Renoprotection by Pentoxifylline and Valsartan in Chronic Kidney Disease (CKD)

• doubling of serum creatinine, ESRD, and death from any cause [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  

• changes of microalbuminuria or proteinuria, and development of heart failure, nonfatal myocardial infarction, and stroke or transient ischemic attack. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  

This study is a multicenter placebo-controlled double-blind randomized clinical trial. The design scheme is depicted in Figure 1. (see below). At the time of screening, all pentoxifylline-naïve participants must have been receiving Diovan 80-160 mg per day for no less than 8 weeks and have stable renal function with serum creatinine elevation < 25% in the preceding 8 weeks. For patients taking maximal dose of Diovan (160 mg/day) for more than 8 weeks, randomization will be started after recruitment. For patients taking submaximal, fixed dose of Diovan (< 160 mg/day) for ≥ 8 weeks, with good BP, i.e., ≤ 130/80 mmHg, randomization can also be started after recruitment. However, for patients taking submaximal dose of Diovan with suboptimal BP, i.e., ＞130/80 mmHg, patients can be recruited but will not be randomized until the dose of Diovan has been fixed for ≥ 8 weeks, or a maximal dose of Diovan (160 mg/day) has been administered for ≥ 8 weeks.The recruited CKD patients will be randomized to receive pentoxifylline (400 mg once or twice a day) or placebo (one tablet once or twice a day). Patients with stage 3 CKD will receive either pentoxifylline one tablet (400 mg) twice a day, or placebo one tablet twice a day.If the patients are still intolerant of the potential side effects, they may withdraw from the study voluntarily. Patients with stage 4 CKD will receive either pentoxifylline one tablet (400 mg) once per day, or placebo one tablet once per day. In patients who develop potential side effects (anorexia, epigastric distention, dizziness, and headache) to the test drug, they may withdraw from the study voluntarily. If patients have SBP > 130 mmHg and/or DBP > 80 mmHg, it is necessary to adjust the other antihypertensive drugs. However, the following medications are not allowed during the study: ARB; ACE inhibitor; phosphodiesterase inhibitor (other than pentoxifylline); direct vasodilators (e.g., hydralazine and minoxidil), as they can blunt the decrease in proteinuria, and chronic immunosuppressive or non-steroidal anti-inflammatory drug (NSAID) therapy.

The randomization is done with the stratifications of CKD stages and diabetic/non-diabetic status. CKD includes stage 3 and 4. CKD stage 3 is further divided to 3A and 3B according to most recent guideline (NICE clinical guideline 73, Chronic kidney disease, September 2008) Two-arm random permuted block randomization with mixed block sizes 6, 8 and 10 will be implemented within each stratum. Double-blind measures will be enforced in each participating hospital. And, extra efforts will be made to avoid noncompliance, missing data, and loss to follow-up during the trial. Patient's renal function will be calculated by the Cockcroft-Gault and simplified MDRD formula. All blood and urine analyses will be performed by the Department of Laboratory Medicine, NTUH. Serum and urine samples are collected before and annually after randomization, and the specimens are allocated and stored at -70°C. Profibrotic or inflammatory markers such as serum and urinary levels of TNF-alpha, MCP-1, TGF-beta1, collagens III(amino-terminal propeptide of type III procollagen) and IV, and fibronectin, urinary NAG, as well as serum fibrinogen and high-sensitive CRP will be measured by using commercially available kits. Genetic polymorphism of MCP-1 and fractalkine receptor will also be analyzed to evaluate their association with renal outcomes.