Renal allograft immunosuppression

We have investigated the impact of triple drug immunosuppression on the occurrence of early inflammatory episodes, as detected by fine needle aspiration biopsy, and of episodes of clinical rejection during the immediate postoperative period. The prospective component of this study includes 128 consecutive first cadaveric renal transplant recipients receiving triple drug treatment consisting of azathioprine (Aza), cyclosporin (CyA) and methylprednisolone (MP). For controls we have used three historical groups: one immunosuppressed with Aza and MP (group A), another with CyA monotherapy (group B), and the third with CyA together with MP (group C) in equivalent drug dosages. On the average, 0.8 episodes of inflammation per patient were recorded during the immediate postoperative period of 30 days with triple drug treatment. This was significantly less than the 1.3 episodes in patients receiving Aza and MP (P<0.01), the 1.7 episodes in patients on CyA monotherapy (P<0.001), or the 1.6 episodes in patients receiving CyA together with MP (P<0.001). Although the first episode of inflammation commenced concurrently in each group and the peak intensity of inflammation was the same, the mean duration of inflammation was significantly shorter-2.7 days-under triple drug treatment than the 7.8–11.7 days for controls (P<0.001). The frequency of rejection episodes under triple treatment was also significantly lower-0.2 per patient-than the 0.8 per patient in controls (P<0.001). The first rejection episode occurred later in the triple drug treatment group-on the average, on day 15.2-than in the historical controls (on days 7.7–11.7). There was, however, no difference in the duration of rejection. There were no differences in patient survival between the four groups. Graft survival was 97% at 10 weeks for triple drug-treated recipients and 79%, 68%, and 87% for first grafts in groups A, B, and C, respectively. Disregarding a minor demographic bias for the triple drugtreated group with respect to preformed antibodies and preoperative dialysis treatment, the study suggests that the triple drug protocol, in the short run, is superior to any conceivable double drug combination or CyA monotherapy.     

Is obesity still a risk factor in renal transplantation?

At our center, since 1982, a body mass index (BMI) of less than 30 has been a prerequisite for placing a patient on the waiting list for renal transplantation. This decision was made because obese transplant recipients seemed to have a less than favorable post-transplant outcome. The aim of this study was to evaluate whether this requirement is still justified. Forty-six patients with a BMI above 30 underwent primary cadaveric renal transplantation between 1972 and 1993. For each of these obese patients, five consecutive non-obese (BMI 20–25) control patients were selected. Patient and graft survival, causes of graft loss, and acute rejection rate were evaluated for the two patient groups before and after the year 1982. Within the first 30 post-transplant days, one patient (2 %) and 11 grafts (24 %) were lost in the group of obese patients whereas seven patients (3 %) and 36 grafts (16 %) were lost in the control group. Among the obese patients, renal circulatory complications were a major cause of graft loss. In the period 1973–1981, the 1-year patient survival rate was 65 % among obese patients versus 75 % among controls from 1982 to 1993, this was 90 % versus 93 %. From 1973 to 1981, the 1-year graft survival rate was 25 % among obese patients versus 53 % among controls (P < 0.05); from 1982 to 1993, it was 68 % versus 84 % (P = NS). Multivariate analysis showed that the immunosuppressive regimen, age of the patient, BMI, and cold ischemia time of the graft had a significant influence on graft survival. The acute rejection rate within the first 30 days was 28 % among obese patients and 35 % among controls (P = NS). We conclude that a BMI below or equal to 30 is still justified as a prerequisite for placement on the waiting list for renal transplantation, for despite an overall improvement, the outcome of renal transplantation in obese patients remains worse than that in non-obese patients. Received: 3 February 1997 Received after revision: 4 April 1997 Accepted: 8 April 1997     

Renal allograft immunosuppression: II. A randomized trial of withdrawal of one drug in triple drug immunosuppression

Abstract. A prospective randomized study was conducted to evaluate the impact of four different conversion protocols on graft outcome in long-term follow-up. Between January 1986 and May 1987, 128 patients with first cadaveric kidney allografts were randomized at the time of transplantation to four treatment groups of 32 patients each, to be assigned 10 weeks post-transplantation. During the first 10 weeks, all patients received triple therapy with low-dose azathioprine (Aza), cyclosporin (CyA), and methylprednisolone (MP). After 10 weeks, one group continued with triple therapy (group A) while the three other groups received different combinations of two drugs, namely, Aza and CyA (group B), Aza and MP (group C), or CyA and MP (group D). Withdrawal of MP (group B) or especially of CyA (group C) was associated with 4/29 (14%) and 10/28 (36%) acute rejection episodes, respectively, for 60 days after conversion. All rejections were mild and reversible. There were no rejections after Aza withdrawal or in the group that continued on triple therapy during the corresponding time period. The most common reason for dropping out after withdrawal, for those patients who could not continue on the originally randomized medication, was azathioprine intolerance (n= 12). Five patients were switched back to triple therapy after CyA withdrawal due to rejection. Steroid intolerance was rare and CyA in low doses was very well tolerated. At 1 year there were no statistically significant differences in graft survival between groups A, B, C, and D-81 %, 88%, 88%, and 88%, respectively-or in patient survival-88%, 88%, 88%, and 97%, respectively. For those patients continuing with the originally randomized treatment protocol, there were no differences in patient or graft survival either, the means being 91% and 89%, respectively. The most common cause of death after withdrawal was cardiovascular in nature, and there were no more fatal infections under triple drug treatment than with double drug regimens. There were no statistically significant differences in mean serum creatinine values at 1 year. The median serum creatinine values for groups A, B, C, and D were 112, 132, 133, and 133 μmol/l, respectively. At 1 year the mean CyA dose in the groups that continued with CyA was 3. 5–4. 2 mg/kg per day and CyA concentrations were equal.     

Activated Protein C Reduces Graft Neutrophil Activation in Clinical Renal Transplantation

We studied the role of endogenous activated protein C (APC), the major physiological anti-coagulant with concomitant anti-inflammatory properties, on ischemia/reperfusion (I/R) in 45 patients participating in a larger trial comparing three immunosuppressive protocols in cadaveric renal transplantation: perioperative anti-thymocyte globulin (ATG, Fresenius AG, Bad Homburg, Germany), perioperative basiliximab and conventional triple therapy. Blood samples for assessing plasma APC, protein C, and lactoferrin concentrations, neutrophil CD11b and L-selectin expressions and blood leukocyte differential counts were obtained preoperatively and before reperfusion from central venous cannula, complemented with simultaneous samples from iliac artery and graft vein for calculation of transrenal differences (Delta) of study parameters at 1 and 5 min after reperfusion. Unlike basiliximab or conventional therapy groups, ATG infusion induced a substantial increase in plasma APC concentration (119 [88-144]% before infusion vs. 232 [85-1246]% after infusion, p<0.001), resulting in renal graft sequestration of APC at 1 min after reperfusion (Delta=-72 [-567 to 12]%, p<0.001). Graft APC consumption was associated with transrenal reduction of neutrophil activation markers (L-selectin r=0.7, p=0.01; lactoferrin r=-0.6, p=0.02; CD11b r=-0.8, p=0.001), and with both warm (r=0.6, p=0.01) and cold ischemia time (r=0.6, p=0.02) and donor age (r=0.6, p=0.01). These findings suggest that APC has an anti-inflammatory role in I/R injury in clinical renal transplantation.     

Auditory event-related potentials and cognitive function of preterm children at five years of age.

OBJECTIVE: In our previous study, auditory event-related potentials (AERPs) in preterm 1-year-old children had a positive deflection at 150-350 ms that correlated positively with their 2-year neurodevelopmental outcome. In a study of the same subjects at age 5, our aim was to assess AERPs and their relationship to neuropsychological test results. METHODS: Preterm small (SGA, n=13), appropriate for gestational age (AGA, n=15), and control (n=13) children were assessed with an Easy paradigm presenting a large frequency change accompanied with occasional novel sounds, and a Challenging paradigm presenting small frequency and duration changes with a rapid rate. The preterm children underwent neurocognitive tests. RESULTS: Easy paradigm. The P1 response to frequency deviant was smaller and MMN larger in the preterm than in the control children. Challenging paradigm. The P1 response to standard, frequency, and duration deviants was smaller in the preterm than in the control children. The N2 response to frequency deviant was larger in the preterm than in the control children. AGA and SGA children had similar AERPs. The P1, N2, and MMN amplitudes correlated with verbal IQ and NEPSY language subtests. CONCLUSIONS: Small P1 response(s) appears to be typical for preterm children. SIGNIFICANCE: Small P1 response in preterm children may suggest altered primary auditory processing.     

Effects of commercial chlorophenolate, 2,3,7,8-TCDD,and pure phenoxyacetic acids on hepatic peroxisome proliferation,xenobiotic metabolism and sister chromatid exchange in the rat

The induction of hepatic peroxisome proliferation and drug metabolizing enzymes and of sister chromatid exchange (SCE) in lymphocytes was studied in male Han/Wistar rats after exposing them for 2 weeks to a commercial chlorophenolate formulation (Ky-5) (100mg/kg/ day), to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; 0.05–5 g/kg/wk) and to the pure phenoxyacetic acids, 2,4-dichlorophenoxyacetic acid (2,4-D; 100 mg/kg/day) and 2-chloro-4-methylphenoxyacetic acid (MCPA; 100 mg/kg/day). The chlorophenolate formulation and pure 2,4-D and MCPA caused significant increases in the number of peroxisomes in liver cells, although the average size of peroxisomes was not affected, whereas the effect of even the highest dose of 2,3,7,8-TCDD remained small. This finding indicates that dioxin impurities do not account for the peroxisome proliferation induced by chlorophenolate. The relative weight of the liver increased significantly in rats treated with the chlorophenolate formulation and with 2,3,7,8-TCDD (5.0 and 0.5 g/kg). The pattern of induction of xenobiotic metabolizing enzymes showed some differences between chlorophenolate treatment and 2,3,7,8-TCDD treatment. Furthermore, the effects of pure phenoxyacetic acids were different from that seen with chlorophenolate and 2,3,7,8-TCDD. The highest dose of 2,3,7,8-TCDD increased the frequency of SCE in circulating lymphocytes slightly, but significantly.     

Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy

The purpose of this work is to evaluate the predictive strength of the relative seriality, parallel and LKB normal tissue complication probability (NTCP) models regarding the incidence of radiation pneumonitis, in a large group of patients following breast cancer radiotherapy, and furthermore, to illustrate statistical methods for examining whether certain published radiobiological parameters are compatible with a clinical treatment methodology and patient group characteristics. The study is based on 150 consecutive patients who received radiation therapy for breast cancer. For each patient, the 3D dose distribution delivered to lung and the clinical treatment outcome were available. Clinical symptoms and radiological findings, along with a patient questionnaire, were used to assess the manifestation of radiation-induced complications. Using this material, different methods of estimating the likelihood of radiation effects were evaluated. This was attempted by analysing patient data based on their full dose distributions and associating the calculated complication rates with the clinical follow-up records. Additionally, the need for an update of the criteria that are being used in the current clinical practice was also examined. The patient material was selected without any conscious bias regarding the radiotherapy treatment technique used. The treatment data of each patient were applied to the relative seriality, LKB and parallel NTCP models, using published parameter sets. Of the 150 patients, 15 experienced radiation-induced pneumonitis (grade 2) according to the radiation pneumonitis scoring criteria used. Of the NTCP models examined, the relative seriality model was able to predict the incidence of radiation pneumonitis with acceptable accuracy, although radiation pneumonitis was developed by only a few patients. In the case of modern breast radiotherapy, radiobiological modelling appears to be very sensitive to model and parameter selection giving clinically acceptable results in certain cases selectively (relative seriality model with Seppenwoolde et al and Gagliardi et al parameter sets). The use of published parameters should be considered as safe only after their examination using local clinical data. The variation of inter-patient radiosensitivity seems to play a significant role in the prediction of such low incidence rate complications. Scoring grades were combined to give stronger evidence of radiation pneumonitis since their differences could not be strictly associated with dose. This obviously reveals a weakness of the scoring related to this endpoint, and implies that the probability of radiation pneumonitis induction may be too low to be statistically analysed with high accuracy, at least with the latest advances of dose delivery in breast radiotherapy.     

Search for large genomic alterations of the BRCA1 gene in a Finnish population

Mutations in the BRCA1 and BRCA2 genes are known to predispose to breast cancer. In Finland, however, only 21% of all breast cancer families have mutations in these genes. Recent studies have shown that large genomic alterations of BRCA1 are common in many countries. Because such alterations will be missed in conventional mutation screening strategies, we decided to screen Finnish breast and ovarian cancer families for genomic alterations by using a multiplex polymerase chain reaction method. The most characteristic features of BRCA1-related breast cancer were used to select patients, namely (1) both breast and ovarian cancer in the family (48 patients), (2) four or more breast cancers in family (22 patients), or (3) young age (< or =40 years) of onset (58 patients). A total of 128 patients were included in the study. All exons of BRCA1 were analyzed but no alterations were found. This study excludes the frequent occurrence of large genomic alterations in the BRCA1 gene in Finland. Here, again, Finland differs from other countries with a mixed population structure. Our results are in agreement with the common hypothesis that there are still unknown breast cancer susceptibility gene(s) that are responsible for breast cancer predisposition.