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NDT Advance Access originally published online on July 5, 2007
Nephrology Dialysis Transplantation 2007 22(10):2778-2780; doi:10.1093/ndt/gfm259
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Renal side effects of anti-VEGF therapy in man: a new test system*

Tammo Ostendorf1, An S. De Vriese2 and Jürgen Floege1

1Division of Nephrology, RWTH University of Aachen, Aachen, Germany and 2The Renal Unit, AZ Sint-Jan AV, Brugge, Belgium

Correspondence and offprint requests to: Dr Tammo Ostendorf, Division of Nephrology, University Hospital Aachen, Pauwelsstr. 30, D-52057 Aachen, Germany. Email: tostendorf{at}ukaachen.de

Humanized, anti-vascular endothelial growth factor (VEGF) antibodies like bevacizumab (Avastin) have been approved by the FDA for systemic treatment in cancer and local application in age-related macular degeneration [1]. In a recent review and meta-analysis of published clinical trials with bevacizumab, a dose-dependent increase in the risk for proteinuria and hypertension was documented [2]. The FDA therefore issued warnings concerning the renal toxicity and thromboembolic events (http://www.fda.gov/cder/drug/InfoSheets/patient/bevacizumabPIS.htm). Preclinical testing of anti-human VEGF agents in the past was often difficult, since most of the anti-human VEGF antibodies failed to neutralize rodent VEGF-A.



   Summary of key findings
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 Summary of key findings
Background
 Take-home-messages
 References
 
In the 27 February issue of Proc Natl Acad Sci USA, Gerber et al. describe an improved mouse model that facilitates the future preclinical testing of anti-human VEGF agents and further unravels the renal sequelae of VEGF inhibition [1]. By gene replacement technology, the group engineered mice [hum-X VEGF knock-in (KI) mice] to express a humanized form of VEGF, which is recognized by many anti-human VEGF antibodies. This murine test system now allows an evaluation of the efficacy and safety of VEGF-antagonists in physiological and pathophysiological circumstances. In their study, Gerber et al. tested different humanized, anti-human VEGF antibodies with different VEGF-A binding affinity in healthy hum-X VEGF KI mice. Long-term treatment had no effect on organs like heart, spleen, pancreas and lung. Changes in the liver were subtle and included increased serum levels of alanine- and aspartate-aminotransferase. In contrast, significant pathology was noted in the kidney, including an activated mesangium, damaged endothelium and podocytes, and finally, glomerulosclerosis. Importantly, the renal toxicity correlated with the target-affinity of the VEGF-A antagonists. Thus, Gerber et al. showed that administration of VEGF antibodies with low affinity effectively reduced tumor growth in RAG2 knockout; hum-X VEGF KI double homozygous mice. However, it had less or no renal side effects in contrast to high affinity antibodies [1]. The latter was also reproduced with other high affinity antagonists like soluble VEGF receptors, which led to similar pathophysiological changes [1].



   Background
Top
 Summary of key findings
 Background
Take-home-messages
 References
 
The VEGF-A (commonly referred to as ‘VEGF’ only) system is a complex interplay of ligands, VEGF receptors, soluble VEGF receptors, e.g. sFlt-1 and modulators of VEGF receptor binding such as heparan sulphate proteoglycans and neuropilin receptors (Figure 1). VEGF-A is a key player in (patho-)physiological angiogenesis [3]. In the normal kidney, VEGF-A is mainly expressed by podocytes and tubular cells [4], with VEGF-165 being the main isoform [5]. VEGF receptors in turn are expressed by the glomerular endothelium [6]. This initially raised the puzzling question of how a growth factor that is produced by podocytes can signal ‘upstream’ in the glomerular endothelium. This question has been beautifully resolved by specifically overexpressing or deleting VEGF-A in podocytes [7,8]. These latter studies provided evidence for an important role of VEGF-A in the maintainance of the glomerular filtration barrier and the mesangium, since even small deviations of the physiologic VEGF-A production by podocytes had detrimental consequences within the glomerular tuft [7,8].


Figure 1
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  		Fig. 1. (A) Schematic outline of VEGF-A isoforms and their receptor interaction domains. Antagonistic isoforms, denoted VEGF165b etc., are not shown. (B) Schematic outline of the various VEGF receptors and their ligands.

 
By now, many studies reported dysregulated VEGF expression in different experimental and human renal pathological situations, partly with contradictory results (extensively reviewed in [6]). Vital for these divergent results are the different time points of VEGF analyses in the respective diseases. In most instances of glomerular pathology, VEGF-A expression is increased early in the disease process and decreases in parallel with advancing glomerulosclerosis, i.e. podocyte loss [6]. Recently, endogenous inhibitory isoforms of VEGF-A have been identified in podocytes, adding a further layer of complexity to the VEGF-A system. The presence of the endogenous inhibitory isoforms has so far not been taken into account in most studies [9]. In other instances, glomerular regulation of VEGF-receptors instead of VEGF-A has been documented during disease [10].

In normal mice and rats, neutralization of circulating VEGF-A by injection of anti-VEGF-A antibodies or soluble VEGF-R1 (sFlt-1) induced proteinuria, glomerular endothelial cell detachment and suppression of nephrin, an important protein for the maintenance of the glomerular slit diaphragm [11,12]. In mice with progressive crescentic GN, VEGF blockade via overexpression of soluble VEGFR-1 (sFlt-1) accelerated renal damage [13]. Also, prevention of glomerular capillary repair with a VEGF-A specific aptamer induced rapid and massive tubulointerstitial fibrosis [14]. In contrast, a murine VEGF neutralizing antibody ameliorated early renal injury in 5/6 nephrectomized rats, in mice fed a high-protein diet and in mice and rats with diabetic nephropathy [15–18]. In all these cases, the outcome within a specific disease entity obviously depended on (i) the time point and duration of intervention, e.g. blocking VEGF-A after rather than during phases of capillary repair [14] may have different consequences for the kidney, (ii) the overall VEGF bioactivity, which e.g. depends on the ratio between agonistic and inhibitory VEGF-A isoforms as well as the expression of other inhbitory/synergistic factors such as angiopoietin 1/2 [19] and finally, as discussed above, (iii) the affinity of the VEGF-A antagonists.



   Take-home-messages
Top
 Summary of key findings
 Background
 Take-home-messages
References
 
Hypertension and proteinuria are important side effects of anti-VEGF therapy in patients with malignancies. The new mouse strain described by Gerber et al. [1] markedly improves the options for preclinical testing of anti-human VEGF compounds. Their data also raise hopes that renal toxicity can be separated from growth inhibition of tumors [1]. The mice also remind us that interference with the VEGF-A system in the kidney, be it VEGF administration or blockade, may be hazardous.

Conflict of interest statement. None declared.



   Notes
 
*Comment on Gerber HP, Wu X, Yu L et al. Mice expressing a humanized form of VEGF-A may provide insights into the safety and efficacy of anti-VEGF antibodies. Proc Natl Acad Sci USA 2007;104: 3478–3483. Back



   References
Top
 Summary of key findings
 Background
 Take-home-messages
 References
 

  1. Gerber HP, Wu X, Yu L, et al. Mice expressing a humanized form of VEGF-A may provide insights into the safety and efficacy of anti-VEGF antibodies. Proc Natl Acad Sci USA (2007) 104:3478–3483.[Abstract/Free Full Text]
  2. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis (2007) 49:186–193.[CrossRef][Medline]
  3. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev (2004) 25:581–611.[Abstract/Free Full Text]
  4. Simon M, Grone HJ, Johren O, et al. Expression of vascular endothelial growth factor and its receptors in human renal ontogenesis and in adult kidney. Am J Physiol (1995) 268:F240–F250.[ISI][Medline]
  5. Kretzler M, Schroppel B, Merkle M, et al. Detection of multiple vascular endothelial growth factor splice isoforms in single glomerular podocytes. Kidney Int Suppl (1998) 67:S159–S161.[Medline]
  6. Schrijvers BF, Flyvbjerg A, De Vriese AS. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int (2004) 65:2003–2017.[CrossRef][ISI][Medline]
  7. Eremina V, Cui S, Gerber H, et al. Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol (2006) 17:724–735.[Abstract/Free Full Text]
  8. Eremina V, Sood M, Haigh J, et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J Clin Invest (2003) 111:707–716.[CrossRef][ISI][Medline]
  9. Cui TG, Foster RR, Saleem M, et al. Differentiated human podocytes endogenously express an inhibitory isoform of vascular endothelial growth factor (VEGF165b) mRNA and protein. Am J Physiol Renal Physiol (2004) 286:F767–F773.[Abstract/Free Full Text]
  10. Ostendorf T, Van Roeyen C, Westenfeld R, et al. Inducible nitric oxide synthase-derived nitric oxide promotes glomerular angiogenesis via upregulation of vascular endothelial growth factor receptors. J Am Soc Nephrol (2004) 15:2307–2319.[Abstract/Free Full Text]
  11. Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest (2003) 111:649–658.[CrossRef][ISI][Medline]
  12. Sugimoto H, Hamano Y, Charytan D, et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem (2003) 278:12605–12608.[Abstract/Free Full Text]
  13. Hara A, Wada T, Furuichi K, et al. Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int (2006) 69:1986–1995.[CrossRef][ISI][Medline]
  14. Ostendorf T, Kunter U, Eitner F, et al. VEGF(165) mediates glomerular endothelial repair. J Clin Invest (1999) 104:913–923.[ISI][Medline]
  15. Schrijvers BF, Flyvbjerg A, Tilton RG, Rasch R, Lameire NH, De Vriese AS. Pathophysiological role of vascular endothelial growth factor in the remnant kidney. Nephron Exp Nephrol (2005) 101:e9–e15.[CrossRef][Medline]
  16. Schrijvers BF, Rasch R, Tilton RG, Flyvbjerg A. High protein-induced glomerular hypertrophy is vascular endothelial growth factor-dependent. Kidney Int (2002) 61:1600–1604.[CrossRef][ISI][Medline]
  17. De Vriese AS, Tilton RG, Elger M, Stephan CC, Kriz W, Lameire NH. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes. J Am Soc Nephrol (2001) 12:993–1000.[Abstract/Free Full Text]
  18. Flyvbjerg A, Dagnaes-Hansen F, De Vriese AS, Schrijvers BF, Tilton RG, Rasch R. Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes (2002) 51:3090–3094.[Abstract/Free Full Text]
  19. Woolf AS, Yuan HT. Angiopoietin growth factors and Tie receptor tyrosine kinases in renal vascular development. Pediatr Nephrol (2001) 16:177–184.[CrossRef][ISI][Medline]
Received for publication: 22. 3.07
Accepted in revised form: 3. 4.07


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