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PubMed1992

Plasma fibronectin levels during acute rejection and acute tubular necrosis in renal transplant patients.

Fibronectin (Fn), an acute phase glycoprotein synthesized by the liver, has an important immunomodulatory role. We have investigated the changes in plasma Fn in patients after renal transplantation in order to determine whether these changes predict graft injury or rejection episodes. Besides normal healthy controls, healthy pregnant controls, and a trauma control group, we used two groups of chronic renal failure patients as controls: group I, patients with end-stage renal failure (ESRF) on peritoneal dialysis; group II, patients with ESRF on hemodialysis. These were compared with two groups of renal transplant patients: group III, patients 3 months after successful renal transplantation; group IV, patients studied sequentially 10 days immediately posttransplantation. The renal transplant patients were treated with low-dose cyclosporine, azathioprine, and steroids. Citrated plasma samples were collected for Fn assay by a sandwich-type ELISA and for SDS-PAGE analysis and Western blotting. The mean plasma Fn levels were as follows: healthy controls 311.6 SEM, 13.5 micrograms/ml; healthy pregnant controls 357 SEM, 5.9 micrograms/ml; trauma controls 262.3 SEM 31.7, micrograms/ml; group I 169 SEM, 25.1 micrograms/ml; group II 199 SEM, 27.2 micrograms/ml; group III 272 SEM, 21.7 micrograms/ml; group IV 212 SEM, 27.4 micrograms/ml (day 3 postop). There was a significant difference in the plasma Fn levels on day 3 posttransplant between the patients with delayed and immediate renal function (P less than 0.03) (group IV). A significant decrease in plasma Fn levels occurred immediately after steroid therapy was stopped (P less than 0.03) in patients treated for acute rejection. Plasma Fn levels were significantly decreased in the presence of delayed graft function but did not predict rejection.

Fibronectins↗

PubMed1989

Influence of cadaveric organ source on delayed renal allograft function.

From 1984 to 1987, 110 locally retrieved cadaveric kidneys were transplanted into 108 local recipients, including 50 kidneys from multiple-organ retrieval (MOR) procedures and 60 from kidney-only (KO) donors. Conventional multiple organ retrieval technique, iced Euro-Collins storage, and cyclosporine-prednisone immunosuppression were employed. Delayed graft function (DGF), defined as dialysis dependence after transplantation, was twice as high in the MOR allografts as in the KO allografts, 46% vs. 22%, P less than 0.01. DGF was associated with longer hospitalization postoperatively and reduced eventual allograft function. The greater concordance of DGF in allograft pairs from the MOR group (25% vs. 7% in the KO group) and the increased incidence of DGF when more complex forms of MOR were used (40% with liver or heart retrieval, 55% with liver and heart retrieval) suggested that retrieval-related factors influenced allograft function. DGF in the MOR allografts was unrelated to other differences in donor, preservation, or recipient characteristics in the comparative groups. Unrecognized warm ischemia during conventional MOR is a plausible cause of DGF in kidneys from multiple-organ donors.

Adult↗

PubMed1990

Role of excretory graft function for erythropoietin formation after renal transplantation.

To examine the role of renal excretory function for erythropoietin (EPO) formation we have determined the kinetics of plasma immunoreactive EPO (irEPO) in patients with end-stage renal disease undergoing renal allotransplantation (RTX). In 13 patients with immediate excretory graft function (imGF) and stable haemoglobin (Hb) concentrations (median Hb 9.5 g dl-1 and median irEPO 18 mU ml-1 before RTX) irEPO increased significantly on day 4 after RTX to a median value of 29 mU ml-1 and 2 days later reached a plateau of 34.4 +/- 3.3 mU ml-1 (mean +/- SD of daily median values during days 6-20). In patients with imGF having acute blood loss and subsequently receiving transfusions, irEPO responded in an inverse fashion to changes in Hb concentrations. In 12 patients with delayed graft function (dGF) (median Hb 8.8 g dl-1 and median irEPO 15 mU ml-1 before RTX) irEPO levels during the period of excretory failure remained either unchanged or displayed marked variations with peak values greatly exceeding those of patients with imGF. These variations were not related to changes in Hb concentrations and irEPO levels did not change following alterations in Hb concentrations. Upon recovery of excretory function irEPO approached the values found in patients with imGF. The results suggest that an intact excretory renal function is not a prerequisite for the capability to produce EPO, but correlates with the oxygen-dependent regulation of EPO formation.

Adolescent↗

PubMed1992

The incidence and impact of early rejection episodes on graft outcome in recipients of first cadaver kidney transplants.

The objective of this study was to define the incidence and significance of acute rejection occurring in the first year following transplantation. The influence of contemporary induction immunosuppression on rejection, as well as the effect of rejection on graft and patient loss, renal function, and maintenance immunosuppression during the first year in 110 recipients of first cadaver renal transplants were analyzed. All patients received CsA, Aza, and prednisone for 30 days with withdrawal of Aza at 30 days and then prednisone at 105 days; 57 patients were prospectively randomized to receive ALG (Merieux) until serum creatinine was less than 300 mumol/L. Short-term ALG administration did not influence the incidence, severity, nature, or outcome of rejection episodes. Fifty-five (50%) patients had at least 1 rejection in the first 90 days. All patients with delayed graft function and 7/8 (88%) sensitized patients (current PRA greater than 50%) had at least 1 rejection episode; 71% (n = 35) of all rejection episodes occurred in the first 30 days posttransplant. Patients rejection free at 90 days remained rejection free the entire first year. Graft loss was 18% for rejections in the first month, 13% for rejections occurring later (P = NS); 20% (n = 11) of patients had a second rejection and 1% (n = 2) had a third rejection. The risk of graft loss was 9% with a first rejection, 38% with a second rejection, and 50% with a third rejection. Of 12 (22%) rejections that were steroid resistant, 10 (83%) were reversed with OKT3. One-year graft survival for patients without rejection, with steroid-sensitive rejection, and with steroid-resistant rejection was 96%, 88% (P = ns), and 58% (P less than 0.001), respectively; 1 year SCr was 168 +/- 93, 196 +/- 77 (P = ns), and 268 +/- 96 microMol/L (P less than 0.05), respectively. Patients free of rejection and with stable renal function continued to do well on maintenance CsA monotherapy, and they were more likely to be on CsA monotherapy than those with rejection episodes (P less than 0.01).

Adult↗

PubMed1992

Patients with a low income have reduced renal allograft survival.

The impact of socioeconomic factors on long-term outcome after renal transplantation is unknown. We examined the effects of family income among 202 patients transplanted between 1976 and 1982 who had an allograft that functioned for at least 1 year. Compared with patients with an adequate income, recipients of medical assistance at the time of transplantation were more likely to return to dialysis after 1 year (16/45 [36%] v 26/157 [17%], P less than 0.01), or after 5 years of graft function (10/38 [26%] v 12/116 [10%], P less than 0.01). Patients who complied with fewer than 85% of visits during the first 2 years were also more likely to return to dialysis after 1 year (17/49 [35%] v 25/153 [16%], P less than 0.01), or after 5 years (8/31 [26%] v 14/123 [11%], P less than 0.05) than were more compliant patients. However, noncompliance was not different in patients with and without a low income (37/157 [24%] v 12/45 [27%], P greater than 0.05). The relative risk for returning to dialysis after 5 years was 2.4 (P less than 0.05) for low income and 3.0 (P less than 0.05) for less than 85% compliance using a Cox proportional hazards model. These effects were independent of prior transplantation, mismatches, pre-formed antibodies, delayed graft function, age, sex, diabetes, alcohol or drug abuse, education, race, distance from the transplant center, and living in an urban environment (relative risk = 2.5, P less than 0.05). Neither income nor compliance could be linked to death.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

The influence of nephrectomy of the primary allograft on retransplant graft outcome in the cyclosporine era.

The present analysis was undertaken to evaluate the influence of primary allograft nephrectomies on the early function, incidence of rejection, and short-term graft survival of subsequent renal retransplants. Among 95 consecutive cyclosporine treated retransplant recipients, 52 were retransplanted without primary allograft nephrectomy; 35 had removal of their primary grafts prior to retransplantation for fever and graft tenderness (30 patients) and persistent hematuria (5 patients); and 8 patients had an elective primary graft nephrectomy at the time of retransplantation. Demographic characteristics and immunosuppressive regimens were otherwise similar in all three groups. Nephrectomy of the primary allograft prior to retransplantation was associated with a significant subsequent rise in preformed cytotoxic antibody levels (57% having PRA greater than 30% compared with 33% in those with retention of primary grafts), a significantly higher incidence of delayed graft function among retransplants (63% compared with 30% in those who did not undergo primary allograft nephrectomy) and a trend toward decreased allograft survival in the subgroup who lost their primary allografts in the first year posttransplant. The incidence of acute rejection and 3-year posttransplant renal function in retransplants were not, however, influenced by nephrectomy of the primary allograft.

Adolescent↗

PubMed1990

[A study on the hemodialysis period following cadaveric kidney transplantation--a comparison between two centers sharing cadaver donor kidney pairs].

To study the hemodialysis period following cadaveric renal transplantation, we reviewed 18 consecutive cadaver donor kidney pairs of which one kidney was transplanted at Shiga University of Medical Science (SUMS) while the contralateral kidney was transplanted at Kyoto Prefectural Medical University (KPMU) between January 1983 and September 1988. Of these 18 pairs, graft function was satisfactory and the recipient was free from hemodialysis in 13 pairs. However, the postoperative hemodialysis periods were different between the two centers. To clarify the factors causing this difference, recipient factors, such as age, HLA matching, total ischemic time of the graft (TIT), immunosuppression, onset of diuresis and postoperative complications were studied. There were no significant differences in age, HLA matching, or immunosuppression. TIT of cases at SUMS was significantly longer than that of cases at KPMU. The postoperative hemodialysis period at SUMS was 25.8 days and that at KPMU was 17.8 days, however, the difference was not statistically significant. The results of this study indicate that TIT seems to be a major factor relating to delayed graft function in cadaveric renal transplantation.

Adolescent↗

PubMed1987

Duodenopancreatectomy for transplantation.

Forty duodenopancreatectomies for transplantation were performed. The technique focused on the maintenance of the cardiovascular hemodynamics of the donor during the procedure, the meticulous dissection and preservation of all vascular supplies to the duodenum and the pancreas, and the suppression of warm ischemia by in situ cooling. Recipient euglycemia was established within two hours of the revascularization in 37 of 38 pancreata transplanted. Only six of the 78 renal transplant recipients receiving more than one organ from the same donor required postoperative dialysis, for a 7.7% incidence of delayed graft function. Immediate function was observed in all six cardiac allograft recipients.

Duodenum↗

PubMed1992

Monoclonal antibodies in renal transplantation: a review.

OKT3 is the first anti-CD3 monoclonal antibody available for treatment in humans. Over the last few years it has proven to be a very powerful immunosuppressive agent in renal transplantation. Clinical studies have shown that OKT3 is superior to high-dose steroids as first-line treatment for acute renal allograft rejection. Furthermore, it is comparable to antithymocyte globulin (ATG) in treating steroid-resistant rejection and is also effective as rescue treatment in ATG- and antilymphocyte globulin-(ALG-) resistant rejection. Despite its excellent rejection-reversal rate, OKT3 treatment is followed by a substantial percentage of re-rejections, most of which respond well to steroids. In the early post-transplantation period, a prophylactic course of OKT3 is very effective in preventing acute rejections, and in this respect it is probably equivalent to ATG. Indirect evidence exists that a prophylactic course of OKT3 may be beneficial in immunologically high-risk patients and in patients with delayed graft function. However, more clinical studies are required to answer the question whether OKT3 should be given as induction treatment, as first-line treatment, or as rescue treatment. To answer this question, the side effects of OKT3 should also be taken into account. First-dose-related side effects, although frequent and disturbing, are usually transient and seldom life-threatening, provided overhydration has been corrected and steroids have been given before the first administration. These side effects are attributed to the release of cytokines as a result of T-cell activation or lysis. After exposure of patients to OKT3 an increased incidence of infections and malignancies has been reported. However, it is not yet clear whether this is due to OKT3 as such, or whether it merely reflects the total burden of immunosuppression. Xeno-sensitization represents an important limitation to OKT3 treatment, although a second or third course can still be effective in patients with low antibody titers. The precise immunosuppressive mechanism of anti-CD3 monoclonal antibodies is yet unknown. Monitoring of patients treated with OKT3 revealed CD3 and/or T-cell antigen receptor depletion and immunological incompetence of remaining T cells. More clinical data are required to establish the correct dose and duration of OKT3 treatment. In conclusion, OKT3 is a powerful immunosuppressive agent but its real value in renal transplantation remains to be determined. A practical approach may be to reserve it for the treatment of steroid-resistant rejections.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗

PubMed1992

Pharmacokinetic strategies for cyclosporin therapy in organ transplantation.

Marked interindividual variations in cyclosporin (CsA) produce disparate clinical results in organ transplant recipients. In an attempt to eliminate marked deviations of insufficient or excessive CsA concentrations consequent to the administration of uniform drug doses, test dose pharmacokinetics were performed on each potential organ transplant candidate. An intravenous 3 mg/kg test dose delivered over 3 h proved to be readily performed, namely 53% perfect studies, and relatively reliable, namely 73% of observed concentrations within 10% of the predicted values. Furthermore, the use of CsA doses predicted by pretransplant studies reduces the incidence of delayed graft function, early rejection episodes and transplant loss. The oral test dose study predicted a suitable amount of CsA to achieve sufficient gastrointestinal absorption but was less accurate than the iv prediction method: namely, 40% of observed post-transplant concentrations were within 10% of the predicted target value. Furthermore, patients who received oral doses predicted by the test dose strategy showed no improvement in the incidence of acute rejection episodes between 7 and 60 days, and only modestly improved serum creatinine values. The lower accuracy of predictions from oral test dose studies may reflect the impact of non-linear oral (as opposed to iv) drug pharmacokinetics, of variable diet, and/or of altered postoperative gastrointestinal function.

Administration, Oral↗

PubMed1992

A novel method of induced renal hypothermia.

When the kidney is removed from cold storage for implantation into the recipient it gradually rewarms (second warm ischaemic time) and a prolonged second warm ischaemic time is a risk factor for delayed graft function. A cooling jacket has been designed to prevent this rewarming during transplantation. This study evaluates the efficacy of this device. Surface and core temperatures of less than 15 degrees Centigrade were maintained for 120 minutes. Renal function was significantly better in cooled than in uncooled kidneys in a single kidney canine model. Induced renal hypothermia, using a device such as this, should be a routine manoeuvre in renal transplantation.

Animals↗

PubMed1991

Transplantation of kidneys from pediatric cadaver donors to adult recipients.

Pediatric donors (less than 12 years old) are a potentially important source of kidneys for adult recipients. Previous reports of decreased graft survival and increased complication rates have made surgeons wary of using such kidneys. In 64 kidneys from younger donors transplanted to adult recipients the delayed graft function rate (41 versus 42%), and 2 and 3-year graft survival rates (67 versus 72% and 61 versus 65%, respectively) were similar to those seen with kidneys from adult donors. Kidneys from donors 24 months old or less experienced an 80% rate of graft loss at 1 year. When these kidneys are excluded the 1-year graft survival rate was similar to kidneys from older and younger donors (70 versus 77%). Mean serum creatinine at 1 year was similar in both groups (155 +/- 21 versus 151 +/- 10). Pediatric kidneys except those obtained from donors 2 years old or less are suitable for adult recipients. However, kidneys from very young donors may be more appropriate to pediatric recipients.

Adult↗

PubMed1987

Significance of immediate preoperative bacteriuria with pyuria in renal transplant recipients.

The presence of bacteriuria and pyuria on urinalysis immediately before renal transplantation has resulted in cancellation of surgery because of concern about post-transplant wound infection. Of 113 renal transplant recipients reviewed 41 (36 per cent) had 5 or more white blood cells per high power field with bacteria in either a voided urine or bladder washout specimen obtained just before grafting. Of those 41 patients 2 suffered postoperative wound infections. Of 72 patients (64 per cent) with less than 5 white blood cells or no bacteria on a preoperative specimen 1 suffered a wound infection (p not significant by Fisher's exact test). Preoperative urine cultures and operative bladder cultures of all 3 patients failed to yield the organisms found later in the wound infections. The factors of sex, insulin-dependent diabetes, delayed graft function, living related versus cadaver donor and pre-transplant splenectomy had no significant relationship to wound infection rates. Renal transplantation can be performed safely in patients who have pyuria and bacteriuria but no signs or symptoms of infection.

Adult↗

PubMed1986

Multivariate analysis of risk factors in cadaver donor kidney transplantation.

Data collected prospectively on 3811 kidney transplants performed between June 1977 and July 1982 with follow-up to July 1984 by the 42 member institutions of the South-Eastern Organ Procurement foundation were analyzed to identify factors associated with graft and patient outcome in patients not receiving cyclosporine. Multivariate Cox regression analysis was used to examine the association and relative risk of 24 variables with three actuarial outcomes: overall graft failure, irreversible rejection, and patient death. Factors having no suggested association with any outcome included: recipient sex, history of pregnancy, blood group, and time on dialysis; organ preservation method, time and source; donor race; crossmatch test sensitivity; and annual center transplant rate. In decreasing order of relative risk, the factors most significantly associated with irreversible rejection were: loss of two or more prior grafts, low HLA-A,B match, lack of pretransplant blood transfusion, high (greater than 60%) pretransplant sensitization to leukocyte (HLA) antigens, and delayed graft function. Splenectomy, insulin-dependent diabetes, and antilymphocyte serum therapy provided the greatest risk of patient death. Factors such as recipient age, race, and native nephrectomy had suggested associations with outcome. By adding each center as a separate covariate in the analysis, other center-dependent factors were quantitated and found in some cases to have a highly significant association with graft and patient outcome. These results provide a basis for evaluating the potential risk of graft loss or patient death for those prospective cadaver kidney transplant recipients not being considered for cyclosporine therapy.

Cadaver↗

PubMed1990

Beneficial effect of cyclosporine on renal transplantation. A multicenter long-term study.

Data were collected prospectively on 8581 cadaveric renal transplants performed by institutions of the South-Eastern Organ Procurement Foundation (SEOPF) during the period November 1, 1983 through December 31, 1987. Cyclosporine was the initial then always used immunosuppressant for 5742 of these patients while 1050 never received cyclosporine. The drug was started late in the course of 481 transplants and stopped early in 378 cases. This allowed for 7651 transplants to be analyzed regarding these four categories of cyclosporine use or non-use. Actuarial graft survival for the cyclosporine "ALWAYS" group was 75% at one year, 68% at two years, 62% at three years, and 59% at four years compared with 55%, 49%, 45%, and 43%, respectively for the cyclosporine "NEVER" group (P less than 0.0001). Inclusion of the 930 cases that could not be categorized regarding cyclosporine use or for which actuarial data was not complete allowed all 8581 transplants to be analyzed by multivariate methods. This analysis disclosed significant effects on graft survival due to delayed graft function, prior transplant, recipient race, HLA match, level of PRA, and cyclosporine use. Organ sharing had no effect on graft outcome. While cyclosporine improves outcome in renal transplantation, the importance of other biologic factors affecting graft survival is not diminished by its use.

Cadaver↗

PubMed1990

A randomized trial comparing double-drug and triple-drug therapy in primary cadaveric renal transplants.

A controlled trial was carried out in 209 primary cadaveric renal transplants to compare the effects of cyclosporine and steroids (double therapy) with those of cyclosporine in lower initial dose, azathioprine, and steroids (triple therapy). Patients have been followed 1-36 months since transplantation. Actuarial two-year graft survival (double 74%, triple 76%) and two-year patient survival (double 90%, triple 93%) were similar for both groups. Further analysis of particular risk factors including age, diabetes, HLA matching, acute renal failure, and use of sequential Minnesota antilymphocyte globulin in patients with delayed graft function also showed similar outcomes with both immunosuppressive regimens. Initial hospitalization time, rate of rejection, incidence of serious infection, and rate of rehospitalization were not different. Mean CsA doses and mean trough whole-blood levels were higher in double-therapy patients at hospital discharge but not by three months posttransplant. There were no differences between the two groups in iothalamate clearance at any time. Hypertension was more frequent six months posttransplant in the triple-therapy group (p less than 0.05). Thus, similar results were obtained with both regimens, and except for hypertension no regimen appeared to have increased side effects up to three years posttransplant.

Adrenal Cortex Hormones↗

PubMed1992

The ability of pretransplant test-dose pharmacokinetic profiles to reduce early adverse events after renal transplantation.

Pretransplant test-dose pharmacokinetic profiles were used to determine individual cyclosporine drug bioavailability and clearance rates in renal transplant patients. Assuming a linear relation between dose and area under the concentration curve (AUC), starting i.v. and p.o. CsA doses were computed from the test-dose results. Target values were 400 ng/ml steady-state concentration (Css) during continuous intravenous infusion, and 500 ng/ml average drug concentration (Cavss = AUC/dosing interval) after oral administration, based upon measurements with the specific monoclonal antibody 3H-tracer radioimmunoassay. The outcomes after dose individualization with a 1-(n = 32), 2-(n = 38), or 3-(n = 41) hr i.v. infusion test dose and a p.o. test dose (n = 111) were compared with 228 historical control patients who received a uniform protocol of CsA i.v. at 2.5 mg/kg/day and p.o. at 14 mg/kg/day. The observed Css after i.v. CsA was within 10% of the target concentration in 73% of recipients tested with the 3-hr protocol, a significantly greater fraction than achieved with either the uniform dose (14%), or the 1-(34%) and 2-(25%) hr protocols. Patients in the 3-hr protocol group showed reduced incidences of delayed graft function, early graft loss, and rejection episodes, and a lower mean serum creatinine value, particularly at 7 but also at 30 days posttransplantation. Administration of the predicted oral dose produced a peak concentration of greater than or equal to 700 ng/ml drug absorption in 60% of recipients at 3 days, 90% at 5 days, and 98% at 7 days. The test-dose method less effectively predicted the appropriate oral CsA dose to produce target Cssav and failed to reduce the 90-day rejection incidence. Despite its limitations with the more-complicated p.o. route, the test-dose method successfully predicts i.v. CsA doses, thereby reducing the incidence of early adverse events.

Administration, Oral↗

PubMed1989

Calcific stenosis of a mitral valve xenograft in a patient in chronic renal failure.

A 61 year old man presented with mitral regurgitation and glomerulonephritis caused by suspected infective endocarditis. His glomerulonephritis remitted on immunosuppression but mitral valve replacement with a Carpentier-Edwards porcine xenograft later proved necessary. The patient became dialysis dependent and cadaveric renal allografting was complicated by delayed graft function and refractory pulmonary oedema. Cardiac catheterisation showed severe calcification and stenosis of the xenograft with a transvalvar gradient of 23 mm Hg and despite emergency valve replacement the patient died. The valve had been in place less than five years. The rapid calcification and stenosis of a bioprosthetic heart valve calls into question the use of such prostheses in patients with chronic renal failure.

Bioprosthesis↗