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Proteinuria

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Background

Proteinuria, defined as the presence of protein in the urine, results from altered permeability of the glomerular filtration barrier for protein. Proteinuria was a concern in phase I and II metastatic breast cancer trials of bevacizumab, although bevacizumab has not been associated with renal impairment. Proteinuria > 150 mg per 24 hours is abnormal and can result from a number of mechanisms, including glomerular injury, because it is believed that vascular endothelial growth factor (VEGF) mediates glomerular endothelial repair.1 Erythropoietin stimulates VEGF release in the glomerulus; therefore, low erythropoietin levels may contribute to proteinuria.2 Proteinuria is assessed and graded based on urine dipstick testing or 24-hour urine collection results (Table 1).3 Analysis of 3 Eastern Cooperative Oncology Group (ECOG)–sponsored bevacizumab trials has shown that proteinuria is uncommon and generally less than grade 2.4 In a study of metastatic CRC, both the incidence and severity of proteinuria were increased in patients receiving bevacizumab compared with the control group.5 Pooled data from clinical trials investigating bevacizumab for cancer treatment show an incidence of 0.5% of nephrotic syndrome, with one patient requiring dialysis and one death.6

Nephrotic syndrome is a clinical complex characterized by 7:

  • Proteinuria > 3.5 g per 24 hours
  • Hypoalbuminemia
  • Edema
  • Hyperlipidemia
  • Lipiduria
  • Hypercoagulability

The 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 is was noted that half the patients developed hypertension first and the other half developed proteinuria.8

There are no specific recommendations for management of proteinuria. However, because of the strong correlation between hypertension and proteinuria, Martel and colleagues recommend that management of hypertension or proteinuria should include 8:

  • Angiotensin-converting enzyme (ACE) inhibitors
  • Angiotensin II receptor blockers (ARBs)

Early intervention may prevent or delay progression of proteinuria and/or hypertension.8 In patients receiving bevacizumab, proteinuria is asymptomatic and reversible.9

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Assessment Tools

Table 1. Common Toxicity Criteria v2.0: Proteinuria

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Grade Description
0 Normal
< 150 mg/24 h
1 1+
> 150 mg to 1.0 g/24 h
2 2+ to 3+
1.0−3.5g/24 h
3 4+
> 3.5 g/24 h
4 Nephrotic syndrome

Data from the National Cancer Institute.3

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Patient Care Algorithm for Management of Proteinuria During
Bevacizumab Therapy

Proteinurea

Data from Genentech Inc,6 Brady et al,7 and Martel et al.8

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References

  1. 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.
  2. Tam BY, Wei K, Ridge JS, et al. VEGF modulates erythropoiesis through regulations of adult hepatic erythropoietin syntheses. Nat Med. 2006;12:793-800.
  3. National Cancer Institute. Common terminology criteria for adverse events v3.0 (CTCAE). Available at: http://ctep.cancer.gov/forms/CTCAEv3.pdf. Go to page 42.
  4. 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. Abstract 241. Click here to access.
  5. 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.
  6. Avastin (bevacizumab) full prescribing information. Available at: http://www.gene.com/gene/products/information/oncology/avastin/insert.jsp.
  7. 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.
  8. Martel CL, Presant CA, Ebrahimi B, et al. Bevacizumab-related toxicities: association of hypertension and proteinuria. Community Oncol. 2006;3:90-93.
  9. Ignoffo RJ. Overview of bevacizumab: a new cancer therapeutic strategy targeting vascular endothelial growth factor. Am J Health-Syst Pharm. 2004;61:S21-S26.

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This page was last modified on 10/11/2006, at 1:16:01 pm ET.

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