Case Report: Insulin hypersensitivity in youth with type 1 diabetes.

Objective: Immediate type I, type III, and delayed type IV hypersensitivity reactions to insulin are rare, but potentially serious complications of exogenous insulin administration required for the treatment of type 1 diabetes (T1D). Methods: We present four cases of insulin hypersensitivity reactions occurring in youth with T1D and a literature review of this topic. Results: Insulin hypersensitivity reactions included types I, III, and IV with presentations ranging from localized urticaria, erythematous nodules, and eczematous plaques to anaphylaxis with respiratory distress. Reactions occurred in youth with newly diagnosed T1D and in those with long-standing T1D who were using both injection and insulin pump therapy. Multidisciplinary care involving pediatric endocrinology and allergy/immunology utilizing trials of many adjunct therapies yielded minimal improvement. Despite the use of various treatments, including antihistamines, topical therapies, immunosuppressant medications, desensitization trials, and intravenous immune globulin, cutaneous reactions, elevated hemoglobin A1c levels, and negative effects on quality of life remain persistent challenges. One patient became one of the youngest pancreas transplant recipients in the world at age 12 years due to uncontrollable symptoms and intolerable adverse effects of attempted therapies. Conclusion: Although rare, insulin hypersensitivity reactions negatively affect glycemic control and quality of life. These cases demonstrate the varying severity and presentation of insulin hypersensitivity reactions along with the limited success of various treatment approaches. Given the life-sustaining nature of insulin therapy, further studies are needed to better understand the underlying pathophysiology of insulin hypersensitivity and to develop targeted treatment approaches.

Effective treatment of diabetes, improved quality of life and accelerated cognitive development after pancreas transplantation in a child with type 1 diabetes and allergy to manufactured insulin preparations.

BACKGROUND: Insulin hypersensitivity reactions are rare but serious and significantly affect the treatment of diabetes in children. METHODS: A 13-year-old girl with type 1 diabetes, hypoglycemic unawareness, and treatment refractory allergy to available insulin preparations underwent a solitary pancreas transplant. Before the pancreas transplantation, she was receiving a continuous subcutaneous infusion of rapid-acting insulin with an increasing need for antihistamines and steroids, negatively impacting her cognitive and social development. Her diabetes was poorly controlled, and her quality of life was progressively worsening. RESULTS: Following the transplant, she recovered well from surgery and achieved euglycemia without needing exogenous insulin. She had two biopsy proven episodes of acute cellular rejection, successfully treated. Her cognitive development also accelerated. Notable improvement was noted both in her personal quality of life and her family's overall well-being. CONCLUSIONS: This is the youngest pancreas transplant recipient with over 1-year graft survival reported in the literature. Pancreas transplant alone in a teenager without indications for kidney transplantation could be considered a last resort treatment for diabetes when continuing insulin therapy presents a high level of morbidity. A pancreas transplant is a feasible treatment modality for patients with refractory insulin allergy.

Early relapse of atypical hemolytic uremic syndrome following ABO-incompatible living-related pediatric kidney re-transplant successfully treated with eculizumab.

BACKGROUND: A 3-year-old girl with clinical features of atypical HUS (complement Factor I mutation inherited from an asymptomatic mother and Factor H autoantibodies) was treated with plasma exchange, progressed to kidney failure (KF) aged 4 years, and received an en bloc kidney DCD transplant aged 8 years with primary graft non-function necessitating transplant nephrectomy at the time of transplantation. She subsequently underwent re-transplantation from her father. This is a retrospective study of electronic patient records and medical notes. CASE-DIAGNOSIS/TREATMENT: A 9-year-old girl received an ABO-incompatible (ABOi) living-related kidney transplant from her father with recipient and donor blood groups of O and A, respectively, with baseline recipient anti-A titers 1:128 reducing to 1:4 at the time of transplant with B lymphocyte depletion with rituximab and four sessions of immunoadsorption. Six hours post-transplant, she had recurrence of aHUS and received the first dose of eculizumab. She continues on monthly home eculizumab infusions with stable kidney allograft function and negative anti-A titers 7 years post-kidney transplantation. CONCLUSIONS: This is the first report of a pediatric high-risk ABOi living-related kidney transplantation in whom early relapse of aHUS was successfully treated with eculizumab with good long-term patient and allograft outcome.

Hematopoietic Cell and Solid Organ Transplantation in the Same Patient: Long-Term Experience at the University of Minnesota.

There is a growing population of transplant survivors receiving both a solid organ transplantation (SOT) and a hematopoietic cell transplantation (HCT). This group remains underreported and not well described. We conducted a single-center retrospective study aimed at assessing safety and long-term survival outcomes of 40 patients receiving both HCT and SOT at the University of Minnesota. Twenty-seven patients underwent HCT followed by SOT (13 kidney, 10 lung, 2 liver, 1 heart, 1 heart/kidney) with a median age of 40 years (range, 5 to 72) at the time of SOT at a median of 88 months (range, 24 to 302) following the HCT. The 1-, 5-, and 10-year overall survival (OS) from the SOT was 93%, 76%, and 49%, respectively, with only 4 organ failures reported. Thirteen other patients received a HCT following a prior kidney (n = 8), liver (n = 4), or pancreas/kidney (n = 1) SOT with a median age of 42 years (range, 3 to 66) at the time of the HCT and a median 154 months (range, 1 to 304) from the SOT. The 1-, 5-, and 10-year OS from HCT were 46%, 46%, and 17% respectively. In patients receiving SOT followed by HCT, survival outcomes were better in kidney transplant recipients and patients subsequently requiring an autologous rather than an allogeneic HCT. There were no HCT engraftment failures. Our findings show that in a select patient population, undergoing a second transplant at a specialized center can lead to favorable outcomes with long-term survival and low incidence of graft rejection, organ failure, and malignant disease relapse. A large-scale study is needed to determine the incidence and risk factors preferred for a successful subsequent SOT or HCT. Those studies are crucial to further guide selection and management of patients who would benefit most from a second transplant.

Predictors of Survival After Liver Transplantation in Patients With the Highest Acuity (MELD ≥40).

OBJECTIVE: To identify factors that accurately predict 1-year survival for liver transplant recipients with a MELD score ≥40. BACKGROUND: Although transplant is beneficial for patients with the highest acuity (MELD ≥40), mortality in this group is high. Predicting which patients are likely to survive for >1 year would be medically and economically helpful. METHODS: The Scientific Registry of Transplant Recipients database was reviewed to identify adult liver transplant recipients from 2002 through 2016 with MELD score ≥40 at transplant. The relationships between 44 recipient and donor factors and 1-year patient survival were examined using random survival forests methods. Variable importance measures were used to identify the factors with the strongest influence on survival, and partial dependence plots were used to determine the dependence of survival on the target variable while adjusting for all other variables. RESULTS: We identified 5309 liver transplants that met our criteria. The overall 1-year survival of high-acuity patients improved from 69% in 2001 to 87% in 2016. The strongest predictors of death within 1 year of transplant were patient on mechanical ventilator before transplantation, prior liver transplant, older recipient age, older donor age, donation after cardiac death, and longer cold ischemia. CONCLUSIONS: Liver transplant outcomes continue to improve even for patients with high medical acuity. Applying ensemble learning methods to recipient and donor factors available before transplant can predict survival probabilities for future transplant cases. This information can be used to facilitate donor/recipient matching and to improve informed consent.

Insights in Transplanting Complex Pediatric Renal Recipients With Vascular Anomalies.

BACKGROUND: Children with end-stage kidney disease may have coexisting iatrogenic or congenital vascular anomalies making transplantation difficult. We describe our approach in 5 recipients with vascular anomalies and significant comorbidities, including one case of blood group incompatibility. METHODS: Five children aged 3 to 17 years (median, 7 years), weighing 14 to 34 kg (median, 18 kg) kg of whom 4 had occluded inferior vena cava or iliac veins and 2 had previous complex vascular reconstructions before transplantation for midaortic syndrome and multiple aortic aneurysms, respectively underwent renal transplantation. To establish implant feasibility surgery was commenced in 2 recipients before the donor surgery. RESULTS: There was 4 (80%) of 5 patient survival after 1 death from sepsis (with a functioning graft) and 2 cases of delayed graft function. At the latest median follow-up of 19 months, there was 100% (death-censored) renal allograft survival with estimated glomerular filtration rates (mL/min per 1.73 m) of 43 to 72 (median, 55). CONCLUSIONS: We conclude that major vascular anomalies do not necessarily preclude transplantation in complex pediatric patients and that surgical exploration of the recipient before commencing the donor surgery is valuable where feasibility and safety are uncertain. In addition, we have developed a novel classification system of congenital vascular abnormalities and propose its use in complex pediatric transplantation.

Desensitization protocol enabling pediatric crossmatch-positive renal transplantation: successful HLA-antibody-incompatible renal transplantation of two highly sensitized children.

BACKGROUND: Renal transplantation improves quality of life (QoL) and survival in children requiring renal replacement therapy (RRT). Sensitization with development of a broad-spectrum of anti-HLA antibodies as a result of previous transplantation or after receiving blood products is an increasing problem. There are no published reports of desensitization protocols in children allowing renal transplantation from HLA-antibody-incompatible living donors. METHODS: We adopted our well-established adult desensitization protocol for this purpose and undertook HLA antibody-incompatible living donor renal transplants in two children: a 14-year-old girl and a 13-year-old boy. RESULTS: After 2 and 1.5 years of follow-up, respectively, both patients have stable renal allograft function despite a rise in donor-specific antibodies in one case. CONCLUSIONS: HLA-incompatible transplantation should be considered in selected cases for sensitized children.

A Re-evaluation of Discarded Deceased Donor Kidneys in the UK: Are Usable Organs Still Being Discarded?

BACKGROUND: A significant proportion of procured deceased donor kidneys are subsequently discarded. The UK Kidney Fast-Track Scheme (KFTS) was introduced in 2012, enabling kidneys at risk of discard to be simultaneously offered to participating centers. We undertook an analysis of discarded kidneys to determine if unnecessary organ discard was still occurring since the KFTS was introduced. METHODS: Between April and June 2015, senior surgeons independently inspected 31 consecutive discarded kidneys from throughout the United Kingdom. All kidneys were biopsied. Organs were categorized as usable, possibly usable pending histology, or not usable for implantation. After histology reports were available, final assessments of usability were made. RESULTS: There were 19 donors (6 donations after brain death, 13 donations after circulatory death), with a median (range) donor age of 67 (29-83) years and Kidney Donor Profile Index of 93 (19-100). Reasons for discard were variable. Only 3 discarded kidneys had not entered the KFTS. After initial assessment postdiscard, 11 kidneys were assessed as usable, with 9 kidneys thought to be possibly usable. Consideration of histological data reduced the number of kidneys thought usable to 10 (10/31; 32%). CONCLUSIONS: The KFTS scheme is successfully identifying organs at high risk of discard, though potentially transplantable organs are still being discarded. Analyses of discarded organs are essential to identify barriers to organ utilization and develop strategies to reduce unnecessary discard.

Immune Desensitization Allows Pediatric Blood Group Incompatible Kidney Transplantation.

BACKGROUND: Blood group incompatible transplantation (ABOi) in children is rare as pretransplant conditioning remains challenging and concerns persist about the potential increased risk of rejection. METHODS: We describe the results of 11 ABOi pediatric renal transplant recipients in the 2 largest centers in the United Kingdom, sharing the same tailored desensitization protocol. Patients with pretransplant titers of 1 or more in 8 received rituximab 1 month before transplant; tacrolimus and mycophenolate mofetil were started 1 week before surgery. Antibody removal was performed to reduce titers to 1 or less in 8 on the day of the operation. No routine postoperative antibody removal was performed. RESULTS: Death-censored graft survival at last follow-up was 100% in the ABOi and 98% in 50 compatible pediatric transplants. One patient developed grade 2A rejection successfully treated with antithymocyte globulin. Another patient had a titer rise of 2 dilutions treated with 1 immunoadsorption session. There was no histological evidence of rejection in the other 9 patients. One patient developed cytomegalovirus and BK and 2 others EBV and BK viremia. CONCLUSIONS: Tailored desensitization in pediatric blood group incompatible kidney transplantation results in excellent outcomes with graft survival and rejection rates comparable with compatible transplants.

Expression of arachidonate metabolism enzymes and receptors in nasal polyps of aspirin-hypersensitive asthmatics.

BACKGROUND: The pathogenesis of rhinosinusitis in aspirin-exacerbated airway disease is closely linked to the disequilibrium in arachidonic acid metabolism. Although considerable amounts of data concerning impaired eicosanoid production are available, the precise mechanism and pathogenesis of the disease are still unknown. The aim of the present study was to assess the expression of enzymes belonging to the arachidonic acid cascade and receptors for arachidonate derivative metabolites in nasal polyps from aspirin- hypersensitive (AH) and aspirin-tolerant (AT) patients with rhinosinusitis. METHODS: Cells expressing cysteinyl leukotriene (CysLT) receptors (CysLT(1) and CysLT(2)), arachidonate 5-lipoxygenase, leukotriene B(4) receptor type 1, E-prostanoid receptors (EP(2) and EP(4)), cyclooxygenase (COX)-1 and COX-2 were detected by immunocytochemistry in nasal polyps obtained from 10 AH patients and 18 AT patients. RESULTS: There was a significantly higher density of cells expressing CysLT(1) and CysLT(2) receptors in nasal polyps from AH patients than from AT patients (p < 0.001). In contrast, the density of cells expressing EP(2) receptor and COX-2 was significantly lower in AH patients than in AT patients (p < 0.02). The number of COX-2-positive epithelial cells was significantly reduced in AH polyps (p < 0.04). CONCLUSIONS: The elevated number of nasal polyp cells expressing CysLT receptors and lack of cells expressing EP(2) receptor and COX-2 may be related to a more severe course of hyperplastic rhinosinusitis in aspirin hypersensitivity.