Sunitinib induced nephrotic syndrome and thrombotic microangiopathy
A 60-year-old man was diagnosed to have right-sided clear cell RCC in June 2003. He underwent radical nephrectomy and received radiotherapy. During follow-up in November 2006, he was detected to have stomach metastases. He was managed with surgical resection and subcutaneous interferon-a for 6 months, 3 million units thrice weekly. Local disease recurrence developed in February 2008 for which oral sunitinib malate (cycle of 50 mg OD for 4 weeks followed by 2 weeks drug free interval) was started. He developed type 2 diabetes mellitus in March 2006 and was started on oral metformin. Fundoscopy did not show evidence of diabetic retinopathy; and urine was negative for proteinuria. Patient developed hypertension in April 2007 and was started on oral metoprolol 50 mg OD. Blood pressure was under control during follow-up. He developed hypothyroidism in June 2009 for which oral thyroxine 75 mg OD was introduced. In March 2010, baseline serum creatinine was 1 mg/dl.\nIn December 2010, he presented with history of progressively increasing edema, abdominal distension, and loss of appetite of 10-day duration. Examination revealed accelerated hypertension (BP, 180/110 mm of Hg) and anasarca. Urinalysis showed 3+ proteinuria and inactive sediments. Blood investigations revealed serum creatinine, 2.4 mg/dl; serum albumin, 2.6 g/dl; total cholesterol, 325 mg/dl; uric acid, 6.7 mg/dl; LDH, 353 U/l; and serum TSH, 42 mIU/l. Hemogram revealed Hb, 14.0 g/dl; platelet, 123 × 109/l; and total leukocyte count, 7.85 × 109/l. Peripheral smear showed normocytic normochromia and thrombocytopenia. Urine protein creatinine ratio (PCR) was 5 600 mg/g. 24-h urine protein excretion was 4 700 mg/d. USG abdomen showed normal sized left kidney that was biopsied. Biopsy revealed 19 viable glomeruli, exhibiting diffuse and global subendothelial widening with frequent microaneurysms []. Subendothelial spaces contained RBCs and fibrin threads. Silver stain showed double contour appearance of glomerular basement membranes without any apparent mesangial cells or endothelial cell proliferation. Tubulointerstitial compartment had insignificant findings. Swollen endothelium was noticed in the arterioles frequently. Immunofluorescence showed segmental trapping of IgM (1+) and fibrin in the capillaries in two of seven glomeruli. Remaining panel (IgG, IgA, C3, and C1q) was negative. Electron microscope examination showed markedly widened lucent subendothelial area comprising fibrin tactoids. Overlying podocytes showed diffuse effacement of foot processes []. Electron dense deposits were not seen.\nSunitinib was stopped and oral prednisolone 1 mg/kg/day was started. Thyroxine dose was increased to 125 mg OD. He continued to have nephrotic range proteinuria and renal dysfunction. Unfortunately, he presented with cough and dyspnea within 20 days of starting prednisolone. X-ray chest showed bilateral lower lobe pneumonia. Blood culture grew Streptococcus pneumoniae. Intravenous piperacillin-tazobactam was started. Renal function deteriorated and serum creatinine increased to 3.6 mg/dl. In view of severe metabolic acidosis (serum bicarbonate 12 mmol/l), hemodialysis was started. He underwent two cycles of hemodialysis after which renal functions started improving and dialysis was stopped. Serum creatinine reduced to 2.4 mg/dl. Oral prednisolone was tapered to 10 mg OD. In February 2011, his serum creatinine further improved to 2 mg/dl. Oral sorafenib (400 mg BD) was started. Prednisolone was further tapered and stopped. Latest follow-up in October 2011 showed serum creatinine, 1.5 mg/dl; serum albumin, 3.6 g/dl; Hb, 13.7 g/dl; platelet, 228 × 109/l; and urinalysis showed 1+ proteinuria with urine PCR of 600 mg/g.