|Year : 2016 | Volume
| Issue : 2 | Page : 290-304
|Multinational observational study on clinical practices and therapeutic management of mineral and bone disorders in patients with chronic kidney disease stages 4, 5, and 5D: The OCEANOS study
Faissal A. M. Shaheen1, Ramprasad Kurpad1, Abdulla A Al-Sayyari1, Muhammad Ziad Souqiyyeh1, Harith Aljubori2, Tarek El Baz3, Waqaruddin Kashif4, Saltanat Tuganbekova5, Kairat Kabulbayev6, Faical Jarraya7, Mohsen Nafar8
1 Saudi Center for Organ Transplantation, Riyadh, Kingdom of Saudi Arabia
2 Al-Qassimi Hospital, Sharjah, United Arab Emirates
3 Al Hussien University Hospital, Al Azhar University, Cairo, Egypt
4 The Aga Khan University Hospital, Karachi, Pakistan
5 Extracorporeal Hemocorrection Unit, Astana, Kazakhstan
6 Kazakh National Medical University, Almaty, Kazakhstan
7 Department of Nephrology, Research Unit UR12ES14, H. Chaker University Hospital, Sfax University, Sfax, Tunisia
8 Department of Nephrology, Labbafinejad Hospital, Tehran, Iran
Click here for correspondence address and email
|Date of Web Publication||11-Mar-2016|
| Abstract|| |
Our aim is to assess the current clinical practices in monitoring and treatment patterns of chronic kidney disease (CKD)-mineral bone disorder and the degree to which these practices met the kidney disease improving global outcome (KDIGO) guidelines. This was an international, multi-center, cross-sectional, observational study in adult patients diagnosed with CKD Stages 4, 5, and 5D. Patients were enrolled from Middle East, South Asia, Eurasia, and Africa; patients with estimated glomerular filtration rate ≥30 mL/min/1.73 m 2 or with any medical/surgical conditions precluding their participation were excluded. Frequency of measurements, levels of serum calcium (Ca), phosphorus and parathormone (parathyroid hormone [PTH], and presence vascular/valvular calcification were recorded. Of the 2250 patients enrolled, data on 2247 patients were evaluated. Overall, only a small percentage of patients met all three target KDIGO ranges of serum Ca, phosphorus, and PTH (13.7% [95% confidence interval: 12.0; 15.4], with a higher proportion among CKD Stage 5D patients (14.8%) than CKD Stage 4 and 5 (5.6%) patients. Majority (84.3%) of the patients received treatment with phosphorous binders, of whom 85.5% received Ca-based phosphate binders. Overall, 57.0% of patients received Vitamin D treatment with a similar frequency among patients with CKD Stages 4, 5, and 5D. Over half (65.7%) of the patients were screened for vascular/valvular calcification; of these, 58.8% had ≥1 calcification. Diabetes status, P, PTH, and low density lipoprotein-cholesterol had significant impact on the prescription pattern of phosphorous binders. The current practices for the management of bone and mineral metabolism in CKD patients in the study region fall far short of meeting the KDIGO target range.
|How to cite this article:|
Shaheen FA, Kurpad R, Al-Sayyari AA, Souqiyyeh MZ, Aljubori H, El Baz T, Kashif W, Tuganbekova S, Kabulbayev K, Jarraya F, Nafar M. Multinational observational study on clinical practices and therapeutic management of mineral and bone disorders in patients with chronic kidney disease stages 4, 5, and 5D: The OCEANOS study. Saudi J Kidney Dis Transpl 2016;27:290-304
|How to cite this URL:|
Shaheen FA, Kurpad R, Al-Sayyari AA, Souqiyyeh MZ, Aljubori H, El Baz T, Kashif W, Tuganbekova S, Kabulbayev K, Jarraya F, Nafar M. Multinational observational study on clinical practices and therapeutic management of mineral and bone disorders in patients with chronic kidney disease stages 4, 5, and 5D: The OCEANOS study. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2019 Nov 12];27:290-304. Available from: http://www.sjkdt.org/text.asp?2016/27/2/290/178266
| Introduction|| |
Chronic kidney disease (CKD) is a major public health problem affecting 8-16% of adults globally.  Untreated CKD can progress rapidly to end-stage renal disease (ESRD).  The incidence of ESRD has been estimated to be 100-140 incident cases/million population in the Middle Eastern countries.  Available data from Middle Eastern countries has demonstrated an increasing burden of ESRD, which is in line with the reported epidemiological data worldwide.  CKD has been identified as a risk factor for cognitive dysfunction, hospitalization, cardiovascular events, cardiovascular mortality, all-cause mortality, hyperparathyroidism, and poor quality of life. ,, Aging population, increasing obesity, diabetes, and hypertension have all been attributed to the rising prevalence of CKD worldwide. 
Progressive loss of kidney function in patients with CKD leads to altered levels of serum calcium (Ca), phosphorous (P) and parathyroid hormone (PTH), abnormalities in Vitamin D metabolism, bone modeling and remodeling, and extra-skeletal calcification in soft tissues and arteries. , In patients with CKD Stages 2 and 3, increased PTH, fibroblast growth factor 23, and decreased calcitriol levels result in normal to near-normal levels of blood Ca and phosphorus.  In later stages of CKD, these compensatory mechanisms eventually fail, resulting in a group of inter-related abnormalities called CKD-mineral bone disorder (CKD-MBD). Thus, although changes in the biochemical parameters of CKD-MBD may begin in CKD Stage 3, the rate and severity vary among patients.  Data from clinical studies have revealed that disturbances in mineral and bone metabolism lead to increased fractures, vascular calcification, progression of renal failure, cardiovascular diseases (CVD), morbidity and mortality. ,,
To improve the quality of care in patients with CKD-MBD, both the kidney disease outcomes quality initiative and kidney disease improving global outcome (KDIGO) guidelines have emphasized on the need to monitor serum Ca, P, and PTH levels in patients with CKD from Stage 3 onwards. , The KDIGO Guidelines (2009) have suggested maintaining serum phophorus in the normal range in patients with CKD Stages 3-5 and lowering of elevated P levels towards the normal range in patients with CKD Stage 5D, and recommend using phosphate-restricted diets in combination with oral phosphate binders in these patients.  However, data from observational studies indicate that current practice for the management of bone and mineral metabolism in CKD patients falls far short of meeting these recommendations. , Although, elevated levels of serum Ca and P have been suggested to be used to guide clinical practice, there is no consensus on the level of control to be achieved in these patients.  Moreover, regulation of mineral metabolic parameters remains an elusive goal for many individuals on dialysis despite clinical guidelines with evidence-based recommendations.  In addition, majority of the studies which have examined the management of patients with CKD-MBD, were conducted in the USA and Western European countries, and only limited data is available from countries outside these regions. As it is expected that bone abnormalities will be high in such regions, there is a need to identify the areas of improvement for management of patients with CKD-MBD, and therefore this study was undertaken.
| Materials and Methods|| |
Study design and duration
This was an international, multi-center, cross-sectional, observational study conducted with a view to reflect the real-life clinical practices and treatment patterns with respect to metabolic bone disorder in patients diagnosed with CKD Stages 4, 5, and 5D. This study was conducted in countries covered under four zones; Middle East, South Asia, Eurasia, and Africa from June 2013 to March 2014. The overall study recruitment period was nine months. The study was performed in accordance with the ethical principles laid down in the Declaration of Helsinki and guidelines for good clinical practice.
Physician and patient selections
Adult patients ≥18 years of age diagnosed with CKD Stages 4, 5, and 5D were included in the study. Written informed consent was obtained from each patient prior to the initiation of the study. Participating physicians were asked to include patients consecutively within a limited period of time (maximum in 2 weeks time). Patients with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m 2 , or those with any medical/surgical condition which in the opinion of the investigator would preclude participation in the study, or had participated in an interventional trial, were excluded. Physician representatives of the country specialized in nephrology and dialysis were randomly selected for participation from study centers.
Definition of chronic kidney disease according to kidney disease improving global outcome guidelines 
According to the KDIGO guidelines, CKD is defined as follows:
- Kidney damage for ≥3 months, as defined by structural or functional abnormalities of the kidney with or without decreased eGFR manifested by either pathophysiological abnormalities, or markers of kidney damage, including abnormalities in the composition of blood or urine, or abnormalities in imaging tests.
- eGFR <60 mL/min/1.73 m 2 for ≥3 months.
The stages of advanced CKD as classified by KDIGO include:
- Stage 4: GFR 15-29 mL/min/1.73 m 2
- Stage 5: GFR <15 mL/min/1.73 m 2
- Stage 5D: GFR <15 mL/min/1.73 m 2 on treatment with dialysis.
Frequency of measurement by chronic kidney disease stage
For CKD Stage 4, serum Ca and P were measured every 3-6 months, and PTH every 6-12 months. For CKD Stage 5 and 5D, serum Ca and P were measured every 1-3 months and PTH every 3-6 months.
Serum calcium, P and parathyroid hormone levels according to the kidney disease improving global outcome guidelines
The KDIGO target ranges recommended for serum Ca are ≥8.5-≤9.5 mg/dL in patients with CKD Stages 4, 5 and 5D. The recommended target ranges for serum phosphorous are ≥2.5-≤4.5 mg/dL in patients with CKD Stages 4 and 5, and toward normal (≥2.5-≤5.5 mg/dL) in patients with Stage 5D, while the ranges for PTH are ≥ lower limit of normal and ≤ upper limit of normal (ULN) in patients with CKD Stages 4 and 5D.
Case report forms (CRFs) were used for collecting data from patients and "Physician's Questionnaire," for data from physicians. Data recorded included patient's date of visit, age, demographics and co-morbidities, vital signs, patient characteristics and medical history, laboratory assessments, history and management of renal disease, current use of medications, presence of vascular/valvular calcifications, and methods of evaluation. Physician's Questionnaire included data on physician's age and gender, specialty and years of practice, main work place, type of institution, number of dialysis per year, number of patients with CKD seen per year, and knowledge and adherence to treatment guidelines. Adverse drug reactions were not collected in the study CRF. However, participating physician had to comply with country regulations for the spontaneous reporting of adverse drug reactions. For sub-group analysis, data were collected for variables which included patient's gender, age, body mass index (BMI), hypercholesterolemia and hypoalbuminemia status, serum Ca, P, and PTH levels for CKD Stage 5D. In addition, data on demography, vital signs, CKD stage, etiology and duration of dialysis, primary evaluation criteria, current/ongoing CKD treatment, presence of calcification, and current medication were also collected.
Data quality control was performed by trained personnel at ≥10% of sites chosen at random in each country. All CRFs were monitored for source documentation and accuracy. Data request forms were generated automatically in response to queries and resolved by the site investigators.
Primary evaluation criteria was the reach of the KDIGO target ranges for serum P, serum Ca levels, and PTH; and reach of all three targets (phosphorus, Ca, PTH). Secondary evaluation criteria were to assess the following:
(a) prescribed medication for the management of CKD-MBD including the type and total dose of medication and duration, (b) uncontrolled MBD (patients not achieving at least one KDIGO threshold target of serum Ca, P, and PTH levels, either in combination or individually), and (c) vascular/valvular calcification including methods used for screening, reporting of ≥1 vascular/valvular calcification, method used for detecting ≥1 calcifications, and treatment with Ca-based phosphate binders used for patients with ≥1 calcification.
As description of primary criteria (reach of the KDIGO targets ranges for serum P, serum Ca levels, and PTH) was performed mainly with percentage, the sample size was computed to insure sufficient precision in the assessment of a percentage. Assuming that between 5% and 50% of patients would be reaching all three KDIGO target ranges, enrollment of 60-400 patients per country would provide a precision between ±12.65% and ±2.14%.
Approximately, 1500 patients were planned to be enrolled from Nephrology Departments or 100 dialysis centers in nine countries that included Algeria, Bangladesh, Iran, Kazakhstan, Saudi Arabia, Lebanon, Pakistan, Turkey, and countries of the Gulf region.
| Statistical analysis|| |
All recorded data were descriptively analyzed. Continuous variable data were summarized using a number of non-missing data, mean ± standard deviation, median, and range. Categorical variable data was assessed using counts and percentages. Primary analyses were performed using counts and percentages with 95% confidence interval (CI) whereas secondary analyses were performed using descriptive statistics. Logistic regression was applied to analyze the association between prescriptions of Ca-based binder and age, gender, diabetes status, stage of disease, serum Ca, P, PTH, alkaline phosphatase, serum creatinine, albumin, low density lipoprotein-cholesterol (LDL-C), and at least one calcification observed during screening.
| Results|| |
A total of 157 physicians and 2250 patients with CKD Stages 4-5D participated in the registry from 13 countries across four zones (Africa, Turkey/Middle East, Eurasia, and South Asia). Of the 2250 patients enrolled, 2247 (99.9%) patients were included for analysis. Information for three patients could not be analyzed because they did not satisfy the inclusion criteria. Of the participating countries, about 50% of the patients were enrolled from seven countries in the Middle East zone and <25% from Africa or South Asia.
Majority (82.2%) of the participating physicians were nephrologists with mean age of 49.6 ± 8.3 years and median duration of practice of 20.8 ± 9.1 years. About 70% of the physicians had treated <1000 CKD patients during past one year and most of them (98.7%) mentioned having knowledge of KDIGO guidelines and 83.2% of the physicians declared that they followed the guidelines.
[Table 1] summarizes the characteristics of the study population. The majority were in the age-group of 40-60 years (42.3%). There was male predominance with a sex-ratio of 1.4 (1310/937). Majority of the patients had CKD Stage 5D (76.7%). The most common etiologies observed in the study population were hypertensive nephrosclerosis (25.2%), diabetic nephropathy (20.8%), and chronic glomerulonephritis (15.2%).
The serum levels of Ca, P, and PTH were measured in the study population. Overall, 47.2% of patients with CKD Stage 4 + 5 (95% CI: 42.7-51.7) and 45.4% of patients with Stage 5D (95% CI: 43.1-47.8) met the KDIGO targets for serum Ca. Nearly one-half of the patients with CKD Stage 4 and Stage 5D had serum P levels within the KDIGO target range [59.7% (95%CI: 53.4-65.8) and 56.3% (95%CI: 53.9-58.6)], respectively, while only one-fourth (26.6%) of patients with CKD Stage 5 had P level within KDIGO defined targets. Slightly more than half of the patients with CKD Stage 5D (51.4%, 95% CI: 48.8-54.0) had PTH level within the KDIGO target range (2 × ULN-9 × ULN) [Figure 1].
|Figure 1: Proportion of chronic kidney disease patients meeting the kidney disease improving global outcome target for serum phosphorus, calcium, and parathyroid hormone levels, by chronic kidney disease stage.|
Click here to view
Overall, only a small percentage of patients met all target KDIGO ranges for Ca, phosphorus, and PTH [13.7% (95% CI: 12.0; 15.4)], with a higher proportion in CKD Stage 5D patients (14.8%) than CKD Stage 4 and 5 (5.6%) patients.
The majority of patients were tested for serum Ca (91.2%), P (91.3%), and PTH (92.4%) within the KDIGO recommended time frame [Table 2]. The recommended frequency of measurement was met in 86.5% of patients (CKD Stage 5D: 85.1% and 4 + 5: 97.0%).
|Table 2: Frequency of measurement as per the kidney disease improving global outcome guidelines by chronic kidney disease stage.|
Click here to view
Finally, adherence to KDIGO guidelines for Ca, phosphorus, and PTH control, defined as the laboratory values meeting all KDIGO target ranges and the tests being performed at the recommended frequency, was 12.4% (95% CI: 10.9; 14.2) when all three tests were performed, lower in CKD Stage 4 and 5 (5.6%) than in CKD Stage 5D (13.4%).
Current and past chronic kidney disease medications
Majority (84.3%) of the CKD patients were currently treated with phosphate binders; this was more pronounced in patients with CKD Stage 5D (87.3%) and Stage 5 (82.3%) than Stage 4 (67.8%). Details of the other medications being administered are given in [Table 3].
|Table 3: Current chronic kidney disease-mineral bone disorder treatment by chronic kidney disease stage.|
Click here to view
Uncontrolled mineral bone density
Overall, 97.0% (n = 2180/2247) of patients had undergone at least one of the three laboratory tests; majority (83.2%, n = 1814/2180) of patients had at least one KDIGO target unmet.
Vascular/valvular calcification screening
Of the total population, 65.7% of the patients (n = 1477/2247) had at least one X-ray or ultrasound or computed tomography (CT) scan performed for vascular/valvular calcification screening. Of these, 58.8% (n = 869/1477) had at least one calcification. X-ray was the most frequently used screening test for calcification compared to ultrasound or CT scan (58.6% vs. 45.4%, and 12.8%, respectively) [Table 4].
|Table 4: Screening test performed and observation of vascular/valvular calcification by chronic kidney disease group and total.|
Click here to view
Cross tabulation between physician data and patient data
Chronic kidney disease stage of patients
Of the total patient population, 92.1% of patients with CKD Stage 4, 93.1% with Stage 5, and 81.1% with Stage 5D were followed-up by nephrologists. The Nephrology Department was the commonly involved work place for patients with CKD Stages 4, 5, and 5D (74.0%, 78.4%, and 48.3%, respectively). Most of the physicians acknowledged knowing and following the KDIGO guidelines. The proportion of patients followed-up by physicians in public institutions was higher than in private institutions for all stages.
Physician's adherence to kidney disease improving global outcome guidelines
Among patients followed-up by the nephrologists, the proportion of patients in whom all KDIGO target ranges were met was 68.4%, and those who adhered to KDIGO guidelines were 65.3%, when all three laboratory tests were performed. The proportion was higher at hemodialysis centers than at Nephrology Departments [Table 5]. The number of years of practice of participating physicians did not impact their adherence to the KDIGO guidelines. Other details are given in [Table 6].
|Table 5: Physicians' characteristics according to current or ongoing chronic kidney disease treatment.|
Click here to view
|Table 6: Physician's characteristics according to patient's adherence to KDIGO guidelines.|
Click here to view
Current chronic kidney disease treatment
[Table 6] shows the details of current CKD treatment among patients on follow-up with a nephrologist and those on follow-up with a physician.
Calcification screening of patients
Details of calcification screening including the screening modality used are given in [Table 7].
|Table 7: Physician's characteristics according to calcification screening of patients.|
Click here to view
In the overall patient population, 838 patients had diabetes (mean age 59.9 ± 11.6 years). The proportion of patients with diabetes (66.5%, n = 557/838) was higher in CKD Stages 4 and 5. Irrespective of diabetes status, there was no influence on the primary and secondary evaluation variables, except for adherence to KDIGO guidelines which was higher in patients with diabetes (15.6%, n = 81/518). The proportion of patients with ≥1 calcification was higher in patients with diabetes (68.9%, n = 364/528) than those without diabetes (53.2%, n = 505/949). Moreover, the proportion of patients with known diabetes was greater in females than males (40.1% vs. 35.3%).
The proportion of males with CKD Stage 5D was slightly higher than females (78.4% vs. 74.3%), while CKD Stages 4 and 5 were higher in female patients than in males. Irrespective of gender, there was no influence on the primary and secondary evaluation variables.
Age-group of patients
The proportion of patients with CKD was higher in the age-group of 40-70 years, and there was male preponderance (58.7% vs. 41.3%). Diabetic nephropathy was the most common cause of CKD in patients ≥70 years of age (49.4%, n = 175/354), chronic glomerulonephritis (32.3%, n = 138/427) in patients aged ≤40 years and hypertensive nephrosclerosis was the most common cause (26.0%, n = 381/1466) in patients aged 40-70 years. The proportion of patients with serum P and PTH values within the KDIGO target range was higher in patients ≥70 years (65.7%, and 55.0%, respectively), than patients between 40-70 years (52.8%, and 46.3%, respectively), and patients ≤40 years of age (47.4% and 46.8%, respectively). Moreover, the proportion of patients with ≥1 calcification was higher in patients ≥70 years (70.3%, n = 175/249) than patients between 40-70 years (62.1%, n = 580/934), and patients ≤40 years of age (38.8%, n = 114/294).
Hypoalbuminemia status of patients
A greater proportion of patients with hypoalbuminemia had known diabetes status than patients without hypoalbuminemia (44.4% vs. 34.9%). The presence or absence of hypoalbuminemia showed no influence on primary and secondary evaluation variables except that the serum Ca levels were more frequently in the KDIGO target range in patients without hypoalbuminemia than those with hypoalbuminemia (47% vs. 36.9%).
Hypercholesterolemia status of patients
Vascular calcification screening was performed more frequently in patients with hypercholesterolemia; however, it had no influence on the proportion of patients with ≥1 calcification.
Body mass index status of patients
There was no influence of BMI on primary and secondary evaluation variables among the study patients.
Analysis of serum calcium and phosphorous by group
The levels of serum Ca and P appeared to be influenced by increasing age, dialysis, and PTH levels. In the sub-group analysis, serum Ca levels increased with age from <8.5 mg/dL at 52.2 years to >9.5 mg/dL at 56.1 years. The proportion of patients with known diabetes was similar across all Ca levels (36.7% at <8.5 mg/dL, 38.2% at 8.5-9.5 mg/dL, and 32.8% at >9.5 mg/dL). The proportion of patients with PTH level within the KDIGO target range decreased with increase in Ca levels from 50.8% with serum calcium <8.5 mg/dL to 42.4% with Ca level >9.5 mg/dL. The serum P levels decreased with age from ≥4.5 mg/dL at 52.9 years to <4.5 mg/dL at 56.6 years. Higher proportion of patients with serum P level ≥4.5 mg/dL received phosphate binder treatment than patients with P level <4.5 mg/dL (88.3% vs. 79.7%). In patients with serum P level ≥4.5 mg/dL, 82.9% had received Ca-based phosphate binder and 31.1% of patients received Ca-free, nonmetal containing phosphate binder. There were no major differences in the primary and secondary evaluation variables for a given serum Ca and P levels.
The multivariate analysis of the association between the prescription of Ca-based binder and patient's characteristics revealed that nondiabetic patients were more often treated with Ca acetate or Ca carbonate than diabetic patients [67.4% vs. 32.6%, odds ratio (OR) 1.93 95% CI: (1.20; 3.10)]. The prescription of phosphate binder treatment was different according to the serum P patients with lower levels of serum P (mean serum P <5.1 ± 1.2) were more often treated with Ca acetate or Ca carbonate than those with higher levels of serum P (>5.9 ± 2.5), more often treated with other phosphate binders [OR = 0.77, 95% CI: (0.67; 0.89)].
| Discussion|| |
The present observational study provides information on the routine clinical practice and treatment patterns for the management of CKD-MBD and the level of control of serum P, Ca, and PTH in patients with CKD Stages 4, 5, and 5D. Majority of the participating physicians were nephrologists, and followed the KDIGO guidelines. The serum Ca, P, and PTH levels remained outside the KDIGO target values in majority of the patients with CKD, with only 13.7% patients meeting all the recommended targets. Despite high rates of calcification, Ca-based phosphate binders were prescribed to the majority (85.5%) of study participants.
Most of the patients participating in this study were in the age-group of 40-60 years, with more females in the predialysis stages (CKD Stage 4 + 5) and more males in the dialysis group (CKD Stage 5D). Consistent with previous studies, , in the current study, the proportion of patients with CKD Stage 4 was higher in older adults (≥70 years of age) whereas proportion of patients with CKD stage 5D was higher in the age-group of 18-40 years, suggesting that younger patients had more advanced CKD at presentation. 
The majority of study participants were monitored for serum Ca and P levels, but monitoring of the PTH levels was performed in only 37.8% of patients with CKD Stage 4 + 5. However, it should be noted that most of the patients with CKD (86.5%) were routinely monitored for progression of MBD within the recommended time frame of KDIGO guidelines. Further, easy access of patients with advanced CKD subjected to dialysis might explain higher number of patients with Stage 5D (97.0%) being available for monitoring within the recommended time frame.
The level of control in terms of serum levels as per KDIGO target range varied for Ca, P, and PTH. Although the mean serum Ca levels in the participants were well within the range, the proportion of patients meeting the KDIGO recommended targets was less than half. Similarly, in all the participants, the mean serum P levels were above the target range with only one-half of them meeting the KDIGO target range. However, a large difference could be observed in the proportion of patients with Stages 4 + 5 (21.7% patients) and Stage 5D (51.4% patients), achieving the KDIGO target range for serum PTH levels. Similar results were observed in a multicenter study conducted in Korea, where a relatively large proportion of patients undergoing chronic hemodialysis had serum Ca, P, and PTH values outside the recommended range [hyperphosphatemia: 40.7%, elevated Ca-phosphorous product levels: 29.3%, uncontrolled secondary hyperparathyroidism (PTH >300 pg/mL): 26.5% and (PTH <150 pg/mL): 42.7%].  Given that 25-hydroxyvitamin D plays an important role in maintaining adequate level of serum Ca, lower prescription rates of Vitamin D therapy in the study participants might explain inadequate serum Ca control observed in majority of patients in the current study.  Indeed, several observational studies have found a significant association between Vitamin D supplementation and serum Ca levels with beneficial effects on survival rates of patients with ESRD. ,,
Optimal maintenance of serum Ca, P, and PTH levels within the KDIGO target range is an important part of the management of CKD. A positive correlation between elevated serum P and PTH levels have been linked to increased morbidity and mortality in dialysis patients.  Analysis of data from an earlier interventional study (OPTIMA) suggests that it may be difficult to control serum P levels if PTH is persistently elevated in dialysis patients.  Based on these observations, it may be anticipated that high PTH levels can significantly impact serum Ca and P levels that can further contribute to bone and mineral disorders in patients with CKD. Despite routine monitoring in all patients, measures to control PTH and serum P levels were not identified. The sub-optimal control of serum P observed in the study participants may be linked to dietary noncompliance, inadequate dialysis, and more importantly, lack of adequate titration of daily doses of P binders by the physicians in the study population.
Elevated serum P levels in patients with CKD is known to induce soft-tissue calcifications and renal osteodystrophy.  Recent evidences implicate that hyperphosphatemia is a vital factor in the development of cardiovascular calcification, CVD, and death in patients with CKD. ,, A systematic review of 12 clinical trials investigating the role of serum phosphate levels and adverse CVD outcome found a graded independent significant association between phosphate levels and mortality, development of CVD and progression of kidney disease.  Therefore, maintaining serum P level within the target range is of vital importance in the management of CKD.
Early initiation of phosphate binders is widely considered as the optimal choice in the management of hyperphosphatemia in patients with CKD.  However, with the advent of different types of phosphate binders such as Ca-based, aluminum-based, and Ca-free binders, the choice of optimal phosphate binder therapy in patients with CKD remains a matter of debate. , Convincing data is available on the benefits of Ca-based phosphate binders to significantly reduce the serum phosphorous levels. ,, In the current study, majority of the patients (85.5%) were prescribed Ca-based phosphate binders. However, evidence from both epidemiologic and randomized control trials support the view that excess Ca administration may independently increase the risk of CVD in patients with CKD and ESRD. , Furthermore, calcium overloading through Cabased binders may enhance progression of vascular calcification both directly and indirectly by increasing systemic Ca load and by reducing the Ca storage in bones.  In a study of 120 stable ESRD patients on hemodialysis, Guιrin et al have reported a positive correlation between increase in the Ca carbonate load and progression of vascular calcification.  The KDIGO guidelines recommend restricting the use of Ca-containing phosphate binders in patients with CKD Stages 3-5D having hyperphosphatemia and arterial calcification. 
On the other hand, Ca-free phosphate binders are considered to be as effective as Ca-based phosphate binders and may be beneficial over Ca-based binders, , since they reduce Ca overload. In a study of 129 incident hemodialysis patients receiving either Ca-based or Cafree phosphate binders for 18 months, a rapid progression in coronary calcification was observed in patients receiving Ca-based phosphate binders  while a significant survival benefit was observed in those treated with Ca-based phosphate binder.  Studies on lanthanum carbonate, a non-Ca, nonaluminum-containing phosphate binder, in the management of hyperphosphatemia in patients with CKD are scarce. 
Interestingly, variations in prescription patterns of Ca-based binders was observed according to patient characteristics; diabetes, serum P, PTH, and LDL-C levels showed an association with prescription patterns. In hemodialysis patients, a higher (≥8.5%) or lower (≤5.4%) level of HbA1c is reported to increase the risk of mortality.  Therefore, Ca-based binders are more often prescribed to nondiabetic patients with near normal HbA1c values. Similarly, Ca-based binders were prescribed only to patients with low serum P and PTH levels, to avoid Ca overloading.
Adherence to guidelines is the key to improve health-related outcomes. Practice guidelines, which reflect "standard of care," for the management of CKD are available from the KDIGO guidelines. The higher proportion (87.6%) of nonadherence to the KDIGO guidelines observed in the current study could be attributed to higher costs involved in renal replacement therapy, and lack of medical reimbursement for dialysis in the participating countries. Similar reports of nonadherence to guidelines (92.0% of patients) is also reported from Tertiary Care Centers of other developing countries such as India.  Success and effectiveness of the treatment for CKD depends on the active cooperation of the patient with the therapeutic regimen, indicating scope for improvement.
| Conclusion|| |
The present study demonstrates the current practice for the management of bone and mineral metabolism, and identifies some lacunae in the management of abnormalities in serum Ca, P, and PTH levels in CKD patients from non-USA/European countries. The results of this study are important as they have potential implications for the management of CKDMBD in the Middle East, South Asia, Eurasia, and African countries. It is expected that the study findings will help physicians in managing MBD in CKD patients more optimally thereby reducing patients' morbidity and mortality. Furthermore, due to treatment gaps between global and local practices, there is a great unmet need to have a uniform method for adherence to guidelines and practice for the management of patients with CKD.
| Acknowledgments|| |
The authors thank Palash Kumar Das, Ph.D., and Vimal Kumar Varma M, Ph.D. from Jeevan Scientific Technology Limited (Hyderabad, India) and Anahita Gouri of Sanofi (India) for providing writing assistance in the development of this manuscript.
Source of Support
This study was sponsored by Sanofi-Aventis.
Conflict of Interest
There is no conflict of interest in connection with the submitted manuscript.
| References|| |
Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: Global dimension and perspectives. Lancet 2013;382:260-72.
Gilbertson DT, Liu J, Xue JL, et al. Projecting the number of patients with end-stage renal disease in the United States to the year 2015. J Am Soc Nephrol 2005;16:3736-41.
Shaheen FA, Souqiyyeh MZ. Kidney health in the Middle East. Clin Nephrol 2010;74 Suppl 1:S85-8.
Hassanien AA, Al-Shaikh F, Vamos EP, Yadegarfar G, Majeed A. Epidemiology of end-stage renal disease in the countries of the Gulf Cooperation Council: a systematic review. JRSM Short Rep 2012;3:38.
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitallization. N Engl J Med 2004;351:1296-305.
Madan P, Kalra OP, Agarwal S, Tandon OP. Cognitive impairment in chronic kidney disease. Nephrol Dial Transplant 2007;22:440-4.
Moranne O, Froissart M, Rossert J, et al. Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol 2009;20: 164-71.
Stevens LA, Viswanathan G, Weiner DE. Chronic kidney disease and end-stage renal disease in the elderly population: current prevalence, future projections, and clinical significance. Adv Chronic Kidney Dis 2010;17: 293-301.
Moorthi RN, Moe SM. CKD-mineral and bone disorder: core curriculum 2011. Am J Kidney Dis 2011;58:1022-36.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 2009; 113;1S1-130.
Kestenbaum B, Sampson JN, Rudser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol 2005;16:520-8.
Young EW, Albert JM, Satayathum S, et al. Predictors and consequences of altered mineral metabolism: the dialysis outcomes and practice patterns study. Kidney Int 2005;67:1179-87.
National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003;42 4 Suppl 3:S1-201.
Andrassy KM. Comments on 'KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease'. Kidney Int 2013;84:622-3.
Kim GH. Gaps between global guidelines and local practices in CKD-MBD. Electrolyte Blood Press 2014;12:35-40.
Wei M, Taskapan H, Esbaei K, Jassal SV, Bargman JM, Oreopoulos DG. K/DOQI guideline requirements for calcium, phosphate, calcium phosphate product, and parathyroid hormone control in dialysis patients: can we achieve them? Int Urol Nephrol 2006;38:739-43.
Drey N, Roderick P, Mullee M, Rogerson M. A population-based study of the incidence and outcomes of diagnosed chronic kidney disease. Am J Kidney Dis 2003;42:677-84.
Shlipak MG, Katz R, Kestenbaum B, et al. Rate of kidney function decline in older adults: a comparison using creatinine and cystatin C. Am J Nephrol 2009;30:171-8.
Rajapurkar MM, John GT, Kirpalani AL, et al. What do we know about chronic kidney disease in India: first report of the Indian CKD registry. BMC Nephrol 2012;13:10.
Kim GH, Choi BS, Cha DR, et al. Serum calcium and phosphorus levels in patients undergoing maintenance hemodialysis: A multicentre study in Korea. Kidney Res Clin Pract 2014; 33:52-7.
Bouillon R, Suda T. Vitamin D: calcium and bone homeostasis during evolution. Bonekey Rep 2014;3:480.
Shoji T, Shinohara K, Kimoto E, et al. Lower risk for cardiovascular mortality in oral 1alphahydroxy Vitamin D3 users in a haemodialysis population. Nephrol Dial Transplant 2004;19: 179-84.
Teng M, Wolf M, Ofsthun MN, et al. Activated injectable Vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol 2005;16:1115-25.
Pilz S, Iodice S, Zittermann A, Grant WB, Gandini S. Vitamin D status and mortality risk in CKD: a meta-analysis of prospective studies. Am J Kidney Dis 2011;58:374-82.
Malluche HH, Monier-Faugère MC. Hyperphosphatemia: pharmacologic intervention yesterday, today and tomorrow. Clin Nephrol 2000;54:309-17.
Frazão 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 hyperparathyroidism? BMC Nephrol 2012;13:76.
Jono S, McKee MD, Murry CE, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000;87: E10-7.
Stevens LA, Djurdjev O, Cardew S, Cameron EC, Levin A. Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes. J Am Soc Nephrol 2004;15:770-9.
McGovern AP, de Lusignan S, van Vlymen J, et al. Serum phosphate as a risk factor for cardiovascular events in people with and without chronic kidney disease: a large community based cohort study. PLoS One 2013;8:e74996.
Dhingra R, Gona P, Benjamin EJ, et al. Relations of serum phosphorus levels to echocardiographic left ventricular mass and incidence of heart failure in the community. Eur J Heart Fail 2010;12:812-8.
Kanbay M, Goldsmith D, Akcay A, Covic A. Phosphate the silent stealthy cardiorenal culprit in all stages of chronic kidney disease: a systematic review. Blood Purif 2009;27:220-30.
Goldsmith D, Covic A. Oral phosphate binders in CKD - Is calcium the (only) answer? Clin Nephrol 2014;81:389-95.
de Francisco AL. Phosphate binders. Is selection determined by price? Yes. Nefrologia 2012;32:235-9.
Cozzolino M, Mazzaferro S, Brandenburg V. The treatment of hyperphosphataemia in CKD: calcium-based or calcium-free phosphate binders? Nephrol Dial Transplant 2011;26: 402-7.
Alfrey AC. Aluminum toxicity in patients with chronic renal failure. Ther Drug Monit 1993; 15:593-7.
Slatopolsky E, Weerts C, Lopez-Hilker S, et al. Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis. N Engl J Med 1986;315:157-61.
Coladonato JA. Control of hyperphosphatemia among patients with ESRD. J Am Soc Nephrol 2005;16 Suppl 2:S107-14.
Molony DA, Stephens BW. Derangements in phosphate metabolism in chronic kidney diseases/end-stage renal disease: therapeutic considerations. Adv Chronic Kidney Dis 2011;18:120-31.
Kuznik A, Mardekian J, Tarasenko L. Evaluation of cardiovascular disease burden and therapeutic goal attainment in US adults with chronic kidney disease: an analysis of national health and nutritional examination survey data, 2001-2010. BMC Nephrol 2013;14:132.
Shroff RC, McNair R, Skepper JN, et al. Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. J Am Soc Nephrol 2010;21:103-12.
Guérin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000;15:1014-21.
Vlassara H, Uribarri J, Cai W, et al. Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease. Clin J Am Soc Nephrol 2012; 7:934-42.
Hutchison AJ, Smith CP, Brenchley PE. Pharmacology, efficacy and safety of oral phosphate binders. Nat Rev Nephrol 2011;7:578-89.
Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 2005;68:1815-24.
Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int 2007;71:438-41.
Albaaj F, Hutchison AJ. Lanthanum carbonate for the treatment of hyperphosphataemia in renal failure and dialysis patients. Expert Opin Pharmacother 2005;6:319-28.
Hill CJ, Maxwell AP, Cardwell CR, et al. Glycated hemoglobin and risk of death in diabetic patients treated with hemodialysis: a meta-analysis. Am J Kidney Dis 2014;63:84-94.
Pavana M, Ranganathb R, Chaudhari AP, Upadhayayac KL, Mehtac HJ. Practice pattern of chronic kidney disease-mineral and bone disorder (CKD-MBD) in hemodialysis patients in a tertiary care centre in India. Dial Transplant 2012;33:110-4.
Faissal A. M. Shaheen
Saudi Center for Organ Transplantation, P. O. Box 27049, Riyadh 11417
Kingdom of Saudi Arabia
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]