High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m2, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%–12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated.

At birth, the newborn mammal undergoes a transition from a sterile uterine environment with a constant nutrient supply, to a microbe-rich environment with intermittent oral intake of complex milk nutrients via the gastrointestinal tract (GIT). These functional challenges partly explain the relatively high morbidity and mortality of neonates. Preterm birth interrupts prenatal organ maturation, including that of the GIT, and increases disease risk. Exemplary is necrotizing enterocolitis (NEC), which is associated closely with GIT immaturity, enteral feeding, and bacterial colonization. Infants with NEC may require resection of the necrotic parts of the intestine, leading to short bowel syndrome (SBS), characterized by reduced digestive capacity, fluid loss, and dependency on parenteral nutrition. This review presents the preterm pig as a translational model in pediatric gastroenterology that has provided new insights into important pediatric diseases such as NEC and SBS. We describe protocols for delivery, care, and handling of preterm pigs, and show how the immature GIT responds to delivery method and different nutritional and therapeutic interventions. The preterm pig may also provide a sensitive model for postnatal adaptation of weak term piglets showing high mortality. Attributes of the preterm pig model include close similarities with preterm infants in body size, organ development, and many clinical features, thereby providing a translational advantage relative to rodent models of GIT immaturity. On the other hand, the need for a sow surgical facility, a piglet intensive care unit, and clinically trained personnel may limit widespread use of preterm pigs. Studies on organ adaptation in preterm pigs help to identify the physiological basis of neonatal survival for hypersensitive newborns and aid in defining the optimal diet and rearing conditions during the critical neonatal period.

The influence of dietary fructooligosaccharide (neosugar) on the fecal flora and activities of reductive enzymes was studied in 12 healthy, adult human subjects fed a controlled diet for 42 d and given 4 g neosugar/d between days 7 and 32. Fecal samples were collected before, during, and after supplementation with neosugar to enumerate total anaerobes, aerobes, bifidobacteria, and enterobacteria, and to assay for beta-glucuronidase, nitroreductase, and glycocholic acid hydroxylase. Although the controlled diet caused an increase in total anaerobes and bifidobacteria, the highest densities occurred during supplementation with neosugar. Total aerobes and enterobacteria were less affected by diet and neosugar. Neosugar caused beta-glucuronidase and glycocholic acid hydroxylase activities to decrease 75% and 90%, respectively; both increased after supplementation with neosugar was stopped. Nitroreductase activity declined 80% after the control diet was started, but was not affected by neosugar. These findings indicate that 4 g neosugar/d alters the fecal flora in a manner perceived as beneficial by decreasing activities of some reductive enzymes.

Prebiotics induce changes in the population and metabolic characteristics of the gastrointestinal bacteria, modulate enteric and systemic immune functions, and provide laboratory rodents with resistance to carcinogens that promote colorectal cancer. There is less known about protection from other challenges. Therefore, mice of the B6C3F1 strain were fed for 6 wk a control diet with 100 g/kg cellulose or one of two experimental diets with the cellulose replaced entirely by the nondigestible oligosaccharides (NDO) oligofructose and inulin. From each diet, 25 mice were challenged by a promoter of colorectal cancer (1,2-dimethylhydrazine), B16F10 tumor cells, the enteric pathogen Candida albicans (enterically), or were infected systemically with Listeria monocytogenes or Salmonella typhimurium. The incidences of aberrant crypt foci in the distal colon after exposure to dimethylhdrazine for mice fed inulin (53%) and oligofructose (54%) were lower than in control mice (76%; P < 0.05), but the fructans did not reduce the incidence of lung tumors after injection of the B16F10 tumor cells. Mice fed the diets with fructans had 50% lower densities of C. albicans in the small intestine (P < 0.05). A systemic infection with L. monocytogenes caused nearly 30% mortality among control mice, but none of the mice fed inulin died, with survival intermediate for mice fed oligofructose. Mortality was higher for the systemic infection of S. typhimurium (>80% for control mice), but fewer of the mice fed inulin died (60%; P < 0.05), with mice fed oligofructose again intermediate. The mechanistic basis for the increased resistance provided by dietary NDO was not elucidated, but the findings are consistent with enhanced immune functions in response to changes in the composition and metabolic characteristics of the bacteria resident in the gastrointestinal tract.