Ora Yadin

PATTERNS OF FGF-23, DMP1 AND MEPE EXPRESSION IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Fibroblast growth factor 23 (FGF-23), dentin matrix protein 1 (DMP1), and matrix extracellular phosphoglycoprotein (MEPE) are skeletal proteins involved in the regulation of phosphate homeostasis and bone metabolism. Circulating FGF-23 levels are increased in patients with chronic kidney disease (CKD); however, FGF-23 skeletal expression and its regulation by DMP1 and MEPE have yet to be evaluated. Thus, expression of these three proteins was characterized by immunohistochemistry in 32 pediatric and young adult patients with CKD stages 2-5. When compared to normal controls, bone FGF-23 and DMP1 expression were increased in all stages of CKD; significant differences in bone FGF-23 and DMP1 expression were not detected between pre-dialysis CKD and dialysis patients. Bone MEPE expression in CKD did not differ from controls. FGF-23 was expressed in osteocyte cell bodies located at the trabecular periphery. DMP1 was widely expressed in osteocyte cell bodies and dendrites throughout bone. MEPE was also expressed throughout bone, but only in osteocyte cell bodies. Bone FGF-23 expression correlated directly with plasma levels of the protein (r=0.43, p<0.01) and with bone DMP1 expression (r=0.54, p<0.01) and expression of both proteins were inversely related to osteoid accumulation. Bone MEPE expression was inversely related to bone volume. In conclusion, skeletal FGF-23 and DMP1 expression are increased in CKD and are related to skeletal mineralization. The patterns of expression of FGF-23, MEPE, and DMP1 differ markedly in trabecular bone, suggesting that individual osteocytes may have specialized functions. Increases in bone FGF-23 and DMP1 expression suggest that osteocyte function is altered early in the course of CKD.

Early Skeletal and Biochemical Alterations in Pediatric Chronic Kidney Disease

BACKGROUND AND OBJECTIVES The relationship between parathyroid hormone, fibroblast growth factor 23 (FGF-23), and indices of bone turnover and mineralization in children with early CKD is unknown; thus, this study characterizes the features of renal osteodystrophy and their relationship to biochemical markers of mineral metabolism. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fifty-two patients 2-21 years of age with predialysis CKD underwent tetracycline-labeled bone biopsy. Anthropomorphic measurements and biochemical values were obtained at the time of biopsy. RESULTS Serum phosphorus levels were increased in 4% of patients with stage 3 CKD and 43% of those with stage 4/5 CKD. Parathyroid hormone concentrations were elevated in 36% of patients with stage 2, 71% with stage 3, and 93% with stage 4/5 CKD, whereas FGF-23 values were elevated in 81% of all patients, regardless of CKD stage. Bone turnover was normal in all patients with stage 2, but was increased in 13% with stage 3 and 29% with stage 4/5 CKD. Defective mineralization was present in 29% of patients with stage 2, 42% with stage 3, and 79% with stage 4/5 CKD. Defective skeletal mineralization was associated with lower serum calcium levels and increased parathyroid hormone concentrations. CONCLUSIONS Elevated circulating FGF-23 levels and defects in skeletal mineralization early in the course of CKD suggest that factors other than the traditional markers of mineral deficiency play a crucial role in the development of renal bone disease.

Recombinant human growth hormone treatment of children following renal transplantation

Nine growth-retarded renal allograft recipients received either thrice weekly or daily subcutaneous recombinant human growth hormone (rhGH) for 6–30 months. The annualized growth velocity for the initial year of rhGH treatment was significantly greater than that of the preceding year (2.5±2.1 vs 5.7±2.7;P<0.0001). There was no advancement in bone age greater than the increase in chronological age, no significant increase in the mean fasting serum glucose or insulin levels, nor significant decrease in the calculated creatinine clearance following rhGH treatment. However, two patients experienced rejection episodes following rhGH treatment indicating the potiental adverse consequences of the treatment on allograft function. This will require further delineation in prospective controlled studies. The serum insulin-like growth factor-1 levels significantly increased at 6 months (P<0.009) and 12 months (P<0.002) following rhGH treatment compared with baseline values. These preliminary data indicate that rhGH treatment may be effective in improving the growth velocity of growth-retarded renal allograft recipients.

Recombinant human growth hormone treatment of children with chronic renal failure: long-term (1- to 3-year) outcome.

Treatment of nine boys, aged 2.8–16.3 years, with growth retardation consequent to chronic renal failure (CRF), with recombinant human growth hormone (rhGH) for 12–36 months demonstrated a significant improvement in growth velocity at each 12-month interval compared with that achieved the year prior to treatment. Despite the acceleration in growth velocity the bone age did not increase more than the increase in chronological age during the period of treatment. The mean calculated creatinine clearance did not decrease significantly during the 36 months of treatment; however, two patients required institution of dialysis at 18 and 30 months following the initiation of rhGH treatment. There was no exacerbation of the glucose intolerance of uremia following rhGH treatment. Currently, six of seven patients who have been treated for more than 24 months have achieved sufficient acceleration of growth velocity to attain a standard deviation score that was more positive than −2.00, and are above the 5th per centile for chronological age on the growth curve. These data indicate that rhGH treatment of growthretarded children with CRF results in accelerated growth velocity during the 2nd and 3rd years of treatment, and demonstrate the potential for such children to achieve normal stature for chronological age despite the continued presence of renal failure.

The impact of short stature on health-related quality of life in children with chronic kidney disease

OBJECTIVES To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) and short stature (SS) with that of children with CKD and normal height (NH), to evaluate the impact of catch-up growth and growth hormone (GH) use on HRQoL, and to describe the concordance of perceptions of HRQoL between children with SS and NH and their parents. STUDY DESIGN Four hundred eighty-three children and/or parents enrolled in the multicenter Chronic Kidney Disease in Children study who had completed the Pediatric Quality of Life Inventory (Version 4.0) on at least 2 Chronic Kidney Disease in Children study visits composed this substudy population. Participants were dichotomized into NH or SS groups. The demographic characteristics that varied at baseline (sex, glomerular filtration rate, and parent education) were controlled for in the main analysis evaluating the impact of catch-up growth and use of GH on HRQoL. RESULTS Multivariate modeling (controlling for confounding variables) revealed a significant association between both catch-up growth and GH use on parent-proxy reports of child physical functioning (P < .05) and social functioning (P < .05). Older children with CKD (15-17 years old) had significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children (8-14 years old). CONCLUSION The finding that height gains and GH use are associated with increases in physical and social functioning by parent report provides additional support for interventions to improve height in children with CKD. The importance of evaluating both the parent and child perceptions of HRQoL is supported by our results.

Hemoglobin Differences by Race in Children With CKD

BACKGROUND There are known racial disparities in the prevalence of anemia in adults with chronic kidney disease (CKD), but these differences have not been well described in children. STUDY DESIGN Cohort study, cross-sectional analysis. SETTING & PARTICIPANTS The Chronic Kidney Disease in Children (CKiD) Study is a multicenter prospective cohort study of children with mild to moderate CKD. This analysis included 429 children of African American or white race. PREDICTOR Race. OUTCOMES & MEASUREMENTS This study examined the association of race with hemoglobin level. Both multiple linear regression and generalized gamma modeling techniques were used to characterize the association between race and hemoglobin level. RESULTS 79% of the cohort was white, 21% was African American. Neither median hemoglobin level nor frequency of erythropoiesis-stimulating agent use differed by race. In multivariate analysis, lower levels of iohexol-measured glomerular filtration rate, African American race, and glomerular disease (vs nonglomerular disease) as the underlying cause of CKD were independently associated with decreased hemoglobin levels; independent of glomerular filtration rate and CKD diagnosis, African American children had average hemoglobin levels that were 0.6 g/dL (95% CI, -0.9 to -0.2 g/dL) lower than those of white children. Generalized gamma modeling showed that differences in hemoglobin levels observed by race become more pronounced when moving from high to low in the overall hemoglobin level distribution. LIMITATIONS Cross-sectional analysis cannot establish causality, and data for iron stores were not available for all patients. CONCLUSIONS African American compared with white children have lower hemoglobin values in CKD independent of the underlying cause of CKD. These racial differences in hemoglobin levels appear to increase at the lower end of the hemoglobin level distribution in this population.

Type III mixed cryoglobulinemia and antiphospholipid syndrome in a patient with partial DiGeorge syndrome

We studied a 14 year-old boy with partial DiGeorge syndrome (DGS), status post complete repair of Tetralogy of Fallot, who developed antiphospholipid syndrome (APS) and type III mixed cryoglobulinemia. He presented with recurrent fever and dyspnea upon exertion secondary to right pulmonary embolus on chest computed tomography (CT). Coagulation studies revealed homozygous methylene tetrahydrofolate reductase 677TT mutations, elevated cardiolipin IgM antibodies, and elevated β2-glycoprotein I IgM antibodies. Infectious work-up revealed only positive anti-streptolysin O (ASO) and anti-DNAse B titers. Autoimmune studies showed strongly positive anti-platelet IgM, elevated rheumatoid factor (RF), and positive cryocrit. Renal biopsy for evaluation of proteinuria and hematuria showed diffuse proliferative glomerulonephritis (DPGN) with membranoproliferative features consistent with cryoglobulinemia. Immunofixation showed polyclonal bands. Our patient was treated successfully with antibiotics, prednisone, and mycophenolate mofetil (MMF). This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection.

Immediate post-transplant nephrosis in a patient with congenital nephrotic syndrome

Abstract A 19-month-old girl with congenital nephrotic syndrome of the Finnish type underwent a living-related renal transplant; 24 h after transplantation she became massively nephrotic. She did not respond to steroids, plasmapheresis, and high-dose cyclosporine. A month later, a renal biopsy showed only glomerular foot process effacement. She was treated with high-dose methylprednisolone pulses and oral cyclophosphamide. She rapidly went into complete remission with no further relapses. Graft function has been stable 2 years after transplantation.

Use of recombinant human growth hormone in children with chronic renal insufficiency : an update

Growth retardation is common in children with chronic renal insufficiency (CRI). Now that dialysis and renal transplantation (TX) have become life sustaining, permanent stunted growth and adult short stature often occurs. Thus, efforts to enhance growth using recombinant human growth hormone (rhGH) have been undertaken in three groups of patients: chronic renal failure (CRF) prior to dialysis; end-stage renal disease (ESRD) on some form of dialysis; and following TX (post-TX) in whom growth retardation persists. Our initial study was in CRF. Eleven males, ages 2.5-16.3 years, with height standard deviation scores (SDS) of > 2.0 below the mean, have been treated with rhGH for 18-48 months. rhGH was started in a dose of 0.125 mg/kg three times a week in the first 8 patients and subsequently changed to daily dosing (0.053 mg/kg/day) within the first 24 months. To date, overall, growth velocity (GV) increased from 5.4 +/- 2.2 to 8.9 +/- 1.6, 7.5 +/- 1.8, 7.5 +/- 1.6 and 6.9 +/- 0.9 cm/year in those completing 12 (n = 11), 24 (n = 9), 36 (n = 7), and 48 (n = 3) months. The mean height SDS increased from > 3.0 to < 1.5 below the mean with 1 patient reaching the 50th centile. Dialysis was initiated in 2 patients, a frequency not different from that expected over time in children with this degree of CRF. In the others, calculated creatinine clearance did not change, and no significant adverse effects were noted as a consequence of the rhGH treatment. Thus, rhGH increases GV and facilitates catch-up growth in CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

Depressive Symptoms in Children with Chronic Kidney Disease

OBJECTIVE To assess depression in children with chronic kidney disease and to determine associations with patient characteristics, intellectual and educational levels, and health-related quality of life (HRQoL). STUDY DESIGN Subjects aged 6-17 years from the Chronic Kidney Disease in Children cohort study completed the Childrens Depression Inventory (CDI), Wechsler Abbreviated Scales of Intelligence, Wechsler Individual Achievement Test-II-Abbreviated, and the Pediatric Inventory of Quality of Life Core Scales 4.0. Regression analyses determined associations of CDI score and depression status with subject characteristics, intellectual and educational levels, and HRQoL. A joint linear mixed model and Weibull model were used to determine the effects of CDI score on longitudinal changes in glomerular filtration rate and time to renal replacement therapy. RESULTS A total of 344 subjects completed the CDI. Eighteen (5%) had elevated depressive symptoms, and another 7 (2%) were being treated for depression. In adjusted analyses, maternal education beyond high school was associated with 5% lower CDI scores (estimate, 0.95; 95% CI, 0.92-0.99). Depression status was associated with lower IQ (99 vs 88; P = .053), lower achievement (95 vs 77.5; P < .05), and lower HRQoL by parent and child reports (effect estimates, -15.48; 95% CI, -28.71 to -2.24 and -18.39; 95% CI, -27.81 to -8.96, respectively). CDI score was not related to change in glomerular filtration rate. CONCLUSION Children with depression had lower psychoeducational skills and worse HRQoL. Identifying and treating depression should be evaluated as a means of improving the academic performance and HRQoL of children with chronic kidney disease.