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Saudi Journal of Kidney Diseases and Transplantation
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RENAL DATA FROM THE ARAB WORLD  
Year : 2013  |  Volume : 24  |  Issue : 4  |  Page : 825-831
Effect of relative hypoparathyroidism on the responsiveness to recombinant human erythropoietin in chronic hemodialysis patients: A single Saudi center experience


1 Prince Salman Center for Kidney Diseases, Riyadh, Kingdom of Saudi Arabia
2 Nephrology Division, Urology and Nephrology Center, Mansoura University, Egypt
3 Internal Medicine Department, Mansoura University, Egypt

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Date of Web Publication24-Jun-2013
 

   Abstract 

Anemia is a common concomitant disorder in dialysis patients. The responsiveness to recombinant human erythropoietin in hemodialysis (HD) patients with relative hypoparathyroidism [4 ≤ intact parathyroid hormone (iPTH) ≤16.5 pmol/L] remains undetermined. We retrospectively studied 70 chronic hemodialysis patients who were divided into two groups: Group A (32 patients) had 16.5 ≤ iPTH levels <33.5 pmol/L and Group B (38 patients) had 4 ≥ iPTH≤16.5 pmol/L during the preceding six months without 1- (OH) Vitamin D3 administration. The percentage of female gender was significantly higher in Group B compared with Group A (P = 0.018). In Groups A and B, the mean weekly recombinant human erythropoietin dose (U/kg/ week) was 227.96 ± 95.24 vs. 154.1 ± 84.9 (P = 0.001) and the mean hemoglobin level was 11.15 ± 0.63 g/dL versus 11.62 ± 0.63 g/dL (P = 0.008). There was no significant statistical difference regarding the other biochemical markers (serum ferritin, iron saturation, serum Ca, serum alkaline phosphatase, C-reactive protein, serum B12, serum folate levels, residual renal function and Kt/v) between the groups. If other factors related to anemia are excluded in chronic HD patients, the lower the iPTH level (relative hypoparathyroidism) the better the responsiveness to recombinant human erythropoietin.

How to cite this article:
Al Saran K, Sabry A, Hassan AH. Effect of relative hypoparathyroidism on the responsiveness to recombinant human erythropoietin in chronic hemodialysis patients: A single Saudi center experience. Saudi J Kidney Dis Transpl 2013;24:825-31

How to cite this URL:
Al Saran K, Sabry A, Hassan AH. Effect of relative hypoparathyroidism on the responsiveness to recombinant human erythropoietin in chronic hemodialysis patients: A single Saudi center experience. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2019 Oct 13];24:825-31. Available from: http://www.sjkdt.org/text.asp?2013/24/4/825/113911

   Introduction Top


Anemia is a common concomitant disorder in dialysis patients. Improving the quality of life in these patients has been achieved by the use of recombinant human erythropoietin (rHuEPO), which became a routine practice in the 1990s. [1] Refractory anemia, or so-called "erythropoietin hyporesponsiveness," in dialysis patients is not fully understood. However, functional iron deficiency, secondary hyperparathyroidism, aluminum toxicity, interaction with other drugs, infection and inflammatory conditions have been considered as predictors of poor response to erythropoietin treatment of anemia. [2],[3] Folic acid or vitamin B12 deficiency, hemolysis, chronic blood loss and primary bone marrow diseases may also contribute to the hyporesponsiveness to erythropoietin therapy. [4],[5]

Hyperparathyroidism may induce a sub-optimal response to erythropoietin in a number of ways. [6],[7] However, the responsiveness to rHuEPO in hemodialysis (HD) patients with relative hypoparathyroidism [4 ≤ intact parathyroid hormone (iPTH) ≤16.5 pmol/L] remains undetermined. [8]

The purpose of this study was to assess the response to rHuEPO during the treatment of anemia in dialysis patients with relative hypoparathyroidism.


   Patients and Methods Top


We studied 70 chronic HD patients treated for at least six months at the Prince Salman Center for Kidney Disease (PSCKD), Riyadh, Kingdom of Saudi Arabia. The following were our inclusion criteria: Age older than 18 years with four or more iPTH measurements available after January 2009. We excluded patients who had total or sub-total parathyroidectomy, pulse intravenous high-dose active vitamin D treatment for the preceding six months, functional iron deficiency, secondary hyperparathyroidism, Angiotensin Converting Enzyme Inhibitors (ACEI) and Angiotensin Receptor Blockers (ARB) intake, infection, inflammatory conditions, hemolysis, chronic blood loss, primary bone marrow diseases or adult polycystic kidney disease.

The patients were divided into two groups according to their iPTH level: Group A consisted of 32 patients (19 males and 13 females) with iPTH values within the target (mean value was 25.28 ± 3.22 pmol/L) as recommended by the K/DOQI guidelines (range 16.5-33.5 pmol/L) and Group B consisted of 38 patients (12 males and 26 females) with relative hypoparathyroidism (the mean value of iPTH was 9.71 ± 2.72 pmol/L and the range was 4 ≤ iPTH ≤16.5 pmol/L) for the preceding six months without administration of 1- (OH) -vitamin D 3 .

All the patients were negative for hepatitis B virus and human immunodeficiency virus infections, and their HD was on volumetric machines (Fresenius S 4008) and disposable high-flux polysulphone membrane (Fresenius Medical Care, Saudi Advanced Renal Services Corporation Ltd., Riyadh, KSA). The dialysate flow ranged from 500 to 800 mL/min and the blood flow rate ranged from 250 to 400 mL/ min. All the patients had thrice-weekly dialysis sessions for 3-4 h each. The bicarbonate dialysate was used in all patients. The following data were collected:

  1. Levels of hemoglobin: The mean monthly hemoglobin levels were calculated.
  2. Human recombinant erythropoietin doses (u/kg/week), the weekly index of rHuEPO responsiveness (mean EPO dose/hemoglobin level) and the weekly index of rHuEPO resistance (mean EPO dose/hematocrit level) were calculated.
  3. iPTH level: Values between 16.5 and 33.5 pmol/L were considered stable or normal and values between 4 ≤ iPTH ≤16.5 pmol/ L were considered as relative hypoparathyroidism.
  4. Serum calcium (corrected), phosphorus, alkaline phosphatase, albumin, C-reactive protein, Kt/V, serum B12 and folate levels, residual renal function for those passing more than 100 mL/day and iron study were recorded for statistical analysis.

   Statistical Analysis Top


Statistical analysis was performed using the Statistical Package for Social Science (SPSS) version 16. Quantitative data were expressed in the form of numbers, percentages, mean and standard deviation. Spearman correlation test, quantitative "t" test and categorical Chi-square test were used for determining the correlation between the variables. P-values less than 0.05 were considered statistically significant.


   Results Top


The mean age for patients in Group A was 53.6 ± 14.7 years (range 29-85 years). Their mean body weight was 66.5 ± 13.9 kg. Fourteen patients were diabetic and 29 patients were seronegative for hepatitis C virus (HCV). The mean duration of HD therapy was 3.71 ± 1.7 years (range 1-10 years). The mean age for patients in Group B was 58.1 ± 12.9 years (range 24-84 years). Their mean duration of HD therapy was 3.91 ± 1.98 years (range 1-12 years) and the mean body weight was 66.4 ± 13.2 kg. Eleven patients were diabetic and 32 patients were seronegative for HCV.

There were no statistically significant differences regarding the demographic data between both groups, apart from the percentage of gender distribution; female gender was significantly higher in Group B (n = 27) compared with Group A (n = 13) (P = 0.018), as shown in [Table 1].
Table 1: Demographic, rHuEPO and biochemical data in both groups.

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No statistically significant differences were observed between the groups regarding the biochemical variables, apart from a higher mean serum phosphorus level and mean Ca × PO 4 product, which was higher in Group A compared with Group B [Table 1].

In Groups A and B, the mean weekly rHuEPO dose (u/kg/week) was 228 ± 93.8 versus 139 ± 85.0 (P = 0.000), the mean hemoglobin level (g/dL) was 11.2 ± 0.65 versus 11.70 ± 0.64 (P = 0.001), the mean rHuEPO responsiveness index was 20.7 ± 8.79 versus 12.1 ± 7.80 (P = 0.000), the mean rHuEPO resistance index "ERI" was 9.90 ± 2.93 versus 4.02 ± 2.61 (P = 0.000) and the mean iPTH (pmol/L) was 25.3 ± 3.22 versus 9.71 ± 2.72, respectively (P = 0.000) [Table 1].

The mean weekly rHuEPO dose correlated positively with the mean iPTH (r = 0.118 and P = 0.004) [Figure 1]), while the mean rHuEPO responsiveness index and the mean hemoglobin correlated negatively with the mean iPTH (r = -0.333, P = 0.000 and r = -0.087, P = 0.013), respectively [Table 2], [Figure 2] and [Figure 3].
Figure 1: Correlation between iPTH and weekly EPO dose (U/kg/week) in both groups.

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Figure 2: Correlation between iPTH and EPO responsiveness index in both groups.

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Figure 3: Correlation between iPTH and hemoglobin (g/dL) in both groups.

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Table 2: Correlation between parameters of rHuEPO responsiveness in both groups.

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   Discussion Top


Anemia of ESRD is a multi-factorial disorder. [9],[10],[11],[12],[13],[14],[15],[16] There is some evidence suggesting that elevated levels of parathyroid hormone may inhibit the endogenous production of erythropoietin or the responsiveness to erythropoietin. [17],[18]

In our present study, we found that patients on chronic HD with relative hypoparathyroidism had better responsiveness to rHuEPO than those with stable iPTH value. Meytes et al [6] stated that iPTH directly inhibits human peripheral blood erythroid colony formation. Furthermore, plasma rHuEPO levels and blood reticulocytes were noted to be dramatically increased one to two weeks after parathyroidectomy in some HD patients. [19]

The results of our study support the idea that the iPTH may actually has a direct negative impact on the responsiveness to rHuEPO in HD patients rather than an indirect impact through bone marrow fibrosis. These results were matched with the results from Shih et al, [8] who found that the lower the iPTH levels in chronic HD patients with relative hypoparathyroidism, the better the responsiveness to rHuEPO. Neither diabetes nor age had any influence on the responsiveness to rHuEPO in our study. This is in agreement with the results from Jinn et al, [20] who found no relationship between diabetes per se and iPTH level or glycemic control and iPTH level, and Ishimura et al [21] suggested that diabetes mellitus is a risk factor for the severity of anemia in patients with renal failure not yet receiving dialysis. Power et al [22] stated that the rHuEPO response to anemia in the elderly is similar to that in the young. In contrast, Yun et al [23] found that a reduced rHuEPO response to anemia could explain the anemia present in diabetics having no advanced diabetic nephropathy and Kario et al [24] suggested that a decreased rHuEPO responsiveness to low hemoglobin concentrations is a contributing factor to anemia in the elderly.

Interestingly, a higher percentage of female gender was found in Group B; however, a direct causal relation or association between female gender and hypoparathyroidism needs further clarification.

In conclusion, our study suggests that the lower the iPTH level in chronic HD patients (relative hypoparathyroidism), the better the rHuEPO responsiveness and, moreover, the better the hemoglobin level.


   Acknowledgments Top


The authors wish to thank the medical and nursing staff of PSCKD for their help in data collection.

 
   References Top

1.Eschbach J, Adamson J. Recombinant human erythropoietin: implication for nephrology. Am J Kidney Dis 1988;11:203-9.  Back to cited text no. 1
    
2.Macdougall IC. Monitoring of iron status and iron supplementation in patients treated with erythropoietin. Curr Open Nephrol Hypertens 1994;3:620-5.  Back to cited text no. 2
    
3.Muirhead N, Hodsman AB. Occult infection and resistance of anemia to rHUEPO therapy in renal failure. Nephrol Dial Transplant 1990; 5:232-4.  Back to cited text no. 3
    
4.Muta K, Krantz SB, Bondurant MC, Wickrema A. Distinct roles of erythropoietin, insulin-like growth factor I, and stem cell factor in the development of erythroid progenitor cells. J Clin Invest 1994;88:34-43.  Back to cited text no. 4
    
5.Nissenson AR. Hyporesponsiveness to erythropoietin: Overview. Perit Dial Int 2010;16:417-20.  Back to cited text no. 5
    
6.Meytes D, Bogin E, Ma C, Dukes PP, Massry SG. Effects of parathyroid hormone on erythropoiesis. J Clin Invest 1981;67:1263-9.  Back to cited text no. 6
    
7.Rao DS, Shih MS, Mohini R. Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med 1993;328:171-5.  Back to cited text no. 7
    
8.Hsu SP, Peng YS, Pai MF, Hung KY, Tsai TJ. Influence of Relative Hypoparathyroidism on the Responsiveness to Recombinant Human Erythropoietin in Hemodialysis Patients. Blood Purif 2003;21:220-4.  Back to cited text no. 8
    
9.IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000. Am J Kidney Dis 2001;37(1 Suppl 1):S182-238.  Back to cited text no. 9
    
10.Nissenson AR, Strobos J. Iron deficiency in patients with renal failure. Kidney Int 1999; 69:S18-21.  Back to cited text no. 10
    
11.Madore F, Lowrie EG, Brugnara C, et al. Anemia in hemodialysis patients: Variables affecting this outcome predictor. J Am Soc Nephrol 1997;8:1921-9.  Back to cited text no. 11
    
12.Kalantar-Zadeh K, Hoffken B, Wunsch H, Fink H, Kleiner M, Luft FC. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era. Am J Kidney Dis 1995;26:292-9.  Back to cited text no. 12
    
13.Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 1999;33:63-72.  Back to cited text no. 13
    
14.Tong EM, Nissenson AR. Erythropoietin and anemia. Semin Nephrol 2001;21:190-203.  Back to cited text no. 14
    
15.Kalantar-Zadeh K, Don BR, Rodriguez RA, Humphreys MH. Serum ferritin is a marker of morbidity and mortality in hemodialysis patients. Am J Kidney Dis 2001;37:564-72.  Back to cited text no. 15
    
16.Thamer M, Richard CM, Klinkmann J, Ivanovich P, Lang G, Cotter DJ. Use of clinical guidelines for treatment of anemia among hemodialysis patients. Artif Organs 2000;24: 91-4.  Back to cited text no. 16
    
17.Drüeke TB. Modulating factors in the hemato-poietic response to erythropoietin. Am J Kidney Dis 1991;18:87-92.  Back to cited text no. 17
    
18.Kcomt J, Sotelo C, Raja R. Influence of adynamic bone disease on responsiveness to recombinant human erythropoietin in peritoneal patients. Adv Perit Dial 2000;16:294-6.  Back to cited text no. 18
    
19.Ureña P, Eckardt KU, Sarfati E, et al. Serum erythropoietin and erythropoiesis in primary and secondary hyperparathyroidism: Effect of parathyroidectomy. Nephron 1991;59:384-93.  Back to cited text no. 19
    
20.Guh JY, Chen HC, Chuang HY, Huang SC, Chien LC, Lai YH. Risk factors and risk for mortality of mild hypoparathyroidism in hemodialysis patients. Am J Kidney Dis 2002; 39:1245-54.  Back to cited text no. 20
    
21.Ishimura E, Nishizawa Y, Okuno S, et al. Diabetes mellitus increases the severity of anemia in non-dialyzed patients with renal failure. J Nephrol 1998;11:83-6.  Back to cited text no. 21
    
22.Powers JS, Krantz SB, Collins JC, et al. Erythropoietin response to anemia as a function of age. J Am Geriatr Soc 1991;39:30-2.  Back to cited text no. 22
    
23.Yun YS, Lee HC, Yoo NC, et al. Reduced erythropoietin responsiveness to anemia in diabetic patients before advanced diabetic nephropathy. Diabetes Res Clin Pract 1999;46:223-9.  Back to cited text no. 23
    
24.Kario K, Matsuo T, Nakao K. Serum erythropoietin levels in the elderly. Gerontology 1991; 37:345-58.  Back to cited text no. 24
    

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Correspondence Address:
Alaa Sabry
Mansoura Urology and Nephrology Center, Mansoura University
Egypt
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DOI: 10.4103/1319-2442.113911

PMID: 23816744

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    Abstract
   Introduction
   Patients and Methods
   Statistical Analysis
   Results
   Discussion
   Acknowledgments
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