Mineralocorticoid receptor antagonists in kidney transplantation: time to consider?

Mineralocorticoid receptor antagonists in kidney transplantation: time to consider? Abstract Although patient survival is significantly improved by kidney transplantation (KT) in comparison with dialysis, it remains significantly lower than that observed in the general population. Graft function is one of the major determinants of patient survival after KT. Mineralocorticoid receptor antagonists (MRAs) could be of particular interest in this population to improve graft function and treat or prevent cardiovascular (CV) complications. In KT, ischaemia/reperfusion injury is a major factor involved in delayed graft function, which is often associated with inferior long-term graft survival. Preclinical studies suggest that MRAs may prevent ischaemia/reperfusion-related lesions in addition to having a protective effect in preventing calcineurin inhibitor-induced nephrotoxicity. Clinical data also support the anti-proteinuric effect of MRAs in chronic kidney disease (CKD). Taken together, MRAs may hence be of particular benefit in improving short- and long-term graft function. Numerous randomized controlled trials (RCTs) have shown the efficacy of MRAs in both heart failure and resistant hypertension. As these comorbidities are frequent in kidney transplant recipients before transplantation or during follow-up, MRAs could represent a useful therapeutic option in those with mild renal function impairment. However, CKD patients are under-represented in RCTs and the CV effects of MRAs in kidney transplant recipients have yet to be specifically assessed in large-scale trials. Available evidence indicates a good safety profile for MRAs in patients with a glomerular filtration rate (GFR) >30 mL/min/1.73 m2. However, as for all patients prescribed an MRA, creatinine and potassium should also be closely monitored following MRA initiation in kidney transplant patients. Given the current evidence suggesting that MRAs prevent ischaemia/reperfusion-related lesions and calcineurin inhibitor-induced nephrotoxicity in kidney transplant recipients as well as CV events in patients at high risk of CV complications (such as those in kidney transplant recipients), trials are urgently needed to fully assess the clinical impact of MRA use in this population. cardiovascular, calcineurin inhibitor, ischemia-reperfusion injury, kidney transplantation, mineralocorticoid receptor antagonist INTRODUCTION Kidney transplantation (KT) faces a double challenge: (i) organ shortage with increased use of grafts from expanded criteria donors (ECDs), which are more susceptible to deleterious ischaemia/reperfusion (I/R) lesions [1], and (ii) increased access to KT for older recipients who experience multiple comorbidities at baseline or during follow-up [2]. Preclinical studies have suggested that pharmacological blockade of the mineralocorticoid receptor (MR) protects against I/R-related lesions and their long-term consequences [3–6]. Mineralocorticoid receptor antagonists (MRAs) may also prevent calcineurin inhibitor-induced nephrotoxicity (CIN) [7–15]. Numerous clinical trials have shown the high efficacy of MRAs in patients with heart failure (HF) [16, 17], myocardial infarction [16] or resistant hypertension (HTN) [18]. Since many kidney graft recipients have a history of HF or coronary artery disease (CAD) before KT or develop these complications during follow-up [2], MRAs may therefore represent a potential therapeutic option in kidney transplant patients. This review aims to present the current evidence supporting the future use of MRAs in KT, either to optimize graft function and/or to improve patient cardiovascular (CV) prognosis. GENERAL DATA ON MRAs Steroidal and non-steroidal MRAs MRAs include steroidal (spironolactone and eplerenone) and non-steroidal (finerenone) antagonists. The balance between clinical efficacy and side effects of MRAs is determined by their selectivity, potency and tissue distribution, as outlined in Table 1. Side effects mainly include (i) hormonal-related side effects due to lack of selectivity and (ii) hyperkalaemia. Table 1. Characteristics of MRAs Characteristics   Steroidal MRA   Non-steroidal MRA   Drug  Spironolactone  Eplerenone  Finerenone  MRA generation  I  II  III  Selectivity  Low  High  High  Potency  High  Low  High  Half-life  Long Active metabolites >12h  Short 4-6h  Short 2h  Tissue distribution (heart vs. kidney)  6× higher in the kidney  3× higher in the kidney  equal  Concentrations of ligand required to inhibit 50% activation of the receptor (IC50), or to achieve 50% activation of the receptor (EC50)*          Mineralocorticoid receptor IC50 (nM)  24  990  17.8    Androgen receptor IC50 (nM)  77  ≥21 240  ≥10 000    Glucocorticoid receptor IC50 (nM)  2410  ≥21 980  ≥10 000    Progesterone receptor EC50 (nM)  740  ≥31 210  ≥10 000  SUMMARY  Spironolactone is a potent competitive MRA Poorly selective → “hormone-related” side effects Rapidly metabolized into several active metabolites with a half-life of approx. 15 hours Tissue distribution: spironolactone is accumulated six-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Eplerenone is much more selective for MR than spironolactone, therefore avoiding “hormone-related “effects Eplerenone is less potent than spironolactone, requiring a higher dosage to achieve similar MR antagonism Eplerenone has no active metabolite → rapid efficacy after administration Eplerenone has a shorter half-life → important for safety concerns in case of adverse event Tissue distribution: Eplerenone accumulated three-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Finerenone has higher selectivity, higher potency Tissue distribution: equivalent in rat heart and kidney → low doses may allow sufficient MR antagonism outside of the kidney Potential reduced risk of hyperkalemia due to balanced extrarenal/renal distribution allowing reduction in dosing  Characteristics   Steroidal MRA   Non-steroidal MRA   Drug  Spironolactone  Eplerenone  Finerenone  MRA generation  I  II  III  Selectivity  Low  High  High  Potency  High  Low  High  Half-life  Long Active metabolites >12h  Short 4-6h  Short 2h  Tissue distribution (heart vs. kidney)  6× higher in the kidney  3× higher in the kidney  equal  Concentrations of ligand required to inhibit 50% activation of the receptor (IC50), or to achieve 50% activation of the receptor (EC50)*          Mineralocorticoid receptor IC50 (nM)  24  990  17.8    Androgen receptor IC50 (nM)  77  ≥21 240  ≥10 000    Glucocorticoid receptor IC50 (nM)  2410  ≥21 980  ≥10 000    Progesterone receptor EC50 (nM)  740  ≥31 210  ≥10 000  SUMMARY  Spironolactone is a potent competitive MRA Poorly selective → “hormone-related” side effects Rapidly metabolized into several active metabolites with a half-life of approx. 15 hours Tissue distribution: spironolactone is accumulated six-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Eplerenone is much more selective for MR than spironolactone, therefore avoiding “hormone-related “effects Eplerenone is less potent than spironolactone, requiring a higher dosage to achieve similar MR antagonism Eplerenone has no active metabolite → rapid efficacy after administration Eplerenone has a shorter half-life → important for safety concerns in case of adverse event Tissue distribution: Eplerenone accumulated three-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Finerenone has higher selectivity, higher potency Tissue distribution: equivalent in rat heart and kidney → low doses may allow sufficient MR antagonism outside of the kidney Potential reduced risk of hyperkalemia due to balanced extrarenal/renal distribution allowing reduction in dosing  * MR inhibition is responsible for the desired action of the drugs. Activation (progesterone) or inhibition (androgen or glucocorticoid) of the other receptors potentially leads to side effects. Adapted from Jaisser and Farman [19] and Bramlage et al. [20] Table 1. Characteristics of MRAs Characteristics   Steroidal MRA   Non-steroidal MRA   Drug  Spironolactone  Eplerenone  Finerenone  MRA generation  I  II  III  Selectivity  Low  High  High  Potency  High  Low  High  Half-life  Long Active metabolites >12h  Short 4-6h  Short 2h  Tissue distribution (heart vs. kidney)  6× higher in the kidney  3× higher in the kidney  equal  Concentrations of ligand required to inhibit 50% activation of the receptor (IC50), or to achieve 50% activation of the receptor (EC50)*          Mineralocorticoid receptor IC50 (nM)  24  990  17.8    Androgen receptor IC50 (nM)  77  ≥21 240  ≥10 000    Glucocorticoid receptor IC50 (nM)  2410  ≥21 980  ≥10 000    Progesterone receptor EC50 (nM)  740  ≥31 210  ≥10 000  SUMMARY  Spironolactone is a potent competitive MRA Poorly selective → “hormone-related” side effects Rapidly metabolized into several active metabolites with a half-life of approx. 15 hours Tissue distribution: spironolactone is accumulated six-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Eplerenone is much more selective for MR than spironolactone, therefore avoiding “hormone-related “effects Eplerenone is less potent than spironolactone, requiring a higher dosage to achieve similar MR antagonism Eplerenone has no active metabolite → rapid efficacy after administration Eplerenone has a shorter half-life → important for safety concerns in case of adverse event Tissue distribution: Eplerenone accumulated three-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Finerenone has higher selectivity, higher potency Tissue distribution: equivalent in rat heart and kidney → low doses may allow sufficient MR antagonism outside of the kidney Potential reduced risk of hyperkalemia due to balanced extrarenal/renal distribution allowing reduction in dosing  Characteristics   Steroidal MRA   Non-steroidal MRA   Drug  Spironolactone  Eplerenone  Finerenone  MRA generation  I  II  III  Selectivity  Low  High  High  Potency  High  Low  High  Half-life  Long Active metabolites >12h  Short 4-6h  Short 2h  Tissue distribution (heart vs. kidney)  6× higher in the kidney  3× higher in the kidney  equal  Concentrations of ligand required to inhibit 50% activation of the receptor (IC50), or to achieve 50% activation of the receptor (EC50)*          Mineralocorticoid receptor IC50 (nM)  24  990  17.8    Androgen receptor IC50 (nM)  77  ≥21 240  ≥10 000    Glucocorticoid receptor IC50 (nM)  2410  ≥21 980  ≥10 000    Progesterone receptor EC50 (nM)  740  ≥31 210  ≥10 000  SUMMARY  Spironolactone is a potent competitive MRA Poorly selective → “hormone-related” side effects Rapidly metabolized into several active metabolites with a half-life of approx. 15 hours Tissue distribution: spironolactone is accumulated six-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Eplerenone is much more selective for MR than spironolactone, therefore avoiding “hormone-related “effects Eplerenone is less potent than spironolactone, requiring a higher dosage to achieve similar MR antagonism Eplerenone has no active metabolite → rapid efficacy after administration Eplerenone has a shorter half-life → important for safety concerns in case of adverse event Tissue distribution: Eplerenone accumulated three-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Finerenone has higher selectivity, higher potency Tissue distribution: equivalent in rat heart and kidney → low doses may allow sufficient MR antagonism outside of the kidney Potential reduced risk of hyperkalemia due to balanced extrarenal/renal distribution allowing reduction in dosing  * MR inhibition is responsible for the desired action of the drugs. Activation (progesterone) or inhibition (androgen or glucocorticoid) of the other receptors potentially leads to side effects. Adapted from Jaisser and Farman [19] and Bramlage et al. [20] MR distribution MR is expressed in the distal nephron (distal tubule and collecting duct), known as the aldosterone-sensitive distal nephron (ASDN), as well as in the distal colon and sweat glands, all sites previously identified as classical targets of aldosterone. MR is also expressed in tissues and cell types where there is no vectorial sodium transport, such as cardiomyocytes, endothelial cells, vascular smooth muscle cells (VSMCs) and immune cells [19]. In the kidney, in addition to the ASDN, MR is expressed in vascular endothelial cells and in VSMCs of inter-lobar arteries [19], as well as in glomerular cells (podocytes, mesangial cells) in disease conditions such as Type 1 diabetes or metabolic syndrome with HTN [19] (Figure 1A). FIGURE 1: View largeDownload slide  (A) Expression of the MR in classical and non-classical renal and non-renal aldosterone targets cells, including the immune system. Common mechanisms involved in the consequences of MR activation in renal and CV systems. (B) Impact of aldosterone in target cells with induction of oxidative stress, fibrosis and inflammation, including the polarization of macrophages into a pro-inflammatory M1 phenotype as well as T lymphocyte differentiation to the pro-inflammatory Th1 and Th17 subsets. A, aldosterone; 11-βHSD2, 11β-hydroxysteroid dehydrogenase Type 2; C, glucocorticoid hormones; Il-6, interleukin 6; MP, macrophage; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; Nox, nicotinamide adenine dinucleotide phosphate oxidase; ROS, reactive oxygen species; TGF-β, transforming growth factor-β; Th1, T helper; TNF-α, tumor necrosis factor α. FIGURE 1: View largeDownload slide  (A) Expression of the MR in classical and non-classical renal and non-renal aldosterone targets cells, including the immune system. Common mechanisms involved in the consequences of MR activation in renal and CV systems. (B) Impact of aldosterone in target cells with induction of oxidative stress, fibrosis and inflammation, including the polarization of macrophages into a pro-inflammatory M1 phenotype as well as T lymphocyte differentiation to the pro-inflammatory Th1 and Th17 subsets. A, aldosterone; 11-βHSD2, 11β-hydroxysteroid dehydrogenase Type 2; C, glucocorticoid hormones; Il-6, interleukin 6; MP, macrophage; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; Nox, nicotinamide adenine dinucleotide phosphate oxidase; ROS, reactive oxygen species; TGF-β, transforming growth factor-β; Th1, T helper; TNF-α, tumor necrosis factor α. Common mechanisms of action of MRAs Aldosterone binds to the MR, the latter being a ligand-dependent transcription factor belonging to the nuclear receptor superfamily. The aldosterone–MR complex binds to glucocorticoid response elements within the promoter region of aldosterone-induced (or repressed) genes to modulate their transcription [19]. In a typical target cell, such as the renal collecting duct principal cell, the apical Na+ channels and the basolateral Na+ pumps and K+ channels are upregulated in the presence of aldosterone leading to a sustained increase in transepithelial sodium reabsorption [19]. The MR binds both aldosterone and glucocorticoid hormones with similar high affinity. Plasma glucocorticoid levels are much higher than plasma aldosterone levels, the main mechanism leading to mineralocorticoid selectivity being the co-expression of MR and 11β-hydroxysteroid dehydrogenase Type 2, which metabolizes glucocorticoid hormones into inactive derivatives with very low affinity for the MR, thus avoiding permanent binding of the MR by glucocorticoids [19] (Figure 1B). The mechanisms underlying the potential benefit of MRAs in kidney and CV protection include (i) the regulation of ion channel expression/activity (the type of ion channels—sodium, potassium, calcium—depending on cell type), (ii) the limiting of oxidative stress production, (iii) the reduction in fibrosis and extracellular matrix remodelling and (iv) the curbing of inflammation. This allows reducing the development of (i) cardiac diseases (avoiding electrophysiological disorders and limiting extracellular matrix remodelling and fibrosis), (ii) vascular disease (limiting HTN, arterial stiffness and reduced organ perfusion) and (iii) renal disease (limiting HTN, glomerulosclerosis and interstitial fibrosis) (Figure 1A). Ion channel remodelling is a general feature of mineralocorticoid signalling [19]. The type of ion channels (sodium, potassium, calcium) is contingent on cell type. In ASDN, aldosterone controls the expression/activity of various ion transporters, modulating sodium and potassium homeostasis and blood pressure (BP). MR signalling also leads to changes in ion channel expression or activity in endothelial cells and VSMC, contributing to the stiffening of endothelial cell membranes and to myogenic tone. In cardiomyocytes, the modulation of ion channels leads to atrial and ventricular arrhythmias. Oxidative stress is a central mechanism in the deleterious effects of aldosterone and MR activation [19]. Aldosterone stimulates oxidative stress in classic and non-classic target cells, with the aldosterone/MR complex upregulating the expression of nicotinamide adenine dinucleotide phosphate oxidase subunits such as Nox2, Nox4 and rac1, thereby affecting Nox activity. Oxidative stress increases DNA damage and protein carbonylation. Nitric oxide (NO) synthase uncoupling decreases the availability of NO for vasorelaxation as well as increases the production of hydrogen peroxide and activation of the nuclear factor κB pathway leading to inflammation and fibrosis [19]. Inappropriate MR activation has been shown to promote CV and renal tubulo-interstitial fibrosis [19]. In randomized controlled trials (RCTs), the beneficial effects of MRA in HF were associated with a reduction in fibrosis biomarkers [21]. MRA may also be useful in limiting arterial stiffness [22, 23]. Pharmacological MR blockade improves the chronic inflammatory state associated with CV disease [19]. Macrophages, dendritic cells and T lymphocytes have more recently been identified as MR target cells [24]. MR activation leads to interleukin (IL)-6 and tumour necrosis factor α expression and nuclear factor κB activation in both immune and non-immune cells. MR activation promotes macrophage activation to the pro-inflammatory M1 phenotype, as well as T lymphocyte differentiation into pro-inflammatory Th1 and Th17 subsets [24]. It also leads to a decrease in the number of anti-inflammatory T regulatory lymphocytes. MR activation in antigen-presenting dendritic cells increases IL-6 and transforming growth factor-β (TGF-β) expression as well as dendritic cell-mediated Th17 polarization of T lymphocytes [24]. Altogether, the above data suggest that aldosterone/MR modulates innate and adaptive immunity, which may have a critical role in end-organ damage. MRA PRESCRIPTION IN KT FOR GRAFT PROTECTION A large body of preclinical evidence currently supports the efficacy of MRAs in preventing I/R lesions in the early phase of KT. Moreover, preclinical models have shown a significant effect of MRA in preventing short- and long-term calcineurin inhibitor nephrotoxicity. While there are only few clinical studies currently available to date, the results are in accordance with the preclinical findings. Prevention of I/R lesions I/R injury (IRI) is one of the main pathophysiological events involved in delayed graft function (DGF), often associated with inferior long-term graft survival. Episodes of IRI associated with DGF lead to decreased glomerular filtration rate (GFR), proteinuria, interstitial fibrosis and inflammation [25]. Several therapeutic strategies have been proven effective in preclinical models but have been poorly translated to the human setting [1, 25]. Moreover, developing novel therapeutic molecules is a costly and long-term process, whereas repositioning old molecules with proven efficacy in other settings may be a more efficient approach in targeting IRI and DGF. Accumulated evidence over the past decade suggests that blocking the MR may be a useful strategy to protect against I/R-related lesions (Figure 2A). Preclinical studies in rodents have demonstrated a beneficial effect of MRAs in preventing acute IRI and were also found to be efficient when administered up to 3 h after IRI [3, 4]. Importantly, data obtained in both mice and rats has been translatable to the Large White pig in which canrenoate potassium was shown to prevent acute kidney injury (AKI) following bilateral IRI. This protective effect was also observed with non-steroidal MRAs [4, 5]. The mechanisms underlying the deleterious effects of MR activation during IRI highlight the critical role of MR-mediated oxidative stress, the latter leading to a specific imbalance of vascular endothelin signalling through post-translational modification of the vasodilatory endothelin B receptor, triggering its functional inactivation and showing a sustained decrease in renal blood flow [4, 6]. FIGURE 2: View largeDownload slide (A) Pathophysiology and histological findings of IRI and AKI-induced CKD: benefit of MRAs in the prevention of IRI and AKI-induced CKD. (B) Pathophysiology and histological findings of acute and chronic CIN: potential benefits of mineralocorticoid receptor antagonists for the prevention of CIN. EC, endothelial cell; MP, macrophage; NO, nitric oxide; PTC, peritubular capillary; ROS, reactive oxygen species; SMC, smooth muscle cell; SMC-MR, smooth muscle cell-mineralocorticoid receptor; TGF-β, transforming growth factor-β. FIGURE 2: View largeDownload slide (A) Pathophysiology and histological findings of IRI and AKI-induced CKD: benefit of MRAs in the prevention of IRI and AKI-induced CKD. (B) Pathophysiology and histological findings of acute and chronic CIN: potential benefits of mineralocorticoid receptor antagonists for the prevention of CIN. EC, endothelial cell; MP, macrophage; NO, nitric oxide; PTC, peritubular capillary; ROS, reactive oxygen species; SMC, smooth muscle cell; SMC-MR, smooth muscle cell-mineralocorticoid receptor; TGF-β, transforming growth factor-β. A pilot clinical trial on living-donor KT [26] demonstrated a beneficial effect of spironolactone on renal oxidative stress when initiated in recipients 1 day prior to KT and administered for 3 days following KT. This treatment was not associated with significantly improved short-term renal function since renal function was already good in the placebo group, as expected for living-donor transplantation. However, mid and long-term renal function was not evaluated in this study. Importantly, decreased urinary levels of an oxidative stress marker (8-isoprostane) were observed in the MRA group, in keeping with the reported benefit of MRA on oxidative stress in rodents and pigs [5, 6]. MRA effects have also been assessed in settings other than KT. In the setting of cardiac surgery, a recent RCT failed to prevent post-operative AKI by the administration of spironolactone 100 mg on the day before the intervention and 25 mg/day for 3 days thereafter [27]. However, the association of MRA with outcome in this trial may have been underestimated because of the higher proportion (31% versus 18%, P = 0.02) of diabetic patients in the MRA arm [27]. Episodes of AKI lead to increased risk of CKD progression and renal failure. Indeed, a single episode of IRI may result in maladaptive repair and lead to CKD [28]. MRA administration during the acute phase of IRI prevents the decline in long-term renal function and tubulo-interstitial fibrosis in rodents [3, 6] as well as in Large White pigs [29]. Steroidal and non-steroidal MRAs are equally effective in preventing CKD progression following IR and/or AKI [3, 6] [29]. The underlying mechanism of the beneficial effect of MRAs lies in the prevention of low-grade inflammation and on the polarization of macrophages towards an anti-inflammatory M2 repair phenotype [29]. Considering that macrophage recruitment plays an essential role during both the injury and repair phases and that the infiltration of inflammatory cells early after an AKI episode plays an important role in defining effective versus maladaptive repair [28], this likely explains why short-term MRA administration during the I/R period only is able to prevent the long-term consequences of IRI. To date, there are no therapeutic approaches in clinical practice able to prevent progression to CKD after an AKI episode. MRA may thus represent a promising approach when administered before or just after the IR phase, even with short-term administration. Whether prevention of CKD progression after IRI also occurs in patients after transplantation remains to be explored. Our group is currently conducting a multicentre RCT to assess the impact of short-term administration of eplerenone (25 mg twice a day, immediately before and 4 days after KT) on 3-month renal graft function in patients receiving a graft from an ECD (EPURE: NCT02490904). ECD grafts are specifically targeted as they are more susceptible to ischaemia insult, and could consequently experience a greater benefit from early MRA use in preventing IRI. Prevention of calcineurin inhibitor toxicity In addition to direct cellular toxicity, the nephrotoxicity of the calcineurin inhibitor involves vasoconstriction and altered renal haemodynamics [7]. MRAs can limit calcineurin inhibitor-induced nephrotoxicity (CIN) in experimental models of either acute [8–10] or chronic [8, 11, 12] CIN. The beneficial effects of MRAs include the regulation of renal remodelling (apoptosis, fibrosis) and modulation of vasoactive factors, which increase (angiotensin II, endothelin) or decrease (nitric oxide, prostaglandins) during calcineurin inhibitor treatment [13] (Figure 2B). The role of vascular MRs in the renal vascular bed has recently been demonstrated in CIN: acute CIN was prevented in mice with genetic inactivation of VSMC MR but not upon deletion of endothelial MR [10]. The renoprotective effect of MRAs in a chronic CIN model was moreover associated with the prevention of TGF-β and extracellular matrix protein (fibronectin, and collagen I and IV) overexpression [11]. In rats, spironolactone was shown to prevent the progression of renal injury in pre-existing chronic CIN. The progression of renal dysfunction was reduced in the MRA group, with limited tubulo-interstitial fibrosis along with significantly reduced arteriolar thickening and a reduced apoptosis index [14]. Finally, spironolactone was found to improve transplant vasculopathy in rats with renal transplants with a reduction in the number of affected intrarenal arteries and a trend towards reduced proteinuria and focal glomerulosclerosis, with reduced glomerular macrophage influx [15]. In clinical practice, CIN is only part of the general process of graft impairment, which includes chronic I/R consequences, non-adherence to treatment and risk of chronic humoral rejection and accelerated vascular impairment [30]. The long-term protective effect of MRA in graft protection (as opposed to short-term graft protection for the prevention of I/R lesions) should be further investigated in clinical trials. In the setting of paediatric KT, a recent RCT involving eplerenone reported promising results in limiting the progression of biopsy-proven chronic graft nephropathy [31]. In this latter study, 13 children received eplerenone 25 mg/day during 24 months whereas 10 children received placebo. Although not reaching statistical significance, likely due to limited statistical power, estimated GFR (eGFR) was 15 mL/min/1.73 m2 higher in the eplerenone group along with a decrease in proteinuria in the eplerenone group as opposed to an increase in the control group during the 24-month follow-up. Histological findings derived from graft biopsies also supported a favourable effect of MRAs. While this trial was clearly underpowered, these encouraging results should nonetheless encourage further appropriately sized trials in order to provide more conclusive evidence. Reduction of proteinuria and CKD progression Although aldosterone has a primarily physiological homeostatic role on sodium balance and BP, a sustained MR activation can lead to renal damage, even in the absence of HTN. In the past 15 years, growing evidence indicates a substantial antiproteinuric effect and possibly a major renoprotective effect of MRAs in CKD; MRAs have emerged as a promising means to reduce proteinuria and to slow CKD progression [27]. Two meta-analyses showed that MRAs, in addition to angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), effectively reduced proteinuria [32, 33]. A strong independent association between proteinuria and the development of end-stage renal disease (ESRD) is well established in non-KT patients [34]. Thus, albuminuria may be a valid surrogate marker for ESRD in many circumstances for non-KT patients. In the two aforementioned meta-analyses [32, 33], the effect of MRA on GFR was either neutral [31] or slightly deleterious [33]. Most of the included studies had a follow-up period of <1 year; hence, the impact of the addition of MRA to ACEi or ARB on long-term renal outcomes remains unknown; none of the studies was sufficiently powered to detect differences in hard renal endpoints. An ongoing study is currently aimed to determine the effect of MRA on long-term renal function change [35]. MRAs are probably of particular interest in diabetic nephropathy. Recently, the ARTS-DN (MinerAlocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy) Study demonstrated a dose-dependent reduction in proteinuria among patients with diabetic nephropathy receiving ACEis or ARBs in combination with the new non-steroidal MRA, finerenone [36]. Two RCTs aiming to enrol a total of 11 200 patients with diabetic nephropathy are ongoing to assess the effect of finerenone on the progression of CKD (FIDELIO-DKD: NCT02545049) and on the occurrence of CV outcomes (FIGARO: NCT02545049). Causes of proteinuria in KT recipients generally differ from those of proteinuria in the general population. Transplant-specific diagnoses, including antibody-mediated rejection (ABMR) and/or chronic transplant glomerulopathy, are commonly reported in biopsy studies of transplant recipients with proteinuria [37]. This probably explains why non-immunological interventions aimed at reducing proteinuria have had little success in KT recipients in decreasing patient mortality, graft dysfunction and failure [38]. Nevertheless, early use of MRA may have a preventive action on the development of non-immunological lesions and may be of particular interest in instances of biopsies exhibiting non-immunological chronic lesions. Only sparse data analysing the effect of MRAs in KT patients are currently available. The addition of spironolactone (25 mg/day) to ACEis or ARBs was found to decrease proteinuria in 11 renal transplant patients (with serum creatinine values under 3 mg/dL) while being neutrally associated with renal function [39]. For kidney transplant patients, the prognostic value of proteinuria on graft and patient survival is well established [40]. Thus, the pharmacological reduction of proteinuria through the use of MRAs may help to improve graft survival, irrespective of the cause of the proteinuria [41]. However, there is no conclusive proof that the decrease in proteinuria in kidney transplant recipients is associated with an improvement in graft survival [42]. PRESCRIPTION OF MRAs IN KT FOR PRIMARY OR SECONDARY CV PREVENTION Beyond graft protection, which indirectly improves patient survival, MRAs are probably of direct interest for CV protection in kidney graft recipients. Indeed, CV comorbidities are highly prevalent in ESRD patients [2]. Kidney transplant patients have lower CV-associated mortality than patients on dialysis, although it still remains much higher than that of the general population [2]. It is conceivable that KT partially reverses vascular and cardiac abnormalities related to impaired renal function; however, immunosuppressive regimens, particularly corticosteroids, calcineurin inhibitors and mTOR inhibitors, cause metabolic disturbances [HTN, new-onset diabetes after transplantation and dyslipidaemia], which may lead to de novo CV risk factors or comorbidities [2]. Importantly, KT is increasingly accessible to older recipients with more comorbidities such as diabetes, CAD or HF. MRAs may therefore be an efficient add-on therapy to target CV risk in dedicated transplant populations. Indeed, MRAs are associated with an impressive improvement in the survival of patients with HF with reduced left-ventricular function or post-myocardial infarction with reduced left-ventricular function [16], and may improve the survival of those with HF with preserved left-ventricular function [17]. These clinical benefits have been observed in addition to those resulting from treatment with ACEis or ARBs and beta-blockers in patients with frequently impaired kidney function (one-third of patients had eGFR <60 mL/min/1.73 m2 although >30 mL/min/1.73 m2). In addition, MRAs also led to a substantial improvement in BP control in resistant HTN [18] in the The Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2 study. In this latter study, all patients had eGFR ≥45 mL/min/1.73 m2 [18]. A recent review from the ERA-EDTA EURECA-m working group (EUropean REnal and CArdiovascular Medicine Working Group from the European Renal Association – European Dialysis and Transplant Association), the Red de Investigación Renal (REDINREN) network and the CV and Renal Clinical Trialists (F-CRIN INI-CRCT) network suggested adding MRAs to a triple BP-lowering combination in CKD patients with resistant HTN if eGFR is ≥30 mL/min/1.73 m2 and in whom plasma potassium concentrations are normal [43]. The authors also recommend prescribing MRAs for Stages 1–4 CKD patients with reduced left function HF. RCTs using MRAs in KT patients with HF or resistant HTN are yet to be conducted. Several studies have assessed the beneficial impact of MRAs on CV outcomes in dialysis [44]. A RCT is currently being conducted among patients on haemodialysis (ALCHEMIST: NCT01848639) to assess the efficacy of spironolactone in reducing CV-associated morbidity and mortality. MRAs may also improve vascular abnormalities related to metabolic disturbances in kidney transplant patients as a result of the immunosuppressive regimen. Indeed, MR activation is a trigger of vascular insulin resistance [45]. The role of aldosterone and MR activation in metabolic syndrome and vascular insulin resistance has been highlighted by several preclinical and clinical studies [46, 47]. In normotensive subjects, aldosterone levels are correlated with body mass index and insulin resistance [48]. Dietary salt restriction, which increases the level of aldosterone, also leads to vascular insulin resistance [49]. Treatment with MRAs has been shown to improve endothelial function in several experimental studies in diabetes. In rats, spironolactone was found to reduce obesity-related diastolic cardiac dysfunction via BP-independent mechanisms [50], while eplerenone improved endothelial dysfunction induced by a high-fat diet in mice [51] as well as in streptozotocin-induced diabetic rats [52]. Spironolactone also prevented high-fat, diet-induced arterial stiffening in mice [53]. The benefit of MRAs in the treatment of metabolic diseases has not been clearly established in clinical studies. While spironolactone was found to improve coronary microvascular function in Type 2 diabetic patients without clinical ischemic disease, it had no effect on lipids, body mass index or fasting glucose [54]. Nevertheless, a 6-month treatment with spironolactone was associated with a significant improvement in insulin resistance in patients with moderate CKD [55]. Taken together, these data suggest that transplant physicians should reassess the indication of MRA in kidney transplant patients with HF and/or a history of myocardial infarction before transplantation, and a fortiori if they have a moderate degree of CKD after transplantation. MRAs could probably be frequently prescribed in patients with eGFR >30 mL/min/1.73 m2. Patients with resistant HTN and/or metabolic syndrome may also benefit from MRA treatment. SAFETY OF MRAs IN CKD PATIENTS AND KT RECIPIENTS CKD patients are largely under-represented in CV outcome in RCTs [56] while organ recipients are also typically excluded from RCTs due to the potential risk of interactions between the study treatment and immunosuppressive therapy. The risk of hyperkalaemia is also a concern in RCTs designed to assess the effect of MRAs, which invariably prompt the exclusion of CKD patients. Safety of MRAs in CKD patients In CKD patients, a meta-analysis by Bolignano et al. [32] showed that spironolactone, in combination with ACEis and/or ARBs, increased the risk of hyperkalaemia [RR (relative risk) = 2.00, 95% confidence interval (CI) 1.25–3.20] relative to ACEis and/or ARBs alone, while spironolactone combined with ACEis and/or ARBs increased serum potassium levels (mean difference 0.26 mmol/L, 95% CI 0.13–0.39). In the meta-analysis of Currie et al. [33], the addition of MRAs to ACEi and/or ARB therapy led to a similar moderate increase in potassium levels of CKD patients from baseline (mean difference 0.19 mmol/L 95% CI 0.07–0.31). MRA treatment was also associated with an increased risk of hyperkalaemia (RR = 3.02, 95% CI 1.75–5.18). In patients with diabetic nephropathy included in the ARTS-DN study [36], only 1.5% of patients receiving finerenone exhibited increases in serum potassium levels of at least 5.6 mmol/L leading to subsequent discontinuation of the study treatment. Of note, the incidence of serum potassium ≥5.6 mmol/L was slightly higher among patients with Stage 3 CKD at baseline (2.7%, 5.4%, 4.1% and 6.3% in the 1.25 mg/day, 7.5 mg/day, 15 mg/day and 20 mg/day fineronone groups, respectively). Importantly, there were no differences in the incidence of the pre-specified secondary outcome of eGFR decrease >30% between placebo and finerenone groups. In haemodialysis-treated patients, a meta-analysis of seven RCTs including 755 patients reported that MRA use was significantly associated with hyperkalaemia (RR = 3.05, 95% CI 1.20–7.71) [44]. In patients with HF and moderate CKD, finerenone has been proposed to have a dissociated profile regarding efficacy and hyperkalaemia risk. Indeed, finerenone (5–10 mg/day) was as effective as spironolactone (25 or 50 mg/day) in reducing the levels of haemodynamic stress biomarkers and was associated with a lower rate of hyperkalaemia [57]. In a posthoc analysis of the EMPHASIS-HF study (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) [58], Eschalier et al. observed that patients in the pre-specified high-risk subgroups (≥75 years of age, presence of diabetes mellitus or CKD defined by an eGFR <60 mL/min/1.73 m2), and those with a systolic BP <123 mmHg (median) at baseline treated with eplerenone had an increased risk of serum potassium levels >5.5 mmol/L, but not of potassium levels >6.0 mmol/L, hospitalization for hyperkalaemia or discontinuation of the study medication due to adverse events. Of note, eplerenone was effective in reducing the primary composite endpoint (hospitalization for HF or death from CV causes) in all subgroups including those with the highest risk of hyperkalaemia. Safety of MRAs in kidney transplant recipients As emphasized above, organ recipients are usually not eligible for inclusion in RCTs due to the potential risk of interactions with immunosuppressive therapy. Nevertheless, eplerenone and spironolactone are not inhibitors or inducers of CYP3A4, which results in a neutral effect of MRA intake on calcineurin inhibitors levels. There is also no drug–drug interaction between mycophenolic acid and MRAs. A recent trial showed the safety of eplerenone 25 mg/day in kidney-transplanted patients treated with cyclosporine [59]. This study included 31 patients with a functional kidney allograft for at least 1 year and an eGFR between 30 and 50 mL/min/1.73 m2. Patients with serum potassium levels ≥5 mmol/L or with a history of severe hyperkalaemia (≥6 mmol/L) were not eligible for the trial, whereas patients treated with ACEi or ARB (61% of patients) could be included. Eight patients experienced mild hyperkalaemia (>5 mmol/L) while treated with eplerenone and one had moderate hyperkalaemia (>5.5 mmol/L) and received potassium-exchange resin. There were no occurrences of severe hyperkalaemia (>6 mmol/L) and one occurrence of acute kidney failure, attributed to diarrhoea. Likewise, spironolactone 50 mg/day was also reported to be safe and found to efficiently reduce renal oxidative stress in a RCT involving KT recipients from living donors [26]. MANAGING THE RISK OF HYPERKALAEMIA ASSOCIATED WITH MRAs IN KIDNEY TRANSPLANT RECIPIENTS Pharmacology of MRAs in CKD The pharmacokinetics of spironolactone and eplerenone clearly differ. Approximately 10–15% of spironolactone and its numerous metabolites are excreted in urine. The impact of CKD or renal replacement therapy on spironolactone pharmacokinetics has not been reported. Much (66%) of the eplerenone is excreted in urine, although total body clearance is unchanged with CKD [60]. The renal elimination of finerenone is minimal [61]. However, moderate and severe renal impairment increases exposure to unbound finerenone by 57% and 47%, respectively, possibly due to the effects of renal impairment on non-renal routes of elimination [61]. The mechanism of action of MRAs intrinsically increases the risk of hyperkalaemia in at-risk patients. In healthy subjects, compensatory mechanisms prevent the increase in plasma potassium levels upon administration of a low MRA dose, whereas in patients with CKD, potassium homeostasis is profoundly altered [62]. The risk of hyperkalaemia is inversely related to the decrease in eGFR and increases when the eGFR is <30 mL/min/1.73 m2. As renal function declines, the cellular uptake of potassium is able to buffer the decrease in potassium excretion capacity. Extra-renal potassium homeostasis is particularly critical in CKD and ESRD patients: indeed, the colon plays a major role in potassium homeostasis in these patients with a 3-fold increase in intestinal potassium secretion (related to the increased expression of a large conductance potassium channel in the colonic epithelium) observed in ESRD patients [63]. Whether the intestinal MR participates in colonic potassium balance in CKD/ESRD patients is unclear. Limiting the risk of hyperkalaemia when using MRAs in kidney transplant recipients Only spironolactone and eplerenone are currently available commercially and can be proposed to kidney transplant patients. Eplerenone should be favoured in the initial transplantation setting, as it is directly active and has a short half-life, thus being easier to manage in case of adverse events. The risk of hyperkalaemia in this specific population of oligo-anuric patients with GFR <15 mL/min/1.73 m2 is obviously a matter of concern, in particular for the risk of cardiac arrhythmias. Accordingly, this risk is one of the pre-specified secondary outcomes of the EPURE-TRANSPLANT study (Eplerenone in Patients Undergoing REnal Transplant) (EPURE: NCT02490904). Of note, transplant patients are intensively monitored and are thus in an appropriate environment to detect and promptly manage hyperkalaemia within the first days following transplantation: the standard close biological monitoring of kidney transplant recipients in the post-operative period (generally twice a day during the first days) may improve the safety of MRAs during this early KT period. Common methods to manage hyperkalaemia (potassium chelation, correction of metabolic acidosis, use of loop diuretics, insulin, β-adrenoceptor agonists and, if necessary, dialysis) are routinely used in post-operative intensive care or nephrology units. One can also speculate that in case of a beneficial effect of MRA on graft recovery among graft recipients from ECD, the anuria period will be shorter among patients receiving MRA, leading to a shorter period of increased hyperkalaemia risk. Moreover, it is important to consider that in the post-operative period, kidney recipients often have limited oral food ingestion, leading to a decreased risk of hyperkalaemia. Kidney transplant recipients are also closely monitored in a chronic setting, with frequent biological tests and dietary counselling that may limit the risk of significant hyperkalaemia. Patient education may also be of particular importance in limiting excess potassium intake and preventing the risk of drug interactions by avoiding the co-administration of drugs known to increase the risk of hyperkalaemia. Moreover, the recent availability in the USA and in the EU of the novel potassium-binding resin patiromer, while sodium zirconium cyclosilicate (ZS-9) is now approved in the EU and is still under Food and Drug Administration review may provide a useful tool to treat hyperkalaemia in patients treated with renin–angiotensin–aldosterone inhibitors [64], potentially including transplanted CKD patients. However, no dedicated trial has been undertaken to date in this specific population. UNMET NEED AND PERSPECTIVES MRA administration may be beneficial in the setting of KT (Figure 3) in the following instances: FIGURE 3: View largeDownload slide Potential beneficial effects of MRAs in KT: acute or chronic graft protection or prevention of primary or secondary CV or metabolic complications in kidney transplant recipients. FIGURE 3: View largeDownload slide Potential beneficial effects of MRAs in KT: acute or chronic graft protection or prevention of primary or secondary CV or metabolic complications in kidney transplant recipients. During the pre- or short-term post-operative period of the transplantation in order to prevent I/R lesions leading to AKI and predisposing patients to chronic graft dysfunction, in particular in the setting of marginal donors or donors after cardiac death so as to mitigate or reduce DGF. Experimental studies are currently ongoing to assess the impact of MRA in perfusion machines in large animal models. The next step in clinical studies could be to administer MRA to the grafts via the perfusion machine, or directly to donors, if ethical issues can be addressed. In chronic use among KT recipients in order to prevent CIN and reduce proteinuria. To prevent CV complications during follow-up of kidney transplant recipients. Dedicated clinical trials are needed to assess the benefit and safety profile of MRAs in these patients. The management of hyperkalaemia risk and its consequence on cardiac arrhythmia should be specifically assessed and compared with the benefit of MRAs on long-term renal function and CV outcomes in kidney transplant recipients. The choice of the most accurate study design for evaluating the long-term impact of MRA on patient and graft protection nonetheless remains challenging, and should take into account the following aspects: capacity of patient recruitment; length and costs of an RCT (sample size and time to event); ability to appropriately characterize the observed effect or to adequately interpret the absence of observed effect. Table 2 depicts the theoretical advantages and drawbacks of various study designs in KT according to the target population (general kidney transplant population versus kidney graft recipients with previous history of CV disease) and to the choice of outcomes (hard outcomes versus soft outcomes). Table 2. Advantages and drawbacks of RCTs in KT according to the target population (general kidney transplant population versus kidney graft recipients with previous history of CV disease) and to the choice of the outcomes (hard outcomes versus soft outcomes)   General transplant population  Kidney graft recipients with previous history of CV disease  Hard outcome  • Patient survival (all-cause and CV mortality)  • MACE  • Graft survival  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest: ↑↑Patient sample size required ↑↑Length of the study/very long time-frame ↑↑Costs of the study Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑Incidence of the event of interest: ↓Patient sample size required ↓Length of the study/shorter time-frame ↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable) Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  Soft outcome/surrogate markers/surrogate endpoints/predictive endpoints  • LVH, PWV  • eGFR/proteinuria, histological findings (glomerulosclerosis, intersitial fibrosis, chronic vascular lesions)  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest:    • ↑Patient sample size required    • ↑Length of the study/long time-frame    • ↑Costs of the study  • Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment  • Soft outcomes:    • ↑Risk of measurement bias    • Specificity of the observed effect?  • Surrogate outcomes: need to be validated  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑↑Incidence of the event of interest: ↓↓Patient sample size required ↓↓Length of the study/very short time frame ↓↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable)  Soft outcomes: ↑Risk of measurement bias Specificity of the observed effect?  Surrogate outcomes: need to be validated    General transplant population  Kidney graft recipients with previous history of CV disease  Hard outcome  • Patient survival (all-cause and CV mortality)  • MACE  • Graft survival  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest: ↑↑Patient sample size required ↑↑Length of the study/very long time-frame ↑↑Costs of the study Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑Incidence of the event of interest: ↓Patient sample size required ↓Length of the study/shorter time-frame ↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable) Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  Soft outcome/surrogate markers/surrogate endpoints/predictive endpoints  • LVH, PWV  • eGFR/proteinuria, histological findings (glomerulosclerosis, intersitial fibrosis, chronic vascular lesions)  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest:    • ↑Patient sample size required    • ↑Length of the study/long time-frame    • ↑Costs of the study  • Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment  • Soft outcomes:    • ↑Risk of measurement bias    • Specificity of the observed effect?  • Surrogate outcomes: need to be validated  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑↑Incidence of the event of interest: ↓↓Patient sample size required ↓↓Length of the study/very short time frame ↓↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable)  Soft outcomes: ↑Risk of measurement bias Specificity of the observed effect?  Surrogate outcomes: need to be validated  LVH, left ventricular hypertrophy; MACE, major adverse cardiovascular event; PWV, pulse wave velocity. Table 2. Advantages and drawbacks of RCTs in KT according to the target population (general kidney transplant population versus kidney graft recipients with previous history of CV disease) and to the choice of the outcomes (hard outcomes versus soft outcomes)   General transplant population  Kidney graft recipients with previous history of CV disease  Hard outcome  • Patient survival (all-cause and CV mortality)  • MACE  • Graft survival  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest: ↑↑Patient sample size required ↑↑Length of the study/very long time-frame ↑↑Costs of the study Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑Incidence of the event of interest: ↓Patient sample size required ↓Length of the study/shorter time-frame ↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable) Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  Soft outcome/surrogate markers/surrogate endpoints/predictive endpoints  • LVH, PWV  • eGFR/proteinuria, histological findings (glomerulosclerosis, intersitial fibrosis, chronic vascular lesions)  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest:    • ↑Patient sample size required    • ↑Length of the study/long time-frame    • ↑Costs of the study  • Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment  • Soft outcomes:    • ↑Risk of measurement bias    • Specificity of the observed effect?  • Surrogate outcomes: need to be validated  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑↑Incidence of the event of interest: ↓↓Patient sample size required ↓↓Length of the study/very short time frame ↓↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable)  Soft outcomes: ↑Risk of measurement bias Specificity of the observed effect?  Surrogate outcomes: need to be validated    General transplant population  Kidney graft recipients with previous history of CV disease  Hard outcome  • Patient survival (all-cause and CV mortality)  • MACE  • Graft survival  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest: ↑↑Patient sample size required ↑↑Length of the study/very long time-frame ↑↑Costs of the study Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑Incidence of the event of interest: ↓Patient sample size required ↓Length of the study/shorter time-frame ↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable) Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  Soft outcome/surrogate markers/surrogate endpoints/predictive endpoints  • LVH, PWV  • eGFR/proteinuria, histological findings (glomerulosclerosis, intersitial fibrosis, chronic vascular lesions)  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest:    • ↑Patient sample size required    • ↑Length of the study/long time-frame    • ↑Costs of the study  • Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment  • Soft outcomes:    • ↑Risk of measurement bias    • Specificity of the observed effect?  • Surrogate outcomes: need to be validated  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑↑Incidence of the event of interest: ↓↓Patient sample size required ↓↓Length of the study/very short time frame ↓↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable)  Soft outcomes: ↑Risk of measurement bias Specificity of the observed effect?  Surrogate outcomes: need to be validated  LVH, left ventricular hypertrophy; MACE, major adverse cardiovascular event; PWV, pulse wave velocity. The use of surrogate markers may confer two advantages. First, the incidence of the studied outcomes may be higher, allowing studies with shorter follow-up and costs. Secondly, the observed effects may be more specific, allowing a more accurate understanding of the pathophysiological mechanisms involved. The two approaches (large studies with hard endpoints and targeted populations with surrogate outcomes), if feasible, would probably provide complementary information. Composite surrogate endpoints may likely be required in order to accurately assess the therapeutic effect of MRAs, allowing shorter follow-up studies than those using the graft or patient survival as primary outcome, although ensuring a precise characterization of the observed effect. Nevertheless, these surrogate endpoints should be precisely evaluated and validated in order to predict long-term graft survival. Finally, considering that chronic ABMR may lead to graft and systemic accelerated vascular ageing, it is crucial to accurately assess the level of humoral alloreactivity at baseline and during follow-up (presence of circulating donor-specific antibodies and/or histological findings of ABMR in the graft biopsy). In order to adequately distinguish non-immunological benefits of MRA in graft protection, investigators should probably select low-immunological risk but high-CV risk graft recipients. In a second phase, MRA may be assessed as a general feature of graft improvement, either with or without an ongoing humoral alloreactivity process. In order to assess the impact of long-term MRA administration in KT, potential surrogate outcomes could include: For graft protection: eGFR and proteinuria, histological findings, possibly combined together. Of note, detailed baseline phenotyping is necessary to accurately interpret the data, since renal function and histological findings are generally related to a complex and multifactorial process in kidney graft recipients. To assess the impact of long-term MRA administration on graft survival, a precise baseline and 1-year graft prognosis assessment is likely necessary in order to properly phenotype the subgroup of patients of interest. This may allow distinguishing the potential non-immunological beneficial effect of MRA administration from immunological processes that lead to graft deterioration. The use of eGFR or proteinuria without this detailed baseline assessment would probably lack accuracy in assessing the potential protective effect of MRAs in the field of KT, considering the various causes of proteinuria among KT recipients. For patient/CV protection: echocardiographic findings (i.e. left ventricular hypertrophy), arterial functional testing (i.e. pulse wave velocity for arterial stiffness evaluation). To assess the impact of long-term MRA administration on CV outcomes, detailed baseline CV risk assessment is mandatory, as well as 1-year post-KT evaluation, considering that the early post-operative KT period is at increased risk of CV events [65]. To summarize, the study design should ideally be a compromise between recruitment capacities, outcome incidence, risk of measurement bias and adequate characterization of the observed effect. In conclusion, the potential indications of MRAs in renal transplantation are numerous although clinical studies are clearly needed to confirm the efficacy and safety of MRAs in this population. The undertaking of such studies is certainly highly worthwhile given the important unmet need in KT. ACKNOWLEDGEMENTS The authors thank Prof. Luc Frimat and Prof. Patrick Rossignol for their critical review of the manuscript. They thank Dr Jacqueline Champigneulle who kindly provided anatomopathology images and Erwan Bozec who helped reformating the Figures. FUNDING This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale, the French Medical Research Foundation (DEQ20160334885), the Investissement Avenir Fight-HF and ANR RENOMIR (ANR-16-CE14-0021-01) and the support of COST-ADMIRE BM1301 network. CONFLICT OF INTEREST STATEMENT F.J. received a research grant from BAYER. REFERENCES 1 Bon D, Chatauret N, Giraud S et al.   New strategies to optimize kidney recovery and preservation in transplantation. Nat Rev Nephrol  2012; 8: 339– 347 Google Scholar CrossRef Search ADS PubMed  2 Jardine AG, Gaston RS, Fellstrom BC et al.   Prevention of cardiovascular disease in adult recipients of kidney transplants. 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J Clin Pharmacol  2005; 45: 810– 821 Google Scholar CrossRef Search ADS PubMed  61 Heinig R, Kimmeskamp-Kirschbaum N, Halabi A et al.   Pharmacokinetics of the novel nonsteroidal mineralocorticoid receptor antagonist finerenone (BAY 94-8862) in individuals with renal impairment. Clin Pharmacol Drug Dev  2016; 5: 488– 501 Google Scholar CrossRef Search ADS PubMed  62 Palmer BF. Potassium homeostasis in chronic kidney disease. Nephrol News Issues  2016; 30: suppl 8– suppl13 63 Martin RS, Panese S, Virginillo M et al.   Increased secretion of potassium in the rectum of humans with chronic renal failure. Am J Kidney Dis  1986; 8: 105– 110 Google Scholar CrossRef Search ADS PubMed  64 Zannad F, Rossignol P, Stough WG et al.   New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: considerations for trial design and regulatory approval. Int J Cardiol  2016; 216: 46– 51 Google Scholar CrossRef Search ADS PubMed  65 Lentine KL, Brennan DC, Schnitzler MA. Incidence and predictors of myocardial infarction after kidney transplantation. J Am Soc Nephrol  2005; 16: 496– 506 Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

Mineralocorticoid receptor antagonists in kidney transplantation: time to consider?

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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0931-0509
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1460-2385
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Abstract

Abstract Although patient survival is significantly improved by kidney transplantation (KT) in comparison with dialysis, it remains significantly lower than that observed in the general population. Graft function is one of the major determinants of patient survival after KT. Mineralocorticoid receptor antagonists (MRAs) could be of particular interest in this population to improve graft function and treat or prevent cardiovascular (CV) complications. In KT, ischaemia/reperfusion injury is a major factor involved in delayed graft function, which is often associated with inferior long-term graft survival. Preclinical studies suggest that MRAs may prevent ischaemia/reperfusion-related lesions in addition to having a protective effect in preventing calcineurin inhibitor-induced nephrotoxicity. Clinical data also support the anti-proteinuric effect of MRAs in chronic kidney disease (CKD). Taken together, MRAs may hence be of particular benefit in improving short- and long-term graft function. Numerous randomized controlled trials (RCTs) have shown the efficacy of MRAs in both heart failure and resistant hypertension. As these comorbidities are frequent in kidney transplant recipients before transplantation or during follow-up, MRAs could represent a useful therapeutic option in those with mild renal function impairment. However, CKD patients are under-represented in RCTs and the CV effects of MRAs in kidney transplant recipients have yet to be specifically assessed in large-scale trials. Available evidence indicates a good safety profile for MRAs in patients with a glomerular filtration rate (GFR) >30 mL/min/1.73 m2. However, as for all patients prescribed an MRA, creatinine and potassium should also be closely monitored following MRA initiation in kidney transplant patients. Given the current evidence suggesting that MRAs prevent ischaemia/reperfusion-related lesions and calcineurin inhibitor-induced nephrotoxicity in kidney transplant recipients as well as CV events in patients at high risk of CV complications (such as those in kidney transplant recipients), trials are urgently needed to fully assess the clinical impact of MRA use in this population. cardiovascular, calcineurin inhibitor, ischemia-reperfusion injury, kidney transplantation, mineralocorticoid receptor antagonist INTRODUCTION Kidney transplantation (KT) faces a double challenge: (i) organ shortage with increased use of grafts from expanded criteria donors (ECDs), which are more susceptible to deleterious ischaemia/reperfusion (I/R) lesions [1], and (ii) increased access to KT for older recipients who experience multiple comorbidities at baseline or during follow-up [2]. Preclinical studies have suggested that pharmacological blockade of the mineralocorticoid receptor (MR) protects against I/R-related lesions and their long-term consequences [3–6]. Mineralocorticoid receptor antagonists (MRAs) may also prevent calcineurin inhibitor-induced nephrotoxicity (CIN) [7–15]. Numerous clinical trials have shown the high efficacy of MRAs in patients with heart failure (HF) [16, 17], myocardial infarction [16] or resistant hypertension (HTN) [18]. Since many kidney graft recipients have a history of HF or coronary artery disease (CAD) before KT or develop these complications during follow-up [2], MRAs may therefore represent a potential therapeutic option in kidney transplant patients. This review aims to present the current evidence supporting the future use of MRAs in KT, either to optimize graft function and/or to improve patient cardiovascular (CV) prognosis. GENERAL DATA ON MRAs Steroidal and non-steroidal MRAs MRAs include steroidal (spironolactone and eplerenone) and non-steroidal (finerenone) antagonists. The balance between clinical efficacy and side effects of MRAs is determined by their selectivity, potency and tissue distribution, as outlined in Table 1. Side effects mainly include (i) hormonal-related side effects due to lack of selectivity and (ii) hyperkalaemia. Table 1. Characteristics of MRAs Characteristics   Steroidal MRA   Non-steroidal MRA   Drug  Spironolactone  Eplerenone  Finerenone  MRA generation  I  II  III  Selectivity  Low  High  High  Potency  High  Low  High  Half-life  Long Active metabolites >12h  Short 4-6h  Short 2h  Tissue distribution (heart vs. kidney)  6× higher in the kidney  3× higher in the kidney  equal  Concentrations of ligand required to inhibit 50% activation of the receptor (IC50), or to achieve 50% activation of the receptor (EC50)*          Mineralocorticoid receptor IC50 (nM)  24  990  17.8    Androgen receptor IC50 (nM)  77  ≥21 240  ≥10 000    Glucocorticoid receptor IC50 (nM)  2410  ≥21 980  ≥10 000    Progesterone receptor EC50 (nM)  740  ≥31 210  ≥10 000  SUMMARY  Spironolactone is a potent competitive MRA Poorly selective → “hormone-related” side effects Rapidly metabolized into several active metabolites with a half-life of approx. 15 hours Tissue distribution: spironolactone is accumulated six-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Eplerenone is much more selective for MR than spironolactone, therefore avoiding “hormone-related “effects Eplerenone is less potent than spironolactone, requiring a higher dosage to achieve similar MR antagonism Eplerenone has no active metabolite → rapid efficacy after administration Eplerenone has a shorter half-life → important for safety concerns in case of adverse event Tissue distribution: Eplerenone accumulated three-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Finerenone has higher selectivity, higher potency Tissue distribution: equivalent in rat heart and kidney → low doses may allow sufficient MR antagonism outside of the kidney Potential reduced risk of hyperkalemia due to balanced extrarenal/renal distribution allowing reduction in dosing  Characteristics   Steroidal MRA   Non-steroidal MRA   Drug  Spironolactone  Eplerenone  Finerenone  MRA generation  I  II  III  Selectivity  Low  High  High  Potency  High  Low  High  Half-life  Long Active metabolites >12h  Short 4-6h  Short 2h  Tissue distribution (heart vs. kidney)  6× higher in the kidney  3× higher in the kidney  equal  Concentrations of ligand required to inhibit 50% activation of the receptor (IC50), or to achieve 50% activation of the receptor (EC50)*          Mineralocorticoid receptor IC50 (nM)  24  990  17.8    Androgen receptor IC50 (nM)  77  ≥21 240  ≥10 000    Glucocorticoid receptor IC50 (nM)  2410  ≥21 980  ≥10 000    Progesterone receptor EC50 (nM)  740  ≥31 210  ≥10 000  SUMMARY  Spironolactone is a potent competitive MRA Poorly selective → “hormone-related” side effects Rapidly metabolized into several active metabolites with a half-life of approx. 15 hours Tissue distribution: spironolactone is accumulated six-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Eplerenone is much more selective for MR than spironolactone, therefore avoiding “hormone-related “effects Eplerenone is less potent than spironolactone, requiring a higher dosage to achieve similar MR antagonism Eplerenone has no active metabolite → rapid efficacy after administration Eplerenone has a shorter half-life → important for safety concerns in case of adverse event Tissue distribution: Eplerenone accumulated three-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Finerenone has higher selectivity, higher potency Tissue distribution: equivalent in rat heart and kidney → low doses may allow sufficient MR antagonism outside of the kidney Potential reduced risk of hyperkalemia due to balanced extrarenal/renal distribution allowing reduction in dosing  * MR inhibition is responsible for the desired action of the drugs. Activation (progesterone) or inhibition (androgen or glucocorticoid) of the other receptors potentially leads to side effects. Adapted from Jaisser and Farman [19] and Bramlage et al. [20] Table 1. Characteristics of MRAs Characteristics   Steroidal MRA   Non-steroidal MRA   Drug  Spironolactone  Eplerenone  Finerenone  MRA generation  I  II  III  Selectivity  Low  High  High  Potency  High  Low  High  Half-life  Long Active metabolites >12h  Short 4-6h  Short 2h  Tissue distribution (heart vs. kidney)  6× higher in the kidney  3× higher in the kidney  equal  Concentrations of ligand required to inhibit 50% activation of the receptor (IC50), or to achieve 50% activation of the receptor (EC50)*          Mineralocorticoid receptor IC50 (nM)  24  990  17.8    Androgen receptor IC50 (nM)  77  ≥21 240  ≥10 000    Glucocorticoid receptor IC50 (nM)  2410  ≥21 980  ≥10 000    Progesterone receptor EC50 (nM)  740  ≥31 210  ≥10 000  SUMMARY  Spironolactone is a potent competitive MRA Poorly selective → “hormone-related” side effects Rapidly metabolized into several active metabolites with a half-life of approx. 15 hours Tissue distribution: spironolactone is accumulated six-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Eplerenone is much more selective for MR than spironolactone, therefore avoiding “hormone-related “effects Eplerenone is less potent than spironolactone, requiring a higher dosage to achieve similar MR antagonism Eplerenone has no active metabolite → rapid efficacy after administration Eplerenone has a shorter half-life → important for safety concerns in case of adverse event Tissue distribution: Eplerenone accumulated three-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Finerenone has higher selectivity, higher potency Tissue distribution: equivalent in rat heart and kidney → low doses may allow sufficient MR antagonism outside of the kidney Potential reduced risk of hyperkalemia due to balanced extrarenal/renal distribution allowing reduction in dosing  Characteristics   Steroidal MRA   Non-steroidal MRA   Drug  Spironolactone  Eplerenone  Finerenone  MRA generation  I  II  III  Selectivity  Low  High  High  Potency  High  Low  High  Half-life  Long Active metabolites >12h  Short 4-6h  Short 2h  Tissue distribution (heart vs. kidney)  6× higher in the kidney  3× higher in the kidney  equal  Concentrations of ligand required to inhibit 50% activation of the receptor (IC50), or to achieve 50% activation of the receptor (EC50)*          Mineralocorticoid receptor IC50 (nM)  24  990  17.8    Androgen receptor IC50 (nM)  77  ≥21 240  ≥10 000    Glucocorticoid receptor IC50 (nM)  2410  ≥21 980  ≥10 000    Progesterone receptor EC50 (nM)  740  ≥31 210  ≥10 000  SUMMARY  Spironolactone is a potent competitive MRA Poorly selective → “hormone-related” side effects Rapidly metabolized into several active metabolites with a half-life of approx. 15 hours Tissue distribution: spironolactone is accumulated six-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Eplerenone is much more selective for MR than spironolactone, therefore avoiding “hormone-related “effects Eplerenone is less potent than spironolactone, requiring a higher dosage to achieve similar MR antagonism Eplerenone has no active metabolite → rapid efficacy after administration Eplerenone has a shorter half-life → important for safety concerns in case of adverse event Tissue distribution: Eplerenone accumulated three-fold more in the kidney than in the heart Risk of hyperkalemia related to decreased urinary potassium excretion via action on the aldosterone-sensitive distal nephron  Finerenone has higher selectivity, higher potency Tissue distribution: equivalent in rat heart and kidney → low doses may allow sufficient MR antagonism outside of the kidney Potential reduced risk of hyperkalemia due to balanced extrarenal/renal distribution allowing reduction in dosing  * MR inhibition is responsible for the desired action of the drugs. Activation (progesterone) or inhibition (androgen or glucocorticoid) of the other receptors potentially leads to side effects. Adapted from Jaisser and Farman [19] and Bramlage et al. [20] MR distribution MR is expressed in the distal nephron (distal tubule and collecting duct), known as the aldosterone-sensitive distal nephron (ASDN), as well as in the distal colon and sweat glands, all sites previously identified as classical targets of aldosterone. MR is also expressed in tissues and cell types where there is no vectorial sodium transport, such as cardiomyocytes, endothelial cells, vascular smooth muscle cells (VSMCs) and immune cells [19]. In the kidney, in addition to the ASDN, MR is expressed in vascular endothelial cells and in VSMCs of inter-lobar arteries [19], as well as in glomerular cells (podocytes, mesangial cells) in disease conditions such as Type 1 diabetes or metabolic syndrome with HTN [19] (Figure 1A). FIGURE 1: View largeDownload slide  (A) Expression of the MR in classical and non-classical renal and non-renal aldosterone targets cells, including the immune system. Common mechanisms involved in the consequences of MR activation in renal and CV systems. (B) Impact of aldosterone in target cells with induction of oxidative stress, fibrosis and inflammation, including the polarization of macrophages into a pro-inflammatory M1 phenotype as well as T lymphocyte differentiation to the pro-inflammatory Th1 and Th17 subsets. A, aldosterone; 11-βHSD2, 11β-hydroxysteroid dehydrogenase Type 2; C, glucocorticoid hormones; Il-6, interleukin 6; MP, macrophage; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; Nox, nicotinamide adenine dinucleotide phosphate oxidase; ROS, reactive oxygen species; TGF-β, transforming growth factor-β; Th1, T helper; TNF-α, tumor necrosis factor α. FIGURE 1: View largeDownload slide  (A) Expression of the MR in classical and non-classical renal and non-renal aldosterone targets cells, including the immune system. Common mechanisms involved in the consequences of MR activation in renal and CV systems. (B) Impact of aldosterone in target cells with induction of oxidative stress, fibrosis and inflammation, including the polarization of macrophages into a pro-inflammatory M1 phenotype as well as T lymphocyte differentiation to the pro-inflammatory Th1 and Th17 subsets. A, aldosterone; 11-βHSD2, 11β-hydroxysteroid dehydrogenase Type 2; C, glucocorticoid hormones; Il-6, interleukin 6; MP, macrophage; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor kappa B; Nox, nicotinamide adenine dinucleotide phosphate oxidase; ROS, reactive oxygen species; TGF-β, transforming growth factor-β; Th1, T helper; TNF-α, tumor necrosis factor α. Common mechanisms of action of MRAs Aldosterone binds to the MR, the latter being a ligand-dependent transcription factor belonging to the nuclear receptor superfamily. The aldosterone–MR complex binds to glucocorticoid response elements within the promoter region of aldosterone-induced (or repressed) genes to modulate their transcription [19]. In a typical target cell, such as the renal collecting duct principal cell, the apical Na+ channels and the basolateral Na+ pumps and K+ channels are upregulated in the presence of aldosterone leading to a sustained increase in transepithelial sodium reabsorption [19]. The MR binds both aldosterone and glucocorticoid hormones with similar high affinity. Plasma glucocorticoid levels are much higher than plasma aldosterone levels, the main mechanism leading to mineralocorticoid selectivity being the co-expression of MR and 11β-hydroxysteroid dehydrogenase Type 2, which metabolizes glucocorticoid hormones into inactive derivatives with very low affinity for the MR, thus avoiding permanent binding of the MR by glucocorticoids [19] (Figure 1B). The mechanisms underlying the potential benefit of MRAs in kidney and CV protection include (i) the regulation of ion channel expression/activity (the type of ion channels—sodium, potassium, calcium—depending on cell type), (ii) the limiting of oxidative stress production, (iii) the reduction in fibrosis and extracellular matrix remodelling and (iv) the curbing of inflammation. This allows reducing the development of (i) cardiac diseases (avoiding electrophysiological disorders and limiting extracellular matrix remodelling and fibrosis), (ii) vascular disease (limiting HTN, arterial stiffness and reduced organ perfusion) and (iii) renal disease (limiting HTN, glomerulosclerosis and interstitial fibrosis) (Figure 1A). Ion channel remodelling is a general feature of mineralocorticoid signalling [19]. The type of ion channels (sodium, potassium, calcium) is contingent on cell type. In ASDN, aldosterone controls the expression/activity of various ion transporters, modulating sodium and potassium homeostasis and blood pressure (BP). MR signalling also leads to changes in ion channel expression or activity in endothelial cells and VSMC, contributing to the stiffening of endothelial cell membranes and to myogenic tone. In cardiomyocytes, the modulation of ion channels leads to atrial and ventricular arrhythmias. Oxidative stress is a central mechanism in the deleterious effects of aldosterone and MR activation [19]. Aldosterone stimulates oxidative stress in classic and non-classic target cells, with the aldosterone/MR complex upregulating the expression of nicotinamide adenine dinucleotide phosphate oxidase subunits such as Nox2, Nox4 and rac1, thereby affecting Nox activity. Oxidative stress increases DNA damage and protein carbonylation. Nitric oxide (NO) synthase uncoupling decreases the availability of NO for vasorelaxation as well as increases the production of hydrogen peroxide and activation of the nuclear factor κB pathway leading to inflammation and fibrosis [19]. Inappropriate MR activation has been shown to promote CV and renal tubulo-interstitial fibrosis [19]. In randomized controlled trials (RCTs), the beneficial effects of MRA in HF were associated with a reduction in fibrosis biomarkers [21]. MRA may also be useful in limiting arterial stiffness [22, 23]. Pharmacological MR blockade improves the chronic inflammatory state associated with CV disease [19]. Macrophages, dendritic cells and T lymphocytes have more recently been identified as MR target cells [24]. MR activation leads to interleukin (IL)-6 and tumour necrosis factor α expression and nuclear factor κB activation in both immune and non-immune cells. MR activation promotes macrophage activation to the pro-inflammatory M1 phenotype, as well as T lymphocyte differentiation into pro-inflammatory Th1 and Th17 subsets [24]. It also leads to a decrease in the number of anti-inflammatory T regulatory lymphocytes. MR activation in antigen-presenting dendritic cells increases IL-6 and transforming growth factor-β (TGF-β) expression as well as dendritic cell-mediated Th17 polarization of T lymphocytes [24]. Altogether, the above data suggest that aldosterone/MR modulates innate and adaptive immunity, which may have a critical role in end-organ damage. MRA PRESCRIPTION IN KT FOR GRAFT PROTECTION A large body of preclinical evidence currently supports the efficacy of MRAs in preventing I/R lesions in the early phase of KT. Moreover, preclinical models have shown a significant effect of MRA in preventing short- and long-term calcineurin inhibitor nephrotoxicity. While there are only few clinical studies currently available to date, the results are in accordance with the preclinical findings. Prevention of I/R lesions I/R injury (IRI) is one of the main pathophysiological events involved in delayed graft function (DGF), often associated with inferior long-term graft survival. Episodes of IRI associated with DGF lead to decreased glomerular filtration rate (GFR), proteinuria, interstitial fibrosis and inflammation [25]. Several therapeutic strategies have been proven effective in preclinical models but have been poorly translated to the human setting [1, 25]. Moreover, developing novel therapeutic molecules is a costly and long-term process, whereas repositioning old molecules with proven efficacy in other settings may be a more efficient approach in targeting IRI and DGF. Accumulated evidence over the past decade suggests that blocking the MR may be a useful strategy to protect against I/R-related lesions (Figure 2A). Preclinical studies in rodents have demonstrated a beneficial effect of MRAs in preventing acute IRI and were also found to be efficient when administered up to 3 h after IRI [3, 4]. Importantly, data obtained in both mice and rats has been translatable to the Large White pig in which canrenoate potassium was shown to prevent acute kidney injury (AKI) following bilateral IRI. This protective effect was also observed with non-steroidal MRAs [4, 5]. The mechanisms underlying the deleterious effects of MR activation during IRI highlight the critical role of MR-mediated oxidative stress, the latter leading to a specific imbalance of vascular endothelin signalling through post-translational modification of the vasodilatory endothelin B receptor, triggering its functional inactivation and showing a sustained decrease in renal blood flow [4, 6]. FIGURE 2: View largeDownload slide (A) Pathophysiology and histological findings of IRI and AKI-induced CKD: benefit of MRAs in the prevention of IRI and AKI-induced CKD. (B) Pathophysiology and histological findings of acute and chronic CIN: potential benefits of mineralocorticoid receptor antagonists for the prevention of CIN. EC, endothelial cell; MP, macrophage; NO, nitric oxide; PTC, peritubular capillary; ROS, reactive oxygen species; SMC, smooth muscle cell; SMC-MR, smooth muscle cell-mineralocorticoid receptor; TGF-β, transforming growth factor-β. FIGURE 2: View largeDownload slide (A) Pathophysiology and histological findings of IRI and AKI-induced CKD: benefit of MRAs in the prevention of IRI and AKI-induced CKD. (B) Pathophysiology and histological findings of acute and chronic CIN: potential benefits of mineralocorticoid receptor antagonists for the prevention of CIN. EC, endothelial cell; MP, macrophage; NO, nitric oxide; PTC, peritubular capillary; ROS, reactive oxygen species; SMC, smooth muscle cell; SMC-MR, smooth muscle cell-mineralocorticoid receptor; TGF-β, transforming growth factor-β. A pilot clinical trial on living-donor KT [26] demonstrated a beneficial effect of spironolactone on renal oxidative stress when initiated in recipients 1 day prior to KT and administered for 3 days following KT. This treatment was not associated with significantly improved short-term renal function since renal function was already good in the placebo group, as expected for living-donor transplantation. However, mid and long-term renal function was not evaluated in this study. Importantly, decreased urinary levels of an oxidative stress marker (8-isoprostane) were observed in the MRA group, in keeping with the reported benefit of MRA on oxidative stress in rodents and pigs [5, 6]. MRA effects have also been assessed in settings other than KT. In the setting of cardiac surgery, a recent RCT failed to prevent post-operative AKI by the administration of spironolactone 100 mg on the day before the intervention and 25 mg/day for 3 days thereafter [27]. However, the association of MRA with outcome in this trial may have been underestimated because of the higher proportion (31% versus 18%, P = 0.02) of diabetic patients in the MRA arm [27]. Episodes of AKI lead to increased risk of CKD progression and renal failure. Indeed, a single episode of IRI may result in maladaptive repair and lead to CKD [28]. MRA administration during the acute phase of IRI prevents the decline in long-term renal function and tubulo-interstitial fibrosis in rodents [3, 6] as well as in Large White pigs [29]. Steroidal and non-steroidal MRAs are equally effective in preventing CKD progression following IR and/or AKI [3, 6] [29]. The underlying mechanism of the beneficial effect of MRAs lies in the prevention of low-grade inflammation and on the polarization of macrophages towards an anti-inflammatory M2 repair phenotype [29]. Considering that macrophage recruitment plays an essential role during both the injury and repair phases and that the infiltration of inflammatory cells early after an AKI episode plays an important role in defining effective versus maladaptive repair [28], this likely explains why short-term MRA administration during the I/R period only is able to prevent the long-term consequences of IRI. To date, there are no therapeutic approaches in clinical practice able to prevent progression to CKD after an AKI episode. MRA may thus represent a promising approach when administered before or just after the IR phase, even with short-term administration. Whether prevention of CKD progression after IRI also occurs in patients after transplantation remains to be explored. Our group is currently conducting a multicentre RCT to assess the impact of short-term administration of eplerenone (25 mg twice a day, immediately before and 4 days after KT) on 3-month renal graft function in patients receiving a graft from an ECD (EPURE: NCT02490904). ECD grafts are specifically targeted as they are more susceptible to ischaemia insult, and could consequently experience a greater benefit from early MRA use in preventing IRI. Prevention of calcineurin inhibitor toxicity In addition to direct cellular toxicity, the nephrotoxicity of the calcineurin inhibitor involves vasoconstriction and altered renal haemodynamics [7]. MRAs can limit calcineurin inhibitor-induced nephrotoxicity (CIN) in experimental models of either acute [8–10] or chronic [8, 11, 12] CIN. The beneficial effects of MRAs include the regulation of renal remodelling (apoptosis, fibrosis) and modulation of vasoactive factors, which increase (angiotensin II, endothelin) or decrease (nitric oxide, prostaglandins) during calcineurin inhibitor treatment [13] (Figure 2B). The role of vascular MRs in the renal vascular bed has recently been demonstrated in CIN: acute CIN was prevented in mice with genetic inactivation of VSMC MR but not upon deletion of endothelial MR [10]. The renoprotective effect of MRAs in a chronic CIN model was moreover associated with the prevention of TGF-β and extracellular matrix protein (fibronectin, and collagen I and IV) overexpression [11]. In rats, spironolactone was shown to prevent the progression of renal injury in pre-existing chronic CIN. The progression of renal dysfunction was reduced in the MRA group, with limited tubulo-interstitial fibrosis along with significantly reduced arteriolar thickening and a reduced apoptosis index [14]. Finally, spironolactone was found to improve transplant vasculopathy in rats with renal transplants with a reduction in the number of affected intrarenal arteries and a trend towards reduced proteinuria and focal glomerulosclerosis, with reduced glomerular macrophage influx [15]. In clinical practice, CIN is only part of the general process of graft impairment, which includes chronic I/R consequences, non-adherence to treatment and risk of chronic humoral rejection and accelerated vascular impairment [30]. The long-term protective effect of MRA in graft protection (as opposed to short-term graft protection for the prevention of I/R lesions) should be further investigated in clinical trials. In the setting of paediatric KT, a recent RCT involving eplerenone reported promising results in limiting the progression of biopsy-proven chronic graft nephropathy [31]. In this latter study, 13 children received eplerenone 25 mg/day during 24 months whereas 10 children received placebo. Although not reaching statistical significance, likely due to limited statistical power, estimated GFR (eGFR) was 15 mL/min/1.73 m2 higher in the eplerenone group along with a decrease in proteinuria in the eplerenone group as opposed to an increase in the control group during the 24-month follow-up. Histological findings derived from graft biopsies also supported a favourable effect of MRAs. While this trial was clearly underpowered, these encouraging results should nonetheless encourage further appropriately sized trials in order to provide more conclusive evidence. Reduction of proteinuria and CKD progression Although aldosterone has a primarily physiological homeostatic role on sodium balance and BP, a sustained MR activation can lead to renal damage, even in the absence of HTN. In the past 15 years, growing evidence indicates a substantial antiproteinuric effect and possibly a major renoprotective effect of MRAs in CKD; MRAs have emerged as a promising means to reduce proteinuria and to slow CKD progression [27]. Two meta-analyses showed that MRAs, in addition to angiotensin-converting enzyme inhibitors (ACEis) or angiotensin receptor blockers (ARBs), effectively reduced proteinuria [32, 33]. A strong independent association between proteinuria and the development of end-stage renal disease (ESRD) is well established in non-KT patients [34]. Thus, albuminuria may be a valid surrogate marker for ESRD in many circumstances for non-KT patients. In the two aforementioned meta-analyses [32, 33], the effect of MRA on GFR was either neutral [31] or slightly deleterious [33]. Most of the included studies had a follow-up period of <1 year; hence, the impact of the addition of MRA to ACEi or ARB on long-term renal outcomes remains unknown; none of the studies was sufficiently powered to detect differences in hard renal endpoints. An ongoing study is currently aimed to determine the effect of MRA on long-term renal function change [35]. MRAs are probably of particular interest in diabetic nephropathy. Recently, the ARTS-DN (MinerAlocorticoid Receptor Antagonist Tolerability Study-Diabetic Nephropathy) Study demonstrated a dose-dependent reduction in proteinuria among patients with diabetic nephropathy receiving ACEis or ARBs in combination with the new non-steroidal MRA, finerenone [36]. Two RCTs aiming to enrol a total of 11 200 patients with diabetic nephropathy are ongoing to assess the effect of finerenone on the progression of CKD (FIDELIO-DKD: NCT02545049) and on the occurrence of CV outcomes (FIGARO: NCT02545049). Causes of proteinuria in KT recipients generally differ from those of proteinuria in the general population. Transplant-specific diagnoses, including antibody-mediated rejection (ABMR) and/or chronic transplant glomerulopathy, are commonly reported in biopsy studies of transplant recipients with proteinuria [37]. This probably explains why non-immunological interventions aimed at reducing proteinuria have had little success in KT recipients in decreasing patient mortality, graft dysfunction and failure [38]. Nevertheless, early use of MRA may have a preventive action on the development of non-immunological lesions and may be of particular interest in instances of biopsies exhibiting non-immunological chronic lesions. Only sparse data analysing the effect of MRAs in KT patients are currently available. The addition of spironolactone (25 mg/day) to ACEis or ARBs was found to decrease proteinuria in 11 renal transplant patients (with serum creatinine values under 3 mg/dL) while being neutrally associated with renal function [39]. For kidney transplant patients, the prognostic value of proteinuria on graft and patient survival is well established [40]. Thus, the pharmacological reduction of proteinuria through the use of MRAs may help to improve graft survival, irrespective of the cause of the proteinuria [41]. However, there is no conclusive proof that the decrease in proteinuria in kidney transplant recipients is associated with an improvement in graft survival [42]. PRESCRIPTION OF MRAs IN KT FOR PRIMARY OR SECONDARY CV PREVENTION Beyond graft protection, which indirectly improves patient survival, MRAs are probably of direct interest for CV protection in kidney graft recipients. Indeed, CV comorbidities are highly prevalent in ESRD patients [2]. Kidney transplant patients have lower CV-associated mortality than patients on dialysis, although it still remains much higher than that of the general population [2]. It is conceivable that KT partially reverses vascular and cardiac abnormalities related to impaired renal function; however, immunosuppressive regimens, particularly corticosteroids, calcineurin inhibitors and mTOR inhibitors, cause metabolic disturbances [HTN, new-onset diabetes after transplantation and dyslipidaemia], which may lead to de novo CV risk factors or comorbidities [2]. Importantly, KT is increasingly accessible to older recipients with more comorbidities such as diabetes, CAD or HF. MRAs may therefore be an efficient add-on therapy to target CV risk in dedicated transplant populations. Indeed, MRAs are associated with an impressive improvement in the survival of patients with HF with reduced left-ventricular function or post-myocardial infarction with reduced left-ventricular function [16], and may improve the survival of those with HF with preserved left-ventricular function [17]. These clinical benefits have been observed in addition to those resulting from treatment with ACEis or ARBs and beta-blockers in patients with frequently impaired kidney function (one-third of patients had eGFR <60 mL/min/1.73 m2 although >30 mL/min/1.73 m2). In addition, MRAs also led to a substantial improvement in BP control in resistant HTN [18] in the The Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2 study. In this latter study, all patients had eGFR ≥45 mL/min/1.73 m2 [18]. A recent review from the ERA-EDTA EURECA-m working group (EUropean REnal and CArdiovascular Medicine Working Group from the European Renal Association – European Dialysis and Transplant Association), the Red de Investigación Renal (REDINREN) network and the CV and Renal Clinical Trialists (F-CRIN INI-CRCT) network suggested adding MRAs to a triple BP-lowering combination in CKD patients with resistant HTN if eGFR is ≥30 mL/min/1.73 m2 and in whom plasma potassium concentrations are normal [43]. The authors also recommend prescribing MRAs for Stages 1–4 CKD patients with reduced left function HF. RCTs using MRAs in KT patients with HF or resistant HTN are yet to be conducted. Several studies have assessed the beneficial impact of MRAs on CV outcomes in dialysis [44]. A RCT is currently being conducted among patients on haemodialysis (ALCHEMIST: NCT01848639) to assess the efficacy of spironolactone in reducing CV-associated morbidity and mortality. MRAs may also improve vascular abnormalities related to metabolic disturbances in kidney transplant patients as a result of the immunosuppressive regimen. Indeed, MR activation is a trigger of vascular insulin resistance [45]. The role of aldosterone and MR activation in metabolic syndrome and vascular insulin resistance has been highlighted by several preclinical and clinical studies [46, 47]. In normotensive subjects, aldosterone levels are correlated with body mass index and insulin resistance [48]. Dietary salt restriction, which increases the level of aldosterone, also leads to vascular insulin resistance [49]. Treatment with MRAs has been shown to improve endothelial function in several experimental studies in diabetes. In rats, spironolactone was found to reduce obesity-related diastolic cardiac dysfunction via BP-independent mechanisms [50], while eplerenone improved endothelial dysfunction induced by a high-fat diet in mice [51] as well as in streptozotocin-induced diabetic rats [52]. Spironolactone also prevented high-fat, diet-induced arterial stiffening in mice [53]. The benefit of MRAs in the treatment of metabolic diseases has not been clearly established in clinical studies. While spironolactone was found to improve coronary microvascular function in Type 2 diabetic patients without clinical ischemic disease, it had no effect on lipids, body mass index or fasting glucose [54]. Nevertheless, a 6-month treatment with spironolactone was associated with a significant improvement in insulin resistance in patients with moderate CKD [55]. Taken together, these data suggest that transplant physicians should reassess the indication of MRA in kidney transplant patients with HF and/or a history of myocardial infarction before transplantation, and a fortiori if they have a moderate degree of CKD after transplantation. MRAs could probably be frequently prescribed in patients with eGFR >30 mL/min/1.73 m2. Patients with resistant HTN and/or metabolic syndrome may also benefit from MRA treatment. SAFETY OF MRAs IN CKD PATIENTS AND KT RECIPIENTS CKD patients are largely under-represented in CV outcome in RCTs [56] while organ recipients are also typically excluded from RCTs due to the potential risk of interactions between the study treatment and immunosuppressive therapy. The risk of hyperkalaemia is also a concern in RCTs designed to assess the effect of MRAs, which invariably prompt the exclusion of CKD patients. Safety of MRAs in CKD patients In CKD patients, a meta-analysis by Bolignano et al. [32] showed that spironolactone, in combination with ACEis and/or ARBs, increased the risk of hyperkalaemia [RR (relative risk) = 2.00, 95% confidence interval (CI) 1.25–3.20] relative to ACEis and/or ARBs alone, while spironolactone combined with ACEis and/or ARBs increased serum potassium levels (mean difference 0.26 mmol/L, 95% CI 0.13–0.39). In the meta-analysis of Currie et al. [33], the addition of MRAs to ACEi and/or ARB therapy led to a similar moderate increase in potassium levels of CKD patients from baseline (mean difference 0.19 mmol/L 95% CI 0.07–0.31). MRA treatment was also associated with an increased risk of hyperkalaemia (RR = 3.02, 95% CI 1.75–5.18). In patients with diabetic nephropathy included in the ARTS-DN study [36], only 1.5% of patients receiving finerenone exhibited increases in serum potassium levels of at least 5.6 mmol/L leading to subsequent discontinuation of the study treatment. Of note, the incidence of serum potassium ≥5.6 mmol/L was slightly higher among patients with Stage 3 CKD at baseline (2.7%, 5.4%, 4.1% and 6.3% in the 1.25 mg/day, 7.5 mg/day, 15 mg/day and 20 mg/day fineronone groups, respectively). Importantly, there were no differences in the incidence of the pre-specified secondary outcome of eGFR decrease >30% between placebo and finerenone groups. In haemodialysis-treated patients, a meta-analysis of seven RCTs including 755 patients reported that MRA use was significantly associated with hyperkalaemia (RR = 3.05, 95% CI 1.20–7.71) [44]. In patients with HF and moderate CKD, finerenone has been proposed to have a dissociated profile regarding efficacy and hyperkalaemia risk. Indeed, finerenone (5–10 mg/day) was as effective as spironolactone (25 or 50 mg/day) in reducing the levels of haemodynamic stress biomarkers and was associated with a lower rate of hyperkalaemia [57]. In a posthoc analysis of the EMPHASIS-HF study (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) [58], Eschalier et al. observed that patients in the pre-specified high-risk subgroups (≥75 years of age, presence of diabetes mellitus or CKD defined by an eGFR <60 mL/min/1.73 m2), and those with a systolic BP <123 mmHg (median) at baseline treated with eplerenone had an increased risk of serum potassium levels >5.5 mmol/L, but not of potassium levels >6.0 mmol/L, hospitalization for hyperkalaemia or discontinuation of the study medication due to adverse events. Of note, eplerenone was effective in reducing the primary composite endpoint (hospitalization for HF or death from CV causes) in all subgroups including those with the highest risk of hyperkalaemia. Safety of MRAs in kidney transplant recipients As emphasized above, organ recipients are usually not eligible for inclusion in RCTs due to the potential risk of interactions with immunosuppressive therapy. Nevertheless, eplerenone and spironolactone are not inhibitors or inducers of CYP3A4, which results in a neutral effect of MRA intake on calcineurin inhibitors levels. There is also no drug–drug interaction between mycophenolic acid and MRAs. A recent trial showed the safety of eplerenone 25 mg/day in kidney-transplanted patients treated with cyclosporine [59]. This study included 31 patients with a functional kidney allograft for at least 1 year and an eGFR between 30 and 50 mL/min/1.73 m2. Patients with serum potassium levels ≥5 mmol/L or with a history of severe hyperkalaemia (≥6 mmol/L) were not eligible for the trial, whereas patients treated with ACEi or ARB (61% of patients) could be included. Eight patients experienced mild hyperkalaemia (>5 mmol/L) while treated with eplerenone and one had moderate hyperkalaemia (>5.5 mmol/L) and received potassium-exchange resin. There were no occurrences of severe hyperkalaemia (>6 mmol/L) and one occurrence of acute kidney failure, attributed to diarrhoea. Likewise, spironolactone 50 mg/day was also reported to be safe and found to efficiently reduce renal oxidative stress in a RCT involving KT recipients from living donors [26]. MANAGING THE RISK OF HYPERKALAEMIA ASSOCIATED WITH MRAs IN KIDNEY TRANSPLANT RECIPIENTS Pharmacology of MRAs in CKD The pharmacokinetics of spironolactone and eplerenone clearly differ. Approximately 10–15% of spironolactone and its numerous metabolites are excreted in urine. The impact of CKD or renal replacement therapy on spironolactone pharmacokinetics has not been reported. Much (66%) of the eplerenone is excreted in urine, although total body clearance is unchanged with CKD [60]. The renal elimination of finerenone is minimal [61]. However, moderate and severe renal impairment increases exposure to unbound finerenone by 57% and 47%, respectively, possibly due to the effects of renal impairment on non-renal routes of elimination [61]. The mechanism of action of MRAs intrinsically increases the risk of hyperkalaemia in at-risk patients. In healthy subjects, compensatory mechanisms prevent the increase in plasma potassium levels upon administration of a low MRA dose, whereas in patients with CKD, potassium homeostasis is profoundly altered [62]. The risk of hyperkalaemia is inversely related to the decrease in eGFR and increases when the eGFR is <30 mL/min/1.73 m2. As renal function declines, the cellular uptake of potassium is able to buffer the decrease in potassium excretion capacity. Extra-renal potassium homeostasis is particularly critical in CKD and ESRD patients: indeed, the colon plays a major role in potassium homeostasis in these patients with a 3-fold increase in intestinal potassium secretion (related to the increased expression of a large conductance potassium channel in the colonic epithelium) observed in ESRD patients [63]. Whether the intestinal MR participates in colonic potassium balance in CKD/ESRD patients is unclear. Limiting the risk of hyperkalaemia when using MRAs in kidney transplant recipients Only spironolactone and eplerenone are currently available commercially and can be proposed to kidney transplant patients. Eplerenone should be favoured in the initial transplantation setting, as it is directly active and has a short half-life, thus being easier to manage in case of adverse events. The risk of hyperkalaemia in this specific population of oligo-anuric patients with GFR <15 mL/min/1.73 m2 is obviously a matter of concern, in particular for the risk of cardiac arrhythmias. Accordingly, this risk is one of the pre-specified secondary outcomes of the EPURE-TRANSPLANT study (Eplerenone in Patients Undergoing REnal Transplant) (EPURE: NCT02490904). Of note, transplant patients are intensively monitored and are thus in an appropriate environment to detect and promptly manage hyperkalaemia within the first days following transplantation: the standard close biological monitoring of kidney transplant recipients in the post-operative period (generally twice a day during the first days) may improve the safety of MRAs during this early KT period. Common methods to manage hyperkalaemia (potassium chelation, correction of metabolic acidosis, use of loop diuretics, insulin, β-adrenoceptor agonists and, if necessary, dialysis) are routinely used in post-operative intensive care or nephrology units. One can also speculate that in case of a beneficial effect of MRA on graft recovery among graft recipients from ECD, the anuria period will be shorter among patients receiving MRA, leading to a shorter period of increased hyperkalaemia risk. Moreover, it is important to consider that in the post-operative period, kidney recipients often have limited oral food ingestion, leading to a decreased risk of hyperkalaemia. Kidney transplant recipients are also closely monitored in a chronic setting, with frequent biological tests and dietary counselling that may limit the risk of significant hyperkalaemia. Patient education may also be of particular importance in limiting excess potassium intake and preventing the risk of drug interactions by avoiding the co-administration of drugs known to increase the risk of hyperkalaemia. Moreover, the recent availability in the USA and in the EU of the novel potassium-binding resin patiromer, while sodium zirconium cyclosilicate (ZS-9) is now approved in the EU and is still under Food and Drug Administration review may provide a useful tool to treat hyperkalaemia in patients treated with renin–angiotensin–aldosterone inhibitors [64], potentially including transplanted CKD patients. However, no dedicated trial has been undertaken to date in this specific population. UNMET NEED AND PERSPECTIVES MRA administration may be beneficial in the setting of KT (Figure 3) in the following instances: FIGURE 3: View largeDownload slide Potential beneficial effects of MRAs in KT: acute or chronic graft protection or prevention of primary or secondary CV or metabolic complications in kidney transplant recipients. FIGURE 3: View largeDownload slide Potential beneficial effects of MRAs in KT: acute or chronic graft protection or prevention of primary or secondary CV or metabolic complications in kidney transplant recipients. During the pre- or short-term post-operative period of the transplantation in order to prevent I/R lesions leading to AKI and predisposing patients to chronic graft dysfunction, in particular in the setting of marginal donors or donors after cardiac death so as to mitigate or reduce DGF. Experimental studies are currently ongoing to assess the impact of MRA in perfusion machines in large animal models. The next step in clinical studies could be to administer MRA to the grafts via the perfusion machine, or directly to donors, if ethical issues can be addressed. In chronic use among KT recipients in order to prevent CIN and reduce proteinuria. To prevent CV complications during follow-up of kidney transplant recipients. Dedicated clinical trials are needed to assess the benefit and safety profile of MRAs in these patients. The management of hyperkalaemia risk and its consequence on cardiac arrhythmia should be specifically assessed and compared with the benefit of MRAs on long-term renal function and CV outcomes in kidney transplant recipients. The choice of the most accurate study design for evaluating the long-term impact of MRA on patient and graft protection nonetheless remains challenging, and should take into account the following aspects: capacity of patient recruitment; length and costs of an RCT (sample size and time to event); ability to appropriately characterize the observed effect or to adequately interpret the absence of observed effect. Table 2 depicts the theoretical advantages and drawbacks of various study designs in KT according to the target population (general kidney transplant population versus kidney graft recipients with previous history of CV disease) and to the choice of outcomes (hard outcomes versus soft outcomes). Table 2. Advantages and drawbacks of RCTs in KT according to the target population (general kidney transplant population versus kidney graft recipients with previous history of CV disease) and to the choice of the outcomes (hard outcomes versus soft outcomes)   General transplant population  Kidney graft recipients with previous history of CV disease  Hard outcome  • Patient survival (all-cause and CV mortality)  • MACE  • Graft survival  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest: ↑↑Patient sample size required ↑↑Length of the study/very long time-frame ↑↑Costs of the study Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑Incidence of the event of interest: ↓Patient sample size required ↓Length of the study/shorter time-frame ↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable) Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  Soft outcome/surrogate markers/surrogate endpoints/predictive endpoints  • LVH, PWV  • eGFR/proteinuria, histological findings (glomerulosclerosis, intersitial fibrosis, chronic vascular lesions)  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest:    • ↑Patient sample size required    • ↑Length of the study/long time-frame    • ↑Costs of the study  • Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment  • Soft outcomes:    • ↑Risk of measurement bias    • Specificity of the observed effect?  • Surrogate outcomes: need to be validated  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑↑Incidence of the event of interest: ↓↓Patient sample size required ↓↓Length of the study/very short time frame ↓↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable)  Soft outcomes: ↑Risk of measurement bias Specificity of the observed effect?  Surrogate outcomes: need to be validated    General transplant population  Kidney graft recipients with previous history of CV disease  Hard outcome  • Patient survival (all-cause and CV mortality)  • MACE  • Graft survival  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest: ↑↑Patient sample size required ↑↑Length of the study/very long time-frame ↑↑Costs of the study Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑Incidence of the event of interest: ↓Patient sample size required ↓Length of the study/shorter time-frame ↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable) Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  Soft outcome/surrogate markers/surrogate endpoints/predictive endpoints  • LVH, PWV  • eGFR/proteinuria, histological findings (glomerulosclerosis, intersitial fibrosis, chronic vascular lesions)  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest:    • ↑Patient sample size required    • ↑Length of the study/long time-frame    • ↑Costs of the study  • Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment  • Soft outcomes:    • ↑Risk of measurement bias    • Specificity of the observed effect?  • Surrogate outcomes: need to be validated  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑↑Incidence of the event of interest: ↓↓Patient sample size required ↓↓Length of the study/very short time frame ↓↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable)  Soft outcomes: ↑Risk of measurement bias Specificity of the observed effect?  Surrogate outcomes: need to be validated  LVH, left ventricular hypertrophy; MACE, major adverse cardiovascular event; PWV, pulse wave velocity. Table 2. Advantages and drawbacks of RCTs in KT according to the target population (general kidney transplant population versus kidney graft recipients with previous history of CV disease) and to the choice of the outcomes (hard outcomes versus soft outcomes)   General transplant population  Kidney graft recipients with previous history of CV disease  Hard outcome  • Patient survival (all-cause and CV mortality)  • MACE  • Graft survival  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest: ↑↑Patient sample size required ↑↑Length of the study/very long time-frame ↑↑Costs of the study Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑Incidence of the event of interest: ↓Patient sample size required ↓Length of the study/shorter time-frame ↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable) Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  Soft outcome/surrogate markers/surrogate endpoints/predictive endpoints  • LVH, PWV  • eGFR/proteinuria, histological findings (glomerulosclerosis, intersitial fibrosis, chronic vascular lesions)  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest:    • ↑Patient sample size required    • ↑Length of the study/long time-frame    • ↑Costs of the study  • Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment  • Soft outcomes:    • ↑Risk of measurement bias    • Specificity of the observed effect?  • Surrogate outcomes: need to be validated  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑↑Incidence of the event of interest: ↓↓Patient sample size required ↓↓Length of the study/very short time frame ↓↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable)  Soft outcomes: ↑Risk of measurement bias Specificity of the observed effect?  Surrogate outcomes: need to be validated    General transplant population  Kidney graft recipients with previous history of CV disease  Hard outcome  • Patient survival (all-cause and CV mortality)  • MACE  • Graft survival  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest: ↑↑Patient sample size required ↑↑Length of the study/very long time-frame ↑↑Costs of the study Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑Incidence of the event of interest: ↓Patient sample size required ↓Length of the study/shorter time-frame ↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable) Hard but non-specific outcomes: complementary studies necessary to investigate the mechanisms involved  Soft outcome/surrogate markers/surrogate endpoints/predictive endpoints  • LVH, PWV  • eGFR/proteinuria, histological findings (glomerulosclerosis, intersitial fibrosis, chronic vascular lesions)  ↑Patient recruitment capabilities ↑External validity (generalization of the results) ↓Incidence of the event of interest:    • ↑Patient sample size required    • ↑Length of the study/long time-frame    • ↑Costs of the study  • Low-risk population: risk of failing to identify the subgroup that may benefit from MRA treatment  • Soft outcomes:    • ↑Risk of measurement bias    • Specificity of the observed effect?  • Surrogate outcomes: need to be validated  ↓Patient recruitment capabilities ↓External validity (no generalization of the results) ↑↑Incidence of the event of interest: ↓↓Patient sample size required ↓↓Length of the study/very short time frame ↓↓Costs of the study High-risk population: Risk of overestimating the benefit/risk balance Risk of limiting MRA efficacy in CV disease is already very severe (not improvable)  Soft outcomes: ↑Risk of measurement bias Specificity of the observed effect?  Surrogate outcomes: need to be validated  LVH, left ventricular hypertrophy; MACE, major adverse cardiovascular event; PWV, pulse wave velocity. The use of surrogate markers may confer two advantages. First, the incidence of the studied outcomes may be higher, allowing studies with shorter follow-up and costs. Secondly, the observed effects may be more specific, allowing a more accurate understanding of the pathophysiological mechanisms involved. The two approaches (large studies with hard endpoints and targeted populations with surrogate outcomes), if feasible, would probably provide complementary information. Composite surrogate endpoints may likely be required in order to accurately assess the therapeutic effect of MRAs, allowing shorter follow-up studies than those using the graft or patient survival as primary outcome, although ensuring a precise characterization of the observed effect. Nevertheless, these surrogate endpoints should be precisely evaluated and validated in order to predict long-term graft survival. Finally, considering that chronic ABMR may lead to graft and systemic accelerated vascular ageing, it is crucial to accurately assess the level of humoral alloreactivity at baseline and during follow-up (presence of circulating donor-specific antibodies and/or histological findings of ABMR in the graft biopsy). In order to adequately distinguish non-immunological benefits of MRA in graft protection, investigators should probably select low-immunological risk but high-CV risk graft recipients. In a second phase, MRA may be assessed as a general feature of graft improvement, either with or without an ongoing humoral alloreactivity process. In order to assess the impact of long-term MRA administration in KT, potential surrogate outcomes could include: For graft protection: eGFR and proteinuria, histological findings, possibly combined together. Of note, detailed baseline phenotyping is necessary to accurately interpret the data, since renal function and histological findings are generally related to a complex and multifactorial process in kidney graft recipients. To assess the impact of long-term MRA administration on graft survival, a precise baseline and 1-year graft prognosis assessment is likely necessary in order to properly phenotype the subgroup of patients of interest. This may allow distinguishing the potential non-immunological beneficial effect of MRA administration from immunological processes that lead to graft deterioration. The use of eGFR or proteinuria without this detailed baseline assessment would probably lack accuracy in assessing the potential protective effect of MRAs in the field of KT, considering the various causes of proteinuria among KT recipients. For patient/CV protection: echocardiographic findings (i.e. left ventricular hypertrophy), arterial functional testing (i.e. pulse wave velocity for arterial stiffness evaluation). To assess the impact of long-term MRA administration on CV outcomes, detailed baseline CV risk assessment is mandatory, as well as 1-year post-KT evaluation, considering that the early post-operative KT period is at increased risk of CV events [65]. To summarize, the study design should ideally be a compromise between recruitment capacities, outcome incidence, risk of measurement bias and adequate characterization of the observed effect. In conclusion, the potential indications of MRAs in renal transplantation are numerous although clinical studies are clearly needed to confirm the efficacy and safety of MRAs in this population. The undertaking of such studies is certainly highly worthwhile given the important unmet need in KT. 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Nephrology Dialysis TransplantationOxford University Press

Published: Apr 17, 2018

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