Effectivity and safety profile of tenapanor, a sodium-hydrogen exchanger isoform 3 inhibitor, as an innovative treatment for hyperphosphatemia in chronic kidney disease: A systematic review of clinical studies

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Declined renal function, particularly in the advanced stage will lead to serum phosphate accumulation due to an inability to excrete serum phosphate which mostly originates from daily intestinal absorption. Osteocytes then release fibroblast growth factor 23 (FGF23) in order to promote renal phosphate excretion. Unfortunately, FGF23 also impair renal 1.25-dihydroxycalcitriol production which disturb intestinal calcium absorption, resulting in hypocalcemia. Parathyroid glands then release parathyroid hormone (PTH) as a compensatory mechanism to increase serum calcium through bone resorption. Calcium and phosphate release from destructed bone will lead to cardiovascular calcification and bone disorders, thus increasing morbidity and mortality in patients with CKD.<a class="elsevierStyleCrossRefs" href="#bib0125">2,3</a>Dialysis, phosphate binders, and calcimimetic agents are available modalities for hyperphosphatemia management in CKD, but they still have some disadvantages including flexibility limitation, hypocalcemia risk, as well as metal overload and cardiovascular calcification.<a class="elsevierStyleCrossRefs" href="#bib0135">4–6</a> Tenapanor is a novel modality option for hyperphosphatemia in CKD with its mechanism which inhibit sodium-hydrogen exchanger isoform 3 (NHE3) in gastrointestinal tract. This new medication has also been indicated for irritable bowel syndrome with constipation (IBS-C).<a class="elsevierStyleCrossRefs" href="#bib0150">7,8</a> In this review, we provide clinical evidences of the effectivity and safety profile of tenapanor in managing hyperphosphatemia in CKD through its NHE3 inhibition.MethodLiterature searching was performed in Pubmed and Science Direct by using “tenapanor”, “chronic kidney disease”, and “hyperphosphatemia” as keywords. The studies then systematically selected by using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) algorithm (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Duplicate literatures were removed. Review articles, books, conferences abstracts, editorials, commentaries, letter to editor, and guidelines were excluded, while research studies were retrieved. Literature screening was performed by using Population, Intervention, Comparison, and Outcome (PICO) criteria which are: CKD patients requiring dialysis as population, tenapanor or its combination with dialysis or phosphate binders as intervention, placebo or other phosphate binders without tenapanor as comparison, as well as serum phosphate and safety profile as the outcome. Studies which meet the criteria then examined for risk of bias as quality assessment and qualitatively synthesized to establish this systematic review.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>ResultRisk of bias assessment in included studiesOur included studies have a relatively similarities in risk of bias. The participants and investigators were all blinded in all of our included studies.<a class="elsevierStyleCrossRefs" href="#bib0160">9–15</a> There are two studies with unclear risk of randomization sequence method as it was not mentioned in the studies.<a class="elsevierStyleCrossRefs" href="#bib0165">10,12</a> Five of included studies have unclear risk of concealment of randomization allocation.<a class="elsevierStyleCrossRefs" href="#bib0165">10,12–15</a> All of our included studies have a low risk of bias in completeness of reported outcomes.<a class="elsevierStyleCrossRefs" href="#bib0160">9–15</a> The general summary of the risk of bias in our included studies can be seen in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>Characteristics of included studiesA total of seven clinical studies were included in our review. All the studies evaluated the decrease of serum phosphate as their primary outcome.<a class="elsevierStyleCrossRefs" href="#bib0160">9–15</a> Four studies use tenapanor or placebo alone as the intervention and comparison by implementing “washout system”,<a class="elsevierStyleCrossRefs" href="#bib0160">9–12</a> while the three other studies still maintained the previous phosphate binders as a combination with tenapanor or placebo.<a class="elsevierStyleCrossRefs" href="#bib0180">13–15</a> Six of seven studies also examined FGF23 levels as the other outcome.<a class="elsevierStyleCrossRefs" href="#bib0165">10–13,15,16</a> The level of PTH was investigated in two studies.<a class="elsevierStyleCrossRefs" href="#bib0170">11,15</a> All of our included studies evaluated the safety profile of tenapanor. The summary of our included studies is described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The role of tenapanor as hyperphosphatemia treatment in chronic kidney diseaseHyperphosphatemia is a frequent metabolic complication of CKD, particularly in end stage disease. This complication is a result of impaired renal function and limitation of conventional dialysis to eliminate serum phosphate originated from dietary phosphate absorption.<a class="elsevierStyleCrossRefs" href="#bib0160">9,12</a>Tenapanor is a selective inhibitor of the sodium-hydrogen exchanger isoform 3 (NHE3), an antiporter located on the surface of the gastrointestinal tract's enterocytes. By inhibiting the sodium-hydrogen exchange, tenapanor causes the accumulation of intracellular protons and subsequently lowers the pH. This decrease in pH alters the tight junction proteins, resulting in a decrease in the permeability of phosphate paracellular diffusion and ultimately lowering the level of serum phosphate.<a class="elsevierStyleCrossRefs" href="#bib0160">9–11,14</a> The mechanism of tenapanor in inhibiting phosphate absorption can be seen in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>.<elsevierMultimedia ident="fig0015"></elsevierMultimedia>Effectivity of tenapanor in lowering serum phosphate in chronic kidney diseaseThere are four studies which investigated the effect of tenapanor as a single therapy to serum phosphate in CKD patients. All the patients underwent 1–3 weeks of washout period before started the treatment.<a class="elsevierStyleCrossRefs" href="#bib0160">9–12</a> The majority dose of tenapanor was 3, 10, and 30mg twice daily (BID),<a class="elsevierStyleCrossRefs" href="#bib0160">9–12</a> though dosage of 3 and 30mg once daily<a class="elsevierStyleCrossRefs" href="#bib0165">10,12</a> as well as 1 and 5mg BID was also found.<a class="elsevierStyleCrossRefs" href="#bib0165">10–12</a> All these studies showed a higher decrease in serum phosphate with tenapanor as a single therapy compared to placebo.<a class="elsevierStyleCrossRefs" href="#bib0160">9–12</a> Significant serum phosphate decrement from baseline was reported with tenapanor dose of 3, 5, 10, and 30mg BID in fixed dose as well as 30mg BID with titration versus placebo in two studies.<a class="elsevierStyleCrossRefs" href="#bib0160">9–11</a> Tenapanor reduces serum phosphate levels in a dose-dependent manner in all four studies.<a class="elsevierStyleCrossRefs" href="#bib0160">9–12</a> In the other hand, tenapanor as single therapy also resulted in higher proportion of patients achieving serum phosphate target of <5.5mg/dL compared to placebo.<a class="elsevierStyleCrossRef" href="#bib0165">10</a>Serum phosphate before the administration of tenapanor and placebo in studies which examined tenapanor effectivity as monotherapy ranged from 7.32 to 8.1mg/dL.<a class="elsevierStyleCrossRefs" href="#bib0160">9–12</a> The lowest serum phosphate reduction was found in tenapanor 1mg BID that ranged from −0.47mg/dL<a class="elsevierStyleCrossRef" href="#bib0175">12</a> to −1.18mg/dL.<a class="elsevierStyleCrossRef" href="#bib0165">10</a> Administration of tenapanor 3mg BID resulted in serum phosphate change of −1.93mg/dL<a class="elsevierStyleCrossRef" href="#bib0165">10</a> to −2.48mg/dL,<a class="elsevierStyleCrossRef" href="#bib0160">9</a> while tenapanor 3mg once daily only decreased serum phosphate up to −1.28mg/dL.<a class="elsevierStyleCrossRef" href="#bib0165">10</a> Tenapanor dosage of 5mg BID was only found in one study which only showed serum phosphate reduction of −0.9mg/dL.<a class="elsevierStyleCrossRef" href="#bib0170">11</a> Tenapanor dosage of 30mg once daily resulted in serum phosphate decline of −1.85mg/dL.<a class="elsevierStyleCrossRef" href="#bib0165">10</a> Serum phosphate reduction in tenapanor 30mg BID is similar between the non-dose-titration group and those with dose-titration.<a class="elsevierStyleCrossRefs" href="#bib0165">10,11</a> In tenapanor 30mg BID without dose titration, the serum phosphate reduction ranged from −1.97mg/dL<a class="elsevierStyleCrossRef" href="#bib0170">11</a> to −2.67mg/dL,<a class="elsevierStyleCrossRef" href="#bib0160">9</a> while in tenapanor 30mg BID with dose titration, the serum phosphate decline ranged from −2.0mg/dL<a class="elsevierStyleCrossRef" href="#bib0170">11</a> to −2.61mg/dL.<a class="elsevierStyleCrossRef" href="#bib0160">9</a>Efficacy of tenapanor as a combination therapy with other phosphate binders was observed in three studies. All the subjects in the studies maintained their pre-existing phosphate binders which then added with tenapanor or placebo.<a class="elsevierStyleCrossRefs" href="#bib0180">13–15</a> The serum phosphate in three studies that used a combination of tenapanor and other phosphate binders as a treatment regimen before the intervention ranged from 6.7 to 7.01mg/dL.<a class="elsevierStyleCrossRefs" href="#bib0180">13–15</a> The dose of tenapanor used in these studies are not as variable as in studies that used tenapanor as monotherapy. Two of three studies use tenapanor 30mg BID as the treatment,<a class="elsevierStyleCrossRef" href="#bib0180">13</a> while one study use tenapanor 5mg BID.<a class="elsevierStyleCrossRef" href="#bib0190">15</a> In all three studies, the combination of tenapanor with phosphate binders revealed a greater reduction of serum phosphate compared to the combination of placebo with phosphate binders.<a class="elsevierStyleCrossRefs" href="#bib0180">13–15</a> Statistical significance was found in two of three studies with tenapanor dose of both 5mg BID and 30mg BID.<a class="elsevierStyleCrossRefs" href="#bib0180">13,15</a> In two studies of tenapanor 30mg BID as combination with other phosphate binders, the mean change of serum phosphate declined were −0.84mg/dL<a class="elsevierStyleCrossRef" href="#bib0180">13</a> and −1.5mg/dL,<a class="elsevierStyleCrossRef" href="#bib0185">14</a> while in study of tenapanor 5mg BID combined with other phosphate binders, the mean change of serum phosphate were up to −2.0mg/dL.<a class="elsevierStyleCrossRef" href="#bib0190">15</a> A higher rate of target achievement for serum phosphate was also found in tenapanor group compared to placebo in all three studies<a class="elsevierStyleCrossRefs" href="#bib0180">13–15</a>, in which two of three studies set the serum phosphate target to <5.5mg/dL,<a class="elsevierStyleCrossRefs" href="#bib0180">13,14</a> while serum phosphate goal ranged from 3.5 to 6.0mg/dL in one other study.<a class="elsevierStyleCrossRef" href="#bib0190">15</a>Besides observing direct effect of tenapanor to serum phosphate, three of four studies which used tenapanor as monotherapy also evaluated the impact of tenapanor to serum phosphate in certain duration after the last administration of tenapanor.<a class="elsevierStyleCrossRefs" href="#bib0160">9–11</a> In a randomized withdrawal period in a study by Block et al. in 2019, participants that had previously been treated with tenapanor then continued with placebo for 4 weeks experienced an increase in serum phosphate with mean change of +0.07mg/dL.<a class="elsevierStyleCrossRef" href="#bib0160">9</a> In the follow-up visit 1–2 weeks after the last intervention in the study by Block et al. in 2017, the serum phosphate was still maintained between 3 and 6mg/dL in all intervention groups, including tenapanor with various dosages.<a class="elsevierStyleCrossRef" href="#bib0165">10</a> A study by Inaba et al. revealed that serum phosphate levels returned to near baseline levels 3 weeks after the last administration of both the full dosage of tenapanor and placebo.<a class="elsevierStyleCrossRef" href="#bib0170">11</a>Pleiotropic effect of tenapanor in interfering fibroblast growth factor 23 and parathyroid hormone in chronic kidney diseaseBesides reducing serum phosphate, tenapanor was also found to have a beneficial effect on FGF23 and PTH levels. A total of six studies showed FGF23 declined with tenapanor.<a class="elsevierStyleCrossRefs" href="#bib0165">10–13,15,16</a> Significant decrease in FGF23 was observed in tenapanor as single therapy at dose of 1, 3, 10, and 30mg BID as well as 3 and 30mg once daily.<a class="elsevierStyleCrossRefs" href="#bib0160">9,10,12</a> Tenapanor as a combination therapy with other phosphate binders also showed its ability to reduce FGF23 levels at doses of both 5mg and 30mg BID.<a class="elsevierStyleCrossRefs" href="#bib0180">13,15</a>Tenapanor was also found to suppress PTH levels other than serum phosphate and FGF23 in two studies.<a class="elsevierStyleCrossRefs" href="#bib0170">11,15</a> As monotherapy, tenapanor at dose of 5, 10, and 30mg BID was able to reduce PTH levels though the significance was not reported.<a class="elsevierStyleCrossRef" href="#bib0170">11</a> In a setting as combination therapy with other phosphate binders, tenapanor 5mg BID was reported to significantly suppress PTH.<a class="elsevierStyleCrossRef" href="#bib0190">15</a>Safety profile of tenapanor in chronic kidney disease populationSafety profile of tenapanor was evaluated in all of our included studies.<a class="elsevierStyleCrossRefs" href="#bib0160">9–15</a> Gastrointestinal symptoms especially diarrhea was the most frequent adverse effect (AE) in all the studies.<a class="elsevierStyleCrossRefs" href="#bib0160">9–15</a> The intensity of diarrhea was dominantly mild to moderate in severity with transient onset in majority of studies.<a class="elsevierStyleCrossRefs" href="#bib0180">13–15</a> In the setting of tenapanor as single therapy, the diarrhea tended to be dose-dependent, as the incidence of diarrhea was higher in tenapanor dose of 10mg and 30mg BID as well as 30mg once daily.<a class="elsevierStyleCrossRefs" href="#bib0160">9–12</a> The same trend was also found in the setting of tenapanor as combination therapy with phosphate binders, in which higher incidence of diarrhea was reported in studies with higher dose of tenapanor.<a class="elsevierStyleCrossRefs" href="#bib0180">13–15</a> Severe diarrhea was reported in one study, which is predominantly in tenapanor dose of 30mg once and twice daily.<a class="elsevierStyleCrossRef" href="#bib0200">17</a>The safety profile of tenapanor was also evaluated with physical examination, laboratory, and electrocardiography (ECG) parameters. In our included studies, tenapanor therapy didn’t lead to any significant change in physical examination, laboratory, and ECG parameters. There was also no death related to tenapanor. From these findings, tenapanor was relatively safe and well tolerated in CKD patients.<a class="elsevierStyleCrossRefs" href="#bib0160">9–11,13,14</a>DiscussionPhosphate retention is frequently found in CKD stage 4 and 5, which is a factor that initiate many other disturbances such as increased FGF23 and PTH, hypocalcemia, and low vitamin D, which in turn will lead to an enhancement in cardiovascular and all causes of morbidity and mortality.<a class="elsevierStyleCrossRef" href="#bib0205">18</a> Phosphate balance is maintained by several mechanism including intestinal phosphate absorption, bone turnover regulation, as well as renal excretion and reabsorption.<a class="elsevierStyleCrossRefs" href="#bib0135">4,19</a> In a normal condition, the kidney excretes approximately ninety percent of phosphate per day.<a class="elsevierStyleCrossRef" href="#bib0215">20</a> As renal phosphate clearance declined in CKD, inhibiting intestinal phosphate absorption can be a promising approach in managing hyperphosphatemia in patients with CKD.<a class="elsevierStyleCrossRefs" href="#bib0135">4,20</a>Generally, phosphate binders only result in maximum 2.0mg/dL of phosphate reduction in their maximal doses.<a class="elsevierStyleCrossRef" href="#bib0160">9</a> Some of our included studies show that 30mg of tenapanor whether as fixed or titrated dose single therapy was able to reduce serum phosphate up to more than 2.0mg/dL.<a class="elsevierStyleCrossRefs" href="#bib0160">9,10</a> This finding can be possible due to tenapanor mechanism which suppress intestinal phosphate absorption through NHE3 inhibition,<a class="elsevierStyleCrossRefs" href="#bib0160">9–11,14</a> as about 90% of phosphate input comes from intestinal absoption.<a class="elsevierStyleCrossRef" href="#bib0215">20</a>Tenapanor works by inhibiting NHE3 which then interferes with sodium and phosphate absorption in the intestinal lumen. By using this mechanism, tenapanor has a promising potency to effectively treat hyperphosphatemia in CKD due to its dominant role in gastrointestinal tract, as around 90% of phosphate are originated from intestinal absorption.<a class="elsevierStyleCrossRefs" href="#bib0160">9–11</a>Our included studies which used tenapanor as monotherapy commonly revealed a dose-dependent phosphate lowering effect.<a class="elsevierStyleCrossRefs" href="#bib0160">9–12</a> Tenapanor 1mg BID showed serum phosphate declined up to −1.18mg/dL.<a class="elsevierStyleCrossRefs" href="#bib0165">10,12</a> Administration frequency also influence the effectivity of tenapanor 3mg, which reduce serum phosphate around −1.28mg/dL in once daily dose<a class="elsevierStyleCrossRef" href="#bib0165">10</a> and up to −2.48mg/dL in BID dose.<a class="elsevierStyleCrossRefs" href="#bib0160">9,10</a> Tenapanor 10mg BID was shown to reduced serum phosphate up to −2.52mg/dL in several studies.<a class="elsevierStyleCrossRefs" href="#bib0160">9–12</a> Tenapanor with dose of 30mg also showed the same frequency-dependent manner in lowering serum phosphate, where twice daily dose resulted in up to −2.67mg/dL serum phosphate reduction, while in once daily dose, the serum phosphate only decreased up to −1.85mg/dL.<a class="elsevierStyleCrossRef" href="#bib0165">10</a> In the other hand, 30mg BID tenapanor with dose titration exhibited an unsignificant difference in phosphate reduction effect compared to non-dose-titration administration of tenapanor 30mg.<a class="elsevierStyleCrossRefs" href="#bib0160">9,10</a> This finding suggest the possible strategy to achieve the highest serum phosphate reduction target by using tenapanor with optimum dose while minimizing the side effects by using dose-titration strategy.<a class="elsevierStyleCrossRefs" href="#bib0160">9,10</a>Unlike the studies that used tenapanor as monotherapy, the phosphate reduction trend is inconsistent with the dose in studies that used tenapanor in combination with other phosphate binders. Tenapanor 30mg BID in combination with the patient's pre-existing phosphate binders resulted in −0.84mg/dL phosphate reduction in a study by Pergola et al.<a class="elsevierStyleCrossRef" href="#bib0180">13</a> and −1.5mg/dL reduction in a study by Shigematsu et al.<a class="elsevierStyleCrossRef" href="#bib0185">14</a> Meanwhile, in the study by Nitta et al., tenapanor 5mg BID in combination with patient's pre-existing phosphate binder reduced the serum phosphate up to −2.0mg/dL,<a class="elsevierStyleCrossRef" href="#bib0190">15</a> which was even higher than tenapanor 30mg BID in studies by Pergola et al.<a class="elsevierStyleCrossRef" href="#bib0180">13</a> and Shigematsu et al.<a class="elsevierStyleCrossRef" href="#bib0185">14</a> This different trend can be possibly caused by the effect of other phosphate binders which could probably have any undiscovered interactions with tenapanor. Further studies which analyze the possible drug-drug interaction between tenapanor and other phosphate binders is needed to explore the exact possible results of combination therapy between tenapanor and other phosphate binders as hyperphosphatemia therapy for patients with CKD. However, until the time of this review is conducted, studies show that tenapanor as monotherapy has a better phosphate reduction effect compared to tenapanor as a combination therapy with other phosphate binders.<a class="elsevierStyleCrossRefs" href="#bib0160">9–15</a>Serum phosphate after the termination of tenapanor is also one of the concerns. In randomized withdrawal period in the study by Block et al. in 2019, patients receiving placebo for 4 weeks after the last dose of tenapanor experienced increasing serum phosphate of only +0.79mg/dL.<a class="elsevierStyleCrossRef" href="#bib0160">9</a> In the study by Block et al. in 2017, the follow-up visit at 1–2 weeks after the last dosage of tenapanor showed that the serum phosphate of all groups were between 3 and 6mg/dL which still didn’t reach the baseline serum phosphate before the beginning of intervention.<a class="elsevierStyleCrossRef" href="#bib0165">10</a> In addition, a study by Inaba et al. revealed that serum phosphate levels were increased near baseline levels in follow-up visit after 3 weeks from the last dosage of tenapanor.<a class="elsevierStyleCrossRef" href="#bib0170">11</a> These findings suggest that serum phosphate maintenance after the last dosage of tenapanor can be variable, which could be possibly influenced by several factors such as the baseline serum phosphate which varies in these studies, duration since the last dosage of tenapanor which only 1–2 weeks in certain studies and up to 4 weeks in the other study, also the dosage and frequency of tenapanor administration, which implies the need for further studies to examine serum phosphate maintenance in more detailed period after the last dosage of tenapanor. However, from these studies, it can be concluded that serum phosphate can still be maintained at levels below the baseline, even until 3–4 weeks after the last dosage of tenapanor.<a class="elsevierStyleCrossRefs" href="#bib0160">9–11</a>In addition to its phosphate lowering effect, tenapanor was also found to have a pleiotropic effect in suppressing the levels of FGF23 and PTH, both as monotherapy and combination therapy with phosphate binders.<a class="elsevierStyleCrossRefs" href="#bib0165">10–13,15,16</a> The exact mechanism of this finding remains unclear, but it can be possibly explained by the role of these two hormones as compensatory mechanism to elevated serum phosphate, thus greater reduction of serum phosphate will suppress FGF23 and PTH production.<a class="elsevierStyleCrossRefs" href="#bib0160">9,11,12,15</a> This pleiotropic effect of tenapanor can be utilized to minimize the morbidity and mortality in CKD, as high FGF23 and PTH will cause extraosseous calcium and phosphate deposition, particularly in the heart valves and vascular. This condition then develop to valve and vascular atherosclerosis through osteochondrogenic differentiation and elastin degradation, leading to increased mortality due to cardiovascular disease.<a class="elsevierStyleCrossRef" href="#bib0220">21</a> Besides that, increased PTH which enhance calcium efflux from bones is the cause of bone mass loss in patients with CKD, resulting in increased morbidity.<a class="elsevierStyleCrossRef" href="#bib0225">22</a> Therefore, the pleiotropic effect of tenapanor in lowering FGF23 and PTH suggesting its potency as future treatment for bone mineral disease and secondary hyperparathyroidism in CKD.Diarrhea is the most common AE caused by tenapanor. However, majority of reported diarrhea was transient and mild to moderate in intensity.<a class="elsevierStyleCrossRefs" href="#bib0180">13–15</a> This side effect appears as the effect of tenapanor mechanism which selectively inhibit the NHE3 in enterocytes, thus suppress the passive transport of phosphate in the intestine. Simultaneously, NHE3 inhibition also suppress intestinal sodium absorption which enhance sodium and water secretion in the intestinal tract.<a class="elsevierStyleCrossRefs" href="#bib0165">10,11</a> Elevated sodium, phosphate, and water content in the intestine then lead to loose stool and increased bowel movement which manifested as diarrhea.<a class="elsevierStyleCrossRefs" href="#bib0160">9,15</a> The incidence of diarrhea due to tenapanor has a higher trend in higher doses.<a class="elsevierStyleCrossRefs" href="#bib0160">9–15</a> Diarrhea side effect of tenapanor is no longer surprising, as tenapanor has also been indicated to treat IBS-C by its mechanism to increase water content in the intestinal lumen and stools. Utilization of tenapanor in IBS-C has been considered as safe and has been recommended by the American Gastroenterological Association (AGA) guideline.<a class="elsevierStyleCrossRefs" href="#bib0150">7,8,23</a> Dose titration can be a good solution for this problem to increase patient's compliance, as titrated dose of tenapanor 30mg BID exhibited a lower incidence of diarrhea while maintaining the same efficacy in reducing serum phosphate and FGF23 compared to fixed dose of tenapanor 30mg BID.<a class="elsevierStyleCrossRef" href="#bib0170">11</a>Minerals deposition and metabolic disturbances are the other concerns in treatment options for hyperphosphatemia in CKD. Available phosphate binders still has systemic mineral and metabolic disadvantages, such as calcium accumulation and increased calcification in calcium based phosphate binders, potential nervous system toxicity in aluminum based phosphate binders, iron overload in iron based phosphate binders, fat-soluble vitamins deficiency and acidosis risk in sevelamer based phosphate binders, as well as possible lanthanum deposits in lanthanum based phosphate binders.<a class="elsevierStyleCrossRefs" href="#bib0135">4–6</a> Tenapanor comes as a solution to counteract these limitations, as tenapanor didn’t cause any meaningful changes in serum calcium, laboratory parameters, ECG, and physical examination.<a class="elsevierStyleCrossRefs" href="#bib0160">9–11,13,14</a> The plausible explanation for this finding is the nature of tenapanor as a calcium free non-metal phosphate reducer, thus it doesn’t cause calcium and metal accumulation. In addition, tenapanor is also a minimally absorbed molecule, resulting in minimum systemic side-effect.<a class="elsevierStyleCrossRefs" href="#bib0160">9,10</a>ConclusionIn conclusion, tenapanor, as a single therapy or in combination with phosphate binders, was effective in managing hyperphosphatemia in CKD. It also has pleiotropic effects in interfering high FGF23 and PTH thus exhibit a promising potency to treat secondary hyperparathyroidism in CKD. Diarrhea is the most common AE but it's only transient, dose-related, and mild to moderate in severity. Starting tenapanor with a low dose can be a solution for diarrhea side effect. Tenapanor doesn’t cause any meaningful change in ECG, serum calcium, and other laboratory and clinical parameters. Generally, tenapanor is safe and well-tolerated in CKD patients.FundingThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Conflict of interestNone." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres2193400" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objectives" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Method" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Outcome" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1843665" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2193399" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Método" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultado" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1843666" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Method" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Result" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Risk of bias assessment in included studies" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Characteristics of included studies" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "The role of tenapanor as hyperphosphatemia treatment in chronic kidney disease" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Effectivity of tenapanor in lowering serum phosphate in chronic kidney disease" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Pleiotropic effect of tenapanor in interfering fibroblast growth factor 23 and parathyroid hormone in chronic kidney disease" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Safety profile of tenapanor in chronic kidney disease population" ] ] ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusion" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Funding" ] 10 => array:2 [ "identificador" => "sec0065" "titulo" => "Conflict of interest" ] 11 => array:2 [ "identificador" => "xack755579" "titulo" => "Acknowledgement" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1843665" "palabras" => array:3 [ 0 => "Chronic kidney disease" 1 => "Hyperphosphatemia" 2 => "Tenapanor" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1843666" "palabras" => array:3 [ 0 => "Enfermedad renal crónica" 1 => "Hiperfosfatemia" 2 => "Tenapanor" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "BackgroundChronic kidney disease (CKD) is a major global health problem. Hyperphosphatemia is frequent in CKD and a reason for increased morbidity and mortality as it generates hyperparathyroidism, high fibroblast growth factor 23 (FGF23), and hypocalcemia. Available hyperphosphatemia therapies still have limitations, including risk of metal overload, cardiovascular calcification, and systemic adverse effects (AEs). Tenapanor is a new hyperphosphatemia treatment in CKD with sodium-hydrogen exchanger isoform 3 (NHE3) inhibition mechanism and low systemic AEs. ObjectivesDiscovering the effectivity and safety of tenapanor as hyperphosphatemia management in CKD. MethodLiterature searching is performed by using “pubmed” and “science direct” with “tenapanor”, “chronic kidney disease”, and “hyperphosphatemia” as keywords. The literatures were selected using PRISMA algorithm version 2020. Literature was screened based on Population, Intervention, Comparison, and Outcome (PICO) criteria which are: CKD patients requiring dialysis as population, tenapanor or its combination with dialysis or phosphate binders as intervention, placebo or other phosphate binders without tenapanor as comparison, and serum phosphate, safety profile, and other pleiotropic benefits related to hyperphosphatemia management as the outcome. The included studies then assessed for risk of bias and qualitatively reviewed. OutcomeTenapanor was able to reduce serum phosphate, generally in a dose-dependent manner. Tenapanor also suppressed FGF23 and parathyroid hormone, probably due to decreased serum phosphate. The frequent AEs were transient mild-to-moderate diarrhea in a dose-dependent manner. Tenapanor was generally well-tolerated with low systemic AEs due to its non-calcium, metal-free, and low-absorbed properties. ConclusionTenapanor is an effective and safe option for hyperphosphatemia management in CKD." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objectives" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Method" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Outcome" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "AntecedentesLa enfermedad renal crónica (ERC) es un importante problema de salud mundial. La hiperfosfatemia es frecuente en la ERC y motivo de aumento de la morbimortalidad ya que genera hiperparatiroidismo, fibroblast growth factor-23 (FGF-23), elevado e hipocalcemia. Las terapias disponibles para la hiperfosfatemia aún tienen limitaciones, incluido el riesgo de sobrecarga de metales, calcificación cardiovascular y efectos adversos (EA) sistémicos. Tenapanor es un nuevo tratamiento de la hiperfosfatemia en la ERC con mecanismo de inhibición de la isoforma 3 del intercambiador de sodio-hidrógeno (NHE3) y EA sistémicos bajos. ObjetivosDescubrir la efectividad y la seguridad del tenapanor como manejo de la hiperfosfatemia en la ERC. MétodoLa búsqueda bibliográfica se realiza utilizando «Pubmed» y «Science direct» con «tenapanor», «chronic kidney disease» e «hyperphosphatemia» como palabras clave. La selección de la literatura se realizó mediante el algoritmo PRISMA versión 2020. La bibliografía se examinó con base en los criterios de Población, Intervención, Comparación y Resultado (PICO, por sus siglas en inglés), que son: pacientes con ERC que requieren diálisis como población, tenapanor o su combinación con diálisis o quelantes de fosfato como intervención, placebo u otros quelantes de fosfato sin tenapanor como comparación, y fosfato sérico, perfil de seguridad y otros beneficios pleiotrópicos relacionados con el manejo de la hiperfosfatemia como resultado. A continuación, los estudios incluidos evaluaron el riesgo de sesgo y se revisaron cualitativamente. ResultadoTenapanor fue capaz de reducir el fosfato sérico, generalmente de una manera dosis/dependiente. Tenapanor también suprimió FGF-23 y la hormona paratiroidea, probablemente debido a la disminución del fosfato sérico. Los EA frecuentes fueron diarrea transitoria leve a moderada de manera dosis/dependiente. En general, el tenapanor fue bien tolerado con EA sistémicos bajos debido a sus propiedades no cálcicas, libres de metales y de baja absorción. ConclusiónTenapanor es una opción eficaz y segura para el manejo de la hiperfosfatemia en la ERC." 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entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pergola et al., 2021 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter, double blind, randomized placebo-controlled trial (RCT), phase 3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=235.CKD patients receiving regular hemodialysis (HD) with hyperphosphatemia. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I: Oral tenapanor 30mg twice daily (BID)+pre-existing phosphate binder.C: Oral placebo BID+pre-existing binder.There was no follow-up visit in this study. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Significantly larger change in serum phosphorus from baseline (baseline phosphate levels: 6.7mg/dL for tenapanor+binder group and 6.9mg/dL for placebo+binder group) to week 4 in tenapanor+binder group (mean change from baseline: −0.84mg/dL) compared to placebo+binder (mean change from baseline: −0.19mg/dL), p<0.001.Significantly larger proportion of patients achieved serum phosphorus<5.5mg/dl in tenapanor+binder group compared to placebo+binder (p<0.01).Significant FGF23 reductions in tenapanor+binder group (p=0.003).Transient mild to moderate diarrhea was the most common adverse effect (AE) with tenapanor+binder, resolved with dose adjustment.No clinical meaningful change in laboratory, electrocardiogram (ECG), and physical examination.No serious AE and death were related to treatment. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Block et al., 2019 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Double blind, RCT, phase 3.Consists of randomized treatment period (RTP) and randomized withdrawal period (RWP) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=164 in RTP, 152 in RWP.Patients with end stage kidney disease (ESKD) receiving maintenance HD. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RTP (8 weeks):I: tenapanor regimens—3 or 10mg fixed dose BID, or 30mg BID which could be titrated.C: -RWP (4 weeks):I: previously assigned dose of tenapanorC: placebo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RTP: significant decreased serum phosphate (p<0.001) in all three tenapanor groups (mean change −2.48mg/dL, −2.52mg/dL, and −2.61mg/dL for tenapanor 3mg BID, 10mg BID, and 30mg BID titration, respectively) from baseline (7.40±1.57mg/dL, 7.46±1.69mg/dL, and 7.62±1.43mg/dL for tenapanor 3mg BID, 10mg BID, and 30mg BID titration, respectively).Reduction of FGF23 in all three tenapanor groups, significant reduction observed in the 3 and 30mg BID.RWP: significant change in serum phosphate between pooled tenapanor group (mean change +0.56mg/dL) compared to placebo (mean change +1.38mg/dL), p=0.003.Diarrhea was the most common AE. There was no treatment discontinuation in RWP.There was no clinically meaningful change in laboratory, ECG, and physical examination.There was no death related to treatment. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Block et al., 2017 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter, double blind, RCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=162Patients with ESKD receiving maintenance HD with hyperphosphatemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I: one of six tenapanor regimens (3 or 30mg once daily or 1, 3, 10, or 30mg BID) C: placebo.Follow-up period after last dosage: 1–2 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baseline phosphate levels were 7.32–7.92mg/dl in tenapanor groups and 7.87mg/dl in placebo group. Tenapanor resulted in dose-dependent reduced serum phosphate from baseline compared to placebo (mean change from baseline in the end of treatment were −1.21, −1.18, −1.28, −1.93, −2.41, −1.85, and −2.67mg/dL for placebo, tenapanor 1mg BID, 3mg once daily, 3mg BID, 10mg BID, 30mg once daily, and 30mg BID, respectively).Largest reductions were found in the tenapanor 10 and 30mg BID compared to placebo (p<0.05).At 1–2 weeks follow-up visit, serum phosphate were still maintained between 3 and 6mg/dL for all groups.Proportion of patients reached serum phosphate<5.5mg/dL in tenapanor was up to 43%, while in placebo only 8%.Significant FGF23 reduction in all tenapanor groups compared to placebo (p<0.05).The most frequent AE was GI symptoms (diarrhea), mostly mild to moderate. Severe diarrhea predominantly found in tenapanor 30mg once or twice daily.No serious AE was related to the treatment.No clinically relevant changes in serum calcium, potassium, or sodium. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Shigematsu et al., 2021 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter, double blind, RCT. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=47CKD patients receiving HD with hyperphosphatemia. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I: Tenapanor 30mg BID+pre-existing phosphate binders.C: Placebo+pre-existing phosphate binders.There was no follow-up visit in this study. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mean baseline serum phosphate were 7.01mg/dL and 6.77mg/dL in placebo and tenapanor 30mg titration, respectively. Larger serum phosphate decrement in tenapanor (mean change −1.5mg/dL) compared to placebo group (mean change −0.5mg/dL).Target achievement of phosphorus<5.5mg/dL was 73.9% with tenapanor+binder and 25% in placebo+binder.Dominant AE was GI symptoms especially transient non-severe diarrhea.There were no significant changes in laboratory, vital signs, or ECG.There was no serious AE and death related to treatment. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inaba et al., 2021 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter, double blind, RCT, phase 2. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=207CKD patients receiving HD with hyperphosphatemia. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I: Tenapanor 5-mg BID, 10-mg BID, 30-mg BID, and 30-mg BID with dose titration.Dose adjustment was only for dose-titration group.C: placeboSecond withdrawal period after last dosage: 3 weeks \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baseline serum phosphate were 7.6mg/dl, 7.5mg/dl, 8.1mg/dl, 7.7mg/dl, and 7.4mg/dl for placebo, tenapanor 5mg BID, 10mg BID, 30mg BID, and 30mg dose titration respectively.Significantly reduced serum phosphate in each tenapanor dosage groups compared to placebo (mean change: −0.9mg/dL, −1.4mg/dL, −1.9mg/dL, −2.0mg/dL, and +0.6mg/dL for tenapanor 5mg BID, 10mg BID, 30mg BID, 30mg BID with dose titration, and placebo respectively), p<0.001.Serum phosphate were back near baseline levels after the end of the treatment period for all intervention groups in the study.No significant changes in serum Ca in any group.Intact PTH and FGF23 decreased in tenapanor groups.Mild to moderate diarrhea was the most frequent AE and it was dose-related, mostly in 30mg BID group. There was no severe diarrhea in tenapanor groups.No clinically relevant alterations in vital signs, laboratory, or electrocardiogram.There were no deaths during the study. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Block et al., 2019 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Multicenter, double blind, RCT, phase 2B. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=162Patients with ESKD receiving HD with hyperphosphatemia. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I: One of six tenapanor regimens (3 or 30mg once daily, or 1, 3, 10 or 30mg BID).C: placebo.There was no follow-up visit in this study. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Serum phosphate after wash-out period were 7.32–7.92mg/dL in tenapanor group and 7.87mg/dL in placebo group.Tenapanor decrease serum phosphate in dose-dependent manner compared to placebo (least-squares mean changes: tenapanor-treated groups, −0.47 to −1.98mg/dL; placebo group, −0.54mg/dL; p=0.01).Highest serum phosphate reduction was in tenapanor 10 and 30mg BID (p<0.05 for each groups vs placebo).FGF23 was significantly reduced in range of 2030–3563pg/mL in all tenapanor groups (p<0.001–0.04), while FGF23 continued to increase in placebo group.Tenapanor dose of at least 3mg per day was needed to significantly reduce FGF23.GI disorders (diarrhea) was the common AE, particularly in high tenapanor groups of 10 BID, 30mg once daily, and 30mg BID. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Nitta et al., 2023 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Double blind, RCT, phase 3. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">N=169CKD patients receiving HD with hyperphosphatemia. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">I: Tenapanor 5mg BID+pre-existing phosphate binders.C: Placebo+pre-existing phosphate binders.There was no follow-up visit in this study. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Baseline serum phosphate were 6.92±1.068mg/dL and 6.76±1.075mg/dL in placebo+other phosphate binders and in tenapanor+other phosphate binders groups.Significantly reduced serum phosphate from baseline in tenapanor+other phosphate binders group compared to placebo+other phosphate binders group (mean change −2.00mg/dL vs −0.24mg/dL), p<0.0001.Higher proportion of serum phosphate target achievement in tenapanor compared to placebo.Serum FGF and PTH were significantly decreased in the tenapanor group, while increased in placebo group.Diarrhea was the dominant AE, all were mild to moderate. There was no treatment discontinuation due to diarrhea. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3582901.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Table of included studies." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:23 [ 0 => array:3 [ "identificador" => "bib0120" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. Bikbov" 1 => "C.A. Purcell" 2 => "A.S. Levey" 3 => "M. Smith" 4 => "A. Abdoli" 5 => "M. Abebe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/S0140-6736(20)30045-3" "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2020" "volumen" => "395" "paginaInicial" => "709" "paginaFinal" => "733" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32061315" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0125" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hyperphosphatemia and chronic kidney disease: a major daily concern both in adults and in children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J. Bacchetta" 1 => "J. Bernardor" 2 => "C. Garnier" 3 => "C. Naud" 4 => "B. Ranchin" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00223-020-00665-8" "Revista" => array:2 [ "tituloSerie" => "Calcif Tissue Int" "fecha" => "2020" ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0130" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Prevention and treatment of hyperphosphatemia in chronic kidney disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.G. Vervloet" 1 => "A.J. van Ballegooijen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.kint.2017.11.036" "Revista" => array:5 [ "tituloSerie" => "Kidney Int" "fecha" => "2018" "volumen" => "93" "paginaInicial" => "1060" "paginaFinal" => "1072" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0135" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of hyperphosphatemia in end-stage renal disease: a new paradigm" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Rastogi" 1 => "N. Bhatt" 2 => "S. Rossetti" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.jrn.2020.02.003" "Revista" => array:6 [ "tituloSerie" => "J Ren Nutr" "fecha" => "2021" "volumen" => "31" "paginaInicial" => "21" "paginaFinal" => "34" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32386937" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0140" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "State-of-the-art management of hyperphosphatemia in patients with CKD: an NKF-KDOQI controversies perspective" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.J. Scialla" 1 => "J. Kendrick" 2 => "J. Uribarri" 3 => "C.P. Kovesdy" 4 => "O.M. Gutiérrez" 5 => "E.Y. Jimenez" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/j.ajkd.2020.05.025" "Revista" => array:6 [ "tituloSerie" => "Am J Kidney Dis" "fecha" => "2021" "volumen" => "77" "paginaInicial" => "132" "paginaFinal" => "141" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32771650" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0145" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Phosphate binders in patients with chronic kidney disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "S. Chan" 1 => "K. Au" 2 => "R.S. Francis" 3 => "D.W. Mudge" 4 => "D.W. Johnson" 5 => "P.I. Pillans" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.18773/austprescr.2017.002" "Revista" => array:5 [ "tituloSerie" => "Aust Prescr" "fecha" => "2017" "volumen" => "40" "paginaInicial" => "9" "paginaFinal" => "14" ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0150" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tenapanor for the treatment of irritable bowel syndrome with constipation" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Sinagra" 1 => "F. Rossi" 2 => "D. Raimondo" 3 => "G. Conoscenti" 4 => "A. Anderloni" 5 => "V. Guarnotta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1080/17512433.2020.1762570" "Revista" => array:6 [ "tituloSerie" => "Expert Rev Clin Pharmacol" "fecha" => "2020" "volumen" => "13" "paginaInicial" => "473" "paginaFinal" => "479" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32478632" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0155" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tenapanor in the treatment of irritable bowel syndrome with constipation: discovery, efficacy, and role in management" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Herekar" 1 => "D. Shimoga" 2 => "A. Jehangir" 3 => "D. Shahsavari" 4 => "Y. Yan" 5 => "T.B. Karunaratne" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2147/CEG.S384251" "Revista" => array:6 [ "tituloSerie" => "Clin Exp Gastroenterol" "fecha" => "2023" "volumen" => "16" "paginaInicial" => "79" "paginaFinal" => "85" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37309470" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0160" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy and safety of tenapanor in patients with hyperphosphatemia receiving maintenance hemodialysis: a randomized phase 3 trial" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G.A. Block" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1681/ASN.2018080832" "Revista" => array:6 [ "tituloSerie" => "J Am Soc Nephrol" "fecha" => "2019" "volumen" => "30" "paginaInicial" => "641" "paginaFinal" => "652" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30846557" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0165" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of tenapanor on serum phosphate in patients receiving hemodialysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G.A. 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Gold" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIR.0000000000000628" "Revista" => array:5 [ "tituloSerie" => "Circulation" "fecha" => "2019" "volumen" => "140" "paginaInicial" => "382" "paginaFinal" => "482" ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0200" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of oral administration of a mixture of probiotic strains on SCORAD index and use of topical steroids in young patients with moderate atopic dermatitis a randomized clinical trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. Navarro-Lopez" 1 => "A. Ramirez-Bosca" 2 => "D. Ramon-Vidal" 3 => "B. Ruzafa-Costas" 4 => "S. Genoves-Martinez" 5 => "E. 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Effectivity and safety profile of tenapanor, a sodium-hydrogen exchanger isoform 3 inhibitor, as an innovative treatment for hyperphosphatemia in chronic kidney disease: A systematic review of clinical studies

Perfil de efectividad y seguridad de tenapanor, un inhibidor de la isoforma 3 del intercambiador de sodio/hidrógeno, como tratamiento innovador para la hiperfosfatemia en la enfermedad renal crónica, una revisión sistemática de estudios clínicos

William Suciangtoa,

Autor para correspondencia

williamsuciangto@gmail.com

Corresponding author.

, Haerani Rasyidb, Anastasya Angelica Vicentec, Winny Suciangtoa

a Department of Medical Doctor Study Program, Faculty of Medicine, Hasanuddin University, Makassar City, South Sulawesi Province, Indonesia

b Division of Nephrology and Hypertension, Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar City, South Sulawesi Province, Indonesia

c Department of Physiology, Faculty of Medicine, Hasanuddin University, Makassar City, South Sulawesi Province, Indonesia

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic kidney disease &#40;CKD&#41; is still a major global health problem&#44; with approximately 697&#46;5 million people worldwide were reported to have CKD in 2017&#44; of which 1&#46;2 million people died due to CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a> Hyperphosphatemia is often found in CKD&#46; Declined renal function&#44; particularly in the advanced stage will lead to serum phosphate accumulation due to an inability to excrete serum phosphate which mostly originates from daily intestinal absorption&#46; Osteocytes then release fibroblast growth factor 23 &#40;FGF23&#41; in order to promote renal phosphate excretion&#46; Unfortunately&#44; FGF23 also impair renal 1&#46;25-dihydroxycalcitriol production which disturb intestinal calcium absorption&#44; resulting in hypocalcemia&#46; Parathyroid glands then release parathyroid hormone &#40;PTH&#41; as a compensatory mechanism to increase serum calcium through bone resorption&#46; Calcium and phosphate release from destructed bone will lead to cardiovascular calcification and bone disorders&#44; thus increasing morbidity and mortality in patients with CKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">2&#44;3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Dialysis&#44; phosphate binders&#44; and calcimimetic agents are available modalities for hyperphosphatemia management in CKD&#44; but they still have some disadvantages including flexibility limitation&#44; hypocalcemia risk&#44; as well as metal overload and cardiovascular calcification&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">4&#8211;6</span></a> Tenapanor is a novel modality option for hyperphosphatemia in CKD with its mechanism which inhibit sodium-hydrogen exchanger isoform 3 &#40;NHE3&#41; in gastrointestinal tract&#46; This new medication has also been indicated for irritable bowel syndrome with constipation &#40;IBS-C&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">7&#44;8</span></a> In this review&#44; we provide clinical evidences of the effectivity and safety profile of tenapanor in managing hyperphosphatemia in CKD through its NHE3 inhibition&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Method</span><p id="par0015" class="elsevierStylePara elsevierViewall">Literature searching was performed in Pubmed and Science Direct by using &#8220;tenapanor&#8221;&#44; &#8220;chronic kidney disease&#8221;&#44; and &#8220;hyperphosphatemia&#8221; as keywords&#46; The studies then systematically selected by using The Preferred Reporting Items for Systematic Reviews and Meta-Analyses &#40;PRISMA&#41; algorithm &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Duplicate literatures were removed&#46; Review articles&#44; books&#44; conferences abstracts&#44; editorials&#44; commentaries&#44; letter to editor&#44; and guidelines were excluded&#44; while research studies were retrieved&#46; Literature screening was performed by using Population&#44; Intervention&#44; Comparison&#44; and Outcome &#40;PICO&#41; criteria which are&#58; CKD patients requiring dialysis as population&#44; tenapanor or its combination with dialysis or phosphate binders as intervention&#44; placebo or other phosphate binders without tenapanor as comparison&#44; as well as serum phosphate and safety profile as the outcome&#46; Studies which meet the criteria then examined for risk of bias as quality assessment and qualitatively synthesized to establish this systematic review&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Result</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Risk of bias assessment in included studies</span><p id="par0020" class="elsevierStylePara elsevierViewall">Our included studies have a relatively similarities in risk of bias&#46; The participants and investigators were all blinded in all of our included studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;15</span></a> There are two studies with unclear risk of randomization sequence method as it was not mentioned in the studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#44;12</span></a> Five of included studies have unclear risk of concealment of randomization allocation&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#44;12&#8211;15</span></a> All of our included studies have a low risk of bias in completeness of reported outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;15</span></a> The general summary of the risk of bias in our included studies can be seen in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Characteristics of included studies</span><p id="par0025" class="elsevierStylePara elsevierViewall">A total of seven clinical studies were included in our review&#46; All the studies evaluated the decrease of serum phosphate as their primary outcome&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;15</span></a> Four studies use tenapanor or placebo alone as the intervention and comparison by implementing &#8220;washout system&#8221;&#44;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;12</span></a> while the three other studies still maintained the previous phosphate binders as a combination with tenapanor or placebo&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#8211;15</span></a> Six of seven studies also examined FGF23 levels as the other outcome&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#8211;13&#44;15&#44;16</span></a> The level of PTH was investigated in two studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">11&#44;15</span></a> All of our included studies evaluated the safety profile of tenapanor&#46; The summary of our included studies is described in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">The role of tenapanor as hyperphosphatemia treatment in chronic kidney disease</span><p id="par0030" class="elsevierStylePara elsevierViewall">Hyperphosphatemia is a frequent metabolic complication of CKD&#44; particularly in end stage disease&#46; This complication is a result of impaired renal function and limitation of conventional dialysis to eliminate serum phosphate originated from dietary phosphate absorption&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Tenapanor is a selective inhibitor of the sodium-hydrogen exchanger isoform 3 &#40;NHE3&#41;&#44; an antiporter located on the surface of the gastrointestinal tract&#39;s enterocytes&#46; By inhibiting the sodium-hydrogen exchange&#44; tenapanor causes the accumulation of intracellular protons and subsequently lowers the pH&#46; This decrease in pH alters the tight junction proteins&#44; resulting in a decrease in the permeability of phosphate paracellular diffusion and ultimately lowering the level of serum phosphate&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;11&#44;14</span></a> The mechanism of tenapanor in inhibiting phosphate absorption can be seen in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Effectivity of tenapanor in lowering serum phosphate in chronic kidney disease</span><p id="par0040" class="elsevierStylePara elsevierViewall">There are four studies which investigated the effect of tenapanor as a single therapy to serum phosphate in CKD patients&#46; All the patients underwent 1&#8211;3 weeks of washout period before started the treatment&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;12</span></a> The majority dose of tenapanor was 3&#44; 10&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg twice daily &#40;BID&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;12</span></a> though dosage of 3 and 30<span class="elsevierStyleHsp" style=""></span>mg once daily<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#44;12</span></a> as well as 1 and 5<span class="elsevierStyleHsp" style=""></span>mg BID was also found&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#8211;12</span></a> All these studies showed a higher decrease in serum phosphate with tenapanor as a single therapy compared to placebo&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;12</span></a> Significant serum phosphate decrement from baseline was reported with tenapanor dose of 3&#44; 5&#44; 10&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg BID in fixed dose as well as 30<span class="elsevierStyleHsp" style=""></span>mg BID with titration versus placebo in two studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;11</span></a> Tenapanor reduces serum phosphate levels in a dose-dependent manner in all four studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;12</span></a> In the other hand&#44; tenapanor as single therapy also resulted in higher proportion of patients achieving serum phosphate target of &#60;5&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL compared to placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Serum phosphate before the administration of tenapanor and placebo in studies which examined tenapanor effectivity as monotherapy ranged from 7&#46;32 to 8&#46;1<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;12</span></a> The lowest serum phosphate reduction was found in tenapanor 1<span class="elsevierStyleHsp" style=""></span>mg BID that ranged from &#8722;0&#46;47<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">12</span></a> to &#8722;1&#46;18<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> Administration of tenapanor 3<span class="elsevierStyleHsp" style=""></span>mg BID resulted in serum phosphate change of &#8722;1&#46;93<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> to &#8722;2&#46;48<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">9</span></a> while tenapanor 3<span class="elsevierStyleHsp" style=""></span>mg once daily only decreased serum phosphate up to &#8722;1&#46;28<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> Tenapanor dosage of 5<span class="elsevierStyleHsp" style=""></span>mg BID was only found in one study which only showed serum phosphate reduction of &#8722;0&#46;9<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a> Tenapanor dosage of 30<span class="elsevierStyleHsp" style=""></span>mg once daily resulted in serum phosphate decline of &#8722;1&#46;85<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> Serum phosphate reduction in tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID is similar between the non-dose-titration group and those with dose-titration&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#44;11</span></a> In tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID without dose titration&#44; the serum phosphate reduction ranged from &#8722;1&#46;97<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a> to &#8722;2&#46;67<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">9</span></a> while in tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID with dose titration&#44; the serum phosphate decline ranged from &#8722;2&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a> to &#8722;2&#46;61<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">9</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Efficacy of tenapanor as a combination therapy with other phosphate binders was observed in three studies&#46; All the subjects in the studies maintained their pre-existing phosphate binders which then added with tenapanor or placebo&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#8211;15</span></a> The serum phosphate in three studies that used a combination of tenapanor and other phosphate binders as a treatment regimen before the intervention ranged from 6&#46;7 to 7&#46;01<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#8211;15</span></a> The dose of tenapanor used in these studies are not as variable as in studies that used tenapanor as monotherapy&#46; Two of three studies use tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID as the treatment&#44;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a> while one study use tenapanor 5<span class="elsevierStyleHsp" style=""></span>mg BID&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">15</span></a> In all three studies&#44; the combination of tenapanor with phosphate binders revealed a greater reduction of serum phosphate compared to the combination of placebo with phosphate binders&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#8211;15</span></a> Statistical significance was found in two of three studies with tenapanor dose of both 5<span class="elsevierStyleHsp" style=""></span>mg BID and 30<span class="elsevierStyleHsp" style=""></span>mg BID&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#44;15</span></a> In two studies of tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID as combination with other phosphate binders&#44; the mean change of serum phosphate declined were &#8722;0&#46;84<span class="elsevierStyleHsp" style=""></span>mg&#47;dL<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a> and &#8722;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a> while in study of tenapanor 5<span class="elsevierStyleHsp" style=""></span>mg BID combined with other phosphate binders&#44; the mean change of serum phosphate were up to &#8722;2&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">15</span></a> A higher rate of target achievement for serum phosphate was also found in tenapanor group compared to placebo in all three studies<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#8211;15</span></a>&#44; in which two of three studies set the serum phosphate target to &#60;5&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#44;14</span></a> while serum phosphate goal ranged from 3&#46;5 to 6&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in one other study&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">15</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Besides observing direct effect of tenapanor to serum phosphate&#44; three of four studies which used tenapanor as monotherapy also evaluated the impact of tenapanor to serum phosphate in certain duration after the last administration of tenapanor&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;11</span></a> In a randomized withdrawal period in a study by Block et al&#46; in 2019&#44; participants that had previously been treated with tenapanor then continued with placebo for 4 weeks experienced an increase in serum phosphate with mean change of &#43;0&#46;07<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">9</span></a> In the follow-up visit 1&#8211;2 weeks after the last intervention in the study by Block et al&#46; in 2017&#44; the serum phosphate was still maintained between 3 and 6<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in all intervention groups&#44; including tenapanor with various dosages&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> A study by Inaba et al&#46; revealed that serum phosphate levels returned to near baseline levels 3 weeks after the last administration of both the full dosage of tenapanor and placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Pleiotropic effect of tenapanor in interfering fibroblast growth factor 23 and parathyroid hormone in chronic kidney disease</span><p id="par0060" class="elsevierStylePara elsevierViewall">Besides reducing serum phosphate&#44; tenapanor was also found to have a beneficial effect on FGF23 and PTH levels&#46; A total of six studies showed FGF23 declined with tenapanor&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#8211;13&#44;15&#44;16</span></a> Significant decrease in FGF23 was observed in tenapanor as single therapy at dose of 1&#44; 3&#44; 10&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg BID as well as 3 and 30<span class="elsevierStyleHsp" style=""></span>mg once daily&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;10&#44;12</span></a> Tenapanor as a combination therapy with other phosphate binders also showed its ability to reduce FGF23 levels at doses of both 5<span class="elsevierStyleHsp" style=""></span>mg and 30<span class="elsevierStyleHsp" style=""></span>mg BID&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#44;15</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Tenapanor was also found to suppress PTH levels other than serum phosphate and FGF23 in two studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">11&#44;15</span></a> As monotherapy&#44; tenapanor at dose of 5&#44; 10&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg BID was able to reduce PTH levels though the significance was not reported&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a> In a setting as combination therapy with other phosphate binders&#44; tenapanor 5<span class="elsevierStyleHsp" style=""></span>mg BID was reported to significantly suppress PTH&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">15</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Safety profile of tenapanor in chronic kidney disease population</span><p id="par0070" class="elsevierStylePara elsevierViewall">Safety profile of tenapanor was evaluated in all of our included studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;15</span></a> Gastrointestinal symptoms especially diarrhea was the most frequent adverse effect &#40;AE&#41; in all the studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;15</span></a> The intensity of diarrhea was dominantly mild to moderate in severity with transient onset in majority of studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#8211;15</span></a> In the setting of tenapanor as single therapy&#44; the diarrhea tended to be dose-dependent&#44; as the incidence of diarrhea was higher in tenapanor dose of 10<span class="elsevierStyleHsp" style=""></span>mg and 30<span class="elsevierStyleHsp" style=""></span>mg BID as well as 30<span class="elsevierStyleHsp" style=""></span>mg once daily&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;12</span></a> The same trend was also found in the setting of tenapanor as combination therapy with phosphate binders&#44; in which higher incidence of diarrhea was reported in studies with higher dose of tenapanor&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#8211;15</span></a> Severe diarrhea was reported in one study&#44; which is predominantly in tenapanor dose of 30<span class="elsevierStyleHsp" style=""></span>mg once and twice daily&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">17</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The safety profile of tenapanor was also evaluated with physical examination&#44; laboratory&#44; and electrocardiography &#40;ECG&#41; parameters&#46; In our included studies&#44; tenapanor therapy didn&#8217;t lead to any significant change in physical examination&#44; laboratory&#44; and ECG parameters&#46; There was also no death related to tenapanor&#46; From these findings&#44; tenapanor was relatively safe and well tolerated in CKD patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;11&#44;13&#44;14</span></a></p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discussion</span><p id="par0080" class="elsevierStylePara elsevierViewall">Phosphate retention is frequently found in CKD stage 4 and 5&#44; which is a factor that initiate many other disturbances such as increased FGF23 and PTH&#44; hypocalcemia&#44; and low vitamin D&#44; which in turn will lead to an enhancement in cardiovascular and all causes of morbidity and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">18</span></a> Phosphate balance is maintained by several mechanism including intestinal phosphate absorption&#44; bone turnover regulation&#44; as well as renal excretion and reabsorption&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">4&#44;19</span></a> In a normal condition&#44; the kidney excretes approximately ninety percent of phosphate per day&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">20</span></a> As renal phosphate clearance declined in CKD&#44; inhibiting intestinal phosphate absorption can be a promising approach in managing hyperphosphatemia in patients with CKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">4&#44;20</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Generally&#44; phosphate binders only result in maximum 2&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dL of phosphate reduction in their maximal doses&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">9</span></a> Some of our included studies show that 30<span class="elsevierStyleHsp" style=""></span>mg of tenapanor whether as fixed or titrated dose single therapy was able to reduce serum phosphate up to more than 2&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;10</span></a> This finding can be possible due to tenapanor mechanism which suppress intestinal phosphate absorption through NHE3 inhibition&#44;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;11&#44;14</span></a> as about 90&#37; of phosphate input comes from intestinal absoption&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">20</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Tenapanor works by inhibiting NHE3 which then interferes with sodium and phosphate absorption in the intestinal lumen&#46; By using this mechanism&#44; tenapanor has a promising potency to effectively treat hyperphosphatemia in CKD due to its dominant role in gastrointestinal tract&#44; as around 90&#37; of phosphate are originated from intestinal absorption&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;11</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Our included studies which used tenapanor as monotherapy commonly revealed a dose-dependent phosphate lowering effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;12</span></a> Tenapanor 1<span class="elsevierStyleHsp" style=""></span>mg BID showed serum phosphate declined up to &#8722;1&#46;18<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#44;12</span></a> Administration frequency also influence the effectivity of tenapanor 3<span class="elsevierStyleHsp" style=""></span>mg&#44; which reduce serum phosphate around &#8722;1&#46;28<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in once daily dose<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> and up to &#8722;2&#46;48<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in BID dose&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;10</span></a> Tenapanor 10<span class="elsevierStyleHsp" style=""></span>mg BID was shown to reduced serum phosphate up to &#8722;2&#46;52<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in several studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;12</span></a> Tenapanor with dose of 30<span class="elsevierStyleHsp" style=""></span>mg also showed the same frequency-dependent manner in lowering serum phosphate&#44; where twice daily dose resulted in up to &#8722;2&#46;67<span class="elsevierStyleHsp" style=""></span>mg&#47;dL serum phosphate reduction&#44; while in once daily dose&#44; the serum phosphate only decreased up to &#8722;1&#46;85<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> In the other hand&#44; 30<span class="elsevierStyleHsp" style=""></span>mg BID tenapanor with dose titration exhibited an unsignificant difference in phosphate reduction effect compared to non-dose-titration administration of tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;10</span></a> This finding suggest the possible strategy to achieve the highest serum phosphate reduction target by using tenapanor with optimum dose while minimizing the side effects by using dose-titration strategy&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;10</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Unlike the studies that used tenapanor as monotherapy&#44; the phosphate reduction trend is inconsistent with the dose in studies that used tenapanor in combination with other phosphate binders&#46; Tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID in combination with the patient&#39;s pre-existing phosphate binders resulted in &#8722;0&#46;84<span class="elsevierStyleHsp" style=""></span>mg&#47;dL phosphate reduction in a study by Pergola et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a> and &#8722;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL reduction in a study by Shigematsu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a> Meanwhile&#44; in the study by Nitta et al&#46;&#44; tenapanor 5<span class="elsevierStyleHsp" style=""></span>mg BID in combination with patient&#39;s pre-existing phosphate binder reduced the serum phosphate up to &#8722;2&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">15</span></a> which was even higher than tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID in studies by Pergola et al&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a> and Shigematsu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a> This different trend can be possibly caused by the effect of other phosphate binders which could probably have any undiscovered interactions with tenapanor&#46; Further studies which analyze the possible drug-drug interaction between tenapanor and other phosphate binders is needed to explore the exact possible results of combination therapy between tenapanor and other phosphate binders as hyperphosphatemia therapy for patients with CKD&#46; However&#44; until the time of this review is conducted&#44; studies show that tenapanor as monotherapy has a better phosphate reduction effect compared to tenapanor as a combination therapy with other phosphate binders&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;15</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Serum phosphate after the termination of tenapanor is also one of the concerns&#46; In randomized withdrawal period in the study by Block et al&#46; in 2019&#44; patients receiving placebo for 4 weeks after the last dose of tenapanor experienced increasing serum phosphate of only &#43;0&#46;79<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">9</span></a> In the study by Block et al&#46; in 2017&#44; the follow-up visit at 1&#8211;2 weeks after the last dosage of tenapanor showed that the serum phosphate of all groups were between 3 and 6<span class="elsevierStyleHsp" style=""></span>mg&#47;dL which still didn&#8217;t reach the baseline serum phosphate before the beginning of intervention&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">10</span></a> In addition&#44; a study by Inaba et al&#46; revealed that serum phosphate levels were increased near baseline levels in follow-up visit after 3 weeks from the last dosage of tenapanor&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a> These findings suggest that serum phosphate maintenance after the last dosage of tenapanor can be variable&#44; which could be possibly influenced by several factors such as the baseline serum phosphate which varies in these studies&#44; duration since the last dosage of tenapanor which only 1&#8211;2 weeks in certain studies and up to 4 weeks in the other study&#44; also the dosage and frequency of tenapanor administration&#44; which implies the need for further studies to examine serum phosphate maintenance in more detailed period after the last dosage of tenapanor&#46; However&#44; from these studies&#44; it can be concluded that serum phosphate can still be maintained at levels below the baseline&#44; even until 3&#8211;4 weeks after the last dosage of tenapanor&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;11</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In addition to its phosphate lowering effect&#44; tenapanor was also found to have a pleiotropic effect in suppressing the levels of FGF23 and PTH&#44; both as monotherapy and combination therapy with phosphate binders&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#8211;13&#44;15&#44;16</span></a> The exact mechanism of this finding remains unclear&#44; but it can be possibly explained by the role of these two hormones as compensatory mechanism to elevated serum phosphate&#44; thus greater reduction of serum phosphate will suppress FGF23 and PTH production&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;11&#44;12&#44;15</span></a> This pleiotropic effect of tenapanor can be utilized to minimize the morbidity and mortality in CKD&#44; as high FGF23 and PTH will cause extraosseous calcium and phosphate deposition&#44; particularly in the heart valves and vascular&#46; This condition then develop to valve and vascular atherosclerosis through osteochondrogenic differentiation and elastin degradation&#44; leading to increased mortality due to cardiovascular disease&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a> Besides that&#44; increased PTH which enhance calcium efflux from bones is the cause of bone mass loss in patients with CKD&#44; resulting in increased morbidity&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">22</span></a> Therefore&#44; the pleiotropic effect of tenapanor in lowering FGF23 and PTH suggesting its potency as future treatment for bone mineral disease and secondary hyperparathyroidism in CKD&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Diarrhea is the most common AE caused by tenapanor&#46; However&#44; majority of reported diarrhea was transient and mild to moderate in intensity&#46;<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">13&#8211;15</span></a> This side effect appears as the effect of tenapanor mechanism which selectively inhibit the NHE3 in enterocytes&#44; thus suppress the passive transport of phosphate in the intestine&#46; Simultaneously&#44; NHE3 inhibition also suppress intestinal sodium absorption which enhance sodium and water secretion in the intestinal tract&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#44;11</span></a> Elevated sodium&#44; phosphate&#44; and water content in the intestine then lead to loose stool and increased bowel movement which manifested as diarrhea&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;15</span></a> The incidence of diarrhea due to tenapanor has a higher trend in higher doses&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;15</span></a> Diarrhea side effect of tenapanor is no longer surprising&#44; as tenapanor has also been indicated to treat IBS-C by its mechanism to increase water content in the intestinal lumen and stools&#46; Utilization of tenapanor in IBS-C has been considered as safe and has been recommended by the American Gastroenterological Association &#40;AGA&#41; guideline&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">7&#44;8&#44;23</span></a> Dose titration can be a good solution for this problem to increase patient&#39;s compliance&#44; as titrated dose of tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID exhibited a lower incidence of diarrhea while maintaining the same efficacy in reducing serum phosphate and FGF23 compared to fixed dose of tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">11</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Minerals deposition and metabolic disturbances are the other concerns in treatment options for hyperphosphatemia in CKD&#46; Available phosphate binders still has systemic mineral and metabolic disadvantages&#44; such as calcium accumulation and increased calcification in calcium based phosphate binders&#44; potential nervous system toxicity in aluminum based phosphate binders&#44; iron overload in iron based phosphate binders&#44; fat-soluble vitamins deficiency and acidosis risk in sevelamer based phosphate binders&#44; as well as possible lanthanum deposits in lanthanum based phosphate binders&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">4&#8211;6</span></a> Tenapanor comes as a solution to counteract these limitations&#44; as tenapanor didn&#8217;t cause any meaningful changes in serum calcium&#44; laboratory parameters&#44; ECG&#44; and physical examination&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#8211;11&#44;13&#44;14</span></a> The plausible explanation for this finding is the nature of tenapanor as a calcium free non-metal phosphate reducer&#44; thus it doesn&#8217;t cause calcium and metal accumulation&#46; In addition&#44; tenapanor is also a minimally absorbed molecule&#44; resulting in minimum systemic side-effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">9&#44;10</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclusion</span><p id="par0125" class="elsevierStylePara elsevierViewall">In conclusion&#44; tenapanor&#44; as a single therapy or in combination with phosphate binders&#44; was effective in managing hyperphosphatemia in CKD&#46; It also has pleiotropic effects in interfering high FGF23 and PTH thus exhibit a promising potency to treat secondary hyperparathyroidism in CKD&#46; Diarrhea is the most common AE but it&#39;s only transient&#44; dose-related&#44; and mild to moderate in severity&#46; Starting tenapanor with a low dose can be a solution for diarrhea side effect&#46; Tenapanor doesn&#8217;t cause any meaningful change in ECG&#44; serum calcium&#44; and other laboratory and clinical parameters&#46; Generally&#44; tenapanor is safe and well-tolerated in CKD patients&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Funding</span><p id="par0130" class="elsevierStylePara elsevierViewall">This research did not receive any specific grant from funding agencies in the public&#44; commercial&#44; or not-for-profit sectors&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Conflict of interest</span><p id="par0135" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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              "titulo" => "The role of tenapanor as hyperphosphatemia treatment in chronic kidney disease"
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              "titulo" => "Effectivity of tenapanor in lowering serum phosphate in chronic kidney disease"
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              "titulo" => "Pleiotropic effect of tenapanor in interfering fibroblast growth factor 23 and parathyroid hormone in chronic kidney disease"
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              "titulo" => "Safety profile of tenapanor in chronic kidney disease population"
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            2 => "Tenapanor"
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            0 => "Enfermedad renal cr&#243;nica"
            1 => "Hiperfosfatemia"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chronic kidney disease &#40;CKD&#41; is a major global health problem&#46; Hyperphosphatemia is frequent in CKD and a reason for increased morbidity and mortality as it generates hyperparathyroidism&#44; high fibroblast growth factor 23 &#40;FGF23&#41;&#44; and hypocalcemia&#46; Available hyperphosphatemia therapies still have limitations&#44; including risk of metal overload&#44; cardiovascular calcification&#44; and systemic adverse effects &#40;AEs&#41;&#46; Tenapanor is a new hyperphosphatemia treatment in CKD with sodium-hydrogen exchanger isoform 3 &#40;NHE3&#41; inhibition mechanism and low systemic AEs&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objectives</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Discovering the effectivity and safety of tenapanor as hyperphosphatemia management in CKD&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Method</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Literature searching is performed by using &#8220;pubmed&#8221; and &#8220;science direct&#8221; with &#8220;tenapanor&#8221;&#44; &#8220;chronic kidney disease&#8221;&#44; and &#8220;hyperphosphatemia&#8221; as keywords&#46; The literatures were selected using PRISMA algorithm version 2020&#46; Literature was screened based on Population&#44; Intervention&#44; Comparison&#44; and Outcome &#40;PICO&#41; criteria which are&#58; CKD patients requiring dialysis as population&#44; tenapanor or its combination with dialysis or phosphate binders as intervention&#44; placebo or other phosphate binders without tenapanor as comparison&#44; and serum phosphate&#44; safety profile&#44; and other pleiotropic benefits related to hyperphosphatemia management as the outcome&#46; The included studies then assessed for risk of bias and qualitatively reviewed&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Outcome</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Tenapanor was able to reduce serum phosphate&#44; generally in a dose-dependent manner&#46; Tenapanor also suppressed FGF23 and parathyroid hormone&#44; probably due to decreased serum phosphate&#46; The frequent AEs were transient mild-to-moderate diarrhea in a dose-dependent manner&#46; Tenapanor was generally well-tolerated with low systemic AEs due to its non-calcium&#44; metal-free&#44; and low-absorbed properties&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusion</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Tenapanor is an effective and safe option for hyperphosphatemia management in CKD&#46;</p></span>"
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        "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La enfermedad renal cr&#243;nica &#40;ERC&#41; es un importante problema de salud mundial&#46; La hiperfosfatemia es frecuente en la ERC y motivo de aumento de la morbimortalidad ya que genera hiperparatiroidismo&#44; <span class="elsevierStyleItalic">fibroblast growth factor-23</span> &#40;FGF-23&#41;&#44; elevado e hipocalcemia&#46; Las terapias disponibles para la hiperfosfatemia a&#250;n tienen limitaciones&#44; incluido el riesgo de sobrecarga de metales&#44; calcificaci&#243;n cardiovascular y efectos adversos &#40;EA&#41; sist&#233;micos&#46; Tenapanor es un nuevo tratamiento de la hiperfosfatemia en la ERC con mecanismo de inhibici&#243;n de la isoforma 3 del intercambiador de sodio-hidr&#243;geno &#40;NHE3&#41; y EA sist&#233;micos bajos&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Descubrir la efectividad y la seguridad del tenapanor como manejo de la hiperfosfatemia en la ERC&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">M&#233;todo</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La b&#250;squeda bibliogr&#225;fica se realiza utilizando &#171;Pubmed&#187; y &#171;Science direct&#187; con &#171;tenapanor&#187;&#44; &#171;chronic kidney disease&#187; e &#171;hyperphosphatemia&#187; como palabras clave&#46; La selecci&#243;n de la literatura se realiz&#243; mediante el algoritmo PRISMA versi&#243;n 2020&#46; La bibliograf&#237;a se examin&#243; con base en los criterios de Poblaci&#243;n&#44; Intervenci&#243;n&#44; Comparaci&#243;n y Resultado &#40;PICO&#44; por sus siglas en ingl&#233;s&#41;&#44; que son&#58; pacientes con ERC que requieren di&#225;lisis como poblaci&#243;n&#44; tenapanor o su combinaci&#243;n con di&#225;lisis o quelantes de fosfato como intervenci&#243;n&#44; placebo u otros quelantes de fosfato sin tenapanor como comparaci&#243;n&#44; y fosfato s&#233;rico&#44; perfil de seguridad y otros beneficios pleiotr&#243;picos relacionados con el manejo de la hiperfosfatemia como resultado&#46; A continuaci&#243;n&#44; los estudios incluidos evaluaron el riesgo de sesgo y se revisaron cualitativamente&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultado</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Tenapanor fue capaz de reducir el fosfato s&#233;rico&#44; generalmente de una manera dosis&#47;dependiente&#46; Tenapanor tambi&#233;n suprimi&#243; FGF-23 y la hormona paratiroidea&#44; probablemente debido a la disminuci&#243;n del fosfato s&#233;rico&#46; Los EA frecuentes fueron diarrea transitoria leve a moderada de manera dosis&#47;dependiente&#46; En general&#44; el tenapanor fue bien tolerado con EA sist&#233;micos bajos debido a sus propiedades no c&#225;lcicas&#44; libres de metales y de baja absorci&#243;n&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusi&#243;n</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Tenapanor es una opci&#243;n eficaz y segura para el manejo de la hiperfosfatemia en la ERC&#46;</p></span>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Authors&#44; years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention &#40;I&#41; and comparison &#40;C&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pergola et al&#46;&#44; 2021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter&#44; double blind&#44; randomized placebo-controlled trial &#40;RCT&#41;&#44; phase 3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>235&#46;CKD patients receiving regular hemodialysis &#40;HD&#41; with hyperphosphatemia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&#58; Oral tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg twice daily &#40;BID&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pre-existing phosphate binder&#46;C&#58; Oral placebo BID<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pre-existing binder&#46;There was no follow-up visit in this study&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Significantly larger change in serum phosphorus from baseline &#40;baseline phosphate levels&#58; 6&#46;7<span class="elsevierStyleHsp" style=""></span>mg&#47;dL for tenapanor<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder group and 6&#46;9<span class="elsevierStyleHsp" style=""></span>mg&#47;dL for placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder group&#41; to week 4 in tenapanor<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder group &#40;mean change from baseline&#58; &#8722;0&#46;84<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; compared to placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder &#40;mean change from baseline&#58; &#8722;0&#46;19<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#46;Significantly larger proportion of patients achieved serum phosphorus<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>5&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl in tenapanor<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder group compared to placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46;Significant FGF23 reductions in tenapanor<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#41;&#46;Transient mild to moderate diarrhea was the most common adverse effect &#40;AE&#41; with tenapanor<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder&#44; resolved with dose adjustment&#46;No clinical meaningful change in laboratory&#44; electrocardiogram &#40;ECG&#41;&#44; and physical examination&#46;No serious AE and death were related to treatment&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Block et al&#46;&#44; 2019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Double blind&#44; RCT&#44; phase 3&#46;Consists of randomized treatment period &#40;RTP&#41; and randomized withdrawal period &#40;RWP&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>164 in RTP&#44; 152 in RWP&#46;Patients with end stage kidney disease &#40;ESKD&#41; receiving maintenance HD&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RTP &#40;8 weeks&#41;&#58;I&#58; tenapanor regimens&#8212;3 or 10<span class="elsevierStyleHsp" style=""></span>mg fixed dose BID&#44; or 30<span class="elsevierStyleHsp" style=""></span>mg BID which could be titrated&#46;C&#58; -RWP &#40;4 weeks&#41;&#58;I&#58; previously assigned dose of tenapanorC&#58; placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RTP&#58; significant decreased serum phosphate &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; in all three tenapanor groups &#40;mean change &#8722;2&#46;48<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; &#8722;2&#46;52<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; and &#8722;2&#46;61<span class="elsevierStyleHsp" style=""></span>mg&#47;dL for tenapanor 3<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 10<span class="elsevierStyleHsp" style=""></span>mg BID&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg BID titration&#44; respectively&#41; from baseline &#40;7&#46;40<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;57<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; 7&#46;46<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;69<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; and 7&#46;62<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;43<span class="elsevierStyleHsp" style=""></span>mg&#47;dL for tenapanor 3<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 10<span class="elsevierStyleHsp" style=""></span>mg BID&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg BID titration&#44; respectively&#41;&#46;Reduction of FGF23 in all three tenapanor groups&#44; significant reduction observed in the 3 and 30<span class="elsevierStyleHsp" style=""></span>mg BID&#46;RWP&#58; significant change in serum phosphate between pooled tenapanor group &#40;mean change &#43;0&#46;56<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; compared to placebo &#40;mean change &#43;1&#46;38<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;003&#46;Diarrhea was the most common AE&#46; There was no treatment discontinuation in RWP&#46;There was no clinically meaningful change in laboratory&#44; ECG&#44; and physical examination&#46;There was no death related to treatment&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Block et al&#46;&#44; 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter&#44; double blind&#44; RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>162Patients with ESKD receiving maintenance HD with hyperphosphatemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&#58; one of six tenapanor regimens &#40;3 or 30<span class="elsevierStyleHsp" style=""></span>mg once daily or 1&#44; 3&#44; 10&#44; or 30<span class="elsevierStyleHsp" style=""></span>mg BID&#41; C&#58; placebo&#46;Follow-up period after last dosage&#58; 1&#8211;2 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baseline phosphate levels were 7&#46;32&#8211;7&#46;92<span class="elsevierStyleHsp" style=""></span>mg&#47;dl in tenapanor groups and 7&#46;87<span class="elsevierStyleHsp" style=""></span>mg&#47;dl in placebo group&#46; Tenapanor resulted in dose-dependent reduced serum phosphate from baseline compared to placebo &#40;mean change from baseline in the end of treatment were &#8722;1&#46;21&#44; &#8722;1&#46;18&#44; &#8722;1&#46;28&#44; &#8722;1&#46;93&#44; &#8722;2&#46;41&#44; &#8722;1&#46;85&#44; and &#8722;2&#46;67<span class="elsevierStyleHsp" style=""></span>mg&#47;dL for placebo&#44; tenapanor 1<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 3<span class="elsevierStyleHsp" style=""></span>mg once daily&#44; 3<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 10<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 30<span class="elsevierStyleHsp" style=""></span>mg once daily&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg BID&#44; respectively&#41;&#46;Largest reductions were found in the tenapanor 10 and 30<span class="elsevierStyleHsp" style=""></span>mg BID compared to placebo &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;At 1&#8211;2 weeks follow-up visit&#44; serum phosphate were still maintained between 3 and 6<span class="elsevierStyleHsp" style=""></span>mg&#47;dL for all groups&#46;Proportion of patients reached serum phosphate<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>5&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in tenapanor was up to 43&#37;&#44; while in placebo only 8&#37;&#46;Significant FGF23 reduction in all tenapanor groups compared to placebo &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;The most frequent AE was GI symptoms &#40;diarrhea&#41;&#44; mostly mild to moderate&#46; Severe diarrhea predominantly found in tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg once or twice daily&#46;No serious AE was related to the treatment&#46;No clinically relevant changes in serum calcium&#44; potassium&#44; or sodium&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Shigematsu et al&#46;&#44; 2021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter&#44; double blind&#44; RCT&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>47CKD patients receiving HD with hyperphosphatemia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&#58; Tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg BID<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pre-existing phosphate binders&#46;C&#58; Placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pre-existing phosphate binders&#46;There was no follow-up visit in this study&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mean baseline serum phosphate were 7&#46;01<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and 6&#46;77<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in placebo and tenapanor 30<span class="elsevierStyleHsp" style=""></span>mg titration&#44; respectively&#46; Larger serum phosphate decrement in tenapanor &#40;mean change &#8722;1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41; compared to placebo group &#40;mean change &#8722;0&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#46;Target achievement of phosphorus<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>5&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dL was 73&#46;9&#37; with tenapanor<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder and 25&#37; in placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>binder&#46;Dominant AE was GI symptoms especially transient non-severe diarrhea&#46;There were no significant changes in laboratory&#44; vital signs&#44; or ECG&#46;There was no serious AE and death related to treatment&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inaba et al&#46;&#44; 2021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter&#44; double blind&#44; RCT&#44; phase 2&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>207CKD patients receiving HD with hyperphosphatemia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&#58; Tenapanor 5-mg BID&#44; 10-mg BID&#44; 30-mg BID&#44; and 30-mg BID with dose titration&#46;Dose adjustment was only for dose-titration group&#46;C&#58; placeboSecond withdrawal period after last dosage&#58; 3 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baseline serum phosphate were 7&#46;6<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; 8&#46;1<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; 7&#46;7<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; and 7&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;dl for placebo&#44; tenapanor 5<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 10<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 30<span class="elsevierStyleHsp" style=""></span>mg BID&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg dose titration respectively&#46;Significantly reduced serum phosphate in each tenapanor dosage groups compared to placebo &#40;mean change&#58; &#8722;0&#46;9<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; &#8722;1&#46;4<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; &#8722;1&#46;9<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; &#8722;2&#46;0<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#44; and &#43;0&#46;6<span class="elsevierStyleHsp" style=""></span>mg&#47;dL for tenapanor 5<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 10<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 30<span class="elsevierStyleHsp" style=""></span>mg BID&#44; 30<span class="elsevierStyleHsp" style=""></span>mg BID with dose titration&#44; and placebo respectively&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#46;Serum phosphate were back near baseline levels after the end of the treatment period for all intervention groups in the study&#46;No significant changes in serum Ca in any group&#46;Intact PTH and FGF23 decreased in tenapanor groups&#46;Mild to moderate diarrhea was the most frequent AE and it was dose-related&#44; mostly in 30<span class="elsevierStyleHsp" style=""></span>mg BID group&#46; There was no severe diarrhea in tenapanor groups&#46;No clinically relevant alterations in vital signs&#44; laboratory&#44; or electrocardiogram&#46;There were no deaths during the study&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Block et al&#46;&#44; 2019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Multicenter&#44; double blind&#44; RCT&#44; phase 2B&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>162Patients with ESKD receiving HD with hyperphosphatemia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&#58; One of six tenapanor regimens &#40;3 or 30<span class="elsevierStyleHsp" style=""></span>mg once daily&#44; or 1&#44; 3&#44; 10 or 30<span class="elsevierStyleHsp" style=""></span>mg BID&#41;&#46;C&#58; placebo&#46;There was no follow-up visit in this study&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Serum phosphate after wash-out period were 7&#46;32&#8211;7&#46;92<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in tenapanor group and 7&#46;87<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in placebo group&#46;Tenapanor decrease serum phosphate in dose-dependent manner compared to placebo &#40;least-squares mean changes&#58; tenapanor-treated groups&#44; &#8722;0&#46;47 to &#8722;1&#46;98<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#59; placebo group&#44; &#8722;0&#46;54<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46;Highest serum phosphate reduction was in tenapanor 10 and 30<span class="elsevierStyleHsp" style=""></span>mg BID &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05 for each groups vs placebo&#41;&#46;FGF23 was significantly reduced in range of 2030&#8211;3563<span class="elsevierStyleHsp" style=""></span>pg&#47;mL in all tenapanor groups &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#8211;0&#46;04&#41;&#44; while FGF23 continued to increase in placebo group&#46;Tenapanor dose of at least 3<span class="elsevierStyleHsp" style=""></span>mg per day was needed to significantly reduce FGF23&#46;GI disorders &#40;diarrhea&#41; was the common AE&#44; particularly in high tenapanor groups of 10 BID&#44; 30<span class="elsevierStyleHsp" style=""></span>mg once daily&#44; and 30<span class="elsevierStyleHsp" style=""></span>mg BID&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nitta et al&#46;&#44; 2023&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Double blind&#44; RCT&#44; phase 3&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">N</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>169CKD patients receiving HD with hyperphosphatemia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">I&#58; Tenapanor 5<span class="elsevierStyleHsp" style=""></span>mg BID<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pre-existing phosphate binders&#46;C&#58; Placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>pre-existing phosphate binders&#46;There was no follow-up visit in this study&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Baseline serum phosphate were 6&#46;92<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;068<span class="elsevierStyleHsp" style=""></span>mg&#47;dL and 6&#46;76<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;075<span class="elsevierStyleHsp" style=""></span>mg&#47;dL in placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>other phosphate binders and in tenapanor<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>other phosphate binders groups&#46;Significantly reduced serum phosphate from baseline in tenapanor<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>other phosphate binders group compared to placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>other phosphate binders group &#40;mean change &#8722;2&#46;00<span class="elsevierStyleHsp" style=""></span>mg&#47;dL vs &#8722;0&#46;24<span class="elsevierStyleHsp" style=""></span>mg&#47;dL&#41;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#46;Higher proportion of serum phosphate target achievement in tenapanor compared to placebo&#46;Serum FGF and PTH were significantly decreased in the tenapanor group&#44; while increased in placebo group&#46;Diarrhea was the dominant AE&#44; all were mild to moderate&#46; There was no treatment discontinuation due to diarrhea&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Table of included studies&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:23 [
            0 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Global&#44; regional&#44; and national burden of chronic kidney disease&#44; 1990&#8211;2017&#58; a systematic analysis for the Global Burden of Disease Study 2017"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46; Bikbov"
                            1 => "C&#46;A&#46; Purcell"
                            2 => "A&#46;S&#46; Levey"
                            3 => "M&#46; Smith"
                            4 => "A&#46; Abdoli"
                            5 => "M&#46; Abebe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/S0140-6736(20)30045-3"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet"
                        "fecha" => "2020"
                        "volumen" => "395"
                        "paginaInicial" => "709"
                        "paginaFinal" => "733"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32061315"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hyperphosphatemia and chronic kidney disease&#58; a major daily concern both in adults and in children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46; Bacchetta"
                            1 => "J&#46; Bernardor"
                            2 => "C&#46; Garnier"
                            3 => "C&#46; Naud"
                            4 => "B&#46; Ranchin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00223-020-00665-8"
                      "Revista" => array:2 [
                        "tituloSerie" => "Calcif Tissue Int"
                        "fecha" => "2020"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevention and treatment of hyperphosphatemia in chronic kidney disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;G&#46; Vervloet"
                            1 => "A&#46;J&#46; van Ballegooijen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.kint.2017.11.036"
                      "Revista" => array:5 [
                        "tituloSerie" => "Kidney Int"
                        "fecha" => "2018"
                        "volumen" => "93"
                        "paginaInicial" => "1060"
                        "paginaFinal" => "1072"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Management of hyperphosphatemia in end-stage renal disease&#58; a new paradigm"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46; Rastogi"
                            1 => "N&#46; Bhatt"
                            2 => "S&#46; Rossetti"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.jrn.2020.02.003"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Ren Nutr"
                        "fecha" => "2021"
                        "volumen" => "31"
                        "paginaInicial" => "21"
                        "paginaFinal" => "34"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32386937"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "State-of-the-art management of hyperphosphatemia in patients with CKD&#58; an NKF-KDOQI controversies perspective"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;J&#46; Scialla"
                            1 => "J&#46; Kendrick"
                            2 => "J&#46; Uribarri"
                            3 => "C&#46;P&#46; Kovesdy"
                            4 => "O&#46;M&#46; Guti&#233;rrez"
                            5 => "E&#46;Y&#46; Jimenez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/j.ajkd.2020.05.025"
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Kidney Dis"
                        "fecha" => "2021"
                        "volumen" => "77"
                        "paginaInicial" => "132"
                        "paginaFinal" => "141"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32771650"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Phosphate binders in patients with chronic kidney disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46; Chan"
                            1 => "K&#46; Au"
                            2 => "R&#46;S&#46; Francis"
                            3 => "D&#46;W&#46; Mudge"
                            4 => "D&#46;W&#46; Johnson"
                            5 => "P&#46;I&#46; Pillans"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.18773/austprescr.2017.002"
                      "Revista" => array:5 [
                        "tituloSerie" => "Aust Prescr"
                        "fecha" => "2017"
                        "volumen" => "40"
                        "paginaInicial" => "9"
                        "paginaFinal" => "14"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tenapanor for the treatment of irritable bowel syndrome with constipation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Sinagra"
                            1 => "F&#46; Rossi"
                            2 => "D&#46; Raimondo"
                            3 => "G&#46; Conoscenti"
                            4 => "A&#46; Anderloni"
                            5 => "V&#46; Guarnotta"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/17512433.2020.1762570"
                      "Revista" => array:6 [
                        "tituloSerie" => "Expert Rev Clin Pharmacol"
                        "fecha" => "2020"
                        "volumen" => "13"
                        "paginaInicial" => "473"
                        "paginaFinal" => "479"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32478632"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tenapanor in the treatment of irritable bowel syndrome with constipation&#58; discovery&#44; efficacy&#44; and role in management"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Herekar"
                            1 => "D&#46; Shimoga"
                            2 => "A&#46; Jehangir"
                            3 => "D&#46; Shahsavari"
                            4 => "Y&#46; Yan"
                            5 => "T&#46;B&#46; Karunaratne"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2147/CEG.S384251"
                      "Revista" => array:6 [
                        "tituloSerie" => "Clin Exp Gastroenterol"
                        "fecha" => "2023"
                        "volumen" => "16"
                        "paginaInicial" => "79"
                        "paginaFinal" => "85"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/37309470"
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                          ]
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                ]
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              "etiqueta" => "9"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Efficacy and safety of tenapanor in patients with hyperphosphatemia receiving maintenance hemodialysis&#58; a randomized phase 3 trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "G&#46;A&#46; Block"
                          ]
                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1681/ASN.2018080832"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Soc Nephrol"
                        "fecha" => "2019"
                        "volumen" => "30"
                        "paginaInicial" => "641"
                        "paginaFinal" => "652"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30846557"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "etiqueta" => "10"
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                    0 => array:2 [
                      "titulo" => "Effect of tenapanor on serum phosphate in patients receiving hemodialysis"
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                          "etal" => false
                          "autores" => array:1 [
                            0 => "G&#46;A&#46; Block"
                          ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1681/ASN.2016080855"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Soc Nephrol"
                        "fecha" => "2017"
                        "volumen" => "28"
                        "paginaInicial" => "1933"
                        "paginaFinal" => "1942"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28159782"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "11"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dose&#8211;response of tenapanor in patients with hyperphosphatemia undergoing hemodialysis in Japan &#8211; a phase 2 randomized trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "M&#46; Inaba"
                            1 => "Y&#46; Une"
                            2 => "K&#46; Ikejiri"
                            3 => "H&#46; Kanda"
                            4 => "M&#46; Fukagawa"
                            5 => "T&#46; Akizawa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ekir.2021.11.008"
                      "Revista" => array:6 [
                        "tituloSerie" => "Kidney Int Rep"
                        "fecha" => "2022"
                        "volumen" => "7"
                        "paginaInicial" => "177"
                        "paginaFinal" => "188"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/35155857"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "identificador" => "bib0175"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "G&#46;A&#46; Block"
                            1 => "D&#46;P&#46; Rosenbaum"
                            2 => "A&#46; Yan"
                            3 => "P&#46;J&#46; Greasley"
                            4 => "G&#46;M&#46; Chertow"
                            5 => "M&#46; Wolf"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1093/ndt/gfy061"
                      "Revista" => array:4 [
                        "tituloSerie" => "Nephrol Dial Transplant"
                        "fecha" => "2019"
                        "paginaInicial" => "339"
                        "paginaFinal" => "346"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A randomized trial of tenapanor and phosphate binders as a dual-mechanism treatment for hyperphosphatemia in patients on maintenance dialysis &#40;AMPLIFY&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
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                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1681/ASN.2020101398"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Am Soc Nephrol"
                        "fecha" => "2021"
                        "volumen" => "32"
                        "paginaInicial" => "1465"
                        "paginaFinal" => "1473"
                      ]
                    ]
                  ]
                ]
              ]
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              "etiqueta" => "14"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Therapeutic effects of add-on tenapanor for hemodialysis patients with refractory hyperphosphatemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "T&#46; Shigematsu"
                            1 => "Y&#46; Une"
                            2 => "K&#46; Ikejiri"
                            3 => "H&#46; Kanda"
                            4 => "M&#46; Fukagawa"
                            5 => "T&#46; Akizawa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000516156"
                      "Revista" => array:4 [
                        "tituloSerie" => "Am J Nephrol"
                        "fecha" => "2021"
                        "paginaInicial" => "496"
                        "paginaFinal" => "506"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Randomized study of tenapanor added"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Nitta"
                            1 => "S&#46; Itoyama"
                            2 => "K&#46; Ikejiri"
                            3 => "J&#46; Kinoshita"
                            4 => "K&#46; Nakanishi"
                            5 => "M&#46; Fukagawa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ekir.2023.08.003"
                      "Revista" => array:4 [
                        "tituloSerie" => "Kidney Int Rep"
                        "fecha" => "2021"
                        "paginaInicial" => "1"
                        "paginaFinal" => "11"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
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              "etiqueta" => "16"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "2018 ACC&#47;AHA&#47;HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay&#58; a report of the American College of Cardiology&#47;American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhyth"
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                        0 => array:2 [
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                          "autores" => array:6 [
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                            2 => "C&#46; Barrett"
                            3 => "J&#46;R&#46; Edgerton"
                            4 => "K&#46;A&#46; Ellenbogen"
                            5 => "M&#46;R&#46; Gold"
                          ]
                        ]
                      ]
                    ]
                  ]
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                    0 => array:2 [
                      "doi" => "10.1161/CIR.0000000000000628"
                      "Revista" => array:5 [
                        "tituloSerie" => "Circulation"
                        "fecha" => "2019"
                        "volumen" => "140"
                        "paginaInicial" => "382"
                        "paginaFinal" => "482"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0200"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effect of oral administration of a mixture of probiotic strains on SCORAD index and use of topical steroids in young patients with moderate atopic dermatitis a randomized clinical trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "V&#46; Navarro-Lopez"
                            1 => "A&#46; Ramirez-Bosca"
                            2 => "D&#46; Ramon-Vidal"
                            3 => "B&#46; Ruzafa-Costas"
                            4 => "S&#46; Genoves-Martinez"
                            5 => "E&#46; Chenoll-Cuadros"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1001/jamadermatol.2017.3647"
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                        "tituloSerie" => "JAMA Dermatol"
                        "fecha" => "2018"
                        "volumen" => "154"
                        "paginaInicial" => "37"
                        "paginaFinal" => "43"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/29117309"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Phosphate balance and CKD &#8211; mineral bone disease"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "S&#46;M&#46; Sprague"
                            1 => "K&#46;J&#46; Martin"
                            2 => "D&#46;W&#46; Coyne"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ekir.2021.05.012"
                      "Revista" => array:6 [
                        "tituloSerie" => "Kidney Int Rep"
                        "fecha" => "2021"
                        "volumen" => "6"
                        "paginaInicial" => "2049"
                        "paginaFinal" => "2058"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34386654"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The importance of phosphate control in chronic kidney disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46; Tsuchiya"
                            1 => "T&#46; Akihisa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/nu13051670"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nutrients"
                        "fecha" => "2021"
                        "volumen" => "13"
                        "paginaInicial" => "1"
                        "paginaFinal" => "22"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33374894"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
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              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hyperphosphatemia"
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                          "etal" => false
                          "autores" => array:2 [
                            0 => "R&#46; Goyal"
                            1 => "I&#46; Jialal"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:3 [
                        "tituloSerie" => "StatPearls NCBI Bookshelf"
                        "fecha" => "2023"
                        "paginaInicial" => "11"
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Vascular calcification in CKD-MBD&#58; roles for phosphate&#44; FGF23&#44; and klotho"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
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                        ]
                      ]
                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bone.2016.11.012"
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                        "tituloSerie" => "Bone"
                        "fecha" => "2017"
                        "volumen" => "100"
                        "paginaInicial" => "87"
                        "paginaFinal" => "93"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27847254"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
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              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Pathophysiology of calcium&#44; phosphorus&#44; and magnesium dysregulation in chronic kidney disease"
                      "autores" => array:1 [
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                          "etal" => false
                          "autores" => array:3 [
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                    ]
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                    0 => array:2 [
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                        "tituloSerie" => "Semin Dial"
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                        "paginaInicial" => "564"
                        "paginaFinal" => "577"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26303319"
                            "web" => "Medline"
                          ]
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                      ]
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                ]
              ]
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "AGAclinical practice guideline on the pharmacological management of irritable bowel syndrome with constipation"
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                          "autores" => array:6 [
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                            3 => "G&#46; Verne"
                            4 => "W&#46; Smalley"
                            5 => "J&#46; Heidelbaugh"
                          ]
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                      ]
                    ]
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                        "paginaInicial" => "118"
                        "paginaFinal" => "136"
                        "link" => array:1 [
                          0 => array:2 [
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Información del artículo

ISSN: 02116995
Idioma original: Inglés

DOI:10.1016/j.nefro.2024.06.007

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