The Incremental Cost of Incompatible Living Donor Kidney Transplantation: A National Cohort Analysis.

Incompatible living donor kidney transplantation (ILDKT) has been established as an effective option for end-stage renal disease patients with willing but HLA-incompatible living donors, reducing mortality and improving quality of life. Depending on antibody titer, ILDKT can require highly resource-intensive procedures, including intravenous immunoglobulin, plasma exchange, and/or cell-depleting antibody treatment, as well as protocol biopsies and donor-specific antibody testing. This study sought to compare the cost and Medicare reimbursement, exclusive of organ acquisition payment, for ILDKT (n = 926) with varying antibody titers to matched compatible transplants (n = 2762) performed between 2002 and 2011. Data were assembled from a national cohort study of ILDKT and a unique data set linking hospital cost accounting data and Medicare claims. ILDKT was more expensive than matched compatible transplantation, ranging from 20% higher adjusted costs for positive on Luminex assay but negative flow cytometric crossmatch, 26% higher for positive flow cytometric crossmatch but negative cytotoxic crossmatch, and 39% higher for positive cytotoxic crossmatch (p < 0.0001 for all). ILDKT was associated with longer median length of stay (12.9 vs. 7.8 days), higher Medicare payments ($91 330 vs. $63 782 p < 0.0001), and greater outlier payments. In conclusion, ILDKT increases the cost of and payments for kidney transplantation.

Quantifying the risk of incompatible kidney transplantation: a multicenter study.

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti-HLA donor-specific antibody (DSA). Program-specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15-2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71-6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28-3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98-7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKT's effect on the risk of being flagged. Compared to equal-quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19-, 1.33- and 1.73-fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22-, 4.09- and 10.72-fold higher odds. Failure to account for ILDKT's increased risk places centers providing this life-saving treatment in jeopardy of regulatory intervention.

DonorNet and the potential effects on organ utilization.

The evolution of communication as donor data flows from organ procurement organization to transplant centers has evolved with the incorporation of DonorNet 2007 into the UNet(SM) system. The ensuing study looks at DonorNet's impact on this process. We established defined time periods for comparison purposes. The study looked at match number for organ placement and overall organ utilization with a focus on ischemia time and graft outcomes. The results of the study demonstrate no significant change in the median match number of organ placement in liver or kidney transplantation. Changes in discard rates were varied amongst transplanted organs and there were noticeable changes in organ sharing with an increase in local allocation for kidney and liver and an ensuing decrease in regional and national distribution. There were no significant differences in the outcomes of livers and kidneys with low offer numbers compared with those with high offer numbers. Overall the study suggests a modest impact by DonorNet on organ placement and utilization, but a longer term study would need to be done to fully evaluate its impact.

Isolated donor specific alloantibody-mediated rejection after ABO compatible liver transplantation.

Antibody-mediated rejection (AMR) after liver transplantation is recognized in ABO incompatible and xeno-transplantation, but its role after ABO compatible liver transplantation is controversial. We report a case of ABO compatible liver transplantation that demonstrated clinical, serological and histological signs of AMR without evidence of concurrent acute cellular rejection. AMR with persistently high titers of circulating donor specific antibodies resulted in graft injury with initial centrilobular hepatocyte necrosis, fibroedematous portal expansion mimicking biliary tract outflow obstruction, ultimately resulting in extensive bridging fibrosis. Immunofluorescence microscopy demonstrated persistent, diffuse linear C4d deposits along sinusoids and central veins. Despite intense therapeutic intervention including plasmapheresis, IVIG and rituximab, AMR led to graft failure. We present evidence that an antibody-mediated alloresponse to an ABO compatible liver graft can cause significant graft injury independent of acute cellular rejection. AMR shows distinct histologic changes including a characteristic staining profile for C4d.

[In vitro evidence for pancreatic lineage: Ngn3 positive cells are endocrine progenitors derived from cultured islets].

OBJECTIVE: Further studies have been conducted to evaluate the roles of Ngn3 in adult islet maintenance and renewal. METHODS: Islets were isolated from 6 - 8 week old male C57BL/6 mice. After common bile duct cannulation, the pancreas was resected and digested in collagenase V (2.5 mg/ml). Islets were then handpicked and 10 - 12 islets were plated in 60 mm culture dish and cultivated with RPMI-1640, which contained 12.5 mmol/L HEPES, 5.2 mmol/L glucose and 2% fetal bovine serum (FBS). Islet cells were analyzed by immunocytochemistry methods for A6, insulin, glucagon, nestin, Ngn3 and 5-bromo-2'-deoxy-uridine (BrdU). RESULTS: The results of these studies indicated that less than 15 percent of proliferated islet cells were Ngn3 expressing cells, in which about one third of the Ngn3 positive cells co-expressed A6. The existence of Ngn3 in cultured islet cells is consistent with the results from other's findings both in embryogenesis and adult islet studies. A significant finding of our study is that the existence of A6 and Ngn3 co-expressing cells in the cultured islet. A6 is a marker for identifying bile duct epithelial cell oriented hepatic progenitor cells. Islet-derived A6 cells are possibly born in the adult pancreatic duct and migrate into islets. A6 cells co-express Ngn3 when these cells commit to endocrine lineage within the islets. More interestingly, islet-derived A6 positive cells have the potential to transdifferentiate into hepatic cells. CONCLUSION: The presence of Ngn3(+) and A6(+) cells in the cultured islets suggests that the four established islet cell types arise from a common endocrine lineage residing within the adult islets. A6 and Ngn3 are useful markers for understanding intra-islet adult stem cell lineages in our future studies. This approach may allow for significant advances in understanding the IPC proliferation and differentiation, and open the possibility of using intra-islet adult stem cells for diabetes treatment.

A model utilizing adult murine stem cells for creation of personalized islets for transplantation.

Clinical islet cell transplantation has demonstrated great promise for diabetes treatment. Two major obstacles are the organ donor shortage and the immunoresponse. The purpose of this study was to create a model using the patient's own adult stem cell sources, possibly in combination with non-self cells, such as pancreatic, hepatic, or embryonic stem cells, to create "personalized" islets. We hypothesize that the reconstructed islets have the normal capability to produce insulin and glucagon with reduced immunoresponses after transplantation. Stem cells are a proliferating population of master cells that have the ability for self-renewal and multilineage differentiation. The recently developed photolithograph-based, biologic, microelectromechanic system (BioMEMS) technique supplies a useful tool for biomedical applications. Our lab has developed a novel method that integrates the adult stem cell and BioMEMS to reconstruct personalized islets. We selected islet-derived progenitor cells (IPC) for repairing and reconstructing STZ-diabetic islets. A6(+)/PYY(+) or A6(+)/ngn3(+) cells were selected to manipulate the neoislets. After 3 to 4 weeks in culture, the reconstructed cells formed islet-like clusters containing insulin or glucagon producing cells. The pilot results showed the ability of these reconstructed islets to correct hyperglycemia when transplanted into a STZ-diabetic isograft mouse model. Although several technical problems remain with the mouse model, namely, the difficulty to collect enough islets from a single mouse because of animal size, the mouse isograft model is suitable for personalized islet development.

Use of transjugular intrahepatic portosystemic shunt as a bridge to liver transplantation in a patient with severe hepatopulmonary syndrome.

Hepatopulmonary syndrome (HPS) is defined by the presence of the triad of liver disease, arterial hypoxemia, and intrapulmonary vascular dilatation. The clinical implication of this disorder is impairment of gas exchange. Numerous reports in the literature show that this condition is reversible with orthotopic liver transplantation (OLT). However, patients with HPS often present with PaO(2) levels that are quite low. OLT with a preoperative PaO(2) less than 50 mm Hg is associated with unacceptably high mortality and morbidity. We report a case of severe HPS in which a transjugular intrahepatic portosystemic shunt was successfully used to improve oxygenation, thus allowing a successful elective OLT.

Technique of right laparoscopic donor nephrectomy: a single center experience.

The majority of laparoscopic donor nephrectomies (LDNs) are limited to the left side due to technical and allograft concerns in using the right. We review our experience with right LDNs. Since June 1997, 15 right LDNs were performed and the records retrospectively reviewed for demographics, operative time, transfusions, complications, and length of stay. Recipient records were also reviewed for delayed graft function, complications, and serum creatinine levels. Overall donor, recipient and graft survivals at 6 months are 100%. Mean operative time was 317 +/- 11.0 min, length of stay was 4.2 +/- 0.2 d, and mean serum creatinine levels at discharge, 1, 3, and 6 months were 1.74 +/- 0.19, 1.59 +/- 0.13, 1.72 +/- 0.13, and 1.68 +/- 0.13 mg/dL, respectively. No transfusions were required. There were no operative or hospital complications. Two recipients (13.3%) experienced delayed graft function, defined as requiring hemodialysis post-transplantation. With hand-assisted laparoscopy, the right laparoscopic donor nephrectomy is safe and allows excellent allograft function.

Intrahepatic chemoembolization in unresectable pediatric liver malignancies.

OBJECTIVE: To determine the effectiveness of a new multidisciplinary approach using neoadjuvant intrahepatic chemoembolization (IHCE) and liver transplant (OLTx) in patients with unresectable hepatic tumors who have failed systemic chemotherapy. MATERIALS AND METHODS: From November 1989 to April 1998, 14 children (2-15 years old) were treated with 50 courses of intra-arterial chemotherapy. Baseline and post-treatment contrast-enhanced CT and alpha-fetoprotein levels were performed. Seven had hepatoblastoma, and 7 had hepatocellular carcinoma (1 fibrolamellar variant). All patients had subselective hepatic angiography and infusion of cisplatin and/or adriamycin (36 courses were followed by gelfoam embolization). The procedure was repeated every 3-4 weeks based on hepatic function and patency of the hepatic artery. RESULTS: Six of 14 children received orthotopic liver transplants (31 courses of IHC). Pretransplant, 3 of 6 showed a significant decrease in alpha-fetoprotein, while only 1 demonstrated a significant further reduction in tumor size). Three of 6 patients are disease free at this time. Three of 6 patients died of metastatic tumor 6, 38, and 58 months, respectively post-transplant. One of 14 is currently undergoing treatment, has demonstrated a positive response, and is awaiting OLTx. Three of 14 withdrew from the program and died. Four of 14 patients developed an increase in tumor size, developed metastatic disease, and were not transplant candidates. Two hepatic arteries thrombosed, and one child had a small sealed-off gastric ulcer as complications of intrahepatic chemoembolization. CONCLUSION: The results of intrahepatic chemoembolization are promising and suggest that some children who do not respond to systemic therapy can be eventually cured by a combination of intrahepatic chemoembolization orthotopic liver transplant. Alpha-fetoprotein and cross-sectional imaging appear to be complementary in evaluating tumor response. IHCE does not appear to convert an anatomically unresectable lesion to a candidate for partial hepatectomy.

Internal biliary stenting in orthotopic liver transplantation.

Biliary complications account for significant morbidity in orthotopic liver transplantation (OLT), with a reported incidence ranging from 6% to 47%, and many centers are reassessing the need and options available for stenting the biliary anastomosis. We report on our experience using a 6F Silastic, double-J, ureteral stent as an internal biliary stent in OLT. From October 15, 1995, to September 30, 1998, a total of 99 patients at our institution underwent 108 OLTs. Of these, 77 patients received an end-to-end choledochocholedochostomy over an internal stent. Three patients died within 1 week post-OLT, leaving 74 patients for evaluation (follow-up, 2 to 38 months). Stents were placed transanastomotic and transsphincteric at the time of OLT and secured with a dissolvable suture. At 4 to 6 weeks post-OLT, stents visible within the biliary tree on kidney, ureters, and bladder radiograph were removed endoscopically. Graft and patient survival rates were 92% and 96%, respectively. There were 12 biliary complications (18%): anastomotic leak in 6 patients (9%), anastomotic stricture in 5 patients (7.6%), and stent migration in 1 patient (1.5%). Thirty-two patients (43%) passed the biliary stent without intervention, whereas 42 patients (57%) underwent esophagogastro duodenoscopy (EGD) stent removal at 4 to 6 weeks without incident. Treatment of the complications included percutaneous drainage, endoscopic dilatation with stenting, and/or conversion to Roux-en-Y choledochojejunostomy. The use of the 6 F Silastic, double-J, ureteral stent provides a safe and effective means of stenting the biliary anastomosis in OLT. Major advantages to this method are that it: (1) is completely internal, (2) is biliary decompressive, (3) is radiopaque, (4) can be spontaneously passed, and (5) is easily accessible for EGD extraction.

Heat-induced relocalization of protein kinase CK2. Implication of CK2 in the context of cellular stress.

Among various other roles described so far, protein kinase CK2 has been involved in cell cycle, proliferation, and development. Here, we show that in response to specific stresses (heat shock or UV irradiation), a pool of the cellular CK2 content relocalizes in a particular nuclear fraction, increasing the activity of the kinase there. Electron microscopic analysis shows that upon heat shock, CK2alpha and CK2beta subunits are both detected in similar speckle structures occurring in the interchromatin space but are differentially targeted inside the nucleolus. This CK2 relocalization process takes place in a time- and dose-dependent manner and is reversible upon recovery at 37 degrees C. Altogether, this work suggests CK2 be involved in the response to physiological stress in higher eukaryotic cells.

Cryptosporidial infections after solid organ transplantation in children.

The diagnosis and treatment of moderate-to-severe diarrhea in solid organ transplant recipients is often a challenge because of the variety of infectious and non-infectious causes. The morbidity associated with this clinical condition is of particular significance in the pediatric population where malnutrition may lead to poor growth and development. Rarely, Cryptosporidium has been identified as the cause of clinically significant diarrhea in pediatric solid organ transplant patients. A retrospective review identified cases of cryptosporidiosis among the 1160 non-renal, abdominal organ transplant recipients cared for at the Children's Hospital of Pittsburgh between 1981 and June 1998. Four cases of clinically significant diarrhea were identified in three liver transplant recipients and one small bowel transplant recipient. Endoscopy and biopsy with histologic confirmation diagnosed three cases; ova and parasitic examination of stool specimens identified the fourth case. Therapy varied among the patients depending on when they had been diagnosed as, over the years, different and newer agents have been indicated for the treatment of cryptosporidiosis. All four patients resolved their infections. Hence, endoscopy and biopsy is recommended for pediatric transplant patients who present with chronic diarrhea of unknown etiology. The patients who may be at a higher risk for cryptosporidial infections include those with an increased immunosuppressive state (i.e. pre-existing immunodeficiency, malignancy, re-transplantation, and those receiving higher doses of immunosuppressive therapy). While cryptosporidiosis is a non-lethal complication, it allows the clinician to gain further insight into the degree of immunosuppression of their patient.

Primary Gianturco stent placement for inferior vena cava abnormalities following liver transplantation.

PURPOSE: To determine the efficacy of primary Gianturco stent placement for patients with inferior vena caval (IVC) abnormalities following liver transplantation. MATERIALS AND METHODS: From August 1996 through March 1999, nine adult patients developed significant IVC abnormalities following liver transplantation. Patients were referred for vena cavography on the basis of abnormal clinical findings, laboratory values, liver biopsy results, Doppler findings, or a combination. Those patients demonstrating a significant caval or hepatic venous gradient were treated with primary Gianturco stent placement. Patients were followed clinically (nine patients), with duplex ultrasound (nine patients), vena cavography (four patients), and biopsy (seven patients). RESULTS: Original pressure gradients ranged from 3 to 14 mm Hg, with a mean of 9 mm Hg. Gradients were reduced to 3 mm Hg or less in all nine patients; presenting signs and symptoms either resolved or improved in eight of nine patients. The ninth patient required repeated transplantation 2 days later. A second patient died 433 days after stent placement of recurrent hepatitis C. Another initially improved following caval stent placement, but underwent repeated transplantation 7 days later due to hepatic necrosis from hepatic arterial thrombosis. Follow-up for the remaining six patients has averaged 491 days, with no clinical, venographic, or ultrasound evidence for recurrent caval stenosis. CONCLUSIONS: Intermediate term results suggest that primary Gianturco stent placement for IVC stenosis, compression, or torsion resulting after liver transplantation is safe and effective.

Use of intrahepatic chemotherapy to treat advanced pediatric hepatic malignancies.

BACKGROUND: To evaluate the effect of intrahepatic arterial chemotherapy (IAC) on children with primary hepatic malignancies. METHOD: A nonrandomized inception cohort of 11 pediatric patients was referred for treatment of advanced primary hepatic malignancies at Children's Hospital of Pittsburgh. None of the patients was a candidate for resection before the initiation of IAC. Tumor response to treatment was observed by determining serum alpha-fetoprotein (AFP) levels and by abdominal computed tomographic scan. The patients received hepatic artery infusions of cisplatin and/or doxorubicin. The last five also received gelfoam embolization. RESULTS: Eight of 11 patients had multiple IAC treatments. Eight patients had AFP-producing tumors, and five of the eight had dramatic reductions in serum levels after IAC treatment. Five of the 11 patients underwent successful orthotopic liver transplantation after receiving IAC therapy, and the five explanted specimens showed varying degrees of tumor necrosis. One-year survival in patients in the authors' center is 67% for those with hepatoblastoma and 40% for those with hepatocellular carcinoma. Three-year survival is 60% and 30% for patients with hepatoblastoma and hepatocellular carcinoma, respectively. CONCLUSION: Intrahepatic arterial chemotherapy therapy can halt the progression and possibly down-stage advanced pediatric hepatic malignancies. This therapy can also be used as a successful adjunct in altering a patient's chance for successful liver transplantation.

Prolongation of murine cardiac allograft survival by microspheres containing TNF alpha and IL1-beta neutralizing antibodies.

Efficient delivery of therapeutic agents to a critical microenvironment may increase the efficacy of drugs used to modulate the allograft rejection response. This study demonstrates the ability of the combination of microspheres containing neutralizing anti-TNF alpha and anti-IL1-beta antibodies to significantly prolong murine cardiac allograft survival. These results suggest that the microsphere technique is an efficacious method to target antibody delivery to prolong allograft survival.