In the presence of agonists, the MR binds to specific genomic sites and alters the transcription rate of a subset of genes. Fig. 12.3 shows the fundamental paradigm of MR function. All nuclear receptors shuttle in and out of the nucleus; however, in the absence of hormones, some, such as the estrogen and vitamin D receptors are predominantly nuclear, whereas others, like glucocorticoid receptors, are almost exclusively cytoplasmic. In the absence of hormones, the MR is distributed relatively evenly between nuclear and cytoplasmic compartments, but in the presence of hormones, it is highly concentrated in the nucleus ( Fig. 12.4 ). ^, It is also notable that in addition to this marked change in MR cellular distribution, its subnuclear organization and protein–protein interactions are also changed. Like its close cousin the glucocorticoid receptor, the unliganded MR (in the absence of hormone) is complexed with a set of chaperone proteins, which include the heat shock proteins hsp90, hsp70, and hsp56 and immunophilins. ^, This chaperone complex is essential for several aspects of MR function, notably high-affinity hormone binding and trafficking to the nucleus. It was thought for many years that after binding hormone, the hsp90-containing chaperone complex is jettisoned. However, it has become clear that this complex remains associated with the receptor and plays an important role in nuclear trafficking. Several members of the immunophilin family, including FKBP52, FKBP51, and CyP40 are present in the chaperone complex and provide a bridge between hsp90 and the cytoplasmic motor protein dynein, which moves the receptor-hsp90 complex retrogradely along microtubules to the nuclear envelope. Here, the receptor is handed off to the nuclear pore protein, importin-α, and translocated into the nucleus, where it functions as a transcription factor, stimulating the transcription of certain genes and repressing the transcriptional activity of others. In the regulation of ion transport, stimulation of key target genes is paramount. Transcriptional repression may be essential for effects in nonepithelial cells including neurons, cardiomyocytes, smooth muscle cells, and macrophages.

General mechanism of aldosterone action through the mineralocorticoid receptor (MR).

This simple schematic shows the general features of MR regulation of a “simple” hormone response element (HRE), common to a large subset (but not all) of aldosterone-stimulated genes. Note that in the absence of hormone, MR is found in both nucleus and cytoplasm (see Fig. 12.4 ). Aldosterone (Aldo) triggers nuclear translocation of cytoplasmic MR, binding as a dimer to HREs, and stimulation of transcription initiation complex formation ( arrow, upstream of the so-called protein-coding gene, defines the site of transcription initiation). See text for further details.

Time-dependent nuclear translocation of the mineralocorticoid receptor (MR) in the presence of aldosterone.

Cultured cells expressing green fluorescent protein–MR fusion protein (GFP-MR) were grown in a steroid-free medium and treated with 1 nmol/L aldosterone. Translocation of GFP-MR was followed in real time, and images were captured at indicated times. It is notable that the nuclear accumulation of GFP-MR started within 30 seconds, was half-maximal at 7.5 minutes, and was complete by 10 minutes. Control: MR distribution before addition of aldosterone.

From Fejes-Toth G, Pearce D, Naray-Fejes-Toth A. Subcellular localization of mineralocorticoid receptors in living cells: effects of receptor agonists and antagonists. Proc Natl Acad Sci U. S. A. 1998; 95[6]:2973−2978.

The MRs of all vertebrates are highly conserved and, like other steroid and nuclear receptors, can be divided into three major domains ( Fig. 12.5 ):

• 1.

  An N-terminal transcriptional regulatory domain

• 2.

  A central DNA-binding domain (DBD)

• 3.

  A C-terminal ligand/hormone-binding domain (LBD)

Domain structure of the mineralocorticoid receptor (MR) .

The size and amino acid designations used here are for rat MR (981 amino acids total); they apply with minor variations to human MR (984 amino acids total). (A) Strip diagram of MR. The N-terminus is to the left, C-terminus to the right. (B) Schematic of MR DNA-binding domain (DBD) , showing the two zinc fingers and the positions of the coordinating Zn ions. Boxed region is the α helix, which intercalates into the major groove of the DNA and provides the major protein–DNA interaction contacts. The dimerization interface comprises amino acids within the second zinc finger, which form van der Waals and salt bridge interactions. LBD, Ligand/hormone−binding domain.

Each of these broadly defined domains has more than one function, and not all the functions can be neatly assigned to separate distinct domains; however, much of the action of MRs can be understood from this point of view.

The major mechanism of MR action is its effects on transcription initiation; however, there may also be effects on transcript elongation. ^, Much has been learned about the generation of an initiation complex and the particular roles that steroid receptors play in this process. Several review articles and book chapters have provided in-depth examinations of the biochemistry of the general transcription machinery, transcription initiation, promoter escape, and processive elongation. Most of the coactivators identified so far interact with the C-terminal AF2 domain and include the prototypical GRIP1/TIF2 and SRC, ^, which sequentially recruit a series of different components of the transcriptional machinery and result in the formation of a preinitiation complex. This preinitiation complex includes all the key components of the transcription machinery including RNA polymerase II. A detailed picture of MR-dependent preinitiation complex formation has not been determined. However, the general features are likely similar to those for estrogen receptor and involve the sequential recruitment by the receptor of the following: 1. chromatin-remodeling SWI/SNF and CARM1/PRTM1 proteins, which promote chromatin remodeling and initiation of complex formation; 2. histone acetylase CBP/P300 (cyclic adenosine monophosphate [cAMP]–responsive element–binding protein), which promotes an active chromatin conformation ; and 3. direct or indirect recruitment of the TATA-binding protein and other components of the general transcription machinery.

The aforementioned mechanisms are generic and are used by many transcription factors including all steroid receptors, through interactions with the C-terminal AF2 domain. The N-terminal region of the MR, which harbors the AF1 domain, diverges from the other steroid receptors, and other studies have identified coregulators that interact selectively with this receptor domain. ELL (11-19 lysine-rich leukemia factor) is a coactivator for the MR that specifically interacts with AF1b and assists in preinitiation complex formation. It was originally identified as an elongation factor, and it may also affect transcript elongation. Other specific coregulators include the synergy inhibitory protein PIAS1, Ubc9, and p68 RNA helicase. In many cases, interactions of these regulators with the MR require receptor posttranslational modifications (e.g., by phosphorylation, acetylation, or sumoylation).

Aldosterone effects in the ASDN have been divided into three major phases: latent, early, and late. This designation goes back to the early observations by Ganong and Mulrow that after aldosterone infusion into experimental animals, no effect was observed for at least 15 to 20 minutes. A similar delay was observed in isolated epithelia. The early phase, which is now known to involve primarily MR-dependent regulation of signaling mediators such as SGK1, culminates in increased apical localization—and, possibly, increased probability of the open state—of the epithelial sodium channel (ENaC). In the late phase, aldosterone stimulates transcription of a variety of effector genes, including those that encode components of the ion transport machinery, notably ENaC and Na ⁺ -K ⁺ –adenosine triphosphatase (Na ⁺ -K ⁺ -ATPase) subunits. The major direct effect is to increase Na ⁺ reabsorption, which is accompanied variably by Cl ⁻ reabsorption and/or K ⁺ secretion and, ultimately, water reabsorption. Aldosterone’s actions in the principal cells of the connecting segment and collecting duct ( Fig. 12.6 ) are of primary significance; however, this has also been shown to influence fluid and electrolyte transport in other tubule segments, as well as in other organs. These actions of aldosterone can be surmised from the clinical features of individuals with aldosterone-secreting tumors; they have volume expansion with high blood pressure and are commonly (>50% of patients) hypokalemic. ^, In general, the effects of aldosterone on Na ⁺ absorption and K ⁺ secretion work together. However, there are ways whereby these actions can be separated, as discussed later.

Schematic of principal cells in the aldosterone-sensitive distal nephron (ASDN).

The ASDN includes the distal third of the distal convoluted tubule (DCT), connecting tubule, and collecting duct. The Na ⁺ -K ⁺ –adenosine triphosphatase (Na ⁺ -K ⁺ -ATPase) establishes the gradients for passive apical entry of sodium through the epithelial sodium channel (ENaC). Transport of sodium through the ENaC creates a negative lumen potential that drives potassium secretion into the lumen. Potassium is also recycled at the basolateral surface, which facilitates potassium exchange across the Na ⁺ -K ⁺ -ATPase. Chloride (Cl ⁻ ) moves via paracellular and transcellular pathways.

Na ⁺ -K ⁺ -ATPase, located on the basolateral membrane (blood side), establishes the essential electrochemical gradients that drive ion transport (see Chapter 5 , Chapter 6 ). Importantly, it operates well below its V _max , and is seldom, if ever, the rate-limiting step in transepithelial Na ⁺ transport. Rather, apical Na ⁺ entry into the cell via the epithelial Na ⁺ channel, ENaC, is the rate-limiting step for Na ⁺ reabsorption by the ASDN and the key locus of regulation.

The discovery of the molecular composition of ENaC in 1993 ^, opened the door to understanding how aldosterone functions to regulate this critically important ion channel. Most Na ⁺ transporters are encoded by a single gene product. In contrast, ENaC is composed of three similar but distinct subunits, each encoded by a unique gene. All three subunits come together (probably as a heterotrimer) to form an ion channel with unique biophysical characteristics, the most striking of which is the relatively long time it stays open or closed. The apical entry of Na ⁺ into the cell via ENaC is the rate-limiting step in both Na ⁺ absorption and K ⁺ secretion. Na ⁺ enters the cell down a steep electrochemical gradient; intracellular [Na ⁺ ] is approximately 10 mmol/L, and the membrane voltage is high (inside negative). Intracellular Na ⁺ is pumped out across the basolateral membrane by Na ⁺ -K ⁺ -ATPase, as addressed in detail in Chapter 6 . Most epithelial cells have a greater density of K ⁺ channels on the basolateral membrane and thus recycle K ⁺ back into the blood. The distal nephron is unique in that it has an unusually high density of K channels on the apical membrane (primarily Kir 1.1 [renal outer medullary potassium (ROMK)] and BK channels) relative to the apical membrane of other epithelia. ^, This distribution of K ⁺ channels permits a large amount of K ⁺ that enters the cell via Na ⁺ -K ⁺ -ATPase to exit the cell into the lumen and be excreted into the urine. The vast majority of K ⁺ that appears in the urine is secreted by the distal nephron.

Much attention has been focused on the early phase of aldosterone action because it appears to be more tractable to dissection, and most changes in Na ⁺ current occur during this phase. This separation is probably somewhat artificial, however, and there is considerable overlap in events that define the early and late phases. Moreover, many efforts to manipulate mediators of the early phase (through overexpression and knockdown experiments) have been evaluated after prolonged alteration. Nevertheless, there is some heuristic value in considering the early and late phases of aldosterone action separately.

In cultured collecting duct cells deprived of corticosteroids and then exposed to high concentrations of aldosterone, an increase in ENaC-mediated Na ⁺ transport can be observed in well under 1 hour, which is consistent with animal studies. ^, Na ⁺ transport continues to increase for 2 to 3 hours, then plateaus for a few hours, and then gradually increases over the next several hours. After 12 hours of exposure to saturating aldosterone concentrations, the increase in ENaC activity is near maximal. The molecular basis for this increase in ENaC activity has been intensively investigated, and several key events are now apparent.

For aldosterone to increase ENaC activity, a change in gene transcription must occur. One of the earliest response genes is SGK1 . This serine-threonine kinase, which mediates a substantial portion of the early effects of aldosterone, ^, is addressed in greater detail later in this chapter, together with its major target, Nedd4-2. The genetic disease Liddle syndrome provided key first clues to ENaC, as addressed further later. ^,

The major action of aldosterone is to increase the number of functional ENaC units on the apical membrane. This process can involve an increase in the number of channel complexes on the surface, and activation of existing complexes, or both. There is evidence to support both, although the bulk of evidence favors the idea that a change in the number of ENaC units predominates. ^{, ,} The redistribution of ENaC to the apical membrane can be detected in less than 2 hours after aldosterone exposure.

It is less well established whether the number of channels is increased through increased insertion, decreased removal, or both. Aldosterone probably contributes to both processes. Rapid insertion of ENaC is best understood with regard to the actions of cAMP. The extent to which the molecules involved in cAMP-mediated insertion are also involved in aldosterone action is uncertain, but some common mechanisms are probably used. Trafficking to the apical membrane appears to involve hsp70, SNARE (soluble NEM-sensitive factor attachment protein receptor) proteins, and the aldosterone-induced protein melanophilin. The mitogen-activated protein kinase pathway may also be involved because interruption of extracellular-signal regulated kinase (ERK) phosphorylation by the glucocorticoid-induced leucine zipper (GILZ) increases ENaC surface expression.

Considerably more is known about how ENaC complexes are retrieved from the apical membrane. This understanding is the direct result of dissecting the molecular consequences of Liddle syndrome, in which mutations in the C-terminus of ENaC lead to increased residence time in the apical membrane. ^, The missing or mutated domains in the β- or γ-subunit of ENaC in this syndrome normally bind to Nedd4-2, a ubiquitin ligase, which ultimately is responsible for initiating endocytosis and degradation. ^, The interaction of Sgk1 and Nedd4-2 in the actions of aldosterone is discussed later. ENaC is internalized via clathrin-coated vesicles, processed into early endosomes, and then further processed into recycling endosomes and late endosomes. ^, Degradation is via lysosomes or proteasomes. ^, The processing of ENaC by vesicular trafficking and its regulation by aldosterone has been reviewed by Butterworth and colleagues.

Phosphatidylinositol-3-kinase (PI3K)–dependent signaling is essential for epithelial Na ⁺ transport. It controls SGK1 activity (see later) and also appears to have independent effects on ENaC open probability through direct actions of 3-phosphorylated phosphoinositides, particularly phosphatidylinositol (3,4,5)-trisphosphate. ^, Ras-dependent signaling may also regulate ENaC and the pump in complex ways that depend on downstream signaling through Raf, mitogen-activated protein kinase kinase (MEK), and ERK, as well as through PI3K.

The late phase of ENaC activation by aldosterone is less well understood than the early phase. A simple evaluation of the late phase is that aldosterone increases the transcription and protein abundance of the ENaC α-subunit. This idea comes from the fact that aldosterone increases the mRNA and protein abundance of α-ENaC in the kidney ^, after a lag of several hours. Although less well studied, aldosterone appears to produce an increase in β- and γ-subunit expression in the colon. ^, Dietary Na ⁺ restriction, a physiologically relevant maneuver that increases aldosterone secretion, clearly increases ENaC surface expression in the renal distal nephron. However, there appear to be some important differences between chronic aldosterone administration to a Na ⁺ -replete animal and chronic dietary Na ⁺ restriction. ^, Furthermore, it should be noted that increased α-ENaC expression, in and of itself, does not increase ENaC activity in models of collecting duct and lung epithelia, although limiting its expression does restrict aldosterone stimulation. It appears that increased expression of α-ENaC may be important for the consolidation of the increase, but it is not sufficient to reproduce the steroid-mediated increase in ENaC activity.

There is general agreement now that whereas the early effects of aldosterone are on apical events, primarily on ENaC, the basolateral and metabolic effects occur later. In addition, the basolateral effects largely result indirectly from the enhanced entry of Na ⁺ into cells. Notably, increased Na ⁺ entry has been found to control more than 80% of increased Na ⁺ -K ⁺ -ATPase activity and basolateral membrane density in the rat ^, and rabbit cortical collecting tubules. Furthermore, striking increases in basolateral membrane folding and surface area occur in aldosterone-treated animals, an effect that is markedly attenuated in animals fed a low-Na ⁺ diet. This result strongly suggests that apical Na ⁺ entry is required for basolateral changes to occur. However, there is good evidence for direct transcriptional stimulation of Na ⁺ -K ⁺ -ATPase subunit expression, ^, as well as reports supporting some direct effects of aldosterone in increasing basolateral pump activity or at least in constituting the pool of latent pumps, which are then recruited to the basolateral membrane in response to a rise in intracellular [Na ⁺ ].

One of the major effects of aldosterone is to increase K ⁺ secretion (and thus excretion), as depicted in Fig. 12.6 . The key feature of this process—with respect to the direct effects of aldosterone per se—involves the stimulation of Na ⁺ absorption via ENaC. The dependence of K ⁺ secretion on Na ⁺ absorption is the basis of the action of the so-called K-sparing diuretics, amiloride and triamterene, both of which inhibit ENaC.

Increasing ENaC activity produces two major secondary effects that in turn enhance K ⁺ secretion. First, the enhanced Na ⁺ conductance of the apical membrane produces depolarization and hence a more favorable electrical driving force for K ⁺ efflux into the lumen. The second effect relates to the activity of the Na ⁺ -K ⁺ pump on the basolateral membrane. The more Na ⁺ that enters across the apical membrane, the more that must be extruded by the pump. Because the pump operates well below its V _max under baseline conditions, a slight increase in intracellular Na ⁺ concentration markedly stimulates pump activity and more K ⁺ enters the cell. In isolated, perfused cortical collecting ducts, the amount of secreted K ⁺ is highly related to the amount of absorbed Na ⁺ when the stimulus for Na ⁺ absorption is mineralocorticoid hormone.

Two types of K ⁺ channels are found in the apical membrane of the ASDN: small conductance (SK, 30−40 picosiemens [pS]) channels encoded by the ROMK gene and large conductance (BK, 100−200 pS) channels found in many other cell types, including the apical membrane of the colon. Most of the K ⁺ channels on the apical membrane of the principal cells appear to be SK, at least as far as can be assessed by patch-clamp analysis. The activity of either channel is not directly increased by aldosterone. ^,

A feature of K ⁺ secretion is that although apical K ⁺ channels are abundant in the proximal portion of the ASDN (connecting tubule and cortical collecting duct), they are strikingly less abundant in the medullary collecting duct. Because apical K channels are not regulated by aldosterone, their absence in the medullary collecting duct might uncouple aldosterone-regulated Na ⁺ reabsorption from K ⁺ secretion in this segment.

The preceding sections establish a picture that parsimoniously accounts for the effect of aldosterone to stimulate Na ⁺ reabsorption and K ⁺ secretion at the same rate. The simple stimulation of electrogenic Na ⁺ reabsorption (via ENaC) is sufficient to stimulate K ⁺ secretion, which fits well for organisms faced with a combined low-Na ⁺ , high-K ⁺ diet, which was maintained most of the time through millions of years of land vertebrate evolution. However, organisms do not ingest a fixed amount of Na ⁺ and K ⁺ , so an inexorable linkage between Na ⁺ absorption and K ⁺ secretion by the ASDN cannot possibly occur all the time. Investigators have proposed several possibilities to explain how these processes can be separated.

Differential Regulation of Intercalated Cell Mineralocorticoid Receptor

It has become increasingly clear that intercalated cell Cl ⁻ transport contributes to collecting duct NaCl absorption, and this plays an important role in allowing distinct responses to aldosterone in states of volume depletion versus hyperkalemia. ^, A central feature of this proposed regulation is differential phosphorylation of the MR LBD in intercalated cells, as shown schematically in Fig. 12.7 . When phosphorylated at S843 in the LBD, the MR cannot bind aldosterone (or cortisol) and thus cannot be activated. This phosphorylation, which is stimulated by hyperkalemia, occurs selectively in intercalated cells but not in principal cells. Angiotensin II, on the other hand, induces S843 dephosphorylation in intercalated cells, markedly increasing ligand binding and therefore activation. Intercalated cells are known predominantly to mediate H ⁺ transport; however, other studies have implicated them in electroneutral NaCl transport via the combined actions of the Na ⁺ -dependent Cl ⁻ -HCO ₃ ⁻ exchanger (NDCBE) and the apical Cl ⁻ -HCO ₃ ⁻ exchanger, pendrin. ^, Thus when the MR is active in these cells (S843 dephosphorylated), electroneutral NaCl transport occurs, without enhancing the driving force for K ⁺ secretion. Because intercalated cells lack 11β-HSD2 under these conditions, it is cortisol that binds to and activates the MR. When the intercalated cell MR is inactive (S843 phosphorylated), aldosterone acts in principal cells to stimulate ENaC-dependent electrogenic Na ⁺ transport, which enhances K ⁺ secretion.

The role of mineralocorticoid receptor (MR) ligand-hormone−binding domain (LBD) phosphorylation in controlling chloride reabsorption by intercalated cells.

When phosphorylated at Ser-843 in the LBD, MR cannot bind ligands and hence cannot be activated. This phosphorylated state of MR is found only in intercalated cells, not in neighboring principal cells. In states of volume depletion, an elevated angiotensin II level decreases MR phosphorylation at Ser-843 (right side), allowing activation. In intercalated cells, MR mediates stimulation of both the proton pump (H ⁺ -ATPase) and Cl ⁻ -HCO ₃ ⁻ exchangers such as pendrin, thereby increasing Cl ⁻ reabsorption and promoting increased plasma volume while inhibiting K ⁺ secretion. In contrast, in states of hyperkalemia, phosphorylation of Ser-843 is increased (left side) and hence Cl ⁻ reabsorption by intercalated cells is decreased and the principal cell–dependent K ⁺ secretion is increased.

From Shibata S, Rinehart J, Zhang J, et al. Regulated mineralocorticoid receptor phosphorylation controls ligand binding and renal response to volume depletion and hyperkalemia. Cell Metab. 2013;18:660−671.

The term “aldosterone-sensitive distal nephron” emphasizes the central role of this steroid in the control of ion transport in this region of the nephron. However, ENaC activity and aldosterone sensitivity exhibit axial heterogeneity from the late distal convoluted tubule (DCT2) through the connecting tubule to the cortical collecting duct and, finally, to the medullary collecting duct. In mice on a standard sodium diet, total ENaC expression increases with progression from the DCT2 to the connecting tubule, although ENaC apical localization and activity are higher in the DCT2. Only under conditions of a low-sodium diet or aldosterone administration does the importance of the connecting tubule in particular, and to a lesser extent the cortical collecting duct, emerge. The total luminal surface area in the DCT2 and connecting tubule is several-fold higher than in the cortical collecting duct, and together these two segments appear to be sufficient to maintain sodium balance, even in the absence of detectable ENaC along the collecting duct. Mice lacking ENaC selectively in the collecting duct come into balance, even on a low-sodium diet. Congruent with these findings, deletion of α-ENaC from the DCT2, connecting tubule, and collecting duct results in severe sodium wasting. Notably, it is the connecting tubule that appears to be most important in the response to aldosterone, whereas DCT2 has the highest baseline transport in the absence of aldosterone. The cortical collecting duct is not as critical as was originally thought for either baseline or aldosterone-stimulated sodium reabsorption, probably due to its smaller surface area. Data have established a key role of aldosterone-independent (likely cortisol-dependent) activation of MR in regulating ENaC in this context. ^, Importantly, although the later part of the DCT (DCT2) and early CNT express MR, ENaC, and ROMK, they express relatively low levels of 11ß-HSD2, and hence MR is activated by cortisol to stimulate K ⁺ secretion. Evidence has also begun to establish a mechanism for aldosterone-independent effects of K ⁺ within principal cells: Local changes in [K ⁺ ] within the kidney stimulate SGK1 phosphorylation by mTORC2, ^, possibly through a WNK-dependent mechanism, as addressed in Chapter 6). Rapid activation of ENaC then drives ROMK-mediated K+ secretion.

As we continue to traverse the nephron, further sodium reabsorption is minimal in the medullary collecting duct, on a normal sodium diet, and is not significantly stimulated by aldosterone.

Under physiologic conditions, approximately 1.3 to 1.8 L of electrolyte-rich fluid is reabsorbed per day from the colonic epithelium. Like the nephron, the proximal colon reabsorbs sodium via an electroneutral, ENaC-independent process. In the distal colon, electrogenic Na ⁺ absorption via ENaC channels is the predominant mode of sodium transport. In the colon, as in the distal nephron, MR signaling is aldosterone selective, reflecting the activity of 11β-HSD2. Aldosterone increases electrogenic sodium absorption and potassium secretion and inhibits electroneutral absorption. This is in contrast to glucocorticoids, which, at higher concentrations, activate glucocorticoid receptors to stimulate electroneutral absorption in the proximal and distal colon. ^, As in the distal nephron, the aldosterone response can be characterized by an early and late response. The early response gene, SGK1, is upregulated by aldosterone via MR. However, in contrast with the kidney, aldosterone and a low-salt diet have been shown to stimulate transcription of β-ENaC but not α-ENaC in rat models. ^,

Aldosterone stimulates electrogenic potassium secretion from colonic epithelia. The significance of this secretion is evident in anuric patients. Potassium secretion from the colon is much higher in patients undergoing long-term hemodialysis than in patients not undergoing dialysis. Indeed, administration of fludrocortisone, a mineralocorticoid agonist, to dialysis patients has been shown to reduce hyperkalemia in small clinical trials. Low doses of the common MR antagonist spironolactone do not result in significant hyperkalemia.

Vectorial transport of salt and water across the distal airway epithelium and alveoli primarily determines fluid clearance from the lung. ENaC is the rate-limiting step in sodium transport in the lung and plays a primary role in several physiologic and pathophysiologic conditions determined by fluid clearance. The molecular apparatus for mineralocorticoid-stimulated fluid reabsorption via ENaC (concomitant MR and 11β-HSD2) is present in late gestational and mature adult lung in humans ^{, ,} and rats, and there is some evidence for a significant physiologic role of aldosterone in ENaC-mediated sodium transport, although glucocorticoids acting via the glucocorticoid receptor are likely to play the predominant role in lung. ^{, ,} Importantly, glucocorticoids, but not mineralocorticoids, play a critical role in lung maturation in humans, and glucocorticoid receptor knockout mice, like α-ENaC knockout mice, die of respiratory insufficiency within hours of birth. In contrast, MR knockout mice demonstrate a severe salt-wasting phenotype but no significant lung phenotype. ^,

ENaC-mediated sodium reabsorption is also measurable in the salivary and sweat glands. The importance of these tissues for sodium and water homeostasis is underscored by rare genetic mutations that result in elevated plasma aldosterone levels and pseudohypoaldosteronism, with normal renal tubular function but significant sodium loss from salivary or sweat glands. ^, ENaC channels also play an important role in transduction of sodium salt taste in the anterior papillae of the tongue. ^, The appropriate molecular machinery for mineralocorticoid-responsive sodium reabsorption is expressed in these organs. ^{, ,} As in colonic epithelia, aldosterone stimulates the expression of β- and γ-ENaC and sodium transport in glands and taste buds in animal models. ^, Moreover, in humans, changes in dietary sodium are inversely proportional to sodium transport across salivary epithelia. Similar to the aldosterone-responsive distal nephron and distal colon, sodium uptake is coupled with potassium secretion in salivary epithelia. This effect is evident in humans with hyperaldosteronism. Such patients have a salivary [Na ⁺ ]/[K ⁺ ] ratio significantly lower than that of subjects without the disorder, ^, although this has not been accepted as a valid means to screen for hyperaldosteronism.

The serine-threonine kinase, SGK1, is the best characterized transcriptional target of MR. ^, Its mRNA levels are increased within 15 minutes, and protein levels within 30 minutes by aldosterone in both cultured cells and in native collecting duct. ^{, , , ,} (notably, more strongly in CNT and cortical collecting duct than in the medulla ^, ). SGK1 is expressed in other nephron segments including glomeruli, proximal tubule, and papillae ^{, ,} ; however, its rapid induction in the ASDN appears to provide most of the basis for its role in aldosterone-regulated sodium and potassium transport. SGK1, induced by high sodium in infiltrating T cells, is also important for inflammation in the kidney and hypertension, although the specific nephron segments are unknown. ^,467 Although it has effects on proliferation and apoptosis in kidney cells, these effects appear to be minor and the control of ENaC and other transporters predominates.

SGK1 gene transcription is induced by a variety of stimuli in addition to MR. As its name implies, these include serum and glucocorticoids but also follicle-stimulating hormone, transforming growth factor-β, and osmotic stress. Some of these, particularly osmotic regulation, may play significant roles in renal physiology. Stimulation of SGK1 kinase activity is primarily through phosphorylation, which, like that of its close relative, Akt, is stimulated by a variety of growth factors including insulin and insulin-like growth factor-1 ; these act through PI3K to trigger phosphorylation at two key residues, an activation loop (residue T256) and a hydrophobic motif (S422). PI3K-dependent kinase 1 (PDK1) phosphorylates T256, and mammalian target of rapamycin [mTOR] complex 2 (mTORC2) phosphorylates S422. ^{, ,} Thus SGK1 serves as a convergence point for different classes of stimuli, which act on the one hand to control its expression (aldosterone and cortisol) and on the other to control its activity (insulin and other activators including K ⁺ ), which results in the coordinate regulation of ENaC.

In the study of the physiologic and pathophysiologic roles of SGK1 in the ASDN, mice lacking SGK1 under different physiologic stimuli have provided considerable insight. Unlike MR knockout mice, mice lacking SGK1 survive the neonatal period and appear normal when consuming a normal sodium/normal potassium diet, albeit with markedly elevated aldosterone. When subjected to a low-sodium diet, these mice have marked sodium wasting, and in the face of a high-potassium diet they develop hyperkalemia, akin to pseudohypoaldosteronism type I. Additional mouse models of SGK1 deletion have demonstrated diminished processing of ENaC subunits I. ^, Notably, this is a significantly milder phenotype than with deletion of MR or α-ENaC. These comparisons suggest that disruption of SGK1 signaling may be insufficient to eliminate aldosterone-mediated sodium transport due to additional aldosterone-induced and aldosterone-repressed proteins, which could compensate for the lack of SGK1.

SGK1 may also play a significant role in states of aldosterone excess or upregulation of hormonal activators of SGK1 (e.g., insulin). SGK1 knockout mice are protected from the development of salt-sensitive hypertension, which accompanies the hyperinsulinemia of the metabolic syndrome. ^, Taken together, SGK1 is an important component of ENaC regulation to maintain both sodium and potassium homeostasis.

Despite its accepted role as a mediator of aldosterone-stimulated sodium reabsorption, the mechanisms whereby SGK1 stimulates ENaC are not fully characterized. Several mechanistic studies have demonstrated that SGK1 is rapidly induced but also rapidly degraded. ^{, ,} The N-terminus of the kinase, which distinguishes SGK1 from other kinase family members (e.g., Akt), is important for stimulation of sodium transport but is also the target for rapid degradation of the kinase via the ubiquitin-proteasome system. The molecular mechanisms of ENaC stimulation by SGK1 can be divided into three known categories ( Fig. 12.9 ): 1. posttranslational effects on the E3 ubiquitin ligase Nedd4-2; 2. posttranslational Nedd4-2–independent effects; and 3. transcription of gene products such as α-ENaC.

Mechanisms of serum- and glucocorticoid-regulated kinase 1 (SGK1) –mediated stimulation of the amiloride-sensitive sodium channel (ENaC) .

Within principal cells of the mammalian kidney, SGK1 is transcriptionally upregulated as an early aldosterone-induced gene product. SGK1 is then phosphorylated twice via a phosphatidylinositol-3-kinase (PI3K) –dependent cascade of upstream kinases leading to active SGK1. Active SGK1 has multiple effects: It increases apical plasma membrane ENaC by inhibiting Nedd4-2 and Raf-1, and it induces transcription of the α-ENaC (thereby influencing late effects of aldosterone). (A–E, clockwise ) Shown are the individual mechanisms that have been elucidated in principal cells. See text for details. InsR, Insulin receptor; IRS1, insulin receptor substrate 1; MR, mineralocorticoid receptor; mTORC2, mammalian target of rapamycin complex 2; PDK1, 3-phosphoinositide-dependent protein kinase type 1.

Early aldosterone-induced mRNAs other than SGK1 have also been implicated in the stimulation of ENaC; these include K-ras, GILZ, kidney-specific WNK1, Usp45, melanophilin, and promyelocytic leukemia zinc finger. ^{, ,}

Evidence has also supported a key role of aldosterone-regulated micro-RNAs in regulating both SGK1 and ENaC. Aldosterone can upregulate or downregulate several micro-RNAs in cultured cells and in vivo. These micro-RNAs can then indirectly increase or decrease protein levels of intermediate regulators of ENaC-mediated transport. The first micro-RNA cluster (mmu-miR-335-3p, mmu-miR-290-5p, and mmu-miR-1983) to be described by Butterworth and colleagues ^, was downregulated by aldosterone within 24 hours and thereby released the 3′ untranslated region of ankyrin 3 to increase apical trafficking of α-ENaC. Aldosterone also increases micro-RNAs that inhibit a negative regulator of ENaC, intersectin 2. Aldosterone has also been shown to promote the rapid induction of SGK1 mRNA by decreasing micro-RNA 466g in cultured cells. Taken together, SGK1 plays a prominent role in transducing the effect of aldosterone to stimulate ENaC for both regulation of blood pressure and potassium homeostasis. Additionally, there are alternate effectors of aldosterone, but the physiologic contexts of these other pathways have not been as well established.

The physiologic glucocorticoid, cortisol (corticosterone in rats and mice), has a high affinity for the MR, equivalent to that of aldosterone, and, as noted earlier, circulates at plasma-free concentrations that are 1000-fold or more higher than those of aldosterone. Central to the ability of the MR to respond to aldosterone selectively in the ASDN is coexpression of the enzyme 11β-HSD2. ^, 11β-HSD2 converts cortisol (corticosterone) to receptor-inactive 11-keto steroids (cortisone in humans, 11-dehydrocorticosterone in rats and mice), using nicotinamide adenine dinucleotide (NAD) as a cosubstrate and generating sufficient amounts of the reduced form of NAD (NADH) to alter the redox potential of the cell. This dependence sets it in contrast to 11β-HSD1, which uses the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), preferentially catalyzes the conversion of glucocorticoids from the oxidized form (cortisone) to the reduced form (cortisol), and hence amplifies glucocorticoid action in metabolic tissues such as liver and adipose tissue. 11β-HSD1 has received substantial attention as a target for the treatment of metabolic syndrome. Aldosterone has a reactive aldehyde group at carbon 18 (see Fig. 12.1 ), which forms an 11,18-hemiacetal and is protected from dehydrogenation by 11β-HSD2. ^,

In the kidney, 11β-HSD2 is expressed throughout the ASDN, ^{, ,} where it is coexpressed with MR and ENaC (see Fig. 12.9 ). It is also coexpressed in DCT, ^, but consensus is building that its expression is relatively low in both DCT and early CNT, allowing cortisol access to MR. ^, Interestingly, expression has also been found in the thick ascending limb, although at substantially lower levels. Expression is the highest in the later connecting tubule and cortical collecting duct. ^, It is also expressed in the aldosterone-sensitive segments of the colon, particularly the distal colon, as is the case for MR, although there is species variability. 11β-HSD2 expression has also been described in several nonepithelial tissues including placenta, the nucleus tractus solitarius in the brain, and the vessel wall, which makes all these tissues potential aldosterone target tissues.

The initial ^, and still widely held interpretation of the role of 11β-HSD2 is that of excluding active glucocorticoids from the epithelial MR, which allows aldosterone unfettered access. This is only part of the picture, however; to reduce the signal-to-noise ratio from 100-fold to 10% would require that 999 of every 1000 cortisol molecules entering the cell be metabolized to cortisone, a tall order in an organ such as the kidney, which commands 20% to 25% of cardiac output. 11β-HSD2 in epithelia (and in other tissues in which it is expressed) clearly reduces glucocorticoid levels by an order of magnitude but still leaves them with intracellular levels well above those of aldosterone. At the same time, although it is clear that when 11β-HSD2 is operative, the glucocorticoid-occupied MR is not transcriptionally active, it is also clear that when enzyme activity is insufficient (as in apparent mineralocorticoid excess) or deficient (as in licorice abuse or by genetic mutation), cortisol can activate the MR and ion transport. Although the subcellular mechanisms involved have yet to be established, it appears that glucocorticoid-MR complexes are conformationally distinct from aldosterone–MR complexes. One intriguing possibility is that these hormone-receptor complexes, in contrast to aldosterone–MRcomplexes, are held inactive by the obligate generation of NADH from the cosubstrate NAD, required for the operation of 11β-HSD2. Direct evidence supports the idea that redox potential affects the activity of the glucocorticoid receptor through effects on thioredoxin.

Apparent mineralocorticoid excess was first described by New, and the molecular mechanisms responsible were established after an intense but fruitless search for a novel mineralocorticoid. The condition reflects a partial or complete deficiency of 11β-HSD2 activity, is more common in consanguinity, and manifests as severe juvenile hypertension (see also Chapter 46 ). Confectionery licorice (or that added to chewing tobacco) contains glycyrrhizic and glycyrrhetinic acids, suicide substrates for 11β-HSD2, which thus acts as a potent inhibitor of the enzyme. Lack of functional 11β-HSD2 results in MR activation by cortisol and inappropriate mineralocorticoid-like stimulation of ENaC-mediated Na ⁺ reabsorption. This causes severe hypertension, often accompanied by hypokalemia. Plasma renin, angiotensin II, and aldosterone are suppressed. Treatment of apparent mineralocorticoid excess is the use of MR antagonists and additional antihypertensives, as required.

Aldosterone at nanomolar concentrations in the human vascular wall causes a rapid rise in the intracellular pH, reflecting nongenomic activation of the Na ⁺ -H ⁺ exchanger. Cortisol alone over a range of doses produced no effect, but when carbenoxolone was added to inhibit 11β-HSD2, cortisol mimicked aldosterone. Inhibitor studies have revealed that the effects of both aldosterone and cortisol are mediated by a classic MR, at least in part through a nongenomic mechanism. Effects in both vascular endothelial cells and smooth muscle cells have been described. Of particular note, a direct role of the smooth muscle cell MR in blood pressure regulation was demonstrated in selective gene knockout studies in mice, and its effects were shown to be at least in part due to regulation of L-type calcium channel (Cav1.2) expression. Evidence also supports a role of smooth muscle cell MR in age-related increases in vasoconstriction and rise in BP. ^, In still other studies, mineralocorticoid antagonists were protective in states of tissue damage, whereas aldosterone or cortisol worsened injury. One inference from these latter results was that cortisol becomes a MR agonist in the context of tissue damage, possibly due to alteration of reactive oxygen species generation and redox potential. To add to the complexity, aldosterone has been shown to have both vasodilatory and vasoconstricting effects in animals and humans. These contradictory results have not been fully reconciled but may well reflect a combination of direct stimulatory effects on vascular smooth muscle myosin light-chain phosphorylation ^, on the one hand and stimulatory effects on endothelial cell nitric oxide synthase on the other. Finally, it is of considerable interest that vascular smooth muscle and endothelial cells express ENaC, in addition to the MR, and that the channel might play a role in setting vascular tone and through these nonrenal mechanisms implicated in hypertension. ^,

It is commonly assumed that in pathophysiologic states of high aldosterone levels, such as primary aldosteronism, the deleterious effects are mediated by aldosterone occupying and inappropriately activating nonprotected MRs in cardiomyocytes, for example. It is plausible that instead of the approximately 1% physiologic occupancy (given the ≈100-fold higher levels of plasma-free cortisol), aldosterone occupancy of cardiomyocyte MRs might rise to 3% to 5%. Relatively minor degrees of MR occupancy have been shown to be effective for spironolactone, acting as a protective inverse agonist ; similarly therefore minor degrees of cardiomyocyte MR occupancy by aldosterone could potentially produce the deleterious effects seen.

This explanation, however, is almost certainly incorrect. Plasma aldosterone levels are as high or higher in chronic sodium deficiency (or in the effectively volume-depleted condition of secondary hyperaldosteronism), with no deleterious cardiovascular effects. In primary and secondary aldosteronism, as well as in chronic sodium deficiency, physiologic target tissues, both renal tubular and coronary vascular, are exposed to (and respond to) maintained high levels of aldosterone. It is thus unlikely that the cardiovascular damage in primary aldosteronism reflects increased MR activation in blood vessels, coronary and peripheral. The key difference between these circumstances is that primary aldosteronism is a state of aldosterone and sodium excess and the others of sodium and volume depletion.

A plausible but untested mechanism of aldosterone-induced damage is that it is secondary to increased renal sodium reabsorption and the action of endogenous ouabain on blood vessels. Endogenous ouabain is incompletely explored, but its levels are elevated in primary aldosteronism. Like aldosterone, its secretion is elevated by ACTH and angiotensin (the latter via AT ₂ R); in stark contrast with aldosterone, it is raised (not lowered) in states of sodium excess. It acts via Na ⁺ -K ⁺ -ATPase in vessel walls as a vasoconstrictor, presumably physiologically to produce a pressure natriuresis as a homeostatic response. Thus it may be that the cardiovascular damage in primary aldosteronism reflects a combination of the effects of aldosterone plus endogenous ouabain on the vasculature; if this is the case, the source and origin of the nonepithelial effects of aldosterone remain squarely in the renal tubule and the exaggerated sodium retention therein.

The initial MR antagonists (MRAs), steroidal molecules, such as spironolactone, were developed shortly after the discovery of aldosterone and available for treatment of volume overload shortly thereafter. The MR was then cloned in 1987 and eplerenone was developed. Spironolactone lacks MR specificity, most notably binding with high affinity to the androgen and progesterone receptors, As well as exerting antiandrogenic and progestogenic adverse side effects (e.g., breast tenderness, gynecomastia, and decreased libido). On the other hand, while eplerenone is more specific, it is less effective in reducing blood pressure. Both agents may cause significant hyperkalemia in select populations. ^, To optimize efficacy and selectivity, nonsteroidal MRAs were developed.

Finerenone, one of several nonsteroidal MRAs, was originally derived from a dihydropyridine calcium channel blocker found to bind to and inhibit the MR. Compared with spironolactone and eplerenone, finerenone differs in tissue distribution, binding site, pharmacokinetics, and mechanism by which it inhibits the MR. ^, Finerenone can alter the transcriptional profile of cells compared with steroidal MRAs. Finerenone is comparable in potency to spironolactone to block the MR but also has comparable specificity to eplerenone, thereby avoiding the endocrine side effects that can plague high doses or long-term use of spironolactone. Due to these differences in the pharmacology of nonsteroidal versus steroidal MRAs, agents such as finerenone have been considered a potential strategy to protect target end-organ tissues at doses that may result in significantly less hyperkalemia. Thus at equinatriuretic doses, finerenone is more potent than steroidal MRAs at protecting against end-organ injury such as cardiac hypertrophy, proteinuria, and glomerulosclerosis in preclinical and clinical studies. ^{, , ,} This is presumably because fineronone causes less MR antagonism in principal cells of the cortical collecting duct. Other nonsteroidal MRAs include esaxerenone, which has been developed and approved outside the United States for the treatment of hypertension, and ocedurenone, which is similar to finerenone but has higher extrarenal tissue distribution and causes less hyperkalemia, especially in patients with advanced chronic kidney disease.

The need for an antialdosterone therapy with more efficacy and specificity than either spironolactone or eplerenone, coinciding with the development of inhibitors of CYP11B1 for inhibition of cortisol synthesis, paved the way for the parallel discovery of inhibitors of CYP11B2 (aldosterone synthase). The aldosterone synthase inhibitor, baxdrostat, and other similar compounds (lorundrostat) are currently in clinical trials. While their clinical utility has not been fully established, aldosterone synthase inhibitors may be distinct from MRAs in that they do not block MR-mediated effects of cortisol, but may not block nongenomic actions of aldosterone.

Amiloride and triamterene are in clinical use as inhibitors of ENaC. These agents cannot inhibit ENaC-independent effects of the MR in kidney epithelial on extrarenal tissues and are primarily used to inhibit potassium secretion in states of ENaC activation, which include genetic (e.g., Liddle syndrome and gain-of-function ENaC) and acquired (licorice ingestion, posaconazole) conditions, classified as syndromes of apparent mineralocorticoid excess.

Clinically, the most prevalent disorder directly involving aldosterone is Conn syndrome, or primary aldosteronism. In this syndrome, aldosterone secretion is elevated and (relatively) autonomous as a result of an adrenal adenoma or, more frequently, bilateral adrenal hyperplasia and, rarely, adrenal carcinoma or familial hyperaldosteronism syndromes. Once considered rare (<1% of all cases of hypertension), necessarily characterized by hypokalemia and relatively benign, primary aldosteronism is now thought to account for at least ∼10% to 20% of all hypertension and a higher percentage of resistant hypertension. ^, In contrast to prior teachings, frank hypokalemia is found in only 25% to 30% of cases, and the incidence of cardiovascular pathology (e.g., fibrosis, fibrillation, infarct, and stroke) is substantially higher than in age-, gender-, and blood pressure–matched individuals with essential hypertension. For further discussion of its role in clinical hypertension, see Chapter 46 ^.

Guidelines for the case detection, diagnosis, and management of primary aldosteronism have been published as a first step in addressing what has been increasingly recognized as an important public health issue. It has long been thought and taught that the role of aldosterone in blood pressure regulation reflects its epithelial effects leading to retention of sodium and with it water, which thus increases circulating volume. This increase, in turn, is reflected in an increased cardiac output, which is reflexively normalized by vasoconstriction and thus elevation of blood pressure (in keeping with the Guyton hypothesis ). Although the epithelial effects of aldosterone on vascular volume are indisputably homeostatically important, there have been compelling experimental and clinical studies to suggest a role for nonepithelial effects in mineralocorticoid-induced hypertension. ^, In addition to MR-mediated central nervous system and vascular effects in hypertension, roles for macrophages have been demonstrated. ^,

Primary hyperaldosteronism may be caused by gain-of-function mutations in genes that regulate aldosterone synthesis in the zona glomerulosa. These findings have emerged from studies of somatic mutations in aldosterone-producing adenomas and germ-line mutations in rare forms of familial hyperaldosteronism. More than 90% of aldosterone-producing adenomas carry somatic mutations in K ⁺ channel Kir3.4 (KCNJ5), Ca ²⁺ channel Ca _V 1.3 (CACNA1D), α-1 subunit of the Na ⁺ /K ⁺ ATPase (ATP1A1), plasma membrane Ca ²⁺ transporting ATPase 3 (ATP2B3), Ca ²⁺ channel Ca _V 3.2 (CACNA1H), Cl ^– channel ClC-2 (CLCN2), β-catenin (CTNNB1), and/or G-protein subunits alpha q/11 (GNAQ/11). Several of these genes, as well as the gene associated with glucocorticoid-remediable hyperaldosteronism (CYP11B1/2), are implicated in familial forms of hyperaldosteronism. ^{, ,} See the earlier section on “Aldosterone Synthesis” for additional details. Treatment of primary aldosteronism may include steroidal MRAs or adrenalectomy for unilateral aldosterone secretion and steroidal MRAs for bilateral aldosterone secretion. For patients eligible for adrenalectomy, clinical studies comparing these treatment modalities for prevention of major adverse cardiovascular or kidney events are lacking. Nonsteroidal MRAs, aldosterone synthase inhibitors, and ENaC inhibitors are of potential benefit in patients with primary aldosteronism who cannot tolerate or are inadequately treated with steroidal MRAs. However, phase 3 noninferiority studies are lacking.

Aldosterone has been implicated in the pathophysiology of congestive heart failure since its discovery in the mid-1950s. ^, Until fairly recently, most of the focus was on the counterproductive effects of aldosterone in epithelia, such as salt and fluid retention. More recently, the beneficial effects of MRAs in congestive heart failure have suggested an additional effect on myocardium itself. In the Randomized Aldactone Evaluation Study (RALES), addition of low-dose (mean, 26 mg/day) spironolactone to standard-of-care treatment in patients with progressive heart failure produced a 30% reduction in mortality and 35% fewer hospitalizations. This result is often attributed to spironolactone inhibition of the effect of aldosterone on cardiomyocyte MRs but actually may reflect inhibition of cortisol, which acts as a MR agonist under ischemic conditions. Subsequently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) examined the effect of the MR antagonist eplerenone, with improved specificity relative to spironolactone, on heart failure due to systolic dysfunction complicating acute myocardial infarction. The study showed that adding eplerenone (25–50 mg/day) to conventional therapy significantly decreased all-cause and cardiovascular mortality. Potassium levels were only slightly higher in the eplerenone-treated group than in the placebo-treated group (4.47 mmol/L and 4.54 mmol/L, respectively). Coupled with studies on the direct vascular effects of aldosterone discussed earlier, these data suggest that MR antagonists have a beneficial effect that cannot be accounted for by diuretic actions in the kidney alone.

It is also notable that a trial (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure [EMPHASIS-HF]) examining the effect of eplerenone in New York Heart Association (NYHA) class II heart failure (milder than previously examined) was stopped early because significant benefit was found in the treated group.

Both spironolactone and eplerenone cause high rates of hyperkalemia. ^, At-risk populations include patients with type 2 diabetes and/or CKD. Thus a nonsteroidal MRA with less effect on ENaC in the ASDN, but with comparable or distinct inhibition of the MR in cardiomyocytes, may be useful for reducing major adverse cardiovascular events in these cohorts. In the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial, eligible patients had type 2 diabetes mellitus and mild to moderate albuminuria and stage 2 to 4 CKD or macroalbuminuria and milder CKD. Patients were similar to the RALES or EPHESUS trials in that patients were already taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. During a median follow-up of 3.4 years, finerenone versus placebo reduced primary outcome events (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with a significantly higher rate of hyperkalemia-induced discontinuation compared with placebo but a historically lower incidence of hyperkalemia-related discontinuation compared with steroidal MRAs. The American Diabetes Association has incorporated nonsteroidal MRAs into their guidelines and recommended use of finerenone for similar indications.

The role of MR blockade in slowing the progression of CKD has been considered. However, the risk of hyperkalemia with steroidal MRAs has precluded major, randomized placebo-controlled trials to slow progression of CKD and/or decrease major adverse kidney events. To assess the role of a nonsteroidal MRA, fnerenone was compared with placebo in the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial.

This study was similar to the FIGARO-DKD trial in its inclusion of patients with type 2 diabetes mellitus and mild to moderate albuminuria with stage 2 to 4 CKD or macroalbuminuria and milder CKD, but it was designed to evaluate renal endpoints instead of cardiovascular endpoints. All the patients were treated with renin-angiotensin system blockade. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. During a median follow-up of 2.6 years, finerenone demonstrated an 18% lower risk of CKD progression and cardiovascular events (hazard ratio, 0.82; 95% confidence interval [CI], 0.73–0.93; P = 0.001). Similar to the FIGARO-DKD trial, patients on finerenone had a significantly higher rate of hyperkalemia-induced discontinuation compared with placebo but a historically lower incidence of hyperkalemia-related discontinuation compared with steroidal MRAs.