Safety and Efficacy of Tenapanor for Long-term Serum Phosphorus Control in Maintenance Dialysis: A 52-Week Randomized Phase 3 Trial (PHREEDOM)

Background: Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia. Methods: In this 52-week phase 3 study (NCT03427125), participants receiving maintenance dialysis with both hyperphosphatemia (serum phosphorus 6.0-10.0 mg/dl) and a 1.5 mg/dl increase following phosphate binder washout were randomized (3:1) to tenapanor 30 mg twice daily for 26 weeks (randomized treatment period) or sevelamer carbonate (52-week safety control). Participants completing 26 weeks' treatment with tenapanor were re-randomized (1:1) to tenapanor or placebo for 12 weeks (randomized withdrawal period) and were eligible to enter the 14-week safety extension period. With input from the US Food and Drug Administration, the primary efficacy endpoint was the difference in the change in serum phosphorus from the end of the randomized treatment period to the end of the randomized withdrawal period among participants who achieved ≥1.2 mg/dl decrease in serum phosphorus during the randomized treatment period (efficacy analysis set). Efficacy was also evaluated in the intention-to-treat (ITT) analysis set. Results: Of 564 eligible participants randomized to receive tenapanor (n=423) or sevelamer carbonate (n=141) during the randomized treatment period, 255 (60%) in the tenapanor group subsequently were re-randomized to tenapanor (n=128) or placebo (n=127) during the randomized withdrawal period. In the efficacy analysis set (n=131), the difference in estimated mean change in serum phosphorus level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was −1.4 mg/dl (P<0.0001); in the ITT analysis set (n=243), the estimated mean difference was −0.7 mg/dl (P=0.002). Loosened stools were the most frequently reported adverse event (53% during the randomized treatment period). Serious adverse events were reported more frequently for participants treated with sevelamer carbonate (16-23% across the three study periods) compared with tenapanor (11-17%). Conclusions: Tenapanor reduced serum phosphorus concentrations and maintained control of serum phosphorus in participants receiving maintenance dialysis, with an acceptable safety and tolerability profile.

Gut Microbiome-Derived Uremic Toxin Levels in Hemodialysis Patients on Different Phosphate Binder Therapies

<b><i>Introduction:</i></b> Constipation is prevalent in patients with kidney failure partly due to the use of medication, such as phosphate binders. We hypothesized that serum levels of gut microbiome-derived uremic toxins (UTOX) may be affected by the choice of phosphate binder putatively through its impact on colonic transit time. We investigated two commonly prescribed phosphate binders, sevelamer carbonate (SEV) and sucroferric oxyhydroxide (SFO), and their association with gut microbiome-derived UTOX levels in hemodialysis (HD) patients. <b><i>Methods:</i></b> Weekly blood samples were collected from 16 anuric HD participants during the 5-week observational period. All participants were on active phosphate binder monotherapy with either SFO or SEV for at least 4 weeks prior to enrollment. Eight UTOX (7 gut microbiome-derived) and tryptophan were quantified using liquid chromatography-mass spectrometry. Serum phosphorus, nutritional, and liver function markers were also measured. For each substance, weekly individual levels, the median concentration per participant, and differences between SFO and SEV groups were reported. Patient-reported bowel movements, by the Bristol Stool Scale (BSS), and pill usage were assessed weekly. <b><i>Results:</i></b> The SEV group reported a 3.3-fold higher frequency of BSS stool types 1 and 2 (more likely constipated, <i>p</i> &#x3c; 0.05), whereas the SFO group reported a 1.5-fold higher frequency of BSS stool types 5–7 (more likely loose stool and diarrhea, not significant). Participants in the SFO group showed a trend toward better adherence to phosphate binder therapy (SFO: 87.6% vs. SEV: 66.6%, not significant). UTOX, serum phosphorus, nutritional and liver function markers, and tryptophan were not different between the two groups. <b><i>Conclusion:</i></b> There was no difference in the gut microbiome-derived UTOX levels between phosphate binders (SFO vs. SEV), despite SFO therapy resulting in fewer constipated participants. This pilot study may inform study design of future clinical trials and highlights the importance of including factors beyond bowel habits and their association with UTOX levels.

EFFICACY OF SEVELAMER CARBONATE IN COMBINATION WITH EDIBLE SOURCES IN HYPERPHOSPHATEMIA CONDITION ASSOCIATED WITH CHRONIC KIDNEY DISORDER

Objective: The main objective of the study was to discover a suitable dietary source of plant origin which can be recommended alongside the medication in case of hyperphosphatemia. Methods: The 2 plant samples chow chow (Sechiumedule) and bitter gourd (Momordica carantia) and two seed samples-Flax seeds (Linumusitatissimum) and Chia seeds (Salvia hispanica) were selected for the study. The samples were extracted using methanol. The filtrate obtained was used for dialysis studies under different conditions. Inorganic phosphate was estimated in each of the conditions. Results: The study indicated perturbation in the absorption of phosphate with the selected plant samples as talked about in the following study. The extreme concentration of phosphate among the four diverse picked plant sources was seen in bitter gourd, which was found to be 0.4686 µmoles/ml. A minimal measure of 0.0693 µmoles/ml of phosphate was found in chia seeds. Chow chow ended up being the best one in hyperphosphatemia condition as the amount of phosphate removed by it along with the drug, sevelamer carbonate, was calculated to be the maximum (0.0561 µmoles). It was followed by chia seeds (0.0429 µmoles) and flax seeds (0.0420 µmoles). Conclusion: The present study concentrates on the impact of various samples of plant extraction that can act on the phosphate absorption in the intestine by the procedure of dialysis.

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.

SEVELAMER CARBONATE MODULATES THE NLRP3 AND NLRP6 INFLAMMASOME EXPRESSION IN PATIENTS WITH DIABETIC NEPHROPATHY

Interaction of microorganisms with the host innate immune system is a crucial factor that could modify diabetes and its associated complications. Recent reports have elucidated the role of NLRP3 inflammasome in diabetes, but to our knowledge there is no data regarding the role of other inflammasomes in diabetes-induced inflammation. To investigate this, blood samples were collected from type 2 diabetes (T2DM) patients with nephropathy as well as from healthy volunteers. After red blood cell lysis, RNA was isolated from all collected blood samples. The expression of NLRP 6, NLRP3, ASC, PRO-IL1Β, and PRO-IL18 was assessed by quantitative Real Time PCR (qRT-PCR). Patients with diabetic nephropathy showed higher NLRP3 inflammasome expression compared to healthy controls whereas no significant differences were observed in case of NLRP6 inflammasome. In addition, Pentraxin 3 expression was elevated in patients with diabetic nephropathy. A detailed analysis of the patient’s clinical data revealed the fact that subjects receiving sevelamer carbonate in their treatment plan harboured low expression of Pentraxin 3 (PTX3) and NLRP3 associated genes.

A Case of Vocal Cord Paralysis and Severe Hypocalcemia

Background: Tetany is the hallmark of hypocalcemia. Vocal cord paralysis is a rare presenting symptom of hypocalcemia, especially without signs of overt tetany or seizures. Clinical case: 18 year old man with history of iron deficiency anemia and dyslipidemia presented with aphasia, right sided upper and lower extremity weakness and facial tingling for 3 days. Physical exam was notable for aphasia, pallor, positive Chvostek and Trousseau sign. Admission labs showed BUN 127 mg/dL (n 8–26 mg/dL), creatinine 12.74 mg/dL (n 0.8–2.00 mg/dL), calcium 5.2 mg/dL (n 8.5–10.5 mg/dL), magnesium (1.8–2.4 mg/dL), phosphorus 10.3 (2.4–4.8 mg/dL), alkaline phosphatase 126 (8–120 U/L), albumin 3.3 g/dL (n 3.0–5.0 g/dL), 25 OH VitD3 9.1 ng/mL (n 30–80 ng/mL), PTH 594 pg/mL (n 15–65 pg.mL), COVID 19 PCR negative. Aphasia resolved with 1 gram calcium gluconate infusion. Patient underwent emergent hemodialysis. He was placed on calcium carbonate 1500 mg oral three times daily, calcitriol 1 mcg oral twice daily, ergocalciferol 50,000 IU weekly, sevelamer carbonate 1600 mg tablet three times daily. Kidney biopsy showed membranoproliferative pattern glomerulonephritis with C3 deposits. He was discharged on hemodialysis and referred to a transplant center. Conclusion: Vocal cord paralysis is rare in adults and mostly seen in patients with pseudohypoparathyroidism caused by hypomagnesaemia.2,3 Identifying vocal cord paralysis as an atypical presentation of hypocalcemia secondary to acute kidney failure requires prompt recognition and treatment. References: 1.Shoback D, Marcus R, Bikle D. Metabolic bone disease. In: Greenspan FS, Gardner DG, editors. Basic and clinical endocrinology. 3rd ed Los Altos (CA): Lange Medical Publications; 2004. p. 3242.van Veelen, M J et al. “Hypocalcaemic laryngospasm in the emergency department.” BMJ case reports vol. 2011 bcr1120103555. 17 Feb. 2011, doi:10.1136/bcr.11.2010.35553.Guise TA, Mundy GR. Clinical review 69: evaluation of hypocalcemia in children and adults. J Clin Endocrinol Metab 1995;80:1473–8

Effects of Sevelamer Carbonate versus Calcium Acetate on Vascular Calcification, Inflammation, and Endothelial Dysfunction in Chronic Kidney Disease

Rationale & Objective: Hyperphosphatemia is present in most patients with end-stage renal disease (ESRD) and has been associated with increased cardiovascular mortality. Phosphate binders (calcium-based and calcium free) are the mainstay pharmacologic treatment to lower phosphorus levels in patients with ESRD. Study Design: We evaluated biochemical markers of vascular calcification, inflammation, and endothelial dysfunction in patients with Chronic Kidney Disease (CKD) treated with sevelamer carbonate versus calcium acetate. Setting & Participants: We enrolled 50 CKD patients (stages 3 and 4) and treated them with sevelamer carbonate and calcium acetate for 12 weeks. Outcomes: At the end of the study the biomarkers of vascular calcification, inflammation, and endothelial dysfunction were analyzed. Results: A significant increase in HDL-cholesterol was observed with sevelamer carbonate but not with calcium acetate. Treatment with sevelamer carbonate reduced serum phosphate, calcium phosphate, and FGF-23 levels and there was no change with calcium acetate treatment. The inflammatory markers IL-8, IFN-γ, and TNFα decreased with response to both treatments. The levels of IL-6 significantly increased with calcium acetate treatment and no change was observed in the sevelamer carbonate treatment group. Conclusion: Sevelamer carbonate showed favorable effects on anti-inflammatory and vascular calcification biomarkers compared to calcium acetate treatment. Funding: Funding was received from Sanofi/Genzyme. Trial Registration: Registered at trial.com, registration number NCT01277497.

Lower gastrointestinal bleeding in a patient receiving sevelamer: Case report

Phosphate binders such as sevelamer are widely used in patients with chronic kidney disease to lower serum phosphate levels. We present a case of a 67-year-old woman with lower gastrointestinal bleeding after 9 days of using sevelamer carbonate (Renvela®). Sigmoidoscopy revealed multiple deep ulcers (diameter 10–15 mm) and mucosal oedema. Histologic examination showed deposition of sevelamer crystals in these rectal ulcers. We hypothesized that the lower gastrointestinal bleeding was caused by deposition of sevelamer crystals. After cessation of sevelamer, gastrointestinal bleeding stopped. Deposition of sevelamer crystals in the gastrointestinal tract is a rare complication of sevelamer therapy. There are only 17 other recorded cases of gastrointestinal deposition of sevelamer crystals. This adverse effect should be considered in all patients taking sevelamer who present with gastrointestinal symptoms, such as gastrointestinal bleeding and abdominal pain. When sevelamer is discontinued, symptoms and mucosal damage appear to revert.