Nils H. Persson

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

A randomized multicenter trial of the anti-ICAM-1 monoclonal antibody (enlimomab) for the prevention of acute rejection and delayed onset of graft function in cadaveric renal transplantation: a report of the European Anti-ICAM-1 Renal Transplant Study Group.

BACKGROUND T-cell activation through T-cell receptor engagement requires co-stimulatory molecules and also adhesion molecules such as ICAM-1. Moreover ICAM-1 mediates leukocyte invasion from the blood into tissue during inflammatory processes. In animal studies using mouse monoclonal antibodies against ICAM-1 (enlimomab), renal allograft survival has been improved and reperfusion damage from ischemia reduced. The European Anti-ICAM-1 Renal Transplant Study (EARTS) was a randomized, double-blind, parallel-group, placebo-controlled study lastingl year and performed in 10 transplant centers in Europe. METHODS A total of 262 recipients of cadaveric kidneys were given either enlimomab or a placebo for 6 days and were given triple immunosuppressive therapy of cyclosporine, azathioprine, and prednisolone. The primary efficacy endpoint was the incidence of the first acute rejection within 3 months, and each event was assessed by a committee including investigators and independent pathologists. RESULTS There was no significant difference in the incidences of first acute rejection at 3 months between the placebo and enlimomab groups (39% vs. 45%), and enlimomab did not reduce the risk of delayed onset of graft function (DGF) (26% vs. 31%). Neither was there a difference in patient survival (95% vs. 91%) or graft survival (89% vs. 84%) at 1 year. Fatal events occurred in 19 (7%) patients (7 placebo, 12 enlimomab). Clinically, the most important non-fatal adverse events were infections; however, there was no statistically significant difference between the incidences in the two groups (70% vs. 79%). CONCLUSION Short term enlimomab induction therapy after renal transplantation did not reduce the rate of acute rejection or DGF.

Optimising islet engraftment is critical for successful clinical islet transplantation

Clinical islet transplantation is currently being explored as a treatment for persons with type 1 diabetes and hypoglycaemia unawareness. Although ‘proof-of-principle’ has been established in recent clinical studies, the procedure suffers from low efficacy. At the time of transplantation, the isolated islets are allowed to embolise the liver after injection in the portal vein, a procedure that is unique in the area of transplantation. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure.

A Randomized, Doubleblind, Placebo-Controlled, Study of Single-Dose Rituximab as Induction in Renal Transplantation

We performed a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. Secondary endpoints were creatinine clearance, incidence of infections, and incidence of rituximab-related adverse event. Results. We enrolled140 patients (44 living donor and 96 deceased donor), and of those, 68 rituximab and 68 placebo patients fulfilled the study. In all the patients receiving rituximab, there was a complete depletion of CD19/CD20 cells, whereas there was no change in the number of CD19/CD20 cells in the placebo group. There were 10 treatment failures in the rituximab group versus 14 in the placebo group (P=0.348). There were eight rejection episodes in the rituximab group versus 12 in the placebo group (P=0.317) Creatinine clearance was 66±22 mL/min in the study group and 67±23 mL/min in the placebo group. There was no difference in the number of bacterial infections, cytomegalovirus infections, and BK virus infections or fungal infections. Conclusion. We performed a placebo-controlled study of rituximab induction in renal transplantation. There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. Although induction with one dose of rituximab induced a complete depletion B cells, there was no increase in the incidence of infectious complications or leukopenia and it seems safe, therefore, to conduct further studies on the use of rituximab in transplantation.

Hepatitis C superinfection in hepatitis C virus (HCV)-infected patients transplanted with an HCV-infected kidney

Hepatitis C virus (HCV) genotypes, determined by polymerase chain reaction with type-specific primers, were studied in 5 already HCV-infected patients receiving kidneys from HCV-infected cadaver donors. Three patients were investigated retrospectively using stored pre- and posttransplantation sera and followed 18-28 months after transplantation. Two recipients with HCV genotype 2b infection had received kidneys from 1 genotype 3a-infected donor. In 1 recipient, HCV 2b was replaced by the donors type; in the other recipient, a prolonged mixed infection of 3a and 2b occurred. Persistent alanine aminotransferase (ALT) elevation (3- to 5-fold) appeared in both patients. The third patient, also HCV 2b infected when transplanted with an HCV 3a-infected kidney, remained infected with HCV 2b only. Two patients, one with HCV genotype 1b and the other with genotype 3a, were followed prospectively with frequent bleeds (initially biweekly) and genotyping over 14 months after they had received kidneys from 1 HCV genotype 1a-infected donor. The HCV 1b-infected recipient remained infected with 1b only and had minimal biochemical signs of liver injury. In the other recipient, mixed infection of 3a and 1a appeared at week 3 and persisted for several weeks, until only genotype 1a could be detected. This patient had elevated ALT levels before transplantation. After onset of mixed infection, ALT levels increased further for several weeks, and returned to pretransplantation levels when only HCV 1a was found. HCV-infected kidneys transplanted into HCV-infected recipients gave 3 different virus patterns. Most patients benefitted in the short term, but some super-infected patients experienced increased liver damage.

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

Xenotransplantation public perceptions: rather cells than organs.

Omnell Persson M, Persson NH, Ranstam J, Hermerén G. Xenotransplantation public perceptions, rather cells than organs. Xenotransplantation 2003; 10: 72–79.

Rescue therapy with tacrolimus (FK 506) in renal transplant recipients--a Scandinavian multicenter analysis.

Abstract All renal allograft recipients (n= 32) in Sweden and Norway who were converted from cy‐closporin(CyA)‐based immunosuppression to FK 506 (tacrolimus) between October 1992 and June 1995 were analyzed retrospectively. The reasons for conversion were acute refractory rejection (n= 21), chronic rejection (n= 4), and suspected CyA toxicity (n= 6); one patient was converted for psychological reasons. The mean time from transplantation to conversion was 29 (range 1–243) weeks and there was a mean follow‐up of 46 (2–143) weeks. Overall graft survival was 59 %, with graft survival 52 % in patients converted because of acute rejection, 50 % in patients converted because of chronic rejection, and 83 % in patients converted because of CyA toxicity. There was no significant correlation between preconversion serum creatinine and outcome. Seventy‐two percent of the patients had significant side effects during FK 506 treatment, the most frequent ones being neurological and gastrointestinal symptoms. These improved after dose reduction. Two patients became overimmunosup‐pressed and developed lymphoma. One patient died of the primary kidney disease, hemolytic uraemic syndrome. We conclude that FK 506 therapy is able to salvage kidneys with acute refractory rejection and that it is an alternative in patients with CyA toxicity. However, the risk of overimmunosuppression must be considered.

Two doses of daclizumab in conjunction with low-dose cyclosporine, mycophenolate mofetil and steroids resulted in a low incidence of acute rejection after renal transplantation.

Five doses of daclizumab, given initially after kidney transplantation, reduce the rate of acute rejection (AR). Without cyclosporin A (CsA), a protocol, including daclizumab, mycophenolate mofetil (MMF) and corticosteroids (CSs), has recently shown efficacy in terms of graft function and survival. The rate of AR was relatively high, however. In this single‐centre study, a CsA low‐dose regimen was combined with two doses of daclizumab (1 mg/kg day 0 and 14), plus MMF (2 g) and CS. Forty‐three cadaver donor renal recipients were included. Following the onset of graft function, target trough levels of CsA were 150–200 ng/ml for 90 days, then 100–150 ng/ml. One year AR rate was 23% (n = 10) and events occurred at a median of 2.9 months (range from 9 days to 9.6 months). Delayed graft function (DGF) (absent spontaneous reduction of serum creatinine day 1) was 51%. Graft survival was 95% and patient survival 98% after 1 year. With respect to our previous experience, we used CsA, azathioprine and CSs (n = 223) from 1988 to 1995, and the rate of AR was 57%. From 1996 to 1998, standard CsA doses, MMF and CS (n = 67) resulted in 31% AR. Median time to AR was 0.8 and 1.0 month, and the rate of DGF was 20 and 22%, respectively. This CsA low‐dose protocol, including two doses of daclizumab, MMF and CS, resulted in a reduction and delay of AR episodes and excellent graft function, graft survival and patient survival, despite an increase in DGF.