Role of mobile passenger lymphocytes in the rejection of renal and cardiac allografts in the rat. A passenger lymphocyte-mediated graft-versus-host reaction amplifies the host response.

It is demonstrated that passenger lymphocytes migrate out of rat renal allografts into host spleens in a radioresistant fashion. These mobile passenger lymphocytes within BN kidney and heart transplants are immunocompetent, since they elicit a graft-versus-host (GVH) reaction in the spleens of (LEW x BN)F2 hybrid hosts. The greater GVH reaction in (LEW x BN)F1 recipients of BN kidneys reflects the greater number of mobile passenger lymphocytes in the kidney when compared to the heart. The mobile passenger lymphocytes within BN renal allografts also cause a proliferative response in the spleens of LEW hosts as well as an accelerated rejection of BN renal allografts when compared to BN cardiac allografts, for the differences between BN kidney and heart, both in terms of splenomegaly elicited in LEW as well as tempo of rejection, are abolished by total body X-irradiation of the donor with 900 rad. Results indicate that a mobile passenger lymphocyte mediated GVH reaction in the central lymphoid organs of the host augments the host response to allogeneic kidneys and contributes materially to first-set renal allograft rejection; this GVH reaction on the other hand is not conspicuously present in LEW recipients of BN cardiac allografts and has therefore little effect on first-set cardiac allograft rejection.

Arterial blood supply of the left lobe of the canine pancreas. II. Electromagnetic flow measurements.

The arterial blood flow through the left lobe of the canine pancreas was assessed by means of electromagnetic flow measurements under three different experimental conditions. First, flow was measured in 14 unmodified left pancreatic segments. The mean segmental blood flow was 9.1 +/- 4.5 ml/min, while the mean blood flow through the splenic artery was 53.3 +/- 21.2 ml/min. Next, flow was measured in seven of these dogs 1/2 hour after occlusion of the ductal system and construction of an end-to-end arteriovenous fistula between the distal splenic vessels. The segmental pancreatic blood flow remained unchanged, and the blood flow in the splenic artery increased more than twofold. Third, flow was measured in seven dogs (eight measurements) at 3 to 8 months after ductal occlusion of the left lobe. No significant decrease in segmental pancreatic blood flow was demonstrable up to 8 months. It is concluded that the arterial blood flow through the left lobe of the canine pancreas amounts to less than 20% of that in the splenic artery, that an end-to-end arteriovenous fistula increases the blood flow through the splenic artery and thus may contribute to the prevention of vascular thrombosis, and that the eventual decrease of endocrine function or occurrence of vascular thrombosis in duct-obliterated pancreatic grafts cannot be readily explained by a reduced blood flow as a consequence of either duct obliteration as such or fibrosis induced by duct obliteration.

Arterial blood supply of the left lobe of the canine pancreas. I. Anatomic variations relevant to segmental transplantation.

The anatomy of the arterial blood supply of the left lobe of the pancreas was studied in 70 beagles. It was found to be supplied by one small artery only, which was called the pancreatic artery. The pancreatic artery originated from the splenic artery (type I) in 56 dogs (80%). However, it originated from the cranial mesenteric artery (type II) in 14 dogs (20%). In the presence of type I anatomy, the surgical technique for segmental pancreatic transplantation can, in general, be performed in a routine fashion. In the presence of type II anatomy, a modification should be applied. This modification is described and illustrated. It is concluded that the pancreatic artery should always be identified at operation, and that the specific surgical procedure chosen should depend upon the anatomy found. In addition, ischemic necrosis of segmental pancreatic grafts can only be explained by vascular thrombosis if the pancreatic artery has been recognized and preserved with certainty at transplantation.

Donor pretreatment-mediated and cold storage-dependent proximal tubular necrosis--a unique form of acute renal insufficiency.

After a 5-hour period of donor pretreatment with cyclophosphamide (CY) and methylprednisolone (P) (100 mg/kg each), cold storage of pretreated canine renal allografts may cause early and severe postoperative renal insufficiency. This renal insufficiency is mediated by CY metabolites and depends on the number of hours of cold storage, for severe renal insufficiency is not observed after 6 hours of cold storage but is invariably present after cold storage beyond 18 hours. The renal insufficiency is associated with coagulation necrosis of the proximal tubules, particularly the pars recta. Since the repair of ischemia-medicated proximal tubular lesions requires mitotic activity, results suggest that the proximal tubules of donor pretreated kidneys are subjected to a concentration of CY metabolites sufficient to cause an extent of DNA damage that, in the absence of a sufficient time for nuclear repair, inevitably leads to cell death and renal insufficiency when the tubular cells are driven to mitosis by cold storage-mediated ischemia.

Orthotopic liver transplantation after preservation without perfusion for up to six hours: A controlled trial evaluating different preservation fluids in dogs and pigs.

The important extension of the ischemic period recently described with a simple hypothermic liver preservation method is attributed to the use of specific preservation fluids. However, there is no consensus about the optimal preservation fluid. In order to investigate the effect of the composition of the preservation fluid on the immediately postoperative transplant function and on subsequent long-term survival, orthotopic liver transplantations were performed in 13 dogs and 12 pigs. To reduce immunologic interference in postoperative transplant evaluation, donor and recipient pairs always were litter mates, the dogs being identical according to lymphocyte typing. The ischemic periods were 1, 3, and 6 hours. Four different preservation fluids were used with marked differences in ionic composition (extracellular vs. intracellular), pH, and osmolarity. Within each ischemic period group the sequence of experiments was randomized with respect to the different preservation fluids. Twenty-four animals survived the transplantation procedure. No differences were found between the preservation fluid groups. Postoperative function of all livers preserved for 6 hours was comparable to those with 1 hour ischemia. Three dogs and four pigs (six of seven with livers preserved for 3 to 6 hours) are still alive more than 1 year after transplantation. So consistently excellent liver function leading to long-term survival in 36 percent of cases can be obtained after liver transplantation with preservation up to 6 hours; for this result the composition of the preservation fluid is of minor importance.

Surgical treatment of renovascular hypertension caused by arteriosclerosis. I. Influence of preoperative factors on blood pressure control early and late after reconstructive surgery.

This study evaluates the long-term efficacy of reconstructive surgery for renovascular hypertension caused by arteriosclerosis, which was performed on 112 patients from 1959 to 1983. Despite medical therapy, all patients had persistent hypertension, with a mean preoperative blood pressure of 188/113 mm Hg. Their median age was 49 years, and the median duration of objectively documented hypertension was 21 months at the time of surgery. Manifestations of extrarenal arteriosclerosis (ERA) were present in 57 patients (51%). Results were evaluated both at a short-term (ST) interval (mean: 8.4 months) and at a long-term (LT) interval (mean: 8.9 years) postoperatively. Patients were classified by means of strict criteria as cured, improved, or unsuccessfully treated. If a patient was cured or if his condition improved, this was considered a beneficial blood pressure response. Beneficial responses were maintained during LT follow-up, since the respective percentages for cure and improvement were 24% and 50% at the ST interval and 18% and 61% at the LT interval. These results had not been influenced by either older age or the presence of ERA, since results were similar in patients older and younger than the median age and in those with and without ERA. The preoperative duration of hypertension was the only pertinent clinical feature that influenced the LT interval results, LT beneficial responses were observed in 95% of the patients with a shorter duration and in 78% of those with a longer duration of preoperative hypertension than the median (p = 0.01). We conclude that surgical therapy for renovascular hypertension caused by arteriosclerosis can effectively reduce blood pressure and that this result is maintained during LT follow-up. In terms of anticipated blood pressure response, older age, longer duration of hypertension, and the presence of ERA do not exclude surgical therapy.

Surgical treatment of renovascular hypertension caused by arteriosclerosis. II. Influence of preoperative risk factors and postoperative blood pressure response on late patient survival.

This study assesses the late survival of 103 patients with renovascular hypertension caused by arteriosclerosis who underwent reconstructive surgery during the period of 1959 through 1982. It provides a detailed analysis of the influence of preoperative factors and the postoperative blood pressure response to fatal and nonfatal cardiovascular events during follow-up. All patients suffered from severe hypertension. Arteriosclerosis was limited to the renal arteries in 52% of the patients, while 48% showed overt extrarenal arteriosclerosis. Hypertensive target organ damage was present in 68% of the patients. At a mean of 8.5 months postoperatively, 80% of the patients showed beneficial and 20% showed unsatisfactory blood pressure responses. These results were not related to the presence or absence of extrarenal arteriosclerosis. Overall, late (10 years) patient survival was significantly lower than the expected survival of a reference population (79% versus 92%; p less than 0.0001). Late patient survival was not influenced by the absence or presence of extrarenal arteriosclerosis (82% versus 82%) or target organ damage (83% versus 82%), but late survival was significantly better with beneficial (87%) than with unsatisfactory blood pressure responses (67%). This effect was especially conspicuous in the presence of extrarenal arteriosclerosis (88% versus 57%; p = 0.04) but not in its absence (86% versus 74%; p = 0.41). In terms of long-term survival, these findings clearly demonstrate the favorable effect of successful surgical treatment of patients with renovascular hypertension caused by arteriosclerosis. Moreover, they illustrate that the mere presence of preoperative extrarenal arteriosclerosis or target organ damage is not sufficient argument against surgical therapy.

Orthotopic liver transplantation: an experimental study on mechanisms of hemorrhagic diathesis and thrombosis.

The hemorrhagic diathesis after transplantation of preserved livers generally is attributed to intravascular coagulation, whereas postoperative "hypercoagulability" of the blood is considered the main cause of thrombosis of the hepatic artery anastomosis. Since our preliminary studies, however, suggested other mechanisms, parameters of coagulation, fibrinolysis, and platelet function were prospectively studied before and after 28 orthotopic liver transplantations, with and without preservation, in dogs and pigs. In addition, the arterial anastomoses were evaluated routinely by angiography and, after removal at reintervention or autopsy, inspected for thrombosis and tested for fibrinolytic activity and fibrin deposition. Concerning the hemorrhagic diathesis, prolongation of bleeding time without concomitant thrombocytopenia was the main abnormality found and occurred only in the nine dogs with liver transplants previously preserved for 3 to 6 hours. As only two of the nine dogs had postoperative hemorrhage of clinical significance, we consider surgically imperfect hemostasis facilitated by an acquired platelet dysfunction the principal cause of hemorrhage. Thrombosis of the arterial anastomosis was found in 38 percent of animals in which an end-to-end anastomosis was made but was not encountered with celiac artery-aorta anastomoses. Local factors due to surgical technique therefore appear most important in the pathogenesis of thrombosis of the hepatic artery anastomosis, although the postoperative hyperfibrinogenemia and diminished local and systemic fibrinolytic activity may contribute as well.

Chronic mesenteric vascular syndrome. Results of reconstructive surgery.

Since 1961, 14 patients at the University Hospital of Leiden, the Netherlands, have undergone reconstructive surgery for treatment of chronic mesenteric vascular syndrome. Of the 42 mesenteric arteries, 31 were severely obstructed (mean, 2.2 stenotic arteries per patient). A total of 23 mesenteric arteries were repaired. Long-term follow-up data were available for all 13 surviving patients (mean follow-up, 11.8 years). Symptoms were relieved immediately after surgery, and relief was maintained during follow-up. Digital subtraction angiography at long-term follow-up evaluation was performed in eight patients (13 reconstructions) with these results: 11 (85%) of the 13 reconstructions were patent and severe stenoses were found in eight (33%) of the 24 mesenteric arteries (mean, 1.0 stenotic artery per patient). We conclude that reconstructive surgery for patients with chronic mesenteric vascular syndrome promptly relieves symptoms, provides excellent patency, and has long-lasting beneficial results.

Influence of preoperative risk factors and the surgical procedure on surgical mortality in renovascular hypertension.

The present study was undertaken to assess surgical risk in 112 severely hypertensive patients with renovascular disease secondary to atherosclerosis. The influence of preoperative risk factors and the surgical procedure on surgical mortality was also investigated. Extrarenal atherosclerosis was present in 51 percent of the patients, and hypertensive target organ damage was present in 66 percent. Renal artery reconstruction was performed unilaterally in 92 patients and bilaterally in 20 patients. Simultaneous aortoiliac operations were performed in 25 patients. There were nine operative deaths (8 percent). The presence of extrarenal atherosclerosis was particularly associated with mortality (14 percent compared with 1.8 percent when it was absent; p = 0.02). The surgical procedure also represented a significant risk; the mortality rate was 1.4 percent if surgery was restricted to unilateral reconstruction, but otherwise it increased to 20 percent (p = 0.001). This increase in mortality rate was clearly associated with aortoiliac surgery (20 percent compared with 4.6 percent when aortoiliac surgery was not performed; p = 0.025) and could be explained by the increased blood loss during operation. We conclude that the surgical treatment of renovascular disease secondary to atherosclerosis can be safely performed, provided that extrarenal atherosclerosis is absent and that simultaneous aortoiliac surgery can be avoided.

Aortoiliac and aortofemoral reconstruction of obstructive disease.

This retrospective study evaluates our strategy to limit prosthetic reconstructions for aortoiliac obstructive disease to the diseased segments in 518 patients. There were 363 (70%) reconstructions without femoral anastomotic sites (FEM-0), 107 (21%) reconstructions with one femoral anastomotic site (FEM-1), and 48 (9%) aortobifemoral reconstructions (FEM-2). The ischemic symptoms and the extent of obstructions were significantly more severe in the FEM-1 and FEM-2 groups than in the FEM-0 group. Early operative results were comparable in all three groups. The difference in outcome became apparent when the long-term results were considered. Long-term follow-up continued for up to 20 years after the operation. Primary and secondary patency rates were significantly higher in the FEM-0 group (9% and 4% recurrent obstructions per 5 years, respectively) than in the FEM-1 and FEM-2 groups (both 14% and 10%, respectively), which was explained by patient selection. Late additional surgery was performed after aortoiliac procedures in most cases for recurrent aortoiliac obstruction and after aortofemoral procedures in most cases for false aneurysms. The risk of late additional operations during long-term follow-up were significantly lower in the FEM-0 group than in the FEM-1 and FEM-2 groups. These results support our strategy to tailor prosthetic reconstructive surgery to the individual status of the aortoiliac arteries.

Simultaneous pancreas and kidney transplantation: a feasible procedure in selected patients.

We analyzed the overall results of 24 simultaneous pancreas and kidney transplantations (SPK), performed in our hospital between April 1986 and June 1990. All patients had type I diabetes mellitus and end-stage renal failure. We used bladder drainage of the pancreatic exocrine secretions through a duodenocystostomy. The blood vessels of both grafts were anastomosed to the iliac vessels. The immunosuppressive management was triple-therapy with cyclosporin, azathioprine and prednisone. All organs were transplanted without matching donors and recipients for HLA. At the time of transplantation, mean recipient age was 37 yr; the average duration of diabetes was 22 yr. After disappointing results in the first 4 patients, the pancreas was placed intraperitoneally instead of extraperitoneally and the antibiotic drug regimen was altered. In the second group (n = 20), patient survival was 100%; 1-yr pancreas and kidney graft survival were 65 and 62%, respectively. Duration of hospitalization and pancreas and kidney graft loss were positively correlated with the number of rejection episodes. After 1 yr of follow-up, the mean creatinine clearance was 62 ml/min and the mean HbA1c was 5.5%. Blood glucose levels and oral glucose tolerance tests were also normal. We conclude that patient and graft survival after SPK are satisfactory, although rejection-related morbidity is still a major problem.

Causes of rethrombosis following arterial reconstructions below the renal arteries.

Causes of rethrombosis after primary reconstructive surgery for arterial occlusive disease below the renal arteries are discussed, based on experience with 1,700 reconstructions since 1958, and data from literature. Important for reoperation is the fact that mortality of secondary procedures is much higher than for the primary ones (13% versus 0.9%). Longterm anticoagulant therapy is advocated. Results of reoperations are excellent.

Vascular complications in 400 consecutive renal allotransplants.

The vascular complications, their management and results of treatment in 400 consecutive renal allotransplants performed at the Leiden University Hospital from March 1966 through July 1979, are presented. There were 50 (12.5%) vascular complications. Among them renal artery stenosis (RAS) occurred in 40 cases (10%), renal artery thrombosis in 7 cases (1.8%), renal vein thrombosis in 2 cases (0.5%) and disruption of the arterial anastomosis in one. Arterial reconstruction was made in 25 patients with RAS, the blood pressure was normalized in 18 patients (72%), in 3 a recurrence of the RAS was found, in another 3 bad results were achieved regarding the blood pressure and in one patient a recurrence of the original glomerulonephritis had taken place. Of the 50 vascular complications 12 patients underwent a removal of the transplant and 3 resulted in death of the patient.

Villous tumors of the duodenum. Presentation of five cases.

Five cases of villous tumors of the duodenum are reported. These tumors have a predilection for the periampullary region and tend to present with jaundice or obstruction of the duodenal lumen. In four of these patients, malignant transformation was seen. Endoscopy and biopsy play a major rôle in attempting to obtain an accurate preoperative diagnosis. Unfortunately, the diagnosis of malignant degeneration is frequently missed, even when multiple biopsies are taken. For this reason villous tumors should always be resected, and the strategy of treatment must depend on pre-, intra- and postoperative histological evaluation, location in the duodenum and intra-operative findings.

Large-pore hemodialytic procedures in pigs with ischemic hepatic necrosis; a randomized study.

In order to define further the therapeutic role of hemodialytic procedures in acute hepatic failure, 20 pigs with ischemic hepatic necrosis underwent randomized hemodialysis against an electrolyte solution (n = 6), hemofiltration with re-infusion of an electrolyte solution (n = 5), control hemofiltration with re-infusion of autologous ultrafiltrate (n = 4) or no extracorporeal procedure at all (n = 5). Pigs on hemodialytic procedures survived significantly longer (51 +/- 11 hrs) than controls (36 +/- 8 hrs). There were no differences in the duration of survival between hemodialysis and hemofiltration, nor between controls undergoing and those not undergoing an extracorporeal procedure. Electroencephalograms showed more rapid (p less than 0.05) deterioration in control animals than in the treatment group. Putative toxins such as ammonia, glutamine, tyrosine, tryptophan, and methionine all decreased transiently in the treatment group; in the control group a continuous increase in the levels of the putative toxins was observed. Comparison of all pigs surviving 35 hrs or less (n = 6) and animals surviving more than 45 hrs (n = 7) showed that long-term survival was significantly associated with lower plasma ammonia and methionine concentrations and fewer abnormalities on the electroencephalogram 10 hrs after the start of extracorporeal procedures; moreover six of the 7 long-term survivors underwent hemodialysis or hemofiltration procedures. We conclude that hemodialytic procedures prolong survival in pigs with ischemic hepatic necrosis by slowing the development of encephalopathy; this effect of hemodialytic procedures may be mediated by the lowering of plasma ammonia and methionine levels.

[Renal artery reconstruction for renovascular hypertension]. / Nierarteriereconstructie wegens renovasculaire hypertensie.

Between 1959 and 1983, 172 patients were treated for hypertension by reconstruction of a renal artery. Reconstruction was preferably performed with autologous material. In a selected group of 29 patients with lesions in the distal renal artery or the hilar branches, an extracorporeal reconstruction with autotransplantation was performed. After a mean follow-up of 8.4 years the hypertension was cured or improved in 82% of the patients. In patients with an arteriosclerotic renal artery stenosis this result was favourably influenced by a short duration of hypertension before the operation. Their life expectancy after the operation was clearly favourably influenced by a beneficial blood pressure response even if arteriosclerotic lesions of coronary arteries, extracranial vessels and/or peripheral vessels were present before the renovascular operation. In selected patients, renal artery reconstruction for treatment of hypertension yields excellent short-term and long-term results, not only with regard to the blood pressure response but also with respect to the patients' life expectancy.

[Possibilities and limitations of heterotopic auxiliary liver transplantation]. / Möglichkeiten und Grenzen der heterotopen auxiliären Lebertransplantation.

Although auxiliary heterotopic liver transplantation offers theoretical advantages over orthotopic liver replacement, clinical results have heretofore been dismal. After development of a technique of reduced size liver grafts provided with portal and arterial blood and venous drainage via the suprahepatic V. cava (HLT) in experimental animals, this method was applied in 21 transplantations in 19 patients. 11 of 16 patients with chronic liver insufficiency and one of three patients with fulminant liver failure survived transplantation for at least 1 year. HLT was well tolerated even by high-risk patients. Possibilities and limitations of this novel approach are discussed.