ACE Inhibitors Make the MDRD Creatinine Worse, So Why Did My Nephrologist Prescribe Them?


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Doctor Aaronson, Omaha, Nebraska's OTHER Oracle. Dr. Michael Aaronson is a kidney physician specializing in Nephrology and hypertension.


R.U.N., DNP: I’m at a conference and the speaker (who is a nephrologist) says ACE inhibitors (used to protect the kidneys and decrease high blood pressure) may worsen kidney function (they can increase the creatinine and cause the GFR to go down). Two questions: how do they cause the creatinine to go up and the GFR to go down? And why do we use ACE inhibitors if they worsen kidney function?

Dr. Aaronson ( Nephrologist): Thank you for your question! The speaker at your conference is correct. But why would kidney doctors recommend medicine that worsens a person’s kidney function? Isn’t the kidney consultant’s job to save the kidneys? All of this sounds very counterintuitive!

First and foremost, Angiotensin Converting Enzyme (ACE) inhibitors lower blood pressure. ACE inhibitors prevent the formation of a hormone called angiotensin II (mechanism shown below), which normally causes blood vessels to constrict, or to become narrower. Said another way, angiotensin II causes hyper (excessive) – tension (the process of stretching a blood vessel tight). ACE inhibitors allow the arterial blood vessels to relax (open up), and the result is lowered blood pressure.

Examples of ACE inhibitors include:

  • Enalapril (Vasotec)
  • Ramipril (Altace)
  • Quinapril (Accupril)
  • Perindopril (Aceon)
  • Lisinopril (Prinivil/Zestril)
  • Benazepril (Lotensin) <– Dr. Aaronson’s favorite because benazepril is very powerful and cost effective!
Michael L Aaronson MD, Omaha's Nephrology Consultant and America's Medical Blogger, offering free blood pressure screenings for Alegent Health Clinic at the Golf Expo to promote awareness of the prevalence of hypertension in the community.

In addition to blood pressure lowering, ACE inhibitors have an added, beneficial effect on the kidneys. ACE inhibitors unload the kidney filters (the glomeruli) so that the kidney filters do not have to work as hard. ACE inhibitors dilate the efferent arterioles, or the vessels that travel away from the kidney.

The kidney is the only organ system in the body where a vein is replaced by an artery.

Every other organ system in the body: artery -> capillary -> vein

The kidney filtering system: afferent artery -> capillary filter (glomerulus) -> efferent artery

Because of this switch, the kidneys have the ability to both constrict and dilate the efferent arteriole which allows for varying pressure on the filters of the kidneys and protection from dehydration and fluid overload. Please note:

The filtration of fluid occurs in the kidney at the glomerulus.The mechanism of action of ACE inhibitors: ACE inhibitors work by opening up the "pipe leaving the kidney filter" (efferent arteriole). This effect results in decreased pressure on the filter, and the filters don't have to "work as hard." In sum, lessening the work of the filter will allow it to work longer. The end result is that ACE inhibitors increase the amount of time a patient can avoid the need for kidney dialysis. However, if the filters don't work as hard as they should, a patient's kidney function may worsen with less toxins cleared from the body. Fortunately, this difference is rarely noticed by the individual.

In addition, by unloading the work of the kidney, less protein in the form of albumin spills into the urine when people take ACE inhibitors:

Vertical (up-down) bars show the risk of patients with chronic kidney disease (CKD) and protein (albumin) in their urine developing kidney failure or cardiovascular disease. ACE inh

So although the kidney function may worsen, the total time to dialysis is prolonged. That's why we tolerate up to a 30 per cent increase in the creatinine as long as the patient does not suffer from high potassium (hyperkalemia) and acute kidney injury. ACE inhibitors increase body potassium by the following mechanism:

Angiotensin converting enzymes, such as benazepril, prevent the conversion of angiotensin I to angiotensin II (#3 in the diagram). This prevents the release of aldosterone (#5 in the diagram) resulting in the inability of the kidney to reabsorb sodium (salt) and get rid of potassium. The end result is an elevated level of potassium in the body in the setting of chronic kidney disease. We check a patient's level of potassium to make sure the ACE inhibitor is safe to take and your level of potassium is not too high.

Additional side effects of ACE inhibitors include dry, hacking cough, low blood pressure, and a rash. For those people unable to tolerate ACE inhibitors, there are other options such as angiotensin receptor blockers (ARBs, #4 in the diagram above) which may be better tolerated in some individuals. Note that losartan is the only ARB that is generic. Be careful "asking your doctor for it" because losartan is still quite expensive, a three month supply of losartan costs $86.65 per month at while a three month supply of benazepril 40 mg daily is only $4.33 per month at most local pharmacies.

In conclusion, realize there is a difference between markers of risk (surrogate markers) and clinical outcomes. Creatinine is a marker of risk. We use it to follow a person's kidney function (see When should I see a kidney specialist?). However, the clinical outcome we want to prevent is the initiation of kidney dialysis. Therefore, if the creatinine increases "a little bit," but the length of time to kidney dialysis is prolonged, the patient wins. In addition, the system wins and we help prevent the healthcare bubble from bursting. By using ACE inhibitors, we can effectively increase the amount of time until a patient with chronic kidney disease needs kidney dialysis / kidney replacement therapy.





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