Cost-effectiveness of kidney transplantation from DCD in Italy.

INTRODUCTION: Kidney transplantation represents the best therapeutic option for patients with end-stage renal disease (ESRD), providing the best outcomes for survival, quality of life, and cost-effectiveness. To increase kidney donations, in 2007, the Italian IRCCS Policlinico San Matteo Foundation in Pavia designed and conducted Programma Alba, a protocol for organ donation after cardiac death (DCD). This study evaluated the costs and health outcomes of DCD transplantation and in all types of transplants compared with current clinical practice. PATIENTS AND METHODS: A Markov-based model was used to assess costs and health outcomes for new ESRD patients for 2008 to 2013. A health care founder perspective was used. Data sources were the Italian National Institute of Statistics and the Lombardy Registry of Dialysis and Transplantation. A microcosting analysis was performed to calculate costs related to clinical pathways for DCD. We assessed costs, survival, quality-adjusted survival, and cost-effectiveness. FINDINGS: Changing the actual practice pattern for new patients with ESRD and increasing the availability of kidneys from DCD to 10 extra transplants per year will induce an incremental cost per quality-adjusted life-year of €4255. Increases in transplantation to reach an extra 10% by transplant type would result in reduced costs and increased patient survival and quality of life compared with the current scenario. INTERPRETATION: Our data show that increasing DCD transplants would result in a cost-effective policy to expand the kidney donor pool compared with current ESRD treatment patterns. Italian policies should make an effort to increase transplant rates to optimize cost-effectiveness in ESRD service supply.

The "Pavia model" of experimental small bowel transplantation in pigs: technical variations for ischemia reperfusion injury studies.

Ischemia reperfusion injury (IRI) is a major field of study in small bowel transplantation because of its implications regarding intestinal immunity. In this study, we have introduced some variations to the described models of IRI in pigs to make possible a complete isolation of the small bowel for IRI studies. In swine, two anatomical barriers make impossible a complete isolation of the small bowel at the origin of superior mesenteric artery (SMA) and vein (SMV): the main colic vessels, which originate distally to form SMA and SMV, and the blood supply of the distal portion of the duodenum and the cephalic part of the pancreas. In a group of Large White pigs (n = 5), we have performed a complete isolation of the small bowel, including sub-total colectomy and pancreaticoduodenectomy. Both SMA and SMV were isolated at the origin from the aorta and at the junction of the splenic vein, respectively. Intestinal continuity was restored with duodenojejunal anastomosis and with ileotransverse colon anastomosis. One pig died on postoperative day 5 from intestinal occlusion due to adhesions. The remaining four pigs were killed on postoperative day 7 after an uneventful postoperative course. No complications were found at autopsy. In swine, resection of part of the pancreas and duodenum and removal of the large bowel does not affect short-term survival, allowing a full isolation of the entire small bowel mimicking the transplantation procedure. Thus, this model appears to be attractive for IRI studies in the field of intestinal transplantation.

Experimental small bowel transplantation from non-heart-beating donors: a large-animal study.

INTRODUCTION: The shortage of organs in the last 20 years is stimulating the development of new strategies to expand the pool of donors. The harvesting of a graft from non-heart-beating donors (NHBDs) has been successfully proposed for kidney and liver transplantation. To our knowledge, no studies are available for small bowel transplantation using NHBDs. In an experimental setting of small bowel transplantation, we studied the feasibility of using intestinal grafts retrieved from NHBDs. MATERIALS AND METHODS: Twenty five Large White piglets underwent total orthotopic small bowel transplantation and were randomly divided as follow: NHBD group (n = 15) received grafts from NHBDs; heart-beating donor (HBD) group (n = 10) received grafts from HBDs. The NHBD pigs were sacrificed inducing the cardiac arrest by a lethal potassium injection. After 20 minutes (no touch period = warm ischemia), they underwent cardiac massage, laparotomy, and aorta cannulation for flushing and cooling the abdominal organs. In HBDs, the cardiac arrest was induced at the time of organ cold perfusion. In both groups, immunosuppression was based on tacrolimus oral monotherapy. The animals were observed for 30 days. The graft absorptive function was studied at day 30 using the D-xylose absorption test. Histological investigation included HE (Hematoxilin and Eosin) microscopical analysis and immunohistological staining. RESULTS: Animals in the NHBD group died due to infection (n = 3), acute cellular rejection (n = 2), technical complications (n = 2), and intestinal failure (n = 8). In the HBD group, all animals but two were alive at the end of the study. The D-xylose absorption was significantly lower among the NHBD compared with the HBD group (P < .05). CONCLUSIONS: This study confirmed that intestinal mucosa is sensitive to ischemic injury. When the intestinal graft is harvested from NHBDs, the infectious-related mortality was higher and the absorptive function lower. Histological examination confirmed a higher grade of ischemic injury in the NHBD grafts that correlated with the clinical data. Therefore, this experimental study suggested that non-heart-beating donation may not be indicated for small bowel transplantation.

Prolonged survival with FK778 (malononitrilamide) monotherapy after small bowel transplantation: a large animal study.

Malononitrilamide 715 (FK778) is a new class of immunosuppressant, derived from the active metabolite of leflunomide A77 1726. We investigated the efficacy of two different immunosuppressive induction protocols with tacrolimus plus FK778 followed by FK778 monotherapy. In a swine model of small bowel transplantation, we observed three groups, divided by different therapy regimens: group 1 (n = 5): no immunosuppressant (control group); group 2 (n = 10): oral tacrolimus (from postoperative day [POD] 0 to 30) and FK778 (from POD 0 to 60); group 3 (n = 8): oral tacrolimus, as group 2, and FK778 (from POD 7 to POD 60). Median survival was 11, 60, and 21 days in groups 1, 2, and 3, respectively. In group 1 all animals died of acute rejection; in group 2 the causes of death were technical complication (n = 1) and sepsis (n = 1); in group 3, one animal died from obstruction, two from pneumonia, one from peritonitis, one from sepsis. Group 2 accounted for 0.5 infection episode/animal versus 0.62 in group 3 (P < .05). Acute rejection was absent or mild in 66% and 75% of group 3 and 2 biopsies, respectively (P < .05). The D-xylose absorption curves from groups 2 and 3 were similar to those of the nontransplanted healthy animals. In conclusion, FK778 monotherapy after a consistent induction period with tacrolimus combined immunosuppression is able to extend survival and preserve optimal absorptive capacity of the small bowel allograft in our pig model. The association of tacrolimus and FK778 from day 1, compared to the delayed administration of FK778 from day 7, results in a significant reduction of infections and postoperative complications.

Elemental enteral nutrition preserves the mucosal barrier and improves the trophism of the villi after small bowel transplantation in piglets.

The main goals for a successful small bowel transplantation (SBTx) are the control of acute rejection and maintenance of the mucosal barrier, which plays a key role in preventing bacterial translocation and preserving absorptive capacity. According to recent evidence that sustaining enteral nutrition (EN) as rehabilitative therapy improves the integrity of the mucosal barrier after SBTx, we studied the trophic effect of a new elemental enteral solution whose proteinic supply is represented by oligomeric-aminoacidic chains. In a swine SBTx model we studied three groups, divided by the different postoperative feeding: group 1 (n = 5): standard swine chow, group 2 (n = 5): polymeric enteral solution, group 3 (n = 5): elemental enteral solution (Peptamen, Nestlè Corp). All animals were immunosuppressed with a tacrolimus/FK778 combined oral therapy. The nutritional indices evaluated were: body weight, episodes of diarrhea, D-xylose absorption test, and histopatological and villi morphometric analysis. Three pigs died before the end of the study, two in group 1 (pneumonia and sepsis), one in group 2 (pneumonia). Mean days of diarrhea were 15, 10, and 3 in groups 1, 2, and 3, respectively (P < .05). The final/starting weight ratio was 1.08 for group 3 and 0.92 for group 2 (P < .05); the D-xylose curves showed a statistically significant difference for group 3 versus the groups 2 and 1 (P < .05), as well as for the villi height (P < .01) and width (P < .05). In conclusion, elemental enteral solution, with its basic protein supply, does not require a very complex enzymatic system to be metabolized. Thus, it may contribute to a faster recovery of the mucosal barrier and to limit the hypercatabolic state.

FK778 does not impair intestinal allograft absorption in a preclinical model of total small bowel transplantation.

Malononitrilamide 715 (FK778), a new low-molecular weight immunosuppressant, inhibits both T-cell and B-cell function by acting on the pathway for de novo pyrimidine biosynthesis. Pyrimidines are important for intestinal trophism; their inhibition may predispose to metabolic and functional impairments, such as diarrhea and malabsorption. In this study we assessed the absorptive capacity of intestinal allografts in a large-animal model of small bowel transplantation (SBTx) in pigs chronically treated with FK778. Ten outbred pigs underwent total orthotopic SBTx. Immunosuppression consisted of oral tacrolimus (trough levels 5-15 ng/mL) and oral FK778 (4 mg/kg per day) administered for 60 days. The D-xylose absorption test was performed at day 60 to evaluate carbohydrate absorption. Results were compared to normal controls. Eight of the 10 animals were alive and in good condition at day 60. All of their allografts were free of rejection. The animals had a mean maximal weight loss of 6.4% during the study period; the final weight was comparable to the initial weight (P > .05). Diarrhea was present in all animals (mean 16% of postoperative days). The D-xylose curves showed that absorption in the transplanted animals at day 60 was similar to that in the untreated controls (P > .05). The absence of differences was confirmed by the statistical analysis. In conclusion, our preclinical study in pigs showed that chronic treatment with FK778 in combination with tacrolimus did not impair carbohydrate absorption by the allograft after SBTx.

FK778 and tacrolimus combination therapy to control acute rejection after pig intestinal transplantation.

Malononitrilamide 715 (FK778) is a new class of low molecular weight immunosuppressant. Experimental studies in heart, liver, and kidney transplantation have shown a strong synergism when FK778 is used in combination with tacrolimus and when its administration is delayed by 7 days after the transplant. Following this indication, in a swine model of orthotopic small bowel transplantation (SBT), we assessed the efficacy of combined low dose tacrolimus and FK778 administered from day 0 or day 7. The entire small bowel was replaced in 16 piglets: group 1 (n = 5), no immunosuppression; group 2 (n = 6) oral tacrolimus to maintain whole blood trough levels between 5 and 15 ng/mL plus FK778 4 mg/kg per day; group 3 (n = 6) oral tacrolimus as in group 2 plus FK778 4 mg/kg per day administered after a 7-day delay posttransplant. The median survival was 8 days in group 1, 60 days in group 2, and 13 days in group 3. The differences between group 2 and 1 and between group 2 and 3 are statistically significant. Three episodes of major bacterial infection were detected in both group 2 and 3 (0.5 episode/animal). The infectious-related mortality was 0% in group 2 and 50% in group 3 (P < .05). Acute cellular rejection was absent or mild in all group 2 and 3 stomal biopsies. In conclusion, combining tacrolimus and FK778 allowed prolonged survival after SBT in swine when FK778 was started at the time of SBT. The delayed administration of FK778 resulted in a high incidence of lethal infectious complications.

Early outcome of different steroid-free regimens in small bowel transplantation: a large-animal study.

The intestine is a highly immunogenic organ that requires heavy immunosuppression (IS); therefore corticosteroid withdrawal after clinical small bowel transplantation (SBT) has not been standardized. In this study, we compared different immunosuppressive regimens (none with steroid or induction treatment) in a SBT pig model. Large White unrelated piglets were transplanted and divided into four groups as follow: group 1 (n = 3): no IS; group 2 (n = 10): IS with tacrolimus only; group 3 (n = 10): IS with tacrolimus and mycophenolate mofetil; group 4 (n = 5): IS with tacrolimus and rapamycin. Follow-up time was 30 days. All IS drugs were given orally; tacrolimus whole blood levels ranged between 5 and 15 ng/mL in all groups except for group 2 whose tacrolimus whole blood levels ranged between 15 and 25 ng/mL. Group 1 pigs died of graft acute rejection (ACR) after a median of 12 days. Overall survival in groups 2, 3, and 4 at day 30 was 40%, 80%, and 60%, respectively. Biochemical parameters, including glycemia and cholesterol, were into the normal range with no significant differences between groups. At the end of the study, one animal in group 2 and another one in group 4 showed histological signs of moderate to severe ACR. The incidence of infection was higher in group 2 (2.1 episodes/pig) compared to group 3 (1.25) and group 4 (1.6). This large-animal study demonstrates that tacrolimus-based IS without corticosteroids allows, in the early postoperative period (30 days) after SBT, good survival rates without an increased risk in the incidence of rejection.

[Biological and HPLC analysis of heparin after thermal treatment]. / Analisi biologica e HPLC di eparina trattata termicamente.

Heparin solutions ampoules have been autoclaved at 105 degrees C-110 degrees C-121 degrees C-134 degrees C for 15 minutes. The biological activity has not decreased after the treatment, but a reduction was observed after a storage period of 36 months at room temperature for sterilizing treatments. Analysis of heparin by size exclusion and reversed phase HPLC with the method developed in our laboratories allowed us to demonstrate a substantial stability of the molecular structure. These methods showed to be suitable for a qualitative evaluation of the heparin itself.