Tumor dormancy in vivo by prevention of neovascularization.

Dormant solid tumors were produced in vivo by prevention of neovascularization. When small fragments of anaplastic Brown-Pearce carcinoma were implanted directly on the iris in susceptible rabbits, they always vascularized. A characteristic growth pattern, consisting of prevascular, vascular, and late phases, was observed, which terminated with destruction of the eye within 2 wk. The beginning of exponential volume increase was shown to coincide with vascularization of the implant, as demonstrated by perfusion with intravenous fluorescein and by histologic sections. In contrast, implants placed in the anterior chamber, at a distance from the iris, did not become vascularized. After initial growth into spheroids, they remained arrested at a small size comparable to prevascular iris implants, for periods as long as 6 wk. Although dormant in terms of expansion, these avascular tumors contained a population of viable and mitotically active tumor cells. When reimplanted on the iris, vascularization was followed by rapid, invasive growth. These observations suggest that neovascularization is a necessary condition for malignant growth of a solid tumor. When a small mass of tumor cells is prevented from eliciting new vessel ingrowth from surrounding host tissues, population dormancy results. These data suggest that the specific blockade of tumor-induced angiogenesis may be an effective means of controlling neoplastic growth.

Histoplasmosis in renal allograft recipients. Two large urban outbreaks.

During two large outbreaks, ten episodes of histoplasmosis were documented in eight renal allograft recipients. Another episode occurred before the outbreaks. Associated infections with cytomegalovirus occurred in five patients and may have further impaired cellular immunity. Prolonged fever was the predominant clinical finding; and dissemination was observed in seven of our nine patients, including three with meningitis. Special stains of tissues and the histoplasmal complement fixation test provided useful diagnostic information rapidly, while cultures were eventually positive in seven patients. Treatment with amphotericin B resulted in prompt clinical improvement in all patients, but relapse occurred in two patients one year following therapy.

Longitudinal study of bone mass in end-stage renal disease patients: effects of parathyroidectomy for renal osteodystrophy.

The effectiveness of parathyroidectomy (PTHX) for the control of secondary hyperparathyroidism was assessed in 46 adult end-stage renal disease (ESRD) patients whose bone mineral content at the midshaft and distal radius was measured using single-photon absorptiometry (SPA) every 6 months before and after the surgery. They were compared to 46 age-, race-, and sex-matched ESRD patient controls who had not undergone surgery but who had had at least five SPA studies at similar intervals. Presurgery midradius bone mass was significantly lower for PTHX patients compared to controls. Comparing changes in bone mass of PTHX patients across surgery to controls in comparable time periods showed that PTHX patients lost significantly less bone mass after surgery. Similar results were obtained when rates of change in bone mass were evaluated. When patient characteristics were examined, the effect of surgery was found to be diminished in elderly patients and in oophorectomized patients. It is concluded that PTHX can have a salutary effect on renal osteodystrophy in the appendicular skeleton, but factors other than bone mass also need to be considered in identifying those patients who will benefit from surgery.

Function of autotransplanted kidneys after 24-hour preservation by hypothermic pulsatile perfusion or simple cord storage.

Canine kidneys, flushed with either Collins solution or autologous cryoprecipitated plasma, were then stored for 24 hr by either simple cold storage (submersion) in the flushing solution, or by continuous hypothermic pulsatile perfusion with cryoprecipitated plasma. After autotransplantation without contralateral nephrectomy, detailed split renal function studies were carried out immediately as well as 2 and 7 days later. Measurements were made of inulin clearance, maximal transport of p-aminohippurate, reabsorption of sodium, chloride, and glucose, and the reabsorption of free water. Contralateral nephrectomy was performed 7 days after transplantation, following measurement of renal functions on that day, and plasma urea nitrogen and creatinine were measured periodically over the ensuing 3 weeks. Renal function after transplantation was affected very little by the choice of flushing solution, and the course of azotemia that developed following contralateral nephrectomy was the same in all groups. However, the detailed functional measurements showed that during the 7-day period after transplantation, renal function was depressed to a much greater extent in kidneys treated by simple cold storage than in those that had been perfused.

Therapy of acute cadaveric renal allograft rejection with adjunctive antithymocyte globulin.

A randomized and controlled study was conducted to evaluate the efficacy of adjunctive antithymocyte globulin (ATG) therapy for the treatment of the initial rejection episode in first cadaveric transplants. When compared to the control group (29), which received only standard antirejection treatment (SAT) of steroid pulsing and local irradiation, the adjunctive ATG treatment group (23) demonstrated significantly faster recovery rates (8.9 +/- 4.1 versus 6.9 +/- 3.7 days, P = 0.05, respectively) and better graft survival rates (62 +/- 9% versus 91 +/- 7%, respectively) after the first rejection. ATG treatment did not result in fewer subsequent rejection episodes than SAT but long-term allograft survival rates remained superior to controls for the entire 3-year study period. By avoiding ATG treatment in those patients who never experienced clinical rejection on maintenance immunosuppressive therapy, i.e., nonresponders (23 of 90), complications associated with excessive immunosuppression were minimized. The combined results of the non-responder group of patients and ATG-treated patients resulted in a 1-year patient survival of 97% and graft survival of 86%. These results suggest that the most efficacious use of ATG is therapeutic and not prophylactic in renal transplant patients.

In vitro effects of cyclosporin A on lymphocyte subpopulations. 1. Suppressor cell sparing by cyclosporin A.

The fungal metabolite, cyclosporin A, is a potent immunosuppressive compound. Experiments were performed in vitro with both human and nonhuman primate peripheral blood lymphocytes to study the effect of this agent on suppressor cell activity. Cyclosporin A did not affect the generation or function of concanavalin A-induced suppressor lymphocytes as measured by their ability to suppress thymidine uptake of lymphocytes in secondary cultures. No evidence of suppressor cell induction was noted by incubation of lymphocytes with only cyclosporin A. We conclude that, although cyclosporin A does not generate or induce suppressor cell lymphocytes, it does spare them, while inhibiting other subpopulations. This effect may create an imbalance in the immune system which results in profound suppression.

Predictive value of enzyme-linked immunosorbent assay-detected IgG anti-HLA antibodies for pediatric renal allograft rejection.

BACKGROUND: Measurement of panel-reactive antibody (PRA) with an enzyme-linked immunosorbent assay using soluble HLA class I molecules (PRA-STAT) in adult renal transplant recipients predicted graft loss and rejection. We sought to confirm this finding in pediatric recipients, an immunologically distinct group. METHODS: The population consisted of 158 renal transplants in 146 patients (age range, 1-21 years). PRA was determined with PRA-STAT and microlymphocytotoxicity (CDC), using final cross-match sera. An elevated test was defined as > or =5% reactivity. Statistical analysis for rejection used the chi-square test and for graft survival used the log-rank test. RESULTS: Thirty-five patients (22%) had %PRA-STAT > or =5%, compared with 26 (16%) with %PRA-CDC > or =5%. The percentage with elevated %PRA-STAT was found to correlate with subsequent transplantations (first, 15%; second, 67%; third, 75%). Subsequent analyses utilized only the 136 primary recipients, of whom 20 (15%) had %PRA-STAT > or =5% and 16 (12%) had %PRA-CDC > or =5%. Elevated %PRA-STAT correlated with rejection at 3 months (65% vs. 36%), 12 months (84% vs. 50%), and 24 months (84% vs. 54%) (P<0.05). No association was found between elevated %PRA-CDC and rejection. Patients with %PRA-STAT > or =5% vs. %PRA-STAT <5% had graft survival at 1 year of 89% vs. 84%, at 2 years of 88% vs. 77%, and at 3 years of 61% vs. 72% (not significant). CONCLUSIONS: Use of %PRA-STAT > or =5% identifies pediatric recipients who are at increased risk for rejection and may benefit from more potent immunosuppression and/or closer monitoring of graft function.

Intraoperative placement of a Wallstent for portal vein stenosis and thrombosis after liver transplantation.

We report a case of orthotopic liver transplantation, in which portal vein thrombosis developed in the immediate postoperative period. Surgical thrombectomy and intraoperative placement of a large caliber Wallstent resulted in long-term patency. The unique feature of this case is the intraoperative placement of the stent via the inferior mesenteric vein under fluoroscopic guidance. The use of a large caliber (16 mm) stent obviated the need for postoperative anticoagulation.

Time course of glomerular endothelial injury related to pulsatile perfusion preservation.

To elucidate the time course of glomerular and arterial endothelial injury resulting from pulsatile perfusion preservation of human kidneys, we examined two kidneys, one at 16 and the other at 42 hr, for which no suitable recipient could be found. The scanning electron microscope revealed subtle changes at 16 hr in the filtration barrier. These included mild endothelial swelling with an increase in the appearance of bulbous processes, and elongated fenestrae. The visceral epithelial surface was normal as was the arterial endothelial surface. By 42 hr the glomerular endothelial surface displayed very prominent cytoplasmic ridges and clearly distorted fenestrae. The arterial endothelium exhibited a tendency to separate from the vessel wall. The proximal tubular epithelium revealed scattered loss of microvilli. These changes are similar in kind to, albeit less severe than, those described after 60 hr of perfusion. They may represent cell swelling following ischemia, or be the result of altered cell permeability engendered by low temperature. The possibility remains that such changes could be minimized by modifying the perfusate. Scanning electron microscopy provides a versatile tool in the study of vascular and other surfaces of tissues stored with perfusion preservation.

Persistence of cyclosporine after withdrawal of the drug in a patient with chronic liver transplant rejection. Role of the monoethylglycinexylidine test.

Patients with chronic rejection of liver allografts may show persistently high cyclosporine levels. This phenomenon may be due to a down-regulation of the P450 cytochrome system. The monoethylglycinexylidine test was useful in confirming this hypothesis.

Anti-idiotype antibody in the primate. 1. Characterization and specificity against cells primed for histocompatibility determinants.

An anti-idiotype serum was raised in a chimpanzee (A) by immunization with autologous lymphocytes primed in vitro against an unrelated chimp (B). This autoantiserum in the presence of complement was cytotoxic for 5 to 7% of the resting lymphocytes from chimp A and for 30 to 45% of the mixed lymphocyte culture (MLC) primed cells (A X Bx), but was not reactive against the lymphocytes of the priming chimp (B). Anti-idiotype antibody and complement treatment of autologous resting or primed cells blocked the ability of these cells to respond in MLC or primed lymphocyte test (PLT) to the stimulator cells from chimp B, but not to cells from a third chimp. When cells from the immunized animal (A) were incubated with the autologous antiserum in vitro, they were stimulated, thus producing cells which had the same activity in PLT as did cells primed against stimulator cells of chimp B. Thus, an autoanti-idiotype serum has been raised in a primate system which identifies the recognition structure on autologous T cells directed against antigeneic determinants on the stimulator cells of a histoincompatible donor.

Glomerular endothelial injury related to renal perfusion. A scanning electron microscopic study.

To elucidate abnormalities in renal morphology related to perfusion preservation, we examined kidneys perfused for 60 hr with a scanning electron microscope. In addition to tubular necrosis and fused glomerular visceral epithelial foot processes, we identified changes in the glomerular endothelial and arterial endothelial surfaces. The glomerular endothelium revealed fenestrae that were smaller and more irregular than normal, as well as abnormal bulbous projections. The arterial endothelium displayed striking degenerative changes. These abnormalities may account for the altered glomerular function and intravascular coagulation that occur in some kidneys preserved by lengthy perfusion.

Prospective study of magnetic resonance imaging and SPECT bone scans in renal allograft recipients: evidence for a self-limited subclinical abnormality of the hip.

We recently reported that typical abnormalities of avascular necrosis (AVN) in magnetic resonance images (MRI) of the hips of asymptomatic renal transplant recipients whose plain radiographs are normal may improve spontaneously and even disappear completely. We present the results of serial bone scans, most of which were performed with single-photon emission computed tomography obtained over periods as long as 24 mo after transplantation in 72 of these patients. Three paired imaging studies (i.e., MR and bone scan performed within 30 days of each other) were available for each of these patients. In three patients, both the MR images and the bone scans showed changes consistent with bilateral AVN within 4 mo after transplantation. All three patients developed hip pain which was bilateral in two and unilateral in one. Two patients (three hips) required surgical intervention at which time AVN was found on pathologic examination of all three hips. None of the remaining 69 patients developed hip pain during the study. However, in nine patients whose MR studies were consistently normal, at least one bone scan was abnormal (13 hips). The presence of AVN was pathologically confirmed in each of the hips subjected to surgery. Where the imaging findings were identical to those in the asymptomatic patients as well as those in whom the imaging abnormality regressed, we suggest that the subclinical imaging abnormalities represent mild AVN, which is reversible in some cases. Since the process was identified in 10 hips by MRI and in 13 hips by bone scan, both studies are needed to detect subclinical AVN. This may be important if treatment of subclinical disease is clearly shown to prevent progression to symptomatic AVN.

Thrombofibrinous sheath occlusion of peritoneovenous shunts.

Thrombofibrinous sheath occlusion of peritoneovenous shunts is described in two case presentations. In reviewing the literature, we found only 17 other such cases mentioned. Most patients were seen initially with recurrence of ascites and only one with superior vena cava syndrome. A shuntogram documented a characteristic sheath in 17 patients, and relocation was the preferred treatment. Relocation was successful in eight of 11 attempts, but long-term follow-up data were not available. Histologic examination of the sheath in our first case study revealed recent and organized thrombus. This would help explain why only one of three patients was successfully treated with fibrinolytic agents.

Vascular complications in human renal transplantation.

There were 13 arterial complications in 202 transplants done in 162 patients, an incidence of 6.5 percent. Renal arterial stenosis was demonstrated by angiogram in six kidneys; four were reconstructed successfully. Four renal arterial occlusions were found in delayed rejected kidneys. Of three arterial dehiscences secondary to infection, all led to graftectomy. One of these patients died 56 days later due to infectious hepatitis, and one underwent a successful retransplant. One patient had an occluded iliac artery which was repaired successfully. A single venous complication occurred in one patient.

Surgical considerations of continuous ambulatory peritoneal dialysis.

The surgical considerations pertaining to 173 continuous ambulatory peritoneal dialysis catheters were reviewed in 140 patients from 1979 through 1983. All catheters were inserted in the operating suite by an open technique. Local anesthesia was used in the majority of patients (59%). Catheter peritonitis was the most frequent complication, 228 episodes/2407 patient months. Twenty-three percent of the patients accounted for 51% of catheter-related peritonitis. Sixteen catheters were removed because of an inability to clear the infection. Intra-abdominal catastrophes were noted in four patients and differentiation from continuous ambulatory peritoneal dialysis peritonitis was based on serial examinations, bacteriologic cultures, and/or a progressive increase in free abdominal air. Surgically-related catheter complications were designated either early (less than 1 month) or late (greater than 1 month) in relation to catheter placement. Frequent early complications were mechanical flow problems and dialysate leaks. Five of 11 mechanical flow difficulties required catheter replacement while none of the dialysate leaks required surgical intervention, and all healed spontaneously. Common late complications included 35 tunnel infections, 23 of which were associated with peritonitis. Nine of these catheters (25%) were removed. Cuff extrusion was also associated with a high incidence (83%) of catheter attrition. Thirty-six patients underwent renal transplantation and in no instance did the catheter increase patient or renal allograft morbidity rates.

Tube jejunostomy in liver transplant recipients.

BACKGROUND: Nutritional support after liver transplantation most often uses intravenous hyperalimentation followed by nasoduodenal tubes until adequate intake is achieved. Because of difficulties with nasoduodenal tubes, we place jejunostomy tubes (j-tube) at the time of the transplantation, allowing immediate postoperative enteral nutrition. This review analyzes the complications of this procedure in transplant recipients. METHODS: J-tubes were placed in 108 of 119 adults who underwent liver transplantation between October 1989 and June 6, 1994. These patients were retrospectively reviewed for the type and frequency of j-tube-related complications. J-tube feeds with a semielemental formula were started within 24 to 48 hours after transplantation. RESULTS: Eighteen complications occurred in 16 patients. Six were mechanical obstructions of the j-tube because of kinking by the fascia. Six exploratory laparotomies were required, two each for infection, small bowel obstruction, or catheter displacement. Four other infections were treated by local incision and drainage or percutaneous drainage. One tube required surgical removal in the operating room. CONCLUSIONS: Tube jejunostomies can be safely placed at the time of liver transplantation with a low risk of serious complications. We recommend the routine use of j-tubes in patients receiving a liver transplant for the immediate posttransplantation institution of enteral nutrition.

Comparison of Minnesota antilymphoblast globulin and Upjohn antithymocyte globulin for induction immunosuppression of human renal allografts.

BACKGROUND: An analysis of heterologous polyclonal antisera in first renal transplants was continued after replacement of Minnesota antilymphoblast globulin (MALG) with antithymocyte globulin (ATGAM), testing the hypothesis that these are functionally equivalent drugs. METHODS: Sequential induction immunosuppression used MALG (20 mg/kg/day, n = 33) or ATGAM (15 mg/kg/day, n = 14), corticosteroids, azathioprine and cyclosporine. White blood cell, platelet, and T-cell subsets were measured. Percent of patients with and time to first rejection were determined. Anti-horse antibody was measured by enzyme-linked immunosorbent assay. Minimum follow-up after transplantation was 1 year. RESULTS: Human leukocyte antigen mismatch, peak and current panel reactive antibodies, age, gender, percent cadaver donors and diabetic recipients were similar. Depletion of CD2, CD3, CD4, and CD8 T-cell subsets and platelet and white blood cells was similar. Early renal function was better with MALG than with ATGAM (p = 0.005, ANOVA), but by 2 weeks the groups were similar. The percent of patients receiving MALG versus patients receiving ATGAM with cytomegalovirus (28 versus 50), anti-horse antibodies (50 versus 62), and rejection (58 versus 50) and the median day of first rejection (48 versus 47) were similar. Three grafts were lost. CONCLUSIONS: MALG and ATGAM are equally effective in eliminating T cells and preventing and delaying the onset of renal allograft rejection.

Renal allograft rupture with iliofemoral thrombophlebitis.

Spontaneous rupture of a renal allograft in the early posttransplant period is associated with tachycardia, hypotension, oliguria, swelling, pain, a falling hematocrit level, and tenderness at the transplant site. Occasionally, the ruptured allograft can be saved by control of the hemorrhage. Deep vein thrombophlebitis, a common occurrence after prolonged surgery and cortocosteroid therapy, is less common in renal allograft transplantation, but may be associated with renal vein thrombosis. The simultaneous occurrence of deep vein thrombophlebitis, renal vein thrombosis, and allograft rupture contraindicates anticoagulent therapy. We present a patient in whom ipsilateral deep vein thrombophlebitis developed eight days after a cadaveric renal allograft, followed in two days by hypotension, a falling hematocrit level, oliguria, and a painfall mass at the allograft site. Surgical exploration revealed a ruptured allograft with iliofemoral and renal vein thrombosis and profuse hemorrhage. A transplant nephrectomy was performed.

Fatal transitional cell carcinoma of bladder in renal transplant recipient.

The risk of development of a malignancy as a consequence of long-term immunosuppression is well documented. Herein, we report the course of a renal allograft recipient in whom a fatal transitional cell carcinoma of the bladder developed eighteen years following transplantation.