted to the histological prognosis, which remains to be evaluated in a randomized study that would take the histological score and other involvements into account. However, integrating kidney histology as a therapeutic decision-making tool exposes us to the technical constraint of interpretation time (24 to 48 h) and the availability of a nephropathologist, as well as complications, particularly the risk of hemorrhage. For this reason, the generalization of this tool and the therapeutic scheme will have to depend on care organization.
Conclusion
In our study on a population with severe AKI having benefited from induction immunosuppressive therapy including therapeutic plasmapheresis, the percentage of normal glomeruli was associated with better kidney function at 12 months, whereas a percentage of less than 20% was associated with poorer kidney function at 1 year.
These results may suggest the benefit of performing systematic kidney biopsies in severe AAV kidney injury to assess the evolution of kidney function in these patients and better guide their follow-up and intensity of treatment. Moreover, in the future, prospective randomized studies to test kidney histology with a view to individualized treatment are required.
Acknowledgements
The authors are particularly grateful to Teresa Sawyers, Medical Writer at the BESPIM, Nîmes University Hospital, France, for expert editing services.
Author contributions
FG contributed to the conceptualization, supervision and writing (review and editing) of the manuscript. LC contributed to the data collection and writing the original draft. OM contributed to the methodology of the research, formal analysis and revising the manuscript. PiR, PaR, SyC, SR, EP, PA, HP, LD, SeC and CD contributed to the investigations and care of the patients. All authors have approved the contents of this manuscript and agree to be held accountable for this work.
Funding
No funding was received for this manuscript.
Data availability
Data are available upon request by e-mail to the corresponding author.
Declarations
Ethical approval
Ethical approval was obtained from the IRB at Nîmes University Hospital (number: 25.01.01) and the study was carried out in accordance with the Helsinki Declaration as revised in 2008. Consent to participate was deemed unnecessary according to the IRB at Nîmes University Hospital.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Olivier Moranne and Florian Garo contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available upon request by e-mail to the corresponding author.