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The accumulation of advanced glycation end products (AGEs) has been reported to be a major contributor to chronic systemic inflammation. AGEs are not efficiently removed by hemodialysis or the kidney of a chronic kidney disease (CKD) patient. The goal of this study was to develop a receptor for AGEs (RAGE)-based bioadsorbent device that was capable of removing endogenous AGEs from human blood. The extracellular domain of RAGE was immobilized onto agarose beads to generate the bioadsorbent. The efficacy of AGE removal from saline, serum, and whole blood; biological effects of AGE reduction; and hemocompatibility and stability of the bioadsorbent were investigated. The bioadsorbent bound AGE-modified bovine serum albumin (AGE-BSA) with a binding capacity of 0.73 ± 0.07 mg AGE-BSA/mL bioadsorbent. The bioadsorbent significantly reduced the concentration of total AGEs in serum isolated from end-stage kidney disease patients by 57%. AGE removal resulted in a significant reduction of vascular cell adhesion molecule-1 expression in human endothelial cells and abolishment of osteoclast formation in osteoclast progenitor cells. A hollow fiber device loaded with bioadsorbent-reduced endogenous AGEs from recirculated blood to 36% of baseline levels with no significant changes in total protein or albumin concentration. The bioadsorbent maintained AGE-specific binding capacity after freeze-drying and storage for 1 year. This approach provides the foundation for further development of soluble RAGE-based extracorporeal therapies to selectively deplete serum AGEs from human blood and decrease inflammation in patients with diabetes and/or CKD.

High adenine phosphate (HAP) diet serves as an animal model of chronic renal failure (RF). Induction of RF and establishment of end organ damage require long exposure periods to this diet. Previously, we have shown that RF is reversible after diet cessation even after protracted administration. In this study, we explored the underlying renal changes and cellular pathways occurring during administration and after cessation of the diet. Kidneys were obtained from rats fed HAP diet for 7 weeks, and from rats fed HAP diet followed a 10 week recovery period on normal diet. The kidneys of HAP diet group were significantly enlarged due to tubular injury characterized by massive cystic dilatation and crystal deposition. Kidney injury was associated with markers of apoptosis as well as with activation of apoptosis related pathways. Diet cessation was associated with a significant reduction in kidney size, tubules diameter, and crystals deposition. The recovery from renal injury was coupled with regression of apoptotic features. This is the first study showing the potential reversibility of long standing RF model, allowing optimal evaluation of uremia-chronic effects.

Bone disease is one of the most challenging complications in patients with chronic kidney disease. Today, it is considered to be part of a complex systemic disorder manifested by disturbances of mineral metabolism and vascular calcifications called chronic kidney disease – mineral bone disorder (CKD-MBD).The term renal osteodystrophy is reserved to define the specific bone lesion in CKD-MBD, whose spectrum ranges from high turnover to low turnover disease. Phosphate retention, decreased serum calcium, and 1,25-dihydroxy vitamin D synthesis are involved in the pathogenesis of high bone turnover. However, the various therapeutic approaches (calcium supplements, phosphate binders, and vitamin D metabolites, among others), the renal replacement modality (hemodialysis or continuous ambulatory peritoneal dialysis), and the types of patients to whom dialysis is offered (more patients who are diabetic or older, or both) may influence the evolution of the bone disorder. As a result, recent studies have reported a greater prevalence of adynamic forms of renal osteodystrophy, especially in diabetic and peritoneal dialysis patients.The present article reviews, for patients treated with peritoneal dialysis, the pathophysiologic mechanisms involved in the evolution and perpetuation of this bone disease and the therapeutic modalities for treating and preventing adynamic bone.

Chronic kidney disease (CKD) is accompanied by disturbances in calcium, phosphate, vitamin D, and parathyroid hormone (PTH) homeostasis known to play an important role in the pathophysiology of renal osteodystrophy. Increased cardiovascular morbidity and mortality rate among CKD patients, correlates with these disturbances in bone and mineral metabolism and underscores the nephrologist’s concern about the effectiveness of the present therapeutic approach. Treatment directed to normalize the calcium/phosphate, vitamin D and PTH abnormalities may adversely affect endothelial, vascular and bone cells activity. This article discusses the therapeutic approaches focuses for renal osteodystrophy.

Osteoporosis (OP), the most frequent bone disease affecting the general population, is associated with high fracture risk. Patients with impaired kidney function have bone and mineral disturbances leading to extraskeletal calcifications and complex changes in bone turnover that predispose them to increased fracture risk accompanied by increased morbidity and mortality. The combination of these two bone disorders seems to have an additive effect with regard to fracture risk and its outcome, so that appropriate diagnosis and treatment of this disorder should be of primary concern when approaching patients with kidney disease. Nevertheless, the clinical and laboratory diagnostic tools used to identify OP in the general population do not suit the requirement for detecting the complex bone and metabolic changes that occur with chronic kidney disease, leading to the lack of or the initiation of inappropriate therapy. This review will focus on the bone pathophysiologic processes involved in OP and renal osteodystrophy and address some of the problems associated with our current diagnostic tools and aspects of the therapeutic approaches.

Background and objective: Substantial data for the relative costs of hospitalisation in paricalcitol and calcitriol-treated patients with chronic kidney disease stage 4 do not exist. The objective of this study was to compare the cost benefit of paricalcitol and calcitriol therapies in chronic kidney disease stage 4 from the perspective of a healthcare payer. Methods: A range of methods were used to estimate the relative costs of hospitalisation in paricalcitol- and calcitriol-treated patients with chronic kidney disease stage 4, extrapolated from observed differences in hospitalisation costs in stage 5 patients. Different values and approaches were used to show a range of values and to show the specific hospitalisation benefit in terms of the all-cause hospitalisation rate and number of all-cause hospital days. Results: The annual dollar impact of use of paricalcitol instead of calcitriol on all-cause hospital admissions was calculated to be a reduction of $US1220–$US4476 and for all-cause number of hospital days a reduction of $US1816–$US8776. A total of 42 cost comparison estimates were generated to compare the cost benefit of calcitriol or paricalcitol. Of these 42 comparisons, 35 showed that the total cost of paricalcitol was lower than the total cost of calcitriol therapy. The cost advantage of paricalcitol over calcitriol substantially increased as patients progressed toward dialysis. Conclusion: Cost analyses suggest that paricalcitol-treated patients have a lower total cost than calcitriol-treated patients.

Aging is associated with alteration in renal tubular functions, including sodium handling and concentrating ability. Na-K-ATPase plays a key role in driving tubular transport, and we hypothesized that decreased concentrating ability of the aging kidney is due in part to downregulation of Na-K-ATPase. In this study, we evaluated Na and K balance, aldosterone levels, and Na-K-ATPase gene expression, protein abundance, and activity in aging rat kidney. Na-K-ATPase activity (assayed microfluorometrically), mRNA (RT-PCR), and protein abundance (immunoblotting) were quantitated in the following isolated nephron segments: PCT, PST, MTAL, DCT, and CCD from 2, 8, 15, and 24 month-old-rats. In the course of aging, creatinine clearance decreased from 0.48 ± 0.02 mL/min/100 g BW to 0.28 ± 0.06 (P 0.001) and aldosterone decreased from 23.6 ± 0.8 ng/dL to 13.2 ± 0.6 (P 0.001). Serum Na(+) and K(+) increased by 4.0% and 22.5%, respectively. Na-K-ATPase activity, mRNA, and protein abundance of the α1 subunit displayed similar trends in all assayed segments; increasing in PCT and PST; decreasing in MTAL and DCT; increasing in CCD: in PCT they increased by 40%, 75%, and 250%, respectively; while in PST they increased by 80%, 50%, and 100%, respectively (P 0.001). In MTAL they declined by 36%, 24%, and 34%, respectively, and in DCT by 38%, 59%, and 60%, respectively (P 0.001). They were higher in CCD by 110%, 115%, and 246%, respectively (P 0.001). Rats maintained Na/K balance; however with a steady state elevated serum K(+). These results reveal quantitative changes in axial distribution of Na-K-ATPase at the level of gene expression, protein abundance, and activity in the nephrons of aging animals and may explain, in part, the pathophysiology of the senescent kidney.

Secondary hyperparathyroidism (SHPT) develops in chronic kidney disease as a consequence of impaired phosphate, calcium, and vitamin D homeostasis. Treatment strategies directed to reduce the parathyroid hormone (PTH) concentrations have included phosphate binders and active vitamin D compounds. The over zealous use of these agents may result in hypercalcemia or overt calcium overload. Severe SHPT, hyperphosphatemia, and total body calcium overload have been implicated in the pathophysiology of skeletal and extraskeletal calcification and associated with increased morbidity and mortality among the dialysis population. Cinacalcet, the recently approved agent to lower PTH, activates the calcium-sensing receptor of the parathyroid gland amplifying the glands' sensitivity to extracellular ionized calcium concentration resulting in suppression of PTH secretion. Several clinical studies conducted in dialysis patients, have shown that cinacalcet in doses from 30 to 180 mg/day, significantly reduce PTH concentrations while simultaneously lowering calcium and phosphate levels. Respective to the National Kidney Foundation-Kidney Disease Outcomes and Quality Initiative (NKF-K/DOQI) recommended targets for bone and mineral metabolism, 41% of cinacalcet-treated patients achieved both PTH and calcium–phosphorus targets. The ability of cinacalcet to reduce PTH secretion, along with reductions in the serum calcium, phosphorus, and calcium–phosphorus product provide an alternative to the traditional treatment paradigm, and should be a welcomed addition to our therapeutic strategy in the management of SHPT.

Background. Osteitis fibrosa cystica (OFC) caused by secondary hyperparathyroidism is the pre-eminent form of uraemic osteodystrophy. In recent years, however, new bone abnormalities have been described. Amongthemadynamicbonedisease(ABD)hasbecome a focus of growing interest. Marked suppression of dynamic bone measurements with normal or nearnormal static bone-forming parameters are the hallmarks of this disorder. Depressed parathyroid hormone (PTH) levels, frequently evident in this entity, have been linked causally with low bone turnover. Methods. We reviewed bone biopsy specimens from 96 patients with end-stage renal disease undergoing chronic haemodialysis. Results. We found OFC in 50% of our patients, 20% had mixed bone disease, 24% showed bone morphology of ABD and a minority (6%) had osteomalacia, mostly due to aluminium accumulation. In the patients that were affected by ABD there was a distinct subgroup with bone morphology featuring a striking increase in osteoclast number and osteoclast surface, whereas the osteoid volume, osteoid thickness, osteoblast surface, tetracycline uptake and bone formation rates were diminished as in ordinary ABD. Similarly the PTH levels in this subgroup were low or undetectable. Conclusion. We describe patients undergoing chronic haemodialysis with static and dynamic bone forming parameters, indistinguishable from that of ABD, but differing from the classic ABD by the presence of increased osteoclastic bone resorption. The suppressed PTH levels in this subgroup suggests that factors other than PTH activate osteoclasts in some patients on chronic haemodialysis. Uraemic cytokines anduor toxic metabolites, including b-microglobulin, may be involved in this disorder. The precise nature of this bone abnormality remains to be defined by further studies.

The K-DOQI guidelines for bone metabolism in chronic kidney disease recommend measuring 25(OH) vitamin D levels and correcting deficiencies in stages 3 and 4 but not in ESRD. Most nephrologists are not concerned with 25(OH) vitamin D deficiency, despite evidence in hemodialysis patients that deficient vitamin D status [as measured by 25(OH) vitamin D levels] plays a role in bone disease. PD patients are often deficient in 25(OH) vitamin D in part because of peritoneal effluent losses, and correction may decrease muscle and bone complaints. Data from other populations are indicative of the importance of vitamin D in cancer surveillance and immune functioning. Randomized controlled trials of correction of 25(OH) vitamin D deficiency in both hemodialysis and peritoneal dialysis patients are urgently needed. vitamin D).

The accumulation of advanced glycation end products (AGEs) has been reported to be a major contributor to chronic systemic inflammation. AGEs are not efficiently removed by hemodialysis or the kidney of a chronic kidney disease (CKD) patient. The goal of this study was to develop a receptor for AGEs (RAGE)-based bioadsorbent device that was capable of removing endogenous AGEs from human blood. The extracellular domain of RAGE was immobilized onto agarose beads to generate the bioadsorbent. The efficacy of AGE removal from saline, serum, and whole blood; biological effects of AGE reduction; and hemocompatibility and stability of the bioadsorbent were investigated. The bioadsorbent bound AGE-modified bovine serum albumin (AGE-BSA) with a binding capacity of 0.73 ± 0.07 mg AGE-BSA/ml bioadsorbent. The bioadsorbent significantly reduced the concentration of total AGEs in serum isolated from end stage kidney disease (ESKD) patients by 57%. AGE removal resulted in a significant reduction of vascular cell adhesion molecule-1 (VCAM-1) expression in human endothelial cells and abolishment of osteoclast formation in osteoclast progenitor cells. A hollow fiber device loaded with bioadsorbent reduced endogenous AGEs from recirculated blood to 36% of baseline levels with no significant changes in total protein and albumin concentration. The bioadsorbent maintained AGE-specific binding capacity after freeze-drying and storage for 1 year. This approach provides the foundation for further development of sRAGE-based extracorporeal therapies to selectively deplete serum AGEs from human blood and decrease inflammation in patients with diabetes and/or CKD.

The Psammomys obesus lives in natural desert habitat on low energy (LE) diet, however when maintained in laboratory conditions with high energy (HE) diet it exhibits pathological metabolic changes resembling those of type 2 diabetes. We have evaluated and correlated the histopathology, metabolic and functional renal alterations occurring in the diabetic Psammomys. Renal function determined by measuring glomerular filtration rate (GFR), protein excretion, protein/creatinine ratio and morpho-immunocytochemical evaluations were performed on HE diet diabetic animals and compared to LE diet control animals. The diabetic animals present a 54% increase in GFR after one month of hyperglycemic condition and a decrease of 47% from baseline values after 4 months. Protein excretion in diabetic animals was 5 folds increased after 4 months. Light microscopy showed an increase in glomeruli size in the diabetic Psammomys, and electron microscopy and immunocytochemical quantitative evaluations revealed accumulation of basement membrane material as well as frequent splitting of the glomerular basement membrane. In addition, glycogen-filled Armanni-Ebstein clear cells were found in the distal tubules including the thick ascending limbs of the diabetic animals. These renal complications in the Psammomys, including changes in GFR with massive proteinuria sustained by physiological and histopathological changes, are very similar to the diabetic nephropathy in human. The Psamommys obesus represents therefore a reliable animal model of diabetic nephropathy.

Renal failure is associated with aortic valve calcification. Using our rat model of uremia-induced reversible aortic valve calcification, we assessed the role of apoptosis and survival pathways in that disease. We also explored the effects of raloxifene, an estrogen receptor modulator, on valvular calcification. Gene array analysis was performed in aortic valves obtained from three groups of rats ( n = 7 rats/group): calcified valves obtained from rats fed with uremic diet, valves after calcification resolution following diet cessation, and control. In addition, four groups of rats ( n = 10 rats/group) were used to evaluate the effect of raloxifene in aortic valve calcification: three groups as mentioned above and a fourth group fed with the uremic diet that also received daily raloxifene. Evaluation included imaging, histology, and antigen expression analysis. Gene array results showed that the majority of the altered expressed genes were in diet group valves. Most apoptosis-related genes were changed in a proapoptotic direction in calcified valves. Apoptosis and decreases in several survival pathways were confirmed in calcified valves. Resolution of aortic valve calcification was accompanied by decreased apoptosis and upregulation of survival pathways. Imaging and histology demonstrated that raloxifene significantly decreased aortic valve calcification. In conclusion, downregulation of several survival pathways and apoptosis are involved in the pathogenesis of aortic valve calcification. The beneficial effect of raloxifene in valve calcification is related to apoptosis modulation. This novel observation is important for developing remedies for aortic valve calcification in patients with renal failure.

Secondary hyperparathyroidism develops relatively early in chronic kidney disease as a consequence of impaired phosphate, calcium, and vitamin D homeostasis. The disease state in chronic kidney disease, which includes the histologic features of bone disease, defined as renal osteodystrophy, and the hormonal and biochemical disturbances, have recently been redefined as a disease syndrome and is referred to as “chronic kidney disease–mineral and bone disorder.” As chronic kidney disease progresses, specific histologic disturbances in the bone develop, which may or may not be predictable from the biochemical and hormonal changes that are associated with chronic kidney disease. In addition, patients may have had underlying bone disease before developing kidney failure or may have been treated with agents that will alter the classical pathologic findings of the bones in chronic kidney disease and their relation to parathyroid hormone. Thus, in stage 5 chronic kidney disease, bone biopsy with quantitative histomorphometric analysis is considered the gold standard in the diagnosis of renal osteodystrophy. In contrast to stage 5 chronic kidney disease, there are very few data on the histologic changes in bone in earlier stages of chronic kidney disease. There also is no adequate information on the etiopathogenesis of bone disease in stages 3 and 4 chronic kidney disease. Thus, because biochemical data cannot predict bone pathology in stages 3 and 4 chronic kidney disease, bone biopsy should be used to define these bone changes and to allow appropriate therapeutic approaches.

Chronic kidney disease (CKD) has been recognized as a significant public health problem, with approximately 20 million Americans, or approximately 11% of the adult population, currently living with CKD. A significant source of morbidity associated with CKD is the development of disturbances of mineral metabolism, which occurs in virtually all patients during the progression of their disease, and is associated with bone loss and fractures, cardiovascular disease, immune suppression, and increased mortality. As kidney disease develops, there is decreased functional renal mass and a tendency to retain phosphorus. The reduction in functional renal mass and the retained phosphorus act to reduce renal 1alpha-hydroxylase activity and thus the renal production of calcitriol. Further compensation to maintain normal serum calcium and phosphorus homeostasis includes increased production and release of PTH and potentially other phosphaturic factors, such as fibroblast growth factor-23 (FGF23). This increase in FGF23 contributes to maintain normal serum phosphate independent of PTH but may worsen calcitriol deficiency by also inhibiting renal 1alpha-hydroxylase activity. The decrease in calcitriol also results in promoting further hyperparathyroidism and parathyroid gland hyperplasia, because calcitriol normally inhibits the production of prepro-PTH and parathyroid cell proliferation.

Osteoporosis (OP), the most frequent bone disease affecting the general population, is associated with high fracture risk. Patients with impaired kidney function have bone and mineral disturbances leading to extraskeletal calcifications and complex changes in bone turnover that predispose them to increased fracture risk accompanied by increased morbidity and mortality. The combination of these two bone disorders seems to have an additive effect with regard to fracture risk and its outcome, so that appropriate diagnosis and treatment of this disorder should be of primary concern when approaching patients with kidney disease. Nevertheless, the clinical and laboratory diagnostic tools used to identify OP in the general population do not suit the requirement for detecting the complex bone and metabolic changes that occur with chronic kidney disease, leading to the lack of or the initiation of inappropriate therapy. This review will focus on the bone pathophysiologic processes involved in OP and renal osteodystrophy and address some of the problems associated with our current diagnostic tools and aspects of the therapeutic approaches.

Chronic kidney disease (CKD) is accompanied by disturbances in calcium, phosphate, vitamin D, and parathyroid hormone (PTH) homeostasis that play an important role in the pathophysiology of renal bone disease. The increased cardiovascular morbidity and mortality observed among patients with CKD has recently been recognized to be associated with these disturbances in mineral metabolism. Thus, disturbances in mineral metabolism observed in renal failure results in a multisystem disorder, making the development of a standardized definition of these disorders a top priority. Therefore, the Board of Directors of Kidney Disease: Improving Global Outcomes proposed to define the broader category of mineral disorders associated with CKD as CKD-mineral and bone disorder (CKD-MBD). This newly proposed definition will include the disorders of mineral metabolism, bone histology (renal osteodystrophy), and the extraskeletal manifestations such as vascular calcification. This new definition and stratification of disease should result in improvement not only in the clinical management of patients but also will facilitate the interpretation and translation of clinical research. Renal osteodystrophy is now considered as 1 component of this disorder and will be defined as a morphologic alteration only, based on unification of the histomorphometric definitions that will include parameters of turnover, mineralization, and volume. An internationally accepted classification system will enable the consensus for bone biopsy evaluation as well as for the role of biomarkers. This article will focus on the newly proposed definitions of bone disease as part of CKD-MBD, based on the complex pathophysiologic process underlying bone disease in CKD stages 2 to 5.

Chronic kidney disease (CKD) has been recognized as a significant public health problem, with 20 million Americans, or 11% of the adult population, currently living with CKD. Life expectancy in patients with CKD is limited by the development of disturbances of mineral metabolism, which occurs in virtually all patients during the progression of their disease, and is associated with bone loss and fractures, cardiovascular disease, immune suppression, and increased mortality. As kidney disease develops, there is decreased functional renal mass and a reduction in renal 1alpha-hydroxylase activity and thus in renal production of calcitriol at very early CKD stages. Recently, a potentially important role of vitamin D receptor activation (VDRa) in the survival of patients undergoing dialysis has been suggested. Beyond the effect on parathyroid hormone suppression, the pleiotropic effect of vitamin D has been associated with improvement of cardiovascular risk factors, including increased renin activity, hypertension, inflammation, insulin resistance, diabetes, and albuminuria. However, the current K/DOQI and KDIGO recommendations limit the administration of VDRa agents for treatment of hyperparathyroidism only. The role of vitamin D administration in the different CKD stages will be discussed in this review.