Coagulation factor V gene mutation increases the risk of venous thrombosis in Behcet's disease

We investigated the prevalence of the coagulation factor V gene G1691A mutation in 64 patients with Behcet's disease (BD) and in 107 apparently healthy individuals. The mutation was present in the heterozygous state in 37.5% of the patients with a history of deep vein thrombosis (12/32) and in 9.4% of the patients without any thrombotic event (3/32). Eleven healthy individuals were also heterozygous for the mutation (10.3%). The prevalence of the mutation in BD patients with and without thrombosis was significantly different (P = 0.0079). We conclude that the factor V gene mutation may play a major role in the development of venous thrombosis in BD

Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

The uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism and a decline in renal excretion. Despite of solid experimental evidence for nephrotoxic effects, the impact of uremic toxins on the progression of CKD has not been investigated in representative patient cohorts. In this analysis, IS and pCS serum concentrations were measured in 604 pediatric participants (mean eGFR of 27 ± 11 ml/min/1.73m2) at enrolment into the prospective Cardiovascular Comorbidity in Children with CKD study. Associations with progression of CKD were analyzed by Kaplan-Meier analyses and Cox proportional hazard models. During a median follow up time of 2.2 years (IQR 4.3-0.8 years), the composite renal survival endpoint, defined as 50% loss of eGFR, or eGFR <10ml/min/1.73m2 or start of renal replacement therapy, was reached by 360 patients (60%). Median survival time was shorter in patients with IS and pCS levels in the highest versus lowest quartile for both IS (1.5 years, 95%CI [1.1,2.0] versus 6.0 years, 95%CI [5.0,8.4]) and pCS (1.8 years, 95%CI [1.5,2.8] versus 4.4 years, 95%CI [3.4,6.0]). Multivariable Cox regression disclosed a significant association of IS, but not pCS, with renal survival, which was independent of other risk factors including baseline eGFR, proteinuria and blood pressure. In this exploratory analysis we provide the first data showing a significant association of IS, but not pCS serum concentrations with the progression of CKD in children, independent of other known risk factors. In the absence of comorbidities, which interfere with serum levels of uremic toxins, such as diabetes, obesity and metabolic syndrome, these results highlight the important role of uremic toxins and accentuate the unmet need of effective elimination strategies to lower the uremic toxin burden and abate progression of CKD

Markers of Bone Metabolism Are Affected by Renal Function and Growth Hormone Therapy in Children with Chronic Kidney Disease

WOS: 000349444900005PubMed ID: 25659076Objectives The extent and relevance of altered bone metabolism for statural growth in children with chronic kidney disease is controversial. We analyzed the impact of renal dysfunction and recombinant growth hormone therapy on a panel of serum markers of bone metabolism in a large pediatric chronic kidney disease cohort. Methods Bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase 5b (TRAP5b), sclerostin and C-terminal FGF-23 (cFGF23) normalized for age and sex were analyzed in 556 children aged 6-18 years with an estimated glomerular filtration rate (eGFR) of 10-60 ml/min/1.73m(2). 41 children receiving recombinant growth hormone therapy were compared to an untreated matched control group. Results Standardized levels of BAP, TRAP5b and cFGF-23 were increased whereas sclerostin was reduced. BAP was correlated positively and cFGF-23 inversely with eGFR. Intact serum parathormone was an independent positive predictor of BAP and TRAP5b and negatively associated with sclerostin. BAP and TRAP5B were negatively affected by increased C-reactive protein levels. In children receiving recombinant growth hormone, BAP was higher and TRAP5b lower than in untreated controls. Sclerostin levels were in the normal range and higher than in untreated controls. Serum sclerostin and cFGF-23 independently predicted height standard deviation score, and BAP and TRAP5b the prospective change in height standard deviation score. Conclusion Markers of bone metabolism indicate a high-bone turnover state in children with chronic kidney disease. Growth hormone induces an osteoanabolic pattern and normalizes osteocyte activity. The osteocyte markers cFGF23 and sclerostin are associated with standardized height, and the markers of bone turnover predict height velocity.KfH Foundation for Preventive Medicine; European Renal Association-European Dialysis and Transplant Association; German Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [01EO0802]; Pfizer Deutschland GmbHThis study has been made possible by grants of the KfH Foundation for Preventive Medicine, the European Renal Association-European Dialysis and Transplant Association (www.era-edta.org), the German Federal Ministry of Education and Research (reference number: 01EO0802) and Pfizer Deutschland GmbH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Distribution of serum bone markers by CKD stage.

<p>Data are given as mean ± SD or median (interquartile range) P values indicate difference of age- and sex-adjusted SDS from reference population. Different superscript letters indicate significant differences (p<0.05) between CKD stages (according to ANOVA using Student-Newman-Keuls grouping).</p><p>A, B & C: Student-Newman-Keuls Grouping—Means with the same letter are not significantly different.</p><p>Distribution of serum bone markers by CKD stage.</p

Predictors of baseline and prospective change in standardized height in total cohort; results of stepwise multiple linear regression analyses.

<p>The prospective change in height SDS during one year of observation was positively associated with higher BAP and TRAP5b SDS, lower baseline height SDS and rhGH therapy.</p><p>Interestingly, physical activity showed a positive association to prospective growth.</p><p>A case-control study was performed to obtain an unbiased analysis of the impact of rhGH on the bone marker pattern. For 41 rhGH treated patients an equal number of untreated control subjects matched by age, sex, country of residence, CKD duration, eGFR and serum phosphorus, iPTH and CRP was identified (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113482#pone.0113482.t005" target="_blank">Table 5</a>).</p><p>Predictors of baseline and prospective change in standardized height in total cohort; results of stepwise multiple linear regression analyses.</p

Subject characteristics.

<p>Data are given as mean ± SD, median (interquartile range) or n (%) as appropriate.</p><p>At the time of bone marker assessment, 42 children (7.4%) were receiving rhGH treatment, excluding 4 patients who either started or stopped rhGH therapy within 3 months prior to analysis. 38 patients were consistently treated with rhGH during the follow-up period of 6–12 months. rhGH treated patients originated from 7 of the 12 participating countries, had a longer preceding duration of CKD (8.1±4.3 vs 5.9±4.5 years, p<0.003), were taller (-0.89±0.87 vs. -1.4±1.4 SDS, p<0.0002) and showed marginally better current growth rates (0.07±0.38 vs. -0.04±0.38, p = 0.08) compared to all non-rhGH treated patients.</p><p>Subject characteristics.</p

Predictors of standardized bone marker concentrations; results of stepwise multiple linear regression analyses.

<p>Predictors of standardized bone marker concentrations; results of stepwise multiple linear regression analyses.</p

Bone markers in groups matched for GH treatment.

<p>Bone markers in groups matched for GH treatment.</p

Patient inclusion criteria and subgroups for cross-sectional analysis of bone markers, influence of rhGH treatment and predictors of height and growth.

<p>Patient inclusion criteria and subgroups for cross-sectional analysis of bone markers, influence of rhGH treatment and predictors of height and growth.</p