Phosphate, Microbiota and CKD.

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventually, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed. Recent data have identified a potential role of the gut microbiota in mineral bone disorders. Thus, parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched in the Th17 cell-inducing taxa segmented filamentous bacteria. Furthermore, the microbiota was required for PTH to stimulate bone formation and increase bone mass, and this was dependent on bacterial production of the short-chain fatty acid butyrate. We review current knowledge on the relationship between phosphate, microbiota and CKD-MBD. Topics include microbial bioactive compounds of special interest in CKD, the impact of dietary phosphate and phosphate binders on the gut microbiota, the modulation of CKD-MBD by the microbiota and the potential therapeutic use of microbiota to treat CKD-MBD through the clinical translation of concepts from other fields of science such as the optimization of phosphorus utilization and the use of phosphate-accumulating organisms.

A High Throughput Isolation Method for Phosphate-Accumulating Organisms.

Hyperphosphatemia is a secondary issue associated with chronic kidney disorder. Use of phosphate binders and dialysis are the treatments for hyperphosphatemia, albeit with harmful side effects and high cost, respectively. A safer and healthier approach is attempted to administer phosphate-accumulating organisms (PAOs) from probiotics to prevent hyperphosphatemia. However, screening and isolation of PAOs are limited by inefficient enrichment of relevant metabolism and contamination. Therefore, we devised a novel strategy to isolate elite PAOs from Lactobacillus casei JCM 1134 and Bifidobacterium adolescentis JCM 1275 (previously reported PAOs). PAOs were first enriched for phosphate uptake and incubated in low-pH phosphate-free media to dormant non-PAOs, and then purified using Percoll density gradient centrifugation. Subsequently, elite PAOs were isolated from centrifuged pellet on a toluidine blue O-supplemented agar-based media. Using this technique, elite PAOs could not only be isolated, but also semi-quantitatively scored for their phosphate accumulation capabilities. Additionally, these scores correlated well with their accumulated phosphate values. The elite PAOs isolated from L. casei and B. adolescentis showed 0.81 and 0.70 [mg-phosphate/mg-dry cell], respectively (23- and 4.34-fold increase, respectively). Thus, our method can be used to successfully isolate elite PAOs, which might be of use to prevent hyperphosphatemia at early stages.

The role of phosphate-containing medications and low dietary phosphorus-protein ratio in reducing intestinal phosphorus load in patients with chronic kidney disease.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a common complication in patients experiencing end-stage renal disease (ESRD). It includes abnormalities in bone and mineral metabolism and vascular calcification. Hyperphosphatemia is a major risk factor leading to morbidity and mortality in patients with chronic kidney disease. Increased mortality has been observed in patients with ESRD, with serum phosphorus levels of >5.5 mg/dL. Therefore, control of hyperphosphatemia is a major therapeutic goal in the prevention and treatment of CKD-MBD. The treatment of hyperphosphatemia includes decreasing intestinal phosphorus load and increasing renal phosphorus removal. Decreasing the intestinal load of phosphorus plays a major role in the prevention and treatment of CKD-MBD. Among the dietary sources of phosphorus, some of the commonly prescribed medications have also been reported to contain phosphorus. However, drugs are often ignored even though they act as a potential source of phosphorus. Similarly, although proteins are the major source of dietary phosphorus, reducing protein intake can increase mortality in patients with CKD. Recently, the importance of phosphorus/protein ratio in food have been reported to be a sensitive marker for controlling dietary intake of phosphorus. This review summarizes the progress in the research on phosphate content in drugs as an excipient and the various aspects of dietary management of hyperphosphatemia in patients with CKD, with special emphasis on dietary restriction of phosphorus with low dietary phosphate/protein ratio.

High-serum phosphate and parathyroid hormone distinctly regulate bone loss and vascular calcification in experimental chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), increases in serum phosphate and parathyroid hormone (PTH) aggravate vascular calcification (VC) and bone loss. This study was designed to discriminate high phosphorus (HP) and PTH contribution to VC and bone loss. METHODS: Nephrectomized rats fed a HP diet underwent either sham operation or parathyroidectomy and PTH 1-34 supplementation to normalize serum PTH. RESULTS: In uraemic rats fed a HP diet, parathyroidectomy with serum PTH 1-34 supplementation resulted in (i) reduced aortic calcium (80%) by attenuating osteogenic differentiation (higher α-actin; reduced Runx2 and BMP2) and increasing the Wnt inhibitor Sclerostin, despite a similar degree of hyperphosphataemia, renal damage and serum Klotho; (ii) prevention of bone loss mostly by attenuating bone resorption and increases in Wnt inhibitors; and (iii) a 70% decrease in serum calcitriol levels despite significantly reduced serum Fgf23, calcium and renal 24-hydroxylase, which questions that Fgf23 is the main regulator of renal calcitriol production. Significantly, when vascular smooth muscle cells (VSMCs) were exposed exclusively to high phosphate and calcium, high PTH enhanced while low PTH attenuated calcium deposition through parathyroid hormone 1 receptor (PTH1R) signalling. CONCLUSIONS: In hyperphosphataemic CKD, a defective suppression of high PTH exacerbates HP-mediated osteogenic VSMC differentiation and reduces vascular levels of anti-calcifying sclerostin.

Factors effective on peritoneal phosphorus transport and clearance in peritoneal dialysis patients
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AIMS: Transport characteristics of phosphorus are different from other small solutes that are evaluated in routine peritoneal equilibration test (PET) in peritoneal dialysis (PD) patients. We aimed to evaluate peritoneal phosphorus clearance and permeability, and their relationship with peritoneal membrane transport type and creatinine clearance as well as factors affecting peritoneal phosphorus clearance. METHODS: 70 adult patients on a PD program were included in our study. Phosphorus transport status was classified according to dialysate/plasma (D/P) phosphorus at the 4th hour of PET as slow transporter (< 0.47), slow-average transporter (0.47 - 0.56), fast-average transporter (0.57 - 0.67), and fast transporter (> 0.67). We evaluated the relationship of peritoneal phosphorus clearance and transport type with PD regime, phosphorus level, and presence of residual renal function in addition to investigating factors that are effective on peritoneal phosphorus clearance. RESULTS: D/P phosphorus and peritoneal phosphorus clearance were positively correlated with D/P creatinine and peritoneal creatinine clearance, respectively. Automated PD and continuous ambulatory PD patients were similar regarding phosphorus and creatinine clearances and transport status based on D/P phosphorus. The major determinant of peritoneal phosphorus clearance was anuria status. Anuric patients had higher dialysate volume (11.6 ± 3.0 L vs. 8.4 ± 2.1 L, p < 0.001) and therefore higher peritoneal phosphorus clearance (61.7 ± 15.1 L/week/1.73 m2 vs. 48.4 ± 14.0 L/week/1.73 m2, p = 0.001). Hyperphosphatemia was present in 40% and 11% of anuric patients and those with residual renal function, respectively (p = 0.005). CONCLUSIONS: Peritoneal phosphorus transport characteristics are similar to that of creatinine. Although increased dialysis dose may increase peritoneal phosphorus clearance, it may be insufficient to prevent hyperphosphatemia in anuric patients.
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Mineral and Bone Disorder and Its Association with Cardiovascular Parameters in Chinese Patients with Chronic Kidney Disease.

BACKGROUND: Mineral 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. METHODS: Chinese 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. RESULTS: Altogether 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. CONCLUSIONS: In 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.

Contemporary management of phosphorus retention in chronic kidney disease: a review.

Hyperphosphatemia is the most common metabolic complications of end-stage kidney disease (ESKD). Large observational studies have identified hyperphosphatemia as an independent risk factor for cardiovascular disease and mortality in dialysis patients and subsequent studies found that subtle increases in serum phosphate levels even within the normal range are also associated with increased risk for death in predialysis and non-kidney disease population. On the basis of these results, current national practice guidelines advocate more aggressive treatment of hyperphosphatemia to lower serum phosphate targets than in the past . Treatment of hyperphosphatemia requires to strict management through dietary restriction, oral phosphate binders, and dialysis. Calcium-based phosphate binders have low cost and widespread use but cause vascular calcification and hypercalcemia. Non-calcium-based phosphate binders are effective but expensive. Bixalomer is a new Ca-free, metal-free, potent phosphate binder, non-hydrochloride, and non-absorptive polymer, which improves metabolic acidosis. FGF-23 appears as a promising target for novel therapeutic approaches to improve clinical outcomes of CKD patients. This review focuses on novel therapeutic approaches dealing with hyperphosphatemia in chronic kidney disease.

Ferric citrate controls phosphorus and delivers iron in patients on dialysis.

Patients on dialysis require phosphorus binders to prevent hyperphosphatemia and are iron deficient. We studied ferric citrate as a phosphorus binder and iron source. In this sequential, randomized trial, 441 subjects on dialysis were randomized to ferric citrate or active control in a 52-week active control period followed by a 4-week placebo control period, in which subjects on ferric citrate who completed the active control period were rerandomized to ferric citrate or placebo. The primary analysis compared the mean change in phosphorus between ferric citrate and placebo during the placebo control period. A sequential gatekeeping strategy controlled study-wise type 1 error for serum ferritin, transferrin saturation, and intravenous iron and erythropoietin-stimulating agent usage as prespecified secondary outcomes in the active control period. Ferric citrate controlled phosphorus compared with placebo, with a mean treatment difference of -2.2±0.2 mg/dl (mean±SEM) (P<0.001). Active control period phosphorus was similar between ferric citrate and active control, with comparable safety profiles. Subjects on ferric citrate achieved higher mean iron parameters (ferritin=899±488 ng/ml [mean±SD]; transferrin saturation=39%±17%) versus subjects on active control (ferritin=628±367 ng/ml [mean±SD]; transferrin saturation=30%±12%; P<0.001 for both). Subjects on ferric citrate received less intravenous elemental iron (median=12.95 mg/wk ferric citrate; 26.88 mg/wk active control; P<0.001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5306 units/wk ferric citrate; 6951 units/wk active control; P=0.04). Hemoglobin levels were statistically higher on ferric citrate. Thus, ferric citrate is an efficacious and safe phosphate binder that increases iron stores and reduces intravenous iron and erythropoietin-stimulating agent use while maintaining hemoglobin.

[Pleiotropic effects of sevelamer: a model of intestinal tract chelating agent]. / Effets pléïotropes du sévélamer, précurseur d'agent chélateur de la voie intestinale.

The number of patients with chronic kidney disease (CKD) with its associated complications has increased dramatically worldwide in recent years. Therefore, many experimental and clinical studies have examined over the last decade the mechanisms involved, in order to explain the sharp increase in cardiovascular mortality. Hyperphosphatemia is a major problem in these patients especially at advanced stages of CKD, and it is associated with cardiovascular and mineral complications in these patients. Sevelamer is a phosphate binder that allows a better control of hyperphosphatemia, like other phosphate binder agents, but it has additional pleiotropic effects such as correcting certain abnormalities of lipid metabolism and clearance of several uremic toxins. These effects of sevelamer, restricted to the intestinal lumen, underline the importance of intestinal pathway in CKD and open the way to new therapeutic strategies for the management of the CKD and its complications.

Correction of hypocalcemia allows optimal recruitment of FGF-23-dependent phosphaturic mechanisms in acute hyperphosphatemia post-phosphate enema.

Both parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are phosphaturic hormones. These hormones should increase in response to phosphate excess. However, they also regulate serum calcium; PTH increases serum calcium concentration and FGF23 suppresses renal production of calcitriol, favoring hypocalcemia. We report the case of an 83-year-old woman with hyperphosphatemia and hypocalcemia resulting from phosphate-containing enemas. PTH and calcitriol increased in response to hypocalcemia, and FGF23 increased in response to hyperphosphatemia. Unexpectedly, peak FGF23 did not coincide with peak serum phosphate. Rather, peak FG23 was observed only after severe hypocalcemia was partially corrected with exogenous calcium administration, even though serum phosphate had been already decreasing for 32 h. Correction of severe hypocalcemia was thus associated with peak FGF23 values and with a precipitous decrease in PTH. Peak FGF23 was followed by an accelerated decrease in serum phosphate and significant phosphaturia. This clinical report is consistent with experimental data in rats showing a blunted FGF23 response to high phosphate in the presence of severe hypocalcemia. Thus, complementary experimental and clinical data suggest that partial correction of severe hypocalcemia is required for optimal FGF23-mediated phosphaturia, which takes place despite correction of PTH levels. We believe this the first human report suggesting blunting of the FGF23 response to high phosphate by severe hypocalcemia.

Nuclear receptor LXR: a new partner for sodium-dependent phosphate cotransporters.

New pharmaceutical research approaches are focusing on trying to alleviate the perturbed phosphate (Pi) homeostasis associated with the onset of chronic kidney disease; this includes activation of some of the nuclear receptors. We have recently reported the down regulation of the intestinal and renal sodium-phosphate (NaPi) cotransporters by the liver X receptor (LXR) agonists, and the consequent decrease of the serum Pi levels. In this review, we describe our current knowledge of the different proteins involved in the renal and intestinal actions of LXR.

Clinical detection, risk factors, and cardiovascular consequences of medial arterial calcification: a pattern of vascular injury associated with aberrant mineral metabolism.

Patients with end-stage renal disease are characterized by extensive vascular calcification and high cardiovascular disease (CVD) risk. Calcification in end-stage renal disease patients represents at least two distinct pathologic processes. Calcification within the tunica intima frequently is associated with lipid-laden, flow-limiting atherosclerotic plaques. These appear as spotty areas of calcification interspersed with noncalcified arterial segments on plain radiography and generally are found near arterial branch points in medium-sized conduit arteries. In contrast, medial arterial calcification (MAC) involves deeper layers of the arterial wall; tends to affect the artery diffusely, appearing as a linear contiguous tram-track pattern of calcification on plain radiography; and often involves smaller muscular arteries such as the radial artery, intermammary arteries, and arteries in the ankle and foot. Both are related to CVD events, but potentially through different mechanisms. Atherosclerotic calcification may be marking the total burden of atherosclerosis, whereas MAC may lead to arterial stiffness and left ventricular hypertrophy. Existing data suggest that altered mineral metabolism may promote MAC, whereas heightened inflammation and oxidative stress contribute to atherosclerosis. Dysregulation of normal anticalcification factors and elastin degradation are common to both processes. Risk of vascular calcification also may be increased by the use of certain medications in the setting of chronic kidney disease. This review compares and contrasts known risk factors for MAC and atherosclerosis, describes existing and emerging technologies to distinguish between them, and reviews the existing literature linking each with CVD events in dialysis patients and in other settings.

Effects of phosphonoformic acid and renagel on renal type IIa sodium-dependent phosphate cotransporter mRNA expression in hyperphosphatemia rats.

OBJECTIVE: To investigate the effects of phosphonoformic acid (PFA) and sevelamer hydrochloride (Renagel) on renal type IIa sodium-dependent phosphate cotransporter (NaPi-2) mRNA expression in hyperphosphatemia rats. METHODS: Thirty rats were randomly divided into five groups based on the diet for 2 weeks after 5/6 nephrectomy (Nx): Nx + high-phosphate (HP; 1.2% P) diet; Nx + low-phosphate (LP; 0.2% P) diet; HP + PFA (injected with 0.15 g/kg PFA daily); HP + Saline (injected with the same amount of saline daily); and HP + Renagel (2%) group. Another 12 rats were sham operated and divided into Sham + HP and Sham + LP groups. Serum ionized calcium, phosphorus (P), and intact parathyroid hormone (iPTH) were measured on days 2, 7, and 14. Serum 1,25(OH)2D3 was measured on day 14 and NaPi-2 mRNA levels were assayed by RT-PCR. RESULTS: PFA decreased iPTH level but had no effect on NaPi-2 mRNA expression. Renagel decreased serum P and iPTH levels, but upregulated renal NaPi-2 mRNA expression. CONCLUSIONS: Both PFA and Renagel are effective drugs to decrease iPTH level and they might be potential candidates for treatment of clinical secondary hyperparathyroidism. Renagel can also decrease serum P and upregulate renal NaPi-2 mRNA expression.

[Pathologies of calcium-phosphate homeostasis]. / Patologie zwiazane z gospodarka wapniowo-fosforanowa.

The colossal progress in understanding of vitamin D and phosphate metabolism introduces new perspectives in chronic kidney disease (CKD) therapy. Increasing demand for phosphate excretion per nephron triggers the vicious cycle that leads to increase in FGF-23 and PTH and decrease in vitamin D and Klotho. Restriction of dietary phosphate intake (low phosphate diet) and administration of phosphate binder can be regarded as the most important interventions in this case. Because the vicious cycle is likely activated long before hyperphosphatemia occurs during CKD progression, phosphate restriction would have been more effective if started before serum phosphate levels increased, perhaps as soon as serum FGF-23 levels rose. Phosphate restriction alleviates phosphate overload per nephron and can disrupt the vicious cycle: phosphate restriction can reduce serum FGF-23 levels and increase vitamin D, which in turn increase Klotho expression in kidney and parathyroid glands. Inhibitors of rennin-angiotensin system (rosiglitazone, angiotensin-converting enzyme inhibitors) and proper vitamin D supplementation may also up-regulate Klotho expression. Increased Klotho in the kidney may improve FGF-23 sensitivity, which further reduce the amount of FGF-23 required for excreting a given amount of phosphate. Increased Klotho in parathyroid may improve the ability of FGF-23 to suppress PTH. Proper supplementation with vitamin D increase the concentration of substrate for local 1,25(OH)2D synthesis 25(OH)D, which directly suppress PTH, increase Klotho, and decrease FGF-23 by proanabolic action on bone. Improving vitamin D status by inhibition of CYP24A is also under evaluation, as well as antibodies against FGF-23, as modern therapies in CKD.

Pharmacotherapy of chronic kidney disease and mineral bone disorder.

INTRODUCTION: Disturbances of the bone and mineral metabolism are a common complication of chronic kidney disease (CKD); these disturbances are known as CKD-mineral bone disorder (CKD-MBD). A better understanding of the pathophysiological mechanisms of CKD-MBD, along with its negative impact on other organs and systems, as well as on survival, has led to a shift in the treatment paradigm of this disorder. The use of phosphate binders changed dramatically over the last decade when noncalcium-containing phosphate binders, such as sevelamer and lanthanum carbonate, became possible alternative treatments to avoid calcium overload. Vitamin D receptor activators, such as paricalcitol and doxercalciferol, with fewer calcemic and phosphatemic effects, have also been introduced to control parathormone production and the interest in native vitamin D supplementation has grown. Furthermore, a new drug class, the calcimimetics, has recently been introduced into the therapeutic arsenal for treating secondary hyperparathyroidism. AREAS COVERED: This review discusses the advantages and disadvantages of the above pharmacological options to treat CKD-MBD. EXPERT OPINION: The individual-based use of phosphate binders, vitamin D and calcimimetics, separately or in combination, constitute a reasonable approach to treat CKD-MBD. These treatments aim to achieve a rigorous control of phosphorus and parathormone levels, while avoiding calcium overload.

[The influence of short-term magnesium carbonate treatment on calcium-phosphorus balance in dialysis patients]. / Wplyw krótkoterminowego leczenia weglanem magnezu na gospodarke wapniowo-fosforanowa u chorych przewlekle hemodializowanych.

INTRODUCTION: The phosphate-binders presently used in the treatment of calcium-phosphorus disorders in dialysis patients remain a crucial element of cardio-vascular protection. The aim of the study was to assess short-time magnesium carbonate treatment efficacy in hemodialysis patients with hyperphosphatemia. MATERIAL AND METHODS: The study involved 64 participants (32 male and 32 female) aged 29-84 years, with end-stage renal disease, hyperphosphatemia (> 1.78 mmol/l), dialysis 3 times a week, mean session time 4 hours 15 minutes. All the patients were divided into three groups: I--30 patients treated with magnesium carbonate 3 x 1 g; group II--10 patients treated with sevelamer hydrochloride 0.8 g--3 x 2 tabl (3 x 1.6 g); group III--24 patients treated with calcium carbonate 3 x 2 g. Participants were categorized randomly to groups I and II and to group III only patients with decreased serum calcium concentration (< 2.1 mmol/1) were assigned. The doses stayed constant within 12 weeks of therapy. RESULTS: In group treated with magnesium carbonate after 3 months of the treatment the decrease of plasma parathormon (iPTH) from 526.1 +/- 463.3 to 443.2 +/- 223.1 (pg/ml), calcium (Ca) from 2.4 +/- 0.2 to 2.3 +/- 0.1 (mmol/1); the highest reduction of phosphate (P) 2.1 +/- 0.5 to 1.6 +/- 0.4 (mmol/1) and calcium phosphate product (Cax P) from 4.6 +/- 2.3 to 3.5 +/- 1.1 (mmol2/ l2) were observed. In group II, iPTH slightly increased from initial 425.26 +/- 192.5 to 445.6 +/- 222.3 (pg/ml); serum calcium decreased from 2.23 +/- 0.17 to 2.0 +/- 0.2 (mmol/l); phosphates dropped from 2.35 +/- 0.43 to 2.0 +/- 0.3 (mmol/l) and Ca x P index from 5.1 +/- 1.2 to 4.1 +/- 0.7 (mmol2/l2). In group treated with calcium carbonate iPTH decreased from 308.2 +/- 196.6 to 301.9 +/- 188.5 (pg/ml). Calcium, phosphate and Ca x P dropped during the treatment from 2.06 +/- 0.23 to 2.05 +/- 0.2 (mmol/l), 2.17 +/- 0.36 to 1.86 +/- 0.45 (mmol/l) and from 4.7 +/- 0.8 to 3.7 +/- 0.9 (mmol2/l2), respectively. Calcium-phosphorus disorders were normalized to actual guidelines only in participants treated with magnesium carbonate. CONCLUSIONS: Magnesium carbonate seems to be the effective treatment of calcium-phosphorus disorders in hemodialysis patients. However its administration, similarly to other non-calcium phosphate-binders, is limited and dedicated to patients with normal serum calcium concentration.

Prevention and control of phosphate retention/hyperphosphatemia in CKD-MBD: what is normal, when to start, and how to treat?

Phosphate retention and, later, hyperphosphatemia are key contributors to chronic kidney disease (CKD)-mineral and bone disorder (MBD). Phosphate homeostatic mechanisms maintain normal phosphorus levels until late-stage CKD, because of early increases in parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). Increased serum phosphorus, and these other mineral abnormalities, individually and collectively contribute to bone disease, vascular calcification, and cardiovascular disease. Earlier phosphate control may, therefore, help reduce the early clinical consequences of CKD-MBD, and help control hyperphosphatemia and secondary hyperparathyroidism in late-stage CKD. Indeed, it is now widely accepted that achieving normal phosphorus levels is associated with distinct clinical benefits. This therapeutic goal is achievable in CKD stages 3 to 5 but more difficult in dialysis patients. Currently, phosphate control is only initiated when hyperphosphatemia occurs, but a potentially beneficial and simple approach may be to intervene earlier, for example, when tubular phosphate reabsorption is substantially diminished. Early CKD-MBD management includes dietary phosphate restriction, phosphate binder therapy, and vitamin D supplementation. Directly treating phosphorus may be the most beneficial approach because this can reduce serum phosphorus, PTH, and FGF-23. This involves dietary measures, but these are not always sufficient, and it can be more effective to also consider phosphate binder use. Vitamin D sterols can improve vitamin D deficiency and PTH levels but may worsen phosphate retention and increase FGF-23 levels, and thus, may also require concomitant phosphate binder therapy. This article discusses when and how to optimize phosphate control to provide the best clinical outcomes in CKD-MBD patients.

Salivary glands: a new player in phosphorus metabolism.

In uremic patients, hyperphosphatemia is associated with cardiovascular calcification and increased cardiovascular mortality. Despite the use of phosphate binders and dietary phosphate limitation in addition to dialysis, only 50% of dialysis patients achieve recommended serum phosphate levels. The identification of other approaches for serum phosphorus reduction is therefore necessary. We have approached this issue by taking into account the relationships between serum phosphate, kidney function, and saliva. Saliva was chosen because the anatomy and/or physiology of acini, the secretive units of salivary glands, shares similarities with that of the renal tubules. Salivary fluid contains electrolytes including phosphate that, when related with the amount of salivary secretion per day, raises the interest in identifying another possible approach for phosphorus removal in uremic patients. This article reports studies from our laboratory in the last 3 to 4 years, which have demonstrated a hyperphosphoric salivary content in patients with chronic renal failure and those with end-stage renal disease under chronic dialysis that, in patients with chronic renal failure, linearly correlates with serum phosphate in patients with chronic renal failure and negatively with GFR. The ingestion of the saliva and later its absorption in the intestinal tract starts a vicious circle between salivary phosphate secretion and fasting phosphate absorption, thereby worsening hyperphosphatemia. Therefore, salivary phosphate binding could be a useful approach to serum phosphate level reduction in dialysis patients. The reduction of salivary phosphate with the salivary phosphate binder, chitosan-loaded chewing gum, chewed during fasting periods, as an add-on to phosphate binders could lead to a better control of hyperphosphatemia, as demonstrated in our study, which confirms the importance of this approach.

Increased parathyroid expression of klotho in uremic rats.

Klotho is a protein of significant importance for mineral homeostasis. It helps to increase parathyroid hormone (PTH) secretion and in the trafficking of Na+/K+-ATPase to the cell membrane; however, it is also a cofactor for fibroblast growth factor (FGF)-23 to interact with its receptor, FGFR1 IIIC, resulting in decreased PTH secretion. Studies on the regulation of parathyroid klotho expression in uremia have provided varying results. To help resolve this, we measured klotho expression in the parathyroid and its response to severe uremia, hyperphosphatemia, and calcitriol treatment in the 5/6 nephrectomy rat model of secondary hyperparathyroidism. Parathyroid klotho gene expression and protein were significantly increased in severely uremic hyperphosphatemic rats, but not affected by moderate uremia and normal serum phosphorus. Calcitriol suppressed klotho gene and protein expression in severe secondary hyperparathyroidism, despite a further increase in plasma phosphate. Both FGFR1 IIIC and Na+/K+-ATPase gene expression were significantly elevated in severe secondary hyperparathyroidism. Parathyroid gland klotho expression and the plasma calcium ion concentration were inversely correlated. Thus, our study suggests that klotho may act as a positive regulator of PTH expression and secretion in secondary hyperparathyroidism.