Did you know your endothelium is hairy?

Just heard an interesting talk on endothelial dysfunction and its relation to nephrology.  One thing I learned is that the vascular endothelium is actually "hairy", as demonstrated from this electron micrograph (taken from this website). These little hairs are the endothelial glycocalyx, a gel-like layer of negatively charged proteoglycans and membrane glycoproteins which helps serve as a protective barrier from blood flow for the endothelial cells. You can't see it on standard light microscopy since it apparently requires special preservation techniques not normally used.  There is some data to suggest that vasculopaths and diabetics have a less developed and overall thinner endothelial glycocalyx compared to healthy controls, suggesting the importance of this structure in maintaining a healthy vasculature. 

In the kidney, the glomerular endothelium is a little different than most other endothelia in that they contain fenestrae:  actual pores in the endothelial cells which are large enough to let most proteins pass through, but small enough to exclude circulating blood cells. The glomerular fenestrated endothelium makes up a component of the glomerular filtration barrier (along with the glomerular basement membrane and the podocyte layers), and the classic teaching is that the negatively charged proteoglycans on this layer help form part of the charge barrier keeping albumin from getting filtered (though this is now being debated by some). Here are some pretty pictures of the glomerular fenestrated endothelium:

Risk Factors for Enhanced CV Mortality in ESRD Patients

Cardiovascular mortality in the general ESRD population is between 10- and 20-fold higher than that of the general population, and is an astounding 65-fold higher in ESRD individuals in the 45-54-year-old subgroup of the Framingham study.  A recent review lists some of the risk factors which have been targeted as being contributers to this enhanced cardiovascular mortality, which include:

1.  Disordered Mineral Metabolism--there has been an increased awareness that calcium-phosphate deposition within the walls of blood vessels could play a role in cardiovascular mortality.

2.  Existence of a pro-inflammatory state--there is good epidemiologic evidence linking hsCRP to mortality in the general population, which appears to also hold true in a dialysis population as well.  

3.  Anemia--it is postulated that anemia drive left ventricular hypertrophy, which is correlated with a worsened cardiovascular mortality.

4.  Dyslipidemia--this is controversial, as LDL levels are often normal in dialysis patients, and treatment of LDL levels with a statin in ESRD patients does not seem to have the same beneficial effect as in the general population.  Perhaps a different altered lipid profile--for example, low HDL and high triglycerides--are responsible for some of the increased cardiovascular disease in ESRD patients.

5.  Endothelial dysfunction--there is some evidence that the endothelium of ESRD patients is less able to synthesize nitric oxide (NO), an inhibitor of vascular smooth muscle cell proliferation and important regulator of blood flow based via its actions as a vasodilator.  

6.  Other biomarkers under investigation--lipoprotein A, hyperhomocysteinemia, and whatever the biomarker-du-jour happens to be--are being investigated into their link between ESRD and cardiovascular mortality.

The difficulty in ascribing any of these risk factors as the predominant cause of the elevated mortality rate seen in ESRD patients is that they are all pretty common in this population.  What dialysis patient doesn't have an elevated hsCRP or anemia at some point?  My guess is, this is a complex problem which is not likely to yield a single answer.

Avastin-induced kidney injury

Avastin (bevacizumab) is one of the commonly used VEGF (vascular endothelial growth factor) inhibitors used to inhibit vascular neogenesis, a process which is required for growth of tumor. It has proven to be a valuable agent in a variety of common cancers, including those of the colon, breast, and lung.

Only problem (from our perspective at least) is that it can result in renal damage. It does so by two main mechanisms: one, it can cause an acute interstitial nephritis (like many drugs) and two (perhaps more interestingly), it can cause a thrombotic microangiopathy which is not unlike the pathophysiology of eclampsia.

Podocytes secrete VEGF, which bind to VEGF receptors on endothelial cells and promote endothelial health; the addition of VEGF inhibitors such as Avastin prevents this interaction and results in endothelial damage. These patients often develop hypertension and may show evidence of a TMA (e.g., elevated LDH, some degree of schistocytes and thrombocytopenia).