BACKGROUND: Renal osteodystrophy (ROD) is a skeletal pathology associated with chronic kidney disease-mineral and bone disorder (CKD-MBD) that is characterized by aberrant bone mineralization and remodeling. ROD increases the risk of fracture and mortality in CKD patients. The underlying mechanisms of ROD remain elusive, partially due to the absence of an appropriate animal model. To address this gap, we established a stable mouse model of ROD using an optimized adenine-enriched diet and conducted exploratory analyses through ribonucleic acid sequencing (RNA-seq). METHODS: Eight-week-old male C57BL/6J mice were randomly allocated into three groups: control group ( n = 5), adenine and high-phosphate (HP) diet group ( n = 20), and the optimized adenine-containing diet group ( n = 20) for 12 weeks. We assessed the skeletal characteristics of model mice through blood biochemistry, microcomputed tomography (micro-CT), and bone histomorphometry. RNA-seq was utilized to profile gene expression changes of ROD. We elucidated the functions of differentially expressed genes (DEGs) using gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and gene set enrichment analysis (GSEA). DEGs were validated via quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: By the fifth week, adenine followed by an HP diet induced rapid weight loss and high mortality rates in the mouse group, precluding further model development. Mice with optimized adenine diet-induced ROD displayed significant abnormalities in serum creatinine and blood urea nitrogen levels, accompanied by pronounced hyperparathyroidism and hyperphosphatemia. The femur bone mineral density (BMD) of the model mice was lower than that of control mice, with substantial bone loss and cortical porosity. ROD mice exhibited substantial bone turnover with an increase in osteoblast and osteoclast markers. Transcriptomic profiling revealed 1907 genes with upregulated expression and 723 genes with downregulated expression in the femurs of ROD mice relative to those of control mice. Pathway analyses indicated significant enrichment of upregulated genes in the sphingolipid metabolism pathway. The significant upregulation of alkaline ceramidase 1 ( Acer1 ), alkaline ceramidase 2 ( Acer2 ), prosaposin-like 1 ( Psapl1 ), adenosine A1 receptor ( Adora1 ), and sphingosine-1-phosphate receptor 5 ( S1pr5 ) were successfully validated in mouse femurs by qRT-PCR. CONCLUSIONS Optimized adenine diet mouse model may be a valuable proxy for studying ROD. RNA-seq analysis revealed that the sphingolipid metabolism pathway is likely a key player in ROD pathogenesis, thereby providing new avenues for therapeutic intervention.
Animals ; Mice ; Chronic Kidney Disease-Mineral and Bone Disorder/genetics* ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Sphingolipids/metabolism* ; Transcriptome/genetics* ; Signal Transduction/genetics* ; X-Ray Microtomography ; Adenine

OBJECTIVE: To observe the effect of Ronghuang granule on serum fibroblast growth factor 23 (FGF23), fibroblast growth factor receptor (FGFRs) and Klotho protein levels in non-dialysis patients with chronic kidney disease-mineral and bone disorder (CKD-MBD) and kidney deficiency and damp heat syndrome. METHODS: Seventy non-dialysis CKD-MBD patients with kidney deficiency and dampness-heat syndrome were randomized into control group (=35) and treatment group (=35). All the patients were given routine treatment combined with traditional Chinese medicine retention enema, and the patients in the treatment group received additional Ronghuang granule treatment (3 times a day). After the 12-week treatments, the patients were examined for changes of TCM syndromes. Serum levels of Ca, P, parathyroid hormone (iPTH), FGF23, FGFRs and Klotho proteins were detected before and after treatment. These parameters were also examined in 20 healthy volunteers. RESULTS: Sixty-five patients completed the study, including 33 in the control group and 32 in the treatment group. The patients in the treatment group showed significantly better treatment responses than those in the control group ( < 0.05 or 0.01). At 4, 8, and 12 weeks of treatment, the patients in the treatment group had significantly lowered scores of TCM syndromes compared with the score before treatment ( < 0.05 or 0.01), while in the control group, significant reduction of the scores occurred only at 12 weeks ( < 0.05); at each of the time points, the treatment group had significantly greater reductions in the score than the control group ( < 0.01). Significant improvements in serum Ca, P and iPTH levels were observed at 4, 8, and 12 weeks in the treatment group ( < 0.05) but only at 12 weeks in the control group ( < 0.05). The patients in the control and treatment groups all showed elevated serum levels of FGF23, FGFRs and Klotho protein compared with the normal subjects ( < 0.01); FGF23, FGFRs and Klotho levels were significantly reduced in the treatment group ( < 0.05) but remained unchanged in the control group (>0.05), showing significant differences between the two groups. CONCLUSIONS Ronghuang granule improves the clinical symptoms of non-dialysis CKD-MBD patients with kidney deficiency and dampness heat syndrome by reducing serum levels of FGF23, FGFRs and Klotho, improving calcium and phosphorus metabolism disorder, and inhibiting secondary hyperparathyroidism.
Calcium ; blood ; Chronic Kidney Disease-Mineral and Bone Disorder ; blood ; therapy ; Drugs, Chinese Herbal ; pharmacology ; Enema ; Fibroblast Growth Factors ; blood ; Glucuronidase ; blood ; Humans ; Parathyroid Hormone ; blood ; Phosphorus ; blood ; Receptors, Fibroblast Growth Factor ; blood ; Renal Insufficiency, Chronic ; blood ; therapy ; Sweating Sickness ; blood ; therapy ; Syndrome

Adult ; China ; epidemiology ; Chronic Kidney Disease-Mineral and Bone Disorder ; epidemiology ; therapy ; Female ; Humans ; Male ; Middle Aged ; Prevalence ; Renal Dialysis ; methods

BACKGROUNDMineral and bone disorder (MBD), especially hyperphosphatemia, is an independently risk factor for adverse prognosis in patients with chronic kidney disease (CKD). However, CKD-MBD among Chinese population was poorly studied. This study aimed to investigate the status of MBD and its association with cardiovascular parameters in Chinese patients with predialysis CKD.

METHODSChinese Cohort Study of Chronic Kidney Disease (C-STRIDE) is a prospective multicenter cohort study involving predialysis CKD patients in China. Markers of MBD, including serum phosphorus, calcium, and intact parathyroid hormone, were measured in baseline samples at the patients' entry. The association between serum phosphorus and abdominal aortic calcification (AAC), left ventricular hypertrophy (LVH) were examined by logistic regression models.

RESULTSAltogether 3194 predialysis patients with mean estimated glomerular filtration of 51.8 ± 33.1 ml.min-1.1.73 m-2 were included. The proportion of patients with hyperphosphatemia were 2.6%, 2.9%, 6.8%, and 27.1% in CKD Stages 3a, 3b, 4, and 5, respectively. Moreover, 71.6% of the patients with hyperphosphatemia did not receive any phosphate-binder (PB). Lateral abdominal X-rays were obtained in 2280 patients, 9.8% of the patients were diagnosed as having AAC. Altogether 2219 patients had data of echocardiography, and 13.2% of them were diagnosed with LVH. Multivariate logistic regression analysis showed that serum phosphorus was independently associated with the presence of AAC and LVH.

CONCLUSIONSIn Chinese patients with CKD, the percentage of hyperphosphatemia is comparable to that of other countries while the usage of PBs is suboptimal. The prevalence of vascular calcification in Chinese patients is relatively lower compared with the Caucasian population.

Adolescent ; Adult ; Aged ; China ; Chronic Kidney Disease-Mineral and Bone Disorder ; blood ; metabolism ; physiopathology ; Female ; Glomerular Filtration Rate ; physiology ; Humans ; Hyperphosphatemia ; blood ; metabolism ; physiopathology ; Hypertrophy, Left Ventricular ; blood ; metabolism ; physiopathology ; Logistic Models ; Male ; Middle Aged ; Phosphorus ; blood ; Prospective Studies ; Renal Insufficiency, Chronic ; blood ; metabolism ; physiopathology ; Vascular Calcification ; blood ; metabolism ; physiopathology ; Young Adult

INTRODUCTIONA complex relationship exists between chronic kidney disease-mineral and bone disorder (CKD-MBD) and adverse outcomes among dialysis patients. This study aimed to report the prevalence of CKD-MBD and examine the impact of achieving target CKD-MBD parameters on morbidity and mortality one year after peritoneal dialysis (PD) initiation.

METHODSIn this retrospective cohort study, patients electively initiated on PD were followed up for one year. Laboratory parameters were collected and the prevalence of CKD-MBD 4-6 months after PD initiation was determined based on the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Linear regression and Cox proportional hazards model were used to evaluate the effects of achieving CKD-MBD targets 4-6 months after PD initiation on hospitalisation, the incidence of peritonitis or exit-site infections (ESIs), and mortality at one year.

RESULTSThe prevalence of CKD-MBD among the 86 patients in this study was 86.0% (KDOQI) and 54.7% (KDIGO). There was no significant difference in hospitalisation duration between patients who achieved targets and those who did not. Patients who failed to meet all the KDIGO CKD-MBD or calcium serum targets had a higher incidence of peritonitis or ESI. A trend toward shorter time to death was observed among patients who failed to meet the KDIGO phosphorus serum targets.

CONCLUSIONThere was moderate (KDIGO) to high prevalence (KDOQI) of CKD-MBD among the patients. Achievement of all the KDIGO CKD-MBD or calcium serum targets was associated with reduced peritonitis or ESI, while achievement of the KDIGO phosphorus serum targets was associated with improved survival.

Adult ; Aged ; Aged, 80 and over ; Chronic Kidney Disease-Mineral and Bone Disorder ; complications ; epidemiology ; Female ; Humans ; Kidney Failure, Chronic ; complications ; therapy ; Linear Models ; Male ; Middle Aged ; Peritoneal Dialysis ; Prevalence ; Proportional Hazards Models ; Quality Control ; Retrospective Studies ; Treatment Outcome

Adolescent ; Bone Diseases ; etiology ; Chronic Kidney Disease-Mineral and Bone Disorder ; complications ; pathology ; Facial Bones ; Female ; Humans ; Hyperparathyroidism, Secondary ; complications ; Kidney Failure, Chronic ; complications ; pathology ; Syndrome