Early Detection Of Acute Rejection Research Articles

A Comprehensive Excursus of the Roles of Echocardiography in Heart Transplantation Follow-Up.

Current guidelines for the care of heart transplantation recipients recommend routine endomyocardial biopsy and invasive coronary angiography as the cornerstones in the surveillance for acute rejection (AR) and coronary allograft vasculopathy (CAV). Non-invasive tools, including coronary computed tomography angiography and cardiac magnetic resonance, have been introduced into guidelines without roles of their own as gold standards. These techniques also carry the risk of contrast-related kidney injury. There is a need to explore non-invasive approaches providing valuable information while minimizing risks and allowing their application independently of patient comorbidities. Echocardiographic examination can be performed at bedside, serially repeated, and does not carry the burden of contrast-related kidney injury and procedure-related risk. It provides comprehensive assessment of cardiac morphology and function. Advanced echocardiography techniques, including Doppler tissue imaging and strain imaging, may be sensitive tools for the detection of minor myocardial dysfunction, thus providing insight into early detection of AR and CAV. Stress echocardiography may offer a valuable tool in the detection of CAV, while the assessment of coronary flow reserve can unravel coronary microvascular impairment and add prognostic value to conventional stress echocardiography. The review highlights the role of Doppler echocardiography in heart transplantation follow-up, weighting advantages and limitations of the different techniques.

Donor-derived cell free DNA as a biomarker in kidney transplantation.

The early detection of acute rejection in the allograft is important as it provides an opportunity for timely therapeutic intervention in order to preserve graft function and achieve longer graft survival. Donor-derived cell-free DNA (dd-cfDNA) has emerged as a new biomarker in the field of kidney transplantation. In this review, we used data from various studies to examine the role of dd-cfDNA in comparison to creatinine and donor-specific antibodies in theearly detection of transplant rejection. We also reviewed the use of dd-cfDNA in other organ transplants as well as the challenges and potential future direction for dd-cfDNA as a diagnostic tool.

Amplification of Plasma MicroRNAs for Non-invasive Early Detection of Acute Rejection after Heart Transplantation With Ultrasound-Targeted Microbubble Destruction.

Acute rejection (AR) screening has always been the focus of patient management in the first several years after heart transplantation (HT). As potential biomarkers for the non-invasive diagnosis of AR, microRNAs (miRNAs) are limited by their low abundance and complex origin. Ultrasound-targeted microbubble destruction (UTMD) technique could temporarily alter vascular permeability through cavitation. We hypothesized that increasing the permeability of myocardial vessels might enhance the abundance of circulating AR-related miRNAs, thus enabling the non-invasive monitoring of AR. The Evans blue assay was applied to determine efficient UTMD parameters. Blood biochemistry and echocardiographic indicators were used to ensure the safety of the UTMD. AR of the HT model was constructed using Brown-Norway and Lewis rats. Grafted hearts were sonicated with UTMD on postoperative day (POD) 3. The polymerase chain reaction was used to identify upregulated miRNA biomarkers in graft tissues and their relative amounts in the blood. Amounts of six kinds of plasma miRNA, including miR-142-3p, miR-181a-5p, miR-326-3p, miR-182, miR-155-5p and miR-223-3p, were 10.89 ± 1.36, 13.54 ± 2.15, 9.84 ± 0.70, 8.55 ± 2.00, 12.50 ± 3.96 and 11.02 ± 3.47 times higher in the UTMD group than those in the control group on POD 3. Plasma miRNA abundance in the allograft group without UTMD did not differ from that in the isograft group on POD 3. After FK506 treatment, no miRNAs increased in the plasma after UTMD. UTMD can promote the transfer of AR-related miRNAs from grafted heart tissue to the blood, allowing non-invasive early detection of AR.

Estimating filling pressures in paediatric heart transplant recipients using echocardiographic parameters and B-type natriuretic peptide.

Longitudinal evaluation of allograft diastolic function in paediatric heart transplant recipients is important for early detection of acute rejection, cardiac allograft vasculopathy, and graft dysfunction. Mean diastolic right atrial and pulmonary capillary wedge pressures obtained at catheterisation are the reference standards for assessment. Echocardiography is non-invasive and more suitable for serial surveillance, but individual parameters have lacked accuracy. This study aimed to identify covariates of post-transplant mean right atrial and pulmonary capillary wedge pressures, including B-type natriuretic peptide and certain echocardiographic parameters. A retrospective review of 143 scheduled cardiac catheterisations and echocardiograms from 56 paediatric recipients transplanted from 2007 to 2011 was performed. Samples with rejection were excluded. Univariate and multivariate linear regression models using backward selection were applied to a database consisting of B-type natriuretic peptide, haemodynamic, and echocardiographic data. Ln B-type natriuretic peptide, heart rate z-score, left ventricular end-diastolic dimension z-score, mitral E/e', and percent interventricular septal thickening in systole were independently associated with mean right atrial pressure. Ln B-type natriuretic peptide, heart rate z-score, left ventricular end-diastolic dimension z-score, left ventricular mass (observed/predicted), and mitral E/e' were independently associated with mean pulmonary capillary wedge pressure. Covariates of B-type natriuretic peptide included mean pulmonary artery and pulmonary capillary wedge pressures, height, haemoglobin, fractional shortening, percent interventricular septal thickening in systole, and pulmonary vascular resistance index. B-type natriuretic peptide and echocardiographic indices of diastolic function were independently related to post-transplant mean right atrial and pulmonary capillary wedge pressures in paediatric heart transplant recipients without rejection.

Circulating Donor Lung-specific Exosome Profiles Enable Noninvasive Monitoring of Acute Rejection in a Rodent Orthotopic Lung Transplantation Model.

There is a critical need for development of biomarkers to noninvasively monitor for lung transplant rejection. We investigated the potential of circulating donor lung-specific exosome profiles for time-sensitive diagnosis of acute rejection in a rat orthotopic lung transplant model. Left lungs from Wistar transgenic rats expressing human CD63-GFP, an exosome marker, were transplanted into fully MHC-mismatched Lewis recipients or syngeneic controls. Recipient blood was collected between 4 h and 10 d after transplantation, and plasma was processed for exosome isolation by size exclusion column chromatography and ultracentrifugation. Circulating donor exosomes were profiled using antihuman CD63 antibody quantum dot on the nanoparticle detector and via GFP trigger on the nanoparticle flow cytometer. In syngeneic controls, steady-state levels of circulating donor exosomes were detected at all posttransplant time points. Allogeneic grafts lost perfusion by day 8, consistent with acute rejection. Levels of circulating donor exosomes peaked on day 1, decreased significantly by day 2, and then reached baseline levels by day 3. Notably, decrease in peripheral donor exosome levels occurred before grafts had histological evidence of acute rejection. Circulating donor lung-specific exosome profiles enable an early detection of acute rejection before histologic manifestation of injury to the pulmonary allograft. As acute rejection episodes are a major risk factor for the development of chronic lung allograft dysfunction, this biomarker may provide a novel noninvasive diagnostic platform that can translate into earlier therapeutic intervention for lung transplant patients.

A URINE SCORE FOR NON-INVASIVE ACCURATE DIAGNOSIS AND PREDICTION OF KIDNEY TRANSPLANT REJECTION

Introduction: Accurate and non-invasive monitoring of renal allografts post-transplant is essential for early detection of acute rejection (AR) and to impact the long-term survival of the transplant. We present the development and validation of a noninvasive, spot urine-based diagnostic assay, based on measurements of six urinary DNA, protein, and metabolic biomarkers. Materials and Methods: Male and female, adult and pediatric, patients receiving a kidney from related, unrelated living donors, or unrelated deceased donors were included. Markers were selected based on legacy urine genomic, metabolomic, and proteomic studies conducted by our group. For microwell-based measurement of cfDNA, we developed a 5’ biotinylated oligonucleotide complementary chemiluminescent immunoprobe for the measurement of specific target cfDNA fragments, as previously described. Streptavidin-HRP (R&D Systems) and SuperSignal ELISA Femto Substrate (Thermo Fisher Scientific) were used for luminescent detection and quantitation. CXCL10, clusterin, and methylated cfDNA (m-cfDNA) were measured using custom-developed assays. Total protein was measured using the Pierce Coomassie Plus (Bradford) Assay Kit (Thermo Fisher Scientific). Urinary creatinine was used to normalize the five other biomarkers for urinary concentration and hydration status and was measured using the Creatinine Assay Kit (BioAssay Systems). Results: The performance of this assay for detecting kidney injury in both native kidneys and renal allografts is presented on a cohort of 601 distinct urine samples. The urinary composite score enables diagnosis of AR, with a receiver-operator characteristic (ROC) curve area-under-the-curve (AUC) of 0.99. In addition, we demonstrate the clinical utility of this assay for predicting AR, prior to a rise in the serum creatinine, enabling earlier detection of rejection than currently possible by standard of care tests.Conclusion: This noninvasive, sensitive, and quantitative approach is a robust and informative method for the rapid and routine monitoring of renal allografts.

Trends of non-coding RNAs research in acute rejection after kidney transplantation

The success of kidney transplantation as the treatment of choice for patients with end-stage kidney diseases (ESKD) is hindered by eventual failure of grafts mainly due to immune mediated rejection. Early detection of acute rejection (AR) for early initiation of proper anti-rejection therapy is very important in preventing allograft damage or loss. Understanding of non-coding RNAs’ (ncRNAs) function and the existence of a highly regulated interplay between mRNA/miRNAs/lncRNAs in allograft rejection has gained the attention of research groups to explore different expression patterns of ncRNAs in the field of organ transplantation. Finding a specific pattern of ncRNAs as biomarker will be extremely important for monitoring the kidney allograft function, diagnosis, treatment and even preventing of AR occurrence. In this review list of miRNAs and lncRNAs have been linked to AR following kidney transplantation until now is presented.

Examination of Serum miRNAs as Possible Biomarkers for the Diagnosis of Acute Rejection after Kidney Transplantation

Introduction Because of the lack of non-invasive, specific biomarkers, early detection of acute rejection after kidney transplantation represents a challenge. microRNAs (miRNAs) belong to a class of small, noncoding RNAs and they were found to be involved in pathological processes that occur following kidney transplantation. We analyzed the association of serum expression levels of miR-15b, miR-16, miR-24, miR-103a and miR-107 with acute rejection episodes that occur during the early phase after transplantation. We also investigated the capability of these miRNAs to differentiate between acute rejection episodes and other pathological processes. Patients and Methods Prospectively collected serum samples of kidney allograft recipients with stable graft function (n=10), urinary tract infection (UTI) (n=9), borderline rejection (n=9), acute tubular necrosis (ATN) (n=9) or biopsy-proven acute rejection (n=9), who were transplanted between 2015 and 2017 were analyzed. In addition, serum samples of 7 patients with an acute rejection episode were also investigated at different time points after kidney transplantation. miRNA expression levels were determined by real-time quantitative reverse-transcription-polymerase chain reaction (RT-PCR). Spiked-in cel-miR-39 was used as a normalization control. The expression levels were determined relative to the levels before transplantation. Results and Discussion As compared to patients with stable graft function, decreased serum levels of miR-15b, miR-16 and miR-24 were observed on post-Tx day 8 in kidney transplant patients with borderline rejection, ATN or acute rejection. miR-15b and miR-24 levels were lower in patients with ATN than in patients with UTI. miR-103a level was also lower in patients with ATN or acute rejection (but not borderline rejection) than in patients with stable function. Although the serum miR-107 level did not significantly differ between patients with acute rejection and stable function, longitudinal analysis of individual patients showed that miR-107 is increased during acute rejection and decreases with the improvement of the kidney function. One patient with ABMR showed extremely decreased levels at all timepoints. Conclusion The determination of serum miR-15b, miR-16, miR-24 and miR-103a levels may allow the detection of allograft damage after kidney transplantation; however, these miRNAs do not seem to distinguish acute rejection from other transplant pathologies. In contrast, the quantification of serum miR-107 appears to be useful for monitoring the therapy success in patients with an acute rejection episode.

Nuclear medicine techniques in transplantation

To evaluate the indications and perspectives of nuclear medicine techniques in transplantation. We performed a systematic review of the literature using PubMed/Medline and Google scholars, with multiple research keywords for each organ accompanying the terms “transplant”, “transplantation”, “graft”, “nuclear imaging”, “scintigraphy”, “PET” and “PET/CT”. The review considers the following organs/systems: kidney, liver, pancreas, heart, lung, bone and salivary glands, as well as a common complication, the post-transplant lymphoproliferative disorder. The references of the retrieved articles were also considered to find supplementary articles. The search was limited to English language. Preoperative workup exploration, preclinical and animal studies were not included in the review. A total of 146 original articles were considered for the review, including 118 retrospective and 28 prospective studies. The functional integrity of the renal graft is safely and reliably assessed using quantitative dynamic scintigraphy with 99mTc-DTPA or 99mTc-MAG3. 18F-FDG PET/CT is a promising method for early detection of acute rejection. The glomerular filtration rate (GFR) of potential donors should ideally be assessed using 51Cr-EDTA, and the split renal function could be quantified using 99mTc-MAG3 or 99mTc-DMSA imaging. In liver transplantation, both 99mTc-GSA and 99mTc-HIDA scintigraphies can be used for evaluating the function of transplanted liver, and 18F-FDG PET/CT increasingly appears as a powerful tool for characterising the aggressiveness of hepatocellular carcinoma and contributes to the decision of transplantation in selected patients. In heart transplants, the major indication is the evaluation of cardiac allograft vasculopathy using myocardial perfusion imaging, either with SPECT or PET. In the context of lung transplantation, perfusion scanning helps select potential donors and contributes to the postoperative follow-up, either early on for detecting primary graft dysfunction or later on in the diagnosis of chronic rejection. Bone scintigraphy and 18F-NaF PET/CT are valuable tools for assessing bone graft viability. This is particularly established in mandible grafts, but convincing data are available in other types of graft. Salivary gland transplantation is not frequently performed, but in such a clinical situation, 99mTcO4 scintigraphy is an elegant way to help select the transplant and to verify the viability of the graft. Finally, 18F-FDG PET/CT is very effective in patients with post-transplant lymphoproliferative disorder (PTLD), both at diagnosis and for evaluating the response to treatment. Nuclear medicine techniques are strongly established as valuable clinical tools in a wide variety of indications, before and after organ transplantation. Furthermore, 18F-FDG PET/CT in PTLD and radio-isotopic evaluation of the renal function in putative kidney donors are recommended in clinical algorithms proposed in international guidelines.

Relationship of Changes in Cystatin-C With Serum Creatinine and Estimated Glomerular Filtration Rate in Kidney Transplantation

BackgroundSerum creatinine (S-Cr) is the most commonly used marker for the assessment of renal function in kidney transplantation (KTx). Cystatin-C (Cys-C) has been proposed as an alternative marker of renal function for the estimated glomerular filtration rate (eGFR), which seems to be more accurate than S-Cr. The aim of this study was to investigate the relationship between changes in S-Cr, Cys-C, and eGFR measurements in KT patients during the early post-transplantation (post-Tx) period. MethodsFifty consecutive patients, aged 15 to 70 years, were subjected to KT. Blood samples were collected at stable time-points on pre-Tx and post-Tx days 2, 6, and 14 and in the third month. Cys-C and S-Cr levels were measured, and GFR was estimated at all time-points using the Cockcroft–Gault and Le Bricon equations. ResultsS-Cr and Cys-C levels decreased significantly post-Tx in all time-point determinations compared with pre-Tx levels. Both markers showed a parallel decrease, reaching normal levels in the third month. Estimated GFR post-Tx by S-Cr and Cys-C exhibited a parallel progressive increase without significant difference between the calculations. Correlation between S-Cr and Cys-C in all time-point determinations was positive and of high significance using Pearson's correlation (r = 0.969, P < .01; r = 0.951, P < .01; r = 0.969, P < .01; r = 0.701, P < .01). Also, the correlation between the eGFR by Cys-C and S-Cr was positive and of high significance in all post-Tx calculations (r = 0.896, P < .01; r = 0.935, P < .01; r = 0.929, P < .01; r = 0.861, P < .01). Ten recipients had acute rejection and were treated successfully with antirejection therapy. Their S-Cr, cys-C, and eGFR results were analyzed separately and showed a significant difference from no-rejection patients, with Cys-C being more sensitive to earlier eGFR changes. ConclusionCystatin-C is an alternative and accurate marker of renal function in KT patients showing similar diagnostic characteristics to S-Cr. However, Cys-C appears superior to S-Cr in reflecting early GFR temporary changes, which is critical for the early detection of acute rejection.

Is microdialysis useful for early detection of acute rejection after kidney transplantation?

IntroductionAcute rejection following kidney transplantation (KTx) is still one of the challenging complications leading to chronic allograft failure. The aim of this study was to investigate the role of microdialysis (MD) in the early detection of acute graft rejection factor following KTx in porcine model. MethodsSixteen pigs were randomized after KTx into case (n = 8, without immunosuppressant) and control groups (n = 8, with immunosuppressant). The rejection diagnosis in our groups was confirmed by histopathological evidences as “acute borderline rejection”. Using MD, we monitored the interstitial concentrations of glucose, lactate, pyruvate, glutamate and glycerol in the transplanted grafts after reperfusion. ResultsIn the early post-reperfusion phase the lactate level in our case group was significantly higher comparing to the control group and remained in higher levels until the end of monitoring. The lactate to pyruvate ratio showed a considerable increase in the case group during the post-reperfusion phase. The other metabolites (glucose, glycerol, glutamate) were nearly at the same levels at the end of our monitoring in both study groups. ConclusionThe increase in lactate and lactate to pyruvate ratios seems to be an indicator for early detection of acute rejection after KTx. Therefore, MD as a minimally invasive measurement tool may help to identify the need to immunosuppression adjustment in the early KTx phase before the clinical manifestation of the rejection.

Expression of lymphocyte coding genes in peripheral blood and lymphocyte infiltration in cardiac tissues influenced by cyclosporin A in heterotopic heart transplantation model in rats

To systematically compare the expression of coding genes with pathological changes of transplanted cardiac tissue and peripheral blood lymphocytes in an allo-heterotopic rat cardiac transplant model. Using SD rats as donors and Wistar rats as recipients, animals were divided into two groups, control and cyclosporine A intervention plus heart transplant groups. After transplant at 1, 3, 7, 10 and 12d, we assessed the ability of lymphocytes to infiltrate into cardiac tissues and levels of leukocyte coding genes in peripheral blood. Histopathological changes were monitored in cardiac tissue to determine the level of transplant rejection. Results: (1) 24h after transplant peripheral blood lymphocytes' transcription and expression were temporarily reduced. (2) CD4+ and CD8+ lymphocytes infiltrate into cardiac tissue and Grade 1R pathological changes were observed 3d–7d after heart transplant. (3)Cyclosporine A was not able to completely block heart transplant rejection.(4) Although cyclosporine A was not able to effectively suppress CD4+ T cell gene expression, it did suppress CD8+ T cell gene transcription. (5) Cyclosporine A did not effectively reduce the rapid infiltration of CD4+ or CD8+ infiltration in 3d, but significantly reduced the degree of CD4+ T cell infiltration in cardiac tissues between 3 and 7d. (6) Differential display (DD-PCR): Graft control group: there were differences in 2,3-bisphosphoglycerate, ribosomal protein S25, 12S ribosomal, gig18, MHC-III and ATPase H+, which occurred 24h before CD4/CD8 surface protein expression. Cyclosporine A group: there were differences in thrombospondin-1, TCR, 2,3-bisphosphoglycerate, sodium channel beta-1, gig18 and TCR. In the cyclosporine A group 2,3-bisphosphoglycerate positive expression was observed 24h after the control group, which indicates that cyclosporine A slowed down the 2,3-bisphosphoglycerate transcription rate in peripheral lymphocytes and delayed its expression time. Cyclosporine A also suppressed gig18 transcription in peripheral lymphocytes. After 24h, sodium channel beta-1 was positively expressed in the cyclosporine A group. The relationship between molecular surface receptor expression and coding genes in cardiac tissue and peripheral blood after transplant indicates that early detection of acute rejection and anti-rejection drugs' curative effect can be assessed.

The Role of Home Spirometry Monitoring of FEV1 in Early Detection of Acute Rejection and Other Adverse Events in Lung Transplant Patients

The Role of Home Spirometry Monitoring of FEV1 in Early Detection of Acute Rejection and Other Adverse Events in Lung Transplant Patients

Are there still roles for exocrine bladder drainage and portal venous drainage for pancreatic allografts?

Controversy remains regarding the best methodology of handling exocrine pancreatic fluid and pancreatic venous effluent. Bladder drainage has given way to enteric drainage. However, is there an instance in which bladder drainage is preferable? Also, hyperinsulinemia, as a result of systemic venous drainage (SVD), is claimed to be proatherosclerotic, whereas portal venous drainage (PVD) is more physiologic and less atherosclerotic. Bladder drainage remains a viable method of exocrine pancreas drainage, but evidence is sparse that measuring urinary amylase has a substantial benefit in the early detection of acute rejection in all types of pancreas transplants. Currently, there is no incontrovertible evidence that systemic hyperinsulinemia is proatherosclerotic, whereas recent metabolic studies on SVD and PVD showed that there was no benefit to PVD. Given the advent of newer immunosuppressive agents and overall lower acute rejection rates, the perceived benefit of bladder drainage as a means to measure urinary amylase as an early marker of rejection has not been substantiated. However, there may be a selective role for bladder drainage in 'high risk' pancreases. Also, without a clear-cut metabolic benefit to PVD over SVD, it remains the surgeon's choice as to which method to use.

Pulmonary circulatory parameters as indices for the early detection of acute rejection after single lung transplantation.

We investigated the relationship between the changes in the pulmonary blood flow and histology during acute rejection following single lung transplantation. In single lung transplantation using adult mongrel dogs, immunosuppression with cyclosporine and azathioprine was discontinued after postoperative day 14 to induce rejection. Doppler flow probes were placed adjacent to the ascending aorta and the left pulmonary artery to measure the blood flow on a daily basis. In addition, chest roentgenograms were also examined daily. The pulmonary pressure was measured using a Swan-Ganz catheter prior to and following the induction of rejection. Open lung biopsies were performed when the left pulmonary artery flow decreased to half of the prerejection value. The pulmonary artery flow decreased to 14.3% of the aortic flow 5 days after the discontinuation of immunosuppression. The graft pulmonary vascular resistance increased significantly compared to the prerejection values (P < 0.001). This was not accompanied by any abnormalities on chest roentgenography. The histology was consistent, with marked perivascular lymphocytic infiltration with little alveolar or interstitial changes. During rejection, the increased pulmonary vascular resistance in the graft was probably the result of perivascular inflammatory cell infiltration, which was seen prior to changes on chest roentgenography. Changes in the left pulmonary artery flow and histology thus appear to be closely correlated in the early stages of acute rejection.

Endoscopic findings in transplanted allo-intestine of rats after discontinuance of immunosuppressive agent.

In clinical practice, graft rejection in small-bowel transplantation should be diagnosed before irreversible condition of the graft. We have already reported the usefulness of endoscopic examination for the early detection of acute rejection in a rat model. Here we evaluated rejection after discontinuance of methyl-deoxyspergualin by endoscopy. Heterotopic small-bowel transplantation was performed by the cuff method from a DA to a LEW rat. Endoscopic and histological examinations were performed through the stomas. Two-week administration of methyl-deoxyspergualin significantly prolonged graft survival. Graft rejection after discontinuance of the agent occurred much more slowly than rejection without the immunosuppressive drug. Erosive mucosal changes were endoscopically observed in the early phase of rejection in rats that did not receive the immunosuppressant. However, endoscopic findings after discontinuance of methyl-deoxyspergualin indicated edematous changes and thickening of the wall without erosion, and, histologically, the grafted intestine showed slowly-progressing rejection with flattened villi. If we pay attention to edematous changes and hardening of intestinal wall, and take selective biopsies, endoscopic examination may improve the early diagnosis of slowly progressive rejection in the clinical setting.

Complement activation during rejection in experimental intestinal transplantation

Clinical intestinal transplantation is plagued by a high incidence of rejection that is often detected late and is frequently intractable. During rejection, disturbance in the mucosal integrity results in bacterial translocation and systemic sepsis. Overzealous attempts to prevent or treat rejection may result in further infective complications and posttransplant lymphoproliferative disorders. Therefore, there is a need not only for reliable and early detection of acute rejection, but also for novel immunosuppressive strategies that can achieve better control of rejection and minimize the toxicity related to immunosuppression. Although rejection of allografts is often regarded as a predominantly cellular phenomenon, the role of humoral mechanisms is being increasingly recognized. There is good evidence of antibody and complement deposition in vascular allograft rejection, in renal allografts with cell-mediated rejection, and complement activation in hyperacute xenograft rejection, which may be prevented by the use of complement regulators such as soluble complement receptor type 1 (sCR1). Despite this evidence from other organ grafts, the role of complement in small bowel allograft rejection has not been studied adequately. In this study, the presence of complement in rat intestinal graft rejection was investigated by immunohistochemistry. Subsequently, based on previously reported success with cobra venom factor (CVF) in controlling hyperacute rejection, the effect of administration of CVF on acute rejection was studied.

MORPHOLOGIC ACTIVATION OF LYMPHOCYTES IN BLOOD DURING REJECTION OF HEART AND LUNG GRAFTS IN RATS

We investigated morphologic activation of lymphocytes in blood in a standardized, infection-free rat model and compared lymphocyte activation during rejection of heart grafts and that of lung grafts with other parameters of rejection. For heart grafts the other parameters were histology and palpation, and for lung grafts they were histology, bronchoalveolar lavage, and chest roentgenography. During acute rejection of heart grafts, lymphocyte activation in blood increased when histology of the heart grafts showed already moderate-to-severe rejection with myocyte necrosis. Lymphocyte activation in blood detected acute heart rejection clearly later than histology but somewhat earlier than palpation. During acute rejection of lung grafts, lymphocyte activation in blood increased when histology of the lung grafts showed the (early) vascular phase of rejection, without apparent tissue damage. Lymphocyte activation in blood detected acute lung rejection only slightly later than histology, at approximately the same time as bronchoalveolar lavage and earlier than chest roentgenograms. Lymphocyte activation was higher during acute lung rejection than during acute heart rejection. During "chronic" rejection of long-surviving heart grafts and lung grafts, lymphocyte activation in blood did not increase consistently. The early and strong increase of morphologic activation of lymphocytes in blood during acute lung rejection may imply for clinical transplantation that monitoring of lymphocyte activation in blood is more useful for early detection of acute rejection after lung transplantation than after heart transplantation.

Non-Obstructive Kidney Transplant Dysfunction: Magnetic Resonance Evaluation

The value of magnetic resonance imaging in the differential diagnosis of non-obstructive dysfunction of renal allografts was studied in a series of 58 examinations at 0.5 T. Four parameters were evaluated: the corticomedullary differentiation; the relative thickness of the cortex; the evolution, with echo number, of the relative signal intensities of kidney parenchyma and adjacent fatty tissue on images generated by a long time to repeat multiecho sequence; and the proximal vascularization. The loss of corticomedullary differentiation is the major finding in acute rejection, but it is not specific as it is also observed in chronic rejection and in the much rarer acute glomerulonephritis. Thickening of the cortex is helpful for the detection of rejected transplants with visible corticomedullary delineation (26% of the cases). Uncomplicated acute tubular necrosis appears as a normal transplant. New immunosuppressive medications, especially cyclo- sporin, have improved the results of kidney transplanta- tion, but they have also added to the difficulty of monitoring the post-transplantation course: cyclosporin nephrotoxicity must now be added to acute tubular necrosis (ATN) and rejection as causes of graft dysfunction. Moreover, cyclosporin decreases the clinical and functional manifestations of acute rejection. Radionuclide scintigraphy and sonography are estab- lished non-invasive modalities in the evaluation of post- transplant renal failure. Sonography is clearly the ideal technique for recognizing urinary obstruction. How- ever, both sonography and scintigraphy lack sensitivity and specificity in the early detection of acute rejection. Experience with magnetic resonance imaging (MRI) is still limited, and the present study was undertaken to assess its usefulness in the evaluation of kidney transplant patients with non-obstructive renal dys- function. Materials and methods Technique Magnetic resonance examinations were performed on a 1.5 T superconductive system (Philips SI5 Gyroscan), operating at 0.5 T. A surface coil was used for signal detection and the regular body coil for spin excitation. Both coils were electronically decoupled (Boskamp, 1985). During initial studies, a rectangular surface coil was used; this was subsequently replaced by a sandwich coil that provided good magnetic coupling with both walls of the hemipelvis. Although the prone position generates less movement artefact, patients were positioned supine, as this position proved to be better

Doppler echocardiography for the diagnosis of acute cardiac allograft rejection

To evaluate the changes in left ventricular filling associated with acute cardiac rejection, serial Doppler echocardiographic examinations were prospectively performed on the same day as endomyocardial biopsy in 55 consecutive patients who successfully underwent orthotopic transplantation and were free of a previous episode of rejection. On average, 8.6 Doppler studies per patient were performed within a 6 month period after transplantation. Recordings of mitral flow were made with pulsed Doppler and twodimensional echocardiography from an apical four chamber view; isovolumic relaxation time, peak early mitral flow velocity and pressure half-tune were measured. The patients were classified into two groups on the basis of the histopathologic findings: group I (25 patients with at least one episode of mild or moderate rejection) and group II (30 patients without rejection).In group I, rejection was associated with a significant decrease of isovolumic relaxation time (p < 0.005) and especially pressure half-time (p < 0.0005) with no change in heart rate and peak early mitral flow velocity. In group II, Doppler indexes remained unchanged. These changes were not associated with alterations in left ventricular systolic function assessed by echocardiography. Isovolumic relaxation time and pressure half-time both returned to values similar to baseline values after immunosuppressive therapy (p < 0.05 and p < 0.0005, respectively). With 20% decrease in pressure half-time as a criterion for acute rejection, sensitivity was 88%, specificity 87% and positive predictive value 85%.Thus, Doppler echocardiographic evaluation of left ventricular diastolic function provides an excellent tool for early detection of acute rejection and noninvasive monitoring of the cardiac transplant recipient.