Clinical trial designs to assess treatment effects on glomerular filtration rate decline.

Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects. Post-hoc analyses of two clinical trials that characterized the effect of an intervention with acute reductions in GFR were conducted. The two trials included a wash-out period (EMPA-REG Outcome testing empagliflozin vs placebo) or an active run-in period with a randomized withdrawal (SONAR testing atrasentan vs placebo). We compared the drug effect on GFR decline calculated from the first on-treatment visit to the end of treatment (chronic slope in a standard randomized trial design) with GFR change calculated from randomization to end of wash out, or GFR change from treatment-specific baseline GFR values (GFR at start-of-run-in for placebo and end-of-run-in for atrasentan) until end-of-treatment. The effect of empagliflozin versus placebo on chronic GFR slope was 1.72 (95% confidence interval 1.49-1.94) mL/min/1.73 m2/year, similar to total GFR decline from baseline to the end of wash-out period using a linear mixed model 1.64 (1.44-1.85) mL/min/1.73 m2/year). The effect of atrasentan versus placebo on chronic GFR slope was 0.72 (0.32-1.11) mL/min/1.73 m2/year, similar to total slope from a single slope model when estimated from treatment specific baseline GFR values 0.77 (0.39-1.14) mL/min/1.73 m2/year). Statistical power of the two designs outperformed the standard randomized design. Thus, wash-out and active-run-in randomized-withdrawal trial designs are appropriate models to compute treatment effects on GFR decline.

Efficacy and Adverse Effects of Atrasentan in Patients with Diabetic Nephropathy: A Meta-Analysis.

Background: About 30% of Type 1 diabetes (T1DM) patients and 40% of Type 2 diabetes (T2DM) patients were diagnosed with diabetic nephropathy, which has also greatly affected the global end-stage renal disease (ESRD) outcome. Atrasentan is a selective endothelin receptor type A (ETA) antagonist initially studied for the potential treatment of cancer. However, the role of Atrasentan was not sure in the DM. Methods: The machine searches eight databases to find studies examining the impact of Atrasentan in people with diabetic nephropathy both domestically and overseas. Type of Study Design RCTs have been published on Atrasentan's effects in patients with chronic kidney disease.Utilizing RevMan 5.3 software, data analysis was carried out following a thorough assessment of the quality of the literature. Results: This meta-analysis has included 4 papers for statistics. They were all regarded as being random controlled trials. According to 4 studies, the test group's urinary albumin/creatinine ratio (UACR) was significantly lower than the control group's (standardized mean difference (SMD): -222.47; 95% confidence interval (CI): -367.57, -77.38; P < .01), as were the test group's prevalence of cardiovascular disease (OR: 0.83; 95% CI: 0.73, 0.95; P < .01) and adverse reactions (OR: 1.00; 95% CI: 1.00). Conclusion: Atrasentan improves the UACR in individuals with chronic kidney disease as compared to the control category. However, these findings need to be confirmed by more high-quality research. Further studies could focus on the effect of the Atrasentan on the diabetic nephropathy management,which will shed light on the treatment of diabetic nephropathy.

Endothelin receptor antagonism improves glucose tolerance and adipose tissue inflammation in an experimental model of systemic lupus erythematosus.

Endothelin-1 (ET-1) is elevated in patients with systemic lupus erythematosus (SLE), an autoimmune disease characterized by high rates of hypertension, renal injury, and cardiovascular disease. SLE is also associated with an increased prevalence of obesity and insulin resistance compared to the general population. In the present study, we tested the hypothesis that elevated ET-1 in SLE contributes to obesity and insulin resistance. For these studies, we used the NZBWF1 mouse model of SLE, which develops obesity and insulin resistance on a normal chow diet. To test this hypothesis, we treated control (NZW) and SLE (NZBWF1) mice with vehicle, atrasentan (ETA receptor antagonist, 10 mg/kg/day), or bosentan (ETA/ETB receptor antagonist, 100 mg/kg/day) for 4 wk. Neither treatment impacted circulating immunoglobulin levels, but treatment with bosentan lowered anti-dsDNA IgG levels, a marker of SLE disease activity. Treatment with atrasentan and bosentan decreased glomerulosclerosis, and atrasentan lowered renal T-cell infiltration. Body weight was lower in SLE mice treated with atrasentan or bosentan. Endothelin receptor antagonism also improved hyperinsulinemia, homeostatic model assessment for insulin resistance, and glucose tolerance in SLE mice. Adipose tissue inflammation was also improved by endothelin receptor blockade. Taken together, these data suggest a potential therapeutic benefit for SLE patients with obesity and insulin resistance.NEW & NOTEWORTHY SLE is an autoimmune disease that is associated with obesity, insulin resistance, and elevated endothelin-1. The present study demonstrated that pharmacological inhibition of endothelin receptors decreased body weight, insulin resistance, and adipose tissue inflammation in a murine model of SLE. The therapeutic potential of endothelin receptor antagonists to treat obesity-related diseases and pathophysiological conditions, such as autoimmune diseases and insulin resistance, has become increasingly clear.

Post hoc analysis of the SONAR trial: potential analgesic effects of atrasentan?

Chan et al. conducted a post hoc analysis of the Study of Diabetic Nephropathy with Atrasentan (SONAR) to demonstrate that atrasentan reduced chronic pain-related adverse events reported by investigators and the initiation of analgesics. This study creates an interesting hypothesis, but it is limited in that the pain information was collected as part of the adverse events and the presence/absence of pain at baseline was unknown. Thus, prospective clinical trials are required to confirm these findings.

Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease.

Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25-75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300-5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72-0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71-0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60-0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD.

Placenta-targeted treatment with nMitoQ prevents an endothelin receptor-A pathway cardiac phenotype observed in adult male offspring exposed to hypoxia in utero.

Prenatal hypoxia is associated with enhanced susceptibility to cardiac ischemia-reperfusion (I/R) injury in adult offspring, however, the mechanisms remain to be fully investigated. Endothelin-1 (ET-1) is a vasoconstrictor that acts via endothelin A (ETA) and endothelin B (ETB) receptors and is essential in maintaining cardiovascular (CV) function. Prenatal hypoxia alters the ET-1 system in adult offspring possibly contributing to I/R susceptibility. We previously showed that ex vivo application of ETA antagonist ABT-627 during I/R prevented the recovery of cardiac function in prenatal hypoxia-exposed males but not in normoxic males nor normoxic or prenatal hypoxia-exposed females. In this follow-up study, we examined whether placenta-targeted treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ) during hypoxic pregnancies could alleviate this hypoxic phenotype observed in adult male offspring. We used a rat model of prenatal hypoxia where pregnant Sprague-Dawley rats were exposed to hypoxia (11% O2) from gestational days (GD) 15-21 after injection with 100 µL saline or nMitoQ (125 µM) on GD15. Male offspring were aged to 4 mo and ex vivo cardiac recovery from I/R was assessed. Offspring born from hypoxic pregnancies and treated with nMitoQ had increased cardiac recovery from I/R in the presence of ABT-627 compared with their untreated counterparts where ABT-627 prevented recovery. Cardiac ETA levels were increased in males born from hypoxic pregnancies with nMitoQ treatment compared with saline controls (Western blotting). Our data indicate a profound impact of placenta-targeted treatment to prevent an ETA receptor cardiac phenotype observed in adult male offspring exposed to hypoxia in utero.NEW & NOTEWORTHY In this follow-up study, we showed a complete lack of recovery from I/R injury after the application of an ETA receptor antagonist (ABT-627) in adult male offspring exposed to hypoxia in utero while maternal treatment with nMitoQ during prenatal hypoxia exposure prevented this effect. Our data suggest that nMitoQ treatment during hypoxic pregnancies may prevent a hypoxic cardiac phenotype in adult male offspring.

Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease.

BACKGROUND: Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. METHODS: We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25-75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300-5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. RESULTS: In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). CONCLUSIONS: More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. TRIAL REGISTRATION: RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.

Sex-specific effects of prenatal hypoxia on the cardiac endothelin system in adult offspring.

Fetal hypoxia, a major consequence of complicated pregnancies, impairs offspring cardiac tolerance to ischemia-reperfusion (I/R) insult; however, the mechanisms remain unknown. Endothelin-1 (ET-1) signaling through the endothelin A receptors (ETA) is associated with cardiac dysfunction. We hypothesized that prenatal hypoxia exacerbates cardiac susceptibility to I/R via increased ET-1 and ETA levels, whereas ETA inhibition ameliorates this. Pregnant Sprague-Dawley rats were exposed to normoxia (21% O2) or hypoxia (11% O2) on gestational days 15-21. Offspring were aged to 4 mo, and hearts were aerobically perfused or subjected to ex vivo I/R, with or without preinfusion with an ETA antagonist (ABT-627). ET-1 levels were assessed with ELISA in aerobically perfused and post-I/R left ventricles (LV). ETA and ETB levels were assessed by Western blotting in nonperfused LV. As hypothesized, ABT-627 infusion tended to improve post-I/R recovery in hypoxic females (P = 0.0528); however, surprisingly, ABT-627 prevented post-I/R recovery only in the hypoxic males (P < 0.001). ET-1 levels were increased in post-I/R LV in both sexes regardless of the prenatal exposure (P < 0.01). ETA expression was similar among all groups, whereas ETB (isoform C) levels were decreased in prenatally hypoxic females (P < 0.05). In prenatally hypoxic males, ETA signaling may be essential for tolerance to I/R, whereas in prenatally hypoxic females, ETA may contribute to cardiac dysfunction. Our data illustrate that understanding the prenatal history has critical implications for treatment strategies in adult chronic diseases.NEW & NOTEWORTHY We demonstrated that prenatal hypoxia (a common condition of pregnancy) can have profound differential effects on treatment strategies in adult cardiovascular disease. Our data using a rat model of prenatal hypoxia demonstrated that, as adults, although inhibition of endothelin (ETA) receptors before an ex vivo cardiac ischemic insult improved recovery in females, it strikingly prevented recovery in males. Our data indicate a sex-specific effect of prenatal hypoxia on the cardiac ET-1 system in adult offspring.

Reduced Glomerular Endothelial Thrombomodulin Is Associated with Glomerular Macrophage Infiltration in Diabetic Nephropathy.

The endothelial glycoprotein thrombomodulin regulates coagulation, inflammation, and apoptosis. In diabetic mice, reduced thrombomodulin function results in diabetic nephropathy (DN). Furthermore, thrombomodulin treatment reduces renal inflammation and fibrosis. Herein, thrombomodulin expression was examined in human kidney samples to investigate the possibility of targeting thrombomodulin in patients with DN. Glomerular thrombomodulin was analyzed together with the number of glomerular macrophages in 90 autopsied diabetic cases with DN, 55 autopsied diabetic cases without DN, and 37 autopsied cases without diabetes or kidney disease. Thrombomodulin mRNA was measured in glomeruli microdissected from renal biopsies from patients with DN and nondiabetic controls. Finally, glomerular thrombomodulin was measured in diabetic mice following treatment with the selective endothelin A receptor (ETAR) blocker, atrasentan. In diabetic patients, glomerular thrombomodulin expression was increased at the mRNA level, but decreased at the protein level, compared with nondiabetic controls. Reduced glomerular thrombomodulin was associated with an increased glomerular influx of macrophages. Blocking the ETAR with atrasentan restored glomerular thrombomodulin protein levels in diabetic mice to normal levels. The reduction in glomerular thrombomodulin in diabetes likely serves as an early proinflammatory step in the pathogenesis of DN. Thrombomodulin protein may be cleaved under diabetic conditions, leading to a compensatory increase in transcription. The nephroprotective effects of ETAR antagonists in diabetic patients may be attributed to the restoration of glomerular thrombomodulin.

Early Response in Albuminuria and Long-Term Kidney Protection during Treatment with an Endothelin Receptor Antagonist: A Prespecified Analysis from the SONAR Trial.

BACKGROUND: Whether early reduction in albuminuria with atrasentan treatment predicts its long-term kidney-protective effect is unknown. METHODS: To assess the long-term effects on kidney outcomes of atrasentan versus placebo in the SONAR trial, we enrolled patients who had type 2 diabetes and CKD (stage 2-4) and a urinary albumin creatinine ratio (UACR) of 300-5000 mg/g; participants were receiving maximum tolerated renin-angiotensin system inhibition. After 6 weeks exposure to 0.75 mg/day atrasentan (enrichment period), participants were randomized (stratified by UACR response during enrichment, ranging from ≤60% to >0%) to continue atrasentan or transition to placebo. Primary kidney outcome was a composite of sustained serum creatinine doubling or ESKD. RESULTS: UACR response to atrasentan during enrichment persisted throughout the double-blind treatment phase and predicted the primary kidney outcome, whereas UACR levels with placebo remained below pre-enrichment values in the two highest UACR response strata, and exceeded pre-enrichment values in the two lowest strata. As a result, early UACR response to atrasentan during enrichment was also associated with the primary kidney outcome during placebo. Accordingly, the predictive effect of early albuminuria changes during atrasentan was eliminated after placebo correction, leading to a consistent relative risk reduction for the primary kidney outcome with atrasentan compared with placebo, irrespective of the initial UACR response. The difference between atrasentan and placebo in UACR during double-blind treatment was also consistent across UACR response strata. CONCLUSIONS: Our findings do not support UACR response as a causal predictor of atrasentan's treatment effect. However, the variable trajectory in UACR with placebo, aspects of the trial design, day-to-day variability in albuminuria, and potential long-lasting effects of atrasentan may have contributed.

Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice.

Treatments with sodium-glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin-angiotensin system (RAS) blockade. Type 2 diabetic mice (db/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2/Ang(1-7)/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model.

Functional Interaction of Endothelin Receptors in Mediating Natriuresis Evoked by G Protein-Coupled Estrogen Receptor 1.

The G protein-coupled estrogen receptor 1 (GPER1) mediates rapid estrogenic signaling. We recently reported that activation of GPER1 in the renal medulla evokes endothelin-1-dependent natriuresis in female, but not male, rats. However, the involvement of the ET receptors, ETA and ETB, underlying GPER1 natriuretic action remain unclear. In this study, we used genetic and pharmacologic methods to identify the contributions of ETA and ETB in mediating this female-specific natriuretic effect of renal medullary GPER1. Infusion of the GPER1-selective agonist G1 (5 pmol/kg per minute) into the renal medulla for 40 minutes increased Na+ excretion and urine flow in anesthetized female ETB-deficient (ETB def) rats and littermate controls but did not affect blood pressure or urinary K+ excretion in either group. Pretreatment with the selective ETA inhibitor ABT-627 (5 mg/kg, intravenous) abolished G1-induced natriuresis in ETB def rats. To further isolate the effects of inhibiting either receptor alone, we conducted the same experiments in anesthetized female Sprague-Dawley (SD) rats pretreated or not with ABT-627 and/or the selective ETB inhibitor A-192621 (10 mg/kg, intravenous). Neither antagonism of ETA nor antagonism of ETB receptor alone affected the G1-induced increase in Na+ excretion and urine flow in SD rats. However, simultaneous antagonism of both receptors completely abolished these effects. These data suggest that ETA and ETB receptors can mediate the natriuretic and diuretic response to renal medullary GPER1 activation in female rats. SIGNIFICANCE STATEMENT: Activation of G protein-coupled estrogen receptor 1 (GPER1) in the renal medulla of female rats evokes natriuresis via endothelin receptors A and/or B, suggesting that GPER1 and endothelin signaling pathways help efficient sodium excretion in females. Thus, GPER1 activation could be potentially useful to mitigate salt sensitivity in females.

Endothelin receptor antagonists for the treatment of diabetic and nondiabetic chronic kidney disease.

PURPOSE OF REVIEW: To summarize new clinical findings of endothelin receptor antagonists (ERA) in various etiologies of kidney disease targeted in clinical trials. RECENT FINDINGS: Endothelin-1 is a multifunctional peptide with potential relevance to glomerular and tubulointerstitial kidney diseases. The phase 3 SONAR trial demonstrated a significant reduction in clinically relevant kidney outcomes for patients with diabetic kidney disease (DKD) after long-term treatment with the ERA, atrasentan, in addition to blockade of the renin-angiotensin-aldosterone system. Promising preclinical disease models and small clinical trials in non-DKD resulted in the initiation of phase 3 trials investigating the effects of long-term treatment with ERA in patients with immunoglobulin A (IgA) nephropathy and focal segmental glomeruloscelerosis (FSGS). The mechanisms by which ERA protects the kidneys have been extensively studied with evidence for the protection of tubule cells, podocytes, mesangial cells, the endothelial glycocalyx, and a reduction in glomerular perfusion pressure. The occurrence of fluid retention during ERA treatment, particularly in susceptible populations, necessitates strategies to support safe and effective treatment. SUMMARY: Treatment with ERA induces long-term kidney protection in DKD. Phase 3 trials are underway to investigate ERA effects in patients with IgA nephropathy and FSGS.

Prenatal endothelin or thromboxane receptor antagonism surpasses sympathoinhibition in improving cardiorenal malfunctions in preeclamptic rats.

Current therapies for preeclampsia (PE) and its complications are limited and defective. Considering the importance of endothelin (ET) and thromboxane A2 (TXA2) signaling in PE pathophysiology, we tested the hypothesis that prenatal blockade of endothelin ETA or thromboxane TXA2 receptors favorably reprograms preeclamptic cardiovascular and renal insults. PE was induced by daily oral administration of L-NAME (50 mg/kg) to pregnant rats for 7 consecutive days starting from gestational day 14. The effects of co-exposure to atrasentan (ETA receptor blocker, 10 mg/kg/day) or terutroban (TXA2 receptor blocker, 10 mg/kg/day) on cardiovascular and renal anomalies induced by PE were assessed on gestational day 20 (GD20) and at weaning time and compared with those evoked by the sympatholytic drug α-methyldopa (α-MD, 100 mg/kg/day), a prototypic therapy for PE management. Among all drugs, terutroban was basically the most potent in ameliorating PE-evoked increments in blood pressure and decrements in creatinine clearance. Cardiorenal tissues of PE rats exhibited significant increases in ETA and TXA2 receptor expressions and these effects disappeared after treatment with atrasentan and to a lesser extent by terutroban or α-MD. Atrasentan was also the most effective in reversing the reduced ETB receptor expression in renal tissues of PE rats. Signs of histopathological damage in cardiac and renal tissues of PE rats were mostly improved by all therapies. Together, pharmacologic elimination of ETA or TXA2 receptors offers a relatively better prospect than α-MD in controlling perinatal cardiorenal irregularities sparked by PE.

Efficacy and safety of endothelin receptor antagonists in type 2 diabetic kidney disease: A systematic review and meta-analysis of randomized controlled trials.

AIM: To analyse the efficacy and safety of endothelin receptor antagonists for people with diabetic kidney disease. METHODS: Randomized controlled trials comparing endothelin receptor antagonists with placebo in people with diabetic kidney disease were identified through PubMed, Embase and the Cochrane Library. We used a random-effect model to calculate the mean difference or risk ratio with the 95% CI. RESULTS: Seven studies with a total of 4730 participants were included. Overall, endothelin receptor antagonists significantly reduced albuminuria compared with placebo (standardized mean difference -0.48, 95% CI -0.64 to -0.33). Atrasentan, in particular, effectively reduced albuminuria (standardized mean difference -0.58, 95% CI -1.00 to -0.17) and the risk of composite renal endpoints (risk ratio 0.65; 95% CI 0.49 to 0.88), with insignificant change in the rate of congestive heart failure (risk ratio 1.40, 95% CI 0.76 to 2.56) and mortality (risk ratio 1.11, 95% CI 0.77 to 1.61). In contrast, although avosentan reduced albuminuria (standardized mean difference -0.47, 95% CI -0.57 to -0.36) and the risk of composite renal endpoints (risk ratio 0.63, 95% CI 0.42 to 0.94), it was associated with a significant increase in congestive heart failure risk (risk ratio 2.61, 95% CI 1.36 to 5.00) and an insignificant increase in mortality risk (risk ratio 1.50, 95% CI 0.81, 2.78). No significant change in efficacy or safety outcomes with bosentan was detected. Dose-response analysis indicated that 0.75 mg/day atrasentan is expected to be optimal for renoprotection, with maximal albuminuria reduction and minimal fluid retention events. CONCLUSIONS: Among the endothelin receptor antagonists, atrasentan and avosentan, but not bosentan, are effective for renoprotection in people with diabetic kidney disease. Compared with other types and doses, atrasentan 0.75 mg/day is the most promising, with maximal albuminuria reduction and minimal fluid retention. Vigilant monitoring of congestive heart failure risk is needed in future clinical practice. (PROSPERO registration no. CRD42020169840).

Inter-individual variability in atrasentan exposure partly explains variability in kidney protection and fluid retention responses: A post hoc analysis of the SONAR trial.

AIM: To evaluate whether atrasentan plasma exposure explains between-patient variability in urinary albumin-to-creatinine ratio (UACR) response, a surrogate for kidney protection, and B-type natriuretic peptide (BNP) response, a surrogate for fluid expansion. METHODS: Type 2 diabetic patients with chronic kidney disease (n = 4775) received 0.75 mg atrasentan for 6 weeks in the active run-in period. Individual area under the concentration-time-curve (AUC) was estimated using a population pharmacokinetic model. The association between atrasentan AUC, other clinical characteristics, and UACR and BNP response, was estimated using linear regression. RESULTS: The median atrasentan AUC was 43.8 ng.h/mL with a large variation among patients (2.5th-97.5th percentiles [P]: 12.6 to 197.5 ng.h/mL). Median UACR change at the end of enrichment was -36.0% and median BNP change was 8.7%, which also varied among patients (UACR, 2.5th-97.5th P: -76.2% to 44.5%; BNP, 2.5th-97.5th P: -71.5% to 300.0%). In the multivariable analysis, higher atrasentan AUC was associated with greater UACR reduction (4.88% per doubling in ng.h/mL [95% confidence interval {CI}: 6.21% to 3.52%], P < .01) and greater BNP increase (3.08% per doubling in ng.h/mL [95% CI: 1.12% to 4.11%], P < .01) independent of estimated glomerular filtration rate, haemoglobin or BNP. Caucasian patients compared with black patients had greater UACR reduction (7.06% [95% CI: 1.38% to 13.07%]) and also greater BNP increase (8.75% [95% CI: 1.65% to 15.35%]). UACR response was not associated with BNP response (r = 0.06). CONCLUSION: Atrasentan plasma exposure varied among individual patients and partially explained between-patient variability in efficacy and safety response.

Beneficial effect on podocyte number in experimental diabetic nephropathy resulting from combined atrasentan and RAAS inhibition therapy.

Podocyte loss and proteinuria are both key features of human diabetic nephropathy (DN). The leptin-deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, type 2 diabetes, and diabetic nephropathy that has many features of advanced human DN, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 type A receptor (ETAR) by atrasentan treatment in combination with renin-angiotensin-aldosterone system inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with DN, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls and suggested that parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ETAR antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of DN in humans and thereby underlies the reduction in proteinuria in patients with diabetes undergoing similar treatment. The benefit of ETAR antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen type IV in both the atrasentan and atrasentan + losartan-treated groups compared with untreated controls.

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. METHODS: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. FINDINGS: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4-2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49-0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85-2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75-1·59]; p=0·65). INTERPRETATION: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. FUNDING: AbbVie.

Determining the optimal dose of atrasentan by evaluating the exposure-response relationships of albuminuria and bodyweight.

This study aimed to identify the optimal dose of the endothelin-1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR-JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin-to-creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P < .01). The individual response curves for UACR and bodyweight crossed at approximately the mean trough concentration of 0.75 mg atrasentan, indicating that 0.75 mg/d of atrasentan is the optimal dose for kidney protection with maximal efficacy (albuminuria reduction) and safety (minimal sodium retention).