PMC7577346_01
Trend of lab values over time in a patient with diabetic retinopathy treated with bevacizumab and subsequent thrombotic microangiopathy. Bev, bevacizumab; Cr, creatinine; dl, deciliter; eGFR, estimated glomerular filtration rate; mg, milligram; ml, milliliter; min, minute.
fmed-07-579603-g0001.jpg
PMC7577346_01_fmed-07-579603-g0001.jpg
F1
After the patient's hypertension was controlled, a kidney biopsy was obtained given the rapid onset of renal dysfunction, worsening proteinuria, and accelerated hypertension (Figure 1).
Biopsy findings in patient 1 with diabetic retinopathy and nephropathy treated with bevacizumab and subsequent thrombotic microangiopathy. (A) One glomerulus showed segmental luminal obliteration by insudates and lipid, with adherence to Bowman's capsule consistent with segmental glomerulosclerosis (arrowhead, methylene blue stain, 400x). (B) Few glomeruli demonstrated segmental duplication of glomerular basement membranes (arrowhead, Jones methenamine silver stain, 400x). (C) Ultrastructural analysis revealed segmental subendothelial electron lucent widening, with very early duplication of basement membrane material (arrowheads, 20,000x). The light and ultrastructural findings were consistent with chronic thrombotic microangiopathy.
fmed-07-579603-g0002.jpg
PMC7577346_01_fmed-07-579603-g0002.jpg
F2
Three glomeruli contained lesions of segmental sclerosis characterized by luminal obliteration by insudates, foam cells, and lipid, with focal adherence to Bowman's capsule (Figure 2A). The glomeruli were normal in size with predominantly single-contoured capillary basement membranes with segmental double contours (Figure 2B) and patent capillary lumina. Focally within these areas, there was accumulation of flocculent and electron lucent debris with mild layering of new basement membrane material (Figure 2C).
PMC7577346_02
Biopsy findings in patient 2 with diabetic retinopathy and nephropathy treated with bevacizumab and subsequent thrombotic microangiopathy. (A) Immunofluorescence microscopy revealed scattered arterioles which displayed strong amorphous intraluminal and vessel wall staining for fibrinogen (400x). (B) Examination of hematoxylin-eosin (H&E)-stained sections from the frozen tissue demonstrated that the fibrin staining corresponded with changes of arteriopathy, including mucoid intimal thickening (arrowhead) and considerable luminal narrowing, consistent with acute thrombotic microangiopathy (400x). (C) Glomeruli showed changes of diffuse and nodular diabetic glomerulosclerosis (600x). (D) Ultrastructural analysis revealed glomerular basement membranes which showed prominent subendothelial electron lucent widening with accumulation of flocculent debris (20,000x). Overall, the findings were consistent with acute thrombotic microangiopathy.
fmed-07-579603-g0003.jpg
PMC7577346_02_fmed-07-579603-g0003.jpg
F3
Immunofluorescence staining revealed prominent staining for fibrinogen within these arterioles (Figure 3A). Arteries displayed mild to moderate intimal fibrosis, and arterioles had muscular hypertrophy, insudates, and mucoid intimal thickening with luminal narrowing and endothelial cell swelling (Figure 3B). Mesangial areas displayed diffuse and nodular expansion by matrix material (Figure 3C). Segmentally, there were subendothelial lucencies with flocculent material as well as segmental mesangial cell interposition with double-contour formation (Figure 3D).
PMC7577346_03
Biopsy findings showing arteriopathy and chronic thrombotic microangiopathy in patient 3. (A) There is severe arterial sclerosis, associated with focal global glomerulosclerosis, periodic acid-Schiff (PAS) stain, 200x. (B) Non-sclerosed glomeruli reveal irregular thickening and segmental remodeling of the capillary loops, with occasional double contours (yellow arrowheads), PAS stain, 400x. (C) There is dull reactivity for fibrin along the glomerular capillary walls on immunofluorescence microscopy, fluorescein isothiocyanate (FITC) stain, 200x. (D) On electron microscopy, glomerular capillary walls reveal subendothelial widening by electron lucent material (red arrowhead), 10,000x.
fmed-07-579603-g0004.jpg
PMC7577346_03_fmed-07-579603-g0004.jpg
F4
The biopsy was dominated by chronic changes, in the setting of severe arterial sclerosis [Figure 4A, periodic acid-Schiff (PAS) stain, 200x]. Outside of this scar, there were up to 10 glomeruli, often revealing irregular thickening and segmental remodeling of the capillary loops, with occasional double-contour formation (Figure 4B, PAS stain, 400x, yellow arrowheads). On immunofluorescence microscopy, no immune-type deposits were present, but there was dull reactivity for fibrin along the glomerular capillary walls [Figure 4C, fibrinogen fluorescein isothiocyanate (FITC) stain, 200x]. Glomerular capillary walls often revealed subendothelial widening by electron lucent material on electron microscopy (Figure 4D, 10,000x, red arrowheads).