Shobha Sahney

Relationship between Plasma Fibroblast Growth Factor-23 Concentration and Bone Mineralization in Children with Renal Failure on Peritoneal Dialysis

CONTEXT Fibroblast growth factor (FGF)-23 is produced in bone, and circulating levels are markedly elevated in patients with end-stage kidney disease, but the relationship between plasma levels of FGF-23 and bone histology in dialysis patients with secondary hyperparathyroidism is unknown. OBJECTIVE The aim of the study was to evaluate the correlation between plasma levels of FGF-23 and bone histology in pediatric patients with end-stage kidney disease who display biochemical evidence of secondary hyperparathyroidism. DESIGN We performed a cross-sectional analysis of the relationship between plasma FGF-23 levels and bone histomorphometry. SETTING The study was conducted in a referral center. STUDY PARTICIPANTS Participants consisted of forty-nine pediatric patients who were treated with maintenance peritoneal dialysis and who had serum PTH levels (1st generation Nichols assay) greater than 400 pg/ml. INTERVENTION There were no interventions. MAIN OUTCOME MEASURE Plasma FGF-23 levels and bone histomorphometry were measured. RESULTS No correlation existed between values of PTH and FGF-23. Bone formation rates correlated with PTH (r = 0.44; P < 0.01), but not with FGF-23. Higher FGF-23 concentrations were associated with decreased osteoid thickness (r = -0.49; P < 0.01) and shorter osteoid maturation time (r = -0.48; P < 0.01). CONCLUSIONS High levels of FGF-23 are associated with improved indices of skeletal mineralization in dialyzed pediatric patients with high turnover renal osteodystrophy. Together with other biomarkers, FGF-23 measurements may indicate skeletal mineralization status in this patient population.

Calcitriol and doxercalciferol are equivalent in controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism.

We compared the effects of calcitriol and doxercalciferol, in combination with either calcium carbonate or sevelamer, on bone, mineral, and fibroblast growth factor-23 (FGF-23) metabolism in patients with secondary hyperparathyroidism. A total of 60 pediatric patients treated with peritoneal dialysis were randomized to 8 months of therapy with either oral calcitriol or doxercalciferol, combined with either calcium carbonate or sevelamer. Bone formation rates decreased during therapy and final values were within the normal range in 72% of patients. A greater improvement in eroded surface was found in patients treated with doxercalciferol than in those given calcitriol. On initial bone biopsy, a mineralization defect was identified in the majority of patients which did not normalize with therapy. Serum phosphate concentrations were controlled equally well by both binders, but serum calcium levels increased during treatment with calcium carbonate, and serum parathyroid hormone levels were decreased by 35% in all groups. Baseline plasma FGF-23 values were significantly elevated and rose over fourfold with calcitriol and doxercalciferol, irrespective of phosphate binder. Thus, doxercalciferol is as effective as calcitriol in controlling serum parathyroid hormone levels and suppressing the bone formation rate. Sevelamer allows the use of higher doses of vitamin D. Implications of these changes on bone and cardiovascular biology remain to be established.

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.

Sevelamer Controls Parathyroid Hormone–Induced Bone Disease as Efficiently as Calcium Carbonate without Increasing Serum Calcium Levels during Therapy with Active Vitamin D Sterols

Little is known about the impact of various phosphate binders on the skeletal lesions of secondary hyperparathyroidism (2 degrees HPT). The effects of calcium carbonate (CaCO3) and sevelamer were compared in pediatric peritoneal dialysis patients with bone biopsy-proven 2 degrees HPT. Twenty-nine patients were randomly assigned to CaCO3 (n = 14) or sevelamer (n = 15), concomitant with either intermittent doses of oral calcitriol or doxercalciferol for 8 mo, when bone biopsies were repeated. Serum phosphorus, calcium, parathyroid hormone (PTH), and alkaline phosphatase were measured monthly. The skeletal lesions of 2 degrees HPT improved with both binders, and bone formation rates reached the normal range in approximately 75% of the patients. Overall, serum phosphorus levels were 5.5 +/- 0.1 and 5.6 +/- 0.3 mg/dl (NS) with CaCO3 and sevelamer, respectively. Serum calcium levels and the Ca x P ion product increased with CaCO3; in contrast, values remained unchanged with sevelamer (9.6 +/- 01 versus 8.9 +/- 0.2 mg/dl; P < 0.001, respectively). Hypercalcemic episodes (>10.2 mg/dl) occurred more frequently with CaCO3 (P < 0.01). Baseline PTH levels were 980 +/- 112 and 975 +/- 174 pg/ml (NS); these values decreased to 369 +/- 92 (P < 0.01) and 562 +/- 164 pg/ml (P < 0.01) in the CaCO3 and the sevelamer groups, respectively (NS between groups). Serum alkaline phosphatase levels also diminished in both groups (P < 0.01). Thus, treatment with either CaCO3 or sevelamer resulted in equivalent control of the biochemical and skeletal lesions of 2 degrees HPT. Sevelamer, however, maintained serum calcium concentrations closer to the lower end of the normal physiologic range, thereby increasing the safety of treatment with active vitamin D sterols.

Evaluation of the safety of short-acting nifedipine in children with hypertension

Abstract. Concerns regarding the safety of nifedipine emerged in 1995 with the report of an increased risk of myocardial infarction associated with adult patients receiving short-acting calcium channel blockers. There have been few case reports of adverse events in children. The purpose of this study is to investigate the effect on blood pressure (BP) and the incidence of adverse events associated with nifedipine in our pediatric population. We conducted a retrospective chart review of pediatric patients who received nifedipine. We recorded the dose administered, all BP measurements and all adverse events reported within six hours of a nifedipine dose regardless of the likelihood that those events were related to the nifedipine dose. 1,746 doses of nifedipine in 166 pediatric patients were reviewed. Systolic BP decreased by a mean of 17% and a maximum of 63%. Diastolic BP decreased by a mean of 28% and a maximum of 89%. Adverse events included: a) change in neurologic status, six cases; b) hypotension, two cases; c) oxygen desaturation, 16 cases. Neurologic events occurred in 33% of patients with acute CNS injury and 3.6% of all patients. Short-acting nifedipine is an important and effective oral antihypertensive agent which can be safely used for the treatment of hypertensive emergencies in children. It should be used with caution in children with acute CNS injury.

Calcineurin inhibitor minimization using sirolimus leads to improved renal function in pediatric heart transplant recipients.

Chinnock TJ, Shankel T, Deming D, Cutler D, Sahney S, Fitts J, Chinnock RE. Calcineurin inhibitor minimization using sirolimus leads to improved renal function in pediatric heart transplant recipients.
Pediatr Transplantation 2011: 15: 746–749.

BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient

Sahney S, Yorgin P, Zuppan C, Cutler D, Kambham N, Chinnock R. BK virus nephropathy in the native kidneys of a pediatric heart transplant recipient.
Pediatr Transplantation 2010:14:E11–E15.

Mycophenolate mofetil in pediatric renal transplantation: non-induction vs. induction with basiliximab.

Abstract:  North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) reports have shown anti‐T cell antibody, OKT3, to be deleterious in pediatric renal transplant recipients treated with mycophenolate mofetil (MMF). Unlike OKT3, basiliximab is a chimeric monoclonal antibody to the alpha subunit of the interleukin‐2 receptor on activated T‐lymphocytes. We sought to examine the outcome of MMF with or without basiliximab induction therapy in pediatric renal transplantation. Between January 1998, and June 2001, 49 pediatric renal transplants were performed at our center and 41 met the criteria for this study. We retrospectively analyzed the records of 25 patients who received MMF, Prednisone, CSA or TAC, alone (group I) and 16 patients who received MMF, CSA or TAC, and Prednisone in combination with basiliximab (group II). The two groups were similar with respect to recipient or donor age, gender, ethnicity, donor source (LD vs. CAD), cold ischemia time, and primary diagnosis. The basiliximab group had a shorter follow up period because of its more recent addition to our pediatric immunosuppression protocol, 12.9 ± 5.9 months vs. 35.5 ± 7.2 months for group I (p < 0.0001). At 6 months, the acute rejection rate was 16% (group I) compared with 25% (group II) (p = 0.689). The patient and graft survival at 6 and 12 months were 100% respectively for both groups. Basiliximab was well tolerated without significant adverse events. At 6 months, there was no significant difference between the groups in the incidence of urinary tract infection or cytomegalovirus infection. These data suggest that in the short‐term, MMF with or without basiliximab induction therapy appears to yield excellent and statistically similar outcomes. However, further controlled studies are necessary to verify these findings as well as to define the role of basiliximab in MMF‐treated pediatric renal transplant recipients.

Comparison of outcomes with low-dose anti-thymocyte globulin, basiliximab or no induction therapy in pediatric kidney transplant recipients: a retrospective study.

Abstract: It is unclear which induction therapy yields the best outcomes in pediatric kidney transplantation. Retrospective data of 88 children receiving a renal allograft between November 1996 and October 2003 were analyzed. Patients received ATGI (n = 12), BI (n = 29), or NAI (n = 47). The mean ATG dose was 5.1 ± 2.1 mg/kg. At 12 months, graft survival rates were 91.7%, 100%, and 97.9% for ATGI, BI, and NAI groups, respectively. Acute rejection rates at 12 months were 0 (ATGI), 20.6% (BI), and 10.7% (NAI). The mean GFR for ATGI (42.4 ± 25.9 mL/min) was lower than for BI (78.3 ± 27.2 mL/min), and NAI (66 ± 28.3 mL/min) at 12 months (p < 0.05). One ATGI patient developed CMV pneumonia but none developed post‐transplant lymphoproliferative disorder. Although there was no renal allograft survival benefit with either ATGI or BI, relative to NAI, the absence of acute rejection and equivalent rates of viral infections in the higher‐risk ATGI recipient group suggests that the treatment strategy is promising. A large prospective study is needed to better define the role of ATGI in pediatric kidney transplantation.

The impact of intercurrent EBV infection on ATP levels in CD4+ T cells of pediatric kidney transplant recipients

Abstract:  ImmuKnow® measures ATP (ng/mL) in PHA‐activated CD4+ T cells from patient’s whole blood. According to published reports, median ImmuKnow® is 258 ng/mL in stable pediatric kidney transplant (PKT) recipients ≥12 yr, and 165 ng/mL in those <12 yr. However, data on the effect of infection or AR on ImmuKnow® are scarce. We studied the effect of Epstein‐Barr virus (EBV) viremia on ImmuKnow® in PKT with GD. Twenty‐eight PKT with GD were reviewed. Group 1 has 19 PKT ≥12 yr, and group 2 has nine PKT <12 yr. Mean follow‐up was 19.4 ± 12 months. All ImmuKnow® values discussed in this study were measured during GD ± fever. None had ImmuKnow® pretransplant. EBV DNA was isolated from patient blood by real‐time PCR. Group 1 has eight boys and 11 girls (mean age = 16.6 ± 2.4 yr). Group 2 has two boys and seven girls (mean age = 6 ± 3.1 yr). Median ImmuKnow® was 292 ng/mL in group 1, and 370 ng/mL in group 2. Nine children developed EBV viremia: two in group1 (median ImmuKnow® = 273 ng/mL), and seven in group 2 (median ImmuKnow® = 475 ng/mL). Overall mean ImmuKnow® in the nine EBV viremic patients was higher than that in the 19 non‐viremic ones (422 ± 176 ng/mL, and 302 ± 113 ng/mL, respectively, unequal variance t‐test, p = 0.08). Eight children developed AR (all in G1, median ImmuKnow® = 272 ng/mL). In group 1, one patient developed concurrent EBV viremia and rejection, while another patient developed EBV viremia six months following a rejection episode. In group 2, none developed simultaneous AR, CMV, or BK virus infection with EBV viremia. None developed post‐transplant lymphoproliferative disease. In summary, EBV viremia was paradoxically associated with high ImmuKnow® in PKT <12 yr. This suggests strong co‐stimulation of PHA‐activated CD4+ T cells by EBV‐transformed B cells.