Publications by authors named "Michael Freundlich"

30 Publications

  • Page 1 of 1

Fibroblast growth factor 23-Klotho and hypertension: experimental and clinical mechanisms.

Pediatr Nephrol 2020 Nov 23. Epub 2020 Nov 23.

Department of Nephrology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.

Hypertension (HTN) and chronic kidney disease (CKD) are increasingly recognized in pediatric patients and represent risk factors for cardiovascular morbidity and mortality later in life. In CKD, enhanced tubular sodium reabsorption is a leading cause of HTN due to augmented extracellular fluid volume expansion. The renin-angiotensin-aldosterone system (RAAS) upregulates various tubular sodium cotransporters that are also targets of the hormone fibroblast growth factor 23 (FGF23) and its co-receptor Klotho. FGF23 inhibits the activation of 1,25-dihydroxyvitamin D that is a potent suppressor of renin biosynthesis. Here we review the complex interactions and disturbances of the FGF23-Klotho axis, vitamin D, and the RAAS relevant to blood pressure regulation and discuss the therapeutic strategies aimed at mitigating their pathophysiologic contributions to HTN.
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http://dx.doi.org/10.1007/s00467-020-04843-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682775PMC
November 2020

Soluble Klotho, a biomarker and therapeutic strategy to reduce bronchopulmonary dysplasia and pulmonary hypertension in preterm infants.

Sci Rep 2020 07 23;10(1):12368. Epub 2020 Jul 23.

Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, USA.

Preterm infants with bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH) have accelerated lung aging and poor long-term outcomes. Klotho is an antiaging protein that modulates oxidative stress, angiogenesis and fibrosis. Here we test the hypothesis that decreased cord Klotho levels in preterm infants predict increased BPD-PH risk and early Klotho supplementation prevents BPD-like phenotype and PH in rodents exposed to neonatal hyperoxia. In experiment 1, Klotho levels were measured in cord blood of preterm infants who were enrolled in a longitudinal cohort study. In experiment 2, using an experimental BPD-PH model, rat pups exposed to room air or hyperoxia (85% O) were randomly assigned to receive every other day injections of recombinant Klotho or placebo. The effect of Klotho on lung structure, PH and cardiac function was assessed. As compared to controls, preterm infants with BPD or BPD-PH had decreased cord Klotho levels. Early Klotho supplementation in neonatal hyperoxia-exposed rodents preserved lung alveolar and vascular structure, attenuated PH, reduced pulmonary vascular remodeling and improved cardiac function. Together, these findings have important implications as they suggest that perinatal Klotho deficiency contributes to BPD-PH risk and strategies that preserve Klotho levels, may improve long-term cardiopulmonary outcomes in preterm infants.
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http://dx.doi.org/10.1038/s41598-020-69296-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378054PMC
July 2020

Fibroblast growth factor 23 and tubular sodium handling in young patients with incipient chronic kidney disease.

Clin Kidney J 2020 Jun 3;13(3):389-396. Epub 2019 Jul 3.

Division of Pediatric Nephrology, Jackson Memorial-Holtz Children's Hospital, University of Miami, Miami, FL, USA.

Background: Experimental studies have shown fibroblast growth factor 23 FGF23)-mediated upregulation of the distal tubule sodium/chloride (NaCl) co-transporter leading to increased Na reabsorption, volume expansion and hypertension. However, data on the associations of FGF23 with renal Na regulation and blood pressure (BP) are lacking in young CKD patients.

Methods: FGF23 and other determinants of mineral metabolism, plasma renin activity (PRA), fractional excretion of Na (FENa) and BP, were analyzed at a single center in 60 patients aged 5-22 years with CKD Stages 1 ( = 33) and Stages 2-3 ( = 27) defined by cystatin C- and creatinine-based estimating equations (estimated glomerular filtration rate, eGFR). Associations between FGF23 and renal Na handling were explored by regression analysis.

Results: Median FGF23 levels were higher in CKD Stages 2-3 versus CKD 1 (119 versus 79 RU/mL; P < 0.05), with hyperparathyroidism [parathyroid hormone (PTH) >69 pg/mL] in only few subjects with CKD Stages 2-3. Median FENa was comparable in both subgroups, but with proportionally more values above the reference mean (0.55%) in CKD Stages 2-3 and 3-fold higher (1.6%) in CKD Stage 3. PRA was higher in CKD Stages 2-3 (P < 0.05). Meanwhile in CKD Stage 1, FGF23 did not associate with FENa, and in CKD Stages 2-3 FGF23 associated positively with FENa ( = 0.4; P < 0.05) and PTH ( = 0.45; P < 0.05), and FENa associated with FE of phosphate ( = 0.6; P < 0.005). Neither FGF23 nor FENa was associated with systolic or diastolic BP in either subgroup. The negative association of eGFR by cystatin with FENa remained the strongest predictor of FENa by multivariable linear regression in CKD Stages 2-3.

Conclusions: The elevated FGF23, FENa and PRA and the positive association of FGF23 with FENa do not suggest FGF23-mediated increased tubular Na reabsorption and volume expansion as causing hypertension in young patients with incipient CKD.
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http://dx.doi.org/10.1093/ckj/sfz081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367134PMC
June 2020

Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy.

Kidney Int 2020 06 28;97(6):1260-1274. Epub 2020 Feb 28.

National Renal Complement Therapeutics Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Complement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK. Electronic address:

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.
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http://dx.doi.org/10.1016/j.kint.2020.01.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242908PMC
June 2020

Effects of Klotho supplementation on hyperoxia-induced renal injury in a rodent model of postnatal nephrogenesis.

Pediatr Res 2020 10 14;88(4):565-570. Epub 2020 Feb 14.

Division of Neonatology, University of Miami Miller School of Medicine, Miami, FL, USA.

Background: Hyperoxia (HO) causes kidney injury in preterm infants; however, whether these effects are modifiable is unknown. We hypothesized that administration of exogenous soluble Klotho, a kidney-derived antioxidant, would attenuate HO-induced kidney injury during postnatal nephrogenesis in rats.

Methods: Sprague Dawley neonatal rats assigned to normoxia (21% O) or HO (85% O) groups from postnatal day (P) 1 to 21 were randomly assigned to receive alternate day intraperitoneal injections of recombinant Klotho or placebo for 3 weeks. They were recovered in normoxia for an additional 3 weeks and sacrificed at 6 weeks. Renal artery resistance and pulsatility indices, tubular injury scores, glomerular area, and renal antioxidant capacity were assessed.

Results: Rodents exposed to HO during postnatal nephrogenesis had reduced kidney Klotho expression, glomerulomegaly, and higher tubular injury scores. Exogenous Klotho administration improved renal perfusion as indicated by decreases in both resistance and pulsatility indices and increased antioxidant enzyme expression.

Conclusions: HO exposure during postnatal nephrogenesis in rodents results in a decline in kidney Klotho expression, decreased renal perfusion, enlarged glomerular size, and tubular injury. The exogenous administration of Klotho attenuated HO-induced kidney injury and augmented antioxidant capacity.
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http://dx.doi.org/10.1038/s41390-020-0803-zDOI Listing
October 2020

Educational review: role of the pediatric nephrologists in the work-up and management of kidney stones.

Pediatr Nephrol 2020 03 4;35(3):383-397. Epub 2019 Jan 4.

Department of Pediatrics, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, N6A 5W9, Canada.

Background: The incidence of nephrolithiasis in children and adolescents is increasing and appears to double every 10 years. The most important role of the pediatric nephrologist is to diagnose and modify various metabolic and non-metabolic risk factors, as well as prevent long-term complications especially in the case of recurrent nephrolithiasis.

Objective: The purpose of this review is to summarize the existing literature on the etiology and management of pediatric nephrolithiasis.

Results: The incidence of kidney stones is increasing; dietary and environmental factors are probably the main causes for this increased incidence. In most pediatric patients, the etiology for the kidney stones can be identified. Metabolic factors, such as hypercalciuria and hypocitraturia, urinary tract infection, and urinary stasis, constitute leading causes. Herein, we review the etiologies, diagnostic work-up, and treatment options for the most prevalent causes of kidney stones. The detrimental effects of excessive dietary sodium, reduced fluid intake, and the benefits of plant-based over animal-based protein consumption on urinary crystal formation are discussed. We also review the long-term complications.

Conclusions: Pediatric nephrologists have an important role in the diagnostic work-up and prevention of recurring nephrolithiasis.
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http://dx.doi.org/10.1007/s00467-018-4179-9DOI Listing
March 2020

Cardioprotective Effects of Paricalcitol Alone and in Combination With FGF23 Receptor Inhibition in Chronic Renal Failure: Experimental and Clinical Studies.

Am J Hypertens 2019 01;32(1):34-44

Division of Pediatric Nephrology, University of Miami Miller School of Medicine, Miami, Florida, USA.

Background: In uremic animals, vitamin D receptor (VDR) agonists like paricalcitol (Pc) attenuate cardiac hypertrophy, but this effect has not been replicated consistently in humans with chronic kidney disease. Elevated fibroblast growth factor 23 (FGF23) levels cause cardiac hypertrophy with activation of the myocardial calcineurin/nuclear factor of activated T cell (NFAT) axis and may antagonize the cardioprotective effects of VDR agonist therapy. We hypothesized that the effectiveness of Pc may depend on the prevailing circulating levels of FGF23 and could be potentiated by the combined administration of a pan-FGF23 receptor (FGFR) blocker agent (PD173074).

Methods: In rats with 5/6 nephrectomy treated with Pc or PD173074 or both agents concurrently, myocardial mRNA expression of renin-angiotensin system, VDR, FGFR4, and calcineurin/NFAT target genes was determined. In adolescents on hemodialysis, we analyzed sequential echocardiograms, blood pressures and serial FGF23 measurements, and their relations to the cumulative administered dose of parenteral Pc.

Results: The ratio of Pc dose/plasma levels of FGF23 correlated inversely (P < 0.005) with the cardiac mass in uremic rats and in hemodialysis patients, independently of hypertension. Despite persistently elevated FGF23 levels and myocardial FGFR4 activation, Pc suppressed upregulated myocardial calcineurin/NFAT target genes, and the effects were amplified by coadministration of PD173074.

Conclusions: The beneficial effects of Pc on uremic cardiac hypertrophy are counterbalanced by the increased FGF23 levels. Blockade of FGF23-mediated signaling increased the Pc-induced suppression of the myocardial calcineurin/NFAT system. Higher doses of Pc should be considered in the treatment of patients with uremic cardiomyopathy.
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http://dx.doi.org/10.1093/ajh/hpy154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284753PMC
January 2019

Cinacalcet as rescue therapy for refractory hyperparathyroidism in young children with advanced chronic kidney disease.

Pediatr Nephrol 2019 01 10;34(1):129-135. Epub 2018 Sep 10.

Division of Pediatric Nephrology, Holtz Children's Hospital, University of Miami, P.O. Box 016960, Miami, FL, 33130, USA.

Background: Studies in the use of the calcimimetic, cinacalcet, in pediatric chronic kidney disease (CKD) are few and limited to older children with secondary hyperparathyroidism (sHPT), a major morbid complication contributing to poor growth, bone deformities, and cardiovascular disease. Our objectives were to determine a safe and effective dosing regimen of cinacalcet in the treatment of infants and young children with sHPT that was refractory to standard care and to examine their growth during treatment.

Methods: Ten young pediatric patients with advanced CKD were studied retrospectively during 11 courses of treatment with cinacalcet. All had severe sHPT with intact parathyroid hormone (iPTH) levels ≥ 500 pg/ml and were refractory to standard therapy with phosphate binders and active vitamin D analogs at high doses for > 30 days. The cinacalcet dose was advanced by 50% every 2-4 weeks to achieve a decline in the iPTH to a goal of 150-300 pg/ml. Linear growth was assessed at 6-month intervals by change in z-scores (△SDS) for length before and during cinacalcet therapy.

Results: Median age at initiation of cinacalcet was 18 months (IQR 6, 36) with an average starting dose of 0.7 ± 0.2 mg/kg/day. Median effective dose required to reach iPTH goal of 150-300 pg/ml was 2.8 mg/kg/day (IQR 2.0, 3.1), and time to goal was 112 days (IQR 56, 259) with a median overall decline in iPTH of 82% from baseline by 6 months (p < 0.0001). No subject experienced a clinical adverse event, although 4 had biochemical asymptomatic hypocalcemia. Linear growth improved significantly during cinacalcet therapy (△SDS - 0.62 ± 1.2 versus + 0.91 ± 1.4; p < 0.005). By multiple regression analysis, the primary determinants of growth were concurrent treatment with growth hormone and age < 2 years (R = 89.6%; p < 0.001). A shorter treatment time required to achieve iPTH goals also was associated with improved growth (r = - 0.75; p < 0.01).

Conclusions: Cinacalcet may be used effectively and safely in infants and small children with refractory sHPT in advanced CKD using a cautious dosing regimen. Cinacalcet successfully brings iPTH to target level and supports growth when other treatments have been ineffective.
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http://dx.doi.org/10.1007/s00467-018-4055-7DOI Listing
January 2019

Oral paricalcitol: expanding therapeutic options for pediatric chronic kidney disease patients.

Pediatr Nephrol 2017 07 27;32(7):1103-1108. Epub 2017 Apr 27.

Division of Pediatric Nephrology, University of Miami Miller School of Medicine, P.O. Box 016960 (M714), Miami, FL, 33101, USA.

The complex pathophysiology of progressive chronic kidney disease (CKD) and the development of mineral and bone disorder, abbreviated as CKD-MBD, is of vital importance to a pediatric patient. Paricalcitol, the 19 nor-1,25(OH)D analogue was shown to be effective and safe in the treatment of secondary hyperparathyroidism (SHPT) in adults almost two decades ago. It also significantly improved survival in dialysis patients compared to the standard calcitriol. The successful treatment of CKD-MBD in children is essential if they are to grow and survive into adulthood. It can be argued that it is more important for children with CKD than adults since they have early and prolonged disease risk exposure. In this issue of Pediatric Nephrology, Webb et.al. report a dual trial of the safety, efficacy, and pharmacokinetics of paricalcitol in children aged 10-16 years with moderate but significant efficacy in meeting the endpoint of >30% decrease in parathyroid hormone (PTH) levels from baseline with minimal adverse events. Much more research needs to be done to expand and develop clinical pharmaceutical trials in the use of paricalcitol in children, especially in the younger age categories. This current study has done much to open the doors for future studies, with the caveat that it has been long coming and much more needs to be done to compensate for this delay in the treatment of children with CKD-MBD and cardiovascular and renal disease progression.
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http://dx.doi.org/10.1007/s00467-017-3675-7DOI Listing
July 2017

Fibroblast growth factor-23 and renin-angiotensin system levels in vitamin-D-dependent rickets type I.

Pediatr Nephrol 2016 07 3;31(7):1189-93. Epub 2016 Mar 3.

Division of Pediatric Nephrology, University of Miami Miller School of Medicine, PO Box 016960(M-714), Miami, FL, 33101, USA.

Background: As 1,25(OH)2D3 vitamin D3 induces fibroblast growth factor-23 (FGF-23) production and suppresses the renin-angiotensin-aldosterone system (RAAS), its absence in vitamin-D-dependent rickets type I (VDDR-I) may have adverse health consequences.

Case Description: An infant presented at age 8 months with hypocalcemia and rickets and very low 1,25(OH)2D3 levels. Genetic analysis confirmed VDRR-I, and calcitriol therapy was initiated. During periods of nonadherence to therapy, chemical measurements revealed detectable FGF-23 levels, with undetectable 1,25(OH)2D3, hypophosphatemia, low tubular reabsorption of phosphate, hypocalcemia, and very elevated parathyroid hormone (PTH) levels. These changes, in addition to elevated RAAS levels, normalized during calcitriol therapy despite elevated FGF-23 levels. At age 12 years, all rachitic manifestations were absent, and bone mineral density (BMD) and the echocardiogram were normal.

Conclusions: Whereas 1,25(OH)2D3 is not indispensable for FGF-23 production, PTH in the absence of vitamin D may maintain FGF-23 secretion despite hypocalcemia. Normalization of urinary phosphate losses despite elevated FGF-23 during calcitriol-mediated suppression of secondary hyperparathyroidism points to a cardinal role of PTH as a cause of the phosphaturia in VDRR-I. Normalization of RAAS by calcitriol may conceivably prevent adverse cardiovascular outcomes.
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http://dx.doi.org/10.1007/s00467-016-3356-yDOI Listing
July 2016

Longitudinal FGF23 and Klotho axis characterization in children treated with chronic peritoneal dialysis.

Clin Kidney J 2014 Oct 8;7(5):457-63. Epub 2014 Aug 8.

Department of Pediatric Endocrinology , Molecular Physiology Laboratory, Faculty of Medicine, Los Andes University , Santiago , Chile.

Background: Fibroblast Growth Factor-23 (FGF23) and cofactor Klotho are key regulators of mineral metabolism in chronic kidney disease (CKD), but little is known about the mechanisms that regulate their production. This study evaluates longitudinal changes of FGF23 and Klotho levels and their regulatory factors in children on chronic peritoneal dialysis (PD).

Methods: FGF23, Klotho, 25(OH) vitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone (PTH) plasma concentrations were measured during 1 year of follow-up in PD children. Anthropometric and dialytical parameters were evaluated in addition to mineral metabolism variables.

Results: Thirty-one patients under chronic PD were followed for 12 months. FGF23 mean plasma levels at Month 1 were significantly increased compared with controls, 215.1 ± 303.6 versus 9.4 ± 5.7 pg/mL, respectively (P < 0.001). Baseline Klotho levels were 41% lower in patients compared with controls, 132.1 ± 58 versus 320 ± 119.4 pg/mL, respectively (P < 0.001), and did not correlate with FGF23 and phosphorus levels. At Month 12, FGF23 (195 ± 300 pg/mL) and Klotho levels (130 ± 34 pg/mL) remained similar to baseline values. Log-FGF23 correlated significantly with height/age Z score (r= -0.38) and residual renal function (r = -0.44), but no correlation was found with serum phosphorus, phosphate intake, PTH and vitamin D levels. The log-FGF23 strongly correlated with calcium levels at Months 1, 6 and 12, however, this relationship was blunted if serum phosphorus was >6 mg/dL. By multiple regression analysis, calcium was the strongest variable determining FGF23 levels.

Conclusions: In this longitudinal study, FGF23 levels are markedly increased, and Klotho levels are reduced in PD children compared with controls. FGF23 levels appeared to be regulated primarily by serum calcium, showing a significant correlation at each time of measurement. This relationship was lost in patients with phosphorus >6 mg/dL. These observations may have important consequences to the therapeutic management of phosphate homeostasis in CKD patients.
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http://dx.doi.org/10.1093/ckj/sfu074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4379333PMC
October 2014

Capillary rarefaction: an early marker of microvascular disease in young hemodialysis patients.

Clin Kidney J 2014 Dec 20;7(6):569-74. Epub 2014 Oct 20.

Division of Pediatric Nephrology , University of Miami/Holtz Children's Hospital , Miami, FL , USA.

Background: Pediatric patients with chronic kidney disease (CKD) are at increased risk of early cardiovascular disease and premature death. Abnormalities in microvascular structure and function may presage end-organ damage including vascular calcification and myocardial ischemia associated with disordered mineral metabolism. Early detection of microvascular rarefaction (reduced density of capillaries) may identify at-risk patients and prompt timely therapeutic interventions. Our objective was to study capillary rarefaction in pediatric hemodialysis (HD) patients and to determine possible associations with mineral metabolism and cardiac risk biomarkers.

Methods: Capillary density (CD) was measured by nailfold capillaroscopy in 19 pediatric HD patients and 20 healthy controls. Demographic and biochemical markers were collected at entry and 6-month follow-up.

Results: CD was significantly decreased in HD patients compared with controls with a deficit of 24 and 31% at baseline and subsequent follow-up. Maximal CD correlated significantly with intact parathyroid hormone (iPTH) (r = -0.45; P = 0.005), serum calcium (r = -0.38; P = 0.02) and 25(OH) vitamin D levels (r = +0.36; P = 0.03) in HD patients. Capillary functional measures were similar to controls. By multivariate analysis, the primary negative determinants of CD were African American race and hyperparathyroidism; whereas, glomerular disease had a positive influence on capillary rarefaction (R (2) = 64.2% variance; P = 0.001).

Conclusion: Pediatric HD patients demonstrate a 'structural deficit' in CD but show preserved 'functional integrity'. Capillary rarefaction, an early risk factor of incipient vascular calcification, was strongly associated with biomarkers of altered mineral metabolism. Further studies are warranted to determine the impact of optimizing blood pressure and metabolic control on changes in capillary rarefaction in young CKD patients.
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http://dx.doi.org/10.1093/ckj/sfu106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389142PMC
December 2014

Abnormalities in renal tubular phosphate handling in children with sickle cell disease.

Pediatr Blood Cancer 2014 Dec 17;61(12):2267-70. Epub 2014 Aug 17.

Division of Pediatric Nephrology, University of Miami, Miami, Florida.

Background: The mechanisms responsible for the hyperphosphatemia in patients with sickle cell disease (SCD) and preserved glomerular filtration rate (GFR) are not fully understood. The role of fibroblast growth factor 23 (FGF23), a phosphaturic hormone has not been investigated in SCD. Hence, we evaluated parameters of renal tubular phosphorus handling and their relation to prevailing FGF23 levels in a cohort of young SCD patients.

Methods: Renal tubular phosphate handling and circulating levels of various analytes including FGF23 and parathyroid hormone (PTH) were measured in 24 children with SCD and normal estimated GFR in a cross sectional study. Correlation and regression analysis were employed to derive relationships between serum phosphorus and several variables.

Results: Most children showed elevated age- adjusted serum phosphorus (5.1 ± 0.7 mg/dl) levels. Tubular re-absorption of phosphorus(TRP) (96.3 ± 2.1%) and tubular maximum re-absorption of phosphorus per unit volume of GFR (TMP/GFR) (4.9 ± 0.6 mg/dl) were both elevated. Plasma intact FGF23 concentrations were elevated (81 ± 38 pg/ml) while the average PTH values were normal in most patients (50 ± 27 pg/ml). Univariate analysis showed significant correlations of serum phosphorus with TMP/GFR, alkaline phosphatase, age, lactate dehydrogenase (LDH), and log intact FGF23. TMP/GFR correlated with log intact FGF23 (r = 0.5, P< or = 0.01) but not with PTH. Multiple regression analysis yielded an independent relationship of serum phosphorus with TMP/GFR.

Conclusion: The elevated serum phosphorus concentrations with simultaneously increased TMP/GFR and elevated FGF23 levels collectively suggest that patients with SCD display proximal tubular resistance to the action of FGF23 before any decline in GFR.
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http://dx.doi.org/10.1002/pbc.25188DOI Listing
December 2014

Forty-four-hour interdialytic ambulatory blood pressure monitoring and cardiovascular risk in pediatric hemodialysis patients.

Clin Kidney J 2014 Feb 23;7(1):33-9. Epub 2013 Dec 23.

Division of Pediatric Nephrology, Department of Pediatrics , University of Miami , Miami, FL , USA.

Background: Children undergoing chronic hemodialysis are at risk of cardiovascular disease and often develop left ventricular hypertrophy (LVH). Twenty-four-hour ambulatory blood pressure monitoring (ABPM) is known to better predict cardiovascular morbidity than casual blood pressure (BP) measurement. Given the BP variability attributed to interdialytic fluid overload, 44-h ABPM should better delineate cardiovascular morbidity in pediatric hemodialysis patients.

Methods: In this cross-sectional study, 17 children (16.7 ± 2.9 years) on chronic hemodialysis underwent 44-h interdialytic ABPM and routine echocardiogram. Left ventricular mass index (LVMI) was calculated by height-based equation; LVH was defined as an LVMI in the ≥95th percentile for height-age and gender. Hypertension was defined by the recommendations of the Fourth Report of the National High Blood Pressure Education Program for casual measurements, and by those of the American Heart Association for ABPM.

Results: Twenty-four percentage of patients were hypertensive by casual post-dialytic systolic BP, whereas 59% were hypertensive by ABPM. Eighty-eight percentage of patients had abnormal cardiac geometry: 53% had LVH. Thirty-five percentage (6 of 17) had masked hypertension, including four with abnormal cardiac geometry, of which, three had LVH. LVMI correlated with ABPM, but not with casual measurements. Strongest correlations with an increased LVMI were with 44-h diastolic BP: at night (r = 0.53, P = 0.03) and total load (r = 0.57, P = 0.02). LVH was similarly associated with 44-h nighttime BP: systolic (P = 0.02), diastolic (P = 0.01) and mean arterial (P = 0.01).

Conclusions: Casual BP measurement underestimates hypertension in pediatric hemodialysis patients and does not correlate well with indicators of cardiovascular morbidity. In contrast, 44-h interdialytic ABPM better characterizes hypertension, with nighttime parameters most strongly predicting increased LVMI and LVH.
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http://dx.doi.org/10.1093/ckj/sft149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4389162PMC
February 2014

Pediatric cardiomyopathies: causes, epidemiology, clinical course, preventive strategies and therapies.

Future Cardiol 2013 Nov;9(6):817-48

Department of Pediatrics, University of Miami Miller School of Medicine, 1601 NW 12th Avenue, 9th Floor, Miami, FL 33136, USA.

Pediatric cardiomyopathies, which are rare but serious disorders of the muscles of the heart, affect at least one in every 100,000 children in the USA. Approximately 40% of children with symptomatic cardiomyopathy undergo heart transplantation or die from cardiac complications within 2 years. However, a significant number of children suffering from cardiomyopathy are surviving into adulthood, making it an important chronic illness for both pediatric and adult clinicians to understand. The natural history, risk factors, prevalence and incidence of this pediatric condition were not fully understood before the 1990s. Questions regarding optimal diagnostic, prognostic and treatment methods remain. Children require long-term follow-up into adulthood in order to identify the factors associated with best clinical practice including diagnostic approaches, as well as optimal treatment approaches. In this article, we comprehensively review current research on various presentations of this disease, along with current knowledge about their causes, treatments and clinical outcomes.
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http://dx.doi.org/10.2217/fca.13.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903430PMC
November 2013

Paricalcitol downregulates myocardial renin-angiotensin and fibroblast growth factor expression and attenuates cardiac hypertrophy in uremic rats.

Am J Hypertens 2014 May 26;27(5):720-6. Epub 2013 Sep 26.

Department of Pediatrics, Division of Pediatric Nephrology, University of Miami Miller School of Medicine, Miami, Florida.

Background: Vitamin D attenuates uremic cardiac hypertrophy, possibly by suppressing the myocardial renin-angiotensin system (RAS) and fibroblast growth factors (FGFs). We compared the suppression of cardiac hypertrophy and myocardial expression of RAS and FGF receptor genes offered by the vitamin D analog paricalcitol (Pc) or the angiotensin-converting enzyme inhibitor enalapril (E) in experimental uremia.

Methods: Rats with 5/6 nephrectomy received Pc or E for 8 weeks. Renal function, systolic blood pressure, and cardiac hypertrophy were evaluated. Myocardial expression of RAS genes, brain natriuretic peptide (BNP), and FGF receptor-1 (FGFR-1) were determined using quantitative reverse-transcription (pRT)-PCR.

Results: Blood pressure, proteinuria, and serum creatinine were significantly higher in untreated uremic animals. Hypertension was significantly reduced by E but only modestly by Pc; however, cardiac hypertrophy in the untreated group was similarly attenuated by Pc or E. Upregulation of myocardial expressions of renin, angiotensinogen, FGFR-1, and BNP in untreated uremic animals was reduced similarly by Pc and E, while the angiotensin II type 1 receptor was downregulated only by E.

Conclusions: Uremic cardiac hypertrophy is associated with activation of the myocardial RAS and the FGFR-1. Downregulation of these genes induced by Pc and E results in similar amelioration of left ventricular hypertrophy despite the different antihypertensive effects of these drugs.
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http://dx.doi.org/10.1093/ajh/hpt177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3978945PMC
May 2014

Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis.

Pediatr Nephrol 2012 Nov 19;27(11):2129-2136. Epub 2012 Jun 19.

Division of Pediatric Nephrology, University of Miami Miller School of Medicine, PO Box 016960 (M-714), Miami, FL, 33101, USA.

Background: Elevated fibroblast growth factor 23 (FGF-23) concentrations associate with left ventricular hypertrophy (LVH) and adverse outcomes in adult patients with chronic kidney disease. We hypothesized that similar associations are present in pediatric patients on maintenance hemodialysis.

Methods: In this retrospective study of 26 young patients on chronic hemodialysis, aged 6-21 years, cardiac structure and geometry were measured by echocardiography, and circulating levels of FGF-23 and calciotropic hormones were obtained.

Results: FGF-23 levels were uniformly elevated in all patients from three- to 835-fold above the upper limit of normal. The average LV mass index (LVMI) was 43 ± 13 g/m(2.7) and reflected LVH in 55 % of patients. Log-transformed FGF-23 concentrations correlated with LVMI (p = 0.03) and were independently associated with the interventricular septal thickness Z-score (p < 0.001). Concentric LVH was associated with the highest FGF-23 concentrations and the highest LVMI measurements (p < 0.001). Each 1 standard deviation increase in log-transformed FGF-23 levels was associated with a 17 % increase in LVMI.

Conclusions: FGF-23 levels are strongly associated with increased LVMI and with prevalent LVH in pediatric hemodialysis patients. Our cross-sectional findings provide observational evidence supporting the hypothesis linking FGF-23 to cardiac hypertrophy in patients with chronic kidney disease.
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http://dx.doi.org/10.1007/s00467-012-2224-7DOI Listing
November 2012

Three decades of progress in treating childhood-onset lupus nephritis.

Clin J Am Soc Nephrol 2011 Sep 28;6(9):2192-9. Epub 2011 Jul 28.

Division of Pediatric Nephrology, University of Miami/Holtz Children's Hospital, Miami, FL 33101, USA.

Background And Objectives: Childhood-onset lupus nephritis (LN) carries a worse renal prognosis compared with adults. Controlled treatment trials in children are lacking. We compared renal and patient survival in a cohort of pediatric patients followed over 3 decades.

Design, Settings, Participants, & Measurements: A retrospective analysis was conducted on 138 patients with childhood-onset systemic lupus erythematosus from 1980 to 2010. The core cohort included 95 with severe LN: 28 progressed to end-stage renal disease (ESRD group) whereas 67 did not (no-ESRD group). Patients were stratified into four "eras" according to the introduction of the primary immuno-suppressive drug: era 1: triple oral therapy with corticosteroids (CS), cyclophosphamide (CYC), and azathioprine (AZA); era 2: intravenous CYC; era 3: mycophenolate mofetil (MMF) ± CYC; era 4: rituximab (RTX) ± CYC ± MMF.

Results: Mean age at diagnosis was 12.3 ± 2.9 years with median follow-up of 5 years. Poor renal function (estimated GFR < 60 ml/min per 1.73 m(2)) and nephrotic proteinuria at diagnosis imparted a poor prognosis. Increasing proteinuria correlated with progression of kidney disease. The addition of MMF in era 3 improved 5-year renal survival from 52% to 91% and overall patient survival from 83% to 97%. African-American ethnicity was associated with significant risk for progression to ESRD whereas Hispanic ethnicity conferred an advantage. Infection and cardiovascular disease were the primary causes of patient demise.

Conclusions: Renal and patient survival in childhood-onset LN has improved during the past 3 decades with progressive treatment regimens. Future trials in children are very much warranted.
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http://dx.doi.org/10.2215/CJN.00910111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359002PMC
September 2011

Long-term risk of chronic kidney disease in unilateral multicystic dysplastic kidney.

Pediatr Nephrol 2011 Apr 15;26(4):597-603. Epub 2011 Jan 15.

Division of Pediatric Nephrology, Holtz Children's Hospital, Department of Pediatrics, University of Miami Miller School of Medicine, PO Box 016960 (M-714), Miami, FL 33101, USA,

The clinical spectrum of renal dysplasia includes the non-functioning multicystic dysplastic kidney (MCDK). We report our experience of the outcome of unilateral MCDK and its contralateral kidney in 101 children with the diagnosis of MCDK from 1985 to 2009. Data collected included urine protein/creatinine ratio, estimated GFR (eGFR), blood pressure, surgical intervention, renal length and abnormalities of the contralateral kidney, and the involution rate. There was a predominance of left-sided MCDK. Diagnosis was made prenatally in 86.7%. Contralateral abnormalities included vesicoureteral reflux (16.8%), UPJ obstruction (4.1%), and megaureter (2.4%). Complete involution of MCDK occurred within 5 years in 60%. Compensatory hypertrophy of the contralateral kidney to >97% occurred in 74.1%. Nephrectomy was performed in 19.8%. There was an increased risk of chronic kidney disease (CKD) stage ≥ 2, and hypertension in those with contralateral abnormalities (p<0.0001; p<0.001 respectively). In those without contralateral abnormalities, hyperfiltration with mean eGFR of 149 ± 13 ml/min/1.73 m(2) was seen in 32% and proteinuria in 9.8%. There was a significantly inverse relationship between proteinuria and eGFR (p<0.0001). In conclusion, children with contralateral abnormalities are at risk for developing decreased kidney function, whereas a substantial number of patients with no obvious contralateral abnormalities have markers of renal injury. Therefore, systematic follow-up of all patients is recommended.
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http://dx.doi.org/10.1007/s00467-010-1746-0DOI Listing
April 2011

Two decades of pediatric kidney transplantation in a multi-ethnic cohort.

Pediatr Transplant 2010 Aug 31;14(5):667-74. Epub 2010 May 31.

Division of Pediatric Nephrology, Department of Pediatrics, Holtz Children's Hospital, Miami, FL 33101, USA.

This study evaluated a 20-yr experience in kidney transplantation in children from a predominantly Hispanic community. A retrospective analysis was carried out in children who received kidney transplants from 1985 to 2005. Of 124 kidney transplants, 81 (65%) were from LD. Racial distribution was Hispanic (48%), followed by AA (24%) and Caucasian (26%). First yr allograft survival was similar in LD and DD and significantly better in LD until seven yr post transplant. eGFR <60 mL/min/1.73 m(2) at one yr post transplant was associated with a median allograft survival of 3.3 yr, compared to 16 yr in those with eGFR > or = 60 mL/min/1.73 m(2) (p < 0.0001). Graft loss in the first five yr was from non-adherence, recurrence of disease, and infections. Those of AA race were more likely to receive a DD and have low socioeconomic status and the poorest median allograft survival compared to Hispanics and Caucasians (6 vs. > or =15 yr; p < 0.001). In conclusion, this predominantly Hispanic cohort emphasizes the disadvantaged profile of AAs compared to other racial groups. Strategies to improve supportive services and living donations in minority populations need to be developed. Long-term renal allograft survival is achievable if GFR is maintained >60 mL/min/1.73 m(2).
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http://dx.doi.org/10.1111/j.1399-3046.2010.01323.xDOI Listing
August 2010

Twenty-five years of infant dialysis: a single center experience.

J Pediatr 2009 Jul 25;155(1):111-7. Epub 2009 Mar 25.

Division of Pediatric Nephrology, University of Miami/Holtz Children's Hospital, Miami, FL, USA.

Objective: To perform a retrospective analysis of the long-term outcome of infants with end-stage kidney disease (ESKD) treated at our center during the past 25 years.

Study Design: The total cohort (n = 52) was divided into era 1 (1983-1995; n = 23) and era 2 (1996-2008; n = 29). Dialysis morbidity, transplantation, and long-term survival rates were assessed and compared between the 2 eras.

Results: Average age at initiation of dialysis was 4.4 +/- 5.3 months (range, 0.5-18 months), with 96% begun on peritoneal dialysis. The predominant diagnoses were dysplasia/obstructive uropathy and autosomal recessive polycystic kidney disease. The overall survival rate is 46%, with current age of survivors ranging from 1.5 to 25 years. Mortality rates in the 2 eras were not significantly different. The predominant mortality occurred within the first year. Twenty-four patients received an initial renal transplant at 2.6 +/- 1.7 years of age. Six patients (25%) required a second renal allograft. Increased risk for mortality included African-American ethnicity, oligoanuria, autosomal recessive polycystic kidney disease, and co-morbid diagnoses.

Conclusions: Long-term survival is possible in infants with ESKD, although mortality and morbidity remain high. Technical innovations are needed to accommodate smaller infants undergoing dialysis. Early initiation of dialysis treatment is preferable because prognostic indicators remain poorly defined.
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http://dx.doi.org/10.1016/j.jpeds.2009.01.007DOI Listing
July 2009

Vitamin D insufficiency and deficiency in children with early chronic kidney disease.

J Pediatr 2009 Jun 23;154(6):906-11.e1. Epub 2009 Feb 23.

Department of Pediatrics, Division of Pediatric Nephrology and Holtz Children's Hospital, Miller School of Medicine, University of Miami, Miami, FL 33101, USA.

Objective: To assess the prevalence of abnormal vitamin D status in children and adolescents with chronic kidney disease (CKD).

Study Design: This was an outpatient cross-sectional, retrospective study of 258 patients, mean age 12.3 +/- 5.2 years, with an average estimated glomerular filtration rate (eGFR) of 106 +/- 51 mL/min/1.73 m2 (range, 0 to 220 mL/min/1.73 m2). Serum 25-hydroxy-vitamin D [25(OH)D], calcium, phosphorus, and parathyroid hormone levels, as well as selected anthropometric variables, were analyzed.

Results: Reduced 25(OH)D concentrations (< 30 ng/mL) were found in 60% of the patients. In 28%, the concentration was < 20 ng/mL, indicating vitamin D deficiency. Patients with more advanced CKD were more likely to have vitamin D deficiency compared with those with incipient CKD or normal GFR (42% vs 26%; P = .03) and displayed more prominent hyperparathyroidism. Suboptimal vitamin D status was similar in males and females, but was significantly more prevalent in older (P < .01), non-Caucasian (P < .01), and overweight (P = .02) patients. Patients with early-stage CKD (eGFR > 60 mL/min/1.73 m2) and with vitamin D deficiency were significantly shorter than their counterparts with 25(OH)D levels > 20 ng/mL (P = .02).

Conclusions: Vitamin D insufficiency and deficiency are very prevalent in pediatric patients across all stages of CKD, particularly in non-Caucasian and obese patients, and may contribute to growth deficits during the earliest stages of CKD.
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http://dx.doi.org/10.1016/j.jpeds.2008.12.006DOI Listing
June 2009

Obesity and preterm birth: additive risks in the progression of kidney disease in children.

Pediatr Nephrol 2009 Jul 12;24(7):1363-70. Epub 2009 Feb 12.

Division of Pediatric Nephrology (M714), University of Miami/Holtz Children's Hospital, 1611 NW 12th Avenue, Annex 5, Miami, FL 33126, USA.

Preterm birth is associated with decreased nephron mass and obesity that may impact on kidney disease progression in later life. Our objectives were to examine the relative risks of obesity and preterm birth on the progression of kidney disease in children. In a retrospective cohort study, 80 (44 obese and 36 non-obese) patients with proteinuric kidney disease were studied for disease progression and glomerular histomorphometry. Of the obese, 22 had been born at term (Obese-T) and 22 had been preterm (Obese-PT). Seventeen non-obese children with focal glomerular sclerosis, born at term (NO-FSGS), and 19 non-obese preterm (NO-PT) children, served as controls. Insulin resistance as measured by the homeostatic model assessment (HOMA-IR) was elevated in all obese children. Obese-PT patients had increased risk of renal demise during childhood when compared with Obese-T children [hazard ratio 2.4; 95% Confidence interval (95% CI) 1.1 to 7.1; P = 0.04]. In obese children, although proteinuria often exceeded nephrotic range, average levels of serum albumin remained normal. Preterm patients were more likely to have reduced renal mass (odds ratio 4.7; P = 0.006), but obesity was not a factor. Renal histomorphometry showed glomerulomegaly in obese patients, regardless of birth weight. Obesity and preterm birth appear to impose additive risks for progression of kidney disease in childhood.
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http://dx.doi.org/10.1007/s00467-009-1120-2DOI Listing
July 2009

Suppression of renin-angiotensin gene expression in the kidney by paricalcitol.

Kidney Int 2008 Dec 27;74(11):1394-402. Epub 2008 Aug 27.

Division of Pediatric Nephrology, Department of Pediatrics, University of Miami, Miami, Florida 33101, USA.

The renal renin-angiotensin system plays a major role in determining the rate of chronic renal disease progression. Treatment with activators of the vitamin D receptor retards the progression of experimental chronic renal disease, and vitamin D is known to suppress the renin-angiotensin system in other organs. Here we determined if the beneficial effects of paricalcitol (19-nor 1,25-dihydroxyvitamin D(2)) were associated with suppression of renin-angiotensin gene expression in the kidney. Rats with the remnant kidney model of chronic renal failure (5/6 nephrectomy) were given two different doses of paricalcitol thrice weekly for 8 weeks. Paricalcitol was found to decrease angiotensinogen, renin, renin receptor, and vascular endothelial growth factor mRNA levels in the remnant kidney by 30-50 percent compared to untreated animals. Similarly, the protein expression of renin, renin receptor, the angiotensin type 1 receptor, and vascular endothelial growth factor were all significantly decreased. Glomerular and tubulointerstitial damage, hypertension, proteinuria, and the deterioration of renal function resulting from renal ablation were all similarly and significantly improved with both treatment doses. These studies suggest that the beneficial effects of vitamin D receptor activators in experimental chronic renal failure are due, at least in part, to down-regulation of the renal renin-angiotensin system.
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http://dx.doi.org/10.1038/ki.2008.408DOI Listing
December 2008

Bisphosphonates in children with hypercalciuria and reduced bone mineral density.

Pediatr Nephrol 2008 Dec 13;23(12):2215-20. Epub 2008 Aug 13.

Pediatric Nephrology, University of Miami, Miami, FL, USA.

Previous studies have demonstrated reduced bone mineral density (BMD) and biochemical changes of excessive bone resorption in some patients with idiopathic hypercalciuria (IH). Consequently, bisphosphonates have been successfully employed in research animals and adults with IH and reduced BMD. We evaluated the effect of treatment with bisphosphonates in seven patients ages 10-16 years with persistent IH and reduced BMD. In five children, preceding traditional therapy failed. All children received oral alendronate and one also IV Zoledronic acid for 6-18 (median 9.0, mean 10.7) months. With treatment, BMD Z scores in the lumbar spine improved from -2.0 +/- 0.3 to -0.8 +/- 0.8 (p = 0.002) and in the femoral neck from -1.8 +/- 0.4 to -0.7 +/- 0.9 (p = 0.01); urine N-telopeptides/creatinine decreased from 372 +/- 289 to 72 +/- 39 nmol/mmol (p = 0.05) and calcium/creatinine from 0.29 +/- 0.12 to 0.13 +/- 0.06 mg/mg (p = 0.009). Height Z scores, normal at baseline in all, remained unaffected, and no new stones or fractures were documented throughout the treatment period. Serum creatinine, electrolytes, calcium, phosphorus and parathyroid hormone remained normal as well. In summary, in children with IH and decreased BMD, treatment with bisphosphonates normalized urine calcium excretion, eliminated urinary symptoms, and significantly improved reduced BMD. These short-term beneficial effects indicate the need for larger prospective studies on the potential of bisphosphonates to serve as a new tool in treating children with IH and reduced BMD.
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http://dx.doi.org/10.1007/s00467-008-0940-9DOI Listing
December 2008

Bone mineral content and mineral metabolism during cyclosporine treatment of nephrotic Syndrome.

J Pediatr 2006 Sep;149(3):383-9

Department of Pediatrics, University of Miami, Miami, Florida, USA.

Objective: Although cyclosporine (Cy) has been associated with bone loss following transplantation, its effects on bone in growing children are largely unknown.

Study Design: Thirty-seven patients (2-16 years of age) with remitting nephrotic syndrome (NS), n = 16 receiving Cy for 39 +/- 27 months and n = 21 without Cy, underwent mineral metabolism and bone turnover assessment. In 28 of 37 patients, bone mineral density (BMD) was obtained while off corticosteroid therapy (Rx).

Results: Urinary calcium (Ca), phosphate (PO(4)), and magnesium (Mg) excretion was normal, but serum Mg was lower in patients receiving Cy (1.8 +/- 0.1 v 1.95 +/- 0.2 mg/dL, P < .05). BMD Z scores were similar at the spine (-0.45 +/- 0.74 v 0.04 +/- 0.9) and femur (-0.17 +/- 0.52 v 0.38 +/- 1.28) with no Z score <-2. Serum bone-specific alkaline phosphatase was normal, and N-telopeptide of type I collagen also normal, was higher on Cy (P < .05). Cumulative prednisone exposure was similar and had no significant effect on height and BMD Z scores. Length of Cy-Rx and time elapsed from onset of NS did not correlate with BMD, height Z score, or markers of bone turnover.

Conclusions: In growing children with NS, during long-term Cy-Rx urinary wasting of Ca and Mg was absent and bone density was preserved.
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http://dx.doi.org/10.1016/j.jpeds.2006.04.060DOI Listing
September 2006

Increased osteoblastic activity and expression of receptor activator of NF-kappaB ligand in nonuremic nephrotic syndrome.

J Am Soc Nephrol 2005 Jul 11;16(7):2198-204. Epub 2005 May 11.

Department of Pediatrics, University of Miami, 8940 N. Kendall Drive, #603 E, Miami, FL 33176, USA.

Patients with nephrotic syndrome (NS), even with normal GFR, often display altered mineral homeostasis and abnormal bone histology. However, the latter, mostly osteomalacia and increased bone resorption, cannot be readily explained by the prevalent concentrations of parathyroid hormone and vitamin D metabolites. The transmembrane receptor activator of NF-kappaB ligand (RANKL) of osteoblasts is essential for osteoclast formation and differentiation. Osteoblasts activity and the expression of RANKL were tested in cultures of normal human osteoblasts with sera obtained from patients with NS and normal GFR (129 +/- 26 ml/min per 1.73 m2) during relapse and remission of their NS. Osteoblasts that were cultured in vitro with sera during relapse displayed elevated concentrations of alkaline phosphatase (AP) and increased expression of RANKL. By contrast, during remission, AP concentrations were significantly lower (P < 0.05) and RANKL expression notably attenuated or absent. AP correlated with the proteinuria (r = 0.5, P < 0.05) and was not significantly affected by the therapeutic administration of corticosteroids. Whereas parathyroid hormone levels were normal (35 +/- 21 pg/ml), the serum markers of bone formation (osteocalcin and bone-specific alkaline phosphatase) were lower during relapse compared with remission. Thus, sera from patients with NS and normal GFR stimulate the activity of osteoblasts and upregulate their expression of RANKL. These alterations, more prominent during clinically active NS, are transient and reversible upon remission. These disturbances of bone biology may play an important pathogenic role in the abnormal bone histology observed in patients with NS even before a decline in GFR occurs.
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http://dx.doi.org/10.1681/ASN.2004121062DOI Listing
July 2005

A novel epithelial sodium channel beta-subunit mutation associated with hypertensive Liddle syndrome.

Pediatr Nephrol 2005 Apr 3;20(4):512-5. Epub 2005 Feb 3.

Department of Pediatrics, University of Miami, Miami, Florida, USA.

Low-renin hypertension responsive to amiloride-thiazide therapy in a 4-year-old Afro-Haitian girl suggested Liddle syndrome. Urine steroid profiling substantiated the diagnosis and DNA analysis of the epithelial sodium channel (ENaC) revealed a novel heterozygous beta ENaC mutation in the patient and in her hypertensive father. Liddle syndrome should be considered as a cause of hypertension in young children particularly with suppressed renin activity.
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http://dx.doi.org/10.1007/s00467-004-1751-2DOI Listing
April 2005

Bone histology in steroid-treated children with non-azotemic nephrotic syndrome.

Pediatr Nephrol 2004 Apr 26;19(4):400-7. Epub 2004 Feb 26.

Department of Pediatrics, University of Miami, Miami, Florida, USA.

Patients with nephrotic syndrome (NS) and normal glomerular filtration rate (GFR) frequently exhibit abnormalities of calcium and vitamin D homeostasis, mainly hypocalcemia and reduced circulating vitamin D metabolites. These abnormalities have been linked to alterations of bone histology in adults with non-azotemic NS, particularly osteomalacia and excessive bone resorption. Whether similar abnormalities of bone histology occur in children and adolescents with NS, particularly in those requiring prolonged treatment with corticosteroids, remains largely unknown. Thus, bone histomorphometry and selected bone-modulating hormones were studied in eight children (aged 2-16 years) with normal GFR (range 85-169 ml/min per 1.73 m(2)) and NS. All patients received corticosteroids for at least 12 months prior to bone biopsy. At the time of bone biopsy, the urine protein/creatinine ratio was elevated (2.1+/-3.6), while the average concentrations of parathyroid hormone (36+/-13 pg/ml), 25-hydroxyvitamin D [25(OH) D] (22+/-14 ng/ml), and 1,25(OH)(2)D (59+/-22 pg/ml) were normal. Bone histomorphometry displayed focal osteomalacia (OM) and mild increased bone resorption in most patients. The mineralization lag time, an indicator of the degree of osteomalacia, correlated with the time elapsed since the original diagnosis of NS ( r=0.93, P<0.0005). Overt hyperparathyroidism was not evident, but increased eroded perimeter and elevated bone formation rate (BFR) were evident in two patients, suggesting high-turnover bone disease. The BFR was inversely correlated with the administered dose of prednisone at the time of biopsy ( r=-0.78, P<0.05) and one patient exhibited low bone turnover changes. The growth velocity standard deviation score (SDS) at time of biopsy ranged from -1.6 to 3.2, resulting in a height SDS range of -1.9 to 0.6. The height SDS at time of bone biopsy correlated inversely with the dose of administered glucocorticoid ( r=-0.71, P<0.05) and with the duration of the disease ( r=-0.7, P=0.05). These data, albeit preliminary, demonstrate that children with NS treated with prolonged corticosteroid therapy exhibit bone histopathological changes without a concomitant impairment in GFR. While the OM appears to be related to the disease process, the alterations of bone formation and the adynamic changes are likely the result of the corticosteroid therapy. The potential consequences of these findings on adult bone mass and ultimate height deserve further studies.
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http://dx.doi.org/10.1007/s00467-003-1378-8DOI Listing
April 2004

Reduced bone mass in children with idiopathic hypercalciuria and in their asymptomatic mothers.

Nephrol Dial Transplant 2002 Aug;17(8):1396-401

University of Miami School of Medicine, Miami, Florida, USA.

Background: Patients with nephrolithiasis and idiopathic hypercalciuria (IH) may exhibit reduced bone mineral density (BMD). Most studies measuring BMD in IH patients employing dual-energy X-ray absorptiometry (DEXA) have been performed in adults, and no study has been conducted in North-American children. Optimal bone mineral accretion during childhood and adolescence is critical to the attainment of a healthy adult skeleton. Bone mineral accretion and eventual adult peak bone mass are largely dependent on genetic factors. Hypercalciuria is also frequently linked to genetic determinants. Therefore, we carried out a cross-sectional evaluation of bone mineral metabolism in children with IH, and in their asymptomatic premenopausal mothers.

Methods: Quantitative BMD using DEXA was performed in 21 children with IH and in their asymptomatic mothers. Bone resorption was assessed by measuring the urinary concentrations of pyridinoline and deoxypiridinoline. Simultaneous calcium-modulating hormonal determinations, including serum intact immunoreactive parathyroid hormone and 1,25(OH)(2)D(3), were performed. The expression of interleukin-1alpha (IL-1alpha) by peripheral blood mononuclear cells (PBMCs) was determined by polymerase chain reaction.

Results: Reduced BMD values were observed in eight children (38%) and in seven mothers (33%). The children of osteopenic mothers exhibited significantly reduced BMD Z-score values of lumbar spine (P<0.05) when compared with children of mothers with normal BMD. Bone resorption markers were normal in most children with IH. Hypercalciuria was detected in five out of 20 (25%) asymptomatic mothers and it correlated (r=-0.81) to femoral BMD in mothers with osteopenia. The expression of IL-1alpha mRNA by PBMCs from IH children did not differ from controls.

Conclusions: Reduced BMD was detected in a large proportion of children with IH. Hypercalciuria and reduced BMD were uncovered in a substantial number of their otherwise healthy asymptomatic mothers. The diminished BMD in adults with IH may start early in life, could be influenced by genetic factors, and may represent a risk factor for osteoporosis later in life.
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http://dx.doi.org/10.1093/ndt/17.8.1396DOI Listing
August 2002