Chronic kidney disease (CKD) is a global health problem, affecting more than 10% of the world’s population and more than half of adults over 70 years of age in the United States. People with CKD are at greater risk for cardiovascular disease (CVD), heart failure, physical function decline, and mortality. Taken together, CKD and its associated comorbid conditions constitute an enormous public health burden. Fibrosis is a dominant factor in the development and progression of CKD, regardless of its etiology.

The TOP-CKD study assessed severity of fibrosis without requiring kidney biopsy through the evaluation of several non-invasive tests: diffusion weighted magnetic resonance imaging (DW-MRI) and several urine biomarkers of fibrosis (including alpha-1-microglobulin (α1M), N-terminal procollagen type 3 peptide (PIIINP), and monocyte chemoattractant protein-1 (MCP-1)). Higher levels of these proteins correspond with greater tubulo-interstitial fibrosis on kidney biopsy and predict kidney function declines independent of eGFR and albuminuria.

The study was a two-center, double-blind, randomized placebo-controlled, phase 2 trial of Pirfenidone (Esbriet) in CKD participants treated for 12 months, with an additional visit after 6 months of passive follow-up. Pirfenidone is an anti-fibrotic drug that was approved by the Food and Drug Administration (FDA) for treatment of idiopathic pulmonary fibrosis (IPF). Pirfenidone is cleared by the liver and had promising preliminary safety data in patients with CKD since it targets fibrosis, a major determinant of CKD progression. The study evaluated the effects of pirfenidone versus placebo on measures of kidney fibrosis by imaging and by urine fibrosis biomarkers. The study used a pirfenidone dose of 1,335 mg per day for optimal efficacy, side effect profile, and ease of dosing (given current formulations of 267 mg capsules).

The primary objectives of the study were to evaluate pirfenidone daily versus matched placebo, as assessed by DW-MRI, over 12 months in participants with eGFR between 30-50 mL/min/1.73 m2 for changes in renal fibrosis and changes in urinary markers of tubulo-interstitial fibrosis. In addition, the study aimed to determine if the effect of pirfenidone on iohexol GFR was similar to that observed by eGFR estimates based on creatinine and cystatin C.

The main outcome measures for the study were the slopes of changes in fibrosis markers (MRI and urine) over 12 months in participants randomized to pirfenidone versus placebo, by intent-to-treat. Two secondary endpoints were evaluated which were the slope of absolute change in eGFR, and the slope of percentile change in urine albumin to creatinine ratio over the 12-month intervention period.

• Participants with eGFR ≥ 20 mL/min/1.73 m2 using the 2012 CKD-EPI Creatinine equation
• Four variable KFRE 5-year risk score > 1% (obtained at http://kidneyfailurerisk.com/)
• Age 21 years or older

• Participants with known autosomal dominant polycystic kidney disease or liver disease
• Use or planned use of drugs that inhibit CYP1A2 which may increase pirfenidone exposure (for example, artemisin, atazanavir, cimetidine, ciprofloxacin, enoxacin, ethinyl estradiol, fluvoxamine, mexiletine, tacrine, thiabendazole, or zileuton)
• Clinical idiopathic pulmonary fibrosis (IPF) by imaging or physician diagnosis (pirfenidone is indicated for participants with IPF)
• Electrocardiogram (ECG) with a QTc interval > 500 msec at screening (pirfenidone can prolong QTc)
• Family or personal history of long QT Syndrome
• Current use (in the past 3 months) of tobacco, including cigarettes, cigars, chewing tobacco, or vaping products
• Physical inability, claustrophobia or other contra-indication to obtaining MRI measurements
• Current participation in another clinical trial (observational studies are exempted)
• Systemic immunosuppressive medications (< 10 mg daily prednisone or inhaled steroids are exempted)
• Malignancy within 2 years (non-melanoma skin and localized prostate carcinoma are exempted)
• Institutionalized individuals (e.g., prisoners, long-term care residents)
• Pregnancy, planning to become pregnant, or currently breast-feeding
• Life expectancy < 12 months as assessed by the site investigator
• Plans to leave the immediate area in < 12 months
• Anticipated need for dialysis or kidney transplantation within 12 months
• Hospitalization within the past 30 days (24-hour observation admissions are exempted)
• Active alcohol or substance abuse within the last 12 months, as assessed by the site investigator
• Active treatment of uncontrolled psychiatric disease, as assessed by the site investigator
• Perceived inability to adhere to the medical regimen or comply with recommendations, or inability or unwillingness to travel to study visits
• Known hypersensitivity to pirfenidone or any condition that, in the opinion of the site investigator, might be significantly exacerbated by the known side effects

Pirfenidone was not associated with changes in estimated GFR, MRI measures of fibrosis, or urine biomarkers of kidney damage. In this study, for participants with moderately advanced CKD, pirfenidone was well-tolerated.