| Abstract|| |
Studies have shown that the mean or median phosphate levels were related to certain factors although applying this finding into the clinical setting is challenging. In this study, we attempted to determine treatment characteristics for patients with end-stage renal disease (ESRD) on maintenance hemodialysis (MHD) having hyperphosphatemia or hypophosphatemia in comparison with those with normal phosphate level. This was a cross-sectional survey conducted at HD units of Central Pahang Cluster Hospitals, Malaysia, in April 2017 involving 110 ESRD patients on MHD. About 40% of the study patients had normo-or hyperphosphatemia. As many as 84.5% (n = 93) of our patients were prescribed calcium carbonate (CC); the phosphate level was not affected by phosphate binder (PB) adherence. None of our patients received more than one type of PBs. Although there were no significant differences in any factors between normo- and hyperphosphatemic patients, 64% (n = 28) of the hyperphosphatemic patients did not receive the recommended maximum PB dose. In addition, 42% (n = 30) of patients with normo- and hyperphosphatemia prescribed CC received more than the recommended daily elemental calcium. On the other hand, our hypophosphatemic patients tended to be significantly older and had lower HD duration compared to normophosphatemic patients. No other significant differences were found in medication factors between normo- and hypophos-phatemic patients. There is potential to maximize phosphate control in hyperphosphatemic patients in Malaysia by maximizing PB therapy. On the other hand, proactive supervision is required in caring and prescribing for hypophosphatemic patients, especially the older patients.
|How to cite this article:|
Mohamed Koya SM. Management of phosphate abnormalities in hemodialysis patients: Findings from Malaysia. Saudi J Kidney Dis Transpl 2019;30:670-7
|How to cite this URL:|
Mohamed Koya SM. Management of phosphate abnormalities in hemodialysis patients: Findings from Malaysia. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 May 31];30:670-7. Available from: http://www.sjkdt.org/text.asp?2019/30/3/670/261343
| Introduction|| |
Chronic kidney disease (CKD) is one of the major noncommunicable diseases worldwide. It has been reported that the annual incidence of end-stage renal disease (ESRD) stood at 282 per million population. Malaysia has reported the prevalence of CKD Stage 5 of around 0.36%. ESRD results in an array of metabolic complications such as phosphate imbalance. While the ideal phosphate level in ESRD on maintenance hemodialysis (MHD) is 1.13-1.78 mmol/L, levels below or above this indicate the presence of hypo-or hyperphos-phatemia. Hyperphosphatemia can lead to detrimental effects such as cardiovascular calcification, renal osteodystrophy, secondary hyperparathyroidism, and increased mortality. Management of hyperphosphatemia involves both lifestyle factors such as diet low in phosphorus and use of medication called phosphate binders (PBs).,
Several PBs have been used for the management of hyperphosphatemia including calcium carbonate (CC), lanthanum carbonate (LC), and sevelamer hydrochloride (SH)., The use of aluminum hydroxide is less favored due to its side effects. In Malaysia, CC is still the main PB used in the management of hyperphosphatemia. However, overdependence on CC might pose some threats toward patient’s health such as cardiovascular calcifications.,
In addition, success of treatment also depends hugely on adherence to PBs,,, despite its inconsistency when it is measured using self-report, medication possession ratio (MPR), or medical electronic monitoring system.,,, Similarly, hypophosphatemia tends to occur in the elderly and is also associated with mortality in patients older than 65 years.
Existing studies have described the occurrence of phosphate abnormalities among MHD population,, along with its association with mortality across different age groups and factors influencing PB adherence or phosphate control.,,, Although treatment for phosphate abnormalities is evolving in developed countries,,,, studies investigating management of phosphate derangement among ESRD patients in Malaysia on MHD are still lacking.
Existing studies also tend to pool subjects with hypo-, normo- and hyperphosphatemia together, and predictably, the mean or median phosphate levels have shown significant associations with certain factors such as PB adherence,, age,, and PB pill burden. However, applying these findings into clinical practice is still challenging, given the nonexis-tence of studies that investigated the roles of these factors in hypo-or hyperphosphatemia in comparison to normophosphatemic patients. Using normophosphatemic patients as a reference, when studying phosphate abnormalities among ESRD patients, pharmacists and clinicians are provided with greater insight into factors influencing phosphate control.,
| Aim|| |
The aim of this study is to determine treatment characteristics for patients with hyper-phosphatemia and hypophosphatemia in comparison to those with normal phosphate level as a reference among ESRD patients on MHD.
| Methods|| |
This cross-sectional survey utilized convenience sampling technique and was conducted in April 2017 at three HD units of Central Pahang Cluster Hospitals, Malaysia. It comprises three different hospitals from different localities. However, all patients from cluster hospitals were managed by the same consultant nephrologist and medical officers.
The inclusion criteria were that the patients must be older than 25 years, had at least 80% HD sessions attendance in the past three months and did not miss the last nephrologist’s follow-up, received 4 h HD thrice weekly, have been on HD treatment for a minimum of three months before the study, and received PB therapy. Patients with language barrier, who refused to participate, or having mental illness and speech and hearing disabilities were excluded from the study. Among the investigated PBs in this cohort were CC, LC, and SH.
Based on a previous study, the prevalence of use of CC among HD patients was found to be around 87%. Using available sample size calculator, the estimated sample size needed was 174 participants, to produce precision of ±0.05. This survey was conducted once the respondents’ written consent was obtained and we allocated between 15 to 30 min to conduct survey for each participant. We used the Malaysian Medication Adherence Scale to assess adherence to PBs. It consists of eight questions with a total mark of eight. Participants who scored between six and eight and less than six were categorized as “adherent” and “nonadherent,” respectively.
Information related to blood parameters, age, and medication was extracted from the patients’ medication records. Blood analysis for phosphate was obtained by the nurses 1 week before the survey
The pill burden of PBs was defined by the total daily PBs taken by the patients. Simple categorization was used to determine the maximum PB dose for each patient. For instance, maximum daily elemental calcium from CC was set at 1500 mg as suggested by the Kidney Disease Outcomes Quality Initiative (KDOQI). Their elemental calcium from CC was calculated using the formula: Elemental calcium from CC = Current dose (in gram, g) × 0.4
For LC and SH, maximum daily doses were set at 4.5 and 13 g, respectively. Those patients with PB dose lower than the maximum dose were classified as not achieving maximum dose.
It was also intended to measure achievement to maximum dose for each PB used among normo- and hyperphosphatemia patients. For CC:
“Percentage to maximum dose” = Current CC dose (in gram) × 0.4 × 100%/1.5 g. For LC:
“Percentage to maximum dose” = Current LC dose (in gram) × 100%/4.5 g. For SH:
“Percentage to maximum dose” = Current SH dose (in gram) × 100%/13 g.
This study was approved by the Medical Research Ethics Committee with NMRR ID: NMRR-17-101-34100 (IIR)
| Statistical Analysis|| |
Analysis was undertaken using the Statistical Package for the Social Sciences (SPSS) for Windows, version 18.0 (SPSS Inc., Chicago, IL, USA). Chi-square test or likelihood ratio was used for analysis between categorical variables. Mann–Whitney U-test was used to determine relationships for scores between categorical and continuous nonparametric variables. Continuous variables were expressed as median with interquartile range (IQR). P < 0.05 was considered statistically significant.
| Results|| |
A total of 113 of the 132 patients approached agreed to participate in the study (response rate, 85.6%). Three patients aged younger than 25 years were excluded from the analysis, hence giving a total sample of 110 participants with precision of ±0.06.
Comparison of characteristics between normo- and hyperphosphatemic patients
In terms of demographics, the occurrence of normophosphatemia was not statistically different to hyperphosphatemia between genders and HD duration. However, we observed that hyperphosphatemic patients tended to be younger, and the median age was 46 years (IQR, 26.8), compared to those with normal phosphate level, median 57.8 (IQR, 17.3), P = 0.019. They also tended to start MHD early, median age 38 years (IQR, 24.7), compared to median 50.8 (IQR, 17.9), in patients with normal phosphate level, P = 0.005. Despite this, the occurrence of hyperphosphatemia was not statistically significant compared to normophosphatemia across the three age groups of 25–44, 45–64, and >65 years. In terms of medication used, the two groups differed significantly (χ2 = 6.161, df = 1, P = 0.013), although other factors such as PB adherence, daily dose frequency, and PB pill burden did not influence the differences between normo- and hyperphosphatemia significantly [Figure 1]. Data are shown in [Table 1].
|Figure 1: Adherence to phosphate binders versus phosphate level in the study patients.|
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|Table 1: Comparison for different characteristics between normo- and hyperphosphatemic patients.|
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As shown in [Figure 2], we noticed that achievement for “percentage to maximum dose” for “other” PBs, namely SH and LC with median of 44.4% (IQR, 48.2) was significantly low compared to CC, median 80% (IQR, 66.7) among subgroups of normoand hyperphosphatemic patients.
|Figure 2: Type of phosphate binders used versus percent to maximum dose.|
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Comparison of characteristics between normoand hypophosphatemic patients
In terms of demographics, the occurrence of hypophosphatemia was statistically different to normophosphatemia between genders (χ2 = 4.400, df = 1, P = 0.036). HD duration was significantly shorter in hypophosphatemic patients, median 41 months (IQR, 53), compared to normophosphatemic patients, median 70 months (IQR, 64), P = 0.016.
We observed that hypophosphatemic patients tend to be older, median age 66.0 years (IQR, 12.3), compared to those with normal phosphate level, median age 57.8 years (IQR, 17.3), P = 0.004. This observation persisted even after age was regrouped into three categories (χ2 = 13.835, df = 1, P = 0.001). Hypophosphatemic patients also tended to start MHD later, median age 61.6 years (IQR, 12.9), compared to median age of 50.8 years (IQR, 17.9) in normophosphatemic patients, P =0.001.
Overall, there was no significant difference in terms of PBs used, adherence, daily dose frequency and PB pill burden. Data are shown in [Table 2].
|Table 2: Comparison for different characteristics between normo- and hypophosphatemic patients.|
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| Discussion|| |
In the current study, age-range of >25 years selected for analysis was in accordance with guidelines provided and previous available study that investigated mortality in HD population. Overall, as many as 40% of our patients had normal phosphate range, which was very similar to 36% among patients in the UK. In terms of hyperphosphatemia, our figure was similar to 41% found in another large study involving 5262 patients across different countries in the Dialysis Outcome and Practice Pattern Study.
Malaysia is a developing country with financial constrains reflected by high use of calcium-based PB compared to some developed countries that have shifted toward use of non-calcium based PBs such as SH and LC.,, One of the benefits of non-calcium-based PBs is the reduction of mortality among
MHD patients,, even though a review of literature has shown rather mixed effect with regard to mortality and vascular calcification. The percentage of our patients prescribed with CC was similar to 87.8% in another study conducted in an urban region of Malaysia. In general, this figure was higher than 10%–37% in developed countries.,,
Similar to previous studies,,, it was found that adherence among our patients was not related to phosphate level. On the contrary, even though the lower phosphate level observed in the older patients was due to decreased tubular absorption compared to the younger patients, studies using both MEMS and questionnaires have shown that good adherence played an important role in attaining good phosphate control among ESRD patients of any age.,, These variations,,,, have made interpretation and application of assessment of adherence into clinical practice rather difficult. Inconsistent data raised concern for factors such as over-or underestimation of patient’s adherence behavior when questionnaire and MPR are used for assessment of adherence., Overestimation of adherence by patients might jeopardize treatment via unnecessary treatment intensification such as dose increment and introduction of new drug by health-care practitioners. On the other hand, prescribers’ refusal to alter treatment regimen based solely on underestimation of patient’s adherence despite the contrary might compromise patient’s well-being resulting in their early demise. Physicians’ overestimation of patient’s adherence toward their medication can also pose some problems. For instance, studies among HIV patients showed that physicians’ estimation of patient’s adherence was not always accurate and adherence overesti-mation could result in unnecessary ordering for resistance testing.,
Even though risk of over-or underestimation of patient’s adherence does occur, the current findings related to PB adherence and phosphate level must be looked from different perspectives due to variations in treatment approaches within our setting compared to the developed countries.,, Several factors such as treatment adequacy and suitability must be taken into consideration when caring for hyper-phosphatemic ESRD patients in Malaysia or any other settings with limited treatment options.
Contrary to another study abroad, our median PB pill burden was only six. Apparently, none of our patients received more than one type of PB compared to 13% to 32% in patients abroad,,, even though this practice is warranted in those with uncontrolled hyperphosphatemia.
Due to this limitation, the maximum amount of PB pill burden to control phosphate level in both normal and hyperphosphatemic patients in the current study logically did not materially differ. The lack of significant difference between patients with normal and hyperphos-phatemia in terms of PB pill burden might indicate that our hyperphosphatemic patients received suboptimized treatment for their condition. This is strengthened by the fact that almost 64% of our hyperphosphatemic patients did not receive maximum dose of therapy with PB recommended for their condition and those receiving LC and SH were mostly affected since they only received a median of 44.4% of the maximum studied daily dose.
Second, use of PB such as aluminum hydroxide has been abandoned at our hospitals even though it is a beneficial drug if used properly. Third, it was observed that as many as 42% of our normo- and hyperphosphatemic ESRD patients who were treated with CC were receiving more than 1500 mg elemental calcium per day which was higher than recommended by KDOQI guideline. Due to this finding, it is vital that evaluation related to CC usage in our HD patients is done regularly in order to prevent complications such as vascular calcification.,
Finally, despite higher phosphate levels in younger patients, the possibility of any ESRD patients developing hyperphosphatemia was not different from those with normal phosphate levels, which might be reflected by the fact that mortality was similar across any age-group with hyperphosphatemia. Hence, instead of overemphasizing on control of hyperphos-phatemia among younger ESRD patients, this issue must be tackled equally in any ESRD patient regardless of age.
Similar to normo- and hyperphosphatemic patients, we found that our hypophosphatemic patients did not differ from those with normo-phosphatemia. However, lower phosphate level was found in older patients among sub-groups of normal and hypophosphatemia ESRD patients on MHD. It is hypothesized that PB pill burden would at least be significantly different between normo- and hypophospha-temia groups. However, it was not observed in the current study. Hence, the concern is the possibility of overprescribing PBs in hypo-phosphatemic patients, especially the elderly, because they are already at risk of hypophos-phatemia due to physiologically decreased phosphate absorption. Overprescribing PBs might only exacerbate hypophosphatemia among older ESRD patients due to their capacity to reduce phosphate absorption further.,, In contrast to hyperphosphatemic patients, the occurrence of hypophosphatemia was significantly different in normophosphatemic patients across different age groups, indicating its seriousness. The current study also found shorter dialysis duration among hypophospha-temic patients compared to those with normal phosphate level, raising suspicion for lower life expectancy among hypophosphatemic patients in Malaysia. This observation certainly calls for the evaluation of management of hypophosphatemia, especially the elderly, due to the fact that hypophosphatemia has been found to cause higher mortality among older ESRD patients compared to the younger patients.
| Strength and Limitations|| |
This was the first study to investigate and highlight phosphate control and its treatment characteristics in Malaysia and as such looking at PB therapy. However, this study has several limitations. First, the sample size was slightly smaller than expected and hence less precise due to resources constraint. Besides, we only recruited ESRD patients from the hospital setting while excluding those from private HD centers and focused on a single race. The study was also conducted in one particular region of Malaysia, which may hinder generalization.
| Conclusions|| |
Despite dependency on CC and limited use of newer PBs, the percentage of our patients with controlled phosphate level was similar to those from developed countries. This could be an indication that has potential to further maximize phosphate control among ESRD patients on MHD from Malaysia or other developing countries. Aside from that, it is of importance to emphasize that high adherence in the face of inadequate dose or treatment will only compromise ability to attain ideal target biomarker such as phosphate level. Finally, we need a higher supervision and regular monitoring regarding use and need of PB in hypophos-phatemic patients, especially the elderly, because they are already at high risk of developing hypophosphatemia.
| Acknowledgment|| |
The author would like to thank Miss. Nur Amirah Zulkepli for her assistance with data collection.
Conflicts of interest: None declared.
| References|| |
Alashek WA, McIntyre CW, Taal MW. Epidemiology and aetiology of dialysis-treated end-stage kidney disease in Libya. BMC Nephrol 2012;13:33.
Hooi LS, Ong LM, Ahmad G, et al.
A population-based study measuring the prevalence of chronic kidney disease among adults in West Malaysia. Kidney Int 2013;84:1034-40.
Levy J, Morgan J, Lawrence A. Oxford Handbook of Dialysis. Oxford: Oxford University Press; 2016.
Lertdumrongluk P, Rhee CM, Park J, et al.
Association of serum phosphorus concentration with mortality in elderly and nonelderly hemodialysis patients. J Ren Nutr 2013;23: 411-21.
Cupisti A, Gallieni M, Rizzo MA, Caria S, Meola M, Bolasco P. Phosphate control in dialysis. Int J Nephrol Renovasc Dis 2013;6: 193-205.
Waheed AA, Pedraza F, Lenz O, Isakova T. Phosphate control in end-stage renal disease: Barriers and opportunities. Nephrol Dial Transplant 2013;28:2961-8.
Gutekunst L. An update on phosphate binders: A Dietitian’s perspective. J Ren Nutr 2016;26: 209-18.
Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. N
Engl J Med 2010;362:1312-24.
Md Yusop NB, Yoke Mun C, Shariff ZM, Beng Huat C. Factors associated with quality of life among hemodialysis patients in Malaysia. PLoS One 2013;8:e84152.
Van Camp YP, Vrijens B, Abraham I, Van Rompaey B, Elseviers MM. Adherence to phosphate binders in hemodialysis patients: Prevalence and determinants. J Nephrol 2014; 27:673-9.
Fissell RB, Karaboyas A, Bieber BA, et al.
Phosphate binder pill burden, patient-reported non-adherence, and mineral bone disorder markers: Findings from the DOPPS. Hemodial Int 2016;20:38-49.
Wang S, Alfieri T, Ramakrishnan K, Braunhofer P, Newsome BA. Serum phosphorus levels and pill burden are inversely associated with adherence in patients on hemodialysis. Nephrol Dial Transplant 2014; 29:2092-9.
Chiu YW, Teitelbaum I, Misra M, de Leon EM, Adzize T, Mehrotra R. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J Am Soc Nephrol 2009;4:1089-96.
Alkatheri AM, Alyousif SM, Alshabanah N, et al.
Medication adherence among adult patients on hemodialysis. Saudi J Kidney Dis Transpl 2014;25:762-8.
] [Full text]
Collinson A, McMullan M, Tse WY, Sadler H. Managing serum phosphate in haemodialysis patients: Time for an innovative approach? Eur J Clin Nutr 2014;68:392-6.
Chua SS, Lai PS, Tan CH, Morisky DE. The development and validation of the Malaysian Medication Adherence Scale (MALMAS) on patients with type 2 diabetes in Malaysia. Int J Pharm Pharm Sci 2013;5:790-4.
National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42:S1-201.
Komaba H, Kakuta T, Suzuki H, Hida M, Suga T, Fukagawa M. Survival advantage of lanthanum carbonate for hemodialysis patients with uncontrolled hyperphosphatemia. Nephrol Dial Transplant 2015;30:107-14.
Patel L, Bernard LM, Elder GJ. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: A meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol 2016;11:232-44.
Malas MB, Canner JK, Hicks CW, et al.
Trends in incident hemodialysis access and mortality. JAMA Surg 2015;150:441-8.
Martins MT, Silva LF, Kraychete A, et al.
Potentially modifiable factors associated with non-adherence to phosphate binder use in patients on hemodialysis. BMC Nephrol 2013; 14:208.
Cirillo M, Ciacci C, De Santo NG. Age, renal tubular phosphate reabsorption, and serum phosphate levels in adults. N
Engl J Med 2008; 359:864-6.
Lam WY, Fresco P. Medication adherence measures: An overview. Biomed Res Int 2015;2015:217047.
Stirratt MJ, Dunbar-Jacob J, Crane HM, et al.
Self-report measures of medication adherence behavior: Recommendations on optimal use. Transl Behav Med 2015;5:470-82.
Murri R, Ammassari A, Trotta MP, et al.
Patient-reported and physician-estimated adherence to HAART: Social and clinic center-related factors are associated with discordance. J Gen Intern Med 2004;19:1104-10.
Miller LG, Liu H, Hays RD, et al.
How well do clinicians estimate patients’ adherence to combination antiretroviral therapy? J Gen Intern Med 2002;17:1-11.
Frazao JM, Braun J, Messa P, Dehmel B, Mattin C, Wilkie M. Is serum phosphorus control related to parathyroid hormone control in dialysis patients with secondary hyperpara-thyroidism? BMC Nephrol 2012;13:76.
Saiful Nizam MV Mohamed Koya
Department of Specialist Pharmacy, Jerantut Hospital, 27000 Pahang
[Figure 1], [Figure 2]
[Table 1], [Table 2]