Malnutrition in children with ichthyosis: Recommendations for monitoring from a multidisciplinary clinic experience.

BACKGROUND: Short stature has been reported in congenital ichthyoses (CI), but few data exist on patients' nutritional status. OBJECTIVE: To describe the nutritional status at the first evaluation of children and young adults with CI. METHODS: Prospective observational study of patients assessed at a multidisciplinary clinic. Clinical variables and ichthyosis severity were collected. Anthropometric assessment was made by measuring weight and height, and nutritional status was classified based on the World Health Organization definitions for malnutrition. Analytical assessment included markers of nutritional status, fat-soluble vitamins, and micronutrients. RESULTS: We included 50 patients with a median age of 5 years (IQR, 1.6-10.3). Undernutrition was found in 32% of patients, and 75% of the undernourished children presented growth impairment. Younger children and those with severe ichthyoses were the most affected. Micronutrient deficiencies were found in 60% of patients. Deficiencies of selenium (34%), iron (28%), vitamin D (22%), and zinc (4%) were the most frequent findings. LIMITATIONS: Our small sample includes a heterogeneous group of ichthyoses. CONCLUSION: Children with CI appear to be at risk of undernutrition, especially at younger ages. Nutritional deficiencies are common and should be monitored. Growth failure in children with ichthyosis could be caused by undernutrition and aggravated by nutritional deficiencies.

Normal fecal calprotectin levels in healthy children are higher than in adults and decrease with age.

BACKGROUND/OBJECTIVES: The paediatric reference range of fecal calprotectin (FC) has not been decisively established and previous studies show a wide within-age variability, suggesting that other factors like anthropometric data or type of feeding can influence FC. Our aims were to establish the normal levels of FC in healthy children grouped by age and analyze whether sex, gestational age, birth weight, type of delivery, type of feeding, or anthropometric data influence FC values. METHODS: This multicentre, cross-sectional, and observational study enrolled healthy donors under 18 years of age who attended their Primary Health Care Centre for their routine Healthy Child Program visits. The exclusion criteria were: (i) immunodeficiency, (ii) autoimmune or (iii) gastrointestinal disease; (iv) medication usage; (v) gastrointestinal symptoms; or (vi) positive finding in the microbiological study. RESULTS: We enrolled 395 subjects, mean age was 4.2 years (range 3 days to 16.9 years), and 204 were male. The median FC was 77.0 mcg/g (interquartile range 246). A negative correlation between age and FC was observed (Spearman's rho = -0.603, P<0.01), and none of the other factors analyzed were found to influence FC levels. CONCLUSIONS: Normal FC values in healthy children (particularly in infants) are higher than those considered to be altered in adults and show a negative correlation with age. It is necessary to reconsider the upper limits of FC levels for paediatric patients according to age, with further studies required to determine other factors that influence FC during infancy.

Noninvasive diagnosis of hypolactasia with 4-Galactosylxylose (Gaxilose): a multicentre, open-label, phase IIB-III nonrandomized trial.

GOALS AND BACKGROUND: Hypolactasia affects over half of the world population. Diagnosis remains problematic as currently available tests, such as the hydrogen breath test, have low reliability and lactose intolerance symptoms are unspecific. We evaluated the diagnostic performance and safety of a new noninvasive diagnostic test based on urine or serum measurement of D-xylose after lactase cleavage of orally administered 4-galactosylxylose (gaxilose). STUDY: In a multicentre, open-label, nonrandomized, phase IIb-III study, consecutive patients with symptoms suggestive of lactose intolerance sequentially underwent intestinal biopsy for direct measurement of lactase activity (reference standard), hydrogen breath test, and blood glucose test after lactose challenge, 4- and 5-hour urine-based gaxilose test, and blood-based gaxilose test. For the gaxilose tests, 0 to 4 and 4 to 5 hours urine samples were taken after a 0.45 g gaxilose dose, whereas serum samples were taken 90 minutes after a 2.7 g dose for D-xylose determination. Genetic testing of hypolactasia was also assessed. RESULTS: Of the 222 patients enrolled, 203 completed all diagnostic tests; 108 were hypolactasic according to biopsy. The sensitivities and specificities and positive and negative predictive values of the gaxilose tests were all >90% versus 69% to 85% for the hydrogen breath test and the blood glucose test. The area under the ROC curve was significantly higher for the gaxilose tests (>0.9, P≤0.007). These tests also had higher sensitivity than genetic testing for hypolactasia and were well tolerated. CONCLUSIONS: The diagnostic performance of the gaxilose tests is excellent and can substantially improve the diagnosis of hypolactasia.

Improvement and validation of d-xylose determination in urine and serum as a new tool for the noninvasive evaluation of lactase activity in humans.

BACKGROUND: The phloroglucinol assay is the current method for d-xylose determination in urine/plasma/serum. However, its sensitivity is limited when low amounts of d-xylose are to be measured, such as in the noninvasive evaluation of intestinal lactase with 4-galactosylxylose (gaxilose). An improved assay was therefore needed. METHODS: We developed and validated a modified version of the phloroglucinol-based assay for quantification of d-xylose in urine/serum samples. A method for gaxilose determination by gas chromatography (GC) was also optimized. RESULTS: Linearity ranged from 0.125 to 5.0 mg/l (5-200 mg/l in original sample). Accuracy at LOQ (0.125 mg/l) was 0.97/2.49% in spiked urine/serum; for other quality controls (QC), it was <1.27%. Intra- and interassay precision at LOQ were 6.02% and 6.45% for urine, and 8.86% and 10.00%, respectively, for serum; for other QC, precision was <2.15%. Linearity of gaxilose determination by GC was 3.90-195.17 for urine and 9.75-195.17 mg/l for serum with acceptable sensitivity and reproducibility. The method proved adequate for the d-xylose determination in healthy and hypolactasic subjects after oral administration of gaxilose. CONCLUSIONS: The modified method provides high sensitivity and robustness for d-xylose quantification in urine/serum for routine clinical use especially in the noninvasive diagnosis of intestinal lactase deficiency with the gaxilose test.

Phase I and phase IB clinical trials for the noninvasive evaluation of intestinal lactase with 4-galactosylxylose (gaxilose).

GOALS AND BACKGROUND: Hypolactasia is widespread, yet reliable diagnostic tests are lacking. A new test based on oral administration of 4-galactosylxylose (gaxilose) and urine or serum measurement of D-xylose after cleavage by intestinal lactase is under clinical development. We investigated the optimal dose of gaxilose and calculate cutoff values of D-xylose for that dose. STUDY: In the randomized, dose-finding, phase I study, urine and serum pharmacokinetics of D-xylose were determined after oral administration of 6 ascending doses of gaxilose (and placebo) to 12 healthy adult volunteers. In the open, parallel, phase Ib study, 30 volunteers received the doses established for the urine and blood tests and D-xylose was measured. Cutoff values were calculated as 1.96 × SD below the mean value. Safety was assessed through reporting of adverse events. RESULTS: Gaxilose administration showed a progressive, dose-dependent increase in D-xylose in urine and serum. An optimal gaxilose dose of 0.45 g and urine collection periods of 4 and 5 hours were selected for further studies. For the blood test, a 2.7 g dose was selected and C max measured at 90 minutes. The calculated cutoff values of D-xylose for normal lactase activity were 27.58 and 37.87 mg for the 4- and 5-hour urine tests, respectively, and 0.97 mg/dL for the blood test. There were no treatment-related adverse events. CONCLUSIONS: The methodology described provides a simple, safe test for the evaluation of lactase activity in vivo. Further evaluation of the test as a noninvasive diagnosis of hypolactasia is ongoing in patients with lactose intolerance.

Plasma levels of mitochondrial and nuclear DNA in patients with massive pulmonary embolism in the emergency department: a prospective cohort study.

INTRODUCTION: Cell-free plasma mitochondrial DNA (mt-DNA) and nuclear DNA (n-DNA) are biomarkers with prognostic utility in conditions associated with a high rate of cell death. This exploratory study aimed to determine the plasma levels of both nucleic acids in patients with massive and submassive pulmonary embolism (PE) and to compare them with other biomarkers, such as heart-type fatty acid-binding protein (H-FABP) and troponin I (Tn-I) METHODS: This was a prospective observational study of 37 consecutive patients with massive PE, 37 patients with submassive PE, and 37 healthy subjects. Quantifications of plasma mt-DNA and n-DNA with real-time quantitative polymerase chain reaction (PCR), and plasma H-FABP and Tn-I by commercial assays, were done on blood samples drawn within 4 hours after presentation at the emergency department. RESULTS: Plasma mt-DNA and n-DNA concentrations were much higher in patients with massive PE (median, 2,970 GE/ml; interquartile range (IQR), 1,050 to 5,485; and 3,325 GE/ml, IQR: 1,080 to 5,790, respectively) than in patients with submassive PE (870 GE/ml and 1,245 GE/ml, respectively; P < 0.01) or controls (185 GE/ml and 520 GE/ml, respectively). Eighteen patients with massive PE died of a PE-related cause by day 15 of observation. Plasma mt-DNA and n-DNA values were 2.3-fold and 1.9-fold higher in the subgroup of nonsurviving patients than in survivors. H-FABP and Tn-I values were also higher in patients with massive PE who died (7.3 ng/ml and 0.023 ng/ml, respectively) than in those who survived (6.4 ng/ml, and 0.016 ng/ml, respectively). By receiver operating curve (ROC) analysis, the best cutoff values for predicting 15-day mortality were 3,380 GE/ml for mt-DNA, 6.8 ng/ml for H-FABP, 3,625 GE/ml for n-DNA, and 0.020 ng/ml for Tn-I, based on the calculated areas under the curve (AUCs) of 0.89 (95% confidence interval (CI), 0.78 to 0.99), 0.76 (95% CI, 0.69 to 093), 0.73 (95% CI, 0.58 to 0.91), and 0.59 (95% CI, 0.41 to 0.79), respectively. By stepwise logistic regression, a plasma mt-DNA concentration greater than 3,380 GE/ml (adjusted odds ratio (OR), 8.22; 95% CI, 1.72 to 39.18; P < 0.001) and a plasma value of H-FBAP >6.8 ng/ml (OR, 5.36; 95% CI, 1.06 to 27.08; P < 0.01) were the only independent predictors of mortality. CONCLUSIONS: mt-DNA and H-FBAP might be promising markers for predicting 15-day mortality in massive PE, with mt-DNA having better prognostic accuracy.

Decreased vascular endothelial growth factor response to acute hypoglycemia in type 2 diabetic patients with hypoglycemic coma.

INTRODUCTION: Plasma vascular endothelial growth factor (VEGF) was shown to increase during acute hypoglycemia and could mediate rapid adaptation of the brain. In this study we examined the neuroendocrine response in patients with type 2 diabetes mellitus (T2DM) in hypoglycemic coma or with acute neuroglycopenic symptoms. METHODS: We prospectively studied 135 consecutive T2DM patients admitted for severe hypoglycemia during a 2-year period. We collected clinical variables and measured plasma concentrations of VEGF, epinephrine, norepinephrine, cortisol and growth hormone at admission and 30min afterwards. RESULTS: Thirty two patients developed hypoglycemic coma and 103 did not lose consciousness. Median plasma VEGF level of coma patients was 3.1-fold lower at baseline than that of non-coma patients, and even 5.3-fold lower 30min afterwards. Plasma epinephrine concentration was significantly lower just at baseline in coma patients. On the contrary, there were no differences in concentrations of the other hormones. Multivariate logistic regression analysis showed that VEGF concentration (OR 0.68; CI 0.51-0.95) was a protective factor against the development of coma. CONCLUSIONS: VEGF and epinephrine responses to acute hypoglycemia are reduced in T2DM patients who develop hypoglycemic coma. An increased plasma VEGF concentration appeared to be a protective factor against the development of hypoglycemic coma.

Acute responses of gastrointestinal hormones to both oral and parenteral intradialytic nutrition.

INTRODUCTION: Intradialytic nutrition (IDN) has been used to improve the nutritional status of malnourished hemodialysis (HD) patients. OBJECTIVE: To evaluate the different effects of parenteral IDN (IDPN) and oral IDN (IDON) on nutrition-related gastrointestinal hormones. PATIENTS AND METHODS: Seven clinically stable HD patients with malnutrition were included. All patients were treated for 1 month with either IDPN or IDON, with a 4-week period of no nutritional support between each type of therapy. On the first day of each nutritional support (IDON or IDPN) we analyzed the acute responses of insulin, ghrelin, and glucagon-like peptide 1 (GLP-1). We compared the areas under the secretory curves (AUC) and the maximum peaks of serum glucose, insulin, ghrelin, and GLP-1. A group of 6 clinically stable HD patients without any type of IDN served as the control group. RESULTS: The acute responses of glucose and insulin to IDN were significantly higher with IDPN than with IDON. The AUC of glucose (602 ± 81 vs. 495 ± 81 mg/dl/h, p < 0.01) and insulin (232 ± 103 vs. 73.8 ± 69 µU/ml/h, p < 0.01) as well as the maximum peaks of glucose (228 ± 41 vs. 177 ± 47 mg/dl, p < 0.05) and insulin (104 ± 46 vs. 29 ± 24 µU/ml, p < 0.01) were significantly higher after IDPN than after IDON. Ghrelin decreased after both IDPN and IDON; however, the decrease was significantly higher with IDPN compared to IDON. The ghrelin nadir was significantly lower in IDPN than in IDON (0.77 ± 0.5 vs. 1.5 ± 0.3, p < 0.05) although the AUC of ghrelin was not significantly different. GLP-1 was significantly increased at 1 h after starting both IDPN and IDON with no significant differences between the groups. CONCLUSION: IDPN induces a higher increase in serum glucose and insulin levels and a greater reduction in serum ghrelin concentrations compared with an equivalent orally administered nutritional supplement.

Prognostic value of cell-free plasma DNA in patients with cardiac arrest outside the hospital: an observational cohort study.

INTRODUCTION: Many approaches have been examined to try to predict patient outcome after cardiopulmonary resuscitation. It has been shown that plasma DNA could predict mortality in critically ill patients but no data are available regarding its clinical value in patients after out-of-hospital cardiac arrest. In this study we investigated whether plasma DNA on arrival at the emergency room may be useful in predicting the outcome of these patients. METHODS: We performed a prospective study of out-of-hospital patients with cardiac arrest who achieved return of spontaneous circulation after successful resuscitation. Cardiovascular co-morbidities and resuscitation history were recorded according to the Utstein Style. The outcome measures were 24 h and overall in-hospital mortality. Cell-free plasma DNA was measured by real-time quantitative PCR assay for the beta-globin gene in blood samples drawn within two hours after the arrest. Descriptive statistics, multiple logistic regression analysis, and receiver operator characteristic (ROC) curves were calculated. RESULTS: Eighty-five consecutive patients were analyzed with a median time to return of spontaneous circulation of 27 minutes (interquartile range (IQR) 18 to 35). Thirty patients died within 24 h and 58 died during the hospital course. Plasma DNA concentrations at admission were higher in non-survivors at 24 h than in survivors (median 5,520 genome equivalents (GE)/ml, vs 2810 GE/ml, P < 0.01), and were also higher in patients who died in the hospital than in survivors to discharge (median 4,150 GE/ml vs 2,460 GE/ml, P < 0.01). Lactate clearance at six hours was significantly higher in 24 h survivors (P < 0.05). The area under the ROC curves for plasma DNA to predict 24-hour mortality and in-hospital mortality were 0.796 (95% confidence interval (CI) 0.701 to 0.890) and 0.652 (95% CI 0.533 to 0.770). The best cut-off value of plasma DNA for 24-h mortality was 4,340 GE/ml (sensitivity 76%, specificity 83%), and for in-hospital mortality was 3,485 GE/ml (sensitivity 63%, specificity 69%). Multiple logistic regression analysis showed that the risk of 24-h and of in-hospital mortality increased 1.75-fold and 1.36-fold respectively, for every 500 GE/ml increase in plasma DNA. CONCLUSIONS: Plasma DNA levels may be a useful biomarker in predicting outcome after out-of hospital cardiac arrest.

Bowel bacterial overgrowth as another cause of malnutrition, inflammation, and atherosclerosis syndrome in peritoneal dialysis patients.

Bowel bacterial overgrowth syndrome (BBOS) is an important cause of gastrointestinal (GI) abnormalities. Proinflammatory cytokines (PICs) are excessively produced and accumulate because of kidney failure in dialysis patients who experience chronic infections such as BBOS. We explored the association between GL function, BBOS, and the malnutrition, inflammation, and atherosclerosis (MIA) syndrome. We studied GI malabsorption and maldigestion by analyzing fecal starch, sugar, fat, and nitrogen; intestinal protein permeability (alpha1-antitrypsin fecal clearance); and fecal chymotrypsin. We evaluated BBOS by breath hydrogen test (BHT) after a 3-day fat-and-carbohydrate-overload diet. Positive BHT was present in 10 patients, showing a high prevalence of GI macronutrient malabsorption and maldigestion, and compared with the other patients, the highest plasma levels of tumor necrosis factor alpha and interleukin 6 and lower levels of albumin and prealbumin. Those 10 patients were treated with a combination of several antibiotics, including neomycin, amoxicillin-clavulanate, and quinolones. Between 2 and 3 months later, the BHT, markers of nutrition, and PIC were re-tested. All treated patients showed an improvement in nutrition status and a lesser inflammatory pattern. The BBOS infectious process is found frequently in dialysis patients in association with GI malabsorption and maldigestion, malnutrition, and systemic inflammation. Hyperproduction of PIC because of BBOS induces MIA through a double pathway: GI disorders and deleterious systemic effects.

Ulcerative Colitis and Atypical Hemolytic-Uremic Syndrome: An Unusual But Potentially Life-threatening Complication.

Hemolytic-uremic syndrome (HUS) is defined as the triad of nonimmune hemolytic anemia, thrombocytopenia, and acute renal failure, in which the underlying lesions are mediated by systemic thrombotic microangiopathy (TMA). The atypical HUS (aHUS) can be considered a subtype of HUS that is rare in childhood and has a worse prognosis. Recent findings have established that the TMA in aHUS are consequences of the disregulation of the complement activation, leading to endotelial damage mediated by the complement terminal pathway.1, 2 Likewise, previous research suggests an important role for the deregulation of the alternative complement cascade in the pathogenesis of inflammatory bowel disease (IBD).3, 4 We report the case of a patient with ulcerative colitis (UC) who developed aHUS during a flare-up of her chronic disease. This association is extremely infrequent and had been previously reported in only 1 patient.5.

Effects of cinacalcet on gastrointestinal hormone release in patients with secondary hyperparathyroidism undergoing dialysis.

UNLABELLED: Objective. Our aim has been evaluating the influence of an acute dose of cinacalcet on the gastrointestinal hormonal responses to a test meal in uraemic patients with secondary hyperparathyroidism undergoing peritoneal dialysis (PD) or haemodialysis (HD). METHODS: Twenty patients (11 PD, 9 HD) on cinacalcet treatment (30-120 mg/day) were studied. Twelve patients (1 PD, 11 HD) who never received cinacalcet were studied as control group. Each patient received a test meal with blood samples at 0, 2 and 4 h. At 0 time, patients in the cinacalcet group received their usual oral dose of this calcimimetic. Plasma concentrations of intact parathyroid hormone (PTH), vasoactive intestinal peptide (VIP), ghrelin, substance P, serotonin, cholecystokinin (CCK) and gastrin were quantified at 0, 2 and 4 h. RESULTS: No significant differences in baseline concentrations of serum VIP, ghrelin, substance P, serotonine, CCK and gastrin were found between controls and cinacalcet-treated patients. In comparison with the control group, cinacalcet administration was followed by a significant decrease in VIP concentration at 4 h and a significant increase in substance P at 4 h. However, the areas under the curves of all studied gut hormones were similar in both groups. CONCLUSION: An acute dose of cinacalcet exerts minimal influence on gut hormone responses to a mixed meal in dialysis patients on chronic therapy with this drug. The small but significant differences between control subjects and patients on cinacalcet in VIP and substance P levels at 4 h should be investigated in symptomatic patients.

Hepatic and Splenic Acoustic Radiation Force Impulse Shear Wave Velocity Elastography in Children with Liver Disease Associated with Cystic Fibrosis.

BACKGROUND: Liver disease associated with cystic fibrosis (CFLD) is the second cause of mortality in these patients. The diagnosis is difficult because none of the available tests are specific enough. Noninvasive elastographic techniques have been proven to be useful to diagnose hepatic fibrosis. Acoustic radiation force impulse (ARFI) imaging is an elastography imaging system. The purpose of the work was to study the utility of liver and spleen ARFI Imaging in the detection of CFLD. Method. 72 patients with cystic fibrosis (CF) were studied and received ARFI imaging in the liver and in the spleen. SWV values were compared with the values of 60 healthy controls. Results. Comparing the SWV values of CFLD with the control healthy group, values in the right lobe were higher in patients with CFLD. We found a SWV RHL cut-off value to detect CFLD of 1.27 m/s with a sensitivity of 56.5% and a specificity of 90.5%. CF patients were found to have higher SWC spleen values than the control group. Conclusions. ARFI shear wave elastography in the right hepatic lobe is a noninvasive technique useful to detect CFLD in our sample of patients. Splenic SWV values are higher in CF patients, without any clinical consequence.

Gastrointestinal and pancreatic function in peritoneal dialysis patients: their relationship with malnutrition and peritoneal membrane abnormalities.

BACKGROUND: Malnutrition is frequent in peritoneal dialysis (PD) patients, but the contribution of gastrointestinal (GI) dysfunction has not been well established. METHODS: We studied GI function in 49 stable PD patients to ascertain its relationship with malnutrition. After an overload fat diet, fecal fat, sugar, starch and nitrogen, intestinal protein permeability (alpha(1)-antitrypsin fecal clearance [C-alpha(1)-AT]), fecal chymotrypsin (CT), GI hormones and gastrin, pepsinogen I and II, cholecystokinin (CCK), gastrin releasing peptide (GRP), and neuropeptide Y (NPY) were measured. Vasoactive intestinal polypeptide (VIP), substance P (SP), and tumor necrosis factor (TNF-alpha) and biochemical nutritional markers were evaluated. RESULTS: All patients showed high fecal sugar. Elevated fecal nitrogen was found in 21 patients, 6 with high C-alpha(1)-AT. High fecal starch levels appeared in 21, fat in 20, and low fecal CT in 39 patients. These determinations showed inverse relation with nutritional markers. Increased fecal C-alpha(1)-AT values were associated with lower serum albumin. Fecal CT values showed a negative linear correlation with serum albumin and were inversely associated with retinol-binding protein, normalized protein nitrogen appearance, and serum iron. High plasma levels of pancreatic stimulating hormones were found: gastrin, CCK, and VIP. These levels were higher in patients with a worse pancreatic exocrine function. Higher values of other GI hormones, gastrin, pepsinogen I and II, CCK, GRP, and TNF-alpha. Normal concentrations of NPY, VIP, and PS were observed. CONCLUSION: GI abnormalities (malabsorption, maldigestion, pancreatic dysfunction, and protein losing enteropathy) are present in an important number of PD patients. These features are negatively associated to nutrition.

Effects of human recombinant erythropoietin on inflammatory status in peritoneal dialysis patients.

Treatment with recombinant human erythropoietin (rHuEPO) in dialysis patients has been associated with improvement of nutritional and immune status through an increase of cytokine production [such as tumor necrosis factor alpha (TNF alpha)]. The high cytokine production can be a double-edged sword owing to the relationship of cytokines with the systemic inflammatory process, which has been associated with many complications of uremic status. Our aim was to analyze the medium-long term effects of rHuEPO treatment on uremic inflammatory markers. We studied 45 peritoneal dialysis (PD) patients divided in two groups: a rHuEPO group (40-70 subcutaneous units/kg weekly) and a control group (no rHuEPO). The treated group was analyzed in four periods. Period 1 (rHuEPO-1) included 24 patients who had been using rHuEPO at long-term. Period 2 (rHuEPO-2; n = 21) looked at the patients 2 months after rHuEPO withdrawal. Period 3 (rHuEPO-3; n = 19) looked at the patients after 2 months under rHuEPO therapy. Period 4 (rHuEPO-4; n = 17) looked at the patients after 4 months on rHuEPO treatment. With the reintroduction of rHuEPO, we observed a progressive, statistically significant (p < 0.05), and temporary increase in TNF alpha plasma levels, from 44 +/- 24 pg/mL (rHuEPO-2) to 76.8 +/- 25 pg/mL (rHuEPO-3), and then to 83 +/- 27 pg/mL (rHuEPO-4). But in the long term, TNF alpha decreased [33.5 +/- 10 pg/mL (rHuEPO-1)]. Similarly, albumin increased in the short term (3.73 +/- 0.5 g/dL to 4 +/- 0.5 g/dL, and then to 4 +/- 0.43 g/dL), and then decreased (3.8 +/- 0.44 g/dL). The normalized protein catabolic rate (nPCR) increased from 1 +/- 0.2 g/kg daily to 1.12 +/- 0.3 g/kg daily (rHuEPO-4). Long term, nPCR decreased to 1.06 +/- 0.3 g/kg daily. Leptin initially increased (60.1 +/- 48 ng/mL to 42.8 +/- 22 ng/mL, and then to 38 +/- 18.2 ng/mL); it also increased in the long term (62 +/- 50.9, p < 0.05). At baseline, we found a significant positive linear correlation (p < 0.05) between TNF alpha and leptin (r = 0.52), TNF alpha and C-reactive protein [(CRP) r = 0.4], CRP and leptin (r = 0.49), fibrinogen and CRP (r = 0.78, p < 0.01), fibrinogen and leptin (r = 0.37), and leptin and body mass index [(BMI) r = 0.67]. In conclusion, rHuEPO induces a temporary, non inflammatory immune hyperactivity mediated by TNF alpha, without the adverse effects associated with that cytokine. By decreasing leptin, rHuEPO could increase food intake and improve the nutritional status of PD patients. At baseline, we confirm the existence of a chronic inflammatory process in uremia.

Leptin as a marker of nutrition and cardiovascular risk in peritoneal dialysis patients.

Anorexia and protein malnutrition, occasionally associated with obesity, are frequently observed in peritoneal dialysis (PD) patients. Both are recognized risk factors for cardiovascular (CV) morbidity and mortality. Leptin is produced by adipocytes and regulates body-fat mass through a satiety central effect. Leptin accumulates in the uremic state. We analyzed the relationship between plasma leptin levels, nutritional status, obesity, CV risk factors, and atherosclerosis in PD patients. Leptin was determined using a polyclonal antibody [radioimmunoassay: Linco Research, St. Louis, MO, U.S.A.]. The normal range was 1-7.8 ng/mL. We studied 38 PD patients. Mean leptin levels were 59.1 +/- 57.5 ng/mL (elevated in 32 patients). Women (n = 21) showed higher leptin levels than did men (80.4 +/- 60 ng/mL vs. 32.3 +/- 43.3 ng/mL, p < 0.01), in spite of both groups having a similar body mass index (BMI). A statistically significant direct correlation was found between leptin and BMI (r = 0.7, p < 0.01) and triceps skin-fold measurement (r = 0.77, p < 0.01). Leptin levels and renal creatinine clearance (CCr) showed no significant correlation. Independent of BMI, higher leptin levels were associated with parameters considered to be CV risk factors (Framingham study), such as serum triglycerides < 150 mg/dL (n = 29) as compared with > 150 mg/dL (44.2 +/- 53.2 ng/mL vs. 80 +/- 58.4 ng/mL, p < 0.05), cholesterol < 250 mg/dL (n = 28) as compared with > 250 mg/dL, (50 +/- 55.6 mg/dL vs. 84.7 +/- 57.7 mg/dL, p < 0.05), uric acid < 7 mg/dL (n = 28) as compared with > 7 mg/dL (47 +/- 53.7 mg/dL vs. 93.1 +/- 56.6 mg/dL, p < 0.05), and the presence or lack of presence of left ventricular hypertrophy [68.8 +/- 60 (n = 30) vs. 29.5 +/- 23.7 (n = 5), p < 0.05]. The patients were classified into two groups according to a clinical atherosclerosis score (CAS). Nineteen patients had low CAS scores, and they showed higher plasma leptin values than did the other patients (82.4 +/- 65.7 ng/mL vs 35.8 +/- 36.6 ng/mL, p < 0.05). Twelve patients with anorexia had lower leptin values than did patients with normal appetite (19.2 +/- 15.8 ng/mL vs. 91.3 +/- 58.8 ng/mL, p < 0.001). In non obese patients (BMI < 25 and CCr < 3 mL/min, n = 14), leptin had a statistically significant direct linear correlation with markers of nutrition, including albumin (r = 0.63, p < 0.05), transferrin (r = 0.4, p < 0.05), cholesterol (r = 0.65, p < 0.05), and triglycerides (r = 0.6, p < 0.05). Finally, plasma leptin levels were notably increased in the PD population, indicating increased production (possibly by chronic hyperinsulinism), or uremic retention, or both. By multivariate analysis, we confirmed the association between leptin levels and sex, leptin and BMI, and leptin levels > 40 ng/mL and sex and LVH. All of those features suggest that plasma leptin levels could be considered a marker of CV risk and food intake in non obese PD patients without inflammation.

True deficiency of antioxidant vitamins E and A in dialysis patients. Relationship with clinical patterns of atherosclerosis.

Atherosclerosis is an important cause of morbidity and mortality in peritoneal dialysis (PD) patients. Oxidative stress plays a role in the pathogenesis of uremic atherosclerosis. Although antioxidant substances (vitamins A and E) are elevated in the plasma of dialysis patients, intracellular and clinical signs of hypovitaminosis are frequently found. Recently, the importance of vitamin/carrier complexes as a marker of vitamin bioavailability has been demonstrated. In the present study, we analyzed vitamin A and E bioavailability, measured as vitamin/carrier complexes, and the relationship of those measurements with clinical atherosclerosis status in PD patients. We studied 45 patients (15 men, 30 women), who were divided into four groups according to clinical atherosclerotic score (CAS). Five cases were scored as CAS grade 1 (low CAS); 9 as CAS-2; 18 as CAS-3; and 13 as CAS-4. Vitamins A and E and their carriers [prealbumin and retinol binding protein (vitamin A), and cholesterol and triglycerides (vitamin E)] were determined. Plasma levels of vitamin A were low in 5 patients, normal in 7 patients, and high in 33 patients. By correcting the values for the carrier levels, we created three groups: 24 patients showed low vitamin A/carrier complex (5 from the low plasma vitamin A group, 6 from the normal-value group, and 13 from the high-value group); 11 patients were in the group with normal vitamin A/carrier (1 from the normal plasma vitamin A group, and 10 from the high-value group); and 10 patients were in the group with high vitamin A/carrier. The vitamin A/carrier complex showed a statistically significant, negative linear correlation with CAS and with serum iron. Low vitamin E plasma levels were found in 1 patient, normal levels in 28 patients, and high levels in 16 patients. When those values were corrected using the carrier values, three groups were also created. The group with low vitamin E/carrier complex contained 24 patients (1 from the low-value group, 22 from the normal-value group, and 1 from the high-value group). The group with normal vitamin E/carrier complex contained 21 patients (15 from the group with high vitamin E values, and 6 from the normal-value group). By univariate logistic regression analysis, significant associations between CAS and vitamin E plasma levels, vitamin E/carrier, age, and serum albumin were found. In the multiple logistic regression analysis, we confirmed that vitamin E/carrier complex, age, and serum albumin showed independent associations with CAS, but not with vitamin-only plasma levels. Our results in PD patients show a vitamin/carrier complex disorder that results in elevated vitamin mobilization from pool and target cells. Our results and the findings of other researchers about intracellular vitamin A and E deficiencies may change the traditional concept of hypervitaminosis A and E in uremic patients.

Ghrelin plasma levels and appetite in peritoneal dialysis patients.

Anorexia-associated malnutrition is a severe complication that increases mortality in peritoneal dialysis (PD) patients. Ghrelin is a recently-discovered orexigenic hormone with actions in brain and stomach. We analyzed, in 42 PD patients, the possible relationship between ghrelin and appetite regulation with regard to other orexigens [neuropeptide Y (NPY), NO3] and anorexigens [cholecystokinin (CCK), leptin, glucose-dependent insulinotropic peptide (GIP), tumor necrosis factor alpha (TNFalpha)]. All orexigens and anorexigens were determined in plasma. Eating motivation was evaluated using a visual analog scale (VAS). The patients were divided into three groups: those with anorexia (n = 12), those with obesity associated with high intake (n = 12), and those with no eating behavior disorders (n = 18). A control group of 10 healthy volunteers was also evaluated. Mean plasma levels of ghrelin were high (3618.6 +/- 1533 mg/mL), with 36 patients showing values above the normal range (< 2600 mg/mL). Patients with anorexia had lower ghrelin and NPY levels and higher peptide-C, CCK, interleukin-1 (IL-1), TNFalpha, and GIP levels than did the other patients. Patients with anorexia also had an early satiety score and low desire and pleasure in eating on the VAS and diet survey. We observed significant positive linear correlations between ghrelin and albumin (r = 0.43, p < 0.05), prealbumin (r = 0.51, p < 0.05), transferrin (r = 0.4, p < 0.05), growth hormone (r = 0.66, p < 0.01), NO3 (r = 0.36, p < 0.05), and eating motivation (VAS). At the same time, negative relationships were observed between blood ghrelin and GIP (r = -0.42, p < 0.05), insulin (r = -0.4, p < 0.05), leptin (r = -0.45, p < 0.05), and creatinine clearance [r = -0.33, p = 0.08 (nonsignificant)]. Ghrelin levels were not related to Kt/V or to levels of CCK and cytokines. Ghrelin plasma levels are elevated in PD patients. Uremic patients with anorexia show relatively lower ghrelin plasma levels than the levels seen in obese patients or in patients with normal appetite. The role of ghrelin in appetite modulation is altered in uremic PD patients, and that alteration is possibly associated with disorders in insulin and growth hormone metabolism.