Prednisolone disposition in cushingoid and noncushingoid kidney transplant patients.

Little information is available on the disposition of prednisolone in kidney transplant patients and whether correlations exist between the pharmacokinetics and therapeutic or toxic effects of this drug. The present study was designed to determine the pharmacokinetics of prednisolone in six noncushingoid and six cushingoid transplant recipients. The elimination half-lives were not significantly different in the noncushingoid and cushingoid patients (2.3 vs. 3.3 h). However, other pharmacokinetic parameters were significantly lower in the cushingoid group: plasma clearance (147 vs. 82 ml/min) and volume of distribution (32 vs. 20 liters). In addition, the availability of prednisolone after oral prednisone administration was considerably variable (overall range, 27-108%) and was not significantly different between the two groups. Thus, in kidney transplant patients it appears that the plasma clearance and volume of distribution of prednisolone may distinguish between noncushingoid and cushingoid patients.

Improved outcome following renal transplantation with reduction in the immunosuppression therapy for rejection episodes.

Renal transplantation is superior to hemodialysis in terms of rehabilitation and cost, but it is offered to only a minority of patients with end-stage renal failure because of complications related to immunosuppression therapy. To reduce morbidity, we modified out therapy of patients with transplant rejection from high dose intravenous methylprednisolone (group A: January 1968--September 1972) to lower dose oral prednisone (group B: September 1972--December 1977). Patient survival in group B was significantly improved over that in group A, both in recipients of cadaver transplants (91 per cent versus 81 per cent, respectively, at one year, p less than 0.0009) and in recipients of transplants from living related donors (99 per cent versus 86 per cent, respectively, at one year p less than 0.001). The improvement in patient survival was the result of a significant decrease in the incidence of infections. Patients with multiple rejection episodes, a very high risk group, experienced an 18 per cent increase in patient survival in group B. With reduction and rapid tapering of corticosteroids for the treatment of patients with acute rejection and curtailment of the therapy of patients with multiple rejection episodes, survival after renal transplantation becomes comparable to that following hemodialysis; in addition, graft function is not compromised.

The role of hypertension in hemodialysis-associated atherosclerosis.

Atherosclerosis in 50 nondiabetic patients undergoing hemodialysis was assessed at the time of renal transplantation by intraoperative examination and histologic evaluation of the iliac vasculature. Patients were grouped accordingly: minimal (group 1), moderate (group 2) or severe (group 3) atherosclerosis. Sixty-two per cent of the patients had atherosclerosis, half of them with severe involvement. No sex differences were noted. There was a significant correlation between the patient's age and the degree of atherosclerosis (p less than 0.02). Thirty-five per cent of the patients under 30 years of age had atherosclerosis whereas similarly studied nonuremic control subjects had no atherosclerosis. Metabolic and lipid abnormalities, and duration of hemodialysis did not correlate with degree of atherosclerosis. Hypertension was present in 90 per cent of the patients in groups 2 and 3. When patients between the ages of 25 and 40 years were selected, atherosclerosis was present only in previously hypertensive patients (p less than 0.02). Atherosclerosis may not be accelerated by hemodialysis and may be prevented by more stringent control of hypertension in uremia.

Function of autotransplanted kidneys after 24-hour preservation by hypothermic pulsatile perfusion or simple cord storage.

Canine kidneys, flushed with either Collins solution or autologous cryoprecipitated plasma, were then stored for 24 hr by either simple cold storage (submersion) in the flushing solution, or by continuous hypothermic pulsatile perfusion with cryoprecipitated plasma. After autotransplantation without contralateral nephrectomy, detailed split renal function studies were carried out immediately as well as 2 and 7 days later. Measurements were made of inulin clearance, maximal transport of p-aminohippurate, reabsorption of sodium, chloride, and glucose, and the reabsorption of free water. Contralateral nephrectomy was performed 7 days after transplantation, following measurement of renal functions on that day, and plasma urea nitrogen and creatinine were measured periodically over the ensuing 3 weeks. Renal function after transplantation was affected very little by the choice of flushing solution, and the course of azotemia that developed following contralateral nephrectomy was the same in all groups. However, the detailed functional measurements showed that during the 7-day period after transplantation, renal function was depressed to a much greater extent in kidneys treated by simple cold storage than in those that had been perfused.

Do blood transfusions enhance the possibility of a compatible transplant?

Blood transfusions prior to first cadaver kidney transplants have a significant beneficial effect on graft survival and, in this sense, appear to enhance the possibility of a compatible transplant. This desirable effect, however, occurs concomitantly with an increased degree of sensitization, which in turn reduces the likelihood of identifying a compatible kidney by direct crossmatch testing. This report illustrates that the beneficial effect is achieved with one to five transfusions prior to transplantation, but that more transfusions afford no additional benefits. In addition, the presence of cytotoxic antibodies per se does not have an adverse influence on graft survival. Liberal transfusion policies are therefore indicated in cadaver transplant candidates, but more than five transfusions prior to transplantation should probably be avoided unless clinically necessary.

An alternative to cadaver kidney transplants for patients with insulin-dependent diabetes mellitus.

The benefits of successful kidney transplants for patients with end stage renal disease associated with insulin-dependent diabetes mellitus are well known, and the potential advantages of earlier transplantation have been emphasized in other reports. Cadaver transplants, which are not always available for these patients, have not provided a high degree of success in many centers. This has discouraged the use of transplants unless well matched related donors are available. Most patients do not have well matched family members who are able to donate. We have attempted to increase the availability of related transplants for diabetic patients by using a new protocol in which related donors who are poorly matched by mixed lymphocyte culture (MLC) testing (stimulation index (SI) greater than or equal to 7) can often serve as the source of the transplant. This protocol of pretransplant donor-specific transfusions (DSTs) has been applied to 20 diabetic patients. Sixteen transplants have been performed after serial immunological studies following the DSTs detected no specific evidence of recipient sensitization to the respective transfusion donors. Only one of the transplants has been rejected, and this occurred in a patient who intentionally terminated immunosuppressive therapy. Graft survival for the group of 16 patients is 93 and 84% at 1 and 3 years, respectively. The quality of renal function for most of the patients is very good, with a mean serum creatinine of 1.9 and 1.5 ml/dl for those transplants at risk for 12 and 24 months. This new method has given encouraging results for poorly matched related transplants in diabetic patients and makes earlier transplantation possible by providing an alternative to cadaver transplants.

A seven-year experience with donor-specific blood transfusions. Results and considerations for maximum efficacy.

Two hundred thirty-nine transplants have been performed following donor-specific blood transfusions (DSTs) since 1978. Graft and patient survival in 1- and 0-haplotype-matched transplants with DST pretreatment is comparable to HLA-identical results through 4 years. Graft survival in 174 consecutive nondiabetic, non-HLA-identical DST recipients shows that the transfusion effect persists for at least 4 years, with graft survival of 88 +/- 3% at that time, compared with 83 +/- 4% in the concurrent HLA-identical group. Graft function, as determined by serum creatinine, was the same in both groups. Graft and patient survival in 20 0-haplotype matched pairs with DST pretreatment is 100% at 2 years. Low-dose Imuran coverage during DST administration (n = 91) was compared with a concurrent group with no Imuran (n = 93). Imuran had its maximum effect in patients undergoing their first transplant and with a pre-DST PRA less than 10% (12% vs. 21% sensitization rate in the no-Imuran group). Imuran did not appear to confer any beneficial effect in primary transplants with high PRAs and in patients undergoing a second or third transplant. The majority of patients formally excluded from transplantation because of a post-DST positive B-warm crossmatch can now be successfully transplanted with the use of flow cytometry analysis to rule out previously undetectable low levels of anti-T-lymphocyte antibodies. Of 62 patients with a positive B-warm crossmatch alone since 1982, 73% had a subsequent negative fluorescence-activated cell sorter (FACS) crossmatch permitting transplantation. Preliminary results of a DST and cyclosporine treatment study are described. In conclusion, a long-term immunologic effect of DST has been confirmed and the indications and considerations for optimum use of the DST protocol have been more clearly defined.

The beneficial effect of pretransplant blood transfusions in cyclosporine-treated cadaver renal allograft recipients.

212 cyclosporine-treated recipients of mismatched first cadaveric renal allografts are evaluated with respect to the effect of pretransplant random blood transfusions. It is determined that transfusions do not effect patient survival or morbidity. Pretransplant random blood transfusions correlate with significantly improved allograft success. There is also a trend, although not statistically significant, for further improvement of allograft survival with increasing numbers of transfusions. The transfusion effect is not related to the time at which the transfusions are given up to 2 years prior to transplantation. Transfused patients have a higher percent reactive antibody (PRA) than untransfused patients, but this does not cause them to wait for a cadaveric allograft significantly longer than the untransfused patients. Rejections are less severe in transfused patients. It is concluded that cyclosporine-treated recipients of first cadaveric renal allografts benefit from pretransplant blood transfusions.

Dramatic improvement in the success rate for renal transplants in diabetic recipients with donor-specific transfusions.

The chance of achieving successful kidney transplants in diabetic patients was previously limited because few of them had optimally-matched (2-haplotype) related donors. Hence, transplants were usually not carried out until renal failure had already occurred. The application of donor-specific transfusions (DSTs) prior to transplantation to poorly matched donor-recipient pairs (1-haplotype) has been associated with a high success rate for type-I diabetic recipients in our center. The rate of graft survival for 35 consecutive transplants in this category was 88%, 80%, and 73% at 1, 2, and 5 years, respectively. Furthermore, the rate of patient survival was 94%, 90%, and 90% at 1, 2, and 5 years. These patient and graft survival data were without significant difference when compared with the corresponding data for 142 optimally-matched (2-haplotype) related transplants performed without DSTs for nondiabetic recipients, and also when compared with the corresponding data for 130 poorly matched (1 or 0-haplotype) related transplants involving nondiabetic recipients who were prepared for transplantation with DSTs. These good results with DSTs in diabetic recipients emphasize that earlier transplantation utilizing poorly matched related donors should be seriously considered for diabetic patients even before the onset of renal failure, as long as the transplants are carried out in association with DSTs.

Magnetic resonance imaging in the diagnosis of acute renal allograft rejection and its differentiation from acute tubular necrosis. Experimental study in the dog.

This study was designed to evaluate the potential utility of magnetic resonance imaging (MRI) for the diagnosis of acute renal allograft rejection and its differentiation from acute tubular necrosis (ATN). Eighteen canines were used. Five animals served as controls. ATN was induced in six animals by cross-clamping of the left renal artery for 90 minutes. In order to study acute renal allograft rejection, seven animals were subjected to exchange allograft transplantation of the left kidney. MRI was performed with a 0.35T superconductive magnet. A double spin-echo technique was used with varying TR and TE parameters. The spin echo images were analyzed for morphology, signal intensity, T1 and T2 relaxation times, and spin density. The most useful MRI criteria for the diagnosis of ATN and acute rejection were found to be the renal size, the intensity difference between cortex and medulla (corticomedullary contrast), and the T1 relaxation time of the cortex. Normal kidneys showed maximal corticomedullary contrast (19% +/-2) on images obtained with TR = 0.5 sec and TE = 28 msec. Cortical T1 relaxation time was 551 msec + /-73. In the ATN group, the kidneys were slightly swollen (P = ns) and the corticomedullary contrast (11% + /-3) was reduced by 42% (P less than .01). T1 of the cortex (689 + /-142) was increased by 25% (P less than .10). In acute rejection, significant renal enlargement was noted (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of presensitization on graft survival rate.

Graft survival rate was evaluated in 61 recipients with greater than 50 percent frequency of performed antibodies to selected panel cells. This includes recipients of primary cadaver grafts, secondary cadaver grafts, and living related grafts. Graft survival rate also was evaluated in 199 recipients with pretransplant antibodies reacting with 10 to 50 percent of panel cells and in nonsensitized patients. The results show that good graft survival can be obtained in many hyperimmunized patients, particularly in recipients of primary renal allografts (66 percent cadaver graft survival rate at 2 years). However, sensitization following rejection of an allograft appears to confer a less favorable prognosis. The nature of recipient presensitization and the precise specificity of each reactivity cannot always be explained. This is exemplified in three patients in whom broadly reactive lymphocytotoxic antibodies were not directed against HL-A antigens. Since the number of sensitized patients who await renal transplantation is increasing, there should be no hesitation in proceeding with transplantation, particularly with primary grafts. Emphasis, however, must be placed on frequent prospective recipient serum sampling so that transient high levels of cytotoxins do not escape detection and therefore can be easily selected out for cross-matching against potential donors.

Dopamine administration in the normotensive pregnant ewe.

Dopamine was administered to pregnant ewes at randomly selected rates of 1, 3, 5, 10, 20, 30, or 40 microgram/kg/min. Doses less than 10 microgram/kg/min produced no significant change in maternal areterial blood pressure, cardiac output, or renal or uterine blood flow. Higher doses increased maternal cardiac output and blood pressure, did not change renal blood flow, but decreased uterine blood flow. Dopamine consistently caused mild maternal and fetal respiratory acidosis.

Diabetic management by insulin infusion during major surgery.

In five insulin-requiring, uremic diabetic patients undergoing renal transplantation, we infused insulin intravenously at a low rate to maintain plasma glucose levels between 100 and 200 mg/100 ml. In those patients receiving 100 mg or more of prednisone per day and 5 per cent dextrose solution, the hourly infusion rate was determined from tthe following equation: insulin (U) = plasma glucose value divided by 100. When prednisone was not given or when the patient was thin, the ratio became: plasma glucose value divided by 150. Results were compared with those of nineteen similar transplant patients treated with conventional subcutaneous insulin therapy during surgery, and significantly better glucose control was achieved with the low dosage, intravenous infusion.

A ten year experience with cadaver kidney preservation using cryoprecipitated plasma.

Between August 1967 and January 1977, 699 cadaver kidneys were preserved and transplanted in our hospital after continuous perfusion with cryoprecipitated plasma. Overall graft survival of primary transplants was 55 +/- 2 per cent at one year and 41 +/- 2 per cent at four years. The results with ninety-six second transplants were similar. The number of HLA antigens shared and the duration of preservation did not influence graft survival. Patient survival among 426 cadaver graft recipients since September 1972, when lower dose immunosuppression was started, was 91 +/- 1 per cent at one year and 84 +/- 2 per cent at four years, significantly better than survival before then. Survival of fifty-two recipients of cadaver retransplants since September 1972 was 86 +/- 5 per cent at one year and 86 +/- 5 per cent at four years, which was better than before. The incidence of posttransplantation dialysis was 30 per cent and did not correlate with the length of preservation. Primary wound infections, primary ureteral extravasation, and vascular complications each occurred with an incidence of 1.1 per cent or less in patients treated with lower dose immunosuppression. Only four kidneys were lost because of complications, and in no instance was the need for transplant nephrectomy directly related to the method of preservation. Perfusion preservation with cryoprecipitated plasma gives excellent results compared with alternative methods.

Peptic ulcer disease in kidney transplant recipients.

The occurrence of peptic ulcer in kidney transplant recipients treated with corticosteroids for immunosuppression is a problem of considerable magnitude and threatens both patient and graft survival. The fact that peptic ulcer usually occurs in the early months after transplantation, and that there are known risk factors including treatment for rejection, sepsis, and hepatitis, demand a high level of clinical suspicion, early and accurate diagnosis, and prompt treatment. Aggressive medical prophylaxis is important, but if it should fail prompt reduction of the dose of corticosteroids is imperative so that continued patient survival is emphasized rather than the continued survival of the transplant. Surgical intervention, when indicated, should also be prompt, and the more definitive operations such as vagotomy with pyloroplasty or gastric resection are preferred because of a lesser occurrence of reoperation among such patients. Prophylactic operations in patients with an antecedent history of peptic ulcer may provide considerable protection against the development of corticosteroid-related ulcers after transplantation.

Is a "low" dose of prednisone better than a "high" dose at the time of renal transplantation?

It has been suggested that a low dose of prednisone initially given post-transplant, besides producing lower patient morbidity, is as effective as high dose regimens in providing positive graft and satisfactory patient outcome. In 1981 and 1982, we prospectively and randomly studied 77 cadaveric kidney recipients who received a high dose (2.0 mg/kg body weight) (H) and 66 who received a low dose of prednisone (0.5 mg/kg body weight) (L) at the time of transplant. Mean time to the first rejection episode was 9.7 +/- 13.8 and 13.3 +/- 12.9 days in the L and H groups, respectively; 10.6% and 15.6% of the patients in the L and H groups, respectively, never had a rejection episode. Among subjects younger than 45 years, graft and patient survival was better for those treated with the high dose (N = 60, 63.9% vs 32.2%, P = 0.032, and 100% vs 88.4%, P = 0.027, respectively) than for those treated with the low dose (N = 46). Patient and graft response to H and L was similar for patients older than 45. Morbidity was similar for both the L and H groups.

Blood transfusions before and on the day of transplantation: effects on cadaver graft survival.

Pre-BTs significantly improve the survival rate for first cadaver transplants, by a mechanism that remains obscure. The maximal influence is seen with smaller numbers of pre-BTs (1-5 units), but is also observed with larger numbers of pre-BTs. The possible beneficial influence of Tx-BTs on graft survival is not proven, and if it exists at all is not nearly as striking as the effect seen with pre-BTs. Tx-BTs neither potentiate nor nullify the benefit of pre-BTs on graft survival. It is therefore recommended that pre-BTs in smaller numbers, such as 1-5 units, be administered to candidates for first cadaver transplants to increase the probability of a successful outcome. Tx-BTs should be utilized when clinically indicated but not with the expectation that they will necessarily improve graft survival.

Graft survival with high levels of cytotoxic antibodies.

In this study, pretransplant transfusions significantly improved the survival of first cadaver kidney transplants. Large numbers of transfusions had the same influence on graft survival as small number of transfusions. Graft survival was not influenced by pretransplant antibody levels, and the beneficial effect of transfusions was also independent of highest pretransplant antibody levels. The positive relationship between transfusions and cytotoxic antibodies was shown to be highly significant. B-warm and T-warm antibodies were both increased by transfusions and tended to occur together. B-cold antibodies occurred independent of transfusions, B-warm and T-warm antibodies. The results of this study suggest, but do not confirm, that B-cold antibodies benefit graft survival, while T-warm antibodies adversely influence graft survival. Transfusions and B-cold antibodies appear to influence graft survival by different mechanisms.

Donor-specific blood transfusions versus cyclosporine--the DST story.

DST provides excellent graft survival in one- and zero-haplotype-matched donor-recipient pairs as well as a trend towards improving graft survival in HLA-identical matches; serum creatinine levels are good in functioning grafts; Imuran coverage does appear to decrease DST sensitization to the blood donor in nonsensitized patients undergoing a first transplant, which encourages early DST and transplantation in this group; flow cytometry has been extremely helpful in excluding subliminal anti-class 1 antigen activity in patients with positive B warm crossmatches alone; DST, in itself, does not appear to preclude subsequent cadaveric transplantation in patients sensitized to their blood donor; and the family history of the blood donor is known, with essentially no risk to the recipients of hepatitis, AIDS, etc. In regards to the issue of whether DST or Cs is better, both have merits, and one must be aware of the circumstances that relate to the optimum application of each therapy. Only a prospective study of DST- and Cs-treated patients with a long-term follow-up will probably resolve the issue of the optimum regimen for one-haplotype-matched living related donor-recipient pairs. The ultimate strategy may involve the selective use of each regimen for the most appropriate circumstances.

HLA typing and primary cadaver graft survival.

Analysis of 463 consecutive primary cadaver renal transplants showed no influence of HLA match grade on renal allograft survival. Additional categorization according to HLA match grade and degree of presensitization again showed no correlation between match grade and graft survival. Mismatches and matches of specific antigens, cross-reacting groups of antigens, and effect of matching at both locus A and B were also evaluated. There was no significant effect on graft survival except when mismatches against donor A2 and cross-reacting group A2, A28 occurred. A trend toward better graft survival was suggested in recipients matched for A9 and cross-reacting group A9, Aw 23, Aw 24. Although HLA match grade did not influence ultimate graft survival, HLA typing remains important, especially to avoid mismatch against donor A2 antigen. In addition, subsequent detection of new specificities, particularly in other than the A and B loci, may provide significance in the future.