Correspondence

personally accountable for the individual’s own contributions and to including hypocalcemia, hyperphosphatemia, hypo-
ensure that questions pertaining to the accuracy or integrity of any vitaminosis D, and elevated levels of fibroblast growth
portion of the work, even one in which the author was not directly
involved, are appropriately investigated and resolved, including
factor 23 (FGF-23) and parathyroid hormone (PTH).1-3
with documentation in the literature if appropriate. Calcitriol (1,25(OH)2D), the activated form of vitamin
Support: This study has been supported by the European Rare D, is a central regulator of mineral metabolism. In CKD-
Kidney Disease Network (ERKNet). ERKNet is co-funded by the MBD, metabolic abnormalities are augmented by
European Union within the framework of the Third Health 1,25(OH)2D and 25-hydroxyvitamin D (25(OH)D) defi-
Programme “ERN-2016 - Framework Partnership Agreement ciency, resulting in secondary hyperparathyroidism. Mul-
2017-2021.” The funders had no role in study design; collection, tiple studies have demonstrated that maintaining 25(OH)D
analysis, and interpretation of data; writing the report; and the
decision to submit the report for publication. levels at ≥30 ng/mL is associated with lower PTH levels in
Financial Disclosure: The authors declare that they have no
early stages of CKD,4-6 but efficacy in late-stage CKD is
relevant financial interests. unclear. The most recent KDIGO guideline recommends
Acknowledgements: We are grateful to the European Society of that vitamin D deficiency in CKD patients be treated
Paediatric Nephrology (ESPN) and the International Paediatric similarly as in the general population.3
Nephrology Association (IPNA) for their support in administering The effects of calcium, phosphorus, vitamin D, and
this study. We are grateful to all colleagues and pediatric glomerular filtration rate (GFR) on PTH are profoundly
nephrology centers contributing cases to this study. interdependent. Currently available data clearly answer
Prior Presentation: Aspects of this work were presented in abstract whether vitamin D supplementation benefits patients with
form at the 53rd ESPN Annual Meeting held in Amsterdam, The
Netherlands, in September 2021.
advanced CKD. We therefore examined the relationships
of serum calcium, 25(OH)D, phosphorus, and estimated
Peer Review: Received February 11, 2022. Evaluated by 2 external
peer reviewers, with direct editorial input from a Statistics/Methods GFR (eGFR) with PTH among a large national sample of
Editor, an Associate Editor, and the Editor-in-Chief. Accepted in patients evaluated during routine clinical practice.
revised form May 18, 2022. The data were extracted from a set of adult patients
Publication Information: © 2022 by the National Kidney Founda- who had GFR estimated at a Labcorp facility in the United
tion, Inc. Published online August 2, 2022 with doi 10.1053/ States from November 2011 through June 2014; the
j.ajkd.2022.05.013 earliest set of simultaneously obtained calcium, phos-
phorus, 25(OH)D, and PTH values was used (Item S1).
Assay platforms were constant over the entire study. To
References eliminate primary hyperparathyroidism cases, individuals
1. Calatroni M, Consonni F, Allinovi M, et al. Prognostic factors
with elevated PTH levels were excluded if serum calcium
and long-term outcome with ANCA-associated kidney vascu- exceeded 10.2 mg/dL. eGFR values were stratified using
litis in childhood. Clin J Am Soc Nephrol. 2021;16(7):1043- KDIGO criteria. 25(OH)D levels were categorized as
1051. doi:10.2215/CJN.19181220 adequate (>40 ng/mL), low (20-40 ng/mL), and
2. €
Ozçelik G, S€onmez HE, Şahin S, et al. Clinical and histopath- depleted (<20 ng/mL). The research was approved by
ological prognostic factors affecting the renal outcomes in the Western–Copernicus Group Institutional Review
childhood ANCA-associated vasculitis. Pediatr Nephrol. Board, with informed consent waived for use of de-
2019;34(5):847-854. doi:10.1007/s00467-018-4162-5
identified data. Analyses used SAS, version 9.4 (SAS
3. Morishita KA, Moorthy LN, Lubieniecka JM, et al. Early out-
comes in children with antineutrophil cytoplasmic antibody-
Institute Inc).
associated vasculitis. Arthritis Rheumatol. 2017;69(7):1470- Entry criteria were met by 153,611 individuals; 56.6%
1479. doi:10.1002/art.40112 were female; mean age was 65.9 ± 14.0 years (Table 1).
4. Sacri A-S, Chambaraud T, Ranchin B, et al. Clinical charac- Figure 1 illustrates the relationship between calcium
teristics and outcomes of childhood-onset ANCA-associated and PTH, stratified by CKD stage and 25(OH)D level. At all
vasculitis: a French nationwide study. Nephrol Dial Transplant. levels of serum calcium in all eGFR categories, vitamin D
2015;30(Suppl 1):i104-i112. doi:10.1093/ndt/gfv011
levels ≥40 ng/mL (vs <20 ng/mL) were associated with
5. Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate mofetil vs
20%-40% lower PTH levels; patients with 25(OH)D levels
azathioprine for remission maintenance in antineutrophil cyto-
plasmic antibody-associated vasculitis: a randomized 20-<40 ng/mL had intermediate PTH levels. PTH levels
controlled trial. JAMA. 2010;304(21):2381-2388. doi:10. were greater at greater CKD stage, and patients in CKD
1001/jama.2010.1658 stages 3-5 with 25(OH)D levels of ≥40 ng/mL had PTH
levels comparable to 25(OH)D-depleted patients with
more normal kidney function. Results were similar when
we included patients with calcium levels up to 12 mg/dL
(Fig S1).
Vitamin D and Parathyroid Hormone Our findings illustrate the interdependencies of cal-
Levels in CKD cium, vitamin D, and eGFR in their association with PTH
To the Editor: level in CKD. Two main points were apparent: 25(OH)D
Chronic kidney disease–bone mineral disorder (CKD- levels ≥40 ng/mL were associated with lower PTH among
MBD) includes multiple interrelated abnormalities, patients in every eGFR category at every level of serum

122 AJKD Vol 81 | Iss 1 | January 2023

Correspondence

Table 1. Clinical Characteristics, by CKD Stage

CKD Stage
1 2 3a 3b 4 5 All
(n = 21,606) (n = 32,512) (n = 29,969) (n = 39,487) (n = 26,219) (n = 3,818) (N = 153,611)
Age, y 51 ± 12 63 ± 12 69 ± 12 71 ± 12 71 ± 13 65 ± 14 69 ± 14
Female sex 73% 63% 49% 50% 54% 52% 57%
Calcium, mg/dL 9.3 ± 0.5 9.5 ± 0.5 9.4 ± 0.5 9.4 ± 0.5 9.3 ± 0.5 9.0 ± 0.7 9.4 ± 0.5
eGFR, mL/min/ 102 ± 10 74 ± 9 51 ± 4 37 ± 4 23 ± 4 10 ± 4 54 ± 27
1.73 m2
Phosphorus, 3.6 ± 0.6 3.5 ± 0.6 3.5 ± 0.6 3.6 ± 0.6 4.0 ± 0.7 4.7 ± 1.1 3.7 ± 0.7
mg/dL
25(OH)D, ng/mL 31 ± 15 33 ± 14 32 ± 13 31 ± 13 29 ± 13 26 ± 13 31 ± 13
PTH, pg/mL 31 [23-43] 35 [25-48] 40 [28-56] 49 [34-71] 72 [46-111] 144 [82-246] 43 [29-66]
Values for continuous variables shown as mean ± standard deviation or median [IQR]. Conversion factors for units: calcium in mg/dL to mmol/L, ×0.2495; phosphorus in
mg/dL to mmol/L, ×0.3229; 25(OH)D in ng/mL to nmol/L, ×2.495.

calcium. Nonetheless, eGFR was the strongest determinant parathyroid gland.8 Maintenance of higher serum 25(OH)
of PTH. These observational data generate a hypothesis that D levels could increase intraparathyroid 25(OH)D, over-
repleting 25(OH)D levels to ≥40 ng/mL could be a come deficient DBP, and restore normal vitamin D
possible intervention to prevent the development of sec- responsiveness in the gland.5
ondary hyperparathyroidism during CKD stages 3-5, Our results are consistent with a trial of oral calcifidiol
despite lack of evidence for vitamin D to reverse estab- in CKD stages 3-4 in which 25(OH)D levels of ≥50.8 ng/
lished hyperparathyroidism. mL were required to reduce PTH and other bone turnover
In CKD, PTH induces CYP27B1, a gene encoding the 1α- markers.9 PTH was maximally suppressed at a mean
hydroxylase that converts 25(OH)D to 1,25(OH)2D; 25(OH)D level of 92 ng/mL, without hypercalcemia,
counter-regulation of CYP27B1 by FGF-23 is inhibited by hyperphosphatemia, or rising FGF-23 levels. Our group
the loss of necessary cofactors, α-klotho and FGFR1.4 observed reduction of PTH among 14,289 CKD patients,
Despite reduced renal 1α-hydroxylation, the oxyphil with no plateau in effects until 25(OH)D levels reached
cells of the parathyroid gland may see 10-fold induction 42-48 ng/mL.10 Taken together, these data suggest that
of 1α-hydroxylase in secondary hyperparathyroidism.7 correcting 25(OH)D deficiency according to general
Excess 1α-hydroxylase in the hypertrophied gland, along population guidelines may be overly conservative.9,10
with reduction in cytosolic vitamin D binding protein Limitations include no information on medication use,
(DBP), may promote a state of “vitamin D hunger” in the use of a single specimen per patient, and lack of certainty

Figure 1. PTH as a function of serum calcium, stratified by eGFR category and vitamin D level, for patients with serum calcium levels
up to 10.2 mg/dL.

AJKD Vol 81 | Iss 1 | January 2023 123

 Correspondence

that dialysis patients were excluded from this cohort. Our Publication Information: © 2022 by the National Kidney Founda-
results constitute associations rather than causation. We tion, Inc. Published online August 2, 2022 with doi 10.1053/
j.ajkd.2022.06.006
cannot conclude that raising 25(OH)D levels in individual
patients would reduce PTH. Despite these limitations,
nutritional vitamin D remains an inexpensive intervention References
with a favorable risk-benefit profile, compared to calcitriol 1. Sprague SM, Marin KJ, Coyne DW. Phosphate balance and
and other activated vitamin D products. Studies to assess CKD-mineral bone disease. Kidney Int Rep. 2021;6(8):2049-
the impact of interventions to raise 25(OH)D levels in CKD 2058. doi:10.1016/j.ekir.2021.05.012
st ages 3-5 are warranted. 2. Isakova T, Cai X, Lee J, et al. Longitudinal evolution of markers
Sangeet Dhillon-Jhattu, MD, Rita L. McGill, MD, Jennifer L. of mineral metabolism in patients with CKD: the Chronic
Renal Insufficiency Cohort (CRIC) Study. Am J Kidney Dis.
Ennis, MD, Elaine M. Worcester, MD, Anna L. Zisman, MD,
2020;75(2):235-244. doi:10.1053/j.ajkd.2019.07.022
and Fredric L. Coe, MD 3. KDIGO 2017 Clinical Practice Guideline update for the diag-
nosis, evaluation, prevention, and treatment of chronic kidney
Supplementary Material disease-mineral and bone disorder (CKD-MBD). Kidney Int
Suppl. 2017;7:1-59. doi:10.1016/j.kisu.2017.04.001
Supplementary File (PDF) 4. Zisman AL, Hristova M, Ho LT, Sprague SM. Impact of
Figure S1; Item S1. ergocalciferol treatment of vitamin D deficiency on serum
parathyroid hormone concentration in chronic kidney dis-
Article Information ease. Am J Nephrol. 2007;27(1):36-43. doi:10.1159/
000098561
Authors’ Affiliations: Section of Nephrology, University of Chicago 5. Al-Aly Z, Qazi RA Gonzalez EA, et al. Changes in serum 25-
Medicine, Chicago, Illinois (SDJ, JLE, EMW, ALZ, FLC); and hydroxyvitamin D and plasma intact PTH levels following
Laboratory Corporation of America Holdings, USA (RLM). treatment with ergocalciferol in patients with CKD. Am J
Address for Correspondence: Rita L. McGill, MD, MS, Section of Kidney Dis. 2007;50(1):59-68. doi:10.1053/j.ajkd.2007.04.
Nephrology, University of Chicago, 5841 S Maryland Avenue, 010
Chicago, IL 60637. Email: [email protected] 6. Kandula P, Dobre M, Schold JD, et al. Vitamin D supplemen-
Authors’ Contributions: Research idea and study design: FC, EW, tation in chronic kidney disease: a systematic review and meta-
AZ, RM, JE, SD-J; data acquisition: FC, JE; data analysis/ analysis of observational studies and randomized controlled
interpretation: FC, EW, AZ, RM, JE, SD-J; statistical analysis: RM; trials. Clin J Am Soc Nephrol. 2011;6(1):50-62. doi:10.2215/
supervision or mentorship: FC, EW, AZ, RM. Each author CJN.03940510
contributed important intellectual content during manuscript 7. Segersten U, Correa P, Hewison M, et al. 25-Hydroxyvitamin
drafting or revision and agrees to be personally accountable for D3-1α-hydroxylase expression in normal and pathological
the individual’s own contributions and to ensure that questions parathyroid glands. J Clin Endocrinol Metab. 2002;87(6):
pertaining to the accuracy or integrity of any portion of the work, 2967-2972. doi:10.1210/jcem87.6.8604
even one in which the author was not directly involved, are 8. Lu CL, Yeih DF, Hou YC, et al. The emerging role of nutritional
appropriately investigated and resolved, including with vitamin D in secondary hyperparathyroidism in CKD. Nutrients.
documentation in the literature if appropriate 2018;10(12):1890. doi:10.3390/nu10121890
Support: EMW, ALZ, and FLC receive support from NIDDK (grant 9. Strugnell SA, Sprague SM, Ashfaq A, Petkovich M,
DK P01 56788). The funders had no role in study design, data Bishop CW. Rationale for raising current clinical guideline
collection, analysis, reporting, or the decision to submit for target for serum 25-hydroxyvitamin D in chronic kidney dis-
publication. ease. Am J Nephrol. 2019;49(4):284-293. doi:10.1159/
Financial Disclosure: JLE is an employee of Labcorp. The remaining 000499187
authors declare that they have no relevant financial interests. 10. Ennis JL, Worcester EM, Coe FL, Sprague SM. Current rec-
Peer Review: Received March 9, 2022. Evaluated by 2 external peer ommended 25-hydroxyvitamin D targets for chronic kidney
reviewers, with direct editorial input from an Associate Editor and the disease management may be too low. J Nephrol. 2016;29(1):
Editor-in-Chief. Accepted in revised form June 15, 2022. 63-70. doi:10.1007/s40620-015-0186-0

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