Chronic Kidney Disease Bone Research Articles

Ex vivo exposure to calcitonin or raloxifene improves mechanical properties of diseased bone through non-cell mediated mechanisms

Raloxifene (RAL) reduces clinical fracture risk despite modest effects on bone mass and density. This reduction in fracture risk may be due to improved material level-mechanical properties through a non-cell mediated increase in bone hydration. Synthetic salmon calcitonin (CAL) has also demonstrated efficacy in reducing fracture risk with only modest bone mass and density improvements. This study aimed to determine if CAL could modify healthy and diseased bone through cell-independent mechanisms that alter hydration similar to RAL.26-week-old male C57BL/6 mice induced with chronic kidney disease (CKD) beginning at 16 weeks of age via 0.2 % adenine-laced casein-based (0.9 % P, 0.6 % C) chow, and their non-CKD control littermates (Con), were utilized. Upon sacrifice, right femora were randomly assigned to the following ex vivo experimental groups: RAL (2 μM, n = 10 CKD, n = 10 Con), CAL (100 nM, n = 10 CKD, n = 10 Con), or Vehicle (VEH; n = 9 CKD, n = 9 Con). Bones were incubated in PBS + drug solution at 37 °C for 14 days using an established ex vivo soaking methodology. Cortical geometry (μCT) was used to confirm a CKD bone phenotype, including porosity and cortical thinning, at sacrifice. Femora were assessed for mechanical properties (3-point bending) and bone hydration (via solid state nuclear magnetic resonance spectroscopy with magic angle spinning (ssNMR)). Data were analyzed by two-tailed t-tests (μCT) or 2-way ANOVA for main effects of disease, treatment, and their interaction. Tukey's post hoc analyses followed a significant main effect of treatment to determine the source of the effect.Imaging confirmed a cortical phenotype reflective of CKD, including lower cortical thickness (p < 0.0001) and increased cortical porosity (p = 0.02) compared to Con. In addition, CKD resulted in weaker, less deformable bones. In CKD bones, ex vivo exposure to RAL or CAL improved total work (+120 % and +107 %, respectively; p < 0.05), post-yield work (+143 % and +133 %), total displacement (+197 % and +229 %), total strain (+225 % and +243 %), and toughness (+158 % and +119 %) vs. CKD VEH soaked bones. Ex vivo exposure to RAL or CAL did not impact any mechanical properties in Con bone. Matrix-bound water by ssNMR showed CAL treated bones had significantly higher bound water compared to VEH treated bones in both CKD and Con cohorts (p = 0.001 and p = 0.01, respectively). RAL positively modulated bound water in CKD bone compared to VEH (p = 0.002) but not in Con bone. There were no significant differences between bones soaked with CAL vs. RAL for any outcomes measured.RAL and CAL improve important post-yield properties and toughness in a non-cell mediated manner in CKD bone but not in Con bones. While RAL treated CKD bones had higher matrix-bound water content in line with previous reports, both Con and CKD bones exposed to CAL had higher matrix-bound water. Therapeutic modulation of water, specifically the bound water fraction, represents a novel approach to improving mechanical properties and potentially reducing fracture risk.

Role of the RANK/RANKL/OPG and Wnt/β-Catenin Systems in CKD Bone and Cardiovascular Disorders.

In the course of chronic kidney disease (CKD), alterations in the bone-vascular axis augment the risk of bone loss, fractures, vascular and soft tissue calcification, left ventricular hypertrophy, renal and myocardial fibrosis, which markedly increase morbidity and mortality rates. A major challenge to improve skeletal and cardiovascular outcomes in CKD patients requires a better understanding of the increasing complex interactions among the main modulators of the bone-vascular axis. Serum parathyroid hormone (PTH), phosphorus (P), calcium (Ca), fibroblast growth factor 23 (FGF23), calcidiol, calcitriol and Klotho are involved in this axis interact with RANK/RANKL/OPG system and the Wnt/β-catenin pathway. The RANK/RANKL/OPG system controls bone remodeling by inducing osteoblast synthesis of RANKL and downregulating OPG production and it is also implicated in vascular calcification. The complexity of this system has recently increased due the discovery of LGR4, a novel RANKL receptor involved in bone formation, but possibly also in vascular calcification. The Wnt/β-catenin pathway plays a key role in bone formation: when this pathway is activated, bone is formed, but when it is inhibited, bone formation is stopped. In the progression of CKD, a downregulation of the Wnt/β-catenin pathway has been described which occurs mainly through the not coincident elevations of sclerostin, Dickkopf1 (Dkk1) and the secreted Frizzled Related Proteins (sFRPs). This review analyzes the interactions of PTH, P, Ca, FGF23, calcidiol, calcitriol and Klotho with the RANKL/RANKL/OPG system and the Wnt/β-catenin, pathway and their implications in bone and cardiovascular disorders in CKD.

Inflammation, Oxidative Stress, and Bone in Chronic Kidney Disease in the Osteoimmunology Era.

Bone is not only a mineralized and apparently non-vital structure that provides support for locomotion and protection to inner organs. An increasing number of studies are unveiling new biologic functions and connections to other systems, giving the rise to new fields of research, such as osteoimmunology. The bone marrow niche, a new entity in bone physiology, seems to represent the site where a complex crosstalk between bone and immune/inflammatory responses takes place. An impressive interplay with the immune system is realized in bone marrow, with reciprocal influences between bone cells and haematopoietic cells. In this way, systemic chronic inflammatory diseases realize a crosstalk with bone, resulting in bone disease. Thus, pathogenetic links between chronic kidney disease-mineral bone disorders and osteoporosis, cardiovascular disease, and ageing are common. The aim of this narrative review is to provide a general view of the progresses in the field of bone research and their potential clinical implications, with emphasis on the links with inflammation and the connections to osteoimmunology and chemokines.

Glycolysis and Lactate Dehydrogenase A in Iron-Mediated Suppression of Osteoblast Function

Background/Objective: &#x0D; An estimated 37 million Americans have Chronic Kidney Disease (CKD), a condition in characterized by gradual decline in kidney function1. Patients with CKD are often afflicted with skeletal fractures, increasing morbidity and mortality. CKD has also shown a strong correlation with iron-deficiency anemia. The underlying mechanisms of how iron-deficiency anemia of CKD affects bone loss are not well understood. Based on RNA-sequencing results, we hypothesize that lactate dehydrogenase A (LDHA) may play a role in iron-deficiency mediated suppression of osteoblast differentiation and function. &#x0D; &#x0D; Methods: &#x0D; Mouse Progenitor Cells (MPC2) were incubated in osteogenic media along with deferoxamine (DFO) to induce differentiation in chronic iron deficiency; samples were collected after 7 and 14 days. Quantitative real-time PCR and western blot were used to validate LDHA mRNA and protein levels in DFO treated MPCs versus control cells. RNA levels of osteoblast genes and LDHA were also assessed in a pre-clinical mouse model of CKD. &#x0D; &#x0D; Results: &#x0D; In vitro, MPCs cultured in DFO media showed a significant increase of LDHA mRNA at 7 days (p=0.015) and returned to near control levels by day 14. Western blots showed a slight increase of total LDHA protein in DFO treated MPCs at 7 days and a large increase of protein at the 14-day mark (p=0.051). In vivo, CKD bone marrow showed a reduction in osteoblast gene expression (osteocalcin and type 1 collagen; p&lt;0.05). LDHA mRNA expression was increased in CKD mice bone marrow when compared to wild-type mice (p=0.051), suggesting an inverse relationship. &#x0D; &#x0D; Conclusion and Potential Impact: &#x0D; Inappropriate activation of glycolysis and LDHA appears to play a role in iron-deficiency mediated suppression of osteoblast function in relation to CKD, both in vitro and in vivo. Further exploration of this relationship could be critical to the development of improved treatment options to maintain bone homeostasis during CKD.

State-of-the-Art Management of Hyperphosphatemia in Patients With CKD: An NKF-KDOQI Controversies Perspective

Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney disease (CKD). In patients with CKD glomerular filtration rate category 3a (G3a) or worse, including those with kidney failure who are receiving dialysis, clinical practice guidelines suggest "lowering elevated phosphate levels towards the normal range" with possible strategies including dietary phosphate restriction or use of binders. Additionally, guidelines suggest restricting the use of oral elemental calcium often contained in phosphate binders. Nutrition guidelines in CKD suggest<800-1,000mg of calcium daily, whereas CKD bone and mineral disorder guidelines do not provide clear targets, but<1,500mg in maintenance dialysis patients has been previously recommended. Many different classes of phosphate binders are now available and clinical trials have not definitively demonstrated the superiority of any class of phosphate binders over another with regard to clinical outcomes. Use of phosphate binders contributes substantially to patients' pill burden and out-of-pocket costs, and many have side effects. This has led to uncertainty regarding the use and best choice of phosphate binders for patients with CKD or kidney failure. In this controversies perspective, we discuss the evidence base around binder use in CKD and kidney failure with a focus on comparisons of available binders.

Cortical unlike trabecular bone loss is not associated with vascular calcification progression in CKD patients

BackgroundVascular calcification progression has been associated with the loss of trabecular bone in chronic kidney disease (CKD) patients. There are few data evaluating the relationship between cortical bone loss and vascular calcification in this population. The aim of this study was to prospectively evaluate the association between changes in cortical bone density and coronary artery calcification (CAC) progression in non-dialyzed CKD patients.MethodsChanges of cortical and trabecular bone, and changes of calcium score, were analyzed using vertebral tomographic images from a prospective study. Automatic delineation of the cortical bone layer was performed by Image J software, and trabecular bone was determined by selecting a region of interest using Vitrea 2® software. Cortical and trabecular bone density (BD) were expressed in Hounsfield Units (HU), and coronary artery calcium score in Agatston Units (AU).ResultsSeventy asymptomatic patients [57.8 ± 10.2 years, 63% males, 20% diabetic, estimated glomerular filtration rate (eGFR) = 37.3 (24.8–51.3) mL/min/1.73m2] were followed for 24 months. The mean cortical and trabecular BD did not change over time. While 49 patients lost either bone, 29 (41%) patients lost cortical [− 4.4%/year (ranging from − 7.15 to − 0.5)] and 39 (56%) lost trabecular bone [− 3.15%/year (− 13.7 to − 0.25)]. There was no association between cortical and trabecular BD changes (p = 0.12). CAC was observed in 33 (46%) patients at baseline, and 30 (91%) of them showed CAC progression. While an inverse correlation between trabecular bone and calcium score changes was observed (p = 0.001), there was no correlation between cortical bone and calcium score changes (p = 0.34).ConclusionCKD patients experience either cortical or trabecular bone loss over time, but these changes do not take place simultaneously in all patients. Cortical, unlike trabecular bone loss, is not associated with vascular calcification progression in these patients.

Time course of rapid bone loss and cortical porosity formation observed by longitudinal μCT in a rat model of CKD.

Rodent studies of bone in chronic kidney disease have primarily relied on end-point examinations of bone microarchitecture. This study used longitudinal in vivo microcomputed tomography (in vivo μCT) to characterize the onset and progression of bone loss, specifically cortical porosity, in the Cy/+ rat of model of CKD. Male CKD rats and normal littermates were studied. In vivo μCT scans of the right distal tibia repeated at 25, 30, and 35 weeks were analyzed for longitudinal changes in cortical and trabecular bone morphometry. In vitro μCT scans of the tibia and femur identified spatial patterns of bone loss across distal, midshaft and proximal sites. CKD animals had reduced BV/TV and cortical BV at all time points but developed cortical porosity and thinning between 30 and 35 weeks. Cortical pore formation was localized near the endosteal surface. The severity of bone loss was variable across bone sites, but the distal tibia was representative of both cortical and trabecular changes. The distal tibia was found to be a sensitive suitable site for longitudinal imaging of both cortical and trabecular bone changes in the CKD rat. CKD trabecular bone loss progressed through ~30 weeks followed by a sudden acceleration in cortical bone catabolism. These changes varied in timing and severity across individuals, and cortical bone loss and porosity progressed rapidly once initiated. The inclusion of longitudinal μCT in future studies will be important for both reducing the number of required animals and to track individual responses to treatment.

Impaired osteocyte maturation in the pathogenesis of renal osteodystrophy

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

Uremic Toxicity and Bone in CKD.

Patients with chronic kidney disease (CKD), especially those on dialysis treatment, are at high risk of bone fracture. In CKD-mineral and bone disorder (CKD-MBD), secondary hyperparathyroidism in patients with advanced CKD induces bone abnormalities, and skeletal resistance to parathyroid hormone (PTH) starts in the early stages of kidney disease. Uremic toxins such as indoxyl sulfate and p-cresyl sulfate reduce the expression of PTH receptor as well as PTH-induced cyclic adenosine 3',5' monophosphate production in osteoblasts. CKD also impairs bone strength, especially quality. In a rat model, kidney damage reduces the bone-storage modulus and changes the cortical bone chemical composition with or without hyperparathyroidism. The oral charcoal adsorbent AST-120 improves CKD-induced bone abnormalities as blood levels of indoxyl sulfate decrease. Uremic osteoporosis, a new concept of CKD-related bone fragility, is a main cause of CKD-induced bone abnormalities, particularly impaired bone quality. There is limited information about the effect and safety of anti-osteoporotic drugs for patients with CKD, especially those on dialysis, but the use of AST-120 and renin-angiotensin system inhibitors may modulate bone quality and decrease the incidence of fracture. Thus, the management of CKD-MBD plus use of other therapeutic interventions for uremic osteoporosis is necessary to prevent bone fragility in patients with CKD.

Direct inhibition of osteoblastic Wnt pathway by fibroblast growth factor 23 contributes to bone loss in chronic kidney disease

Bone loss and increased fractures are common complications in chronic kidney disease. Because Wnt pathway activation isessential for normal bone mineralization, we assessed whether Wnt inhibition contributes to high-phosphorus-induced mineralization defects in uremic rats. By week 20after 7/8 nephrectomy, rats fed a high-phosphorus diethad the expected high serum creatinine, phosphorus, parathyroid hormone, and fibroblast growth factor 23(FGF23) levels and low serum calcium. There was a 15%reduction in tibial mineral density and a doubling ofbone cortical porosity compared to uremic rats fed a normal-phosphorus diet. The decreases in tibial mineral density were preceded by time-dependent increments in gene expression of bone formation (Osteocalcin and Runx2) and resorption (Cathepsin K) markers, which paralleled elevations in gene expression ofthe Wnt inhibitors Sfrp1 and Dkk1 in bone. Similar elevations of Wnt inhibitors plus an increased phospho-β-catenin/β-catenin ratio occurred upon exposure of the osteoblast cell line UMR106-01 either to uremic serum or tothe combination of parathyroid hormone, FGF23, and soluble Klotho, at levels present in uremic serum. Strikingly, while osteoblast exposure to parathyroid hormone suppressed the expression of Wnt inhibitors, FGF23 directly inhibited the osteoblastic Wnt pathway through a soluble Klotho/MAPK-mediated process that required Dkk1 induction. Thus, the induction of Dkk1 byFGF23/soluble Klotho in osteoblasts inactivates Wnt/β-catenin signaling. This provides a novel autocrine/paracrine mechanism for the adverse impact of high FGF23levels on bone in chronic kidney disease.

Estrogen Deficiency Leads to Further Bone Loss in the Mandible of CKD Mice.

BackgroundChronic kidney disease (CKD) has been regarded as a grave public health problem. Estrogen is a critical factor for both renal protection and bone remodeling. Our previous study demonstrated that CKD impairs the healing of titanium implants. The aim of this study was to investigate the effects of estrogen deficiency on the mandibular bone in CKD mice.MethodsForty eleven-week-old female C57BL mice were used in this study. Uremia and estrogen deficiency were induced by 5/6 nephrectomy and ovariectomy (OVX), respectively. After 8 weeks, the mice were sacrificed, and their mandibles were collected for micro-CT analysis and histological examination.ResultsAll the mice survived the experimental period. Serum measurements confirmed a significant increase in BUN in the CKD group that was further increased by OVX. OVX led to significant decreases in both the BV/TV and cortical thickness of the mandibular bone in CKD mice.ConclusionIn summary, our findings indicate that estrogen deficiency leads to further mandibular bone loss in CKD mice.

Recent Clinical Trials of Pharmacologic Cardiovascular Interventions in Patients with Chronic Kidney Disease: An Update.

As a consequence of both traditional and non-traditional risk factors, cardiovascular disease is over-represented, and the leading cause of mortality, among patients with Chronic Kidney Disease (CKD). Whilst recommendations for reducing cardiovascular risk in the general population exist, their applicability to the CKD population is questionable due to the exclusion of CKD patients from the majority of contemporary cardiovascular interventional studies. The aim of this review is to critically evaluate the literature regarding pharmacologic cardiovascular interventions in patients with CKD, with an emphasis on studies published since our 2008 review. Interventions discussed include erythropoiesis-stimulating agents (TREAT, U.S. Normal Hematocrit, CHOIR, CREATE, Palmer meta-analysis); statins (SHARP, AURORA, PPP, 4D, ALERT); Fibrates (VA-HIT); Folic Acid (ASFAST, US FOLIC acid trial, HOST); Antihypertensive Agents, Including Angiotensin-Converting Enzyme Inhibitors, angiotensin-receptor blockers, Beta-blockers and Combination therapy (Cice et al, FOSDIAL, Agarwal et al, ONTARGET); sevelamer (DCOR); Cinacalcet (ADVANCE, EVOLVE, Cunningham meta-analysis); Anti-oxidants (SPACE, HOPE, ATIC); Aspirin (HOT study re-analysis); vitamin D analogues (PRIMO); and multidisciplinary intervention (LANDMARK). Unfortunately, there remains a paucity of evidence in this area and a large number of methodologically poor quality studies with negative results. It is possible that these interventions do not have the same positive effect in CKD patients due to differences in the pathogenesis driving cardiovascular disease burden, such as altered bone metabolism and calcific vascular disease. Further well-designed studies with appropriately selected study populations and patient level outcomes are required. Until such time, physicians must consider on an individual patient basis the appropriateness of these interventions.

Novel biological markers of bone: from bone metabolism to bone physiology.

Biochemical markers of bone turnover have been used for decades in the management of bone diseases, to assess the prognosis of these conditions and to monitor treatments. The new markers, however, also reflect specific physiological mechanisms in the bone or other organs. Periostin may be more specific to the periosteum; cathepsin K is an osteoclastic enzyme that may be involved in the cardiovascular system and joints; Dickkopf-1 is involved in bone formation and vascular calcification; sclerostin is a major regulator of bone formation in response to mechanical loading and may also play a role in chronic kidney disease bone and mineral disorder; sphingosine-1-phosphate is a lipid mediator interacting with bone resorption. Some of the bone markers are in fact hormones produced by the bone that affect various physiological and pathological functions in other organs. Thus, osteocalcin is produced by osteoblasts and participates in the regulation of insulin sensitivity and fertility in men. Fibroblast growth factor 23 is produced by osteocytes to regulate phosphorus and 1,25(OH)2D3, but it also plays a major role in the adverse consequences of declining renal function, in particular with respect to the myocardium. Micro RNAs are single-stranded RNAs that regulate several pathways, including the development timing, organogenesis, cell apoptosis, proliferation and differentiation. Their serum concentration may reflect the links between bone physiology and certain conditions in other organs, for example, the cardiovascular system.

Bone Disorders in Chronic Kidney Disease: An Update in Diagnosis and Management.

Renal osteodystrophy (ROD) is a bone disorder that occurs in chronic kidney disease (CKD) patients and is associated with 2- to 14-fold increased fracture risk compared to the general population. Risk of fractures is also increased in kidney transplant recipients especially within the first 5 years after transplantation. Fractures in CKD patients are associated with increased morbidity and mortality; thus, proper screening and management of CKD bone complications is critical to improving clinical outcomes. Tetracycline double-labeled transiliac crest bone biopsy with histomorphometry is the gold standard for the diagnosis and classification of ROD. However, bone biopsy is not practical to obtain in all patients. Thus, there is great interest in noninvasive approaches that can be used in the clinic to assess ROD. Here, we discuss the role of surrogate measures of bone health in CKD patients, such as dual energy X-ray absorptiometry (DXA) and novel high-resolution imaging, in conjunction with biochemical biomarkers of bone turnover. Recommended guidelines for diagnosis and management of CKD-MBD are discussed.

Parathyroid Surgery in the Treatment of Pediatric Chronic Kidney Disease-Mineral and Bone Disorder: Regional Experience and Review

Background: Childhood-onset chronic renal failure is an important disease entity within Australasia and the associated mineral and bone disorder causes faltering mobility and growth, and significant cardiovascular morbidity in early adulthood. A poorly described group of children will require parathyroid surgery because of refractory disease. Aim: To review paediatric cases requiring parathyroid surgery in the treatment of Chronic Kidney Disease-Mineral and Bone Disorder at Starship Hospital between 1996-2010. A secondary objective was to estimate the percentage of children requiring parathyroid surgery amongst those children at risk i.e. those on renal replacement therapy. Methods: The departmental renal database was searched and eleven cases were found from a total of 310 children-years treated with renal replacement during the study period. Retrospective medical record review was performed including operative indications, renal replacement modalities, growth parameters, operative technique, biochemical assays, follow-up and recurrence. Results: Indications for surgery were biochemical as well as clinical: bone pain, pathological fractures, faltering mobility and growth retardation. The type of surgery varied, but the majority involved subtotal parathyroid excision. All parathyroid tissue excised was hypertrophic. Surgery provided relief of symptoms within months and parathyroid hormone levels reduced on average from 100.7 pmol/L to 3.1 pmol/L two months following the operation. After a median follow-up of 9 years there has been one case of recurrence of hyperparathyroidism. Conclusions: Subtotal parathyroid excision is safe and effective in treating refractory Chronic Kidney Disease-Bone and Mineral Disorder in children. The risk of requiring parathyroid surgery while on renal replacement therapy is estimated as 3.5% per children-year treated.

Serum calcium and bone: effect of PTH, phosphate, vitamin D and uremia.

Hyperparathyroidism develops in chronic kidney disease (CKD). A decreased calcemic response to parathyroid hormone (PTH) contributes to the development of hyperparathyroidism and is presumed due to reduced calcium efflux from bone. Contributing factors to the decreased calcemic response to PTH in CKD include: 1) hyperphosphatemia; 2) decreased serum calcitriol; 3) downregulation of the PTH1 receptor; 4) large, truncated amino-terminal PTH fragments acting at the carboxy-PTH receptor; and 5) uremic toxins. Also, prolonged high dose calcitriol administration may decrease the exchangeable pool of bone calcium independent of PTH. The goal of the review is to provide a better understanding of how the above cited factors affect calcium efflux from bone in CKD. In conclusion, much remains to be learned about the role of bone in the regulation of serum calcium.

Healthy Bone Marrow Cells Reduce Progression of Kidney Failure Better than CKD Bone Marrow Cells in Rats with Established Chronic Kidney Disease

Chronic kidney disease (CKD) is a major health care problem. New interventions to slow or prevent disease progression are urgently needed. We studied functional and structural effects of infusion of healthy and CKD bone marrow cells (BMCs) in a rat model of established CKD. CKD was induced by 5/6 nephrectomy (SNX) in Lewis rats, and disease progression was accelerated with L-NNA and 6% NaCl diet. Six weeks after SNX, CKD rats received healthy eGFP(+) BMCs, CKD eGFP(+) BMCs, or vehicle by single renal artery injection. Healthy BMCs were functionally effective 6 weeks after administration: glomerular filtration rate (GFR; inulin clearance) (0.48±0.16 vs. 0.26±0.14 ml/min/100 g) and effective renal plasma flow (RPF; PAH clearance) (1.6±0.40 vs. 1.0±0.62 ml/min/100 g) were higher in healthy BMC- versus vehicle-treated rats (both p < 0.05). Systolic blood pressure (SBP) and proteinuria were lower 5 weeks after treatment with healthy BMCs versus vehicle (SBP, 151±13 vs. 186±25 mmHg; proteinuria, 33±20 vs. 59±39 mg/day, both p < 0.05). Glomerular capillary density was increased, and less sclerosis was detected after healthy BMCs (both p < 0.05). Tubulointerstitial inflammation was also decreased after healthy BMCs. eGFP(+) cells were present in the glomeruli and peritubular capillaries of the remnant kidney in all BMC-treated rats. CKD BMCs also reduced SBP, proteinuria, glomerulosclerosis, and tubular atrophy versus vehicle in CKD rats. However, CKD BMC therapy was not functionally effective versus vehicle [GFR: 0.28±0.09 vs. 0.26±0.16 ml/min/100 g (NS), RPF: 1.15±0.36 vs. 0.78±0.44 ml/min/100 g (NS)], and failed to decrease tubulointerstitial inflammation and fibrosis. Single intrarenal injection of healthy BMCs in rats with established CKD slowed progression of the disease, associated with increased glomerular capillary density and less sclerosis, whereas injection of CKD BMCs was less effective.

Osteoporosis and adynamic bone in chronic kidney disease

Among the chronic kidney disease-mineral bone disease (CKD-MBD) disorders, osteoporosis and adynamic bone are highly prevalent, and they have been consistently associated with low bone mass, bone fractures, vascular calcifications and greater mortality in general and CKD populations. Despite the fact that osteoporosis and adynamic bone have similar clinical outcomes, they have different pathogeneses and clinical management. In osteoporosis, there is a lack of balance between bone formation and bone resorption, and less new bone is formed to replace bone losses. Osteoporosis is defined by the World Health Organization as "a disease characterized by low bone mineral density and micro architectural deterioration leading to low bone strength and increased risk of fractures." In the general population, there is a good correlation between dual-energy X-ray absorptiometry measurements and bone fractures, but this is not the case with CKD patients. Despite the fact that we have a great number of active antiosteoporotic drugs, the experience in CKD patients is limited. Adynamic bone is suspected based on biochemical parameters, mainly parathyroid hormone (PTH) and bone alkaline phosphatase, but it needs to be proven using a bone biopsy, where a low or zero bone formation rate and a reduction or absence of osteoblasts and osteoclasts should be found. The clinical management of adynamic bone has important limitations and currently does not allow taking many active measures. Treatment is mainly based on the prevention of risk factors known to induce PTH oversuppression, such as aluminium and calcium load and very high doses of vitamin D receptor activators. Due to the limitations in the treatment of both conditions, prevention plays a key role in the management of these disorders.

Fibroblast Growth Factor 23 and the Bone-Vascular Axis: Lessons Learned From Animal Studies

Calcification of arteries and cardiac valves is observed commonly in dialysis patients and represents a major determinant of the heightened cardiovascular risk observed during chronic kidney disease (CKD) progression. Recent advances from clinical and basic science studies suggest that vascular calcification should be considered a systemic disease in which pathologic processes occurring in the bone and kidney contribute to calcium deposition in the vasculature. Among the factors potentially involved in the vascular-bone axis dysregulation associated with CKD, there now is increasing interest in the role of the phosphaturic hormone fibroblast growth factor 23 (FGF-23). Increased FGF-23 plasma levels are observed with a decrease in kidney function and predict the risk of future cardiovascular mortality. However, clinical data are still unclear about whether a direct pathogenetic effect of FGF-23 on vascular/kidney/bone health exists. In the last few years, a series of basic science studies, performed using engineered mice, have contributed important pathophysiologic information about FGF-23 activities. This review summarizes findings from these studies and discusses the potential role of FGF-23 during the pathologic interplay between kidney, vessels, and bone in CKD.

Chronic kidney disease--mineral and bone disorder: a complex scenario.

The chronic kidney disease-bone and mineral disorders (CKD-MBD) represents a dinamic area of research. Recently, new factors such as FGF-23 have been added to the classic list of regulators of bone metabolism, which include calcium, phosphorus, PTH and calcitriol. Vascular calcification, one of the most important complication of CKD-MBD is regulated by a complex variety of&nbsp; promoters and inhibitors. The relationship between vascular calcification, bone loss and mortality, together with the existence of likely common signaling pathways are subject of interesting investigations.