Introduction

Parathyroid hormone (PTH) abnormalities and alterations of phosphate (po4) and calcium (ca) was common in maintenance hemodialysis patients (HD), they can associated with cardiac valve calcification (CVC) (1), and increase mortality and morbidity (2) (3) (4) (5) (6 ) only few studies failed to find an association with all these three factors or some of them. (7) (8) (9).

Guidelines applied for control of S. PTH, S. Po4 and S. ca like Kidney Disease Outcome Quality Initiative (K/DOQI) 2003 (10), and Kidney Disease Improving Global Outcome (KDIGO) 2009 which differ from the first one (11) (12), here S.PTH- 2 – 9 times the assay used, S. po4 and S. ca in their normal range and taken separately rather that product, these guideline was beneficial (13) and achieved by minority of patients (10).

CVC was common in (HD) patients (14), prevalence of aortic valve calcification (52%), mitral valve (44.5%) both valves (58.7%) (9), it tend to occur earlier in age, rapid course, higher stenosis and/ or regurge, aortic valve affected more than mitral and higher association with coronary artery disease and early death than general population. (15) (16) (17) (18)

Risk factors for CVC include: advanced age, longer duration of HD (15), hypertension (HTN), diabetes (DM) (16), use of drugs that increase ca load (19) ( 20 ) , hyperphosphatemia, hypercalcemia and hyperparathyroidism ( 9 ) (15) (16 ) a dynamic bone disease (ABD) (21) , malnutrition, inflammation, atherosclerosis and decrease fetuin – A. (22)

CVC a kin atherosclerotic process with inflammation and tissue remodeling at areas of high shear stress. (23) (24) (25)

The aim of the study

To verify the role of risk factors that contributed to aortic and mitral valve calcification and the importance and applicability of KDIGO guideline for S. PTH, S. ca, S.po4 in HD patients.

Patients and Methods

Cross section study of (52) HD patients exclusion criteria history of congenital and Rheumatic valvular heart disease and HD less than three months.

All patients asked about their ages, duration of HD in months, use of drugs (ca. based po4 binders and vitamin D and it's analogue), subjective global assessment (SGA) using 7 point score with A= normal nutrition B= mild- moderate malnutrition and c= severe ,which was validated .

Blood sample for all patients for B. urea, S. creatinine S. po4 and corrected S. ca) in mg/dl, S. albumin in gm/l, C. reactive protein (CRP) , S.PTH in pg / ml , normal range for this assay ( 8 – 80 ) pg / ml and echocardiography for evidence of CVC (11).

The patients then divided into two groups (C and D) according to the presence and absence of CVC then compared depend on their association with CVC risk factors.

The two groups also compared according to their percentage of hyperphosphatemia and hypercalcemia to determine the importance of KDIGO guideline.

The two groups compared at three levels, above the target of KDIGO for S. PTH ( ˃ 9 times assay used), within the target 2 – 9 0f the assay used and below the target ( ˂ 2 times) to determine the role of PTH abnormalities as risk factor for CVC and the benefit of KDIGO guideline.

Statistical analysis

All results expressed as data of all patients in both groups with duplicates and percentages an t- test for two independent samples and chi- square test using SPSS V16, differences with P- value ˂ 0.05 and P- value ˂ 0.01 were considered as statistically significant.

Results

Total of (52) patients, and (29) female, (23) male, mean age= 48.25 ± (16.76), mean duration of HD= 42.17 ± (26.39) months, all their information was tabulated (table 1).

Aortic valve calcification = (50%), mitral valve calcification = (14%), both valve= (36%) table (3).

Group (C) patients with CVC No= 14 patients, (8) female and (6) male, Group (D) patients without CVC No= 38, (21) female, (17) male, all data tabulated (table 2 and 4).

Comparison of the two groups according to CVC risk factors and KDIGO guideline target show.

Group (C) patients were older than (D), mean age= 58.71 ± (12.70) vs 44.39 ± (16.57) year, p- value = 0.005 mean duration of HD for group (C) = 44.21 ± (26.57) month vs 41.52 ± (26.57) for D, p- value= 0.748.

Use of ca based po4 binders in (C) = 93% vs 82% in (D) , p- value= 0.317.

Use of vitamin D and it's analgue in (C)= 93% vs 87% in group (D), p- value = 0.317.

Hypertension in (C) = 50% vs 29% in (D), p- value = 0.157.

Diabetes in (C) = 29% vs 18% in D, p- value = 0.427.

SGA score (B) in group (C ) = 29% vs 42%, p- value= 0.375.

(CRP) in group (C ) = 14% vs 37% in group (D), p- value = 0.114.

Hypercalcemia in (C) = 14% vs 5% in D, p- value = 0.279.

Hyperphosphatemia in ( C ) = 86% vs 76% in (D), p- value = 0.462.

PTH above target in (C) = 7% vs 16% in (D), p – value = 0.719.

PTH within the target of KDIGO for (C) = 36% vs 31% for D, p- value= 0.719.

PTH below target in group (C) = 57 % in group (C) vs 53% in group (D), p- value = 0.719.

Table 1 Demographic and Lab Variables for all Patients
Variables No. percentage
Use of ca.bosed po4 binder yes 44 85%
no 8 15%
Use of vitamin D and its analogue yes 46 88%
no 6 12%
Causes of ESRD HTN 19 36%
D.M 10 19%
ADPCKD 4 8%
neurogenic bladder 2 4%
Post acute Kidney injury 1 2%
Rheumatiod arithritis 1 2%
Lupus nephritis 1 2%
Obstructive nephropathy 1 2%
Unknown causes 13 25%
SGA A ( normal nutrition ) 32 62%
B (mild- moderate ) 20 38%
mean Std. deviation
Age / years 48.25 16.76
Duration of HDmonths 42.17 26.39
S.ca 7.78 1.717
S.po4 6.07 1.78
S.PTH 328.24 440.44
CRP 10.15 14.62
S.albumin 36.03 6.313
B.urea 152.93 97.67
S.creatinine 8.89 2.92

Table 2 Group (C) Variables
Variables No. percentage
HTN yes 7 50%
no 7 50%
D.M yes 4 29%
no 10 71%
SGA A 10 71%
4 29%
Use of Calciumbased po4 binders yes 13 93%
negative 1 7%
Use of vitamin D or its metabolites yes 13 93%
negative 1 7%
mean Std. deviation
Age / years 58.71 12.70
Duration of HDmonths 44.21 26.57
S.ca 8.55 1.64
S.po4 5.76 1.22
S.PTH 242.76 270.08
CRP 6.35 10.80

Table 3 Percentage of aorticand/ or mitral valve calcification for all patients
No. percentage
Aortic value 7 50%
Mitral value 2 14%
Combined aortic and mitral value 5 36%

Table 4 Group (D)
Variables No. percentage
HTN yes 11 29%
no 27 71%
D.M yes 7 18%
no 31 82%
SGA A 22 58%
16 42%
Use of Calciumbased po4 binders yes 31 82%
no 7 18%
Use of vitamin D or its metabolites yes 33 87%
no 5 13%
mean Std. deviation
Age / years 44.39 16.57
Duration of HDmonths 41.52 26.57
S.ca 7.50 1.67
S.po4 6.17 1.94
S.PTH 359.53 487.85
CRP 11.55 15.69

Table 5 Differences between(C) and (D)
Variables C = 14 D = 38 p-value
No. percentage No. percentage
HTN yes 7 50% 11 29% 0.157
no 7 50% 27 71%
D.M yes 4 29% 7 18% 0.427
no 10 71% 31 82%
SGA A 10 71% 22 58% 0.374
4 29% 16 42%
Use of Calciumbased po4 binders yes 13 93% 31 82% 0.317
no 1 7% 7 18%
Use of vitamin D or its analogue yes 13 93% 33 87% 0.547
no 1 7% 5 13%
S.ca Above 10.4 2 14% 2 5% 0.279
Below 8.4-10.4 12 86% 36 95%
S.po4 Above 4.5 12 86% 29 76% 0.462
Below 2.8-4.5 2 14% 9 24%
S.PTH Above 720 1 7% 6 16% 0.719
Between 160-720 5 36% 12 31%
Less than 160 8 57% 20 53%
CRP Result < 6 2 14% 14 37% 0.118
normal 12 86% 24 63%
C = 14 D = 38 p- value
mean Std. deviation mean Std. deviation
Age / years 58.71 12.70 44.39 16.57 0.005*
Duration of HDmonths 44.21 26.57 41.52 26.57 0.748

Discussion

From these results CVC was common in maintenance HD patients and aortic valve affected more than mitral( aortic valve = 50% , mitral = 14% , both valve calcification = 36% ) , the age was the strongest risk factor as group (C), was older than (D) with statistically significant difference .

For other factors, duration of HD, use of drugs that increase ca load, hypertension, diabetes, hyperphosphatemia, hypercalcemia and ABD (less than lower limit of S. PTH guideline target), there is a difference although statistically not significant and also they are risk factors for CVC and global guideline for hyperphosphatemia, hypercalcemia and ABD was beneficial because they are a risk factors (15) (21).

Overlap results noticed for patients at level higher than guideline limits for S. PTH (2-9 times of the assay used for S. PTH) and within these limits because of a wide range for the guideline limits, there is no association between higher than recommended values for S. PTH and CVC noticed and no remarkable reduction in the risk of CVC for patients within these limits were hyperparathyroidism can be diagnosed at level of 400 pg/ml for S. PTH (27) and the upper limit of the target was = 720 pg/ml in this study according to that guideline which is much higher than S. PTH value that’s diagnostic for hyperparathyroidism and many patients with hyperparathyroidism would be missed within the recommended target, this study not found an association between malnutrition and inflammation with CVC , SGA score B in group C = 29% vs 42% for D and CRP higher than 6 ( positive ) in C = 14% vs 37% in D .

Conclusion and Recommendation

Risk factors for CVC in HD patients should be known because many of them are treatable and global guideline for minerals was beneficial although the upper limit of S. PTH target need another review.1, 2, 3, 4, 5, 6, 7, 8 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27

References

  1. Importance of low serum intact parathyroid hormone as a predictor of mortality in hemodialysis and peritoneal dialysis patients: 14 years of prospective observation Avram Morrell M., Mittman Neal, Myint Maung M., Fein Paul. American Journal of Kidney Diseases.2001;38(6):1351-1357.
  2. Coronary - Artery Calcification in Young Adults with End- Stage Renal Disease who are Undergoing Dialysis Goodman W G, Goldin J, Kuizan D. N Engl J Med.2000;342:1474-1483.
  3. Spectrum of Calcification Aortic valve Disease, pathogenesis, Disease Progression, and Treatment Strategies 23- Rosario V, Freeman, Catherine M, Otto. Circulation.2005;111:3316-3342.
  4. Mitral Annular Calcification in CAPD patients with a Low degree of Hyperparathroidism. An Analysis of Other Possible Risk factors Reyes M J, Bajo Anxiliadora, Robles M, P. Nephrol Dial Tranplant.1995;10(11):2090-2095.
  5. Multicenter Study of the Validity and Reliability of Subjective Global Assessment in the Hemodialysis Population Steiber Alison, Leon Janeen B., Secker Donna, McCarthy Maureen, McCann Linda, Serra Monica, Sehgal Ashwini R., Kalantar-Zadeh Kamyar. Journal of Renal Nutrition.2007;17(5):336-342.
  6. Aortic valve stenosis: an active atheroinflammatory process Helske Satu, Kupari Markku, Lindstedt Ken A, Kovanen Petri T. Current Opinion in Lipidology.2007;18(5):483-491.
  7. possible role for most cell- Derived cathepsin G in the Adverse remodeling of Sterotic Aortic Valves 24- Heleske S, Syvaranta S, Kupari M. Eur Heart J.2006;27:1495-1495.
  8. Which targets in Clinical Practice guidelines are Associated with improved Survival in a Large Dialysis Organization ? - Tentori F, Hunt W C, Rohrsche M. J Am Soc Nephrol.2007;18(8):2377-84.
  9. Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease Covic A., Kothawala P., Bernal M., Robbins S., Chalian A., Goldsmith D.. Nephrology Dialysis Transplantation.2009;24(5):1506-1523.
  10. Low Dose Inteavenous Calcitriol Treatment of Secondary Hyperparathyroidisim in Hemodialysis Patients - Maurizio G, Paola Diego B, P. Kidney Int.1992;42:1191-1198.
  11. Renal Data System Annual Report 14- USRD: U. S.. Am j Kidney Dis.1998;32(1):581-588.
  12. Association of Serum Fetuin- A with Malnutrition, Inflammation, Atherosclerosis and Valvular Calcification Syndrome and Outcome in Peritoneal Dialysis Patients Wang Angela Yee- Moon, Jeen W. Nephrol Dial Transplant.2005;20(8):1676-1685.
  13. Relationship between Bone and Mineral Metabolism in African- American Hemodialysis patients 12- Moore C, Yee J, Malluche. Clin J Am Soc Nephrol.2009;4:1484-1484.
  14. Calcific Aortic Stenosis: A Complication of Chronic Uraemia Maher E.R., Pazianas M., Curtis J.R.. Nephron.1987;47(2):119-122.
  15. Prevalence and Risk factor of Valvular Calcification in Hemodialysis patients Sayarlioglu Gurnkan, Acar Murat, Sahin Iranian Journal of Kidney Diseases.2013;7:129-163.
  16. Calcification of the Aortic valve in the Dialysis patient London G M, Pannier B, Marchais S J, Guerin A. J Am Soc Nephrol.2000;11(4):774-784.
  17. Mineral Metabolism, Mortality, and Morbidity in Maintenance Hemodialysis Block G. A.. Journal of the American Society of Nephrology.2004;15(8):2208-2218.
  18. 10- National Kidney Foundation. K/ DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease Am J Kidney Disease.2003;42:51-51.
  19. Mitral annular calcification predicts mortality and cardiac disease in end stage renal disease SHARMA R, PELLERIN D, GAZE D, COLLINSON P, GREGSON H, STREATHER C, BRECKER S. European Journal of Echocardiography.2007;8(3):S30-S30.
  20. Feehally - John, Jurgen F, Marcello T, Richard J J. Clinical Nephrology.2016;:979-995.
  21. cardiac valve Calcification in Hemodialysis patients: Role of Calcium- Phosphate Metabolism Ribeiro Silvia, O, Ramos Aaura, Brandao Antonio. Nephrol Dial Transplant.1998;13:2037-2040.
  22. Differential effects of vitamin D receptor activators on vascular calcification in uremic rats Mizobuchi M., Finch J.L., Martin D.R., Slatopolsky E.. Kidney International.2007;72(6):709-715.
  23. Prevalence of valve Calcium with Coronary Artery disease in End Stage Renal Disease, Atherosclerotic Vascular Disease, and all cause Mortality in 137 patients Undergoing Hemodialysis for Chronic Renal failure - Varma R, Aronow W S, Clung M, J A. Am J cardiol.2005;95:742-743.
  24. predictors and Consequences of altered mineral metabolism: the dialysis outcomes and practice pattern study Ew Albert J M, Satayathum S. Kidney Int.2005;67:1179-1179.
  25. Morbidity and mortality in end- stage renal disease Foley R V, Parfey P S, Harnett J D. AM J Nephrol.1996;16(5):386-93.
  26. Clinical Practice Guidelines for the Diagniosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease- Mineral and Bone Disorder (CKD- MBD) Kidney Int.2009;76(113):51-51.
  27. Electron beam computed tomography in the evaluation of cardiac calcifications in chronic dialysis patients Braun Johann, Oldendorf Manfred, Moshage Werner, Heidler Rudolf, Zeitler Eberhard, Luft Friedrich C.. American Journal of Kidney Diseases.1996;27(3):394-401.