Original Full Length ArticleIndoxyl sulfate exacerbates low bone turnover induced by parathyroidectomy in young adult rats
Introduction
Abnormalities of bone turnover are commonly observed in patients with chronic kidney disease (CKD), and this condition has recently been termed CKD-related mineral and bone disease (CKD-MBD) [1]. The Kidney Disease Improving Global Outcomes (KDIGO) CKD-MBD Work Group analyzed the prevalence of various types of bone disease in patients with CKD between 1983 and 2006 [2]. The group reported that 84% of the patients with CKD at stages 3–5 had some kind of bone abnormality including osteitis fibrosa, which is a high-turnover bone disease (32%), adynamic bone disease, which is a low-turnover bone disease (18%), osteomalacia (8%), and mixed disease (20%). A more recent study reported that low bone turnover accounted for more than 60% in 543 white patients with CKD stage 5 [3].
Low-turnover bone disease, so-called adynamic bone disease, is mainly characterized by an abnormally low bone formation rate [4], [5] and the disease is recognized to be associated with low serum PTH level [5], [6], [7] and skeletal resistance to parathyroid hormone (PTH) [5], [8], [9]. Analyses of the prevalence of bone turnover abnormalities in patients with end-stage renal disease showed that patients with adynamic bone disease had the lowest serum concentration of intact parathyroid hormone (PTH) compared to patients with other bone abnormalities [10], [11]. Other studies also reported an association between reduced serum PTH levels and increases in fractures [12] and all-cause mortality [13] in patients on dialysis.
Renal dysfunction leads to an accumulation of uremic toxins in CKD patients [14], [15], and more than 100 substances have been proposed as uremic toxins as of 2008 [14], [16]. Some uremic toxins have a negative impact on many body functions such as cardiovascular systems in CKD patients and CKD model animals [16], [17]. Indoxyl sulfate (IS) is one of the organic anion uremic toxins that belongs to the family of protein-bound retention solutes [14]. The metabolic pathway for the synthesis of IS is shown in Fig. 1. In the intestine, dietary tryptophan is metabolized to indole by intestinal bacteria. Indole is absorbed and transported to the liver where it is converted to IS via indoxyl [18]. IS is rapidly excreted into urine in healthy subjects, but accumulates in the blood of patients with impaired renal function [19], [20], [21]. Several reports indicate that IS is related to glomerular sclerosis and renal fibrosis, and accelerates the progression of CKD in rats [19], [22].
Iwasaki et al. [23] reported that administration of an oral charcoal adsorbent (AST-120), which adsorbs uremic toxins and/or their precursors in the intestine, to partially nephrectomized rats suppresses progression of low-turnover bone disease and reverses the down-regulation of PTH receptor gene in osteoblasts, which is implicated as a cause of PTH resistance. Subsequently, Nii-Kono et al. [24] showed that IS suppresses PTH-stimulated intracellular cAMP production and PTH receptor expression, and induces oxidative stress in primary cultured osteoblastic cells. Moreover, a clinical study reported a significant negative correlation between IS and bone-specific alkaline phosphatase (r = − 0.34) independent of PTH in 47 hemodialysis patients [25]. These results suggest that IS has an important role in the pathogenesis of low bone turnover through induction of skeletal resistance to PTH. However, the effects of IS on low bone turnover have not been elucidated. In the present study, we fed an indole-supplemented diet to rats with low bone turnover induced by parathyroidectomy (PTX) to increase blood IS level via biological metabolic pathways. Using this model, we examined whether IS exacerbates low bone turnover.
Section snippets
Animals
Eight-week-old male SD rats (Crl:CD) weighing 280 to 310 g were purchased from Charles River Japan (Kanagawa, Japan). Rats were housed in polycarbonate cages and in an animal room under controlled illumination (12-h light/dark cycle), temperature (22 ± 2 °C), and humidity (55 ± 10%). During 6 days of acclimatization, they were allowed free access to standard powder diet CE-2 (containing approximately 1% calcium; CLEA Japan Inc., Tokyo, Japan) and tap water. All experimental procedures were approved by
Induction of low bone turnover by PTX
The body weights of parathyroidectomized rats were 8.5% lower than those of sham-operated rats at 2 weeks after PTX. Serum PTH and Ca levels are shown in Fig. 2. Marked decreases in serum PTH level were observed in 21 of 24 animals in the PTX group (Fig. 2A). The results provided evidence for successful resection of the parathyroid glands in 21 animals. Serum Ca levels in these animals decreased dramatically (Fig. 2B).
Effects of indole-supplemented feeding on serum bone turnover markers in PTX rats
As shown in Fig. 3A, body weights in the PTX and PTX + ID groups were lower than
Discussion
Animal models of CKD with low bone turnover are usually produced by partial nephrectomy combined with PTX [23], [30], [31]. Moreover, Iwasaki et al. [23] constructed a rat model of renal failure with skeletal resistance to PTH by continuous infusion of a physiological level of 1–34 PTH in addition to PTX and nephrectomy. Thus, models commonly used for the evaluation of bone metabolism represent low bone turnover with skeletal resistance to PTH. In these models, partial nephrectomy is conducted
Competing interest statement
The authors declare no competing interests relevant to this work.
Acknowledgments
We thank Rie Takagi, Sayaka Seki, Misaki Miyamoto, and Ayumi Hirano for technical assistance, and Kaori Kikuchi for assistance with measurement of serum IS levels.
References (38)
- et al.
Kidney Disease: Improving Global Outcomes (KDIGO). Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO)
Kidney Int
(2006) - et al.
Low bone turnover in patients with renal failure
Kidney Int Suppl
(1999) - et al.
Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease
Kidney Int
(1993) - et al.
Skeletal resistance to the calcemic action of parathyroid hormone in uremia: role of 1,25 (OH)2 D3
Kidney Int
(1976) - et al.
The spectrum of bone disease in end-stage renal failure—an evolving disorder
Kidney Int
(1993) - et al.
Bone disease in predialysis, hemodialysis, and CAPD patients: evidence of a better bone response to PTH
Kidney Int
(1995) - et al.
PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis
Am J Kidney Dis
(2006) - et al.
Review on uremic toxins: Classification, concentration, and interindividual variability
Kidney Int
(2003) - et al.
New insights in uremic toxins
Kidney Int Suppl
(2003) - et al.
Serum indoxyl sulfate levels in patients with diabetic nephropathy: Relation to renal function
Diabetes Res Clin Pract
(2009)
ndoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells
Kidney Int
Metabolomic search for uremic toxins as indicators of the effect of an oral sorbent AST-120 by liquid chromatography/tandem mass spectrometry
J Chromatogr B Analyt Technol Biomed Life Sci
Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-κB and free radical in proximal tubular cells
Kidney Int
The uremic solute indoxyl sulfate induces oxidative stress in endothelial cells
J Thromb Haemost
p-Cresyl sulfate induces osteoblast dysfunction through activating JNK and p38 MAPK pathways
Bone
KDIGO clinical practice guideline for the diagnosis, evaluation, prevention and treatment of Chronic Kidney Disease-Mineral and Bone Disorder(CKD-MBD)
Kidney Int
Renal osteodystrophy in the first decade of the new millennium: Analysis of 630 bone biopsies in black and white patients
J Bone Miner Res
Adynamic bone disease in uremia: May it be idiopathic? Is it an actual disease?
Nephron
Adynamic renal osteodystrophy: Is there a problem?
J Am Soc Nephrol
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