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Proteinuria in a Patient Receiving Anti-VEGF Therapy for Metastatic Renal Cell Carcinoma

Summary and Introduction

Summary

Background: A 59-year-old man who had undergone a left nephrectomy for renal cell carcinoma was found to have metastatic disease during a restaging examination. The patient was started on treatment with interferon α2b plus bevacizumab, a humanized monoclonal anti-vascular endothelial growth factor antibody. After 9 months of this therapy, the patient developed proteinuria, which gradually increased to over 6 g/day.
Investigations: Physical examination, urine and blood analysis, biopsy of the right kidney, and histologic evaluation of the non-neoplastic portion of the left nephrectomy specimen.
Diagnosis: Thrombotic microangiopathy and IgA immune-complex deposition in the glomerular capillary walls and mesangium.
Management: Discontinuation of interferon α2b and bevacizumab, control of blood pressure with an angiotensin-converting-enzyme inhibitor and an angiotensin-receptor blocker.

Introduction

A 59-year-old white male with a past medical history significant only for well-controlled hypertension and type II diabetes mellitus presented with progressive fatigue, abdominal pain and weight loss. An abdominal CT scan revealed two large left renal masses indicative of malignancy. The patient underwent a left radical nephrectomy. Examination of the tumor demon

strated conventional clear cell renal carcinoma staged as T3aN0M0.

Three months after nephrectomy, a restaging investigation showed evidence of metastatic disease in the lungs. Treatment with interferon α2b plus bevacizumab was initiated. Bevacizumab is a humanized monoclonal anti-vascular endothelial growth factor (anti-VEGF) antibody,[1] thought to inhibit tumor growth by blocking the angiogenesis that is supported by VEGF-induced endothelial cell proliferation and survival.[2] Corticosteroids were not used. A detailed chronology of changes in the patient's k

idney function, proteinuria, and blood pressure is presented in Table 1 . At the start of therapy, the patient's serum creatinine level was 115 μmol/l and urinalysis was unremarkable–specifically there was no proteinuria or hematuria. Four months later, the patient's serum creatinine level had increased to 141 μmol/l and his angiotensin-converting-enzyme inhibitor (quinapril) was discontinued. His serum creatinine level remained elevated. Nine months after therapy was started, serial dipstick evaluations of the patient's urine demonstrated the development of grade 1-2+ proteinuria. A 24-hour urine collection at this time contained 1,836 mg of protein. Between 9 months and 14 months after the start of therapy, proteinuria remained in the range 600-1,500 mg/day; however, it then increased significantly, despite i

nitiation of an angiotensin-receptor blocker (telmisartan) at 13 months ( Table 1 ). Interferon α2b was discontinued after 15 months because of neuropsychiatric symptoms including anxiety and depression. Bevacizumab was stopped after 15.5 months as a result of the proteinuria and elevated serum creatinine level. The patient achieved complete remission of metastatic renal cell carcinoma and remains disease-free 25 months after therapy was started.

As a result of continued nephrotic-range proteinuria and renal insufficiency after stopping interferon α

2b and bevacizumab, the patient was referred to a nephrology clinic for evaluation approximately 2 months after these therapies were discontinued ( tablet 1 ). Physical examination found a thin, but not cachectic, white male in no distress. His blood pressure was 142/80 mmHg. He had no cervical lymphadenopathy, findings from his cardiopulmonary exam were normal, and his abdomen showed a well-healed scar, no masses, and no enlargement of the liver or spleen. He had mild to moderate bilateral lower extremity edema to the level of the midshin. Analysis of the patient's urine sediment showed 3-4 white blood cells per high power field, 0-2 red blood cells per high power field, no dysmorphic red blood cells, and an occasional white blood cell cast. Hepatitis, autoimmune, and HIV serologies were all negative and complement levels were normal. Serum and urine immunofixation did not show a monoclo

nal gammopathy. There was no indication of a hypercoagulable state, as evidenced by normal values for INR (international normalized ratio), partial thromboplastin time, D-dimer, and anticardiolipin (IgG and IgM) antibodies, and a negative lupus anticoagulant test. During the course of therapy with interferon α2b and bevacizumab, the patient developed a mild microcytic anemia (mean corpuscular volume 77 fl) with a nadir hemoglobin of 105 g/l, leukopenia with a nadir white blood cell count of 2.6 × 109/l, a

nd mild thrombocytopenia with a nadir platelet count of 126 × 109/l. Cardiac function showed a normal ejection fraction. An ultrasound-guided renal biopsy was performed about 2 months after interferon α2b and bevacizumab were discontinued.

Kidney Biopsy Findings

Up to seven enlarged glomeruli were present in each of the sections prepared for light microscopy. Methenamine silver staining showed that these glomeruli had markedly thickened capillary walls with double contours (Figure 1). One arteriole was occluded by amorphous eosinophilic material (Figure 2) and an adjacent artery showed

mucoid intim

al thickening. Mild focal arterial fibrous intimal thickening was present. Neither glomerular nor arteriolar fibrin thrombi were observed, and no fragmented red blood cells were seen. The interstitium displayed very mild patchy fibrosis and tubular atrophy, involving approximately 10% of the cortex.

Figure 1. (click image to zoom)

Light microscopy of the kidney biopsy. Thickened glomerular capillary walls are shown by (A) periodic acid-Schiff and (B) methenamine silver staining. The silver stain also shows double contours in some capillary loops (arrows; original magnification of both images ×400.)

Figure 2. (click image to zoom)

Light microscopy of the kidney biopsy. Amorphous eosinophilic debris in an arteriole (arrow) and glomerular capillary hyalinosis (arrowhead) are shown (hematoxylin and eosin stain; original magnification ×200).






Frozen sections prepared for direct immunofluorescence microscopy contained up to five glomeruli, and showed strong diffuse granular IgA deposits in the glomerular capillary walls and mesangial areas (Figure 3). These deposits also demonstrated moderate fluorescence for kappa and lambda light chains, and mild fluorescence for IgG and IgM. The glomerular capillary walls and mesangial regions showed mild, segmental granular staining for the complement component C3, and only trace staining for C1q. There was moderate to prominent segmental glomerular capillary wall and mesangial fibrinogen staining.