Helpful Resources

Proteinuria and Hypertension in Vascular Endothelial Growth Factor (VEGF) Inhibition

Why proteinuria may occur

VEGF inhibition and proteinuria

  • Proteinuria, or an excess of protein in the urine, can occur with cancer and some cancer therapies1-3

  • In a clinical setting, impairment of the glomeruli that make up the kidney may be a pathologic cause of persistent proteinuria4

  • In the preclinical setting, inhibition of VEGF, a key endothelial growth factor, has been shown to impair glomerular endothelial cells5

The kidney is made up of about 2.5 million glomeruli. Glomeruli are made up of a basement membrane, epithelial cells, and endothelial cells. Healthy glomerular endothelial cells help filter the plasma. Water and small solutes pass through the glomeruli, but not proteins or cells.6-8

Why hypertension may occur

VEGF interacts with nitric oxide to regulate vascular tone

  • Nitric oxide is a messenger molecule (a molecule that carries signals between cells) that can regulate various physiologic functions, including blood pressure9,10

  • Some studies suggest that VEGF increases nitric oxide production, resulting in vasodilation9-13

  • Reducing nitric oxide production results in vasoconstriction; it has been hypothesized that this process could play a role in hypertension9-14

The presence of VEGF is associated with the production of nitric oxide.9-13

Proteinuria Monitoring and Management

Diagnosing and monitoring proteinuria15

  • Urine dipstick or urinalyses are performed to detect proteinuria in most cases

  • While 24-hour collection has been the standard of care for quantitative measurement of proteinuria, the urine protein-to-creatinine (UPC) ratio is increasingly being used

  • Patients should be monitored for the development or worsening of proteinuria with serial urinalyses

CTC* Grade16 (version 3.0)
Adverse Event01234
Proteinurianormal or <0.15
g/24 hours		1+ or 0.15–1.0
g/24 hours		2+ to 3+ or >1.0–3.5
g/24 hours		4+ or >3.5
g/24 hours		nephrotic syndrome
  • 1+, 2+, 3+, and 4+ values obtained with urine dipstick analysis.
  • *Common toxicity criteria

Diagnosis and incidence of proteinuria in Avastin clinical trials1

  • In Studies 1, 3, and 5, the incidence of NCI-CTC grade 3 and 4 proteinuria, characterized as >3.5 g/24 hours, ranged up to 3.0% in Avastin-treated patients

  • Across clinical trials, nephrotic syndrome occurred in 7 of 1459 (0.5%) patients receiving Avastin—Avastin should be permanently discontinued in patients who develop nephrotic syndrome

Monitoring and management of proteinuria in Avastin clinical trials1

  • Patients receiving Avastin should be monitored for the development or worsening of proteinuria with serial urinalyses

  • In most clinical trials, Avastin was interrupted at urine protein levels of ≥2 g/24 hours and resumed when protein levels decreased to <2 g/24 hours

  • Patients with moderate to severe proteinuria based on 24-hour collections should be monitored regularly until improvement and/or resolution is observed

  • The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated

  • Avastin should be temporarily suspended in patients with moderate to severe proteinuria

Hypertension Monitoring and Management

Monitoring blood pressure (BP)1

  • BP monitoring should be conducted every 2 to 3 weeks during treatment with Avastin

  • Patients who develop hypertension may require BP monitoring at more frequent intervals, even if they have discontinued therapy (hypertension may persist following discontinuation)

Incidence of hypertension in Avastin clinical trials1

 Avastin clinical studiesStudy E4599 (first-line NSCLC)Study 2107 (first-line MCRC)Study E3200 (second-line MCRC)
Grade 3–4 hypertension in patients receiving Avastin8%–18%16%12%9%

  • Grade 3 hypertension is defined as a recurrent or symptomatic increase of >20 mm Hg (diastolic), or an increase to >150/100 mm Hg if previously within normal limits, that requires therapy or more intensive therapy than previously required. Grade 4 hypertension is defined as hypertension with life-threatening consequences, such as hypertensive crisis16

  • Development or worsening of hypertension has resulted in hospitalization or discontinuation of therapy in up to 1.7% of patients1

  • Complications can include hypertensive encephalopathy (in some cases fatal) and CNS hemorrhage1

Management of hypertension in Avastin clinical trials1

  • In clinical trials, standard oral antihypertensives were used in the management of grade 3 hypertension: angiotensin-converting enzyme (ACE) inhibitors, beta blockers, diuretics, and calcium channel blockers

  • Avastin should be temporarily suspended in patients with severe hypertension that is not controlled with medical management and permanently discontinued in patients with hypertensive crisis or hypertensive encephalopathy

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References
  1. Avastin Prescribing Information. Genentech, Inc. March 2008.
  2. Rudman D, Chawla RK, Nixon DW. Trans Assoc Am Phys. 1978;91:229-241.
  3. Ferrari S, Pieretti F, Verri E, et al. Anti-Cancer Drugs. 2005;16:733-738.
  4. Eknoyan G. Cleve Clin J Med. 2003;70:493-501.
  5. Ostendorf T, Kunter U, Eitner F, et al. J Clin Invest. 1999;104:913-923.
  6. Sugimoto H, Hamano Y, Charytan D, et al. J Biol Chem. 2003;278:12605-12608.
  7. Wikipedia Web site. http://en.wikipedia.org/wiki/Glomerulus_%28kidney%29. Accessed December 12, 2007.
  8. Haraldsson B, Sorensson J. News Physiol Sci. 2004;19:7-10.
  9. Wu HM, Huang Q, Yuan Y, Granger HJ. Am J Physiol. 1996;271:H2735-H2739.
  10. Hood JD, Meininger CJ, Ziche M, Granger HJ. Am J Physiol. 1998;274:H1054-H1058.
  11. Hariawala MD, Horowitz JR, Esakof D, et al. J Surg Res. 1996;63:77-82.
  12. Shen BQ, Lee DY, Zioncheck TF. J Biol Chem. 1999;274:33057-33063.
  13. Yang R, Thomas GR, Bunting S, et al. J Cardiovasc Pharmacol. 1996;27:838-844.
  14. Kimura H, Esumi H. Acta Biochem Pol. 2003;50:49-59.
  15. National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl):S1-S266.
  16. National Cancer Institute. Cancer Therapy Evaluation Program. Common toxicity criteria for adverse events, Version 3.0. http://ctep.cancer.gov/reporting/ctc.html. Accessed December 4, 2007.