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Endothelin antagonists for diabetic and non-diabetic chronic kidney disease.

ABSTRACT: Numerous pre-clinical studies have implicated endothelin-1 in the pathogenesis of diabetic and non-diabetic chronic kidney disease (CKD). Renal endothelin-1 production is almost universally increased in kidney disease. The pathologic effects of endothelin-1, including vasoconstriction, proteinuria, inflammation, cellular injury and fibrosis, are likely mediated by the endothelin A (ETA) receptor. ETA antagonism alone, and/or combined ETA/B blockade, reduces CKD progression. Based on the strong pre-clinical data, several clinical trials using ETA antagonists were conducted. Small trials involving acute intravenous endothelin receptor blockade suggest that ETA, but not ETB, blockade exerts protective renal and vascular effects in CKD patients. A large phase 3 trial (ASCEND) examined the effects of avosentan, an endothelin receptor antagonist, on renal disease progression in diabetic nephropathy. Proteinuria was reduced after 3-6 months of treatment. However the study was terminated due to increased morbidity and mortality associated with avosentan-induced fluid retention. Several phase 2 trials using avosentan at lower doses than in ASCEND, atrasentan or sitaxsentan (the latter two being highly ETA-selective) showed reductions in proteinuria on top of renin-angiotensin system blockade. Infrequent and clinically insignificant fluid retention was observed at the most effective doses. Additional trials using ETA blockers are ongoing or being planned in patients with diabetic nephropathy or focal segmental glomerulosclerosis. Moving forward, such studies must be conducted with careful patient selection and attention to dosing in order to minimize adverse side effects. Nonetheless, there is cause for optimism that this class of agents will ultimately prove to be effective for the treatment of CKD.

SUBMITTER: Kohan DE

PROVIDER: S-EPMC3791980 | biostudies-other | 2013 Oct

REPOSITORIES: biostudies-other

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Endothelin antagonists for diabetic and non-diabetic chronic kidney disease.

Kohan Donald E DE Pollock David M DM

British journal of clinical pharmacology 20131001 4

Numerous pre-clinical studies have implicated endothelin-1 in the pathogenesis of diabetic and non-diabetic chronic kidney disease (CKD). Renal endothelin-1 production is almost universally increased in kidney disease. The pathologic effects of endothelin-1, including vasoconstriction, proteinuria, inflammation, cellular injury and fibrosis, are likely mediated by the endothelin A (ETA) receptor. ETA antagonism alone, and/or combined ETA/B blockade, reduces CKD progression. Based on the strong p ...[more]

PMID: 23228194

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Project description:Background: Widespread neural and microvascular injuries are common in chronic kidney disease (CKD), increasing risks of neurovascular complications and mortality. Early detection of such changes helps assess the risks of neurovascular complications for CKD patients. As an extension of central nervous system, the retina provides a characteristic window to observe neurovascular alterations in CKD. This study aimed to determine the presence of retinal neurovascular impairment in different stages of CKD. Methods: One hundred fifteen non-diabetic and non-dialytic CKD patients of all stages and a control group of 35 healthy subjects were included. Retinal neural and microvascular parameters were obtained by optical coherence tomography angiography (OCTA) examination. Results: CKD 1-2 group (versus control group) had greater odds of having decreased retinal ganglion cell-inner plexiform layer thickness (GC-IPLt) (odds ratio [OR]: 0.92; 95% confidence interval [CI]: 0.86-0.98), increased ganglion cell complex-focal loss volume (GCC-FLV) (OR: 3.51; 95% CI: 1.27-9.67), and GCC-global loss volume (GCC-GLV) (OR: 2.48; 95% CI: 1.27-4.82). The presence of advanced stages of CKD (CKD 3-5 group versus CKD 1-2 group) had greater odds of having decreased retinal vessel density in superficial vascular plexus (SVP)-WholeImage (OR: 0.77, 95% CI: 0.63-0.92), SVP-ParaFovea (OR: 0.83, 95% CI: 0.71-0.97), SVP-ParaFovea (OR: 0.76, 95% CI: 0.63-0.91), deep vascular plexus (DVP)-WholeImage (OR: 0.89, 95% CI: 0.81-0.98), DVP-ParaFovea (OR: 0.88, 95% CI: 0.78-0.99), and DVP-PeriFovea (OR: 0.90, 95% CI: 0.83-0.98). Besides, stepwise multivariate linear regression among CKD patients showed that β2-microglobulin was negatively associated with GC-IPLt (β: -0.294; 95% CI: -0.469 ∼ -0.118), and parathyroid hormone was positively associated with increased GCC-FLV (β: 0.004; 95% CI: 0.002∼0.006) and GCC-GLV (β: 0.007; 95% CI: 0.004∼0.01). Urine protein to creatinine ratio was positively associated with increased GCC-FLV (β: 0.003; 95% CI: 0.001∼0.004) and GCC-GLV (β: 0.003; 95% CI: 0.001∼0.006). Conclusion: Retinal neuronal impairment is present in early stages of CKD (stages 1-2), and it is associated with accumulation of uremic toxins and higher UACR, while retinal microvascular hypoperfusion, which is associated with worse eGFR, was only observed in relatively advanced stages of CKD (stages 3-5). The results highlight the importance of monitoring retinal neurovascular impairment in different stages of CKD.

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Endothelin antagonists for diabetic and non-diabetic chronic kidney disease.

Publications

Endothelin antagonists for diabetic and non-diabetic chronic kidney disease.

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