Recurrent disease after pediatric renal transplantation.

BACKGROUND: Recurrent disease after kidney transplant remains an important cause of allograft failure, accounting for 7-8% of graft loss and ranking as the fifth most common cause of allograft loss in the pediatric population. Although the pathophysiology of many recurrent diseases is incompletely understood, recent advances in basic science and therapeutics are improving outcomes and changing the course of several of these conditions. METHODS: Review of the literature. RESULTS: We discuss the diagnosis and management of recurrent disease. CONCLUSION: We highlight new insights into the pathophysiology and treatment of post-transplant primary hyperoxaluria, focal segmental glomerulosclerosis, immune complex glomerulonephritis, C3 glomerulopathy, lupus nephritis, atypical hemolytic uremic syndrome, and IgA nephropathy.

Comparison of estimated GFR using cystatin C versus creatinine in pediatric kidney transplant recipients.

BACKGROUND: An accurate, rapid estimate of glomerular filtration rate (GFR) in kidney transplant patients affords early detection of transplant deterioration and timely intervention. This study compared the performance of serum creatinine (Cr) and cystatin C (CysC)-based GFR equations to measured GFR (mGFR) using iohexol among pediatric kidney transplant recipients. METHODS: CysC, Cr, and mGFR were obtained from 45 kidney transplant patients, 1-18 years old. Cr- and CysC-estimated GFR (eGFR) was compared against mGFR using the Cr-based (Bedside Schwartz, U25-Cr), CysC-based (Gentian CysC, CAPA, U25-CysC), and Cr-CysC combination (CKiD Cr-CysC, U25 Cr-CysC) equations in terms of bias, precision, and accuracy. Bland-Altman plots assessed the agreement between eGFR and mGFR. Secondary analyses evaluated the formulas in patients with biopsy-proven histological changes, and K/DOQI CKD staging. RESULTS: Bias was small with Gentian CysC (0.1 ml/min/1.73 m2); 88.9% and 37.8% of U25-CysC estimations were within 30% and 10% of mGFR, respectively. In subjects with histological changes on biopsy, Gentian CysC had a small bias and U25-CysC were more accurate-both with 83.3% of and 41.7% of estimates within 30% and 10% mGFR, respectively. Precision was better with U25-CysC, CKiD Cr-CysC, and U25 Cr-CysC. Bland-Altman plots showed the Bedside Schwartz, Gentian CysC, CAPA, and U25-CysC tend to overestimate GFR when > 100 ml/min/1.72 m2. CAPA misclassified CKD stage the least (whole cohort 24.4%, histological changes on biopsy 33.3%). CONCLUSIONS: In this small cohort, CysC-based equations with or without Cr may have better bias, precision, and accuracy in predicting GFR.

Racial-ethnic diversity in ambulatory blood pressure monitoring in children with chronic kidney disease.

BACKGROUND: Black adults with chronic kidney disease (CKD) have higher rates of hypertension as compared to White adults with CKD. Little is known of how race and ethnicity associate with the prevalence of hypertension in pediatric CKD patients. The aim was to compare ambulatory blood pressure monitoring (ABPM) results for patients with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study across racial-ethnic groups. METHODS: Patients from the CKiD study who identified as non-Hispanic White, non-Hispanic Black, or Hispanic were included to analyze differences in ABPM results across these racial-ethnic groups. The outcomes were fitted using 3 progressively adjusted models. RESULTS: This study included 501 CKiD participants with at least one successful ABPM study. Compared to White participants, Black participants had 4.2 mmHg higher mean sleep systolic blood pressure and 2.7 mmHg higher mean sleep diastolic blood pressure (p = 0.001 and p = 0.004, respectively). Additionally, Black participants had higher odds of abnormal wake systolic load (OR 1.88, 1.21-2.91, p = 0.005), wake diastolic load (OR 1.68, 1.03-2.73, p = 0.04), sleep systolic load (OR 2.19, 1.36-3.5, p = 0.001), sleep diastolic load (OR 2.01, 1.28-3.15, p = 0.002), systolic non-dipping (OR 2.02, 1.31-3.10, p = 0.001), and diastolic non-dipping (OR 2.69, 1.60-4.51, p < 0.001). Compared to White participants, Hispanic participants demonstrated only a lower sleep diastolic load (OR 0.54, 0.31-0.95, p = 0.03). CONCLUSIONS: Black children with CKD have higher absolute nocturnal blood pressures and higher rates of abnormal dipping. Further studies are needed to determine the etiology of these differences and the clinical implications of racial-ethnic differences in ABPM outcomes within the pediatric CKD population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Renal fluid and acid/base balance during refeeding in restrictive eating disorders.

BACKGROUND AND OBJECTIVES: Fluid shifts have been ascribed to central diabetes insipidus in patients with anorexia nervosa hospitalized for refeeding. Recent data, however, suggest that vasopressin production is not dysregulated in this population. Our objective was to describe the trajectory of fluid imbalances in relationship to kidney function, electrolyte disturbances, and acid/base balance during refeeding. METHODS: A retrospective review of daily fluid balance and biochemical values was performed in 70 sequential unique patients admitted to University of California at Los Angeles Hospital Medical Stabilization Program for Eating Disorders from December 2018 to November 2020. RESULTS: Participants (2 males/68 females) were between 10 and 24 years of age and with a median body mass index of 16.1 (14.3, 18.1) kg/m2 . A severe negative fluid balance (>-900 ml/day) was observed in 80% of patients at some point during hospitalization. Serum sodium concentrations were normal on admission and remained stable during refeeding. Serum bicarbonate concentrations were 25 ± 1 mEq/dl on admission and increased above the normal range in 31% of patients. Metabolic alkalosis was inversely associated with the development of a negative fluid balance. Estimated glomerular filtration rate was impaired in 54% of patients, improved with refeeding, and was not associated with the development of a severe negative fluid balance or metabolic alkalosis. DISCUSSION: Chronic energy deprivation alters the physiology of renal fluid and bicarbonate handling in ways that are independent of vasopressin and glomerular filtration. Further studies are warranted to understand the renal adaptations that occur during energy restriction and subsequent refeeding. PUBLIC SIGNIFICANCE: Massive urinary fluid losses occur in patients with restrictive eating disorders hospitalized for refeeding. In addition, many patients have impaired renal bicarbonate excretion. These findings suggest that chronic energy deprivation impairs the kidney's ability to handle the shifts in fluid and acid/base balance that occur when appropriate oral nutrition is re-introduced.

Gut microbiome, parathyroid hormone, and bone.

PURPOSE OF REVIEW: Microorganisms in the gut (the 'microbiome') and the metabolites they produce (the 'metabolome') regulate bone mass through interactions between parathyroid hormone (PTH), the immune system, and bone. This review summarizes these data and details how this physiology may relate to CKD-mediated bone disease. RECENT FINDINGS: The actions of PTH on bone require microbial metabolite activation of immune cells. Butyrate is necessary for CD4+ T-cell differentiation, T-reg cell expansion and CD8+ T-cell secretion of the bone-forming factor Wnt10b ligand. By contrast, mice colonized with segmented filamentous bacteria exhibit an expansion of gut Th17 cells and continuous PTH infusion increases the migration of Th17 cells to the bone marrow, contributing to bone resorption. In the context of CKD, a modified diet, frequent antibiotic therapy, altered intestinal mobility, and exposure to multiple medications together contribute to dysbiosis; the implications for an altered microbiome and metabolome on the pathogenesis of renal osteodystrophy and its treatment have not been explored. SUMMARY: As dysregulated interactions between PTH and bone ('skeletal resistance') characterize CKD, the time is ripe for detailed, mechanistic studies into the role that gut metabolites may play in the pathogenesis of CKD-mediated bone disease.

Vitamin C overload may contribute to systemic oxalosis in children receiving dialysis.

BACKGROUND: Malnutrition and anorexia are common in children with chronic kidney disease (CKD) and gastrostomy tubes (GT) as well as nasogastric tubes (NGT) have been recommended to maximize nutritional support. The optimal requirement of vitamin C in children with CKD remains to be defined but oxalate is a breakdown product of vitamin C. Elevated vitamin C intake and bone oxalate were identified in two formula-fed dialyzed children with negative genetic testing for primary hyperoxaluria. METHODS: We evaluated the impact of nutritional support on serum ascorbic acid and plasma oxalate levels in 13 dialyzed infants and young children. RESULTS: All patients were fed by GT or NGT since the first months of life; overall patients were receiving between 145 and 847% of the age-specific DRI for vitamin C. Mean serum ascorbic acid and plasma oxalate levels were elevated (244.7 ± 139.7 µM/L and 44.3 ± 23.1 µM/L, respectively), and values did not differ according to the degree of residual kidney function. Ascorbic acid levels did not correlate with oxalate levels (r = 0.44, p = 0.13). CONCLUSIONS: Excessive vitamin C intake may contribute to oxalate accumulation in dialyzed children.

Associations among erythropoietic, iron-related, and FGF23 parameters in pediatric kidney transplant recipients.

BACKGROUND: In pediatric kidney transplant recipients, anemia is common and oftentimes multifactorial. Hemoglobin concentrations may be affected by traditional factors, such as kidney function and iron status, as well as novel parameters, such as fibroblast growth factor 23 (FGF23). METHODS: Here, we evaluated associations among erythropoietic, iron-related, and FGF23 parameters in a cohort of pediatric kidney transplant recipients, hypothesizing that multiple factors are associated with hemoglobin concentrations. RESULTS: In a cross-sectional analysis of 59 pediatric kidney transplant recipients (median (interquartile range) age 16.3 (13.5, 18.6) years, median estimated glomerular filtration rate (eGFR) 67 (54, 87) ml/min/1.73 m2), the median age-related hemoglobin standard deviation score (SDS) was -2.1 (-3.3, -1.1). Hemoglobin SDS was positively associated with eGFR and calcium, and was inversely associated with erythropoietin (EPO), mycophenolate dose, and total, but not intact, FGF23. In multivariable analysis, total FGF23 remained inversely associated with hemoglobin SDS, independent of eGFR, iron parameters, EPO, and inflammatory markers, suggesting a novel FGF23-hemoglobin association in pediatric kidney transplant patients. In a subset of patients with repeat measurements, only delta hepcidin was inversely associated with delta hemoglobin SDS. Also, delta EPO positively correlated with delta erythroferrone (ERFE), and delta ERFE inversely correlated with delta hepcidin, suggesting a possible physiologic role for the EPO-ERFE-hepcidin axis in the setting of chronic kidney disease (CKD). CONCLUSION: Our study provides further insight into factors potentially associated with erythropoiesis in pediatric kidney transplant recipients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Nephropathic Cystinosis: A Distinct Form of CKD-Mineral and Bone Disorder that Provides Novel Insights into the Regulation of FGF23.

BACKGROUND: The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD-mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD-mineral and bone disorder. METHODS: We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis. RESULTS: The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3-5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate. CONCLUSIONS: Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.

Pathophysiology and treatment of cardiovascular disease in pediatric chronic kidney disease.

Life expectancy in patients with all stages of chronic kidney disease (CKD) falls far short of that in the general population. Cardiovascular disease is the leading cause of mortality in pediatric patients with CKD. In contrast to the intimal atherosclerotic lesions that characterize cardiovascular disease in the general population, vascular endothelial dysfunction, medial arterial calcification, and cardiac dysfunction contribute to cardiovascular pathological conditions in CKD. The pathogenesis of these lesions, the origins of which can be identified in the absence of traditional cardiovascular risk factors, is incompletely understood. CKD-mediated vascular calcification in CKD is characterized by a transition of vascular smooth muscle cells to an osteoblast-like phenotype and altered bone and mineral metabolism are strongly linked to progressive cardiovascular disease in this population. Renal osteodystrophy therapies, including phosphate binders, vitamin D analogs, and calcimimetics, have an impact on the progression of cardiovascular disease. However, cardiovascular disease has its origins before the development of secondary hyperparathyroidism, and optimal therapeutic regimens that minimize cardiac dysfunction, vascular calcification, and early mortality remain to be defined.

Kidney-on-a-chip: untapped opportunities.

The organs-on-a-chip technology has shown strong promise in mimicking the complexity of native tissues in vitro and ex vivo, and recently significant advances have been made in applying this technology to studies of the kidney and its diseases. Individual components of the nephron, including the glomerulus, proximal tubule, and distal tubule/medullary collecting duct, have been successfully mimicked using organs-on-a-chip technology and yielding strong promises in advancing the field of ex vivo drug toxicity testing and augmenting renal replacement therapies. Although these models show promise over 2-dimensional cell systems in recapitulating important nephron features in vitro, nephron functions, such as tubular secretion, intracellular metabolism, and renin and vitamin D production, as well as prostaglandin synthesis are still poorly recapitulated in on-chip models. Moreover, construction of multiple-renal-components-on-a-chip models, in which various structures and cells of the renal system interact with each other, has remained a challenge. Overall, on-chip models show promise in advancing models of normal and pathological renal physiology, in predicting nephrotoxicity, and in advancing treatment of chronic kidney diseases.

Impaired osteocyte maturation in the pathogenesis of renal osteodystrophy.

Pediatric renal osteodystrophy is characterized by skeletal mineralization defects, but the role of osteoblast and osteocyte maturation in the pathogenesis of these defects is unknown. We evaluated markers of osteocyte maturation and programmed cell death in iliac crest biopsy samples from pediatric dialysis patients and healthy controls. We evaluated the relationship between numbers of fibroblast growth factor 23 (FGF23)-expressing osteocytes and histomorphometric parameters of skeletal mineralization. We confirmed that chronic kidney disease (CKD) causes intrinsic changes in bone cell maturation using an in vitro model of primary osteoblasts from patients with CKD and healthy controls. FGF23 co-localized with the early osteocyte marker E11/gp38, suggesting that FGF23 is a marker of early osteocyte maturation. Increased numbers of early osteocytes and decreased osteocyte apoptosis characterized CKD bone. Numbers of FGF23-expressing osteocytes were highest in patients with preserved skeletal mineralization indices, and packets of matrix surrounding FGF23-expressing osteocytes appeared to have entered secondary mineralization. Primary osteoblasts from patients with CKD retained impaired maturation and mineralization characteristics in vitro. Addition of FGF23 did not affect primary osteoblast mineralization. Thus, CKD is associated with intrinsic changes in osteoblast and osteocyte maturation, and FGF23 appears to mark a relatively early stage in osteocyte maturation. Improved control of renal osteodystrophy and FGF23 excess will require further investigation into the pathogenesis of CKD-mediated osteoblast and osteocyte maturation failure.

Efficacy and safety of sevelamer carbonate in hyperphosphatemic pediatric patients with chronic kidney disease.

BACKGROUND: Treatment for hyperphosphatemia in chronic kidney disease (CKD) involves dietary control of phosphorus intake, dialysis, and treatment with oral phosphate binders, none of which were approved by the Federal Food and Drug Administration in pediatric patients at the time of this study. METHODS: This was a phase 2, multicenter study (NCT01574326) with a 2-week, randomized, placebo-controlled, fixed-dose period (FDP) followed by a 6-month, single-arm, open-label, dose-titration period (DTP), with the aim to evaluate the safety and efficacy of sevelamer carbonate (SC) in hyperphosphatemic pediatric patients with CKD. Following a 2-4 week screening phase, pediatric patients with a serum phosphorus level higher than age-appropriate levels were randomized to receive either SC or placebo as powder/tablets in 0.4-1.6 g doses, based on body surface area. The primary efficacy outcome was the change in serum phosphorus from baseline to end of the FDP in the SC versus placebo arms (analysis of covariance). The secondary outcome was mean change in serum phosphorus from baseline to end of DTP by treatment group and overall. Treatment-emergent/serious adverse events (AEs) were recorded. RESULTS: Of 101 enrolled patients (29 centers), 66 completed the study. The majority of patients were adolescents (74%; mean age 14.1 years) and on dialysis (77%). Renal transplant was the main reason for discontinuation. SC significantly reduced serum phosphorus from baseline levels (7.16 mg/dL) during the FDP compared to placebo (least square mean difference - 0.90 mg/dL, p = 0.001) and during the DTP (- 1.18 mg/dL, p < 0.0001). The safety and tolerability of SC and placebo were similar during the FDP, with patients in both groups reporting mild/moderate gastrointestinal AEs during the DTP. CONCLUSIONS: Sevelamer carbonate significantly lowered serum phosphorus levels in hyperphosphatemic children with CKD, with no serious safety concerns identified.

Osteocyte dysfunction and renal osteodystrophy: not just calcium and phosphorus anymore.

In an important new cross-sectional analysis in this issue, Graciolli and colleagues present bone data from 148 adult patients across the spectrum of chronic kidney disease that confirm that disrupted osteocyte function and abnormal bone histology characterize all stages of chronic kidney disease and suggest that osteocytic Wnt signaling and osteocyte maturation may play a role in the pathogenesis of renal osteodystrophy. These concepts may alter how the skeletal, cardiovascular, and infectious complications of chronic kidney disease are managed.

Effects of acute kidney injury and chronic hypoxemia on fibroblast growth factor 23 levels in pediatric cardiac surgery patients.

BACKGROUND: Fibroblast growth factor-23 (FGF23) levels are elevated in cardiopulmonary bypass (CPB)-associated acute kidney injury (AKI); however, it is unknown how much of the circulating FGF23 is intact and bioactive. Hypoxia may induce FGF23 production, yet its impact in humans is unknown. Pediatric cardiac surgery patients have both a high incidence of CPB-associated AKI and a high prevalence of chronic hypoxemia. METHODS: We assessed the effects of hypoxemia and CPB-associated AKI on C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 32 pediatric cardiac surgery patients with normal estimated glomerular filtration rate (eGFR). Plasma cFGF23 and iFGF23 were measured preoperatively and serially postoperatively. RESULTS: Despite normal renal and ventricular function, preoperative cFGF23 levels were high and elevated out of proportion to iFGF23 levels. Preoperative oxygen saturation measurements correlated inversely with FGF23 levels. Preoperative cFGF23 and oxygen saturation both predicted postoperative AKI. Postoperatively, cFGF23 and iFGF23 increased by 2 h postreperfusion; iFGF23 then returned to baseline, but cFGF23 remained elevated through 24 h postreperfusion. Group status (AKI vs. non-AKI) modified the effect of time on changes in iFGF23 levels but not cFGF23 levels. CONCLUSIONS: Preoperative cFGF23 may predict CPB-associated kidney dysfunction. Changes over time in cFGF23 and iFGF23 levels post-CPB differ. Chronic hypoxemia may affect FGF23 production in humans.

Primary osteoblast-like cells from patients with end-stage kidney disease reflect gene expression, proliferation, and mineralization characteristics ex vivo.

Osteocytes regulate bone turnover and mineralization in chronic kidney disease. As osteocytes are derived from osteoblasts, alterations in osteoblast function may regulate osteoblast maturation, osteocytic transition, bone turnover, and skeletal mineralization. Thus, primary osteoblast-like cells were cultured from bone chips obtained from 24 pediatric ESKD patients. RNA expression in cultured cells was compared with RNA expression in cells from healthy individuals, to RNA expression in the bone core itself, and to parameters of bone histomorphometry. Proliferation and mineralization rates of patient cells were compared with rates in healthy control cells. Associations were observed between bone osteoid accumulation, as assessed by bone histomorphometry, and bone core RNA expression of osterix, matrix gla protein, parathyroid hormone receptor 1, and RANKL. Gene expression of osteoblast markers was increased in cells from ESKD patients and signaling genes including Cyp24A1, Cyp27B1, VDR, and NHERF1 correlated between cells and bone cores. Cells from patients with high turnover renal osteodystrophy proliferated more rapidly and mineralized more slowly than did cells from healthy controls. Thus, primary osteoblasts obtained from patients with ESKD retain changes in gene expression ex vivo that are also observed in bone core specimens. Evaluation of these cells in vitro may provide further insights into the abnormal bone biology that persists, despite current therapies, in patients with ESKD.

The BRC canopy: an important player in bone remodeling.

This Commentary highlights the article by Andersen et al, which describes structural changes in bone associated with increased bone resorption in osteoporotic post-menopausal women.

The role of bone in CKD-mediated mineral and vascular disease.

Cardiovascular disease is the leading cause of death in pediatric patients with chronic kidney disease (CKD), and vascular calcifications start early in the course of CKD. Based on the growing body of evidence that alterations of bone and mineral metabolism and the therapies designed to treat the skeletal consequences of CKD are linked to cardiovascular calcifications, the Kidney Disease, Improving Global Outcomes (KDIGO) working group redefined renal osteodystrophy as a systemic disorder of mineral and bone metabolism due to CKD, and this newly defined disorder is now known as "chronic kidney disease-mineral bone disorder (CKD-MBD)". Elevated fibroblast growth factor 23 (FGF23), a bone-derived protein, is the first biochemical abnormality to be associated with CKD-MBD, and high FGF23 levels correlate with increased cardiovascular morbidity and mortality, suggesting that bone is central to both initiating and perpetuating the abnormal mineral metabolism and vascular disease in CKD. The current standard therapies for CKD-MBD affect FGF23 levels differently; non-calcium-based binders with or without concurrent use of dietary phosphate restriction reduce FGF23 levels, while calcium-based binders seem to either increase or have no effect on FGF23 levels. Active vitamin D sterols increase FGF23 levels, whereas therapy with calcimimetics decreases FGF23 levels. Thus, the appropriate therapy that will minimize the rise in FGF23 and prevent cardiovascular morbidity remains to be defined.

Cortical and trabecular bone in pediatric end-stage kidney disease.

BACKGROUND: Cortical bone represents nearly 80 % of human bone mass and is the major determinant of bone strength; however, cortical bone parameters and their relationship to trabecular bone in the pediatric chronic kidney disease (CKD) population have not been evaluated. METHODS: Biochemical values and cortical and trabecular bone parameters were assessed in 22 pediatric dialysis patients: 12 with high and 10 with normal to low trabecular bone turnover. RESULTS: Trabecular bone turnover and osteoid volume correlated with parathyroid hormone (PTH) levels (r = 0.86, p < 0.01 and r = 0.93, p < 0.01, respectively). Internal cortical osteonal bone formation rate was directly related to alkaline phosphatase (r = 0.45, p < 0.05) and inversely related to insulin-like growth factor (IGF)-1 values (r = -0.55, p < 0.01), and internal cortical porosity was also related to serum alkaline phosphatase levels (r = 0.57, p < 0.01). A similar relationship was not found between external cortical bone formation rate and parameters of bone turnover and porosity, however. No relationship was found between trabecular and cortical bone formation rates. CONCLUSIONS: Secondary hyperparathyroidism was associated with increased external cortical, relative to internal cortical, osteonal activity in pediatric dialysis patients. The clinical consequences of these changes and their response to therapy for secondary hyperparathyroidism remain to be defined.

Defective skeletal mineralization in pediatric CKD.

Although traditional diagnosis and treatment of renal osteodystrophy focused on changes in bone turnover, current data demonstrate that abnormalities in skeletal mineralization are also prevalent in pediatric chronic kidney disease (CKD) and likely contribute to skeletal morbidities that continue to plague this population. It is now clear that alterations in osteocyte biology, manifested by changes in osteocytic protein expression, occur in early CKD before abnormalities in traditional measures of mineral metabolism are apparent and may contribute to defective skeletal mineralization. Current treatment paradigms advocate the use of 1,25(OH)2vitamin D for the control of secondary hyperparathyroidism; however, these agents fail to correct defective skeletal mineralization and may exacerbate already altered osteocyte biology. Further studies are critically needed to identify the initial trigger for abnormalities of skeletal mineralization as well as the potential effects that current therapeutic options may have on osteocyte biology and bone mineralization.