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Meta-analysis: Vitamin D Compounds in Chronic Kidney Disease

Suetonia C. Palmer, MBChB; David O. McGregor, PhD; Petra Macaskill, PhD; Jonathan C. Craig, PhD; Grahame J. Elder, PhD; and Giovanni F.M. Strippoli, MD, MPH(Hons), MM
[+] Article and Author Information

From the Christchurch School of Medicine and Health Sciences, Christchurch, New Zealand; School of Public Health, University of Sydney, and Centre for Transplant and Renal Research, Westmead Millennium Institute, Sydney, Australia; and National Health and Medical Research Council Centre for Clinical Research Excellence in Renal Medicine and The Children's Hospital at Westmead, Westmead, Australia.


Acknowledgment: The authors thank Narelle Willis (Review Group Coordinator of the Cochrane Renal Group), Ruth Mitchell (Trials Search Coordinator of the Cochrane Renal Group), and the Cochrane Renal Group for assistance with preparation of this study.

Financial Support: Partial funding for this project was provided by the Cochrane Renal Group.

Potential Financial Conflicts of Interest:Employment: G.F.M. Strippoli (Diaverum). Consultancies: G.J. Elder (Abbott). Honoraria: G.J Elder (Abbott).

Requests for Single Reprints: Suetonia C. Palmer, MBChB, Department of Medicine, Christchurch School of Medicine and Health Sciences, PO Box 4345, Christchurch 8001, New Zealand; or e-mail Dr. Strippoli at strippoli@negrisud.it.

Current Author Addresses: Dr. Palmer: Department of Medicine, Christchurch School of Medicine and Health Sciences, PO Box 4345, Christchurch, 8001, New Zealand.

Dr. McGregor: Department of Nephrology, Christchurch Hospital, Canterbury District Health Board, PO Box 4710, Christchurch, 8001, New Zealand.

Dr. Macaskill: The School of Public Health, Edward Ford Building, The University of Sydney, NSW 2006, Australia.

Dr. Craig: Cochrane Renal Group, Centre for Kidney Research Excellence in Renal Medicine, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia.

Dr. Elder: Department of Renal Medicine, Westmead Hospital, Westmead, NSW 2145, Australia.

Dr. Strippoli: Department of Clinical Pharmacology and Epidemiology, Consorzio Mario Negri Sud, Via Nazionale, 66030 Santa Maria Imbaro (Ch), Italy.

Author Contributions: Conception and design: S.C. Palmer, J.C. Craig, G.F.M. Strippoli.

Analysis and interpretation of the data: S.C. Palmer, G.J. Elder, J.C. Craig, P. Macaskill, G.F.M. Strippoli.

Drafting of the article: S.C. Palmer, G.F.M. Strippoli.

Critical revision of the article for important intellectual content: G.J. Elder, J.C. Craig, D.O. McGregor, G.F.M. Strippoli.

Final approval of the article: S.C. Palmer, G.J. Elder, J.C. Craig, D.O. McGregor, P. Macaskill, G.F.M. Strippoli.

Statistical expertise: P. Macaskill.

Administrative, technical, or logistic support: G.F.M. Strippoli.

Collection and assembly of data: S.C. Palmer, G.F.M. Strippoli.


Ann Intern Med. 2007;147(12):840-853. doi:10.7326/0003-4819-147-12-200712180-00004
Text Size: A A A

Background: Vitamin D compounds are widely used to prevent and treat secondary hyperparathyroidism.

Purpose: To determine whether vitamin D therapy improves biochemical markers of mineral metabolism and cardiovascular and mortality outcomes in chronic kidney disease.

Data Sources: MEDLINE (January 1966 to July 2007), EMBASE (January 1980 to July 2007), and Cochrane databases were searched without language restriction.

Study Selection: Randomized, controlled trials of vitamin D compounds in chronic kidney disease were identified.

Data Extraction: Two authors independently extracted data.

Data Synthesis: Seventy-six trials were identified for inclusion; 3667 participants were enrolled. Vitamin D compounds did not reduce the risk for death, bone pain, vascular calcification, or parathyroidectomy. Compared with placebo, established vitamin D sterols were associated with an increased risk for hypercalcemia (relative risk, 2.37 [95% CI, 1.16 to 4.85]) and hyperphosphatemia (relative risk, 1.77 [CI, 1.15 to 2.74]) but did not show a consistent reduction in parathyroid hormone (PTH) levels. Compared with placebo, more recently developed vitamin D analogues were associated with hypercalcemia (relative risk, 5.15 [CI, 1.06 to 24.97]) but not hyperphosphatemia, and levels of PTH were reduced (weighted mean difference, −10.77 pmol/L [CI, −20.51 to −1.03 pmol/L]). For suppression of PTH, intravenous administration was superior to oral vitamin D, but higher intravenous doses were used.

Limitations: Few studies reported patient-level outcomes, including mortality (8 of 76 trials), and only 5 trials directly compared the effects of treatment with newer vitamin D compounds versus established ones. Heterogeneity in some comparisons remained unexplained by metaregression analyses.

Conclusion: Vitamin D compounds do not consistently reduce PTH levels, and beneficial effects on patient-level outcomes are unproven. The value of vitamin D treatment for people with chronic kidney disease remains uncertain.

Figures

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Appendix Figure 1.
Study flow diagram.

Reasons for exclusions and the number of trials reporting each outcome are provided. RCT = randomized, controlled trial.

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Figure 1.
Effect of vitamin D versus placebo or other comparator interventions on the risk for hypercalcemia in people with chronic kidney disease.
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Figure 2.
Effect of vitamin D versus placebo or other comparator interventions on the end-of-treatment serum phosphorus concentration in people with chronic kidney disease.

To convert phosphorus values from mmol/L to mg/dL, divide by 0.323.

Grahic Jump Location
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Figure 3.
Effect of vitamin D versus placebo or other comparator interventions on the end-of-treatment parathyroid hormone concentration in people with chronic kidney disease.

To convert parathyroid hormone values from pmol/L to pg/mL, divide by 0.11.

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Appendix Figure 2.
Effect of vitamin D versus placebo or other comparator interventions on end-of-treatment serum alkaline phosphatase levels in people with chronic kidney disease.
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Tables

References

Letters

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Comments

Submit a Comment
Methodological Problems with Vitamin D Meta Analysis
Posted on January 14, 2008
Daniel W Coyne
Washington University
Conflict of Interest: None Declared

Palmer's meta-analysis concludes Vitamin D compounds "do not consistently reduce PTH".(1) PTH suppression by "established vitamin D" is based on just six studies encompassing 187 patients. Of the five studies I could locate, none appeared to titrate vitamin D to achieve PTH suppression, nor had PTH suppression as a primary goal. Active vitamin D treatment did cause significant improvements in the three studies examining bone histology, and the one examining bone mineral density. Meta -analyses must carefully assess the goals of trials from differing eras. Four of these studies were done in the 1980's and therefore, must have employed C-terminal PTH assays which detect PTH fragments that accumulate in renal failure.

Palmer's efficacy analysis excluded a 266 patient, 32 week, intravenous calcitriol versus paricalcitol trial(2) presumably because there was no placebo arm. Goal PTH suppression of >50% was achieved in 80% and 90% of patients with the hormone and analog, respectively. This trial had more calcitriol-treated patients than all the efficacy studies examined by Palmer.

Analyzing the PTH suppressive effects of "newer vitamin D", Palmer examines just three trials containing 163 patients. Palmer excludes the above study(2) and a 6 month double-blind placebo-controlled trial in 220 CKD patients where paricalcitol capsules achieved >30% PTH suppression in 91% of patients (mean reduction 42%).(3, 4) This study served as the basis for FDA approval of paricalcitol for treatment of hyperparathyroidism in CKD.

Palmer chooses hyperphosphatemia and hypercalcemia events as biochemical markers of "cardiovascular and mortality outcomes".(1) However, reductions in these events have not been validated by randomized trials to improve survival. Recently, a 2103 patient randomized mortality study found no survival benefit for dialysis patients treated with non- calcium phosphorus binders versus calcium-based binders, despite increased serum calcium and hypercalcemic episodes with calcium-based binders.(5) Predicting the effect on mortality of any drug based on its potential changes in calcium and phosphorus is speculative.

Palmer(1) combines all "newer vitamin D products" together despite preclinical and human research study evidence of significant differences among agents. In examining hypercalcemia of newer agents, Palmer includes a dose-ranging study of 22-oxacalcitriol by Akizawa which accounts for 82% (27/33) of the hypercalcemic events in their analysis.

Hormonal calcitriol deficiency increases in prevalence throughout CKD,(6) severity of deficiency correlates with decreased survival on dialysis, and replacement with Vitamin D repeatedly has been associated with improved survival.(6) Clinical trials to assess the actions of these hormonal analogs on non-PTH outcomes are ongoing.

Daniel W. Coyne MD Professor of Medicine, Renal Diseases Washington University School of Medicine

References

1. Palmer, SC, McGregor, DO, Macaskill, P, Craig, JC, Elder, GJ & Strippoli, GF: Meta-analysis: vitamin D compounds in chronic kidney disease. Ann Intern Med, 147:840-53, 2007.

2. Sprague, SM, Llach, F, Amdahl, M, Taccetta, C & Batlle, D: Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int, 63:1483-90, 2003.

3. Coyne, D, Acharya, M, Qiu, P, Abboud, H, Batlle, D, Rosansky, S, Fadem, S, Levine, B, Williams, L, Andress, DL & Sprague, SM: Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD. Am J Kidney Dis, 47:263-76, 2006.

4. Abboud, H, Coyne, D, Smolenski, O, Anger, M, Lunde, N, Qiu, P, Hippensteel, R, Pradhan, RS, Palaparthy, RV, Kavanaugh, A, Melnick, JZ, Williams, LA & Batlle, D: A comparison of dosing regimens of paricalcitol capsule for the treatment of secondary hyperparathyroidism in CKD stages 3 and 4. Am J Nephrol, 26:105-14, 2006.

5. Suki, WN, Zabaneh, R, Cangiano, JL, Reed, J, Fischer, D, Garrett, L, Ling, BN, Chasan-Taber, S, Dillon, MA, Blair, AT & Burke, SK: Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients. Kidney Int, 72:1130-7, 2007.

6. Wolf, M, Shah, A, Gutierrez, O, Ankers, E, Monroy, M, Tamez, H, Steele, D, Chang, Y, Camargo, CA, Jr., Tonelli, M & Thadhani, R: Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int, 72:1004-13, 2007.

Conflict of Interest:

Consultant: Abbott, INEOS Speaker: Abbott Research Support: Abbott and Amgen

Vitamin D in Stage III and IV Chronic Kidney Disease (CKD)
Posted on January 17, 2008
Kenneth N. Scissors
VAMC Grand Junction, Co.
Conflict of Interest: None Declared

To The Editor,

Palmer et al are to be congratulated for exposing the lack of outcome data to support current guidelines and practices involving Vitamin D therapy in CKD(1). It should be noted, however, that their study addressed stage V and end-stage CKD treated mostly with "active" Vitamin D by nephrologists. But the vast majority of patients with CKD are stage III or IV, treated with common Vitamin D2 or D3 by primary care physicians. The findings of the Palmer study should not be extrapolated to imply that therapy in Stage III and IV patients may not be beneficial in treating Vitamin D deficiency and preventing osteodystrophy.

In the Department of Internal Medicine at the VAMC in Grand Junction, Co., we reviewed Vitamin D therapy in stage III and IV CKD. Not surprisingly, we found the studies inadequate and the published guidelines inconsistent and confusing (2,3), which accounts for our admitted treatment inertia. In response, we consulted experts in the field (4) and distilled the available data and guidelines to develop our own user-friendly protocol. There exists no good data to support or refute these or any other guidelines, but we believe ours are at least easy to follow, unlikely to cause harm, and hold reasonable potential to be beneficial if applied with good clinical judgment.

Our protocol is:

1. Check and correct calcium and phosphorus levels.

2. Measure 25-OH Vitamin D. Goal: > 30 ng/ml.

3. Measure PTH. Goal: <150 pg/ml.

4. Treatment protocol:

-PTH and Vit D level both normal: multi-vitamin with or without extra Vit D3..

-Vit D deficient: Vit D3 2000 units daily for 6 months, then 1000u daily forever.

-PTH > 150: add calcitriol .25mcg daily to above Vit D3 regimen.

5. If using calcitriol, Check 25-OH Vit D, PTH, Ca, Phos every 3 months twice, then every 6-12 months.

Our experience is limited so far, but at least providers are finding this approach easy to follow, safe, and cost-effective. Since Vitamin D3 is a generic, over-the counter product, there may not be much support to conduct clinical trials with this therapy. It is our hope that research institutes interested in preventive therapy and not dependant on industry support are conducting studies to answers the questions surrounding the management of Vitamin D deficiency and bone metabolism in stage III and stage IV CKD, which will then lead to evidence based, practical guidelines.

Kenneth Scissors M.D. Veteran's Administration Medical Center Grand Junction, Co.

Potential Financial Conflicts of Interest: none disclosed

References

1. Palmer SC, McGregor DO, Macaskill JC, Craig JC, Elder GJ, Strippoli GFM. Meta-analysis: Vitamin D Compounds in Chronic Kidney Disease. Ann Intern Med. 2007; 147:840-853.

2. Holick MF. Vitamin D Deficiency. N Engl J Med 2007; 357: 266-81.

3. National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42:S1-201. (PMID: 14520607).

4. Coyne DW: How to Manage Vitamin D Deficiency. Renal and Urology News; October 2007; 38-40.

Conflict of Interest:

None declared

Vitamin D in chronic kidney disease meta-analysis - Letter in response
Posted on February 27, 2008
Suetonia C Palmer
University of Otago, New Zealand
Conflict of Interest: None Declared

Like Dr. Scissors, our preference is for clinical practice to be based upon randomized controlled trials; we also recognise that until the required trials are done, a sensible approach to distilling existing data and informing practice should be used. However, we need to emphasise that our inclusion criteria were not limited to stage V chronic kidney disease (CKD), and we searched for any trials of any vitamin D compound, including generic, over-the-counter products. There were no trial data available evaluating the effects of these products, and very few biochemical data for any product in stage III/IV CKD . Until these trials are done, we would be more circumspect than Dr Scissors and suggest that use of these products for this indication may not be safe.

Dr Coyne raised a number of specific issues with our meta-analysis, but all concern biochemical or surrogate outcomes. He presumably concurs with our major conclusion that the effects of vitamin D compounds on clinically important outcomes are largely unknown. We agree that the design of most studies was fixed-dose vitamin D studies rather than target parathyroid hormone (PTH) studies. We agree that there was an improvement in bone histomorphometry, but we are unaware of trial data to demonstrate a causal relationship between bone histomorphometry and clinical outcomes. Trials of established vitamin D compounds utilised several different assay types for measurement of PTH; however, there was no significant effect modification of interventions on outcomes when different PTH assay types used in the trials were included as a covariate in our meta-regression analysis.

Contrary to Dr Coyne's assertion, we did not exclude a 266 patient, calcitriol versus paricalcitol trial (Appendix Table 2(1)). Simply, this trial is not included in the forest plots because we used the outcome of end of treatment PTH values, as prospectively defined in our a priori- based study protocol and because this was the PTH outcome reported by most trials(2). The choice of the primary outcome of >50% reduction in PTH used in this trial, even if it occurred more frequently in the analogue arm, does not appear to be validated with hard endpoints any more than other PTH outcomes. According to Dr Coyne we excluded a placebo-controlled trial of paricalcitol which served as the basis for FDA approval of paricalcitol(3). This is incorrect. The study is included, but end of treatment PTH values were not available. Dr Coyne notes we chose hyperphosphatemia and hypercalcemia as markers of cardiovascular and mortality outcomes. We describe these end points as surrogate outcomes. We agree most strongly that predicting patient relative outcomes like cardiovascular endpoints from treatment changes in calcium and phosphorus remains speculative and requires randomized trials which show concordance between these outcomes. Dr Coyne states we combine newer vitamin D products despite evidence of differences between compounds. Data are really so scarce on any intervention and all data are included, but differences in interventions are also clearly described in text, table, and graphical form. Grouping by the same intervention exactly would not change our primary conclusion.

Finally, Dr Coyne notes vitamin D is associated with improved survival in dialysis (in cohort studies). We agree, but suggest this is not strong evidence that vitamin D intake causes improved outcomes because of residual confounding and other well established biases, which are typical of observational studies. Recent examples of discrepant results between trials and cohort studies have been well publicised. (4, 5). While trials for vitamin D compounds are ongoing, none detailed in major clinical trials registries are designed to examine clinical outcomes. To restate our conclusions: for decades we have used vitamin D compounds, a potentially beneficial intervention. The perils of accepting interventions in practice have now changed, and adequately powered trials need to be done for us to consider that drugs have "˜proven' efficacy. Our patients deserve this and better.

1. Palmer SC, McGregor DO, Macaskill P, Craig JC, Elder GJ, Strippoli GFM. Meta-analysis: Vitamin D compounds in chronic kidney disease. Annals of Internal Medicine. 2007;147:840-853.

2. Palmer SC, McGregor DO, Craig JC, Elder G, Strippoli GF. Vitamin D analogues for treatment and prevention of bone disease in chronic kidney disease. Cochrane Database of Systematic Reviews. 2006(Issue 1):Art. No., CD005633.

3. Coyne D, Acharya M, Qiu P, et al. Paricalcitol capsule for the treatment of secondary hyperparathyroidism in stages 3 and 4 CKD. American Journal of Kidney Diseases. 2006;47(2):263-76.

4. Paniagua R, Amato D, Vonesh E, et al. Effects of increased peritoneal clearances on mortality rates in peritoneal dialysis: ADEMEX, a prospective, randomized, controlled trial. Journal of the American Society of Nephrology. 2002;13(5):1307-1302.

5. Churchill DN, Thorpe KE, Nolph KD, Keshaviah PR, Oreopoulos DG, Page D. Increased peritoneal membrane transport is associated with decreased patient and technique survival for continuous peritoneal dialysis patients. The Canada-USA (CANUSA) Peritoneal Dialysis Study Group. Journal of the American Society of Nephrology. 1998;9(7):1285-1292.

Conflict of Interest:

None declared

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