Assessing bone formation in patients with chronic kidney disease using procollagen type I N-terminal propeptide (PINP): The choice of assay makes a difference

Abstract

Background: Measurement of procollagen type I N-terminal propeptide (PINP) concentration in serum reflects the rate of type I collagen synthesis and can therefore be used as a bone formation marker. There are two methods of PINP quantification; the first measures the trimeric propeptide (intact PINP) and the second measures both the trimeric and monomeric propeptides (total PINP). Trimeric PINP is excreted via hepatic endothelial cells whereas monomeric PINP is cleared renally. Therefore in renal failure the total assay has a positive bias with respect to the intact assay, due to monomeric PINP accumulation. The aim of this study was to compare the performance of both assays across all stages of chronic kidney disease (CKD). Methods: Serum was taken from male (n=111) and female (n=105) patients attending a metabolic bone clinic and these were partitioned into stages of CKD 1-5. Each serum sample was analysed using the Roche electrochemiluminescence immunoassay for total PINP and the Immunodiagnostic Systems chemiluminescence immunoassay for intact PINP. Results: Passing-Bablok regression analysis comparing both methods showed that with advancing CKD there was a proportional positive bias affecting the total assay when compared to the intact assay. This proportional positive bias was statistically significant for CKD stages 3b, 4 and 5. Conclusions: Based on this method comparison study, usage of the total PINP assay should be avoided in CKD stages 3b, 4 & 5 (eGFR <u><</u>44 ml/min/1.73m<sup>2</sup>) and instead an intact assay used as the total assay overestimates PINP levels due to monomeric PINP accumulation.

Effects of empagliflozin on collagen biomarkers in patients with heart failure: Findings from the EMPEROR trials

“…PINP may reflect ongoing bone turnover which is enhanced in patients with renal disease, which may help explaining the independent association between higher PINP levels and adverse renal outcomes. 36,51,52 . .…”

“…PRO‐C6 is a C‐terminal neo‐epitope of collagen type VI which has not been correlated with cardiac fibrosis, 1 but has been found to reflect renal fibrosis; 49,50 findings supporting the association between higher PRO‐C6 levels and adverse renal outcomes in the ‘standard model’. PINP may reflect ongoing bone turnover which is enhanced in patients with renal disease, which may help explaining the independent association between higher PINP levels and adverse renal outcomes 36,51,52 …”

Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis

“…The N-terminal propeptide of type I procollagen (P1NP) has been identified by the International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry (IFCC) to be one of the reference markers of bone turnover (formation) for fracture risk prediction and monitoring of OP treatment ( Vasikaran et al, 2011 ). It is important to take into account the fact that only the measurement of intact P1NP is not affected by the decreased renal function in patients with CKD ( Bover et al, 2021a ; Tridimas et al, 2021 ). Alkaline phosphatase (AP, especially the bone isoform) can also be used to evaluate bone turnover in CKD ( Bover et al, 2021a ).…”

“…PTH appears to increase the amount of OB precursors in the bone marrow through a direct action. The bone marrow cells capable of differentiating to OBs are the colony-forming units-fibroblast (CFU-F) and old studies already demonstrated that the administration of PTH ( Kalantar-Zadeh et al, 2021 ; Csaba, 2022 ; Alberto Ortiz, 2022 ; Elshahat et al, 2020 ; Moe et al, 2006 ; Kidney Disease: Improving Global Outcomes KDIGO CKD-MBD Update Work Group, 2017 ; Wang et al, 2018 ; Kidney Disease: Improving Global Outcomes KDIGOCKD–MBD Work Group, 2009 ; Vervloet et al, 2014 ; Torregrosa et al, 2022 ; Llach et al, 2000 ; Lucas, 1883 ; Hruska et al, 2017 ; Goltzman et al, 2018 ; Day et al, 2005 ; Takada et al, 2007 ; Guo et al, 2010 ; Vasikaran et al, 2011 ; Tridimas et al, 2021 ; Bover et al, 2021a ; Bover et al, 2018 ; Bover et al, 2021b ; Wada et al, 2006 ; Gori et al, 2000 ; Luo et al, 2016 ; Luo et al, 2009 ; Filipowska et al, 2022 ; Luxenburg et al, 2007 ; Wheater et al, 2013 ; Rochefort et al, 2010 ; Orlando, 2020 ; Richter and Faul, 2018 ; Vervloet, 2020 ; Gutiérrez et al, 2008 ) to rats for 1 week resulted in the doubling of CFU-F compared with placebo-treated rats ( Nishida et al, 1994 ).…”

The Use of Bone-Turnover Markers in Asia-Pacific Populations

“…Measuring BTMs in the blood (and urine if the patient is still producing urine) may give misleading results by not accurately reflecting bone turnover. Plasma CTX and total PINP concentrations are both affected by renal failure, and their measurements are not recommended in patients with an eGFR of <30 mL/min/1.73 m 2 [ 49 , 50 ]. Intact-PINP assays are not affected by renal failure, making them potentially suitable for use in patients with advanced CKD [ 50 ].…”