Evaluating Sucralfate as a Phosphate Binder in Normal Cats and Cats with Chronic Kidney Disease
Control of hyperphosphatemia is an important part of the management of chronic kidney disease (CKD). The purpose of this study was to determine the efficacy of sucralfate as a phosphate binder in normal cats and normophosphatemic CKD cats. A 500 mg sucralfate slurry was administered orally q 8 hr for 2 wk, and serum phosphorus, urine fractional excretion of phosphorus, and fecal phosphorus concentrations were measured. In normal cats treated with sucralfate, significant changes in serum phosphorus concentration or urinary excretion of phosphorus were not detected, and vomiting occurred after 14.7% of administrations. Of the five normophosphatemic cats with CKD treated with sucralfate, three experienced clinical decompensation, including vomiting, anorexia, constipation, and increased azotemia. Administration of sucralfate did not result in significant changes in fecal phosphorus concentration in these cats. The effects of sucralfate administration on serum phosphorus concentration and urinary excretion of phosphorus in CKD cats was difficult to determine because of dehydration and worsening azotemia associated with decompensation. Due to side effects and the apparent lack of efficacy of the medication, the study was discontinued. This study was unable to confirm efficacy of this sucralfate formulation as a phosphate binder, and side effects were problematic during the study.
Introduction
Chronic kidney disease (CKD) is a common syndrome in older cats and is associated with azotemia, hypokalemia, and hyperphosphatemia.1 Hyperphosphatemia is due primarily to decreased renal excretion of phosphorus secondary to declining kidney function. Hyperphosphatemia is associated with a poorer prognosis in CKD cats, predicts progression of disease, and also contributes to the induction of renal secondary hyperparathyroidism.2–4 Management of this element confers a renoprotective effect and is critical in the prevention of renal secondary hyperparathyroidism and progression of disease.5 Dietary phosphorus restriction is a commonly utilized method, but as renal disease progresses, additional phosphate-binding therapy is often needed.1,2,6
A number of products can be administered orally in the attempt to manage hyperphosphatemia in cats with CKD; aluminum hydroxide products are commonly prescribed.1,2 However, cats often do not tolerate aluminum hydroxide administration due to poor palatability; thus, alternative treatments are sought. Although sucralfate has been mentioned in the human literature for decades as a phosphate binder,2,7–11 its efficacy in cats has not been evaluated. Sucralfate may also provide additional therapeutic effects for the gastritis and gastric ulcerations that are thought to be associated with uremia.7,12 The purpose of this study was to assess the safety and efficacy of sucralfate as a phosphate binder in normal cats and cats with CKD.
Materials and Methods
The study was designed to be conducted sequentially in normal, purpose-bred, research cats; normophosphatemic cats with CKD; and hyperphosphatemic cats with CKD. The study was approved by the Institutional Animal Care and Use Committee at Colorado State University, and all owners signed consent forms prior to participation.
Experiment 1: Normal Cats
Six healthy, 1.5-year-old, purpose-bred cats of mixed sex with normal complete blood count, serum biochemistry, and urinalysis results were administered 500 mg of sucralfatea orally as a slurry in 1.5 mL of water, q 8 hr with food for 14 consecutive days. This dose regimen was selected because it is the recommended dose for gastric ulceration in cats and is also mentioned to be a potentially effective phosphate binder.13,14 Cats were free-fed maintenance diet throughout the course of the study. Blood and urine samples were collected 3 days during the week prior to sucralfate administration (Monday [M],Wednesday [W], and Friday [F] mid-morning), 6 days during the 2 wk of sucralfate administration (M,W,F mid-morning), and 2 days during the week post-administration (M,W mid-morning). Concentrations of phosphorus, calcium, potassium, sodium, and creatinine were measured on all serum and urine samples. Fractional excretions of phosphorus, calcium, potassium, and sodium in urine were calculated using the following formula: % Excretion N = Nu × Cs/Cu × Ns × 100, where Nu is the concentration in meq/l or mg/dl of the analyte of interest in urine, Ns is the concentration of the same analyte in serum using the same units, Cu is the concentration in mg/dl of creatinine in urine, and Cs is the concentration of creatinine in serum.15 In this experiment, fecal phosphorus content analysis was not performed because the cats were housed as a group, which precluded collection of individual fecal samples. Serum phosphorus concentration and urinary fractional excretion of phosphorus were averaged for pre-treatment, treatment, and post-treatment periods and analyzed using repeated measures ANOVA, and equality of variances was also performed for the fractional excretion data.b
Experiment 2: Normophosphatemic CKD Cats
Ten normophosphatemic (serum phosphorus 3–6 mg/dL) client-owned cats with stable CKD were enrolled. Six cats were International Renal Interest Society (IRIS) CKD Stage III and 4 cats were IRIS CKD Stage II. Sample collections were identical for all 10 cats but only 5 randomly determined cats (3 IRIS CKD Stage III cats, 2 IRIS CKD Stage II cats) received 500 mg of sucralfate as an oral slurry, q 8 hr with food for 14 days. Cats were maintained on the same diet (whatever they had previously been eating) throughout the course of the study; 4 of 5 cats that were treated with sucralfate were being fed a phosphorus-restricted, commercial, renal diet. Blood and urine samples were collected twice during the week prior to sucralfate administration (variable non-consecutive weekdays) and twice during sucralfate administration (variable non-consecutive weekdays). Concentrations of phosphorus, calcium, potassium, sodium, and creatinine were measured on all serum and urine samples, and fractional excretion of phosphorus in urine was calculated as described for experiment 1. Serum phosphorus concentration and urinary fractional excretion of phosphorus were averaged for pre-treatment and treatment periods analyzed using repeated measures ANOVA.c Fecal samples were collected for determination of phosphorus levelsd on 3 cats that received sucralfate once during the week prior to sucralfate administration and once at least 7 days after starting sucralfate. A Wilcoxon signed rank test was used to analyze fecal phosphorus concentration before and after sucralfate administration.d
Results
Normal Cats
No significant difference in serum phosphorus concentration (Figure 1) or urinary fractional excretion of phosphorus (Figure 2) was seen between the treatment and non-treatment samples. A statistical trend was observed (P = 0.06) for a decrease in variance of phosphorus excretion during the treatment phase (Figure 1). Vomiting was noted within 4–6 hr of administration after 6 of 42 (14.7%) administration events; however, the number of individual cats that vomited was not known because of group housing. No vomiting was recorded during time periods when sucralfate was not administered.
Citation: Journal of the American Animal Hospital Association 52, 1; 10.5326/JAAHA-MS-6213
Citation: Journal of the American Animal Hospital Association 52, 1; 10.5326/JAAHA-MS-6213
Normophosphatemic CKD Cats
Of the five cats administered sucralfate in experiment 2, apparent clinical decompensation occurred in three cats, as evidenced by vomiting at variable times throughout the treatment period (three cats), anorexia (three cats), constipation (one cat), and increased azotemia (two cats). Hospitalization with IV fluid therapy was required for one cat. The two other cats improved after sucralfate was discontinued and recovered with supportive care in the home environment. While the sample collections were identical to the treated cats, none of the five untreated control cats exhibited signs of clinical decompensation. No significant difference in serum phosphorus concentration (Figure 3) or urinary fractional excretion of phosphorus (Figure 4) was seen between the treated or control groups of cats. Fecal phosphorus content in three cats prior to sucralfate administration averaged 2.5% by weight (range 0.8–3.6) compared to 1.9% by weight (range 1–2.5) after sucralfate administration and was not statistically significant.
Citation: Journal of the American Animal Hospital Association 52, 1; 10.5326/JAAHA-MS-6213
Citation: Journal of the American Animal Hospital Association 52, 1; 10.5326/JAAHA-MS-6213
Discussion
In this study, the safety and efficacy of sucralfate as a phosphate binder was assessed in healthy cats and normophosphatemic cats with CKD. In normal cats administered sucralfate, significant changes in serum phosphorus concentration or urinary excretion of phosphorus were not detected and vomiting occurred after 14.7% of administrations. As vomiting was not noted during the periods of time that sucralfate was not administered, it was concluded that this is a side effect of sucralfate administration. Sucralfate can potentially cause hypophosphatemia, as has been reported in people,16 but neither hypophosphatemia nor a decrease in serum phosphorus was observed in the cats in this study. Despite administration of sucralfate, healthy kidneys may be capable of compensation that would result in stable serum phosphorus. However, this hypothesis has not been proven in cats, to our knowledge. A trend towards less variation in the amount of phosphorus eliminated via renal excretion was noted when normal cats received sucralfate. This may represent renal regulatory mechanisms. Alternatively, the administered dose may not have been adequate to result in a change in serum phosphorus. Variable information regarding the equivalency of sucralfate and aluminum hydroxide doses is found in the literature. Statements include that 475 mg of aluminum hydroxide or 1 g of sucralfate contain 160 mg elemental aluminum, and 1 g of sucralfate contains 190 mg of elemental aluminum, while 1 g of aluminum hydroxide contains 346 mg of elemental aluminum.8,9 Although a rough estimate, the dose of sucralfate administered in this study was two to three times higher than equivalent recommended starting aluminum hydroxide dose (30 mg/kg three times daily titrated to effect)2 and should have been sufficient to bind phosphorus. Additionally, a study in human CKD patients found that when the phosphate-binding efficacy of sucralfate was compared to aluminum hydroxide, a smaller dose of sucralfate (based on the amount of elemental aluminum) was required to maintain serum phosphorus at the same level.8
The effect of sucralfate administration on serum phosphorus concentration or urinary excretion of phosphorus in cats with CKD was difficult to determine because of dehydration and worsening azotemia associated with decompensation in several cats, and this may have confounded the ability of this study to determine the true efficacy of this drug. Fractional excretion data were likely affected by GFR variability in CKD cats, as values are considered only valid for patients with CKD if comparisons are made with repeated measurements from the patient, without change in renal function. Additionally, it has been previously shown that the correlation between spot fractional excretion values and 24 hr urinary excretion is poor, particularly when such variability is present.17 Fecal phosphorus content did not appear to be affected by administration of sucralfate in this study. In contrast, a previous study assessing the efficacy of the phosphate binder lantharenol administered for 2 wk to normal cats eating a non-phosphorus restricted diet demonstrated a statistically significant increase in fecal phosphorus.18 Thus, a similar result was expected for the current study. A potential limitation of the study was that normal cats and some CKD cats did have food available to them at times in the day other than when sucralfate was administered. However, this is sometimes reported by owners for feline CKD patients. Other potential methods of assessing the efficacy of sucralfate as a phosphate binder would have been the measurement of parathyroid hormone levels and/or FGF-23 levels.6,19 At the time this study was conducted, the potential significance of FGF-23 in the pathophysiology of feline CKD was not yet described.
While cats can develop a variety of clinical abnormalities, including vomiting after periods of stress, the five client-owned cats with stable CKD that were not treated were handled identically to sucralfate-treated cats but developed no detectable abnormalities. Thus, we conclude that the formulation and dose of sucralfate used in this study was the cause of vomiting in normal cats as well as other clinical abnormalities in three of five client-owned cats with stable CKD. While different formulations of sucralfate exist, the failure to find benefits from a high dose in the normal cats described here, combined with the concerns about safety of administration of this drug, makes additional studies to determine efficacy seem pointless. The initial study design also included assessment of the safety and efficacy of sucralfate in hyperphosphatemic cats, but this portion of the study was not performed after the poor outcome for normophosphatemic CKD cats. Based on our experience with this study, the proposed benefit of sucralfate over other phosphate binders—treatment of uremic gastritis and ulceration—does not outweigh the possible disadvantages of administration, particularly because the incidence of gastric abnormalities in cats with kidney disease is unknown.
Conclusion
In this study, administration of sucralfate did not result in a decrease in serum phosphorus concentration and caused vomiting in normal cats and clinical decompensation in several CKD cats. As several new phosphate binders have recently become commercially available,2,18,20 we conclude that sucralfate cannot be recommended as a phosphate binder in cats with CKD.
This study was funded by a grant from the Center for Companion Animal Studies at Colorado State University (http://csu-cvmbs.colostate.edu/vth/veterinarians/research/companion-animals/Pages/default.aspx). The sponsors that donated money to the Center had no role in study design, collection, analysis, data interpretation, writing of the manuscript, or decision to submit the manuscript for publication.
Serum phosphorus in six normal cats. No significant difference is detected between baseline and after administration of sucralfate.
Fractional excretion of phosphorus in six normal cats. No significant difference is detected between baseline and after administration of sucralfate. A trend towards less variance is detected (P = 0.06).
Serum phosphorus concentrations before and after sucralfate treatment in five cats with CKD in comparison to five control cats. No significant difference is detected after administration of sucralfate.
Fractional excretion of phosphorus before and after sucralfate treatment in five cats with CKD in comparison to five control cats. No significant difference is detected after administration of sucralfate.
Contributor Notes
