Timing of antirejection therapy.

In order to determine the optimal time for treating rejection, groups of immunosuppressed rats bearing heart allografts were treated with single pulses of methylprednisolone on days 0, 2, 4, 6, or 8 after transplantation. Untreated rats rejected their grafts in 8 days. Treatment on day 0 prolonged the survival of the transplants in this group, but treatment on days 2 or 4 was largely ineffective. However, significant prolongation of graft survival was achieved when methylprednisolone was given on days 6 or 8. In a separate study, the electrical activity of nine heart allografts in immunosuppressed rats was recorded every 2nd day and biopsies were obtained on days 4, 6, and 8. These observations showed that rejection was well advanced on days 6 and 8, times when rejection treatment was most successful. In this model, therefore, it would seem that rejection treatment is more effective when given late (days 6 and 8) than when given early (days 2 and 4). Treatment on the day of transplantation (day 0) was also effective.

The use of fine-needle intrarenal manometry in the management of renal transplant patients receiving cyclosporine.

The pressure inside a renal transplant can be measured by means of a fine (25-G) needle passed into the kidney, and we have shown previously that a rise in pressure to more than 40 mmHg commonly occurs during rejection episodes. A rise was not observed in patients with cyclosporine nephrotoxicity or acute tubular necrosis, so we have now used this test prospectively as part of our management of 37 patients undergoing renal transplantation. Fine needle intrarenal pressure was recorded weekly during the first three weeks after transplantation, with more frequent measures taken in patients with deteriorating or absent renal function. Treatment was dictated by the result of these tests. Deteriorating function in a kidney registering a normal pressure was diagnosed as cyclosporine nephrotoxicity and the dose of cyclosporine was reduced appropriately. A pressure reading in excess of 40 mmHg was regarded as rejection--and, after obtaining a conventional needle biopsy of the kidney, antirejection treatment was commenced immediately. Nineteen episodes of nephrotoxicity were confirmed and there was only one false-positive result. Twenty-eight of twenty-nine rejection episodes (observed in twenty-three patients) were associated with a significant rise in intrarenal pressure and were treated appropriately. In six patients who were oliguric at the time, as a result of posttransplant acute tubular necrosis, this rise in pressure was the first indication of rejection. A high pressure was recorded on the first day that the creatinine rose in two-thirds of the cases. In the remainder the pressure was seen to rise more slowly, particularly when the rejection was of the chronic vascular type and was occurring two months or more after transplantation. Fine-needle intrarenal manometry accurately identified rejection episodes in newly transplanted patients--and, because the results were unaffected by cyclosporine nephrotoxicity and acute tubular necrosis, the test was of most value in monitoring patients with these conditions.

Trasylol (aprotinin) and kidney preservation.

Experiments carried out in rats and sheep have shown that Trasylol (aprotinin) is helpful in protecting kidneys from the harmful effects of ischaemia. After critical periods of ischaemia, renal failure was less frequent in the treated groups, and glomerular leakage of 131I-labelled albumin was greatly reduced.

The relevance of pressure changes in transplanted hearts and kidneys in immunosuppressed rats.

The pressure within rat cardiac and renal allografts has been observed to rise during rejection. We wished to see if this pressure rise could be prevented or reversed with immunosuppression. Transplants were performed from Lewis or DA donors to Lewis recipients. The rats received either a heterotopic cardiac transplant or an orthotopic renal transplant and were then treated with different immunosuppressive protocols. Intramyocardial pressure was recorded using a fine-gauge needle connected to an air pressure manometer. In the case of the renal transplants, a pressure transducer was used as well and the two methods compared. Intramyocardial and intrarenal pressures rose dramatically in unimmunosuppressed recipients of DA allografts. No such rise was seen in isografted organs, although the pressures recorded remained significantly higher than those found in untransplanted hearts and kidneys. Cyclosporine 20 mg/kg/day was effective in suppressing rejection in both models, and inhibited any rise in intraorgan pressure. Cyclosporine 10 mg/kg/day was less effective, and with 2 mg/kg/day allograft function was considerably impaired, one-third of the cardiac grafts being rejected by 16 days. In both models intraorgan pressures became raised. The addition of methylprednisolone 16 mg/kg i.p. on days 7 and 8 to this low dose regimen of cyclosporine 2 mg/kg/day rapidly reversed the rise in pressure and restored graft function to normal. Intraorgan pressure levels therefore accurately reflected the state of function of transplanted hearts and kidneys. When a manometer and a transducer were compared as a means of measuring the pressure in the renal transplants, the manometer method was found to be superior.

Human immunity to rat antigens.

A test has been devised with the object of assaying immune responsiveness in normal and immunodepressed persons. It has been based on the graft-versus-host model of Ford et al. (Transplantation 10: 258, 1970) and employs rat antigens as the immunological stimuli. Peripheral blood lymphocytes were injected into the hind feet of young Wistar rats, and 7 days later the popliteal lymph nodes were removed and weighed. It was found that the unwanted host-versus-graft activity could be suppressed in the rats by total body irradiation. Inactivated lymphocytes were injected into the right hind foot as a control and the result was expressed as a ratio: weight of left node to weight of right node. Lymphocytes from 45 healthy individuals were examined in this way. The response was readily suppressed by administering daily injections of steroid or antilymphocyte globulin to the rats, but was not influenced by the presence or absence of antirat antibodies in these individuals.

Intraorgan pressure changes in rejecting kidney, liver, and heart transplants in the rat.

Intraorgan pressure was measured in DA kidneys, livers, and hearts after transplantation into Lewis rats. Recordings were obtained by passing a fine needle into the graft and measuring the resistance to the flow of saline. Rats with organ isografts (Lewis-to-Lewis) were used as controls, and a further control group comprised Lewis rats that had undergone left ureteric ligation. Following transplantation a rise in pressure was recorded from some of the isografts, it returned to base line levels by the second or third day. Similar changes were observed in the organ allografts, except that a second, much greater (P less than .05) rise soon followed. This was observed from day 3 onward in the case of the kidney and liver transplants, and from day 4 in the cardiac transplants. Control experiments showed that ligation of the ureter (as performed in all the kidney transplants) did not influence intrarenal pressure. It is concluded that a rise in intraorgan pressure is an early feature of rejection, and that pressure monitoring might be useful in patients with cardiac or liver transplants--in addition to those with kidney transplants in whom the test has been shown to be of value.

A controlled trial of steroids in cyclosporine-treated renal transplant recipients.

In a randomized controlled clinical trial, 117 recipients of a kidney transplant were treated with cyclosporine (15-17 mg/kg/day) either alone or with prednisolone 0.3 mg/kg/day in addition. There were no exclusions and all patients have been followed-up from 14 to 39 months. No differences in the survival of the patients or their transplants were seen between the two groups. Actual survival of first cadaver grafts was 73% at one year in the group receiving cyclosporine alone and 76% in the group with added steroids. Survival of second or third grafts in the steroid group was somewhat worse but not significantly so. All 6 recipients of living-donor grafts are currently alive with good function. Infective complications were significantly less common in the group not receiving routine steroids, and these patients were also at less risk of developing a changed facial appearance. However, half the patients in this group have subsequently required steroids because of previous rejections, and cyclosporine nephrotoxicity has been significantly more common. Nonetheless, we have found no overall advantage in combining cyclosporine with low-dose maintenance prednisolone, and we advise that patients undergoing renal transplantation receive cyclosporine alone in the first instance.

Human immunity to rat antigens. II. Immune responses in dialysis patients.

The immune status of 35 patients with renal failure was studied shortly after they had commenced treatment by chronic haemodialysis to see if a group with poor immunological responses could be identified. Of 27 patients who were unimmunised to start with, only two developed lymphocytoxic antibodies after a year of treatment. The routine immunological tests that were carried out on these patients failed to predict which of them would develop antibodies, and the values that were obtained for the group of cytotoxic negative patients were no different from those obtained for the two patients who became immunised and six others who had previously rejected a kidney transplant. By using a new test that measured cellular immunity to rat antigens, eight patients could be identified as "poor responders." These individuals had in addition failed to develop cytotoxic antibodies during dialysis, had serum IgG levels that were significantly lower than normal, and were uniformly unresponsive to purified protein derivative. This group of patients might be a favoruable one to transplant.

Immunosuppressive drugs and the foetus.

Two infants born to mothers who had been given a renal transplant and who were receiving azathioprine and prednisone have been followed up for over 2 years. Initially both had lower than normal lymphocyte counts and cortisol levels. Chromosomal aberrations similar to those found in the lymphocytes of the mothers were present at birth but had disappeared by 32 and 20 months, respectively. The significance of these findings is discussed.

Prolonged allograft survival with niridazole, azathioprine, and prednisolone.

The immunosuppressive properties of niridazole, an antihelminthic drug, have been investigated in rats. When given orally in a dose of 50 mg/kg, it extended the median survival of cardiac allografts from 7 to 20 days. The immunosuppressive effect was not increased by giving either azathioprine or prednisolone concurrently but when all three drugs were combined, immunosuppression was profound and only two of eight grafts were rejected. Drug combinations incorporating niridazole at a lower dosage or for a shorter period were less effective, and azathioprine and prednisolone on their own or used together prolonged graft survival only marginally in this model. It is concluded that niridazole is a powerful immunosuppressive drug in this species and a synergistic effect can be obtained by using it in combination with azathioprine and prednisolone.

Blood transfusions, suppressor T cells, and renal transplant survival.

Fifteen men undergoing chronic hemodialysis were transfused with 2 units of packed red cells, none of these patients having been previously transfused. They were studied before and after transfusion to determine suppressor T cell numbers and activity, and to monitor the appearance of cytotoxic antibodies. Although the number of suppressor T cells did not change, their function was significantly increased three weeks after the transfusion. This had largely returned to normal by 20 weeks. No cytotoxic antibodies were produced. Twelve of the patients subsequently received cadaveric renal transplants and nine of these kidneys are currently functioning more than a year after transplantation. Although the blood transfusions may have helped to produce these satisfactory results, it is accepted that the nonspecific increase in suppressor cell function may not have been the only mediator because this activity had returned to normal in most cases by the time the patients were transplanted.

Medical research council trial of antilymphocyte globulin in renal transplantation. A multicenter randomized double-blind placebo controlled clinical investigation.

A total of 173 patients who received live donor or cadaveric primary or secondary renal transplants at five British hospitals were entered into a randomized double-blind controlled clinical trial of equine antilymphocyte globulin (ALG) administered prophylactically to prevent rejection. The ALG was prepared in the early 1970s and used cultured human lymphoblasts as antigen. Following transplantation all patients were treated with a standard immunosuppressant regimen of steroids and azathioprine and, in addition, were given either 30 mg/kg ALG or placebo daily for 10 days by intravenous infusion. In comparison with more recently produced materials, the ALG employed in this study was of moderate potency in prolonging skin graft survival in monkeys. Primary graft failure occurred in 27 patients (15/86 ALG and 12/87 placebo). At three to five years after transplantation 50 of the remaining patients had died, almost all from diseases relating to their renal condition, and 25 more had suffered complete graft failure. No significant differences were found between patients treated with ALG and placebo in the numbers with functioning grafts during the 3 years following transplantation, in the time between transplantation and the first rejection episode, or in the number of episodes during the first six months after transplantation. This applied whether live or cadaveric grafts were employed. Within the first 6 months of operation, infection was given as a major contributory cause of death in 12 patients treated with ALG and in 5 who received placebo (P greater than 0.1). Infections were also slightly more common during the two weeks following transplantation in those receiving ALG (13/86 ALG, 10/87 placebo). As expected, graft survival was significantly better in patients who received live donor grafts (P = 0.001) and in patients with the least donor-recipient histocompatibility mismatches (P = 0.008). The results of this multicenter trial show no therapeutic benefit to renal graft recipients from the administration of ALG, and suggest that the risks of fatal infection may have been aggravated. Use of such equine ALG in similar dose regimens is therefore, not, justified in renal transplantation, especially if some part of the apparent effects on fatal infections is real. It is stressed that these findings are relevant only to the equine ALG used in this study, which was raised with cultured human lymphoblasts as the antigen, and to ALG prepared in a similar way and of similar potency. It should not be inferred that these results are applicable to ALG prepared in other ways.

Monitoring of rejection in renal transplantation.

With better immunosuppression, the results of kidney transplantation have improved greatly during the last 10 years. It has never been possible to completely suppress rejection, and transplant physicians and surgeons still need to maintain a constant vigilance in order that rejection does not go unrecognised in their patients. 1.1. CLINICAL FEATURES. These are often absent, although the patient may have noted a decreased urine volume and gain in weight. The kidney is sometimes tender and enlarged. 1.2. BIOCHEMICAL FEATURES. There is a rise in the plasma urea and creatinine and a reduced creatinine clearance. Unfortunately, other conditions such as cyclosporin nephrotoxicity can produce similar changes. 1.3. RADIOLOGICAL FEATURES. Isotope renography may demonstrate reduced renal perfusion and excretion but this is also seen in ATN. Ultrasound may demonstrate an increase in renal size. On Duplex renal ultrasonography changes in renal perfusion patterns can often be demonstrated. MRI has shown a loss of cortico-medullary differentiation during rejection, but this is not very specific. 1.4. CYTOLOGICAL FEATURES. The presence of lymphocytes in the urine is often indicative of rejection, as is the finding of inflammatory cells in fine needle aspirates from the transplanted kidney. 1.5. HISTOLOGICAL FEATURES. Renal biopsies are best obtained using a Biopty Gun under ultrasound control. Cellular rejection is characterised by a heavy infiltrate of lymphocytes which invade the renal tubules (tubulitis). Vascular rejection is characterised by endothelial proliferation and fibrinoid necrosis of the vessel wall. 1.6. CONCLUSION. Several of the above tests are often required to establish the presence or absence of rejection.

Antilymphocyte globulin for the treatment of steroid non-responsive acute renal allograft rejection.

Antilymphocyte globulin (ALG) 30 mg/kg was administered daily i.v. for seven days to patients with renal transplants who were experiencing severe acute rejection which had failed to respond to large doses of i.v. methylprednisolone. Twenty-eight of the thirty-three patients had already recommenced hemodialysis when the treatment was started. Seventeen kidney transplants recovered and sixteen of these continue to function four to thirty months later. Such recovery was seen only twice in a comparable group of patients not given ALG.

Is graft irradiation of value in renal transplant rejection?

Thirty-six patients who received renal transplants and who subsequently underwent rejection episodes were randomized into two groups before undergoing treatment. One group received high doses of steroid drugs, and the other group received in addition 600 rads of radiotherapy to the graft. After 3 years (minimum follow-up 12 months) the groups were compared with respect to initial response to treatment, patient and graft survivals, and level of transplant function. No benefit was obtained by the group receiving radiotherapy.

Niridazole as an immunosuppressive agent.

The immunosuppressive properties of niridazole, an antihelminthic drug, have been investigated in rats. When given orally at a dosage of 50 mg/kg it extended the median survival of cardiac allografts from 7 to 20 days. The immunosuppressive effect was not increased by giving either azathioprine or prednisolone concurrently, but when all three drugs were combined the immunosuppression was profound, and only 2 of 8 grafts were rejected. Drug combinations incorporating niridazole at a lower dosage or for a shorter period were less effective, and azathioprine and prednisolone on their own or together prolonged graft survival only marginally in this model.

Autotransplantation for renovascular hypertension with complete renal artery occlusion.

We report a personal series of 13 autotransplantation procedures in 12 patients who suffered from severe renovascular hypertension. In all of these cases preoperative investigation demonstrated a viable kidney, despite complete occlusion of the affected renal artery. One-half the patients had stenosis of a milder degree affecting the contralateral kidney. In eight of these patients the operation was considered successful. One patient died due to postoperative superior mesenteric artery thrombosis and two had infarction of the transplanted kidney. A fourth patient lost the autotransplant because of postoperative haemorrhage. It is suggested that if medical treatment fails then autotransplantation should be considered in place of nephrectomy for cases of renovascular hypertension with complete occlusion of the renal artery.