Increased kidney stone risk following total pancreatectomy with islet autotransplantation.

BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is associated with increased risk of calcium-oxalate kidney stones, likely due to enteric hyperoxaluria. However, the risk of kidney stones for patients with CP after total pancreatectomy with islet autotransplantation (TPIAT) is unknown. We aimed to evaluate kidney stone risk in patients with CP after TPIAT. METHODS: A retrospective analysis of 629 patients who underwent TPIAT was conducted to identify patients who developed kidney stones post-TPIAT. Kaplan-Meier analysis estimated time to first event. An Anderson-Gill proportional-hazards analysis of all kidney stone events described key clinical associations. RESULTS: Mean age at TPIAT was 33 years (SD 15.3, range 3-69); 69.8 % (n = 439) were female. The estimated chance of any kidney stone episodes by 5 years post-TPIAT was 12.8 % (95 % CI: 8.8-16.6 %); by 10 years, 23.2 % (CI: 17.5-28.6 %); by 15 years, 29.4 % (CI: 21.8-36.2 %). Significant associations with kidney stones post-TPIAT included older age (HR 1.25 per 10 years), smoking history (HR 1.72), mild chronic kidney disease (HR 1.96), renal cysts (HR 3.67), pre-TPIAT kidney stones (HR 4.06), family history of kidney stones (HR 4.10), and Roux-en-Y reconstruction (HR 2.68). Of the 77 patients who developed kidney stones, 34 (44.1 %) had recurrent episodes. Of 143 total kidney stone events, 35 (24.5 %) required stone removal, 79 (55.2 %) resolved spontaneously, and 29 (20.3 %) were missing this data. CONCLUSIONS: Patients with CP post-TPIAT commonly have kidney stones: nearly 3 in 10 have ≥1 kidney stone episodes within 15 years. Clinicians should be aware of this risk and counsel patients on prevention.

Impact of Elevated Serum Triglycerides on Children with Acute Recurrent or Chronic Pancreatitis from INSPPIRE-2.

OBJECTIVE: To determine if mild-moderate hypertriglyceridemia (HTG) is associated with increased development of chronic pancreatitis (CP) or pancreatitis-associated complications in children with acute recurrent or CP. STUDY DESIGN: Longitudinal data from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE-2 (INSPPIRE-2) cohort of children with acute recurrent or CP (n = 559) were analyzed. Subjects were divided into normal triglycerides (<150 mg/dL; 1.7 mmol/L), any HTG (≥150 mg/dL; ≥1.7 mmol/L), mild-moderate HTG (150-499 mg/dL; 1.7-5.6 mmol/L), moderate HTG (500-999 mg/dL; 5.6-11.3 mmol/L), and severe HTG groups (≥1000 mg/dL; ≥11.3 mmol/L), based on highest serum triglyceride value. Laboratory, imaging, pancreatitis and hospital events, complications, and quality of life data were analyzed. RESULTS: In children with acute recurrent or CP and HTG, there was no increase in the number of pancreatitis attacks per person-years, nor an increase in CP prevalence. However, HTG severity was associated with increased pancreatic inflammation, pancreatic cysts, pain, hospital days, number of hospitalizations, intensive care, and missed school days. CONCLUSIONS: Mild-moderate HTG in children with acute recurrent or CP was not associated with increased pancreatitis frequency, nor increased development of CP, but was associated with increased pancreatitis complications and disease burden. As a treatable condition, treatment of mild-moderate HTG may be considered to reduce pancreatitis-associated complications and medical burden in children with acute recurrent or CP.

Essential Fatty Acid Deficiency Is Common After Total Pancreatectomy and Islet Autotransplantation.

OBJECTIVES: Total pancreatectomy and islet autotransplantation (TPIAT) for pancreatitis may induce risk for essential fatty acid deficiency (EFAD) due to exocrine pancreatic insufficiency and intestinal alterations. The prevalence of EFAD post-TPIAT is currently unknown. METHODS: We abstracted essential fatty acid (EFA) profiles (n = 332 samples) for 197 TPIAT recipients (72% adult, 33% male). Statistical analyses determined the prevalence of, and associations with, EFAD post-operatively. EFAD was defined as a Triene-to-Tetraene ratio ≥0.05 if <18 years old, or ≥0.038 if ≥18 years old. RESULTS: Prevalence of EFAD was 33%, 49%, and 53.5% at 1, 2, and ≥3 years. At 1-year post-TPIAT, older age at transplant ( P = 0.03), being an adult versus a child ( P = 0.0024), and obstructive etiology ( P = 0.0004) were significant predictors of EFAD. Only 6% of children had EFAD 1-year post-TPIAT versus 46% of adults. The alpha-linolenic acid levels were lower with lower body mass index at transplant ( P = 0.011). EFAD was associated with the presence of other intestinal diseases ( P < 0.0001). CONCLUSIONS: One-third of individuals had EFAD 1-year post-TPIAT, highlighting the need for systematic monitoring. Older age at transplant increased risk and adults were more affected than children. Other diagnoses affecting intestinal health may further increase risk for EFAD.

Nutrition support in the pediatric total pancreatectomy with islet autotransplantation recipient.

For children with diminished quality of life and chronic pain caused by acute recurrent or chronic pancreatitis who are undergoing total pancreatectomy with islet autotransplantation, postoperative nutrition support has several unique characteristics. Surgical complications may lead to delays in nutrition support initiation or require modifications to the regimen. Early postoperative dysmotility requires the use of temporary enteral nutrition until this improves. The resultant complete exocrine pancreatic insufficiency necessitates lifelong pancreatic enzyme replacement therapy and fat-soluble vitamin supplementation. A low-oxalate diet is recommended to prevent kidney stones. Carbohydrate counting is needed for the provision of short-term insulin dosing and possibly long-term as well, depending on the transplanted islet yield. Children should have careful nutrition assessment and monitoring at several follow-up visits during the first year, then annually, and at any time with concerns.

Early Metabolic Measures Predict Long-term Insulin Independence in Recipients of Total Pancreatectomy and Islet Autotransplantation.

Background: Although diabetes after total pancreatectomy and islet autotransplantation (TP-IAT) is one of the biggest concerns for TP-IAT recipients and physicians, reliable prediction of post-TP-IAT glycemic control remains unestablished. This study was conducted to identify early predictors of insulin independence and goal glycemic control by hemoglobin A1c (HbA1c) ≤ 6.5% after TP-IAT. Methods: In this single-center, retrospective study, patients who underwent TP-IAT (n = 227) were reviewed for simple metabolic markers or surrogate indices of ß-cell function obtained 3 mo after TP-IAT as part of standard clinical testing. Long-term metabolic success was defined as (1) insulin independence and (2) HbA1c ≤ 6.5% 1, 3, and 5 y after TP-IAT. Single- and multivariate modeling used 3-mo markers to predict successful outcomes. Results: Of the 227 recipients, median age 31 y, 30% male, 1 y after TP-IAT insulin independence, and HbA1c ≤ 6.5% were present in 39.6% and 72.5%, respectively. In single-predictor analyses, most of the metabolic markers successfully discriminated between those attaining and not attaining metabolic goals. Using the best model selected by random forests analysis, we accurately predicted 1-y insulin independence and goal HbA1c control in 77.3% and 86.4% of the patients, respectively. A simpler "clinically feasible" model using only transplanted islet dose and BETA-2 score allowed easier prediction at a small accuracy loss (74.1% and 82.9%, respectively). Conclusions: Metabolic testing measures performed 3 mo after TP-IAT were highly associated with later diabetes outcomes and provided a reliable prediction model, giving valuable prognostic insight early after TP-IAT and help to identify recipients who require early intervention.

Nutritional Risks in Patients Undergoing Total Pancreatectomy Islet AutoTransplantation in the POST Consortium.

BACKGROUND AND AIMS: Total pancreatectomy with islet autotransplantation (TPIAT) can relieve pain for individuals with acute recurrent or chronic pancreatitis. However, TPIAT may increase the risk of poor nutritional status with complete exocrine pancreatic insufficiency, partial duodenectomy, and intestinal reconstruction. Our study's objective was to evaluate nutritional status, anthropometrics, and vitamin levels before and after TPIAT. METHODS: The multicenter Prospective Observational Study of TPIAT (POST) collects measures including vitamins A, D, and E levels, pancreatic enzyme dose, and multivitamin (MVI) administration before and 1-year after TPIAT. Using these data, we studied nutritional and vitamin status before and after TPIAT. RESULTS: 348 TPIAT recipients were included (68% adult, 37% male, 93% Caucasian). In paired analyses at 1-year follow-up, vitamin A was low in 23% (vs 9% pre-TPIAT, p < 0.001); vitamin E was low in 11% (vs 5% pre-TPIAT, p = 0.066), and 19% had vitamin D deficiency (vs 12% pre-TPIAT, p = 0.035). Taking a fat-soluble multivitamin (pancreatic MVI) was associated with lower risk for vitamin D deficiency (p = 0.002). Adults were less likely to be on a pancreatic MVI at follow-up (34% vs 66% respectively, p < 0.001). Enzyme dosing was adequate. More adults versus children were overweight or underweight pre- and post-TPIAT. Underweight status was associated with vitamin A (p = 0.014) and E (p = 0.02) deficiency at follow-up. CONCLUSIONS: Prevalence of fat-soluble vitamin deficiencies increased after TPIAT, especially if underweight. We strongly advocate that all TPIAT recipients have close post-operative nutritional monitoring, including vitamin levels. Pancreatic MVIs should be given to minimize risk of developing deficiencies.

Metabolic measures before surgery and long-term diabetes outcomes in recipients of total pancreatectomy and islet autotransplantation.

In this single-center, retrospective cohort study, we aimed to elucidate simple metabolic markers or surrogate indices of ß-cell function that best predict long-term insulin independence and goal glycemic HbA1c control (HbA1c ≤ 6.5%) after total pancreatectomy with islet autotransplantation (TP-IAT). Patients who underwent TP-IAT (n = 371) were reviewed for metabolic measures before TP-IAT and for insulin independence and glycemic control at 1, 3, and 5 years after TP-IAT. Insulin independence and goal glycemic control were achieved in 33% and 68% at 1 year, respectively. Although the groups who were insulin independent and dependent overlap substantially on baseline measures, an individual who has abnormal glycemia (prediabetes HbA1c or fasting glucose) or estimated IEQs/kg < 2500 has a very high likelihood of remaining insulin dependent after surgery. In multivariate logistic regression modelling, metabolic measures correctly predicted insulin independence in about 70% of patients at 1, 3, and 5 years after TP-IAT. In conclusion, metabolic testing measures before surgery are highly associated with diabetes outcomes after TP-IAT at a population level and correctly predict outcomes in approximately two out of three patients. These findings may aid in prognostic counseling for chronic pancreatitis patients who are likely to eventually need TP-IAT.

Fat-soluble Vitamin Deficiency is Common in Children With Chronic Pancreatitis Undergoing Total Pancreatectomy With Islet Autotransplantation.

ABSTRACT: The prevalence of fat-soluble vitamin (FSV) deficiency in children undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis (CP) is unknown. We quantified FSV deficiency in 100 children (age ≤18) undergoing TPIAT. FSV levels (vitamins A, E, D) and clinical history were abstracted from medical records. Vitamin A was low in 4% before and 7% at 1 year after TPIAT, vitamin E in 17% and 18%, and vitamin D in 22% and 24%, respectively, regardless of pancreatic enzyme or vitamin supplement dosing. Longer duration of CP was associated with pre-TPIAT vitamin D insufficiency (P = 0.0002). This remained significant in a multivariate regression model (adjusted P = 0.01). On multivariate analysis, there were no significant predictors of low FSV levels post-TPIAT. FSV deficiencies are common among children undergoing TPIAT and patients who have had longer disease duration may be at increased risk. All children should be monitored for FSV deficiency after TPIAT.

Early use of continuous glucose monitoring in children and adolescents after total pancreatectomy with islet autotransplantation.

BACKGROUND: Children undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis require intensive insulin therapy early after TPIAT with narrow glycemic targets, which can a present significant care burden. Outpatient use of continuous glucose monitoring (CGM) systems by children and caregivers early after TPIAT is inadequately studied. METHODS: In this open-label study, we randomized 14 children and adolescents (mean age 15.4 years) after hospital discharge for TPIAT to Dexcom G6 CGM (n = 7) or standard care with a glucometer (n = 7) to assess acceptability and glycemic control with use of CGM versus usual care (glucometer). Participants in the control arm also wore a blinded CGM for 1 week. RESULT: Children randomized to real-time CGM had lower mean sensor glucose values compared with controls (p = 0.002), and high overall satisfaction with CGM. CONCLUSIONS: Our data indicate that CGM is a useful adjunct to diabetes management for children who have recently undergone TPIAT.

Progress in individualizing autologous islet isolation techniques for pediatric islet autotransplantation after total pancreatectomy in children for chronic pancreatitis.

Total pancreatectomy with islet autotransplantation is performed to treat chronic pancreatitis in children. Successful islet isolation must address the challenges of severe pancreatic fibrosis and young donor age. We have progressively introduced modifications to optimize enzymatic and mechanical dissociation of the pancreas during islet isolation. We evaluated 2 islet isolation metrics in 138 children-digest islet equivalents per gram pancreas tissue (IEQ/g) and digest IEQ per kilogram body weight (IEQ/kg), using multiple regression to adjust for key disease and patient features. Islet yield at digest had an average 4569 (standard deviation 2949) islet equivalent (IEQ)/g and 4946 (4009) IEQ/kg, with 59.1% embedded in exocrine tissue. Cases with very low yield (<2000 IEQ/g or IEQ/kg) have decreased substantially over time, 6.8% and 9.1%, respectively, in the most recent tertile of time compared to 19.2% and 23.4% in the middle and 34.1% and 36.4% in the oldest tertile. IEQ/g and IEQ/kg adjusted for patient and disease factors improved in consistency and yield in the modern era. Minimal mechanical disruption during digestion, warm enzymatic digestion using enzyme collagenase:NP activity ratio < 10:1, coupled with extended distension and trimming time during islet isolation of younger and fibrotic pediatric pancreases, gave increased islet yield with improved patient outcomes.

Rapid Infliximab Infusion in the Pediatric Population.

OBJECTIVES: To compare infusion reaction rates between rapid infliximab (REMICADE, Janssen Biotech Inc) infusions and previous standard 2- to 3-hour infusions; additionally, to assess patient satisfaction and reduction in chair time associated with rapid infliximab infusions. METHODS: Pediatric rheumatology and gastroenterology patients receiving maintenance infliximab therapy using a standard 2- to 3-hour titrated infusion had the opportunity to enroll in the non-titrated rapid 1-hour infusion protocol following tolerance of induction dosing at 0, 2, and 6 weeks. Patients were included from December 1, 2017, to March 31, 2018, via retrospective chart review and patient satisfaction surveys. RESULTS: Data were collected on 55 patients receiving a total of 160 rapid infliximab infusions. There were 2 infusion reactions during the enrollment and data collection period, resulting in an overall infusion reaction rate of 1.3%. The patient satisfaction survey results showed all patients were at minimum satisfied with the information provided regarding rapid infliximab, decreased time spent in clinic, ease of scheduling, and overall process. CONCLUSIONS: Our data suggest rapid infliximab infusions are safe in pediatric rheumatology and gastroenterology patients receiving maintenance infliximab infusion therapy. The overall infusion reaction rate of 1.3% in this study is well below the accepted infusion reaction rate of standard-length infliximab infusions of 2% to 3%.

Safety and Clinical Outcomes of Using Low-Molecular-Weight Dextran During Islet Autotransplantation in Children.

OBJECTIVES: The objective of this study was to evaluate potential safety and clinical benefit of low-molecular-weight dextran (dextran) use in patients undergoing total pancreatectomy with islet auto transplantation (TPIAT). METHODS: We evaluated 124 children undergoing TPIAT at a single institution, either with (n = 72) or without (n = 52) perioperative dextran infusion. Data on islet graft function and postoperative complications were collected through electronic medical records and patient-reported outcomes from research questionnaires. RESULTS: Islet graft failure was less likely at 1 year (odds ratio, 0.186; 95% confidence interval, 0.04-0.65) and 2 years (odds ratio, 0.063; 95% confidence interval, 0.003-0.35) post-TPIAT in the dextran group. This finding remained significant at 2 years in multivariate logistic regression modeling adjusting for islet mass, body surface area, and sex. Likewise, in multivariate regression, the odds of partial islet graft function were higher at 1 and 2 years in the dextran group. Dextran use was overall safe, although it did lead to a higher incidence of postoperative bleeding requiring blood transfusions (P < 0.001). CONCLUSIONS: These findings suggest that dextran use may increase the likelihood for sustained post-TPIAT islet graft function, potentially mitigating severity of postoperative diabetes for these children.

Risk Factors Associated With Progression Toward Endocrine Insufficiency in Chronic Pancreatitis.

OBJECTIVE: Little data exist describing the change over time in islet function and glycemic control in patients with chronic pancreatitis (CP). METHODS: In 325 CP patients who underwent 2 mixed meal tolerance tests and/or glycated hemoglobin (HbA1c) levels, we estimated the rate of change in metabolic measures per 6 months and assessed the association between potential risk factors for diabetes and rate of change using multivariate regression models. RESULTS: Per 6-month time, HbA1c increased by 0.062% with a standard error of 0.029% (P = 0.037) and the ratio (area under the curve (AUC) C-peptide to AUC glucose from mixed meal tolerance testing) decreased by 0.0028 with a standard error of 0.0011 (P = 0.014). We observed more rapid decline in smokers (AUC C-peptide, P = 0.043) and patients with surgical drainage (AUC glucose, P = 0.001; ratio, P = 0.03) or with calcific pancreatitis (HbA1c, P = 0.003). In multivariate models, AUC C-peptide and ratio declined at a greater rate in smokers and HbA1c in those with pancreatic calcifications (both P < 0.05). CONCLUSIONS: We observed a measurable decline in ß-cell function and glycemic control in patients with CP. Patients with a history of tobacco smoking, surgical drainage, or pancreatic calcification may be at highest risk.