Small Intestinal Phosphate Absorption: Novel Therapeutic Implications

<b><i>Background:</i></b> Chronic kidney disease (CKD) affects approximately 15% of adults in the USA. As CKD progresses, urinary phosphate excretion decreases and results in phosphate retention and, eventually, hyperphosphatemia. As hyperphosphatemia is associated with numerous adverse outcomes, including increased cardiovascular mortality, reduction in phosphorus concentrations is a guideline-recommended, established clinical practice. Dietary phosphate restriction, dialysis, and phosphate binders are currently the only options for phosphate management. However, many patients with hyperphosphatemia have phosphorus concentrations &#x3e;5.5 mg/dL, despite treatment. <b><i>Summary:</i></b> This review pre­sents recent advances in the understanding of intestinal phosphate absorption and therapeutic implications. Dietary phosphate is absorbed in the intestine through two distinct pathways, paracellular absorption and transcellular transport. Recent evidence indicates that the paracellular route accounts for 65–80% of total phosphate absorbed. Thus, the paracellular pathway is the dominant mechanism of phosphate absorption. Tenapanor is a first-in-class, non-phosphate binder that inhibits the sodium-hydrogen exchanger 3 or solute carrier family 9 member 3 (SLC9A3) encoded by the SLC9A3 gene, and blocks paracellular phosphate absorption. <b><i>Key Messages:</i></b> Targeted inhibition of sodium-hydrogen exchanger 3 effectively reduces paracellular permeability of phosphate. Novel therapies that target the paracellular pathway may improve phosphate control in chronic kidney disease.

Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality

<b><i>Background:</i></b> Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality. <b><i>Summary:</i></b> Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to &#x3c;5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels &#x3c;5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. <b><i>Key Messages:</i></b> Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.

FC 077LONG-TERM SAFETY OF TENAPANOR FOR THE CONTROL OF SERUM PHOSPHORUS IN PATIENTS WITH CKD ON DIALYSIS

Background and Aims Tenapanor, a first-in-class, phosphate absorption inhibitor blocks the paracellular absorption of phosphate in the GI tract by local inhibition of the sodium-hydrogen exchanger (NHE3). It therefore provides a novel, non-binder approach for managing hyperphosphatemia. Tenapanor is dosed as one small pill twice daily. In three pivotal trials, tenapanor met its primary phosphorus-lowering outcome. This report evaluates long-term safety data from the longest of these trials. Method This 52-week study consisted of a 26-week, open-label, randomized treatment period with a 12-week placebo-controlled randomized withdrawal period, followed by a 14-week open label safety extension period. Maintenance dialysis patients with serum phosphorus ≥ 6.0 mg/dL and a 1.5 mg/dL increase in serum phosphorus following phosphate binder washout were randomized 3:1 to receive tenapanor 30 mg twice daily or sevelamer carbonate, dosed per package insert. At end of the randomized treatment period all patients in the tenapanor arm were re-randomized 1:1 to either tenapanor or placebo for the randomized withdrawal period followed by tenapanor for the safety extension period. Sevelamer was used as a safety control for comparisons of serious adverse events/hospitalizations to tenapanor. Results Tenapanor was generally well tolerated, with diarrhea the only adverse event reported by &gt;5% of patients during the randomized treatment period. Diarrhea was typically mild-to-moderate in severity, transient, and occurred more commonly during the randomized treatment period than the randomized withdrawal or safety extension periods. Rates of serious adverse events leading to hospitalization were higher in patients treated with sevelamer than tenapanor (35.8% vs 24.6%). The highest reported percentages of serious adverse events were infections and infestations (16.1% vs 9.3%) cardiac disorders (8.0% vs 5.7%), respiratory, thoracic and mediastinal disorders (8.8% vs 5.5%), and metabolism and nutritional disorders (7.3% vs 3.6%) for sevelamer and tenapanor, respectively. Adverse events leading to death were higher in patients treated with sevelamer than tenapanor (3.6% vs 2.9%). Conclusion Among maintenance dialysis patients with hyperphosphatemia, tenapanor, a novel, non-binder, phosphate absorption inhibitor that blocks paracellular absorption of phosphorus with a one tablet twice daily dose, has an acceptable safety profile, and, if approved, may offer a new approach to the treatment of hyperphosphatemia.

Transient Hypophosphatemia: A Dangerous Event in Multiple Myeloma

Patients with malignancies frequently experience multiple electrolyte disturbances. In multiple myeloma, hypercalcemia and hyperphosphatemia are one of the most common metabolic disturbances observed as part of pathogenesis of the disease. However, in rare occasions and during the course of the disease, many patients can develop hypophosphatemia due to multiple factors that affects the phosphate absorption and excretion. We hereby present a 56 y/o woman recently diagnosed with multiple myeloma who developed severe hypophosphatemia during medical treatment. We should note that the following manuscript was presented at the 2019 American Association of Clinical Endocrinologists (AACE) 28th Annual Scientific and Clinical Congress.