**5. Single photon (gamma) imaging and positron emission tomography**

*al.* published an excellent review on imaging of inflammation discussing different techniques,

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

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

93

AR is associated with the expression of cell adhesion molecules like vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), carcinoembryonic antigenrelated cell adhesion molecule 1 (CEACAM1), LFA-1 (lymphocyte function-associated anti‐ gen-1, and endothelial leukocyte adhesion molecule (E-selectin) on the endothelium of organs undergoing rejection. They are "essentially needed" for the adherence and transmigration of leukocytes into the parenchyma. Because radiolabeled antibodies exist for some of these easily accessible vascular targets, they can be addressed by noninvasive imaging. However, data regarding adhesion markers in SPECT/PET-based imaging are rare and have not been trans‐

Because recruitment and activation of inflammatory cells, i.e. lymphocytes, is crucial to AR, efforts have been made to image infiltration by means of labeled leukocytes. Application of *ex vivo* radiolabeled leukocytes is clinically well established particularly in the diagnostic workup of infectious disorders without a focus. Hitherto, white blood cells (WBC) are labeled using for instance 99mTc-HMPAO or 111In-oxine for SPECT and 18F-FDG or 64Cu for PET analysis, respectively [29]. These cells are considered to accumulate highly specific in inflamed tissues

After injection of labeled leukocytes a typical distribution pattern can be observed. First, cells shortly accumulate in the lungs and then continuously migrate from the blood pool into spleen, liver, and bonemarrow, the so called reticulo-endothelial system, and certainly in inflamed sites [34-36]. After endothelial adhesion, labeled leukocytes migrate through the vessel`s wall to the focus of inflammation providing a typical radioactivity pattern indicating infiltration. For instance, Forstrom *et al.* have shown that 18F-FDG labeled leukocytes exhibit comparable distribution patterns in normal human subjects compared with 111In or 99mTc-labeled WBC [37]. Although 18F-FDG seems to exhibit the lowest labeling stability when compared to 111In and 64Cu only neglectible free 18F-FDG uptake can be observed [37]. However, labeling stability is relevant in order to assure that assessed activity refers to accumulation of labeled leukocytes and not to the unlabeled tracer only. Since half-life time of 18F-FDG is 109 min, longtime stability of 18F-FDG labeled leukocytes for clinical analysis is not of interest. However, if longtime sta‐ bility is of interest this could be addressed using other tracers like 99mTc with a half life of

Successful imaging using labeled leukocytes depends on viability of labeled cells. Several studies assessed cell viability after labeling concluding satisfactory and comparable viability rates for 111In, 99mTc, 18F-FDG and 64Cu in the first 4h after labeling [38]. However, cell viability significantly decreases within one day limiting long term monitoring of AR using a single shot

targets, and approaches [27].

**5.2. Vascular adhesion molecules**

ferred to renal AR imaging yet.

[30-33].

approximately 66h.

approach.

**5.3. Imaging using** *ex vivo* **radiolabeled leukocytes**

Because gamma camera/ single photon emission computer tomography (SPECT) and positron emission tomography (PET) offer high intrinsic activity, excellent tissue penetration (depend‐ ing on the tracer), cover the whole organ/ body, are relatively independent of the experience of the investigator and provide a huge variety of clinically tested molecular imaging agents/ tracer, SPECT and PET-based approaches for the detection of renal AR are discussed in the following [27;28]. Steps of AR addressed by SPECT or PET-based approaches include recruit‐ ment of activated leukocytes into the transplant with consecutive cytokine release, cell death, edema, hypoxia and loss of function.


A comprehensive overview of the studies performed is provided in Table 1.

A Medline literature search by PubMed was performed to select papers in which AR and SPECT/PET play any role. The search period was set from 1970 to July 2012. We used ("Acute renal or kidney rejection" and "positron emission to‐ mography (PET)" or "single photon gamma imaging (SPECT)" or "molecular imaging") as search query. Only papers with an English abstract have been included.

**Table 1.** Results of literature analysis: SPECT/PET-based diagnosis of renal AR.

#### **5.1. Inflammation**

Sterile inflammation is central to the rejection process. Hence, it seems logically to assess in‐ flammatory targets for the diagnosis of AR. In inflammation imaging, one can focus on target mechanisms such as measurement of the metabolic activity (i.e. with the "classical" tracer 18Ffluordesoxyglucose (FDG)), binding to cytokines/chemokines (receptors), assessment of phys‐ ically trapped tracers in the inflammatory edema, or using leukocytes. Recently, Signore *et* *al.* published an excellent review on imaging of inflammation discussing different techniques, targets, and approaches [27].

### **5.2. Vascular adhesion molecules**

**5. Single photon (gamma) imaging and positron emission tomography**

A comprehensive overview of the studies performed is provided in Table 1.

**Target Molecular Marker Graft/Organ Species References** Fibrin thrombi 99mTc-Sulfur Colloid Kidney Human, dog [64;65] Proximal tubule uptake 99mTc-DMSA Kidney Human [66;67] Renal uptake and excretion 99mTc-MAG3 Kidney Human [68] Renal perfusion and filtration 99mTc-pentetate (DTPA) Kidney Human [69;70] Leukocytes 99mTc-OKT3 Kidney Human [40] Inflammation 99mTc- Leukocytes Kidney Human [39]

Renal function 131I-OIH Kidney Human [71]

Metabolism/Inflammation 18F-FDG Kidney Rat [43;44] Leukocytes 18F-FDG-Leukocytes Kidney Rat *In press*

A Medline literature search by PubMed was performed to select papers in which AR and SPECT/PET play any role. The search period was set from 1970 to July 2012. We used ("Acute renal or kidney rejection" and "positron emission to‐ mography (PET)" or "single photon gamma imaging (SPECT)" or "molecular imaging") as search query. Only papers with

Sterile inflammation is central to the rejection process. Hence, it seems logically to assess in‐ flammatory targets for the diagnosis of AR. In inflammation imaging, one can focus on target mechanisms such as measurement of the metabolic activity (i.e. with the "classical" tracer 18Ffluordesoxyglucose (FDG)), binding to cytokines/chemokines (receptors), assessment of phys‐ ically trapped tracers in the inflammatory edema, or using leukocytes. Recently, Signore *et*

67Ga citrate Kidney Human [64;65]

edema, hypoxia and loss of function.

92 Current Issues and Future Direction in Kidney Transplantation

an English abstract have been included.

**5.1. Inflammation**

**Table 1.** Results of literature analysis: SPECT/PET-based diagnosis of renal AR.

**SPECT**

PET

Because gamma camera/ single photon emission computer tomography (SPECT) and positron emission tomography (PET) offer high intrinsic activity, excellent tissue penetration (depend‐ ing on the tracer), cover the whole organ/ body, are relatively independent of the experience of the investigator and provide a huge variety of clinically tested molecular imaging agents/ tracer, SPECT and PET-based approaches for the detection of renal AR are discussed in the following [27;28]. Steps of AR addressed by SPECT or PET-based approaches include recruit‐ ment of activated leukocytes into the transplant with consecutive cytokine release, cell death,

AR is associated with the expression of cell adhesion molecules like vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), carcinoembryonic antigenrelated cell adhesion molecule 1 (CEACAM1), LFA-1 (lymphocyte function-associated anti‐ gen-1, and endothelial leukocyte adhesion molecule (E-selectin) on the endothelium of organs undergoing rejection. They are "essentially needed" for the adherence and transmigration of leukocytes into the parenchyma. Because radiolabeled antibodies exist for some of these easily accessible vascular targets, they can be addressed by noninvasive imaging. However, data regarding adhesion markers in SPECT/PET-based imaging are rare and have not been trans‐ ferred to renal AR imaging yet.
