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PubMed2000

Contrast-induced nephrotoxicity in renal allograft recipients.

BACKGROUND: Intravenous administration of radiographic contrast agents is an important cause of acute renal failure, accounting for one third of the cases of hospital-acquired acute renal failure in patients with native kidneys. The safety of intravenous contrast has not been studied in renal allograft recipients since the availability of cyclosporine as a maintenance immunosuppressive therapy. As patients with renal transplantation may be at a higher risk of contrast-induced nephrotoxicity (CIN) due to concomitant use of cyclosporine and higher prevalence of diabetes and renal insufficiency, we retrospectively studied development of CIN in these patients. PATIENTS AND METHODS: We identified 44 patients (1988 1997) with functioning renal allograft who underwent different intravenous or intraarterial contrast studies (ICS). Pre- and post-ICS renal function tests were done in 35 of these patients. The following were the various ICS done in these patients: coronary angiogram (6), CT scan with intravenous contrast ( 11), angiogram for evaluation of peripheral vascular disease (11), allograft angiogram with angioplasty (5), pulmonary angiogram (1) and intravenous pyelogram (1). The mean age of the patients was 42 +/- 2.1 years and the mean serum creatinine was 2.3 +/- 0.25 mg/dl (mean +/- SEM). Fourty percent of patients (14 of 35) had diabetes, and 25.7% (9 of 35) had chronic rejection. Ninety four percent (33 of 35) of the patients were taking cyclosporine at the time of ICS. RESULTS: Nine patients had > or = 25% increase in serum creatinine from baseline after ICS. Two of these patients were excluded from the analysis as renal functions in these patients had deteriorated prior to ICS and renal failure was attributed to sepsis. Of the remaining 7 patients, 5 had diabetes and 2 had chronic rejection. Only 4 of these 7 patients with CIN received prophylaxis (I/V hydration) prior to ICS. The baseline serum creatinines were not different in patients who had no change in renal function to those who developed CIN (1.97 +/- 0.20 vs 1.54 +/- 0.17 mg/dl, p = 1.5, mean +/- SEM). More than 50% increase in baseline serum creatinine was seen in only 3 of these 7 patients, 2 of these patients had diabetes and third had chronic rejection and congestive heart failure. None of these patients received prophylaxis for CIN. Dialysis was not required in any patient. Three patients also had a > 25% decrease in baseline serum creatinine after ICS, and all of them had allograft angiography with angioplasty for renal artery stenosis. CONCLUSION: In our retrospective study, the incidence of CIN in renal allograft recipients applying a broader classification of > or = 25% increase in baseline serum creatinine was 21.2% (7 of 33 patients). The incidence of CIN was lower 15.3% (4 of 26) in patients who received intravenous hydration compared to 42.8% (3 of 7) in patients who received no prophylaxis prior to ICS.

Acute Kidney Injury↗
PubMed1986

Indefinite survival of rat parathyroid allografts without postoperative immunosuppression.

Methods that avoid long-term immunosuppression must be developed for human parathyroid allotransplantation to be feasible. Pretransplant treatment of the graft to eliminate passenger cells is one such method. An alternative approach is short-term treatment of the recipients with cyclosporine (CsA). In this study, parathyroid glands from Lewis X Brown Norway rats were cultured for 1 week and treated with antiserum directed against class II major histocompatibility complex antigens. Treated glands were transplanted into hypocalcemic Wistar-Furth recipients that previously received 30 mg/kg of CsA once a day for 3 days before transplantation. At 280 days after transplantation, 67% of the recipients had functional parathyroid allografts. Control rats (no CsA; fresh, untreated glands) rejected these grafts within 28 days. Control rats given 3 days of CsA and transplanted with fresh, untreated glands had functional grafts for greater than 56 days (median survival, 80.5 days). Prolongation of allograft survival with short-term, preoperative CsA demonstrates the efficacy of immunosuppression given at the time of antigen presentation. This course of CsA is even more effective when the recipient receives a graft whose passenger cells are eliminated.

Animals↗
PubMed1993

Lectin-dependent cell-mediated cytotoxicity and natural killer function in rejecting and infected lung allografts.

Differentiation between rejection and infection of lung allografts remains difficult. The effects of these two pathologic entities on the cytolytic activity of bronchoalveolar lavage (BAL) and PBL were investigated. Left lung allotransplantation was performed on 16 mongrel dogs of which 12 were available for complete studies. All animals received CA, AZA, and PRED for 2 weeks. Four grafts developed left lower lobe Gram negative pneumonia. The eight remaining recipients progressed gradually to severe rejection after acute reduction of immunosuppression. Cytolytic activity of blood and left lung BAL lymphocytes was quantitated by the natural killer (NK) and lectin-dependent cell-mediated cytotoxicity (LDCMC) assays. Two additional groups serving as controls were either given a 10-day course of immunosuppressants or had right lower lobe pneumonia induced by transbronchial inoculation of gram negative bacteria. Immunosuppressed control animals showed significant depression of PBL and BAL lymphocyte LDCMC and NK activity. Similarly, BAL lymphocytes expressed very low LDCMC in normal allografts (2.8 +/- 0.8%). Once rejection developed and progressed, LDCMC became significantly higher (15.6 +/- 2.2 and 52.7 +/- 2.8% in mild and severe rejection, respectively). There was no detectable NK activity in rejecting lung allografts. BAL lymphocytes from infected allografts, on the other hand, showed an elevation of both NK and LDCMC activity (9.1 +/- 1.1 and 14.6 +/- 1.0%, respectively). Similarly, bacterial pneumonia in control animals manifested an increase in NK and LDCMC activity in lung and blood. PBL lymphocytes of lung allograft recipients, however, had increased NK and LDCMC activity in both rejection and infection. LDCMC/NK activity ratio (LM/NK index) of lung lymphocytes was significantly higher in rejecting allografts (11.2 +/- 1.0 and 12.4 +/- 1.6 for mild and severe rejection, respectively) than in infected ones (1.2 +/- 0.3, P < 0.0001). It appears, from this study, that rejection of the lung allograft results in alterations in BAL lymphocyte phenotypes and functions that differ from those associated with bacterial infection. Such differences may be useful in distinguishing episodes of acute allograft rejection from bacterial infection.

Animals↗
PubMedDate not supplied

Routine assessment of viability in split-thickness skin.

Effective quality control of allograft skin that is cryopreserved for transplantation requires a simple, reproducible technique for the assessment of cell viability. Tetrazolium reduction assays and an oxygen consumption technique have been the two methods of choice to determine the metabolic function of allograft skin after it has been thawed. In this study, we investigated the use of a novel tetrazolium salt, WST-1 (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzen e disulfonate), that is cleaved to a water-soluble formazan product. Porcine split-thickness skin in minimal essential medium without cryoprotectant was subjected to a graded freezing protocol to generate progressive amounts of cryoinjury. Recovery as determined with WST-1 was compared with measurements made with the use of the oxygen consumption technique. The similarity of the resulting recovery curves indicates that WST-1 is a simple, effective, and convenient technique for the assessment of metabolic function in porcine split-thickness skin. The WST-1 assay is applicable for the routine assessment of tissue viability in cryopreserved allograft skin.

Animals↗
PubMed1997

Predictive performance of renal function estimate equations in renal allografts.

AIMS: Various mathematical models have been developed to estimate glomerular filtration rate (GFR) incorporating variables such as age, gender, height, weight, serum creatinine, and body surface area (BSA). Because adjustments in drug dosing are often based on estimated values of renal function, it is important to define which, if any, of the available models, is appropriate for a specific patient population. A study was undertaken to determine the bias and precision of four mathematical models to estimate GFR in renal allograft recipients. METHODS: A retrospective review of 142 stable renal allograft patients, using iohexol clearance as a determinant of GFR, was performed. Renal allograft recipients followed in an outpatient clinic setting underwent iohexol clearance studies as part of clinical monitoring in the post-transplant period. Measured GFR values were compared with four mathematical models used to estimate GFR: the Cockcroft-Gault equation, the Jelliffe equation, the Walser equation, and the Mawer equation. Bias and precision were determined for each model as the mean squared error and the mean squared error, respectively. RESULTS: Patients had a mean age of 44 +/- 13 years, 92 were male, and 50 were female. The serum creatinine concentration was 176.8 +/- 88.4 mumol l-1 (mean +/- s.d.). The mean time post-transplant was 5.1 +/- 5.0 years and 38% of patients had insulin-requiring diabetes mellitus. The bias and precision results for the Jelliffe, Walser, Cockcroft-Gault, and Mawer models were: -3 and 414; -5 and 381; 16 and 688; and 23 and 1084, respectively. CONCLUSIONS: The Jelliffe and Walser equations gave the least biased and most precise estimations of GFR when compared with iohexol-derived measures in patients with renal allografts.

Adult↗
PubMed1991

Highly sensitized patients with delayed graft function: a management protocol.

The postoperative management of the highly sensitized renal transplant recipient with delayed graft function on cyclosporine is complicated. Allografts with delayed graft function are reported to have a 20 to 30% poorer 1-year survival than allografts without delayed graft function. Several factors may be implicated in this poorer 1-year survival. A decrease in or cessation of cyclosporine dosage frequently is used in an attempt to minimize nephrotoxicity. Such under-immunosuppression can result in irreversible rejection. Occasionally, a pessimistic view of the prognosis for the transplant may result in early abandonment of the allograft with discontinuation of immunosuppression and allograft nephrectomy. We report on 3 highly sensitized patients whose kidneys had delayed graft function and were deliberately maintained on high doses of cyclosporine throughout the period of delayed graft function. Each graft achieved function (2, 4 and 5 months) after transplantation. The serum creatinine levels 20, 28 and 38 months after transplantation were 2.7, 2.0 and 1.0 mg./dl., respectively. We suggest that the maintenance of high cyclosporine levels throughout the delayed graft function period is useful in highly sensitized recipients and was an important factor in their successful outcome. A management protocol for such patients is proposed.

Adolescent↗
PubMed1998

Aortic root replacement with a pulmonary autograft in young adults: medium-term results in 70 patients.

BACKGROUND: Pulmonary autograft aortic valve replacement has been introduced in our institution in selected adult patients in light of the known disadvantages and limitations of conventional prosthetic valves. METHODS: We prospectively evaluated the use of the pulmonary autograft in a series of 70 young adults (31.2+/-8.7 years, range 16 to 49 years) operated on from March 1992 to April 1997 with aortic root replacement only. RESULTS: There were no in-hospital deaths and two noncardiac-related late deaths during follow-up of up to 62 months (mean 33 months). Thromboembolic complications were not observed. One patient required reoperation for infective endocarditis 4.3 years after surgery. Discharge echo-Doppler studies showed normal autograft and allograft valve function. Serial echo-Doppler studies showed no significant progression of aortic insufficiency and no dilatation of the autograft. A severe stenosis of the pulmonary allograft developed in 1 patient. CONCLUSION: Aortic root replacement with a pulmonary autograft, although more complex than conventional prosthetic valve replacement, is a safe, effective, and reproducible procedure in properly selected adult patients. Long-term results remain to be evaluated.

Adolescent↗
PubMed1984

Concentration of In-111-oxine-labeled autologous leukocytes in noninfected and nonrejecting renal allografts: concise communication.

Autologous leukocytes labeled with In-111 oxine (ILL) concentrated in the renal allografts of eight patients for whom transplant rejection, infection, or acute tubular necrosis (ATN) could be excluded. All patients had good-to-adequate renal function at the time of ILL scintigraphy, and none developed rejection or renal transplant failure during a 1-mo follow-up period. It is concluded that normally functioning renal allografts without evidence of rejection, infection, or ATN often will concentrate ILL. When a baseline study is not available for comparison, this phenomenon limits the value of ILL scintigraphy as a diagnostic test for transplant rejection or infection.

Adult↗
PubMed2004

Late calcineurin inhibitor withdrawal as a strategy to prevent graft loss in patients with suboptimal kidney transplant function.

UNLABELLED: Chronic allograft nephropathy is a major cause of progressive renal failure in renal transplant recipients. Its etiology is multifactorial and may include both immunologic and nonimmunologic causes. In this observational cohort study we set out to see if calcineurin inhibitor withdrawal would reduce the likelihood of graft loss. METHODS: One hundred and five renal transplant recipients with impaired kidney function (mean serum creatinine 3.0 +/- 0.1 mg/dl) and biopsy-proven chronic allograft nephropathy had the dose of their calcineurin inhibitors, cyclosporine (CSA), or tacrolimus (FK), reduced or discontinued with either the addition of, or continuation of mycophenolate mofetil and low-dose corticosteroids. This intervention occurred at a mean of 29.0 +/- 2.7 months after transplantation. Follow-up after intervention was 54.3 +/- 4.1 months in the reduced CSA group (n = 64), 41.6 +/- 3.2 months in the reduced FK group (n = 28), and 75.5 +/- 6.7 months in the calcineurin inhibitor withdrawal group (n = 13). RESULTS: There were 24 graft failures in the reduced CSA group, 9 graft failures in the reduced FK group, and 1 graft lost in the calcineurin inhibitor withdrawal group. The unadjusted relative risk for graft failure in the CSA and FK groups combined (confidence interval 1.05-31.6), was 4.07 using the calcineurin inhibitor withdrawal group as the reference, p = 0.05. A Cox proportional hazards model adjusting for baseline covariates including age, gender, race, type of transplant, delayed graft function, baseline blood pressure and random serum glucose and cholesterol demonstrated that only calcineurin inhibitor dose reduction but not withdrawal, older age, delayed graft function, higher serum creatinine at the time of intervention, and higher diastolic blood pressure and serum glucose, correlated with graft loss. Only 6 of the 105 patients developed Banff grade acute rejection. All responded to steroid therapy. We conclude that although this observational cohort study may have a selection bias, late calcineurin inhibitor withdrawal in patients with chronic allograft nephropathy and impaired kidney function appears safe and durable as a treatment strategy to reduce the likelihood of graft failure.

Adult↗
PubMed1976

Altered reticuloendothelial function in long-term renal allograft recipients.

Using the clearance of microaggregated iodinated human serum albumin reticuloendothialial system (RES) phagocytic function was tested in 48 long-term renal allograft recipients and was found to be defective at the time of testing in 70%. Depression of RES phagocytosis could be related to total steroid dosage in the previous year and to the patients liability to bacterial infections. Evidence from this test does not suggest an immunosuppressive effect of cytomegalovirus. However, three patients are discussed who have developed chronic active hepatitis that is not due to type B virus.

Female↗
PubMed1987

Extension of survival of rat parathyroid allografts by depletion of Ia donor cells plus preoperative cyclosporine.

Methods that avoid chronic immunosuppression of transplant recipients must be developed to eliminate the various risk factors associated with such treatment (e.g., increased infections and malignancies). Pretransplant treatment of the graft with anti-Ia serum plus complement to eliminate "passenger cells" is one such method. An alternative approach is short-term treatment of the recipients with cyclosporine (CsA). In this study, parathyroid glands from Lewis X Brown Norway rats were cultured for one week at 37 degrees C and treated with anti-Ia and complement. Treated glands were transplanted into parathyroidectomized, hypocalcemic Wistar-Furth recipients that had received 30 mg/kg of CsA once a day for the three days prior to transplant. At 1 year posttransplant, 67% of the recipients had functional parathyroid allografts. Control rats (no CsA; fresh, untreated glands) rejected their grafts within 28 days. Controls given three days of CsA and transplanted with fresh, untreated glands all had functional grafts for greater than 56 days (median survival: 80.5 days). Prolongation of allograft survival with short-term, preoperative CsA demonstrates the efficacy of immunosuppression given only at the time of antigen presentation. This course of CsA allowed for indefinite graft survival when the recipient received a graft previously cultured and treated with Ia antiserum. These results are encouraging and should be evaluated further to determine whether similar approaches will be useful in human transplants.

Animals↗
PubMed1994

The recurrence of recurrent membranous glomerulopathy in a renal transplant recipient: case report and literature review.

We describe the first reported case of a renal transplant patient who had two consecutive recurrences of membranous glomerulopathy in his allografts. Both recurrences were detected 1 year posttransplant. The first transplanted kidney was a none of six antigen match and his second was a four of six antigen match. The patient required a second kidney transplantation within 2 years of detection of the first recurrence. The second allograft has functioned adequately for nearly 4 years after diagnosis. The case and literature review illustrate that membranous glomerulopathy can recur in both poorly and well-matched allografts, that recurrence does not always occur faster in the better-matched kidneys, that cyclosporine does not prevent recurrent disease, and that the course of recurrent membranous glomerulopathy is unpredictable.

Glomerulonephritis, Membranous↗
PubMed2002

Hepatic reticuloendothelial function during parenteral nutrition including an MCT/LCT or LCT emulsion after liver transplantation - a double-blind study.

It has been demonstrated that total parenteral nutrition (TPN) modulates the function of the hepatic reticuloendothelial system (RES). The objective of this study was to evaluate the impact of two different TPN lipid emulsions on the recovery of allograft RES function after orthotopic liver transplantation (OLTx). In a prospective, double-blind study, OLTx patients were randomly assigned to two treatment groups. Group I ( n=13) received a TPN regimen that included long-chain triglycerides (LCT). Group II ( n=9) received a TPN regimen that included a fat emulsion consisting of both medium-chain triglycerides (MCT) and LCT. At baseline, i.e., on days 2 or 3 after OLTx ( t1), before lipids for TPN were started, hepatic RES function was determined using the human serum albumin millimicrosphere technique (K-value, 1/min). A second measurement ( t2) was obtained after 7 days of TPN, including one of the study's two fat emulsions. The mean (+/- SD) K-value (1/min) was 0.48+/-0.16 in the LCT group and 0.55+/-0.28 in the MCT/LCT group at t1, and it improved to 0.62+/-0.21 in the LCT group and to 0.86+/-0.32 in the MCT/LCT group at t2. RES function recovery was significantly better in the MCT/LCT group ( P< or = 0.05). MCT/LCT emulsion appears to be the TPN fat emulsion of choice after OLTx as it seems to have less impact on hepatic RES recovery.

Double-Blind Method↗
PubMed1987

Rejection of combined heart-lung transplants in rats. Function and pathology.

Clinical experience with combined heart-lung transplantation has made it clear that several aspects of the rejection of combined organ transplants need further investigation. In this study, the rejection process of combined heart-lung allografts was examined for determining whether it affects the lung and heart synchronously and whether it differs from rejection when these organs are transplanted alone. The lungs of the combined allografts were functionally rejected prior to the heart (6 and 11 days, respectively). Accordingly, the pathologic changes were most severe in the lungs. The rejection pathology of these combinedly transplanted organs was similar to that described for lungs and hearts transplanted separately, except that the airways were found to be more extensively involved than had been appreciated in previous studies. It is concluded that after combined transplantation the lung is more prone to rejection than the heart. On the basis of the present observations, the definition of sequential rejection phases in the lung was slightly altered.

Animals↗
PubMed1998

Methylenetetrahydrofolate-reductase gene C677T variant and kidney-transplant survival.

UNLABELLED: BACKGROUND. Hyperhomocysteinaemia, a risk factor for atherosclerosis, is common in haemodialysis and renal-transplant patients. As atherosclerotic lesions in hyperhomocysteinaemia resemble those of chronic allograft injury, we examined the hypothesis that the C677T variant of the methylenetetrahydrofolate reductase (MTHFR) gene, which is linked to elevated plasma homocysteine levels in patients with renal failure, determines renal allograft survival. METHODS: DNA was prospectively collected from 336 patients undergoing renal transplantation in our clinic between 1988 and 1994 and their corresponding donors. Patient and allograft survival was analysed by blinded review of all case records over a follow-up period of 36 months. Additionally, we recruited 83 patients surviving with a functional kidney allograft for at least 10 years (mean: 156, range 120-240 months). MTHFR-C677T genotype was determined by a PCR-RFLP technique. The influence of genotype on transplant survival was analysed by Kaplan-Meyer life-table analysis and two-tailed global log-rank testing. RESULTS: Frequency of the MTHFR-C677T allele in the cohort group was identical in recipients (0.35) and donors (0.34), and comparable to that in the longterm allograft survivors (0.37). Furthermore, life-table analysis revealed a similar allograft survival over 36 months between the genotype groups (CC 74%, CT 69%, TT 75%). Other risk factors including donor and recipient age, hypertension, body-mass index, and number of rejection therapies were evenly distributed between the different genotype groups. CONCLUSIONS: These findings do not support the hypothesis that the C677T variant of the MTHFR gene is an important determinant of renal-transplant survival.

Adult↗
PubMed1991

Synergy between cyclosporine and anti-IL-2 receptor monoclonal antibodies in rats. Functional studies of heart and kidney allografts.

Although cyclosporine has improved results of organ transplantation, treatment regimens using multiple agents are being evaluated both experimentally and clinically in attempts to diminish its often profound nephrotoxicity; some therapies act synergistically by differential inhibition of distinct steps of the rejection cascade. The effects on graft function of a full dose or a subclinical dose of CsA, ART-18, a monoclonal antibody (mAb) directed against the IL-2 receptor expressed on activated host cells, and a combination of low-dose CsA and ART-18, have been tested in rat recipients of both heart and kidney allografts. Renal graft function was assessed by several classic techniques; heart function by isolated perfusion methods. Full-dose CsA and combination treatment were most effective in both organ graft systems, with at least one-third of grafts surviving indefinitely. At seven days after transplantation, glomerular filtration rates and renal plasma flow of all grafted recipients were decreased as compared with normal; at 14 days, function in the best treatment groups had improved toward that of isografts. Similarly, cardiac output and stroke work index of best treatment groups were comparable to that of isografts. These functional studies complement previously reported immunological and immunohistological findings stressing that synergy occurs between subclinical doses of CsA and anti-IL-2-R mAb in two rat organ graft systems.

Animals↗
PubMed2006

The universal NF-kappaB inhibitor a20 protects from transplant vasculopathy by differentially affecting apoptosis in endothelial and smooth muscle cells.

Transplant vasculopathy (TV) is an accelerated form of atherosclerosis resulting in chronic rejection of vascularized allografts. The causes of TV are multifactorial and integrate at the level of the vascular wall, leading to a phenotypic switch of endothelial cells (ECs) and smooth muscle cells (SMCs). A20 is a NF-kappaB-dependent stress response gene in ECs and SMCs with potent anti-inflammatory effect in both cell types through blockade of NF-kappaB. A20 expression in ECs and SMCs correlates with the absence of TV in rat kidney allografts and long-term functioning human kidney allografts. We demonstrate that A20 protects ECs from tumor necrosis factor, Fas, and natural killer cell-mediated apoptosis by inhibiting proteolytic cleavage of caspase 8. A20 also safeguards ECs from complement-mediated necrosis. Hence, effectively shutting down cell death pathways initiated by inflammatory and immune offenders associated with TV. In contrast, A20 sensitizes SMCs to cytokine and Fas-mediated apoptosis through a novel nitric oxide (NO)-dependent mechanism. The unexpected proapoptotic effect of A20 in SMCs translates in vivo by the regression of established neointimal carotid lesions following balloon angioplasty in rats. Antedating apoptosis of SMCs, expression of the inducible NO synthase increases in A20-expressing neointimal SMCs, corroborating the involvement of NO in causing the proapoptotic effect of A20 in SMCs. Combined anti-inflammatory and anti- or proapoptotic functions of A20 in ECs and SMCs respectively qualify the positive effect of A20 upon vascular remodeling and healing. We propose that A20-based therapies may be effective in prevention and treatment of TV.

Animals↗