Simmons Rl

INCREASED INCIDENCE OF MALIGNANCY DURING CHRONIC RENAL FAILURE

The incidence of cancer in 646 dialysis/transplant patients before uraemia developed, during the period of progressive uraemia, and post-transplantation was compared. 10 tumours (3 breast, 2 kidney, 1 leukaemia, 1 lung, 1 insulinoma, 1 thyroid, 1 cervix in situ) developed in 9 patients during the period of progressive uraemia, a significant increase over the expected number in the age-matched general population. 6 of these patients have received transplants and have no evidence of recurrent disease 6 months to 4 years post-transplantation. 11 de-novo tumours have developed in 530 transplant recipients (4 cervix in situ, 2 skin, 2 reticulum-cell sarcoma, 1 lip, 1 dysgerminoma, 1 colon)--a significant increase over the age-matched general population. The cancers in the uraemic patients are relatively common types of mesenchymal tumours while the cancers in the transplant recipients are epithelial and lymphoproliferative. This difference may reflect the presence of the graft in the transplant patient or may be due to different patterns of immunosuppression in these two populations.

Recurrence of idiopathic nephrotic syndrome after renal transplantation.

Abstract Three patients with steroid-resistant idiopathic nephrotic syndrome were studied at onset and during recurrent nephrotic syndrome after renal transplantation. Renal biopsies at the onset of the nephrotic syndrome showed typical features of the idiopathic nephrotic syndrome; no or minimal focal glomerular abnormalities were present by light microscopy and glomerular-basement-oriented deposits were not demonstrated by immunofluorescent or electron microscopy. Progression to renal failure occurred in 2, 2, and 6 years. Recurrence of nephrotic syndrome was noted 1, 11/2, and 5 months after transplantation. Renal biopsies done 11/2, 5, and 7 months after transplantation when proteinuria was 12·8, 7·6, and 8·5 g. per 24 hours, respectively, showed minimal or no glomerular abnormalities by light microscopy. Immunofluorescent and electron microscopic studies revealed no evidence suggesting immunological injury. Subsequent kidney specimens after transplantation obtained from two of these patients with recurrent nephrotic syndrome showed focal segmental glomerulosclerosis limited primarily to the juxtamedullary glomeruli—a feature further suggesting recurrence of the original disease in the transplanted kidney. These observations suggest that the pathogenesis of the steroid-resistant idiopathic nephrotic syndrome may involve systemic circulating factors; this hypothesis would account for development of a recurrent nephrotic syndrome in the transplanted kidney.

The impact of cyclosporine and combination immunosuppression on the incidence of posttransplant diabetes in renal allograft recipients

The incidence of posttransplant diabetes mellitus (PTDM) was compared in three groups of renal transplant recipients: nondiabetic patients who had been randomized between 1980 and 1983 to receive antilymphoblast globulin (ALG), azathioprine (AZA), and prednisone (P) (group 1) or cyclosporine (CsA) plus prednisone (group 2). Group 3 consisted of a more recent (1984-85) cohort who were given a combination of azathioprine, cyclosporine, and prednisone (+/- ALG). PTDM developed in 20 of 173 previously nondiabetic 18-55-year-old patients. Three of 47 patients (6.4%) in group 1, 4 of 58 patients (6.9%) in group 2, and 13 of 68 patients in group 3 (19.1%) developed PTDM. Thus in the two groups composing the concurrent prospective randomized trial (groups 1 and 2) the incidence of PTDM did not differ. The subsequent patients who were given a combination of ALG, azathioprine, cyclosporine, and prednisone developed a significantly greater incidence of PTDM even though the total dose of cyclosporine and prednisone were lower than in groups 1 and 2. PTDM usually occurred within two months of transplantation, and 11 of 17 patients who initially required insulin are still dependent upon exogenous insulin. The incidence of PTDM was not significantly affected by sex of the recipient, HLA-type, primary renal disease, rejection episodes, primary vs. secondary transplant, or prior splenectomy. The incidence of PTDM is greater in patients older than 45 (34.2% vs. 5.2%), and heavier than 70 kg (21.1% vs. 5.1%); in recipients of cadaveric allografts (15.7% vs. 4.6%); and in patients who were hospitalized for infections (22.4% vs. 4.7%). CsA levels tended to be higher in the group 2 and 3 patients who developed PTDM than in those who remained nondiabetic. One-year actuarial patient survival in those with PTDM was 83.3% vs. 98% (P less than .01) in the nondiabetic and graft survival was 77.1% vs. 87.1% (NS). The combination of Minnesota ALG, azathioprine, cyclosporine, and prednisone appears to predispose older, heavier recipients of cadaver allografts to the development of PTDM. The risk of PTDM must be weighed against the more usual results of improved patient and graft survival using this combination of immunosuppression.

A single institution, randomized, prospective trial of cyclosporin versus azathioprine-antilymphocyte globulin for immunosuppression in renal allograft recipients.

Between September 26, 1980 and December 31, 1983, 230 splenectomized, transfused renal allograft recipients were randomized to treatment with either cyclosporin-prednisone (N = 121, 68 diabetic and 53 nondiabetic recipients; 73 cadaver and 48 related donor grafts) or azathioprine-prednisone-antilymphocyte globulin (N = 109, 61 diabetic and 48 nondiabetic recipients; 69 cadaver and 40 related donor grafts). The results were analyzed on March 31, 1984. Actuarial patient survival rates at 2 years were 88% in the cyclosporin and 91% in the azathioprine groups (p = 0.649). Graft survival rates at 2 years were 82% in all cyclosporin and 77% in all azathioprine-treated recipients (p = 0.150); the corresponding figures in the recipients of related donor grafts were 87% vs. 83% (p = 0.656), and in the recipients of cadaver donor grafts were 78% vs. 73% (p = 0.178). The 2-year graft survival rates were 81% in cyclosporin and 74% in azathioprine-treated diabetic recipients (p = 0.150) and 83% in cyclosporin and 81% in azathioprine-treated nondiabetic recipients (p = 0.604). Within the cyclosporin and azathioprine treatment groups, the differences in graft survival rates between diabetic and nondiabetic recipients were not significant (p = 0.822 and 0.423, respectively). Although there were no significant differences in graft survival rates, the cumulative incidence of rejection episodes within the first post-transplant year was significantly lower in the cyclosporin (34%) than in the azathioprine (60%) treated recipients (p = 0.001). In recipients of technically successful cadaver kidney grafts, the incidence of acute tubular necrosis (ATN) was 31% in cyclosporin and 30% in azathioprine-treated recipients (p = 0.822). Graft survival rates in azathioprine- and cyclosporin-treated recipients who did or did not undergo ATN were 72% vs. 89% (p = 0.011). The mean (+/- S.D.) serum creatinine levels (mg/dl) at 1 year were higher in cyclosporin (2.0 +/- 0.6) than in azathioprine (1.5 +/- 0.5) treated recipients (p = less than 0.001). A reduction in cyclosporin dose because of nephrotoxicity was required in 96 of the cyclosporin-treated patients (70%), and 25 were switched to treatment with azathioprine (21%). The incidence of all infections in cyclosporin-treated patients was approximately half of that in azathioprine-treated patients, and only nine per cent of the cyclosporin-treated patients were diagnosed to have cytomegalovirus infections during the first post-transplant year vs. 28% in azathioprine-treated patients (p = 0.002).(ABSTRACT TRUNCATED AT 400 WORDS)

Ten Year Experience With Renal Transplantation in Juvenile Onset Diabetics

Between 1968 and 1978, 305 juvenile onset diabetic patients with uremia and 462 nondiabetic uremic patients of similar age received primary renal allografts at the University of Minnesota. Two hundred eight of the diabetic patients are alive and 190 have functioning renal grafts three months to ten years after transplantation. Cumulative patient survival rates at two years for diabetic recipients of kidneys from HLA identical siblings, other related and cadaver donors are 90, 73 and 68%, respectively; the corresponding graft functional survival rates are 90, 67 and 55%. For nondiabetic patients receiving kidneys from the same donor categories the corresponding patient survival rates are 97, 86 and 75%, while the graft functional survival rates are 94, 77 and 64%. The differences in patient and graft survival between diabetic and nondiabetic recipients are statistically significant only for the patients receiving grafts from HLA-nonidentical related donors. For all recipients under the age of 30, there are no statistically significant differences in patient and graft survival. Regardless of the age of the patient or the source of the kidney, the survival of diabetic patients treated with transplantation at our institution is better than the use of chronic hemodialysis, alone. Technical complications do not occur more frequently in diabetic transplant recipients. Cardiovascular disease is responsible for most of the late deaths in these diabetic patients. Amputations of digits or extremities have been required in 15% of the diabetic patients. On the positive side, the vision of 88% of these recipients remained stable or had improved visual acuity, and 82% of the diabetic patients were actively rehabilitated after transplantation. Kidney transplantation is the treatment of choice for end-stage renal failure in diabetic patients, just as it is for most uremic patients.

Seven years' experience with antilymphoblast globulin for renal transplantation from cadaver donors.

Antibody of the IgGab type can be isolated from horses immunized with cultured human lymphoblasts plus complete Freunds adjuvant. The essential steps for the production of a safe, potent anti-human lymphoblast globulin (ALG) are: A) the use of early bleedings after immunization to reduce the titer of antibodies which react with red blood cells and platelets; B) careful absorption with human red blood cell stroma and platelets; C) stabilization with non-crystalline silica dioxide; D) chromatography through QAE sephadex to remove pyrogens, microaggregates and possible inhibitors of ALG activity; E) careful safety testing in animals for toxicity and pyrogenicity; and F) testing in vitro for sterility. Such a purified horse ALG (IgGab) can be administered safely intravenously to patients to supplement a standardized immnnosuppressive regimen incorporating azathioprine and prednisone. Under these circumstances, allergic reactions are very rare, antibodies to horse IgG do not develop, skin tests to horse IgG remain negative, and immune elimination of circulating horse IgG from the human circulation cannot be demonstrated. The overall results of ALG patient survival and transplant function after 184 consecutive first cadaver transplants at the University of Minnesota demonstrate a statistically significant improvement in both parameters accompanying increases in ALG dose while rigidly utilizing standardized doses of azathioprine and prednisone. There is a significant reduction in the number of grafts lost to rejection; significant reduction in the number of rejection episodes; significant delay in the onset of rejection episodes; but there is no increase in septic loss of patients or kidneys. These efforts could be seen in the gross data or when subgroups controlling for patient age, tissue typing were analyzed. Excluding patients at high risk did not alter the results. The beneficial effects of ALG were particularly striking in good matches. In the highest doses, ALG may be dangerous for older patients with poor matches who develop an increased incidence of septic loss of kidney and/or life. Thus, ALG appears to be a useful adjunct in the early management of cadaver transplants by reducing the incidence and frequency of rejection episodes. The dose should probably be reduced in the older patients who receive kidneys from badly mismatched donors. One cannot conclude from this study that ALG manufactured in other centers by this or other techniques, will accomplish the same results since the multiplicity of factors involved in the success and failure of transplants must be controlled so that the influence of intravening variables in the assessment of ALG effectiveness can be assessed.

Single-center 1-15-year results of renal transplantation in patients with systemic lupus erythematosus.

Initially, poor long-term prognosis in patients with SLE and fear of recurrent disease dissuaded renal transplantation in this group of patients. However, in 1975 the Advisory Committee to the Renal Transplant Registry reported satisfactory 1-2-year results in 56 patients with SLE from 36 institutions. Subsequently, renal transplantation for SLE patients with end-stage renal disease has become more accepted, though it has been recommended that transplantation be postponed for at least one year after initiating dialysis. Five cases of recurrent lupus nephritis have been reported in the literature. However, since the long-term outcome after transplantation in this group of patients is not well established, we have examined the long-term outcome in SLE patients who underwent renal transplantation at the University of Minnesota. Thirty-two SLE patients receiving 33 transplants between December 1969 and December 1987 were studied retrospectively and compared with controls matched for age, sex, donor source, HLA match, date of transplant, and diabetic status. A total of 69% (22/32) of patients underwent less than 1 year of dialysis prior to transplantation, and 50% (16/32) experienced biopsy-proved acute rejection, which was reversible in 67% (11/16). Actuarial graft function and patient survival rate in SLE patients were not significantly different from those in the matched control group. Duration of prior dialysis did not affect outcome. Surviving grafts have excellent function as measured by serum creatinine (1.3 +/- 0.4 mg/dl, means +/- SD). Causes of death were sepsis (5) and myocardial infarction (1). One patient lost the graft from rejection after withdrawal of immunosuppression because of a malignancy one month posttransplant. Three patients lost graft function due to chronic rejection. To date no patients have had evidence of recurrent SLE nephritis.

Chronic antigenic stimulation, herpesvirus infection, and cancer in transplant recipients.

An increased incidence of malignancy has been reported in transplant recipients. The pathogenesis of this increase was originally attributed to immunosuppressive therapy. However, not all tumours are increased in proportion to their occurrence in the general population-75% of reported tumours are lymphorproliferative or carcinoma of the skin, lip, or cervix. This cannot be explained by impaired immunosurveillance, and alternative hypotheses must be considered. 90% of transplant recipients develop clinical or serological evidence of herpesvirus infection. Herpesviruses have been implicated in the pathogenesis of lymphorproliferative tumours and carcinoma of the skin and cervix. They can remain in latent form and be reactivated by allogeneic stimulation and/or immunosuppression. These viruses localise to skin, cervix, and neural tissue-i.e., exactly those sites where cancer develops in transplant patients. Herpesvirus infections in association with the presence of an allogeneic graft in an immunosuppressed patient may be responsible for the increased incidence of both lymphoproliferative tumours and carcinoma of the skin, lip, and cervix in the transplant recipient.

Intra-abdominal infections in pancreas transplant recipients.

During a 7-year period, 116 pancreas transplants were performed in 98 diabetic patients (49 with and 49 without previous kidney transplants) at the University of Minnesota. The posttransplant clinical course of 26 recipients (22%) was complicated by an intra-abdominal infection (8 with and 18 without previous kidney transplants). Infections occurred in 19/57 cases (33%) in which exocrine secretions were managed by enteric drainage, in 5/15 cases (33%) managed by free drainage into the peritoneal cavity, in 1/39 cases (3%) in which the duct was injected with a synthetic polymer, and in 1/2 cases (50%) in which a pancreaticocystostomy was performed. The organisms Escherichia coli, enterococci, bacteroides, and several anaerobes were cultured from the patients with enteric drainage, while staphylococci were associated with the open duct drainage. Fungal infections with Candida were found with all techniques. Surgical and percutaneous drainage was performed in all patients. In 14 patients, functioning and, in four patients, nonfunctioning grafts were removed. In five patients, the infection resolved while the grafts were functioning, and these patients are currently alive and well. Seven of the 26 patients with infections died (27% mortality rate), five after graft removal and two with the graft still in place (1 with and 1 without function), five in the open-duct, and one each in the enteric and urinary drainage categories. In the 90 cases without intra-abdominal infection, only six patients died (4 cardiovascular, 1 anaphylaxis, 1 cytomegalovirus infection), for a mortality rate of 7%.

Immunopathology of renal extracellular membranes in kidneys transplanted into patients with diabetes mellitus.

Kidneys of patients with severe diabetic nephropathy demonstrate marked linear immunofluorescent staining of extracellular membranes, including the tubular and glomerular basement membranes (TBM and GBM) and Bowmans capsule. Immunofluorescent studies were carried out on kidney tissue obtained from 12 diabetic and 17 nondiabetic patients from two to 12 years following renal transplantation. The frequency and intensity of IgG and albumin staining of these membranes were significantly greater in the diabetic than in the nondiabetic patients (P <0.0005). TBM, GBM, and Bowmans capsule staining did not occur in any of the seven kidneys studied at the time of their transplantation into diabetic recipients. Thus, the abnormalities leading to the deposition or trapping of proteins in renal extracellular membranes occur early after the placement of normal kidneys into the abnormal metabolic environment of the diabetic transplant recipient. The present study supports the concept that basement membrane alterations in diabetes are a consequence of the biochemical perturbations of diabetes rather than a separately inherited genetically linked disorder.