Transcription factor HNF4α2 promotes osteogenesis and prevents bone abnormalities in mice with renal osteodystrophy.

Renal osteodystrophy (ROD) is a disorder of bone metabolism that affects virtually all patients with chronic kidney disease (CKD) and is associated with adverse clinical outcomes including fractures, cardiovascular events, and death. In this study, we showed that hepatocyte nuclear factor 4α (HNF4α), a transcription factor mostly expressed in the liver, is also expressed in bone, and that osseous HNF4α expression was dramatically reduced in patients and mice with ROD. Osteoblast-specific deletion of Hnf4α resulted in impaired osteogenesis in cells and mice. Using multi-omics analyses of bones and cells lacking or overexpressing Hnf4α1 and Hnf4α2, we showed that HNF4α2 is the main osseous Hnf4α isoform that regulates osteogenesis, cell metabolism, and cell death. As a result, osteoblast-specific overexpression of Hnf4α2 prevented bone loss in mice with CKD. Our results showed that HNF4α2 is a transcriptional regulator of osteogenesis, implicated in the development of ROD.

Calf Circumference Predicts Falls in Older Adults on Hemodialysis.

OBJECTIVE: Older patients with chronic kidney disease (CKD) undergoing maintenance hemodialysis are at a higher risk of falling. However, there is no standard method to screen patients at higher risk. We have evaluated whether calf circumference (CC) measurement would be able to predict falls in this population. METHODS: This is a prospective study that enrolled patients aged ≥65 years on conventional hemodialysis, followed for 6 months. The presence of falls was associated with demographical, clinical, and biochemical data. Reduced CC was set at <34 cm for men and <33 cm for women. We evaluated physical status using Duke activity status index (DASI) and hand grip strength (HGS). RESULTS: Ninety-one patients were included (age 73.7 ± 5.4 years, 69.2% men, 56% with diabetes). Mean CC was 32.6 ± 3.7 cm, with a high prevalence of reduced CC (61.5%). During the follow-up, 13 falls were identified (1 had a fracture and died). These patients were older and heavier (P = .017 and P = .025, respectively). Most falls occurred in patients with sarcopenic obesity (BMI >27 kg/m2 plus reduced HGS or reduced CC). In a logistic regression model, reduced CC (hazard ratio (HR) 7.81, confidence interval (CI): 1.13-53.86, P = .037), higher age (HR 1.19, CI: 1.04-1.36, P = .011), and higher body weight (relative risk (RR) 1.13, CI: 1.04-1.22, P = .003) were independently associated with falls in a fully adjusted model. CONCLUSION: CC measurement, an easy and nonexpensive tool, was able to predict falls in older patients on HD. Further studies should test the inclusion of CC in a fall risk assessment in older patients on hemodialysis.

Potential Biomarkers of the Turnover, Mineralization, and Volume Classification: Results Using NMR Metabolomics in Hemodialysis Patients.

Bone biopsy is still the gold standard to assess bone turnover (T), mineralization (M), and volume (V) in CKD patients, and serum biomarkers are not able to replace histomorphometry. Recently, metabolomics has emerged as a new technique that could allow for the identification of new biomarkers useful for disease diagnosis or for the understanding of pathophysiologic mechanisms, but it has never been assessed in the chronic kidney disease-mineral and bone disorder (CKD-MBD) scenario. In this study, we investigated the association between serum metabolites and the bone TMV classification in patients with end-stage renal disease by using serum NMR spectroscopy and bone biopsy of 49 hemodialysis patients from a single center in Brazil. High T was identified in 21 patients and was associated with higher levels of dimethylsulfone, glycine, citrate, and N-acetylornithine. The receiver-operating characteristic curve for the combination of PTH and these metabolites provided an area under the receiver-operating characteristic curve (AUC) of 0.86 (0.76 to 0.97). Abnormal M was identified in 30 patients and was associated with lower ethanol. The AUC for age, diabetes mellitus, and ethanol was 0.83 (0.71 to 0.96). Low V was identified in 17 patients and was associated with lower carnitine. The association of age, phosphate, and carnitine provided an AUC of 0.83 (0.70 to 0.96). Although differences among the curves by adding selected metabolites to traditional models were not statistically significant, the accuracy of the diagnosis according to the TMV classification seemed to be improved. This is the first study to evaluate the TMV classification system in relation to the serum metabolome assessed by NMR spectroscopy, showing that selected metabolites may help in the evaluation of bone phenotypes in CKD-MBD. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Association of parathormone and alkaline phosphatase with bone turnover and mineralization in children with CKD on dialysis: effect of age, gender, and race.

BACKGROUND: Studies investigating bone histology in children with chronic kidney disease (CKD) are scarce. METHODS: Forty-two patients, mean age 11.3 ± 4.3 years with stage 5 CKD on dialysis, underwent double tetracycline labeling bone biopsy and the relationship between clinical features, biochemical markers, and bone densitometry (DXA) was investigated. RESULTS: Low bone turnover was present in 59% of patients, abnormal mineralization in 29%, and low bone volume in 7%. Higher bone formation rate was found in non-Caucasian patients, whereas abnormal mineralization occurred in older and shorter children. We found no impact of gender and etiology of renal disease in our population. Parathormone (PTH) and alkaline phosphatase (AP) showed positive associations with bone turnover. ROC curve analysis showed a fair performance of biomarkers to predict TMV status. PTH < 2 times ULN independently associated with low bone turnover (RR 5.62, 95% CI 1.01-31.24; p = 0.049), in a model adjusted for race, calcitriol dosage, and calcium. It was also associated with abnormal mineralization (RR 1.35, 95% CI 1.04-1.75; p = 0.025), in a model adjusted for BMD scores, AP, age, and calcitriol. PTH and AP significantly predicted turnover and mineralization defect, although with low specificity and sensitivity, reaching a maximum value of 64% and 67%, respectively. CONCLUSIONS: While PTH and AP were associated with turnover and mineralization, we recognize the limitation of their performance to clearly distinguish high from low/normal bone turnover and normal from abnormal mineralization. Our results reinforce the need to expand knowledge about renal osteodystrophy in pediatric population through prospective bone biopsy studies. Graphical abstract.

Bone Histomorphometry in Young Patients With Type 2 Diabetes is Affected by Disease Control and Chronic Complications.

CONTEXT: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of fractures. No study has evaluated the correlation of bone histomorphometry (BH) parameters with glycemic control and presence of chronic complications (CCs) in premenopausal women with T2DM. OBJECTIVES: To evaluate BH and correlate them with the degree of glycemic control and presence of CCs. DESIGN, SETTINGS, AND PATIENTS: This was a cross-sectional study conducted at a tertiary medical center. Twenty-six premenopausal women with T2DM were divided into groups with glycated hemoglobin HbA1c < 7% (good control, GC; n = 10) and HbA1c > 7% (poor control, PC; n = 16), and further subdivided into groups with (n = 9) and without (n = 17) CCs. BH parameters (bone volume [bone volume per total volume, BV/TV], trabecular thickness [Tb.Th], trabecular number [Tb.N], trabecular separation [Tb.Sp], osteoid thickness [O.Th], osteoid surface [osteoid surface per bone surface, OS/BS]), mineralizing surface [MS/BS], bone formation rate [BFR]), mineral apposition rate [MAR]) as well as serum pentosidine (PEN) and insulin-like growth factor (IGF)-1 were measured. The BH data were compared among the groups and with a BH control group (control group, CG, n = 15) matched by age, sex, and race. RESULTS: BV/TV was increased in GC (P < .001) and PC (P = .05) groups and O.th (P = .03) was smaller in the PC group than in the CG. A comparison of the groups with and without CCs with the CG showed in the group with CCs, O.Th was smaller(P = .01) and BV/TV similar to the CG (P = .11). HbA1c correlated negatively with O.Th (P = .02) and OS/BS (P = .01). There was no correlation of BH to PEN and IGF-1. CONCLUSION: BH in premenopausal patients with T2DM is affected by disease control and chronic complications.

Treatment of Human Immunodeficiency Virus Infection With Tenofovir Disoproxil Fumarate-Containing Antiretrovirals Maintains Low Bone Formation Rate, But Increases Osteoid Volume on Bone Histomorphometry.

Bone mineral density (BMD) loss is a known complication of human immunodeficiency virus (HIV) infection and its treatment, particularly with tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimens. Although renal proximal tubular dysfunction and phosphaturia is common with TDF, it is unknown whether BMD loss results from inadequate mineralization. We evaluated change in BMD by dual-energy X-ray absorptiometry (DXA) and bone histomorphometry by tetracycline double-labeled transiliac crest biopsies in young men living with HIV before (n = 20) and 12 months after (n = 16) initiating TDF/lamivudine/efavirenz. We examined relationships between calciotropic hormones, urinary phosphate excretion, pro-inflammatory and pro-resorptive cytokines, and bone remodeling-related proteins with changes in BMD and histomorphometry. Mean age was 29.6 ± 5.5 years, with mean CD4 + T cell count of 473 ± 196 cells/mm3 . At baseline, decreased bone formation rate and increased mineralization lag time were identified in 16 (80%) and 12 (60%) patients, respectively. After 12 months, we detected a 2% to 3% decrease in lumbar spine and hip BMD by DXA. By histomorphometry, we observed no change in bone volume/total volume (BV/TV) and trabecular parameters, but rather, increases in cortical thickness, osteoid volume, and osteoblast and osteoclast surfaces. We did not observe significant worsening of renal phosphate excretion or mineralization parameters. Increases in PTH correlated with decreased BMD but not histomorphometric parameters. Overall, these data suggest abnormalities in bone formation and mineralization occur with HIV infection and are evident at early stages. With TDF-containing antiretroviral therapy (ART), there is an increase in bone remodeling, reflected by increased osteoblast and osteoclast surfaces, but a persistence in mineralization defect, resulting in increased osteoid volume. © 2019 American Society for Bone and Mineral Research.

Effects of parathyroidectomy on the biology of bone tissue in patients with chronic kidney disease and secondary hyperparathyroidism.

Secondary hyperparathyroidism is a complication of chronic kidney disease that compromises skeletal integrity. In patients with secondary hyperparathyroidism undergoing parathyroidectomy, parathyroid hormone levels dramatically decrease. The effects of parathyroidectomy on bone tissue are poorly understood, especially regarding the proteins expressed by osteocytes, such as fibroblast growth factor 23, dentin matrix protein 1, matrix extracellular phosphoglycoprotein, sclerostin, receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin, which regulate bone turnover. The objective of this study was to characterize the bone expression of these proteins by immunohistochemistry and correlate these results with those of bone histomorphometry before and after parathyroidectomy. We studied bone biopsies that were obtained from 23 patients before and 12 months after parathyroidectomy. We observed an improvement in bone microarchitecture, but impaired mineralization after parathyroidectomy. We found significant increases in sclerostin and osteoprotegerin expression and a decrease in the RANKL/osteoprotegerin ratio after parathyroidectomy, suggesting that their expression is regulated by parathormone. These proteins correlated with structural and bone formation parameters. We conclude that after parathyroidectomy, significant changes occur in the bone expression of osteocyte proteins and that these proteins potentially regulate bone remodeling.

Comparison of clinical, biochemical and histomorphometric analysis of bone biopsies in dialysis patients with and without fractures.

Chronic kidney disease-mineral bone disorders (CKD-MBD) are associated with increased risk of fracture. Studies report about 3% of fractures in CKD patients, and these occur earlier than in the general population, namely 16 and 13 years earlier for men and women, respectively. Better understanding of the pathophysiology of fractures would probably contribute to new therapeutic approaches. This study aimed to evaluate report of long bone fractures from a bone biopsies bank from patients on hemodialysis and compare clinical and biochemical characteristics, as well as the results of the histomorphometric analysis of trabecular and cortical bone of these patients with a control group (without fractures), paired for age, gender, and time on hemodialysis. Bone proteins (SOST, DMP1 and MEPE) were evaluated by immunohistochemistry. Seventeen patients with fracture and controls were studied. Fracture prevalence was 0.82/1000 patients/year. Serum phosphorus levels were significantly lower in the fracture group. Histomorphometric analysis revealed that all the patients had high turnover disease, and the fracture group had smaller volume and trabecular thickness, greater osteoid surface, smaller eroded surface, smaller mineralizing surface, formation rate and longer mineralization lag time when compared to controls; the DMP1 expression in the cortical bone was smaller and the SOST in the trabecular bone was higher in fractured patients. As conclusion, we found low prevalence of fractures. Both groups had high turnover disease, but the fractured ones presented more impaired bone microarchitecture, as well as lower formation and greater mineralization defect. Bone proteins expression correlated with parameters involved in bone remodeling.

The unexpected presence of iron in bone biopsies of hemodialysis patients.

PURPOSE: Bone biopsy defines classical diseases that constitute the renal osteodystrophy. There is a recent concern regarding other histological findings that are not appreciated by using the turnover, mineralization, and volume (TMV) classification. Iron (Fe) overload has been considered a new challenge and the real significance of the presence of this metal in bones is not completely elucidated. Therefore, the main goal of the current study was to not only to identify bone Fe, but also correlate its presence with demographic, and biochemical characteristics. METHODS: This is a cross-sectional analysis of bone biopsies performed in 604 patients on dialysis from 2010 to 2014 in a tertiary academic Hospital. RESULTS: Histomorphometric findings revealed the presence of Fe in 29.1%. Fe was associated with higher levels of serum ferritin and serum calcium. No TMV status was related to Fe bone overload. CONCLUSION: Our study has highlighted that the presence of Fe in one-third of bone samples has unknown clinical significance. The lack of other contemporary bone biopsy study reporting Fe prevents us from comparison. The findings presented here should be specifically addressed in a future research and will require attention prior to implementation of any clinical guideline. If any proposed treatment, however, would change the bone Fe-related morbidity is undetermined.

The effect of vitamin D and zoledronic acid in bone marrow adiposity in kidney transplant patients: A post hoc analysis.

PURPOSE: Osteoblasts and adipocytes are derived from mesenchymal stem cells. An imbalance in the differentiation of these lineages could affect the preservation of bone integrity. Several studies have suggested the importance of this imbalance in the pathogenesis of osteoporosis after kidney transplant (KT), but the role of bone marrow adiposity in this process is not well known, and if the treatment with the anti-absorptive (zoledronic acid-ZA) drugs could attenuate bone loss. Thus, our objective was compare bone marrow adiposity, osteoblasts and osteocytes before and after KT, verify an association between bone remodeling process (Turnover, Volume, and Mineralization-TMV classification), the osteocyte sclerostin expression to evaluate if there is a role of Wnt pathway, as well as the effect of ZA on these cells. METHODS: We studied 29 new living-donor KT patients. One group received ZA at the time of KT plus cholecalciferol for twelve months, and the other group received only cholecalciferol. Bone biopsies were performed at baseline and after 12 months of treatment. Histomorphometric evaluation was performed in bone and bone marrow adipocytes. Sclerostin (Scl) expression in osteocytes was evaluated by immunohistochemistry. RESULTS: Some bone marrow adiposity parameters were increased before KT. After KT, some of them remained increased and they worsened with the use of ZA. In the baseline, lower bone Volume and Turnover, were associated with increased bone marrow adiposity parameters (some of them). After KT, both groups showed the same associations. Osteocyte Scl expression after KT decreased with the use of ZA. We observed also an inverse association between bone adiposity parameters and lower osteocyte sclerostin expression 12 months after KT. CONCLUSION: In conclusion, the present study suggests that KT fails to normalize bone marrow adiposity, and it even gets worse with the use of ZA. Moreover, bone marrow adiposity is inversely associated with bone Volume and Turnover, which seems to be accentuated by the antiresorptive therapy.

Hypovitaminosis D in patients undergoing kidney transplant: the importance of sunlight exposure.

OBJECTIVES:: Recent studies have shown a high prevalence of hypovitaminosis D, defined as a serum 25-hydroxyvitamin D level less than 30 ng/ml, in both healthy populations and patients with chronic kidney disease. Patients undergoing kidney transplant are at an increased risk of skin cancer and are advised to avoid sunlight exposure. Therefore, these patients might share two major risk factors for hypovitaminosis D: chronic kidney disease and low sunlight exposure. This paper describes the prevalence and clinical characteristics of hypovitaminosis D among patients undergoing kidney transplant. METHODS:: We evaluated 25-hydroxyvitamin D serum levels in a representative sample of patients undergoing kidney transplant. We sought to determine the prevalence of hypovitaminosis D, compare these patients with a control group, and identify factors associated with hypovitaminosis D (e.g., sunlight exposure and dietary habits). RESULTS:: Hypovitaminosis D was found in 79% of patients undergoing kidney transplant, and the major associated factor was low sunlight exposure. These patients had higher creatinine and intact parathyroid hormone serum levels, with 25-hydroxyvitamin D being inversely correlated with intact parathyroid hormone serum levels. Compared with the control group, patients undergoing kidney transplant presented a higher prevalence of 25-hydroxyvitamin D deficiency and lower serum calcium, phosphate and albumin but higher creatinine and intact parathyroid hormone levels. CONCLUSIONS:: Our results confirmed the high prevalence of hypovitaminosis D in patients undergoing kidney transplant. Therapeutic strategies such as moderate sunlight exposure and vitamin D supplementation should be seriously considered for this population.

Hypovitaminosis D in patients undergoing kidney transplant: the importance of sunlight exposure

OBJECTIVES: Recent studies have shown a high prevalence of hypovitaminosis D, defined as a serum 25-hydroxyvitamin D level less than 30 ng/ml, in both healthy populations and patients with chronic kidney disease. Patients undergoing kidney transplant are at an increased risk of skin cancer and are advised to avoid sunlight exposure. Therefore, these patients might share two major risk factors for hypovitaminosis D: chronic kidney disease and low sunlight exposure. This paper describes the prevalence and clinical characteristics of hypovitaminosis D among patients undergoing kidney transplant. METHODS: We evaluated 25-hydroxyvitamin D serum levels in a representative sample of patients undergoing kidney transplant. We sought to determine the prevalence of hypovitaminosis D, compare these patients with a control group, and identify factors associated with hypovitaminosis D (e.g., sunlight exposure and dietary habits). RESULTS: Hypovitaminosis D was found in 79% of patients undergoing kidney transplant, and the major associated factor was low sunlight exposure. These patients had higher creatinine and intact parathyroid hormone serum levels, with 25-hydroxyvitamin D being inversely correlated with intact parathyroid hormone serum levels. Compared with the control group, patients undergoing kidney transplant presented a higher prevalence of 25-hydroxyvitamin D deficiency and lower serum calcium, phosphate and albumin but higher creatinine and intact parathyroid hormone levels. CONCLUSIONS: Our results confirmed the high prevalence of hypovitaminosis D in patients undergoing kidney transplant. Therapeutic strategies such as moderate sunlight exposure and vitamin D supplementation should be seriously considered for this population.

The complexity of chronic kidney disease-mineral and bone disorder across stages of chronic kidney disease.

Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (CKD-MBD) is a complex disease that is not completely understood. However, some factors secreted by the osteocytes might play an important role in its pathophysiology. Therefore, we evaluated the bone expression of proteins in a group of patients with CKD 2-3, CKD 4, and CKD 5 on dialysis and healthy individuals. We also tested several bone remodeling markers, and correlated these levels with bone biopsy findings. As expected, as serum calcium decreased, serum phosphate, alkaline phosphatase, fibroblast growth factor-23 (FGF-23), parathyroid hormone, and osteoprotegerin increased, as CKD progressed. Additionally, there was a gradual increase in bone resorption associated with a decrease in bone formation and impairment in bone mineralization. Bone expression of sclerostin and parathyroid hormone receptor-1 seemed to be increased in earlier stages of CKD, whereas FGF-23 and phosphorylated ß-catenin had increased expression in the late stages of CKD, although all these proteins were elevated relative to healthy individuals. Immunohistochemical studies showed that FGF-23 and sclerostin did not co-localize, suggesting that distinct osteocytes produce these proteins. Moreover, there was a good correlation between serum levels and bone expression of FGF-23. Thus, our studies help define the complex mechanism of bone and mineral metabolism in patients with CKD. Linkage of serum markers to bone expression of specific proteins may facilitate our understanding and management of this disease.

Predictive Factors of One-Year Mortality in a Cohort of Patients Undergoing Urgent-Start Hemodialysis.

BACKGROUND: Chronic kidney disease (CKD) affects 10-15% of adult population worldwide. Incident patients on hemodialysis, mainly those on urgent-start dialysis at the emergency room, have a high mortality risk, which may reflect the absence of nephrology care. A lack of data exists regarding the influence of baseline factors on the mortality of these patients. The aim of this study was to evaluate the clinical and laboratory characteristics of this population and identify risk factors that contribute to their mortality. PATIENTS AND METHODS: We studied 424 patients who were admitted to our service between 01/2006 and 12/2012 and were followed for 1 year. We analyzed vascular access, risk factors linked to cardiovascular disease (CVD) and mineral and bone disease associated with CKD (CKD-MBD), and clinical events that occurred during the follow-up period. Factors that influenced patient survival were evaluated by Cox regression analysis. RESULTS: The patient mean age was 50 ± 18 years, and 58.7% of them were male. Hypertension was the main cause of primary CKD (31.8%). Major risk factors were smoking (19.6%), dyslipidemia (48.8%), and CVD (41%). Upon admission, most patients had no vascular access for hemodialysis (89.4%). Biochemical results showed that most patients were anemic with high C-reactive protein levels, hypocalcemia, hyperphosphatemia, elevated parathyroid hormone and decreased 25-hydroxy vitamin D. At the end of one year, 60 patients died (14.1%). These patients were significantly older, had a lower percentage of arteriovenous fistula in one year, and low levels of 25-hydroxy vitamin D. CONCLUSIONS: The combined evaluation of clinical and biochemical parameters and risk factors revealed that the mortality in urgent-start dialysis is associated with older age and low levels of vitamin D deficiency. A lack of a permanent hemodialysis access after one year was also a risk factor for mortality in this population.

Serum levels of fibroblast growth factor 23 are elevated in patients with active Lupus nephritis.

BACKGROUND: Fibroblast growth factor 23 (FGF23), a phosphate-regulating hormone is an established cardiovascular risk factor. Recently, FGF23 has been related to inflammation. Lupus is an inflammatory disease, and whether FGF23 is associated with Lupus nephritis (LN) activity is unknown. MATERIALS AND METHODS: We studied 15 pre-menopausal patients with recent LN diagnose (⩽2months) and compared them to 1:1 age-matched healthy control group. We measured serum levels of intact FGF23, interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and urinary levels of monocyte chemotactic protein (MCP1). RESULTS: LN patients (29.5±10years) presented proteinuria of 4.7±2.9g/day, and estimated glomerular filtration rate of 37 (31-87)ml/min/1.73m2. They demonstrated higher FGF23 levels when compared to healthy controls [106.7 (80.3-179) vs. 33.6 (25.8-60.9) pg/ml, p<0.001]. FGF23 levels correlated with urinary MCP1 (r=0.62, p<0.001), serum TNFα (r=0.58, p<0.001) and serum IL-6 (r=0.46, p=0.01). Only the correlation between FGF23 and MCP1 remained significant after adjustments for 25(OH) vitamin D and renal function. CONCLUSION: Newly diagnosed LN patients demonstrated elevated FGF23 levels that were positively correlated to urinary MCP1, independently of vitamin D levels and kidney function. If FGF23 may predict clinical outcomes in LN warrants further evaluation.

Can we compare serum sclerostin results obtained with different assays in hemodialysis patients?

PURPOSE: Sclerostin, secreted by osteocytes, plays a key role in antagonizing bone formation. Recent studies, which seldom include chronic kidney disease (CKD) patients, have reported on the association of sclerostin and mortality, with contradictory results. The assay-linked variability may contribute to these discrepant results. METHODS: We have compared sclerostin results obtained with two assays (TECO and Biomedica) in a cohort of 91 CKD patients undergoing hemodialysis. RESULTS: We found a strong correlation (r = 0.870, p < 0.0001) between the serum sclerostin concentrations measured by the two assays. Bland-Altman plot shows that, although there was a partial agreement between the assays, differences found for individual values (-0.27 ± 0.54; ranging from -1.3 to 0.8 ng/ml) were quite unpredictable. By using TECO, there was a significant relationship between serum sclerostin, and calcitonin (r = 0.224), IL-6 (r = 0.251) and FGF23 (r = 0.331) levels while no correlation was found with PTH or total alkaline phosphatase. Regarding Biomedica, there was a significant correlation with calcitonin (r = 0.260), and ß2 microglobulin (r = 0.210), but no correlation with PTH or total alkaline phosphatase. Overall, 25.3% among the patients had different classifications as to normal or high values, according to the manufacturer. CONCLUSION: Sclerostin levels should be interpreted with caution, as they can vary widely according to the assay used. Further studies are clearly needed before considering sclerostin as a true marker of mortality. Moreover, we do not know at present which serum sclerostin levels should be regarded as either normal or potentially dangerous in patients with CKD.

Correction of metabolic acidosis in hemodialysis: consequences on serum leptin and mineral metabolism.

PURPOSE: Hyperleptinemia and metabolic acidosis (MA) are frequently observed in patients on hemodialysis (HD). While the role of leptin in patients on HD is not completely understood, HD only partially corrects MA. Both leptin and acidosis have effect on bone disease. The goal of the present study was to evaluate the effects of MA correction on chronic kidney disease-mineral and bone disorder laboratory parameters and leptin levels. METHODS: Forty-eight patients on HD, aged 43±19 years, were prospectively studied. Individual adjustments in the bicarbonate dialysate concentration were made to maintain pre-dialysis concentration≥22 mEq/l. Blood gas analysis was done monthly for 4 months (M1-M4). RESULTS: From M0 to M4, serum albumin increased (from 3.5 ±0.3 to 4.0±0.3 g/l, p<0.0001) while ß2 microglobulin decreased (from 27.6±8.3 to 25.8±6.8 µg/ml, p=0.025). Serum leptin decreased in all but three patients, as well as leptin/adiponectin ratio (p<0.0001). There was a decrease in ionized serum calcium (from 5.0±0.5 to 4.7±0.5 mg/dl, p =0.002) and an increase in parathyroid hormone (PTH) [from 191 (85, 459) to 446 pg/ml (212, 983), p<0.0001] and in serum phosphate (from 5.4±1.4 to 5.8±1.1 mg/dl, p=0.048). CONCLUSION: MA correction in HD patients can decrease leptin, an atherogenic marker. The impact of such treatment extends to uremic bone disease, as decrease in serum calcium and increase in PTH. However, this could be an undesirable effect because it may aggravate a secondary hyperparathyroidism. Whether the reduction in leptin levels has impact on outcomes in patients on hemodialysis deserves further investigation.

Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease.

Chronic kidney disease--mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins, and dialysis modality. Although extensively studied in hemodialysis (HD) patients, only a few studies exist for peritoneal dialysis (PD) patients. Since most of these older studies contain no bone biopsy data, we studied the pattern of renal osteodystrophy in 41 prevalent PD patients. The most common presentation was adynamic bone disease (49%). There was a significant inverse association between serum sclerostin (a Wnt/ß-catenin pathway inhibitor that decreases osteoblast action and bone formation) and the bone formation rate. Bone alkaline phosphatase had the best sensitivity and specificity to detect both high- and low-turnover diseases. The comparison between nondiabetic PD and HD patients, matched by age, gender, parathyroid hormone level, and length of dialysis, revealed low 25-hydroxyvitamin D levels, worse bone mineralization, and low bone turnover in the nondiabetic PD group. Thus, adynamic bone disease was the most frequent type of renal osteodystrophy in PD patients. Sclerostin seems to participate in the pathophysiology of adynamic bone disease and bone alkaline phosphatase was the best serum marker of bone turnover in these patients.