Author's response to reviews

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1 Author's response to reviews Title: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 Authors: Matthias Klingele (matthias.klingele@uks.eu) Sarah Seiler (sarah.seiler@uks.eu) Aaron Poppleton (aaron.poppleton@gmail.com) Philip Lepper (philip.lepper@uks.eu) Danilo Fliser (danilo.fliser@uks.eu) Roland Seidel (roland.seidel@uks.eu) Version:2Date:3 September 2014 Author's response to reviews: see over

2 SAARLAND UNIVERSITY HOSPITAL Department of Internal Medicine IV Nephrology, Hypertension Head: Univ.-Prof. Dr. med. D. Fliser BMC Nephrology BioMed Central 236 Gray's Inn Road London WC1X 8HB United Kingdom Homburg/Saar, Dear Dr Orlando Gutierrez, Please find enclosed our revised manuscript entitled 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 which we would like to re-submit for consideration for publication in BMC Nephrology. We have considered the fair and constructive criticisms of the reviewers, and have revised our manuscript according to their suggestions. Please find enclosed our point-by-point reply to the reviewers comments, addressing all aspects in detail. We feel that the amendments made to the manuscript in response to the reviewers suggestions have resulted in a significant improvement in the article s quality. We therefore request reconsideration of the manuscript for publication in BMC Nephrology. We thank you in advance for your time and efforts. Yours sincerely Danilo Fliser, MD Matthias Klingele, MD for the authors Author's response to reviews: see over

3 Reviewer's report Title: 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 Version:1 Date: 30 July 2014 Reviewer: David Leaf Reviewer's report: Major compulsory revisions It would be helpful if Figure 1 was higher quality, with more clear labeling of the axes, and with inclusion of a timeline of events, including fractures, initiation of bisphosphonates, initiation of androgens, timing of CT scans, etc. We wholeheartedly agree that including a timeline of events would enhance the information content of Figure 1. We have therefore added to figure 1, including timings of CT imaging (grey triangles with number indicating the day after start of dialysis), occurrence of spontaneous fracture (broad arrow) and the time point of initiation of bisphosphonates and androgen therapy. We have also added two double arrows representing the gap between mean daily calcium substitution and the theoretical calcium need of 1.7mmol/l for two days. These aforementioned additions have been included in the description of Figure 1 (page 11 - lines 280 to 384) Minor essential revisions: There are numerous typos and grammatical errors throughout which need to be fixed. Thank you for your note regarding the linguistic shortcomings in the manuscript. We have improved or corrected those already mentioned below. Moreover, the entire manuscript was revised critically by a British colleague. We are therefore certain that it will now meet the language requirements. Page 2 of 9

4 page 4, line 95, "exspecially" This sentence has been amended page 5, line 108, "14,25 mol" instead of "14.25 mol" This was corrected as suggested (now line 106) Page 4 - line 77 - please specify what you mean by "CRRT". Is this CVVH, CVVHD, or CVVHDF? We agree that information about dialysis modality should be given. We have therefore amended page 4 - line 77 to say using CVVHD for continuous renal replacement therapy as suggested. Page 5 - line is this total or free testosterone? Total testosterone is the measurement of choice within our laboratory. We have added this information to page 5 line 108. Page 5 - line "between 2009 and 2012" means very little to me. The authors should use terms relative to the current admission. For example, "during the three years prior to the current admission..." We recognise that our data did not place the events in time. In light of this we have amended the article to refer to the current admission or the day of CRRT as suggested within the text (page 5 lines 121 to 128, and in Figure 2 (page 11 lines 291 to 300). Page 7 - line not clear to me what the authors mean by "heparin-based anticoagulation...additionally normalises hypercalcaemia." Page 3 of 9

5 Thank you for this helpful hint. Heparin-based anticoagulation does not interfere with the serum calcium. Increased liberation of calcium from the bone during a period of immobilisation would result in hypercalcaemia in anuric patients. However, an adequate dialysis dose effectively removes calcium - hence hypercalcaemia remains undiagnosed when heparin is used for anticoagulation in haemodialysis. We have amended the text to clarify this on page 7 lines 169 to 173: 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 Level of interest: An article whose findings are important to those with closely related research interests Quality of written English: Needs some language corrections before being published Statistical review: No, the manuscript does not need to be seen by a statistician. Declaration of competing interests: I declare that I have no competing interest Page 4 of 9

6 Reviewer's report Title: 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 Version: 1 Date: 4 August 2014 Reviewer: Ashita Tolwani Reviewer's report: The authors present highlighting a case increasing the awareness of the problem of delayed detection of hypercalcemia of immobility in patients treated with regional citrate anticoagulation with CRRT. This has been reported to occur in case report form in the literature. I have the following comments: Major revisions: 1. As the authors have eluded to, this patient seemed to be an increased risk of fractures from immobility due to use of steroids from lung tx. I am also assuming the patient was on calcineurin inhibitors which also increase risk for bone loss. Was the patient on any other contributing medications? Thank you for this important clarifying statement concerning further risk factors for bone loss and fractures apart of immobilisation. Our patient was on steroids, calcineurin inhibitors, and mycophenolate for lung transplantation. We have added this information as suggested on page 6 line 154. The patient was not on any other medication contributing to the bone loss. 2. Did the patient already have known osteoporosis or osteopenia prior to admission? Was osteopenia commented on the radiological studies? The authors state that radiological imaging was performed several times. However it is unclear as to timing of these studies given that the authors never report the days of hospitalization or CRRT. The authors report "although little change in BMD was seen between 2009 Page 5 of 9

7 and September 2012, a decreased to 52 HU was noted by January 2013". It is unclear as to the relation of these dates as to the patient's hospital course and initiation of CRRT. This needs to be clarified and added to the graph. Thank you for these questions concerning pre-existing osteoporosis and the timing of radiological imaging with respect to admission and start of CRRT. Three years prior to the current admission computer tomography scans showed a physiological mineralisation and an age-adjusted configuration within normal limits for the thoracolumbar vertebrae, with bone mineral density (BMD) within the physiological range (242 HU). Radiological imaging at admission showed little change in BMD. Therefore we conclude that the patient did not have osteoporosis or osteopenia prior to admission. We have included this information and have related radiological imaging with regards to the current hospital admission and the first day of CRRT as suggested. The text has been amended (page 5 lines 121 to 128) and in the description of Figure 2 (page 11 lines 294 to 300) accordingly.). 3. When were vit D levels and ipth levels measured during the course of hospitalization and, specifically, when in relation to citrate CRRT? And how often? Was vitamin D replacement initiated for elevated ipth with secondary osteodystrophy from renal failure? Perhaps these information can be added to the graph. At admission our patient showed normal renal function (egfr (CKD-EPI) 143ml/min and calculated GFR based on cystatin C 105ml/min and serum calcium within the normal range (2,5mmol/l)). Although ipth was not determined at admission we can exclude a pre-existing elevation of ipth levels. ipth level was measured at day 152, 181, and 222 of CRRT (237 to 424pg/ml, normal range 10-55pg/ml). This information has been added as suggested to page 5 lines 116 to 120. Vitamin D level at admission was 30.2ng/ml i.e. within the normal range ( 30ng/ml). During hospital stay vitamin D level was measured at day 32, 152, 181, 194, 204 and 209 of CRRT decreasing over time (9 to 19ng/ml). This information has been added as suggested to page 5 lines Page 6 of 9

8 Substitution of vitamin D is routinely initiated after transplantation with the aim of counteracting bone loss due to steroids and calcineurin inhibitors. Serum calcium level is closely monitored. The measurement of vitamin level would normally only be performed when hypercalcaemia occurs. 4. Was a bone specific alkaline phosphatase measured? You are right to ask after a bone-specific alkaline phosphatase measurement. Unfortunately this was not determined at any time as bone-specific alkaline phosphatase is not a routine laboratory parameter. Moreover, this value would have had no effect on the clinical or therapeutic course. This explains why in our retrospective case description bone-specific alkaline phosphatase was not determined despite its significance in bone metabolism. 5. The patients suggest using the gap between theoretical and actual calcium substitution as a way of estimating the calcium loss in critically ill patients during immobilization and dialysis. It is not clear to me how this calculation is superior to just the clinician being aware of a declining need for calcium substitution in patients on CRRT? Does the calculation help change management? It seems already evident that bone resorption owing to immobilization and secondary hyperparathyroidism is occurring when the calcium substitution amount decreases on CRRT. In fact many of these patients may not even require any form of calcium infusion. We are in complete agreement with you that that a clinician should be aware of declining need for calcium substitution in patients on CRRT and anticoagulation with citrate. We also share the experience that some patients do not require any calcium substitution within a certain duration of CRRT. The problem of demineralisation and bone loss secondary to immobilisation in critically ill patients may be recognised through a declining need for calcium substitution. However in clinical practice this is generally considered as less important with respect to disease severity and the context of intensive care. The method presented here allows total calcium loss to be easily estimated and set in Page 7 of 9

9 proportion to total body calcium i.e. within the skeleton. We feel that this is helpful to highlight, given the clinical problem of immobilisation associated bone loss in the foreground. Although it is not clear which treatment is most effective in such a situation, estimating total calcium loss could help to push clinicians to measure all laboratory parameters relevant for bone metabolism. This could at least help support treatment of obvious deficiencies e.g. androgen deficiency as observed in our case. We have now included aspects of the above discussion to the manuscript clarifying this area (page 8 lines 186 to 189). 6. Even though it is important for the clinician to be aware of this problem and that citrate anticoagulation may delay the recognition of hypercalcemia from immobility due to binding of the calcium and masking hypercalcemia, it is not clear what treatment can be given to prevent this from happening. Besides adequate calcium supplemention of calcium prior to hypercalcemia and vit D replacement if indicated, there are not many options for patients in renal failure. Bisphosphonates are contraindicated in renal failure and may not be effective according to the literature. Also, they may induce adynamic bone disease. Calcitonin is limited as well as other treatments which may not be safe in this patient population. We must admit that we do not know which treatment can most effectively prevent bone loss secondary to immobilisation. We are in complete agreement that adequate calcium substitution and/or vitamin D replacement are undisputed therapeutic strategies. However in the case presented here and in many other cases this may not be sufficient. Moreover, bisphosphonates are contraindicated in such patients and calcitonin may not be safe in critically ill patients. As stated above, the extension of laboratory tests used could help to detect deficiencies influencing bone metabolism e.g. androgen deficiency. Adequate substitution of these deficiencies is an undeniable and efficient treatment. Minor revisions Page 8 of 9

10 Under long-term dialysis in literature, the authors state that heparin normalizes hypercalcemia. I am not aware of how heparin "normalizes" calcium. Heparin is associated with osteoporosis and would not mask the effects of hypercalcemia from immobilization. We agree that heparin-based anticoagulation does not normalise hypercalcaemia. Our intention was to explain that an increased release of calcium from the bone over the course of immobilisation would result in hypercalcaemia in anuric patients. However, an adequate dialysis dose effectively removes calcium - hence hypercalcaemia remains undetected when heparin is used for anticoagulation. We have amended the text to clarify this on page 7 lines 169 to 173: 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 Level of interest: An article of importance in its field Quality of written English: Acceptable Statistical review: No, the manuscript does not need to be seen by a statistician. Declaration of competing interests: I have a patent on a formulation of citrate that is not available in the United states. Page 9 of 9