Infection-related glomerulonephritis with IgA deposits, rarely reported in Europe [13, 14], affects mostly patients who present with staphylococcal infection, hematuria, proteinuria and acute kidney injury with a proliferative glomerulonephritis. This presentation is comparable to that observed in American and Asian populations with some particularities in European patients. Moreover, the wide spectrum of both clinical presentation and histologic pattern can make the diagnosis challenging .
In our cohort, most patients affected were males over 60. This finding is comparable to previous results reporting that 75 to 86% of the patients are male with a mean age of 55 to 65 years [9, 10, 12, 16,17,18,19,20]. It must be noted that the youngest of our patients is a 5-year-old boy, indicating that IRGN-IgA, although rarely reported, can be observed in pediatric patients. In this case and in other reported pediatric cases, children with Staphylococcus-related GN had the same presentation as adults, namely proteinuria and renal function impairment .
Poststaphylococcal GN can occur in various immunocompromised backgrounds and a poor prognosis is mainly related to age and comorbidities [5, 6]. The initial description by Nasr et al. reported diabetic nephropathy in all biopsies. Nevertheless, the association between diabetes and IRGN-IgA is inconstant, reported in 8 to 55% of patients in previous studies and in 44% of patients in our study [10, 12, 16,17,18, 22,23,24]. As seen since the first report, Staphylococcus represents the most frequent germ (78% in our study, 60 to 100% in other studies) [10, 12, 17, 18, 24]. A higher frequency of MRSA was observed in Asian and American studies (50 to 60%) compared to our cohort (15%). This observation is consistent with the low incidence of MRSA observed in France .
Regarding the histological features of IRGN-IgA, we noticed some differences compared to Asian and American studies. Most of them reported a similar proportion of mesangial proliferation, crescentic proliferation and fibrinoid necrosis. In our study, endocapillary proliferation (89% vs 23 to 63% in previous series) involved neutrophils in most cases (81% vs 15 to 63% in previous series) and was more frequent than pure mesangial proliferation [9, 10, 12, 17, 18, 20]. We also noticed differences when comparing histological patterns as classified in acute, subacute and resolving by Haas et al. in 2008 . The authors reported more resolving (62%) and less acute (15%) or subacute (23%) patterns compared to our cohort (26, 63 and 11% respectively). It is possible that the time between infection and renal biopsy was shorter in these patients than in patients from other cohorts. The relationship between the infection-to-biopsy delay and histological pattern supports the concept that these patterns represent different evolving aspects of the same disease.
C4d staining is not routinely performed on native kidney biopsy, however it is increasingly studied in various types of glomerulonephritis. We assumed that C4d staining could provide additional information about complement activation in IRGN-IgA. C4d deposits were observed in 65% of our biopsies. Diffuse and global (C4d 2+) capillary wall staining was observed in biopsies with proliferative pattern (acute and subacute), and with a shorter delay between infection and biopsy assessment. These observations are in favor of the activation of the complement pathway, at least during the active phase of infection. According to Sethi et al., C4d deposits in infection-related GN could be related to activation of the classical pathway or lectin pathway of complement . However, in a significant number of cases (34% in our study, 46% in their study), no C4d deposits were observed. Two mechanisms can be proposed: first, complement alternative pathway could be abnormally activated in some patients; second, it is possible that the infection was no longer active in patients in the time elapsing between the onset of infection and the renal biopsy. The latter hypothesis is supported by the longer time lapse observed in patients with segmental and focal or no deposits compared to patients with diffuse and global C4d staining.
Regarding deposits, in addition to subepithelial “humps” deposits which are commonly described in IRGN-IgA, we also observed large subendothelial deposits with hyaline thrombi in 11% of the biopsies. These deposits are rarely encountered but were previously reported by Satoskar et al. in one biopsy, by Worawichawong et al. in 2 biopsies, and by Khalighi et al. in 5 biopsies [18, 24, 27]. This cryoglobulin-like presentation most frequently occurred in patients with Staphylococcus aureus infection. This leads Khalighi et al. to suggest a potential role of staphylococcal toxin as a superantigen responsible for activation of B cells and production of antibodies. Khalighi et al. reported 20% deaths and 80% end-stage renal disease in patients with cryoglobulin-like features (vs 63% of ESRD in patients without cryoglobulinemic presentation). In our cohort, 66% (2 out of 3) of patients with cryoglobulinemic features died (vs. 13% in non-cryoglobulinemic), and none of them had an eGFR> 60 mL/min/1.73m2 (vs. 26% in non-cryoglobulinemic). This presentation probably corresponds to more severe presentation of IRGN-IgA.
IRGN-IgA is a renal disease with poor prognosis. According to the literature data, the risk of end-stage renal disease varies from 20 to 80% of patients, and risk of death reaches 30% [5, 12, 18, 20]. In our study, 33% of patients required hemodialysis during the acute phase of GN, 15% the patients progressed to ESRD, and 23% died. Some authors observed that patients with renal recovery had less frequent acute tubular injury, interstitial inflammation or IF/TA [5, 18]. Our results confirmed the association between the severity of IF/TA and renal prognosis in French patients.
Whether treatment with corticosteroids modified the outcome is unsure. Ten patients (37%) in our study received corticosteroids in addition to antibiotics, and were patients with the more severe renal presentation. No significant improvement in renal outcome was observed. The use of corticosteroids remains controversial. For some authors , steroids may have a place in the treatment of patients who fail to respond to antibiotic therapy or patients with crescentic proliferation, whereas for other authors  it can be deleterious in this form of GN in which infection is often ongoing.
IgAN and IRGN-IgA have similarities which may lead to misdiagnosis, particularly when infections are undiagnosed for a long time. Satoskar et al. summarized both clinical and histologic features that could be helpful in distinguishing these two diagnoses [18, 19]. In our cohort, arguments in favor of IRGN-IgA are: older age (89% were over 50 vs < 30 in most patients with IgAN); nephrotic range proteinuria (70% in our cohort but rare in patients with IgAN); low C3 (16% in our cohort and usually normal in IgAN); severe acute renal failure (all cases except for one in our cohort but uncommon in IgAN). Of note, C4 staining could be an additional distinctive point, it remains classically negative in IgAN because of the activation of the alternative pathway of complement . We performed C4d staining in a small number of supplemental biopsies including 7 classical postinfectious GN and 9 IgAN (data not shown). Interestingly, none of these 16 biopsies presented diffuse capillary wall C4d staining, leading us to speculate that the presence of capillary wall C4d staining could help to distinguish both entities. However, C4d staining was previously observed in some cases of IgAN, corresponding to the activation of lectin pathway of complement, and predictive of a poorer prognosis . A recent study reported 26.4% of capillary wall C4d staining in IgAN, correlated to endocapillary proliferation, rendering C4d inaccurate for differential diagnosis with IRGN-IgA . Some authors hypothesized that IgAN can develop secondary to Staphylococcus aureus infection . However, this hypothesis does not explain the pathophysiology of IRGN-IgA due to other pathogens (25% of our cohort).
IgA deposits due to liver disease represent another differential diagnosis for IRGN-IgA. Most of the previous series of IRGN-IgA included patients with chronic hepatic disease. The largest series reported by Satoskar et al., included 28% of patients with hepatitis C, and at least two of them had liver cirrhosis . According to Hemminger et al., the autopsy series report incidental IgA in about 65% of patients with cirrhosis, but this finding is not associated with renal dysfunction . In our cohort, the 2 patients with hepatic cirrhosis had acute renal failure. They hypothesized that glomerular IgA deposits may be due to both excessive immune complex deposition secondary to bacterial infection and poor clearance secondary to liver dysfunction. The mechanisms, not yet understood, require further pathophysiologic explorations.