Nicholas J. Feduska

Deliberate donor-specific blood transfusions prior to living related renal transplantation. A new approach.

In order to select MLC incompatible one-haplotype related donor-recipient pairs that would achieve better graft survival and in an effort to alter the recipient immune response, 45 patients received three fresh blood transfusions from their prospective kidney donors. Recipient sensitization was evaluated by cross-match testing weekly sera obtained during and after the blood transfusions against donor T- and B-lymphocytes at 5 C (cold) and 37 C (warm). Thirteen (29%) of the 45 potential related recipients developed a positive warm T-cell cross-match or a persistent warm B-cell cross-match to their blood donor and related transplantation was not performed. Thirty-two (71%) patients had an appropriate negative cross-match to their blood donor. Thirty of these patients subsequently received kidneys from their blood donor. Ninety-seven per cent of the kidneys are functioning from one to 25 months with a single graft failure due to a patient discontinuing immunosuppressive medication. In addition to the excellent graft survival there was an unusually low incidence of rejection episodes in the recipients of kidneys from their blood donor so that the posttransplant course paralleled that of HLA-identical siblings. This approach may have future application with two-haplotype mismatched donor-recipient pairs, both related and unrelated.

The Role of Hypertension in Hemodialysis-Associated Atherosclerosis

Atherosclerosis in 50 nondiabetic patients undergoing hemodialysis was assessed at the time of renal transplantation by intraoperative examination and histologic evaluation of the iliac vasculature. Patients were grouped accordingly: minimal (group 1), moderate (group 2) or severe (group 3) atherosclerosis. Sixty-two per cent of the patients had atherosclerosis, half of them with severe involvement. No sex differences were noted. There was a significant correlation between the patients age and the degree of atherosclerosis (p less than 0.02). Thirty-five per cent of the patients under 30 years of age had atherosclerosis whereas similarly studied nonuremic control subjects had no atherosclerosis. Metabolic and lipid abnormalities, and duration of hemodialysis did not correlate with degree of atherosclerosis. Hypertension was present in 90 per cent of the patients in groups 2 and 3. When patients between the ages of 25 and 40 years were selected, atherosclerosis was present only in previously hypertensive patients (p less than 0.02). Atherosclerosis may not be accelerated by hemodialysis and may be prevented by more stringent control of hypertension in uremia.

Long-term renal function in kidney donors. Sustained compensatory hyperfiltration with no adverse effects.

Twenty patients who underwent uninephrectomy for kidney donation between 1964 and 1968 participated in a long-term study of the function of the solitary kidney. Mean follow up after uninephrectomy was 15.8 +/- .3 years. One patient with a strong family history of essential hypertension developed de novo mild hypertension. The current creatinine clearance of the donors was 80 +/- 4 ml/min. The 1-week, 3-6 months and 14-18 years postuninephrectomy percentages of predonation creatinine clearance were 72 +/- 3%, 76 +/- 3% and 78 +/- 2%, respectively. The 24-hr urine protein excretion in kidney donors was significantly higher than in controls (141 +/- 20 mg vs. 74 +/- 3 mg, respectively, P less than .0005). Except for one donor who may have developed glomerulonephritis, the donors had normal urinary albumin excretion. The cause of the slightly elevated nonalbumin proteinuria is not known. However, this long-term study of kidney donors shows no adverse effects on the blood pressure and renal function after many years of compensatory hyperfiltration.

Urological complications of renal transplantation can be prevented or controlled.

Our incidence of urological complications in 860 consecutive renal transplants in 3.4 per cent. A further reduction in incidence is demonstrated in the most recent 250 transplants of this series. Urological complications have been kept to a minimum by strict adherence to certain principles in donor nephrectomy, management of multiple and small arteries, and the technique of graft implantation. When urological complications were suspected early and judicious use of 131I hippurate scintiphotographic techniques has proved to be the most helpful method to evaluate patients. If a urological complication did occur prompt recognition and treatment were responsible for a high rate of graft salvage, low incidence of sepsis and absence of patient mortality.

Results and Significance of Angiography in Potential Kidney Donors

Multiple renal arteries originating from the aortoiliac vessels were identified angiographically in 44% of 444 prospective renal donors. Bilateral multiple renal arteries were identified in 12%. With good immunological donor-recipient matching, 17 kidneys with multiple renal arteries were transplanted with excellent results; therefore, presence of multiple renal arteries should not be considered a contraindication to kidney transplantation. A high proportion (17%) of the prospective donors, acceptable by all other means of evaluation, had abnormmal angiographic findings that led to reconsideration of their acceptance. In addition to multiple renal arteries, neither renovascular atherosclerosis nor fibromuscular dysplasia proved to be an absolute contraindication to transplantation.

The clinical course of IgA-nephropathy and Henoch-Schönlein purpura following renal transplantation.

Recurrence of IgA-nephropathy and Henoch-Schönlein purpura is a common finding after renal transplantation. From 1970 to 1984, 1788 transplants were performed at our center. 13 patients had IgA-nephropathy and 3 patients had Henoch-Schönlein purpura. No patient with Henoch-Schönlein purpura had a proved recurrence. Six patients with IgA-nephropathy had a recurrence of IgA disease in the allograft within 3 to 8 months of transplantation. Three patients with a recurrence have retained their kidneys with stable renal function (follow-up of 1.7-2.7 years). Two of these patients lost their graft from severe rejection. One patient, who received an HLA-identical transplant, lost the graft from recurrent IgA disease associated with crescenteric glomerulonephritis. We found no difference in the prevalence of HLA-B 35 among the IgA patients compared with our total transplant population. IgA patients who received living related transplants had a higher recurrence rate of IgA in their allograft when compared with recipients of cadaveric kidneys (83% vs. 14%). Some caution is recommended in using related donors, especially HLA-identical siblings in patients with renal failure secondary to IgA-nephropathy.

A seven-year experience with donor-specific blood transfusions. Results and considerations for maximum efficacy.

Two hundred thirty-nine transplants have been performed following donor-specific blood transfusions (DSTs) since 1978. Graft and patient survival in 1-and O-haplotype-matched transplants with DST pretreatment is comparable to HLA-identical results through 4 years. Graft survival in 174 consecutive nondiabetic, non-HLA-identical DST recipients shows that the transfusion effect persists for at least 4 years, with graft survival of 88\pm3% at that time, compared with 83\pm4% in the concurrent HLA-identical group. Graft function, as determined by serum creatinine, was the same in both groups. Graft and patient survival in 20 O-haplotype matched pairs with DST pretreatment is 100% at 2 years. Low-dose Imuran coverage during DST administration (n=91) was compared with a concurrent group with no Imuran (n=93). Imuran had its maximum effect in patients undergoing their first transplant and with a pre-DST PRA less than 10% (12% vs. 21% sensitization rate in the no-Imuran group). Imuran did not appear to confer any beneficial effect in primary transplants with high PRAs and in patients undergoing a second or third transplant. The majority of patients formally excluded from transplantation because of a post-DST positive B-warm crossmatch can now be successfully transplanted with the use of flow cytometry analysis to rule out previously undetectable low levels of anti-T-lymphocyte antibodies. Of 62 patients with a positive B-warm crossmatch alone since 1982, 73% had a subsequent negative fluorescence-activated cell sorter (FACS) crossmatch permitting transplantation. Preliminary results of a DST and cyclosporine treatment study are described. In conclusion, a long-term immunologic effect of DST has been confirmed and the indications and considerations for optimum use of the DST protocol have been more clearly defined.

Immunologic factors determining survival of cadaver-kidney transplants. The effect of HLA serotyping, cytotoxic antibodies and blood transfusions on graft survival.

We assessed immunologic factors determining graft survival in 510 recipients of primary cadaver allografts at one center. The degree of HLA match grade did not directly affect graft survival (54 per cent in no-antigen match, and 42 per cent in three-antigen match, at two years). There was no correlation between the HLA match grade and the degree of stimulation of the mixed lymphocyte culture. Patients receiving more than five blood transfusions had a significantly better graft survival than nontransfused recipients (52 versus 23 per cent, respectively, at two years, P less than 0.001). The beneficial effect of transfusions was noted whether or not lymphocytotoxic antibodies were produced, provided adequate screening was performed before transplantation. Transfusions did not alter the degree of stimulation in the mixed lymphocyte culture. More liberal use of transfusions and frequent screening for cytotoxic antibodies would probably result in more effective cadaver-kidney transplantation.

Improved outcome following renal transplantation with reduction in the immunosuppression therapy for rejection episodes

Renal transplantation is superior to hemodialysis in terms of rehabilitation and cost, but it is offered to only a minority of patients with end-stage renal failure because of complications related to immunosuppression therapy. To reduce morbidity, we modified out therapy of patients with transplant rejection from high dose intravenous methylprednisolone (group A: January 1968--September 1972) to lower dose oral prednisone (group B: September 1972--December 1977). Patient survival in group B was significantly improved over that in group A, both in recipients of cadaver transplants (91 per cent versus 81 per cent, respectively, at one year, p less than 0.0009) and in recipients of transplants from living related donors (99 per cent versus 86 per cent, respectively, at one year p less than 0.001). The improvement in patient survival was the result of a significant decrease in the incidence of infections. Patients with multiple rejection episodes, a very high risk group, experienced an 18 per cent increase in patient survival in group B. With reduction and rapid tapering of corticosteroids for the treatment of patients with acute rejection and curtailment of the therapy of patients with multiple rejection episodes, survival after renal transplantation becomes comparable to that following hemodialysis; in addition, graft function is not compromised.

De novo and recurrent membranous glomerulopathy following kidney transplantation.

Membranous glomerulopathy, de novo or recurrent, in the allograft kidney is a recognized, albeit uncommon, clinical entity. We examined the records of 936 renal allograft recipients in a seven and one-half year period. De novo membranous glomerulopathy developed in six patients. The mean onset of nephrotic-range proteinuria after transplantation was at 18.1 months (with a range of from 4 to 30 months). De novo membranous glomerulopathy did not adversely affect graft survival. Twenty-five patients were transplanted for end-stage renal disease caused by membranous glomerulopathy. The rate of recurrence of membranous glomerulopathy in patients who did not lose their allograft to rejection in the immediate posttransplant period was 7%. Additional prednisone therapy to the standard immunosuppressive protocol did not appear to be beneficial. One patient, who developed a recurrence of the original lesion, received an HLA-identical kidney. Onset of nephrotic-range proteinuria occurred four weeks post-transplant. Recurrent membranous glomerulopathy has been reported in five other patients. In the two recipients of living related allografts nephrotic-range proteinuria developed within two weeks of the transplant. Patients with end-stage renal disease caused by membranous glomerulopathy who receive a living related allograft, especially one that is HLA-identical, may be at a higher risk for morbidity and for early recurrence. We recommend caution in the use of a living related transplant for patients with end-stage renal disease caused by membranous glomerulopathy.