Mineralocorticoid Receptor Antagonist for Renal Protection

Abstract

The renin–angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular and renal diseases. In chronic kidney disease (CKD), blockade of RAS by angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) has been shown to reduce proteinuria and retard the progression of renal function deterioration. However, aldosterone, another key hormone of the RAS, is not directly targeted by ACEI or ARB. Hyperaldosteronism, apart from promoting sodium and fluid retention, causes inflammation and fibrosis in the heart and kidney. Studies have shown that although plasma aldosterone level shows an initial decrease following ACEI or ARB treatment, it returns to pretreatment level or even increases paradoxically after prolonged treatment. This “aldosterone breakthrough” forms the basis of adding mineralocorticoid receptor (MR) antagonist on top of ACEI or ARB for renal protection. New insights into the pathophysiological role of aldosterone in CKD further expands its potential indications, and there was a growing body of evidence in the past 10 years, which showed a substantial antiproteinuric effect and possibly a considerable renoprotective effect of MR antagonist. Since aldosterone does not act on the efferent glomerular arteriole and has no effect on intraglomerular hemodynamics, the very fact that MR antagonist ameliorates proteinuria sheds light on the physiology of glomerular permeability barrier. This review summarizes the data regarding the theoretical benefit as well as clinical use of MR antagonist in renal diseases.

• proteinuria
• chronic kidney disease
• hypertension

INTRODUCTION

Activation of the renin–angiotensin system (RAS) plays a pivotal role in the pathophysiology of a wide range of diseases, including hypertension, stroke, myocardial infarction, heart failure, and chronic kidney disease (CKD). Blockade of the RAS by angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) has been shown to confer additional cardiovascular and renal protection on top of their antihypertensive effect.¹ Currently, both ACEI and ARB are considered the standard of care in CKD based on their ability to reduce proteinuria and retard the progression of renal function deterioration.² Nevertheless, a significant proportion of CKD patients continue to deteriorate and develop end-stage renal disease even with optimization of ACEI and/or ARB therapy. Despite the early enthusiasm from multiple small, uncontrolled studies, which showed a significant reduction in proteinuria by ACEI and ARB combination therapy,³ a recent large-scale randomized controlled study showed that combination of ramipril and telmisartan was associated with more adverse events without an increase in benefit when compared with either treatment alone.⁴ Although the combination of ramipril and telmisartan did reduce proteinuria to a greater extent than monotherapy, the risk of renal composite end point (dialysis, doubling of serum creatinine, and death) was actually increased.⁵

Aldosterone, another key hormone of the RAS, is not directly targeted by ACEI or ARB. There is an accumulating evidence that hyperaldosteronism causes inflammation and fibrosis of the kidney⁶ and the heart.⁷ Previous studies showed that although plasma aldosterone level decreased initially following ACEI treatment, it returned to pretreatment level or even increased paradoxically after prolonged treatment.⁸ It was once thought that this phenomenon of “aldosterone breakthrough” was a consequence of the effect of non-ACE enzymes (e.g., chymase, cathepsin G, chymostatin-sensitive angiotensin II-generating enzyme), which are capable of cleaving angiotensin I to angiotensin II and subsequently stimulate aldosterone release.⁹ However, the same problem of aldosterone breakthrough was also observed in patients receiving ARB therapy. Although the exact mechanism of this problem remains uncertain, it forms an important theoretical basis for adding mineralocorticoid receptor (MR) antagonist on top of ACEI or ARB therapy for renal protection.

The first available MR antagonist, spironolactone (SPL), was introduced in 1953 and had been effectively used for many clinical conditions (e.g., ascites in liver cirrhosis, primary hyperaldosteronism, severe congestive heart failure, hirsutism, polycystic ovarian syndrome, Bartter’s syndrome, and Gitelman’s syndrome). However, being also a progesterone agonist and androgen antagonist, SPL is associated with side effects such as breast tenderness and menstrual irregularities in women and, more importantly, erectile dysfunction and gynecomastia in men. In contrast, eplerenone (EPL) is a new-generation and highly selective MR antagonist, which has a substantially lower incidence of endocrine side effects. Over the past decade, there has been a growing body of evidence to show that MR antagonist has a significant antiproteinuric effect and possibly a considerable renoprotective effect. Since aldosterone does not directly act on efferent glomerular arteriole (the site of action of angiotensin II) and has no effect on intraglomerular hemodynamics, the very fact that MR antagonist ameliorates proteinuria sheds light on the physiology of glomerular permeability barrier. In this review, we summarize the data regarding the theoretical benefit as well as clinical use of MR antagonist in renal diseases.

ALDOSTERONE AS A MEDIATOR OF KIDNEY INJURY

Although aldosterone was first isolated by Simpson and Tait in 1953,¹⁰ the association between aldosterone and proteinuria was not appreciated until 1996. Nonetheless, in the original series of Conn et al.¹¹ which consisted of 145 cases of primary aldosteronism, nearly 85% of the patients had significant proteinuria. However, proteinuria was initially attributed to the effect of hypertension and hypokalemia (kaliopenic nephropathy), and the pathophysiological role of aldosterone per se was not appreciated. Greene et al.¹² first demonstrated in the rat remnant kidney model that exogenous aldosterone infusion induces hypertension, proteinuria, and glomerulosclerosis, and administration of SPL reduced proteinuria at least transiently. In addition, adrenalectomy reduced proteinuria in this remnant kidney model.

Aldosterone is now recognized as an important mediator of renal vascular remodeling.⁶ Aldosterone-induced kidney injury is likely to be multifactorial, including its effect on systemic blood pressure, renal vasculature, local inflammation, and fibrosis. Various potential pathways and mediators have been proposed, including plasminogen activator inhibitor-1,¹³ transforming growth factor-β1,¹⁴ reactive oxygen species,¹⁵ angiotensin type 1 receptor,¹⁶ vascular endothelial growth factor,¹⁷ as well as changes in vascular smooth muscle¹⁸ and endothelial cells¹⁹ (Table 1).

Table 1. Possible pathways of aldosterone-induced renal vascular remodeling.

Pathway	Effects of aldosterone
Cells
Vascular smooth muscles	• Potentiates the vasopressor response of angiotensin^18
	• Inhibits the uptake of norepinephrine
Endothelial cells	• Reduces endothelial-dependant vasodilatation
	• Inhibits nitric oxide synthesis in vascular smooth muscle cells and stimulates thromboxane A2 and prostacyclin production^40
	• Leads to microthrombus formation, tissue microinfarction, and subsequently fibrosis
Mediators
Plasminogen activator inhibitor-1 (PAI-1)	• PAI-1 inhibits the production of plasmin, which is responsible for degradation of fibrin and extracellular matrix (ECM)
	• Stimulates PAI-1 expression in vascular smooth muscle cells and endothelial cells, which in turn causes thrombosis, accumulation of ECM, and fibrosis^13
	• PAI-1 mediates glomerulosclerosis and interstitial fibrosis^13
Transforming growth factor-β1 (TGF-β1)	• Promotes proliferation of intrarenal fibroblasts and epithelial–mesenchymal transition (tubular cells transforming into fibroblasts), collagen synthesis, and deposition, and inhibits the release of collagenase^14
Reactive oxygen species (ROS)	• The profibrotic action of aldosterone is mediated partly by ROS generation and associated with nicotinamide adenine dinucleotide phosphate (NAPDH) oxidase activation^15
Angiotensin type 1 receptor (AT1R)	• Increases AT1R expression, with subsequent increase in expression of profibrotic factors, such as connective tissue growth factor (CTGF)^16
Vascular endothelial growth factor (VEGF)	• Upregulates VEGF in cultured cortical collecting duct epithelial cells^17

In addition to the traditional nuclear receptor and transcription mediation pathway, aldosterone could alter a number of cellular signaling within minutes by the presumably “non-genomic” actions. Examples of non-genomic action include sodium flux,²⁰ calcium flux,²¹ change in intracellular pH,²² and protein kinase C activity.²³ However, the pathophysiological role of these non-genomic actions on progressive renal injury is not fully understood.

In addition to the traditional pathway, in renal tubular epithelial cells, activation of MR in non-epithelial tissues has been shown to cause hypertrophy and fibrosis.²⁴ Nonetheless, it remains unknown how physiologic glucocorticoids can mimic aldosterone action in epithelial MR, but act as antagonists in many non-epithelial tissues, and how aldosterone activates unprotected MR (i.e., with no type 2 11β-hydroxysteroid dehydrogenase) in the face of orders of magnitude higher than circulating glucocorticoid concentrations.²⁴ In fact, emerging data reveal that aldosterone is not a sole regulator of MR activity. For example, Rafiq et al.²⁵ recently showed that chronic glucocorticoid excess could activate MR and induce the development of renal injury, while Shibata and Fujita²⁶ identified the signaling crosstalk between MR and small GTPase Rac1 as a novel pathway to facilitate MR signaling. Such a local control system for MR can also be relevant to the pathogenesis of salt-sensitive hypertension, and future studies will clarify the detailed mechanism for the intricate regulation of the aldosterone/MR cascade.

PHARMACOLOGY OF MR ANTAGONISTS

SPL and EPL are the two commercially available aldosterone antagonists. They are steroid analogues structurally similar to aldosterone and therefore act as competitive antagonists. However, they have significant differences in terms of pharmacokinetic and pharmacodynamic properties, as well as side effect profiles (Table 2).

Table 2. Comparison between SPL and EPL.

	EPL	SPL
Receptor binding affinity^a (aldosterone = 1)	5.1 × 10^−3	1.1 × 10^−1
Sex steroid receptor cross-reactivity	Minimal	Yes
Absorption	Can be taken with or without food	Taken with food to enhance absorption
Half-life (h)	4–6	1.4
Metabolism	Hepatic cytochrome P450 3A4	Adrenocortical NADPH -dependent enzymes and hepatic microsomal enzymes
Active metabolites	No	Yes
Excretion	Urine and bile	Urine and bile
Side effects	Hyperkalemia	Hyperkalemia; breast tenderness and menstrual irregularities in women; erectile dysfunction and gynecomastia in men

Notes: EPL, eplerenone; SPL, spironolactone, NADPH, nicotinamide adenine dinucleotide phosphate.

^aThe high levels of plasma binding of SPL but not EPL partly offset the difference in receptor affinity in vivo.

Table 3. Effects of MR antagonist for renal protection.

Authors	Design	Subjects	No. of patients	Daily dosage	Duration	Proteinuria	Mean BP (mmHg)	eGFR	Potassium (mmol/L)
SPL
Rossing et al. ^28	Crossover	Type 2 DM with macroalbuminuria	20	25 mg	16 weeks	↓ 33%	↓ 6	NS	NS
van den Meiracker et al.^29	RCT	Type 2 DM with macroalbuminuria	59	25–50 mg	1 year	↓ 40%	↓ 7	↓ 12.9	↑ 0.5
Schjoedt et al.^30	Crossover	Type 1 DM with macroalbuminuria	20	25 mg	4 weeks	↓ 30%	NS	NS	NS
Schjoedt et al.^31	Crossover	Type 1 or 2 DM, albuminuria > 2.5 g/day	20	25 mg	4 weeks	↓ 32%	↓ 7	NS	NS
Chrysostomou et al.^32	RCT	Proteinuria > 1.5 g/day; serum creatinine < 200 μmol/L	41	25 mg	3 months	↓ 42%	NS	NS	↑ 0.5
Furumatsu et al.^33	RCT	Nondiabetic CKD, proteinuria > 0.5 g/day	32	25 mg	1 year	↓ 58%	NS	NS	NS
Tylicki et al.^34	Crossover	Nondiabetic CKD, proteinuria > 0.3 g/day	18	25 mg	24 weeks	↓ 55%	NS	NS	↑ 0.3
Bianchi et al.^35	RCT	Idiopathic GN, proteinuria > 1 g/g Cr	165	25 mg	1 year	↓ 57%	↓ 3	↓ 15	↑ 0.8
EPL
Epstein et al.^36	RCT	Type 2 DM, albuminuria > 50 mg:g Cr	268	50–100 mg	12 weeks	↓ 45%	NS	↓ 3	NS
Boesby et al.^37	Crossover	Nondiabetic CKD, proteinuria > 0.3 g/day	40	25–50 mg	16 weeks	↓ 22%	↓ 4	NS	↑ 0.1

Note: BP, blood pressure; CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m²); EPL, eplerenone; NS, no significant change; RCT, randomized controlled trial; SPL, spironolactone; MR, mineralocorticoid receptor.

SPL is a nonselective aldosterone receptor antagonist, which is metabolized extensively by the liver to generate active metabolites. It is structurally similar to progesterone and has a high affinity to androgen and progesterone receptors, which accounts for its progestogenic and antiandrogenic side effects. EPL is a highly selective aldosterone receptor antagonist derived from SPL, with a low affinity to progesterone and androgen receptors. Since EPL is predominantly metabolized by cytochrome P450 (CYP) isoenzyme 3A4, it is susceptible to drug interactions with CYP3A4 inducers (e.g., St. John’s wort) or inhibitors (e.g., clarithromycin).

MR ANTAGONISTS FOR KIDNEY PROTECTION: EARLY TRIALS

All clinical studies in the literature evaluated the effect of adding MR antagonist to ACEI and/or ARB. There was no placebo-controlled study on MR antagonist as a single therapy for renal protection. Early case series involving patients with chronic proteinuric nephropathy demonstrated that SPL 25 mg daily significantly reduced proteinuria by 15–54%.²⁷ However, these studies involved a small number of patients and a short duration of treatment. In a systematic review of 436 patients with proteinuric kidney disease from 15 studies, the addition of either SPL or EPL to ACEI and/or ARB therapy resulted in significant reduction of proteinuria (from 5% to 54%), without causing significant hyperkalemia or worsening of renal function.²⁷ However, these studies varied greatly in their methodology and study population, and almost all had a relatively short duration of follow-up. The low risk of hyperkalemia could also be a result of patient selection bias.

Table 3 summarizes the randomized controlled trials (RCT) on MR antagonist for renal protection. It is, however, important to realize many studies do not report critical end points such as initiation of renal replacement therapy (RRT), cardiovascular events, hospitalizations, and all-cause mortality.

SPL FOR KIDNEY PROTECTION

Diabetic Nephropathy

In an early crossover RCT , Rossing et al.²⁸ enrolled 20 patients with type 2 diabetes and macroalbuminuria, who were receiving a maximal dose of ACEI and/or ARB. Each patient received 8 weeks of SPL 25 mg once daily (QD) and 8 weeks with matched placebo in random order. During treatment with SPL, albuminuria was reduced by 33%, mean 24-h systolic blood pressure (SBP) was reduced by 6 mmHg, and mean diastolic blood pressure (DBP) by 4 mmHg. While on SPL, there was a significant increase in plasma creatinine and potassium levels (from 4.0 to 4.3 mmol/L). One patient was withdrawn from the study due to severe hyperkalemia.

In another placebo-controlled, double-blind, parallel-group trial, van den Meiracker et al.²⁹ randomized 59 patients with type 2 diabetes and macroalbuminuria despite ACEI or ARB to either SPL or placebo. After 1 year of treatment, albuminuria was reduced by 40.6%, and SBP by 7 mmHg, in SPL group, but did not change in the placebo group. However, there was a worrying drop in estimated glomerular filtration rate (eGFR) by 12.9 mL/min/1.73 m² in the SPL group, and 5 of the 29 patients in the SPL group withdrew from the study due to hyperkalemia. In addition, the SPL group had significantly better baseline renal function than the placebo group (eGFR 87 vs. 64 mL/min/1.73 m²), suggesting an intrinsic problem in the randomization procedure.

The beneficial effect of SPL has also been evaluated in nephropathy due to type 1 diabetes. Schjoedt et al. recruited 20 patients with type 1 diabetes with persistent albuminuria despite ACEI and/or ARB treatment in a crossover RCT. Patients were treated in random order with SPL or matched placebo, each for 2 months.³⁰ In this study, SPL reduced albuminuria by 30%. There was no significant improvement in 24-h mean blood pressure, although daytime SBP and DBP were reduced by 10 and 5 mmHg, respectively. Plasma creatinine level and eGFR were not significantly affected by SPL treatment. Using similar study methods, the same group of investigators subsequently found that SPL 25 mg daily significantly reduced proteinuria by 32% in a group of patients with overt diabetic nephropathy (defined as albuminuria > 2.5 g/day) without worsening of renal function.³¹

The major drawbacks of these studies are their small sample size and relatively short duration of follow-up. The effect of a higher dose of SPL, which is often recommended for cirrhotic patients, was not addressed.

Nondiabetic Chronic Proteinuric Nephropathy

Chrysostomou et al.³² randomly assigned 41 patients with persistent proteinuria >1.5 g/day and serum creatinine <200 μmol/L after treatment with ACEI for at least 6 months into ramipril, ramipril plus irbesartan, ramipril plus SPL, and all three agents. In this study, SPL-containing regimes provided significantly greater reduction of proteinuria at 3 months. In patients who received ramipril monotherapy and ramipril/irbesartan dual therapy, addition of SPL after the study period produced significant reduction in proteinuria by 42.1% and 37%, respectively. There was no significant difference in blood pressure or renal function at 3 and 6 months between the groups. Hyperkalemia occurred in 14.3% of patients receiving SPL.

In an open-label, multicenter, prospective controlled study involving 32 patients with nondiabetic CKD and persistent proteinuria, Furumatsu et al.³³ compared the treatment of SPL to trichlormethiazide or furosemide. After 1 year of treatment, proteinuria was reduced by 58% in the SPL group but did not change significantly in the control group. SPL treatment had no observable effect on renal function, serum potassium, or blood pressure.

In another small crossover RCT involving 18 nondiabetic patients with CKD, Tylicki et al.³⁴ randomly assigned the patients to either ACEI/ARB dual therapy for 8 weeks followed by the addition of SPL 25 mg daily (triple therapy) for another 8 weeks, or vice versa. In this study, SPL reduced proteinuria by over 70%. Urinary excretion of other markers of tubular injury and fibrosis were also decreased. Serum potassium levels increased significantly with SPL, but no patient needed to stop this treatment because of this adverse effect.

In a large prospective, open-label randomized study, Bianchi et al.³⁵ randomly assigned 165 patients with idiopathic glomerulonephritis and proteinuria >1 g/g Cr to SPL in addition to ACEI/ARB or ACEI/ARB alone for 1 year. Although there was a statistically significant reduction of eGFR in the initial 4 weeks in patients receiving SPL, renal function remained stable afterward. After 1 year, the overall decline of renal function was lower in patients treated with SPL than the placebo group. Patients with a baseline eGFR < 60 mL/min/1.73 m² had a more pronounced decline in renal function during SPL treatment. Four patients (4.8%) of the SPL group had to be withdrawn after 3 months because of persistent hyperkalemia.

EPL FOR KIDNEY PROTECTION

In a multicenter RCT, Epstein et al.³⁶ enrolled 268 patients with type 2 diabetes and albuminuria despite enalapril treatment. Patients were randomized to three treatment arms for 12 weeks: EPL 50 mg daily; EPL 100 mg daily; or placebo. At 12th week, proteinuria was reduced by 41.0% in the group treated with EPL 50 mg daily, 48.4% in the group with EPL 100 mg daily, and 7.4% in the placebo group. The incidence of sustained or severe hyperkalemia was similar between the groups. However, the EPL groups had a significantly lower eGFR as compared to the placebo group at 12 weeks (67 vs. 72 mL/min/1.73 m²).

For nondiabetic CKD, a recent randomized crossover study of 40 patients found that adding EPL for 8 weeks to the standard antihypertensive treatment (including RAS blockade) resulted in 22% reduction in albuminuria, with only a modest effect on blood pressure and renal function.³⁷ The ongoing EVALUATE study is another double-blinded, randomized, placebo-controlled trial, which evaluates the antiproteinuric effect of EPL 50 mg daily in 340 hypertensive patients with albuminuria and would provide further insight in this respect.³⁸

DISCUSSION

Physiological Implication

The glomerular filtration barrier guards against proteinuria. It is generally believed that increased permeability of this filtration barrier leads to proteinuria. Since aldosterone does not directly act on efferent glomerular arteriole and has no effect on intraglomerular hemodynamics, it seems surprising to find MR antagonist has an antiproteinuric effect.

However, it is now known that podocytes and glomerular slit diaphragm are the major barriers of glomerular permeability. Animal studies have shown that MRs are found in podocytes, and aldosterone induces podocyte injury. For example, in Dahl salt-hypertensive rats (prone to hypertensive glomerulosclerosis), salt loading caused severe hypertension, proteinuria, glomerulosclerosis, and podocyte foot process effacement; immunostaining for nephrin was attenuated, whereas expressions of damaged markers of podocyte were upregulated, and this process was inhibited by EPL but not hydralazine.³⁹ In uninephrectomized rats, aldosterone infusion caused podocyte injury by inducing oxidative stress and expression of aldosterone effector kinase Sgk1; both processes were ameliorated by EPL.⁴⁰ In transgenic (mRen2)27 (Ren2) rats, which have elevated serum aldosterone levels and increased tissue aldosterone activity, SPL reduces albuminuria and reverts the loss of podocyte-specific proteins and podocyte foot process effacement.⁴¹ These experiments support the hypothesis that MR antagonist has renal protective effect by reducing proteinuria through the restoration of podocyte integrity.

Renal Protection

Current evidence suggests that MR antagonists further reduce proteinuria in patients with CKD, who are already on ACEI and/or ARB. Nevertheless, most studies were small and had short duration of follow-up. Study quality was also variable. For instance, allocation concealment was adequate in only some of the studies.^30–32,36 Participants and investigators were not blinded in any of the studies. Only one study performed intention-to-treat analysis.³⁶

In a recent Cochrane review of 10 studies and 845 patients, the addition of SPL to ACEI and/or ARB reduced proteinuria by a mean of 0.80 g/day, SBP by 3.40 mmHg, and DBP by 1.79 mmHg.⁴² Proteinuria was reduced by 0.46 g/day for diabetic nephropathy and 0.99 g/day for nondiabetic chronic proteinuric nephropathy. However, such reduction in proteinuria and blood pressure may not translate into an improvement in eGFR. The long-term effects on renal outcomes (e.g., doubling of serum creatinine, progression or regression of proteinuria, need of RRT, hospitalization rates, and all-cause mortality) were largely unknown.

Hyperkalemia

The majority of potassium (95%) is excreted through the kidneys. With more extensive blockade of the RAS, the risk of hyperkalemia substantially increases. For instance, in patients with diabetic nephropathy, although ACEI was not found to be associated with a significant increase in the risk of hyperkalemia, ARB was associated with a 5.41-fold increased risk of hyperkalemia.⁴³ With dual therapy of ACEI and ARB, the ONTARGET study found a even higher incidence of hyperkalemia and renal dysfunction as compared to ACEI or ARB treatment alone.⁴ Notably, after the publication of the RALES study ,⁴⁴ Juurlink et al. ⁴⁵ reported a surge in hospital admission for hyperkalemia, which was in parallel with the increase in SPL use in patients with congestive heart failure. Similarly, in patients with chronic proteinuric nephropathy, there was a threefold increase in the risk of hyperkalemia when SPL is added to ACEI or ARB treatment.⁴² In patients who receive triple therapy of SPL, ACEI, and ARB, the risk of hyperkalemia was even higher (Relative risk (RR) : 4.30; 95% Confidence interval (CI): 1.12–16.51). The risk of hyperkalemia was also increased with EPL treatment.⁴² Recently, it was shown that several factors are associated with a significantly higher risk of incident hyperkalemia after initiation of MR antagonist, including baseline eGFR ≤ 45 mL/min/1.73 m², reduction in SBP > 15 mmHg, and decline in eGFR > 30%.⁴⁶ These patients should be closely monitored and dose adjustment or cessation of therapy should be considered if necessary.

Gynecomastia

Bianchi et al.³⁵ reported that 6 out of the 83 patients in the SPL group developed gynecomastia, although only one patient required discontinuation of medication. In the report of Furumatsu et al.³³ 1 of the 15 patients in the SPL group developed gynecomastia. Overall, the RR of developing gynecomastia from SPL treatment is 6.62 as compared to placebo (95% CI: 0.80–54.58).⁴² In the RALES study,⁴⁴ gynecomastia or breast pain was reported in 10% of the patients. Endocrine side effects were rare in patients receiving EPL. In the EPHESUS study,⁴⁷ the risk of endocrine disorders was only 1.0% in patients receiving EPL, compared with 0.7% in the placebo group.

Since SPL has antiandrogenic activity, it would actually be interesting to know if it has equal antiproteinuric effect in male and female patients. To the best of our knowledge, this possibility has not been explored in any published study.

What Should Be the Best Approach to Renin–Angiotensin–Aldosterone Blockade?

It is important to note that most studies that assessed the efficacy of MR antagonist were conducted before publication of the ONTARGET study ⁴ and allowed ACEI/ARB/MR antagonist triple therapy. Not surprisingly, these patients were at particularly high risk of hyperkalemia. Contrary to expectation, data from the ONTARGET study showed that the combined risk of dialysis, doubling of serum creatinine, and death was significantly higher with ramipril/telmisartan combination therapy than either of them alone.⁵ Therefore, although triple therapy may help to reduce proteinuria to a greater extent, it may not be entirely desirable to have an almost complete blockade of the renin–angiotensin–aldosterone system.

Then, how much blockade of the system would be desirable? In a double-blind, placebo-controlled trial involving 81 patients with diabetes, hypertension, and macroalbuminuria, who were already treated with lisinopril 80 mg daily, Mehdi et al. randomly assigned these patients to placebo, losartan 100 mg daily, or SPL 25 mg daily for 48 weeks. SPL reduced proteinuria by 34.0% while losartan reduced proteinuria by 16.8%.⁴⁸ Blood pressure control, creatinine clearance, and glycemic control did not differ between groups. Serum potassium level was significantly higher than the placebo group with the addition of either SPL or losartan. Similarly, Chrysostomou et al.³² found that ramipril plus SPL produced a greater degree of proteinuria reduction than ramipril plus irbesartan (42.0% vs. 15.7%). The results of these studies seem to suggest that dual therapy of ACEI and MR antagonist may offer better renal protection than ACEI/ARB dual therapy, although further studies are needed to confirm this point.

Contrary to being an add-on therapy, MR antagonist as a single therapy (i.e., without ACEI and ARB) for chronic proteinuric diseases has not been tested in human study. Single therapy of MR antagonist could, at least in theory, cause a feedback increase of renin and Ang II formation, which could have undesirable consequences in CKD patients. To the best of our knowledge, there is no published study that explored the effect of combined therapy with MR antagonist and direct renin inhibitor in CKD.

CONCLUSIONS

MR antagonist represents an attractive therapy in CKD patients who have persistent proteinuria despite ACEI and/or ARB treatment. It reduces proteinuria substantially irrespective of the underlying kidney disease, but the risk of hyperkalemia and worsening of renal function are not negligible. For proteinuria reduction, MR antagonist should be initiated at the lowest dose (e.g., SPL 25 mg/day or EPL 50 mg/day), with close monitoring of serum potassium and renal function. In our opinion, a higher dose of SPL or EPL has not been adequately tested for proteinuria reduction, and, given the risk of adverse effect, should not be routinely considered. Since the long-term renoprotective effects of these agents have not been established, long-term studies that evaluate “hard” clinical end points (such as doubling of serum creatinine, progression or regression of proteinuria, need of RRT, hospitalization rates, and all-cause mortality) are warranted.

Declaration of interest:The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.