#386 Primary Aldosteronism, MRAs, and Renovascular Hypertension: NephMadness Pod Crawl 2023

March 20, 2023 | By Matthew Watto, MD

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We demystify primary aldosteronism, MRAs (mineralocorticoid receptor antagonists), non-steroidal MRAs, and how to recognize and treat renovascular hypertension with nephrologist/hypertension expert, Dr. Matt Luther (@DrJMLuther) as part of the NephMadness  PodCrawl 2023. Fill out a bracket for NephMadness and check out all eight NephMadness PodCrawl participants at NephMadness.com/podcrawl (list below) and the MRA region write-up by Micah Schub (@AcidBassMD).

• The Curbsiders gets the skinny on mineralocorticoid receptor antagonists
• Core IM will be covering Kidney Transplant in their classic Five Pearl format
• The CardioNerds will be covering the effect of Heart Failure Devices on Kidney Health
• Freely Filtered will try to understand thrombotic microangiopathy
• ISN Global Kidney Care goes deep on IgA nephropathy
• The Cribsiders look at transitions, first the Pediatrics to Adult nephrology transition and then from living to death with palliative nephrology 
• Fellow on Call will be covering Onconephrology
• And finally, The Nephron Segment looks at Transgender Health and CKD

Claim free CME for this episode at curbsiders.vcuhealth.org!

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Show Segments

• Intro
• Diagnosis and Management of Primary Aldosteronism (PA)
• MRAs vs non-steroidal MRAs (mineralocorticoid receptor antagonists)
• NephMadness MRA region picks
• Renovascular Hypertension
• Outro

CME Partner: VCU Health CE

Top Pearls

1. Primary aldosteronism (PA) is common! Test all patients with hypertension at least once for primary aldosteronism with early morning aldosterone and renin.
2. PA suspected? Check EKG for LVH +/- repolarization abnormalities, proteinuria/albuminuria & creatinine trends; assess for glomerulonephritis, and excess cortisol production.
3. Aldosterone excess causes renal hyperfiltration, and treatment with MRA or adrenalectomy often results in “unmasking” renal dysfunction, so expect an initial decline in eGFR!
4. Both primary aldosteronism and renovascular hypertension confer an increased risk for cardiac and renal disease, so aggressive medical management is warranted!
5. Renin will become elevated when spironolactone (or eplerenone) reach appropriate doses, so titrate them accordingly. 
6. We must be selective about who we work-up for renovascular hypertension because revascularization is not more effective than medical therapy in most patients.
7. Renovascular hypertension should first be treated with standard blood pressure medications and cardiovascular risk reduction.
8. Serial imaging can be pursued if renovascular disease is suspected because renal atrophy can occur over the course of several months and sometimes the initial read is inaccurate.

Primary Aldosteronism, MRAs, Renovascular HTN Show Notes

Primary Aldosteronism (PA)

Dr. Luther’s spiel on primary aldosteronism

PA is a common reason for resistant hypertension in Dr. Luther’s hypertension clinic. It’s caused by the inappropriate production of aldosterone by the adrenal gland which makes the kidneys reabsorb salt and excrete potassium. About half the time it’s due to a nodule that can be removed surgically and about half the time it is treated with medications. 

When to suspect PA

Testing for PA is recommended for all patients with resistant hypertension. Further, some experts recommend testing all patients with primary hypertension (HTN) at least once for primary aldosteronism (Young, 2019). Check an early morning plasma aldosterone concentration (PAC), and plasma renin activity (PRA) or plasma renin concentration (PRC). Hypertension, intermediate or elevated aldosterone levels, and suppressed renin are suggestive of primary aldosteronism (Young, 2019). Further, suppressed renin in a patient on a thiazide diuretic, and ACEI/ARB is suspicious for primary aldosteronism (PA). 

Spontaneous or provoked hypokalemia is not always present in primary aldosteronism (Young, 2019). 

Initial steps if concern for PA

Dr. Luther performs the following investigations when primary aldosteronism is suspected. 

• Look for end-organ damage: Does the EKG have LVH or repolarization abnormalities? If so, get an echo. Evaluate for CKD. Trend proteinuria/albuminuria, and serum creatinine.
• Don’t miss glomerulonephritis in the patient with hematuria, proteinuria, AKI, and hypertension
• Re-evaluate previous imaging (e.g. CT scan) for Hounsfield units, nodules, and hyperplasia
• Rule out cortisol excess (see Curbsiders episode #377 for details)

PA causes hyperfiltration

Aldosterone excess causes glomerular hyperfiltration (Young, 2019). Thus, patients with PA often have underlying renal dysfunction that is not reflected by their pretreatment creatinine. Once aldosterone is adequately suppressed and hyperfiltration goes away, patients will have a rise in serum creatinine as their renal dysfunction is “unmasked” (Young, 2019). In the long run, this is a good thing, but patients and clinicians should be prepared for eGFR to drop (Utsumi, 2017) and for creatinine to settle at a new, higher baseline. Utsumi and colleagues developed nomograms to predict patients who will experience a >25% postoperative decrease in eGFR or new eGFR <45 ml/min. 

The long-term risk for cardiovascular and kidney events is increased in primary aldosteronism compared to essential hypertension (Millez, 2005; Monticone, 2018; Chauhan, 2022). 

Primary Aldosteronism Treatment 

Dr. Luther notes patients should still get first-line hypertension agents (Calcium channel blocker, ACEI/ARB, and a diuretic) before adding spironolactone. 

• He often switches hydrochlorothiazide (HCTZ) to chlorthalidone for its greater potency and to make room for spironolactone, especially if the patient has hyperkalemia (expert opinion).
• Spironolactone can be added at the same visit that a patient is switched from HCTZ to chlorthalidone.
• An SGLT2 inhibitor may also be added if needed to control HTN, treat proteinuria, and/or lower potassium (expert opinion).

MRAs

Spironolactone can be started at 12.5 mg daily, and a metabolic panel should be checked in about 1-2 weeks to monitor creatinine and potassium (Young, 2019). Dr. Luther’s practice includes checking renin, which will rise once a patient is successfully treated with an MRA. He notes that spironolactone doses in CKD are limited by hyperkalemia, but in patients without CKD doses of 100-200 mg per day are commonly reached. 

Due to its short half-life, eplerenone should be dosed twice daily and is typically started at 25 mg twice daily (Young, 2019). It is only about half as potent as spironolactone and doses of 200-300 mg daily may be needed. Eplerenone has less binding affinity at androgen receptors and is less likely to cause gynecomastia (Young, 2019). Dr. Luther recommends allowing spironolactone to “wash out” for a few days before starting eplerenone (expert opinion). Dr. Luther has run into issues with pharmacies not wanting to fill higher doses because it’s only FDA-approved for 100 mg per day, and/or due to high cost. 

Kashlak Pearl: Trimethoprim-sulfamethoxazole can cause severe hyperkalemia if combined with spironolactone (Antoniou, 2015), amiloride, or other agents that raise potassium. Warn your patients and proceed with caution! 

Finerenone is the first non-steroidal approved for use in patients with diabetes, CKD, and proteinuria based on FIDELIO (Bakris, 2020) and FIGARO (Pitt, 2021). It has not been approved for PA, and as of this writing, no trials are registered at clinicaltrials.gov. Finerenone has less hyperkalemia, but also less blood pressure lowering effect (Agarwal, 2023) than spironolactone (Agarwal (AMBER), 2019). 

Renovascular HTN

We must be selective about who we work-up for renovascular hypertension because revascularization is not more effective than medical therapy in most patients (ACC/AHA guidelines by Bhalla, 2022). First, treat medically. Don’t look for renovascular hypertension unless patients can’t be controlled medically or exhibit certain clinical syndromes (Bhalla, 2022) e.g. fibromuscular dysplasia (FMD) with hypertension, hypertensive encephalopathy, flash pulmonary edema or suspicion for bilateral renal artery stenosis* with worsening renal function.

*Kashlak Pearl: Dr. Luther suspects bilateral renal artery stenosis in a patient with severe hypertension who develops a decline in renal function once blood pressure is reduced followed by another rise in blood pressure followed by another decline in renal function when the blood pressure is controlled. This cycle repeats over time. 

A stenosis from renovascular disease must be severe (often >70% stenosis) to cause ischemic injury to the kidney (Bhalla, 2022 figure 2). Dr. Luther looks at a patient’s prior imaging for a discrepancy in kidney size**. He prefers CT angiogram to ultrasound or MRI when looking for renovascular disease (expert opinion). In Dr. Luther’s opinion renal duplex ultrasound can be misleading and should be interpreted by experienced radiologists. He often repeats imaging because in his experience an ischemic kidney can change in size over the course of months. In the case of FMD, patients might require invasive angiography for proper hemodynamic assessment to assess the need for angioplasty (Bhalla, 2022). 

**Kashlak Pearl: Dr. Luther points out that kidney size discrepancy can be caused by things other than renovascular disease e.g. prior infection, stone disease, or congenital diseases including sickle cell or thalassemia (Davran, 2014). Suspect renovascular disease in patients with traditional vascular risk factors such as vascular disease in other territories (e.g. low ankle-brachial index).

Fibromuscular dysplasia can present later in life, but the classic patient is a younger woman with early-onset, accelerated, malignant, or resistant hypertension, a small kidney without uropathy, or arterial bruit on exam (abdomen, flank, or neck, or FMD in another vascular territory) –(Bhalla, 2022).

Treatment of renovascular hypertension

Renovascular hypertension is a cardiovascular risk equivalent (Wollenweber, 1968; Weber, 2014) and should be treated with aggressive risk reduction (lipid-lowering, smoking cessation, lifestyle changes, etc.). The approach to blood pressure treatment is similar to that in patients without renovascular hypertension. Renal function should be monitored closely (Bhalla, 2022).

ASTRAL and CORAL were negative trials of revascularization for renal artery stenosis. Invasive treatment is reserved for highly selected patients and may include stenting, angioplasty, or open bypass (Bhalla, 2022). 

Links

1. Primary Aldosteronism Review by William Young J Int Med 2019 
2. AHA 2022 statement on Renovascular Hypertension 

Hypertension Secrets (book) by EV Lerma, JM Luther, S Hiremath

Goal

Listeners will discuss primary aldosteronism, MRAs, and renovascular hypertension

Learning objectives

After listening to this episode listeners will…

1. Discuss the mechanism of action for non-steroidal MRAs and MRAs
2. Interpret testing for primary aldosteronism and start appropriate medical therapy
3. Recognize and treat renovascular hypertension

Disclosures

Dr. Luther reports the following disclosures – Mineralys: membership on advisory committees or review panels, board membership, etc (relationship has not ended); Bayer: honoraria (relationship has ended); American Heart Association: membership on advisory committees or review panels, board membership, etc (relationship has not ended); Elsevier – Hypertension Secrets: royalties or patent beneficiary (relationship has not ended). The Curbsiders report no relevant financial disclosures. 

Citation

Watto MF, Luther JM, Williams PN. “#386 Primary Aldosteronism, MRAs, and Renovascular Hypertension: NephMadness Pod Crawl 2023”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date March 20, 2023.