Correspondence
VEGF Inhibition and Renal Thrombotic Microangiopathy
N Engl J Med 2008; 359:205-207July 10, 2008
- Article
To the Editor:
The article by Eremina et al. (March 13 issue)1 suggests that the survival of glomerular endothelial cells depends on vascular endothelial growth factor (VEGF) from podocytes. The authors propose that VEGF might be transported across the glomerular basement membrane simply by diffusion. However, their proposal is contrary to the general concept that it is unlikely for any molecules to move against the flow of glomerular filtration. Therefore, we used a simple model to calculate whether VEGF could ultimately reach the capillary lumen (Figure 1Figure 1
A Model for VEGF Transport against Glomerular Filtration Flow.).To our surprise, we calculated that VEGF secreted from podocyte foot processes would reach the capillary lumen and accumulate there at a magnitude of up to nearly one third of the concentration generated in the subslit space. Apart from a decreased secretory capacity of the podocytes, this model and the derived equation (equation 4) suggest that the endocapillary VEGF concentration would also be adversely affected by decreased size selectivity of the slit diaphragm (proteinuria), increased thickness of the glomerular basement membrane (diabetes), and glomerular hyperperfusion and hyperfiltration (chronic kidney disease). Until more data are available, we suggest that these conditions might be regarded as potential risk factors for renal thrombotic microangiopathy in patients receiving VEGF inhibitors.
4 ReferencesPisut Katavetin, M.D.
Paravee Katavetin, M.D.
Chulalongkorn University, Bangkok 10330, Thailand
pkatavetin@yahoo.com 1
Eremina V ,Jefferson JA ,Kowalewska J , et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med 2008;358:1129-1136
Full Text | Web of Science | Medline2
Bohle A ,Aeikens B ,Eenboom A , et al. Human glomerular structure under normal conditions and in isolated glomerular disease. Kidney Int Suppl 1998;67:S186-S188
CrossRef | Medline3
Berk DA ,Yuan F ,Leunig M ,Jain RK . Fluorescence photobleaching with spatial Fourier analysis: measurement of diffusion in light-scattering media. Biophys J 1993;65:2428-2436
CrossRef | Web of Science | Medline4
Deen WM ,Lazzara MJ ,Myers BD . Structural determinants of glomerular permeability. Am J Physiol Renal Physiol 2001;281:F579-F596
Web of Science | Medline
To the Editor:
Eremina et al.1,2 have reported that VEGF is important in glomerular disease, elucidating mechanisms of glomerular lesions of thrombotic microangiopathy in the mutant mouse and, now, in humans, when VEGF synthesis by podocytes is inhibited. Thrombotic microangiopathy in mice resulted from direct targeting to delete VEGF from podocytes and, in humans, resulted from exposure to an agent that inhibits VEGF.
We previously reported thrombotic microangiopathy in a patient receiving anti-VEGF treatment for renal-cell carcinoma.3 The glomeruli showed numerous capillary-loop double contours, fibrin thrombi, endotheliosis, and mesangiolysis.3 The thrombotic microangiopathy was dose-dependent, disappearing clinically on cessation of anti-VEGF therapy, then relapsing when therapy was resumed. Podocytes that were identified with two specific markers, anti-VEGF and podocalyxin, showed that podocytes adjacent to mesangiolysis were diminished or absent. Anti-VEGF staining revealed the presence of isolated pedicels on the glomerular wall, although the bodies of the podocytes had disappeared. In humans, anti-VEGF thrombotic microangiopathy is similar to preeclampsia, both morphologically and clinically, in that each can resolve when the placenta is delivered4 or anti-VEGF is stopped.3
4 ReferencesDominique Nochy, M.D.
Georges Pompidou European Hospital, 75015 Paris, France
dominique.nochy@egp. aphp. fr Carmen Lefaucheur, M.D.
Saint Louis Hospital, 75010 Paris, FranceGary Hill, M.D.
Georges Pompidou European Hospital, 75015 Paris, France1
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
Web of Science | Medline2
Eremina V ,Cui S ,Gerber H , et al. Vascular endothelial growth A signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. J Am Soc Nephrol 2006;17:724-735
CrossRef | Web of Science | Medline3
Frangie C ,Lefaucheur C ,Medioni J ,Jacquot C ,Hill GS ,Nochy D . Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol 2007;8:177-178
CrossRef | Web of Science | Medline4
Nochy D ,Heudes D ,Glotz D , et al. Preeclampsia associated with focal and segmental glomerulosclerosis and glomerular hypertrophy: a morphometric analysis. Clin Nephrol 1994;42:9-17
Web of Science | Medline
Author/Editor Response
We are grateful to Katavetin and Katavetin for presenting a kinetic model of VEGF synthesis that supports our suggestion that VEGF diffuses from the podocytes to the endothelial cells. The Peclet number (Pe) reveals the importance of convection relative to diffusion1 in the following way: [(ΦKc)×vδ] ÷ [(ΦKd)×D∞], where v denotes filtration velocity, δ membrane thickness, Φ partition coefficient, D diffusion constant for the solute, and Kc and Kd hindrance factors for convection and diffusion, respectively.
Measurements on isolated glomerular basement membranes2 suggest that ΦKc=0.2 and ΦKd=0.02. The latter value shows that diffusion is markedly impaired in the glomerular basement membrane as compared with diffusion in water (2% of D), but convective transport is also restricted. The key point is whether diffusion is more limited than convection; the Pe reflects this. A Pe above unity indicates that transport occurs mainly by convection, and a Pe of less than 1 reflects diffusion-dominated transport.
The Pe in glomerular basement membrane for VEGF can be estimated by using a value of v close to 4×10−4 cm per second and δ close to 2×10−5 cm. VEGF has a Stokes–Einstein radius (rs) of 2.6 nm, which implies that D2.6 nm is 1.26×10−6 cm2 per second. Inserting these values into equation 1 results in a Pe of 0.063. It is safe to conclude that VEGF is transported by diffusion, and diffusion alone, across the glomerular basement membrane.
The model presented by Katavetin and Katavetin has the virtue of simplicity but would appear to be an oversimplification. For example, one needs to incorporate the effects of serial barriers1 to allow for better predictions of concentrations at the endothelium.
Also, as stated by Katavetin and Katavetin, the general perception is that transport across the glomerular barrier is completely dominated by convection. In fact, the opposite is true.2 Thus, the flow conditions in the glomerular basement membrane resemble not a waterfall but, rather, a great lake with slow flow velocity. Consequently, diffusion dominates the transport of most solutes in the glomerular basement membrane.2
We thank Nochy et al. for pointing out an additional published case report by Frangié et al.3 The issue of reversibility of thrombotic microangiopathy raised by the authors is important.4 Although renal function improved in the six cases we reported, we were unable to determine whether it returned to baseline. Frangié et al. found that although hypertension and hemolysis improved, the proteinuria persisted between cycles; this may reflect podocyte loss and segmental sclerosis, as shown in their report. We are aware of a patient at the University of Toronto in whom irreversible chronic kidney injury apparently developed and progressed to end-stage renal failure, despite discontinuation of the VEGF inhibitor.
4 ReferencesBorje Haraldsson, M.D., Ph.D.
Sahlgrenska University Hospital, SE-413 45 Gothenburg, SwedenLaura Barisoni, M.D.
New York University School of Medicine, New York, NY 10016Susan E. Quaggin, M.D.
University of Toronto, Toronto, ON M5S 1A8, Canada
quaggin@mshri.on. ca 1
Haraldsson B ,Nystrom J ,Deen WM . Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev 2008;88:451-487
CrossRef | Web of Science | Medline2
Deen WM ,Lazzara MJ ,Myers BD . Structural determinants of glomerular permeability. Am J Physiol Renal Physiol 2001;281:F579-F596
Web of Science | Medline3
Frangie C ,Lefaucheur C ,Medioni J ,Jacquot C ,Hill GS ,Nochy D . Renal thrombotic microangiopathy caused by anti-VEGF-antibody treatment for metastatic renal-cell carcinoma. Lancet Oncol 2007;8:177-178
CrossRef | Web of Science | Medline4
Patel TV ,Morgan JA ,Demetri GD , et al. A preeclampsia-like syndrome characterized by reversible hypertension and proteinuria induced by the multitargeted kinase inhibitors sunitinib and sorafenib. J Natl Cancer Inst 2008;100:282-284
CrossRef | Web of Science | Medline
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