**1. Introduction**

biomarker to diagnose subclinical and acute cellular rejection in kidney transplant

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tubular cells. *J Am Soc Nephrol,* 14, S36–S41.

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patients with chronic kidney disease. *J Am Soc Nephrol,* 18, 1558-1565.

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the intensive care unit. *Nephrol Dial Transplant,* 18, 543–551.

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88 Current Issues and Future Direction in Kidney Transplantation

*Transplantation,* 27, 86, 12, 1713-1719.

*Hyperten,* 15, 6, 637-642.

9, 2114-2125.

9, 759-768.

The number of patients treated for end-stage renal failure continuously increases. Because treatment alternatives are limited and transplants are often the first therapeutic choice, the numbers of patients joining the waiting lists in countries world-wide rises. At present trans‐ plantation medicine is one of the most progressive fields of medicine. Gradually the "half-life" of renal transplants improved and the five years survival rate ranges now above 80% [1;2]. Despite of the advances made within the last decades, acute rejection (AR) is still a risk for graft survival. The incidence of rejection episodes depends on several factors, e.g., the organ (status), co-morbidities, medication and compliance. Thus, in different situations the incidence of AR varies between 13-53% in the first year after transplantation [3], and, in most cases, cellular and humoral immunity mediated rejections can be distinguished. Usually, AR pro‐ ceeds substantially as an acute cellular rejection whereas humoral rejection comprises only a smaller proportion of AR [4]. Every single episode of an AR is a negative prognostic factor, increasing the risk for development of chronic allograft deterioration and worsening long-term graft survival [5;6]. Interestingly, the impact of AR on chronic renal allograft failure as the main cause for death-censored graft-loss after kidney transplantation increases, whereas the severity of the episode itself is an independent risk factor [7-9]. Therefore, early detection and rapid and effective treatment of AR are essential to preserve graft`s function. Clinically established screening methods such as elevated serum creatinine, occurrence or aggravation of proteinu‐ ria, oliguria, hypertension, graft tenderness, or peripheral edema, often lack the desired sen‐ sitivity and specificity for early diagnoses of AR. Hence,a compelling need for high sensitive

© 2013 Grabner et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and specific detection of early AR exists, with core needle biopsy still being the "gold-stand‐ ard" in rejection diagnostics. However, biopsy as an invasive procedure is cumbersome to the patient, carries the risk of graft injury, and cannot be applied in patients taking anticoagulant drugs. Additionally, the sampling site is small and one might miss AR, i.e., when rejection is focal or patchy. Thus, in diagnostics, non-invasive image-based methods visualizing the whole graft would be superior.

future, this method might offer significant potential, whereas at present studies are at best at

Non-Invasive Diagnosis of Acute Renal Allograft Rejection − Special Focus on Gamma Scintigraphy and Positron…

http://dx.doi.org/10.5772/54737

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Computed tomography (CT) is commonly available, technology and techniques as well as the applied contrast media constantly improve. CT contrast agents allow accurate evaluation of parenchymal, perirenal, renal sinus, pyeloureteral and vascular diseases in renal transplanta‐ tion in great detail and at lower costs than by magnetic resonance (MR) imaging. Information gathered by CT indicating AR are loss of corticomedullary differentiation, decreased graft enhancement, and delayed or absent contrast excretion [19]. However, this information is rather unspecific and the contrast media used still are nephrotoxic. Thus, at present CT has no

Kalb *et al*. provide a recent overview about MR-based approaches for functional and structural evaluations of renal grafts including a section on diagnostics of AR [20]. Beside exact anatom‐ ical information, MR can assess different aspects of renal function. Typical MR findings oc‐ curring in AR are enlargement of the graft (due to edema) with loss of corticomedullary differentiation and elevated cortical relative signal. There might be edema of and surrounding the kidney and the ureter. The high spatial and temporal resolution of MR allows perfusion imaging which might be useful to distinguish AR from ATN. 3D gradient echo perfusion imaging might show enhancement of the cortex and markedly delayed excretion of contrast [20]. Recent research with blood-oxygen level-dependent (BOLD) MR was promising for dif‐ ferentiating AR from ATN and a normal functioning kidney [21,22]. Furthermore, MR renog‐ raphy has been applied for diagnosis of the cause of acute dysfunction after kidney transplantation [23,24]. These two studies rely on quantitative evaluation of the shape of the renal enhancement curve to diagnose acute dysfunction. One can observe delayed and lower medullary enhancement in ATN whereas cortical and medullary enhancement curves de‐ crease in AR. However, further studies verifying the results are needed and still some issues about gadolinium-containing contrast agents and nephrogenic systemic fibrosis and gadoli‐ nium nephrotoxicity need to be resolved. More recently, Yamamoto *et al*. proposed a new quantitative analysis method of MR renography, including a multicompartmental tracer ki‐ netic renal model for diagnosis of AR and ATN, but state in their paper that findings in patients with normal graft function, AR, and ATN showed a substantial overlap with those of the normal population [25]. Another strategy followed was imaging of macrophage infiltration with ultrasmall superparamagnetic iron oxide particles [26]. Grafts with AR showed signifi‐ cant accumulation of iron particles but only within a time frame of 72 h which is much too late

experimental stage and are completely lacking in patients with renal AR.

**3. Computed tomography**

role in diagnostics of renal AR.

for potential clinical application.

**4. Magnetic resonance imaging**

Allograft rejection is the result of interactions between the recipient`s innate and adaptive immune system and the graft antigens serving as a target. Cytotoxic T lymphocytes (CTLs) are central effectors within AR whereas B cells and parts of the congenital immunosystem such as the complement system, monocytes/macrophages, neutrophilic granulocytes, and dendritic cells, have their share, too [4;10]. By recognition of their donor antigen CTLs are activated, undergo clonal expansion and differentiation into effector cells. Subsequently, they migrate into the transplant initiating its destruction [4;10;11]. Before CTLs reach the graft parenchyma, they have to pass the vascular endothelium. This extravasation is mediated by chemoattractant cytokines/chemokines. Chemokines induce the expression of vascular adhesion molecules al‐ lowing leukocytes to roll, adhere, and transmigrate into the parenchyma [12]. CTLs destroy their targets through the release of perforin and granzyme or by initiation of the Fas/FasL pathway inducing cell death by triggering the inherent caspase-mediated apoptotic response or caspase-independent cell death [13]. These two cell death-inducing strategies account for almost all contact-dependent target kills. However, activated CTLs can release additional cy‐ tokines, such as tumor-necrosis factor and interferon causing apoptosis or necrosis upon se‐ cretion [11,13]. Moreover, inflammatory edema and micro thrombi / hemorrhage caused by damaged endothelium add ischemia-dependent hypoxic damage to the graft [11]. All of these single, simplified processes sum up and promote allograft dysfunction. However, if they are characterized at least in part, they can be addressed by different imaging technologies dis‐ cussed in the following.
