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Statin use is associated with improved function and survival of lung allografts.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are widely used antilipidemic agents that are also immunomodulatory. We evaluated possible effects of these agents after lung transplantation by comparing outcomes of 39 allograft recipients, who were prescribed statins for hyperlipidemia, with those of 161 contemporaneous control recipients who did not receive these drugs. Acute rejection (>or= Grade II) was less frequently found in the statin group (15.1 versus 25.6% of biopsies, p < 0.01). None of 15 recipients started on statins during postoperative Year 1 developed obliterative bronchiolitis, whereas the cumulative incidence of this complication among control subjects was 37% (p < 0.01). Total cellularity, as well as proportions of inflammatory neutrophils and lymphocytes, were significantly lower in bronchoalveolar lavages of statin recipients. Among double lung recipients, those taking statins had significantly better spirometry: FVC (80 +/- 2 versus 70 +/- 1%) and FEV1 (87 +/- 2 versus 70 +/- 1%), as percentages of predicted values, and absolute FEV1/FVC (83.4 +/- 1.2 versus 78.6 +/- 0.5) (all p < 0.01). The 6-year survival of recipients taking statins (91%) was much greater than that of control subjects (54%) (p < 0.01). These data suggest statin use may have substantial clinical benefits after pulmonary transplantation.

Acute Disease↗

Effects of fluvastatin on cardiac events in renal transplant patients: ALERT (Assessment of Lescol in Renal Transplantation) study design and baseline data.

BACKGROUND: Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ('statins') reduces morbidity and mortality from coronary heart disease in diverse patient populations. STUDY AIMS: The aim of the present ALERT (Assessment of Lescol in Renal Transplantation) study is to determine whether renal transplant recipients would also benefit from statin therapy. ALERT is a multicentre, randomized, double-blind, placebo-controlled trial to assess the effect of fluvastatin in renal transplant recipients with mild-to-moderate hypercholesterolaemia. The primary objective is to investigate the effects of fluvastatin on major adverse cardiac events (MACE). In addition, the effects on cardiovascular and all-cause mortality, as well as renal function, will be addressed. STUDY POPULATION: The study population contains patients with functioning renal allografts of more than 6 months' duration, recruited from 75 centres in Northern Europe and Canada. Patients of both sexes, aged 30-75 years, with a total cholesterol level of 4.0-9.0 mmol/l (155-348 mg/dl) were included, except for those with a history of myocardial infarction, where the upper limit for inclusion was 7.0 mmol/l (270 mg/dl). STUDY DESIGN: A total of 2100 patients were recruited by the end of October 1997 and will be followed for up to 6 years. This report presents the design features of the study (recruitment, follow-up, sample size, data analysis and study organization), along with baseline results. ALERT is the first large-scale prospective, randomized, double-blind study to address the prevention of cardiovascular mortality in renal transplant patients receiving an HMGCoA reductase inhibitor.

Adult↗

Clipless management of the renal vein during hand-assist laparoscopic donor nephrectomy.

BACKGROUND: Laparoscopic live donor nephrectomy has become the preferred method of donor nephrectomy at many transplant centers. The laparoscopic stapling device is commonly used for division of the renal vessels. Malfunction of the stapling device can occur, and is often due to interference from previously placed clips. We report our experience with a clipless technique in which no vascular clips are placed on tributaries of the renal vein at or near the renal hilum in order to avoid laparoscopic stapling device misfires. METHODS: From December 20, 2002 to April 12, 2005, 50 patients underwent hand-assisted laparoscopic left donor nephrectomy (LDN) at our institution. Clipless management of the renal vein tributaries was used in all patients, and these vessels were divided using either a laparoscopic stapling device or the LigaSureTM device (Valleylab, Boulder, CO). The medical and operative records of the donors and recipients were reviewed to evaluate patient outcomes. RESULTS: The mean follow-up time was 14 months. Of the 50 LDN procedures, there were no laparoscopic stapling device malfunctions and no vascular complications. All renal allografts were functioning at the time of follow-up. CONCLUSION: Laparoscopic stapling device failure due to deployment across previously placed surgical clips during laparoscopic live donor nephrectomy can be prevented by not placing clips on the tributaries of the renal vein. In our series, there were no vascular complications and no device misfires. We believe this clipless technique improves the safety of laparoscopic donor nephrectomy.

Female↗

Novel delivery of pancreatic islet cells to treat insulin-dependent diabetes mellitus.

Immune protective devices containing pancreatic islets are designed to treat insulin-dependent diabetes mellitus by providing glycaemic control without immunosuppression. The immune protection is achieved by separating allogeneic or xenogeneic islets from the host by semipermeable membranes that allow only small molecules such as glucose, insulin and nutrients to pass through. Lymphocytes and immunoglobulins are excluded by the membrane and unable to cause rejection of the islets. Three types of immune protective devices, i.e. microcapsules, diffusion chambers and perfusion devices (vascularised artificial pancreas), have been studied. Microcapsules injected into the abdominal cavity in a large quantity achieved glycaemic control, but required a small amount of immunosuppression to prevent fibrosis around the the capsules. A clinical attempt to use microcapsulated human islets in a diabetic patient who has maintained functional kidney allografts has been reported. Intra-abdominal placement of diffusion chambers containing allogeneic islets achieved excellent glycaemic control without immunosuppression in diabetic dogs. However, their use was limited by the eventual breakage of tubular chambers. We have extensively used the vascularized artificial pancreas for treatment of experimental diabetes mellitus. Excellent biocompatibility of the device was evidenced by the extraordinary longevity of the patency of the device in healthy dogs. Long term control of severe diabetes mellitus was achieved in totally pancreatectomised dogs without immunosuppression by devices seeded with allogeneic (canine) and xenogeneic (porcine) islets. The vascularised artificial pancreas could be an excellent alternative to Diabetes Control and Complication Trial (DCCT)-type intensive insulin therapy or pancreatic transplantation by providing tight glycaemic control with minimal exogenous insulin therapy without immunosuppression.

Animals↗

Reversal of diabetes in outbred mice by islet allotransplantation.

The combination of donor pretreatment with cyclophosphamide, organ culture in 95% O2:5% CO2 for 7-10 days, and short-term immunosuppression of recipients with cyclosporin A (CsA) were necessary to obtain 100% survival of single-cluster BALB/c islet allografts in outbred mice. In vivo and in vitro pretreatment of the donor tissue alone resulted in the acceptance of 45% of the islet allografts in nonimmunosuppressed outbred mice. CsA treatment of recipients alone yielded 40% survival of the untreated allografts. CsA treatment played an important role in maintaining the capacity of islet allografts to function in outbred mice. During CsA treatment, 88% of streptozocin-treated mice showed graft-dependent reversal of diabetes; the remainder showed no evidence of graft function, and CsA treatment failed to prevent acute graft rejection. After withdrawal of CsA immunosuppression, 38% of this total group remained normoglycemic. These findings suggest that modulation of both donor-tissue immunogenicity and recipient responsiveness will be required for successful pancreatic islet transplantation in diabetic humans.

Animals↗

Cotransplantation of allogeneic islets with allogeneic testicular cell aggregates allows long-term graft survival without systemic immunosuppression.

We prepared single-cell suspensions of Lewis rat ¿RT1(1/l)¿ testicular cells and cultured these in vitro for 48 h under conditions that promoted the formation of cellular aggregates. In the absence of systemic immunosuppression, the transplantation of a sufficient quantity of these aggregates (containing 11 x 10(6) cells, (75% Sertoli cells), together with 2,000 purified Lewis rat islets, reversed the diabetic state for >95 days in 100% (5/5) of the chemically diabetic Wistar-Furth ¿RT1(u/u)¿ recipients. Similar grafts consisting of islets alone or islets plus 50% fewer testicular cell aggregates survived for only 10 days. Functioning composite allografts harvested from normoglycemic animals at approximately 100 days showed healthy beta-cells in close association with Fas ligand-expressing Sertoli cells. Because no gene therapy protocol is required, the transplantation of composite grafts consisting of purified human allogeneic islets plus human allogeneic testicular cell aggregates can be applied in clinical islet transplantation as soon as it has been proven in a large animal model.

Animals↗

Lipid status after pancreas-kidney transplantation.

OBJECTIVE: This study was performed to determine the net effects of euglycemia, resolution of renal failure, immunosuppressant drugs, and hyperinsulinemia on fasting lipid profiles of patients with renal failure and insulin-dependent diabetes mellitus (IDDM) after combined pancreas-kidney transplantation (PKT). RESEARCH DESIGN AND METHODS: Thirty subjects with IDDM received PKT between April 1989 and October 1990, and all were studied. Mean +/- SE age was 35.2 +/- 1.3 yr; 19 recipients were men, and 11 were women. All had a functioning pancreatic allograft post-PKT. Fasting lipid profiles including total cholesterol (C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-chol), and C/HDL-chol were compared before and after PKT (38-555 days divided into groups: preoperation and 0-2, 3-8, and 9-19 mo). RESULTS: Significant hyperlipidemia was observed preoperatively (means +/- SE): C, 5.92 +/- 0.27 mM; HDL-chol, 1.07 +/- 0.09 mM; TG, 5.85 +/- 0.56 mM; and C/HDL-chol, 6.49 +/- 0.83. All lipids and C/HDL-chol dropped immediately after PKT (0-2 mo vs. preoperation, all P less than 0.01, except HDL-chol). After this immediate postoperative period, C, HDL-chol, and TG stabilized at new concentrations. C (5.44 +/- 0.22 mM) and TG (4.54 +/- 0.48 mM) levels were less than preoperation (not statistically significant and P less than 0.05, respectively). HDL-chol was greater than preoperative values (1.29 +/- 0.06 mM, P less than 0.05). C/HDL-chol dropped after PKT (0-2 mo, 4.85 +/- 0.18, P less than 0.01) and continued to decrease throughout the observation period (3-8 mo, 4.42 +/- 0.23; 9-19 mo, 4.23 +/- 0.23; both P less than 0.01 vs. preoperation). There was no statistical difference between lipid concentrations in male and female subjects. CONCLUSIONS: The lipid status of subjects with IDDM and renal failure was abnormal before PKT and once lipid concentrations stabilized after PKT (greater than 2 mo), HDL-chol was higher and TG and C/HDL-chol levels were significantly lower than preoperative values. If these changes are sustained, risk of future cardiovascular disease in this group of patients might be significantly reduced.

Adult↗

Determination of autofluorescence of red blood cells (RbCs) in uremic patients as a marker of oxidative damage.

AIM: It is suggested that the red blood cells (RBCs) of uremic patients have increased oxidative damage. The activities of different antioxidant enzymes and the levels of several antioxidants or lipid peroxidation products in RBCs are usually determined to estimate the oxidative stress in uremia. The autofluorescence of RBCs as measured by flow cytometry is caused by the formation of conjugated Schiff base compounds from aldehydes derived from lipid peroxidation and amino groups of phospholipids or cell proteins, and has been proposed as a marker of oxidative stress. The aim of this study was to evaluate if this method is suitable for estimation of oxidative stress in the RBCs of patients with different degrees of renal insufficiency. PATIENTS AND METHODS: To determine the oxidative damage in RBCs in uremia, the autofluorescence of RBCs was measured by flow cytometry in the following 3 groups of patients: group A: 16 patients with chronic renal failure (CRF); group B: 16 hemodialysis (HD) patients; group C: 16 patients with a well-functioning renal allograft. Twenty-four healthy volunteers served as controls. The basal value of RBC autofluorescence and the autofluorescence of RBCs after oxidative damage by treatment with 0.1 mM hydrogen peroxide (H2O2)/0.7 mM sodium azide were determined. RESULTS: In basal RBC autofluorescence values, no differences were found between the 3 groups and the controls. However, there was a significant correlation between the increase of serum creatinine and RBC autofluorescence in the group of patients with CRF (r = 0.521; p = 0.038). After H2O2 treatment, the RBC autofluorescence rose markedly in all individuals. This increase in RBC autofluorescence was significantly higher in the patients with CRF (p = 0.003) and in the HD patients (p = 0.001) compared to the controls. In contrast, there was no difference in RBC autofluorescence between the patients with renal allograft and the controls after H2O2 treatment. CONCLUSIONS: In conclusion, flow cytometry is a useful tool for determining oxidative damage in RBCs. The RBCs of uremic patients are more susceptible to oxidative damage induced by H2O2, likely caused by diminished antioxidant defense in the RBC membrane. Successful renal transplantation leads to a normal autofluorescence response in the RBCs after H2O2 treatment.

Aged↗

Occurrence of cancers in immunosuppressed organ transplant recipients.

The findings in this study emphasize the need for lifetime follow-up of organ transplant recipients. Although, a high percentage of posttransplant tumors are low grade malignancies that are readily amenable to treatment, cancer has become a major cause of death in patients otherwise successfully treated by transplantation (14). In an Australian study of the causes of death of patients who survived for at least 10 years with a functioning renal allograft compared with those on dialysis for at least 10 years without transplantation, or with a failed transplant, showed that the proportions of deaths caused by cancer were 26%, 1% and 3%, respectively. Nonetheless the future holds promise. Attempts are being made to modify the present blunderbuss attack on the immune system with more specific methods of control of certain of its components. Much work is currently being done to induce states of immune unresponsiveness directed specifically, and only, at the foreign antigens of the allograft. Hopefully these efforts will eliminate the need for long-term or intense immunosuppressive therapy and the problem of posttransplant malignancies will be relegated to a footnote in the history of organ transplantation.

Australia↗

The effect of FasL expression on pancreatic islet allografts.

OBJECTIVE: To investigate the immune privilege induced by the Fas ligand (FasL) expressed by cotransplanted testicular Sertoli cells in islet allografts, and the effect of FasL gene transfection on islet cells in pancreatic islet allografts. METHODS: Allogeneic islets and testicular cells were cotransplanted into diabetic recipients. Pancreatic islets were infected with the recombinant adenovirus, AdV-FasL, and transplanted into diabetic recipients. Allograft survival, islet function, apoptosis of infiltrative lymphocytes in allografts and gene transfected islet allografts were analyzed. RESULTS: All animals receiving islet allograft alone returned to a diabetic state in a few days (mean survival time 6.3 +/- 0.6 days). When the quantity of testicular cells cotransplanted with islets increased to 1 x 10(7), all animals remained normoglycemic throughout the follow-up period (60 days). FasL expression by cotransplanted Sertoli cells induced apoptosis of activated lymphocytes. Rejection of allografts in the FasL gene transfer group was accelerated and allograft survival was shortened to 3.4 +/- 0.2 days (P < 0.05). Pancreatic islets infected with AdV-FasL demonstrated positive staining for FasL at 24h after transplantation, with increased intensity at 48h. Apoptosis assays of pancreatic islet allografts at 24h and 48h revealed apoptosis of transfected islets. CONCLUSIONS: FasL-expressing testicular Sertoli cells can induce apoptosis of activated lymphocytes. Cotransplantation of testicular cells allows long-term survival of allogeneic islets because of immune privilege, but the direct expression of FasL on islet allografts infected with AdV-FasL accelerates islet rejection via islet apoptosis and granulocyte infiltration.

Animals↗

The spectrum of chronic liver disease in renal transplant recipients.

Chronic liver disease has been reported to be an important cause of late morbidity and mortality in renal transplant recipients. We have examined the prevalence and nature of chronic liver disease among 538 patients with functioning renal allografts managed at the Western Infirmary, Glasgow, between 1980 and 1989. Thirty-seven patients (7 per cent) satisfied biochemical criteria for chronic liver dysfunction. Liver biopsies were obtained from 24 of these, and autopsy tissue was available from three other patients. Chronic hepatitis of variable severity was present in 15 patients, haemosiderosis in 12 patients and nodular regenerative hyperplasia in five patients. Nineteen patients (51 per cent) had serological evidence of infection with the hepatitis C virus, and one of these developed chronic hepatitis B and D infection as well. Although a variety of chronic liver diseases occurred in our transplant population, the frequency of serious sequelae from liver dysfunction was much lower than that reported from transplant centres in other countries.

Chronic Disease↗

[Recurrent polyomavirus infections in kidney transplants (BK virus nephropathy)].

BK-virus nephropathy was recently recognised as a new complication that affects renal allografts and causes dysfunction. We report a case of a recipient of simultaneous kidney-pancreas allografts. Fourteen months after the transplant, the renal allograft became dysfunctional with elevation of serum creatinine level. The diagnosis of BK-virus nephropathy was established by needle renal biopsy with immunohistochemical detection of human polyoma virus. Immunosuppressive therapy was reduced but progressive dysfunction developed and the patient had to undergo a renal retransplantation 11 months after the diagnosis of the infection. Due to repeated renal dysfunction, needle biopsy was performed, and the diagnosis of repeated BK-virus nephropathy was established six months after the retransplantation. The pancreas allograft has functioned well for the entire period.

Adult↗

Concomitant donor heart coronary artery bypass grafting during orthotopic heart transplantation.

A 54-year-old diabetic woman with severe cardiomyopathy was placed on our heart transplant candidate list. The patient's condition rapidly worsened and a potential donor-a 45-year-old man whose blood was compatible with that of our patient-was located. Because of the donor's age, coronary arteriography was done, and stenosis in the midleft anterior descending coronary artery was identified. Since the patient's status was critical, the donor heart was accepted despite the presence of stenosis. We used the recipient's internal mammary artery to bypass the stenosis in the left anterior descending artery of the donor heart after performing a standard orthotopic heart transplant. The patient's postoperative course has been relatively free of complications, and the cardiac allograft has functioned well. The early results in this patient are comparable to those of our historical transplant control group. We suggest that the impact of donor organ shortages may be lessened by use of innovative procedures and extended donor selection criteria.

Journal Article↗