Editor's Choice - Nationwide Analysis of Patients Undergoing Iliac Artery Aneurysm Repair in the Netherlands.

OBJECTIVE: The new 2019 guideline of the European Society for Vascular Surgery (ESVS) recommends consideration for elective iliac artery aneurysm (eIAA) repair when the iliac diameter exceeds 3.5 cm, as opposed to 3.0 cm previously. The current study assessed diameters at time of eIAA repair and ruptured IAA (rIAA) repair and compared clinical outcomes after open surgical repair (OSR) and endovascular aneurysm repair (EVAR). METHODS: This retrospective observational study used the nationwide Dutch Surgical Aneurysm Audit (DSAA) registry that includes all patients who undergo aorto-iliac aneurysm repair in the Netherlands. All patients who underwent primary IAA repair between 1 January 2014 and 1 January 2018 were included. Diameters at time of eIAA and rIAA repair were compared in a descriptive fashion. The anatomical location of the IAA was not registered in the registry. Patient characteristics and outcomes of OSR and EVAR were compared with appropriate statistical tests. RESULTS: The DSAA registry comprised 974 patients who underwent IAA repair. A total of 851 patients were included after exclusion of patients undergoing revision surgery and patients with missing essential variables. eIAA repair was carried out in 713 patients, rIAA repair in 102, and symptomatic IAA repair in 36. OSR was performed in 205, EVAR in 618, and hybrid repairs and conversions in 28. The median maximum IAA diameter at the time of eIAA and rIAA repair was 43 (IQR 38-50) mm and 68 (IQR 58-85) mm, respectively. Mortality was 1.3% (95% CI 0.7-2.4) after eIAA repair and 25.5% (95% CI 18.0-34.7) after rIAA repair. Mortality was not significantly different between the OSR and EVAR subgroups. Elective OSR was associated with significantly more complications than EVAR (intra-operative: 9.8% vs. 3.6%, post-operative: 34.0% vs. 13.8%, respectively). CONCLUSION: In the Netherlands, most eIAA repairs are performed at diameters larger than recommended by the ESVS guideline. These findings appear to support the recent increase in the threshold diameter for eIAA repair.

An association between chronic obstructive pulmonary disease and abdominal aortic aneurysm beyond smoking: results from a case-control study.

OBJECTIVES: It is currently unclear whether the parallels between abdominal aortic aneurysms (AAAs) and chronic obstructive pulmonary disease (COPD) are explained by common risk factors alone, such as cigarette smoking, or by a predetermined cause. Given the persistent controversy with regard to the association between AAA and COPD, we studied this association in depth. METHODS: We conducted a case-control study comparing patients with a small AAA (maximum infrarenal diameter 35-50 mm, n = 221) with controls diagnosed with peripheral artery disease (PAD, n = 87). The controls were matched to the cases for lifetime cigarette smoking. Pulmonary function was measured by spirometry, and all subjects completed a questionnaire on medical history and smoking habits (current, former and never smokers). RESULTS: Aneurysm patients were similar to controls with respect to gender (p = 0.71), lifetime cigarette smoking (39 vs. 34 pack years, p = 0.23) and history of cardiovascular disease (45% vs. 55%, p = 0.12). Aneurysm patients had more airway obstruction (forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) (0.69 ± 0.12 vs. 0.78 ± 0.11, p < 0.001)), which was most pronounced in never smokers (0.73 ± 0.07 vs. 0.86 ± 0.07, p < 0.001). COPD was more prevalent in aneurysm patients (44%; 98/221) than in controls (20%; 17/87) (adjusted odds ratio (OR) 3.0; 95% confidence interval (95%CI) 1.6-5.5, p < 0.001). In particular, a major proportion of AAA patients was newly diagnosed with COPD; only 40 of 98 patients (41%) with COPD (mild, moderate or severe/very severe) were known before with obstructive pulmonary defects and received treatment. CONCLUSIONS: This study confirms an association between AAA and COPD and shows that this association is independent from smoking. Findings also demonstrate that COPD is under-diagnosed in AAA patients.

Effectiveness of a hospital-based vascular screening programme (SMART) for risk factor management in patients with established vascular disease or type 2 diabetes: a parallel-group comparative study.

AIMS: Modification of vascular risk factors is effective in reducing mortality and morbidity in patients with symptomatic atherosclerosis; however, it is difficult to achieve and maintain. The aim of the Risk management in Utrecht and Leiden Evaluation (RULE) study was to assess risk factor status after referral in patients with established vascular disease or type 2 diabetes who took part in the multidisciplinary hospital-based vascular screening programme, Second Manifestations of ARTerial disease, compared with a group who did not participate in such a programme. METHODS AND RESULTS: Patients with type 2 diabetes, coronary artery disease, cerebrovascular disease or peripheral arterial disease referred by general practitioners to the medical specialist at the University Medical Center (UMC) Utrecht (a setting with a vascular screening programme of systematic screening of risk factors followed by treatment advice) and the Leiden UMC (a setting without such a screening programme), were enrolled in the study. Blood pressure, levels of lipids, glucose and creatinine, weight, waist circumference and smoking status were measured in patients 12-18 months after referral to the two hospitals. A total of 604 patients were treated in the setting with a vascular screening programme and 566 in the setting without such a programme; 70% of all patients were male, with a mean age of 61 +/- 10 years. Amongst screened patients, systolic blood pressure [2.5 mmHg, 95% confidence interval (CI) 0.3-4.6] and the level of LDL cholesterol (0.3 mmol L(-1), 95% CI 0.2-0.4) were lower compared with the group that received usual care, after a median of 16 months from referral. CONCLUSION: Systematic screening of risk factors, followed by evidence-based, tailored treatment advice contributed to slightly better risk factor reduction in patients with established vascular disease or type 2 diabetes. However, a large proportion of patients did not reach the treatment goals according to (inter)national guidelines. Systematic screening of vascular risk factors alone is not enough for adequate risk factor management in high-risk patients.

A comparison of the Doppler-derived maximal systolic acceleration versus the ankle-brachial pressure index or detecting and quantifying peripheral arterial occlusive disease in diabetic patients.

AIM: The aim of this study was to assess the diagnostic accuracy of the Doppler derived maximal systolic acceleration (ACCmax) as a novel technique for evaluating peripheral arterial occlusive disease (PAOD) in patients with diabetes mellitus, who are known for a falsely elevated ankle-brachial index (ABI). METHODS: In this retrospective analysis ACCmax was measured at ankle level in a series of 163 consecutive patients referred to the vascular laboratory for initial assessment of PAOD. Patients were classified according to the presence or absence of diabetes. In the non-diabetic patients PAOD was defined as ABI < or =0.90. This group was used to establish the association between ACCmax and ABI in a linear regression model. The result was then used to predict the presence or absence of PAOD in the diabetic patients. RESULTS: The authors examined 301 lower limbs. The study group consisted of 166 limbs of patients without diabetes and 135 limbs of patients with diabetes. PAOD was present in 52% of limbs in the nondiabetic group versus 59% of limbs in the diabetic group (ABI < or =0.90, or in case of non-compliant vessels toe-brachial index (TBI) < or =0.70). An ACCmax cut-off value of >10 m/s2 was found to be highly predictive for the exclusion of PAOD (negative predictive value 95%). In addition, the ACCmax cut-off value of <6.5 m/s2 was highly predictive for the detection of PAOD (positive predictive value 99%). A strong quadratic association was found between ACCmax and ABI in the non-diabetic group (R2=0.85). In the diabetic patients R2 values were 0.81 and 0.79 after ABI and TBI measurement respectively. CONCLUSION: DUS-derived ACCmax is an accurate marker that could offer significant benefits for the diagnosis of PAOD, especially in diabetic patients.

Vascular training and endovascular practice in Europe.

OBJECTIVE: To evaluate the influence of the status of vascular surgery (VS) training paradigms on the actual practice of endovascular therapy among the European countries. METHODS: An email-based survey concerning vascular surgery training models and endovascular practices of different clinical specialties was distributed to a VS educator within 14 European countries. European Vascular and Endovascular Monitor (EVEM) data also were processed to correlate endovascular practice with training models. RESULTS: Fourteen questionnaires were gathered. Vascular training in Europe appears in 3 models: 1. Mono-specialty (independence): 7 countries, 2. Subspecialty: 5 countries, 3. An existing specialty within general surgery: 2 countries. Independent compared to non-independent certification shortens overall training length (5.9 vs 7.9 years, p=0.006), while increasing overall training devoted specifically to VS (3.9 vs 2.7 years, p=0.008). Among countries with independent certification an average of 76% of aortic and 50% of peripheral endovascular procedures are performed by vascular surgeons, while the corresponding values, for countries with a non-independent certification, are 69% and 36% respectively. Countries with independent vascular certification, despite their lower average endovascular index (procedures per 100,000 population), reported a higher growth rate of aortic endovascular procedures (VS independent 132% vs VS non-independent 87%), within a four-year period (2003-2007). Peripheral endovascular procedures, though, have similar growth rates in both country groups (VS independent 62% vs VS non-independent 60%). CONCLUSIONS: In European countries with VS as an independent specialty, vascular surgeons have a shorter total training period but spend more time in VS training, although they may not undertake a greater proportion of the endovascular procedures their countries appear to have adopted endovascular technologies more rapidly compared to the ones with non-independent VS curricula. Whether such differences influence patient outcomes requires investigation in future studies.

Natural killer cells and CD4+ T-cells modulate collateral artery development.

OBJECTIVE: The immune system is thought to play a crucial role in regulating collateral circulation (arteriogenesis), a vital compensatory mechanism in patients with arterial obstructive disease. Here, we studied the role of lymphocytes in a murine model of hindlimb ischemia. METHODS AND RESULTS: Lymphocytes, detected with markers for NK1.1, CD3, and CD4, invaded the collateral vessel wall. Arteriogenesis was impaired in C57BL/6 mice depleted for Natural Killer (NK)-cells by anti-NK1.1 antibodies and in NK-cell-deficient transgenic mice. Arteriogenesis was, however, unaffected in J alpha281-knockout mice that lack NK1.1+ Natural Killer T (NKT)-cells, indicating that NK-cells, rather than NKT-cells, are involved in arteriogenesis. Furthermore, arteriogenesis was impaired in C57BL/6 mice depleted for CD4+ T-lymphocytes by anti-CD4 antibodies, and in major histocompatibility complex (MHC)-class-II-deficient mice that more selectively lack mature peripheral CD4+ T-lymphocytes. This impairment was even more profound in anti-NK1.1-treated MHC-class-II-deficient mice that lack both NK- and CD4+ T-lymphocytes. Finally, collateral growth was severely reduced in BALB/c as compared with C57BL/6 mice, 2 strains with different bias in immune responsiveness. CONCLUSIONS: These data show that both NK-cells and CD4+ T-cells modulate arteriogenesis. Promoting lymphocyte activation may represent a promising method to treat ischemic disease.

Vascular growth in ischemic limbs: a review of mechanisms and possible therapeutic stimulation.

Stimulation of vascular growth to treat limb ischemia is promising, and early results obtained from uncontrolled clinical trials using angiogenic agents, e.g., vascular endothelial growth factor, led to high expectations. However, negative results from recent placebo-controlled trials warrant further research. Here, current insights into mechanisms of vascular growth in the adult, in particular the role of angiogenic factors, the immune system, and bone marrow, were reviewed, together with modes of its therapeutic stimulation and results from recent clinical trials. Three concepts of vascular growth have been described to date-angiogenesis, vasculogenesis, and arteriogenesis (collateral artery growth)-which represent different aspects of an integrated process. Stimulation of arteriogenesis seems clinically most relevant and has most recently been attempted using autologous bone marrow transplantation with some beneficial results, although the mechanism of action is not completely understood. Better understanding of the highly complex molecular and cellular mechanisms of vascular growth may yet lead to meaningful clinical applications.

Intramuscular or combined intramuscular/intra-arterial administration of bone marrow mononuclear cells: a clinical trial in patients with advanced limb ischemia.

AIM: Recent evidence indicates that bone marrow mononuclear cells (BMC) promote collateral vessel formation in patients with severe peripheral arterial disease (PAD). However, aspects concerning optimal administration mode, durability and long-term safety require consideration. Combined intra-arterial (IA) plus intramuscular (IM) BMC delivery may be more effective than exclusive intramuscular injections. The aim of this study was to evaluate feasibility, safety and effect of exclusive IM versus combined IM+IA delivery of autologous BMC in patients who were not candidates for surgical or endovascular treatment. METHODS: Twenty-seven patients were treated with either combined IA+IM (N=12) or sole IM (N=15) administration of autologous BMC. Efficacy was assessed after 1, 6 and 12 months. Limb salvage, pain-free walking distance, ankle-brachial pressure index (ABI) and pain scores were evaluated. RESULTS: There were no adverse reactions related to injection of the cells. Three patients died within the first year of follow-up due to non-procedure related causes. Two patients in the IA+IM group required limb amputation because of ongoing critical ischemia versus 7 patients in the IM group (P=0.17). BMC treatment in the remaining patients resulted in a significant and sustained (>12 months) improvement. Pain-free walking distance improved from 81+/-56 meters at baseline to 257+/-126 meters at t=6 months (P=0.0002). Mean ABI increased 23% after 6 months (P=0.01) and pain score reduced for up to 50% as shown by Brief Pain Inventory (P=0.001). CONCLUSION: Both IM and combined IM/IA delivery of autologous BMC are safe, and result in relevant and sustained improvement in a considerable proportion of patients with severe PAD who are not amenable for conventional treatment.

Inhibition of complement component C3 reduces vein graft atherosclerosis in apolipoprotein E3-Leiden transgenic mice.

BACKGROUND: Venous bypass grafts may fail because of development of intimal hyperplasia and accelerated atherosclerosis. Inflammation plays a major role in these processes. Complement is an important part of the immune system and participates in the regulation of inflammation. The exact role of complement in the process of accelerated atherosclerosis of vein grafts has not yet been explored, however. METHODS AND RESULTS: To assess the role of complement in the development of vein graft atherosclerosis, a mouse model, in which a venous interposition was placed in the common carotid artery, was used. In this model, vein graft thickening appeared within 4 weeks. The expression of complement components was studied with the use of immunohistochemistry on sections of the thickened vein graft. C1q, C3, C9, and the regulatory proteins CD59 and complement receptor-related gene y could be detected in the lesions 4 weeks after surgery. Quantitative mRNA analysis for C1q, C3, CD59, and complement receptor-related gene y revealed expression of these molecules in the thickened vein graft, whereas C9 did not show local mRNA expression. Furthermore, interference with C3 activation with complement receptor-related gene y-Ig was associated with reduced vein graft thickening, reduced C3 and C9 deposition, and reduced inflammation as assessed by analysis of influx of inflammatory cells, such as leukocytes, T cells, and monocytes. In addition, changes in apoptosis and proliferation were observed. When C3 was inhibited by cobra venom factor, a similar reduction in vein graft thickening was observed. CONCLUSIONS: The complement cascade is involved in vein graft thickening and may be a target for therapy in vein graft failure disease.

Anti-MCP-1 gene therapy inhibits vascular smooth muscle cells proliferation and attenuates vein graft thickening both in vitro and in vivo.

OBJECTIVE: Because late vein graft failure is caused by intimal hyperplasia (IH) and accelerated atherosclerosis, and these processes are thought to be inflammation driven, influx of monocytes is one of the first phenomena seen in IH, we would like to provide direct evidence for a role of the MCP-1 pathway in the development of vein graft disease. METHODS AND RESULTS: MCP-1 expression is demonstrated in various stages of vein graft disease in a murine model in which venous interpositions are placed in the carotid arteries of hypercholesterolemic ApoE3Leiden mice and in cultured human saphenous vein (HSV) segments in which IH occurs. The functional involvement of MCP-1 in vein graft remodeling is demonstrated by blocking the MCP-1 receptor CCR-2 using 7ND-MCP-1. 7ND-MCP1 gene transfer resulted in 51% reduction in IH in the mouse model, when compared with controls. In HSV cultures neointima formation was inhibited by 53%. In addition, we demonstrate a direct inhibitory effect of 7ND-MCP-1 on the proliferation of smooth muscle cell (SMC) in HSV cultures and in SMC cell cultures. CONCLUSIONS: These data, for the first time, prove that MCP-1 has a pivotal role in vein graft thickening due to intimal hyperplasia and accelerated atherosclerosis.

Development of fibrinous thrombus analogue for in-vitro abdominal aortic aneurysm studies.

PURPOSE: To develop different thrombus analogues, with mechanical properties similar to those of human fibrinous thrombus, for in-vitro aneurysm sac pressure studies. METHODS: Using dynamic mechanical analysis we determined the E-modulus (/E(*)/) at 0.8, 1.0, 1.5 and 3.9 Hz of ten different human fibrinous thrombus samples. We also determined loss and storage modulus to quantify the visco-elastic properties. For comparison, we measured the E-modulus (|E(*)|), loss and storage modulus of gelatin, Novalyse ST8, ST14 and ST20 with and without contrast agent. RESULTS: Mean E-modulus of the thrombus samples (SD) at 0.8, 1.0, 1.5 and 3.9 Hz was 39 (16), 37 (15), 37 (15) and 38 (14)kPa, respectively. Median (SD) storage and loss modulus were 35 (12) and 8 (4)kPa, respectively. Median (SD) tandelta was 0.25 (0.06). The E-modulus of gelatin, Novalyse ST8, ST14 and ST20 was 4, 27, 48 and 60 kPa, respectively. The E-modulus of Novalyse ST8, ST14 and ST20 mixed with contrast agent was 18, 23 and 33 kPa, respectively. Median (SD) storage, loss modulus and tan delta of the six Novalyse samples were 30 (15), 3 (1) and 0.087 (0.04), respectively. CONCLUSION: All the thrombus analogues, except gelatin, had an E-modulus in the range of human fibrinous thrombi. Novalyse samples are validated thrombus analogues for in-vitro aneurysm sac pressure studies. Gelatin is not appropriate to simulate fibrinous thrombus.

European continuing medical education in vascular surgery: 5-year results of congresses approved by the Union Européenne des Médecins Spécialistes Section of Vascular Surgery.

AIM: Continuing medical education (CME) can be defined as ''educational activities that serve to maintain, develop, or increase the knowledge, skills and professional performance of a physician to provide services for patients, the public, or the profession''. CME is a major professional responsibility. The European Board of Vascular Surgery of the Union Européenne des Médecins Spécialistes (UEMS) Section of Vascular Surgery has, through its European Vascular CME (EVCME) Committee, accredited 74 congresses during the 5-year period from 2000-2004. METHODS: Official evaluation forms were completed by the congress participants for a personal appraisal of the quality of the activities. The data in this manuscript focused on questions that were the most relevant and of the greatest interest to the participants. A statistical analysis of the results was performed utilizing ANOVA and Robust tests of equality of means as well as a posthoc analysis for further investigation, and non parametric Wilcoxon signed ranks test. RESULTS: The educational needs of participants regarding new diagnostic and therapeutic modes were stated as ''important'' and ''extremely important'' in the responses at over 80% in total. Over 75% of the participants answered ''extremely important'' and ''important'' to the question ''how important is evidence-based practice to your practice''. CONCLUSION: This survey indicates that the EVCME approved congresses had a positive impact for the vascular surgeon by updating overall knowledge on vascular surgery; the majority of comments by the participants also indicates that EVCME is fulfilling its aim to bring as much evidence-based practice as possible into the daily work schedule of the surgeon by turning knowledge acquired by CME into performance of the participants.

Accelerated atherosclerosis and calcification in vein grafts: a study in APOE*3 Leiden transgenic mice.

Vein grafts fail due to development of intimal hyperplasia and accelerated atherosclerosis. Many murine genetic models in which genes are overexpressed, deleted, or mutated have been introduced recently. Therefore, mouse models are very well suited to dissect the relative contribution of different genes in the development of accelerated atherosclerosis. In the present study, we evaluated whether accelerated atherosclerosis in human vein grafts could be mimicked in hypercholesterolemic APOE*3 Leiden transgenic mice. Venous bypass grafting was performed in the carotid artery in APOE*3 Leiden mice fed either a standard chow diet or a high cholesterol-rich diet for 4 weeks. At several time points (0 hour to 28 days), mice were euthanized and the morphology of the vein grafts was analyzed. In normocholesterolemic mice, vein graft thickening up to 10-fold original thickness, predominantly consisting of alpha-smooth muscle cell actin-positive cells, was observed after 28 days. In hypercholesterolemic mice, accelerated atherosclerosis with accumulation of lipid-loaded foam cells was observed within 7 days after surgery. This accelerated atherosclerosis progressed in time and resulted in significant increase in vein graft thickening up to 50 times original thickness with foam cell-rich lesions and calcification within 28 days after surgery. The atherosclerotic lesions observed in these murine grafts show high morphological resemblance with the atherosclerotic lesions observed in human vein grafts. This accelerated, diet-dependent induction of atherosclerotic-like lesions in murine vein grafts provides a valuable tool in evaluating the mechanisms of accelerated atherosclerosis and therapeutic interventions of vein graft disease.

Inhibition of accelerated atherosclerosis in vein grafts by placement of external stent in apoE*3-Leiden transgenic mice.

OBJECTIVE: Vein grafts fail because of the development of intimal hyperplasia and accelerated atherosclerosis. Placement of an external stent around vein grafts resulted in an inhibition of intimal hyperplasia in several animal studies. Here, we assess the effects of external stenting on accelerated atherosclerosis in early vein grafts in carotid arteries in hypercholesterolemic apolipoprotein E*3-Leiden transgenic mice. METHODS AND RESULTS: Venous interposition grafting was performed in apolipoprotein E*3-Leiden mice fed standard chow or a highly cholesterol-rich diet for 4 weeks. After engraftment, external stents with different inner diameters (0.4 or 0.8 mm) were placed. In unstented vein grafts in hypercholesterolemic mice, thickening up to 50 times the original thickness, with foam cell-rich lesions, calcification, and necrosis, was observed within 28 days. The atherosclerotic lesions observed show high morphological resemblance to atherosclerotic lesions observed in human vein grafts. In stented vein grafts in hypercholesterolemic mice, no foam cell accumulation or accelerated atherosclerosis was observed. Compared with unstented vein grafts, stenting of vein grafts in a hypercholesterolemic environment resulted in a 94% reduction of vessel wall thickening. These effects were independent of stent size. CONCLUSIONS: Extravascular stent placement results in strong inhibition of accelerated vein graft atherosclerosis in hypercholesterolemic transgenic mice and thereby provides a perspective for therapeutic intervention in vein graft diseases.

Perioperative mortality of elective abdominal aortic aneurysm surgery. A clinical prediction rule based on literature and individual patient data.

BACKGROUND: Abdominal aortic aneurysm surgery is a major vascular procedure with a considerable risk of (mainly cardiac) mortality. OBJECTIVE: To estimate elective perioperative mortality, we developed a clinical prediction rule based on several well-established risk factors: age, gender, a history of myocardial infarction, congestive heart failure, ischemia on the electrocardiogram, pulmonary impairment, and renal impairment. METHODS: Two sources of data were used: (1) individual patient data from 246 patients operated on at the University Hospital Leiden (the Netherlands) and (2) studies published in the literature between 1980 and 1994. The Leiden data were analyzed with univariate and multivariate logistic regression. Literature data were pooled with meta-analysis techniques. The clinical prediction rule was based on the pooled odds ratios from the literature, which were adapted by the regression results of the Leiden data. RESULTS: The strongest adverse risk factors in the literature were congestive heart failure and cardiac ischemia on the electrocardiogram, followed by renal impairment, history of myocardial infarction, pulmonary impairment, and female gender. The literature data further showed that a 10-year increase in age more than doubled surgical risk. In the Leiden data, most multivariate effects were smaller than the univariate effects, which is explained by the positive correlation between the risk factors. In the clinical prediction rule, cardiac, renal, and pulmonary comorbidity are the most important risk factors, while age per se has a moderate effect on mortality. CONCLUSIONS: A readily applicable clinical prediction rule can be based on the combination of literature data and individual patient data. The risk estimates may be useful for clinical decision making in individual patients.

Risk factors for delayed graft function in cadaveric kidney transplantation: a prospective study of renal function and graft survival after preservation with University of Wisconsin solution in multi-organ donors. European Multicenter Study Group.

BACKGROUND: Delayed graft function (DGF) remains an important complication in renal transplantation. In this multicenter study, we investigated the influence of donor and recipient factors on the occurrence of DGF and DGF's effect on long-term graft survival. METHODS: A total of 547 transplanted kidney allografts, retrieved from multi-organ donors, were analyzed, and results were compared with literature on kidney-only donors. RESULTS: Median follow-up of patients without graft failure was 3.4 years. Twenty-four percent of the recipients developed DGF. In univariate analysis, the following factors significantly increased the incidence of DGF: (a) among the donor factors, mean creatinine level >120 micromol/L and prolonged cold ischemia time (CIT); and (b) among the recipient factors, previous transplant(s), no intraoperative use of mannitol, poor quality of reperfusion, absence of intraoperative diuresis, and pretransplant anuria or oliguria. After stepwise logistic regression, donor age, CIT, recipient's number of previous transplants, and intraoperative diuresis proved to be of independent prognostic value for the occurrence of DGF. Overall graft survival was 91%, 87%, and 72% at 3 months, 1 year, and 4 years after transplantation, respectively. In case of DGF, graft survival was approximately 10% lower when compared with cases with immediate graft function (P<0.001). No difference in incidence of DGF was found between grafts of multi-organ donors and kidney-only donors. CONCLUSIONS: DGF results in an approximately 10% higher rate of graft failure. DGF incidence can be reduced by the administration of mannitol during transplantation, which minimizes CIT and optimizes donor management. Grafts from multi-organ donors and kidney-only donors appear to be of equal quality.

Long-term cardiovascular morbidity and mortality in autosomal dominant polycystic kidney disease patients after renal transplantation.

Patients with autosomal dominant polycystic kidney disease (ADPKD) have an increased incidence of hypertension and cardiovascular abnormalities. In this long-term follow-up study (5.88 years on average), we evaluated cardiovascular disease and patient and graft survival in 101 ADPKD patients and 692 nondiabetic control patients receiving cadaveric renal transplants between March 1967 and April 1991 at the Leiden University Hospital. Graft and patient survival was not different between patient groups, using the same immunosuppressive therapy. However, death with functioning graft, mainly due to cardiovascular disease, was significantly more frequent in the ADPKD patients than in controls using AZA (P < 0.01). Multivariate analysis of pretransplant data showed that ADPKD patients on AZA therapy demonstrated an elevated age-adjusted relative risk of 2.07 (95% confidence interval [95% CI]: 1.12-3.80) for cardiovascular events and 2.88 (95% CI: 1.41-5.90) for cardiovascular mortality alone. After adjustment for age, gender, and other cardiovascular risk factors, a relative risk of 2.39 (95% CI: 1.06-5.40) was found. This was 2.87 (95% CI: 1.04-7.93) when cardiovascular mortality was the dependent variable. With posttransplant data, the age-adjusted relative risk for cardiovascular morbidity and mortality in ADPKD patients using AZA was 2.16 (95% CI: 1.12-4.15) and 2.97 (95% CI: 1.40-6.27), with only cardiovascular mortality as the dependent variable. After adjustment for age, gender, and other cardiovascular risk factors, this was 1.59 (95% CI: 0.64-3.91) and 2.28 (95% CI: 0.79-6.53), respectively. With CsA treatment, an elevated risk for cardiovascular morbidity and mortality in ADPKD patients was present, but the corresponding 95% CI were wide and include unity, due to the shorter period of follow-up (CsA: 3.81 +/- 2.50 years vs. AZA: 7.28 +/- 6.74 years). Survival of ADPKD patients using AZA was less in those patients without pretransplant nephrectomy as compared with control patients, but the morbidity and mortality of pretransplant nephrectomies should be taken into account. We conclude that ADPKD patients show a similar graft and patient survival after renal transplantation as control patients, but they are especially at risk for cardiovascular disease after renal transplantation.

Effect of warm ischemia time and HLA (A and B) matching on renal cadaveric graft survival and rejection episodes.

In a retrospective single-center study the influence of warm ischemia time and simultaneous influence of HLA (A and B) matching on one-year renal graft survival was analyzed in 170 adult recipients of primary cadaveric renal grafts. One-year survival of grafts with warm ischemia times longer than 50 min was only 40% (n = 10). When warm ischemia time was shorter than 50 min, a 1-min increase of warm ischemia time correlated with 1% decrease in one-year graft survival as a result of rejection. This detrimental effect of warm ischemia time on graft survival was not yet significant one month after transplantation, but became more evident as follow-up time was lengthened. Warm ischemia time also correlated with the number of reversible rejection episodes in patients with a graft functioning for longer than one year (P less than 0.04). The beneficial influence of HLA (A and B) matching on one-year graft survival was significant (P less than 0.05 log linear test). This influence was even more evident with longer warm ischemia times. It is concluded that warm ischemia has a detrimental influence on graft survival that is mediated by rejection, and it is suggested that this might be due in part to altered presentation or expression of HLA-antigens of ischemically damaged kidney tissues.

Donor-specific lysis of human kidney proximal tubular epithelial cells by renal allograft-infiltrating lymphocytes.

In the present study methods are described to obtain both graft infiltrating cells (GIC) of host origin and proximal tubular epithelial cells (PTEC) of donor origin simultaneously from biopsy material of renal allografts undergoing rejection. The identity of PTEC cultures was established using monoclonal antibodies. GIC were shown to exhibit T cell functional activity. These GIC were shown to lyse trypsinized PTEC as well as PTEC monolayers grown from the corresponding biopsy, and not PTEC isolated from biopsies obtained from other patients. Therefore the lytic activity appeared to be donor-specific. Major histocompatibility complex class I antigens were involved since donor PHA-blasts, a target population well known to express class I molecules, were lysed by GIC, and the anti-class I MoAb W6/32 blocked cytolytic activity of GIC against donor PHA-blasts and against donor PTEC. We thus established that donor-specific lysis of a defined population of kidney epithelial cells, namely PTEC, may occur. This model system, in which GIC and PTEC can be propagated from one biopsy specimen may be useful for further study of cell-cell interactions involved in allograft rejection.

The relation between acute vascular and interstitial renal allograft rejection and subsequent chronic rejection.

Chronic rejection of renal allografts is a major cause of late graft loss. However, time of onset, relation with acute early rejection episodes, and risk factors are largely unknown. We undertook a cohort study of 482 consecutive patients from a single center who received a cadaveric renal allograft between January 1983 and April 1991. During the first 3 months after transplantation, 76 (15.8%) patients developed vascular rejection and 115 (23.9%) developed interstitial rejection. One-year graft survival of patients without rejection, with interstitial rejection, and with vascular rejection was 87.8%, 87%, and 48.7%, respectively. Five-year graft survival was 73.5% for the group without rejection, 71.4% for patients with interstitial rejection, and 34.3% for patients with vascular rejection. The adjusted relative risk of graft loss was 4.92 (95% CI 3.25-7.43) for patients with vascular rejection and 1.27 (95% CI 0.80-2.02) for patients with interstitial rejection compared with patients without early rejection, taking the time dependency of the rejection events and prognostic factors into account. The incidence of vascular rejection was increased in patients with primary nonfunction (RR 1.69, 95% CI 1.01-2.84), with 1 HLA-DR mismatch (RR 2.38, 95% CI 1.44-3.93), with 2 HLA-DR mismatches (RR 3.24, 95% CI 1.25-8.42), with a prolonged cold ischemia time (RR 1.03, 95% CI 1.00-1.06 per hr), and with 1 or more previous transplantations (RR 1.76, 95% CI 1.01-3.07). Risk of developing vascular rejection was decreased in patients using CsA as compared with azathioprine (RR 0.41, 95% CI 0.24-0.67). Early vascular rejection, occurring within 3 months after transplantation, is the most important predicting variable of both early and late graft loss. Use of CsA, less HLA-DR mismatching, and a cold ischemia time of short duration possibly prevent the development of vascular rejection.