Chronic kidney disease (CKD) is a major cause of morbidity and premature mortality and represents a significant global public health issue. Underlying this burden are the many complications of CKD, including mineral and bone disorders, anemia, and accelerated cardiovascular disease. Hyperphosphatemia and elevated levels of fibroblast growth factor 23 (FGF23) have been identified as key independent risk factors for the adverse cardiovascular outcomes that frequently occur in patients with CKD. Auryxia^® (ferric citrate; Keryx Biopharmaceuticals, Inc., Boston, MA, USA) is an iron-based compound with distinctive chemical characteristics and a mechanism of action that render it dually effective as a therapy in patients with CKD; it has been approved as a phosphate binder for the control of serum phosphate levels in adult CKD patients treated with dialysis and as an iron replacement product for the treatment of iron deficiency anemia in adult CKD patients not treated with dialysis. This review focuses on Auryxia, its mechanism of action, and the clinical attributes that differentiate it from other, non-pharmaceutical-grade, commercially available forms of ferric citrate and from other commonly used phosphate binder and iron supplement therapies for patients with CKD. Consistent with the chemistry and mechanism of action of Auryxia, multiple clinical studies have demonstrated its efficacy in both lowering serum phosphate levels and improving iron parameters in patients with CKD. Levels of FGF23 decrease significantly with Auryxia treatment, but the effects associated with the cardiovascular system remain to be evaluated in longer-term studies.

Purpose of review

In this paper, we review the pathogenesis and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD), especially as it relates to pediatric CKD patients.

Recent findings

Disordered regulation of bone and mineral metabolism in CKD may result in fractures, skeletal deformities, and poor growth, which is especially relevant for pediatric CKD patients. Moreover, CKD-MBD may result in extra-skeletal calcification and cardiovascular morbidity. Early increases in fibroblast growth factor 23 (FGF23) levels play a key, primary role in CKD-MBD pathogenesis. Therapeutic approaches in pediatric CKD-MBD aim to minimize complications to the growing skeleton and prevent extra-skeletal calcifications, mainly by addressing hyperphosphatemia and secondary hyperparathyroidism. Ongoing clinical trials are focused on assessing the benefit of FGF23 reduction in CKD. CKD-MBD is a systemic disorder that has significant clinical implications. Treatment of CKD-MBD in children requires special consideration in order to maximize growth, optimize skeletal health, and prevent cardiovascular disease.

In chronic kidney disease, systemic inflammation is common and associated with mortality. The present study demonstrates that fibroblast growth factor 23 (FGF23) contributes to uremic inflammation by increasing hepatic expression and secretion of inflammatory cytokines. FGF23 binds to hepatic FGFR4, inducing calcineurin/nuclear factor of activated T-cell signaling, resulting in increased expression of interleukin 6 and C-reactive protein. The proinflammatory effects of FGF23 are inhibited by an isoform-specific FGFR4 blocking antibody and by cyclosporine, a calcineurin inhibitor.

Purpose of review

We will review non-renal-related mechanisms of fibroblast growth factor 23 (FGF23) pathophysiology.

Recent findings

FGF23 production and metabolism may be affected by many bone, mineral, and kidney factors. However, it has recently been demonstrated that other factors, such as iron status, erythropoietin, and inflammation, also affect FGF23 production and metabolism. As these non-mineral factors are especially relevant in the setting of chronic kidney disease (CKD), they may represent emerging determinants of CKD-associated elevated FGF23 levels. Moreover, FGF23 itself may promote anemia and inflammation, thus contributing to the multifactorial etiologies of these CKD-associated comorbidities. CKD-relevant, non-mineral-related, bidirectional relationships exist between FGF23 and anemia, and between FGF23 and inflammation. Iron deficiency, anemia, and inflammation affect FGF23 production and metabolism, and FGF23 itself may contribute to anemia and inflammation, highlighting complex interactions that may affect aspects of CKD pathogenesis and treatment.

Background

Healthy African-Americans are known to have greater bone mineral density and decreased risk of fracture when compared to Caucasians. In fact, comparisons of bone histomorphometry in healthy South African children and adults reveal greater cortical thickness in Black subjects as compared to White. How these differences are reflected in the bone of American children and young adults on dialysis is unknown.

Methods

Using tetracycline-labeled, iliac crest bone biopsies obtained in prior research protocols in pediatric and young adult dialysis patients, we compared trabecular and cortical parameters between non-Hispanic African-American subjects and non-Hispanic Caucasian subjects matched by age and gender. A linear regression model controlled for trabecular turnover and mineralization was used to further investigate the association of race with cortical thickness.

Results

The matched cohort consisted of 52 subjects-26 African-American and 26 Caucasian. Turnover, mineralization and volume parameters in trabecular bone did not show significant differences between racial groups. Characterizing subjects by renal osteodystrophy type did not show a statistically significant difference although Caucasian patients had double the prevalence of mineralization defects. Consistent with this was a trend toward better mineralization parameters in African-Americans including shorter osteoid maturation time and lower osteoid volume. A sub-cohort of patients with cortical measures demonstrated greater median (IQR) cortical thickness in African-Americans (541 μm [354, 694]) than in Caucasians (371 μm [336, 446], p = 0.08). In a linear regression model controlling for trabecular turnover and mineralization, African-American subjects had 36.2% (95% CI 0.28 to 85.1%, p = 0.048) greater cortical thickness as compared to White subjects. There was no significant difference in cortical porosity.

Conclusions

Although likely limited by sample size, our findings suggest that, similar to findings in populations of normal children, African-American race in pediatric and young adults on dialysis is associated with greater cortical thickness. Additionally, there was a trend toward greater mineralization defects in Caucasian children. Both findings require further exploration with larger patient samples in order to thoroughly explore these racial differences and the implications on CKD-MBD treatment.

Calcific uremic arteriolopathy (CUA) is a rare, life-threatening disease, typically affecting patients with end-stage renal disease. It is characterized by widespread vascular calcification, endothelial fibrosis and end-organ ischemia. The mortality rate is high with infection and sepsis being the most common causes of death. Common therapies include restoration of calcium and phosphorous homeostasis, wound care and pain control. Although soft tissue calcification is a known complication in children with advanced renal disease, the incidence of CUA in pediatrics remains unknown. Additionally, current literature regarding its management in pediatric patients is lacking. We report the case of a 17-year-old African–American male patient with end-stage renal disease secondary to Wegener’s granulomatosis who developed CUA after 3 years on peritoneal dialysis. Treatment with sodium thiosulfate (STS) and hyperbaric oxygen (HBO) therapy alone was ineffective, forcing the patient to undergo bilateral below the-knee-amputation (BKA) 5 months after presentation. It was not until peritoneal dialysis had been changed to daily hemodialysis, while continuing STS and HBO therapy, that the patient demonstrated complete resolution of CUA on repeat bone scan. Based on these findings, and the extremely high mortality rate associated with this disease, CUA management requires early and aggressive intervention with multi-faceted therapy, including prompt conversion from peritoneal dialysis to hemodialysis, STS infusions and hyperbaric oxygen therapy.

Bone deformities and fractures are common consequences of renal osteodystrophy in the dialysis population. Persistent hypophosphatemia may be observed with more frequent home hemodialysis regimens, but the specific effects on the skeleton are unknown. We present a patient with end-stage renal disease treated with frequent home hemodialysis who developed severe bone pain and multiple fractures, including a hip fracture and a tibia-fibula fracture complicated by nonunion, rendering her nonambulatory and wheelchair bound for more than a year. A bone biopsy revealed severe osteomalacia, likely secondary to chronic hypophosphatemia and hypocalcemia. Treatment changes included the addition of phosphate to the dialysate, a higher dialysate calcium concentration, and increased calcitriol dose. Several months later, the patient no longer required a wheelchair and was able to ambulate without pain. Repeat bone biopsy revealed marked improvements in bone mineralization and turnover parameters. Also, with increased dialysate phosphate and calcium concentrations, as well as increased calcitriol, circulating fibroblast growth factor 23 levels increased.

Background and objectives

Mineral and bone disorders (MBDs) are common in long-term dialysis patients and are risk factors for unfavorable outcomes. The associations between pretransplant levels of MBD surrogates and outcomes after kidney transplantation are not clear.

Design, setting, participants, & measurements

Data from the Scientific Registry of Transplant Recipients up to June 2007 were linked to the 5-year (July 2001-June 2006) cohort of a large dialysis organization in the United States. All dialysis patients who received a kidney transplant during this period were identified and divided into groups according to increments of pretransplant MBD markers. Unadjusted and multivariate adjusted predictors of transplant outcomes were examined.

Results

The 11,776 patients were aged 47 ± 14 years and 39% were women. Compared with recipients with pretransplant time-averaged serum alkaline phosphatase of 80-120 U/L, recipients with pretransplant serum alkaline phosphatase of 120-160 and ≥160 U/L had 49% and 64% higher graft failure censored all-cause mortality in multivariable adjusted models. There was no significant association between time-averaged serum alkaline phosphatase categories and risk of death censored graft failure, delayed graft function (DGF), or acute rejection (AR). Compared with recipients with pretransplant time-averaged serum parathyroid hormone (PTH) levels of 150-300 pg/ml, there was no significant association with graft censored death among recipients with pretransplant serum PTH ≥800 pg/ml. In addition, the risk of graft failure, DGF, and AR did not show any association with time-averaged serum intact PTH level. There was no significant association between time-averaged serum calcium categories and risk of graft failure censored death, DGF, and AR.

Conclusions

In this cohort, hemodialysis patients with pretransplant serum alkaline phosphatase >120 U/L have unfavorable post-transplant mortality, whereas there was no association between serum PTH and serum calcium levels and post-transplant outcomes.

Sevelamer hydrochloride (HCl), a calcium-free phosphate binder, is increasingly used due to concerns related to calcium exposure and the development of vascular calcifications. However, a common side effect of sevelamer HCl, metabolic acidosis, is particularly concerning in children, as it can contribute to poor growth. Sevelamer carbonate is now available and has been shown to increase serum bicarbonate in adult patients. We conducted a prospective single-center study of pediatric dialysis patients comparing serum bicarbonate before and 3 months after a switch from sevelamer HCl to sevelamer carbonate. Inclusion criteria were a minimum of 3 months of dialysis therapy and either a serum bicarbonate <20 mmol/L or the need for sodium bicarbonate supplementation. Ten hemodialysis and 14 peritoneal dialysis patients, aged 16 ± 3 years, were enrolled. Whereas serum calcium and phosphorus remained unchanged, serum bicarbonate increased from 20 (17.2–22.0) to 24.5 (20.75–26) mmol/L (p < 0.001) after 3 months of sevelamer carbonate therapy. Sodium bicarbonate supplementation was stopped in all patients (n = 10), reducing the mean daily sodium intake by an average of 2.3 g per patient. These results demonstrate that sevelamer carbonate is an effective phosphate binder that improves acid-base status in pediatric dialysis patients.

Calcium (Ca)-containing phosphate binders have been recommended for the treatment of hyperphosphatemia in children with chronic kidney disease. To study the effects of high Ca levels on trabecular bone volume (BV) and osteoprotegerin (OPG) expression in uremic young rats, a model of marked overcorrection of secondary hyperparathyroidism was created by providing a diet of high Ca to 5/6 nephrectomized young rats (Nx-Ca) for 4 weeks. The results of chondrocyte proliferation and apoptosis, osteoclastic activity, OPG expression and BV were compared among intact rats given the control diet, intact rats given a high Ca diet and 5/6 nephrectomized rats given the control diet (Nx-Control) and the high Ca diet (Nx-Ca). Ionized Ca levels were higher and parathyroid hormone levels were lower in Nx-Ca rats than in the other groups. Final weight, final length and final tibial length of Nx-Ca rats were significantly less than those of the other groups, although the length gain did not differ among the groups. The hypertrophic zone width was markedly enlarged in Nx-Ca rats. Chondrocyte proliferation rates did not differ among the groups, whereas osteoclastic activity was decreased in Nx-Ca rats compared with the Nx-Control animals. The OPG expression and BV were increased in Nx-Ca rats compared with the Nx-Control rats. Increased BV should improve bone strength, whereas disturbance of osteoclastogenesis interferes with bone remodeling. Bone quality has yet to be determined in high Ca-fed uremic young rats.