Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma

A 70-year-old white man had undergone a left total nephrectomy in 1999 for a clear-cell renal carcinoma, with a residual glomerular filtration rate (GFR) of 41 mL/min per 1·73m2 without proteinuria. In March, 2005, the patient was diagnosed with a pulmonary metastasis, and treatment with interferon alfa was started. Renal function remained stable with no proteinuria, but because of increasingly severe hypertension, treatment was stopped after 7 months. Treatment with bevacizumab was started a month later at a dose of 10 mg/kg every 2 weeks. After the second injection of bevacizumab, renal status changed abruptly with the presence of severe hypertension (210/130 mmHg), a nephrotic syndrome as defined by an albuminuria creatinuria ratio of 539 mg/mmol, and a GFR of 21 mL/min per 1·73m2. There was evidence of a haemolytic-uraemic syndrome with intravascular haemolysis (haptoglobin <0.08 mg/L, lactic dehydrogenase 389 UI/L, haemoglobin 102 g/L), and persistent thrombopenia. Coombs test, complement factors, and factor B, H, and I antigens were negative or normal, but the activity of von Willebrand protease factor was reduced to 53%. Viral, bacteriological, and immunological studies were all aetiologically negative. Transjugular renal biopsy revealed a glomerular thrombotic microangiopathy with many capillary-loop double contours, fibrin thrombi, zones of mesangiolysis (figure 1) strongly positive for antifibrinogen, and endothelial lesions in an interlobular artery. Podocyte lesions were identified by two specific markers: anti-vascular endothelial growth factor (anti-human VEGF monoclonal antibody, clone C1, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and podocalyxin (MLC48A8, INSERM U702, Hôpital Tenon, Paris, France). Staining showed that podocytes adjacent to the zones of mesangiolysis were diminished or absent altogether. Anti-VEGF staining further revealed the persistence of isolated pedicels on the glomerular wall, although the bodies of the podocytes had disappeared (figure 2). Response to stopping bevacizumab was favourable, with normalising blood pressure, disappearance of the stigmata of haemolysis, and return of renal function to previous baseline levels. However, there was persistence of proteinuria with an albuminuria creatinuria ratio of 232 mg/mmol. 2 months after the episode of haemolytic-uraemic syndrome, a second course of anti-VEGF was started, this time with sunitinib, which acts as an inhibitor of the intracellular signalling pathway for VEGF. Sunitinib was stopped after 3 weeks of treatment as a result of the recurrence of a severe haemolytic-uraemic syndrome, with asthenia, severe hypertension (220/120 mmHg under triple treatment), nausea, oedema, and acute renal insufficiency with a GFR of 12 mL/min per 1·73m2. Haptoglobin was undetectable and lactic dehydrogenase concentration was raised to 526 UI/L. Severe thrombopenia had a nadir of 19 000/mm3 of haemoglobin and anaemia had a nadir of 70 g/L. The activity of von Willebrand protease factor was lowered to 27%. Once again, the response of this second episode of haemolytic-uraemic syndrome was favourable in the days after stoppage of sunitinib, although ten courses of plasma exchange were initially needed. Figure 2Podocytes stained with anti-VEGF monoclonal antibody Show full caption Intracytoplasmic staining of normal podocytes present in centre of glomerulus (blue arrow), but staining of certain zones of glomerular basement membrane in periphery (green arrow) is limited to pedicels, with no podocyte cell body visible. (Magnification ×1000). View Large Image Figure Viewer Download Hi-res image Intracytoplasmic staining of normal podocytes present in centre of glomerulus (blue arrow), but staining of certain zones of glomerular basement membrane in periphery (green arrow) is limited to pedicels, with no podocyte cell body visible. (Magnification ×1000).