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Previous studies in vitro and in rodent transplantation models have suggested that an analogue of cyclosporin, SDZ-IMM-125, has immunosuppressive properties at least equivalent to that of cyclosporin. As the bioavailability of the drug was considered to be greater than that of cyclosporin, it was hoped that lower doses could be used with the avoidance of nephrotoxicity. Renal allografts were undertaken between beagle dogs from two partially inbred breeding colonies. After transplantation, SDZ-IMM-125 was given orally at a dosage of 5, 7.5, 10 or 20 mg/kg/day, and graft survival compared to that in dogs given cyclosporin 10 mg/kg or in untreated animals. The results showed that SDZ-IMM-125 is immunosuppressive in dogs and prolongs graft survival up to 50 days at a dosage of 20 mg/kg/day. However, at this dose histological changes suggestive of liver toxicity were observed in one dog, and mild anaemia was produced,but there was no evidence of nephrotoxicity. Absorption profiles suggested that the drug is rapidly absorbed and metabolized, and that a more frequent daily dosage may be appropriate. Overall, there appeared to be no significant advantage for the analogue SDZ-IMM-125 over cyclosporin. The transplant model was associated with a high spontaneous renovascular thrombosis rate, particularly after cyclosporin administration, which was prevented by the daily administration of aspirin.

A group of renal pathologists, nephrologists, and transplant surgeons met in Banff, Canada on August 2-4, 1991 to develop a schema for international standardization of nomenclature and criteria for the histologic diagnosis of renal allograft rejection. Development continued after the meeting and the schema was validated by the circulation of sets of slides for scoring by participant pathologists. In this schema intimal arteritis and tubulitis are the principal lesions indicative of acute rejection. Glomerular, interstitial, tubular, and vascular lesions of acute rejection and "chronic rejection" are defined and scored 0 to 3+, to produce an acute and/or chronic numerical coding for each biopsy. Arteriolar hyalinosis (an indication of cyclosporine toxicity) is also scored. Principal diagnostic categories, which can be used with or without the quantitative coding, are: (1) normal, (2) hyperacute rejection, (3) borderline changes, (4) acute rejection (grade I to III), (5) chronic allograft nephropathy ("chronic rejection") (grade I to III), and (6) other. The goal is to devise a schema in which a given biopsy grading would imply a prognosis for a therapeutic response or long-term function. While the clinical implications must be proven through further studies, the development of a standardized schema is a critical first step. This standardized classification should promote international uniformity in reporting of renal allograft pathology, facilitate the performance of multicenter trials of new therapies in renal transplantation, and ultimately lead to improvement in the management and care of renal transplant recipients.

Spontaneous renal allograft rupture occurring within 14 days of transplantation occurred in 15 patients from 791 consecutive transplants. In each of eight patients treated with azathioprine and prednisolone there was pathological evidence of rejection and only two patients had thrombosis of the renal vein. Of the seven cases occurring in patients treated with triple therapy regimen (low dose cyclosporin, prednisolone and azathioprine), histological evidence of rejection was present in only three cases, but renal vein thrombosis was found in all seven. Spontaneous rupture of a transplanted kidney, a relatively uncommon complication, is more likely to be due to renal vein thrombosis than to rejection in the cyclosporin era.

Renal biopsies were taken from 42 patients at seven and 21 days after renal transplantation. Paraffin sections from these specimens were examined immunocytochemically for the presence of platelet microthrombi in glomerular capillaries using the monoclonal antibody Y2/51. Patients were treated by one of four different immunosuppressive regimes, three of which included cyclosporin A, either alone or in combination with steroids and azathioprine. Microthrombi were detected in approximately 30% of biopsies and were much commoner in patients receiving multi-drug therapy. We conclude that, contrary to previous suggestions, glomerular capillary thromboses are not frequent in patients on cyclosporin A alone. They are found mainly in patients on multiple drug therapy, particularly when steroids are included. The detection of microthrombi is unlikely to be of assistance in the earlier detection of cyclosporin toxicity.

The histology of renal allografts was compared in a series of 107 biopsies from patients receiving cyclosporin and 126 biopsies from patients receiving azathioprine and prednisolone. Patients receiving cyclosporin were converted to azathioprine and prednisolone 90 days after transplantation. Biopsies were taken routinely at 7, 21, 90, and 365 days, irrespective of clinical graft function and were examined "blind" by two independent observers. Interstitial haemorrhage was more common in patients treated with azathioprine and prednisolone corresponding with their poorer graft survival. Analysis of glomerular, tubular, vascular, and interstitial changes showed no other important differences between the two groups despite clinical evidence of reversible cyclosporin nephrotoxicity. Quantitation of interstitial fibrosis in 90 day biopsies showed it to be equal in prevalence after treatment with azathioprine and prednisolone and cyclosporin. It was preceded by diffuse interstitial cellular infiltration, a common finding in early biopsies. Diffuse cellular infiltrates were generally associated with higher serum creatinine concentrations and, if persistent, a poorer graft prognosis than focal infiltrates, but they were not always associated with renal dysfunction.

Thirty-five patients given an HLA-DR-incompatible cadaver kidney that was diuresing immediately after transplantation were randomly allocated to treatment with cyclosporine alone for 3 months followed by conversion to azathioprine and prednisolone (AP), or to conventional treatment with AP. Although many patients had to be converted to AP before 90 days because of rejection requiring more than two treatment courses of high-dose i.v. methylprednisolone, 16 of 21 grafts were functioning at 3 months, and 12 of 14 grafts in the control group were functioning. However 3 further grafts were lost from chronic rejection in the control group, and none were lost from chronic rejection in the cyclosporine group. All but one patient on cyclosporine had depressed renal function, and in all these patients function improved on conversion to AP. This depression of renal function is attributed both to cyclosporine nephrotoxicity and to a low-grade rejection reaction, the latter suggesting that the addition of steroids to cyclosporine might be beneficial in some patients. The strategy of a three-month course of cyclosporine followed by conversion to AP provides satisfactory immunosuppression, and it may be of value if long-term side effects of cyclosporine emerge with further experience.

A renal transplant involving a recipient with a positive serological cross-match against donor lymphocytes generally results in hyperacute rejection of the graft. 13 cadaveric renal transplants were performed in recipients with a known positive serologic cross-match against donor B lymphocytes. 12 of these serological cross-matches were positive against donor blood, node, or spleen lymphocytes, but the reactivity was directed against donor B lymphocytes only. 3 transplants failed, 2 because of rejection and 1 because of renal-artery thrombosis. 10 transplants are functioning, 6 to 42 weeks after the operation. Of these 10 successful grafts, 3 had no acute rejection episodes, while 7 had an early acute rejection episode which responded to treatment. Histologically, the grafts showed a cellular rejection, similar to that in enhanced renal allografts in the rat. It is possible to transplant a kidney in a high-risk patient with a positive B lymphocyte cross-match with a low risk of failure. In addition active enhancement of the graft might sometimes occur.

Hypertension is a common complication after renal transplantation and is associated with increased mortality. Cyclosporine is known to be nephrotoxic and raises blood pressure in recipients of cardiac and bone marrow transplants, but there is conflicting data on the role of cyclosporine after renal transplantation. We have examined this question in patients entered into the second Oxford prospective randomized comparison of short-term cyclosporine treatment alone with conversion to azathioprine and prednisolone at 90 days (CsA group), and conventional therapy with azathioprine and prednisolone throughout (AP group). Blood pressure and antihypertensive medication were similar in the CsA and AP treatment groups during the first 90 days. Following conversion from cyclosporine, mean blood pressure fell from 155/94 to 142/81 within 7 days, and this fall correlated with the change in plasma creatinine over the same period (r = 0.44, P less than 0.05). Blood pressure was subsequently lower in the converted patients than in those treated with AP throughout. Six months after transplantation patients converted from cyclosporine not only had lower blood pressure but also required fewer antihypertensive drugs than AP patients. This study demonstrates that cyclosporine may elevate the blood pressure in recipients of renal transplants. This effect may either be direct or mediated through the effect of cyclosporine on renal function. Administration of corticosteroids during the first three months after transplantation is implicated as a possible cause of persisting high blood pressure.