Adam M. Frank

Transplantation for Type I Diabetes: Comparison of Vascularized Whole-Organ Pancreas With Isolated Pancreatic Islets

Objective:We sought to compare the efficacy, risks, and costs of whole-organ pancreas transplantation (WOP) with the costs of isolated islet transplantation (IIT) in the treatment of patients with type I diabetes mellitus. Summary Background Data:A striking improvement has taken place in the results of IIT with regard to attaining normoglycemia and insulin independence of type I diabetic recipients. Theoretically, this minimally invasive therapy should replace WOP because its risks and expense should be less. To date, however, no systematic comparisons of these 2 options have been reported. Methods:We conducted a retrospective analysis of a consecutive series of WOP and IIT performed at the University of Pennsylvania between September 2001 and February 2004. We compared a variety of parameters, including patient and graft survival, degree and duration of glucose homeostasis, procedural and immunosuppressive complications, and resources utilization. Results:Both WOP and IIT proved highly successful at establishing insulin independence in type I diabetic patients. Whole-organ pancreas recipients experienced longer lengths of stay, more readmissions, and more complications, but they exhibited a more durable state of normoglycemia with greater insulin reserves. Achieving insulin independence by IIT proved surprisingly more expensive, despite shorter initial hospital and readmission stays. Conclusion:Despite recent improvement in the success of IIT, WOP provides a more reliable and durable restoration of normoglycemia. Although IIT was associated with less procedure-related morbidity and shorter hospital stays, we unexpectedly found IIT to be more costly than WOP. This was largely due to IIT requiring islets from multiple donors to gain insulin independence. Because donor pancreata that are unsuitable for WOP can often be used successfully for IIT, we suggest that as IIT evolves, it should continue to be evaluated as a complementary alternative to rather than as a replacement for the better-established method of WOP.

The adipose tissue production of adiponectin is increased in end-stage renal disease

Adiponectin has anti-diabetic properties and patients with obesity, diabetes and insulin resistance have low plasma adiponectin levels. However, although kidney disease is associated with insulin resistance, adiponectin is elevated in end stage renal disease. Here we determine if adipose tissue production of adiponectin is increased in renal disease in a case-control study of 36 patients with end stage renal disease and 23 kidney donors. Blood and tissue samples were obtained at kidney transplantation and donation. The mean plasma adiponectin level was significantly increased to 15.6 mg/ml in cases compared to 8.4 mg/ml in controls. Plasma levels of the inflammatory adipokines tumor necrosis factor α, interleukin 6 and high sensitivity C-reactive protein were significantly higher in cases compared to controls. Adiponectin mRNA and protein expression in visceral and subcutaneous fat was significantly higher in cases than controls while adiponectin receptor 1 mRNA expression was significantly increased in peripheral blood cells, muscle and adipose tissue in cases compared to controls. Thus, our study suggests that adipose tissue production of adiponectin contributes to the high plasma levels seen in end stage renal disease.

Acute Humoral Rejection in a Zero Mismatch Deceased Donor Renal Transplant Due to an Antibody to an HLA-DP α

We present a case of a highly sensitized 54-year-old African American male with three prior failed transplants who received a zero mismatch deceased donor kidney and had antibody-mediated rejection directed against a human leukocyte antigen (HLA)-DP donor-specific antigen. The donor was a 21-year-old man with normal renal function. The recipient’s calculated panel reactive antibody was 99%. The standard anti-human globulin-enhanced T-cell and National Institute of Health (NIH) B-cell cytotoxicity crossmatches were negative. Flow cytometric Band T-cell crossmatches were weakly positive by a few channels over the established cutoffs. Intraoperatively, 1 mg/kg antithymocyte globulin, 250 mg methylprednisolone, and 1 g/kg intravenous immunoglobulin (IVIG) were given. Postoperatively, an additional four daily doses of 1 mg/kg antithymocyte globulin, a tapering dose of steroids, and two doses of 500 mg/kg of IVIG were given. The recipient did not have delayed graft function but presented 2 weeks later with increased creatinine and oliguria. Biopsy revealed both borderline acute cellular and acute antibody-mediatedrejection with diffuse C4d positivity in the peritubular capillaries on immunofluorescence. High-resolution HLA typing of the donor was pursued, and a mismatch at the DPA1 locus was identified. Singleantigen bead screening of pretransplant and posttransplant sera revealed a strong complement-fixing antidonor antibody (Luminex C1q antibody fixing assay, reference laboratory: Stanford University Blood Center Histocompatibility Laboratory) against DPA1*0103 with a titer by doubling dilution of 1/1024. The patient received high-dose steroids, multiple rounds of alternate day plasmapheresis, each followed by 100 mg/kg IVIG and 1 g rituximab. His antibody titers decreased to 1/64 and his creatinine nadired at 1.4 mg/ dL. Six months later, he had another 1a cellular and chronic antibody-mediated rejection with a creatinine of 2.1 mg/dL. The United Network for Organ Sharing allocates zero-mismatched kidneys based on six antigens derived from the paired loci A, B, and DR encoded by the major histocompatibility complex located on chromosome 6. The rationale for this policy is improved graft survival in the setting of a more favorable immunologic environment. High-resolution HLA typing is not routinely performed for renal transplantation, and thus, DP status is usually unknown. DPA1 and DPB1 are similarlypolymorphicasA,B,andDR,andasof January 2010, they have 28 and 138 known alleles, respectively (1). DP antigens were discovered in 1980 in restimulation experiments of previously primed T cells. They belong to HLA class II major histocompatibility complex and are composed of polymorphic and chains of similar molecular weight (32 kDa). They are characterized by weak primary allogeneic proliferative response but strong secondary cellmediated cytotoxicity (2). HLA DP mismatches do not influence first kidney transplants but significantly impact outcomes for retransplants (3–5). It has been shown that donor-recipient pairs matched at A, B, and DR have a greater than 80% probability of being mismatched at DP loci (6, 8). We pursued DP typing for the donor, and our pair was matched at A, B, Cw, DR, and DQ alleles as determined by high-resolution (allele level) DNA sequence-specific priming typing (Table 1). The pretransplant sera of recipient contained a strong antidonor antibody against the donor’s DPA1*0103 allele, with a mean fluorescence intensity in the range of 8000 to 14,000. An additional mismatch at DPB1*0601 was revealed and studied, but the antibodies against this allele were found to have mean fluorescence intensity less than 1000. Clinically significant antidonor antibodies to DPB1 have been associated with rejection in both variably matched and zero-mismatched renal allografts (7–9). In addition, antibodies to DPB1 have also been implicated in chronic humoral rejection in retransplants and have been found to share epitope with other HLA molecules (10). Further epitope classification of DPB1 has been pursued, which has helped in the identification of antibodies directed against them (11). It is known that failed renal allografts can elicit an antibody response to DP (12). However, rejection related to antibodies to DPA1 has not been described previously, and our case is unique as it is the first one to report antibody-mediated rejection because of a high-strength antibody to DPA1. It is logical to think that incorporating appropriate donor and recipient HLA-Cw and DP antigens/alleles and antibody information using luminex solid phase assays into UNet would improve concordance between the virtual crossmatching being used for kidney allocation and the actual flow crossmatches. For zero-mismatched grafts, Cw concordance is likely, whereas DP is not. We think that the data forming the basis for virtual crossmatch TABLE 1. Our donor and recipients’ typing by high-resolution DNA sequence-specific priming method

Completely steroid-free immunosuppression in liver transplantation: a randomized study.

Corticosteroids (CS) have been standard immunosuppression to prevent and treat rejection. However, CS are associated with increased risk of infection, obesity, hypertension, hyperlipidemia, diabetes, and accelerated hepatitis C virus (HCV) recurrence post‐orthotopic liver transplantation (OLT). This study assesses the safety and efficacy of CS‐free immunosuppressive regimen in adult OLT.

Sensitization trends after renal allograft failure: the role of DQ eplet mismatches in becoming highly sensitized.

Sensitization following renal allograft failure (AF) is highly variable. Some patients remain non‐sensitized (NS), while others become highly sensitized (HS). We studied 66 NS patients who experienced AF after initial kidney transplantation. Post‐failure, two main groups of NS panel reactive antibody (PRA) class I and II <10% and HS patients (PRA class I or II ≥80%) were identified. The impact of acute rejection (AR), immunosuppression withdrawal (ISW) at AF, allograft nephrectomy, graft intolerance syndrome (GIS), and both standard serologic and eplet‐based mismatches (MM) in inducing HS status after failure was examined. Late PRA testing post‐failure revealed 18 patients remained NS and 34 patients became HS. African American recipients, ISW at AF, DQB1 eplet MM, and presence of GIS were associated with becoming HS. Presence of total zero eplet MM, zero DQA1/B1 eplet MM, continuation of immunosuppression after failure, and a hyporesponsive immune status characterized by recurrent infections were features of NS patients. DQ eplet MM represents a significant risk for becoming HS after AF. Studies comparing ISW vs. continuation in re‐transplant candidates with high baseline DQ eplet MM burden should be performed. This may provide insights if sensitization post‐AF can be lessened.

Robotic-Assistance Does Not Enhance Standard Laparoscopic Technique for Right-Sided Donor Nephrectomy

Robotic-assistance did not improve outcomes associated with laparoscopic donor nephrectomy in this study.

Peritransplant kidney biopsies: comparison of pathologic interpretations and practice patterns of organ procurement organizations.

Singh P, Farber JL, Doria C, Francos GC, Gulati R, Ramirez CB, Maley WR, Frank AM. Peritransplant kidney biopsies: comparison of pathologic interpretations and practice patterns of organ procurement organizations. 
Clin Transplant 2012 DOI: 10.1111/j.1399‐0012.2011.01584.x. 
© 2012 John Wiley & Sons A/S.

Successful treatment of donor‐derived hepatitis C viral infection in three transplant recipients from a donor at increased risk for bloodborne pathogens

We report here the successful treatment of hepatitis C virus (HCV) transmitted from a nucleic acid testing (NAT)‐negative donor to three HCV‐negative recipients—two renal transplants and one liver. Both renal recipients underwent standard deceased‐donor renal transplantation with immediate graft function. The liver recipient underwent standard orthotopic liver transplantation and recovered uneventfully. The donor was a 39‐year‐old woman with a terminal serum creatinine of 0.7 mg/dL. She was high risk for bloodborne pathogens, based upon a history of sexual contact with an HCV‐infected male partner. Recipient 1 was a 45‐year‐old man with a history of end‐stage renal disease from systemic lupus erythematosus. Recipient 2 was a 62‐year‐old woman with a history of end‐stage renal disease caused by hypertension and insulin‐dependent diabetes. Recipient 3 was a 42‐year‐old man with acute liver failure from acetaminophen ingestion. All recipients became HCV polymerase chain reaction positive on post‐transplant follow‐up. Both kidney recipients were treated with ledipasvir/sofosbuvir combination therapy for 12 weeks without side effects or rejection episodes. Recipient 3 was treated with ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks without side effects. All patients achieved a sustained viral response at 12 weeks and are considered cured of HCV. The kidney recipients maintained good allograft function with a serum creatinine of 1.4 mg/dL and 1.0 mg/dL, respectively. Both renal recipients maintained normal liver function post treatment and did not develop any evidence of fibrosis. The liver recipients liver function tests returned to normal without further incident. This case report provides evidence for the successful treatment of donor‐derived HCV in transplant recipients.

Use of enteric-coated mycophenolate sodium in liver transplant patients with intestinal intolerance caused by mycophenolate mofetil.

Abstract:  Background:  Post‐transplant gastrointestinal (GI) side effects can impair a patient’s quality of life (QoL). This study investigates the improvement in GI side effects and related QoL changes in recipients of liver transplantation (OLT) after converting patients from mycophenolate mofetil (MMF) to enteric‐coated mycophenolate sodium (EC‐MPS).

Acute hypotensive transfusion reaction during liver transplantation in a patient on angiotensin converting enzyme inhibitors from low aminopeptidase P activity

Acute hypotensive transfusion reactions are newly characterized transfusion reactions in which hypotension is the prominent feature. The pathophysiology of acute hypotensive transfusion reactions is related to the bradykinin function and its metabolism. A liver transplant recipient on treatment with an angiotensin converting enzyme inhibitor developed sudden hypotension, that is, systolic pressure of 60 mm Hg, after receiving 200 mL of a blood product mixture without significant surgical blood loss. He responded to the resuscitation measure, although hypotension developed again after a challenge transfusion of 200 mL of the blood mixture. A severe hypotensive reaction to the blood transfusion and diffuse bleeding from the dissection surfaces forced the transplantation to be aborted after the common bile duct had been divided. We hypothesized that the patient had an acute hypotensive transfusion reaction due to disordered bradykinin metabolism. Analysis of his blood showed low levels of both angiotensin converting enzyme and aminopeptidase P enzyme activity, confirming that the patient experienced an acute hypotensive transfusion reaction that was due to the use of the angiotensin converting enzyme inhibitor and was precipitated by an abnormality in the metabolic enzyme pathway. It is recommended to discontinue angiotensin converting enzyme inhibitors and switch to a different class of antihypertensive medications for patients with a high Model for End‐Stage Liver Disease score on the waiting list for liver transplantation. Liver Transpl 14:684–687, 2008.