TAFRO syndrome as a cause of glomerular microangiopathy: a case report and literature review

Abstract

Background: TAFRO syndrome is a systemic inflammatory disorder that manifests as thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Renal dysfunction is frequently complicated with TAFRO syndrome, however, it is challenging to perform kidney biopsy in patients with TAFRO syndrome in the presence of thrombocytopenia. Renal histology in TAFRO syndrome mainly shows membranoproliferative glomerulonephritis (MPGN)-like lesions or thrombotic microangiopathy (TMA)-like glomerulopathy. We review our case and previous reports of TAFRO syndrome with kidney biopsy findings and discuss the renal pathophysiology of TAFRO syndrome.

Case presentation: We describe a previously healthy 48- year-old woman with TAFRO syndrome. Kidney biopsy performed before the treatment showed diffuse global endocapillary proliferative changes with endothelial cell swelling, double contours of partial capillary walls, and mesangiolysis, consistent with TMA-like glomerulopathy. Glucocorticoid therapy including steroid pulse was ineffective and she developed anasarca, renal dysfunction and oliguria. Hemodialysis was required. However, the anti-Interleukin (IL)-6 receptor antibody (tocilizumab) therapy was very effective. An increase in urinary volume was achieved about 2 weeks after the tocilizumab therapy and hemodialysis was discontinued. To investigate the renal pathophysiology of TAFRO syndrome, we performed immunohistological staining of vascular endothelial growth factor (VEGF)-A, CD34, and D2-40, in our case and a normal control kidney. Glomerular VEGF-A was especially positive in podocytes both, in the control and in the case, with no significant difference and there was a significant increase of VEGF-A staining area in the cortical peritubular capillaries in the case. Both glomerular and renal cortical CD34 expression were significantly decreased in our case. D2-40 expression in cortex was not significantly different.

Conclusions: We reviewed our case and other 10 previous reports about renal biopsy findings in TAFRO syndrome and found that glomerular microangiopathy was a common finding. IL-6-VEGF-axis-induced glomerular microangiopathy may play a crucial role in developing acute kidney injury in TAFRO syndrome and the anti-IL-6 receptor antibody therapy may be useful for TAFRO syndrome refractory to glucocorticoids. About the pathophysiology of VEGF in TAFRO syndrome, VEGF balance in the glomerulus and perhaps in the peritubular capillary system as well may be critical. Further investigation is needed.

Keywords: Castleman disease; Interleukin (IL)-6; Membranoproliferative glomerulonephritis (MPGN); TAFRO syndrome; Thrombotic microangiopathy (TMA); Tocilizumab; Vascular endothelial growth factor (VEGF).

Fig. 1

Kidney Biopsy Findings. Periodic-acid-Schiff staining section shows (a) diffuse global endocapillary proliferative changes with endothelial swelling in the glomerulus. Periodic acid-silver- methenamine staining section shows (b) double contours of partial capillary walls and mesangiolysis. Electron microscopy findings (c). There was marked edema in the subendothelial space and in the mesangial area. There were no electron dense deposits. Epithelial cells showed partial foot process effacement and microvillous transformation. (Original magnification, a-b,× 400)

Fig. 2

VEGF-A, CD34, and D2–40 staining in kidney biopsy. Glomerular VEGF-A was mainly positive in podocytes both, in the control (a) and in the case (b) with no significant difference. Cortical VEGF-A positive staining area was significantly increased in our case (h) than in the control (g). CD34, a marker of endothelium, was positive in glomerular and peritubular capillaries, and arterioles both, in the control (c and i) and in the case (d and j). Both glomerular and cortical CD34 positive staining area were significantly decreased in our case compared to the control. D2–40, a marker of lymphatic vessels, was negative in the glomerulus both in the control (e) and in the case (f). In addition, D2–40 was negative in the targeted cortex area both in the control (k) and in the case (l). Each Fig. 2a, c, or e shows a same glomerulus in the control and each figure (b), (d), or (f) shows a same glomerulus in our case. Each Fig. 2g, i, or k shows a same cortical interstitium area in the control and each Fig. 2h, j, or l shows a same cortical interstitium area in the case. In the cortical interstitium of the case, VEGF-A was mainly positive in the peritubular capillaries but not in the lymphatic vessels. (Original magnification,× 1000)

Fig. 3

Clinical course of the patient. After the diagnosis of TAFRO syndrome, steroid pulse therapy (500 mg/day of intravenous methylprednisolone) was initiated for 3 days from the 11th hospital day. Thereafter, 40 mg/day of prednisolone was administered orally. However, she developed anasarca, renal dysfunction, and oliguria. Hemodialysis was required from the 15th hospital day. Moreover, serum CRP level remained high, and she experienced considerable painful; therefore, treatment with an anti-IL-6 receptor antibody (tocilizumab) was started at a dose of 8 mg/kg (400 mg/day). Her pain reduced considerably; there was gradual improvement in her condition with respect to renal function and edema. Tocilizumab was administered again after 2 weeks. There was an increase in the urinary volume about 2 weeks after the tocilizumab therapy, and hemodialysis was discontinued. Serum VEGF and IL-6 levels after the second tocilizumab therapy were lower at 39.6 pg/mL (normal < 38.3) and 110 pg/mL (normal < 8), respectively. After the dose of prednisolone was tapered to 35 mg/day, 150 mg/day of cyclosporine was administered orally. However, oral cyclosporine was stopped because of adverse effects such as liver dysfunction and vomiting. She was discharged on hospital day 58. Abbreviations: BW: body weight; Cre: Creatinine; CRP: C-reactive protein; CyA: cyclosporine; IL: Interleukin; m-PSL: methylprednisolone; Plt: platelets; PSL: Prednisolone; TCZ: tocilizumab; VEGF: Vascular endothelial growth factor