ABSTRACT
Diabetic Kidney Disease (DKD) is a major microvascular complication for diabetic patients and is the most common cause of chronic kidney disease (CKD) and end-stage renal disease. Antidiabetic drugs, such as metformin and canagliflozin, have been shown to exert renoprotective effects. Additionally, quercetin recently showed promising results for the treatment of DKD. However, the molecular pathways through which these drugs exert their renoprotective effects remain partly unknown. The current study compares the renoprotective potential of metformin, canagliflozin, metformin + canagliflozin, and quercetin in a preclinical rat model of DKD. By combining streptozotocin (STZ) and nicotinamide (NAD) with daily oral N(ω)-Nitro-L-Arginine Methyl Ester (L-NAME) administration, DKD was induced in male Wistar Rats. After two weeks, rats were assigned to five treatment groups, receiving vehicle, metformin, canagliflozin, metformin + canagliflozin, or quercetin for a period of 12 weeks by daily oral gavage. Non-diabetic vehicle-treated control rats were also included in this study. All rats in which diabetes was induced developed hyperglycemia, hyperfiltration, proteinuria, hypertension, renal tubular injury and interstitial fibrosis, confirming DKD. Metformin and canagliflozin, alone or together, exerted similar renoprotective actions and similar reductions in tubular injury and collagen accumulation. Renoprotective actions of canagliflozin correlated with reduced hyperglycemia, while metformin was able to exert these effects even in the absence of proper glycemic control. Gene expression revealed that the renoprotective pathways may be traced back to the NF-κB pathway. No protective effect was seen with quercetin. In this experimental model of DKD, metformin and canagliflozin were able to protect the kidney against DKD progression, albeit in a non-synergistic way. These renoprotective effects may be attributable to the inhibition of the NF-κB pathway.
Subject(s)
Diabetes Mellitus, Experimental , Diabetic Nephropathies , Hyperglycemia , Metformin , Male , Rats , Animals , Diabetic Nephropathies/metabolism , Canagliflozin/pharmacology , Canagliflozin/therapeutic use , Metformin/pharmacology , Metformin/therapeutic use , Metformin/metabolism , NF-kappa B/metabolism , Quercetin/pharmacology , Rats, Wistar , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Kidney/metabolism , Hyperglycemia/metabolismABSTRACT
Vascular calcification significantly contributes to mortality in chronic kidney disease (CKD) patients. Sevelamer and pyrophosphate (PPi) have proven to be effective in preventing vascular calcification, the former by controlling intestinal phosphate absorption, the latter by directly interfering with the hydroxyapatite crystal formation. Since most patients present with established vascular calcification, it is important to evaluate whether these compounds may also halt or reverse the progression of preexisting vascular calcification. CKD and vascular calcification were induced in male Wistar rats by a 0.75 % adenine low protein diet for 4 weeks. Treatment with PPi (30 or 120 µmol/kg/day), sevelamer carbonate (1500 mg/kg/day) or vehicle was started at the time point at which vascular calcification was present and continued for 3 weeks. Hyperphosphatemia and vascular calcification developed prior to treatment. A significant progression of aortic calcification in vehicle-treated rats with CKD was observed over the final 3-week period. Sevelamer treatment significantly reduced further progression of aortic calcification as compared to the vehicle control. No such an effect was seen for either PPi dose. Sevelamer but not PPi treatment resulted in an increase in both osteoblast and osteoid perimeter. Our study shows that sevelamer was able to reduce the progression of moderate to severe preexisting aortic calcification in a CKD rat model. Higher doses of PPi may be required to induce a similar reduction of severe established arterial calcification in this CKD model.
Subject(s)
Diphosphates/pharmacology , Durapatite/antagonists & inhibitors , Renal Insufficiency, Chronic/complications , Sevelamer/pharmacology , Vascular Calcification/pathology , Animals , Aorta/pathology , Chelating Agents/pharmacology , Male , Rats , Rats, Wistar , Vascular Calcification/etiologyABSTRACT
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.
Subject(s)
Calcium/metabolism , Carbamates/pharmacology , Cellulose/pharmacology , Gastrointestinal Tract/physiology , Lanthanum/pharmacology , Polyamines/pharmacology , Adult , Animals , Chelating Agents/pharmacology , Female , Humans , Male , Phosphates/chemistry , Phosphates/metabolism , Rats , Rats, Wistar , Renal Insufficiency, Chronic/metabolism , Sevelamer , Young AdultABSTRACT
Renal osteodystrophy (ROD) is a complex and serious complication of chronic kidney disease (CKD), a major global health problem caused by loss of renal function. Currently, the gold standard to accurately diagnose ROD is based on quantitative histomorphometric analysis of trabecular bone. Although this analysis encompasses the evaluation of osteoblast and osteoclast number/activity, tfigurehe interest in osteocytes remains almost nihil. Nevertheless, this cell type is evidenced to perform a key role in bone turnover, particularly through its production of various bone proteins, such as sclerostin. In this study, we aim to investigate, in the context of ROD, to which extent an association exists between bone turnover and the abundance of osteocytes and osteocytic sclerostin expression in both the trabecular and cortical bone compartments. Additionally, the effect of parathyroid hormone (PTH) on bone sclerostin expression was examined in parathyroidectomized rats. Our results indicate that PTH exerts a direct inhibitory function on sclerostin, which in turn negatively affects bone turnover and mineralization. Moreover, this study emphasizes the functional differences between cortical and trabecular bone, as the number of (sclerostin-positive) osteocytes is dependent on the respective bone compartment. Finally, we evaluated the potential of sclerostin as a marker for CKD and found that the diagnostic performance of circulating sclerostin is limited and that changes in skeletal sclerostin expression occur more rapidly and more pronounced. The inclusion of osteocytic sclerostin expression and cortical bone analysis could be relevant when performing bone histomorphometric analysis for diagnostic purposes and to unravel pathological mechanisms of bone disease.
Subject(s)
Chronic Kidney Disease-Mineral and Bone Disorder , Renal Insufficiency, Chronic , Rats , Animals , Osteocytes/metabolism , Bone and Bones/metabolism , Bone Remodeling , Parathyroid Hormone/metabolism , Chronic Kidney Disease-Mineral and Bone Disorder/metabolism , Renal Insufficiency, Chronic/complicationsABSTRACT
The most common cause of death in the intensive care unit (ICU) is the development of multiorgan dysfunction syndrome (MODS). Besides life-supporting treatments, no cure exists, and its mechanisms are still poorly understood. Catalytic iron is associated with ICU mortality and is known to cause free radical-mediated cellular toxicity. It is thought to induce excessive lipid peroxidation, the main characteristic of an iron-dependent type of cell death conceptualized as ferroptosis. Here we show that the severity of multiorgan dysfunction and the probability of death are indeed associated with plasma catalytic iron and lipid peroxidation. Transgenic approaches underscore the role of ferroptosis in iron-induced multiorgan dysfunction. Blocking lipid peroxidation with our highly soluble ferrostatin-analogue protects mice from injury and death in experimental non-septic multiorgan dysfunction, but not in sepsis-induced multiorgan dysfunction. The limitations of the experimental mice models to mimic the complexity of clinical MODS warrant further preclinical testing. In conclusion, our data suggest ferroptosis targeting as possible treatment option for a stratifiable subset of MODS patients.
Subject(s)
Ferroptosis , Animals , Cell Death , Humans , Iron/metabolism , Lipid Peroxidation , Mice , Multiple Organ Failure/prevention & controlABSTRACT
BACKGROUND: Hyperphosphataemia is a risk factor for arterial calcification contributing to the high cardiovascular mortality in patients with chronic kidney disease. Calcium-based phosphate binders can induce hypercalcaemia and are associated with progression of vascular calcification. Therefore, the effect of lanthanum carbonate, a non-calcium phosphate binder, on the development of vascular calcification was investigated in uraemic rats. METHODS: Chronic renal failure (CRF) was induced by feeding rats an adenine-enriched diet for 4 weeks. After 2 weeks, 1% or 2% lanthanum carbonate was added to the diet for 6 weeks. Calcification in the aorta, carotid and femoral arteries was evaluated histomorphometrically, biochemically and by ex vivo micro-CT. Chondro-/osteogenic conversion of vascular smooth muscle cells was also analysed in the rat aorta. RESULTS: Treatment with 1% lanthanum carbonate (1% La) did not reduce vascular calcification, but in the 2% lanthanum carbonate (2% La) group vascular calcium content and area% Von Kossa positivity were decreased compared with control CRF rats. The aortic calcified volume measured with ex vivo micro-CT was significantly reduced in rats treated with 2% La. Although calcification was inhibited by treatment with 2% La, the chondrocyte transcription factor sox-9 was abundantly expressed in the aorta. CONCLUSION: Treatment of CRF rats with 2% La reduces the development of vascular calcification by adequate phosphate binding resulting in a decreased supply of phosphate as a substrate for vascular calcification.
Subject(s)
Calcinosis/prevention & control , Kidney Failure, Chronic/drug therapy , Kidney Failure, Chronic/metabolism , Lanthanum/therapeutic use , Phosphates/metabolism , Vascular Diseases/prevention & control , Animals , Arteries/drug effects , Arteries/metabolism , Arteries/pathology , Bone and Bones/drug effects , Bone and Bones/metabolism , Bone and Bones/pathology , Calcinosis/metabolism , Calcinosis/pathology , Chondrogenesis/drug effects , Hyperphosphatemia/drug therapy , Hyperphosphatemia/metabolism , Hyperphosphatemia/pathology , Kidney Failure, Chronic/pathology , Lanthanum/administration & dosage , Male , Osteogenesis/drug effects , Rats , Rats, Wistar , Vascular Diseases/metabolism , Vascular Diseases/pathologyABSTRACT
OBJECTIVE: Chronic renal failure (CRF) is associated with a 10- to 20-fold increase in cardiovascular risk. Vascular calcification is a prominent feature of cardiovascular disease in patients with end-stage renal failure and contributes to the excess mortality in this population. In this study, we explored in vivo X-ray microtomography (micro-CT) as a tool to detect and follow-up vascular calcifications in the aorta of living rats with adenine-induced CRF. METHODS AND RESULTS: With in vivo micro-CT, calcification of the aorta in uremic rats was clearly discernible on transversal virtual cross-sections. Micro-CT findings correlated well with tissue calcium content and histology. Repetitive scans in animals with light, moderate, and severe vascular calcification showed good reproducibility with minimal interference of motion artifacts. Moreover, both calcified volume and area could be quantified with this method. CONCLUSIONS: In vivo micro-CT scanning is a sensitive method to detect vascular calcifications in CRF rats, allowing follow-up and quantification of the development, and potential reversal during treatment, of vascular calcifications in living animals.
Subject(s)
Aortic Diseases/diagnostic imaging , Aortic Diseases/etiology , Calcinosis/diagnostic imaging , Calcinosis/etiology , Kidney Failure, Chronic/complications , Tomography, X-Ray Computed , Animals , Aorta, Thoracic/metabolism , Aortic Diseases/metabolism , Aortic Diseases/pathology , Calcinosis/metabolism , Calcinosis/pathology , Calcium/metabolism , Feasibility Studies , Image Processing, Computer-Assisted , Imaging, Three-Dimensional , In Vitro Techniques , Models, Cardiovascular , Rats , Reproducibility of Results , Sensitivity and Specificity , Severity of Illness IndexABSTRACT
The remnant kidney rat model has been extensively used for the evaluation of bone changes due to uremia. The present study aimed to assess the effect of the dietary phosphorus availability and of the severity of renal failure on bone histomorphometric changes and various biochemical markers over time in this model. Chronic renal failure (CRF) was induced in male Wistar rats by 5/6th nephrectomy. Half of the number of animals received a standard rat diet (STD) (0.67% P, containing low bioavailable phosphorus of plant origin); the other animals were fed a high phosphorus diet (HPD) (0.93% P, containing inorganic phosphorus with high bioavailability). Every two weeks, blood and urine samples were collected. At sacrifice after 6 or 12 weeks, bone samples were taken for the measurement of histological and histodynamic parameters. Serum creatinine measurements indicated the development of mild to moderate renal failure in both diet groups. Phosphaturia was unexpectedly low in all animals that received the STD, indicating relative phosphorus depletion despite the normal dietary phosphorus content. In the HPD CRF group, a decrease in calcemia and a rise in phosphatemia were seen after 12 weeks of CRF, which were more pronounced in animals with higher serum creatinine. Serum iPTH levels were distinctly increased in CRF rats fed a HPD, especially those with more pronounced renal failure. Serum osteocalcin and to a lesser extend tartrate-resistant acid phosphatase and urinary pyridinoline and deoxypyridinoline crosslinks were higher in the CRF animals compared to the shams, particularly in the animals of the HPD group with more pronounced CRF. In both diet groups, the CRF animals had significantly higher amounts of osteoid compared to shams. Only the animals that received a HPD developed distinct histological signs of secondary hyperparathyroidism (sHPTH), that is, an increased bone formation rate, mineral apposition rate, osteoblast perimeter, and eroded perimeter. Again, this effect was most prominent in rats with more severe CRF. In conclusion, data of the present study indicate that in experimental studies using the remnant kidney rat model, both the dietary phosphorus bioavailability and the degree of renal failure in the development of hyperparathyroidism should be considered.
Subject(s)
Chronic Kidney Disease-Mineral and Bone Disorder/etiology , Hyperparathyroidism, Secondary/etiology , Kidney Failure, Chronic/complications , Phosphorus, Dietary/adverse effects , Uremia/complications , Animals , Biomarkers/blood , Biomarkers/urine , Body Weight/drug effects , Bone and Bones/metabolism , Bone and Bones/pathology , Chronic Kidney Disease-Mineral and Bone Disorder/metabolism , Chronic Kidney Disease-Mineral and Bone Disorder/pathology , Eating/drug effects , Hyperparathyroidism, Secondary/blood , Hyperparathyroidism, Secondary/urine , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/urine , Male , Rats , Rats, Wistar , Uremia/blood , Uremia/urine , UrineABSTRACT
BACKGROUND: We have previously shown that administration of the new phosphate binder lanthanum (La) carbonate at high doses during 12 weeks induces a mineralization defect (MD) in chronic renal failure (CRF) rats most likely due to the powerful phosphate binding. In this study, we want to investigate the fate and possible biological activities of La once it is accumulated in bone. METHODS: CRF animals (5/6th nephrectomy) received La carbonate (2,000 mg/kg/day) via oral gavage for 2 or 6 weeks and were sacrificed immediately at the end of the treatment period and after a wash out period of 2 and 8 weeks. Bone histomorphometry and measurement of bone La content were performed. Control CRF animals received vehicle only. RESULTS: After 2 weeks of La treatment, 75% of the animals showed signs of MD compared to 14% in CRF controls despite similar bone La levels. Two weeks after arrest of La treatment, bone La levels remained unchanged, yet 87% showed normal bone histology. A similar evolution was noted in the animals treated for 6 weeks. Bone histology showed a reduction of number of animals with a MD from 62.5% at 6 weeks of La treatment to 20% and 28% 2 and 8 weeks after arrest of La treatment respectively. CONCLUSION: The phosphate-binder-induced MD may appear and disappear without any change in either the perimeter of active osteoblasts or in bone La levels. Bone histology in CRF animals normalized after arrest of the La administration, thereby presenting further arguments for the MD in La-treated animals to result from the high phosphate binding capacity of La rather than being the consequence of a direct effect of La on bone.
Subject(s)
Bone Density/drug effects , Kidney Failure, Chronic/drug therapy , Kidney Failure, Chronic/pathology , Lanthanum/pharmacology , Animals , Bone and Bones/metabolism , Bone and Bones/pathology , Calcification, Physiologic/drug effects , Calcium/blood , Calcium/urine , Lanthanum/blood , Male , Phosphates/blood , Phosphates/urine , Rats , Rats, WistarABSTRACT
Because current rat models used to study chronic kidney disease (CKD)-related vascular calcification show consistent but excessive vascular calcification and chaotic, immeasurable, bone mineralization due to excessive bone turnover, they are not suited to study the bone-vascular axis in one and the same animal. Because vascular calcification and bone mineralization are closely related to each other, an animal model in which both pathologies can be studied concomitantly is highly needed. CKD-related vascular calcification in rats was induced by a 0.25% adenine/low vitamin K diet. To follow vascular calcification and bone pathology over time, rats were killed at weeks 4, 8, 10, 11, and 12. Both static and dynamic bone parameters were measured. Vascular calcification was quantified by histomorphometry and measurement of the arterial calcium content. Stable, severe CKD was induced along with hyperphosphatemia, hypocalcemia as well as increased serum PTH and FGF23. Calcification in the aorta and peripheral arteries was present from week 8 of CKD onward. Four and 8 weeks after CKD, static and dynamic bone parameters were measurable in all animals, thereby presenting typical features of hyperparathyroid bone disease. Multiple regression analysis showed that the eroded perimeter and mineral apposition rate in the bone were strong predictors for aortic calcification. This rat model presents a stable CKD, moderate vascular calcification, and quantifiable bone pathology after 8 weeks of CKD and is the first model that lends itself to study these main complications simultaneously in CKD in mechanistic and intervention studies.
Subject(s)
Aorta/physiopathology , Bone and Bones/physiopathology , Renal Insufficiency, Chronic/blood , Vascular Calcification/physiopathology , Animals , Aorta/metabolism , Bone Remodeling , Disease Models, Animal , Disease Progression , Fibroblast Growth Factors/metabolism , Hypercalcemia/blood , Hyperphosphatemia/blood , Male , Osteogenesis , Parathyroid Hormone/blood , Rats , Rats, Wistar , Regression Analysis , Vitamin K/metabolismABSTRACT
BACKGROUND: Various biochemical markers have been evaluated in dialysis patients for the diagnosis of renal osteodystrophy (ROD). However, their value in predialysis patients with end-stage renal failure (ESRF) is not yet clear. METHODS: Bone histomorphometric evaluation was performed and biochemical markers of bone turnover were determined in serum of an unselected predialysis ESRF population (N = 84). RESULTS: Significant (P < 0.005) differences between the five groups with ROD (ie, normal bone [N = 32], adynamic bone [ABD; N = 19], hyperparathyroidism [N = 8], osteomalacia [OM; N = 10], and mixed lesion [N = 15]) were noted for intact parathyroid hormone, total (TAP) and bone alkaline phosphatase (BAP), osteocalcin (OC), and serum calcium levels. Serum creatinine and (deoxy)pyridinoline levels did not differ between groups. For the diagnosis of ABD, an OC level of 41 microg/L or less (< or =7.0 nmol/L) had a sensitivity of 83% and specificity of 67%. The positive predictive value (PPV) for the population under study was 47%. The combination of an OC level of 41 ng/L or less (< or =7.0 nmol/L) with a BAP level of 23 U/L or less increased the sensitivity, specificity, and PPV to 72%, 89%, and 77%, respectively. ABD and normal bone taken as one group could be detected best by a BAP level of 25 U/L or less and TAP level of 84 U/L or less, showing sensitivities of 72% and 88% and specificities of 76% and 60%, corresponding with PPVs of 89% and 85%, respectively. In the absence of aluminum or strontium exposure, serum calcium level was found to be a useful index for the diagnosis of OM. CONCLUSION: OC, TAP, BAP, and serum calcium levels are useful in the diagnosis of ABD, normal bone, and OM in predialysis patients with ESRF.
Subject(s)
Alkaline Phosphatase/blood , Bone and Bones/pathology , Chronic Kidney Disease-Mineral and Bone Disorder/diagnosis , Kidney Failure, Chronic/complications , Adult , Aged , Biomarkers , Bone and Bones/anatomy & histology , Calcium/blood , Chronic Kidney Disease-Mineral and Bone Disorder/blood , Chronic Kidney Disease-Mineral and Bone Disorder/etiology , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Osteocalcin/blood , Parathyroid Hormone/blood , ROC Curve , Renal Dialysis , Sensitivity and SpecificityABSTRACT
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.
Subject(s)
Bone and Bones/drug effects , Bone and Bones/metabolism , Kidney Failure, Chronic/metabolism , Magnesium/pharmacology , Phosphates/metabolism , Vascular Calcification/metabolism , Acetates/metabolism , Acetates/pharmacology , Animals , Biomarkers/blood , Biomarkers/metabolism , Biomarkers/urine , Bone Remodeling/drug effects , Calcium Compounds/metabolism , Calcium Compounds/pharmacology , Diet , Disease Models, Animal , Magnesium/metabolism , Male , Phosphorus/metabolism , RatsABSTRACT
BACKGROUND: We recently reported that administration of high doses of lanthanum carbonate (1000 mg/kg/day) to chronic renal failure (CRF) rats can result in a mineralization defect. Our results suggested, however, that the impaired mineralization was not due to a direct toxic action of lanthanum on the bone, but rather was an indirect consequence of a phosphate depletion resulting from the compound's high phosphate-binding capacity. To further substantiate these results, in the present study, the effects of lanthanum carbonate on bone were compared to the effects of sevelamer, a nonabsorbed, non-metal-containing polymeric phosphate-binding agent. METHODS: Male Wistar rats underwent a 5/6th nephrectomy to induce chronic renal failure, after which they were treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) by oral gavage for 12 weeks. RESULTS: CRF animals treated with either sevelamer (500 or 1000 mg/kg/day) or lanthanum carbonate (1000 mg/kg/day) developed a phosphate depletion after 4 weeks of treatment, as evidenced by a marked reduction in phosphaturia. At sacrifice after 12 weeks of treatment, bone histomorphometry showed that a mineralization defect had developed in two out of six animals in the lanthanum-carbonate-treated group, in four out of seven animals in the 1000 mg/kg/ day sevelamer group, and in one out of nine animals in the 500 mg/kg/day sevelamer group. CONCLUSIONS: These results corroborate our previous findings that the administration of a powerful phosphate-binding agent to CRF rats can induce phosphate depletion, resulting in a mineralization defect.
Subject(s)
Bone and Bones/drug effects , Epoxy Compounds/adverse effects , Kidney Failure, Chronic/drug therapy , Lanthanum/adverse effects , Phosphates/metabolism , Polyethylenes/adverse effects , Animals , Bone Density , Bone and Bones/pathology , Disease Models, Animal , Epoxy Compounds/pharmacology , Kidney Failure, Chronic/pathology , Kidney Function Tests , Lanthanum/pharmacology , Male , Nephrectomy/methods , Osteoporosis/chemically induced , Osteoporosis/pathology , Phosphates/blood , Polyamines , Polyethylenes/pharmacology , Probability , Rats , Rats, Wistar , Sensitivity and Specificity , Sevelamer , Statistics, NonparametricABSTRACT
BACKGROUND: Patients with impaired renal function can accumulate strontium in the bone, which has been associated with the development of osteomalacia. A causal role for strontium in the development of the disease was presented in chronic renal failure (CRF) rats. Strontium-ranelate has been put forward as a therapeutic agent in the treatment of osteoporosis. Since the target population for strontium treatment consists mainly in postmenopausal osteoporotic women, who may have a reduced renal function, the risk for osteomalacia should be considered. METHODS: To determine the time evolution and reversibility of the strontium-induced mineralization defect, CRF rats were loaded with strontium (2 g/L) (+/- 200 mg/kg/day) during 2, 6, and 12 weeks, followed by a washout period of 0, 2, 4, or 8 weeks. RESULTS: Histologic examination of the bone of the animals treated with strontium revealed signs of osteomalacia already after 2 weeks. Animals that received strontium during 6 and 12 weeks had a significantly higher osteoid perimeter, area and thickness as compared to CRF controls. After 12 weeks, the mineralization was significantly affected, as evidenced by a lower double-labeled surface, mineral apposition and bone formation rate in combination with an increased osteoid maturation time and mineralization lag time. The osteoblast perimeter was significantly lower in the strontium-treated animals. After the washout periods, these effects were reversed and the bone lesions evolved to the values of CRF controls. This went along with an 18% reduction of the bone strontium content. A significant rise in serum alkaline phosphatase (ALP) activity was apparent in the strontium-treated animals as compared to CRF controls. This was not only due to higher levels of the bone ALP but also to those of the liver and the intestinal isoenzymes. Serum parathyroid hormone (PTH) levels decreased during strontium treatment. After cessation of the treatment, the serum ALP activity and PTH concentration reversed to control levels. CONCLUSION: In this study evidence is provided for the rapid development of a mineralization defect in strontium-loaded CRF rats, accompanied by a reduced osteoblast number, reduced PTH synthesis or secretion, and increased serum ALP levels. These effects can be rapidly reversed after withdrawal of the compound.
Subject(s)
Kidney Failure, Chronic/metabolism , Osteomalacia/chemically induced , Strontium/toxicity , Alkaline Phosphatase/blood , Animals , Calcification, Physiologic/drug effects , Kidney Failure, Chronic/complications , Male , Osteoblasts/drug effects , Parathyroid Hormone/blood , Rats , Rats, Wistar , Strontium/blood , Time FactorsABSTRACT
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.
Subject(s)
Bone Diseases/drug therapy , Bone Remodeling/drug effects , Kidney Failure, Chronic/complications , Lanthanum/pharmacokinetics , Phosphates/metabolism , Alkaline Phosphatase/blood , Animals , Bone Diseases/blood , Bone Diseases/pathology , Bone and Bones/drug effects , Bone and Bones/metabolism , Bone and Bones/pathology , Calcium/blood , Creatinine/blood , Eating , Lanthanum/blood , Male , Osteoblasts/drug effects , Osteocalcin/blood , Parathyroid Hormone/blood , Phosphorus/blood , Rats , Rats, Wistar , Vitamin D/bloodABSTRACT
BACKGROUND: During the last few years the spectrum of renal osteodystrophy (ROD) in dialysis patients has been studied thoroughly and the prevalence of the various types of ROD has changed considerably. Whereas until a decade ago most patients presented with secondary hyperparathyroidism (HPTH), adynamic bone (ABD) has become the most common lesion within the dialysis population over the last few years. Much less is known about the spectrum of ROD in end-stage renal failure (ESRF) patients not yet on dialysis. METHODS: Transiliac bone biopsies were taken in an unselected group of 84 ESRF patients (44 male, age 54+/-12 years) before enrolment in a dialysis programme. All patients were recruited within a time period of 10 months from various centres (n=18) in Macedonia. Calcium carbonate was the only prescribed medication in patients followed up by the outpatient clinic. RESULTS: HPTH was found in only 9% of the patients, whilst ABD appeared to be the most frequent renal bone disease as it was observed in 23% of the cases next to normal bone (38%). A relatively high number of patients (n=10; 12%) fulfilled the criteria of osteomalacia (OM). Mixed osteodystrophy (MX) was diagnosed in 18% of the subjects. There was no significant difference between groups in age, creatinine, or serum and bone strontium and aluminium levels. Patient characteristics associated with ABD included male gender and diabetes, whilst OM was associated with older age (>58 years). CONCLUSIONS: In an unselected population of ESRF patients already, 62% of them have an abnormal bone histology. ABD is the most prevalent type of ROD in this population. In the absence of aluminium or strontium accumulation the relatively high prevalence of a low bone turnover as expressed by either normal bone or ABD and OM is striking.
Subject(s)
Chronic Kidney Disease-Mineral and Bone Disorder/epidemiology , Kidney Failure, Chronic/complications , Osteomalacia/epidemiology , Adult , Aged , Bone Remodeling , Chronic Kidney Disease-Mineral and Bone Disorder/classification , Chronic Kidney Disease-Mineral and Bone Disorder/etiology , Chronic Kidney Disease-Mineral and Bone Disorder/pathology , Creatinine/blood , Female , Humans , Logistic Models , Male , Middle Aged , Osteomalacia/etiology , Prevalence , Prospective Studies , Renal Dialysis , Republic of North Macedonia , Risk FactorsABSTRACT
BACKGROUND: We previously reported on increased bone strontium (Sr) levels in dialysis patients with osteomalacia versus those presenting other types of renal osteodystrophy. A causal role of strontium in the development of osteomalacia was established in a chronic renal failure (CRF) rat model. METHODS: In the present study we investigated whether the effect of Sr on bone was related to dosage. Four groups of CRF rats were studied: a control group (control-CFR; N=6) not receiving strontium and three groups of animals loaded orally with Sr during 18 weeks by adding the element as the SrCl2. H20 compound to the drinking water at concentrations of 0.03 g/100mL (Sr-30; N=6), 0.075 g/100mL (Sr-75; N=6), or 0.15 g/100mL (Sr-150; N=6) respectively. A fifth group consisting of seven animals with intact renal function (control-NRF), not receiving Sr served as controls for the effect of CRF on bone histology. RESULTS: As compared to the control-NRF and control-CRF groups, Sr administration resulted in a dose-dependent increase in bone and serum Sr levels. No difference in body weight and biochemical serum and urinary parameters [i.e., calcium (Ca), phosphorus (P), and creatinine] was noted between the various CRF groups. At sacrifice, intact parathyroid hormone (iPTH) levels of CRF groups were significantly (P < 0.05) higher than the values measured in the control-NRF group indicating the development of hyperparathyroidism secondary to the installation of the CRF. This is further supported by the differences in bone histomorphometry between the control-CRF and control-NRF animals, which, respectively, showed an increased amount of osteoid (mean +/- SEM 3.4 +/- 1.2% vs. 0.37 +/- 0.14%, P < 0.05) in combination with a distinct osteoblastic activity (35 +/- 11% vs. <2%, P < 0.05) and an increased bone formation rate [(BFR), 677 +/- 177 microm 2/mm2/day vs. 130 +/- 50 microm 2/mm2/day, P < 0.05]. Bone surface area and erodic perimeter did not differ between the various study groups. In the Sr-30 group, Sr loading went along with a dramatic reduction of the BFR as indicated by the total absence of double tetracyclin labels and osteoblastic activity, which in the presence of a low to normal amount of osteoid (2.7 +/- 1.9%) points to the development of the adynamic type of renal osteodystrophy. Interestingly, compared to the control-CRF group, histodynamic and histologic parameters of the Sr-75 group did not differ significantly and a substantial osteoblastic activity (7.6 +/- 4.0%) was seen also. In the Sr-150 group, the various osteoid parameters were significantly (P < 0.05) increased vs. all other groups and were accompanied by a reduced BFR and mineral apposition rate (MAR) and an increased mineralization lag time (MLT), indicating a mineralization defect and the development of osteomalacia. CONCLUSIONS: Our findings indicate that the role of Sr in the development of bone lesions in renal failure is complex and that, depending on the dose, the element may act via multiple pathways.