Acute Rejection Group Research Articles

SHORT-TERM MYCOPHENOLATE MOFETIL COMBINED WITH CYCLOSPORINE COMPARED TO STANDARD MAINTENANCE REGIMENS OF CYCLOSPORINE WITH MYCOPHENOLATE MOFETIL OR AZATHIOPRINE IN KIDNEY TRANSPLANTATION: INTERIM ANALYSIS

927 Purpose: This study compares the efficacy and tolerability of the microemulsion oral formulation of cyclosporine (NEORAL®), given in combination with three immunosuppressive regimens, in patients undergoing first renal transplantation from a living or cadaver donor. Methods: In a prospective, 12-month, parallel group, open label, multicenter study, 477 patients were randomized to one of three treatment groups with NEORAL initiated at 10 mg/kg/day as baseline therapy in addition to steroids. Group 1 received mycophenolate mofetil (MMF) for 3 months, replaced by azathioprine (AZA) for a further 9 months. Groups 2 and 3 received either MMF or AZA for 12 months. Starting doses of MMF or AZA were fixed at 2g/day and 1-2 mg/kg/day, respectively. The dose of NEORAL was adjusted to reach predetermined trough level ranges. All study medications were adjusted for tolerability. The primary endpoint is treatment failure at 12 months, defined as death, graft loss, biopsy-proven or treated rejection, or discontinuation. Results: Interim analysis (ITT) at 6 months of 276/477 randomized patients (Group 1: n=89; Group 2: n=92; Group 3: n=95) showed that baseline and demographic characteristics were comparable between the three groups. As expected, the incidence of treatment failure at month 3 was lower for the groups randomized to MMF (Group 1: 31.5%; Group 2: 37.0%) versus the group randomized to AZA (49.5%). This was mainly attributable to a lower rate of acute rejection (Group 1: 15.7%; Group 2: 19.6%; Group 3: 32.6%). The switch from MMF to AZA at month 3 in Group 1 did not affect the incidence of rejections (Group 1: +2.2%; Group 2: +1.1%; Group 3: +2.1%), nor the occurrence and severity of drug-related adverse events (Group 1: 16.9%; Group 2: 15.2%; Group 3: 15.8%) during the following 3 months. At month 6, the same pattern was observed for treatment failure (Group 1: 34.8%; Group 2: 39.1%, Group 3: 54.7%; Group 1 vs. Group 2: p=0.49; Groups 1 or 2 vs. Group 3: p<0.05). Overall the incidence and severity of adverse events was comparable between the groups, while the types of adverse events were compatible with the known tolerability profiles of the study medications. Conclusion: These interim results indicate that replacement of MMF by AZA after 3 months provides comparable efficacy and similar tolerability to the maintenance of MMF for 6 months. This therapeutic approach, if confirmed by the 12-month results, may offer substantial savings in treatment costs for the long-term maintenance of renal grafts. This research was funded by Novartis Pharma AG, Basel, Switzerland

Role of serum tumour necrosis factor alpha and its soluble receptors in predicting acute renal allograft rejection

Tumour necosis factor alpha (TNF-?) is known to be involved in pathogenesis of acute renal allograft rejection. However, measurement of cytokine serum levels alone are not a reliable index of acute rejection episodes. TNF-?induces the release of soluble receptors (TNF-SR55 and TNF-SR75) that have an inhibitory activity and catabolized by the kidney. Twenty nine transplant recepients were studied and compared to ten healthy controls. TNF-?, TNF-SR55 and TNF-SR75 were measured before and after renal transplantation. The mean pre-transplantation values were 26.3 9.7 pg/ml, 28.2 8.3 and 42.5 11.1 ng/ml respectively. According to post-transplant course patients were divided into 3 groups. Group I (stable transplant group: no= 17): The mean level of TNF-?value was 7.5 4.6 pg/ml, TNF-SR55 6.4 4.7 and TNF-SR75 12.5 8 ng/ml (p NS). Group II (acute allograft rejection group: no = 8): The mean values were 37.2 16.2 pg/ml, 16.9 9.6 and 30.9 13.4 ng/ml respectively (p 0.05). Thus, TNF-? and its soluble receptor levels might be of diagnostic value in renal allograft rejecion. In conclusion: 1) TNF-? and its soluble receptors are highly increased during hemodialysis. 2) There is no significant difference between healthy controls and patients with stable grafts. 3)There is highly significant increase of TNF-? and its receptors during acute rejection episodes and the day (R-2) prerejection in contrast to internal controls. 4) There is insignificant decrease of TNF-? during CS nephrotoxicity with highly significant increase of TNF-SR55, TNF-SR75 when compared to internal controls. 5) The ratios of TNF-?to SR55 & SR75 showed highly significant increase during acute rejection episodes and insignificant decrease during CS nephrotoxicity when compared to internal controls.

Renographic indices for evaluation of changes in graft function.

Radionuclide renal diagnostic studies play an important role in assessing renal allograft function, especially in the early post-transplant period. In the past two decades various quantitative parameters have been derived from the radionuclide renogram to evaluate changes in perfusion and/or function of the kidney allograft. In this review article we discuss the quantitative parameters that have been used to assess graft condition, with emphasis on the early postoperative period. These quantitative methods are divided into parameters used for assessing renal graft perfusion and parameters used for evaluating parenchymal function. The blood flow in renal transplants can be quantified (a) by measuring the rate of activity appearance in the kidney graft, (b) by calculating the ratio of the integral activity under the transplanted kidney and arterial curves and (c) by calculating the renal vascular transit time. In this article we review a number of parenchymal uptake and excretion indices, such as the accumulation index, the graft uptake capacity at 2 and 10 min, the excretion index and the elimination index. The literature on these parameters shows that they have some practical disadvantages. In addition, values suffer from significant overlap when various graft pathologies coexist. A retrospective study was designed in our institution to evaluate the clinical usefulness of some of the frequently used previously published methods in which the graft function is quantitatively assessed in the early post-transplant period. The quantitative parameters studied which were reasonably reproducible in our hands included: global perfusion index (GPI), cortical perfusion index (CPI), vascular transit time, and the parenchymal parameters uptake capacity at 2 min (UC2) and elimination index (K3/20). The patient population in this study consisted of 43 patients with 157 technetium-99m mercaptylacetyltriglycine renograms. The perfusion indices GPI and CPI did not allow differentiation of the acute tubular necrosis (ATN) group from the acute rejection (AR) group; however, they were of value in monitoring the improvement in the condition of the graft dysfunction in both the AR and ATN groups. As for the parenchymal parameters, both UC2 and K3/20 were able to differentiate stable graft function (SGF) versus AR and ATN groups but were unable to separate AR from ATN dysfunction. The ability of these parenchymal parameters to detect improvement in the graft function was poor and statistically non-significant. From the literature data and our own findings it is concluded that radionuclide scintigraphy of renal transplants has assumed an important role, especially if performed serially, in monitoring graft function in the post-transplant period. Many quantitative parameters have been derived from the radionuclide renogram to evaluate changes in perfusion and/or function of the kidney allograft. It appears that these quantitative numerical values are unable to differentiate unequivocally between grafts with ATN and AR cases. The real value of these parameters lies in the follow-up of the dysfunction processes, which helps the clinician to determine the appropriate therapeutic regimen.

Kidney transplantation in children younger than 1 year using cyclosporine immunosuppression.

The optimal age for transplantation in children with end-stage renal disease remains controversial. Supported by national data, many centers recommend dialysis until the child reaches a certain minimum age. The authors' policy, however, has been to encourage living donor (LD) transplants for young children, with no minimum age restriction. Between January 1, 1984, and December 31, 1996, the authors performed 248 kidney transplants in children younger than age 13 years, using cyclosporine as the primary immunosuppressive agent. Recipients were analyzed in three age groups: group 1, younger than age 1 year (n = 26); group 2, age 1 through 4 (n = 92); and group 3, age 5 through 13 (n = 130). Almost all recipients in group 1 underwent a primary LD transplant. Therefore, to compare results more meaningfully among the three age groups, only primary LD transplants were analyzed (group 1, n = 25; group 2, n = 59; group 3, n = 58). In primary LD transplants, no significant difference was noted among the age groups in 1-and 5-year patient or graft survival rates. To date, all 25 recipients from group 1 are alive and well; 19 still have a functional original graft. Causes of graft loss in the remaining six recipients were chronic rejection (n = 3), vascular thrombosis (n = 2), and recurrent disease (n = 1). The incidence of acute rejection in group 1 recipients was lower than in the two older groups. However, the incidence of delayed graft function was slightly higher in the youngest group than in the two older groups. For recipients in group 1, growth (as measured by weight) improved significantly posttransplant: the mean standard deviation score rose from -2.8 pretransplant to -0.2 by age 5 and to +1.8 by age 10. The improvement in height was not as dramatic: the mean standard deviation score rose from -3.2 pretransplant to -1.6 by age 5 and to -1.4 by age 10. Kidney transplantation in young children, including those younger than 1 year old, can achieve results comparable to those in older children. As long as an adult LD is available, the timing of the transplant should be based on renal function rather than age.

Cytokine analysis of human renal allograft aspiration biopsy cultures supernatants predicts acute rejection.

A Th1 response is said to be associated with transplant rejection and Th2 with tolerance, although this is not agreed by all. Cytokines evaluation in peripheral blood and urine in kidney transplants produces variable results. We hypothesized that measurement of major cytokines involved in Th1/Th2 paradigm on transplant renal-infiltrating cells could bring valuable scientific and clinical information. Fifty-six adult cadaver kidney transplants were subdivided into 21 stable patients (group A), 22 suffering acute rejection (group B), 10 with chronic rejection (group C) and three with CMV disease (group D). Fine-needle aspiration biopsies were cultured and their supernatants analysed for IL-2, IL-4, IL-10 and IFN-gamma. Group A produced small amounts of both IL-2 and IL-10 while group B synthetized significantly higher IL-2 and significantly lower IL-10 amounts than group A. Group B produced significantly more IL-2 than A on day 7 post-transplantation, several days before rejection supervened. Group C produced IL-10 and very low amount of IL-2. Group D produced both IL-2 and IL-10. We did not find any IL-4, and IFN-gamma was present in a few samples. For IL-2, sensitivity, specificity, negative and positive predictive values for acute rejection were 100, 87.2, 94.7 and 83.3%, respectively. Cytokine analysis in fine-needle aspiration biopsy cultures supernatants is a very useful immunological screening method for kidney transplants. IL-2 synthesis on day 7 post-transplantation reliably predicted the risk of impending acute rejection during the first weeks. The cytokine pattern suggests that acute rejection is associated with Th1, stable patients with Th0/Th2, and chronic rejection with Th2 patterns.

Frequent occurrence of hepatocytic apoptosis in acute rejection of the grafted rat liver.

The present study was conducted to examine the histopathological changes of rat liver grafts in the early post-transplantation period. A total of 44 orthotopic liver transplantations were performed using cuff techniques without anastomosis of the hepatic artery. They were divided into four groups: (i) group 1 (syngeneic, Lewis-->Lewis; n = 10); (ii) group 2 (allogeneic, ACI-->Lewis; n = 20); (iii) group 3 (allogeneic with immunosuppression, ACI-->Lewis; n = 12); and (iv) long-surviving grafts (PVG-->Lewis; n = 2). The histological findings were classified into four categories: (i) mild dilatation of Disse's spaces due to ischemia; (ii) bile duct proliferation; (iii) acute rejection; and (iv) zonal necrosis. Bile duct proliferation occurred on day 6 in all three groups and in one of the two long-surviving grafts (120 days). Acute rejection occurred on day 3 and progressed in groups 2 and 3. Zonal necrosis developed in group 2 after day 6, while acute rejection subsided after day 4 in group 3 receiving 15-deoxyspergualin. A few single cell deaths or acidophilic bodies were variably noted. Most of these cells showed signals by in situ nick end-labeling in their nuclei, implying the cells were undergoing apoptosis. The number of apoptotic hepatocytes increased as the progress and decreased with the regression of acute rejection in group 3. Thus, the extent of hepatocytic apoptosis may reflect the magnitude of acute rejection. More frequent distribution of apoptotic hepatocytes in periportal areas suggests that apoptosis may be induced by a variety of pathological stimuli, including the direct cytotoxic effects of lymphocytes, various cytokines and local circulatory disturbances.

Central venulitis in the allograft liver: a clinicopathologic study.

Central venulitis denotes a histologic lesion of the allograft liver characterized by perivenular and subendothelial mononuclear inflammation of the terminal hepatic venules associated with varying degrees of perivenular hepatocyte dropout. Although this lesion has generally been considered a manifestation of acute rejection, some have suggested that it instead represents tacrolimus hepatotoxicity. We therefore compared the clinicopathologic features of 30 episodes of isolated central venulitis with 22 episodes of combined central venulitis and typical portal acute rejection occurring in 27 patients. Nineteen of the patients received tacrolimus and eight received cyclosporine as primary immunosuppression. No significant differences were found between the two groups, except that isolated central venulitis more often displayed a mild inflammatory component (P=0.007) with small lymphocytes as the predominant cell type (P=0.002). None of the patients had tacrolimus or cyclosporine levels that exceeded the therapeutic range, and none had other clinical evidence of drug toxicity. Usual antirejection therapy was instituted in all but two episodes; response was evident in 93% (28 of 30) of the isolated central venulitis and 86% (19 of 22) of the central venulitis-portal acute rejection group, with histologic regression documented in all follow-up specimens (four and five, respectively). Due to persistent central venulitis, two cyclosporine patients were switched to tacrolimus, with prompt resolution. These findings are inconsistent with the concept that central venulitis represents drug toxicity and indicate instead that it is a form of acute allograft rejection.

Impact of acute rejection and early allograft function on renal allograft survival.

Both acute rejection and the function of a renal allograft early after transplantation correlate with long-term graft survival. In this study we assessed the relationship between these two factors in 843 adult recipients of first cadaveric renal grafts, transplanted at a single institution and followed for a minimum of 3.5 years. Patients were divided into four groups according to (1) history of acute rejection (AR) during the first 6 months after transplantation, and (2) concentration of serum creatinine at 6 months after transplantation (SCr(6mo) < or > or = 2 mg/dl). Death censored allograft survival was not significantly different among patients without AR and with low SCr(6mo) (group 1, n=376), patients without AR but with an elevated SCr(6mo) (group 2, n=117), and patients with AR but low SCr(6mo) (group 3, n=185). In contrast, graft survival was significantly worse in patients with AR and an elevated SCr(6mo) (group 4, n=165) compared with patients in the other three groups (Cox, P<0.0001). The elevated SCr(6mo) in group 4 patients was not necessarily the consequence of AR, as 32% of patients in group 4 had a SCr at 10 days after transplantation (SCr(10d)), before they had AR, that was equal to or higher than the SCr(6mo). Based on this observation we investigated the implications of the SCr(10d) concentration for graft prognosis. The SCr(10d) correlated weakly with graft survival (Cox, P=0.05). However, an elevated SCr(10d) correlated with other potential risk factors for graft survival including: Older donors (P<0.0001), male recipients (P<0.0001), and heavier recipients (P<0.0001, all by multivariate regression); and posttransplant factors such as, increasing numbers of AR (P<0.0001), higher posttransplant blood pressure (P<0.0001), and lower doses of cyclosporine (P<0.0001, all by multivariate regression). In conclusion, graft dysfunction predicts poor graft survival only when associated with AR. Similarly, AR predicts a poor renal allograft survival only when associated with graft dysfunction. The SCr(10d) is an indicator of risk factors from both the donor and recipient, and an elevated SCr(10d) predicts a higher risk of acquiring additional risk factors early after transplantation.

Sequential monitoring of urine-soluble interleukin 2 receptor and interleukin 6 predicts acute rejection of human renal allografts before clinical or laboratory signs of renal dysfunction.

The significance of noninvasive techniques to the early diagnosis of acute rejection in kidney transplants remains elusive. In this study, we examined whether an early posttransplant increase in serum- and urine-soluble interleukin (IL) 2 receptor (sIL-2R) and IL-6 levels predicted acute rejection. Sequential determinations of serum and urine sIL-2R and IL-6 were performed in the first 30 postoperative days in 40 renal transplant patients. Changes during the posttransplant period observed in 26 patients who had one or more episodes of acute rejection (group A) were compared with those recorded in 14 patients who did not experience acute rejection of their graft (group B). Serum sIL-2R was higher than normal in patients of groups A and B without statistical differences between the two groups. In the first 3 days after transplantation, urinary sIL-2R was higher than normal in group A but not in group B. Urinary sIL-2R at days 2 and 3 was significantly higher (P<0.05) in group A than in group B. In the first 5 days after transplantation, urinary IL-6 was persistently higher than normal in group A, whereas it progressively decreased to normal value on day 4 in group B. Sudden increases (doubling within 24 hr) in urine IL-6 preceded clinical diagnosis of acute rejection by a mean period of 2 days, with an 87% sensitivity and a 64% specificity, and also predicted recurrent rejection episodes. Sequential monitoring of urinary sIL-2R and IL-6 levels does allow very early diagnosis of rejection without invasive procedures. Specifically, high urinary sIL-2R in the first 5 posttransplant days identifies the subgroup of patients at risk. In the subsequent days, a sudden increase in urinary IL-6 occurs in those of the above patients who will indeed reject their graft.

Late pancreas allograft rejection. Preliminary experience with factors predisposing to rejection.

A case series of 31 cadaveric pancreas transplant recipients who were insulin-independent at least for one year was analyzed for the factors predisposing to late acute rejection (> 12 months posttransplant). Sixty-two pancreas transplants were performed in 61 patients, of whom 53 had functioning allografts 3 months posttransplant; 31 of these had a follow-up > 12 months. Twenty had no evidence of late rejection, whereas 11 had evidence of acute rejection after 12 months. All patients received quadruple induction immunosuppression. No demographic or clinical factors-including donor age, organ cold time, HLA mismatch, age, sex, or race-could distinguish the late acute rejection group. The presence of acute rejection in the first year posttransplant was similar in the late rejectors (21 episodes in 9 of 11 patients) compared with patients without late rejection (31 episodes in 16 of 20 patients). Antilymphocyte induction therapy type had no influence, but the amount of immunosuppression with prednisone and cyclosporine (CsA) at 3 months posttransplant was significantly lower in those patients who experienced late rejection. After the first year posttransplant, CsA 12-hr trough levels were significantly lower in late rejection months (121 +/- 7 ng/ml) compared with each patient's own stable months (183 +/- 5 ng/ml, P < 0.0001). Neither prednisone nor azathioprine dosages differed between teh two groups after the first year posttransplant. Our preliminary results suggest that early under immunosuppression with prednisone and CsA in the first year and 12-hr trough CsA levels less than approximately 180 ng/ml after the first year posttransplant predispose to late pancreatic rejection.

Pancreas allograft rejection: correlation of transduodenal core biopsy with Doppler resistive index.

To determine the usefulness of sonographically obtained resistive indexes (RIs) in the diagnosis of pancreas allograft rejection. Findings were studied from 78 transduodenal pancreas allograft biopsies that were ultrasound-guided and cystoscopically directed. The 78 biopsies included 40 that were compared directly with baseline RI data. Biopsies were categorized by result and correlated with concurrent RIs (including 26 RIs obtained within 24 hours of biopsy) with the chi2 test for categoric variables and the Student t test for continuous variables. Sensitivity, specificity, and positive and negative predictive values were calculated with standardized formulas. The mean RIs between the no rejection, mild acute rejection, and moderate acute rejection groups were not statistically significantly different; however, the mean RI associated with chronic rejection was statistically significantly higher (P < .05) than that in the other groups. The sensitivity, specificity, and positive and negative predictive values of either an elevated RI (> 0.70) or greater than 10% increase in the RI above the baseline value in the diagnosis of acute rejection were approximately 50%. Neither the absolute level of the RI nor the relative increase was correlated with acute rejection proved at biopsy. Changes in RIs after pancreas transplantation were a poor indicator of acute rejection, but the absolute value of the RI was elevated in cases of chronic rejection.

An Analysis of Monocyte/Macrophage Subsets and Granulocyte-Macrophage Colony-Stimulating Factor Expression in Renal Allograft Biopsies

The role of infiltrating macrophages in the pathogenesis of acute rejection was investigated in biopsy specimens obtained from human transplanted kidneys using immunohistochemical methods. Thirty-one allograft tissue specimens obtained from 26 patients were histologically classified into 18 with acute rejection, 7 with borderline change and 6 with chronic rejection according to the Banff working classification (1993). These specimens were analyzed by avidin-biotin peroxidase complex method on frozen sections in order to examine the utility of some antimonocyte/macrophage monoclonal antibodies in differentiating acute rejection from other conditions. The ratio of CD68, CD11b, LeuM3, OKM5 and HAM56-positive infiltrating monocytes/macrophages to leukocyte common antigen (LCA)-positive cells in the renal cortex were calculated. As a result, the ratio of the positive cells for CD68, which stains mature macrophages, significantly increased in the cases of acute rejection compared with those of other groups. In addition, a strong expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) was observed in the acute rejection group. In our study, the expression of class II major histocompatibility antigens (HLA-DR) in the proximal epithelial tubules was also strongly observed in the cases of acute rejection. It was thus concluded that the increase of CD68-positive infiltrating cells and the expression of GM-CSF may play a possible role as a reaction effector in the process of acute renal allograft rejection.

Expression of the cytotoxic T cell mediator granzyme B during liver allograft rejection

Cytotoxic T lymphocytes (CTL) constitute a major component of the alloreactive response following organ transplantation. The molecular mechanisms of CTL killing remain to be determined but multiple candidate molecules involved in CTL-mediated cytotoxicity have been identified. Granzyme B, a serine protease, participates in perforin-dependent pathways of cytotoxicity and is necessary for induction of DNA fragmentation in target cells. In this study the expression of granzyme B in liver biopsies obtained from liver allograft recipients was determined by semiquantitative reverse transcriptase polymerase chain reaction. Biopsies were classified into four groups—no evidence of rejection, preservation injury, acute rejection, or resolving rejection—according to histopathological criteria. There was a significantly higher frequency of transcripts for granzyme B in the acute rejection group (82.8%) compared to the no rejection (20.0%), resolving rejection (12.5%) and preservation injury (0%) groups. Analysis of granzyme B gene expression in sequential samples from individual patients prior to, and after, treatment for rejection revealed an inverse correlation between granzyme B mRNA and response to treatment. These findings indicate that the cytopathic mediator granzyme B may participate in CTL-mediated cytotoxicity during liver allograft rejection.

Tissue type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) in transplanted kidneys

We have studied the involvement of fibrinolysis in acute rejection after kidney transplantation by analyzing changes in urinary levels of substances such as FDP, D-dimer, tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). Fibrinolytic activity was found to be low (that is, PAI is dominant) during acute rejection, and it was elevated (that is, PA became dominant) as acute rejection subsided. It appears that the dominance of PA leads to an increase in the products of fibrinolysis and an elevation in the D-dimer/FDP ratio, resulting in disappearance of the acute rejection. Based on these findings, we thought it necessary to administer t-PA to kidney recipients so that PA becomes dominant earlier and the acute rejection can be reduced. It is necessary for us to directly study the phenomena within the kidneys. Therefore, we recently conducted a histochemical study of the distribution of t-PA, Urokinase type PA (u-PA) and PAI in transplanted kidneys. Transplanted kidney, which functioned well or showed signs of acute or chronic rejection, were biopsied. These renal samples as well as control samples (biopsied from normal nongrafted kidney) were examined as to distribution of t-PA, u-PA and PAI by the indirect enzyme complement method. In conclusion, t-PA, u-PA and PAI were detected in the glomeruli, arterioles, tubule and interstices of the control kidneys, well functioning grafts, acutely rejected grafts chronically rejected grafts. All samples showed intense chromatic responses in the arterioles and part of the tubules. On the whole, the chromatic response tended to be more intense in the acute rejection group than in the other group.

Early diastolic left ventricular function as a marker of acute cardiac rejection: a prospective serial echocardiographic study

Changes in left ventricular early diastolic time intervals are sensitive indicators of incipient left ventricular dysfunction. We tested the hypothesis that acute rejection in cardiac transplant recipients is associated with alteration of early diastolic myocardial function, as expressed by the time interval Te, a parameter derived from digitized M-mode echocardiograms. Te is defined as the time interval between maximal posterior wall contraction and the point of peak posterior wall endocardium retraction velocity, as determined by the nadir of the computed first derivative curve. In trasplant patients without rejection (group A, n = 48), Te was prolonged compared to healthy individuals (group C, n = 35) (79.0 ± 12.5 ms vs 64.0 ± 7.9 ms; p < 0.0001). During acute rejection (group B, n = 18) transplant patients had significantly longer mean Te values compared to transplant patients without rejection (group A) (97.8 ± 17.9 ms vs 79.0 ± 12.5 ms; p < 0.0001). Longitudinal studies in individual patients (group D, n = 18) demonstrated that rejection is associated with prolongation of Te (94.5 ± 16.0 ms during rejection vs 79.0 ± 10.3 ms before rejection; p < 0.0002) and that Te returns to individual baseline values in response to treatment (79.2 ± 9.4 ms after therapy vs 79.0 ± 10.3 ms before rejection; NS). In a prospective study, Te changes in transplant patients (group E, n = 96) were correlated with myocardial biopsy results. Sixty-one biopsies showed acute rejection, and 115 biopsies were negative. Taking a 20% increase in Te compared to pre-rejection values as the criterion for an acute rejection, the sensitivity, specificity, positive and negative predictive values were 80, 94, 88, and 90%, respectively. We conclude that the parameter Te is a useful non-invasive marker of acute cardiac rejection.

Sonography of renal transplants in dogs: the effect of acute tubular necrosis, cyclosporine nephrotoxicity, and acute rejection on resistive index and renal length.

Results of studies on the accuracy of the resistive index as a predictor of acute renal transplant rejection have varied widely. Clinical evaluations are limited by the inability to control the numerous coincidental factors that affect vascular resistance. We performed a controlled study in dogs to isolate the effects of acute tubular necrosis, cyclosporine toxicity, and acute rejection on the resistive index, and to compare them with a population of normal control subjects. By doing so, we hoped to identify the patterns of change in the resistive index over time and possibly explain the wide spectrum of resistive index data reported in the literature. Resistive index, a parameter calculated from relative systolic and diastolic velocity, indicates parenchymal resistance to perfusion. Since an increase in renal length also has been reported useful in predicting rejection, we studied changes in length in each of the isolated conditions. The normal control group (four dogs) had heterotopic autotransplantation with minimal cold ischemic time. The acute tubular necrosis group (six dogs) had heterotopic autotransplantation with 1 hr of warm ischemic time. The cyclosporine toxicity group (four dogs) was allowed approximately 3 months to heal from heterotopic autotransplantation. Very high (toxic) doses of cyclosporine were then administered. The acute rejection group (five dogs) had heterotopic allografting with minimal cold ischemic time. No medications were administered. In all groups, the abnormalities induced were confirmed by biopsy. Creatinine levels were also used to monitor cyclosporine toxicity. In the normal control and acute tubular necrosis groups, resistive index increased immediately after surgery, returning to baseline within 10 days. Renal length increased slightly in both groups, but the duration of increase was longer in the acute tubular necrosis group. No significant change in resistive index or renal length was seen in the cyclosporine toxicity group. In the acute rejection group, an initial decrease in resistive index during the mild to moderate phase was followed by a rapidly progressive increase with worsening rejection. Renal length increased progressively beginning immediately after surgery. Our study determined the patterns of change in resistance and renal length over time as caused by the isolated pathologic states. Our finding that vascular resistance decreased in mild to moderate acute rejection was unexpected, since almost all the literature reports resistive index elevation. This may explain some of the conflicting results obtained in Doppler investigations of rejection. Our results on renal length reinforce the positive clinical reports of its predictive value in rejection.

Long-term beneficial effects of azathioprine addition to ongoing cyclosporine-prednisone protocol in renal transplantation.

Delayed addition of azathioprine (Aza) to an ongoing cyclosporine-prednisone protocol was started 11.3 +/- 9.9 months after renal transplantation in 31 patients. Group I (n = 10) had chronic renal function deterioration due to chronic rejection, group II (n = 11) had repeated or severe acute rejection episodes and group III (n = 10) had cyclosporine (Cs) toxicity despite drug tapering. In group I, SCr had risen over the 6 months prior to Aza addition (P < 0.05), renal function declining at a rate of -0.13 +/- 0.12 SCr(-1). In the 6 months post-Aza, renal function improved at a rate of 0.05 +/- 0.07 SCr(-1), and during the entire follow-up at a rate of 0.05 +/- 0.12 SCr(-1) (P < 0.01) with stable Cs levels. In group II the decline in renal function was greater, though the rate of decline was stopped after Aza. In group III, renal function improved in eight patients. After 23 +/- 12 months of follow-up, 15 patients had improved graft function, two were stable, 12 had worsened (nine on dialysis) and two had died. Amelioration of chronic graft dysfunction can be achieved by delayed addition of Aza to Cs-prednisone-treated renal allograft patients with chronic rejection or Cs toxicity, with long-term beneficial effects in a high proportion of patients.

Ten Years Experience with Plasma Exchange in Renal Transplantation

Plasma exchange has been used in our renal transplantation programme for over ten years to treat 86 patients divided into four groups. Five patients had preformed cytotoxic antibodies before transplantation (group A); 13 sensitized patients (greater than 60% PRA) underwent prophylactic plasma exchange in the immediate post-operative period (group B); 62 patients were treated for acute vascular rejection (group C); six patients had chronic graft rejection (group D). Plasma exchange is a valid tool for the treatment of acute vascular rejection, provided that it is started before irreversible graft damage occurs: 75% rejection crises were reversed by plasma exchange and the actuarial graft survival from the rejection episode was 75% at one year, 66% at two and 50% at five years. Serum creatinine before treatment and glomerular thrombosis at graft biopsy correlated with the response to plasma exchange. In sensitized patients and in those with chronic rejection the results were disappointing and suggest that in these clinical conditions plasma exchange should be used only in selected cases.

Duplex Doppler sonography of renal transplants. Correlation with histopathology.

The correlation of histopathologic findings with duplex Doppler sonography (DDS) in 24 biopsies in 21 patients was studied. The resistive indices (RI) of the acute rejection group were statistically different (p = .04) from those that were negative for rejection or clinical controls. Although the number of cases of moderate to severe interstitial and/or vascular rejection was relatively small compared to the mild group, patients with the more severe forms of rejection (moderate to severe interstitial with or without vascular rejection) tended to have higher RIs (.89 +/- .04) than those with the milder forms of rejection (.75 +/- .05).