Hemodiafiltration maintains a sustained improvement in blood pressure compared to conventional hemodialysis in children-the HDF, heart and height (3H) study

BACKGROUND: Hypertension is prevalent in children on dialysis and associated with cardiovascular disease. We studied the blood pressure (BP) trends and the evolution of BP over 1 year in children on conventional hemodialysis (HD) vs. hemodiafiltration (HDF). METHODS: This is a post hoc analysis of the "3H - HDF-Hearts-Height" dataset, a multicenter, parallel-arm observational study. Seventy-eight children on HD and 55 on HDF who had three 24-h ambulatory BP monitoring (ABPM) measures over 1 year were included. Mean arterial pressure (MAP) was calculated and hypertension defined as 24-h MAP standard deviation score (SDS) ≥95th percentile. RESULTS: Poor agreement between pre-dialysis systolic BP-SDS and 24-h MAP was found (mean difference - 0.6; 95% limits of agreement -4.9-3.8). At baseline, 82% on HD and 44% on HDF were hypertensive, with uncontrolled hypertension in 88% vs. 25% respectively; p < 0.001. At 12 months, children on HDF had consistently lower MAP-SDS compared to those on HD (p < 0.001). Over 1-year follow-up, the HD group had mean MAP-SDS increase of +0.98 (95%CI 0.77-1.20; p < 0.0001), whereas the HDF group had a non-significant increase of +0.15 (95%CI -0.10-0.40; p = 0.23). Significant predictors of MAP-SDS were dialysis modality (β = +0.83 [95%CI +0.51 - +1.15] HD vs. HDF, p < 0.0001) and higher inter-dialytic-weight-gain (IDWG)% (β = 0.13 [95%CI 0.06-0.19]; p = 0.0003). CONCLUSIONS: Children on HD had a significant and sustained increase in BP over 1 year compared to a stable BP in those on HDF, despite an equivalent dialysis dose. Higher IDWG% was associated with higher 24-h MAP-SDS in both groups

Hemodiafiltration Is Associated With Reduced Inflammation and Increased Bone Formation Compared With Conventional Hemodialysis in Children: The HDF, Hearts and Heights (3H) Study

BACKGROUND: Patients on dialysis have a high burden of bone-related comorbidities, including fractures. We report a post hoc analysis of the prospective cohort study HDF, Hearts and Heights (3H) to determine the prevalence and risk factors for chronic kidney disease-related bone disease in children on hemodiafiltration (HDF) and conventional hemodialysis (HD). METHODS: The baseline cross-sectional analysis included 144 children, of which 103 (61 HD, 42 HDF) completed 12-month follow-up. Circulating biomarkers of bone formation and resorption, inflammatory markers, fibroblast growth factor-23, and klotho were measured. RESULTS: Inflammatory markers interleukin-6, tumor necrosis factor-α, and high-sensitivity C-reactive protein were lower in HDF than in HD cohorts at baseline and at 12 months (P < .001). Concentrations of bone formation (bone-specific alkaline phosphatase) and resorption (tartrate-resistant acid phosphatase 5b) markers were comparable between cohorts at baseline, but after 12-months the bone-specific alkaline phosphatase/tartrate-resistant acid phosphatase 5b ratio increased in HDF (P = .004) and was unchanged in HD (P = .44). On adjusted analysis, the bone-specific alkaline phosphatase/tartrate-resistant acid phosphatase 5b ratio was 2.66-fold lower (95% confidence interval, −3.91 to −1.41; P < .0001) in HD compared with HDF. Fibroblast growth factor-23 was comparable between groups at baseline (P = .52) but increased in HD (P < .0001) and remained unchanged in HDF (P = .34) at 12 months. Klotho levels were similar between groups and unchanged during follow-up. The fibroblast growth factor-23/klotho ratio was 3.86-fold higher (95% confidence interval, 2.15–6.93; P < .0001) after 12 months of HD compared with HDF. CONCLUSION: Children on HDF have an attenuated inflammatory profile, increased bone formation, and lower fibroblast growth factor-23/klotho ratios compared with those on HD. Long-term studies are required to determine the effects of an improved bone biomarker profile on fracture risk and cardiovascular health

A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules

Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck. For example, the yeast platform for artemisinic acid production is estimated to have taken >150 person years to develop. Here we demonstrate the power of plant transient transfection technology for rapid, scalable biosynthesis and isolation of triterpenes, one of the largest and most structurally diverse families of plant natural products. Using pathway engineering and improved agro-infiltration methodology we are able to generate gram-scale quantities of purified triterpene in just a few weeks. In contrast to heterologous expression in microbes, this system does not depend on re-engineering of the host. We next exploit agro-infection for quick and easy combinatorial biosynthesis without the need for generation of multi-gene constructs, so affording an easy entrée to suites of molecules, some new-to-nature, that are recalcitrant to chemical synthesis. We use this platform to purify a suite of bespoke triterpene analogs and demonstrate differences in anti-proliferative and anti-inflammatory activity in bioassays, providing proof of concept of this system for accessing and evaluating medicinally important bioactives. Together with new genome mining algorithms for plant pathway discovery and advances in plant synthetic biology, this advance provides new routes to synthesize and access previously inaccessible natural products and analogs and has the potential to reinvigorate drug discovery pipelines

Ambulatory blood pressure monitoring and renal functions in children with a solitary kidney

The aim of this study is to investigate the blood pressure (BP) profile, microalbuminuria, renal functions, and relations with remaining normal kidney size in children with unilateral functioning solitary kidney (UFSK). Sixty-six children with UFSK were equally divided into three groups: unilateral renal agenesis (URA), unilateral atrophic kidney (UAK), and unilateral nephrectomy (UNP). Twenty-two age-, weight-, and height-matched healthy children were considered as a control group. The serum creatinine level and first-morning urine microalbumin and creatinine concentrations were determined by the standard methods. Also, the BP profile was determined by ambulatory blood pressure monitoring (ABPM). We found that the serum creatinine level was higher and creatinine clearance was lower in each patient groups compared to those of the control group (p < 0.05). Compared with the controls, each group of patients had mean office, 24-h, daytime, and night-time systolic and diastolic BP values similar to those of the controls (p > 0.05). An inverse correlation was found between the renal size standard deviation scores (SDS) of normal kidneys and 24-h systolic and diastolic BP load SDS in all of the patients (p < 0.05; r = −0.372, r = −0.295, respectively). The observed relationship between renal size SDS and 24-h mean arterial pressure (MAP), systolic and diastolic BP load SDS suggests that children with UFSK should be evaluated by using ABPM for the risk of hypertension

Acute changes in endothelin after hemodialysis in children

WOS: 000072505800019PubMed ID: 9543379The purpose of this study was to investigate the acute changes in endothelin (ET) levels immediately after hemodialysis and to determine whether these changes vary with the use of different membranes and hemodialysis solutions. Ten children were included in the study. Three different hemodialysis sessions were performed on all patients: session 1, acetate-based dialysate and polycarbonate membrane; session 2, bicarbonate-based dialysate and polycarbonate membrane; session 3, acetate-based dialysate and polysulfone membrane. In all cases blood samples were obtained before and after dialysis. Pre-and post-hemodialysis ET levels of the patients with acetate-based dialysate and polycarbonate membrane were 33.68 +/- 11.51 pg/ml and 28.27 +/- 12.85 pg/ml, respectively. The fall in ET levels after this session was statistically significant (P = 0.015). We did not observe a statistically significant change in ET levels in the other sessions. Post-dialysis mean arterial pressure values were significantly lower than the pre-dialysis values in all three dialysis sessions (P < 0.01). A positive correlation was observed between plasma ET levels and blood urea nitrogen and serum potassium; a negative correlation was observed between plasma ET levels and hematocrit

Glycosaminoglycan excretion in children with nephrotic syndrome

PubMedID: 15714313Although most childhood nephrotic syndromes respond to steroid treatment, steroid resistant nephrotic syndrome (SRNS) is also common and is particularly difficult to treat. This study investigated the role of glycosaminoglycans (GAG) in the pathogenesis and clinical course of nephrotic syndrome in children. Thirty-four children (21 males and 13 females, mean age 3.7±1.6 years) with steroid-sensitive nephrotic syndrome and 20 children with steroid-resistant nephrotic syndrome (12 males and 8 females, mean age 10.9±3.8 years; of the twenty, four had primary SRNS (FSGS) and the others had secondary SRNS) were included the study. Mean urine levels of GAG relative to creatinine (UGAG/UCr) in patients with SRNS (n=20, 113.01±78.46 mg g-1 Cr) and in patients experiencing the nephrotic period of steroid-sensitive nephrotic syndrome (n=34, 132.15±101.55 mg g-1Cr) were both significantly higher than mean UGAG/UCr for control subjects (n=30, 51.83±47.66 mg g-1Cr) (P &lt;0.01 for both). Patients excreted significantly more GAG during the nephrotic period of steroid- sensitive nephrotic syndrome than during remission (132.15±101.55 vs 39.11±42.73 mg g-1 P &lt;0.01). There was, however, no significant difference between UGAG/UCr for patients with steroid-resistant nephrotic syndrome and UGAG /UCr in the nephrotic period of steroid-sensitive nephrotic syndrome. Urine GAG excretion correlated significantly with the severity of proteinuria. The results suggest that GAG play a significant role in the pathogenesis of nephrotic syndrome but that GAG excretion is not a marker for response to steroid treatment in pediatric patients with this condition. © IPNA 2005

The role of endothelin in radiocontrast nephropathy

PubMedID: 9413771In the present study we investigated the role of endothelin and AT II in radio-contrast nephropathy induced in rats with reduced renal mass (70-75%). Thirty-five male Wistar albino rats weighing between 280 and 400 g were anaesthetized with ketamine (130 mg/kg b.w.) and right total, left 50% nephrectomy were performed. After this operation, the rats were kept under observation for six to eight weeks and then they were randomly separated into three groups. Group I rats were infused with 8.9 ml/kg (or 2.9 g of iodine/kg body weight) Na diatrizoate (Urovision, 1500 mosm/kg). Group II rats were infused with 0.9% NaCl in an equal volume with the radiocontrast material. Group III rats were given 4.5% NaCl that had the same volume and osmolality as the radiocontast material. Two hours after the drug infusions, blood and accumulated urine samples were collected from all the rats and tested for endothelin, AT II, BUN, creatinine, uric acid, electrolytes, calcium and phosphorus. We found that the plasma endothelin levels in Group I (77.64 ± 29.62 pg/ml) were significantly higher than in Group II (20.52 ± 5.83 pg/ml) and Group III (15.04 ± 5.15 pg/ml) (t = 8.34 and t = 9.14, respectively, p < 0.001). Therefore elevation in circulating endothelin might have been an additional factor leading to the radiocontrast-induced nephrotoxicity

Peritoneal clearance of biochemical markers of bone turnover in children with end stage renal failure on peritoneal dialysis

PubMedID: 16848114Renal osteodystrophy is one of the important complications in children with end stage renal disease. Non-invasive tools for evaluation of bone metabolism have been proposed in recent years. The aim of this study was to investigate the markers of metabolic bone disease and peritoneal clearance of these markers in children treated with continuous ambulatory peritoneal dialysis (CAPD). In this study, serum osteocalcin (OC) levels were found significantly higher in patients (107.98±99.99 ng/ml) than in the healthy control group (41.94±12.94 ng/ml; p<0.05). Mean peritoneal clearance (Clp) of OC was 0.87±0.91 ml/min. There was no correlation between serum OC and Clposteocalcin. There was a positive correlation between serum phosphorus (P) and OC (r=0.394, p=0.031), alkaline phosphatase (ALP) and OC (r=0.520, p=0.003), and parathyroid hormone (PTH) and OC (r=0.441, p=0.017), whereas no correlation was found between OC and calcium (Ca) and OC and magnesium (Mg). There was also a significant correlation between serum ALP and PTH (r=0.714, p=0.0001). A positive correlation was found between serum PTH and Clp of PTH (r=0.471, p=0.009). In conclusion, Clp-osteocalcin is of no interest as a non-invasive marker of metabolic bone disease in children treated with CAPD. But significant correlation between serum OC and PTH, P, and ALP shows that serum OC could be used as a valuable non-invasive biochemical marker of metabolic bone disease

Urinary nephrocalcin excretion in children with urolithiasis

PubMedID: 12972707The aim of this study was to investigate the role of nephrocalcin in childhood urolithiasis. Forty-one patients with urinary stones and 25 age- and sex-matched healthy controls were admitted to the study. Blood and timed urine samples were taken from both patient and control groups for biochemical analysis. Serum and urine creatinine (Cr) and urinary nephrocalcin (NC) were measured. NC excretion was expressed as a NC/Cr (mg/g) ratio. NC-PreA/Cr and NC-D/Cr ratios were found to be significantly higher in patients than in the control group. No statistically significant differences were found in NC-A/Cr, NC-B/Cr, NC-C/Cr ratios between the patient and control groups. The high NC-PreA/Cr ratio (p = 0.012) observed in stone-forming patients indicates that this ratio may also be an important stimulatory factor for urinary stone disease. Copyright © 2003 S. Karger AG, Basel