Intercellular mediators in bone remodeling regulation in the experimental renal pathology / Mediadores intercelulares de la regulación de la remodelación ósea en un modelo experimental de patología renal

Bone metabolism disorders are characterized by an imbalance of bone resorption and formation in the bone remodeling process. Glucocorticoids that are used to treat kidney diseases exacerbate these disorders. P-selectin and galectin-3 are molecules involved in the sclerotic process in kidney, whereas bone resorption is regulated by the interaction between the nuclear factor activator kappa b receptor (RANK), its ligand (RANKL) and the RANKL decoy receptor osteoprotegerin (OPG). The aim of this study was to investigate the cellular and molecular mechanisms of disruption of bone remodeling regulation processes, reflected by intercellular mediators (RANKL, OPG, P-selectin and galectin-3) in chronic kidney disease experimental model treated with glucocorticoids. Rats were divided into four groups of 10 animals each. The first group, the control group, included intact animals. The second group consisted of rats with impaired bone remodeling resulting from chronic kidney disease (experimental group (CKD). The third group was a group of animals with impaired bone remodeling due to exposure to glucocorticoids (experimental group (GCs)). The fourth group consisted of rats with impaired bone remodeling in chronic kidney disease, followed by exposure to glucocorticoids (experimental group (CKD + GCs)). The effects of CKD and glucocorticoid were evaluated biochemically, histologically and by measuring bone density. An enzymelinked immunoassay was used to measure intercellular mediator levels in the serum. The bone density in the experimental groups was reduced compared to the control group. RANKL levels in animals of three experimental groups were higher than in intact animals. Serum levels of OPG were higher in CKD and GCs groups than in intact animals. At the same time, in the animals' blood serum of the CKD + GCs group, the levels of OPG were lower, than those in animals from the control group. The levels of galectin-3 in the serum of the experimental groups GCs and CKD + GCs were lower than in intact animals. The serum levels of galectin-3 in animals of the CKD group were higher than those in animals from the control group. The levels of P-selectin were lower in the serum of the GCs group than in intact animals. At the same time, the levels of P-selectin were higher in the CKD and CKD + GCs groups, than those in animals from the control group. In conclusion, the study of the complex system of bone remodeling regulation, which includes many factors and their interactions, may lead to the development of new methods for treating patients with chronic kidney disease in order to prevent osteoporosis in the future. (AU)

Las enfermedades metabólicas óseas se caracterizan por un desequilibrio en el proceso de remodelación ósea en los que participan mediadores tales como receptor del activador del factor nuclear- kappa- b (RANK), su ligando (RANKL) y la osteoprotegerina (OPG). Los glucocorticoides, recuentemente empleados en el tratamiento de la enfermedad renal crónica, exacerban este desequilibrio. En la enfermedad esclerótica renal, las moléculas de adhesión celular P-selectina and galectina-3 tienen un rol fundamental. El objetivo de esta trabajo fue estudiar las alteraciones en los mediadores de la remodelación ósea (RANKL, OPG, P-selectina and galectina-3) en un modelo de enfermedad renal crónica con tratamiento glucocorticoideo. Ratas Wistar hembras fueron divididos en 4 grupos: control (C); enfermedad renal crónica con afección de la remodelación ósea (ERC); animales con afección de la remodelación ósea expuestos a glucocorticoides (GC); enfermedad renal crónica con afección de la remodelación ósea tratados con glucocorticoides (ERC+GC). Los efectos de la ERC y los GC fueron evaluados bioquímicamente, histológicamente y por medición de la densidad ósea. RANKL, OPG, Pselectina and galectina-3 se cuantificaron en muestras de sangre venosa empleando enzimoinmuno análisis. En los 3 grupos experimentales la densidad ósea se evidenció reducida y los niveles séricos de RANKL elevados respecto al grupo control. Los niveles de OPG en los grupos ERC y GC fueron superiores mientras que en el grupo ERC+GC menores respecto a los animales controles. Galectina 3 plasmática en GC y ERC+GC se encontró reducida y aumentada en los animales ERC, en comparación con los animales controles. La concentración sérica de P-selectina sérica fue mayor en los grupos ERC y ERC+GC, y menor en los animales GC respecto a los niveles plasmáticos de los animales intactos. El avance del conocimiento sobre la regulación de la remodelación ósea a través de la interacción de mediadores sistémicos, en un futuro, puede conducir al desarrollo de nuevas estrategias terapéuticas para la prevención de la osteoporosis en pacientes con enfermedad renal crónica. (AU)

Sclerostin in chronic kidney disease-mineral bone disorder think first before you block it!

Canonical Wnt signalling activity is a major player in physiological and adaptive bone metabolism. Wnt signalling is regulated by soluble inhibitors, with sclerostin being the most widely studied. Sclerostin's main origin is the osteocyte and its major function is blockade of osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Consequently, blocking sclerostin via human monoclonal antibodies (such as romosozumab) represents a promising perspective for the treatment of (postmenopausal) osteoporosis. However, sclerostin's physiology and the effects of sclerostin monoclonal antibody treatment are not limited to the skeleton. Specifically, the potential roles of sclerostin in chronic kidney disease (CKD) and associated pathologies covered by the term chronic kidney disease and mineral bone disorder (CKD-MBD), which also includes accelerated cardiovascular calcification, warrant specific attention. CKD-MBD is a complex disease condition in which sclerostin antibodies may interfere at different levels and influence the multiform interplay of hyperparathyroidism, renal osteodystrophy and vascular calcification, but the clinical sequelae remain obscure. The present review summarizes the potential effects of sclerostin blockade in CKD-MBD. We will address and summarize the urgent research targets that are being identified and that need to be addressed before a valid risk-benefit ratio can be established in the clinical setting of CKD.

Ifosfamide induced renal rickets.

Ifosfamide is commonly used as a chemotherapeutic agent in children. The authors report a 4-y-old boy who developed proximal renal tubulopathy with florid rickets a year after completion of ifosfamide therapy for Ewing's sarcoma. After initiation of treatment, there was complete healing of rickets and he did not need supplements beyond 18 mo. Growth monitoring and musculoskeletal system examination is important in all children who have received ifosfamide therapy. Routine monitoring for nephrotoxicity during and after ifosfamide therapy helps in early identification and intervention.

Type 2 diabetes and bone fractures.

PURPOSE OF REVIEW: To discuss current literature and hypotheses pertaining to the pathophysiology of increased bone fragility and fracture in men and women with type 2 diabetes mellitus. RECENT FINDINGS: Despite high bone mineral density, studies have shown that men and women with type 2 diabetes mellitus (T2DM) are at increased risk for fracture. Complications of T2DM including retinopathy and autonomic dysfunction may contribute to bone fracture by increasing fall risk. Nephropathy may lead to renal osteodystrophy. Lean mass and potentially fat mass, may additionally contribute to skeletal health in diabetes. There is increasing acknowledgement that the marrow microenvironment is critical to efficient bone remodeling. Medications including thiazolidinediones and selective serotonin reuptake inhibitors may also impair bone remodeling by acting on mesenchymal stem cell differentiation and osteoblastogenesis. T2DM is associated with significant alterations in systemic inflammation, advanced glycation end-product accumulation and reactive oxygen species generation. These systemic changes may also directly and adversely impact the remodeling cycle and lead to bone fragility in T2DM, though more research is needed. SUMMARY: Fracture is a devastating event with dismal health consequences. Identifying the extrinsic and intrinsic biochemical causes of bone fracture in T2DM will speed the discovery of effective strategies for fracture prevention and treatment in this at-risk population.

Moderate strontium loading induces rickets in rats with mild chronic renal failure.

BACKGROUND/AIMS: Renal osteodystrophy and eventually osteoporosis are serious long-term complications in children with end-stage renal disease before and after renal transplantation. Strontium (Sr) salts are used for treatment of osteoporosis in adults. METHODS: To evaluate the time-dependent effects of Sr on growth plate morphology and their reversibility, chronic renal failure (CRF) rats received either normal or Sr-loaded drinking water (2 g/l; ±200 mg/kg/day) for periods of 2, 6 and 12 weeks with or without subsequent washout periods of 0, 2, 4 or 8 weeks. RESULTS: While weight gain was not affected by Sr loading, a significant enlargement of the entire growth plate, mainly due to expansion of the hypertrophic zone, was already present after 2 weeks. Sr-loaded animals showed increased osteoid areas and reduced bone formation rates at 2, 6 and 12 weeks compared to controls. This was accompanied by reduced PTH levels and increased serum bone alkaline phosphatase activity. After the washout periods these effects were reversed. In general, the height of the hypertrophic zone was positively correlated with osteoid area and negatively correlated with bone formation rate. CONCLUSION: Moderate Sr loading in CRF rats results in rapid development of rickets, which is reversible after washout.

Mutant FGF23 prevents the progression of chronic kidney disease but aggravates renal osteodystrophy in uremic rats.

Phosphorus is one of the important factors that accelerate the progression of chronic kidney disease. Phosphorus restriction or phosphate binders have been reported to have the ability to prevent the progression of chronic kidney disease. FGF23 is a circulating factor that regulates renal phosphorus reabsorption and 1 alpha-hydroxylase activity. We focused on the phosphaturic activity of FGF23 and investigated whether a pharmacological dose of FGF23 is beneficial to the progression of renal insufficiency in uremic rats. To this end, we administered one of the mutant FGF23 expression plasmids into irreversible Thy1 rats. Chronic renal failure rats were established by intravenous injection of anti-rat CD90 (Thy1.1) monoclonal antibody to unilaterally nephrectomized Wistar rats. The rats were then intravenously injected every 2 wk with a naked DNA solution containing 10 microg of MOCK vector or a mutant FGF23 expression plasmid for 13 wk. Renal function was assessed biochemically and histopathologically. Mutant FGF23 significantly decreased serum creatinine and serum urea nitrogen. The marked glomerular sclerosis observed in uremic rats receiving the MOCK vector was ameliorated in rats treated with mutant FGF23. However, mutant FGF23 not only significantly decreased serum 1,25(OH)(2)D and calcium but also aggravated high-turnover renal osteodystrophy from extremely high levels of PTH. These results might be a result of the mechanisms of FGF23 such as phosphaturic activity and lowering the level of 1,25(OH)(2)D. In conclusion, mutant FGF23 prevented the progression of chronic renal failure by regulating serum phosphorus but aggravated renal osteodystrophy from the lowered levels of 1,25(OH)(2)D.

Screening plasma aluminum levels in relation to aluminum bone disease among asymptomatic dialysis patients.

Aluminum accumulation in plasma and tissues is a well-described complication among persons undergoing peritoneal dialysis or hemodialysis. Excess bone aluminum is associated with low bone formation rates and increased risk for fractures. Current recommendations for care of patients with end-stage renal disease include screening for aluminum toxicity with plasma aluminum levels; patients with levels below 40 microg/L are considered to be at low risk for aluminum bone disease (ABD). We examined data from the Toronto Renal Osteodystrophy Study to evaluate the performance of plasma aluminum levels in screening for ABD. Two hundred fifty-eight unselected patients undergoing peritoneal dialysis (n = 143) or hemodialysis (n = 115) underwent diagnostic bone biopsy and measurement of plasma aluminum level. Sixty-nine patients (26.7%) were identified as having ABD, defined as low or normal bone formation rates with 25% or more bone surface aluminum staining. Plasma aluminum level was strongly associated with the presence of ABD; the odds ratio was 1.4 for each increase of 10 microg/L (95%CI, 1.2, 1.6). However, only 50.1% of patients with a plasma aluminum level of 40 microg/L or greater had ABD, whereas 14.2% of patients with a level below this threshold also had ABD. Using this cutoff level of 40 microg/L, the sensitivity and specificity were 65.2% and 76.7%, respectively. We conclude that although there is a correlation between high aluminum levels and ABD, a patient's plasma aluminum level does not predict well the presence of ABD in spite of a relatively high prevalence of disease.

Growth hormone and renal osteodystrophy: a case report.

A 14-year-old male with end-stage renal disease on hemodialysis was treated with recombinant growth hormone for growth retardation. He developed severe renal osteodystrophy, which responded only to the discontinuation of growth hormone.

Does renal osteodystrophy develop and/or progress during the course of rhGH treatment?

Recent expansion of the use of recombinant growth hormone (GH) to non-GH-deficient patients demands close attention to possible complications in these patients, including the effects on bone. Recent studies on the use of GH in children with chronic renal failure (CRF) provide some early data. In several studies of GH in CRF no significant differences in radiographic osteodystrophy scores, serum calcium, phosphorus or parathyroid hormone (PTH) levels between treated and untreated groups have been found. Alkaline phosphatase increases transiently. The effect of ROD on growth response has not yet been reported. Children with CRF treated with GH should be serially monitored for ROD with serial radiographs and for serum calcium, phosphorus, alkaline phosphatase and PTH levels.

Experimental osteodystrophy of chronic renal failure induced by aluminum- and ferric-nitrilotriacetate in Wistar rats.

The aluminum (AI) and iron (Fe) chelate complexes of nitrilotriacetate (NTA) cause renal insufficiency when they are administered intraperitoneally to rats. Their effects on bone metabolism were studied in 4 week old Wistar rats. Daily intraperitoneal administration of AI-NTA (3mg AI/kg for 11 weeks) induced osteomalacia, impaired bone growth, decreased bone mineral density, lower serum PTH levels than normal as well as renal insufficiency. Al staining showed diffuse deposition in the trabecula and a strong linear band of aluminum deposited at the mineralization front and along the cement line. The osteoid seen markedly within the trabecula was probably the decalcified portion of the bone, the calcium apatite of which was defectively fabricated because of diffuse Al deposition in the trabecula. Al deposition along the cement line would make it much more susceptible to external shear stress than normal. Although daily intraperitoneal administration of Fe-NTA (6 mg Fe/kg for 11 weeks) caused impaired bone growth, decreased bone mineral content and renal insufficiency, the osteoid volume did not increase. Fe staining showed that Fe was deposited diffusely in the cytoplasm of osteoblasts. The results of this study demonstrated that during renal insufficiency, different minerals exhibit different modes of action on bone metabolism, and that Al-NTA is useful for experimental animal models of Al-induced osteomalacia in renal insufficiency.

Renal osteodystrophy and hypercalcemia.

The occurrence of aluminum-related bone disease should be completely prevented in uremic patients by restricting the use of aluminum-phosphate binders, which can be safely replaced by oral calcium carbonate. Factors other than aluminum may lead to adynamic bone disease in uremic patients. Radiolucent bone cysts are indicative of amyloid deposits, and their occurrence and progression may be influenced by the membranes used for hemodialysis. Bone disease may persist after successful renal transplantation, and the additional deleterious effect of immunosuppressive drugs should be emphasized. Primary hyperparathyroidism is the most frequent cause of hypercalcemia in the general population. Surgery should be undertaken when there is evidence of active disease, even in asymptomatic patients. The consequences of primary hyperparathyroidism on bone mass and bone fragility remain controversial, and histologic bone studies suggest that hyperparathyroidism leads to increased bone turnover without any deleterious effect on bone volume or trabecular architecture. The diagnostic value of a newly developed immunoassay for intact parathyroid hormone and parathyroid hormone-related protein is clearly demonstrated. New bisphosphonates are of major value for the management of hypercalcemia in malignancy.

Detection of subtle aluminum-related renal osteodystrophy.

We compared the sensitivity of aurin tricarboxylic acid (ATA) or acid solochrome azurine (ASA) for detecting bone aluminum histochemically in 87 biopsy specimens obtained between 1983 and 1987 from 84 patients receiving dialysis therapy. Two consecutive biopsy sections were stained, one with ATA and the other with ASA, and then interpreted independently by two experienced observers. Three groups were established: group 1 (N = 61) had positive results of both ATA and ASA staining, group 2 (N = 25) had negative ATA but positive ASA sections, and group 3 (N = 1) had negative results of both ATA and ASA. No significant differences existed between groups 1 and 2 for age of the patients or serum calcium or immunoreactive parathyroid hormone levels. Patients in group 1 had significantly higher bone aluminium content (110 versus 61 micrograms/g dry ash weight), higher serum aluminum levels (151 versus 26 ng/ml), and longer duration of dialysis (85 versus 30 months) than did patients in group 2. Bone biopsy diagnoses (group 1 versus group 2) included low-turnover bone disease, 8 versus 7; osteomalacia, 26 versus 0; mixed uremic bone disease, 10 versus 1; hyperparathyroidism, 12 versus 14; and mild uremic bone disease, 5 versus 4. On the basis of ATA staining, 7 of 15 patients with low-turnover and 1 of 11 patients with mixed uremic bone disease may have been incorrectly diagnosed as having non-aluminum-related bone disorders. The levels of bone and serum aluminum were lower in group 2 than in group 1 but still much higher than normal.(ABSTRACT TRUNCATED AT 250 WORDS)

[Bone histology and clinical diagnostic criteria in aluminum-induced bone disease].

Bone remodeling and aluminum (Al) staining were carried out in 429 bone biopsies from patients with uremic bone disease, 273 cases were Al positive (64%). In high-turnover, low-turnover and mixed type of renal osteodystrophy the Al-positive rate was 29%, 75% and 80%, and Al deposition on bone surfaces was 44 +/- 33%, 80 +/- 30% and 62 +/- 35% respectively. Thus the low-turnover and mixed type have a higher Al-positive rate and more Al deposition than the high-turnover type. Animal experiments using decalcified bone matrix implants showed that Al inhibited all bone remodeling processes except cartilage formation. These and other data indicate that Al induces low-turnover bone disease, i.e., osteomalacia or aplastic bone disease. Osteomalacia in our series showed increased osteoid area and mineralization lag time, and decreased calcified bone area, bone mineralization rate and cells number. Aplastic bone disease was similar with that but had reduced osteoid and a normal ratio of steroid to calcified bone. The relationship of these studies to clinical diagnostic criteria of Al-induced bone disease is discussed.

Hysteresis of the parathyroid hormone response to hypocalcemia in hemodialysis patients with low turnover aluminum bone disease.

During the study of parathyroid function in 19 hemodialysis patients with low turnover aluminum bone disease, it was observed that serum parathyroid hormone (PTH) levels were higher during the induction of hypocalcemia than during the recovery from hypocalcemia. This type of PTH response has been termed hysteresis. Hypocalcemia was induced during hemodialysis with a calcium-free dialysate. When the total serum calcium level decreased to 7 mg/dL, the dialysate calcium concentration was changed to 3.5 mEq/L and the dialysis session was completed. One week later, hypercalcemia was induced during hemodialysis with a high-calcium dialysate. The mean basal PTH level was 132 +/- 37 pg/mL (normal, 10 to 65 pg/mL; immunoradiometric (IRMA), Nichols Institute, San Juan Capistrano, CA) and increased to a maximal PTH level of 387 +/- 91 pg/mL during hypocalcemia. For the same ionized calcium concentration, the PTH level was higher during the induction of hypocalcemia than during the recovery from hypocalcemia. Conversely, for the same ionized calcium concentration, the PTH level was greater when hypercalcemia was induced from the nadir of hypocalcemia than when hypercalcemia was induced from basal serum calcium. The set point of calcium (defined as the serum calcium concentration required to reduce maximal PTH by 50%) was greater during the induction of hypocalcemia than during the recovery from hypocalcemia (4.44 +/- 0.10 versus 4.25 +/- 0.09 mg/dL; P = 0.03). The mean basal ionized calcium concentration and the mean ionized calcium concentration at the intersection of the two PTH-calcium curves were the same (4.61 +/- 0.13 versus 4.61 +/- 0.12 mg/dL).(ABSTRACT TRUNCATED AT 250 WORDS)

Ifosfamide, Fanconi's syndrome, and rickets.

Three of 218 children treated with ifosfamide plus the uroprotectant mesna, in single- or combination-agent protocols, have developed Fanconi's renal syndrome, all of whom were in a subgroup of 86 children who had also received cisplatin or carboplatin therapy. Patients receiving ifosfamide who have received prior cisplatin (or carboplatin) are at significantly higher risk of developing Fanconi's syndrome than are those who have received no prior nephrotoxic therapy (P = .04). The role of prior nephrotoxic therapy, including cisplatin and its derivatives, and the total dose of ifosfamide should be considered in the assessment of this rare but serious and apparently irreversible side effect.