H. K. Oh

A prospective controlled trial of cold-storage versus machine-perfusion preservation in cadaveric renal transplantation.

A prospective controlled study was carried out in 60 consecutive cadaver renal donors comparing cold storage to pulsatile machine-perfusion preservation. Each donor served as its own control, by allocating one of the kidneys to each of the two preservation methods. There were 51 evaluable pairs of kidneys. Recipient age, panel-reactive antibody level, history of prior renal transplant, and immunosuppressive regimen were similar in the two preservation groups. Almost all recipients were treated with cyclosporine, and over 50% received antilymphoblast globulin. Total cold ischemic time was 1262 +/- 387 min in the machine-perfused group and 1309 +/- 426 min in the cold-storage group (P = NS). Prolonged ischemia (greater than 24 hr) occurred in 31% of machine-perfused and 22% of cold-stored kidneys (P = NS). Post-operative serum creatinine levels at 1, 7, and 30 days posttransplant were similar in both groups. Dialysis requirements were also similar, with 21 recipients of machine-perfused kidneys (41%) requiring at least one dialysis treatment compared to 16 patients (31%) in the cold-stored group (P = NS); the mean number of dialysis treatments required was 3.14 +/- 1.46 and 3.06 +/- 1.29, respectively (P = NS). Long ischemic time (greater than 24 hr) was associated with a higher rate of dialysis requirement in both groups, but in neither case did this achieve statistical significance. The distribution of graft losses within the first 30 days was similar in both groups, and the incidence of preservation-related graft failure was not significantly different. These results demonstrate that, in the cyclosporine era, machine perfusion offers no significant advantages over cold storage for cadaver renal preservation. Because machine perfusion is considerably more expensive and cold storage is simpler and facilitates the logistics of organ sharing, we recommend simple hypothermic storage of renal allografts as the preservation method of choice.

Complete replacement of methylprednisolone by azathioprine in cyclosporine-treated primary cadaveric renal transplant recipients

In cylosporine (CsA)-treated renal transplant recipients complete corticosteriod withdrawl followed by CsA monotherpy has been associted with severe rejection episodes in a significance proportion of patients. We report the results of replacements of steroids by azathioprine (AZA) in 25 primary cadaveric renal transplant recipients initially treated with CsA and methylprednisolone (MP). MP taper was started 8.85.6 months posttrasplant when the MP dose was either 10mg/day or 20 mg every other day. MP was tapered off over a 5-month period. At the initation of MP taper, AZA was added at 1 mg/kg/day and increased to 1.5 mg/kg/day after two months. The CsA dose was adjusted to maintain trough serum levels as measured by radioimmunoasay (RIA) of 50–75 ng/ml, during and after MP with drawl. Seventeen patients have remained continuously off MP for 14.65.0 months with stable renal function. Reinstitution of MP at 10 mg/day was required in 8 patients, 6 for rejection (1.80.7 months after MP with drawl), 1 for AZA-indiced leukopenia, and 1 for denovo glomerulopathy. Renal function returned to baseline in all 6 patients have again been successfully retapered off MP. In the patients withdrawn from MP, body weight and mean arterial blood pressure had decreased by 2.11.3 kg (P<.05) and 117 mmHg (P<.05), respectively, at the time of the most recent follow-up compared with values at the initiation of steroid withdrawal. The number of blood pressure medications per patient decresed by 38% (P<.05) and 6 patients were able to discontinue all antihyupertansive drugs after cessation of steroids. Discontinuation of MP also resulted in a decrease in serum cholesteorl concentration from 24850 to 21755 mg/dl (P<.05). We conclude that steroids can be replaced by AZA in the majority of CsA-treated primary cadaveric renal transplant recipients by the end of the first posttransplant year withour an adverse effect on graft survival. This protocol resulted in significant reductions in serum cholesterol, mean arterial blood pressure, and body weight, and may avoid the long-term siode effects of steroid therapy.

Removal Of Lymphocytotoxic Antibodies By Pretransplant Immunoadsorption Therapy In Highly Sensitized Renal Transplant Recipients

A high level of panel-reactive antibodies (PRA) in potential renal transplant recipients is associated with a long waiting time until transplantation and correlates inversely with graft outcome. We report our experience with the employment of immunoadsorption (IA) using a column composed to sepharose-bound staphylococcal protein A (which has a relatively selective affinity for binding IgG compared with other immunoglobulins) to decrease the PRA levels and expedite transplantation in 6 highly sensitized potential renal transplant recipients (1 primary and 5 awaiting second transplants). All patients had PRA levels of greater than or equal to 70% for a duration of 1 year prior to IA. Only patients with antibody specificity localized to 1 or 2 HLA A or B antigens were accepted for the study. IA procedures were performed on alternate days until a twofold decrease in antibody titer had occurred (maximum: 6 procedures). Repeat procedures were initiated if the HLA antibody titer returned to its baseline value. Intravenous cyclophosphamide (CY) (10 mg/kg/day every 3 weeks) and methylprednisolone (MP) (0.5 mg/kg/day) were provided as adjunctive immunosuppression until transplantation. A total of 44 immunoadsorption procedures were performed (27 primary and 17 repeat) with treatment of 2.49 +/- 0.02 plasma volumes per session. Serum IgG concentration decreased 95 +/- 3% and PRA activity decreased 75 +/- 16% after the primary treatment course. Four patients received cadaveric grafts within 3.7 +/- 1.2 months following the last IA procedure. Three grafts are functioning at 1 year, 8 months, and 8 weeks posttransplant. The remaining graft demonstrated primary nonfunction. All four patients had a past positive crossmatch using pre-IA sera with their respective donors. Patients not transplanted exhibited rapid resynthesis of IgG and a return of the PRA towards baseline levels within a few weeks after IA. We conclude that IA can effectively remove HLA antibodies and expedite graft availability in highly sensitized patients.

Histologic and immunophenotypic evaluation of pretreatment renal biopsies in OKT3-treated allograft rejections

The histologic features immunophenotype of intragraft mononuclear populations, and HLA-Dr expression in pretreatment formalin-fixed renal allograft biopsies were correlated with outcome of OKT3 therapy in 35 steroid resistant renal transplant rejections. Therapeuic response (63% overall) was better in pure acute cellular rejections (ACR) (13/15, 87%) than ACR with interstitial fibrosis (4/12, 33%) or with vascular injury (5/8, 62%). Intragraft T lymphocytes were more numerous in vascular rejection (mean 566/mm2) compared with pure ACR (mean 265/mm2, P=.049), and macrophages were greater in pure ACR (203/mm2) compared with ACR with interstitial fibrosis (83/mm2, P=.051). Distribution of T cells, B cells, plasma cells, and macrophages among various histologic categories was otherwise statistically similar. There was no correlation between therapeutic response to OKT3 and intragraft

Sequential use of Minnesota antilymphoblast globulin and cyclosporine in cadaveric renal transplantation

The use of Cyclosporine (CsA) immediately after renal transplantation may be associated with an increased incidence and duration of acute tubular necrosis (ATN) and permanent primary graft nonfunction. To avoid this potential interaction we treated recipients of primary cadaveric grafts initially with azathioprine (AZA), methylprednisolone (MP), and 5 daily doses of Minnesota antilymphoblast globulin (MAG) (postoperative days 3–7). AZA was discontinued and CsA started on day 6 if the graft was functioning by then. If ATN persisted beyond day 6, AZA and MAG (maximum 12 doses) were continued and CsA withheld until graft function was established (group 1—33 patients). This protocol is compared to our previous regimen of MAG (14 doses over the first 3 weeks), AZA and MP (group 2—68 primary cadaveric graft recipients). Improved one-year graft survival (81% vs. 60%, P<0.05) and patient survival (93% vs. 81%, P<0.05) were seen in group 1. The incidence and duration of ATN did not differ in the two groups. During the first year after transplantation more patients in group 1 were completely free of rejection episodes (40% vs. 20%, P<0.05) and the number of rejection episodes per patient was also lower in this group (1.0\pm.15 vs. 1.6\pm.49, P<0.05). The incidence of infections was not different in the two groups. No tumors have developed in either group. We conclude that in primary cadaveric renal transplantation the initial administration of a short course of MAG followed by CsA therapy results in excellent graft and patient survival while avoiding the potential adverse effect of CsA on an allograft already subjected to preservation injury.

Effective long-term immunosuppression maintained by low cyclosporine levels in primary cadaveric renal transplant recipients

Nephrotoxicity and cost are the major problems in the use of cyclosporine (CsA) in renal transplantation. Thus, maintenance of CsA levels at the lower limits of the therapeutic range is desirable. The lowest CsA level effective in preventing rejection while avoiding nephrotoxicity has not been defined. We report on 44 primary cadaveric renal transplant recipients treated with a protocol that involved a progressive reduction in the trough CsA levels. CsA was initiated at an oral dose of 15 mg/kg, and this dose was adjusted to achieve serum trough levels, as measured by radioimmunoassay, of 150–200 ng/ml during the first month, 100–150 ng/ml during the second month, 75—100 ng/ml during the third month, and 50—75 ng/ml thereafter. Patient and graft survival at 18 months were 94% and 83.6%, respectively. The mean daily CsA doses were 6.7±3.1 mg/kg at 6 months, 5.5±3.2 mg/kg at 12 months, and 4.7±2.4 mg/kg at 18 months. Corresponding trough serum CsA levels were 94±59 ng/ml, 64±22 ng/ml, and 44±21 ng/ml at 6, 12, and 18 months, respectively. Mean serum creatinine concentrations were 1.8±0.6 mg/dl at 6 months, 1.7±0.5 mg/dl at 12 months, and 1.6±0.5 mg/dl at 18 months. The mean serum creatinine concentration at 18 months was not significantly different from that of 18 conventionally treated primary cadaveric renal transplant recipients (1.6±0.5 vs. 1.4±0.4 mg/dl, P=.31). A total of 67% of patients did not have any rejection episodes under this protocol, while 71% of patients never developed CsA nephrotoxicity. No patient was taken off CsA for progressive nephrotoxicity. We conclude that trough serum CsA levels of 50—75 ng/ml, as measured by radioimmunoassay, are sufficient to maintain effective immunosuppression in the long-term management of primary cadaveric renal transplant recipients. These values are much lower than previously recommended, and this approach ameliorates chronic CsA nephrotoxicity.