Blog entry by Arif Khwaja

Anyone in the world

There is an interesting publication in JASN online by Remuzzi’s group looking at the effect of angiotensin II inhibition on glomerular vasculature. They use micro-CT and scanning EM to study the effect of RAS inhibition in Munich Wistar Fromter (MWF) rats that spontaneously develop kidney disease with age. Untreated MWF rats develop glomerusclerosis and interstitial fibrosis and micro-CT data showed a reduction of spatial density in arteries and veins in the kidney - in essence a reduction in vascular volume relative to total kidney volume. This effect was reversed by treatment with losaratan and lisinopril which the authors describe as regeneration of the vasculature on the basis that vascular volume increased once treatment started. Scanning electron microscopy data appeared to show that RAS blocked increased glomerular capillary (GC) volume and length. The authors state that this results in increased functional GC and thereby increasing filtering surface area. Losartan and Lisinopril both appeared to reduce mRNA expression of profibrotic mediators such as TGFbeta and endothelin as well as reducing the expression of alpha-smooth muscle actin in both glomerular and interstitial capillaries - which the authors take as a sign of inhibition of endo-mesenchymal transition.

RAS blockade also inhibited endothelial cell apoptosis and increased Nrf2 expression -Nrf2 is thought to be a mediator of endothelial cell dynamics and angiogenesis. In summary the authors conclude that RAS blockade has anti-fibrotic effects via TGFbeta and endothelin (these have been well described in the literature in in vivo and in vitro models) coupled with the angiogenic effects of RAS blockade seen in this model highlights the ‘regenerative’ ability of anti-RAS agents.
My brief thoughts:
i) striking that there was no control group treated with an other anti-hypertensive - therefore impossible to know whether the histological and vascular changes were a RAS blockade-specific effect or a generic effect of lowering blood pressure - I’m very surprised that the reviewers in such a high impact journal didn’t insist that the authors at least acknowledge this point.
ii) this lack of blood pressure control is even more worrying when making claims that RAS blockers can promote regression of glomerusclerosis - we all know that in patients with accelerated hypertension there is regression of glomerular changes with improved blood pressure control.
iii) the EM data is very difficult to interpret and the conclusions made by inferring changes in physiology on the basis of morphological changes seem too simplistic to me .
iv) the whole story is just all too ‘neat’ - RAS blockers inhibit fibrosis via TGFbeta and promote vascular ‘regeneration’ by effects on endothelial cell apoptosis and endothelial-mesenchymal transition and… bingo you have a regenerating kidney. Yet the reality is that these models of kidney disease (e.g. MWF) don’t replicate the complexity of kidney disease in humans where multiple insults (ischaemia, diabetes, hypertension, smoking and ageing) all combine to produce CKD which is usually non-progressive and doesn’t, as the authors suggest, lead ‘invariably to ESRD’. If the story was so simple then the widespread use of RAS blockers would have ‘solved’ the problem of ESRD - yet it clearly hasn’t. Indeed the real world data suggest that these agents maybe positively harmful in certain settings or have absolutely no impact on progression particularly in the elderly population. Furthermore data from the NEPHRON D study (as well as in ONTARGET)  showed that the increased risk of AKI/dialysis with aggressive RAS blockade far outweighed any hypothetical benefits on organ fibrosis - and this is a phenomena not just seen in clinical trials but also in the real world as highlighted by this analysis of primary care admissions.
 
In summary RAS blockers are excellent anti-hypertensive agents. They have risks in certain patient groups (e.g. elderly arteriopaths with ischaemic nephropathy) and whilst they maybe be able to slow down progression of certain kidney diseases as a result of tight BP control, the idea they they can lead to clinically meaningful ‘regeneration’ of fibrosed kidneys seems, to me, fanciful.
 
[ Modified: Thursday, 1 January 1970, 1:00 AM ]