Anders Lindholm

Ischemic heart disease - major cause of death and graft loss after renal transplantation in Scandinavia.

Causes of graft loss and death were studied in 1347 recipients of primary renal transplants followed for 5 years after transplantation irrespective of graft function. Immunosuppression consisted of high or medium dose CsA and prednisolone or low dose CsA and prednisolone and azathioprine. In recipients of cadaver grafts, death with a functioning transplant was more common than graft rejection after the first posttransplant year, accounting for 49% and 41% of the graft losses, respectively. Of deaths with a functioning graft, 53% were due to ischemic heart disease (IHD) and 10% were due to other vascular disease. In the 55− to 64-year-old age group, the risk of death from IHD was 6.4 times higher in the transplanted nondiabetic patients, 8.6 times higher in the dialysis patients (European Dialysis and Transplant Association figures), and 20.8 times higher in the transplanted diabetic patients than in the general population (national figures). A multivariate Cox regression analysis showed that old age, diabetes mellitus, occurrence of acute rejection, pretransplant transfusions, delayed onset of graft function, and male gender were significant for death in IHD. We conclude that, in comparison to reports from other regions, Scandinavian renal transplant recipients are at high risk of dying of HID. Future advances in long-term renal graft survival will depend largely on the success of preventing myocardial infarction and death in this patient population.

The impact of acute rejection episodes on long-term graft function and outcome in 1347 primary renal transplants treated by 3 cyclosporine regimens.

To characterize factors of importance for the occurrence of acute rejection as well as study the impact of these episodes on long-term renal survival and function, a total of 819 acute rejection episodes were studied in 951 primary cadaveric donor kidney recipients (CD) and in 396 primary living donor kidney recipients (LD). The patients were treated by three immunosuppressive schedules, namely, CsA given in a high dose, a medium dose, or a low dose. Additionally, all patients received PRED and patients in the low-dose group received AZA. The incidence of acute rejection was higher and occurred earlier after transplantation in the CsA medium dose and low dose groups than in the CsA high dose group (P < 0.05 and P < 0.01, respectively). Although the incidence of first acute rejection was similar in CD and LD patients, 59.1% vs. 60.6%, it was successfully reversed by antirejection treatment in a higher percentage in LD patients. The estimated graft half-life was shorter in patients who had acute rejection episodes than those who did not, 6.6 years vs. 12.5 years in CD pa

The adverse impact of high cyclosporine. Clearance rates on the incidences of acute rejection and graft loss.

The influence of cyclosporine pharmacokinetic parameters on clinical events and outcome after transplantation was studied in 100 renal transplant recipients who underwent a pre-as well as posttransplant CsA pharmacokinetic evaluation. Among the patients, 30 were black and 50 were white. Black recipients had significantly lower bioavailability (F) pre-as well as posttransplantation than white recipients, the post-transplant mean F values being 25.8±9.0% and 38.1→ 16.7%, respectively (P<0.002). The posttransplant CsA clearance rate (CL) and oral clearance (clearance/bio-availability; CLoral) were significantly higher in patients who had acute rejection than in those who did not, with CL mean values of 425±141 ml/min and 359±131 ml/min, respectively (P<0.02). The initial posttransplant F was significantly lower, and the CLoral higher in patients who eventually lost their grafts than in those who did not, the mean F values being 26.5±12.8% and 38.7± 17.5%, respectively (P<0.002). Thus, several important relationships between CsA pharmacokinetic parameters and clinical events following renal transplantation were documented. The CLoral decreased during the first 3 months after transplantation (P<0.0001), but it was stable thereafter. Neither the bioavailability nor the clearance of CsA showed a correlation with administered dose. These results indicate that certain recipient groups, such as black patients, and individuals with rapid CL, may benefit from larger CsA doses and/or shorter dosage intervals, in order to compensate for these interpatient variabilities.

On the intraindividual variability and chronobiology of cyclosporine pharmacokinetics in renal transplantation.

SummaryThe intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period.The absolute percentage intraindividual difference in daytime AUC (0–12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0–12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t1/2, tmax and Cmax were more variable than the AUC (0–12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng · ml−1 versus 223 ng · ml−1. This, together with a significantly longer t1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA.In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime.It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.

A randomized trial of cyclosporine and prednisolone versus cyclosporine, azathioprine, and prednisolone in primary cadaveric renal transplantation.

A randomized trial was performed with the aim to compare two immunosuppressive treatment schedules in adult recipients of first cadaveric renal transplants. A total of 229 patients were randomized to double therapy with cyclosporine and prednisolone and 234 patients were randomized to triple therapy with cyclosporine, azathioprine, and prednisolone. Minimum follow-up was 4 years. The actuarial 5-year patient survival was 79.8% in the double therapy group and 82.3% in the triple therapy group (n.s.). The corresponding graft survival figures were 54.4% and 59.6% in the two groups, respectively (n.s.). There were no differences between the groups regarding cause of death or cause of graft loss. Renal function as determined by serum creatinine did not differ between the groups and was stable throughout the observation period. Azathioprine was instituted in a total of 51 patients randomized to double therapy. This subgroup of patients

Pharmacokinetics of 15-deoxyspergualin studied in renal transplant patients receiving the drug during graft rejection

Abstract The pharmacokinetics of the novel immunosuppressant 15‐deoxyspergualin (DSG) were studied in five renal transplant patients who participated in a dose‐finding study for the treatment of renal graft rejection. DSG, in a dose of 4 or 6 mg/kg per day, was given in a 3‐h i. v. infusion for 5 days, in combination with a 4‐day course of i. v. methylpredni‐solone. Analyses of DSG in plasma and urine were performed by high‐performance liquid chromatography (HPLC). Plasma samples were taken up to 12 h following infusion on treatment day 2 and again on day 4 or 5. Urine was collected during the infusion and up to 12 h following the infusion. DSG was rapidly eliminated from the plasma in an apparently biexponential manner. The mean t1/2 alpha was 0.5 h (range 0.1‐1.1 h) and the mean t1/2 beta 2.4 h (range 1.0–5.9 h). The mean Cmax was 4117 ng/ml (range 1944–7166 ng/ml) and the mean AUC 12505 ng.ml‐1.h (range 5642–24435 ng.ml‐1.h). Clearance ranged from 375 to 945 ml/min (mean 653 ml/min) and volume of distribution ranged from 0,2 to 1,4 l/kg (mean 0,7 l/kg). A small fraction (mean 1.6%, range 0.1%‐2.7 %) of the DSG dose given was excreted unmetabolized in the urine. The amount of DSG in the urine correlated strongly to renal function (P= 0.0019). Pharmacokinetics were otherwise not affected by the degree of renal function. There were no significant differences in the pharmacokinetic determinants and no accumulation of the drug on study day 4 or 5, as compared to day 2. Therefore, the drug can safely be given to patients with impaired renal function. DSG did not affect cyclosporine pharmacokinetics.

SERUM HORMONE LEVELS IN MEN WITH END STAGE RENAL DISEASE

Serum concentrations of testicular and adrenal androgens and androgen precursors, cortisol, unconjugated (E1) and total estrone (tE1; greater than or equal to 85% E1 sulfate), pituitary hormones, sex hormone binding globulin (SHBG) and albumin were measured in 14 male patients with non-diabetic end stage renal disease and in 28 age-matched healthy controls. The serum levels of the adrenal androgens 4-androstene 3,17-dione and dehydroepiandrosterone (DHA) were significantly lower and the levels of cortisol, LH, prolactin and tE1 significantly higher in the patients than in the controls. The ratios between E1 and tE1 and between DHA and DHA sulfate were strongly decreased in the patients. The findings are suggested to reflect different effects of the disease upon the metabolism of cortisol and of adrenal androgens and also the reduced or even absent urinary excretion, leading to a decreased metabolism of steroid conjugates.

Ciclosporin-Associated Hypertrichosis Is Not Related to Sex Hormone Levels following Renal Transplantation

To study a possible relationship between ciclosporin-induced hypertrichosis and sex hormone pattern, the hair growth in different areas of the body was graded and hormone levels were assayed before and up to 6 months after kidney transplantation. Increased hair growth was observed in 100% (23/23) of the patients in skin areas connected with androgen action and in 78% of the patients in androgen-insensitive areas. After renal transplantation the pituitary, testicular and adrenal hormone levels normalized. The posttransplantation levels of these hormones would not explain the observation of increased hairgrowth. Thus, ciclosporin induces hypertrichosis via a mechanism independent of sex hormones.

A novel assay for pancreatic cellular damage. III: Use of a pancreas-specific protein as a marker of pancreatic graft dysfunction in humans

Pancreas-specific protein (PASP) is a recently isolated and partially characterized major protein in the human pancreas. It has not been described previously. Serum levels of PASP and amylase were analyzed in 21 patients subjected to combined renal and segmental pancreatic transplantation with both organs obtained from the same donor and in eight kidney transplant patients. In the pancreas transplant patients, PASP and amylase levels were elevated in episodes of graft pancreatitis. With chronic graft rejection, PASP rose to high levels long before other indications. In episodes of renal rejection, the levels of PASP, but not always of amylase, were elevated on several occasions. They decreased after antirejection therapy. This may indicate accompanying pancreatic graft rejection. PASP and amylase levels were stable in kidney transplant patients and were not affected by serum creatinine levels, renal rejection, or antirejection therapy. The results support earlier observations that renal rejection in combined pancreas and renal transplant patients may or may not be accompanied by a rejection process in the pancreatic graft. PASP may be the means by which to tell when the pancreatic graft is involved.

A randomized multicenter trial of cyclosporin and prednisolone versus cyclosporin, azathioprine, and prednisolone following primary living donor renal transplantation

A total of 195 consecutive recipients of primary living donor renal transplants were randomized to receive either cyclosporin (CyA) and prednisolone (double therapy) or CyA, prednisolone, and azathioprine (triple therapy). There was no significant difference in patient or graft survival, incidence of acute rejection episodes, or major complications between the groups. The graft survival at 5 years was 71.5% in patients receiving double therapy and 71.6% in patients receiving triple therapy. In a Cox regression analysis, recipient age and occurrence of acute rejection were the only independently significant variables affecting graft survival, whereas treatment schedule did not. Renal function was stable throughout the observation period and did not differ between the double and triple therapy groups. A linear regression analysis showed that recipient age, donor age, gender, and occurrence of acute rejection significantly influenced the serum creatinine level. This and previous similar prospective studies in cadaveric renal transplantation indicate that there is no advantage of routinely adding azathioprine to a double drug regimen.