Diabetic nephropathy with marked extra-capillary cell proliferation: a case report

In the past report, renal biopsy in 273 patients with type 2 diabetes mellitus revealed DN in 24.9%, non-diabetic renal disease in 64.1%, and mixed type in 11.0%. The histological types of non-diabetic renal diseases vary widely [3].

In this case, we initially thought the patient had crescentic GN superimposed on DN because of the marked extra-capillary hypercellularity. There are several reports of DN complicated by crescentic GN, such as ANCA-associated nephritis [4, 5]. On the other hand, there are also reports of DN with crescent formation [4, 6]. Elfenbein et al. reported the rate of crescent formation in cases of renal biopsy or autopsy-confirmed DN. They described that 25.3% of biopsied cases and 17.98% of autopsy cases had crescents and that the rate of crescents was associated with blood urea nitrogen and serum creatinine levels [6]. Otani et al. reported a case with a clinical background and pathologic features similar to our case. They made a diagnosis of crescentic DN and did not administer immunosuppressive treatment [7].

Salvatore et al. retrospectively examined 534 patients with diabetes mellitus who were biopsied for increased urinary protein levels or worsened renal function [8]. The extra-capillary cell proliferation observed in DN was reported to be similar to a pseudo-crescent observed in collapsing glomerulopathy (CG), and 26 (5%) patients had CG findings in addition to DN. Patients with CG findings often had advanced DN, and severe arteriosclerotic findings. Therefore, they hypothesized that ischemia may trigger CG onset in DN.

Mottl et al. examined the pathology associated with renal prognosis in 109 biopsied cases with sole findings of diabetic nephrosclerosis [9]. They reported segmental sclerosis and extra-capillary hypercellularity as poor prognostic factors for end-stage renal failure. They also described that extra-capillary hypercellularity in DN resembles that of CG rather than crescentic GN.

Gaut et al. examined cellular crescents in diabetic glomerulosclerosis by staining for claudin-1 and nephrin and compared them to inflammatory crescents [10]. Claudin-1 is a transmembrane protein expressed at the tight junctions of PEC, and nephrin is a slit membrane protein in podocytes. They reported that diabetic glomeruli with crescents had cells that co-expressed claudin-1 and nephrin. Co-stained cells were not observed in the inflammatory crescent. These findings were similar to those in the present case.

Andeen et al. examined podocyte and PEC markers in DN and reported that claudin-1-positive cells increase in the tuft as DN progressed, which leads to "capping" in the sclerotic region [11]. They also reported cells co-expressing podocyte markers p57 and claudin-1. They hypothesized that podocyte progenitor cells in the PECs or Bowman's capsule migrate to the tuft as compensation for podocyte loss.

It is still controversial whether the origin of extra-capillary cell proliferation in FSGS is from the podocytes or PECs [12,13,14,15]. In our study, we examined two cases of FSGS: the collapsing and NOS variant. Both showed decreased nephrin staining in sclerotic lesions, and proliferating epithelial cells were positive for claudin-1. Although not observed in our study, there are several reports of podocyte and PEC markers co-staining in segmental sclerotic lesions [15, 16].

Podocyte injury and loss have been reported to be common findings in both FSGS and DN indicating glomerular injury [17, 18]. We hypothesize that DN and FSGS share similar pathological and immunohistochemical features due to sharing common pathogenesis.

On the other hand, extra-capillary hypercellularity in crescentic GN is also positive for PEC markers [8, 19, 20]. However, co-staining for podocyte and PEC markers has not been reported.

In this report, we examined a patient with anti-GBM antibody GN. The patient presented as a representative example of anti-GBM antibody GN had a history of diabetes mellitus for approximately 2 years and early DN. Its pathological findings were classified as Renal Pathology Society (RPS) classification class I, with thickening of the GBM, as revealed by electron microscopy. Some extra-capillary hypercellularity lesions were suspected to be co-stained with claudin-1 and nephrin (Fig. 4b). It would be difficult to determine whether the extra-capillary hypercellularity was caused by the anti-GBM antibody GN or DN. Previous reports have shown that the duration of diabetes mellitus in DN with extra-capillary hypercellularity ranges from 0 to 18 years [21]. In contrast, glomerular involvement in DN with extra-capillary hypercellularity is seen in patients with RPS classification class IIa or higher. The more advanced the glomerular lesion, the more often extra-capillary hyperplasia is present. In our GBM antibody GN case, the major findings were crescentic GN with 90% of glomeruli having crescent, whereas findings of DN were mild as class I according to the RPS classification. Therefore, the extra-capillary hypercellularity in this case may be a crescentic GN.

The limitations of this study include the fact that this was a single case. In addition, the involvement of CD44-positive activated PECs and renal progenitor cells has recently been investigated in diseases involving extra-capillary cell proliferation [19, 22]; however, the involvement of these cells was not examined in this study.

In conclusion, although DN with extra-capillary hypercellularity is a rare condition, investigation of extra-capillary lesions using immunostainings may be meaningful.

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