Bevacizumab Linked to Increased Risk for High-Grade Proteinuria and Nephrotic Syndrome

Emma Hitt, PhD

June 11, 2010

June 11, 2010 (UPDATED June 14, 2010) — Bevacizumab is associated with an increased risk for high-grade proteinuria and nephrotic syndrome, according to the findings of a new meta-analysis.

Shenhong Wu, MD, PhD, from the Division of Hematology and Oncology at Stony Brook University Medical Center, in New York, and colleagues reported the findings online June 10 in the Journal of the American Society of Nephrology.

In a previous analysis, the researchers reported that the risk for any grade of proteinuria ranged from about 1.4-fold to 2.2-fold for a dose of 2.5 and 5.0 mg/kg per week, respectively. With the current systematic review, they sought to determine the effect of bevacizumab on the development of only high-grade proteinuria.

Dr. Wu and colleagues analyzed data from 16 studies that included 12,268 patients with various cancer types. The incidence of only grade 3 or 4 proteinuria with bevacizumab was 2.2% (95% confidence interval [CI], 1.2% - 4.3%). When compared with chemotherapy alone, bevacizumab combined with chemotherapy significantly increased the risk for high-grade proteinuria by nearly 5-fold (relative risk, 4.79; 95% CI, 2.71 - 8.46; P < .001), and the risk for nephrotic syndrome by nearly 8-fold (relative risk, 7.78; 95% CI, 1.80 - 33.62; P = .006).

The risk for proteinuria increased with higher dosages of bevacizumab. The researchers also found that renal cell carcinoma was associated with the highest risk for proteinuria, with a cumulative incidence of 10.2%. No difference was noted depending on whether platinum-based chemotherapy was used.

"It is important for medical oncologists, nephrologists, and patients to recognize the risk with adequate management to prevent renal failure and cardiovascular complications," Dr. Wu and colleagues note.

They add that the development of high-grade proteinuria may be a class effect of vascular endothelial growth factor (VEGF) inhibitors and that "other VEGF-signaling blockers including axitinib, VEGF Trap, sorafenib, and sunitinib have also been associated with severe proteinuria."

According to the study authors, the mechanism of proteinuria induced by VEGF inhibition may involve multiple pathways that result in injury from reduced VEGF expression of podocytes located in glomerular capillary endothelial cells.

"Patients should be monitored for proteinuria before each bevacizumab administration, particularly those with kidney cancer or receiving [a] high dose of bevacizumab," Dr. Wu told Medscape Medical News. "If patients develop severe proteinuria, bevacizumab treatment should be on hold until it improves," he added.

Independent commentator Toni K. Choueiri, MD, MS, from Harvard Medical School in Boston, Massachusetts, noted that this is an important study and suggests that physicians should be monitoring proteinuria carefully, probably at every patient visit.

However, he pointed out that the test used to measure proteinuria in the studies analyzed was a simple urinalysis test, and "most nephrologists agree that this is not an optimal test to quantify the amount of protein in the urine because results are susceptible to fluctuations in the water content of the urine," he told Medscape Medical News in an interview.

According to Dr. Choueiri, the gold standard for protein quantification is a 24-hour urine collection, but the urine protein-to-creatinine ratio correlates well with the 24-hour urine test and is less cumbersome.

Dr. Wu received honoraria from Onyx Pharmaceuticals, Novartis, and Wyeth, and has been a speaker for Onyx, Pfizer Inc, and Novartis. The other authors have disclosed no relevant financial relationships. Dr. Choueiri is on the advisory board for Genentech.

J Am Soc Nephrol. Published online June 10, 2010.

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