Endothelin Receptor Antagonists in Kidney Protection For Diabetic Kidney Disease And Beyond? Ⅱ

4 | THE PHARMACOLOGY OF ENDOTHELIN RECEPTOR ANTAGONISTS 

Table 1 lists the selective ETA receptor ERAs and non-selective ETA/ETB receptor ERAs currently available for clinical use.48–68 Both classes of ERAs vary in their half-life and time of onset though data on their oral bioavailability are limited. Most are metabolized by cytochrome P450 (CYP) 3A4 and/or 2C9 apart from the aprocitentan (non-selective ERA) which undergoes CYP-independent metabolism. Overall, apart from their selectivity for the endothelin receptor, the two classes of ERAs do not significantly differ in terms of their pharmacokinetics or their safety profile. Pre-clinical data also suggests that kidney protection from ERAs is mostly mediated through ETA receptor inhibition and accordingly, most RCTs reporting the effect of ERAs on kidney endpoints evaluated ETA receptor inhibitors (Table 2).11,12,69,70

FIGURE 2 Regulation of sodium and water homeostasis by the actions of ET-1 on the collecting ducts. ET-1-mediated ETB receptor activation causes natriuresis by inhibiting sodium reabsorption at the cortical collecting duct and inhibiting water reabsorption at the medullary collecting duct. Cortical collecting duct (upper figure): ET- 1-mediated ETB receptor activation leads to: (1) inhibition of epithelial sodium channel (ENaC) functioning activity (nitric oxide and MAPK dependent pathways), (2) promote ENaC endocytosis. Medullary collecting duct (lower figure): ET-1-mediated ETB receptor activation leads to: (1) inhibition of vasopressin activity, and (2) inhibition of aquaporin-2 (AQP2)-mediated water reabsorption. Therefore, nonselective ERAs (especially inhibition of ETB antagonism) can lead to sodium retention and water resorption.31 Created with Biorender. com. AC, adenylyl cyclase; β1Pix, beta 1 Pix; DAG, diacylglycerol; ENaC, epithelial sodium channel; IP3, inositol trisphosphate; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C.

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5 | CURRENT RCTS OF ENDOTHELIN RECEPTOR ANTAGONISTS REPORTING ON KIDNEY OUTCOMES 

We reviewed all RCTs with a study duration of at least 12 weeks reporting on the effect of ERAs on kidney endpoints such as doubling of serum creatinine or kidney failure, or surrogate endpoints such as changes in kidney function or albuminuria. We included four trials of DKD, two trials of cardiovascular disease, and one trial of resistant hypertension comparing ERAs with placebo.11,12,69–73 A total of 7606 participants were included (73% with DKD). The median age was 61.8 years, and the median duration of follow-up 16 weeks (interquartile range 38). (Table 2). The Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With Atrasentan (RADAR) trial was a multicentre, double-blind RCT assessing the effect of the selective ETA receptor inhibitor atrasentan on albuminuria over 12 weeks in 211 participants with CKD due to T2DM, an eGFR between 30– 75 ml/min/1.73 m2 and urine albumin-to-creatinine ratio (UACR) of 300–3500 mg/g despite RAAS blockade.69 The Avosentan on Time to Doubling of Serum Creatinine, End Stage Renal Disease or Death in Patients With Type 2 Diabetes Mellitus and Diabetic Nephropathy (ASCEND) trial evaluated the selective ETA receptor inhibitor avosentan on a composite outcome of doubling of serum creatinine, kidney failure or death in 1402 participants with CKD due to T2DM, serum creatinine of 106–265 μmol/l and UACR ≥309 mg/g despite RAAS blockade.12 In the SONAR trial, following a 6-week enrichment period where all 5117 participants with CKD due to T2DM, an eGFR between 25–75 ml/min/1.73 m2, UACR 300–5000 mg/g despite RAAS blockade received atrasentan, 2648 responders (defined as ≥30% reduction in UACR, no significant fluid retention and rise in serum creatinine of ≤44 μmol/l and ≤20% from baseline) and 1020 non-responders were randomized to atrasentan or placebo.11 The Endothelin Antagonist with Bosentan and Lowering of Events (ENABLE) trial evaluated the non-selective ETA/ETB receptor inhibitor bosentan in 1613 diabetic or non-diabetic participants with New York Heart Association class III and IV heart failure with reduced ejection fraction.70 Reriani et al.71 evaluated the effect of atrasentan or placebo on coronary artery blood flow in 47 participants with coronary artery disease over 6 months. Weber et al.72 investigated the effect of the selective ETA receptor inhibitor atrasentan on blood pressure in 379 participants with resistant hypertension over 14 weeks. Finally, Wenzel et al.73 reported the effect of avosentan on albuminuria over 12 weeks in 286 participants with diabetic nephropathy, preserved kidney function, and macroalbuminuria despite RAAS blockade.

6 | EVIDENCE OF KIDNEY PROTECTION BY ENDOTHELIN RECEPTOR ANTAGONISTS 

6.1 | Effect of ERAs on albuminuria

Selective  ERAs using atrasentan or avosentan in the RADAR, ASCEND, SONAR, Weber et al., and Wenzel et al. studies significantly reduced albuminuria by 34%–58% compared with placebo over a period of 12 weeks to 2.2 years (Figure 3).11,12,69,72,73

6.2 | Effect of ERA on kidney function (eGFR or creatinine clearance)

In RADAR, Weber et al. and Wenzel et al., selective ERAs (atrasentan, atrasentan, and avosentan) showed no overall acute effect on eGFR or creatinine clearance over 12 to 14 weeks compared with placebo.69,72,73 In ASCEND, eGFR declined significantly faster with avosentan 50 mg daily compared with placebo over 6 months (
4.1 vs.
2.5 ml/min/1.73 m2 ) though there was no difference between avosentan 25 mg daily and placebo.12 In comparison, Reriani et al.71 reported no difference in creatinine clearance between atrasentan 10 mg daily and placebo over 6 months.

By contrast, SONAR demonstrated a long-term benefit in significantly slowing the rate of eGFR decline compared with placebo over 2.2 years (
2.4 vs.
3.1 ml/min/1.73 m2 per year).11 Patient populations were similar in both RADAR and SONAR in terms of age, severity of albuminuria, blood pressure, and glycaemic control though the baseline eGFR was lower in SONAR compared with RADAR (43.8 vs. 49.3 ml/min/1.73 m2 ). By contrast, participants in ASCEND had a lower baseline eGFR (33.1 ml/min/1.73 m2 ) and higher albuminuria (median 1425–1531 mg/g compared with 671–878 mg/g), while participants in studies by Reriani et al., Weber et al., and Wenzel et al. had higher baseline kidney function (eGFR 76–81 ml/min/1.73 m2 and creatinine clearance 58–84 ml/min).

6.3 | Effect of ERAs on blood pressure 

In RADAR, atrasentan significantly reduced both 24-h ambulatory systolic blood pressure (
4.5 to
5.4 mmHg from baseline) and diastolic blood pressure (
4.2 to
4.6 mmHg from baseline) in a dose-dependent manner over 12 weeks.69 In SONAR, atrasentan demonstrated a smaller but significant long-term reduction in systolic blood pressure compared with placebo (mean between-group difference
1.6 mmHg).11 In ASCEND, avosentan also reduced systolic blood pressure (
4.3 to
6.1 mmHg) and diastolic blood pressure (
3.6 to
4.4 mmHg), though the effect was not dose-dependent.12 The anti-hypertensive effects of atrasentan appear to be greater, reducing 24-h ambulatory systolic blood pressure (
17 to
18 mmHg from baseline) and diastolic blood pressure (
10 to
11 mmHg from baseline) over 14 weeks, though these differences may reflect higher baseline blood pressure and lack of CKD in the study population of the study by Weber et al.72 In ENABLE, bosentan reduced the systolic and diastolic blood pressure by 1–2 mmHg compared with placebo over 78 weeks.70

6.4 | Effect of ERAs on kidney endpoints (defined as a composite of doubling of creatinine or 50% decline in eGFR, kidney failure requiring dialysis or transplantation, or death due to kidney disease)

There is a consistent beneficial effect of ERAs on kidney composite endpoints in RCTs. Kidney endpoints were adjudicated in SONAR, ASCEND, and ENABLE trials. SONAR was the only study powered to assess the effect of ERAs on patient-level kidney endpoints. Despite the lower-than-expected clinical event rate, SONAR demonstrated a 35% reduced risk of a composite of doubling of serum creatinine or end-stage kidney disease with atrasentan compared with placebo over 2.2 years, which did not differ from the responder (hazards ratio [HR] 0.65, 95% confidence interval [CI] 0.49–0.88) and non-responder group (HR 0.75, 95% CI 0.55–1.03).11 In ENABLE, kidney failure captured in serious adverse event reporting occurred in 7% of the bosentan group and 9% of the placebo group.70 Overall, ERAs show a consistent reduction of the composite of the doubling of serum creatinine or kidney failure by 24% (Figure 4) with similar treatment effects across the three studies. However, the quality of this evidence is limited by the paucity of studies and heterogeneity in the reported outcomes.

7 | ARE ENDOTHELIN RECEPTOR ANTAGONISTS SAFE?

The ASCEND trial was terminated prematurely due to an excess of cardiovascular events with avosentan, mostly driven by increased heart failure in 4%–6% of participants, with an associated study drop-out of 20% in the avosentan group.12 Despite the enrichment period, exclusion of participants with heart failure, and liberal use of diuretics in the SONAR trial, atrasentan compared with placebo was still associated with an increased risk of fluid retention (38% vs. 33%), anemia (18% vs. 11%) and a trend towards increased heart failure which did not reach statistical significance (6% vs. 4%). The mechanism of anaemia is unclear but is thought to be haemodilution secondary to fluid retention.74 In the atrasentan group, 10% of responders and 14% of non-responders discontinued due to side effects though this did not differ compared with the placebo group.11 Similarly, new or worsening peripheral edema was reported in 42% of patients on high-dose atrasentan in RADAR though this was not different compared with placebo.69

Interestingly, ENABLE included only participants with NYHA class III or IV heart failure with reduced ejection fraction and found no difference between bosentan or placebo for hospitalization for heart failure (38% vs. 39%) though there was an increased risk of peripheral edema (10% vs. 8%) and anaemia (10% vs. 5%).70 Neither SONAR or ENABLE found any difference between ERAs and placebo for the composite outcome of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, hospitalization for heart failure, or death from any cause.

It is difficult to compare the relative safety of selective ERAs (atrasentan, atrasentan, and avosentan) and non-selective ERAs (bosentan) in CKD due to differences in the study populations of ENABLE compared to other trials reporting the effect of selective ERAs on kidney endpoints (Table 2). Regarding the relative specificity of selective ETA receptor inhibitors, avosentan was associated with a higher risk of hospitalization for heart failure in ASCEND compared to atrasentan (a more selective ETA receptor inhibitor than avosentan) in SONAR (HR 2.76, 95% CI 1.68-4.54 versus HR 1.33, 95% CI 0.85- 2.07).11,81 The difference in heart failure risk can be likely attributed to the different ETA selectivity of the two agents (avosentan being less selective than atrasentan), the high dose of avosentan used in the ASCEND trial compared to the much lower dose of atrasentan, and the precautionary measures included in the design of the SONAR trial including the careful patient selection. The lesson from the ASCEND and SONAR trials is that the risk of fluid retention and heart failure can be substantially mitigated, although additional research is required to identify patients most likely to benefit while minimizing harm.

8 | ENDOTHELIN RECEPTOR ANTAGONISTS FOR THE TREATMENT OF NON-DIABETIC CHRONIC KIDNEY DISEASE?

A dual ETA and AT1 receptor antagonist, spartan has been evaluated in the phase 2b study in patients with Primary Focal Segmental Glomerulosclerosis (FSGS), the DUET trial, which demonstrated a significantly higher likelihood of achieving the FSGS partial remission endpoint (FPRE) (defined as urine protein-to-creatinine ratio [UP/C] ≤1.5 g/g and a >40% reduction in proteinuria from baseline) with spartan compared with irbesartan over 8 weeks (28% vs. 9%).75 This is currently being further evaluated in the phase 3 DUPLEX study (NCT03493685) which will assess the effect of spartan compared with irbesartan on the eGFR slope at week 108 in participants with primary FSGS. A press release recently reported the DUPLEX study has met its protocol-specified interim analysis showing a statistically significant higher FPRE of spartan compared with the active control at 36 weeks (42% vs. 26%, p = .0094).76 In a parallel ongoing phase 3 trial, the PROTECT study (NCT03762850) will examine the safety and efficacy of 400 mg of spartan, compared with 300 mg of irbesartan, in 404 adults with biopsy-proven IgA nephropathy with persistent proteinuria despite 3 months of RAAS inhibition. A protocol-specified interim analysis of 280 PROTECT participants demonstrated a threefold reduction of proteinuria from baseline after 36 weeks of treatment, compared with irbesartan (p < .0001).77 Both studies reported spartan has been generally well-tolerated and consistent with the observed safety profile to date. Both DUPLEX and PROTECT trials have completed recruitment and are ongoing, with the final study outcomes anticipated in 2023. The FDA has accepted and granted for accelerated approval of spartan for the treatment of IgA Nephropathy.78

Another phase 3 study Atrasentan in Patients With IgA Nephropathy (ALIGN) (NCT04573478) is underway evaluating the effect of atrasentan compared with placebo in individuals who are receiving maximally tolerated RAAS inhibition on change in UP/C and eGFR in participants with IgA nephropathy with persistent proteinuria of ≥1 g/ day. The expanded indications of ERAs have been examined in another phase 2, open-label, basket study using Atrasentan in Patients With Proteinuric Glomerular Diseases (AFFINITY) (NCT04573920). There are four cohorts of patients in each group (n = 20 in each group), namely (1) IgA nephropathy with UP/C ratio between 0.5 and 1.0 g/g, (2) FSGS, (3) Alport syndrome, and (4) DKD on top of background care of a RAAS inhibitor and SGLT2 inhibitor. A protocol-prespecified interim analysis of the IgAN cohort of the AFFINITY trial reported the baseline characteristic of this cohort at the European Renal Association meeting, in 2022. Following a 12 and 24-week of treatment with atrasentan, there was a mean 24-h urine protein reduction from baseline of 50% and 59%, respectively with no significant weight gain or acute change in eGFR.79 Finally, aprocitentan, an orally active, daily dosing, non-selective ERA has an ongoing phase 3 randomized clinical trial (PRECISION) evaluating its efficacy and safety in patients with treatment-resistant hypertension receiving multiple antihypertensives (NCT03541174). A press release recently reported the PRECISION study achieved its primary endpoint measure of systolic blood pressure reduction at 4 weeks in both the aprocitentan 12.5 mg (p < .005) and 25 mg (p < .005) groups compared with placebo, and was welltolerated.80

9 | DISCUSSION

Activation of the endothelin system through its ETA and ETB receptors has been associated with the pathogenesis and progression of CKD, irrespective of its primary aetiology. ERAs, especially selective ETA antagonism, are orally available, promising therapeutic agents that have been examined in both diabetic and non-diabetic CKD. Pooled analysis in this review from published RCTs of ERAs reporting on kidney outcomes has shown a consistent reduction in composite kidney endpoints (doubling of creatinine or 50% decline in eGFR, kidney failure requiring dialysis or transplantation, or death due to kidney disease), with consistent effects on albuminuria reduction. Several ongoing large-scale clinical trials will determine the long-term efficacy and safety of ERAs in FSGS and IgA nephropathy.

Despite these kidney protective effects, the future clinical use of ERAs will depend on their safety, in particular the risk of fluid retention and heart failure. The SONAR trial demonstrated that careful identification of patients using an enrichment design can minimize but not completely abrogate the risk of fluid retention. Although the incidence of cardiac failure was not statistically significant, it was numerically higher in the atrasentan group compared with placebo (5.5% vs. 3.9%).

Current strategies to prevent fluid retention include judicious use of diuretics, which lowered body weight in participants receiving avosentan in the ASCEND trial,81, and careful selection of patients at low risk of heart failure. In the SONAR trial, participants at relatively low risk of heart failure were selected,11 and subsequent ERA trials have focused on non-diabetic CKD populations such as FSGS and IgA nephropathy who tend to be younger, less comorbid and therefore have a lower risk of heart failure.76–78 Another strategy would be the addition of an SGLT2 inhibitor, which is known to have mild diuretic effects. Post hoc analyses from SONAR suggest that participants who received combined atrasentan and SGLT2 inhibitor had a lower weight gain and a greater percentage of albuminuria reduction as compared with atrasentan alone during the 6-week enrichment period suggesting a potential role of this combination therapy.82 We eagerly await the results of the Zibotentan and Dapagliflozin for the Treatment of CKD (ZENITH-CKD) phase 2 trial (NCT04724837) evaluating the efficacy and safety of combined ERA and SGLT2 inhibitor therapy for the treatment of non-diabetic CKD.

On the other hand, sparsentan (PROTECT and DUPLEX trial) and atrasentan (AFFINITY) are reportedly well-tolerated in patients with FSGS and IgA nephropathy. Unlike the diabetic population, individuals with IgAN and FSGS are likely to be younger with lower cardiovascular risk. Despite that, more granular data on fluid retention and weight gain is anticipated once these studies are completed and published in the near future. In a hypertension study of participants with normal or near-normal kidney function, the incidence of peripheral oedema appears to be lower with the non-selective ETA/ETB antagonist aprocitentan (1.2%).63,83 Therefore, close monitoring and judicious use of diuretics may be useful in selected populations treated with ERAs.32 There may be potential synergistic effects of combining ERAs with potassium-sparing diuretics especially in non-selective ETA/ETB antagonists since potassium-sparing diuretics such as amiloride inhibit the epithelial sodium channel in collecting tubules, which is responsible for fluid retention activated by ETB antagonism. However, this requires further robust testing in an adequately powered RCT.

We should acknowledge the limitations of the data on kidney protection, which we interpret with caution since most trials are short-term with a median duration of 16 weeks. Although the effect on albuminuria is consistent across all trials, the effects on eGFR are not consistent across all seven trials. Only the SONAR and ENABLE trials provide long-term data on kidney endpoints, and the data on kidney failure in the ENABLE trial is obtained from serious adverse event reporting. The DUPLEX, PROTECT, and ALIGN trials will provide crucial long-term data on proteinuria reduction and eGFR decline to better determine the kidney protective effects of ERAs

Overall, it is an exciting period for the discovery of novel therapeutic strategies in delaying progressive CKD. There are strong clinical data demonstrating the anti-albuminuric effect and promising long-term kidney protective effects of ERAs, especially selective ERAs when added onto standard-of-care, which make it an attractive treatment for both diabetic and non-diabetic CKD.

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2. Bikbov B, Purcell CA, Levey AS, et al. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the global burden of disease study 2017. Lancet. 2020;395(10225):709-733. 

3. Wang H, Naghavi M, Allen C, et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the global burden of disease study 2015. Lancet. 2016;388(10053):1459-1544. 

4. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860. 

5. Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861-869. 

6. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288(19): 2421-2431. 

7. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; 380(24):2295-2306. 

8. Heerspink HJ, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15): 1436-1446.

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