There is little information regard- ing the combination of aldosterone antagonists with NSAIDs or COX-2 inhibitors, but as with ACE-Is and ARBs, caution is warranted. Both spironolactone and eplerenone interact with cytochrome P-450, but definitive information regarding any effect on calcineurin inhibitors (CNIs) is not available. Caution is also advised when aldosterone antagonists are combined with other cytochrome P-450 metabolized agents such as verapamil. Direct renin inhibitors. The first clinically available DRI, aliskiren, was approved by the US Food and Drug Administration (FDA) in 2007. It binds to renin, preventing the conversion of angiotensin I to angiotensin II. Data relevant to DRIs were not available at the time of publication of the KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensives Agents in Chronic Kidney Disease in Dose considerations in CKD patients. The usual dose of aliskiren is 150 to 300 mg given once daily. The dose is not modified according to kidney function. It has been reported that cyclosporine administration increases the half-life of aliskiren in healthy subjects.111 Indications for DRIs. Although approved by the US FDA only for the treatment of hypertension, it is uncertain whether the indications for DRIs will eventually be similar to those of ACE-Is and ARBs. There has been one large study of aliskiren in CKD patients, in which the drug was used in combination with the ARB losartan in patients who also had type 2 diabetes with A total of 599 patients were randomized to losartan, 100 mg daily, either alone (control group) or plus aliskiren 150 mg daily for 3 months and then 300 mg daily for 3 months. The addition of the 300 mg dose of aliskiren reduced the urinary albumin/creatinine ratio (ACR) by 20% as compared with the use of losartan alone. 