Sodium zirconium cyclosilicate pretreatment for formula in vitro reduces potassium intake in infants with chronic kidney disease : Chinese Medical Journal

Secondary Logo

Journal Logo


Sodium zirconium cyclosilicate pretreatment for formula in vitro reduces potassium intake in infants with chronic kidney disease

Liu, Boxuan1; Wang, Teng2; Chen, Zhi3

Editor(s): Ni, Jing

Author Information
Chinese Medical Journal ():10.1097/CM9.0000000000002461, January 12, 2023. | DOI: 10.1097/CM9.0000000000002461
  • Open
  • PAP

To the Editor: Hyperkalemia is a common life-threatening complication of advanced chronic kidney disease (CKD) in infants. To manage hyperkalemia, dietary potassium intake restrictions is the most convenient, safe, and effective treatment. Kidney Disease Outcomes Quality Initiative (KDOQI) guideline recommends that the general restriction of potassium is 40 to 120 mg·kg−1·day−1 for infants and 30 to 40 mg·kg−1·day−1 for older children with CKD.[1] Thus, commercial infant formulas as the main alternative source of nutrition for infants are not suitable for infants with CKD, because of their high potassium content, which may initiate or further aggravate hyperkalemia of them. Sodium polystyrene sulfonate (SPS) as a non-selective resin has been widely used in the clinic for >60 years and has shown good effectiveness to decrease potassium intake in adult patients with CKD.[2] However, oral administrating of SPS is not suitable for an infant with CKD, which may increase the risk for necrotizing enterocolitis. It is also not feasible to retention enema with SPS, because of infants’ immature gastrointestinal tracts and slower gut motility.[2]

Pretreated infant formula by using SPS in vitro to decrease the content of potassium may be a prefered protocol for the infant with CKD, which could not only decrease the intake of potassium but also avoid SPS causing serious gastrointestinal adverse reactions effectively. To achieve the effects, SPS should be added to it simultaneously when infant formula was prepared. Following shaking for 2 min, the feeding bottle was sat in a refrigerator at 4°C for about 120 min, to allow sufficient time for SPS separated from the milk and settled at the bottom of the feeding bottle, then the milk supernatant with lower potassium was obtained. The clinical effect of this protocol to pretreat infant formula for the treatment of CKD infants with hyperkalemia has been demonstrated in previous studies.[3,4] However, it is noteworthy that, SPS is a non-specific binding resin, cation exchange is not limited to potassium; calcium, magnesium, and other metal ions may also bind to the resin. Especially for calcium, pretreatment of infant formula with SPS would decrease the calcium concentration by 8% to 29%. So, additional calcium must be supplemented for infants. Moreover, 1 g of SPS contains 100 mg of sodium. Sodium would be released into the milk by exchange of sodium and potassium, when pretreated infant formulas using SPS in vitro, and increased the sodium concentration of it by 86% to 300%.[3] So, the protocol should be avoided in infants with severe edema, hypertension, or congestive heart failure, they are more sensitive to small increases in formulas’ sodium levels. To avoid these limitations, exploring a higher specific binding resin is urgently needed. Recently, sodium zirconium cyclosilicate (SZC) has been known by more and more physicians, because of the high efficiency and safety in the emergency treatment of hyperkalemia and the maintenance treatment in patients with CKD.[5,6] The potassium-decreasing effect of SZC is based on its zirconium silicate crystal structure, which could trap potassium through size-selective micropores, and the binding capacity to potassium is >125 times over calcium.[7] However, the clinical application of SZC for children has not been approved, so no clinical trials have been conducted concerning the treatment of SZC for CKD infants with hyperkalemic, or pretreated infant formulas using SZC in vitro. In consideration of safety, the present study analyzed the effects of SZC pretreated on infant formulas in vitro; to assess the feasibility of this protocol for CKD infants, to lay a foundation for the subsequent clinical application.

Kabrita (goat's milk-based infant formula, Kabrita Leeuwarden, The Netherland) and Similac (cow's milk-based infant formula, Abbott, Chicago, USA) formulas were chosen as the test samples and prepared to five diverse volumes according to their instruction menus, respectively: 90, 120, 150, 180, and 210 mL. Each brand of formula was divided into two groups: high-dose intervention group and low-dose intervention group. We set two doses according to the SZC instructions and preliminary experiments. In addition, preliminary experiments show that a higher dose of the drug will reduce the performance price ratio and increase the economic burden on patients. Five volumes of prepared milk mentioned above were in each group. SZC (LOKELMA, AstraZeneca, Wilmington, USA) powder was added to the prepared milk in accordance with the potassium content. The concentration is 0.5 g SZC/mmol potassium in the high-dose intervention group, and 0.25 g SZC/mmol potassium in the low-dose intervention group. After being vigorously shaken for 15 s, the supernatant milk samples were collected at different time points for further analysis. The concentration of potassium, sodium, and calcium in samples was evaluated by radial inductively coupled plasma-optical emission spectrometry (ICP/OES) (Vista-pro CCD simultaneous ICP/OES instrument, Agilent Technologies, Santa Clara, CA, USA) just as in previous studies.[3,4] The pH values of the samples were measured by an electronic pH meter (BPH-600 Bell Technologies, Dalian, China). The content of macronutrients in samples was measured by HMA 2000 Milk analyzer (HMA 2000, Hong Yang Co. Ltd., Hangzhou, China). The results revealed that, by pretreatment of SZC, the potassium concentrations of milk samples were all decreased significantly within 5 min in each intervention group (Figure 1). In the high-dose intervention group, the potassium concentration in Kabrita milk samples was decreased from 27.48 ± 0.36 mmol/L to 14.36 ± 0.54 mmol/L (P <0.01) after 5 min pretreatment of SZC, and from 24.92 ± 0.44 mmol/L to 11.69 ± 0.37 mmol/L (P < 0.01) in Similac milk samples. The decreased rate was 47.75 ± 2.04% and 53.12 ± 0.70%, respectively, much more higher compared with that in the low-dose intervention group (25.18 ± 0.65% and 26.46 ± 0.38%, respectively) (P < 0.01). While the increased rates of sodium concentration in Kabrita milk samples were 10.75 ± 1.39% in the high-dose intervention group and 9.26 ± 0.69% in the low-dose intervention group, while in Similac milk samples were 14.74 ± 1.22% in the high-dose intervention group and 7.79 ± 0.29% in the low-dose intervention group. The decreased rates of calcium concentration in Kabrita milk samples were 7.01 ± 0.06% in the high-dose intervention group and 7.02 ± 0.69% in the low-dose intervention group. There were no statistically significant calcium concentrations in Similac milk samples (P > 0.05). Due to the different milk sources of the two formulas, the basal calcium content of the goat milk (Kabrita) was nearly twice higher than that of the cow milk (Similac); therefore, at the beginning of the experiment, the calcium content of Kabrita formula decreased more statistically significant than that of Similac. In the following 4 h, the concentration of sodium increased, and the concentration of calcium decreased gradually with the extension of time, but the change rates were all slightly. Meanwhile, the difference in the protein, fat, lactose, and pH values at different time points in each group was not statistically significant (P > 0.05).

Figure 1:
The concentration curve of (A) potassium, (B) sodium, (C) calcium, and (D–G) macronutrients in each group. (D) 0.5 g SZC/mmol K+ in Kabrita, (E) 0.25 g SZC/mmol K+ in Kabrita, (F) 0.5 g SZC/mmol K+ in Similac, and (G) 0.25 g SZC/mmol in K+ Similac. SZC: Sodium zirconium cyclosilicate.

It can be seen from our investigation that, the potassium content of Kabrita and Similac infant formulas is 27 and 24 mmol/L, respectively. When it has been chosen as the main alternative source of nutrition for infants with CKD, the amount of potassium intake would reach 120 to 140 mg·kg−1·day−1, and far beyond the recommended dose of KDOQI guideline, which may increase the risk of initiating or aggravating hyperkalemia significantly. By pretreatment of SZC for only 5 min, the potassium concentration of prepared milk samples decreased by about 50%, thus the amount of potassium intake was reduced to 60 to 70 mg·kg−1·day−1 and reached the relevant requirement regard to infants with CKD in KDOQI guideline completely. Meanwhile, there was no significantly effect on pH values, calcium, sodium, and macronutrients.

In conclusion, compared with SPS, which is the major potassium lowering drug widely used in clinics currently, SZC could decrease the potassium content more rapidly, when it was used for pretreatment of infant formulas in vitro, and without affecting the other main ions and nutritional elements too much. For infants with CKD, this protocol would ensure that the intake of potassium is maintained in a more reasonable range, decrease the occurrence of hyperkalemia effectively, and more conducive to their outcome. SZC mimics potassium channel structure, it is mainly used in patients with kidney disease; therefore, our study focused on potassium, sodium, and calcium ions. In future studies, other ions such as magnesium and iron can be further included. The safety of this protocol in the clinical application will be further evaluated in ensure studies.

Conflicts of interest



1. Shaw V, Anderson C, Desloovere A, Greenbaum LA, Haffner D, Nelms CL, et al. Nutritional management of the infant with chronic kidney disease stages 2–5 and on dialysis. Pediatr Nephrol 2022. doi: 10.1007/s00467-022-05529-x.
2. Beccari MV, Meaney CJ. Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: an evidence-based review. Core Evid 2017;12:11–24. doi: 10.2147/CE.S129555.
3. Taylor JM, Oladitan L, Carlson S, Hamilton-Reeves JM. Renal formulas pretreated with medications alters the nutrient profile. Pediatr Nephrol 2015;30:1815–1823. doi: 10.1007/s00467-015-3115-5.
4. Picq C, Asplanato M, Bernillon N, Fabre C, Roubeix M, Ricort JM. Effects of water soaking and/or sodium polystyrene sulfonate addition on potassium content of foods. Int J Food Sci Nutr 2014;65:673–677. doi: 10.3109/09637486.2014.908172.
5. Peacock WF, Rafique Z, Vishnevskiy K, Michelson E, Vishneva E, Zvereva T, et al. Emergency potassium normalization treatment including sodium zirconium cyclosilicate: a phase II, randomized, double-blind, placebo-controlled study (ENERGIZE). Acad Emerg Med 2020;27:475–486. doi: 10.1111/acem.13954.
6. Takkar C, Nassar T, Qunibi W. An evaluation of sodium zirconium cyclosilicate as a treatment option for hyperkalemia. Expert Opin Pharmacother 2021;22:19–28. doi: 10.1080/14656566.2020.1810234.
7. Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS. Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS One 2014;9:e114686. doi: 10.1371/journal.pone.0114686.
Copyright © 2023 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.