The gap between calculated and actual calcium substitution during citrate anticoagulation in an immobilised patient on renal replacement therapy reflects the extent of bone loss – a case report

Total CVVHD duration was 254 days, with a mean dialysis period of 22.5 hours per day. Applied dialysis dose averaged at 37.8 ml/kg/h. For anticoagulation a mean of 4.0 mmol (3.4 to 4.3) citrate per litre blood was given, permitting a mean circuit lifespan of 64.4 hours. Mean calcium substitution was 0.5 mmol/l dialysate. Initial requirements of 1.7 mmol/l decreased after 27 days as shown in Figure 1. The lowest level of calcium substitution was 0.2 mmol/l. The calculated gap between actual calcium substitution and the theoretical need resulted in an estimated total calcium loss of 14.25 mol (about 571 g). Bisphosphonate therapy was initiated when spontaneous fracture occurred, and testosterone substituted after measurement of total testosterone level (0.76 ng/ml - normal range: 2.49-8.36 ng/ml).

At admission our patient showed normal renal function (eGFR (CKD-EPI) 143 ml/min, calculated GFR based on cystatin C 105 ml/min). Serum calcium measured within the normal range (2.5 mmol/l). Although iPTH was not determined at admission, pre-existing elevated iPTH levels had been noted. Parathyroid hormone levels were measured at day 152, 181, and 222 of CVVHD with values between 237–424 pg/ml (normal range: 10–50 pg/ml, Table 1). Serum calcitonin, vitamin A, and thyroid hormone levels remained within physiological parameters. Mean serum phosphate was 3.2 ± 0.84 mg/dl (1.03 ± 0.26 mmol/l). Initial vitamin D levels lay within the target range of >30 ng/ml and decreased over time despite substitution (Table 1).Computed tomographic imaging was performed at several points during the hospital stay. Bone density of the lower thoracic vertebrae was used as the basis for radiological comparison. Semi-quantitative assessment of bone demineralisation by radiodensity was described in Hounsfield Units (HU). Three years prior to admission thoracolumbar vertebrae showed a mineralisation with age-adjusted configuration within normal limits. At 242 HU bone mineral density (BMD) was within physiological limits (Figure 2). Although little change in BMD was seen at admission, a decrease to 52 HU was noted at 4.5 months after admission (day 95 of CVVHD). A parallel reduction in vertebral body height was clearly visible. Imaging 9 months after admission showed vertebral height remained unchanged, with an increase in BMD (90 HU) permitting differentiation between the trailing edge of the vertebral bodies and the spinal canal.

Published data concerning calcium loss secondary to bone demineralisation following immobilisation remain sparse and somewhat inconsistent within literature. Immobilisation trials amongst volunteers and astronauts have reported a calcium loss of 200-300 mg per day [5], and a renal urinary calcium excretion of up to 73 mmol per day (around 2.9 g per day) has been observed [6]. In studies measuring bone mineral content (BMC) and bone mineral density (BMD) by dual-energy X-ray absorptiometry [7‐9] a decrease in bone density of between 0.5% and 1.3% per month of immobilisation is described [6]. However, no supportive data are available to allow estimation of real calcium loss with respect to radiological findings.

We therefore present an alternative means of estimating calcium loss in immobilised critically ill patients requiring dialysis. During CRRT and anticoagulation with citrate the gap between theoretical and actual calcium substitution represents the effective calcium loss [2], when intake and intestinal loss are similar and anuria prevents renal loss. In the current case a declining need for calcium supplementation occurred after 4 weeks, in keeping with publications reporting significant bone demineralisation after several weeks of immobilisation [10‐13]. A cumulative estimated calcium loss of 571 g was noted over the 254 day period of CVVHD. This loss correlates with a semiquantative radiological measurement achieved through sequential comparison of bone density of the same skeletal region. As previous studies have reported total skeletal calcium content at 1–1.5 kg [14] the estimated calcium loss of 571 g reported here seems plausible, albeit with neither spontaneous fractures nor the semiquantative radiological assessment clinically proving this.

An average calcium loss of 2.2 g per day is however somewhat higher than observed in most previous studies. This could be accounted for by an accelerated bone loss secondary to immunosuppression used after lung transplantation i.e. calcineurin inhibitors and steroid therapy [15], the observed androgen deficiency [16], or the exceptionally long duration of immobilisation [7].

Bisphosphonates were given to stop bone calcium loss secondary to immobilisation, a practice first described in the 1970s [4]. With the intention of increasing bone mineralisation, androgens were administered as proposed by Gruenewald [16]. Together they resulted in a small increase in need for calcium substitution during CVVHD and anticoagulation with citrate, reflecting a reduction in bone calcium loss. A concomitant increase in bone radiodensity was noted.

A total CVVHD duration of 254 days is exceptional compared to reported prolonged CRRT-durations of >20 days [2, 17]. As such, the extent to which citrate anticoagulation could promote bone demineralisation remains an important unanswered question. Heparin-based anticoagulation in CRRT is often contraindicated in the critically ill. Furthermore, an adequate dialysis dose effectively removes calcium meaning hypercalcaemia remains ‘invisible’ when heparin-based anticoagulation is used, masking a relative immobilisation hypercalcaemia [2]. Using citrate for anticoagulation a further negative calcium balance is maintained via continuous calcium losses in the CRRT effluent [2]. However, the declining need for substitution indicates indirectly the raising release of calcium from the bone – this would remain invisible using heparin for anticoagulation. Furthermore, long-term treatment with heparin can also result in osteoporosis [18].

Due to the study design, markers with respect to bone remodeling, bone formation, and bone resorption cannot be provided. Dietary calcium intake was assumed to be unchanged over time; however actual daily calcium intake was not recorded in detail.