What parathyroid hormone levels should we aim for in children with stage 5 chronic kidney disease; what is the evidence?

Clearly, the only way we can know the rate of bone turnover is by bone biopsy, but this is an invasive and expensive procedure, currently undertaken in very few paediatric centres. PTH is, therefore, currently used as the best available surrogate marker of bone turnover. Recommendations for optimum PTH levels are based on the pioneering work of Salusky, who has been the leader in the field of paediatric bone biopsy and who has been able to correlate plasma PTH levels with bone turnover [8, 9, 10] (Table 1, Fig. 1).

The first description of bone histology in children with CKD was from Australia in 1982. Bone abnormalities included high turnover, osteomalacia and mixed lesions and were present in all 23 children with a glomerular filtration rate (GFR) <20 ml/min per 1.73 m² body surface area. PTH levels were high, but the assay available at that time picked up carboxy terminal fragments as well as the intact hormone [11]. A paper from Toronto in 1988 showed that treatment with 1 alpha-hydroxycholecalciferol resulted in significant improvement in PTH levels and bone histology in 12 peritoneal dialysis (PD) patients [12]. There are five paediatric studies since 1990, and unpublished data from our centre, that have used newer “intact” PTH assays to look at their correlation with bone histology (Table 1). The first three studies [8, 9, 10] are all from Salusky’s group, and are of patients dialysed in their unit between 1983 and 1992. There are two more recent studies from Poland [13] and Turkey [14]. The patients from our unit had bone biopsies taken prior to starting dialysis, at the time of insertion of access or at transplantation.

High-turnover bone was characterised by PTH levels above normal in all studies, although the variation was wide, ranging from just above the upper limit of normal (76 ± 14 pg/ml), when changes were mild [8], to 16-times normal (1,122 ± 603 pg/ml) with osteitis fibrosa [15].

Patients with ABD clearly had lower PTH levels than those with osteitis fibrosa (although not lower than those with mild hyperparathyroidism) [8]. However, the ability of PTH levels to distinguish between ABD and normal histology is less clear. Figure 1 shows the PTH levels in the three studies that have identified patients with normal bone and ABD. Even within the same centre, there was no consistency, with PTH levels being lower with normal bone than with ABD in patients on haemodialysis (HD) [8], but the reverse in PD patients [9]. Levels were particularly high in the second study, with a wide scatter, but analysis of results in these patients suggested that PTH <150 pg/ml and calcium >10 mg/dl (>2.50 mmol/l) was indicative of low turnover, and PTH >200 pg/ml with calcium <10 mg/dl (2.50 mmol/l) indicated high turnover [9]. In the Polish group a PTH level of <50 pg/ml was suggestive of ABD, but the difference from normal bone was not significant [13]. Other evidence for PTH levels associated with ABD comes from a study of the role of intermittent oral administration compared with intraperitoneal administration of calcitriol (dose 1.26 (0.61–2.88) μg × 3 per week for a year) in 14 patients with high-turnover disease. There were no patients with normal histology results. Six patients developed ABD, with a mean PTH of approximately 200 pg/ml, whereas the mean for high-turnover disease was around 400 pg/ml. However, again, the standard errors were wide [10].

What are the potential problems with these studies? Patient numbers are small in some; there are very few young children, and, indeed, some patients might have ceased growing; some children in the earlier studies had received aluminium, and two had undergone parathyroidectomies (both recognised causes of ABD); some had transplants that had failed; phosphate control and vitamin D doses were variable, and the majority received dialysate calcium of 1.75 mmol/l, which is higher than is most commonly used now.

Intuitively, it might be expected that poor growth would occur with ABD, and, conversely, that, if a child is growing well, ABD is unlikely. The only published paper to look at bone histology and growth is by Salusky’s group in 1998 [15]. Their purpose was also to study the effect of different ways of administering vitamin D. Sixteen patients were treated for a year with intermittent doses of calcitriol in comparison to daily treatment during the preceding year. The rate of growth was unchanged in the patients taking calcitriol daily, but, in the patients taking intermittent doses of calcitriol, PTH correlated with the change in height standard deviation score (HtSDS). Growth was particularly affected in the four patients who developed ABD, possibly because of the inhibiting effects of large, intermittent, doses of calcitriol on chondrocyte activity within the growth plate cartilage. In our 11 patients (Table 1) the rate of growth did not vary with the type of bone histology. Change in HtSDS over the previous 1.0 (0.5–1.6) years was +0.06 (−0.11 to+0.15) in patients with ABD, −0.29 (−0.07 to −0.50) in those with mixed lesions, and 0.02 (−0.34 to+0.34) in patients with high-turnover disease. However, numbers are small, and only much larger studies would be able to clarify the relationship between growth and bone histology.

Overall, reports of growth in children on dialysis are variable, with the majority showing a decline in HtSDS. It is difficult to dissect out the effects of renal bone disease from malnutrition, anaemia, inadequate dialysis and other causes of poor growth. On the other hand, we have found, in a review of the growth of 35 prepubertal children on dialysis for more than 1 year in our unit, that, even with PTH levels only slightly above normal, it is possible to prevent decline in HtSDS, and significant catch-up growth can occur in children less than 2 years [16, 17].

Adynamic bone disease due to aging, parathyroidectomy, aluminium and high doses of calcium-containing phosphate binders is associated with vascular calcification in adults [18]. Is there any evidence to associate PTH levels and vascular disease and calcification in children? This is a difficult question to answer, because of the inextricable relationships between phosphate, which is possibly the most potent vascular toxin, vitamin D, and PTH. Soft tissue calcification in paediatric patients is not a new phenomenon. The presence of coronary artery abnormalities at post-mortem in children who had been on HD was reported as long ago as 1976 [19], and autopsies of 120 children with uraemia, on dialysis, or following renal transplantation from 1960 to 1983 revealed soft tissue calcification in 60% [20]. More recently, histological evidence of intimal thickening and atherosclerotic plaques was found in five of 12 children with a mean (range) age of 14.6 (11–17) years on HD who were undergoing transplantation and was associated with calcification in the iliac artery of two [21].

Most studies of the effect of childhood end-stage renal failure (ESRF) on vascular outcomes are of young adults. As well as survival data, surrogate markers of structural and functional disease and calcification, such as carotid intima media thickness (CIMT) and distensibility, and pulse wave velocity (PWV), electron beam computed tomography (EBCT) and multi-slice CT scanning have been used to assess the development of vascular abnormality. Inevitably, because a significant number of patients in these follow-up cohorts have died from cardiovascular disease, the true incidence and severity of vascular abnormalities is likely to be greater than reports using surrogate markers would suggest. Duration of ESRF management and, in particular, dialysis, has been linked to worse outcomes in all studies.

Not all studies have addressed the effect of abnormalities of mineral metabolism on vascular anomalies; arterial stiffness was shown to be increased in the Dutch long-term follow-up study, but data on mineral metabolism were not available [22]. In a study from Germany, coronary artery calcification (CAC) was reported in 38% of 16 patients aged 14–39 years, but correlations with PTH were not made [23]. Three studies have concentrated on this aspect in young adults. In a second German study, CAC was found in 92% of 39 patients aged 19–39 years on dialysis or after transplantation, and CIMT was increased. Calcification scores and CIMT correlated with the calcium × phosphate product and with PTH, particularly if the level of C-reactive protein (CRP) was raised [24]. A further study from Salusky’s group identified CAC in 88% of 16 patients aged over 20 years on dialysis, but in none of 23 patients aged less than this. The plasma calcium, calcium x phosphate product and intake of calcium, but not PTH levels, were greater in those with calcification [25]. The most recent paper included 40 patients aged 23.6 ± 5.5 years, of whom nine were on dialysis and 31 had received transplants. CIMT was not increased, but left ventricular hypertrophy was present in 62.5%, and four (10%) had CAC. Again, calcium intake from phosphate binders and vitamin D correlated with these abnormalities, and PTH was an independent predictor of left ventricle (LV) mass index [26].

There are five studies that address the problem principally in children, although in four of these studies patients in their twenties are included, i.e. patients who no longer have the dimension of growth affecting mineral balance. Increased plasma phosphate, calcium phosphate product, phosphate binder and calcitriol doses, and PTH predicted abnormal vascular structure and function, and PTH also correlated with left ventricle mass (LVM) index and poor diastolic function, in 16 patients on dialysis [27]. CIMT was increased in 37 patients on dialysis and in 34 after transplantation, particularly in the dialysis patients, and CIMT correlated with calcium × phosphate product, calcium-based phosphate binder and vitamin D intake, but not with PTH [28]. Spiral CT scanning in 53 patients (39 on dialysis, 14 after transplantation) detected CAC in 15%. Mineral metabolism was a significant association, including higher time integrated phosphate, calcium × phosphate product and PTH, and calcium-containing phosphate binders and vitamin D intake [29]. A recent paper from the USA of 11 patients (four on HD, seven after transplantation) reported that seven had CAC. This included all the patients on dialysis. The only significant influencing factor was the dose of calcitriol. PTH levels were very high in all patients [30]. We have studied CIMT, PWV and CAC in 85 children of a younger age range (5 years to 18 years) who had undergone dialysis for at least 6 months. CIMT and calcification correlated with PTH levels. There was no difference from controls in CIMT and PWV in patients with PTH levels < 2 × the upper limit of normal (44 children), but those with PTH levels > 2 × the upper limit of normal (ULN) (41 children) had thicker CIMT, stiffer vessels and increased calcification. The dose of vitamin D strongly influenced all vascular measures [31]. Further investigation of 61 children on dialysis identified a bimodal effect of plasma levels of 1,25 (OH)2D3, such that levels both above and below the normal range were associated with increased CIMT and vascular calcification [32]. In summary, PTH was correlated with surrogate markers of vascular calcification in three out of the five paediatric studies [27, 29, 31] and two out of the three studies of young adults that have looked at this relationship [24, 26].