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La Clinica Terapeutica May 2021Tertiary hyperparathyroidism (HPT III) occurs when an excess of parathyroid hormone (PTH) is secreted by parathyroid glands, usually after longstanding secondary... (Review)
Review
Tertiary hyperparathyroidism (HPT III) occurs when an excess of parathyroid hormone (PTH) is secreted by parathyroid glands, usually after longstanding secondary hyperparathyroidism. Some authorities reserve the term for secondary hyperparathyroidism that persists after successful renal transplantation. Long-standing chronic kidney disease (CKD) is associated with several metabolic disturbances that lead to increased secretion of PTH, including hyperphosphatemia, calcit-riol deficiency, and hypocalcaemia. Hyperphosphatemia has a direct stimulatory effect on the parathyroid gland cell resulting in nodular hyperplasia and increased PTH secretion. Prolonged hypocalcaemia also causes parathyroid chief cell hyperplasia and excess PTH. Af-ter correction of the primary disorder CKD by renal transplant, the hypertrophied parathyroid tissue fails to resolute, enlarge over and continues to oversecrete PTH, despite serum calcium levels that are within the reference range or even elevated. They also may become resistant to calcimimetic treatment. The main indication for treatment is persistent hypercalcemia and/or an increased PTH, and the primary treatment is surgery. Three procedures are commonly performed: total parathyroidectomy with or without autotransplantation, subtotal parathyroidectomy, and limited parathyroidectomy. It is important to remove superior parts of thymus as well. The most appropriate surgical procedure, whether it be total, subtotal, or anything less than subtotal including "limited" or "focused" parathyroidectomies, continues to be unclear and controversial. Surgical complications are rare, and para-thyroidectomy appears to be a safe and feasible treatment option for HPT III.
Topics: Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Hyperplasia; Hypocalcemia; Kidney Transplantation; Parathyroid Glands; Parathyroid Hormone; Parathyroidectomy; Renal Insufficiency, Chronic; Transplantation, Autologous
PubMed: 33956045
DOI: 10.7417/CT.2021.2322 -
Kidney International May 2018Hyperphosphatemia has consistently been shown to be associated with dismal outcome in a wide variety of populations, particularly in chronic kidney disease (CKD).... (Review)
Review
Hyperphosphatemia has consistently been shown to be associated with dismal outcome in a wide variety of populations, particularly in chronic kidney disease (CKD). Compelling evidence from basic and animal studies elucidated a range of mechanisms by which phosphate may exert its pathological effects and motivated interventions to treat hyperphosphatemia. These interventions consisted of dietary modifications and phosphate binders. However, the beneficial effects of these treatment methods on hard clinical outcomes have not been convincingly demonstrated in prospective clinical trials. In addition, exposure to high amounts of dietary phosphate may exert untoward actions even in the absence of overt hyperphosphatemia. Based on this concept, it has been proposed that the same interventions used in CKD patients with normal phosphate concentrations be used in the presence of hyperphosphatemia to prevent rise of phosphate concentration and as an early intervention for cardiovascular risk. This review describes conceptual models of phosphate toxicity, summarizes the evidence base for treatment and prevention of hyperphosphatemia, and identifies important knowledge gaps in the field.
Topics: Animals; Biomarkers; Chelating Agents; Humans; Hyperphosphatemia; Phosphates; Phosphorus, Dietary; Recommended Dietary Allowances; Renal Insufficiency, Chronic; Risk Factors; Risk Reduction Behavior; Treatment Outcome
PubMed: 29580635
DOI: 10.1016/j.kint.2017.11.036 -
Kidney & Blood Pressure Research 2020Tumor lysis syndrome (TLS) is an oncologic emergency due to a rapid break down of malignant cells usually induced by cytotoxic therapy, with hyperuricemia, hyperkalemia,... (Review)
Review
BACKGROUND
Tumor lysis syndrome (TLS) is an oncologic emergency due to a rapid break down of malignant cells usually induced by cytotoxic therapy, with hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and serious clinical consequences such as acute renal injury, cardiac arrhythmia, hypotension, and death. Rapidly expanding knowledge of cancer immune evasion mechanisms and host-tumor interactions has significantly changed our therapeutic strategies in hemato-oncology what resulted in the expanding spectrum of neoplasms with a risk of TLS.
SUMMARY
Since clinical TLS is a life-threatening condition, identifying patients with risk factors for TLS development and implementation of adequate preventive measures remains the most critical component of its medical management. In general, these consist of vigilant laboratory and clinical monitoring, vigorous IV hydration, urate-lowering therapy, avoidance of exogenous potassium, use of phosphate binders, and - in high-risk cases - considering cytoreduction before the start of the aggressive agent or a gradual escalation of its dose. Key Messages: In patients with a high risk of TLS, cytotoxic chemotherapy should be given in the facility with ready access to dialysis and a treatment plan discussed with the nephrology team. In the case of hyperkalemia, severe hyperphosphatemia or acidosis, and fluid overload unresponsive to diuretic therapy, the early renal replacement therapy (RRT) should be considered. One must remember that in TLS, the threshold for RRT initiation may be lower than in other clinical situations since the process of cell breakdown is ongoing, and rapid increases in serum electrolytes cannot be predicted.
Topics: Acute Kidney Injury; Animals; Disease Management; Humans; Hyperkalemia; Hyperphosphatemia; Hyperuricemia; Incidence; Risk Factors; Tumor Lysis Syndrome
PubMed: 32998135
DOI: 10.1159/000509934 -
Journal of Renal Nutrition : the... Jan 2021Bone and mineral metabolism becomes dysregulated with progression of chronic kidney disease (CKD), and increasing levels of parathyroid hormone serve as an adaptive...
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.
Topics: Calcimimetic Agents; Chelating Agents; Diet; Humans; Hyperphosphatemia; Kidney Failure, Chronic; Vitamin D
PubMed: 32386937
DOI: 10.1053/j.jrn.2020.02.003 -
Journal of the American Society of... Mar 2021In patients on maintenance dialysis, cardiovascular mortality risk is remarkably high, which can be partly explained by severe coronary artery calcification (CAC).... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In patients on maintenance dialysis, cardiovascular mortality risk is remarkably high, which can be partly explained by severe coronary artery calcification (CAC). Hyperphosphatemia has been reported to be associated with the severity of CAC. However, the optimal phosphate range in patients on dialysis remains unknown. This study was planned to compare the effects on CAC progression of two types of noncalcium-based phosphate binders and of two different phosphate target ranges.
METHODS
We conducted a randomized, open-label, multicenter, interventional trial with a two by two factorial design. A total of 160 adults on dialysis were enrolled and randomized to the sucroferric oxyhydroxide or lanthanum carbonate group, with the aim of reducing serum phosphate to two target levels (3.5-4.5 mg/dl in the strict group and 5.0-6.0 mg/dl in the standard group). The primary end point was percentage change in CAC scores during the 12-month treatment.
RESULTS
The full analysis set included 115 patients. We observed no significant difference in percentage change in CAC scores between the lanthanum carbonate group and the sucroferric oxyhydroxide group. On the other hand, percentage change in CAC scores in the strict group (median of 8.52; interquartile range, -1.0-23.9) was significantly lower than that in the standard group (median of 21.8; interquartile range, 10.0-36.1; =0.006). This effect was pronounced in older (aged 65-74 years) versus younger (aged 20-64 years) participants ( value for interaction =0.003). We observed a similar finding for the absolute change in CAC scores.
CONCLUSIONS
Further study with a larger sample size is needed, but strict phosphate control shows promise for delaying progression of CAC in patients undergoing maintenance hemodialysis.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
Evaluate the New Phosphate Iron-Based Binder Sucroferric Oxyhydroxide in Dialysis Patients with the Goal of Advancing the Practice of EBM (EPISODE), jRCTs051180048.
Topics: Adult; Aged; Calcinosis; Coronary Artery Disease; Disease Progression; Drug Combinations; Female; Ferric Compounds; Humans; Hyperphosphatemia; Lanthanum; Male; Middle Aged; Phosphates; Renal Dialysis; Sequestering Agents; Sucrose; Young Adult
PubMed: 33547218
DOI: 10.1681/ASN.2020050598 -
American Journal of Kidney Diseases :... Jan 2021Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney...
Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney disease (CKD). In patients with CKD glomerular filtration rate category 3a (G3a) or worse, including those with kidney failure who are receiving dialysis, clinical practice guidelines suggest "lowering elevated phosphate levels towards the normal range" with possible strategies including dietary phosphate restriction or use of binders. Additionally, guidelines suggest restricting the use of oral elemental calcium often contained in phosphate binders. Nutrition guidelines in CKD suggest<800-1,000mg of calcium daily, whereas CKD bone and mineral disorder guidelines do not provide clear targets, but<1,500mg in maintenance dialysis patients has been previously recommended. Many different classes of phosphate binders are now available and clinical trials have not definitively demonstrated the superiority of any class of phosphate binders over another with regard to clinical outcomes. Use of phosphate binders contributes substantially to patients' pill burden and out-of-pocket costs, and many have side effects. This has led to uncertainty regarding the use and best choice of phosphate binders for patients with CKD or kidney failure. In this controversies perspective, we discuss the evidence base around binder use in CKD and kidney failure with a focus on comparisons of available binders.
Topics: Calcium; Chelating Agents; Clinical Trials as Topic; Humans; Hyperphosphatemia; Patient Care Management; Phosphates; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 32771650
DOI: 10.1053/j.ajkd.2020.05.025 -
Journal of the American Society of... Jun 2021Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hyperphosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of action-tenapanor, an inhibitor of paracellular phosphate absorption, and phosphate binders-is safe and effective for the management of hyperphosphatemia in patients receiving maintenance dialysis.
METHODS
This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperphosphatemia (defined in this trial as serum phosphorus 5.5-10 mg/dl inclusive) despite receiving phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4.
RESULTS
Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (-0.84 versus -0.19 mg/dl, <0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively.
CONCLUSIONS
A dual-mechanism treatment using both tenapanor and phosphate binders improved control of hyperphosphatemia in patients undergoing maintenance dialysis compared with phosphate binders alone.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
AMPLIFY, NCT03824587.
Topics: Adult; Aged; Chelating Agents; Diarrhea; Double-Blind Method; Drug Therapy, Combination; Female; Fibroblast Growth Factor-23; Humans; Hyperphosphatemia; Isoquinolines; Male; Middle Aged; Phosphorus; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer; Sodium-Hydrogen Exchanger 3; Sulfonamides
PubMed: 33766811
DOI: 10.1681/ASN.2020101398 -
Pflugers Archiv : European Journal of... Aug 2022Phosphate is essential in living organisms and its blood levels are regulated by a complex network involving the kidneys, intestine, parathyroid glands, and the... (Review)
Review
Phosphate is essential in living organisms and its blood levels are regulated by a complex network involving the kidneys, intestine, parathyroid glands, and the skeleton. The crosstalk between these organs is executed primarily by three hormones, calcitriol, parathyroid hormone, and fibroblast growth factor 23. Largely due to a higher intake of ultraprocessed foods, dietary phosphate intake has increased in the last decades. The average intake is now about twice the recommended dietary allowance. Studies investigating the side effect of chronic high dietary phosphate intake suffer from incomplete dietary phosphate assessment and, therefore, often make data interpretation difficult. Renal excretion is quickly adapted to acute and chronic phosphate intake. However, at the high ends of dietary intake, renal adaptation, even in pre-existing normal kidney function, apparently is not perfect. Experimental intervention studies suggest that chronic excess of dietary phosphate can result in sustained higher blood phosphate leading to hyperphosphatemia. Evidence exists that the price of the homeostatic response (phosphaturia in response to phosphate loading/hyperphosphatemia) is an increased risk for declining kidney function, partly due by intraluminal/tubular calcium phosphate particles that provoke renal inflammation. High dietary phosphate intake and hyperphosphatemia are progression factors for declining kidney function and are associated with higher cardiovascular disease and mortality risk. This is best established for pre-existing chronic kidney disease, but epidemiological and experimental data strongly suggest that this holds true for subjects with normal renal function as well. Here, we review the latest advances in phosphate intake and kidney function decline.
Topics: Fibroblast Growth Factors; Humans; Hyperphosphatemia; Kidney; Phosphates; Renal Insufficiency, Chronic
PubMed: 35511366
DOI: 10.1007/s00424-022-02691-x -
Journal of the American Society of... Apr 2019Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Guidelines recommend reducing elevated serum phosphate in patients with CKD. Tenapanor, a minimally absorbed inhibitor of gastrointestinal sodium/hydrogen exchanger 3 (NHE3), reduces paracellular phosphate transport.
METHODS
In this phase 3 randomized, double-blind trial, we randomly assigned patients with hyperphosphatemia receiving maintenance hemodialysis to receive twice-daily oral tenapanor (3, 10, or 30 mg [the latter down-titrated, if needed]) for 8 weeks. Patients were then rerandomized 1:1 to receive either their previously assigned dose or placebo for a 4-week 'withdrawal' period. We measured serum phosphate levels over the course of the trial. The primary end point was mean change in serum phosphate over the 4-week withdrawal period for the tenapanor group (using pooled data) versus the placebo group.
RESULTS
Of 219 patients randomized, 152 completed both study phases. During the initial 8-week treatment period, all three treatment groups experienced significant decreases in mean serum phosphate (reductions of 1.00, 1.02, and 1.19 mg/dl, corresponding to the 3, 10, and 30 mg [down-titrated] dose groups, respectively). Tenapanor also showed a significant benefit over placebo during the withdrawal period, with a mean increase of 0.85 mg/dl in the placebo group versus a mean increase of 0.02 mg/dl in the pooled tenapanor group. Adverse events were largely limited to softened stool and a modest increase in bowel movement frequency, resulting from increased stool sodium and water content, stemming from tenapanor's mechanism of action.
CONCLUSIONS
Tenapanor significantly reduced elevated serum phosphate in patients with hyperphosphatemia receiving maintenance hemodialysis. Adverse effects were limited to those induced by its known mechanism of action, which increases stool sodium and water content.
Topics: Adult; Aged; Diarrhea; Double-Blind Method; Female; Humans; Hyperphosphatemia; Isoquinolines; Kidney Failure, Chronic; Male; Middle Aged; Phosphates; Renal Dialysis; Sodium-Hydrogen Exchanger 3; Sulfonamides
PubMed: 30846557
DOI: 10.1681/ASN.2018080832 -
Nutrients Apr 2021Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate... (Review)
Review
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.
Topics: Animals; Chelating Agents; Chronic Kidney Disease-Mineral and Bone Disorder; Disease Models, Animal; Disease Progression; Gastrointestinal Microbiome; Holistic Health; Humans; Hyperphosphatemia; Mice; Parathyroid Hormone; Phosphorus, Dietary; Probiotics; Renal Insufficiency, Chronic; Th17 Cells
PubMed: 33924419
DOI: 10.3390/nu13041273