P. R. F. Bell

In situ replacement of infected aortic grafts with rifampicin-bonded prostheses: The Leicester experience (1992 to 1998)

Abstract Purpose : Prosthetic graft infection after aortic aneurysm surgery is a life-threatening complication. Treatment options include total graft excision and extra-anatomic bypass grafting or in situ replacement of the graft. The latter option is gaining increasing popularity, but the long-term outcome remains uncertain, particularly in light of the increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA). We performed a prospective nonrandomized study to assess the outcome after graft excision and in situ replacement with a rifampicin-bonded prosthesis for the treatment of major aortic graft infection. Methods: In a 6-year period from January 1992 to December 1997, 11 patients (eight men, three women) with major aortic graft infection underwent total graft excision and in situ replacement with a rifampicin-bonded prosthesis. The median age of the patients was 66 years (range, 49 to 78 years). Four patients had a hemorrhage from an aortoenteric fistula, three had a retroperitoneal abscess, two had graft occlusion, one had a perigraft collection shown by means of computed tomography, and one had a ruptured suprarenal false aneurysm. Organisms were cultured from 10 patients. Results: MRSA was isolated in two patients, both of whom had originally undergone repair of a ruptured abdominal aortic aneurysm. Two patients died (18.2%) within 30 days, and three patients (27.6%) had nonfatal complications (peritoneal candidiasis, transient renal impairment, and profound anorexia). Two patients died late in the follow-up period. Seven patients remain alive and clinically free of infection. Conclusion: The long-term results after total graft excision and in situ replacement with a rifampicin-bonded prosthesis appear to be favorable. However, MRSA aortic graft infection appears to be associated with a poor prognosis. (J Vasc Surg 1999;30:92-8.)

The relative influence of delayed graft function and acute rejection on renal transplant survival

Three hundred and eight cadaveric renal transplants were analysed to establish the effects of acute rejection in the first 90 days and delayed graft function (DGF) on graft outcome. There were 120 patients (39%) with no DGF and no rejection (group 1), 101 patients (33%) with rejection but no DGF (group 2), 41 patients (13%) with DGF but no rejection (group 3) and 46 patients (15%) with both rejection and DGF (group 4). The actuarial 4-year graft survival rates for groups 1,2,3 and 40.4%, respectively. The acute rejection rate was 101/221 (46%) in patients with initial graft function compared with 46/87 (53%) for those with DGF (χ2=1.02, P=0.31). Cox stepwise logistic regression analysis demonstrated that DGF was a more powerful predictive factor for poor graft survival (P=0.001) than acute rejection occurring in the first 90 days post-transplant (P=0.034). Further efforts at improving graft outcome should concentrate on reducing the incidence of DGF.

The beneficial effects of oral nifedipine on cyclosporin-treated renal transplant recipients- a randomised prospective study

The aim of this study was to test the hypothesis that nifedipine will improve graft survival in cyclosporin A (CyA)-treated renal transplant recipients. One hundred and forty-seven patients were randomised to one of three regimens. Group A received CyA, 7 mg/kg per day, and prednisolone; group B followed the same regimen as group A plus oral nifedipine and group C received CyA, 4 mg/kg per day, prednisolone and azathioprine. Calcium channel blockers were avoided in groups A and C. The crude 2-year (P=0.0223) and 4-year (P=0.0181) graft survival was significantly better in group B (86% and 81%, respectively) than in group A (75% and 63%, respectively). Delayed initial function was seen least frequently in group B (10.2%) compared to groups A (31%) and C (28%; P<0.01). Group B also experienced fewer rejection episodes than groups A and C (P<0.05). We conclude that the combination of oral nifedipine and CyA significantly improves initial graft function, rejection frequency and long term graft survival.

Donor-recipient age difference—an independent risk factor in cyclosporin-treated renal transplant recipients

Whilst HLA matching is routine in renal transplantation the possible benefits of matching donor to recipient age have not been previously explored. The simultaneous effect on graft survival of donor and recipient age was therefore investigated for 274 consecutive first cadaver transplant recipients treated by cyclosporin immunosuppression in two centres. The overall graft survival was 77%, and was not significantly different between the two centres. Individually there was no significant effect of donor or recipient age but taken together, the difference in age significantly affected graft survival (P<0.01) regard-less of the mode of failure. The 1-year graft survival for all failures was 66.2% when the donor was 5 or more years older, 84.5% when the donor was 5 or more years younger and 71.7% when the donor was within 5 years of the recipients age. Multivariate analysis, taking into account other variables (HLA matching, dialysis time and type, donor/recipient sex, local/imported kidneys, sensitivity, operation time, total ischaemic time, pre-operative transfusions) indicated that age difference was the single most important variable (P<0.01). The only other important covariate risk factor in improving graft survival was HLA-DR matching (P<0.05). Donor-recipient age difference is a potentially important recipient selection criterion in cyclosporin-treated renal transplant patients.

Nifedipine improves immediate, and 6- and 12-month graft function in cyclosporin A (CyA) treated renal allograft recipients.

To investigate the effect of oral nifedipine, a calcium channel blocker known not to modify cyclosporin A (CyA) pharmacokinetics, on immediate transplant function and CyA nephrotoxicity, 68 adult renal transplant recipients were pre-operatively randomized to one of three regimes: A (high-dose CyA, initial dose 17 mg/kg per day, maintenance dose 7 mg/kg per day); B (regime A plus oral nifedipine); C low-dose CyA, initial dose 10 mg/kg per day, maintenance 4 mg/kg per day plus azathioprine 1 mg/kg per day). All three groups received identical steroid regimes. Calcium channel blockers of all types were avoided in groups A and C. Delayed graft function (dialysis dependence by day 4) was seen least frequently in group B (P < 0.02). Group B had improved graft function at 6 months compared with group A, identified by differences in serum creatinine (P < 0.05), GFR (P < 0.01) and ERPF (P < 0.05). Similar differences in serum creatinine (P < 0.05) and GFR (P < 0.05) were also identified at 12 months. Group C also had better 6- and 12-month GFR values than group A (P < 0.05 each). The three groups did not differ in donor or recipient age, HLA matching, ischaemic or anastomosis times, frequency of early rejection or whole-blood CyA levels. These results indicate that nifedipine significantly improves immediate and medium-term graft function.

Cyclosporin A abolishes renal reserve capacity.

Renal functional reserve (RFR) was investigated in a group of renal transplant recipients taking cyclosporin A (CyA) immunosuppressive therapy. Nine patients received a 93 g oral protein load containing 5983 mg of glycine. GFR and ERPF were measured using isotope infusions of 51Cr EDTA and 125I OIH, respectively, before and for 3 h after the meal. Patients studied demonstrated a wide range of baseline GFRs (20.9-89.5 mL/min, mean 50.09 mL/min). However, few patients demonstrated an individual RFR, regardless of original level of function. Overall, no significant change in either GFR or ERPF was demonstrated after the protein stimulus. CyA is known to alter intrarenal prostanoid synthesis in favor of vasoconstriction and RFR is thought to be mediated by prostanoids. Therefore a mechanism for the absence of RFR in patients receiving CyA therapy is suggested.

The importance of E-selectin as a marker for renal transplant rejection

Vascular endothelial cells express membrane bound adhesion molecules which play a direct role in the localization and subsequent movement of leucocytes from the blood into sites of inflammation. E-Selectin is a cytokine induced adhesion molecule, known to be expressed by endothelial cells in inflammatory conditions, which binds to various leucocyte subpopulations. In a prospective study we have investigated the expression and distribution of E-selectin on renal allograft needle biopsies taken from 16 pretransplant kidneys and 119 post-transplant kidneys. Post-transplant biopsies were taken at times of graft dysfunction and at times of normal graft function. Formal histology was also performed and assessed independently. E-Selectin was found predominantly on the intertubular endothelium and on the endothelium of larger vessels. E-Selectin was present, at low intensity, in some pretransplant biopsies and also some post-transplant biopsies which were reported histologically as normal. In post-transplant biopsies taken for dysfunction E-selectin was present in the majority of cases. Expression was strong in biopsies showing acute cellular rejection and this was associated with a CD4 positive cellular infiltrate. Biopsies showing other causes of dysfunction, in particular acute tubular necrosis, also were E-selectin and CD4 positive with lower intensity than those with acute cellular rejection. These results suggest that E-selectin is a good marker for endothelial activation in renal transplant biopsies. Its presence in histologically apparently normal biopsies suggests that its in vivo kinetics may differ from previously reported in vitro kinetics. E-Selectin may be a potential target for therapeutic intervention.

The role of screening blood tests in patients with arterial disease attending vascular outpatients

OBJECTIVEnTo evaluate the benefits of a policy of performing screening blood tests in new patients with arterial disease referred to the vascular outpatients department.nnnMETHODSnClinical audit over a 12-month period of all new referrals with arterial disease to the vascular outpatients department at the Leicester General Hospital.nnnRESULTSnTwo hundred and seventy-two patients had at least one blood test performed at their outpatient visit. All of these patients had a full blood count performed, of which 21 results (21%) were abnormal. Further investigation of patients with abnormal results revealed one case of bladder cancer, one case of leukaemia and one patient with polycythaemia. Urea and electrolytes were measured in 269 patients (99%). Of these, 26 (10%) were expectedly abnormal in patients with known renal impairment. A further 27 patients (10%) were identified to have some degree of unrecognised renal impairment. Serum non-fasting glucose was measured in 252 patients (93%). There were 11 unexpectedly raised results, but further investigation of these patients only diagnosed one of these patients as diabetic. Serum cholesterol was measured in 201 patients (74%). One hundred and thirty-two patients (66%) had an abnormally raised serum cholesterol level. Of these, only 12 patients (6%) were known to have hyperlipidaemia.nnnCONCLUSIONSnScreening new patients with arterial disease in vascular outpatients does identify significant abnormalities, in particular renal impairment and hyperlipidaemia. Correction of these abnormalities may reduce the morbidity associated with contrast induced nephrotoxic acute renal failure, and also contribute to secondary prevention of vascular events associated with raised lipids.

A prospective randomised study of the effect of nicardipine on ischaemic renal injury in renal allografts

In a prospective doubleblind trial, 127 kidneys were randomised to receive Eurocollins (n=65) or Eurocollins plus nicardipine (n=62) as a second flush solution at the time of organ retrieval. Delayed graft function occurred in 18 of 65 control kidneys (28%) and in 20 of 62 nicardipine kidneys (32%; P=0.7, Fischers exact test). The mean (SD) serum creatinine at 6 weeks was 197 (138) μmol/l in the Eurocollins group and 195 (159) μmol/l in the nicardipine group (P=0.95). Eighteen recipients (28%) in the controlled Eurocollins group experienced a rejection episode in the first 6 weeks post-transplant compared to 17 (27%) in the nicardipine group (χ2 with Yates correction=0.027; P≧0.95). In this study, the addition of nicardipine to the kidney perfusion fluid did not have a beneficial effect on kidney function following transplantation.

Lack of correlation and soluble E-selectin level with renal transplant rejection

E-Selectin is a 115-kDa cell surface glycoprotein transiently expressed on vascular endothelium in response to interleukin-1 and tumour necrosis factor-alpha with a peak in expression at four hours. Its distribution in transplant biopsies has been associated with inflammatory events such as allograft rejection. Recently, a soluble isoform of E-selectin has been detected in the culture medium of cytokine activated endothelial cells by an ELISA method. In this study soluble E-selectin levels in renal allograft recipients were compared with the incidence of rejection, acute tubular necrosis (ATN), cyclosporin A (CyA) toxicity, and use of orthoclone OKT3 (muromonab-CD3) to establish whether early endothelial activation and inflammatory damage could be detected. The mean soluble E-selectin level in normal volunteers was 89 ng/ml serum compared to 120 ng/ml for a group of chronic renal failure patients. Soluble E-selectin levels declined upon transplantation but this was not significant, nor was the difference in samples from patients experiencing rejection, ATN or CyA toxicity. A dramatic and sustained rise in soluble E-selectin levels was found within 24 hours of the first dose of OKT3 treatment. This study shows that soluble E-selectin does not provide early unequivocal indication of pathological sequelae in renal transplantation, although extensive endothelial activation can be demonstrated with OKT3 treatment.