Amy Gallo

IL-18 Is Induced and IL-18 Receptor α Plays a Critical Role in the Pathogenesis of Cigarette Smoke-Induced Pulmonary Emphysema and Inflammation

Th1 inflammation and remodeling characterized by local tissue destruction coexist in pulmonary emphysema and other diseases. To test the hypothesis that IL-18 plays an important role in these responses, we characterized the regulation of IL-18 in lungs from cigarette smoke (CS) and room air-exposed mice and characterized the effects of CS in wild-type mice and mice with null mutations of IL-18Rα (IL-18Rα−/−). CS was a potent stimulator and activator of IL-18 and caspases 1 and 11. In addition, although CS caused inflammation and emphysema in wild-type mice, both of these responses were significantly decreased in IL-18Rα−/− animals. CS also induced epithelial apoptosis, activated effector caspases and stimulated proteases and chemokines via IL-18Rα-dependent pathways. Importantly, the levels of IL-18 and its targets, cathepsins S and B, were increased in pulmonary macrophages from smokers and patients with chronic obstructive lung disease. Elevated levels of circulating IL-18 were also seen in patients with chronic obstructive lung disease. These studies demonstrate that IL-18 and the IL-18 pathway are activated in CS-exposed mice and man. They also demonstrate, in a murine modeling system, that IL-18R signaling plays a critical role in the pathogenesis of CS-induced inflammation and emphysema.

Current options for management of biliary atresia.

It is encouraging that we are improving the technical aspects of treatment modalities for biliary atresia. However, it is clear that more needs to be done to best develop new treatment plans while applying the modalities we have (porto‐enterostomy or liver transplantation or both) in a way that will afford the best survival and quality‐of‐life. This review article will discuss a number of points that are vital to improving care and illustrates the need to further scrutinize treatment decisions.

Changes in natural killer cell subsets in pediatric liver transplant recipients.

Pham B, Piard‐Ruster K, Silva R, Gallo A, Esquivel CO, Martinez OM, Krams SM. Changes in natural killer cell subsets in pediatric liver transplant recipients. 
Pediatr Transplantation 2012: 16: 176–182.

Pediatric deceased donor renal transplantation: An approach to decision making I. Pediatric kidney allocation in the USA: The old and the new.

Renal transplantation is the treatment of choice for children with end‐stage renal disease. More than 50% of children receive a deceased donor renal transplant. Marked disparity between the number of children on the renal transplant wait list and the supply has prompted numerous advances to increase supply as well as maximize the utility of donor organs. Allocation of deceased donor kidneys is based on several criteria. The organ allocation system policy is continually evaluated and changed incrementally to optimize allocation. We, in the United Sates, are in the process of transitioning into a new kidney allocation system to enhance post‐transplant survival benefit, increase utilization of donated kidneys, and increase transplant access for biologically disadvantaged candidates. This review will provide a brief overview of the organ sharing system in the United States, compare the “old” and the “new” allocation system, and discuss the considerations for the pediatric nephrologist while accepting a deceased donor kidney for a particular pediatric patient.

Impact of the kidney allocation system on young pediatric recipients

The kidney allocation system (KAS) altered pediatric candidate prioritization. We determined KASs impact on pediatric kidney recipients by examining delayed graft function (DGF) rates from 2010 to 2016. A propensity score‐matched pediatric recipients pre‐ and post‐KAS. A semiparametric decomposition analysis estimated the contributions of KAS‐related changes in donor characteristics and dialysis time on DGF rate. The unadjusted odds of DGF were 69% higher post‐KAS for young (<10 years at listing) recipients (N = 1153, P = .02) but were not significantly increased for older pediatric (10‐17 years at listing) recipients (N = 2624, P = .48). Post‐KAS, young recipients received significantly fewer pediatric (<18 years) donor kidneys (21% vs 32%, P < .01) and had longer median pretransplant dialysis time (603 vs 435 days, P < .01). After propensity score matching, post‐KAS status increased the odds of DGF in young recipients 71% (OR 1.71, 95% CI 1.01‐2.46). In decomposition analysis, 24% of the higher DGF rate post‐KAS was attributable to donor characteristics and 19% to increased recipient dialysis time. In a confirmatory survival analysis, DGF was associated with a 2.2 times higher risk of graft failure (aHR2.28, 95% CI 1.46‐3.54). In conclusion, KAS may lead to worse graft survival outcomes in children. Allocation changes should be considered.

Recurrent hepatocellular carcinoma and poorer overall survival in patients undergoing left-sided compared with right-sided partial hepatectomy.

Goals: We aimed to determine the incidence and predictors of recurrent hepatocellular carcinoma (HCC) after partial hepatectomy. Background: Liver transplantation is the preferred treatment for selected patients with HCC, but access to donor organs is limited. Partial hepatectomy is another accepted treatment option; however, postoperative recurrence is frequently observed. Methods: This is a retrospective cohort study of 107 consecutive patients who underwent partial hepatectomy for HCC between January 1993 and February 2011 at a US University Medical Center. Study endpoints were recurrent HCC, death, loss to follow-up, or last visit without HCC. Results: The study cohort was 78% male with a median age of 61 years and 59% Asians. A total of 50 patients developed recurrent HCC (46.7%) after a median follow-up of 12 (1 to 69) months postresection. Recurrent HCC was significantly higher in patients with left-sided resection (41% at year 1, 54% at year 2, 62% at year 3, 81% at year 4, and 90% at year 5) compared with right-sided resection (18% at year 1, 34% at year 2, 36% at year 3, 44% at year 4, and 72% at year 5). In multivariate Cox proportional hazards model also inclusive of anatomic resection and TNM stage 3/4, left-sided resection was significantly associated with increased HCC recurrence (hazard ratio, 2.13; P=0.02; 95% confidence interval, 1.08-4.2) compared with right-sided resection. Conclusions: HCC recurrence rate is higher among those undergoing left-sided resection: 54% at year 2 and 81% at year 4. Liver transplantation should be considered in patients who are at high risk for recurrence.

Pediatric deceased donor renal transplantation: An approach to decision making II. Acceptability of a deceased donor kidney for a child, a snap decision at 3 AM.

Allocation of deceased donor kidneys is based on several criteria; however, the final decision to accept or reject the offered kidney is made by the potential recipients transplant team (surgeon/nephrologist). Several considerations including assessment of the donor quality, the HLA match between the donor and the recipient, several recipient factors, the geographical location of the recipient, and the organ all affect the decision of whether or not to finally accept the organ for a particular recipient. This decision needs to be made quickly, often on the spot. Maximizing the benefit from this scarce resource raises difficult ethical issues. The philosophies of equity and utility are often competing. This article will discuss the several considerations for the pediatric nephrologist while accepting a deceased donor kidney for a particular pediatric patient.

Sclerosing peritonitis after kidney transplantation: a not-so-silky cocoon.

A 55-year-old woman with end-stage renal disease secondary to systemic lupus erythematosus had undergone two renal transplants over a 15-year period. Of note, her renal replacement between the two transplants was via peritoneal dialysis for a 5-year period while she awaited a deceased donor kidney. Her past medical history was also significant for hypertension, hyperlipidemia, anemia, and depression. Following her second successful kidney transplant, she had persistent nausea and vomiting, which she considered similar to her preoperative state and not disruptive to her daily activities. She was admitted to a community hospital several months following the transplant complaining of worsening vomiting over 3 weeks. She also experienced early satiety, belching, epigastric fullness, crampy abdominal pain and daily watery stools, and she had lost 30 lb over the preceding months. At the time of admission, her creatinine was elevated at 2.2 mg/dl, but corrected to 1.3 mg/dl with hydration. A computed tomography (CT) scan demonstrated edema of the bowel wall and a pelvic fluid collection. Upper endoscopy revealed mild duodenitis, gastritis, and an atonic and dilated stomach. She was transferred to Stanford University Medical Center with the preliminary diagnosis of gastroparesis. On our exam, she had a firm, mildly distended, but nontender abdomen. Total parenteral nutrition (TPN) was initiated. A gastric emptying study was attempted, but could not be completed due to vomiting. Repeat CT scan showed a large fluid collection in the abdomen and pelvis with a thick enhancing wall (Figs. 1, 2). There was also dilation of the duodenum and stomach with an abrupt transition at the proximal jejunum consistent with mechanical obstruction due to sclerosing peritonitis (Fig. 3). The interventional radiology team placed a drain in the abdomen and 1 l of sterile serosanguineous fluid was extracted. A nasogastric tube was placed for bowel decompression. Repeat endoscopy did not demonstrate any obstruction at the proximal jejunum, but did reveal reflux esophagitis. An upper GI series with small bowel followthrough then revealed high-grade obstruction at the level of the proximal jejunum (Fig. 4). Given the high-grade obstruction and her failure to improve with nonoperative management, she underwent exploratory laparotomy. At surgery, she was found to have thickened peritoneum encasing all of her small bowel. The entire small bowel contents were compressed into a tight ball or ‘‘abdominal cocoon.’’ She also had complete interloop adhesions. One loop of very proximal jejunum in the left upper quadrant appeared particularly kinked, near the site of obstruction that had been observed on the upper GI series. Extensive lysis of adhesions was performed during a 5-h operation. She did not undergo any bowel resection, but from the lysis of adhesions alone, it appeared that 25% of the small intestine had been deserosalized because it was not possible to effectively peal loops of bowel from one another. All of the serosa on the outer surface of the cocoon E. H. Morrow (&) Department of Surgery, Stanford University Medical Center, Palo Alto, CA, USA e-mail: emorrow@stanford.edu

Late hepatic artery thrombosis in pediatric liver transplantation: an incomplete story.

It has now been 50 years since the first pediatric liver transplant, and the success of these transplants— patient and graft survival—still largely depends on our ability to maintain artery patency. Although many interventions, medical and technical, have been implemented, the truth remains that a high percentage of arteries continue to become occluded and thus compromise patient outcomes. Early thrombosis often leads to graft compromise and failure, and this requires reoperation and retransplantation. The prevalence and clinical relevance of late hepatic artery thrombosis (HAT) remain unclear. In this issue of Liver Transplantation, Kivel€ a et al. present a cross-sectional study of 34 liver transplant patients less than 18 years old over a 10-year period (starting in 1987) with a median follow-up of 9.5 years (interquartile range 5 4.0-16.4 years). Ninety-nine pediatric patients originally underwent transplantation in that time frame. Thirty-two percent of these patients were deceased. Thirty-four of the surviving 66 patients were available to undergo magnetic resonance imaging (MRI) with contrast for an evaluation of HAT. Interestingly, they report that 44% of these 34 patients had evidence of late arterial thrombosis, with late thrombosis defined as thrombosis 1 month after the date of transplantation; this was much higher than the previously reported rates (1.2%-2.7%). As the discussion makes clear, this could represent 23% of patients in the best case scenario and 71% in the worst case scenario because only 52% of the whole population underwent imaging. By comparing the MRI findings with ultrasonography, laboratory, biopsy, and clinical data, the authors have done a comprehensive job of analyzing these patients at time points surrounding MRI. They bring attention to the possibility that late HAT is wildly underdiagnosed during the standard follow-up of pediatric patients. Our 2 most pressing concerns regarding these data are (1) whether the late HAT rate of 44% is accurate for longterm pediatric transplant survivors and (2) what the clinical application of this knowledge should be as we go forward. One of the biggest concerns in accepting this high percentage for late thrombosis is that the MRI technique described in the article’s methodology was not consistently angiographic. Without angiography, it may be hard to draw convincing conclusions about HAT, especially without any indication of flow issues on a similarly timed ultrasound examination. It is well known that ultrasound is not the gold standard for the detection of HAT; however, changes in flow can suggest a need for a closer investigation. It is surprising that there was no suggestion of intrahepatic changes in flow on ultrasound for these patients. In addition, if we agree that ultrasound accuracy is as poor as suggested at this institution (40% sensitivity), it is possible that a percentage of these patients had unrecognized early HAT if ultrasound was the only imaging performed in the early posttransplant period. For comparison, in the year 2008 at our institution, Lucile Packard Children’s Hospital at Stanford, 40 transplants were performed in children less than 18 years of age (43% were <1 year of age). Early HAT was diagnosed in 1 child, who required retransplantation (2.5%). The 5-year graft survival rate for this cohort was 92.5%. There have been no patients diagnosed with late HAT so far. In light of Kivel€ a et al.’s study, it might be assumed that late HAT has been severely underdiagnosed at our institution, presumably because, just as at other centers, computed

464BK Virus Genetic Changes in Pediatric Kidney Transplant Patients with Prolonged BK Viral Load

with Prolonged BK Viral Load Sharon F. Chen, MD, MS; Malaya K. Sahoo, PhD; Fiona Yamamoto, Msc; Kalyan Mallempati, MSc; Lynn Kjelson, MPH, MMS, PA-C; Matthew W. Anderson, MD, PhD; Amy Gallo, MD; Paul Grimm, MD; Waldo Concepcion, MD; Benjamin A. Pinsky, MD, PhD; Beatrix Kapusinszky, Msc, PhD; Katie Concepcion; Pediatrics, Stanford University School of Medicine, Palo Alto, CA; Pathology, Stanford University School of Medicine, Palo Alto, CA; Diagnostic Laboratories, Bloodcenter of Wisconsin, Milwaukee, WI; Surgery, Stanford University School of Medicine, Palo Alto, CA; Pathology, Stanford Hospital and Clinics, Palo Alto, CA