Changing relationships between serum IL-1, IL-6, and TNF-{alpha} and dynamic tests of parathyroid gland function in haemodialysis patients with severe hyperparathyroidism in response to calcitriol therapy

A. J. Jaroszynski and A. Ksiazek

Lublin, Poland.

Sir,

Despite persisting methodological and interpretational controversies, the PTH–calcium relationship curve has been accepted by many authors as a method of investigating the dynamic status of parathyroid glands in haemodialysis patients [1,2]. Since increased secretion of IL-1, IL-6 as well as TNF-{alpha} stimulates bone resorption in vitro [3,4], these cytokines may play a significant role in the pathogenesis of renal osteodystrophy [36]. The aim of our study was to establish possible relationships among IL-1, IL-6, TNF-{alpha}, and PTH–calcium curve parameters in haemodialysis patients with severe hyperparathyroidism, and to determine if calcitriol can modify these relationships.

Eleven haemodialysis patients with a serum i-PTH level over 1000 pg/ml and a serum aluminium level <10 µg/l were studied. Haemodialysis patients who were dialysed three times a week were given i.v. calcitriol at the end of each dialysis session. In the first month the received 1 µg per session, then 1.5 µg in the following month, and a mean of 2.1±0.9 µg according to CaxP product in the 3rd month (not to exceed 70 mg/dl). Both before and after 3 months of calcitriol therapy the parameters of the PTH–calcium relationship curve (PTHmin, PTHmax–steady value, set point of calcium, slope of the curve, and PTHbasal/PTHmax ratio) were established for each patient according to the Felsenfeld definition [2]. Serum levels of IL-1, IL-6, TNF-{alpha} and osteocalcin (BGP) were measured by ELISA. Plasma tartrate-resistant acid phosphatase (TRAP), a marker of osteoclastic activity, was measured by a colorimetric method. Group means were compared by Student's t test for dependent samples. Spearman correlation analysis was used to determine correlation between variables. Values for P of less than 0.05 were considered significant.

Results are shown in Table 1Go. Calcitriol administration led to a decrease in PTH basal, minimal, and maximal, PTHbasal/PTHmax ratio, as well as in serum TRAP, and to an increase in serum calcium and phosphorus. We found no significant influence of calcitriol on calcium set point, slope of the curve, or serum IL-1, IL-6 and TNF-{alpha} levels. Positive significant correlations were observed between IL-6 and pre-treatment values of PTHbasal (r=0.637 P=0.018), PTHmax (r=0.642 P=0.017), PTHmin (r=0.541 P=0.043), PTHbasal/PTHmax ratio (r=0.621 P=0.021), and TRAP (r=0.580 P=0.031). After calcitriol treatment, correlations between IL-6 and all other study parameters were no longer significant. TNF-{alpha} as well as IL-1 showed no significant correlations with any of the investigated parameters.


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Table 1. Relationships between cytokines, markers of bone turnover, and dynamic parameters of parathyroid gland function in haemodialysis patients with severe hyperparathyroidism before and after calcitriol treatment

 
We would like to comment on several aspects of our study. IL-6 is synthesized and released from osteoblasts in response to resorptive stimuli, and this cytokine increases the recruitment of immature osteoclasts and the transformation into mature functioning osteoclasts [3]. The observed significant positive correlations between IL-6 and pre-treatment PTH basal, max, min, and PTHbasal/PTHmax ratio as well as TRAP provide evidence in favour of a role for IL-6 in renal osteodystrophy and especially in bone resorption. This is in agreement with in vitro [3,5], as well as in vivo studies by Montalban et al. [6], who found correlations between IL-6 and basal PTH as well as carboxy-terminal telopeptide of collagen I in haemodialysis patients.

Furthermore, the lack of correlation between IL-6 and serum PTH, as well as TRAP values after calcitriol treatment, may result from the fact that PTH levels decreased after treatment. This is in agreement with the previous suggestion [6] that IL-6 may mediate bone resorption, particularly in cases of severe hyperparathyroidism.

References

  1. Hardy-Yverneau P, Shenouda M, Moriniere P, Legallais C, Achard J, Fournier A. The dependency of calcium set point on basal plasma calcium in dialysis patients: a better explanation for the discrepancies regarding its link with PTH secretion than methodological differences. Clin Nephrol1998; 50: 236–246[ISI][Medline]
  2. Rodriguez M, Caravaca F, Fernandez E et al. Parathyroid function as a determinant of the response to calcitriol treatment in the hemodialysis patients. Kidney Int1999; 56: 306–317[ISI][Medline]
  3. McIntyre C, Schroeder N, Burrin J, Cunningham J. Effects of new analogues of vitamin D on bone cells: Implications for treatment of uremic bone disease. Kidney Int1999; 55: 500–511[ISI][Medline]
  4. Tsukamoto Y, Nagaba Y, Izumida I, Morishita T, Saitoh M. Comparison of effects of calcitriol and calcium carbonate on secretion of interleukin-1 beta and tumour necrosis factor-alpha by uraemic peripheral blood mononuclear cells. Nephrol Dial Transplant1996; 11 [Suppl 3]: 15–21[ISI][Medline]
  5. Langub M, Koszewski N, Turner H, Monier-Faugere M, Geng Z, Malluche H. Bone resorption and mRNA expression of IL-6 and IL-6 receptor in patients with renal osteodystrophy. Kidney Int1996; 2: 515–520
  6. Montalban C, Garcia Unzueta M, De Francisco A, Amado J. Serum interleukin 6 in renal osteodystrophy: relationship with serum PTH and bone remodeling markers. Horm Metab Res1999; 31: 14–17[ISI][Medline]




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