Experience with Simulect.
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Actuarial Analysis↗
Biomedical subjects
R P Pelletier
Publications and source records attributed to R P Pelletier.
Murine renal allografts: spontaneous acceptance is associated with regulated T cell-mediated immunity.
It was shown >20 yr ago that mice will spontaneously accept renal allografts in the absence of immunosuppression, but the mechanism responsible for this is not understood. We transplanted DBA/2 (H-2(d)) kidneys into nephrectomized C57BL/6 (H-2(b)) mice, and the allografts were spontaneously accepted for >60 days without immunosuppression. In contrast, nonimmunosuppressed cardiac and skin allografts in the same strain combination are rejected within approximately 10 days. The accepted renal allografts have a prominent leukocytic infiltrate, suggesting an ongoing, local immune response. At 60 days post-transplant, the recipients of accepted renal allografts display DBA/2-reactive alloantibodies. They also display DBA/2-reactive delayed-type hypersensitivity responses that are actively counter-regulated by DBA/2-induced TGF-beta production, but not by IL-10 production. These data suggest that a donor-reactive, cell-mediated immune mechanism involving TGF-beta is associated with the spontaneous acceptance of renal allografts in mice.
Animals↗
A randomized prospective trial of OKT3 induction in the current immunosuppression era.
Recent improvements in immunosuppression and subsequent decreases in the incidence of acute rejection have brought into question the benefit of the use peri-transplant antibody therapy (i.e. induction therapy). In the current era of immunosuppression that includes mycophenolate mofetil (MMF) and cyclosporine emulsion (Neoral, Novartis, Basle, Switzerland), we designed and have completed a prospective, randomized trial to address this question. Cadaveric and living donor renal allograft recipients were randomized to receive either OKT3/MMF/delayed Neoral/prednisone or MMF/immediate Neoral/prednisone without OKT3. The incidence of rejection episodes was the primary end point. Patients with delayed graft function were excluded. All rejection episodes were biopsy proven and all patients have been followed for a minimum of 2 yr. Fifty-four patients received OKT3 induction, of which 6 patients suffered a rejection episode (11%), while 13 patients (27%) not receiving OKT3 (p=0.04) had a rejection episode. Four patients in the no OKT3 group suffered multiple rejections, while there were only 2 with more than one episode in the OKT3 group. There was no increased incidence of infectious complications in the group receiving OKT3. Hospital costs tended to be higher in the OKT3-treated group, but were not significantly different. The low incidence of rejection in the OKT3-treated group was intriguing and validates the use of antibody therapy in the early post-operative periods even in the era of improved baseline immunosuppression.
Adolescent↗
Elevated blood pressure predicts the risk of acute rejection in renal allograft recipients.
BACKGROUND: Acute rejection (AR) is a strong predictor of renal allograft survival. Recent advances in immunosuppression have reduced considerably the incidence of AR. Still, approximately 25% of patients have AR early post-transplant, and the factors that predispose to AR have not been fully clarified. METHODS: The study includes 1641 adults, recipients of first cadaveric (CAD, N = 1195) or living related renal grafts (LRD, N = 446), transplanted in one institution. The variables associated with the occurrence of AR during the first year post-transplant were identified. RESULTS: By univariate analyses, AR was associated with the following variables: younger (P < 0.001); heavier (P = 0.003); and African American recipients (P = 0.002); CAD transplants (P = 0.001); higher number of HLA mismatches (P = 0.001); delayed graft function (DGF, P = 0.001); higher levels of serum creatinine post-transplant (P = 0.003); and higher levels of systolic and/or diastolic blood pressure (BP) post-transplant (P < 0.001). Higher BP levels were also associated with earlier AR episodes (P < 0.0001). By multivariable analysis AR was significantly associated with recipient age, number of HLA mismatches, DGF, pre-PRA and systolic BP. Analysis of BP measured weekly post-transplant indicated that elevated BP levels, even three weeks prior to the AR episode, were significantly associated with AR. For every level of BP, the use of BP medications was associated with a lower incidence of AR (P < 0.0001). Furthermore, the use of calcium channel blockers was also associated with lower incidence of AR (P = 0.001). Of note, 81% of recipients whose BP increased after the transplant had AR. In contrast, 22% of patients whose BP declined post-transplant had AR. CONCLUSIONS: Elevated BP levels post-transplant identify patients at high risk of AR independently of graft function. Treatment of BP and reduction of BP levels appears to be associated with a decreased risk of AR. We hypothesize that high BP may be an indicator of a particular type of allograft damage, perhaps ischemic, that may predispose to AR.
Acute Disease↗
Mechanisms of graft acceptance: evidence that plasminogen activator controls donor-reactive delayed-type hypersensitivity responses in cardiac allograft acceptor mice.
We have used delayed-type hypersensitivity (DTH) responses to probe the mechanisms of drug-induced cardiac allograft acceptance in mice. DBA/2-->C57BL/6 cardiac allograft recipients treated transiently with gallium nitrate accept their grafts for >90 days and fail to display DBA/2-reactive DTH responses. These DTH responses are restored when anti-TGF-beta Abs are included at the challenge site, and cell depletion studies showed that this DTH inhibition is mediated by CD4+ cells. Real-time PCR analysis revealed that allograft acceptor mice produce no more than background levels of TGF-beta mRNA at DTH challenge sites. This suggests that DTH regulation in allograft acceptor mice may involve TGF-beta activation, rather than TGF-beta production. The protease, plasmin, can activate TGF-beta, and activated T cells can express a receptor for the plasmin-producing enzyme urokinase-type plasminogen activator (uPA), and can also produce both uPA and tissue-type plasminogen activator (tPA). We observed that Abs to tPA or uPA can replace anti-TGF-beta mAb for the restoration of donor-reactive DTH responses in allograft acceptor mice. Histologic analysis revealed that accepted cardiac allografts express uPA, tPA, and active TGF-beta, whereas accepted cardiac isografts express only tPA, but not uPA or activated TGF-beta. These data demonstrate that local tPA and uPA contribute to DTH regulation in allograft acceptor mice and suggest that these elements of the fibrinolytic pathway are used to control donor-reactive cell-mediated immunity in allograft acceptor mice.
Animals↗
Pulmonary Rhizopus infection in a diabetic renal transplant recipient.
Infectious complications after renal transplantation remain a major cause of morbidity and mortality. Mucormycosis is a rare infection in renal transplant recipients; however, mortality is exceedingly high. Risk factors predisposing to this disease include prolonged neutropenia, diabetes, and patients who are immunosuppressed (Singh N, Gayowski T, Singh J, Yu LV. Invasive gastrointestinal zygomycosis in a liver transplant recipient: case report and review of zygomycosis in solid-organ transplant recipients, Clin Infect Dis 1995: 20: 617). Life-threatening infections can occur, as this fungus has the propensity to invade blood vessel endothelium, resulting in hematological dissemination. We report a case of cavitary Rhizopus lung infection, 2 months after renal transplantation, where the patient was treated successfully with Amphotericin B and surgical resection of the lesions with preservation of his allograft function. In this era of intensified immunosuppression, we may see an increased incidence of mucormycosis in transplant population. Invasive diagnostic work-up is mandatory in case of suspicion; Amphotericin B and, in selected cases, surgical resection are the mainstays of therapy.
Diabetic Nephropathies↗
Human allograft acceptance is associated with immune regulation.
The ultimate goal of transplantation is drug-free allograft acceptance, which is rarely encountered in transplant recipients. Using a novel human-to-mouse "trans vivo" delayed-type hypersensitivity assay, we assessed donor-reactive cell-mediated immune responses in kidney and liver transplant patients, four of whom discontinued all immunosuppression. One of these subjects (J.B.) rejected his graft after 7 years of stable function, while the others (D.S., R.D., M.L.) continue to have excellent graft function 5, 28, and 4 years after the cessation of immunosuppression. PBMCs from J.B. exhibited strong responses to both donor and recall antigens whereas PBMCs from patients D.S., R.D., and M.L. responded strongly to recall, but not donor, antigens. Furthermore, when donor and recall antigens were colocalized, the recall response in these three patients was inhibited. This donor antigen-linked nonresponsiveness was observed in four other patients who are still maintained on immunosuppression. The weakness of donor-reactive DTH responses in these patients is due to donor alloantigen-triggered regulation that relies on either TGF-beta or IL-10. In D.S., regulation is triggered by a single donor HLA Class I antigen, either in membrane-bound or soluble form. This demonstrates that allograft acceptance in humans is associated with an immune regulation pattern, which may be useful in the diagnosis and/or monitoring of transplant patients for allograft acceptance.
Animals↗
Obese living kidney donors: short-term results and possible implications.
BACKGROUND: Living kidney donation has increased recently as the shortage of cadaveric organs continues. This increase has occurred in part, due to expanded donor criteria, including obese patients. This is a potential concern because obesity is associated with surgical complications, possibly death, and chronic medical problems. To address this concern, we examined the outcome of a large group of obese (ObD) and nonobese living kidney donors (NObD). METHODS: A total of 107 obese (body mass index> or =27 kg/m2) and 116 nonobese (body mass index<27 kg/m2) living kidney donors donating at a single institution between 1990 and 1996 were studied. Surgical complications, operative duration, and hospital length of stay were assessed. Preoperative blood pressure, serum creatinine, creatinine clearance, protein excretion, fasting glucose, and hemoglobin A1C were measured and first degree relatives with diabetes were identified. RESULTS: Overall complications were significantly more common in ObD, 16.8 vs. 3.4% (P=0.0012). The majority of complications in the entire cohort, 56%, were wound related and were significantly more common in ObD (P=0.016). There was no significant increase in nonwound-related infections, bleeding, or cardiopulmonary events. There were no deaths or major complications. Operative time was significantly longer in ObD 151+/-30 vs. 141+/-29 min (P<0.05) but hospital duration was no different. Predonation, blood pressure in ObD was significantly higher, (P<0.05) and they more often had a family history of diabetes, 46 vs. 30% (P<0.05) than nonobese donors. Renal function, proteinuria, fasting glucose, or hemoglobin A1C were no different. CONCLUSION: With prudent selection, the use of obese living kidney donors appears safe in the short term. They experience more minor complications, usually wound related, and slightly longer operations. Given a higher baseline blood pressure and family history of diabetes, the long-term effect on the remaining solitary kidney in ObD needs to be examined.
Adult↗
Pathologic classification of chronic allograft nephropathy: pathogenic and prognostic implications.
BACKGROUND: After transplantation renal allografts frequently develop interstitial fibrosis and tubular atrophy, and these pathologic changes are the hallmarks of chronic allograft nephropathy (CN). However, the diagnosis of CN has no specific pathogenic implications. In this study we sought to determined whether a subclassification of CN according to vascular pathology correlates with posttransplant events, particularly acute rejection, and graft survival. METHODS: A total of 419 patients with moderate to severe CN were subdivided into: (1) transplant arteriopathy (TA, n=233, 56%); (2) arteriolar hyalinosis (AH, n=89, 21%); and (3) no characteristic vascular pathology (IFb, n=97, 23%). RESULTS: Patients with AH differed significantly from patients with TA or IFb in the following parameters: (1) AH was diagnosed later after transplantation (P=0.001); (2) fewer patients with AH had acute rejection (AR) before the diagnosis of CN (P<0.0001). For example, 44% of AH and 75% of TA had AR before CN; (3) patients with AH also had fewer AR episodes than the other two groups (P<0.0001); finally, (4) graft survival was better in patients with AH than in patients with TA (P=0.01 by chi2, P=0.001 by Cox). In contrast, there were no significant differences between patients with TA and IFb. By multivariate analysis the survival of grafts with CN correlated with: (1) serum creatinine at diagnosis (P<0.0001), (2) recipient's weight (P=0.004); (3) presence of FGS or level of proteinuria (P=0.03); and (4) the occurrence of AR after the diagnosis of CN (P<0.0001). Regarding the latter, AR were more common (P=0.007) and more numerous (P=0.005) in patients with TA or IFb than in AH. CONCLUSIONS: CN can be classified according to vascular pathology in the majority of cases, and this classification correlates with graft survival. Although some forms of CN are closely associated with the occurrence of AR others are not. This study also uncovered several variables that correlate with the survival of grafts with CN.
Adult↗
Increased incidence of gastrointestinal surgical complications in renal transplant recipients with polycystic kidney disease.
BACKGROUND: We had the impression that, although our renal transplant recipients with polycystic kidney disease (PKD) had excellent long-term renal graft function, they had an increased incidence of postoperative gastrointestinal (GI) complications. METHODS: Over a 10-year period (1987 through 1996), 1467 renal transplants were performed in 1417 patients; 145 of these transplants involved PKD recipients. In the PKD group, 18 patients (12.4%) developed a posttransplant complication necessitating GI surgery (PKD-GI), an incidence twice that in the non-PKD recipients (73 patients or 6.2%, non-PKD-GI). RESULTS: PKD and non-PKD recipients displayed no significant difference in mortality. The PKD patients had better long-term renal graft survival than the non-PKD patients (P=0.08). There was no difference in mortality (P>0.6) or renal graft survival (P>0.6) between the PKD-GI and PKD-non-GI groups. The PKD-GI group had no increased mortality over the non-PKD-GI patients (P>0.6), despite a higher incidence of GI surgical complications in the PKD group versus the non-PKD group (overall: 12.4 vs. 6.2%, P<0.01; within 90 days of transplant: 7.6 vs. 3.3%, P<0.02) and a greater propensity for small and large bowel complications (overall: 9.0 vs. 2.6%; P< 0.001; less than 90 days: 6.9 vs. 2.0%, P<0.002). The PKD-GI recipients tended toward less long-term graft loss than their non-PKD-GI counterparts (11.1 vs. 27.4%; P=.22). The PKD-GI recipients suffered no acute rejection episodes within 90 days after their GI operation versus 11 of 73 non-PKD-GI recipients (O vs. 15.1%; P=0.075). CONCLUSIONS: PKD recipients of renal grafts should be watched closely early after transplant because of their increased risk of GI complications. These complications resulted in no increase in mortality or graft loss compared to non-PKD recipients with GI complications despite the PKD group's higher incidence of bowel perforation and increased age at time of transplant.
Adult↗
Comparison of crossmatch results obtained by ELISA, flow cytometry, and conventional methodologies.
The complement-dependent lymphocytotoxicity crossmatch (CXM) is the presently accepted standard for detection of donor-reactive alloantibodies in transplant patients. However, the newer flow cytometric (FXM) and ELISA (EXM) crossmatch technologies are increasingly used as substitutes for the CXM. We have compared the sensitivity and reproducibility of FXM vs. EXM and, in general, find them to be quite similar. However, when we compared the agreement of FXM vs. EXM in 112 donor/recipient combinations, we found that they identified different subsets of donor-specific alloantibodies in about 35% of the tests. When compared to the standard CXM method, the EXM correlated much better than did the FXM, yielding a much lower rate of false positive (2.5% vs. 8%) and false negative (7% vs. 18.5%) results. The reduction in time required to obtain a result (3 h) and the cost of materials ($25/test) was identical for the EXM and FXM. We conclude that the ELISA method for crossmatching has advantages over the flow cytometric method as a substitute for the present standard complement-dependent lymphocytotoxicity method.
Cytotoxicity Tests, Immunologic↗
Focal segmental glomerulosclerosis in renal allografts with chronic nephropathy: implications for graft survival.
De novo focal segmental glomerulosclerosis (FSGS) in renal allografts most often is diagnosed in association with chronic allograft nephropathy (CN). In this study, we assessed the clinical and pathological variables that correlate with the presence of de novo FSGS and the implications of FSGS for the survival of grafts with CN. The study population included 293 renal allograft recipients (52 living related donor, 241 cadaveric donor) diagnosed with CN by biopsy more than 6 months after transplantation. Patients with recurrent FSGS or FSGS associated with other glomerulopathies were excluded. FSGS was present in 87 patients with CN (30%). FSGS was diagnosed more commonly in the following groups of patients: young (P = 0.04), black (P = 0.02), and those with elevated serum cholesterol levels (P = 0.002) and/or high-grade proteinuria (P < 0. 0001, all univariate analysis). FSGS was diagnosed later after transplantation than CN without FSGS (P < 0.0001), and FSGS correlated with the presence of arteriolar hyalinosis in the biopsy specimen (P = 0.04). Compared with CN without FSGS, FSGS was associated with significantly worse death-censored graft survival (P = 0.008, univariate Cox). In addition, when we analyzed all patients with CN, graft survival correlated by multivariate analysis with the following parameters: serum creatinine level (P < 0.0001) and proteinuria (P = 0.004) at the time of diagnosis, presence of FSGS (P = 0.03), and degree of interstitial fibrosis and tubular atrophy (CN score; P < 0.0001, Cox). Of interest, the use of lipid-reducing agents was also associated with improved graft survival in patients with CN (P = 0.0002, univariate Cox), although total lipid levels were not significantly less in patients receiving these drugs. In conclusion, de novo FSGS presents late after transplantation and in association with arteriolar hyalinosis, suggesting these lesions may be related to chronic cyclosporine toxicity. In CN, the presence of FSGS and the severity of interstitial fibrosis are negative independent predictors of graft survival. The possible relationship between lipid-reducing agents and graft survival clearly needs to be examined carefully in future studies.
Adult↗
Renal allograft survival following acute rejection correlates with blood pressure levels and histopathology.
BACKGROUND: Acute rejection (AR) is a strong predictor of renal graft survival, but the negative impact of AR on survival is variable, suggesting that other factors modulate this relationship. In this study, we examined the variables that correlate with graft survival after AR, particularly the impact of blood pressure (BP), graft function, and histopathology. METHODS: The study population included patients with no AR (N = 942) and patients with one (N = 407) or two (N = 156) AR during the first year post-transplant. Patients were adults who were recipients of living related (LRD, N = 410) or cadaveric grafts (CAD, N = 1095) and who were transplanted in a single institution and followed for 5.8 +/- 4 years. RESULTS: Compared with patients without AR, those with AR were significantly younger, had more human lymphocyte antigen mismatches, and included more CAD recipients. Graft survival was analyzed beyond six-months post-transplant. In patients with AR, reduced survival correlated (multivariate) with (a) younger recipients (P = 0.01), (b) AR occurring later during the first-year post-transplant (P = 0.0006), (c) elevated serum creatinine (Cr) before (P = 0.05), at the time (P = 0.0001) of, or after AR (P = 0.0004), and (d) average BP levels after AR [systolic BP (P = 0.003 logistic, P < 0.0001 by Cox), diastolic BP (P = 0.007), mean arterial pressure (P < 0.0001)]. This latter correlation was independent of graft function and recipient race. Thus, post-AR BP levels correlated with graft survival in patients with post-AR creatinine </=2 mg/dl (N = 408, P = 0.0009), in Caucasian recipients (P = 0.001), and in African American recipients (P = 0.01). In contrast, there was no significant correlation between BP levels and graft survival in patients without AR. AR histopathology, analyzed in patients with one AR episode, correlated with graft survival only the first six months after AR but not thereafter. CONCLUSIONS: Graft survival after AR can be predicted independently by graft function and BP levels after the event. Patients with elevated BP post-AR have poor graft survival even if they have excellent graft function.
Acute Disease↗
Clinical implications of the diagnosis of renal allograft infarction by percutaneous biopsy.
BACKGROUND: Herein we investigated the relationships between acute rejection (AR), infection, and renal allograft infarcts, particularly those infarcts that occur beyond the immediate posttransplant period and that affect functioning grafts. METHODS: Infarcts (n=59) were classified as: (1) early (EI; <2 months after transplant; n=32); or (2) late (LI; >2 months; n=27). Controls included patients with severe AR but without infarction (n=84). RESULTS: There were not significant differences in donor or recipient characteristics between infarcts and controls. At diagnosis, patients with infarcts were more likely to be infected (30%) than controls (14%, P=0.01); 15% of infarcts and 1% of controls had disseminated cytomegalovirus (P=0.04). Infarct and AR coexisted in the biopsy specimens of 66% of patients with EI and 62% of patients with LI, but the AR severity ranged from borderline to severe. Furthermore, 30% of patients with EI/LI had a history of severe AR. Graft survival was 47% in patients with EI, 22% in patients with LI (NS), and 71% in controls (P<0.0001, chi-square and Cox regression). Correlates of better graft survival in infarcts included: older recipient (P=0.03); smaller area of infarction in the biopsy specimen (P=0.04); and use of anti-AR therapy (P=0.03). Therapy was effective in patients with EI (treated, 71% survival; untreated, 29%, P=0.02) but not in patients with LI (25% vs. 23%). CONCLUSIONS: Allograft infarcts are associated with AR in 64% of patients, but the AR may be mild. Infarcts are associated with infections. Graft survival is worse in patients with infarcts than in patients with severe AR, consequently these two pathologic diagnoses should not be considered as a single entity.
Adult↗
Function and survival of renal allografts from the same donor transplanted into kidney-only or kidney-pancreas recipients.
BACKGROUND: The aim of this study was to assess whether kidney-pancreas transplantation (KPT) compromises the prognosis of kidney transplantation (KT). METHODS: This study included 368 paired recipients who received grafts from the same donor (184 KPT/184 KT), i.e., renal grafts with the same pretransplant functional and pathologic characteristics. RESULTS: KPT recipients (KPR) were significantly younger and included fewer African-Americans (22% vs. 6%, P=0.0005) than recipients of kidney alone (KR). During year 1 after transplant surgery, KPR were re-admitted more often than KR (4.2+/-2 vs. 2.8+/-2, P < 0.0001). The number of acute rejections (AR) and the serum creatinine were not significantly different in KR and KPR up to 3 years after transplant. After 44+/-29 months, 13% of KR and 17% of KPR died (NS), and 17% of KR and 16% of KPR lost their kidneys (NS). In KPR, reduced renal graft survival did not correlate with AR (P=0.44), but it correlated with: older donors, younger recipients, elevated serum creatinine at 6 months, pancreas loss, and the number of episodes of acute graft dysfunction evaluated by biopsy (multivariate analysis). By Cox, graft and patient survival were not significantly different in KR and KPR. However, the patient survival of KPR < 40 years of age was lower than that of KR (P=0.02). Renal biopsies (n=165) in 40 paired recipients showed no significant differences in AR, interstitial fibrosis, or vascular pathology. CONCLUSIONS: Renal graft function, structure, and survival are not different in KPR and KR, but the correlates of renal graft survival are different in these two groups of recipients.
Adult↗
Outcome of 300 consecutive pancreas-kidney transplants.
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Graft Rejection↗
Simultaneous pancreas/kidney transplantation: comparison of mycophenolate mofetil versus azathioprine.
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Azathioprine↗
Acute rejection following renal transplantation. Evidence that severity is the best predictor of subsequent graft survival time.
UNLABELLED: Timely recognition of risk factors influencing graft survival time following kidney transplantation could facilitate the development of clinical interventions that would increase the longevity of graft survival. To identify these risk factors, we performed a retrospective analysis of the clinical outcome of 1949 renal transplants performed at The Ohio State University Transplant Program between 22 September 1982 and 14 June 1996. The number of acute rejection (AR) episodes was most predictive of shorter graft survival time. The first AR episode severity (indexed using the difference between post-treatment serum creatinine (RxCr) and baseline serum creatinine (BCr), or DeltaCr = RxCr - BCr) was the best predictor of graft survival time (r = 0.27, p < 0.0001) in patients experiencing AR. Subsequent AR episodes occurred more frequently in patients with a higher DeltaCr. However, DeltaCr was the best predictor of graft survival time (r = 0.44, p < 0.0001) in patients who had only one AR episode. The severity of the first AR episode (DeltaCr) correlated with the risk of subsequent AR episodes, the severity of a second AR episode and the average of mean blood pressures obtained after, but not before, the first AR episode. Therefore, we conclude that the severity of the first AR episode was the best predictor of renal allograft survival time in all patients experiencing AR, independent of subsequent AR episodes and correlated with subsequent clinical events which also influence renal allograft survival time. Thus, early diagnosis and aggressive treatment of the first AR episode are warranted to minimize AR severity and thereby maximize subsequent graft survival time. CONCLUSIONS: The severity of the first acute rejection episode following renal transplantation is the best determinant of graft survival time and correlates with subsequent clinical events which could further reduce graft survival time.
Acute Disease↗