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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 6  |  Page : 1166-1177
Trends of elevated parathormone serum titers in hemodialysis patients on intensive therapy for bone disease: A multicenter study


1 The Kanoo Kidney Center, Dammam Medical Complex, Dammam, Saudi Arabia
2 The Jeddah Kidney Center, Jeddah, Saudi Arabia
3 The Prince Salman Kidney Disease Center, Riyadh, Saudi Arabia
4 The Saudi Center for Organ Transplantation, Riyadh, Saudi Arabia

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Date of Web Publication10-Nov-2014
 

   Abstract 

To determine the prevalence of controlled parathyroid hormone (PTH) serum levels with intensified therapy for chronic kidney disease mineral and bone disorder (CKD-MBD) in the dialysis population, we studied 563 chronic hemodialysis patients recruited from three different dialysis centers from three different major cities in the Kingdom of Saudi Arabia. The trend of the routine monthly chemistries related to CKD-MBD was evaluated besides the whole-molecule PTH serum levels over 28 months (January 2011 to April 2013). The cost ratios of the medications to the estimated dialysis total cost were calculated. There were 323 (57.4%) males in the study, and the mean age of the patients was 50.2 ± 15.2 years; 371 (65.9%) patients were initiated on dialysis before 2011. The causes of the original kidney disease included diabetes mellitus in 163 (29%) patients. Parathyroidectomy was performed in 23 (4.1%) patients and only six (23%) patients underwent the operation during the study period; most of the parathyroidectomies (69%) were performed before 2011. The trend of the medians of monthly serum levels of calcium, phosphorus, albumin, bicarbonate, alkaline phosphatase, serum levels of PTH and vitamin D25 assays showed better control of the levels with time. The added cost of cinacalcet was more significant than the other drugs, including vitamin D and phosphate binders, but the cost was minimal in comparison with the whole dialysis bill. The ratios of the discontinuation rates to the total patient-months of treatment for the different drugs were in the range of 3-4% and mostly due to transient overdosing of medications. We conclude that the trends of the median serum levels of PTH and related minerals in the CKD patients in our dialysis patients suggested a good inclination toward control and prevention of the vascular calcifications prevalent in the CKD-MBD. The popularity of use of new drugs such as cinacalcet is promising and does not seem to add much to the current out-patient cost of chronic dialysis.

How to cite this article:
Karkar A, Sinha AK, Abdelrahman M, Mushtaque F, Awn NM, Qadi Y, Nassar M, Algareeb A, Taha MI, Abdulkader M, Sabry A, Souqiyyeh MZ, Shaheen FA. Trends of elevated parathormone serum titers in hemodialysis patients on intensive therapy for bone disease: A multicenter study. Saudi J Kidney Dis Transpl 2014;25:1166-77

How to cite this URL:
Karkar A, Sinha AK, Abdelrahman M, Mushtaque F, Awn NM, Qadi Y, Nassar M, Algareeb A, Taha MI, Abdulkader M, Sabry A, Souqiyyeh MZ, Shaheen FA. Trends of elevated parathormone serum titers in hemodialysis patients on intensive therapy for bone disease: A multicenter study. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2022 Jan 27];25:1166-77. Available from: https://www.sjkdt.org/text.asp?2014/25/6/1166/144249

   Introduction Top


There have been several improvements in the management of the chronic kidney disease mineral and bone disorders (CKD-MBD). For example, cinacalcet is now available as a member of a new family of drugs that control the synthesis and secretion of parathormone (PTH) by increasing the sensitivity of calcium (Ca) receptors in the parathyroid glands in a more unique mechanism than the other conventional approaches, including vitamin D and phosphate binders. [1],[2],[3],[4],[5],[6]

The mechanisms of CKD-MBD include the initial decrease of 1-25 dihydroxy-vitamin D 3 (vit D) serum levels at an early stage of CKD accompanied by a trade-off phenomenon with increased PTH serum levels; all occur before the decrease of glomerular filtration rate (GFR) <30 mL/min. [7],[8] Later, with a further decrease of GFR, elevated phosphorus (Po 4 ) and decreased Ca serum levels are detected in the majority of CKD patients. [9]

The current prevalence of CKD-MBD is reported to remain elevated with a change in pattern from mixed hyperparathyroidism and osteomalacia to adynamic bone disease with increased vascular calcifications. [10],[11],[12],[13],[14],[15],[16],[17] A conti­nuously increased prevalence of elevated Po 4 serum levels is still predominant in the CKD population. [14],[15],[16],[17]

We underscore the importance of the CKD-MBD as a cause of significant morbidity (e.g., fractures and vascular calcifications) and mor­tality (e.g., cardiovascular) in advanced CKD and dialysis patients. [16],[17],[18],[19],[20],[21]

The approach of physicians to evaluate the CKD-MBD is still not adequately aggressive or accurate. For example, the assessment and therapy of the secondary hyperparathyroidism in the CKD patients include determination of PTH serum levels, an important parameter for CKD-MBD, [22] which should be performed every two to three months in the advanced CKD and dialysis patients. Many physicians in our country still obtain the PTH serum levels at longer intervals than recommended in the guidelines. [10],[11],[12],[13]

Furthermore, the success rates to achieve control of Ca, Po 4 and PTH according to the international guidelines are still <50%, when each parameter is considered alone, and around 20% when considered together in the CKD population, [23],[24],[25],[26],[27],[28] despite widespread pres­cription of vit D, [29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39] phosphate binders [40],[41],[42],[43] and cinacalcet. [44],[45],[46],[47],[48],[49],[50],[51],[52]

The chronic dialysis population is growing in Saudi Arabia (more than 15,000 patients in 2014) and, in the face of paucity of CKD-MBD studies in this country over the last 10 years, it is prudent to evaluate the effect of the current therapy with vit D and phosphate bin­ders in controlling the PTH serum levels in this population and need for further control with cinacalcet.

We aimed in our study to determine the pre­valence of controlled PTH serum levels with intensified therapy that includes vit D, phos­phate binders and dialysis and the need for further control with cinacalcet in a large co­hort that comprises patients of several dialysis centers. We also aimed to compare the side-effects and the related dropouts in addition to the treatment economics related to the CKD-MBD in this population.


   Patients and Methods Top


This is a multicenter study of a cohort of 563 chronic hemodialysis patients who were on regular dialysis for not less than 12 h per week and on intensified therapy to control the CKD-MBD, including vit D, phosphate binders and/or cinacalcet for three months or more. The patients were recruited from three different dialysis centers: Kanoo Kidney Center-Dammam, Jeddah Kidney Center-Jeddah and Prince Salman Center for Kidney Diseases-Riyadh) located in three different major cities in the Kingdom of Saudi Arabia (Dammam, Jeddah and Riyadh, respectively) in a cross-sectional, case-population, observational study. The nephrologists in the participating centers filled the data in the study files prepared by the investigators at the Saudi Center for Organ Transplantation (SCOT). The data in the files were entered in a database and analyzed according to the aims of the study.

The patient study files covered the demo­graphic data, causes of kidney disease and clinical features of bone disease besides the review of systems, comorbidities, current me­dications and past medical records, including hospitalizations in addition to physical examination. The reported laboratory investigations included all the routine monthly chemistries over 28 months (January 2011 to April 2013) of calcium, PO 4 , bicarbonate, alkaline phosphatase (alk. phos) and serum albumin, besides complete blood count and KT/V. Whole-PTH molecule serum levels in all the participants during the same period were recorded; patients included in the study had at least three determinations of PTH during the study. The data collection was completed in the period from November 2013 to May 2014.

The adequacy of dialysis was determined by the urea reduction ratio on a monthly basis for the patients who were dialyzed at least three times per week for a total time of 4 h per dialysis session.

Comparison of the cost of the medications considered the median doses and the current prices. Subsequently, the ratio of the cost of the treatment by the medications targeting the CKD-MBD and the total dialysis cost was calculated in order to compare the economics of the treatment over time.


   Statistical Analysis Top


Data were entered in a Microsoft Excel file. However, the description of data and analysis were performed using the statistical program (SPSS version 16).

All data were compiled descriptively in tables and frequencies. The analysis of the data addressed the validity of the data in connection with the key questions in the patients' files and end-points.

Pearson's Chi-square test was used through­out the analysis to test the significance of differences between groups and sub-groups for the non-continuous variables, while the Student "t" test was used for the comparison of the means of the continuous variables. Statistical significance was set at P <0.05.


   Results Top


There were 191 patients recruited from the Kanoo Kidney Center, 188 patients from the Jeddah Kidney Center and 184 patients from the Prince Salman Center for Kidney Diseases. There were 323 (57.4%) males in the study, and the patients' mean age was 50.2 ± 15.2 years; 501 (89%) patients were Saudis. There were 371 (65.9%) patients who were initiated on dialysis before 2011, 88 (15.1%) in 2011, 76 (13.5%) in 2012 and 28 (5%) in 2013.

The causes of the original kidney disease included diabetes (DM) in 163 (29%) patients followed by hypertensive nephropathy in 151 (26.8%), and the label "unknown cause" was noted in 166 (29.5%) patients, besides several miscellaneous causes of CKD.

Of the DM patients, 103 (63%) patients were receiving insulin at the time of the study and 25 (15%) were on oral hypoglycemic agents. Of the 371 (65.9%) hypertensive (HTN) study patients, 170 (45.8%) were treated with one antihypertensive medication, 141 (38%) with two medications, 49 (13.2%) with three medi­cations, 10 (2.7%) with four medications and one (0.3%) with five medications. There were 492 (87%) patients receiving erythropoietin-stimulating agents for the treatment of CKD-related anemia.

At least one kidney was transplanted in 89 (15.8%) patients before 2011, and those grafts failed at a variable time before returning to dialysis, while 474 (84.2%) patients did not re­ceive any transplants.

[Table 1] shows the clinical symptoms and signs and investigations related to bone disease. Only 351 (65%) patients had X-rays to detect calcifications (vascular and soft tissue) during the study period and only one patient had a bone biopsy.
Table 1: The frequencies of the clinical and X-ray manifestations of CKD-MBD in the study patients.

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Parathyroidectomy was performed in 23 (4.1%) patients and only six (23%) patients underwent the operation during the study period. Most of the parathyroidectomies (69%) were performed before 2011, while 30% of them were performed during the study period. The causes of parathyroidectomy included hyperparathyroidism not responding to treatment in 21 (91.4%) pa­tients and parathyroid adenoma in two (8.6%) patients.

The monthly laboratory investigations showed that the median of the urea reduction rates was 86% (KT/V > 2.7). The medians for the whole period of the study of monthly Ca, Po 4 , albumin, bicarbonate, alk. phos, serum levels of PTH and vitamin D25 assays are shown in [Figure 1]. The results show better control of the levels of the different parameters with time.
Figure 1: The medians of the serum levels of calcium, phosphate, albumin, bicarbonate and alkaline phosphatase besides parathormone and 25 vitamin D assays (infrequently used with a trend for more use by some centers toward the end of the study). There was improvement of the levels over time in the study patients.

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The median doses of the different drugs used in the control of CKD-MBD over time are shown in [Figure 2]. The ratios of the treated patient-months to the total number of patient-months for all the CKD-MBD medications are shown in [Figure 3]. The ratios of the cost of the treatment of the different medications to the total cost of dialysis over time are shown in [Figure 4]; the cost ratios took into conside­ration the ratios of the treated patients shown in [Figure 3] and the current prices of the medications and estimated dialysis total cost. The added cost of cinacalcet was more significant than the other drugs, but the cost was minimal in comparison with the whole dialysis bill.
Figure 2: The medians of the doses of the different drugs used in the treatment of chronic kidney disease mineral and bone disease (CKD-MBD) in the study patients.

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Figure 3: The ratio of the treated patients to the total number of study patients for each drug in each month of the study period. There was a trend for more use of the different drugs with time.

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Figure 4: The ratios of the cost of the different drugs for treated patient-months to the total cost of dialysis patient-months.

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The frequency and reasons for discontinua­tion of the different medications in our study patients are shown in [Table 2]. The ratios of the discontinuation rates to the total patient-months of treatment for the different drugs were in the range of 3-4%. The causes for disconnuation of the medications were mostly related to their overdosing reflected by the excessive change in the targeted mineral or hormone serum levels. The comparisons of the study patients included their subgroups according to their affiliation with the dialysis centers, the PTH levels above and below 300 pg/mL, the starting dialysis date and the addition of cinacalcet to the other medications for treatment of CKD-MBD.
Table 2: The reasons for discontinuing the medications in the study patients and their ratios to the total patient-months of treatments.

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The comparison of the study patients accor­ding to their dialysis centers showed no diffe­rences in age compared with the mean age, but one center had fewer male patients (47%) than the mean (57%), P <0.001. The clinical evi­dence for bone disease was not different from the mean, and the X-ray evidence of vascular calcification was low in one center (4%) than the mean (29%), due mostly to a lesser fre­quency of X-rays obtained in that center (33% vs. 65% for the whole study group). The parathyroidectomy rate was not different among the centers, but the kidney transplantation rate was variable among them (9%, 22% and 15%, respectively, P <0.02). The median levels of Ca, Po 4 , albumin, bicarbonate and alk. phos were not significantly different from those of the whole study group in most of the months of the study. The parathyroid median serum levels were 570, 900 and 406 pg/mL, respec­tively (P <0.001) for the three centers for the whole period of the study. In addition, the me­dian percentages of the patients with PTH levels more than 300 pg/mL (triple normal levels) were 73%, 91% and 58% for the three centers, P <0.001. The combined or singular use of calcium carbonate and sevelamer in terms of median doses and patient-months of treatment was not significantly different among the three centers from the median of the whole study group. There was no signi­ficant difference in the patient-months of treatment with oral or i.v. vit. D among the three centers from the median of the whole study group for most of the months of the study; the same findings were noted in the use of cinacalcet by the three centers.

The comparison of the study patients accor­ding to the starting dates of dialysis before and after 2011 (the start of the study period) dis­closed several important points. The number of patients starting dialysis before and after 2011 were 391 (69.4%) and 191 (30.6%), respectively. The vascular calcifications detec­ted on X-ray were 25% and 13% (P <0.02) and parathyroidectomy was noted in 4.9% of the patients vs. 0.5% (P <0.04). The patients of both groups did not differ in their median serum levels of Ca, Po 4 , albumin, bicarbonate, alk phos and PTH for most of the months of the study. The patients were significantly more frequently treated with higher doses of sevelamer (P <0.04) and cinacalcet (P <0.02) if they were started on dialysis before 2011, and the differences continued throughout the study period.

The patients with high median PTH levels (>300 pg/mL) were compared with those with the lower levels. There were 415 patients with median PTH levels >300 pg/mL and 144 with median PTH levels <300 pg/mL. The vascular calcifications were detected on X-rays in 26% of the patients vs 7.0%, P <0.001. The PO 4 median serum levels were significantly higher in the patients with PTH levels >300 pg/mL than in those with PTH levels <300 pg/mL for most of the months of the study (P <0.001), and also were the alk. phos levels (P <0.0001). In addition, patients with PTH levels >300 pg/mL were on a significantly higher calcium carbonate median dose (1700 mg/d) than those with lower PTH levels (1500 mg/d) (P <0.01), and significantly higher sevelamer median dose (3200 vs. 2700 mg/d, respectively, P <0.001) and higher cinacalcet median dose (42 vs. 30 mg/d respectively, P <0.0001).

The patients who were treated with cinacalcet in addition to the other therapies for CKD-MBD versus those who were only on other therapy were compared in terms of all the clinical parameters and therapy. There were 310 (55%) patients on cinacalcet therapy and 253 (45%) patients who were on only other therapy (non-cinacalcet). The cinacalcet was used in the patients variably among the three centers, ranging from 24% to 55% of the pa­tients. The vascular calcifications were detec­ted on X-rays in 30% of the patients on cinacalcet and 9% in the non-cinacalcet group, P <0.0001. The patients treated with cinacalcet versus the non-cinacalcet group had signi­ficantly higher PO 4 median serum levels (5.7 vs. 4.7 mg/dL, respectively, P <0.0001), PTH median serum levels (860 vs. 320 pg/mL, respectively, P <0.001) and higher alk. phos median serum levels (212 vs. 136 unit/L, res­pectively, P <0.0001) for most of the months of the study. The cinacalcet patients were on higher calcium carbonate median daily doses than the non-cinacalcet patients (1700 vs. 1200 mg/d, respectively, P <0.006), higher sevelamer median daily dose (3300 vs. 2800 mg/d, respectively, P <0.0001) and higher oral vit D median dose (0.5 vs. 0.25 μg/d, respectively, P <0.001), but lower i.v. vit D median doses (2.3 vs. 3.1 μg/dialysis session, respectively, P <0.01). The characteristics of the cinacalcet-treated group having elevated PTH, PO 4, and vascular calcifications justified the use of cinacalcet by the attending physicians to con­trol these parameters after the failure of the other therapeutic measures.


   Discussion Top


Our results disclosed several points related to the aim of the study. The design of our study depended on increasing the power of the study to a high level of confidence by pooling pa­tients from three different major dialysis centers. The locations of the centers with mini­mal differences among them in the size, staffing and approaches to management of CKD-MBD increased further the confidence in the results of the study. We studied the clinical parameters including the original kidney di­sease, the past and present dialysis history and physical condition of the patients besides our focus on the CKD-MBD clinical features and imaging and laboratory investigations. The fol­low-up of monthly investigations and therapy of CKD-MBD ensured the evaluation of their trends and their reflection on the current approaches of management of CKD-MBD on a large scale of patients. We could also eva­luate the trends of economy of treatment of CKD-MBD in dialysis patients.

The results of our study suggested the con­tinuation of the prevalence of the main features of CKD-MBD and the presence of evidence of calcifications detected in routine X-rays, which were more sensitive than the clinical signs of the disease. In general, the trends of the medians of the serum levels of the main CKD-MBD-related minerals showed improved recent PO 4 , calcium, albumin and bicarbonate levels besides the alk. phos and vit D assays. The PTH levels accordingly fol­lowed a trend toward better control and closer to the recommended levels by the international guidelines. [10],[11],[12],[13] The algorithm of therapy fol­lowed a good strategy in most of the patients with the use of phosphate binders and active vit D analogues. The addition of cinacalcet has been escalated in the last few years in the different dialysis centers as an adjuvant the­rapy in case of continuously elevated PTH levels despite adequate dialysis markers and intensive treatment with phosphate binders and vit D. The tendency to higher utilization of cinacalcet by physicians in the dialysis patients in the recent years was obvious in our results.

The parathyroidectomy rate in our study showed that patients still undergo resection of the parathyroid glands because of uncontrol­lable secondary hyperparathyroidism; this has been the experience of others as well. [54],[55],[56],[57],[58],[59] There is still an increased number of dialysis patients with elevated PTH levels despite intensive prescriptions of phosphate binders and oral vit D. The controlled therapy with i.v. vit D besides cinacalcet may help in decrea­sing the need for future parathyroidectomy in many patients. [58],[59] In our study, patients with higher PTH despite intensive therapy were prescribed cinacalcet more than those with levels lower than double to triple normal. This reflects the knowledge of the treating physi­cians about the proper place for cinacalcet in the algorithm of therapy for CKD-MBD and their preference to the recommendations of K-DOQI over K-DIGO for more tight control of PTH levels. [10],[11],[12],[13]

The patients with elevated PTH are still at a high risk of developing significant morbidity from vascular calcifications, especially those with a longer duration on dialysis as shown in our study patients. [60],[61] There is increased popularity of the cinacalcet use in dialysis patients as shown in [Figure 3]. We believe that avoiding parathyroidectomy still justifies the cost of the cinacalcet added to the cost of dialysis as shown in [Figure 4], especially the patients with significantly elevated PTH le­vels, as shown by other studies from the dif­ferent countries. [62],[63],[64],[65],[66],[67],[68],[69],[70],[71]

The reasons for discontinuation of treatments and the frequencies of the dropouts were addressed by our study to reveal the side-effects of the used medications. The most frequent reasons of the dropouts were due to overdosing of the drugs, which were adjusted later by the attending physicians who restarted the therapy with the same medications at lower doses later in many patients.

The first limitation of our study was its retrospective design, but we tried to overcome this limitation by including for analysis the trends of the monthly investigations and dosing of medications over 28 months for each patient as shown in our [Figure 1] and [Figure 2]; in real-life clinical practice, we always evaluate the effect of our management of chronically ill patients such as those with CKD through the trends of investigations not the cross-sectional evaluations. The second limitation was the variability of practice in some dialysis centers, especially the performance of routine X-rays to evaluate the soft tissue and vascular calcifi­cations. However, the performance of the other centers could give a good evaluation for this variability and avoidance of erroneous conclu­sions about the prevalence of vascular calci­fication in our population.

We conclude that the trends of the median serum levels of PTH and related minerals in the CKD patients in our dialysis patients suggested a good, although not yet optimal, inclination toward control and prevention of the vascular calcifications prevalent in the CKD-MBD, and this is due mostly to the appropriate decision making of the treating physicians in the approach to treatment of CKD-MBD according to the recommended algorithm of the international guidelines. The popularity of use of new drugs such as cinacalcet is promising and does not seem to add much to the current outpatient cost of chronic dialysis.


   Acknowledgment Top


The authors would like to thank Mr. Michael V. Abeleda for his help in the secretarial work and data entry and Mr. Elamin Kheir for his analysis of the study.

 
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Correspondence Address:
Muhammad Ziad Souqiyyeh
The Saudi Center for Organ Transplantation, P.O. Box 27049, Riyadh 11417
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DOI: 10.4103/1319-2442.144249

PMID: 25394432

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