|Year : 2016 | Volume
| Issue : 7 | Page : 62-80
|Mineral bone disorder and its management among hemodialysis patients in the Gulf Cooperation Council: Initial findings from the dialysis outcomes and practice patterns study (2012-2015)
Issa Al Salmi1, Mona AlRukhaimi2, Ali AlSahow3, Faisal A. M. Shaheen4, Saeed M. G. Al-Ghamdi5, Fadwa AlAli6, Sumaya AlGhareeb7, Yacoub Al Maimani1, Mohammed AlGhonaim8, Brian Bieber9, Francesca Tentori10, Ronald L Pisoni9, GCC-DOPPS 5 Study Group11
1 The Renal Medicine Department, The Royal Hospital, Muscat, Oman
2 Dubai Medical College, Dubai, United Arab Emirates
3 Division of Nephrology, Jahra Hospital, Jahra, Kuwait
4 Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia
5 Department of Medicine, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
6 Department of Nephrology, Hamad General Hospital, Doha, Qatar
7 Department of Nephrology, Salmaniya Medical Complex, Manama, Bahrain
8 Nephrology Division, Department of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
9 Arbor Research Collaborative for Health, Ann Arbor, MI, USA
10 Arbor Research Collaborative for Health, Ann Arbor, MI; Vanderbilt University, Nashville, TN, USA
11 Study Group in Acknowledgment
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|Date of Web Publication||1-Dec-2016|
| Abstract|| |
The prospective cohort Dialysis Outcomes and Practice Patterns Study (DOPPS) initiated data collection in national samples of hemodialysis (HD) units (total of 41 study sites) in all six Gulf Cooperation Council (GCC) countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates) in late 2012. Here, we report initial results regarding mineral bone disorders (MBDs) and its management in the GCC countries. Forty-one randomly selected HD facilities, treating >23 HD patients each, were sampled and represent care for >95% of GCC HD patients. Descriptive results for the GCC countries based on a random sample of 20-30 HD patients in each study facility. Initial results for the GCC are from 931 HD patients treated at 41 dialysis units (ranging from 1 unit in Bahrain to 21 in Saudi Arabia). Results are presented as weighted estimates, accounting for the sampling fraction in each unit. Baseline descriptive statistics (e.g., mean, median, or percentage), weighted by facility sampling fraction were calculated for the study sample. For analyses examining the percent of facility patients having (a) serum phosphorus >6.0 mg/dL or (b) parathyroid hormone (PTH) >600 pg/mL, analyses were restricted to facilities having at least 10 HD patients with a reported serum phosphorus or PTH measurement, respectively. Logistic regression analyses of the indicated binary outcomes were based on the use of generalized estimating equations and were adjusted for GCC country, patient age category (<45 years, 45-65 years, and >65 years old), sex, and whether the patient was diagnosed with diabetes mellitus. Logistic models accounted for clustering of patients within facilities, assuming an exchangeable working correlation matrix. Mean age of HD patients in the GCC countries was 53 years vs. 61-64 years in the three other DOPPS regions. MBD markers showed slightly lower mean serum Calcium in the GCC countries, similar mean serum phosphorus, and intermediate median PTH levels compared with the three other DOPPS regions. Among GCC countries, the country mean value of MBD markers ranged from 8.6-9.0 mg/dL for serum calcium, 4.4-5.4 mg/dL for serum phosphorus, whereas median PTH ranged from 163-389 pg/mL. Similar to other DOPPS regions, PTH was higher among patients who were younger or without diabetes, and serum phosphorus was lower with older age (P <0.001 for each). History of parathyroidectomy was lower in the GCC countries versus other regions but did not differ when adjusted for age and dialysis vintage. Among treatments used for managing MBD, the GCC countries showed one of the highest uses of cinacalcet (24%) and phosphorus binder use (81%), whereas intravenous Vitamin D use (24%) was slightly higher than that in EURANZ. A much larger fraction of HD patients in the GCC countries had a dialysate calcium bath ≥3.5 mEq/L (43%) versus 0-4% in the three other DOPPS regions. Although many aspects of MBD management and MBD marker achievement are similar in the GCC countries to that seen in other DOPPS study regions, large variability was seen across countries and facilities in the GCC. Mean serum calcium was lower in the GCC despite the much greater use of dialysate Ca of ~3.5 mEq/L which may be due to the relatively low use of vitamin D and higher cinacalcet use, meriting further study. Future work will focus on GCC facility HD practices and patient characteristics most strongly related to the achievement of MBD target levels and associated outcomes.
|How to cite this article:|
Al Salmi I, AlRukhaimi M, AlSahow A, Shaheen FA, Al-Ghamdi SM, AlAli F, AlGhareeb S, Al Maimani Y, AlGhonaim M, Bieber B, Tentori F, Pisoni RL, GD. Mineral bone disorder and its management among hemodialysis patients in the Gulf Cooperation Council: Initial findings from the dialysis outcomes and practice patterns study (2012-2015). Saudi J Kidney Dis Transpl 2016;27, Suppl S1:62-80
|How to cite this URL:|
Al Salmi I, AlRukhaimi M, AlSahow A, Shaheen FA, Al-Ghamdi SM, AlAli F, AlGhareeb S, Al Maimani Y, AlGhonaim M, Bieber B, Tentori F, Pisoni RL, GD. Mineral bone disorder and its management among hemodialysis patients in the Gulf Cooperation Council: Initial findings from the dialysis outcomes and practice patterns study (2012-2015). Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2021 Apr 16];27, Suppl S1:62-80. Available from: https://www.sjkdt.org/text.asp?2016/27/7/62/194902
| Introduction|| |
Calcium, phosphate and the calciotropic hormones, parathyroid hormone (PTH), fibroblast-growth factor-23, and Vitamin D metabolites, especially the 1,25-dihydroxyvitamin D metabolite, interplay in a well-balanced physiological rhythm to set up and maintain a proper bone mineral metabolism (BMM) control. , Chronic kidney disease (CKD) is associated with progressive alterations in BMM that interacts with vascular biology producing a syndrome of bone and extraskeletal calcifications called mineral bone disorder (MBD).  Secondary hyperparathyroidism (sHPT) is a physiological response of parathyroid gland to phosphate retention and reduction in synthesis of Vitamin D and hypocalcemia.  It has been shown that sHPT is associated with high morbidity and mortality. 
Over the last few decades, socioeconomic changes have resulted in improvements in the living status of persons within the six Gulf Cooperation Council (GCC) Countries [Bahrain, Qatar, Kuwait, Oman, Saudi Arabia, and the United Arab Emirates (UAE)], and over this time period, an epidemiological transition from infectious to noncommunicable chronic diseases has occurred. For example, females have developed various metabolic abnormalities, , and Vitamin D deficiency in the general population, due to low daily sunlight exposure, is of special significance for particular chronic diseases. ,
CKD and end-stage kidney disease (ESKD) patients are progressively increasing over the last decade throughout all these countries.  These patients, in addition to sociocultural factors, are being exposed to worse MBD in the context of also being exposed more often to various other chronic diseases for many years. Many dialysis patients are not within the target ranges recommended by the Kidney Disease Outcome Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcome (KDIGO) guidelines for MBD, suggesting gaps between global guidelines and local practices. Studies regarding the status of MBD treatment in developing countries, especially in GCC dialysis patients are extremely limited. The Dialysis Outcomes and Practice Patterns Study (DOPPS)  is an international, observational, prospective hemodialysis (HD) study with detailed data collection of HD care and outcomes across 21 countries. The DOPPS provides a unique opportunity for contemporaneous evaluation of MBD on an international scale across a diverse set of health-care delivery/financing systems. 
The DOPPS study has shed light on numerous different practices and outcomes for various regions around the world. Furthermore, this DOPPS study will examine practice variations and outcomes concerning MBD management and related markers, among countries within the same region or geographical areas such as for the GCC countries.
| Methods|| |
Patients and data collection
The DOPPS is an international, prospective, observational cohort study of HD patients ≥18 years old. Patients in the DOPPS are selected randomly from a representative sample of randomly selected dialysis facilities within each country at the start of each study phase, as described previously. ,,,, Depending on the size of the HD facility, 20-30 patients per study site were randomly selected to participate in DOPPS for the current study from 41 randomly selected HD units providing representation for each of the six GCC countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the UAE). This GCC-DOPPS study was carried out from 2012- 2015. Institutional review boards in each country approved the study, and informed patient consent was obtained in accordance with local requirements. The main analyses were based on 931 adult chronic HD patients who were enrolled at the start of the GCC-DOPPS phase 5 study from 41 of the GCC HD units participating in DOPPS 5. All study HD patients were ≥18 years old at the time of study entry. Further details of the GCC-DOPPS study design are provided in the "The DOPPS Phase 5 Study in the Gulf Cooperation Council (GCC) Countries: Design and Study Methods" paper by Pisoni et al in this special supplement issue of the Saudi Journal of Kidney Disease and Transplantation.
Baseline descriptive statistics (e.g., mean, median, or percentage) weighted by facility sampling fraction were calculated for the study sample. For analyses examining the percent of facility patients having (a) serum phosphorus >6.0 mg/dL or (b) PTH >600 pg/mL, analyses were restricted to facilities having at least ten HD patients with a reported serum phosphorus or PTH measurement, respectively.
Logistic regression analyses of the indicated binary outcomes were based on the use of generalized estimating equations and were adjusted for GCC country, patient age category (<45 years, 45-65 years, and >65 years old), sex, and whether the patient was diagnosed with diabetes mellitus. Logistic models accounted for clustering of patients within facilities, assuming an exchangeable working correlation matrix.
All statistical analyses were performed using SAS software, version 9.4.
| Results|| |
As shown in [Table 1], a total of 41 HD facilities had participated in GCC-DOPPS 5, with data prospectively collected from 931 randomly selected prevalent patients representing the entire cohort of the participating study sites. The majority of the study HD units were from Saudi Arabia (21 facilities) and the UAE (9 facilities) with 429 and 220 patients, respectively. Bahrain had one facility with 25 patients, Qatar had two facilities with 58 patients, whereas Kuwait and Oman each had four facilities with 116 and 89 study patients, respectively.
Mean age varied from 51 years of age in Bahrain, Oman, and Saudi Arabia, to approximately 55 years in the UAE and Kuwait, and nearly 62 years in Qatar. The percentage of male participants was 52% from Oman, 54-56% in Kuwait, Saudi Arabia, and Bahrain, and 61% in Qatar and the UAE. The median dialysis vintage ranged from 1.8 years in Kuwait to 3.5 years in Oman. Mean body mass index (BMI) was the lowest in Oman (23.9 kg/m 2 , intermediate in Saudi Arabia, the UAE, and Qatar (25.7-26.7 kg/m 2 , and the highest in Bahrain and Kuwait (27.2 and 28.9 kg/m 2 , respectively). The larger BMI observed for HD patients in Kuwait may in part be due to the very high proportion of Kuwaiti HD patients with diabetes (71%) which was the highest among the GCC countries. However, diabetes also was highly prevalent among HD patients from Qatar (66%), the UAE (56%), and Bahrain (50%), with a slightly lower prevalence of diabetes in Oman (42%) and Saudi Arabia (40%).
For HD patients in phase 5 of GCC-DOPPS, we examined key aspects of the three commonly used measures of mineral and bone disorder: PTH, serum phosphorus, and serum calcium. As shown in [Table 1], serum phosphorus was reported for 95-100% of patients in each country. PTH was reported for 100% of patients in Bahrain and Qatar, 90% of patients in Oman, and 81-85% of patients in the UAE, Kuwait, and Saudi Arabia.
Median PTH concentrations showed substantial variation across the GCC countries ranging from 370-403 pg/mL in Qatar, Bahrain, and the UAE, 438-444 pg/mL in Kuwait and Oman, and 523 pg/mL in Saudi Arabia [Table 1]. Cross-tabulations of age categories, sex, and diabetes status with serum PTH levels were investigated [Figure 1]. Notably, higher PTH levels were much more common among patients of younger age, with a PTH >600 pg/mL reported for 12% of patients >65 years old versus 33% of patients <45 years of age. Furthermore, the prevalence of high PTH (>600 pg/mL) was nearly 2-fold higher among non-diabetic (32%) versus diabetic (12%) HD patients. In contrast, the distribution of PTH levels was very similar to female versus male HD patients. Multivariate logistic regression analysis was used to determine the odds of a patient having a PTH >600 pg/mL (yes vs. no) with simultaneous adjustment for patient age, sex, diabetes, and GCC country. This analysis indicated that compared to patients >65 years old, patients <45 years old had a 2.1fold higher odds [95% confidence interval (CI): 1.15, 3.98; P = 0.02] of PTH >600 pg/mL, and patients 45-65 years age had a 1.7-fold higher odds (95% CI: 1.02, 2.94; P = 0.05) of PTH >600 pg/mL. Furthermore, a 2.2-fold higher odds (95% CI: 1.5, 3.2; P <0.001) of PTH >600 pg/mL was observed for nondiabetic versus diabetic HD patients.
|Figure 1: Serum parathyroid hormone (PTH) by age group, sex, and diabetes; weighted by facility sampling fraction (GCC DOPPS 5, 2013).|
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Large variation also was seen across GCC HD facilities (n = 33 facilities) in the percent of HD patients having a PTH >600 pg/mL [Figure 2]: although the median facility had 17% of patients with a PTH >600 pg/mL, this varied 5-fold from 8% of patients to 39% of patients for the 10th-90th percentile of the facility distribution of this laboratory measure (interquartile range: 14-27% of facility patients).
|Figure 2: Facility % of GCC DOPPS patients with serum phosphorus >6.0 mg/dL or PTH >600 pg/mL (2013).|
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Study site medical directors indicated the lower and upper limits for their PTH target for their HD patients within his/her HD facility [Figure 3]: 71% of GCC facilities had an upper target limit of 300 pg/mL, 11% of facilities with an upper target limit of 400 pg/mL, and 18% with an upper target limit of ≥500 pg/mL. The most common lower PTH target limit was 150 pg/mL (57%) of facilities. However, 33% of facilities had a lower PTH target limit ≤100 pg/mL.
|Figure 3: GCC DOPPS facility MBD targets as reported by medical directors (GCC DOPPS 5, 2012-2015; n = 29 facilities that completed at least one of the MBD target questions.|
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Similar to PTH, mean serum phosphorus concentrations showed substantial variation across the GCC countries ranging from 4.4-4.5 mg/dL in Bahrain and Qatar, ~5.0 mg/dL in Kuwait and Oman, and 5.2-5.4 mg/dL in Saudi Arabia and the UAE [Table 1]. Crosstabulations of age categories, sex, and diabetes with serum phosphorus levels [Figure 4] indicated a strong relationship with age. High serum phosphorus levels (>6.0 mg/dL) were observed among only 18% of elderly patients (>65 years old) compared to 23% of patients 45-65 years old, and 39% of patients <45 years old. Very little difference in the serum phosphorus distribution was seen by sex. However, the prevalence of high serum phosphorus levels (>6.0 mg/dL) was greater among nondiabetic patients (31%) versus diabetic (21%) HD patients. Logistic regression analysis when adjusted for age, sex, diabetes, and country confirmed the strong relationship between patient age and odds of serum phosphorus >6.0 mg/dL. Compared to patients >65 years old, younger patients (ages <45 years) had a 3.0-fold higher odds of having a serum phosphorus >6.0 mg/dL (95% CI: 2.0, 4.4; P <0.001) whereas a 1.6 times greater odds of high serum phosphorus >6.0 mg/dL (95% CI: 188.8.131.52; P = 0.01) was seen for patients 45-65 years old. In the multivariate logistic regression analyses, a trend toward higher odds of having a high serum phosphorus (>6.0 mg/dL) also was seen for nondiabetic versus diabetic HD patients [adjusted odds ratio (AOR) = 1.39, 95% CI: 0.97, 1.8, P = 0.08].
|Figure 4: Serum phosphorus by age group, sex, and diabetes; weighted by facility sampling fraction (GCC DOPPS 5, 2013).|
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Large variation also was seen across GCC HD facilities (n = 36 facilities) in the percent of HD patients having a serum phosphorus >6.0 mg/dL [Figure 2]: Although the median facility had 25% of patients with a phosphorus >6.0 mg/dL, this varied nearly 5-fold from 11% of patients to 52% of patients for the 10th-90th percentile of the facility distribution of this laboratory measure (interquartile range: 16% to 39% of facility patients). Study site medical directors indicated the lower and upper limits for their serum phosphorus target for their facility HD patients [Figure 5]: 69% of GCC facilities had an upper target limit of 5.5 mg/dL, whereas 24% of facilities had an upper target limit for phosphorus of either 4.5 or 5.0 mg/dL. Substantial heterogeneity was seen in the most common lower serum phosphorus target limit which largely varied over the range from 2.5- 3.5 mg/dL for the great majority of GCC HD units.
|Figure 5: GCC DOPPS facility MBD targets as reported by medical directors (GCC DOPPS 5, 2012-2015); n = 29 facilities that completed at least one of the MBD target questions.|
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Mean total serum calcium concentrations varied moderately across the GCC countries ranging from 8. 6 mg/dL in the UAE to approximately 8.7-9.0 mg/dL in Bahrain, Kuwait, Qatar, and Saudi Arabia [Table 1]. Cross-tabulations of age categories, sex, and diabetes with serum calcium levels [Figure 6] suggested that mean serum calcium levels were slightly higher for older age groups compared to younger age groups as well as for females versus males while similar mean serum calcium levels were observed for diabetics versus nondiabetics. High serum calcium levels (>10.0 mg/dL) were observed for 5% of patients, with 30% of patients having a serum calcium level <8.4 mg/dL.
|Figure 6: Serum calcium (total) by age group, sex, and diabetes; weighted by facility sampling fraction (GCC DOPPS 5, 2013).|
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Study site medical directors differed considerably in the upper limit reported for their serum calcium target [Figure 7] with 43% indicating an upper target limit of 9.5 mg/dL, 25% with an upper target limit of 10.0 mg/dL, and 21% with a serum calcium upper target limit of 10.5 mg/dL. Greater consensus is seen for the lower limit of the serum calcium target whereby 73% indicated a lower limit of 8.5 mg/dL for the serum calcium target and 17% having a lower target of 8.0 mg/dL for total serum calcium.
|Figure 7: GCC DOPPS facility MBD targets as reported by medical directors (GCC DOPPS 5, 2012-2015); n = 29 facilities that completed at least one of the MBD target questions.|
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Use of medications for the management of MBD marker levels
Prescription of medications for MBD management varied across GCC countries. In the GCC, overall, 81% of patients were prescribed phosphate binders with 84%, 77%, 89%, 97%, 81%, and 74% in Bahrain, Kuwait, Oman, Qatar, Saudi, and the UAE, respectively [Table 1].
Although an average of 23% of GCC patients overall were prescribed cinacalcet, the percentage of participants prescribed cinacalcet was quite variable across GCC countries with 0% cinacalcet use in Oman, 23-26% use in Qatar, Saudi, and the UAE, and 31-33% cinacalcet use in Bahrain and Kuwait [Table 1]. The average percentage of patient's prescribed oral Vitamin D was 34% in GCC. The percentage of prescribed oral Vitamin D was 10-22% in Kuwait, Qatar, and the UAE, 40-44% in Saudi Arabia and Oman, and 91% in Bahrain, [Table 1]. Intravenous (IV) Vitamin D percentage utilized by participants was 23% in GCC and range from 0-3% in Bahrain and Oman, 20- 24% in Kuwait and Saudi Arabia, and 35-36% in Qatar and the UAE [Table 1].
Among patients prescribed IV or oral Vitamin D, the average percentage of patients prescribed only paricalcitol was 2% in GCC and was 7% in the UAE, whereas it was 0% in all other GCC countries. The average percentage of patients prescribed only alfacalcidol was 83% across the GCC and was 100%, 95%, 93%, 79%, 92%, and 51% in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the UAE, respectively. The average percentage of patients prescribed only calcitriol was 14%, in GCC, and was 0%, 0%, 0%, 21%, 7%, and 40% in Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the UAE, respectively. The average percentage of patients prescribed other IV Vitamin D drugs apart from above medications was 2%. No GCC DOPPS patients were prescribed doxercalciferol alone for their Vitamin D preparation [Table 1].
Variations among HD patients and across HD facilities were reported for the dialysate calcium bath used during HD [Figure 8]. Dialysate calcium bath <2.5 mEq/L was not utilized in the GCC for HD. Overall, 20% of patients were prescribed a dialysate calcium bath of 2.5 mEq/L, and which varied from 71% in Qatar, 33-37% in Kuwait and the UAE, and 0-1% in Saudi Arabia, Bahrain, and Oman. An intermediate dialysate calcium bath of 3.0 mEq/L was prescribed to 67% and 43% in Saudi Arabia and the UAE, respectively, 20% in Kuwait, and 0-5% in Oman, Bahrain, and Qatar. The highest dialysate calcium bath of 3.5 mEq/L was prescribed for 41% of HD patients in the GCC countries ranging from 95-100% in Oman and Bahrain, 47% in Kuwait, 29-32% in Qatar and Saudi Arabia, and 19% in the UAE.
| Discussion|| |
The current analyses leveraged the prospective data collected in DOPPS 5 from 2012 to 2015 from 41 HD facilities in the GCC, with this being the first study phase with the GCC represented as a new study region in this large international study. The DOPPS is particularly well suited to analyze guidelines compliance because it involves representative samples of HD facilities and patients from many countries with a large population of HD patients. The characteristics of DOPPS patients differ among various DOPPS regions. ,,, This has also been seen when comparing the GCC DOPPS sample to other regions as described in some of the other GCC-DOPPS papers contained within this special supplement: GCC DOPPS participants were younger, had shorter dialysis vintage, higher prevalence of diabetes and other comorbidities, and higher C-reactive protein (CRP) levels. Dialysis prescription was also different in the GCC countries, with more patients receiving HD <3 times per week, shorter mean treatment time, and achieving lower Kt/V. Use of high calcium dialysate bath (=3.5 mEq/L) was more common in the GCC countries compared to other DOPPS study regions.
Large variability in MBD management practices was observed across GCC countries
In Bahrain, 100% of patients were dialyzed with high dialysate calcium bath. Reflecting in part this practice, patients also had 12% of patients with a high serum calcium level of >10.0 mg/dL which was >2-fold higher than the average for all of the GCC countries. However, Bahrain had the lowest proportion of patients with hyperphosphatemia (16% with phosphorus >6.0 mg/dL) and a lower percentage (16%) of patients than the GCC average of 22% regarding high PTH >600 pg/m despite the fact that IV Vitamin D was not used; 91% of patients were prescribed oral Vitamin D, 33% prescribed cinacalcet, and small percentage prescribed both Vitamin D and cinacalcet. We believe that the use of high calcium bath and higher oral Vitamin D are responsible for the higher serum calcium and the lower PTH in Bahraini dialysis patients.
Kuwait HD population has the lowest dialysis vintage of 1.8 years compared to GCC average of 2.5 years, and this is possibly due to the higher transplant average than the rest of GCC countries. Also, its patients have the highest BMI (28.9) compared to GCC average (26.3) which is associated with high prevalence of diabetes. Kuwait achieved a good, calcium level of 8.8 that is the same as GCC average, phosphate level of 5.0 that is similar to GCC level (5.1), and PTH level of 438 compared to GCC average (452). This was achieved through various treatment modalities, where 47% of patients were treated with 3.5 mEq/L dialysate calcium bath, compared to GCC average (41%). Also, it utilizes phosphate binders by 79% of patients, IV Vitamin D by 24%, and cinacalcet by 31% compared to GCC average of 81%, 23%, and 23% respectively.
Oman with a younger population compared to GCC average and with a lower BMI, managed a reasonable control of BMD by utilizing 3.5 mEq/L dialysate calcium bath by 95% of their patients compared to GCC average of 42% and with no cinacalcet utilization (not available at the time of the study). However, median PTH levels in Oman were second highest across the six GCC countries, and with HD patients in Oman having the second highest percentage of patients (23%) with a high PTH >600 pg/mL which was slightly higher than the GCC average of 22%.
Excellent MBD management and excellent PTH levels were observed in Qatar. This was achieved by higher use of phosphate binder (97% vs. GCC average of 81%), and higher use of IV Vitamin D (36% vs. GCC average of 23%) with lower use of oral Vitamin D (16% vs. GCC average of 34%). The most common dialysate calcium bath used in Qatar was 2.5 mEq/L used in 71% of patients (vs. 20% for the GCC average).
The UAE displayed the highest proportion of patients (38%) in the GCC with a high serum phosphorus of >6.0 mg/dL compared with the GCC average of 26%. This could be attributed to lower percentage utilization of phosphate binders (75% vs. 81%) and higher percentage utilization of IV Vitamin D (36% vs. 23%) although dietary intake can be a very important contributor to serum phosphorus levels in dialysis patients. In the GCC-DOPPS nutritionrelated paper by Al Ali et al within this special supplement, the UAE appeared to have nutritional measures similar to the GCC average regarding serum albumin, normalized protein catabolic rate, and serum creatinine levels. Furthermore, UAE had a lower mean serum calcium level (8.6 mg/dL) and highest percentage of patients (39%) with low serum calcium <8.4 mg/dL compared to the GCC average of 8.8 mg/dL and 29%, respectively. This could be explained by the fact that UAE uses the least of high calcium bath (3.5 mEq) in 19% compared to average 52% in GCC countries and due to the higher use of cinacalcet in 24% of the cases.
Saudi HD patients displayed a higher mean PTH level (523 pg/mL) compared to the GCC average (452 pg/mL) and with Saudi HD patients having the highest percentage of patients (26%) with a PTH >600 pg/mL. Saudi Arabia utilized calcium bath of 3.0 mEq and 3.5 mEq/L in 67% and 32%, respectively, whereas use of IV vitamin D, oral Vitamin D, and cinacalcet in Saudi Arabia was similar to that of the average for the GCC for these different medications. Saudi HD patients had a lower percentage of patients (22%) with hyperphosphatemia compared with the GCC average of 26%, whereas the percentage of Saudi patients with hypercalcemia (5%) was the same as the average for the GCC countries. Saudi Arabia had the lowest mean HD treatment time of 202 min compared to the GCC average of 213 min (see Alyousef et al in this Special Supplement) and higher inflammatory marker (CRP) compared to GCC average which may contribute to the observed values of some of these measures of MBD management.
GCC population is generally Vitamin D deficient, especially among females, despite ample sunshine.  This gets even worse among CKD population and even poorer among dialysis population. , This is likely attributed to socioeconomic changes and cultural practices over the last few decades resulting in reduced sun exposure for the GCC population. Furthermore, changes in diet and workplaces practices, in addition to a more sedentary lifestyle and low consumption of dairy products may also have contributed to greater Vitamin D deficiency in the recent years. A study of peritoneal dialysis patients from the GCC found that the mean serum Vitamin D 25 (OH) level was 16.1 ± 8.23 nmol/L and none of their patients had 25 OH levels within the normal range [i.e., above 75 nmol/L (30 ng/mL)]. , In addition, 60% patients had Vitamin D 25 OH <15 nmol/L (severe deficiency) whereas eight (30%) patients had levels between 15 and 25 nmol/L (Vitamin D insufficiency).
Overall, more than 50% of patients were treated with some form of Vitamin D therapy. Parenteral Vitamin D therapy was less utilized in GCC countries (38%) than in North America (52%).  Oral Vitamin D was utilized by 59% of the HD patients in the GCC countries with great variability between countries. Vitamin D was underused among patients in GCC, especially the parenteral form despite their mean of PTH level was 294 pg/mL. The use of parenteral Vitamin D preparations was mainly in Qatar and the UAE (36%) followed by Kuwait (24%). However, there might be relatively high Vitamin D use even among patients with a lower PTH concentration such as in Qatar with a mean of 370 pg/mL and relatively low use among patients with a PTH concentration above 400 pg/mL, especially in Saudi Arabia with mean of 523 pg/mL. In addition, the mean percentage of patients with PTH >600 pg/mL (triple normal level) was quite high (17%).
Phosphorus binders (PBs) were taken by 81% in the GCC countries with a mean phosphate level of 5.1 mg/dL. It is noteworthy that among GCC HD patients, the standard deviation (SD) in serum phosphorus level is quite wide suggesting a substantial percentage of patients with poor phosphate control. For example, there is relatively high serum phosphate among patients in the UAE with serum phosphate of 5.5 mg/dL, compared to Japan with a better SD and hence better control. , It has been reported that nonadherence to PB prescription is associated with serum phosphate >5.5 mg/dL and PTH >600 pg/mL.  This less optimal control may contribute to high cardiac morbidity and mortality, , especially for an HD population that is quite young compared with other DOPPS regions. Younger age HD patients (<45 years vs. >65 years) have twice the risk of having a PTH >600 pg/mL and three times the risk for a high phosphate level >6.0 mg/dL. Recently, Fissel et al reported that half of the HD patients were prescribed at least 6 PB pills per day and skipping PBs at least once in the past month was reported for almost 45% of HD patients. 
The optimal range for PTH was considered to be 150-300 pg/mL in earlier KDOQI guidelines and approximately 130-600 pg/mL in the 2009 KDIGO guidelines. , The present study showed that 71% of GCC facilities had an upper target limit of 300 pg/mL, 11% of facilities with an upper target limit of 400 pg/mL, and 18% with an upper target limit of ≥500 pg/mL. The most common lower PTH target limit was 150 pg/mL (57%) of facilities. However, 33% of facilities had a PTH lower target limit ≤100 pg/mL. A Saudi study of patients with high median PTH levels (>300 pg/mL) were compared with those having lower PTH levels and found that there was a high percentage of patients with median PTH levels >300 pg/mL. Vascular calcifications were detected on X-rays in 26% of the patients with PTH levels >300 pg/mL versus 7.0% in patient with PTH levels <300 pg/mL, P <0.001.  In comparison to the GCC countries, the PTH concentration was below 300 pg/mL in most HD patients from Japan [118 (61, 190) pg/mL] whereas the mean PTH (CI) was 241 (129, 442) and 325 (198, 519) pg/mL in Europe and North America, respectively.  Serum phosphorus levels were significantly higher in patients with PTH levels >300 pg/mL versus <300 pg/mL. These variations in upper and lower limit of various parameters of CKDMBD in GCC countries suggest less adherence to published international guidelines than what anticipated. This might reflect less organized rules of health-care delivery in GCC countries and might reflect the diverse physicians' background in GCC countries.
It is notable that among all DOPPS regions, the GCC displays one of the highest percentages (22%) for patients having high PTH >600 pg/mL. This could be attributed possibly to the other parameters such as higher phosphate, lower calcium level, and lower Vitamin D usage.  In addition, it has been reported that non-adherence to PB prescription and diet was associated with high serum phosphate (>5.5 mg/dL) and PTH (>600 pg/mL).  Adherence to PB is a challenge for many HD patients and may be related to the number of PB pills and other multiple medications prescribed. Hence, adherence to orally prescribed medications may be lower in the GCC, thus contributing to poor phosphate and PTH control. Prescription of a simplified PB regimen and conversion to IV medications during dialysis could improve patient adherence and perhaps improve serum phosphate and PTH.  In addition, giving food with phosphate binders during dialysis time may further enhance compliance problems. Thus, we hypothesized that non-adherence to low phosphate diet and to phosphate binders might be responsible for the observed variance. This needs to be substantiated by future targeted research to the degree of non-adherence.
It has been shown that low PTH (<150 pg/dL) was proportionally associated with the dialysate calcium bath and inversely associated with black race and Vitamin D therapy. , GCC countries utilize high dialysate calcium bath to primarily control PTH level. Similarly, PTH concentrations above the guideline limit have been shown to be inversely associated with the dialysate calcium bath, suggesting a potentially modifiable dialysis management practice that results in excessive PTH stimulation. High PTH (>300 pg/dL) was found to be associated with duration of ESKD, and Vitamin D therapy, and was inversely associated with older age, male sex, dialysis dose, diabetes, and treatment. In contrast, low and high PTH was negatively and positively associated, respectively, with Vitamin D therapy, suggesting the general appropriateness of prescribing Vitamin D in response to PTH level. , GCC countries have an HD patient population that is predominantly male, of younger age, lower dialysis treatment time, and high diabetes prevalence.
The recommended range limit for serum calcium concentration is 8.4-9.5 mg/dL. The pre-sent study showed that the majority of the patients were within the normal range with a GCC average of 8.8 and only 5% of patients having a serum calcium >10.0 mg/dL. However, there is a considerable variation among these countries with Bahrain having a mean serum calcium level of 8.98 (2.97) and 12% having a hypercalcemic level of >10.0 mg/dL. In contrast, the UAE had a lower mean serum calcium level of 8.54 mg/dL with 39% of the UAE HD patients having a serum calcium level below the recommended range. Prior studies have shown that a serum calcium concentration below the target range was significantly more likely in males and in patients with higher serum albumin concentration , and was inversely associated with age, duration of ESKD, hemoglobin concentration, and treatment modalities of MBD. ,
In general, high serum calcium levels are well controlled among HD patients in GCC countries. This serum calcium level has been achieved differently among various countries. ,, The dialysate calcium concentration varies considerably across different international regions and countries. , In general, high calcium bath (3.0 and 3.5 mEq) was used to bring calcium level within target level more than other DOPPS regions. , However, Qatar HD facilities had managed to bring PTH to target level by utilizing more of IV Vitamin D and more of cinacalcet in a moderately high PTH level, which is possibly a more expensive approach. Bahrain, on the other hand, utilizes high oral Vitamin D prescription (91%) and high dialysate calcium bath (3.5 mEq/L) to control PTH level along with high percentage use of cinacalcet (33%) compared to the rest of the GCC. However, the added cost of cinacalcet was found to be significantly higher than that of other treatment modalities including Vitamin D and phosphate binders.  Hence, higher usage of cinacalcet is possibly not a cost-effective approach and a better utilization of less costly strategies such as higher calcium dialysate and IV Vitamin D and a better phosphate control as early as possible is the best approach in achieving a better PTH control. On the other hand, one must also consider the entire spectrum of MBD management, and not only one laboratory measure. Thus, for example, in Bahrain with good control of PTH, one must also address the question of having a large fraction of patients with hypercalcemia >10.0 mg/dL and is this due in part to the exclusive use of high dialysate calcium bath of 3.5 mEq/L. Previous work indicated higher mortality rates for HD patients dialyzed with high dialysate calcium bath and who were prescribed calcium-containing phosphate binders. ,,, Thus, less costly treatment strategies need to be considered carefully in terms of simultaneous control of all MBD measures for providing optimal outcomes for patients and what the tradeoffs may be in using different treatment strategies.
The likelihood of achieving consistent control for each MBD measure increases when other parameters are concomitantly in range. Missing a scheduled HD treatment session recently was found to be higher for HD patients in the GCC compared to HD patients in Europe, Australia/ New Zealand, and Japan DOPPS regions.  Missed dialysis sessions were associated with a lower likelihood of achieving consistent control of calcium, phosphate, and calcium × phosphate product levels, whereas abbreviated sessions were inversely associated with the consistent achievement of phosphate and calcium × phosphate product target levels. 
Although the prevalence of primary hyperparathyroidism is higher in diabetics than that in the general population, the reverse is true for sHPT in HD patients. A previous DOPPS study by Young et al  indicated that diabetic people on HD were less likely (AOR = 0.65) to have hyperparathyroidism (PTH >300 pg/mL) compared with nondiabetic HD patients. Furthermore, our study showed that there was a 2.2-fold higher odds of PTH >600 pg/mL in nondiabetic versus diabetic HD patients in the GCC whereas PTH levels >300 pg/mL were slightly higher in male (52%) versus female (45%) HD patients in the GCC countries. This finding regarding diabetic HD patients can be explained as follows: (1) synthesis and secretion of PTH is suppressed by hyperglycemia and high blood glucose might inhibit the secretion by inhibiting PTH synthesis and depleting the PTH storage pool of parathyroid cell; our population of HD patients has a higher percentage of diabetes, and poor diabetes control may be a major issue, (2) advanced glycated end-products may impair PTH secretion. It has been demonstrated that the increase in PTH secretion in response to a low serum calcium concentration is inhibited by AGEs,  (3) diabetic nephropathy leads to deficiency of insulin growth factor which leads to adynamic bone disease. ESKD in our HD population is caused by diabetes nephropathy in an average of 50% of new ESKD patients, and (4) diabetic nephropathy patients tend to have lower magnesium compared to nondiabetic. Hyperglycemia that leads to osmotic diuresis also causes magnesium depletion. It is possible that the reduced PTH secretion occurring in patients with poorly controlled diabetes is related to low serum magnesium. In support of the above points, it has been found that poor glycemic control was associated with reduced serum PTH level and good glycemic control with higher serum PTH. ,,,,, Murakami et reported that serum PTH levels at the start of HDs were significantly lower in patients with diabetes than without diabetes.  They concluded that status of glycemic control in diabetic HD patients affects the serum PTH levels. 
It has been found that the incidence of malnutrition was significantly higher in diabetic versus nondiabetic HD patients. ,, Thus, the occurrence and development of low turnover renal bone disease are highly suspected in diabetic patients having low PTH status. Hence, the parathyroid tissue is less stimulated since malnutrition and low level of serum phosphorus in diabetic HD patients, thus leading to the decrease of PTH secretion. In diabetic hemodialyzed patients, impaired PTH secretion appears to be the principal reason accountable for decreased bone turnover and "adynamic bone disease," as reports have proposed a similar degree of PTH biological action on bone in the diabetic and nondiabetic population. ,
Since excessive emphasis is placed on the achievement of calcium and phosphorus targets clinically, Vitamin D receptor agonists in some situations appear to be overused. Hence, the HD patients who have low PTH levels may still be prescribed Vitamin D agonists. Therefore, improper treatment is a possible cause of low PTH. Furthermore, Kalantar-Zadeh et al  found a clear association between poor glycemic control and increased mortality and cardiovascular death risk in diabetic patients on HD. Both low and very high PTH serum levels correlate with increased cardiovascular morbidity and mortality.  The role of PTH as a potential predictor of cardiovascular morbidity and mortality in HD patients certainly deserve more attention, and randomized clinical trials are urgently needed as numerous large observational studies have shown poorer outcomes for HD patients having PTH levels >300 pg/mL or higher.
One limitation of the current study is that in the absence of a common laboratory, laboratory measurements may vary across GCC countries. Similarly, variability in the management of CKD-MBD among GCC countries may be due to the various background of treating physicians as it is the case in GCC countries. Nonetheless, there are major strengths of the study and include: (1) large sample size of the cohort, (2) randomly selected dialysis centers within each country, and (3) use of the same data collection tool across all countries which provides for consistent collection of data across countries along with centralized data quality checks through the DOPPS Coordinating Center.
| Conclusion|| |
Large variability is seen across countries and facilities in the GCC with regard to many aspects of MBD management and MBD marker achievement. Mean serum calcium was lower in the GCC despite the much greater use of higher dialysate calcium bath of 3.0-3.5 mEq/L which may be due to the relatively low use of vitamin D and higher cinacalcet use, meriting further study. Serum phosphorus levels in the GCC countries are similar to the average seen across other international regions in DOPPS. However, the prevalence of high PTH levels within the GCC countries is one of the highest reported among the 21 countries participating in the international DOPPS 5 study. Future work will focus on GCC facility HD practices and patient characteristics most strongly related to the achievement of MBD target levels and associated outcomes.
| Acknowledgments|| |
The authors wish to thank the devoted efforts of GCC-DOPPS 5 Study Group members for their numerous contributions to this study including Country Investigators (Dr. Sameer Al-Arrayed, Dr. Sumaya Al Ghareeb, Dr. Bassam Al Helal, Dr. Naser Alkandari, Dr. Ali Alsahow, Dr. Anas AlYousef, Dr Mohammad AlAzmi, Dr. Yaqob Ahmed Almaimani, Dr. Issa Al Salmi, Dr. Nabil Salmeen Mohsin, Dr. Fadwa Al Ali, Dr. Mohamed El-Sayed Abdel Fatah, Dr. Ashraf Fawzy, Dr Abdulla Hamad, Dr. Saeed M. G. Al-Ghamdi, Dr. Mohammed Al Ghonaim, Dr. Jamal Al Wakeel, Dr. Fayez Hejaili, Dr. Ayman Karkar, Dr. Faissal Shaheen, Dr. Samra Abouchacra, Dr. Ali Abdulkarim Al Obaidli, Dr. Mohamed Hassan, Dr. Mona Nasir Al Rukhaimi, and Dr. Abdul Kareem Saleh, Dr. Sylvia Ramirez, Dr. Bruce Robinson, and Dr. Ronald Pisoni), Clinical Research Associates and Project Coordinators/Managers (Dr. Amgad El-Baz El-Agroudy, Dr. Balaji Dandi, Ms. Cherry Flores, Mrs. Ph. Fatma Al Raisi, Ms. Ibtisam Al-Hasni, Dr. Ashraf Fawzy, Dr. Haroun Zakaria Ahmed, and Mr. Dan Santiago from the Saudi Center for Organ Transplantation, Mr. Muhammad Awwad, Ms. Roberta Al Housani-Blakely, Christina Pustulka, Anne Vandermade, Melissa Fava, Anna Hogan, Michelle Maxim, and Justin Albert), Biostatisticians (Brian Bieber), and Study Site Medical Directors and Study Coordinators: Dr. Hamid Ali Alyousif, Ms. Sohair Abdulroof Albably, Dr. Ahmed Eid Alkady, Dr. Samir Al Muielo, MD, Dr. Fakreldein Elamien Ali, Dr. Ayman El Monger, Dr. Sameh Mohammed Al-sammad, Dr. Baraa Rajab, Dr. Atif Hanan, Tarek Abdelfattah Ahmed Ali, Dr. Ayman Karkar, Dr. Mohammed Abdelrahman, Dr. Mohammed Hussein, Dr. Wael Abdlah, Dr. Faisal Mushtaq, Dr. Salah Eldin El Sheik Beshir, Dr Medhat Abdelmonem Shalaby, Dr. Mustafa Khaleel Al Obeid, Dr. Mohamad El Hadary, Dr. Alaa Al Shamy; Dr. Aboud Mamari, Dr. Mohammed Raily, Dr. Mustafa Ahmed; Ramzi AbouAyache, Dr. Hormoz Dastoor, Dr. Mohamed Hassan, Dr. Bassam Bernieh, Dr. Hareth Muthanna Mohammed Saaed, Dr. Mustafa Kamel, Prof. Abdel Basset Hassan, MD, PhD, FASN, Dr. Hassan Khammas, Dr. Balaji Dandi, Dr. Sumaya Al-Ghareeb, Dr. Fadwa Al Ali, Dr. Anas Alyousef, Dr. Nasser AlKandari, Dr. Ali Alsahow, Dr. Bassam AlHelal, Dr. Ahmed Mandour, Dr. Yaqob Ahmed Almaimani, Dr. Amer Ahmed Alaamri, Dr. Ibrahim Sayed Ibrahim, Dr. El Badri Abdelgadir, Dr. Mohammed Al-Sayed Seleem, Dr. Ali Hassan Hakami; Dr. Samir Beshay, Dr. Nayer Morsy, Mr. Menwer Al-ofi, Ms. Sohair Abdulroof Albably, Dr. Huda Mohammed Saeed Ahmed, Ola Al-Marhoon; Dr. Samir Al Muielo, Ms. Joynalyn Barrios, Ms. Fatima Cruza; Ligaya Battad, Mr. Abdullah A. K. Al Harbi, Dr. Sameh Mohammed Al-sammad, Ms. Manal Ahmed Hamdan, Jennifer Samson, Mr. Ahmed Mousa Khawaji, Ms. Eman Al-Hejji, Ms. Rosalinda Lamis, Ms. Lagrimas Codotco, Dr. Wael Abdlah, Mrs. Priyanka Prasad, RN, Mr. Bander Faisal Justinia, Mr. Faisal Al Enazy, Sarah Brazil, Dr. Naemah Abdullah, Dr. Alaa Al Shamy, Dr. Aboud Mamari, Mely Gari Piling, Dr. Fakhriya Al Alwai, Rusmina Binti Sudin, Dr. Chandra Mauli Jha, MD; Katheryn Jamilano, Basima Khaddah, Hilal Al Rasbi, Muhy Eddin Hashem Hasan, Sr. Ekram Awadh Salem, Walid Gouiaa, Mini Issac, Jiby Mammen, Mary Ellen Monday, Mrs. Afrah Al Jamri, Mr. Yasser Khalil Abbas, Mrs. Rania Abd El-Aziz, Rania Abd El-Aziz, Cherry Flores, Mini Kumari Ramakrishnan, Shanty Mannaraprayil, Maria Charisse Bernardo, Bassam AlHelal, Evangeline Valdez, Rosily Joseph, Mrs. Ghaniya Al-Shukaili, Adel Mohamed Bayoumy, Hamid Alshahri, Amira Balkhair, Amina Said Al Shezawi, Sultan Saif Ali Alroshdi, Dr. Shaninaz Faisal Bashir, Dr. Ahmed Mousa Dawood, Keirin Porras, Dr. Anthonimuthu Victor, and Mr. Sultan Al-Toqi.
| Source of Support|| |
The DOPPS program is supported by Amgen, Kyowa Hakko Kirin, AbbVie, Sanofi Renal, Baxter Healthcare, and Vifor Fresenius Medical Care Renal Pharma. Additional support for specific projects and countries is provided by Keryx Biopharmaceuticals, Merck Sharp & Dohme Corp., Proteon Therapeutics, Relypsa, and F. Hoffmann-LaRoche; in Canada by Amgen, BHC Medical, Janssen, Takeda, and the Kidney Foundation of Canada (for logistics support); in Germany by Hexal, DGfN, Shire, and the WiNe Institute; and for PDOPPS in Japan by the Japanese Society for Peritoneal Dialysis (JSPD). All supports are provided without restrictions on publications.
Conflicts of interest: None declared.
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Issa Al Salmi
The Renal Medicine Department, The Royal Hospital, P. O. Box 1331, Code 111, Muscat
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]