Dr. Gregory Weiss provides perspective on recent data detailing the potential for kidney damage as a result of long-term inhibition of the renin-angiotensin system.
Hypertension is one of the most common conditions in the world and is a significant risk factor for kidney disease, stroke, and cardiovascular disease. The primary pathophysiological feature seen with prolonged hypertension is a thickening of arterial walls which, over time, can lead to organ damage.
Maria Luisa Sequeira-Lopez MD, a physician at the University of Virginia, has uncovered a peculiar association between the pathophysiology of hypertension and the long-term use of a ubiquitous class of blood pressure medications.
A primary target in the management of hypertension is the renin-angiotensin-aldosterone system (RAA). The RAA is primarily responsible for maintaining an adequate blood pressure such that organs are perfused and the organism in question is able to survive and function. The pathology of hypertension is linked to an overactive RAA system. As such angiotensin-converting-enzyme inhibitors (ACEi) were developed as a treatment for hypertension. These drugs prevent the conversion of angiotensin to its vasoconstricting form, angiotensin II. The peculiarity Sequeira-Lopez and colleagues found was that long-term use of ACEi’s lead to the same arteriolar thickening and organ dysfunction, in a mouse model and in humans, that long-term hypertension itself produced.
Sequeira-Lopez looked at mice with an ablated renin gene. What they found was a progressive thickening of the afferent arterioles and interlobular arteries in the mouse kidneys.1 Stranger still, the arteriolar thickening was due to an increase in renin cells within the walls.1 This same phenomenon was seen in human kidneys following extended inhibition of the RAA system.1 At closer examination it was found that the invasive renin cells were not the classic endocrine cells but of a matrix-secretory type that is pathological to kidney arterioles.1 In both cases, human inhibition of the RAA system or renin knock-out mice, invasion of the kidney arteriole by pathological renin cells led to reduced blood flow and ischemia.1
These findings are both interesting from a basic science perspective and troubling from a clinical viewpoint. Drugs targeting the RAA system are the mainstay of many hypertension treatment regimens. In fact, ACEi’s and angiotensin receptor blockers (ARBs) are often employed to protect the kidneys in diabetic patients with and without hypertension. Not only are these drugs being used by millions of patients worldwide, they have also been shown to reduce the risk of developing major cardiovascular events including heart attacks, strokes, and death.2
These conflicting findings present a bit of a dilemma. For Sequeira-Lopez’s part she does not advocate for discontinuation of ACEi or ARB treatments at this time. She does however call for prospective, randomized, controlled investigations aimed at defining the real-life implications of her findings. Ultimately, we as clinicians measure the effectiveness of our treatments based on outcomes. Even though these data indicate that drugs targeting the RAA system cause thickening of renal arterioles the fact that these drugs are associated with better survival and in most cases increased quality of life should be the driving factor. The role of basic science research is to determine what the figuratively microscopic factors are that produce our macroscopic clinical picture. Now that these authors have uncovered a potential problem with a trusted and proven hypertension treatment it will be up to others to examine the clinical implications in the short and long term.
With over a billion people suffering from hypertension worldwide this discovery warrants a closer look. How can it be that the very treatment produces the same pathological sequelae as the disease itself? It is not uncommon for a study to raise more questions than answers. This is the basis of discovery. By building on good science, we find answers and start asking more questions. With a fresh look at an old treatment, we see here that the book isn’t closed on RAA inhibition.