Search

Preliminary crossmatching usually eliminates highly sensitized patients from consideration for renal transplantation. However, if the crossmatch is positive because of the presence of IgM antibody, this activity can be eliminated by treatment with the reducing agent Dithiothreitol (DTT). Successful transplantation may then be possible in patients whose crossmatch is positive due to the presence of IgM antibody. After treatment with DTT, the sera of 25 highly sensitized patients were measured for cytotoxicity against a selected panel of 40 cells. Those whose high %PRA could be attributed to blood transfusions or previous transplants did not change with DTT. Only two patients who had developed high panel reactivity, without a clear cause, had little reactivity remaining after DTT treatment of their sera. To select patients whose crossmatch might be rendered negative by DTT treatment, we developed a "minipanel" screening protocol. Patients whose monthly PRA cells increased greater than 30% from baseline had their serum samples treated with DTT to reduce IgM. The treated sera were tested against a panel of six cells. If there was little or no cytotoxicity, it was assumed that IgM antibody was responsible for the positive crossmatches. All subsequent cadaver donor crossmatches were done with and without DTT treated sera. Five patients (2 living-related; 3 cadaver) with current crossmatches positive before, but negative after, DTT treatment continue to have functioning kidneys 3-15 months after renal transplantation. There were no hyperacute rejections. We conclude that patients with IgM antibody can be successfully transplanted if they have a negative cross-match after reduction of IgM antibody in their serum samples. A "minipanel" helps to identify patients who will benefit from DTT treatment.

Recent reports cite better survival when repeatedly rejecting renal allografts are removed and patients returned to hemodialysis. However, the criteria for graft removal remain undefined; although some reports recommend removing all kidneys undergoing a third rejection. In our series (1968-1973) of 316 patients with technically successful first grafts followed 2(1/2)-8 years, graft survival was inversely related to the number of rejection episodes. One hundred per cent of kidneys without rejection are currently functioning or functioned at the time of death compared to 90% with one rejection, 67.4% with two and 21% with three. However, 40% of kidneys having three rejection episodes functioned longer than one year after treatment of the third rejection episode. In an attempt to determine the predictability of one year graft survival or failure following treatment of the third rejection, a formula was developed that correctly predicted in 33 of 38 (87%) patients. The formula was based on information available prior to treatment of the third rejection episode, and represents an index of baseline renal function (serum creatinine after second rejection episode) and two indices of the severity of rejection episodes (serum creatinine change between the first and second rejection episodes; rapidity of sequential rejection).Following its derivation, the formula was applied to a second group (1974) of 19 patients having had three rejection episodes. The formula correctly predicted one year allograft survival or failure following treatment of the third rejection episode in 68% of these patients. A striking finding of our review was a significant difference in current patient survival between those having no rejection episodes (89%) and those having one or more rejection episodes (65%) (p < .00001). There was no significantly greater long-term curtailment in survival if more than one rejection eipsode was treated. Patients having one rejection eipsode seemed to die from varying causes and at varying time periods. Patients dying after two or more rejection episodes had an increased incidence of deaths due to bacterial infection.

In order to alleviate the shortage of vital organs for transplant, we propose a system of routine removal of cadaver organs with an option of informed refusal by family. Unless an individual registered an objection during his or her lifetime, or unless the family objected to the procedure, clinicians would be permitted routinely to salvage vital organs for transplant. Our proposal charts a middle path between the current ineffective policy based on "encouraged voluntarism" and "presumed consent" policies that promise effectiveness at the cost of violating traditional ethical and legal principles. In this article, we analyze the failure of the current regime, articulate a policy of routine removal subject to the right of informed refusal, and defend this policy against several possible objections.

Malignant lymphoma developed in two patients after renal transplantation. In both, the central nervous system was involved. Histologic study of the tumors showed that they were composed of a monomorphous proliferation of cells characterized by a large vesicular nucleus, prominent basophilic nucleolus and strongly pyroninophilic cytoplasm. The tumors thus would be classified as "diffuse large lymphoid lymphomas with pyroninophilia" or "immunoblastic sarcomas" as described in the literature. Tumor cells resembled cells observed in the paracortex of antigenically stimulated lymph nodes, cells from malignant lymphomas in mice that were antigenically stimulated and from malignant lymphomas in patients with immunodeficiency diseases or autoimmune disorders. The distinctive morphologic features of the tumors in the transplant recipients described provide further evidence that long-term antigenic stimulation may be important in their pathogenesis.

Renal failure developed in 20 patients following blunt civilian trauma. Ten recovered normal renal function; 8 currently survive. Survivors and nonsurvivors did not differ in age, time from trauma to anuria, mean blood urea nitrogen or creatinine level prior to the first or to subsequent dialyses. However, there was an increased incidence of sepsis and liver failure in those who died. When outcome was related to site of injury, patients with closed head injury and/or intra-abdominal injury had a worse prognosis than those with thoracic or extremity injury only. Only 2 patients with perforated bowel survived; both had peritoneal dialysis combined with peritoneal lavage with antibiotic solutions. Mortality in patients with posttraumatic renal failure remains high; however, death is usually a result of associated complications rather than a result of the renal failure. Aggressive management of other complications of the trauma, especially sepsis or potential sepsis, is necessary. We recommend peritoneal dialysis combined with peritoneal antibiotic lavage where there is a potential for posttraumatic intra-abdominal sepsis associated with renal failure.

In patients with delayed graft function (DGF), the use of cyclosporine (CsA) has been reported to prolong DGF, increase the number of required dialyses, increase the duration of hospitalization, and be associated with decreased graft survival. Routine postoperative antilymphocyte globulin (ALG) use has been advocated, but ALG is associated with increased viral infection. We studied outcome of individualization of immunosuppression. Between 11/84 and 8/86, first-cadaver transplant recipients whose serum creatinine (Cr) fell greater than or equal to 30% in the first 24 hr (immediate function) were started on CsA and prednisone (P) (group 1, n = 26). The remainder were randomized to P and azathioprine (group 2, n = 32) or P and ALG (group 3, n = 26), and switched to CsA when serum Cr fell greater than 30% (minimum 5 days ALG for the ALG group). P taper was the same in all groups. Patients with DGF (groups 2 and 3) had longer preservation time and higher peak PRA (P less than .05) than group 1. Groups were otherwise equivalent. One and 2-year patient survival was 96% (3 cardiovascular deaths; all with functioning grafts). One-year graft survival was 87% for group 1, 87% for group 2, and 82% for group 3(NS). In patients requiring dialysis, mean day off dialysis was 12 +/- 3 in both groups 2 and 3. Mean hospital stay was 12.5 +/- 1.3 days for group 1, 21.6 +/- 2.1 days for group 2 (P less than .05 vs. 1 & 3), and 14.5 +/- 1.2 days for group 3 (NS vs. 1). The increased hospital stay for group 2 patients was mainly due to increased in-hospital rejections: 75% for group 2, (P less than .05 vs. group 1 [35%], and group 3 [11.5%]). In addition, more group 2 in-hospital 1st rejections were steroid resistant as compared to group 1; 46% group 1 patients have remained rejection free as compared to 0% group 2 (P less than .05 vs. 1 and 3) and 35% of group 3 (P less than .05 vs. 1 and 2). Mean serum creatinine at 6-12 months remained higher in patients with DGF (group 1 P less than .05 vs. 2 and 3). Rejection was the major cause of graft loss in all groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Following renal transplantation, immunosuppression is usually increased to treat presumed rejection episodes. However, a) many conditions mimic rejection in the post-transplant period, and b) many rejection episodes are irreversible. As increased immunosuppressive therapy is associated with an increased risk of infection, it would be ideal to limit antirejection therapy to only the rejection episodes that are reversible. The role of percutaneous allograft biopsy was studied as an aid to decide which patients to treat for rejection, to limit unnecessary immunosuppression and to predict allograft survival. One hundred thirty-five patients with suspected rejection underwent 206 allograft biopsies without complication. Two hundred four biopsies were available for study. Biopsies were coded on a 1-4 scale (minimal, mild, moderate, severe) for acute and chronic tubulointerstitial infiltrate and vascular rejection, as well as no rejection (e.g., recurrence of original disease). Treatment decisions were made on the basis of the biopsy combined with clinical data. All patients have been followed two years and outcome correlated with biopsy findings (death, nephrectomy, and return to dialysis defined as kidney loss). The results were the following: 1) biopsies represented changes within the kidney. Of 16 kidneys removed within one month of biopsy, no nephrectomy specimen showed less rejection than that seen on biopsy. 2) Eighty-one biopsies (39.7%) led to tapering or not increasing immunosuppression (either no rejection, minimal rejection, or irreversible changes). 3) Kidneys having either severe acute or chronic vascular rejection (less than 30% function at three months) had significantly (p less than 0.05) decreased survival three to 24 months postbiopsy than those with minimal or mild vascular rejection or tubulointerstitial infiltrate (83% function at three months). 4) Kidneys with moderate chronic vascular rejection and those with severe acute tubulointerstitial infiltrate had significantly (p less than 0.05) decreased survival at six to 24 months. 5) Kidneys with moderate chronic vascular rejection (MCV) without an acute infiltrate (ATI) had significantly better survival than those having both MCV and ATI. 6) Similarly, kidneys having severe ATI alone had better survival than those with ATI plus vascular rejection. It was concluded that a) percutaneous allograft biopsy can be done without graft loss or infection; b) biopsy represents changes throughout the kidney; c) biopsy aids in deciding when to treat for rejection and in deciding when to withhold increased immunosuppression, and d) allograft biopsy predicts the outcome of treatment of a rejection episode.

In all, 473 renal transplants were performed at the University of Minnesota in 386 children 1-17 years old between August 14, 1963 and December 31, 1988. Standard immunosuppressive protocols, pretransplant blood transfusions, and discontinuation of routine splenectomy have led to improving graft and patient survival rates. Children receiving living-related donor kidneys had better graft and patient survival rates, compared to cadaver kidneys. Graft and patient survival rates were better in children who received primary grafts, compared to retransplants. Children who received DST plus conventional immunosuppression had poorer graft survival, compared to quadruple immunosuppression during the same era. Recently, 1-year graft survival rates with quadruple immunosuppression are equal for children receiving primary, living-related donor or cadaver kidneys. Graft and patient survival rates in children 1-4 years old are identical to those in children 5-17 years old. Age no longer appears to be a risk factor for children undergoing kidney transplantation. Good patient and graft survival rates can be achieved at centers specializing in kidney transplantation for small children. Currently, transplantation is the treatment of choice for all children who are candidates for renal replacement therapy.

It has been suggested that areas with large inner-city Black and Latino populations have worse organ donation rates than those with large suburban and rural White populations. Yet data are sparse. We studied family refusal rates (FRRs) to cadaver organ donation between 1/84 and 5/87 in three United States city-areas (New York, Los Angeles, and Miami) with large Black and distinct Latino populations. Blacks are at least 18% and Latinos at least 25% of the combined general population of the three cities, totaling over three and four million people, respectively. In addition, Blacks and Latinos represent 42% of cadaver transplant recipients, 49% of patients on waiting lists, and 57% of the patients on dialysis in the three cities. Combining the data from the three cities, Black (45%) and Latino (43%) FRRs were similar (P = .78), and each was significantly higher than that in the White population (17%) (P less than 0.0001). The overall refusal rate in NYC (42%) was significantly higher (P less than .0001) than in LA (26%) or Miami (21%), and LA's refusal rate was significantly higher than Miami (P = .03). The refusal rates for the White (31%) and Black (55%) populations in NYC were each significantly higher than their respective populations in LA (14% and 33%) or Miami (11% and 36%) (P less than .05). Although Miami Latinos had a lower FRR (35%) than Latinos in NYC (46%) or LA (45%), the difference was not statistically significant (P = .19 and P = .20, respectively). In the three cities combined, 515 of a possible 1772 medically and legally eligible organ donors were lost during the 40 months studied due to families' refusal of consent. This represents approximately 1000 transplantable kidneys and large numbers of extrarenal organs. Further studies are needed to elucidate the reasons for differences in donation rate among groups and regions in the United States.

Mutant acatalasemic mice provide a prototype of congenital enzyme deficiency disease. Normal blood catalase levels were achieved permanently in congenitally acatalasemic mice by transplantation of bone marrow cells from congeneic normal catalasemic mice using relatively small numbers of cells following whole body irradiation. The increase in blood catalase activity was physiologically effective as demonstrated by the protection of the previously acatalasemic mice against the otherwise lethal effects of hydrogen peroxide injections. Bone marrow transplantation has the potential to provide a continuous source of some enzymes and may be applicable as treatment for certain congenital enzyme deficiency diseases.

Total or near total pancreatectomy is the surest way to relieve the pain of chronic pancreatitis but is rarely applied because the metabolic consequences are so severe. For most patients drainage procedures are applicable, but pancreatectomy may be the only alternative for small duct disease or where procedures to improve duct drainage have failed. Preservation of endocrine function is a major problem in patients who require pancreatectomy. Experiments in pancreatectomized dogs have shown that intrasplenic or intraportal transplantation of unpurified pancreatic islet tissue dispersed by collagenase digestion can prevent diabetes. We have applied this technique to ten patients with chronic pancreatitis, small ducts, and intractable pain. The entire pancreas of > 95% of the pancrease was excised, minced, dispersed by collagenase digestion and infused into the portal vein < 2 1/2 hours after removal. Mean (+/- SD) rise in portal pressure was 17 +/- 8 cm of water. Liver function tests were altered minimally. All patients were relieved of pain. One patient died of a complication not related to the islet autotransplant; viable islets were identified in the liver at autopsy. Of the remaining nine patients, three have been insulin independent for 1, 9, and 38 months. One patient was insulin indpendent for 15 months and now takes 12 units of insulin daily. Three have nonketosis prone diabetes (tested by insulin withdrawal) and take 15--30 units of insulin per day. C-peptide studies in these patients show that functioning islets are present. Two patients are diabetic and require 35 and 60 units of insulin per day. In eight of nine patients tested serum insulin concentrations fell to undetectable levels during the interval between pancreatectomy and islet transplantation. Serum insulin levels during the first few hours after islet transplantation predicted success. In the insulin independent or in the patients with mild diabetes, insulin levels were persistently greater than or equal to 6 microU/ml. In the other two patients, the increase in insulin concentration was not sustained. Islet tissue preparation from a diseased pancreas is difficult. The surgeon and the patient must still be willing to accept diabetes for relief of pain when performing this operation. In some patients, however, islet autotransplantation can prevent or partially ameliorate diabetes after pancreatectomy, and preservation of endocrine function is worthwhile.

Serum creatinine level is used as a major measure of post-transplant renal function at most centers. A significant elevation of creatinine level suggests allograft rejection. However, other factors affect renal function in the transplant recipient and each may cause an elevation in serum creatinine level, suggesting a rejection episode. It is important to make the correct diagnosis and not treat these episodes with anti-rejection therapy. We reviewed the course of patients transplanted between 1969 and 1974 to determine the pathogenesis of creatinine elevations retrospectively found to be due to causes other than rejection. Six distinct causes were found: hyperglycemia, ureteral obstruction, infection, lymphocele, arterial stenosis, and recurrence of the original disease. Each of these is discussed individually. In order to make the diagnosis of pseudorejection, a high index of suspicion is necessary.

We report a man who developed renal failure due to membranoproliferative glomerulonephritis (MPGN) type 1 which recurred in two cadaveric kidney transplants. This is the third such case in the literature. Nephrotic syndrome developed within 1 month following transplantation and histologic evidence of disease recurrence was documented in both kidneys 2 months after transplantation. Both grafts failed within 18 months. Factors which determine disease recurrence remain obscure.

Transplantation of adult rat pancreatic islet tissue as a free graft requires the separation of islet from exocrine tissue to avoid host injury or graft destruction by digestive enzymes. The poor yield from islet isolation techniques currently necessitates the use of multiple donors to ameliorate diabetes in a single recipient. DL-ethionine (DLE) is an agent selectively toxic to the exocrine pancreas. We examined the effect of DLE administration on pancreatic digestive enzyme content and islet mass in adult Lewis rats and the ability of such pancreatic tissue dispersed by collagenase digestion without specific islet isolation to ameliorate diabetes when transplanted to the portal vein of syngeneic rats with streptozotocin induced diabetes. Rats fed normal chow supplemented with 0.5% DLE for 14-20 days showed a logarithmic loss of pancreatic mass. Total pancreatic amylase content declined to 0.3 + 0.1 mg, less than 3% of control values (14.3 +/- 1.0 mg). Total insulin content in DLE treated rats was 87 +/- 8 microg, not significantly different from control rats (101 +/- 7 microg). Histological examination confirmed the selective atrophy of exocrine tissue in DLE treated rats. Fresh pancreatic tissue prepared from a single DLE treated donor ameliorated diabetes 75% of the time when transplanted to one or two recipients and 65% of the time when divided between three of four recipients. Tissue prepared from a single DLE treated donor and stored for 24-48 hours ameliorated diabetes 91% of the time when divided between one or two recipients. Only four of 31 diabetic rats transplanted with fresh pancreatic tissue from untreated adult donors became normoglycemic. Pretreatment of adult rats with DLE induces selective exocrine atrophy, permits dispersed pancreatic tissue from a single donor to ameliorate experimental diabetes in up to four recipients, and allows tissue to be preserved by culture for up to 48 hours without specific islet isolation.

In selected patients with localized infection of polytetrafluoroethylene graft arteriovenous fistulas, the access route can be preserved by treatment with antibiotics and surgical drainage. However, such treatment may result in exposure of the graft, which in itself is a threat to continued survival of the graft. This article describes a simple method that has been successfully used to achieve skin coverage of such grafts.

Antibody of the IgGab type can be isolated from horses immunized with cultured human lymphoblasts plus complete Freund's 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 immunosuppressive 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.

Cadaver kidneys remain a scarce resource, yet single pediatric donor kidneys are underutilized at some centers. Between 1967 and 1984, 133 single pediatric and 318 adult donor cadaver transplants were performed. Patient and graft survival, renal function, and complications in adult recipients grouped by donor age were compared. Recipient age for all groups was similar (34-36 years). Life table analysis revealed no difference in graft survival in recipients of kidneys from donors aged 2, 3, 4, 5-10, and 11-15 when compared with adult donors. Graft survival in these groups improved over time with current 1-year survival over 75%. Recipients from donors less than 24 months of age demonstrated significantly poorer results, with no kidney surviving greater than 2 months. Serum creatinine of grafts functioning greater than 6 months was similar in all groups. It is concluded that single pediatric kidneys from donors greater than 2 years of age can be successfully transplanted to adults with good long-term results.

Serum creatinine elevation in a stable transplant recipient most often suggests rejection of the transplant and requires further evaluation and management. In our series of juvenile diabetic patients who have received kidney transplants, we frequently have observed creatinine elevations in association with hyperglycemia. Correction of the hyperglycemia resulted in return of serum creatinine to normal levels and no rejection therapy was required. To better define this syndrome, 2,734 paired measurements of blood glucose and serum creatinine were obtained in 52 stable post-transplant diabetic patients. A mean increase in blood glucose of 100 mg. per 100 ml. was found to increase serum creatinine by 0.5 mg. per 100 ml. in these patients (r=0.93; p less than or equal to 0.001). Evidence strongly suggests that the pathogenesis of this phenomenon is not a result of a laboratory artifact due to the technique used to determine serum creatinine. The pathogenesis may be due to the increased serum osmolarity and resulting intracellular dehydration associated with hyperglycemia. Recognition of this syndrome is important to all centers participating in the care and management of the diabetic transplant recipient.

Pericardial drainage via percutaneous catheter placement and local nonabsorbable steroid instillation was employed as definitive therapy for uremic patients who had intractable pericardial effusions. Twelve patients are reported. Prior daily dialysis, and in one case systemic steroids, were not curative. 11 of 12 cases suffered severe tamponade requiring pericardiocentesis. One patient had an organized pericardial effusion, making pericardiocentesis impossible. He required pericardiectomy with prolonged hospitalization (2 weeks) due to postoperative complications. There were no complications in the 11 patients where catheter drainage and local steroid instillation were employed. No patient had recurrence of his pericardial effusion (followed from 2 weeks to 32 months). Instillation of a relatively nonabsorbable steroid through an indwelling pericardial catheter provides immediate and lasting relief without either the inconvenience or postoperative complications and prolonged hospitalization associated with the surgical procedure of pericardial fenestration. This report offers initial evidence that the percutaneous approach may be a safe and effective alternative to pericardial fenestration in most uremic patients with pericardial effusion.

Immunofluorescent studies have demonstrated that actomyosin (AMY) is present in the mesangium in a restrictive pattern, whereas fibroblast surface antigen (FSA) has a more extensive mesangial distribution. Antibody to glomerular basement membrane (GBM) is localized to the GBM. One hundred ninety-six tissue samples, including 17 from normal subjects, 94 from patients with primary renal diseases, and 85 from transplanted kidneys, were examined for changes in distribution of AMY, FSA, and GBM antigens. The distribution of AMY and FSA in the mesangium is markedly increased in width in patients with diabetic nephropathy, and the GBM is thickened. AMY and FSA are mildly increased in patients with glomerulonephritis and GBM is normal. Patients with membranoproliferative glomerulonephritis (MPGN) show a loss of all glomerular antigens. Increased mesangial AMY was found in 12 of 37 transplanted kidneys in diabetic patients vs 4 of 33 nondiabetics 0 to 4 years after transplantation (P < 0.025). This difference is more notable at 2 to 4 years, with 5 of 9 diabetics showing increased AMY vs 0 of 6 nondiabetic patients (P < 0.0005). In MPGN, 5 of 8 tissues showed decreased mesangial AMY vs 3 of 36 diabetic patients (P < 0.0005) and 1 of 32 patients with other glomerulopathies (P < 0.0005). GBM thickening is not associated with specific pretransplant diseases. In transplanted kidneys, the pattern of FSA is dissociated from that of AMY: over half of all patients have increased FSA, even when AMY is normal. Whether this unique finding in transplanted kidneys reflects an increase in the synthesis of FSA by mesangial cells or the failure to clear this (circulating) antigen from the mesangial matrix is unknown.