Background: Interstitial fibrosis in the protocol biopsy specimens of transplanted kidneys is regarded as the most reliable predictor of future impaired renal function. Type I and III collagens are the main components of renal fibrosis. During the synthesis and deposition of type III collagen, an amino-terminal propeptide (PIIINP) of a molecular weight of 44 kDa is degraded from the collagen and secreted into surroundings. Increased circulating PIIINP has been shown to reflect ongoing fibrotic processes.
Methods: The extent of interstitial fibrosis in 6-month protocol biopsy specimens was recorded, and the urinary excretion of PIIINP in 24-hr urine specimens was measured in 79 graft patients. We also measured the urinary excretion of transforming growth factor (TGF)-beta 1, alpha(1)-microglobulin (alpha(1)M), and albumin and recorded the changes in creatinine clearance during 0.5 to 6 (mean, 4.3) posttransplant follow-up years.
Results: The urinary excretion of PIIINP was significantly lower in patients with no interstitial fibrosis compared with patients with mild or moderate interstitial fibrosis (P<0.01). The urinary PIIINP-to-creatinine ratio correlated closely with the extent of interstitial fibrosis (r=0.410, P<0.001), with TGF-beta 1-to-creatinine (r=0.585, P<0.001) and alpha(1)M-to-creatinine (r=0.438, P<0.001) but not with the albumin-to-creatinine ratio. There was a close correlation between urinary TGF-beta 1 and alpha(1)M (r=0.508, P<0.001), whereas no correlation was found between urinary and serum PIIINP or between urinary PIIINP-to-creatinine ratio and glomerular filtration rate (GFR). During the follow-up, the GFR decreased in 42% of patients with a PIIINP-to-creatinine ratio over 100 ng/mmol, but only in 8% of patients with a ratio less than 100 ng/mmol (P<0.01).
Conclusions: These findings show that the urinary PIIINP-to-creatinine ratio reflects the ongoing fibrotic processes in the kidney. Tubular epithelial cell injury may initiate the fibrotic processes, and elevated concentrations of urinary TGF-beta 1 and alpha(1)M may associate with the increased production and deposition of collagen type III in the graft. We conclude that measurements of urinary excretion of PIIINP can be used as an early noninvasive indicator of renal fibrosis after kidney transplantation.