- Proteinuria results from alterations in the permeability of the glomerular filtration barrier for protein
- Proteinuria is closely correlated with hypertension in patients receiving bevacizumab
- Bevacizumab therapy should be held if protein = 2 g in 24 hours and permanently discontinued in the presence of nephrotic syndrome
Proteinuria is an abnormally high amount of protein in the urine resulting from altered permeability of the glomerular filtration barrier for protein. A urine protein level = 0.15 g/24 h is considered an abnormal finding.1 Proteinuria occurs in 27% to 38% of patients receiving bevacizumab.2 It is usually asymptomatic. Grade 3/4 proteinuria is rare, occurring in approximately 1% of bevacizumab-treated patients.2
Proteins (albumin and immunoglobulin) are normally present in the blood, where they aid in coagulation, balance body fluids, and fight infection. The kidneys remove wastes from protein-rich blood through millions of tiny filtering screens called glomeruli. Most proteins are too large to pass through the glomeruli into the urine. The glomeruli are negatively charged, so they repel the negatively charged proteins. Thus, a size and charge barrier keeps protein molecules from entering the urine. When the glomeruli are damaged, proteins of various sizes pass through them and are excreted in the urine, resulting in measurable, but usually asymptomatic, proteinuria.1
The mechanism of proteinuria is not fully understood, but recent research finds that renal thrombotic microangiopathy secondary to impaired vascular endothelial growth factor (VEGF) signaling within the glomerulus may be a factor in the development of bevacizumab-associated proteinuria.3 VEGF is essential to the integrity of the glomerular filtration barrier.4 Glomerular endothelial repair may require VEGF, and anti-VEGF therapy interferes with glomerular endothelial integrity.5,6 Erythropoietin stimulates VEGF release in the glomerulus; therefore, low erythropoietin levels may contribute to proteinuria.7,8 Although proteinuria has not been directly associated with renal dysfunction, Uy and colleagues4 reported a case of nonremitting renal thrombotic microangiopathy and progression to nephrotic syndrome following exposure to bevacizumab. (Note: the patient in that case had ovarian cancer, not CRC.) In most cases, proteinuria improves and usually resolves after bevacizumab is stopped.8,9
The focus of the Uy et al4 article is bevacizumab-associated proteinuria; therefore, in that context, exposure to bevacizumab is the primary risk factor. Comorbid conditions such as hypertension and diabetes increase the risk, independent of bevacizumab exposure.1,10 In a retrospective study of patients (N = 27) who received bevacizumab, Choi et al11 found a statistically nonsignificant correlation between African-American (AA) race and bevacizumab-induced proteinuria (maximum grade 2) and hypertension toxicity. Proteinuria occurred in 50% of AA subjects, compared with 33% of non-AA subjects. In that study, hypertension toxicity was associated with an increased risk of proteinuria.11
Proteinuria is usually an asymptomatic condition; however, patients with more severe (grade 3/4) or longstanding proteinuria may exhibit foamy urine or edema. Secondary edema generally occurs only when proteinuria is in the nephrotic syndrome range.1
Proteinuria is assessed and graded based on urine dipstick testing or 24-hour urine collection results (Table 1).12 Analysis of 3 Eastern Cooperative Oncology Group (ECOG)–sponsored bevacizumab trials has shown that proteinuria is uncommon and generally less than grade 2.13 In a study of metastatic CRC, both the incidence and severity of proteinuria were increased in patients receiving bevacizumab, compared with the control group.2 Pooled data from clinical trials investigating bevacizumab for cancer treatment show an incidence of 0.5% of nephrotic syndrome, with 1 patient requiring dialysis and 1 death.9
Nephrotic syndrome is a clinical complex characterized by14The presence of proteinuria during bevacizumab therapy is statistically associated with hypertension, although a causative relationship has not yet been established. No temporal relationship was found in an observational study in which it was noted that half the patients developed hypertension first and the other half developed proteinuria.15
- Proteinuria > 3.5 g/24 h
Table 1. Common Terminology Criteria for Adverse Events v4.02: Proteinuria
Data from the National Cancer Institute Cancer Therapy Evaluation Program.12
Excessive protein in the urine predominately albumin, but also globulin
< 0.15 g/24 h
0.15-1.0 g/24 h
> 1.0-3.4 g/24 h
> 3.5 g/24 h
Gobel10 reviewed nursing considerations for bevacizumab use, including information on assessment and management of proteinuria. Patients on bevacizumab therapy should undergo serial monitoring of urine protein levels by dipstick or 24-hour urine collection because hydration and nutrition affect urine density and volume. Comorbidities that can contribute to proteinuria, such as hypertension and diabetes, should be considered.10 Temporary suspension of bevacizumab is recommended in patients with evidence of moderate to severe proteinuria pending further evaluation. The risk of continuation or temporary suspension of bevacizumab in patients with moderate to severe proteinuria is unknown.9,10,15
There are no specific recommendations or guidelines for management of proteinuria. Early intervention may prevent or delay progression of proteinuria and/or hypertension.10,15 Because of the strong correlation between hypertension and proteinuria, Martel and colleagues recommend that management of hypertension or proteinuria include15
- Angiotensin-converting enzyme (ACE) inhibitors
- Angiotensin II receptor blockers (ARBs)
Algorithm for Management of Proteinuria During Bevacizumab Therapy
Data from Genentech Inc,9 Gobel,10 Brady et al,14 and Martel et al.1
- Carroll MF, Temte JL. Proteinuria in adults: a diagnostic approach. Am Fam Phys. 2000;62:1333-1340.
- Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335-2342.
- Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358:1129-1136.
- Uy AL, Simper NB, Champeaux AL, Perkins RM. Progressive bevacizumab-associated renal thrombotic microangiopathy. NDT Plus. 2009;2:36-39.
- Cobleigh MA, Langmuir VK, Sledge GW, et al. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol.2003;30(suppl 16):117-124.
- Ostendorf T, Kunter U, Eitner F. VEGF mediates glomerular endothelial repair. J Clin Invest. 1999;104:913-923.
- Tam BY, Wei K, Ridge JS, et al. VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nat Med. 2006;12:793-800.
- Alvarez Arroyo A, Castilla MA, Gonzalez Pacheco FR. Role of vascular endothelial growth factor on erythropoietin-related endothelial cell proliferation. J Am Soc Nephrol. 1998;9:1998-2004.
- Avastin (bevacizumab) full prescribing information. Genentech/Roche. 2008. http://www.avastin.com/avastin/index.jsp. Accessed February 18, 2010.
- Gobel BH. Nursing considerations of bevacizumab use in multiple tumor types. Oncol Nurs Forum. 2007;34:693-701.
- Choi YM, Shord S, Cuellar S, Villano J. Examining ethnic differences for bevacizumab-induced hypertension and proteinuria. J Clin Oncol. 2007;25(suppl). Abstract 21168.
- National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v4.02 (CTCAE).http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf [page 59]. Accessed February 18, 2010.
- Giantonio BJ, Catalano PJ, Meropol NJ, et al. The addition of bevacizumab (anti-VEGF) to FOLFOX4 in previously advanced colorectal cancer (advCRC): an updated interim toxicity analysis of the Eastern Cooperative Oncology Group (ECOG) study E3200. Presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, 2004. Abstract 241. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=27&abstractID=554. Accessed February 18, 2010.
- Brady H, O’Meara Y, Brenner B. The major glomerulopathies. In: Braunwald E, Fauci A, Kasper D, et al, eds. Harrison’s Principles of Internal Medicine. 15th ed. New York, NY: McGraw-Hill.
- Martel CL, Presant CA, Ebrahimi B, et al. Bevacizumab-related toxicities: association of hypertension and proteinuria. Community Oncol. 2006;3:90-93.
glomerulus/glomeruli—small unit(s) in the kidney made up of capillaries and nerve fibers where blood filtration takes place
lipiduria—the presence of lipids (fatty bodies) in the urine
nephrotic syndrome—a clinical complex characterized by proteinuria > 3.5 g/24 h, hypoalbuminemia, edema, hyperlipidemia, lipiduria, and hypercoagulability
proteinuria—the presence of protein in the urine
renal thrombotic microangiopathy—clots or thrombi in arterioles and capillaries of the kidneys