Pearls of Wisdom: Diabetic Proteinuria

Question: Alma, a 62-year-old hypertensive, diabetic Hispanic woman, has achieved goal blood pressure, blood glucose, and lipids levels. Her current medications include: metformin and glipizide for diabetes mellitus, ramipril and amlodipine for hypertension, and atorvastatin for lipids.

For a patient who continues to experience diabetic proteinuria despite treatment with an angiotensin-converting enzyme inhibitor, what might be a treatment consideration?

A. Spironolactone
B. Add an angiotensin receptor blocker (eg, candesartan)
C. Add a dihydropyridine calcium channel blocker (eg, amolodipine)
D. Protein supplementation to compensate for renal protein losses

What is the correct answer?
(Answer and discussion on next page)

Louis Kuritzky, MD, has been involved in medical education since the 1970s. Drawing upon years of clinical experience, he has crafted each year for almost 3 decades a collection of items that are often underappreciated by clinicians, yet important for patients. These “Pearls of Wisdom” often highlight studies that may not have gotten traction within the clinical community and/or may have been overlooked since their time of publishing, but warrant a second look.

Now, for the first time, Dr Kuritzky is sharing with the Consultant360 audience. Sign up today to receive new advice each week.


Answer: Spironolactone

Many experts believe that the pharmacologic treatment of choice for patients with diabetic or hypertensive proteinuria is an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB). There is also some consensus that use of a dihydropyridine calcium channel blocker monotherapy (eg, nifedipine, amlodipine) is probably not a good choice.

The putative mechanism by which ACE/ARBs improve proteinuria is a decrease in intraglomerular pressure provided by the complementary effects of combined relaxation of both the afferent and efferent glomerular arterioles (with efferent arteriolar dilation being prominent).

In contrast, even though dihydropyridine calcium channel blockers (eg, amlodipine) relax the glomerular afferent arteriole, they do not appear to affect the efferent arteriole. This results in a relative increase of flow into the glomerulus, which can—at least transiently—increase intraglomerular pressure.

Proteinuria and Renal Failure in an Older Man
Early Renal Disease


One of my favorite trials use to be the CALM trial, for the simple reason that I could actually remember what CALM stood for: Candesartan and Lisinopril for Microalbuminuria. And I even liked the results of the trial: ACE works, ARB works, both seem to work a little better together.

Microalbuminuria: The CALM Trial1


But I am not allowed to like it any longer, because some larger trials have found that the combination of ACE+ARB in hypertensive patients may actually worsen some renal endpoints. The Canadian Hypertension Guidelines were the first to proscribe ACE+ARB to treat hypertension.

Microalbuminuria: The CALM Trial Study Design1

 study design

Well, if ACE+ARB is out-of-bounds, what might one choose? A small trial suggested that adding spironolactone might improve proteinuria. After a year of treatment with an ACE inhibitor, the addition of spironolactone improved urinary albumin excretion (UAE) by more than 50%.

Microalbuminuria: The CALM Trial Results1

trial results

The idea of trying to reduce urinary protein excretion to normal seems intuitively appealing, but data are lacking as to what degree of improvement of proteinuria is optimum. Recalling that our most recent United States Hypertension Guidelines (JNC 8) have become more relaxed about the specific blood pressure goals, it is clear that improving proteinuria improves some outcomes—but it is not clear how much proteinuria reduction should be the goal.

Microalbuminuria: The CALM Trial: Candesartan + Lisinopril?1

 Candesartan and lisinopril

At any rate, if one chooses to combine spironolactone (or its sister compound, eplerenone) with an ACE or an ARB, one needs to consistently monitor potassium levels, since each of these agents tends to retain potassium, and the combination of the 2 increases the risk for hyperkalemia.

What’s the “Take Home”?  

Although the presence of urinary albumin is a harbinger of renal disease, there is uncertainty about optimum goals for reducing urinary albumin excretion levels. ACE inhibitors and ARBs are the most frequently advocated agents. For clinicians who feel that the degree of urinary albumin excretion attained by ACE or ARB monotherapy is insufficient, consideration might be given to adding an aldosterone antagonist, such as spironolactone. If clinicians choose to add an aldosterone antagonist to an ACE or ARB, potassium monitoring must be regularly performed.   


1. Morgensen CE, Neldam S, Tikkanen I. Randomized controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ. 2000;321(7274):1440-1444.