A blood test for acute rejection after renal transplantation? Commentary on “Osteopontin level correlates with acute cellular renal allograft rejection”

A blood test for acute rejection after renal transplantation? Commentary on “Osteopontin level correlates with acute cellular renal allograft rejection”

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A blood test for acute rejection after renal transplantation? Commentary on “Osteopontin level correlates with acute cellular renal allograft rejection” Brad M. Gandolfi, MD, and I. Michael Leitman, MD* Department of Surgery, Albert Einstein College of Medicine, Beth Israel Medical Center, New York, New York

article info Article history: Received 26 August 2012 Received in revised form 26 August 2012 Accepted 28 August 2012 Available online 19 September 2012

End-stage renal disease affects over 500,000 patients each year in the United States. Currently, over 92,000 people wait on the kidney transplant list in the United States alone, where approximately 16,000 transplants occur annually [1]. With such a discrepancy between supply and demand, graft survival is critical. Yet, even with advances in transplantation technique and immunosuppression, year one acute rejection rates remain between 10% and 20% [2]. Acute rejection begins subclinically and progression may lead to irreversible organ damage or graft loss. Research has been focused on finding early markers of rejection. Traditionally, renal allografts have been monitored using urinalysis, serum creatinine levels, and renal biopsies. Urinalysis provides a basic substrate to monitor renal function and graft rejection. Proteinuria has long correlated with chronic kidney disease and is also positively associated with rejection. However, proteinuria is indicative of an inflammatory process that has already advanced to irreversible kidney injury. Evidence has emerged that shows a relationship between microproteinuria and rejection, which may prove beneficial in

graft surveillance but is still in study [3]. Another marker of renal function used to assess allografts is serum creatinine. As with creatinine levels taken from individuals with native kidneys, a rise in serum creatinine suggests a decrease in the glomerular filtration rate. However, serum creatinine levels have been shown to be variable in posttransplant patients. Further, serum creatinine begins to rise only after substantial nephron injury has already occurred and therefore is not ideal for predicting early rejection [4]. The diagnostic gold standard for acute rejection is percutaneous renal biopsy. Renal biopsy has proven effective in the diagnosis of subclinical rejection, which is estimated to occur in up to 30% of transplanted kidneys in the first year. Still, the procedure is uncomfortable, expensive, and not without risk. Because of these risks, protocol biopsies of the kidney are still controversial in the asymptomatic patient without other signs of rejection [5]. The perfect screening tool for renal allograft acute rejection is one that is sensitive, specific, noninvasive, and cost-effective. Recent investigation has focused on the identification of early markers of inflammation and their

DOI of original article: 10.1016/j.jss.2012.08.006. * Corresponding author. Department of Surgery, Beth Israel Medical Center, 10 Union Square East, Suite 2M, New York, NY 10003. Tel.: þ1 212 844 8570; fax: þ1 212 844 8440. E-mail address: [email protected] (I.M. Leitman). 0022-4804/$ e see front matter ª 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2012.08.056


j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 5 ( 2 0 1 3 ) e 4 9 ee 5 0

association with acute rejection. One particular pathway of interest involves interferon gamma (IFN-g) and the chemokine receptor CXCR3, a receptor activated by IFN-g. The CXCR3 receptor is expressed on activated T lymphocytes [6]. Two ligands of CXCR3 have shown promise in the identification of acute rejection: monokine induced by IFN-g (MIG) and IFNinducible protein 10 (IP-10). In the past decade, multiple studies have shown a correlation between elevated MIG and IP-10 and acute allograft rejection. Hu et al. published a sensitivity of 86% and a specificity of 91% using urine MIG and IP-10 to differentiate acute graft dysfunction from other clinical conditions [7]. Using IP-10 mRNA in the urine, Tatapudi et al. predicted allograft rejection with a sensitivity of 100% and a specificity of 78% [8]. Hauser et al. similarly found a sensitivity of 93% and a specificity of 89% using urinary MIG to predict acute rejection [9]. Additionally, in animal models the blockage of CXCR3 has been shown to suppress rejection [10]. Outside of IP-10 and MIG, many other pathways and factors are being actively investigated, most notably urine mRNA of cyclophilin B, granzyme B, perforin, and FOXP3 [3,8,11e13]. In a paper recently published in the Journal of Surgical Research, Wang et al. [14] describe how elevated osteopontin levels correlate with acute cellular rejection in renal transplant recipients. Osteopontin is a ubiquitous protein that serves a variety of functions. The protein is concentrated in bone, teeth, brain tissue, kidneys, and circulating macrophages and lymphocytes [15]. In the kidney, it is concentrated in the loop of Henle, where it plays a role in calcium metabolism. More importantly in this instance, osteopontin is secreted by T lymphocytes immediately after activation [16]. The upregulation of this protein and its presence in high levels in the plasma and urine are therefore an early marker of inflammation. In the present study, patients with biopsy-proven acute cellular rejection (ACR) were compared with protocol biopsy-proven nonrejection patients. Although no mention is made as to whether the biopsy-proven ACR patients were found on protocol biopsy or due to symptomatic rejection, the latter can be inferred due to the difference in serum creatinine seen at time of biopsy of the two groups (202 mmol/L for the ACR group versus 119 mmol/L for the control group). Thus, osteopontin’s role in the early diagnosis of acute rejection, at a time before serum creatinine has yet to rise, is yet to be determined. Others have also suggested that elevated serum osteopontin levels may predict acute renal rejection [17e19]. However, since elevated serum osteopontin levels also correlate with cyclosporine [20] and tacrolimus toxicity [21], immunosuppressant toxicity might prove difficult to distinguish from acute allograft rejection. Osteopontin levels are also found to be elevated in ischemic perfusion injury in renal allografts [22]. Further work to evaluate trends in patients after renal transplantation is necessary to determine whether osteopontin levels can assist in the early identification of rejection and the potential salvage of renal allografts.









[9] [10]





[15] [16] [17] [18]


[20] [21]

[22] [1] Health Resources and Services Administration, United States Department of Health and Human Services, Healthcare

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