Combined kidney and pancreas transplantation. A 3-year experience.

Between May 1988 and September 1991, we performed 26 simultaneous kidney and pancreas transplants and one pancreas transplant after a kidney transplant. All transplants consisted of bladder drainage via a duodenal segment. Actuarial patient, kidney, and pancreas graft survival rates at 12 months were 96%, 88%, and 85%, respectively, and at 24 months were 96%, 88%, and 81%, respectively, and were not significantly different from those of diabetic recipients of cadaver kidney transplants alone. Excellent long-term glycemic control was obtained as monitored by fasting blood glucose and glycosylated hemoglobin levels and by oral glucose tolerance tests. The mean period of hospitalization and number of hospital admissions in the first year posttransplant were significantly greater for patients who received combined kidney and pancreas transplants than for those who received cadaver kidney transplants alone. Combined kidney and pancreas transplants can be performed with patient and graft survival comparable to those of kidney transplants alone, with excellent long-term glycemic control, but result in increased morbidity in the first postoperative year.

Use of Dacron cuffed silicone catheters as long-term hemodialysis access.

Sixty-five Dacron cuffed, dual lumen, silicone central venous dialysis catheters (Quinton PermCath, Seattle, WA) were inserted in 51 patients as the sole form of permanent access for chronic hemodialysis. Six and 12 month actuarial survival rates of patients for all catheters were 53% and 35%, respectively. When calculations included revisions, 6 and 12 month actuarial catheter survival rates were 61% and 43%, respectively. The major limiting factors in survival using long-term catheters remain infection and thrombosis. Dacron cuffed, dual lumen, central venous, dialysis catheters can provide long-term vascular access for hemodialysis in high risk patients.

Increased infection rate in diabetic dialysis patients exposed to cocaine.

Three hundred ninety-seven insulin-dependent diabetic dialysis patients were screened by nursing staff for analgesic-seeking behavior. Thirty-eight patients were identified and classified as prescription abusers (n = 26) or illicit drug users (n = 12). The nine cocaine users, when compared with 14 insulin-dependent diabetics on dialysis matched by protocol, were found to be similar in terms of diabetic retinopathy and metabolic neuropathy. Although statistically not significant, cerebrovascular and cardiovascular complications were more common in the study group. Gastroenteropathy with malnutrition was more common the study group (P less than 0.025). Infection rate and severity were markedly worse in the cocaine group: bacterial cellulitis, sepsis, and abscess each increased greater than fourfold. All the visceral infections were in the cocaine-using group. Hepatitis viral antigen and antibody was increased 10-fold in the cocaine users. Recommendations for management of dialysis patients with analgesic-seeking behavior are formulated in light of these findings.

Immunoradiometric assay for antibodies recognizing antigenic gangliosides.

An immunoradiometric assay for monoclonal antibodies (MoAb) recognizing gangliosides as antigens (Ag) is described and exemplified by the determination of the immunoreactive fraction of 125I-radiolabeled monoclonal A2B5 and 3G5 IgM antibodies. The assay was performed in 96-well microtiter plates equipped with cellulose filter membranes, using the antigens extracted from cloned rat insulinoma cells (RINm5F). The selectivity of the assay was demonstrated by studying the interactions of A2B5 and 3G5 with specific Ag and irrelevant gangliosides. The binding of 125I-A2B5 and 125I-3G5 to the RINm5F extract containing Ag exceeded 35% of the total applied radioactivity and depended on the degree of protein damage caused by radiolabeling, whereas irrelevant glycolipids bound 0.4% (s.d. 0.3%) of total applied 125I-3G5 and 1.2% (s.d. 0.3%) of 125I-A2B5 regardless of the initial amount of the radiolabeled MoAb used. Additional support for the specificity of this method was acquired in experiments with the A1D2 IgG antibody that interacts with a glycoprotein expressed by RINm5F cells but not with the gangliosidic antigens present in the same cell line. 125I-A1D2 bound neither Ag (0.47%; s.d. 0.12%) nor brain extracts containing irrelevant gangliosides (0.32%; s.d. 0.17%). The data for the specific MoAb-Ag systems were analyzed using a modified Lineweaver-Burk graph. By plotting the reciprocal of the fraction of specifically bound MoAb versus the reciprocal of the antigen concentration, the immunoreactive fraction was determined. The present method is rapid, convenient, and independent of variability in antigen expression on the cell surface.

Monoclonal antibody internalization by tumor cells: an experimental model for potential radioimmunotherapy applications.

The monoclonal IgM 3G5, which reacts with the surface membranes of rat insulinoma cells RINm5F, was purified by HPLC and labeled with 125I using Protag-125; bovine IgG (bIgG) was similarly radiolabeled, and used as a control. 125I-3G5 was incubated with RINm5F cells either at 4 degrees C or at 37 degrees C. 125I-3G5 bound onto RINm5F cells growing in Petri dishes remained approx. constant over 44 h when incubated at 4 degrees C, whereas at 37 degrees C radioactivity was released back in the medium starting at 3 h (plateau at approx. 20 h). At the end of incubation at 37 degrees C, activity in the medium included a high percentage of free 125I (15.69 vs 2.62% for bIgG, and 1% for 3G5 at 4 degrees C). In a cell suspension experiment, cell-bound 125I-3G5 also remained constant over a 24 h incubation at 4 degrees C, whereas at 37 degrees C it decreased to 37.5% of its initial value (64.1% at 4 h). Concomitant microautoradiography showed diffuse radioactive deposits within the RINm5F cells following incubation with 125I-3G5 (but not 125I-bIgG) at 37 degrees C. These results indicate that 3G5-IgM reacts with a surface antigen on the RINm5F cells, but is rapidly internalized by the cells: within the cells, this antibody undergoes some metabolic processing which results in the release of free 125I outside the cells.

Application of the ambulatory 24-hour electrocardiogram in the prediction of cardiac death in dialysis patients.

The value of a 24-hour ambulatory electrocardiogram (AmECG) in assessing the risk of cardiac death was studied in 122 stable-condition dialysis patients followed up from two to six years after monitoring. An abnormal AmECG was defined by second-degree or greater AV block or by Lown grade 3 or greater ventricular ectopy. The incidence of cardiac mortality or an abnormal AmECG was not influenced by hypokalemia or beta-blockers. Digitalis was associated with both an abnormal AmECG and a twofold increase in mortality whether or not the AmECG was normal. Cardiac mortality accounted for 26 of 33 deaths within the first year after the AmECG. In the absence of coronary artery disease, survival at six months was 100% in patients with normal AmECG vs 90% (abnormal AmECG). In the presence of coronary artery disease, survival at six months was 83% (normal AmECG) vs 54% (abnormal AmECG).

Effect on platelet function of hypoalbuminemia in peritoneal dialysis.

Chronic renal failure is associated with functional platelet defects. Peritoneal dialysis is associated with improvement in platelet function. This study demonstrates that the hypoalbuminemia resulting from peritoneal dialysis may account for part of the improvement. Platelet aggregation was measured when plasma albumin was less than 3 g/dl and again when the albumin level was raised to greater than 4 g/dl. Normal albumin levels were associated with decreased platelet function when the slope of aggregation to ADP and epinephrine were used as the study parameters. Patients with peritoneal dialysis given albumin to correct their plasma albumin level also acquired reduced platelet aggregation.

Acquired defect in interleukin-2 production in patients with type I diabetes mellitus.

Deficient production of interleukin-2 has been reported in Type I diabetes, but its cause has not been elucidated. We therefore measured interleukin-2 production in 27 patients with Type I diabetes, 20 patients with Type II diabetes (6 requiring insulin), 5 monozygotic twin pairs discordant for Type I diabetes, and 10 nondiabetic persons with islet-cell antibodies. Interleukin-2 production was decreased in patients with Type I diabetes as compared with controls (35.8 +/- 2.5 vs. 61.6 +/- 4.6 percent, P less than 0.001). Interleukin-2 production did not differ between patients with Type II diabetes and controls, regardless of whether the patients used insulin. Twins with Type I diabetes had decreased interleukin-2 production as compared with normal controls (33.2 +/- 5.4 vs. 61.6 +/- 4.6 percent, P less than 0.001) and with their nondiabetic twins (33.2 +/- 5.4 vs. 54.5 +/- 3.4 percent, P less than 0.005). Interleukin-2 production in nondiabetic twins and in nondiabetic persons with islet-cell antibodies was normal. There was no correlation between glycosylated hemoglobin levels and interleukin-2 production in any diabetic group. We conclude that patients with Type I diabetes have an acquired defect in interleukin-2 production, whereas patients with Type II diabetes do not, and that this defect is not correlated with an ongoing autoimmune process, with hyperglycemia, or with insulin administration or oral hypoglycemic therapy. Thus, the defect appears to be related to marked beta-cell destruction, although not to the metabolic consequences thereof or the responsible autoimmune process.

Non-human primate (baboon) anti-carcinoembryonic antigen antibody infusion in patients with metastatic adenocarcinoma. A phase I study.

A total of 14 patients with advanced visceral carcinoma which produced carcinoembryonic antigen (CEA) were treated in a Phase I study with IV infusion of affinity purified baboon anti-CEA antibody (dosage range from 0.1 to 2 mg/kg body weight). In all 14 patients, the antibody infusion caused a decrease (26% to 97%) in the plasma level of CEA. The degree of decrease depended upon the patients initial CEA level and the amount of antibody given. In 12 of the 14 patients "free" circulating antibody was observed. The plasma half-life of the antibody ranged from 0.7 to 21 h and the duration of detectable free antibody ranged from 3 to 216 h postinfusion. No toxicity was observed for the dosage range of antibody tested. In 9 of the 14 patients a low titer anti-baboon antibody response occurred between 14 and 28 days postinfusion. No clinical regression of carcinoma was documented. In 7 of the 14 patients disease remained stable during the 28-day study period. By the end of the 28-day study period plasma CEA levels had returned to at least the preinfusion level in 11 of the 14 patients.

Lack of utility of routine screening tests for early detection of peritonitis in patients requiring intermittent peritoneal dialysis.

A prospective study was undertaken to examine the clinical presentation of peritonitis in patients maintained on intermittent peritoneal dialysis and to determine the value of qualitative and quantitative dialysate cultures, gram stain, neutrophil counts, and a semi-quantitative leukocyte test strip for case detection. Seven cases of peritonitis developed among 30 patients who underwent 553 dialyses. In most cases, neutrophil counts, cultures, and leukocyte test strip determinations were done within 48 hours prior to the clinical onset of peritonitis and in all instances failed to provide clues for incipient infection. Peritonitis was associated with a dialysate neutrophil count of greater than 500/mm3 and leukocyte test strips were highly sensitive and specific for the detection of this quantity of neutrophils. A total of 16 dialysate cultures was positive in asymptomatic patients who did not have peritonitis. None of these patients subsequently developed peritonitis with the same organism. Dialysate gram stains, cultures, neutrophil counts or leukocyte test strips did not provide an early diagnosis of peritonitis and their use in the absence of symptoms is therefore not recommended.

Amyloid deposition in serosal membranes. Its occurrence with cardiac tamponade, bilateral ureteral obstruction, and gastrointestinal bleeding.

Widely dispersed amyloid deposition of the serosa occurring in a patient produced impairment of cardiac, renal, and gastrointestinal integrity by encasement. This patient survived the acute complications of both cardiac tamponade and bilateral ureteral obstruction due to amyloid. This case demonstrates the utility of resorting to aggressive life-support mechanisms despite an apparently systemic spread of amyloid disease in selected cases.

Cardiorenal failure: treatment of refractory biventricular failure by peritoneal dialysis.

Fifteen patients with New York Heart Association Class IV functional cardiac disability whose mild-to-moderately severe renal failure had produced life-threatening fluid overload underwent dialytic therapy. Ten were dialyzed by the peritoneal route initially and five were switched from hemodialysis to peritoneal dialysis because of hemodynamic instability. All patients improved, resulting in renewed responsiveness to more conservative measures (2), stabilization for cardiac surgery (4), or less-restricted lifestyle out of hospital (9). We recommend consideration of peritoneal dialysis when biventricular and renal failure are refractory to conventional therapy.

Type I diabetes mellitus in monozygotic twins: chronic progressive beta cell dysfunction.

In a prospective 21-year study, islet cell antibodies and beta cell function were serially assessed in 24 monozygotic twins initially discordant for type I diabetes mellitus. Eighteen of 21 twins typed had HLA-DR3 or HLA-DR4 antigens. During the follow-up, 4 twins developed type I diabetes mellitus, and in 3 of these 4 twins islet cell antibodies preceded the diagnosis of clinical diabetes mellitus by greater than 8, 5 and 7 years respectively. During the "prediabetic phase," the presence of islet cell antibodies was temporally associated with a progressive decline in first phase insulin response to intravenous glucose. Elevations in fasting blood glucose and abnormalities on oral glucose tolerance tests appeared only later during the course of the disease. Of the remaining 20 twins who continue to be discordant for type I diabetes mellitus, two have had islet cell antibodies for greater than 1.5 and 1 year respectively. One of these islet cell antibody-positive non-diabetic twins was restudied; despite a fasting blood glucose level of 64 mg/dL, she had a total absence of first phase insulin response to intravenous glucose. There was no evidence of transient islet cell antibody positivity in any of the twins studied. Type I diabetes mellitus in monozygotic twins has a prolonged prediabetic phase of progressive beta cell dysfunction with associated immunologic abnormalities.

Muscle capillary basement membrane width and its relationship to diabetes mellitus in monozygotic twins.

Quadriceps (Q) and gastrocnemius (G) muscle capillary basement membrane width (CBMW) were measured in 18 pairs of monozygotic (MZ) twins. Thirteen of these twin pairs were discordant for insulin-dependent diabetes (IDD) and five pairs were concordant for either IDD (two pairs) or for non-insulin-dependent diabetes (NIDD). In 12 of the 13 nondiabetic (ND) twin mates of IDD, 50 oral glucose tolerance tests performed in the years before or after determination of CBMW revealed mean blood glucose levels in the 36-52 percentile range, compared with normal controls. The mean (+/-SD) age at the onset of IDD in discordant twins was 18.7 +/- 10.1 (range 8-37) yr and the mean duration of discordance at the time of biopsy was 13.6 +/- 8.3 (range 3-32) yr. CBMW data were compared within each twin (Q versus G) and between twin mates and age- and sex-matched controls. Overall, CBMW of IDD twins was greater than that of their ND twin mates. Differences between IDD and ND twins, however, were much more marked in gastrocnemius (1859 +/- 643 versus 1222 +/- 307 A, P less than 0.0003) than in quadriceps (1291 +/- 319 versus 1112 +/- 302 A; P less than 0.04). CBMW in gastrocnemius was significantly thicker than that in the quadriceps of IDD twins (t = 4.55, P less than 0.0008) but not in their ND twin mates (t = 1.15, P less than 0.27). CMBW was significantly thicker in IDD than in their ND twin mates (in quadriceps and/or gastrocnemius) in 10 of the 12 twin pairs.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term renal allograft survival in rats preimmunized with donor strain RT1.B antigens.

Rat renal allograft survival was enhanced by active immunization with donor strain RT1.B (Ia) antigens. Lewis (LEW) rats (16) were immunized with Brown Norway (BN) lymphocyte extracts containing RT1.B, but not RT1.A antigens, prior to receiving (LEW X BN)F1 renal allografts. Group 1 (8 rats) was immunized with lymphocyte membrane fragments group 2(8 rats) was primed with lymphocyte supernatant extract. Longterm survivors (greater than 60 days; 12 animals) had a mean blood urea nitrogen of 75 +/- 31 mg% and serum creatinine of 2.0 +/- 0.8 mg% at one month. Death occurred in 90% of control allograft recipients within 10 days. Anti-BN RT1.B but not RT1.A antibodies were detected in sera from actively enhanced rats following immunization and at day 7 posttransplantation. We conclude that preimmunization with cell extracts containing donor RT1.B antigens has a protective effect on the allograft, and that the phenomenon of active immunologic enhancement can be produced without immunization to RT1.A antigens.

Coagulopathy associated with the use of cephalosporin or moxalactam antibiotics in acute and chronic renal failure.

Nine azotemic patients who developed a coagulopathy associated with the use of either cephalosporin or moxalactam antibiotics are reported. The acute renal failure patients had neoplastic disorders and were considered to be septic at the time that multiple antibiotics were administered. Four of 5 chronic hemo- or peritoneal dialysis patients also received multiple antibiotics. Nevertheless, the coagulopathy seemed to be most closely associated with the administration of the cephalosporin. One patient received moxalactam as part of the combination therapy for diffuse pulmonary infiltration during renal transplant rejection. Bleeding occurred into the gastrointestinal tract in four patients, into the kidney-urinary tract in three patients, into vascular surgical sites in two patients, and one each into the pulmonary-bronchial and cerebral-ventricular systems. Five operations were performed in four patients: a nephrectomy for massive subcapsular hemorrhage with a prothrombin time that exceeded 100 seconds; arteriovenous graft complicated by post-operative bleeding associated with prolongation of the prothrombin time; elective femoral-popliteal bypass complicated by a prolonged prothrombin time, bleeding into the graft site, hypotension, and a subendocardial myocardial infarction; elective cholecystectomy complicated by a two unit bleed associated with a slightly prolonged prothrombin time, followed by elective femoral-popliteal bypass complicated by a fatal intercerebral bleed associated with a more than twice normal prothrombin time. Cephalosporins are most likely associated with Vitamin K deficiency. Moxalactam is more likely to be associated with platelet dysfunction. Monitoring of the prothrombin time for cephalosporins or the bleeding time for moxalactam is the most reliable way to prevent what may be rapid emergence of clinical bleeding in patients with renal failure.

Reversible acute pulmonary edema due to uncontrolled hyperglycemia in diabetic individuals with renal failure.

On eight separate occasions, four functionally anephric diabetic patients (on maintenance hemodialysis) experienced episodes of severe hyperglycemia with acute interstitial and alveolar pulmonary edema demonstrated clinically and by chest x-ray without electrocardiographic or enzymatic evidence of an acute myocardial lesion. Three patients had normal stress 201T1 scanning. The fourth patient, who experienced three such episodes, had normal coronary angiograms and only a mild elevation of the left-ventricular end-diastolic pressure. Clinical and chest x-ray improvement were immediate following insulin therapy and control of hyperglycemia, without phlebotomy or dialysis. Since these episodes were observed during a 1-yr period, this syndrome may be more common than suspected. It is concluded that in functionally anephric diabetic individuals: (1) pulmonary edema can be precipitated by uncontrolled diabetes; (2) endogenous fluid shifts may contribute to the cause of acute pulmonary edema; (3) clinical and radiologic improvement can be achieved with adequate insulin therapy; and (4) blood glucose levels should be monitored and controlled in diabetic patients with renal failure.