MANAGEMENT OF CALCIUM AND PHOSPHORUS METABOLISM IN CHRONIC KIDNEY DISEASE PATIENTS

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1 JNRT 10 (1) 2018 : Journal of Nephrology and Renal Transplantation (JNRT) Original article MANAGEMENT OF CALCIUM AND PHOSPHORUS METABOLISM IN CHRONIC KIDNEY DISEASE PATIENTS Farzanehsadat Minoo 1,2, Ali Ghafari* 1,2, Seyed Mansour Gatmiri 1,2, Masoumeh Vasheghani-Farahani 1. Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran. 1 Center of Excellence in Nephrology, Tehran University of Medical Science, Tehran, Iran. 2 corresponding author: Ali Ghafari,MD, Emam Khomeini hospital complex, Keshavarz Blvd, Tehran, Iran *,Fax: Abstract , ghaf_ali@yahoo.com Keywords Calcium; Phosphorus; CKD; MBD Introduction: The objective of this study was to determine how many therapeutic targets of calcium, phosphate, vitamin D, and parathyroid hormone (PTH) homeostasis were achieved in Chronic Kidney Disease (CKD )patients, under supervision of nephrology clinics. [Continued ] 2018 Journal of Nephrology and Renal Transplantation. All rights reserved 1. Introduction It is well-documented that Chronic kidney disease (CKD), a worldwide health problem, is accompanied by higher risk for progressing to end-stage renal disease and dying prematurely due to cardiovascular diseases. (1, 2) In this regard, major disturbances in calcium, phosphate, vitamin D, and parathyroid hormone (PTH) homeostasis and generally CKD mineral and bone disorder (CKD- MBD) have received considerable attention in recent years. Prevention, early detection, and management of CKD- MBD are now a priority for prevention of musculoskeletal disorders and cardiovascular calcifications, and ultimately, reduction of its morbidity and mortality rates (3, 4). Kausz et al observed that only 50% and 12% of patients with CKD had at least 1 measurement of serum phosphorus and plasma PTH, respectively, during the 2 years before beginning dialysis. More interestingly, Winkelmayer et al found that only 3.4% of CKD patients had plasma PTH levels measured and only 0.3% had vitamin D levels measured during the year immediately prior to the start of dialysis.(5) According to Kidney Disease Outcomes Quality Initiatives (K/DOQI) guidelines, all patients at stage 3 CKD or above (i.e. those with a GFR <60 ml/min per 1.73 m 2 ), should be evaluated frequently for homeostasis of calcium, phosphorus, PTH and vitamin D. It has been recommended to measure the levels of calcium, phosphorus and PTH each 12 months in stage 3 CKD and each 3 months in stage 4 CKD. The recommended interval for stage 5 patients is even shorter and is every 3 months and every 1 month

2 respectively for PTH and Ca and P levels. There are also specific targets for serum levels of the aforementioned indices which should be tried to be achieved.it is advised to maintain serum levels of phosphorus between 2.7 mg/dl and 4.6 mg/dl and serum level of corrected total calcium in normal range of laboratory in stage 3 and 4.Serum level of calcium and phosphorus should be maintained between8.4 to 9.5mg/dl and 3.5 to 5.5 mg/dl respectively in stage 5 (6). CKD clinics have been established to implement K/DOQI guidelines and thus to slow disease progression, its complication and also improve outcomes (7-9). However, it is necessary to assess the success of these clinics in achieving the recommended targets, quantitatively. The objective of this study was to determine how much these targets were achieved in those, under supervision of nephrology clinics [Abstract Continued ] Patients& Methods: Demographic and clinical data of all diagnosed patients with CKD admitted to our nephrology clinic between 2004 and 2010 were reviewed. Data on calcium, phosphorus, PTH and vitamin D levels at baseline and at 1-year and 2-year time points were compared to the recommended ranges by the K/DOQI work group in different stages of CKD. Statistical significance defined by p Results: This cohort study included 410 newly diagnosed adult CKD patients under nephrology supervision for at least 1 year. Two-hundred and thirty six (57.3%) of the study patients were male. The mean age of patients was 65.7 ±13.8 years. Diabetic nephropathy was the cause of kidney failure in 32.8%. The rate of K/DOQI target for phosphorus (p = 0.008) and calcium level (p = 0.042) achievement declined significantly over time. 35.9% of the patients had PTH levels within the recommend range. The mean concentration of Vit D was 31.4 ± 18.4 ng/ml ( ) and 53.7% had insufficient Vit D levels (less than30 ng/ml) at baseline. Conclusion: There is still room for improving adherence to the K/DOQI guidelines for CKD-MBD in terms of frequency of measurement of indices and looking for new methods to help healthcare services to guarantee better cooperation of CKD patients with prescription and or diet restrictions Journal of Nephrology and Renal Transplantation. All rights reserved 2. Material and methods The medical files of all diagnosed patients with CKD who consecutively admitted to a nephrology clinic in Tehran between October 2004 and October 2010 were reviewed. Those with at least 6 months duration of supervision were included in the study. The exclusion criteria were primary hyperparathyroidism, previous parathyroidectomy, neoplasia, osteoporosis under treatment with biphosphonates or calcitonin. Forty one patients were excluded due to inadequate number of laboratory examinations.in this study, demographic data, causes of CKD, as well as data regarding the calcium, phosphorus, PTH and 25(OH) vit D levels in addition to albumin and creatinine at baseline and at 1-year and 2-year time points were extracted from medical files and enrolled for final analysis. The treatment program consisted of drugs for blood pressure and bone mineral metabolism indices control and other parameters according to each patient situation. Nutritional and compliance instruction were given for salt and water restriction, phosphate content of different foods and protein consumption in each visit. The study protocol was reviewed and accepted by ethics committee of Tehran University of Medical Sciences. The CKD stages were mutually exclusive as defined by the K/DOQI system of classification, and the baseline estimated glomerular filtration rate (egfr) was used to categorize patients: Stage 3 as 30 egfr >60 ml/min/1.73 m 2, Stage 4:15 egfr <30 ml/min/1.73 m 2 and as Stage 5, if egfr values

3 was less than 15 ml/min/1.73 m 2 but the patients did not initiated dialysis therapy. All CKD 5 stage started dialysis till the end of 1 st year but their data were followed for the study. The patients were classified based on the stage of CKD at the baseline. Kolmogorov-Smirnov test was applied to examine normal distribution. Continuous variables were expressed as mean ± SD and categorical variables were presented as absolute frequencies with percentages. Two-way repeated measure ANOVA test with a Greenhouse-Geisser correction was used for evaluation of the trend of calcium and phosphorus levels during 2 years of follow up in different stages of CKD. For pair wise comparisons Banferroni s post hoc test was applied. All p values were 2-tailed with significance defined as p For the statistical analysis, the statistical package SPSS version 13.0 for windows (SPSS Inc, Chicago, Illinois, USA) was used. All p values were 2-tailed with a statistical significance of p Results This cohort study included 410 newly diagnosed adult CKD patients in different stages (stage 3:248; stage 4:145 and stage 5:17 patients) who had been under management at our nephrology clinic for 36.0 ± 25.2 months. Two-hundred and thirty-six (57.3%) of patients were male. The mean age of patients was 65.7 ±13.8 years ( year). Diabetic nephropathy was the leading cause of kidney failure in 32.8% of subjects. Table1 shows the demographic and baseline clinical and laboratory characteristics of the study population. Follow up duration to compare K/DOQI targets achievement in different stages was defined 2 years because of the low number of patients in stage 5. The results regarding mortality and the need for RRT as the end points of the cohort was presented elsewhere (7). A two-way repeated measure ANOVA with a Greenhouse-Geisser correction determined that the rate of K/DOQI target achievement for phosphorus level declines significantly during the time [F (1.92, 305.1) = 5.1, p = 0.008], which was similar for calcium (p = 0.042). Post hoc tests using the Bonferroni correction revealed that patients in stage 3 CKD had significantly different (p = 0.005) course from those in stage 4 CKD regarding the achievement to K/DOQI targets (no significant change in stage 3 compared to stage 4). Table2 shows the frequency of reached K/DOQI guideline targets for serum calcium and phosphorus levels. Figure 1 demonstrates the frequency of cases who achieved K/DOQI targets for calcium during 2-year follow up. Significant difference was not observed at baseline (p=0.508) but gradually the difference got significance during the following two years in different stages even under supervision of physicians. Figure 2 shows the fluctuation of serum calcium levels during years of follow up. Ca-P product target achievement was also decreased over time [F (1.5, 235.9), p= 0.037] Figure 3 presents the course of phosphorus target achievement in different stages of CKD during 2 years of medical management. Serum PTH levels was available only in 146 patients. An analysis of achievement to recommended goals of K/DOQI regarding the PTH is shown in Table 2. Overall 35.9% of the patients had PTH levels within the recommend range. The mean concentration of 25(OH) vit D was 31.4 ± 18.4 ng/ml ( ) and 53.7% had insufficient Vit D levels (less than 30 ng/ml) at baseline which was corrected in follow up visits. A sub-analysis was performed on 131 cases that had available data on calcium, phosphorus and Ca-P product levels after 2 years of supervision in nephrology clinic. Table 3 demonstrates the frequency of achievement to different levels of K/DOQI goals for these indices.

4 stage3 stage4 stage5 0 ca4th year ca2nd year cabaseline Fig-1. Frequency of K/DOQI guideline target achievement for serum calcium levels (P value of Baseline, 1 st year and 2 nd year were 0.508, and respectively) Fig-2. Trend of serum calcium levels during time of follow up.

5 % target achievement PBaseline Phosphorus control during time P1st yr P2nd yr P3rd yr P4th yr stage3 stage4 stage5 Fig-3. Frequency of K/DOQI guideline target achievement for serum phosphorus levels (P value of Baseline, 1 st year and 2 nd year was <0.001) Fig-4: Trend of serum phosphorus levels during time of follow up Table1. Demographic and clinical characteristics of the study patients at baseline Characteristic CKD Stage CKD Stage CKD Stage 5 17 Male /Female 145/103 80/65 11/ Age(year) 66.1±13.7(18-100) 67.6±13.9(22-94) 60.0±11.7(40-81) Time of follow up 37.9±24.9(6-119) 32.6±25.7(6-124) (months) Calcium (mg/dl) 9.4±0.7(7.9-11) 9.2±0.8( ) 8.9±0.5( ) Phosphorus(mg/dl) 3.9±0.8( ) 4.1±0.8( ) 5.5±1.5(4-7.8) <0.001* PTH 79.0±72.4( ) 96.5±89.7(12-465) 186.7±216.3( ) 0.03 Cardiovascular& Cerebrovascular events 26(10.5%) 17(11.7%) 1(5.9%) CKD: chronic kidney disease.

6 Table2. Achievement of K/DOQI guideline targets during follow up till 4 years. Stage Stage 3 Stage4 Stage5 DOQI Absolute (%) Absolute (%) Absolute (%) Ca Baseline Ca1year Ca2year Ca3year Ca4year P Baseline P1year P2year P3year P4year 45(84.9) 172(87.8) 147(91.3) 126(94) 101(94.4) 42(82.4) 151(84.8) 117(73.6) 124(92.5) 98(92.5) 35(76.1) 107(79.9) 79(87.8) 49(90.7) 28(82.4) 33(73.3) 102(81.6) 47(52.2) 41(74.5) 30(88.2) 6(85.7) 16(100) 4(57.1) 2(50) 2(50) 3(75) 1 5(71.4) P Baseline P1year P2year P3year P4year Ca ph product 0 Ca ph product 1 Ca ph product 2 Ca ph product 3 Ca ph product 4 PTH of 1 st year within target Less than target Higher than target 42(82.4) 151(84.8) 117(73.6) 124(92.5) 98(92.5) 49(98) 177(99.4) 150(93.8) 133(99.3) 106(100) 40(40.4) 18(18.2%) 41(41.4) 33(73.3) 102(81.6) 47(52.2) 41(74.5) 30(88.2) 44(97.8) 125(100) 77(85.6) 52(96.3) 3 12(30) 18(45) 10(25) 3(75) 1 5(71.4) 4(80) 1 7(87.5) 0(0) 5(83.3) 1(16.7) Absolute frequencies with percentages within parentheses. Table3. The number of K/DOQI guideline targets achievement for calcium, phosphorus and Ca-P product after 2 years of nephrologist supervision. No of achieved goals Stage3 (n=118) Stage4 (n = 59) Stage5 (n=6) Total (n=183) 0 1 (0.8%) 0 (0.0%) 0 (0.0%) 1 (0.5%) 1 4 (3.4%) 8 (13.6%) 1 (16.7%) 13 (7.1%) 2 16 (13.6%) 19 (32.2%) 3 (50.0%) 38 (20.8%) 3 97 (82.2%) 32 (54.2%) 2 (33.3%) 131 (71.6%) Absolute frequencies with percentages within parentheses.

7 4. Discussion We observed that less than 50% of our CKD patients had sufficient serum level of 25 (OH) vit D at baseline. It has been shown that low levels of 25(OH) D is associated with increased morbidity and mortality. (10) Meanwhile, Metzger et al in their study on 929 CKD patients found that PTH concentration rose sharply when circulating 25(OH)D levels fell to less than 20 ng/ml.(11) This deficiency is the easiest one which can be treated by vitamin D administration. It has reno-protective activity by regulating multiple signaling pathways important in renal injury process (12). The percentage of vitamin D deficiency was 11.2% in in stage 5 CKD in Li et al study on 2,924 patients with CKD(13). Although all patients had the data of calcium, phosphorus just 145 patients had their PTH measured which is consistent with the previous studies on the field which reported inconsistent and infrequent biochemical testing for disturbances in mineral metabolism of CKD patients. (14) The K/DOQI targets for PTH levels at different stages were reached differently, most patients in stage 3 and 4 had lower than normal PTH level based on the recommended level in K/DOQI (45% and 83.3% respectively). Inkert et al in their cross sectional analysis of patients found prevalence of hyperparathyroidism increased from 28.2% in stage 3 to 72.5% in stage 4(15) compared with 41% and 25% in our stage 3 and 4 in our study respectively. However, this ratio seems to decrease after starting hemodialysis. In the study on 2630 patients from 56 dialysis units 48.1% had less than normal PTH level (16). In Craver study on 1836 CKD patients recommended targets for ipth in K/DOQI guidelines were achieved in 42.4%, 24.6% and 46.8% of CKD stage 3,4 and 5 patients respectively.although their results were better than ours, they similarly showed the negative impact of severity of CKD on reaching the K/DOQI target.(17) Another valuable finding of our study was preserved serum calcium level within recommended range in majority of (> 85%) patients in stage 3 during follow up (fig-1) but it decreased with more advanced CKD, comparable to other studies. Similarly, frequency of hyperphosphatemia and increased ipth levels showed a negative correlation with renal function. (13, 17) It is important to mention that the sharp fall of K/DOQI target achievement for calcium in stage 5 after 2-years as seen in fig- 1 can also be due to very few number of remaining patients in this group and start of dialysis. Craver in a cross-sectional study found that serum calcium level target was achieved in 90.7%, 85.6% and 55% in stage 3-5 respectively. (17) His findings were overall higher than ours but did not have followed up data and did not evaluate the change of indices by the time which seems the strength point of our study. As figure 3 shows, there was a decline in target achievement of serum phosphorus in stage 4 and 5 patients. Although the decline is found in other studies ours is more profound. (13, 17)Doubtlessly, more effective strategies are needed to maintain the homeostasis of phosphorus in parallel with the progression of the CKD. Li et al also found no significant decline in serum calcium level in patients with stages 1-4 but significant in stage 5 ( p < 0.001). (13). Regarding the achievement of K/DOQI recommended targets, the vast majority of the previous studies have only examined the situation of mineral metabolism in haemodialysis patients [5, 7] and predialysis CKD patients have received less attention.(17) Our findings were in agreement with the few previous studies about the achievement to K/DOQI targets. Serum phosphate: 90.9, 77.1 and 70.3; ipth 42.4, 24.6 and 46.8 and Ca-P product 99.9, 99.6 and 83.8, respectively (17). Lenz and colleagues reported that only 20% of stage 4 CKD patients, followed by a nephrologist for at least 6 months had plasma PTH levels within the K/DOQI target range, whereas 91% of patients had acceptable serum calcium levels and 80% had acceptable serum phosphorus levels.(18) In another study from Thailand(19), the mean percentage of target achievements were: 79.3% for serum calcium, 78.1% for serum phosphate, 95.8% for serum Ca-P product and 26.3% for serum PTH. The maintenance of serum calcium and phosphorus levels within the recommended range is difficult due to many reasons. The two main obstacles are patient noncompliance and the use of phosphate binders that contain calcium (3, 4, 16, 20, 21). The main phosphate binder administered in Iran is calcium carbonate in CKD patients.(7) In addition to mentioned factors, progression of the CKD, contributes seriously to the deteriorating status of CKD-MBD management of our patients during the follow up.

8 Regarding the number of achieved targets Craver found the ratio of those who got all 4 items in recommended range were 34.9, 18.4 and 21.6 for stages 3, 4 and 5, respectively.(17)the percentage of our patients who could achieve 3 targets of calcium, phosphorus and calcium phosphorus product were 82.2%, 54.2% and 33.3% in stage 3,4 and 5 respectively. Interestingly, hemodialysis patients could have similar results in 34.2 %(16) In conclusion, there is still room for improving adherence to the K/DOQI guidelines for CKD- MBD in terms of frequency of measurement of indices and looking for new methods to help healthcare services in academic nephrology clinics to guarantee better cooperation of CKD patients with prescription and or diet restrictions. ACKNOWLEDGEMENTS This specialist thesis was supported by Tehran University of Medical Science. Conflict of interest: None REFERENCES [1] Isakova T. Comparison of mineral metabolites as risk factors for adverse clinical outcomes in CKD. Semin Nephrol Mar;33(2): [2] Weiner DE, Tabatabai S, Tighiouart H, Elsayed E, Bansal N, Griffith J, et al. Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis Sep;48(3): [3] Young EW. Mineral metabolism and mortality in patients with chronic kidney disease. Adv Chronic Kidney Dis Jan;14(1): [4] Bellasi A, Kooienga L, Block GA. Phosphate binders: new products and challenges. Hemodial Int Jul;10(3): [5] Winkelmayer WC, Levin R, Avorn J. The nephrologist's role in the management of calcium-phosphorus metabolism in patients with chronic kidney disease. Kidney Int May;63(5): [6] K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis Oct;42(4 Suppl 3):S [7] Mahdavi-Mazdeh M, Hatmi ZN, Shahpari-Niri S. Does a medical management program for CKD patients postpone renal replacement therapy and mortality? A 5-year-cohort study. BMC Nephrol. 2012;13:138. [8] Mahdavi-Mazdeh M, Zamani M, Zamyadi M, Rajolani H, Tajbakhsh K, Heidary Rouchi A, et al. Hemodialysis cost in Tehran, Iran. Hemodial Int Oct;12(4): [9] St Peter WL, Schoolwerth AC, McGowan T, McClellan WM. Chronic kidney disease: issues and establishing programs and clinics for improved patient outcomes. Am J Kidney Dis May;41(5): [10] Brandenburg VM, Kruger T. Calcifediol-more than the stepchild of CKD-MBD therapy? Curr Vasc Pharmacol May 16. [11] Metzger M, Houillier P, Gauci C, Haymann JP, Flamant M, Thervet E, et al. Relation between circulating levels of 25(OH) vitamin D and parathyroid hormone in chronic kidney disease: quest for a threshold. J Clin Endocrinol Metab Jul;98(7): [12] Li YC. Vitamin D in chronic kidney disease. Contrib Nephrol. 2013;180: [13] Li Y, Zhang W, Ren H, Wang W, Shi H, Li X, et al. Evaluation of anemia and serum ipth, calcium, and phosphorus in patients with primary glomerulonephritis. Contrib Nephrol. 2013;181: [14] Kausz AT, et al. General medical care among patients with chronic kidney disease: opportunities for improving outcomes. J Am Soc Nephrol. 2005;16(10):

9 [15] Inker LA, Tonelli M, Hemmelgarn BR, Levitan EB, Muntner P. Comparison of concurrent complications of CKD by 2 risk categorization systems. Am J Kidney Dis Mar;59(3): [16] Mahdavi-Mazdeh M, Zamyadi M, Norouzi S, Heidary Rouchi A. Management of Calcium and Phosphorus Metabolism in Hemodialysis Patients in Tehran Province, Iran. Iran J Kidney Dis. 2007;1(1):25-8. [17] Craver L, Marco MP, Martinez I, Rue M, Borras M, Martin ML, et al. Mineral metabolism parameters throughout chronic kidney disease stages 1-5--achievement of K/DOQI target ranges. Nephrol Dial Transplant Apr;22(4): [18] Lenz O, Mekala DP, Patel DV, Fornoni A, Metz D, Roth D. Barriers to successful care for chronic kidney disease. BMC Nephrol. 2005;6:11. [19] Panawong W, Chaiyakum A, Pongskul C. Adherence to mineral and bone disorder clinical practice guidelines in chronic kidney disease. J Med Assoc Thai Oct;94(10): [20] Gal-Moscovici A, Sprague SM. Bone health in chronic kidney disease-mineral and bone disease. Adv Chronic Kidney Dis Jan;14(1): [21] Young EW, Akiba T, Albert JM, McCarthy JT, Kerr PG, Mendelssohn DC, et al. Magnitude and impact of abnormal mineral metabolism in hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis Nov;44(5 Suppl 2):34-8.