As clinicians we offer our patients Angiotensin-Converting Enzyme Inhibitors or more commonly ‘ACE Inhibitors’ for renal protection but along with their ‘sister’ drug ARB’s (Angiotensin-2 receptor blocker’s) they are in the Top 5 most frequently implicated drugs in acute kidney injury (AKI) (1). How can this paradox be? How can something protect the kidneys but also precipitate injury?
Let’s muse on the thought and breakdown the premises which lead to these seemingly paradoxical conclusions.
But first, to do this, we need to go back to basics.

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What are ACE Inhibitors?
The first ACE inhibitor to enter the market was Captopril in 1981. Medicinal chemists were studying the blood pressure lowering effects of a certain snake venom which blocked the conversion of Angiotensin 1 to Angiotensin 2 via inhibiting the enzyme which catalyses the conversion. Using the chemical found in the venom as a starting point and realising the potential pharmacological benefits of this blood pressure lowering effect they synthesised a series of chemicals structurally similar, which then through modulation became the range of ACE Inhibitors we use today.

The Renin Angiotensin Aldosterone System (RAAS) is the endogenous hormone system off concern here. It is essential for the homeostatic regulation of blood pressure and fluid balance. A brief schematic is shown below (Fig 1) as a summary:

 

 

The kidneys play a crucial in the RAAS and so ACE Inhibitors inherently affect the Kidneys. As ACE Inhibitors block the catalysis of Angiotensin 2, they block the physiological effects of Angiotensin 2 from taking place. This is how they produce their pharmacological effects our patients benefit from in practice.

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ACE Inhibitors and the Kidneys
The renal effects of ACE Inhibitors are of THREE main types; Renal arterial and glomerulus afferent arteriole vasodilation, less mesangial cell contraction and increased sodium excretion via the kidneys (4). The overall effect is reduced arterial resistance in the kidneys and glomeruli, diuresis and natriuresis leading to reduced blood volume and pressure. This is where the paradox is born.

Let’s talk AKI
In certain circumstances a drop in renal perfusion can precipitate acute renal injury. This could be caused by blood loss, heat failure or sepsis for example. We have already mentioned how ACE inhibitors can also reduce blood volume and pressure – decreasing renal perfusion. In normal circumstances, this isn’t enough to cause AKI, however a drop in eGFR is commonly seen when renal function blood tests after initiation are compared to base line readings. But for example, in one of these pathologies which also reduces renal perfusion, it could collectively be enough to precipitate AKI. However, there is another element which makes this more likely; glomeruli efferent arteriole vasodilation. This decreases the resistance to the blood leaving the glomeruli, in a situation where the afferent blood flow has been reduced, increasing the efferent blood flow will result in further decreasing the perfusion. Again, increasing the likelihood of developing AKI.

Let’s talk nephroprotection
Above we talked about how the renal effects of ACE Inhibitors can influence the development of AKI. However, it is precisely one of these effects that we as clinicians’ harness to confer renal protection. The Renal Association has produced guidelines on proteinuria and when to give an ACE I or ARB as renal protection. Proteinuria itself is benign, however it is a significant risk factor for renal and cardiovascular disease (6). This is because proteinuria is a sign that the renal filtration of the blood, at one or more stages, has become pathological. Commonly this is due to either Diabetes Mellitus or Hypertension – this is called nephropathy, as the damage caused is located within the renal nephrons. In both of these pathologies complex and not fully understood mechanisms cause damage to areas and cell types in the glomerulus, this results in impaired blood filtration and disruptions in fluid and electrolyte balance.
The nephroprotective effects of ACE Inhibitors seems, in part, to be dissociated from their haemodynamic effects. One hypothesis is that the glomerulus efferent arteriole vasodilation they cause, decreases the glomeruli microcirculation pressure – reducing pressure on the already compromised system (5). This seems to fit, as ACE Inhibitors have been shown to reduce proteinuria and disrupt the progression of renal disease. However, other mechanism have also been identified which include altering glomeruli growth and permeability selectivity (5).

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Conclusion
As we can see from this discussion the two prominent effects ACE Inhibitors can elicit on the kidneys – arterial vasodilation and increased sodium excretion – separately confer different clinical benefits in different clinical scenarios. However, under certain circumstances, can converge to push the scales towards AKI, where otherwise eGFR would have been maintained. This is an essential point when using ACE Inhibitors in practise whether that’s in pathological scenarios or where drug-drug and drug-disease interactions are concerned. Together with other renally ‘toxic’ factors they can easily push the patient in to AKI, something extremely dangerous, but also avoidable with the correct monitoring, foresight and clinical competence. Interestingly, in certain circumstances stopping an ACE Inhibitor may actually be detrimental, take heart failure for example (7). In this group it may be beneficial to continue using the ACE Inhibitor during AKI and should be stopped only under specialist advice.
So like all of us, ACE Inhibitors are neither friend or foe exclusively, but both, depending on the circumstance.

 

Author: Matthew J Burgoyne

References
1 – The Pharmaceutical Journal, April 2017, Vol 298, No 7900, online | DOI: 10.1211/PJ.2017.20202504. Available at: https://www.pharmaceutical-journal.com/news-and-analysis/news/drug-classes-commonly-implicated-in-causing-kidney-injury-identified/20202504.article?firstPass=false
2 – University of Copenhagen, Discovery of the ACE-Inhibitor Captopril. Online. Available at: https://studies.ku.dk/masters/medicinal-chemistry/profile-and-career/case_stories/discovery_of_the_ace-inhibitor_captopril/
3 – Figure 1: Sourced by M J Burgoyne via GFDL (http://www.gnu.org/copyleft/fdl.html)
4 – Speller J. 2018. The Renin-Angiotensin-Aldosterone System. Online. Teachmephysiology.com. Available at: http://teachmephysiology.com/urinary-system/regulation/the-renin-angiotensin-aldosterone-system/
5 – Orth S, et al. 1993. Nephroprotective effect of ACE inhibitors. Drugs. Online. 46 Suppl 2:189-95; discussion 195-6. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7512474
6 – The Renal Association. Proteinuria. Online. Available at: https://renal.org/information-resources/the-uk-eckd-guide/proteinuria/
7 – Think Kidneys, Guidelines for Medicines Optimisation in Patients with Acute Kidney Injury. NHS. 2016. Online. Available at: https://www.thinkkidneys.nhs.uk/aki/wp-content/uploads/sites/2/2016/03/Guidelines-for-Medicines-optimisation-in-patients-with-AKI-final.pdf

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