Selection Committee Member: Matt Luther @DrJMLuther
Matt Luther is Associate Professor at Vanderbilt Medical Center, where he directs the Hypertension Center. He completed Internal Medicine, Nephrology, and Clinical Pharmacology training at Vanderbilt prior to joining the faculty there. His research program investigates the role of aldosterone, epoxyeicosatrienoic acid, and related hormones in the pathogenesis of hypertension and diabetes.
Writer: Micah Schub @AcidBassMD
Micah Schub is a second-year nephrology clinical fellow at Duke University. He is a graduate of University of Pittsburgh School of Medicine in Pittsburgh, PA, and completed his residency at Duke University in Durham, NC. His clinical and research interests include kidney transplantation, clinical reasoning, and medical education.
Competitors for the Mineralocorticoid Receptor Antagonists (MRAs) Region
What if I told you that the one you were meant to spend your life with is from your past? They were right under your nose the whole time. Now, you’ve both grown up, dated others and found purpose outside of your past relationship. Is now the time to rekindle that old flame? You may think that I’m describing the premise of the reality television show “The One That Got Away” on Amazon Prime, but clearly we are talking about mineralocorticoid receptor antagonists (MRAs) for the treatment of chronic kidney disease. In this region we will be pitting the old flame against the shiny new thing—steroidal versus nonsteroidal MRAs.
The global prevalence of chronic kidney disease (CKD) is roughly 9.1% of the world’s population, which equates to approximately 800 million people, highlighting the massive scale of this problem. Since the early 1990s, it’s been well established that renin-angiotensin system (RAS) inhibition with either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB), slows the progression of chronic kidney disease in patients with proteinuria. This benefit is present in patients with and without diabetes.
Within the last 10 years, sodium-glucose cotransporter 2 (SGLT2) inhibitors have burst onto the scene, further slowing the progression of CKD in patients on ACEi and ARB therapy. Despite these medical success stories, two thirds of patients with CKD will have a decline in their kidney function over time, and 1%-2% of these patients will progress to kidney failure. This epidemiologic data highlights the clear need for additional treatments to slow the progression of CKD. Enter MRAs.
There are many proposed mechanisms to explain the kidney protective effects of MRAs, here are but a few:
- Decreased intraglomerular pressure – This prevents podocyte injury and ameliorates proteinuria, and is mediated by a decrease in renal vasoconstriction and overall improvement in intraglomerular hemodynamics. As has been seen in studies of RAS inhibitors and SGLT2 inhibitors, there is an initial drop in estimated glomerular filtration rate (eGFR) followed by a slowing of kidney function decline over time. There may also be a contribution from the renoprotection afforded by decreased systemic blood pressure.
- Attenuating aldosterone breakthrough – Up to 50% of patients treated with RAS inhibitors will have an increase in their serum aldosterone levels after starting treatment. This is known as “aldosterone breakthrough.” Not only do aldosterone levels increase in these patients, but urinary albumin excretion was higher. The addition of spironolactone in patients with aldosterone breakthrough led to a further reduction of urinary albumin excretion. Other studies have also shown a trend toward improved kidney protection afforded by MRAs in patients on RAS inhibition compared to patients not on RAS inhibition. It is tempting to think that it is the patients with aldosterone breakthrough that are responsible for this difference. All of this clinical and preclinical data goes to show that aldosterone is a potent mediator of kidney dysfunction independent from angiotensin II.
- Cardiovascular protective effects – This is not only due to the improved decongestion secondary to MRAs diuretic properties, but also direct cardiac benefits aimed at reducing perivascular inflammation and interstitial fibrosis. Furthermore, there is evidence of smooth muscle MR activation in the pathogenesis of hypertension, atherosclerosis, and vascular aging.
- Reduced oxidative stress and inflammation in the kidney – Aldosterone leads to MR-dependent activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and reactive oxygen species generation. Endothelial MR receptors facilitate an inflammatory response mediated by perivascular infiltration and increased expression of inflammatory mediators. In mouse models of salt and aldosterone-induced hypertension, kidney biopsies showed severe vascular and glomerular sclerosis, fibrinoid necrosis, and thrombosis consistent with hypertensive kidney disease. There was also a significant inflammatory component of leukocytic infiltration and a myriad of inflammatory mediators. Treatment of these mice with the steroidal MRA eplerenone decreased leukocytic infiltration and decreased gene expression of inflammatory mediators including osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, and IL-1.
Of course, the elephant in the room when discussing MRAs is the dreaded side effect of hyperkalemia. This is due to downregulation of epithelial sodium channels (ENaC) in the principal cell of the collecting duct and decreased activity of sodium-potassium (Na/K) ATPase. This leads to decreased intracellular potassium and a more positive luminal electrochemical gradient, and ultimately to decreased potassium secretion into the tubular lumen. Hyperkalemia thus is an on-target effect, and when present indicates adequate blockade of the MR. Now that we’ve discussed the basis for mineralocorticoid receptor antagonism, let’s get to the matchup.
Team 1: Steroidal MRA
2001 was a year of numerous important events: Wikipedia was launched, the Microsoft Xbox was released, Harry Potter and the Sorcerer’s Stone burst into theaters, Justin Timberlake and Britney Spears wore all denim to the MTV VMAs. But perhaps most significantly, this was the year that spironolactone was first shown to reduce proteinuria in patients with reduced kidney function already on RAS inhibition. Patients in this study had proteinuria >1 g/day despite treatment with enalapril for 1 year. After 4 weeks of taking a modest 25 mg dose of spironolactone, a 54% reduction in proteinuria was observed. The improvement couldn’t be attributed to blood pressure, as it did not change. Despite this being a small, uncontrolled, observational study (only 8 patients), the reduction in proteinuria was hard to ignore. Furthermore, these findings have held up in larger studies and controlled trials.
Proteinuria reduction is nice, and multiple studies have shown that reducing proteinuria correlates with kidney protection. Despite proteinuria reduction, hard data on eGFR decline and reducing need for kidney replacement therapy (KRT) is needed to convince the masses that steroidal MR antagonism is truly kidney protective. The good news is, those studies have existed for years. In a trial of 165 patients comparing spironolactone 25 mg versus standard of care treatment with RAS inhibition, the spironolactone arm showed a decrease in eGFR over the first month but then a stabilization of eGFR. After the first month, the control arm experienced a progressive decline in eGFR. When the study ended at 1 year, there was no difference in eGFR giving this trial the label of “negative study”. But similar to our other renoprotective medicines (RAS inhibitors, SGLT2 inhibitors), the initial drop in eGFR muddied the picture and the primary outcome. 1 year was not long enough to see a benefit when studying these medicines. The spironolactone group had begun moving toward an improved eGFR, and had the trial continued, the groups likely would have separated.
The spironolactone group did show an increased incidence of hyperkalemia, including severe hyperkalemia (K >5.5 mg/dL), although more than half the patients were on combination ACE inhibitor and ARB therapy and this appeared largely responsible for the hyperkalemia.
Now we know what you’re thinking when you hear about 10-year-old studies and proteinuria reduction—does any of this matter now that SGLT2 inhibitors have become standard of care? The short answer is “probably.” The Rotate 3 trial aimed to address this with 2 important questions:
- Does the addition of a MRA (eplerenone) to an SGLT2 inhibitor (dapagliflozin) reduce albuminuria
- Will some patients respond to one drug and not the other?
With regards to question #1, the answer was “yes.” The trial showed an additive reduction of albuminuria when the medication classes were used in combination. This additive effect was similar to findings in DAPA-CKD for patients already on an MRA. The combination group also saw a reduction in hyperkalemia compared to the eplerenone alone group, demonstrating another benefit of combination treatment. Interestingly, there was no association between individual UACR changes during the dapagliflozin and eplerenone periods. The fact that the same patient would respond to one class but not the other indicates an important role for both MRAs and SGLT2 inhibitors. These results not only support an additive effect of combined SGLT2 inhibitor and steroidal MRA treatment, but also a role for MRAs in patients who don’t see a reduction in albuminuria with SGLT2 inhibitor therapy alone.
The greatest barrier limiting uptake of Team Steroidal MRAs for kidney disease is that pesky side effects, namely hyperkalemia. The RALES trial was published in 1999 showing a reduction in all cause mortality by treating heart failure with reduced ejection fraction (HFrEF) with 25 mg of spironolactone. Hyperkalemia leading to discontinuation of the drug was not higher in the spironolactone group. Unfortunately, publication of this trial led to a massive spike in spironolactone prescriptions and hospitalizations for hyperkalemia increased, indicating that hyperkalemia outside of a trial was a significant risk. Similar issues with hyperkalemia have been seen in the resistant hypertension population, indicating that this is not isolated to the heart failure population. These findings have largely limited the uptake of these drugs.
Since that time, safe and effective potassium binders have been introduced, calling into question the applicability of a study like this. The use of potassium binders to allow for continued MRA use in the CKD population was studied in the AMBER trial. Patients in the trial all had an eGFR between 25 and 45 and were being treated for resistant hypertension. The investigators were able to show that use of patiromer in conjunction with spironolactone decreased the rate of spironolactone discontinuation when compared to spironolactone alone. The difference in the rate of discontinuation between the 2 groups was more profound at lower eGFRs, indicating a particular benefit to using potassium binders in advanced CKD. With increased monitoring and the use of potassium binders, steroidal MRAs are safer than ever. The increasing efficacy and safety profile of these medicines has to make one wonder, “Was true love in plain sight?”
Check out this podcast episode of The Curbsiders featuring Matt Luther:
Team 2: Nonsteroidal MRA
Ludwig Van Beethoven is arguably the greatest classical composer to ever live. He was prolific in his contribution to the orchestral and instrumental literature, but only wrote one opera (We promise this will come back to MRAs, bear with us). Originally titled “Leonore”, the story follows the politically imprisoned Florestan and his wife Leonore’s exploits in trying to free him. Leonore disguised herself as a boy named Fidelio in order to infiltrate her husband’s prison and free him. The opera underwent 2 revisions after lackluster premieres, and was later rebranded as “Fidelio” to rave reviews and a permanent place in the operatic zeitgeist.
Finerenone, the most prominent member of Team Nonsteroidal MRA, has a history as an imposter not dissimilar to Leonore. In the search for new antihypertensive medicines, it was discovered that dihydropyridine calcium channel blockers display mineralocorticoid receptor antagonist activity. Finerenone is a dihydronaphthyridine and a close cousin of nimodipine, a calcium channel blocker. The specific configuration of finerenone was found to have potent and selective inhibition of the mineralocorticoid receptor. Thus, an obscure relative of a calcium channel blocker was rebranded as a nonsteroidal MRA, and a successful premier followed.
In 2010, initial interest in MRAs as kidney protective agents had lost steam, and gave way to SGLT2 inhibitors as the nephrology community’s primary pharmacologic focus. The introduction of finerenone and the nonsteroidal MRAs has reignited the conversation around mineralocorticoid receptor antagonism as a kidney protective strategy. Early trials on finerenone showed that when compared to placebo, finerenone led to decreased proteinuria. Although these studies demonstrated promise for CKD treatment they did not include patients with low eGFR or assess hard kidney outcomes (due to short duration), obscuring both the true risk of hyperkalemia and the benefit in addressing a composite kidney outcome.
FIDELIO-DKD enters, stage right (the intro to this section is finally making sense). This trial explored the effect of finerenone with primary kidney endpoints in patients with type 2 diabetes. It was a multi-centre, international, randomized, double-blinded, interventional trial comparing finerenone to placebo. Participants had a urinary albumin to creatinine ratio (UACR) between 300 and 5000 mg/g and an eGFR ≥ 25 but < 75 mL/min/1.73 m2. UACRs down to 30 mg/g were included if diabetic retinopathy was present. Almost 90% of patients in the trial had an eGFR <60 mL/min/1.73 m2. The primary outcome was a composite of death from kidney causes, kidney failure (dialysis ≥ 90 days, transplantation, or eGFR < 15 ml/min), and a sustained decrease of at least 40% in the eGFR from the baseline. The primary outcome occurred in 17.8% of patients in the finerenone group and 21.1% in the placebo group. The absolute, between-group difference was 3.4% after 3 years (hazard ratio 0.82 [0.73-0.93; P=0.001]), yielding a Number Needed to Treat of 29 over 3 years. The primary outcome was driven mostly by the 40% decrease in eGFR, as this was responsible for more than two thirds of total events. It should also be noted that in contrast to the large Flozin trials, including DAPA-CKD and EMPA-KIDNEY, there was no significant difference found in progression to kidney failure. As of now, these results are only applicable to the diabetic kidney disease population, but the FIND-CKD trial that is currently underway will address the efficacy of finerenone in patients with CKD without diabetes and UACR of 200-3500 mg/g and eGFR 25-90 mL/min/1.73 m2.
Rates of hyperkalemia were more common in the finerenone group (18.3%) than placebo (9%). Serious hyperkalemia occurred in an overall small subset of the population (1.6% on finerenone versus 0.4% on placebo). 2.3% of participants receiving the study drug discontinued the trial because of a high potassium, compared to 0.9% in the placebo arm. While these results appear to present a favorable picture of the hyperkalemia risk, this may be obscured by the trial’s run-in period. 13,911 patients were enrolled in the trial and 2,181 patients were excluded due to a serum potassium >4.8 mmol/L. A total of 7,114 patients made it to the run-in period where, over 12 weeks, the doses of ACE inhibitors and ARBs were escalated to maximally tolerated doses. A further 640 patients (9.0%) had serum potassium >4.8 mmol/L at the end of this period and were excluded from the trial. This run-in period has been referred to as a hyperkalemia stress test (primarily by the authors of this region). The uptitration of ACE inhibitors and ARBs to maximal doses may have exposed patients who would have been susceptible to hyperkalemia with the addition of an MRA. The exclusion of these patients from the trial could be part of the explanation for why the hyperkalemia side effect profile appeared so favorable. Additionally, use of potassium binders was not equal between the 2 groups. After the start of the study 307 patients (10.8%) in the finerenone group and 184 patients (6.5%) in the placebo group were started on potassium binders. Without any head-to-head trials between steroidal and nonsteroidal MRA, we cannot be certain of the hyperkalemia risk, although the data from FIDELIO-DKD is promising and gives a framework for helping to identify the patients at risk and strategies to mitigate hyperkalemia. Gynecomastia was all but absent in FIDELIO-DKD, similar to studies of eplerenone. This is in contrast to high dose spironolactone, where prevalence of gynecomastia reaches upwards of 50% (see figure below showing the specificity of MR antagonists to various receptors).
Only 5% of patients were on SGLT2 inhibitors in FIDELIO-DKD, as the recruitment period was from 2015-2018, prior to publication of the large flozin trials. Now that flozination has become standard of care, it becomes difficult to interpret the results of this trial. Unlike steroidal MRAs and the ROTATE-3 study, there has yet to be a larger randomized trial with primary kidney endpoints assessing the use of finerenone in conjunction with SGLT2 inhibitors. Fortunately the CONFIDENCE trial, which will be assessing finerenone in combination with empagliflozin, is currently enrolling. We are hopeful that combination therapy will lead to not only a reduction in albuminuria, but also a mitigation of hyperkalemia. FIDELIO-DKD is a large, well-designed randomized control trial clearly showing the kidney protective effects of nonsteroidal mineralocorticoid receptor antagonists. It’s also well argued that these drugs are safe with appropriate monitoring. The cardiovascular effects of finerenone are also demonstrated in the 7,437-patient RCT FIGERO-DKD. This study examined cardiovascular primary outcomes in patients with type 2 diabetes and CKD (eGFR 25-90 and UACR of 30-300 mg/g or and eGFR >60 mL/min/1.73 m2 and UACR of 300-500 mg/g). The composite cardiovascular outcome in this trial was positive driven by decreased hospitalization for heart failure. Key secondary kidney outcomes were not positive but close.
While finerenone is the most prominent and well-studied nonsteroidal MRA, this class of medications is growing. Exaserone has been approved in Japan for the treatment of hypertension with growing use in heart failure and ocedurenone is currently being studied for the treatment of poorly controlled hypertension in CKD. With the promising findings in FIDELIO and the ongoing studies of new agents, it does appear that the time is now for this exciting class of medications. Nonsteroidal MRAs have reignited the conversation around the renoprotective benefits of MRA, and thrust this class of medicines into the next frontier of renoprotection.