Adverse Effects
Although the antiandrogenic effects of spironolactone-such as gynecomastia-are well known and may be troublesome, these side effects were not reported in the referred studies. The relatively low daily dose of spironolactone prescribed and the fact that most studies had a short duration may account for this. Development of hyperkalemia is a feared side effect of aldosterone-receptor antagonism. The risk of hyperkalemia is especially high in patients with impaired kidney function already using an ACE inhibitor or angiotensin II receptor antagonist. Indeed, development of hyperkalemia was reported in five out of the eight studies in 5-17% of participants (see Table 2). Baseline renal function is probably the most important determinant for the development of hyperkalemia. For instance, in the study published by our group the median serum creatinine concentration was 162 μmol/l in patients who developed hyperkalemia, defined as a serum potassium concentration >5.5mol/l, versus 91μmol/l in patients in whom serum potassium remained below 5.5μmol/l. With progressive renal failure, plasma aldosterone concentration is frequently elevated to counteract the associated hyperkalemia.³⁵ This defense mechanism is interrupted by the administration of an aldosterone receptor antagonist and hence may increase the risk of hyperkalemia.

Conclusions and Future Perspectives 
From the evidence now available it can be concluded that add-on therapy with aldosterone receptor antagonists in patients with diabetic nephropathy already treated with an ACE inhibitor or angiotensin II receptor anatagonist results in a considerably antiproteinuric effect. The mechanism underlying this effect remains speculative, but, based on the rapidly expanding knowledge from experimental studies, hemodynamic and nonhemodynamic mechanisms are likely to be involved.

There is convincing clinical evidence that proteinuria by itself is a determinant for progressive renal function deterioration as well as for cardiovascular morbidity and mortality. It might be inferred, therefore, that reduction of proteinuria should be advantageous both from the perspective of maintenance of kidney function as well as of prevention of cardiovascular disease.

The challenge now is to set up long-term studies with low-dose aldosteronereceptor antagonists in patients with (diabetic) nephropathy and proteinuria in order to confirm the promise that these agents are truly beneficial as evidenced by a decrease in hard end-points, including mortality.

Acknowledgement PMJ is supported by the Dutch Kidney Foundation (Grant C05.2151).