Patricia Sorroche

Effect of deflazacort versus methylprednisone on growth, body composition, lipid profile, and bone mass after renal transplantation

Abstract Kidney function, growth velocity, weight/ height ratio, body composition, lipid profile, and bone mass were studied in a randomized, multicenter trial of deflazacort versus methylprednisone in 27 prepubertal patients with kidney transplantation. Methylprednisone (0.20±0.03) was replaced by deflazacort (13 patients, 0.30±0.03 mg/kg per day). After 12 months, creatinine clearance decreased significantly only during methylprednisone therapy. Growth velocity increased only in patients treated with deflazacort from 3.3±0.6 to 5.6±0.5 cm/year. Serum levels of several components of the insulin-like growth factor axis did not change. Weight/height ratio was increased in methylprednisone-treated patients (P<0.05) and decreased in deflazacort-treated patients (P<0.005). Lean body mass increased in both groups (P<0.005). Fat body mass and serum leptin increased only in methylprednisone-treated patients (P<0.025). Total cholesterol and low-density lipoprotein-cholesterol increased in methylprednisone-treated patients by 9.9% (P<0.05) and 12.5% (P<0.025). High-density lipoprotein-cholesterol increased by 21% (P<0.005) and apolipoprotein B decreased by 11% (P<0.005) in deflazacort-treated patients. Total skeleton and lumbar spine bone mineral density decreased in both groups, but at 1 year methylprednisone-treated patients had lost 50% more bone. Bone mineral content decreased only in methylprednisone-treated patients (P<0.01). Our data suggest that substituting deflazacort for maintenance methylprednisone might prevent height loss, excessive bone loss, and fat accumulation; and leads to an improvement in the lipoproteins of these children.

Altered lipidome and antioxidative activity of small, dense HDL in normolipidemic rheumatoid arthritis: Relevance of inflammation

OBJECTIVE High-density lipoprotein (HDL) particles exert potent antiatherogenic activities, including antioxidative actions, which are relevant to attenuation of atherosclerosis progression. Such activities are enriched in small, dense HDL and can be compromised under conditions of chronic inflammation like rheumatoid arthritis (RA). However, structure-function relationships of HDL largely remain indeterminate. METHODS The relationships between HDL structure and function were evaluated in normolipidemic patients with active RA (DAS28 > 3.2; n = 12) and in normolipidemic age-matched controls (n = 10). Small, dense HDL3b and 3c particles were isolated from plasma or serum by density gradient ultracentrifugation and their physicochemical characteristics, lipidome (by LC/MS/MS) and antioxidative function (as protection of normolipidemic LDL from free radical-induced oxidation) were evaluated. RESULTS As expected, active RA patients featured significantly elevated plasma levels of high-sensitivity C-reactive protein (hsCRP; p < 0.001) and serum amyloid A (SAA; p < 0.01) relative to controls. Antioxidative activity and weight % chemical composition of small, dense HDL did not differ between RA patients and controls (p > 0.05), whereas HDL phosphosphingolipidome was significantly altered in RA. Subgroup analyses revealed that RA patients featuring high levels of inflammation (hsCRP>10 mg/l) possessed small, dense HDL with reduced antioxidative activities (p < 0.01). Furthermore, antioxidative activity of HDL was inversely correlated with plasma hsCRP (p < 0.01). CONCLUSIONS These data revealed that (i) despite normolipidemic state, the lipidome of small, dense HDL was altered in RA and (ii) high levels of inflammation can be responsible for the functional deficiency of small, dense HDL in RA.

High risk of cardiovascular disease in iron overload patients

Eur J Clin Invest 2011; 41 (5): 479–486

Hyperhomocysteinemia In Stable Pediatric, Adolescents, And Young Adult Renal Transplant Recipients

Background. High total plasma homocysteine (tHcy) levels are accompanied by an increased risk for premature development of atherosclerosis and atherothrombosis. Adult renal transplant recipients have elevated tHcy levels. Corresponding data in pediatric, adolescent, and young adult renal transplant recipients are scarce. We investigated whether tHcy levels were elevated in stable renal transplant recipients who received kidney grafts before age 18. Methods. This cross-sectional study was conducted during routine posttransplantation follow-up. Fasting tHcy levels, serum creatinine, and lipoprotein profile were measured in 38 clinically stable renal transplant recipients with different degrees of renal function. No patient was receiving B vitamin or folic acid supplementation. Estimated glomerular filtration rate (GFR) was assessed according to Schwartz’s formula. All patients followed a triple-drug immunosuppressive regimen, with the exception of three patients (deflazacort and azathioprine). Forty-one apparently healthy subjects constituted the control group. tHcy levels were determined by fluorescence polarization immunoassay in an IMx analyzer. Results. Mean tHcy levels in transplant recipients were significantly higher than in controls (16.8±8.7 &mgr;mol/L and 9.5±2.3 &mgr;mol/L, respectively;P <0.01). A significant positive correlation between tHcy and serum creatinine levels was observed for both transplant recipients (rS=0.70, P <0.01) and controls (rS=0.54, P <0.01). In transplant recipients, tHcy correlated negatively with estimated GFR (rS=[minus]0.47, P <0.05). Fasting tHcy levels in excess of 14.6 &mgr;mol/L (>95th percentile in controls) were present in 19 (50%) patients; 14 of these patients had an estimated GFR<60 ml/min per 1.73 m2. When the renal transplant recipients were analyzed by renal function, mean tHcy was significantly higher in patients with an estimated GFR<60 ml/min per 1.73 m2 compared with patients with an estimated GFR≥60 ml/min per 1.73 m2 (20.5±9.9 vs. 13.2±5.8 &mgr;mol/L, P <0.01). Both groups were significantly different from controls (P <0.01). No relationship was found between tHcy level and either cumulative cyclosporine or cumula-tive methylprednisone doses. No differences were observed in tHcy levels or lipoprotein profile between patients who were receiving deflazacort and those on methylprednisone. Conclusions. Hyperhomocysteinemia in renal transplant recipients is a common condition. Testing for fasting tHcy level might be a useful tool to identify patients at increased risk for development of vascular disease.

Endocrine and inflammatory profiles in type 2 diabetic patients with and without major depressive disorder

BackgroundThere is a high prevalence of depression in individuals with type 2 diabetes mellitus. Depressive disorders are associated with increased medical morbidity and mortality in individuals with diabetes. It has been demonstrated that there is a higher prevalence of diabetic complications among individuals with diabetes and depression compared to those without depression. Several biological alterations have been reported in individuals with depressive disorders, particularly abnormal levels of endocrine-inflammatory markers.This study aims to determine the prevalence of major depressive disorder (MDD) in type 2 diabetes patients, the prevalence of cardiovascular events in individuals with and without MDD and to compare the endocrine-inflammatory profile between groups.MethodsThe study was approved by the “Comité de Etica de Protocolos de Investigación del Departamento de Docencia e Investigación del Hospital Italiano de Buenos Aires” with the number “1262” and included only patients who provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki and the Habeas Data law on protection of personal data (Law Nª 25326, Argentina).Type 2 diabetes patients (n = 61) were included and they were classified as having MDD or not according to DSM-IV. Macrovascular disease was obtained from the medical history. Additionally, the intima-media thickness of the common carotid, carotid bifurcations and internal carotid arteries was measured non-invasively by two-dimensional ultrasound imaging. Fasting glucose, fasting lipid profile, inflammatory (CRP, TNF-α) and endocrine (urine free cortisol and saliva cortisol) markers. Student t tests were used to compare means for normally distributed variables and Mann-Whitney test for variables without normal distribution. Relative frequencies were calculated and a chi-square analysis was conducted. Data were expressed as mean ± standard deviation (SD) or median and interquartile range. Multivariable logistic regression was used to determine the relative odds of clinical cardiovascular disease in individuals with compared to those without depression. Differences were considered significant using a two-sided p < 0.05.Results21 patients (34%) had MDD and 40 patients (66%) didn’t have MDD. Diabetic patients with MDD had significantly higher CRP levels (4.1(1.9-7.6) vs 1.5(0.5-4.4) mg/l; p = 0.02) and 24-hour urine free cortisol (71.4 ± 21.3 vs 59.8 ± 29.3 ug/24 h; p = 0.03). The other metabolic and inflammatory parameters were not statistically different between groups. There was a significantly higher prevalence of cardiovascular events in individuals with MDD: 38% for the depressive group vs 15% for non-depressive group, p = 0.04). Patients with MDD had a 3.5-fold greater odd of having cardiovascular disease.ConclusionsDiabetic patients with depression are more likely to have cardiovascular events, and different factors can determine this high association.

Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small, dense HDL3c

High-density lipoprotein (HDL) possesses multiple biological activities; small, dense HDL3c particles displaying distinct lipidomic composition exert potent antiatherogenic activities which can be compromised in dyslipidemic, hyperglycemic insulin-resistant states. However, it remains indeterminate (i) whether such functional HDL deficiency is related to altered HDL composition, and (ii) whether it originates from atherogenic dyslipidemia, dysglycemia, or both. In the present work we analyzed compositional characteristics of HDL subpopulations and functional activity of small, dense HDL3c particles in treatment-naïve patients with well-controlled (n=10) and poorly-controlled (n=8) type 2 diabetes (T2D) and in normolipidemic age- and sex-matched controls (n=11). Our data reveal that patients with both well- and poorly-controlled T2D displayed dyslipidemia and low-grade inflammation associated with altered HDL composition. Such compositional alterations in small, dense HDL subfractions were specifically correlated with plasma HbA1c levels. Further analysis using a lipidomic approach revealed that small, dense HDL3c particles from T2D patients with poor glycemic control displayed additional modifications of their chemical composition. In parallel, antioxidative activity of HDL3c towards oxidation of low-density lipoprotein was diminished. These findings indicate that defective functionality of small, dense HDL particles in patients with T2D is not only affected by the presence of atherogenic dyslipidemia, but also by the level of glycemic control, reflecting compositional alterations of HDL.

Proatherogenic disturbances in lipoprotein profile, associated enzymes and transfer proteins in women with iron deficiency anaemia

OBJECTIVE To characterize the lipid-related atherogenic risk factors in iron deficiency anaemia (IDA) patients. DESIGN AND METHODS Twenty IDA women were compared to healthy age-matched controls. Lipoprotein profile, cholesteryl ester transfer protein (CETP), paraoxonase (PON) 1 and lipoprotein-associated phospholipase A(2) (LpPLA(2)) activities and plasma levels of oxidized-LDL were evaluated. RESULTS Triglycerides were higher (median [range]) (1.0 [0.5-1.9] vs. 0.7 [0.5-1.5] mmol/L, p<0.05) and HDL-C lower (mean + or - SD) (1.3 + or - 0.3 vs. 1.6 + or - 0.4 mmol/L, p<0.01) in the patients group. CETP (197 + or - 29% vs. 151 + or - 29% mL(-1) h(-1), p<0.001), PON 1 (122 + or - 17 vs. 140 + or - 33 micromol mL(-1) min(-1), p<0.05) and LpPLA(2) (9.6 + or - 2.0 vs. 8.1 + or - 1.7 micromol mL(-1) h(-1), p<0.05) activities were different in IDA women. No difference was observed in oxidized-LDL. Haemoglobin correlated negatively with triglycerides (r=-0.35, p<0.05), CETP (r=-0.62, p<0.001) and LpPLA(2) (r=-0.34, p<0.05), while ferritin was positively associated with HDL-C (r=0.39, p<0.05) and inversely with CETP (r=-0.49, p<0.005). CONCLUSION The alterations in lipoprotein profile, CETP, PON 1 and LpPLA(2) activities described in the present study indicate that non-treated IDA might represent a proatherogenic state.

Déficit de alfa 1 antitripsina en pacientes con EPOC: estudio de corte transversal

INTRODUCTION Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with early onset chronic obstructive pulmonary disease (COPD) and liver disease. It is also a highly under-diagnosed condition. As early diagnosis could prompt specific interventions such as smoking cessation, testing of family members, genetic counselling and use of replacement therapy, screening programs are needed to identify affected patients. OBJECTIVE To estimate the prevalence of severe AATD in COPD patients by routine dried blood spot testing and subsequent genotyping in patients with alpha-1 antitrypsin (AAT) levels below an established threshold. MATERIALS AND METHODS Cross-sectional study of adult COPD patients attending the Hospital Dr. Antonio Cetrángolo (Buenos Aires, Argentina) between 2009 and 2012. The study consisted of capillary blood collection via finger stick to determine AAT levels, clinical evaluation and lung function tests. Genotype was determined in AAT-deficient patients. RESULTS A total of 1,002 patients were evaluated, of whom 785 (78.34%) had normal AAT levels, while low AAT levels were found in 217 (21.66%). Subsequent genotyping of the latter sub-group found: 15 (1.5%, 95% CI 0.75-2.25) patients with a genotype associated with severe AATD, of whom 12 were ZZ (1.2%, 95% CI 0.52-1.87) and 3 SZ (0.3%, 95% CI 0-0.64). The remaining 202 patients were classified as: 29 Z heterozygotes (2.89%, 95% CI 1.86-3.93), 25 S heterozygotes (2.5%, 95% CI 1.53-3.46) and 4 SS (0.4%, 95% CI 0.01-0.79). A definitive diagnosis could not be reached in 144 patients (14.37%, 95% CI 12.2-16.54). CONCLUSION The strategy using an initial serum AAT level obtained by dried blood spot testing and subsequent genotyping was a satisfactory initial approach to a screening program for severe AAT, as a definitive diagnosis was achieved in 87% of patients. However, results were not obtained for logistical reasons in the remaining 13%. This major obstacle may be overcome by the use of dried blood spot phenotyping techniques. We believe this approach for detecting AATD in COPD patients, in compliance with national and international guidelines, is supported by our results.

Effect of therapy with deflazacort on dyslipoproteinemia after pediatric renal transplantation.

Deflazacort is an oxazolone compound derived from prednisolone, with similar immunosuppressive action but fewer side effects. Kidney function, weight/height ratio, serum triglycerides, cholesterol, high-density lipoprotein (HDL) cholesterol, very-low-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein A, apolipoprotein B, and lipoprotein (a) were studied before and 6 months after substitution of deflazacort (mean +/- SEM, 0.3 +/- 0.1 mg/kg per day) for methylprednisone (0.2 +/- 0.1 mg/kg per day) in 14 patients treated with cyclosporine, aged 3.1 to 20.3 years, 3 years after renal transplantation. Serum creatinine and calculated creatinine clearance did not change significantly, and weight/height ratio decreased from 20.0% +/- 7.1% to 12.5% +/- 6.5% (P < .005) during deflazacort therapy. Total cholesterol was reduced by 15.9% (from 233 +/- 15 mg/dL to 196 +/- 13 mg/dL, P < .01), LDL cholesterol by 25.5% (from 153 +/- 14 mg/dL to 114 +/- 12 mg/dL, P < .01), and TC/HDL cholesterol ratio by 28.3% (from 5.3 +/- 0.4 to 3.8 +/- 0.4, P < .01), whereas HDL cholesterol increased 18% (from 45 +/- 2 mg/dL to 53 +/- 2 mg/dL) and apolipoprotein A by 8.3% (from 122 +/- 5 mg/dL to 132 +/- 5 mg/dL, P < .05) during deflazacort therapy. Our data suggest that substituting deflazacort for maintenance methylprednisone therapy leads to an improvement in the lipoprotein profile of children after renal transplantation.

Metabolic alterations, HFE gene mutations and atherogenic lipoprotein modifications in patients with primary iron overload.

Iron overload (IO) has been associated with glucose metabolism alterations and increased risk of cardiovascular disease (CVD). Primary IO is associated with mutations in the HFE gene. To which extent HFE gene mutations and metabolic alterations contribute to the presence of atherogenic lipoprotein modifications in primary IO remains undetermined. The present study aimed to assess small, dense low-density lipoprotein (LDL) levels, chemical composition of LDL and high-density lipoprotein (HDL) particles, and HDL functionality in IO patients. Eighteen male patients with primary IO and 16 sex- and age-matched controls were recruited. HFE mutations (C282Y, H63D and S65C), measures of insulin sensitivity and secretion (calculated from the oral glucose tolerance test), chemical composition and distribution profile of LDL and HDL subfractions (isolated by gradient density ultracentrifugation) and HDL functionality (as cholesterol efflux and antioxidative activity) were studied. IO patients compared with controls exhibited insulin resistance (HOMA-IR (homoeostasis model assessment-estimated insulin resistance): +93%, P< 0.001). Metabolic profiles differed across HFE genotypes. C282Y homozygotes (n=7) presented a reduced β-cell function and insulin secretion compared with non-C282Y patients (n=11) (-58% and -73%, respectively, P< 0.05). In addition, C282Y homozygotes featured a predominance of large, buoyant LDL particles (C282Y: 43±5; non-C282Y: 25±8; controls: 32±7%; P< 0.001), whereas non-C282Y patients presented higher amounts of small, dense LDL (C282Y: 23±5; non-C282Y: 39±10; controls: 26±4%; P< 0.01). HDL particles were altered in C282Y homozygotes. However, HDL functionality was conserved. In conclusion, metabolic alterations and HFE gene mutations are involved in the presence of atherogenic lipoprotein modifications in primary IO. To what extent such alterations could account for an increase in CVD risk remains to be determined.