InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Urology and Nephrology » "Current Issues and Future Direction in Kidney Transplantation", book edited by Thomas Rath, ISBN 978-953-51-0985-3, Published: February 13, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 4

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

By Alexander Grabner, Dominik Kentrup, Uta Schnöckel, Michael Schäfers and Stefan Reuter
DOI: 10.5772/54737

Article top


Representative PET-images of dynamic whole body acquisitions of a series of an allogeneically kidney transplanted rat on postoperative day 4 60 min and 120 min after tail vein injection of 30 x 106
							18F-FDG labeled CTL. While the parenchyma (yellow circle) of renal allograft developing AR accumulates 18F-FDG-CTLs, the native kidney (green circle) does not show any accumulation at any time. Please note that the renal pelvis can contain eliminated 18F-FDG/18F-fluoride. Therefore, it has to be excluded from the measurements. ID: injected dose
Figure 1. Representative PET-images of dynamic whole body acquisitions of a series of an allogeneically kidney transplanted rat on postoperative day 4 60 min and 120 min after tail vein injection of 30 x 106 18F-FDG labeled CTL. While the parenchyma (yellow circle) of renal allograft developing AR accumulates 18F-FDG-CTLs, the native kidney (green circle) does not show any accumulation at any time. Please note that the renal pelvis can contain eliminated 18F-FDG/18F-fluoride. Therefore, it has to be excluded from the measurements. ID: injected dose
Representative PET-images of dynamic whole body acquisitions of a series of an allogeneically kidney transplanted rat (POD 1 (A), 2 (B), 4 (C), and 7 (D), after tail vein injection of 18F-FDG. While the parenchyma (yellow circle) of renal allograft developing AR accumulates 18F-FDG with a maximum on post operative day (POD) 4, the native kidney (green circle) does not show any accumulation at any time. Please note that the renal pelvis can contain eliminated 18F-FDG/18F-fluoride. Therefore, it has to be excluded from the measurements. Figure taken from [43]. Scale bar: percent injected dose
Figure 2. Representative PET-images of dynamic whole body acquisitions of a series of an allogeneically kidney transplanted rat (POD 1 (A), 2 (B), 4 (C), and 7 (D), after tail vein injection of 18F-FDG. While the parenchyma (yellow circle) of renal allograft developing AR accumulates 18F-FDG with a maximum on post operative day (POD) 4, the native kidney (green circle) does not show any accumulation at any time. Please note that the renal pelvis can contain eliminated 18F-FDG/18F-fluoride. Therefore, it has to be excluded from the measurements. Figure taken from [43]. Scale bar: percent injected dose

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

Alexander Grabner1, Dominik Kentrup1, Uta Schnöckel2, Michael Schäfers3 and Stefan Reuter1

1. Introduction

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 transplantation 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 proceeds 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 proteinuria, oliguria, hypertension, graft tenderness, or peripheral edema, often lack the desired sensitivity and specificity for early diagnoses of AR. Hence,a compelling need for high sensitive and specific detection of early AR exists, with core needle biopsy still being the “gold-standard” 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.

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 allowing 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 cytokines, such as tumor-necrosis factor and interferon causing apoptosis or necrosis upon secretion [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 discussed in the following.

2. Ultrasound

Standard care in detection of AR includes (Doppler-) ultrasound examination. Typical ultrasound findings in cases of AR are rejection-related graft enlargement (swelling, more globular shape), reduction of corticomedullary differentiation, increased echogenicity, prominent medullary pyramids, or irregularities in the graft perfusion (reversed plateau of diastolic flow), but its specificity and sensitivity for AR is limited, even when echo enhancers are applied [14;15]. Elevated resistance indices can occur in the presence of acute as well as chronic rejection. However, values lower than 0.8 are expected and usually values above 0.8 indicate increased intrarenal pressure as it occurs for example in acute tubular necrosis (ATN) or AR and is linked to a poor longterm renal allograft function [16-18]. Notably, sensitivity and reliability of this method mainly depend on the investigators experience. A comprehensive overview of “What ultrasound can do and cannot do” in diagnostics of renal transplant pathologies was published by Cosgrove and Chan [16]. Using contrast agent or targeted ultrasound in the future, this method might offer significant potential, whereas at present studies are at best at experimental stage and are completely lacking in patients with renal AR.

3. Computed tomography

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 transplantation 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 role in diagnostics of renal AR.

4. Magnetic resonance imaging

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 anatomical information, MR can assess different aspects of renal function. Typical MR findings occurring 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 differentiating AR from ATN and a normal functioning kidney [21,22]. Furthermore, MR renography 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 decrease in AR. However, further studies verifying the results are needed and still some issues about gadolinium-containing contrast agents and nephrogenic systemic fibrosis and gadolinium nephrotoxicity need to be resolved. More recently, Yamamoto et al. proposed a new quantitative analysis method of MR renography, including a multicompartmental tracer kinetic 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 significant accumulation of iron particles but only within a time frame of 72 h which is much too late for potential clinical application.

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

Because gamma camera/ single photon emission computer tomography (SPECT) and positron emission tomography (PET) offer high intrinsic activity, excellent tissue penetration (depending 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 recruitment 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.

Target Molecular Marker Graft/Organ Species References
Fibrin thrombi 99mTc-Sulfur ColloidKidneyHuman, dog[64;65]
Proximal tubule uptake 99mTc-DMSAKidneyHuman[66;67]
Renal uptake and excretion 99mTc-MAG3KidneyHuman[68]
Renal perfusion and filtration 99mTc-pentetate (DTPA)KidneyHuman[69;70]
Leukocytes 99mTc-OKT3KidneyHuman[40]
Inflammation 99mTc- LeukocytesKidneyHuman[39]
67Ga citrateKidneyHuman[64;65]
Renal function 131I-OIHKidneyHuman[71]
Metabolism/Inflammation 18F-FDGKidneyRat[43;44]
Leukocytes 18F-FDG-LeukocytesKidneyRat In press

Table 1.

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

[i] - 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 tomography (PET)" or "single photon gamma imaging (SPECT)" or "molecular imaging") as search query. Only papers with an English abstract have been included.

5.1. Inflammation

Sterile inflammation is central to the rejection process. Hence, it seems logically to assess inflammatory 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 18F-fluordesoxyglucose (FDG)), binding to cytokines/chemokines (receptors), assessment of physically 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

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 antigen-related cell adhesion molecule 1 (CEACAM1), LFA-1 (lymphocyte function-associated antigen-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 transferred to renal AR imaging yet.

5.3. Imaging using ex vivo radiolabeled leukocytes

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 [30-33].

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 stability is of interest this could be addressed using other tracers like 99mTc with a half life of approximately 66h.

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 approach.

At present only a few preclinical and clinical studies are published dealing with labeled leukocytes and detection of AR in intestine, hearts, pancreas islets and skin. Only one study performed in a small cohort of kidney transplant recipients evaluated 99mTc-mononuclear cell scintigraphy for diagnosis of AR. In this study, the authors were able to show that AR was diagnosed correctly and successfully discriminated from ATN [39]. In a further development of their approach, we established leukocyte PET imaging using very low amounts of 18F-FDG for the diagnosis of AR in a rat kidney transplant model. Ex vivo 18F-FDG labeled human CTLs were able to diagnose renal AR within a time frame of 1 h after application and discriminate AR from important differential diagnoses such as acute cyclosporine toxicity or ATN (Grabner et al. in press) (Fig. 1).


Figure 1.

Representative PET-images of dynamic whole body acquisitions of a series of an allogeneically kidney transplanted rat on postoperative day 4 60 min and 120 min after tail vein injection of 30 x 106 18F-FDG labeled CTL. While the parenchyma (yellow circle) of renal allograft developing AR accumulates 18F-FDG-CTLs, the native kidney (green circle) does not show any accumulation at any time. Please note that the renal pelvis can contain eliminated 18F-FDG/18F-fluoride. Therefore, it has to be excluded from the measurements. ID: injected dose

Since infiltration of leukocytes, especially CTLs, in allografts appears before physiologic or mechanical manifestations of organ dysfunction is apparent, nuclear imaging employing leukocytes might be a promising tool for specific, sensitive and early detection of AR.

5.4. Imaging using in vivo radiolabeled leukocytes

Instead of employing ex vivo labeled leukocytes, radiolabeled monoclonal antibodies (fragments) (mAbs) have been established for detection of leukocyte (related) antigens. Their advantages include standardized production, easier storage and handling, while they are highly specific for their target leading to a good background/target ration. However, limitations might be the targeting of extravascular antigens and potential but rare allergic complications, when using the antibodies in a patient.

As discussed, CTLs are the major cell type involved in AR. Martins et al. used 99mTc-OKT3 targeting CTLs in recipients of renal transplants [40]. In their preliminary results they state that out of 22 patients they successfully identified 3 patients with AR using 99mTc-OKT3 scans. Apparently, their results published in 2004 have to be confirmed in further studies. A recently published attractive, being somehow better biocompatible, alternative might be CD3 targeting 99mTc-SHNH-visilizumab which needs to be evaluated in the future [41].

5.5. Metabolic activity (18F-FDG)

18F-FDG is a daily routine tracer to assess regional glucose metabolism as a surrogate for metabolic activity widely used for the PET-based routine detection of tumors, infection and inflammation. The major energy source in leukocytes during the metabolic burst is glucose. Analogously, activated leukocytes highly accumulate 18F-FDG (in the same way they take up glucose but without further processing) which can be quantified by PET [42]. A clear limitation when using free 18F-FDG is that an increased uptake can be observed in any kind of cellular activation (high glycolytic activity). Hence, 18F-FDG is not a disease or target specific tracer.

Nevertheless, 18F-FDG is one of the few tracers successfully applied for the non-invasive detection of AR. Others have applied 18F-FDG in settings of lung, heart and liver transplantations. We have demonstrated very promising results for 18F-FDG-PET in diagnostics of renal AR [43;44]. Using a rat model of renal AR, 18F-FDG-PET performed well in terms of early, accurate detection and follow-up of AR [43] (Fig. 2). Using 18F-FDG, we discriminated AR non-invasively from important differential diagnoses like ATN or acute cyclosporine toxicity. Moreover, therapy response monitoring by 18F-FDG might be useful to identify treatment unresponsive AR for earlier escalation of immunosuppressive regimen [44]. This might reduce graft damage by shortening AR episodes because at present (steroid) resistant rejection is diagnosed lately [45].

One important issue of imaging of kidney AR with 18F-FDG is that it is eliminated with the urine in contrast to normal glucose. Thus, drainage of 18F-FDG into the renal pelvis must be taken care of when assessing 18F-FDG-uptake in the renal parenchyma. We avoided this problem by using late acquisitions after 18F-FDG injection to reduce the instantaneous amount of tracer in the urine during the PET scan. Moreover, an impact of renal function on 18F-FDG-uptake has to be excluded e.g. by renal fluoride clearance (a non-invasive measure of renal function) [46].


Figure 2.

Representative PET-images of dynamic whole body acquisitions of a series of an allogeneically kidney transplanted rat (POD 1 (A), 2 (B), 4 (C), and 7 (D), after tail vein injection of 18F-FDG. While the parenchyma (yellow circle) of renal allograft developing AR accumulates 18F-FDG with a maximum on post operative day (POD) 4, the native kidney (green circle) does not show any accumulation at any time. Please note that the renal pelvis can contain eliminated 18F-FDG/18F-fluoride. Therefore, it has to be excluded from the measurements. Figure taken from [43]. Scale bar: percent injected dose

5.6. Matrix metalloproteinases

One step further, one cannot assess infiltrating leukocytes only but rather their tissue damaging activity by detection of activated matrix metalloproteinases (MMPs). Leukocyte-derived MMPs, like MMP-2 or MMP-9, were found to be active in AR [47;48]. Since MMP activity can be assessed using radiolabeled MMP-inhibitors in SPECT or PET this approach for detection of AR might be evaluated in future studies [49-52]. Maybe one can gather additional information regarding graft`s prognosis because MMPs are involved in tissue remodelling, too.

5.7. Hypoxia

Acute tissue inflammations regardless of their origin present with a unique and challenging microenvironment including hypoxia (low oxygen), anoxia (complete lack of oxygen), hypoglycemia (low blood glucose), acidosis (high H+ concentration) and abundant free oxygen radicals. These conditions are characteristic features of inflamed tissues, along with the influx of leukocytes. In renal allografts, hypoxia and hypoxic adaptation are common within 2 weeks after surgery whereas graft hypoxia assessed in the long run is associated with clinical/subclinical rejection [53]. Therefore, assessment of hypoxia by targeting hypoxia (related gene products), i.e. hypoxia inducible factors (HIF), might offer additional diagnostic information in subclinical or ambiguous cases of AR.

Two major classes of hypoxia tracer, nitroimidazoles and bis(thiosemicarbazonato)copper(II) complexes, have been extensively investigated for measuring hypoxia. The applications of both tracer as well as several alternative reagents tested e.g., 18F-fluoroerythronitroimidazole (18F-FETNIM) and 18F-fluoroazomycin-arabinofuranoside (18F-FAZA), are summarized in a review recently published by Krohn et al. [54]. Until present and to the best of our knowledge, no study has been performed assessing hypoxia in renal AR by SPECT or PET so far. At least one has to evaluate if the SPECT and PET-based approaches are advantageous when compared to BOLD MR.

5.8. Apoptosis

Apoptosis in AR is probably the result of different events occurring in AR. It may be a direct consequence of different cytokines discharged by leukocytes or directly provoked e.g. by CTLs. Within the inflammatory milieu of AR apoptosis might, among other factors, also be related to hypoxia, acidosis, or reactive oxygen species. Non-invasive detection of apoptosis in AR might be attractive because it may not serve for early detection of AR only, but also for monitoring of rejection kinetics and therapy response. Especially, early assessment of therapeutic success or failure is interesting to promptly adjust the therapeutic regimen. Likewise, quantification of apoptosis might provide information regarding the extent of graft damage and therefore for its prognosis. However, small studies with different tracers targeting different steps in apoptosis have been performed in both, animal and man. A comprehensive review on detecting cell death in vivo has been recently published by us [55]. Two main operational strategies are followed. While imaging of caspases` activity using substrate-derived agents offers high selectivity, the detection of membrane phospholipid redistribution using extracellular agents has the advantage of high target density and accessibility [56]. We and others recently proposed different isatin analogues for 18F-labeling and detection of apoptosis [55]. However, studies detecting apoptosis in renal grafts using radiotracers for evaluation of their potential clinical value in AR have not been performed yet.

5.9. Imaging allograft function

A rather unspecific but reasonable approach is to simply determine graft function as a surrogate for stable function or (acute) graft affection.

Especially scintigraphic methods have been established for the assessment of renal function. Primarily, two types of imaging are common: static and dynamic. 99mTc-dimercaptosuccinic acid (DMSA) is the tracer used in static imaging allowing on the one hand identification of pathological conditions such as anatomical abnormalities or scarring, on the other hand accurate assessment of the differential function of the kidneys [57]. DMSA uptake correlates with the effective renal plasma flow, glomerular filtration rate, and creatinine clearance. Therefore, DMSA has been successfully applied in the evaluation of renal function in living donors (before and after transplantation) and in kidney recipients [58]. For dynamic imaging 99mTc-mercaptoacetyltriglycine (MAG-3) and diethylenetriaminepentaacetic acid (DTPA) are the most commonly used tracers, whereas MAG-3 is going to replace DTPA because of superior extraction efficiency. It was proposed that MAG-3 scintigraphy can be useful for discrimination of AR from ATN [59]. Despite a reasonable perfusion and tracer extraction in ATN as assessed in these studies, tracer excretion rate is low, whereas one of the typical findings in AR is impaired perfusion. This fact was already taken into account by Hilson et al. in the seventies who developed a DTPA-based perfusion index which allows separation of rejection from ATN and, particularly, rejection from healthy kidneys [60]. These findings are somehow discrepant to typical findings in ultrasound when assessing RI which reflects renal perfusion as well. High RIs can be observed in ATN as well as in AR denying a differentiation of these entities by ultrasound-based measure of renal perfusion. Potentially, the modified renal perfusion index using 18F-fluoride developed by us can be used for further clarification [61]. Aside from this recent studies using PET for the evaluation of renal function other approaches have been emerged. Renal blood flow for instance was successfully measured with H215O in rats and man [62,63]. Furthermore, we established 18F-fluoride clearance for assessment of renal function in different renal failure models including AR [43,46]. As said before, decreased renal function is not disease specific but can assist in the differential diagnoses of AR.

6. Conclusion

The diagnosis and therapy follow-up of AR in transplant recipients demands for non-invasive and serial imaging approaches in vivo. Molecular and cellular imaging has significant potential for transplantation medicine as it may serve for monitoring the graft. With more optimal tracers as they are numerously being developed, PET (and other devices) may serve as valuable tools for the diagnosis and management of renal AR. In this term, these techniques will find their share to impact on detection of AR, graft function, assessment of therapy response as well as of the progression of lesions and therefore on graft´s prognosis.

Taken the new developments in molecular imaging into account, non-invasive methods including ultrasound, magnetic resonance, as well as SPECT and PET get increasingly helpful for research. Currently, nearly all of these promising new approaches are still at an experimental stage and have to evidence their potential in humans in daily routine in the future.


This work was supported by the Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereich 656, Münster, Germany (SFB 656 C7).


1 - K. E Lamb, S Lodhi, H. U Meier-Kriesche, Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant 2011Mar;11345062
2 - A Lemy, M Andrien, A Lionet, M Labalette, C Noel, C Hiesse, et alPosttransplant Major Histocompatibility Complex Class I Chain-Related Gene A Antibodies and Long-Term Graft Outcomes in a Multicenter Cohort of 779 Kidney Transplant Recipients. Transplantation 2012Mar 29.
3 - D. J Cohen, M. L St, L. L Christensen, R. D Bloom, R. S Sung, Kidney and pancreas transplantation in the United States, 19952004Am J Transplant 2006;6(5 Pt 2):1153-69.
4 - L. D Cornell, R. N Smith, R. B Colvin, Kidney transplantation: mechanisms of rejection and acceptance. Annu Rev Pathol 20083189220
5 - A. J Matas, K. J Gillingham, W. D Payne, J. S Najarian, The impact of an acute rejection episode on long-term renal allograft survival (t1/2). Transplantation 1994Mar 27;5768579
6 - O Wu, A. R Levy, A Briggs, G Lewis, A Jardine, Acute rejection and chronic nephropathy: a systematic review of the literature. Transplantation 2009May 15;87913309
7 - H. U Meier-kriesche, A. O Ojo, J. A Hanson, D. M Cibrik, J. D Punch, A. B Leichtman, et alIncreased impact of acute rejection on chronic allograft failure in recent era. Transplantation 2000Oct 15;7071098100
8 - J. R Chapman, O Connell, P. J Nankivell, BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol 2005Oct;1610301526
9 - Z. A Massy, C Guijarro, M. R Wiederkehr, J. Z Ma, B. L Kasiske, Chronic renal allograft rejection: immunologic and nonimmunologic risk factors. Kidney Int 1996Feb;49251824
10 - V Nickeleit, K Andreoni, Inflammatory cells in renal allografts. Front Biosci 200813620213
11 - E Ingulli, Mechanism of cellular rejection in transplantation. Pediatr Nephrol 2010Jan;2516174
12 - R. L Dedrick, S Bodary, M. R Garovoy, Adhesion molecules as therapeutic targets for autoimmune diseases and transplant rejection. Expert Opin Biol Ther 2003Feb;318595
13 - M Barry, R. C Bleackley, Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2002Jun;264019
14 - T Fischer, S Filimonow, J Dieckhofer, T Slowinski, M Muhler, A Lembcke, et alImproved diagnosis of early kidney allograft dysfunction by ultrasound with echo enhancer--a new method for the diagnosis of renal perfusion. Nephrol Dial Transplant 2006Oct;211029219
15 - A Kirkpantur, R Yilmaz, D. E Baydar, T Aki, B Cil, M Arici, et alUtility of the Doppler ultrasound parameter, resistive index, in renal transplant histopathology. Transplant Proc 2008Jan;4011046
16 - D. O Cosgrove, K. E Chan, Renal transplants: what ultrasound can and cannot do. Ultrasound Q 2008Jun;2427787
17 - J Radermacher, M Mengel, S Ellis, S Stuht, M Hiss, A Schwarz, et alThe renal arterial resistance index and renal allograft survival. N Engl J Med 2003Jul 10;349211524
18 - R Kramann, D Frank, V. M Brandenburg, N Heussen, J Takahama, T Kruger, et alPrognostic impact of renal arterial resistance index upon renal allograft survival: the time point matters. Nephrol Dial Transplant 2012Jan 13.
19 - C Sebastia, S Quiroga, R Boye, C Cantarell, M Fernandez-planas, A Alvarez, Helical CT in renal transplantation: normal findings and early and late complications. Radiographics 2001Sep;215110317
20 - B Kalb, D. R Martin, K Salman, P Sharma, J Votaw, C Larsen, Kidney transplantation: structural and functional evaluation using MR Nephro-Urography. J Magn Reson Imaging 2008Oct;28480522
21 - E. A Sadowski, S. B Fain, S. K Alford, F. R Korosec, J Fine, R Muehrer, et alAssessment of acute renal transplant rejection with blood oxygen level-dependent MR imaging: initial experience. Radiology 2005Sep;23639119
22 - E. A Sadowski, A Djamali, A. L Wentland, R Muehrer, B. N Becker, T. M Grist, et alBlood oxygen level-dependent and perfusion magnetic resonance imaging: detecting differences in oxygen bioavailability and blood flow in transplanted kidneys. Magn Reson Imaging 2010Jan;2815664
23 - A. L Wentland, E. A Sadowski, A Djamali, T. M Grist, B. N Becker, S. B Fain, Quantitative MR measures of intrarenal perfusion in the assessment of transplanted kidneys: initial experience. Acad Radiol 2009Sep;169107785
24 - J. A De Priester, den Boer JA, Christiaans MH, Kessels AG, Giele EL, Hasman A, et al. Automated quantitative evaluation of diseased and nondiseased renal transplants with MR renography. J Magn Reson Imaging 2003Jan;17195103
25 - A Yamamoto, J. L Zhang, H Rusinek, H Chandarana, P. H Vivier, J. S Babb, et alQuantitative evaluation of acute renal transplant dysfunction with low-dose three-dimensional MR renography. Radiology 2011Sep;26037819
26 - O Hauger, N Grenier, C Deminere, C Lasseur, Y Delmas, P Merville, et alUSPIO-enhanced MR imaging of macrophage infiltration in native and transplanted kidneys: initial results in humans. Eur Radiol 2007Nov;17112898907
27 - A Signore, S. J Mather, G Piaggio, G Malviya, R. A Dierckx, Molecular imaging of inflammation/infection: nuclear medicine and optical imaging agents and methods. Chem Rev 2010May 12;1105311245
28 - L. T Hall, A. F Struck, S. B Perlman, Clinical Molecular Imaging with PET Agents other than (18)F-FDG. Curr Pharm Biotechnol 2010Apr 26.
29 - N Dumarey, D Egrise, D Blocklet, B Stallenberg, M Remmelink, M Del, V, et alImaging infection with 18F-FDG-labeled leukocyte PET/CT: initial experience in 21 patients. J Nucl Med 2006Apr;47462532
30 - F. L Datz, Indium-111-labeled leukocytes for the detection of infection: current status. Semin Nucl Med 1994Apr;24292109
31 - A. M Peters, The utility of [99mTc]HMPAO-leukocytes for imaging infection. Semin Nucl Med 1994Apr;24211027
32 - A. M Peters, H. J Danpure, S Osman, R. J Hawker, B. L Henderson, H. J Hodgson, et alClinical experience with 99mTc-hexamethylpropylene-amineoxime for labelling leucocytes and imaging inflammation. Lancet 1986Oct 25;285139469
33 - J. G Mcafee, M. L Thakur, Survey of radioactive agents for in vitro labeling of phagocytic leukocytes. I. Soluble agents. J Nucl Med 1976Jun;1764807
34 - M Isobe, E Haber, B. A Khaw, Early detection of rejection and assessment of cyclosporine therapy by 111In antimyosin imaging in mouse heart allografts. Circulation 1991Sep;843124655
35 - L. A Forstrom, W. L Dunn, F. A Rowe, M Camilleri, In-oxine-labelled granulocyte dosimetry in normal subjects. Nucl Med Commun 1995May;16534956
36 - H. J Eisen, S. B Eisenberg, J. E Saffitz, R. M Bolman, III, Sobel BE, Bergmann SR. Noninvasive detection of rejection of transplanted hearts with indium-111-labeled lymphocytes. Circulation 1987Apr;75486876
37 - L. A Forstrom, W. L Dunn, B. P Mullan, J. C Hung, V. J Lowe, L. M Thorson, Biodistribution and dosimetry of [(18)F]fluorodeoxyglucose labelled leukocytes in normal human subjects. Nucl Med Commun 2002Aug;2387215
38 - K. K Bhargava, R. K Gupta, K. J Nichols, C. J Palestro, In vitro human leukocyte labeling with (64)Cu: an intraindividual comparison with (111)In-oxine and (18)F-FDG. Nucl Med Biol 2009Jul;3655459
39 - Lopes de Souza SABarbosa da Fonseca LM, Torres GR, Salomao PD, Holzer TJ, Proenca Martins FP, et al. Diagnosis of renal allograft rejection and acute tubular necrosis by 99mTc-mononuclear leukocyte imaging. Transplant Proc 2004Dec;361029973001
40 - F. P Martins, S. A Souza, R. T Goncalves, L. M Fonseca, B Gutfilen, Preliminary results of [99mTc]OKT3 scintigraphy to evaluate acute rejection in renal transplants. Transplant Proc 2004Nov;36926647
41 - L Shan, m Tc-labeled, succinimidyl-6hydrazinonicotinate hydrochloride (SHNH)-conjugated visilizumab. 2004
42 - D Pellegrino, A. A Bonab, S. C Dragotakes, J. T Pitman, G Mariani, E. A Carter, Inflammation and infection: imaging properties of 18F-FDG-labeled white blood cells versus 18F-FDG. J Nucl Med 2005Sep;469152230
43 - S Reuter, U Schnockel, R Schroter, O Schober, H Pavenstadt, M Schafers, et alNon-invasive imaging of acute renal allograft rejection in rats using small animal F-FDG-PET. PLoS One 2009e5296.
44 - S Reuter, U Schnockel, B Edemir, R Schroter, D Kentrup, H Pavenstadt, et alPotential of noninvasive serial assessment of acute renal allograft rejection by 18F-FDG PET to monitor treatment efficiency. J Nucl Med 2010Oct;5110164452
45 - R. D Guttmann, J. P Soulillou, L. W Moore, M. R First, A. O Gaber, P Pouletty, et alProposed consensus for definitions and endpoints for clinical trials of acute kidney transplant rejection. Am J Kidney Dis 1998Jun;31(6 Suppl 1):S40S46.
46 - U Schnockel, S Reuter, L Stegger, E Schlatter, K. P Schafers, S Hermann, et alDynamic 18F-fluoride small animal PET to noninvasively assess renal function in rats. Eur J Nucl Med Mol Imaging 2008Dec;3512226774
47 - B Edemir, S. M Kurian, M Eisenacher, D Lang, C Muller-tidow, G Gabriels, et alActivation of counter-regulatory mechanisms in a rat renal acute rejection model. BMC Genomics 2008
48 - G Einecke, J Reeve, B Sis, M Mengel, L Hidalgo, K. S Famulski, et alA molecular classifier for predicting future graft loss in late kidney transplant biopsies. J Clin Invest 2010Jun;1206186272
49 - S Wagner, H. J Breyholz, C Holtke, A Faust, O Schober, M Schafers, et alA new 18F-labelled derivative of the MMP inhibitor CGS 27023A for PET: radiosynthesis and initial small-animal PET studies. Appl Radiat Isot 2009Apr;67460610
50 - H. J Breyholz, S Wagner, A Faust, B Riemann, C Holtke, S Hermann, et alRadiofluorinated pyrimidine-2,4,6-triones as molecular probes for noninvasive MMP-targeted imaging. ChemMedChem 2010May 3;5577789
51 - V Hugenberg, H. J Breyholz, B Riemann, S Hermann, O Schober, M Schafers, et alA new class of highly potent matrix metalloproteinase inhibitors based on triazole-substituted hydroxamates: (radio)synthesis and in vitro and first in vivo evaluation. J Med Chem 2012May 24;5510471427
52 - D Schrigten, H. J Breyholz, S Wagner, S Hermann, O Schober, M Schafers, et alA new generation of radiofluorinated pyrimidine-2,4,6-triones as MMP-targeted radiotracers for positron emission tomography. J Med Chem 2012Jan 12;55122332
53 - C Rosenberger, J Pratschke, B Rudolph, S. N Heyman, R Schindler, N Babel, et alImmunohistochemical detection of hypoxia-inducible factor-1alpha in human renal allograft biopsies. J Am Soc Nephrol 2007Jan;18134351
54 - K. A Krohn, J. M Link, R. P Mason, Molecular imaging of hypoxia. J Nucl Med 2008Jun;49 Suppl 2:129S-48S.
55 - A Faust, S Hermann, S Wagner, G Haufe, O Schober, M Schafers, et alMolecular imaging of apoptosis in vivo with scintigraphic and optical biomarkers--a status report. Anticancer Agents Med Chem 2009Nov;9996885
56 - M Zhao, Molecular Recognition Mechanisms for Detecting Cell Death In Vivo. Curr Pharm Biotechnol 2010May 24.
57 - S. F Hain, Renal imaging. Clin Med 2006May;632448
58 - E Even-sapir, A Weinbroum, H Merhav, H Lerman, G Livshitz, R Nakache, Renal allograft function prior to and following living related transplantation: assessment by quantitative Tc99m DMSA SPECT. Transplant Proc 2001Sep;33629245
59 - G. N Sfakianakis, E Sfakianaki, M Georgiou, A Serafini, S Ezuddin, R Kuker, et alA renal protocol for all ages and all indications: mercapto-acetyl-triglycine (MAG3) with simultaneous injection of furosemide (MAG3-F0): a 17-year experience. Semin Nucl Med 2009May;39315673
60 - A. J Hilson, M. N Maisey, C. B Brown, C. S Ogg, M. S Bewick, Dynamic renal transplant imaging with Tc-99m DTPA (Sn) supplemented by a transplant perfusion index in the management of renal transplants. J Nucl Med 1978Sep;1999941000
61 - D Kentrup, S Reuter, U Schnockel, A Grabner, B Edemir, H Pavenstadt, et alHydroxyfasudil-mediated inhibition of ROCK1 and ROCK2 improves kidney function in rat renal acute ischemia-reperfusion injury. PLoS One 2011e26419.
62 - N Kudomi, N Koivuviita, K. E Liukko, V. J Oikonen, T Tolvanen, H Iida, et alParametric renal blood flow imaging using [15O]H2O and PET. Eur J Nucl Med Mol Imaging 2009Apr;36468391
63 - L Juillard, M. F Janier, D Fouque, L Cinotti, N Maakel, B. D Le, et alDynamic renal blood flow measurement by positron emission tomography in patients with CRF. Am J Kidney Dis 2002Nov;40594754
64 - E. A George, J. E Codd, W. T Newton, H Haibach, R. M Donati, Comparative evaluation of renal transplant rejection with radioiodinated fibrinogen 99mTc-sulfur collid, and 67Ga-citrate. J Nucl Med 1976Mar;17317580
65 - E. A George, J. E Codd, W. T Newton, R. M Donati, Ga citrate in renal allograft rejection. Radiology 1975Dec;117(3 Pt 1):731-3.
66 - E Even-sapir, M Gutman, H Lerman, E Kaplan, A Ravid, G Livshitz, et alKidney allografts and remaining contralateral donor kidneys before and after transplantation: assessment by quantitative (99m)Tc-DMSA SPECT. J Nucl Med 2002May;4355848
67 - N. V Budihna, M Milcinski, M Kajtna-koselj, M Malovrh, Relevance of Tc-99m DMSA scintigraphy in renal transplant parenchymal imaging. Clin Nucl Med 1994Sep;1997824
68 - M. T Bajen, J Mora, J. M Grinyo, A Castelao, M Roca, R Puchal, et alStudy of renal transplant by deconvoluted renogram with 99m Tc-mercaptoacetyltriglycine (Mag3)]. Rev Esp Med Nucl 2001Oct;20645361
69 - E. V Dubovsky, C. D Russell, A Bischof-delaloye, B Bubeck, T Chaiwatanarat, A. J Hilson, et alReport of the Radionuclides in Nephrourology Committee for evaluation of transplanted kidney (review of techniques). Semin Nucl Med 1999Apr;29217588
70 - S Sundaraiya, I Mendichovszky, L Biassoni, N Sebire, R. S Trompeter, I Gordon, Tc-99m DTPA renography in children following renal transplantation: its value in the evaluation of rejection. Pediatr Transplant 2007Nov;1177716
71 - O Salvatierra, Jr., Powell MR, Price DC, Kountz SL, Belzer FO. The advantages of 131I-orthoiodohippurate scintiphotography in the management of patients after renal transplantation. Ann Surg 1974Sep;180333642