B. Eklund

Single bolus antithymocyte globulin versus basiliximab induction in kidney transplantation with cyclosporine triple immunosuppression: efficacy and safety.

Background. The aim of this prospective randomized study was to examine the effect of induction immunosuppression and low initial cyclosporine (CsA) on the onset of graft function and its long-term consequences. Methods. During 1999–2001, 155 patients were randomized to single 9 mg/kg dose antithymocyte globulin (ATG)-Fresenius (group A) or two 20-mg doses of basiliximab (group B) with reduced dose CsA or conventional CsA triple therapy without induction (group C). Results. Delayed function (DGF) was lower in group A than in groups B or C (5.7% vs. 24.1% and 15.9%, P<0.025) and need of dialysis was less in groups A and B compared to C (10.3 and 10.4 vs. 20.0 days, P<0.05). Acute rejections occurred in 11.3%, 12.1% and 20.5%, and the mean (median) time to rejection was 16 (13), 97 (46) and 101 (35) days in groups A, B, and C, respectively (P<0.005). One-and 5-year graft survivals (GS) were 98.1% and 90.6% (group A), 96.6% and 96.6% (group B), and 93.2% and 84.1% (group C). Five-year GS was significantly better in group B than in group C (P<0.05). The death censored 5-year GS in groups A, B, and C were 94.3%, 96.6%, and 90.0% (P=NS). Single high-dose ATG induction was associated with hemodynamic and pulmonary disturbances without, however, serious or long-term consequences. Conclusions. ATG induction significantly reduced DGF. Both induction regimens together with low initial CsA led to significantly less posttransplant dialysis and excellent survival. The high dose ATG was associated with significant hemodynamic and pulmonary side effects during drug infusion.

Fine-needle aspiration biopsy in the monitoring of liver allografts. II. Applications to human liver allografts.

Serial fine-needle aspiration biopsies (FNAB) were used for clinical monitoring of human liver allografts. Nine liver allograft recipients were monitored with FNAB at 1–3-day intervals. No complications were recorded. All patients underwent at least 1 inflammatory episode of acute rejection; altogether 11 episodes, all reversible, were recorded. The inflammatory infiltrate consisted mainly of lymphoid cells, including lymphoid blasts, with minor involvement of monocytes, monoblasts, and macrophages. Further analysis of lymphoid cell subpopulations by immunoperoxidase techniques demonstrated an increase of T cells during rejection, both the CD4 (T4) and CDS (T8) subsets were increased. A slight increase of B cells in the graft was also seen. The CD4/CD8 (T4/T8) ratio was first low, peaked at the onset, and decreased toward the end of the episode. No clear correlations to the intragraft cellular events were recorded in corresponding blood specimens. However, an episode of eosinophilia was seen in the blood at the beginning of rejection, correlating with fever in the recipient. Degenerative changes in the parenchymal cells and bile droplets in the hepatocytes, indicating cholestasis and hepatocyte damage, were seen during all episodes of rejection, and these changes persisted even 10 days after the inflammation had subsided. The FNAB-findings correlated well with biochemical laboratory parameters, but the diagnosis of rejection could be established by the FNAB already 1–5 days earlier than elevated serum values indicated liver dysfunction.

Peritoneal dialysis access : A comparison of peritoneoscopic and surgical insertion techniques

Prospectively collected data were analysed comparing 108 consecutive peritoneoscopically (n = 65) and surgically (n = 43) placed peritoneal dialysis catheters during a three-year period. Catheter-linked mechanical complications occurred more often in the peritoneoscopical group, and pericatheteral leakage ended in catheter loss in 13.8%. Overall probability of catheter survival in the peritoneoscopic group at 12, 24 and 36 months was 73%, 56% and 24%, and in the surgical group 87%, 87% and 66%, respectively (p < 0.05). Rates of infectious complications, peritonitis and exit site infections were similar.

Weak humoral posttransplant alloresponse after a well-HLA-matched cadaveric kidney transplantation.

Background: Screening of donor-specific antibodies or alloantibodies after kidney transplantation has not been performed routinely. The aim of this study was to evaluate the humoral antidonor and alloresponse of immunologically low-risk recipients of cadaveric renal allografts during the first posttransplant year. Methods: Alloresponse against the donor was analyzed by means of T-cell immunoglobulin (Ig)G and IgM and B cell IgG flow cytometric crossmatch (FCXM) tests with sera from days 0, 21, 90, and 365 posttransplant. In addition, panel reactive anti-human leukocyte antigen (HLA) class I and class II antibodies (PRA I and PRA II) were analyzed using flow cytometric methods. The recipients were treated either with a low initial cyclosporine regimen with single-bolus antithymocyte globulin (ATG) or basiliximab induction or conventional cyclosporine triple therapy. Results: No significant posttransplant anti-HLA class I or class II sensitization was found in the recipients as a whole. Recipients receiving a single-bolus ATG showed significantly higher proportion of PRA I positivity in the day 21 sample compared with the other groups. Flow cytometric donor-specific T- and B-cell IgG alloresponses remained low, but the proportion of T-cell IgM crossmatch-positive recipients increased during the study. Positive T-cell IgM FCXM was found to be associated with acute rejection episodes and cytomegalovirus (CMV) infections. Conclusions: In immunologically low-risk kidney-graft recipients, positive T-cell IgM FCXM at transplantation was found to be a risk factor for rejection episodes. Conversion of T-cell IgM FCXM to positive was found to be associated with CMV infections.

Renal allograft immunosuppression

The long-term effects of different immunosuppressive drugs and regimens on renal allograft histology are virtually unknown. Therefore, in order to investigate the long-term effects of triple drug treatment versus different combinations of two immunosuppressive drugs on allograft histology, a prospective, randomized trial was performed. One group received triple therapy consisting of low-dose cyclosporin (CyA), azathioprine (Aza), and methylprednisolone (MP), and three groups received combinations of two drugs, i.e., Aza plus CyA, Aza plus MP, and CyA plus MP. At 2 years, there were no significant differences with regard to graft (80%) or patient (87%) survival, or to graft function between the four groups. After 2 years, a protocol core biopsy was taken of all 102 patients having a functioning graft. Of these patients, 61 (60%) were still following the original, randomized treatment protocol; in the remaining cases, changes had occurred in the original protocol and so these cases were considered drop-outs in this study. Histological specimens were examined blindly by two independent observers. Most of the 34 histological variables examined showed no changes. Diffuse fibrosis was most frequent in the CyA plus MP group (70%) and significantly more severe than in the triple therapy group. Mesangial matrix increase in glomeruli was significantly less common in the triple therapy group (8%) than in any one of the double drug combination groups (47%). Two other changes in glomeruli — Bowman capsular thickening and global glomerular sclerosis — were also less frequent in the triple therapy group. Vascular changes other than intimal proliferation (39%) and arteriosclerosis (24%) were uncommon in all groups and least frequent in the triple therapy group. Isometric vacuolation in proximal tubules was found in every group using CyA. It was least prominent in the triple therapy group and most prominent in the CyA plus MP group; it was not seen in the Aza plus MP group. Other specific findings for the groups treated with Cya could not be identified. To summarize, the changes shown were mild and rather similarly distributed in the four treatment groups. Histopathological alterations comparable with chronic rejection, i.e., persistent interstitial inflammation with pyroninophilic cells, vascular intimal proliferation, and arteriosclerosis, were seen in all groups, but these changes were least prominent in the group receiving triple therapy.

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.

Diagnosis of acute rejection in liver transplantation

Eleven acute rejections were found in 9 patients with liver transplantation due to end-stage liver cirrhosis. The rejections were diagnosed with fine-needle aspiration biopsy (FNAB) giving the cellular picture of immunoactivation in the liver graft when compared to a simultaneous sample of peripheral blood. s-Alkaline phosphatase and s-bilirubin increased within 1 week after onset of rejection in 7 and 10 cases, respectively. s-Alanine amino-transferase and b-ammonium were of no value in the diagnosis of acute rejection. A core biopsy was obtained only in a case of severe liver damage, mainly to estimate the need for retransplantation. One year after grafting, 6 out of 7 cirrhotic patients are well, all with normal liver function. Two have died of sepsis. One patient died from pulmonary metastases of occult liver carcinoma 6 months after the transplantation. FNAB seems helpful in detecting early acute rejection and also excluding such an event in the liver graft.

The value of repeated renal retransplantations

The outcome of 64 repeated renal retransplantations (50 third, 13 fourth, and 1 fifth) during a period of 25 years was retrospectively evaluated. The prognosis of third and subsequent grafting was greatly improved if cyclosporine was included in the induction immunosuppressive regimen (one-year graft survival 79.9%, compared with 32.4% if CsA was not used). The onset of graft function was not delayed by CsA and the proportion of never functioning grafts was significantly lower (5.3%) in patients treated with CsA than in those treated without it (43.2%). Survival of the previous grafts for longer than one year favorably influenced the outcome of the subsequent grafts.

Renal allograft immunosuppression. I. Early inflammatory and rejection episodes in triple drug treatment compared to double drug combinations or cyclosporin monotherapy.

Abstract. 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 drug‐treated 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.

The effect of intravesically applied antibiotic solution in the prophylaxis of infectious complications of renal transplantation

Abstract. The effect of intravesically applied antibiotic solution in the prevention of infectious complications of renal transplantation was evaluated in a prospective, randomized study. The bladder was filled preoperatively with saline solution containing cephalotin in the test group, and with saline solution only in the controls. Both groups of patients received IV doses of cephamandole during, and once after, surgery. Two hundred consecutive patients were randomly allocated to the study groups. The overall incidence of urinary tract infection was 10. 4% during the first 4 postoperative weeks; that of wound infections was 1. 6% and of septicemia 3. 3%. The addition of cephalotin to the bladder irrigation fluid did not have any effect on the overall incidence of infectious complications.