Clinical Kidney Journal, 2021, vol. 14, no. 2, 681–687 doi: 10.1093/ckj/sfaa226 Advance Access Publication Date: 1 February 2021 Original Article Clinical Kidney Journal Downloaded from https://academic.oup.com/ckj/article/14/2/681/6125308 by Fundacio Biblioteca Josep Laporte user on 26 January 2023 ORIGINAL ARTICLE Real-world management of hyperphosphataemia with sucroferric oxyhydroxide: the VELREAL multicentre study Juan F. Navarro-González 1,2,3,4, Marı́a Dolores Arenas5, Fernando Henrı́quez-Palop6, Marı́a Jesús Lloret 7, Pablo Molina 8, Francisco Rı́os Moreno9, Marı́a Asunción Macia-Lagier10, Laura Espinel11, Emilio Sánchez12, Mar Lago13, Antonio Crespo14 and Jordi Bover3,7 1 Servicio de Nefrologı́a y Unidad de Investigación, Hospital Universitario Nuestra Sen ~ ora de Candelaria, Santa 2 Cruz de Tenerife, Spain, Instituto de Tecnologı́as Biomédicas, Universidad de La Laguna, Santa Cruz de Tenerife, Spain, 3Red de Investigación Renal (REDINREN – RD16/0009), Instituto de Salud Carlos III, Madrid, Spain, 4ERA-EDTA Working Group on CKD-MBD, Parma, Italy, 5Servicio de Nefrologı́a, Hospital del Mar, Barcelona, Spain, 6Centro de Diálisis Avericum Norte, Las Palmas de Gran Canaria, Spain, 7Servicio de Nefrologı́a, Fundació Puigvert, Barcelona, Spain, 8Servicio de Nefrologı́a, Hospital Universitario Dr. Peset, Valencia, Spain, 9Centro Diálisis San Luciano, Madrid, Spain, 10Servicio de Nefrologı́a, Hospital General de La Palma, Santa Cruz de La Palma, Spain, 11Servicio de Nefrologı́a, Hospital Universitario de Getafe, Madrid, Spain, 12Servicio de Nefrologı́a, Hospital Universitario de Cabuen~ es, Gijón, Spain, 13Servicio de Nefrologı́a, Complejo Hospitalario Universitario Insular, Las Palmas de Gran Canaria, Spain and 14Servicio de Nefrologı́a, Hospital Marina Baixa, Alicante, Spain Correspondence to: Juan F. Navarro-González; E-mail: jnavgon@gobiernodecanarias.org ABSTRACT Background. The efficacy and safety of sucroferric oxyhydroxide (SO) have been reported in clinical trials. However, real-life data are scarce. This study presents data on the use, efficacy and safety of SO in real clinical practice. Methods. We performed a retrospective multicentre study, without any influence on the prescription decisions, that included 220 patients from 11 Spanish centres. Demographic, treatment, analytical and nutritional parameters and adherence, side effects and dropout rates were collected during 6 months. Results. SO was initiated due to inadequate control of serum phosphate (P) in 70% of participants and in 24.5% to reduce the number of tablets. Monotherapy with SO increased from 44% to 74.1%, with a reduction in the average daily number of sachets/tablets from six to two. Serum P decreased by 20% (4.6 6 1.2 versus 5.8 6 1.3 mg/dL; P < 0.001), with a significant reduction in intact parathyroid hormone levels (P < 0.01). The percentage of patients with adequate serum P control at threshold levels of 5 and 4.5 mg/dL increased by 45.4% and 35.9%, respectively. Serum ferritin was not modified, while the Received: 18.6.2020; Editorial decision 17.9.2020 C The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 681 682 | J.F. Navarro-González et al. transferrin saturation index increased significantly (P ¼ 0.04). Serum albumin and normalized protein catabolic rate, when normalized by serum P, increased, averaging 37% and 39%, respectively (P < 0.001). Adherent patients increased from 28.2% to 52.7%. Adverse effects were reported by 14.1% of participants, with abandonment of treatment in 9.5%. Conclusions. The use of SO in real-life results in better control of serum P, a reduction in the number of tablets and an improvement in therapeutic adherence. In addition, it may be beneficial with regards to secondary hyperparathyroidism and nutritional status. Keywords: haemodialysis, hyperphosphataemia, nutritional status, sucorferric oxyhydroxide, therapeutic adherence Downloaded from https://academic.oup.com/ckj/article/14/2/681/6125308 by Fundacio Biblioteca Josep Laporte user on 26 January 2023 INTRODUCTION intake of an excessive number of P binder tablets that, in the opinion of the investigator, would likely be reduced by the use Hyperphosphataemia is a practically universal complication of of SO (most of the investigators considered that four or more P chronic kidney disease (CKD) and is especially frequent in the binder tablets was an excessive number of pills) or ongoing more advanced stages of the disease and the dialysis popula- treatment with another P binder that could be substituted by SO tion. Serum phosphorus (P) concentrations above the recom- according to the investigator’s criteria with respect to adverse mendations of the Kidney Disease: IMproving Global Outcomes effects or intolerance. (KDIGO) and Kidney Disease Outcomes Quality Initiative Exclusion criteria included age <18 years, renal replacement (KDOQI) guidelines have been associated with increased mortal- therapy other than HD, hypersensitivity to drugs containing ity in dialysis patients [1, 2]. Dietary control and dialysis treat- iron, history of parathyroidectomy, existence of inflammatory ment are in most cases insufficient to achieve adequate control or immunological diseases, kidney transplant recipient, steroid of serum P, so the use of P binders at the intestinal level to pre- or immunosuppressive therapy, active infectious processes and vent its absorption is common. This P binding is achieved using certain divalent and trivalent cations that are capable of react- infection with hepatitis B, C or human immunodeficiency virus. ing with soluble P salts present in the diet, thereby forming in- soluble and non-absorbable P in the digestive tract. Ideally, Biochemical analysis and other study variables these drugs should be effective with a small number of tablets, The different variables were collected at the time of initiation of not be absorbable at the digestive level, present minimal ad- SO treatment and then monthly until completion of the 6- verse effects and be low cost [3]. month follow-up. Demographic data and treatment characteris- One of the P binders most recently incorporated into clinical tics were collected, including the reasons for prescribing SO practice is sucroferric oxyhydroxide (SO) [4], a complex whose treatment and the number of tablets used throughout the activity depends on the presence of iron in an oxidized state follow-up. The following clinical and analytical variables were and which has a marked chemical capacity to react with P collected: bone mineral metabolism parameters [calcium (Ca), P groups, forming insoluble salts. This process is fundamentally and intact parathyroid hormone (iPTH)], ferrokinetics [ferritin due to two consecutive and complementary mechanisms: the and transferrin saturation (TSAT) index], haemoglobin and hae- absorption of the P molecules present in the lumen of the diges- matocrit levels, doses of erythropoiesis-stimulating agents, se- tive tract and the formation of ferric P. rum albumin and C-reactive protein. Ca levels were corrected Several clinical trials have demonstrated the efficacy and for serum albumin. The erythropoietin (EPO) resistance index safety of SO in haemodialysis (HD) patients [5–7], although with was defined as the weekly EPO dose (U/kg/weight) divided by very limited real-life data. This multicentre study aims to pre- the haemoglobin level (g/dL). Protein intake was estimated indi- sent data on the use, efficacy and safety of SO in patients on HD rectly by calculating the normalized protein catabolic rate within the setting of real clinical practice. (nPCR), while the dialysis dose was estimated using the Kt/V according to the Daugirdas formula [8]. MATERIALS AND METHODS From the point of view of nutritional assessment, serum al- Study design and patients bumin and nPCR were each divided by serum P to calculate P- attuned albumin and nPCR (Alb/P and nPCR/P), respectively. VELphoro in REAL clinical practice (VELREAL) is an observa- These parameters allowed us to assess the effect of the reduc- tional, retrospective multicentre study on the use of SO in HD tion of serum P without restricting protein intake [9, 10]. patients in real clinical practice, without any influence on the Finally, adherence to SO treatment was analysed using the prescription decisions of the physicians, in which 11 Spanish simplified medication adherence questionnaire (SMAQ), an in- centres participated and a total of 220 patients were included. strument based on questions to the patients about their medi- Informed consent was obtained from the participants. The pro- cation habits, which has been used in previous studies to cedures were in accordance with the ethical standards of the re- evaluate compliance with P binder treatment in HD patients [11, sponsible committee on human experimentation and with the 12]. In addition, side effects and the treatment dropout rate Helsinki Declaration of 1975 and its latest revision. were analysed throughout the study. The inclusion criteria were as follows: age >18 years, CKD Stage 5D under maintenance renal replacement therapy with Statistical analysis HD for >6 months, commencement of treatment with SO during the year prior to inclusion in the study and one of the following Continuous variables were described as mean and standard de- three conditions: a serum P concentration >4.5 mg/dL (regard- viation (SD) or median and interquartile range (IQR) according less of whether or not the patient had received prior treatment to their distribution. Categorical variables were described as with P binders); a serum P level lower than this level but with means of their frequency distribution. Intragroup comparisons SO in real clinical practice | 683 were made using Student’s t-test for paired samples or the agents. The mean serum level of 25-hydroxyvitamin D was Wilcoxon test. For intergroup comparison, the independent 26.9 6 7.9 ng/mL and 112 patients were receiving native vitamin samples Student’s t-test or Mann–Whitney U-test was used. The D. A total of 116 patients were receiving active vitamin D treat- comparison between categorical variables was performed using ment (62% were on paricalcitol) and 86 were being treated with the chi-square test or the McNemar test as appropriate. calcimimetics. Throughout the study there were no significant Comparisons of the same variables at different visits were ana- variations in the doses of any of these drugs. The distribution of lysed using a repeated measures analysis of variance test. The the CKD mineral and bone disorder–related drugs is shown in multivariable logistic regression analyses were performed to Table 2. evaluate the factors associated with the better control of hyper- Downloaded from https://academic.oup.com/ckj/article/14/2/681/6125308 by Fundacio Biblioteca Josep Laporte user on 26 January 2023 phosphataemia under SO therapy. We used the achievement of Treatment with SO a serum P concentration <5 mg/dL as the dependent variable A total of 194 patients (88.2%) had received previous treatment and age, sex, presence of diabetes, time on dialysis, online hae- with other P binders, while in 26 (11.8%) the SO was the first modiafiltration (HDF), use of calcimimetics, treatment with na- binder used in treatment. Of the previously treated patients, tive or active vitamin D, Kt/V, nPCR and serum concentrations of 63.4% had received monotherapy, the most frequently used P, Ca PTH, 25-hydroxyvitamin D and albumin as baseline covari- binders being sevelamer carbonate, Ca acetate–magnesium car- ates. A P-value <0.05 was considered statistically significant. bonate combination and lanthanum carbonate. Statistical analyses were performed using SPSS Statistics ver- A serum P concentration at baseline <5 mg/dL was present sion 24 (IBM, Armonk, NY, USA). in 25% of patients and 15.9% had a P level <4.5 mg/dL. The indi- cations for initiation of SO treatment were lack of adequate con- RESULTS trol of serum P levels in 70% of cases, an attempt to reduce the number of tablets in 24.5% and adverse effects/intolerance to Patient characteristics previous binders in 5.4%. The baseline characteristics of the study participants are shown At baseline, before switching to SO, the average daily num- in Table 1. A total of 220 patients were included: 125 males and ber of sachets/tablets of P binders received by the patients was 95 females. Their mean age was 64 6 13 years and 25% were dia- 6.3 6 2.6 (range 2–15). The SO treatment was started as mono- therapy in 97 patients (44%). Among the 123 patients who betic. The mean time on HD was 46 6 38 months; 89 patients started SO combination therapy, the other binders used were (40.5%) received online HDF. The Ca concentration in the dialy- sevelamer (38.2% of cases), lanthanum carbonate (31.7%), Ca ac- sis fluid varied among patients, from 2.5 to 3 mEq/L; however, in etate–magnesium carbonate (23.5%) and Ca-only binders (6.5%). each of the participants the concentration remained constant After 6 months of treatment the mean number of SO tablets throughout the study. Most of patients (68.7%) received HD per day was 2 6 1, with the maximum number of tablets admin- treatment through a native vascular access at baseline; this pro- istered being 3 (41.4% of cases). At the end of this period, 163 portion did not change at the end of the study (69%). The aver- patients (74.1%) were receiving SO treatment as monotherapy, age values of Kt/V and nPCR at baseline were 1.77 6 0.55 and representing an increase of 30% with respect to baseline. The 1.15 6 0.37 g/kg/day, respectively, without significant variations during the study. Table 2. Evolution of biochemical parameters and CKD mineral and As regards concomitant treatments at baseline, most pa- bone disorder–related drugs tients (84.1%) were receiving iron supplements, in the vast ma- jority of cases (97.2%) in the form of intravenous iron therapy, P- and 87.7% were being treated with erythropoiesis-stimulating Parameters Baseline Final value P (mg/dL), mean 6 SD 5.8 6 1.3 4.6 6 1.2 <0.001 Table 1. Baseline characteristics of the patients Ca (mg/dL), mean 6 SD 8.9 6 0.6 8.9 6 0.7 NS Age (years), mean 6 SD 64 6 13 iPTH (pg/mL), median (IQR) 345 (189–525) 324 (201–456) <0.01 Men/women, n/n 125/95 Albumin (g/dL), median (IQR) 3.7 (3.4–4.1) 3.8 (3.5–4.1) NS Diabetes, % 25 C-reactive protein (mg/L), 1.15 (0.44–5.0) 1.18 (0.39–5.0) NS Time on dialysis (months), mean 6 SD 46 6 38 median (IQR) Online HDF, % 40.5 Haemoglobin (g/dL), mean 6 SD 11.6 6 1.3 11.7 6 1.1 NS P (mg/dL), mean 6 SD 5.8 6 1.3 Haematocrit (%), mean 6 SD 35.6 6 4.3 35.8 6 4.6 NS Ca (mg/dL), mean 6 SD 8.9 6 0.6 Ferritin (mg/dL), mean 6 SD 366 6 243 388 6 290 NS iPTH (pg/mL), mean 6 SD 410 6 300 TSAT index (%), mean 6 SD 27.9 6 9.5 29.6 6 10.6 <0.05 Serum 25-hydroxyvitamin D (ng/mL), mean 6 SD 26.9 6 7.9 Kt/V, mean 6 SD 1.77 6 0.55 1.81 6 0.46 NS Albumin (g/dL), median (IQR) 3.7 (3.4–4.1) nPCR (g/kg/day), mean 6 SD 1.15 6 0.37 1.13 6 0.30 NS C-reactive protein (mg/L), median (IQR) 1.15 (0.44–5) P-normalized albumin ( 0.65 (0.56–0.79)0.85 (0.72–0.97) <0.001 Haemoglobin (g/dL), mean 6 SD 11.6 6 1.3 103), median (IQR) Haematocrit (%), mean 6 SD 35.6 6 4.3 P-normalized nPCR ( 0.20 6 0.08 0.24 6 0.10 <0.001 Ferritin (mg/dL), mean 6 SD 366 6 243 103 dL/kg/day), mean 6 SD TSAT index (%), mean 6 SD 27.9 6 9.5 CKD-mineral and bone Kt/V, mean 6 SD 1.77 6 0.55 disorder-related drugs, nPCR (g/kg/day), mean 6 SD 1.15 6 0.37 n (%) P-normalized albumin (103), median (IQR) 0.65 (0.56–0.79) Native vitamin D 112 (50.9) 107 (48.6) NS P-normalized nPCR (103 dL/kg/day), mean 6 SD 0.20 6 0.08 Active vitamin D 116 (52.7) 107 (48.6) NS Patients with P <5 mg/dL, % 25 Calcimimetics 86 (39) 77 (35) NS Patients with P <4.5 mg/dL, % 15.9 NS, not significant. 684 | J.F. Navarro-González et al. 90 Table 3. Bimonthly evolution of serum P, number of tablets and per- centage of patients under control after initiation of SO 80 Parameters Baseline Month 2 Month 4 Month 6 70 Serum P (mg/dL), mean 6 SD 5.8 6 1.3 4.8 6 1 4.6 6 1 4.6 6 1.2 60 Number of tablets, 6.3 6 2.6 2.1 6 0.9 2 6 0.9 261 mean 6 SD 50 Control of P at threshold level of 5 mg/dL % Percentage of patients 25 60 69 70.4 Downloaded from https://academic.oup.com/ckj/article/14/2/681/6125308 by Fundacio Biblioteca Josep Laporte user on 26 January 2023 40 Percent increase versus 35 9 1.4 previous 30 Control of P at threshold level of 4.5 mg/dL Percentage of patients 15.9 36.8 50.7 51.8 20 Percent increase versus 20.9 13.9 1.1 10 previous 0 Start ≤ Start > End ≥ Baseline Final 3 tablets/ 3 tablets/ 3 tablets/ monotherapy monotherapy Table 4. Decrease of serum P after treatment with SO in different sachets sachets sachets subgroups FIGURE 1: Distribution of patients according to the number of tablets/sachets of P binders at the beginning and end of the study and the percentage of mono- Serum P reduction, therapy cases at baseline and at the end of the study. Parameters median (IQR) P-value Gender Male 0.9 (0.3–2.0) Female 1.3 (0.3–2.2) 0.60 Diabetes Yes 1.2 (0.6–2.0) 80 No 1.2 (0.5–2.1) 0.33 Baseline 45.4% Final Online HDF 70 Yes 1.2 (0.4–2.2) No 0.9 (0.2–2.0) 0.21 60 Dialysate Ca concentration 24.5% 2.5 mEq/L 1.1 (0.3–2.0) 35.9% 3 mEq/L 1.3 (0.3–2.2) 0.26 50 Serum PTH Tertil 1 (<251.9 pg/mL) 1.3 (0.3–2.2) % 40 Tertil 2 (251.9–451 pg/mL) 1.2 (0.3–2.0) 0.90 Tertil 3 (>451 pg/mL) 1.1 (0.4–2.0) 30 Serum 25-hydroxyvitamin D 30 ng/mL 1.1 (0.2–2.2) 20 <30 ng/mL 1.0 (0.2–2.3) 0.92 Active vitamin D therapy Yes 0.9 (0.1–1.7) 10 No 1.5 (0.3–2.3) <0.05 Treatment with calcimimetics 0 Yes 1.3 (0.5–2.3) P < 5 mg/dl P < 4.5 mg/dl Adherence No 0.8 (0.1–1.7) 0.01 FIGURE 2: Variation in therapeutic adherence and in the percentage of patients with a serum P concentration <5 mg/dL and <4.5 mg/dL. obtained adequate control of serum P at threshold levels of 5 percentage distribution of the patients in relation to the number and 4.5 mg/dL increased by 45.4% and 35.9%, respectively, com- of tablets at the end of the study and the monotherapy treat- pared with baseline (Figure 2). The bimonthly evolution of se- ment at baseline and the end of the follow-up period are shown rum P, number of tablets and percentage of patients with an in Figure 1. adequate control of serum P at threshold levels of 5 and 4.5 mg/ dL after initiation of SO therapy are shown in Table 3. Subgroup analyses were performed to evaluate the response Biochemical analysis to SO according to sex, presence of diabetes, online HDF, Ca con- The evolution of the biochemical parameters is shown in centration in the dialysate fluid, baseline serum PTH and 25- Table 2. The mean serum concentration of P was reduced from hydroxyvitamin D and treatment with active vitamin D or calci- 5.8 6 1.3 mg/dL at baseline to 4.6 6 1.2 mg/dL after 6 months of mimetics (Table 4). There were no significant differences be- treatment (P < 0.001), representing an average decrease of 20%. tween subgroups, except for patients treated with active There was no significant change in Ca concentration, although vitamin D, who showed a lower reduction in serum P, and sub- a slight but significant reduction in iPTH levels (P < 0.01) was ob- jects receiving calcimimetics, who exhibited a greater decrease served. At the end of the study, the percentage of patients who in serum P. SO in real clinical practice | 685 Regarding haematological parameters, no significant differ- increase in the percentage of patients who achieve adequate ences were observed in haemoglobin concentration or in hae- control of serum P, with a smaller number of tablets and with matocrit level after treatment with SO. Likewise, serum ferritin an improvement in therapeutic adherence. concentrations were not modified, although an increase in the The reason for the prescription of SO was lack of adequate TSAT index was evident: 29 6 10.6% at the end of the follow-up control of serum P levels in more than two-thirds of the versus 27.2 6 7.9% at the start of the study (P ¼ 0.04). When ana- patients, while in almost 25% of cases SO was prescribed to re- lysing the change in the TSAT depending on whether patients duce the number of tablets administered. In this respect, two had received treatment with iron or not, no sig- facts should be highlighted. First, with the prescription of SO, nificant differences were observed between the two groups the average number of tablets decreased from six at the begin- Downloaded from https://academic.oup.com/ckj/article/14/2/681/6125308 by Fundacio Biblioteca Josep Laporte user on 26 January 2023 (þ2.5 6 0.9% versus þ0.3 6 0.7%; P ¼ 0.28). It should be noted that ning of the study to two at the end of the study. Importantly, there was no significant change in the doses of iron or the mean number of tablets at the initiation of SO was two per erythropoiesis-stimulating agents throughout the study, nor day, which did not change throughout the study. Second, al- was there any variation in the EPO resistance index. most 60% of patients received only one or two tablets per day at From the point of view of nutritional assessment, we ob- the end of the study, representing a reduction in the average served that although there were no changes in serum albumin number of tablets of >65%. Also, 74% of the patients received SO concentration or nPCR, when these parameters were normal- as the only P binder at the end of the study, which represents a ized by the level of serum P (Alb/P and nPCR/P), significant 30% increase in SO prescription as monotherapy compared with increases averaging 37% and 39%, respectively, were evident at baseline. the end of the study (P < 0.001). The preceding data are even more relevant in the context of Finally, the results of the multivariate logistic regression the evolution of the parameters of bone mineral metabolism analysis showed that better control of hyperphosphataemia un- since after treatment with SO a significant reduction, averaging der SO therapy (defined as the achievement of a serum P con- 20%, was observed in serum P concentration. Importantly, the centration <5 mg/dL) was positively associated with higher Kt/V percentage of patients who achieved a P concentration <5 mg/ fodds ratio [OR] 9.0 [95% confidence interval (CI) 1.11–73.70], dL at the end of the study rose from 25.1% to 70.5%, while for a P P < 0.05g and the use of calcimimetics [OR 12.4 (95% CI 2.74– threshold of 4.5 mg/dL this percentage increased from 15.9% to 51.8%. It is noteworthy that there was a progressive increase in 56.68), P < 0.05], whereas it was negatively related to baseline se- the number of patients who achieved adequate serum P control rum P [OR 0.61 (95% CI 0.42–0.96), P < 0.05] and treatment with throughout the study, although the most significant increment active vitamin D compounds [OR 0.53 (95% CI 0.21–0.87), was observed within the first 2 months of treatment. P < 0.01]. These results are consistent with those observed in clinical trials and in previous studies on the use of SO in real life, both Adherence and safety in HD and in peritoneal dialysis, in which the reduction in P Assessment of adherence to treatment using the SMAQ showed concentration has been verified by an increase in the percent- age of patients reaching adequate levels, together with a de- that before the start of SO therapy, 28.2% of patients were ad- crease in the number of tablets [5, 9, 10, 13]. Finally, these data herent to therapy, a percentage that increased to 52.7% at the are especially relevant with regard to a P level of 4.5 mg/dL, the end of the study (Figure 2). No significant difference was ob- value denoting the upper limit of the normal range in most lab- served in the percentage of non-adherent patients among the oratories. On the other hand, the guidelines of the Spanish participants who did not obtain adequate control of serum P at Society of Nephrology for the management of bone mineral me- the two threshold levels of 5 mg/dL and 4.5 mg/dL. tabolism disorders in CKD patients recommend that the serum Regarding tolerance and safety aspects (Table 5), 31 patients P concentration should be <4.5 mg/dL in all stages of CKD but (14.1%) reported an adverse effect, 21 of which led to abandon- that levels up to 5 mg/dL should be tolerated in dialysis patients ment of treatment (9.5% of patients). The most frequent adverse [14]. effects were digestive, with diarrhoea in 13 patients and consti- Considering a serum concentration <5 mg as a threshold for pation in 6. Most of the treatment dropouts (76%) occurred in adequate serum P control, logistic multivariate analysis was the first 3 months after starting the drug. performed to identify factors associated with the response to SO. The results showed that the better control of hyperphos- DISCUSSION phataemia under SO therapy was positively associated with Kt/ V and the use of calcimimetics, whereas it was negatively re- The results of this study show that, in real clinical practice, SO lated to baseline serum P and treatment with active vitamin D treatment in patients previously treated with other P binders compounds. Although insufficient in most cases, P removal by achieves a significant reduction in serum P levels, with an dialysis is a main factor in the management of hyperphospha- taemia in patients under renal replacement therapy. Thus a Table 5. Adverse effects and causes of treatment dropout higher Kt/V, reflecting better dialysis optimization, results in in- creased P removal capacity, explaining the positive association Adverse effects, n (%) with a better response to SO. However, online HDF was not re- Diarrhoea 13 (5.9) lated to this response, a finding in agreement with studies that Digestive discomfort (nausea, flatulence, 12 (5.7) have shown no beneficial effect of HDF compared with high- meteorism and abdominal pain) flux HD on the control of mineral metabolism parameters, in- Constipation 6 (2.7) cluding P levels [15, 16]. Another factor influencing serum P lev- Treatment dropout, n (%) Adverse effects 15 (6.8) els is the use of drugs for treating secondary Rejection of organoleptic properties 5 (2.3) hyperparathyroidism, which can affect the response to P bind- Kidney transplant 1 (0.5) ers. Available drugs differ in their effects on serum P. Thus ac- tive vitamin D derivatives increase intestinal P absorption and 686 | J.F. Navarro-González et al. increase its serum levels [17], while calcimimetics lower serum a 24.5% increase in the percentage of patients adhering to P [18]. These divergent effects may explain the different associa- treatment. tions with the response to SO observed in our study. The observational and multicentre nature of this study en- It is worth noting the reduction of iPTH levels in our study sured provision of information relating to actual clinical prac- after SO treatment, which, although moderate, reached statisti- tice in a broad geographic context. However, some limitations cal significance. This is an aspect that distinguishes our study must be recognized. First, although a database was designed to from previous works in which an increase in the concentrations collect all the variables of interest, this was a retrospective of this hormone was observed [9, 13]. A probable explanation for study where data collection was carried out from previously this difference relates to Ca levels, since while in our study existing electronic records not specifically established to meet Downloaded from https://academic.oup.com/ckj/article/14/2/681/6125308 by Fundacio Biblioteca Josep Laporte user on 26 January 2023 there was no variation, in previous studies a slight but signifi- the objectives of the study. Regarding nutritional data, we did cant decrease in Ca concentrations was observed, which could not have direct information from patients or dieticians on the have provided a stimulus for iPTH production. This finding sug- dietary intake of P or proteins, and a definitive causal relation- gests that SO potentially has an adjuvant effect on the control ship between intake of SO and the change in nutritional param- of secondary hyperparathyroidism, but on the condition that eters could not be established. Another limitation stems from serum Ca concentrations remain stable. the fact that not all measurements were done during the same SO was developed as an iron-based P binder with low iron- dialysis shift, either morning, noon or evening, and therefore releasing capacity [19–21]. Previous studies have shown varying the circadian variation of phosphataemia may have affected the results in relation to changes in the concentration of ferritin results. Finally, we did not have information on parameters and in TSAT, as well as in the use and doses of iron or erythropoiesis-stimulating agents [9, 10, 13, 22]. The majority of such as acute phase reactants or residual renal function. patients in our study received intravenous iron supplementa- In conclusion, SO is an effective P binder for the treatment of tion, being treated with erythropoiesis-stimulating agents in al- hyperphosphataemia in real clinical practice. It results in an in- most 90% of cases, with no change observed in either the crease in the percentage of patients who achieve adequate con- number of patients or the doses of these therapies at the end of trol of serum P levels, as well as a significant reduction in the the study. Regarding haematological parameters, after SO treat- number of tablets taken and an improvement in therapeutic ment there were no significant changes in haemoglobin or hae- adherence. In addition, it has associated effects that may be matocrit or in serum ferritin. However, a small but significant beneficial in relation to secondary hyperparathyroidism and increase was observed in the TSAT, with no difference accord- nutritional parameters. ing to whether the patients received iron treatment. This change in the TSAT is consistent with the changes previously ACKNOWLEDGEMENTS reported in a post hoc analysis of a Phase 3 clinical trial [19], as well as in studies of the use of SO in actual clinical practice [9, Database management was provided by Trialance 10, 13]. The increase in the TSAT has been related to the low (Barcelona, Spain) and medical writing support was pro- level of absorption of iron from SO, which presents a minimal vided by Welocalize Life Sciences (Barcelona, Spain), both risk of accumulation or overload of iron in the long-term but funded by Vifor Pharma Espan~ a S.L. which may be beneficial since the TSAT reflects the circulating iron available for the production of haemoglobin [23–25]. AUTHORS’ CONTRIBUTIONS Dietary management is a very important element in the achievement of adequate control of serum P in HD patients. J.F.N.G. and J.B. were responsible for the conception and de- Diet must be closely monitored to avoid excessive restriction of sign of the study. M.D.A., M.J.L., P.M., L.E. and E.S. contrib- protein intake with subsequent reduction in nPCR and serum uted to the final design of the database. M.D.A., F.H.P., M.J.L., albumin and the development of a protein-energy wasting syn- P.M., F.R.M., M.A.M.L., L.E., E.S., M.L. and A.C. collected the drome, which has been associated with a reduction in quality of data. J.F.N.G. performed the statistical analysis and wrote life and an increase in mortality [26–28]. In our study we did not the article. J.F.N.G., M.D.A., P.M., E.S. and J.B. contributed to observe variations in nPCR or serum albumin concentration, the interpretation of results and discussion. All authors indicating that there was no significant change in protein in- have read and agreed to the final version of the manuscript. take. To assess the impact of P reduction without restriction of protein intake, new nutritional analysis parameters based on normalization of albumin and nPCR values by serum P concen- CONFLICT OF INTEREST STATEMENT tration have recently been introduced: Alb/P and nPCR/P [9, 10]. Similar to observations in previous studies with SO in actual The results presented in this article have not been published practice [9, 10, 29], these parameters increased significantly by previously in whole or part, except in abstract format at the the end of the study period, indicating achievement of control XLVII Congress of the Spanish Society of Nephrology and of serum P without a reduction in protein intake. the 56th ERA-EDTA Congress. Lack of adequate therapeutic adherence is a significant issue in patients with CKD; this is especially true in relation to P bind- DATA AVAILABILITY STATEMENT ers, with the frequency of inadequate adherence exceeding 60% in those receiving dialysis [30]. 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