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Diabetic Nephropathy


Figure 1: Comparison of the Anti-albuminuric Effects (Panel A) and Side Effects (Panel B) of Endothelin Receptor Antagonists in the Three Published Clinical Trials in Diabetic Nephropathy26–28


A


10 20


-50 -40 -30 -20 -10 0


-60 Placebo B


10 20 30 40 50


0 Placebo


Avosentan (median, SPEED II26


)


5 mg/–/ 0.25 mg


10 mg/–/ 0.75 mg


Avosentan (median, ASCENT27


)


25 mg/25 mg/ 1.75 mg


Atrasentan


(geometric mean, Kohan et al.28


)


UAER = urinary albumin excretion rate. The x-axes show the respective doses of endothelin receptor antagonists (avosentan or atrasentan) studied in the three trials.26–28


50 mg/ 50 mg/–


5 mg/–/ 0.25 mg


10 mg/–/ 0.75 mg


25 mg/25 mg/ 1.75 mg


50 mg/ 50 mg/–


1.75 mg atrasentan), a significant rise in the frequency of side effects is seen without any relevant additive antiproteinuric effect (see Figure 1).26–28


Fluid overload becomes increasingly significant, especially in patients with advanced disease such as those studied in the ASCEND trial (CKD IIIb). Whether low dietary sodium and/or a adequately dosed diuretic regimen will be effective remains to be seen. We believe that these treatments are mandatory when any drug that causes fluid retention is given.


We know from experimental trials that ET promotes sodium excretion, mainly via ETBs at the level of the collecting duct.29


Consequently,


when ET receptor antagonists are used that also block the ETB, at least partially, sodium retention will be a major concern. In fact, in healthy volunteers, the administration of avosentan for one week reduced sodium excretion and increased body weight for one to two days, but body weight subsequently normalised, presumably with the onset of compensatory mechanisms.30


been postulated that ET has a sodium-independent effect on vasopressin-dependent excretion of electrolyte-free water.29


While, in


the atrasentan study by Kohan et al., the drug had no significant effect on body weight, the lowering of haemoglobin levels suggested an internal fluid shift – i.e., redistribution of fluid into the vascular compartment.28


Furthermore, it has


In clinical practice, patients treated with ET receptor antagonists, particularly if their GFR is markedly reduced, should be advised to reduce sodium intake and should also be given adequate doses of diuretics – keeping in mind that, in proteinuric patients, the dose–response relationship is altered because of intratubular protein binding of diuretics.31


Data Safety and Monitoring Board terminated the study prematurely, because of an excessive frequency of oedema, fluid overload and congestive heart failure.27


Finally, a recently published trial by Kohan et al. assessed the effects of the newly developed, more ETA-selective receptor antagonist atrasentan (0.25, 0.75 and 1.75 mg) in 89 patients with DN (CKD stage II–IIIa).28


Challenges for the Future – Effects and Side Effects of Endothelin Receptor Antagonists Today, progression of DN still occurs despite treatment according to guideline recommendations, including RAS blockade. ET receptor antagonists are one of the most promising classes of drugs on the horizon because of their antiproteinuric, anti-inflammatory and antiproliferative properties. The use of the currently available ET receptor antagonists is limited by their side effects, mainly the result of sodium-dependent and sodium-independent fluid retention leading to oedema and heart failure, particularly when administered at higher doses and in predisposed patients with higher stages of renal disease (i.e., CKD III or higher).


UAER


was reduced by up to 35 % compared with placebo. Peripheral oedema occurred in up to 46 % of patients, mainly in the high doses.


In all three trials, GFR was unchanged after treatment with the respective ET receptor antagonist.26–28


What Can We Learn from these Three Important Clinical Trials? There is no doubt that the ET receptor antagonists studied in the three trials – i.e., avosentan and atrasentan – dramatically reduce proteinuria and thus are likely to be highly nephroprotective. However, their use in this setting is currently still limited by their side effects – mainly fluid overload.


When we compare the effects and side effects of the two drugs in the three trials, it is evident that lower doses of both avosentan and atrasentan are antiproteinuric, with a low rate, if any, of side effects. In contrast, with higher doses (i.e., 25 and 50 mg avosentan and


34


It is worthwhile looking beyond renoprotection. Even a minor reduction of renal function is associated with a dramatic increase in non-fatal and fatal cardiovascular events. In this context, again, ET receptor antagonists are of considerable interest: in the heart, they improve cardiac structure and microvascular architecture and reduce mitochondrial damage, and in the vasculature they reduce vascular remodelling and vessel wall hypertrophy, at least under experimental conditions.24,32


Apart from their renoprotective properties, ET receptor antagonists will also be welcome because a significant proportion of patients with CKD also have cardiac problems and resistant hypertension, which will justify the use of ET receptor antagonists as additional antihypertensive and (potentially) somewhat cardioprotective agents.33


In many discussions, the following issues have been raised: should ET receptor antagonists be abandoned because of their side effects? Do the potential problems with fluid overload negate the beneficial


EUROPEAN ENDOCRINOLOGY


Oedema/fluid overload (%)


Median or mean relative change in UAER (%)


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