Renoprotective effects of sucroferric oxyhydroxide in a rat model of chronic renal failure.

INTRODUCTION: Sucroferric oxyhydroxide (PA21) is an efficacious, well-tolerated iron-based phosphate binder and a promising alternative to existing compounds. We compared the effects of PA21 with those of a conventional phosphate binder on renal function, mineral homeostasis and vascular calcification in a chronic kidney disease-mineral and bone disorder (CKD-MBD) rat model. METHODS: To induce stable renal failure, rats were administered a 0.25% adenine diet for 8 weeks. Concomitantly, rats were treated with vehicle, 2.5 g/kg/day PA21, 5.0 g/kg/day PA21 or 3.0 g/kg/day calcium carbonate (CaCO3). Renal function and calcium/phosphorus/iron metabolism were evaluated during the study course. Renal fibrosis, inflammation, vascular calcifications and bone histomorphometry were quantified. RESULTS: Rats treated with 2.5 or 5.0 g/kg/day PA21 showed significantly lower serum creatinine and phosphorus and higher ionized calcium levels after 8 weeks of treatment compared with vehicle-treated rats. The better preserved renal function with PA21 went along with less severe anaemia, which was not observed with CaCO3. Both PA21 doses, in contrast to CaCO3, prevented a dramatic increase in fibroblast growth factor (FGF)-23 and significantly reduced the vascular calcium content while both compounds ameliorated CKD-related hyperparathyroid bone. CONCLUSIONS: PA21 treatment prevented an increase in serum FGF-23 and had, aside from its phosphate-lowering capacity, a beneficial impact on renal function decline (as assessed by the renal creatinine clearance) and related disorders. The protective effect of this iron-based phosphate binder on the kidney in rats, together with its low pill burden in humans, led us to investigate its use in patients with impaired renal function not yet on dialysis.

Inhibition of vascular calcification by inositol phosphates derivatized with ethylene glycol oligomers.

Myo-inositol hexakisphosphate (IP6) is a natural product known to inhibit vascular calcification (VC), but with limited potency and low plasma exposure following bolus administration. Here we report the design of a series of inositol phosphate analogs as crystallization inhibitors, among which 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), (OEG2)2-IP4, displays increased in vitro activity, as well as more favorable pharmacokinetic and safety profiles than IP6 after subcutaneous injection. (OEG2)2-IP4 potently stabilizes calciprotein particle (CPP) growth, consistently demonstrates low micromolar activity in different in vitro models of VC (i.e., human serum, primary cell cultures, and tissue explants), and largely abolishes the development of VC in rodent models, while not causing toxicity related to serum calcium chelation. The data suggest a mechanism of action independent of the etiology of VC, whereby (OEG2)2-IP4 disrupts the nucleation and growth of pathological calcification.

Use of lanthanum for water treatment A matter of concern?

Among several other eutrophication management tools, Phoslock®, a lanthanum modified bentonite (LMB) clay, is now frequently used. Concerns have been raised as to whether exposure to Phoslock®-treated water may lead to lanthanum accumulation/toxicity in both animals and humans. In the present experimental study, rats were administered lanthanum orally as either lanthanum carbonate, lanthanum chloride or Phoslock® at doses of either 0.5 or 17 mg/L during 10 weeks. Controls received vehicle. The gastrointestinal absorption and tissue distribution of lanthanum was investigated. Extremely strict measures were implemented to avoid cross-contamination between different tissues or animals. Results showed no differences in gastrointestinal absorption between the different compounds under study as reflected by the serum lanthanum levels and concentrations found in the brain, bone, heart, spleen, lung, kidney and testes. At sacrifice, significant but equally increased lanthanum concentrations versus vehicle were observed in the liver for the highest dose of each compound which however, remained several orders of magnitude below the liver lanthanum concentration previously measured after long-term therapeutic administration of lanthanum carbonate and for which no hepatotoxicity was noticed in humans. In conclusion, (i) the use of LMB does not pose a toxicity risk (ii) gastrointestinal absorption of lanthanum is minimal and independent on the type of the compound, (iii) with exception of the liver, no significant increase in lanthanum levels is observed in the various organs under study, (iv) based on previous studies, the slightly increased liver lanthanum levels observed in a worst case scenario do not hold any risk of hepatotoxicity.

Human health risk associated with the management of phosphorus in freshwaters using lanthanum and aluminium.

The use of geo-engineering materials to manage phosphorus in lakes has increased in recent years with aluminium and lanthanum based materials being most commonly applied. Hence the potential impact of the use of these compounds on human health is receiving growing interest. This review seeks to understand, evaluate and compare potential unintended consequences on human health and ecotoxicological risks associated with the use of lanthanum- and aluminium-based materials to modify chemical and ecological conditions in water bodies. In addition to their therapeutic use for the reduction of intestinal phosphate absorption in patients with impaired renal function, the phosphate binding capacity of aluminium and lanthanum also led to the development of materials used for water treatment. Although lanthanum and aluminium share physicochemical similarities and have many common applications, their uptake and kinetics within the human body and living organisms importantly differ from each other which is reflected in a different toxicity profile. Whilst a causal role in the development of neurological pathologies, skeletal lesions, hematopoietic disorders and respiratory effects has unequivocally been demonstrated with increased exposure to aluminium, studies until now have failed to find such a clear association after exposure to lanthanum although caution is warranted. Our review indicates that lanthanum and aluminium have a distinctly different profile with respect to their potential effects on human health. Regular monitoring of both aluminium and lanthanum concentrations in lanthanum-/aluminium-treated water by the responsible authorities is recommended to avoid acute accidental or chronic low level accumulation.

A magnesium based phosphate binder reduces vascular calcification without affecting bone in chronic renal failure rats.

The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover.

DPP IV inhibitor treatment attenuates bone loss and improves mechanical bone strength in male diabetic rats.

Dipeptidyl peptidase IV (DPP IV) modulates protein activity by removing dipeptides. DPP IV inhibitors are currently used to improve glucose tolerance in type 2 diabetes patients. DPP IV substrates not only increase insulin secretion but also affect bone metabolism. In this study, the effect of DPP IV inhibitor sitagliptin on bone was evaluated in normal and streptozotocin-induced diabetic rats. This study included 64 male Wistar rats divided into four groups (n = 16): two diabetic and two control groups. One diabetic and one control group received sitagliptin through drinking water. Tibiae were scanned every 3 wk using an in vivo µCT scanner. After 6 and 12 wk, rats were euthanized for histomorphometric analysis of bone parameters. The mechanical resistance of femora to fracture was assessed using a three-point bending test, and serum levels of bone metabolic markers were measured. Efficient DPP IV inhibition was achieved in sitagliptin-treated groups. Trabecular bone loss, the decrease in trabecular number, and the increase in trabecular spacing was attenuated through sitagliptin treatment in diabetic rats, as shown by in vivo µCT. Bone histomorphometry was in line with these results. µCT analysis furthermore showed that sitagliptin prevented cortical bone growth stagnation in diabetic rats, resulting in stronger femora during three-point bending. Finally, the serum levels of the resorption marker CTX-I were significantly lower in sitagliptin-treated diabetic animals compared with untreated diabetic animals. In conclusion, sitagliptin treatment attenuates bone loss and increases bone strength in diabetic rats probably through the reduction of bone resorption and independent of glycemic management.

Differences in gastrointestinal calcium absorption after the ingestion of calcium-free phosphate binders.

Both calcium-containing and noncalcium-containing phosphate binders can increase gastrointestinal calcium absorption. Previously, we observed that lanthanum carbonate administration to rats with renal failure is not associated with increased calciuria. Additionally, lanthanum carbonate treatment in dialysis patients has been associated with a less pronounced initial decrease in serum parathyroid hormone compared with other phosphate binders. For 8 days, male Wistar rats received a diet supplemented with 2% lanthanum carbonate, 2% sevelamer, 2% calcium carbonate, or 2% cellulose. Calciuria was found to be increased in animals with normal renal function treated with sevelamer or calcium carbonate but not with lanthanum carbonate. In animals with renal failure, cumulative calcium excretion showed similar results. In rats with normal renal function, serum ionized calcium levels were increased after 2 days of treatment with sevelamer, while calcium carbonate showed a smaller increase. Lanthanum carbonate did not induce differences. In animals with renal failure, no differences were found between sevelamer-treated, calcium carbonate-treated, and control groups. Lanthanum carbonate, however, induced lower ionized calcium levels within 2 days of treatment. These results were confirmed in normal human volunteers, who showed lower net calcium absorption after a single dose of lanthanum carbonate compared with sevelamer carbonate. In conclusion, these two noncalcium-containing phosphate-binding agents showed a differential effect on gastrointestinal calcium absorption. These findings may help to improve the management of calcium balance in patients with renal failure, including concomitant use of vitamin D.

Restoration of bone mineralization by cinacalcet is associated with a significant reduction in calcitriol-induced vascular calcification in uremic rats.

The present study investigated to what extent normalization of bone turnover goes along with a reduction of high-dose calcitriol-induced vascular calcifications in uremic rats. Five groups of male Sprague-Dawley rats were studied: sham-operated controls (n = 7), subtotally nephrectomized (SNX) uremic (CRF) animals (n = 12), CRF + calcitriol (vitD) (0.25 µg/kg/day) (n = 12), CRF + vitD + cinacalcet (CIN) (10 mg/kg/day) (n = 12), and CRF + vitD + parathyroidectomy (PTX) (n = 12). Treatment started 2 weeks after SNX and continued for the next 14 weeks. High-dose calcitriol treatment in hyperparathyroid rats went along with the development of distinct vascular calcification, which was significantly reduced by >50 %, in both CIN-treated and PTX animals. Compared to control animals and those of the CRF group, calcitriol treatment either in combination with CIN or PTX or not was associated with a significant increase in bone area comprising ±50 % of the total tissue area. However, whereas excessive woven bone accompanied by a dramatically increased osteoid width/area was seen in the CRF + vitD group, CIN treatment and PTX resulted in significantly reduced serum PTH level, which was accompanied by a distinct reduction of both the bone formation rate and the amount of osteoid. These data indicate that less efficient calcium and phosphorus incorporation in bone inherent to the severe hyperparathyroidism in vitamin D-treated uremic rats goes along with excessive vascular calcification, a process which is partially reversed by CIN treatment in combination with a more efficacious bone mineralization, thus restricting the availability of calcium and phosphate for being deposited in the vessel wall.

Selenium, lead, and cadmium levels in renal failure patients in China.

Whole blood and serum samples of Chinese stable chronic renal failure (CRF) patients (n = 81), hemodialysis patients (n = 135), posttransplant patients (n = 60), and subjects with normal renal function (NRF; N = 42) were collected, as well as water and dialysate samples from five dialysis centers. The concentration of selenium (Se), lead (Pb), and cadmium (Cd) was measured by atomic absorption spectrometry. The mean serum Se levels in patients with different degrees of renal failure were significantly lower than those of subjects with NRF (p < 0.01). Pb levels were not increased in renal failure patients, while the Cd levels in patients with various degrees of renal failure were higher than in subjects with NRF (p < 0.05). After correcting the results of Pb and Cd for hematocrit (Hct) however, Pb levels of dialysis patients were also increased. In the dialysis population under study, blood Pb and Cd levels were closely related to the time on dialysis, while contamination of the final dialysate may also contribute to the increased blood Cd and to a less extent Pb levels. Correction for Hct may be recommended to accurately compare blood Pb and Cd levels in dialysis patients and CRF patients with varying degrees of anemia to those of subjects with NRF.

Does the phosphate binder lanthanum carbonate affect bone in rats with chronic renal failure?

Adequate control of phosphate levels remains an important issue in patients with chronic renal failure (CRF). Lanthanum carbonate has been proposed as a new phosphate binder. Previous studies have shown a high phosphate binding capacity (>97%) and low gastrointestinal absorption of lanthanum, without serious toxic side effects in the presence of a normal renal function (NRF). Because of lanthanum's physicochemical resemblance to calcium, the possible effects of it on bone have to be considered. The aim of this study was to investigate the effects of lanthanum carbonate on bone histology in NRF and CRF rats after oral administration of the compound with doses of 100, 500, or 1000 mg/kg per d for 12 wk. Bone histomorphometry showed that CRF animals that received vehicle developed secondary hyperparathyroidism. Urinalysis of lanthanum-loaded CRF animals showed a dose-dependent decrease in urinary phosphorus excretion, which was clearly more pronounced in the CRF groups compared with NRF animals. Phosphatemia, however, remained normal. Lanthanum carbonate administration induced a dose-dependent decrease in bone formation rate and increase in osteoid area in CRF animals. Three of seven animals in the CRF-1000 group and one of eight animals in the NRF-100 group were classified as having a mineralization defect. The number of cuboidal osteoblasts, however, was not affected, indicating that bone changes were not due to a toxic effect of lanthanum on the osteoblast. Furthermore, lanthanum concentrations in the femur remained low and did not correlate with histomorphometric parameters. These findings suggest that the administration of high doses of phosphate binder (1000 mg/kg per d lanthanum carbonate), in combination with decreased 25-(OH) vitamin D(3) in the uremic state, resulted in phosphate depletion and followed by an increased mobilization of phosphorus out of bone and/or reduced incorporation into bone. There was no evidence that lanthanum had a direct toxic effect on osteoblasts.

Lanthanum carbonate: a new phosphate binder.

PURPOSE OF REVIEW: Hyperphosphatemia remains an important aspect in the management of end-stage renal disease patients. Consequently, there is a need for new, efficient and well-tolerated phosphate binders. In this review, a new phosphate-binding drug, lanthanum carbonate, with an attractive preclinical efficacy profile compared with existing binders, is discussed. Although the available human efficacy and safety data over 3 years are encouraging, the consequences of low-level tissue deposition continue to be evaluated in longer-term clinical studies. RECENT FINDINGS: Lanthanum carbonate has been shown in clinical studies of up to 3 years to be an effective, well-tolerated phosphate binder. Reported adverse effects are mainly gastrointestinal, and do not differ from those of calcium carbonate. The gastrointestinal absorption of lanthanum is very low. Whereas the element is mainly excreted by the liver, renal excretion of the absorbed fraction is less than 2%. Bone lanthanum levels seen after long-term treatment (up to 4 years) seem not to affect the physicochemical process of mineralization, or osteoblast number/function. Preliminary data on the localization of lanthanum in bone have shown the element to be present at both active and quiescent sites of bone mineralization, independent of the type of renal osteodystrophy, a profile distinct from aluminum, as well as diffusely distributed throughout the mineralized bone matrix especially in rats/humans with an increased bone turnover. A randomized, comparator-controlled, parallel group, open-label study comparing lanthanum carbonate with calcium carbonate in dialysis patients showed no evolution towards low bone turnover in the lanthanum group, and no aluminum-like effect on bone. SUMMARY: Lanthanum carbonate seems to be a potent phosphate-binding drug, minimally absorbed from the gut, with an encouraging safety profile, and no deleterious effects on bone.