Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients

The FAVORIT Trial

M. Park; R. Katz; M. G. Shlipak; D. Weiner; R. Tracy; V. Jotwani; J. Hughes-Austin; F. Gabbai; C. Y. Hsu; M. Pfeffer; N. Bansal; A. Bostom; O. Gutierrez; M. Sarnak; A. Levey6 and J. H. Ix

Disclosures

American Journal of Transplantation. 2017;17(10):2640-2649. 

In This Article

Abstract and Introduction

Abstract

Cardiovascular risk remains high in kidney transplant recipients (KTRs) despite improved kidney function after transplant. Urinary markers of kidney fibrosis and injury may help to reveal mechanisms of this risk. In a case–cohort study among stable KTRs who participated in the FAVORIT trial, we measured four urinary proteins known to correlate with kidney tubulointerstitial fibrosis on biopsy (urine alpha 1 microglobulin [α1m], monocyte chemoattractant protein-1 [MCP-1], procollagen type I [PINP] and type III [PIIINP] N-terminal amino peptide) and evaluated associations with cardiovascular disease (CVD) events (n = 300) and death (n = 371). In adjusted models, higher urine α1m (hazard ratio [HR] per doubling of biomarker 1.40 [95% confidence interval [CI] 1.21, 1.62]), MCP-1 (HR 1.18 [1.03, 1.36]), and PINP (HR 1.13 [95% CI 1.03, 1.23]) were associated with CVD events. These three markers were also associated with death (HR per doubling α1m 1.51 [95% CI 1.32, 1.72]; MCP-1 1.31 [95% CI 1.13, 1.51]; PINP 1.11 [95% CI 1.03, 1.20]). Higher concentrations of urine α1m, MCP-1, and PINP may identify KTRs at higher risk for CVD events and death. These markers may identify a systemic process of fibrosis involving both the kidney and cardiovascular system, and give new insights into mechanisms linking the kidney with CVD.

Introduction

Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease (CVD) and death.[1] In kidney transplant recipients (KTRs), despite improved kidney function after transplant, the incidence of CVD remains high[2] and is the leading cause of death.[3] As in nontransplanted CKD patients, urine albumin-to-creatinine ratio (ACR) and level of estimated glomerular filtration rate (eGFR) are important independent predictors of adverse risk in KTRs. Higher ACR predicts graft loss and death,[4] while lower eGFR is associated with CVD risk.[5,6]

While ACR indicates predominantly glomerular injury, markers indicating injury of kidney tubules may provide new insights into mechanisms of kidney injury and have been a focus of recent research. Understanding tubular function as well as glomerular function is likely to add prognostic and mechanistic information about overall kidney health. Kidney fibrosis may be of particular relevance in KTRs, as interstitial fibrosis and tubular atrophy (IFTA) on kidney allograft biopsy are strongly predictive of future graft loss, independent of eGFR and ACR.[7] The degree of kidney tubulointerstitial fibrosis is not well captured by eGFR and ACR[8] and therefore is invisible to clinicians in the absence of a kidney biopsy. Although kidney biopsies are performed more frequently in KTRs than in nontransplanted CKD patients, they are still invasive, carry risk of bleeding, and are used primarily for diagnostic purposes; they are only rarely repeated to monitor responses to change in therapy.

We evaluated urine concentrations of alpha 1 microglobulin (α1m), monocyte chemoattractant protein-1 (MCP-1), and procollagen amino-terminal pro-peptides of type I and type III collagen (PINP and PIIINP) in stable KTRs. We chose these markers because they have been associated with the severity of tubulointerstitial fibrosis on kidney biopsy in prior studies. Briefly, α1m is a low-molecular-weight protein freely filtered at the glomerulus but reabsorbed by proximal tubular epithelial cells under healthy conditions.[9] With kidney tubule dysfunction, elevated urine α1m levels indicate decreased proximal tubular reabsorptive capacity as seen after prolonged cold ischemia times[10,11] and higher urine α1m concentrations correlate with IFTA on biopsy.[7] MCP-1 is a potent chemokine expressed by renal tubular epithelial cells, which induces recruitment of macrophages and renal interstitial fibroblasts and leads to both interstitial and mesangial fibrosis.[12] Higher urine concentrations have been associated with greater fibrosis in diabetic nephropathy and with disease progression.[13] PINP and PIIINP are cleaved from type 1 and type 3 collagen fibrils during collagen deposition, which is an important step in fibrogenesis.[14] Urine PIIINP is the N-terminal fragment of type III collagen and is released during newly deposited collagen type III and is correlated with interstitial fibrosis[11] and kidney function decline[15] in patients with CKD of different etiologies[16] and in KTRs.[11]

When evaluating risk of allograft failure, we recently showed that urine α1m and MCP-1 were strongly associated with future allograft failure, independent of eGFR, ACR, or other risk factors in the Folic Acid for Vascular Outcomes Reduction in Transplantation (FAVORIT) trial, whereas PINP and PIIINP were not.[17] Whether or not these markers of tubular fibrosis may give insights to the link between the kidney and CVD above and beyond the classical glomerular markers of eGFR and ACR in KTRs is uncertain. We designed this study to evaluate associations between noninvasive urine markers of tubulointerstitial fibrosis and long-term CVD events and death in the FAVORIT trial. Our main goal is to provide new insights into possible pathways and mechanisms of disease supported by biomarker associations. The FAVORIT trial is uniquely positioned to address this question, given the large sample size, long-term follow-up, and availability of adjudicated CVD endpoints, which were the primary outcomes of the trial. We hypothesized a priori that higher urine concentrations of each marker would be associated with risk of CVD events and death independent of CKD and CVD risk factors, baseline eGFR, and ACR.

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