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.

Management of Hyperphosphatemia in End-Stage Renal Disease: A New Paradigm.

Bone and mineral metabolism becomes dysregulated with progression of chronic kidney disease (CKD), and increasing levels of parathyroid hormone serve as an adaptive response to maintain normal phosphorus and calcium levels. In end-stage renal disease, this response becomes maladaptive and high levels of phosphorus may occur. We summarize strategies to control hyperphosphatemia based on a systematic literature review of clinical trial and real-world observational data on phosphorus control in hemodialysis patients with CKD-mineral bone disorder (CKD-MBD). These studies suggest that current management options (diet and lifestyle changes; regular dialysis treatment; and use of phosphate binders, vitamin D, calcimimetics) have their own benefits and limitations with variable clinical outcomes. A more integrated approach to phosphorus control in dialysis patients may be necessary, incorporating measurement of multiple biomarkers of CKD-MBD pathophysiology (calcium, phosphorus, and parathyroid hormone) and correlation between diet adjustments and CKD-MBD drugs, which may facilitate improved patient management.

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.

[Metabolic complications in chronic kidney disease: hyperphosphatemia, hyperkalemia and anemia]. / Complications métaboliques en insuffisance rénale chronique : hyperphosphatémie, hyperkaliémie et anémie.

Metabolic complications of chronic kidney disease (CKD) are frequent; the aims of this review are to present a 2018 update for hyperkalemia, hyperphosphatemia and anemia. Hyperkalemia is defined by a plasma level above 5.0 mmol/L, after ruling out pre-analytical problems such as hemolysis. It is frequent in CKD, most often due to drugs and notably renin/ angiotensin blockers. Chronic hyperkalemia is deleterious, with an increased risk of mortality. Therapeutic strategies to decrease the incidence and severity of hyperkalemia are therefore crucial in nephrology: experts recommend to maintain the renin/angiotensin blockers as long as possible, whilst associating diuretics and potassium binders. There are apparent discrepancies between optimal protein intake and decreased phosphate intake in CKD; this is even more important in dialysis since protein decrease is associated with denutrition and subsequent increased risk of mortality. Nutritional phosphate intake from vegetables are less absorbed; in contrast, phosphate additives are almost completely absorbed in the gastro-intestinal tract. These "hidden" intake may increase the total daily phosphate intake by 1 000 mg. As such in addition to optimized dialysis, phosphate binders should be used but compliance may be challenging on the long-term. Educational programs focused on phosphate are also mandatory in CKD patients. "Absolute" iron deficiency is less frequent than "functional" iron deficiency in CKD patients: both require the use of iron supplementation, and the latter may benefit from additional erythropoietin stimulating agents (ESA) when hemoglobin is below 10 g/dL. Intravenous iron is more efficient to correct iron deficiency both in pre-dialysis and dialysis especially in patients with chronic deficiency. Last generation intravenous preparations have largely demonstrated their safety. One indication of iron supplementation one should not forget in nephrology is the patient with moderate CKD and heart failure since the expected benefits are multiple, notably in terms of quality of life, renal function and functional capacity. Cet article fait partie du numéro supplément Innovations en Néphrologie réalisé avec le soutien institutionnel de Vifor Fresenius Medical Care Renal Pharma.

Effect of restricted protein diet supplemented with keto analogues in end-stage renal disease: a systematic review and meta-analysis.

AIM: To evaluate the efficacy and safety of the restricted protein diet supplemented with keto analogues when applied in end-stage renal disease (ESRD). METHODS: The Cochrane Library, PubMed, Embase, CBM and CENTRAL databases were searched and reviewed up to January 2017. Clinical trials were analyzed using RevMan 5.3 software. RESULTS: Five randomized controlled trials were selected and included in this study according to our inclusion and exclusion criteria. Changes in serum albumin, PTH, triglyceride, cholesterol, calcium, phosphorus, hemoglobin, Kt/v and CRP before and after treatment were analyzed. Meta-analysis results indicated that, compared with normal protein diet, low-protein diet (LPD) supplemented with keto analogues (sLPD) could improve serum albumin (P < 0.00001), hyperparathyroidism (P < 0.00001) and hyperphosphatemia (P = 0.008). No differences in triglyceride, cholesterol, hemoglobin, Kt/v and CRP were observed between different protein intake groups. CONCLUSION: Restricted protein diet supplemented with keto analogues (sLPD) may improve nutritional status and prevent hyperparathyroidism in ESRD patients. The current data were mainly obtained from short-term, single-center trails with small sample sizes and limited nutritional status indexes, indicating a need for further study.

[Modelling of phosphorus transfers during haemodialysis]. / Modélisation des transferts de phosphore pendant l'hémodialyse.

Chronic kidney disease causes hyperphosphatemia, which is associated with increased cardiovascular risk and mortality. In patients with end-stage renal disease, haemodialysis allows the control of hyperphosphatemia. During a 4-h haemodialysis session, between 600 and 700mg of phosphate are extracted from the plasma, whereas the latter contains only 90mg of inorganic phosphate. The precise origin of phosphates remains unknown. The modelling of phosphorus transfers allows to predict the outcome after changes in dialysis prescription (duration, frequency) with simple two-compartment models and to describe the transfers between the different body compartments with more complex models. Work using 31P nuclear magnetic resonance spectroscopy performed in animals showed an increase in intracellular phosphate concentration and a decrease in intracellular ATP during a haemodialysis session suggesting an intracellular origin of phosphates.

Hyperphosphatemia and hs-CRP Initiate the Coronary Artery Calcification in Peritoneal Dialysis Patients.

Background. Coronary artery calcification (CAC) contributes to high risk of cardiocerebrovascular diseases in dialysis patients. However, the risk factors for CAC initiation in peritoneal dialysis (PD) patients are not known clearly. Methods. Adult patients with baseline CaCS = 0 and who were followed up for at least 3 years or until the conversion from absent to any measurable CAC detected were included in this observational cohort study. Binary logistic regression was performed to identify the risk factors for CAC initiation in PD patients. Results. 70 patients recruited to our study were split into a noninitiation group (n = 37) and an initiation group (n = 33) according to the conversion of any measurable CAC during their follow-up or not. In univariate analysis, systolic blood pressure, serum phosphorus, fibrinogen, hs-CRP, serum creatinine, and triglycerides were positively associated with the initiation of CAC, while the high density lipoprotein and nPCR did the opposite function. Multivariate analysis revealed that hyperphosphatemia and hs-CRP were the independent risk factors for CAC initiation after adjustments. Conclusions. Hyperphosphatemia and hs-CRP were the independent risk factors for CAC initiation in PD patients. These results suggested potential clinical strategies to prevent the initiation of CAC in PD patients.

Management of phosphorus load in CKD patients.

Disturbances in mineral and bone metabolism play a critical role in the pathogenesis of cardiovascular complications in patients with chronic kidney disease (CKD). The term "renal osteodystrophy" has recently been replaced with "CKD-mineral and bone disorder (CKD-MBD)", which includes vascular calcification as well as bone abnormalities. In Japan, proportions of the aged and long-term dialysis patients are increasing which makes management of vascular calcification and parathyroid function increasingly more important. There are three main strategies to manage phosphate load: phosphorus dietary restriction, administration of phosphate binder and to ensure in the CKD 5D setting, an adequate dialysis.

Severe hyperphosphatemia after oral laxative administration in a 7-year-old patient.

Sodium phosphate based laxatives are commonly used for constipation and pre-procedural bowel cleansing. Phosphate intoxication related with these preparations is well recognized. Herein, we present a case of severe hyperphosphatemia and seizure in a 7-year-old male patient after administration of an oral sodium phosphate based laxative. At the time of admission, serum phosphorus level was 25.6 mg/dl. Aggressive fluid therapy was started. Although serum phosphorus level decreased to 20.9 mg/dl eight hours after admission, hemodialysis was performed because of the preexisting renal disease and declined glomerular filtration rate. Serum phosphorus level and blood gas analysis returned to normal after hemodialysis and the patient was discharged on hospital day two. In conclusion, sodium phosphate based laxatives should be used carefully in patients with preexisting renal diseases. Intravenous hydration and correction of hypocalcemia are important components of treatment. Hemodialysis is indicated in patients with renal failure.

Psychosocial Factors That Create Barriers to Managing Serum Phosphorus Levels in Pediatric Dialysis Patients: A Retrospective Analysis.

OBJECTIVE: Abnormal phosphorus homeostasis is among the medley of metabolic disturbances commonly associated with chronic kidney disease. We sought to determine the psychosocial factors that create barriers to controlling serum phosphorus levels in children on dialysis and to evaluate the perceptions of children and caregivers on the ease or difficulty of following a dietary phosphorus restriction and taking phosphorus binder medications. DESIGN: Single center cross-sectional study. SETTING: Pediatric dialysis unit at a children's hospital. SUBJECTS: Forty-eight patients on chronic hemodialysis or peritoneal dialysis (mean age: 11.03 ± 6.88 years; 69% male). MAIN OUTCOME MEASURE: Serum phosphorus levels were recorded from electronic health records and converted to a mean phosphorus standard deviation score (SDS) for each individual. Mean phosphorus SDS values were compared to each independent categorical variable using an analysis of variance test, continuous variables were analyzed using linear regression, and logistic regression was used to determine odds ratios. RESULTS: There was a significant relationship between age and phosphorus SDS (P < .001), with patients over 13 years of age having the highest prevalence of hyperphosphatemia (88%). Patients and caregivers who identified phosphorus levels as "controlled" had lower phosphorus SDS values compared to the other subjects (P = .003). However, of the patients and caregivers who reported that serum phosphorus levels were "controlled," 46% were hyperphosphatemic. Furthermore, 73% and 87% of patients and caregivers reported that following a phosphorus-restricted diet and taking phosphorus binders were "easy"; yet, 40% and 49% of these patients were hyperphosphatemic, respectively. CONCLUSION: In the present study, elevated serum phosphorus levels were most common in adolescent dialysis patients. There also appears to be a disconnect between the perceived ease of following a phosphorus-restricted diet and taking phosphorus binders and the achievement of normal serum phosphorus levels. These data further emphasize the importance of ongoing education regarding dietary and medical management requirements.

Long-Term Evaluation of Colestilan in Chronic Kidney Disease Stage 5 Dialysis Patients with Hyperphosphataemia.

BACKGROUND: This study investigated in a North American patient population the longer-term treatment effects of the phosphate binder, colestilan, in patients with CKD Stage 5D and hyperphosphataemia. METHODS: One hundred and sixteen CKD Stage 5D patients with hyperphosphataemia were entered into a multi-centre, open-label study where they received flexible dose colestilan (6-15 g/day) to maintain serum phosphorus levels between 3.5 and 5.5 mg/dl. The primary endpoint was safety, assessed by treatment-emergent adverse events. Efficacy was assessed by changes in serum phosphorus, mineral metabolism, lipids, HbA1c, uric acid and bone markers. RESULTS: Serum phosphorus was significantly reduced by 1.18 mg/dl (p < 0.001), from 6.99 mg/dl at baseline to 5.80 mg/dl at week 52. LDL-cholesterol was also significantly reduced as well as uric acid. Significant change was observed only for one bone marker - PINP. Most adverse events were of mild or moderate intensity. Nausea (22.4%), vomiting (21.6%), and diarrhoea (19.8%) were most commonly reported. CONCLUSIONS: Long-term flexible dosing with colestilan reduces serum phosphorus and demonstrates an acceptable safety and tolerability profile.

A Pilot Randomized Trial of Financial Incentives or Coaching to Lower Serum Phosphorus in Dialysis Patients.

OBJECTIVE: Among chronic hemodialysis patients, hyperphosphatemia is common and associated with mortality. Behavioral economics and complementary behavior-change theories may offer valuable approaches to achieving phosphorus (PO4) control. The aim was to determine feasibility of implementing financial incentives and structured coaching to improve PO4 in the hemodialysis setting. DESIGN AND METHODS: This pilot randomized controlled trial was conducted in 3 urban dialysis units for 10 weeks among 36 adults with elevated serum PO4 (median >5.5 mg/dL over 3 months). INTERVENTIONS: Twelve participants each were randomized to: (1) financial incentives for lowering PO4, (2) coaching about dietary and medication adherence, or (3) usual care. PO4 was measured during routine clinic operations. Each incentives arm participant received the equivalent of $1.50/day if the PO4 was ≤5.5 mg/dL or >5.5 mg/dL but decreased ≥0.5 mg/dL since the prior measurement. The coach was instructed to contact coaching arm participants at least 3 times per week. MAIN OUTCOME MEASURES: The outcome measures included: (1) enrollment rate, (2) dropout rate, and (3) change in PO4 from beginning to end of 10-week intervention period. RESULTS: Of 66 eligible patients, 36 (55%) enrolled. Median age was 53 years, 83% were black race, and 78% were male. Median baseline PO4 was 6.0 (interquartile range 5.6, 7.5). Using stratified generalized estimation equation analyses, the monthly decline in PO4 was -0.32 mg/dL (95% CI -0.60, -0.04) in the incentives arm, -0.40 mg/dL (-0.60, -0.20) in the coaching arm, and -0.24 mg/dL (-0.60, 0.08) in the usual care arm. No patients dropped out. All intervention arm participants expressed interest in receiving similar support in the future. CONCLUSIONS: This pilot trial demonstrated good feasibility in enrollment and implementation of novel behavioral health strategies to reduce PO4 in dialysis patients.

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.

Renal formulas pretreated with medications alters the nutrient profile.

BACKGROUND: Pretreating renal formulas with medications to lower the potassium and phosphorus content is common in clinical practice; however, the effect of this treatment on other nutrients is relatively unstudied. We examine whether nutrient composition is affected by pretreating renal formulas with sodium polystyrene sulfonate (SPS) suspension and sevelamer carbonate. METHODS: Fixed medication doses and treatment times were utilized to determine changes in the nutrient composition of Suplena® and Similac® PM 60/40. The effect of simultaneously adding both medications (co-administration) to the formula on the nutrient composition of Suplena® was also evaluated. RESULTS: Pretreatment of Suplena® with SPS reduced the concentrations of calcium (11-38 %), copper (3-11 %), manganese (3-16 %), phosphorus (0-7 %), potassium (6-34 %), and zinc (5-20 %) and increased those of iron (9-34 %), sodium (89-260 %), and sulfur (19-45 %) and the pH (0.20-0.50 units). Pretreatment of Similac® PM 60/40 with SPS reduced the concentrations of calcium (8-29 %), copper (5-19 %), magnesium (3-26 %), and potassium (33-63 %) and increased those of iron (13-87 %) and sodium (86-247 %) and the pH (0.40-0.81 units). Pretreatment of both formulas with the SPS suspension led to significant increases in the aluminum concentration in both formulas (507-3957 %). No differences in potassium concentration were observed between treatment times. Unexpectedly, the levels of neither phosphorus nor potassium were effectively reduced in Suplena® pretreated with sevelamer carbonate alone or when co-administered with SPS. CONCLUSIONS: Pretreating formula with medications alters nutrients other than the intended target(s). Future studies should be aimed at predicting the loss of these nutrients or identifying alternative methods for managing serum potassium and phosphorus levels in formula-fed infants. The safety of pretreating formula with SPS suspension should also be examined.

[Phosphorus: a new cardiovascular risk factor?]. / Il Fosforo: nuovo fattore di rischio cardiovascolare?

Phosphorus is an essential mineral in the regulation of many metabolic processes. However, is known as alterations in serum phosphate levels, compared to the normal range, have clinical relevance: many studies about phosphorus and cardiovascular risk have shown that high serum phosphate levels are associated with clinical and subclinical cardiovascular disease, in CKD and non-CKD patients. In recent years, serum phosphate level within the upper limits of normal range is also identified as a "stealthier killer", and has emerged as a risk factor of cardiovascular mortality and progression of CKD. This mounting evidence suggests the possibility that lowering serum phosphate levels may be a future target of cardiovascular disease management, also through the use of early biomarkers of phosphate overload, such as FGF23, Klotho or the urinary fractional excretion of phosphate. The goal must be an early diagnosis and treatment of disordered phosphorus metabolism, before end-organ damage occurs. Since the western diet is rich in phosphate, a dietary restriction associated with the use of phosphate binders, as well as the use of intervention such as calcitriol supplementation, certainly will have a positive influence on the phosphate-regulatory axis.

Hemodialysis for near-fatal sodium phosphate toxicity in a child receiving sodium phosphate enemas.

OBJECTIVE: This study aimed to demonstrate the importance of considering hemodialysis as a treatment option in the management of sodium phosphate toxicity. METHODS: This is a case report of a 4-year-old who presented to the emergency department with shock, decreased mental status, seizures, and tetany due to sodium phosphate toxicity from sodium phosphate enemas. RESULTS: Traditional management of hyperphosphatemia with aggressive hydration and diuretics was insufficient to reverse the hemodynamic and neurological abnormalities in this child. This is the first report of the use of hemodialysis in a child without preexisting renal failure for the successful management of near-fatal sodium phosphate toxicity. CONCLUSIONS: Hemodialysis can safely be used as an adjunctive therapy in sodium phosphate toxicity to rapidly reduce serum phosphate levels and increase serum calcium levels in children not responding to conventional management.

Educational intervention for metabolic bone disease in patients with chronic kidney disease: a systematic review and meta-analysis.

Metabolic bone disease (MBD) is a common complication of chronic kidney disease (CKD). The currently accepted international guidelines for treatment of CKD-MBD has been published, unfortunately adequate control of serum markers of disorder, especially hyperphosphatemia, is poorly achieved. Whether educational intervention is an effective way for improving CKD-MBD remains controversial. A systematic review of educational intervention versus routine care to improve patients with CKD-MBD was conducted. All randomized controlled trials (RCTs) and quasi-RCTs examining the efficacy of educational intervention to improve patients with CKD-MBD were included. We performed a comprehensive search of several databases and sources to identify eligible trials. In addition, we searched unpublished studies by tracking the SIGLE (System for Information on Grey Literature) database. Finally, 8 RCTs and 2 quasi-RCTs containing 775 participants were included in our systematic review. The result of our study revealed that the educational intervention to patients with CKD-MBD led to an improvement of the serum phosphorus and calcium by phosphate product. Educational intervention is a beneficial supplement method in improving CKD-MBD and putting off deterioration of the disease.