Changes in bone matrix mineralization after growth hormone treatment in children and adolescents with chronic kidney failure treated by dialysis: a paired biopsy study.

BACKGROUND: Patients with chronic kidney disease (CKD) develop renal osteodystrophy with alterations in bone turnover, mineralization, and volume (TMV). A specific skeletal complication in children is growth impairment, which currently is treated by recombinant human growth hormone (rhGH). The effects on bone material properties are poorly understood. This study assesses the effects of rhGH treatment on bone matrix mineralization. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 18 short children and adolescents (aged 3.6-16 years) with CKD on dialysis therapy. PREDICTOR: rhGH treatment for 1 year. OUTCOMES: Tetracycline-labeled bone biopsy classified according to the TMV system. MEASUREMENTS: Bone mineralization density distribution (BMDD) was evaluated by quantitative backscattered electron imaging in trabecular and cortical compartments. Additional data for patients' height and biochemical bone serum parameters were obtained. RESULTS: Prior to rhGH treatment, our cohort showed low bone turnover and high mineralization densities versus reference data: Ca(mean) (weighted mean calcium content) in cancellous bone, +3.3% (P = 0.04); Ca(mean) in cortical bone, +6.7% (P < 0.001); Ca(peak) (mode of the BMDD) in cancellous bone, +5.0% (P < 0.001); Ca(peak) in cortical bone, +8.2% (P < 0.001); Ca(width) (heterogeneity in mineralization), no significant difference for cancellous (P = 0.2) and cortical (P = 0.1) bone; Ca(high) (portion of fully mineralized bone) in cancellous bone, 5-fold greater (P < 0.001); Ca(high) in cortical bone, 14-fold greater (P < 0.001); Ca(low) (portion of low mineralized bone) in cancellous bone, +23.9% (P = 0.02); Ca(low) in cortical bone, -22.2% (P = 0.05). After rhGH treatment, height increased by 9.1 cm (P < 0.001) and bone turnover indices to normal values or beyond. Matrix mineralization was lesser and more heterogeneous compared to baseline: Ca(width) for cancellous bone, +15.3% (P < 0.001); Ca(width) for cortical bone, +34.1% (P < 0.001). Ca(mean), Ca(peak), and Ca(high) for cancellous bone and Ca(mean) and Ca(peak) for cortical bone were no longer significantly different from reference data. Ca(high) for cortical bone dramatically decreased after treatment but was still substantially greater than reference data. LIMITATIONS: Low case number per TMV subgroup, no measurements of fibroblast growth factor 23. CONCLUSIONS: Children and adolescents with CKD and growth deficiency are at risk of having low bone turnover. rhGH treatment improves height and concomitantly bone modeling/remodeling, which appears beneficial for bone matrix mineralization.

Continuous veno-venous hemodiafiltration in methotrexate intoxication.

UNLABELLED: Methotrexate is a highly nephro- and hepatotoxic drug used in osteosarcoma treatment protocols, in children and adults. High dose methotrexate therapy may lead to kidney injury and decrease of methotrexate clearance, followed by an increase of its serum concentration. As a result, systemic intoxication may develop. Prophylaxis based on intensive fluid therapy and urine alkalization may not be sufficient to prevent the formation of methotrexate crystals in kidney tubules. THE AIM of the study was to present three cases of methotrexate intoxication treated with continuous veno-venous hemodiafiltration. PATIENTS AND METHODS: Three children aged 9-16 years old with tibial or fibular osteosarcoma were admitted to the Nephrology Department due to severe methotrexate intoxication. All children presented with multiorgan injury, including liver, kidney, gastrointestinal tract and bone marrow impairment. Methotrexate concentration, 24 hours after drug administration, was 660-1238 µmol/L. Although intensive fluid therapy, urine alkalisation and administration of high doses of folinic acid (leucovorin), methotrexate serum concentration remained toxic. Effective reduction of methotrexate concentration (<1.5 µmol/L) was achieved 24-156 hours after CVVHDF initiation. Kidney and liver function recovered completely in all of the patients. CONCLUSION: Continuous veno-venous hemodiafiltration is an effective supportive method in methotrexate elimination in patients with severe intoxication.

Anaemia treatment in chronically dialysed children: a multicentre nationwide observational study.

OBJECTIVE: Erythropoiesis-stimulating agents (ESAs) are applied as a standard therapy in children with anaemia in chronic kidney disease. The aim of this study was to describe the efficacy and details of ESA treatment in a population of dialysed children in Poland. MATERIAL AND METHODS: The study had a prospective observational design and was performed in 12 dialysis centres. The study group comprised 117 dialysed children with a mean age at enrolment of 165.33 (97.18-196.45) months. RESULTS: Dialysed children were treated mostly with epoietin beta and darbepoietin. The mean dose of ESA was 99 (68-147) U/kg/week with a significant difference between patients on peritoneal dialysis [83 (54-115)] and haemodialysis [134 (103-186)] (p < 0.0001). The mean haemoglobin of all the time-point tests during 6 months was 10.91 ± 1.18 g/dl. The efficacy of anaemia treatment was unsatisfactory in 52% of subjects. In multivariate analysis, initial haemoglobin level <10 g/l, any infection, younger age at first dialysis, malnutrition and inadequate ESA dosage remained significant predictors of anaemia. CONCLUSIONS: The study revealed that anaemia treatment in Polish children is unsatisfactory. Late commencement of the treatment, inadequate dosing, malnutrition and infections could constitute risk factors for therapy failure.

[Glomerulopathies as causes of end-stage renal disease in children]. / Klebuszkowe choroby nerek jako przyczyna schylkowej niewydolnosci nerek.

UNLABELLED: The aim of the study was assessment of the frequency of glomerular diseases (GD) as a cause of end-stage renal disease (ESRD) in children. PATIENTS AND METHODS: Retrospectively, causes of ESRD, frequency, duration of the disease until diagnosis of ESRD in 195 children treated in 1973-2008 were analysed. RESULTS: Among children with ESRD, GD were diagnosed in 94 (48.2%)--mean age 10.9 +/- 4.3 years, congenital abnormalities of urinary tract in 61 (31.2%) aged 10.6 +/- 4.3 years and other causes in 40 (20.5%). Among 94 children with GD the 49 (52%) patients had primary glomerulonephritis (GN): 24--crescentic GN, 9--focal segmental glomerulosclerosis, 8--mesangioproliferative GN, 5--IgA nephropathy, 3--membranoproliferative GN. In 37 (39.5%) the causes of ESRD were secondary glomerulopathies: 20--amyloidosis, 10--hemolytic-uremic syndrome, 6--Schönlein-Henoch nephropathy, 1--Wegener granulomatosis. In 8 (8.5%) patients causes of ESRD were: Alport syndrome in 2, congenital nephrotic syndrome in 1 and in 5 type of glomerulopathy was unknown. Time between diagnosis of nephropathy and start of dialysis was 0-13.75 years, median 1.1 in patients with GD and was significantly shorter (p<0.003) than this time in the group with congenital abnormalities of the urinary tract (0-14.9 years; median 3.83). There was no difference between primary GN and secondary glomerulopathies. CONCLUSIONS: Chronic glomerulopathies were the most frequent cause of ESRD in investigated group. Time between diagnosis of chronic renal disease and initiation of renal replacement therapy was significantly shorter in children with glomerulopathies than with congenital abnormalities of urinary tract.

[Fetuin A in children with renal diseases]. / Fetuina A u dzieci z chorobami nerek.

UNLABELLED: Fetuin A, 59 kDa protein, produced in the liver is a circulating inhibitor of vascular calcification. The aim of the study was to estimate a concentration of fetuin A in children with renal diseases. Fifty three children were examined: 18 with idiopathic nephrotic syndrome (NS) aged 2.5 to 14.5 years, mean 6.6 +/- 3.6 and 35 with chronic renal failure (CRF) aged 4.5 to 20 years, mean 13.3 +/- 3.9. The control group (K) consisted of 22 healthy children, aged from 6.5 to 17.5 years, mean 10.8 +/- 3.3. In all children serum concentration of fetuin A (ELISA method, BioVendor), calcium (sCa), phosphorus (sP), protein (P), albumin (Alb), total cholesterol (TC) and triglycerides (TG) were measured. The daily protein excretion in children with proteinuria (mg/kg/day) and the serum parathormone (PTH) level in children with CRF were analysed. RESULTS: The concentration of fetuin A was the lowest in children with NS (78.1 +/- 24.5 ng/ml) and was statistically different (p=0.0003) than in group K (101.4 +/- 11 ng/ml) and group CRF (106.7 +/- 13.7 ng/ml). In group NS significant correlations were found between concentrations of fetuin A and sCa (r=0.62, p<0.01), P (r=0.59, p= 0.01) and Alb (r=0.64, p<0.01) and negative correlations with concentration of TC (r=-0.68, p<0.01) and daily proteinuria (r=-0.79, p<0.001). In groups K and CRF the correlations of fetuin A level and analysed parameters were not found. CONCLUSION: Low concentration of fetuin A in children with nephrotic syndrome may be the additional agent to promote the atherogenic lesions.

[Congenital and genetic related causes of end-stage renal disease--data from Polish Registry of Renal Rreplacement Therapy in Children 2000-2004]. / Genetycznie uwarunkowane i wrodzone choroby nerek prowadzace do schylkowej niewydolnosci nerek--dane z polskiego rejestru dzieci leczonych nerkozastepczo (2000-2004).

UNLABELLED: One of the objectives of Polish Registry of Renal Replacement Therapy in Children established on 31st Dec. 2000 was to collect complete data on etiology of end stage renal disease (ESRD) in polish children. MATERIAL AND METHODS: Data on 469 patients (251 boys, 218 girls) aged 0-22 years treated with renal replacement therapy (RRT) at 13 pediatric dialysis units in Poland from 2000 to 2004 were analyzed. The mean age at start of dialysis was 10 years and 3 months. Renal diseases were defined according to EDTA coding system. Data is presented for the whole group, in 5-year age groups and separately for both sexes. RESULTS: Congenital and genetic renal diseases were the cause of ESRF in 56% of the polish population of children and adolescents on RRT. 39% of causes were acquired diseases, 5% remained unidentified. Congenital and genetic causes dominated in children < 5 years of age (71%). They accounted for 49%, 61% and 45% of causes in the consecutive 5-year age groups. The most numerous group of congenital diseases leading to ESRF were uropathies 37% and 25% of causes in the consecutive age groups. In boys the most frequent uropathy was obstructive uropathy (25%), the majority caused by posterior urethral valves. In girls the most frequent uropathies were reflux nephropathy (10%) and nephropathy secondary to neurogenic bladder (9%). Uropathies were followed by renal hypo-dysplasia without urinary tract anomalies (11%) and cystic diseases (10%). CONCLUSIONS: Congenital kidney anomalies and genetic diseases are the leading cause of end-stage renal disease in children up to 15 years of age.

[Osteoprotegerin and calcium-phosphorus metabolism parameters in children with chronic renal failure]. / Osteoprotegeryna a parametry przemiany wapniowo-fosforanowej u dzieci z przewlekla niewydoinoscia nerek.

UNLABELLED: Osteoprotegerin (OPG), a member of the TNF receptor superfamily is a natural inhibitor of osteoclastogenesis and important inhibitor of vascular calcification. The aim of the study was to estimate a correlation of serum OPG level and the other parameters calcium-phosphorus metabolism in children with chronic renal failure. Seventy four children with chronic renal insufficiency, 48 on conservative treatment (CRF) aged 13 +/- 3 years with creatinine clearance 45 +/- 21 ml/min/1.73m2 and 26 with end-stage renal disease (ESRD) aged 14 +/- 5 years were examined. The control group (K) consisted of 23 healthy children aged 10.8 +/- 3 years. In all children serum concentration of OPG, calcium (sCa), phosphorus (sP), PTH, CAP (cyclase activating PTH), CIP (cyclase inactive PTH) and osteocalcin (OC) were measured. OPG was determined by ELISA method (Biomedica), PTH and OC by IRMA (Duo-PTH, Scantibodies, USA and Osteo-Riact firm CIS, F). RESULTS: The concentration of OPG was higher in ESRD group (3 +/-1.6 pmol/l) than in K (1.95 +/- 0.56 pmol/l), p<0.005. The concentration of OPG in CRF group (2.42 +/- 1.4 pmol/l) was not different from this in K and ESRD. The concentration of OPG did not correlate with serum creatinine level. In CRF group no correlation was found between OPG level and the other parameters, in group ESRD the significant correlation between OPG and OC was found (R=0.55, p=0.006). The level of OPG in children CRF + ESRD correlated with PTH concentration (R=0.27, p<0.03), CAP (R=0.29, p<0.02), CIP (R=0.23, p<0.05) and OC (R=0.25, P<0.04). In patients with higher PTH level (> 200 pg/ml) the higher correlations between OPG and PTH, CAP and CIP were found. No significant correlation between PTH and OPG in patients with lower PTH level (< 200 pg/ ml) was found. No significant correlation between OPG and OC in patients with lower and higher PTH was found. CONCLUSION: The elevated levels of OPG in children with ESRD may reflect the higher bone turnover in these patients.

Minimizing bone abnormalities in children with renal failure.

Renal osteodystrophy (ROD), a metabolic bone disease accompanying chronic renal failure (CRF), is a major clinical problem in pediatric nephrology. Growing and rapidly remodeling skeletal systems are particularly susceptible to the metabolic and endocrine disturbances in CRF. The pathogenesis of ROD is complex and multifactorial. Hypocalcemia, phosphate retention, and low levels of 1,25 dihydroxyvitamin D(3) related to CRF result in disturbances of bone metabolism and ROD. Delayed diagnosis and treatment of bone lesions might result in severe disability. Based on microscopic findings, renal bone disease is classified into two main categories: high- and low-turnover bone disease. High-turnover bone disease is associated with moderate and severe hyperparathyroidism. Low-turnover bone disease includes osteomalacia and adynamic bone disease. The treatment of ROD involves controlling serum calcium and phosphate levels, and preventing parathyroid gland hyperplasia and extraskeletal calcifications. Serum calcium and phosphorus levels should be kept within the normal range. The calcium-phosphorus product has to be <5 mmol(2)/L(2) (60 mg(2)/dL(2)). Parathyroid hormone (PTH) levels in children with CRF should be within the normal range, but in children with end-stage renal disease PTH levels should be two to three times the upper limit of the normal range. Drug treatment includes intestinal phosphate binding agents and active vitamin D metabolites. Phosphate binders should be administered with each meal. Calcium carbonate is the most widely used intestinal phosphate binder. In children with hypercalcemic episodes, sevelamer, a synthetic phosphate binder, should be introduced. In children with CRF, ergocalciferol (vitamin D(2)), colecalciferol (vitamin D(3)), and calcifediol (25-hydroxyvitamin D(3)) should be used as vitamin D analogs. In children undergoing dialysis, active vitamin D metabolites alfacalcidol (1alpha-hydroxy-vitamin D(3)) and calcitriol (1,25 dihydroxyvitamin D(3)) are applied. In recent years, a number of new drugs have emerged that hold promise for a more effective treatment of bone lesions in CRF. This review describes the current approach to the diagnosis and treament of ROD.