Kyung Hoon Paik

Inflammation and cachexia in chronic kidney disease

Chronic inflammation is associated with cachexia and increased mortality risk in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Inflammation suppresses appetite and causes the loss of protein stores. In CKD patients, increased serum levels of pro-inflammatory cytokines may be caused by reduced renal function, volume overload, oxidative or carbonyl stress, decreased levels of antioxidants, increased susceptibility to infection in uremia, and the presence of comorbid conditions. Cachexia is brought about by the synergistic combination of a dramatic decrease in appetite and an increase in the catabolism of fat and lean body mass. Pro-inflammatory cytokines act on the central nervous system to alter appetite and energy metabolism and to provide a signal—through the nuclear factor-κB and ATP-ubiquitin-dependent proteolytic pathways—that causes muscle wasting. Further research into the molecular pathways leading to inflammation and cachexia may lead to novel therapeutic therapies for this devastating and potentially fatal complication of chronic disease.

Peptide YY, Cholecystokinin, Insulin and Ghrelin Response to Meal did not Change, but Mean Serum Levels of Insulin is Reduced in Children with Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a contiguous gene syndrome characterized by uncontrollable eating or hyperphagia. Several studies have confirmed that plasma ghrelin levels are markedly elevated in PWS adults and children. The study of anorexigenic hormones is of interest because of their regulation of appetite by negative signals. To study the pattern and response of the anorexigenic hormones such as cholecystokinin (CCK) and peptide YY (PYY) to a meal in PWS, we measured the plasma CCK, PYY, ghrelin and serum insulin levels in PWS patients (n=4) and in controls (n=4) hourly for a day, and analyzed hormone levels and hormonal responses to meals. Repeated measures of ANOVA of hormone levels demonstrated that only insulin levels decreased (p=0.013) and CCK (p=0.005) and ghrelin (p=0.0007) increased in PWS over 24 hr. However, no significant group x time interactions (ghrelin: p=0.89, CCK: p=0.93, PYY: p=0.68 and insulin: p=0.85) were observed; in addition, there were no differences in an assessment of a three-hour area under the curve after breakfast. These results suggest that the response pattern of hormones to meals in PWS patients parallels that of normal controls. In addition, the decrease of insulin levels over 24 hr, in spite of obesity and elevated ghrelin levels, suggests that the baseline insulin level, not the insulin response to meals, may be abnormal in patients with PWS.

Continuous renal replacement therapy in neonates weighing less than 3 kg

Purpose Continuous renal replacement therapy (CRRT) is becoming the treatment of choice for supporting critically ill pediatric patients. However, a few studies present have reported CRRT use and outcome in neonates weighing less than 3 kg. The aim of this study is to describe the clinical application, outcome, and complications of CRRT in small neonates. Methods A retrospective review was performed in 8 neonatal patients who underwent at least 24 hours of pumped venovenous CRRT at the Samsung Medical Center in Seoul, Korea, between March 2007 and July 2010. Data, including demographic characteristics, diagnosis, vital signs, medications, laboratory, and CRRT parameters were recorded. Results The data of 8 patients were analyzed. At the initiation of CRRT, the median age was 5 days (corrected age, 38+2 weeks to 23 days), and the median body weight was 2.73 kg (range, 2.60 to 2.98 kg). Sixty-two patient-days of therapy were reviewed; the median time for CRRT in each patient was 7.8 days (range, 1 to 37 days). Adverse events included electrolyte disturbances, catheter-related complications, and CRRT-related hypotension. The mean circuit functional survival was 13.9±8.6 hours. Overall, 4 patients (50%) survived; the other 4 patients, who developed multiorgan dysfunction syndrome, died. Conclusion The complications of CRRT in newborns are relatively high. However, the results of this study suggest that venovenous CRRT is feasible and effective in neonates weighing less than 3 kg under elaborate supportive care. Furthermore, for using potential benefit of CRRT in neonates, efforts are required for prolonging filter survival.

Successful dialysis in a boy with methylmalonic acidemia.

We would like to describe a 7-year-old boy with methylmalonic acidemia (mut0 phenotype) who has been managed for 4 years by hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) without any serious neurological complications. In extreme cases of methylmalonic acidemia (MMA, McKusick 251000), methylmalonyl CoA mutase activity is completely absent (mut0). Most patients die within 2 months of diagnosis and those who survive have a complicated clinical course, with frequent hospitalizations and both growth and mental retardation [1, 2, 3]. Cardiomyopathy and chronic progressive loss of renal function are frequent and serious complications of longterm survivors [4]. In the literature, there is only one reported case of methylmalonic acidemia treated with CAPD [5]. A 2.72-kg male infant was born by cesarean section at 38 weeks as the second baby of a twin birth. The elder twin brother died during the 1st week of life because of severe acidosis. Laboratory tests revealed metabolic acidosis and hyperammonemia (449 mg/dl). The urine was positive for methylmalonic acid (MMA). A lowprotein diet with special formula feeding was started. Complementation analysis of cultured fibroblasts (performed in Dr. Rosenblatt’s laboratory in Canada) showed that he had mut0 type apoenzyme deficiency. The clinical course was complicated, and was characterized by severe metabolic acidosis, recurrent vomiting, and dehydration. Vitamin B12 therapy did not result in a decrease in urinary MMA and did not ameliorate the clinical course. Over the next 33 months, he had 14 hospitalizations because of metabolic decompensation and was treated with sodium bicarbonate, hydration, and a protein-restricted diet. At 34 months of age, he commenced thrice-weekly hemodialysis for 2-h sessions. His weight was 11.7 kg (3th–10th percentile) and height 88.6 cm (10th–25th percentile). For the next 10 months, he had only 2 hospitalizations due to metabolic decompensation. However, thereafter he was frequently admitted nearly every month for 1 year, despite daily hemodialysis. We recommended liver transplantation, but the parents preferred dialysis. At 5 years of age, he commenced CAPD with the aim of increasing the excretion of MMA and discontinuing hemodialysis. MMA was measured by isotope dilution gas chromatography-mass spectrometry [6]. Before CAPD, the MMA level of a 24-h urine sample was 482.02 mmol/day and serum MMA was 116.12 mmol/l. Dialysis involved four changes of a standard solution of 500 ml of 1.5% dextrose. After 1 week of dialysis, 24-h urine MMA was 263.56mmol/day and 24-h dialysis fluid MMA was 2,290.44 mmol/day. Serum MMA was 46.11 mmol/l. We confirmed that this regimen could eliminate 2,554 mmol of MMA in urine and dialysate per day. However, serum MMA concentrations (46.11– 196.61 mmol/l) were not normalized. In the 24 months after CAPD was started, his improvement has been dramatic. He had only 2 hospitalizations due to metabolic crises, despite progressive relaxation of the restriction of protein. He is currently 7 years old. His present weight is 25 kg (75th percentile) and his height is 118 cm (25th–50th percentile). The percentiles of weight and height have increased. His renal function is normal. K. H. Paik · D.-K. Jin Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

p-Cresyl sulfate and indoxyl sulfate in pediatric patients on chronic dialysis

Purpose Indoxyl sulfate and p-cresyl sulfate are important protein-bound uremic retention solutes whose levels can be partially reduced by renal replacement therapy. These solutes originate from intestinal bacterial protein fermentation and are associated with cardiovascular outcomes and chronic kidney disease progression. The aims of this study were to investigate the levels of indoxyl sulfate and p-cresyl sulfate as well as the effect of probiotics on reducing the levels of uremic toxins in pediatric patients on dialysis. Methods We enrolled 20 pediatric patients undergoing chronic dialysis; 16 patients completed the study. The patients underwent a 12-week regimen of VSL#3, a high-concentration probiotic preparation, and the serum levels of indoxyl sulfate and p-cresyl sulfate were measured before treatment and at 4, 8, and 12 weeks after the regimen by using fluorescence liquid chromatography. To assess the normal range of indoxyl sulfate and p-cresyl sulfate we enrolled the 16 children with normal glomerular filtration rate who had visited an outpatient clinic for asymptomatic microscopic hematuria that had been detected by a school screening in August 2011. Results The baseline serum levels of indoxyl sulfate and p-cresyl sulfate in the patients on chronic dialysis were significantly higher than those in the children with microscopic hematuria. The baseline serum levels of p-cresyl sulfate in the peritoneal dialysis group were significantly higher than those in the hemodialysis group. There were no significant changes in the levels of these uremic solutes after 12-week VSL#3 treatment in the patients on chronic dialysis. Conclusion The levels of the uremic toxins p-cresyl sulfate and indoxyl sulfate are highly elevated in pediatric patients on dialysis, but there was no significant effect by probiotics on the reduction of uremic toxins in pediatric dialysis patients. Therefore, studies for other medical intervention to reduce uremic toxins are also necessary in pediatric patients on dialysis.

Ghrelin Levels in Gastric Mucosa before and after Eradication of Helicobacter pylori

BACKGROUND/AIMS The relationship between Helicobacter pylori infection and ghrelin is controversial. We compared ghrelin levels in gastric mucosa and plasma between H. pylori-positive and -negative subjects, and between before and after H. pylori eradication. METHODS We compared the ghrelin levels in the antrum, body, and fundus between H. pylori-positive and -negative subjects; in stomach tissues between before and after H. pylori eradication; and in plasma and tissue in 10-person cohorts between before and after H. pylori eradication therapy. Body mass index, age, and sex were controlled for when comparing ghrelin levels. RESULTS Stomach ghrelin levels (in the antrum, body, and fundus) did not differ significantly between H. pylori-positive and -negative samples (p=0.095, 0.316, and 0.897, respectively), or between before and after H. pylori eradication (p=0.19, 0.178, and 0.513, respectively). In the ten-person cohort study, plasma ghrelin levels in the eight H. pylori-positive subjects were 2,260 pg/mL (range, 1,280-3,770 pg/mL) and 1,900 pg/mL (range, 1,350-5,200 pg/mL) before and after eradication therapy (p=0.871). Stomach ghrelin levels did not differ significantly in the eight H. pylori-positive subjects between before and after H. pylori eradication (p=0.732, 0.618, and 0.435 in the antrum, body, and fundus, respectively), or between six eradicated and two noneradicated subjects (p=0.071, 0.857, 0.429, and 0.857 in the antrum, body, fundus, and plasma, respectively). CONCLUSIONS These results show that H. pylori infection has no effect on stomach ghrelin levels and that eradication therapy does not influence plasma or tissue ghrelin levels.

Correlation between Hyperghrelinemia and Carotid Artery Intima-Media Thickness in Children with Prader-Willi Syndrome

Purpose Prader-Willi syndrome (PWS) is a genetic disorder characterized by childhood-onset obesity and endocrine dysfunction that leads to cardiovascular disability. The objective of the study is to assess the relationship between carotid intima-media thickness (IMT) and atherosclerotic risk factors. Materials and Methods Twenty-seven PWS children and 24 normal controls were enrolled. Correlations of IMT with atherosclerotic risk factors were assessed. Results IMTs in the PWS group did not differ from those in the controls (p = 0.172), although total ghrelin levels were higher in the PWS children (p = 0.003). The multivariate analysis revealed positive correlations between total ghrelin levels (ρ = 0.489, p = 0.046) and IMT in the PWS group and between body mass index-standard deviation score (BMI-SDS) (ρ = 0.697, p = 0.005) and IMT in the controls. Conclusion Considering the positive correlation of IMT with total ghrelin levels and the high level of ghrelin in PWS children, a further study is warranted to evaluate the role of elevated ghrelin on atherosclerosis for PWS.

The impact of inflammation on bone mass in children

Bone is a dynamic tissue. Skeletal bone integrity is maintained through bone modeling and remodeling. The mechanisms underlying this bone mass regulation are complex and interrelated. An imbalance in the regulation of bone remodeling through bone resorption and bone formation results in bone loss. Chronic inflammation influences bone mass regulation. Inflammation-related bone disorders share many common mechanisms of bone loss. These mechanisms are ultimately mediated through the uncoupling of bone remodeling. Cachexia, physical inactivity, pro-inflammatory cytokines, as well as iatrogenic factors related to effects of immunosuppression are some of the common mechanisms. Recently, cytokine signaling through the central nervous system has been investigated for its potential role in bone mass dysregulation in inflammatory conditions. Growing research on the molecular mechanisms involved in inflammation-induced bone loss may lead to more selective therapeutic targeting of these pathological signaling pathways.

Renal function after tandem high-dose chemotherapy and autologous stem cell transplantation in children with Wilms tumor.

Lee SH, Paik KH, Sung KW, Son MH, Yoo KH, Koo HH, Kim JY, Cho EJ. Renal function after tandem high‐dose chemotherapy and autologous stem cell transplantation in children with Wilms tumor. Pediatr Transplantation 2011: 15: 855–860.

Transcriptome Analysis of the Response of Cultured Murine Podocytes to Puromycin Aminonucleoside

Aims: Idiopathic nephrotic syndrome is known as a disease of the renal glomerular epithelial cells (podocytes). Recent advances in podocyte biology showed that podocytopathy is the culprit of nephrotic syndrome. To obtain comprehensive information about the response of podocytes to injury, we investigated the gene expression profile of podocytes in response to puromycin aminonucleoside (PAN)-induced injury. Methods: Differentiated mouse podocyte cell line (MPC5) cells were treated with 25 µg/ml PAN for 24, 48, or 72 h. Gene expression profiles of these cells were analyzed. Real time PCR analysis was used to confirm the findings of microarray. Results: Expression levels of 23 genes (differentially expressed genes, DEGs), including laminin α1 and MMP3, were significantly different between PAN-treated podocytes and untreated cells. Gene ontology of DEGs indicated that their functional categories were cell adhesion, extracellular matrix (ECM) formation, and ECM degradation. Real-time PCR and indirect immunohistochemistry of PAN-treated and untreated podocytes confirmed the differential expression of DEGs. Conclusion: Using unbiased global gene expression profiling, we found that podocytes respond to PAN-induced injury by down-regulating the expression of genes involved in cell adhesion and extracellular matrix.