Patient characteristics at baseline are reported in Table 2. A total of 170 patients (101 males) with IgAV-N were included. The median age at diagnosis was 7.8 years (IQR 5.7-10.9). The median time from IgAV onset to IgAV-N diagnosis was 17 days (IQR 10-34).
The median highest protein-to-creatinine ratio was 369 mg/mmol (IQR 197-704). Forty-six patients (27.1%) presented with NS. The median eGFR was 118 ml/min per 1.73 m2 (IQR 102-141). Only 14 patients (8.4%) had a decreased eGFR < 90 ml/min per 1.73 m2 at diagnosis.
The median time from IgAV-N diagnosis to kidney biopsy was 17 days (IQR 10-39). The kidney biopsy reports were reviewed by two pathologists (no full review of biopsies) and were classified as ISKDC grade I in 23 patients (13.5%), grade II in 73 patients (42.9%), grade III in 68 patients (40.0%) including 44 patients with grade IIIA and 24 with grade IIIB, grade IV in two patients (1.2%) and grade VI in four patients (2.4%). Endocapillary proliferation was described in 125 patients, 87 patients with endocapillary proliferation observed in < 50% of the glomeruli and 38 patients with endocapillary proliferation in > 50% of the glomeruli. Chronic lesions were present in 42 patients (24.7%). Specifically, interstitial fibrosis was present in 22 biopsies (12.9%), glomerular sclerosis in 15 biopsies (8.8%) with a median number of 5.5% (IQR 3.7-9.7) per biopsy, and fibrous crescents in 15 biopsies (8.8%) with a median number of 6.3% (IQR 4.8-5.7) per biopsy. In patients with chronic lesions, the median time from IgAV-N diagnosis to kidney biopsy was 30 days (IQR 12-59) versus 17 days (IQR 9-32) in patients without chronic lesions (p<0.01). The median follow-up duration was 21 months (IQR 12-39), which was similar for patients with and without chronic lesions.
Treatment of IgAV-N
Corticosteroids were administered orally in 153 patients (90.0%) for a median of 4.6 months (IQR 3.9-6.4), with 103 patients (60.6%) also receiving three methylprednisolone pulses. ACEis or ARBs were administered in 155 patients (91.2%). Twenty-five patients (14.7%) received other immunosuppressive treatments in addition to or following steroid therapy, as follows: cyclophosphamide (20 patients), mycophenolate mofetil (2 patients), intravenous immunoglobulin (2 patients), and azathioprine (1 patient). The median duration of any immunosuppressive drugs combined was 2.8 months (IQR 2.4-2.9). The median duration of cyclophosphamide treatment was 2.7 months (IQR 2.5-2.8). In 2 patients treated with mycophenolate mofetil, the duration of treatment was 19.4 months and 3.2 months, and in patients treated with azathioprine, the duration was 9.8 months.
One patient with a severe clinical and histological presentation was treated by plasma exchange (10 sessions). At 1 month from IgAV-N diagnosis, 5 patients received two methylprednisolone pulses. Three of them had already received methylprednisolone pulses at diagnosis of IgAV-N.
Factors associated with proteinuria at diagnosis
At diagnosis, children under 10 years (p=0.029) and those with endocapillary proliferation in more than 50% of their glomeruli (p=0.001) had a higher protein-to-creatinine ratio in the multivariate analysis (Table 3). In addition, patients with established NS at diagnosis had more severe histological lesions, with higher ISKDC grades as follows: 3.0 (IQR 2.0-4.0) vs. 2.0 (IQR 2.0-3.0) (p=0.004), a higher prevalence of extracapillary proliferation: 10.3% (IQR 0.0-20.6) vs. 5.3% (IQR 0.0-6.5) (p=0.03), and more extensive endocapillary proliferation: 39.3% (IQR 20.7-55.0) vs. 23.3% (IQR 0.0-33.3) (p=0.001) (Table 4).
Overall, the cumulative prevalence of remission was 30%, 51%, 70%, 76%, 81% and 83% at 3, 6, 12, 24, 36 and 48 months, respectively (Figure 1). Nineteen patients had at least one additional biopsy during follow-up. Among these patients with recurrent biopsies, three patients without chronic lesions but with endocapillary proliferation in the initial biopsy had interstitial fibrosis during follow-up biopsies.
In the multivariate analysis, interstitial fibrosis on initial kidney biopsy was associated with the protein-to-creatinine ratio at 3 months (β = +178, p = 0.008). In addition, the time between IgAV-N diagnosis and the introduction of corticosteroids was significantly associated with the protein-to-creatinine ratio at the 6-month follow-up (β = +0.1, p <0.0001); the shorter the time between IgAV-N diagnosis and the introduction of corticosteroids, the lower was the protein-to-creatinine ratio at 6 months.
(supplementary data S2).
Outcome at last follow-up
The median follow-up was 21 months, with 30% of patients being followed for more than 3 years. At the last follow-up, two-thirds of patients (115/170, 68%) had no kidney sequelae (no residual proteinuria or decreased kidney function, i.e., group A). Of these 115 patients, 105 were treated with oral corticosteroids, of whom 69 (60%) also received methylprednisolone pulses, and 10 (9%) received additional immunosuppressive therapy. Thirty percent of patients (51/170) had moderate urinary abnormalities (group B). Of these 51 patients, only five received ACEis, and 13 patients received several treatments (ACEis, corticosteroids, and immunosuppressants). Only 2 patients had more severe kidney impairment (group C). Both had severe IgAV-N with NS and an ISKDC grade IIIB kidney biopsy at IgAV-N onset. Two patients were lost to follow-up immediately after the diagnosis of IgAV-N.
At the last follow-up, the kidney outcome was significantly associated with confirmed NS at IgAV-N diagnosis (p=0.045) and the presence of cellular crescents (p=0.027) and chronic lesions such as glomerular sclerosis (p=0.046) and fibrous crescents (p=0.046) in the kidney biopsy (Table 5).