David M. A. Francis

Renal xenografts from triple-transgenic pigs are not hyperacutely rejected but cause coagulopathy in non-immunosuppressed baboons.

BACKGROUND The genetic modification of pigs is a powerful strategy that may ultimately enable successful xenotransplantation of porcine organs into humans. METHODS Transgenic pigs were produced by microinjection of gene constructs for human complement regulatory proteins CD55 and CD59 and the enzyme alpha1,2-fucosyltransferase (H-transferase, HT), which reduces expression of the major xenoepitope galactose-alpha1,3-galactose (alphaGal). Kidneys from CD55/HT and CD55/CD59/HT transgenic pigs were transplanted into nephrectomised, nonimmunosuppressed adult baboons. RESULTS In several lines of transgenic pigs, CD55 and CD59 were expressed strongly in all tissues examined, whereas HT expression was relatively weak and did not significantly reduce alphaGal. Control nontransgenic kidneys (n=4) grafted into baboons were hyperacutely rejected within 1 hr. In contrast, kidneys from CD55/HT pigs (n=2) were rejected after 30 hr, although kidneys from CD55/CD59/HT pigs (n=6) maintained function for up to 5 days. In the latter grafts, infiltration by macrophages, T cells, and B cells was observed at days 3 and 5 posttransplantation. The recipients developed thrombocytopenia and abnormalities in coagulation, manifested in increased clotting times and an elevation in the plasma level of the fibrin degradation product D-dimer, within 2 days of transplantation. Treatment with low molecular weight heparin prevented profound thrombocytopenia but not the other aspects of coagulopathy. CONCLUSIONS Strong expression of CD55 and CD59 completely protected porcine kidneys from hyperacute rejection and allowed a detailed analysis of xenograft rejection in the absence of immunosuppression. Coagulopathy appears to be a common feature of pig-to-baboon renal transplantation and represents yet another major barrier to its clinical application.

Successful ABO-incompatible kidney transplantation with antibody removal and standard immunosuppression.

ABO‐incompatible (ABOi) kidney transplantation is an established therapy, though its implementation to date has been in part limited by the requirement for additional immunosuppression. Here, we describe the outcomes of 37 patients undergoing ABOi kidney transplantation utilizing perioperative antibody depletion and receiving an identical tacrolimus‐based immunosuppressive regimen to contemporaneous ABO‐compatible (ABOc) recipients, with the exception that mycophenolate was commenced earlier (7–14 days pretransplant). Antibody depletion was scheduled according to baseline anti‐ABO antibody titer (tube IAT method: median 1:128, range 1:8 to 1:4096). Patient and graft survival for the 37 ABOi recipients was 100% after a median 26 months (interquartile range [IQR] 18–32). Eight rejection episodes (two antibody‐mediated and six cellular) in ABOi recipients were successfully treated with biopsy‐proven resolution. Latest median eGFR is 50 mL/min × 1.73 m2 (IQR 40–64) for ABOi patients and 54 mL/min × 1.73 m2 (IQR 44–66) in the ABOc patients (p = 0.25). We conclude that ABOi transplantation can be performed successfully with perioperative antibody removal and conventional immunosuppression. This suggests that access to ABOi transplantation can include a broader range of end‐stage kidney disease patients.

Protective Effects of Recombinant Human Antithrombin III in Pig-to-Primate Renal Xenotransplantation

Delayed rejection of pig kidney xenografts by primates is associated with vascular injury that may be accompanied by a form of consumptive coagulopathy in recipients. Using a life‐supporting pig‐to‐baboon renal xenotransplantation model, we have tested the hypothesis that treatment with recombinant human antithrombin III would prevent or at least delay the onset of rejection and coagulopathy. Non‐immunosuppressed baboons were transplanted with transgenic pig kidneys expressing the human complement regulators CD55 and CD59. Recipients were treated with an intravenous infusion of antithrombin III eight hourly (250 units per kg body weight), with or without low molecular weight heparin. Antithrombin‐treated recipients had preservation of normal renal function for 4–5 days, which was twice as long as untreated animals, and developed neither thrombocytopenia nor significant coagulopathy during this period. Thus, recombinant antithrombin III may be a useful therapeutic agent to ameliorate both early graft damage and the development of systemic coagulation disorders in pig‐to‐human xenotransplantation.

Association of renal adenocarcinoma and BK virus nephropathy post transplantation.

While most BK virus infections are asymptomatic, immunosuppression has been associated with BK virus reactivation and impaired graft function or ureteric ulceration in renal transplant patients and hemorrhagic cystitis in bone marrow transplant patients. Oncogenicity is also postulated and this is the first report of a child with a carcinoma of the donor renal pelvis following BK virus allograft nephropathy. Removal of the primary tumor and cessation of immunosuppression led to regression of secondary tumors and a return to health.

Triple immunosuppression with subsequent prednisolone withdrawal: 6 years' experience in paediatric renal allograft recipients

Thirty-four children (≤15 years of age) with end-stage renal failure received 39 renal allografts between 1985 and 1991 and were treated with cyclosporin A (CyA), azathioprine and low-dose prednisolone (PNL). We aimed to withdraw PNL by 6 months after transplantation. Median duration of follow-up was 2 years 4 months (range 0.1 month to 6 years, 4 months). There were no deaths. Crude graft survival for living-related grafts (n=9) was 100%, although only 1 patient has been followed for >2 years. For cadaveric grafts (n=30), 1- and 5-year actuarial graft survivals were 90% and 79% respectively. At 12 months posttransplant, the median (range) glomerular filtration rate for all patients was 63 (19–109) ml/min per 1.73 m2 (n=25) and at 5 years was 48 (17–64) ml/min per 1.73 m2 (n=9). Complications observed included rejection episodes which occurred after discontinuation of PNL. Long-term (after 12 months), 28% of patients remain on PNL. Hypertension was present in more than 50% of patients. Severe CyA nephrotoxicity was not seen. Catch-up growth as determined by the change (Δ) in mean height standard deviation score (Ht-SDS) was noted at 1 year [ΔSDS/year=+0.60;P<0.001 (n=18)] and at 2 years [ΔSDS/year=+0.27;P<0.01 (n=16)] in pre-pubertal patients. The median Ht-SDS at 2 years for pre-pubertal children was −0.71 SD and growth velocity did not improve thereafter. In pubertal patients, the mean ΔSDS per year at 1 year (n=7) was +0.43 and at 2 years (n=4) was +0.17. The catch-up growth in pubertal patients did not reach statistical significance. It was concluded that the use of this immunosuppression regime was associated with an excellent patient and graft survival. Catch-up growth is especially encouraging in pre-pubertal patients. However routine discontinuation of PNL may require review.

Two-stage brachiobasilic arteriovenous fistula for chronic haemodialysis access

Background:  Many haemodialysis patients are unable to have or maintain distal upper limb arteriovenous (AV) fistulas because of inadequate veins or arteries and therefore require more proximal access. We have reviewed our experience with a two‐stage brachiobasilic AV haemodialysis fistula fashioned in the arm.

Adverse influence of recipient lymphoid resistance to in vitro immunosuppression on the outcome of kidney transplants.

The study investigated whether preoperative in vitro sensitivity of lymphocytes from potential renal transplant recipients could identify patients at increased risk of acute rejection following transplantation and immunosuppression with cyclosporine, azathioprine, and prednisolone. Mixed lymphocyte culture responses were measured preoperatively in the presence of methylprednisolone, CsA, and antithymocyte globulin, and without immunosuppressive agents in 50 transfused recipients of primary cadaver renal transplants. Patients were classified as sensitive if all three immunosuppressive agents produced more than 50% inhibition of their MLC responses, and as resistant if one or more agents failed to produce 50% inhibition. All patients received postoperatively a standardized triple immunosuppressive regimen. Acute rejection was confirmed histologically and treated with Pred with or without ATG or monoclonal antibody OKT3. A total of 29 patients (58%) were sensitive and 21 (42%) were resistant; 4 patients were resistant to 3 agents, 5 were resistant to MP and ATG, 6 were resistant to MP and CsA, and 6 were resistant to MP alone. Sensitive and resistant groups did not differ in age, sex, transfusion history, HLA A, B and DR mismatches or duration of follow-up. The resistant group had a higher rate of graft loss from acute rejection (chi 2 = 6.0, d.f. = 1, P less than 0.02), more episodes of acute rejection (chi 2 = 8.7, d.f. = 3, P less than 0.05), and a higher proportion of patients in whom reflux nephropathy was the cause of renal failure (chi 2 = 18.3, d.f. = 1, P less than 0.001). The resistant group also had a higher proportion of highly sensitized patients and higher serum creatinine concentrations than the sensitive group, although the differences did not reach statistical significance. The study indicates that patients at high risk of acute rejection of renal allografts can be identified by a pretransplant in vitro assay, a finding that could influence recipient selection and immunosuppression.

A case of craniomandibular dermatodysostosis associated with focal glomerulosclerosis

This paper reports an isolated case of the exceedingly rare cutaneo-skeletal condition craniomandibular dermatodysostosis, in which focal glomerular sclerosis and end-stage renal failure developed and renal transplantation was required.

Pyeloureterostomy in the Management of Renal Allograft Ureteral Complications: An Alternative Technique

Pyeloureterostomy is the standard procedure for reconstructing renal allograft ureteral complications. Most reports describe an end-to-end technique with or without native nephrectomy. An alternative is an end-to-side anastomosis, leaving the native ureter in continuity. We report our experience with the latter method. Since July 1983, 437 renal transplantations have been performed at our institution. End-to-side pyeloureterostomy has been used in 5 cases for urological reconstruction after renal transplantation following ureteral ischemic necrosis or stenosis. In 1 patient the native kidneys had been removed several years previously but in the remaining 4 the native kidneys were left in situ. There have been no significant complications following this procedure. We believe that by not significantly mobilizing, ligating or dividing the native ureter the chance of anastomotic breakdown due to ischemia may be decreased.

Paediatric cadaveric renal transplantation. Initial experience with a triple therapy immunosuppressive regimen.

Since June 1985 ten consecutive paediatric cadaveric renal transplant recipients (aged from 7 to 15 years) have been studied prospectively to evaluate a triple immunosuppressive regime of low-dose cyclosporin A (CyA), azathioprine (AZA) and prednisolone (PNL) with the aim of eliminating PNL from the regime within 6 months. Follow-up has been over 6–18 months. Patient and graft survival are both 100%. Median (range) serum creatinine values at 6 months were 0.09 (0.05–0.14) mmol/l (n=10) and 0.09 (0.06–0.16) mmol/l (n=5) at 12 months. Readily reversible acute rejection episodes occurred in five patients (50%); two of these episodes occurred soon after cessation of PNL. Six months post-transplantation, PNL had been discontinued in six patients (60%). After 12 months, three of five patients were still not receiving PNL. Complications included hypertension (seven patients), cytomegaloviral infections (three patients), labial herpes simplex (one patient), leucopenia (two patients), marked hirsuitism (four patients) and transient CyA nephrotoxicity (one patient). Following transplantation, all children had growth velocities greater than 5 cm/year and seven have growth patterns which suggest that “catch-up growth” may be occurring. This preliminary study shows that a triple immunosuppressive regime of low-dose CyA, AZA and PNL allows excellent patient survival, graft survival and graft function and has been associated with few complications, including a low incidence of CyA nephrotoxicity. Growth rates are very encouraging and in a high proportion of children it has been possible to discontinue PNL completely.