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Long-term effects of hypercalcemia in kidney transplant recipients with persistent hyperparathyroidism

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Abstract

Background

Hypercalcemia is highly prevalent in kidney transplant recipients with hyperparathyroidism. However, its long-term impact on graft function is uncertain.

Methods

We conducted a prospective cohort study investigating adverse graft outcomes associated with persistent hypercalcemia (free calcium > 5.2 mg/dL in ≥ 80% of measures) and inappropriately elevated intact parathyroid hormone (> 30 pg/mL) in kidney transplant recipients. Asymptomatic mild hypercalcemia was monitored unless complications developed.

Results

We included 385 kidney transplant recipients. During a 4-year (range 1–9) median follow-up time, 62% of kidney transplant recipients presented persistent hypercalcemia. Compared to kidney transplant recipients without hypercalcemia, there were no significant differences in graft dysfunction (10% vs. 12%, p = 0.61), symptomatic urolithiasis (5% vs. 3%, p = 0.43), biopsy-proven calcium deposits (6% vs. 5%, p = 1.0), fractures (6% vs. 4%, p = 0.64), and a composite outcome of urolithiasis, calcium deposits, fractures, and parathyroidectomy indication (16% vs. 13%, p = 0.55). In a subset of 76 kidney transplant recipients, subjects with persistent hypercalcemia had higher urinary calcium (median 84 [43–170] vs. 38 [24–64] mg/day, p = 0.03) and intact fibroblast growth factor 23 (median 36 [24–54] vs. 27 [19–40] pg/mL, p = 0.04), and lower 25-hydroxyvitamin D levels (11.3 ± 1.2 vs. 16.3 ± 1.4 ng/mL, p < 0.001). In multivariate analysis, pretransplant intact parathyroid hormone < 300 pg/mL was associated with a reduced risk of post-transplant hypercalcemia (OR 0.51, 95% CI 0.32–0.80).

Conclusions

Long-term persistent mild hypercalcemia (tertiary hyperparathyroidism) was frequent in kidney transplant recipients in our series. This condition presented with lower phosphate and 25-hydroxyvitamin D, and higher urinary calcium and intact fibroblast growth factor 23 levels compared to kidney transplant recipients without hypercalcemia, resembling a mild form of primary hyperparathyroidism. Despite these metabolic derangements, the risk of adverse graft outcomes was low.

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Data availability statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Abbreviations

KTR:

Kidney transplant recipient.

IQR:

Interquartile range.

PTH:

Parathyroid hormone.

iPTH:

Intact parathyroid hormone.

DSA:

Donor-specific HLA-antibodies.

eGFR:

Estimated glomerular filtration rate.

ESRD:

End stage renal disease

iFGF23:

Intact fibroblast growth factor 23.

OPG:

Osteoprotegerin.

OC:

Osteocalcin.

OPN:

Osteopontin.

25(OH)D:

25-Hydroxyvitamin D.

IL-6:

Interleukin-6.

BMD:

Bone mineral density.

DEXA:

Dual-energy X-ray absorptiometry.

CV:

Coefficient of variation.

SD:

Standard deviation.

ROC:

Receiver operating characteristic.

AUC:

Area under the curve.

URL:

Upper reference limit.

CI:

Confidence interval.

ALP:

Alkaline phosphatase.

CKD:

Chronic kidney disease.

ADPKD:

Autosomal dominant polycystic kidney disease.

SLE:

Systemic lupus erythematosus.

HLA:

Human leukocyte antigen

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Acknowledgements

We thank the study participants and Dr. Hugo E. Chávez-Chávez for help in coding subjects data for the period from 2012 through 2014.

Funding

The authors received no specific funding for this work.

Author information

Authors and Affiliations

  1. Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15, colonia Sección XVI, 14080, Mexico City, CDMX, Mexico

    Juan Carlos Ramirez-Sandoval, Lluvia Marino, Gabriel Cojuc-Konigsberg, Estefania Reul-Linares, Nathalie Desire Pichardo-Cabrera, Cristino Cruz, Elisa Naomi Hernández-Paredes, Nathan Berman-Parks, Vanessa Vidal-Ruíz, Jonathan Mauricio Estrada-Linares, Ricardo Correa-Rotter & Luis Eduardo Morales-Buenrostro

  2. Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

    Alfredo Adolfo Reza-Albarrán

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  1. Juan Carlos Ramirez-Sandoval
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Contributions

JCR-S: participated in all phases of the study: conception and design, patient recruitment and data acquisition, data analysis and interpretation, drafting of manuscript, revision and approval of final version. LM: participated in all phases of the study: conception and design, patient recruitment and data acquisition, data analysis and interpretation, drafting of manuscript, revision and approval of final version. GC-K: participated in data acquisition, data analysis and interpretation, drafting of manuscript, revision and approval of final version. ER-L: participated in patient recruitment and data acquisition and data analysis. NDP-C: participated in patient recruitment and data acquisition and data analysis. CC: participated in patient recruitment and data acquisition, data analysis, and contributed to new reagents or analytic tools. ENH-P: participated conception and design, patient recruitment and data acquisition, and data analysis and interpretation. NB-P: participated conception and design, patient recruitment and data acquisition, and data analysis and interpretation. VV-R: participated in the performance of the research. JMEL: participated in the performance of the research. RC-R: participated in conception and design, data analysis and interpretation, drafting of manuscript, revision and approval of final version. AAR-A: participated in conception and design, data analysis and interpretation, drafting of manuscript, revision and approval of final version. LEM-B: participated in conception and design, data analysis and interpretation, drafting of manuscript, revision and approval of final version.

Corresponding author

Correspondence to Juan Carlos Ramirez-Sandoval.

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Conflict of interest

The results presented in this paper have not been published previously. The authors of this paper declare that the paper is original, is not plagiarized, is submitted for first publication in this journal, and has not been published or submitted for publication elsewhere, and that there is no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript that may affect the reporting of the article submitted. No pharmaceutical or biotechnology company, foundation, or any other source participated in the design, monitoring, data collection, and analysis. Dr. Juan Carlos Ramírez-Sandoval is a member of the Review Board of Frontiers in medicine, has received honoraria from Bayer México, and has lectured for Abbvie, Amgen, Synthom, Bayer, and AstraZeneca. Dr. Ricardo Correa-Rotter is a member of the Review Board of Blood Purification, has received honoraria as consultant from AbbVie, AstraZeneca, GlaxoSmithKline, Bayer, and Boehringer Ingelheim, participates in research from: Boehringer Ingelheim, Baxter, AstraZeneca and has lectured for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim and Sanofi. Luis E. Morales-Buenrostro has received honoraria from AstraZeneca, Boehringer Ingelheim, Sanofi, Asofarma, and Roche. Lluvia Marino Gabriel Cojuc-Konigsberg, Estefania Reul-Linares, Nathalie Desire Pichardo-Cabrera, Cristino Cruz, Elisa Naomi Hernández-Paredes, Nathan Berman-Parks, Vanesa Vidal Ruiz, Jonathan Mauricio Estrada Linares, and Alfredo A. Reza-Albarrán have no competing interest to declare.

Ethical approval

This study was approved by the local Human Research and Ethics Boards (NMM-4220-22-23-1) and adhered to the principles outlined in the 1964 Helsinki Declaration and its subsequent amendments.

Human and animal rights

This study does not contain any studies with animals performed by any of the authors.

Informed consent

Participants who underwent biomarker assessment provided informed consent.

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Ramirez-Sandoval, J.C., Marino, L., Cojuc-Konigsberg, G. et al. Long-term effects of hypercalcemia in kidney transplant recipients with persistent hyperparathyroidism. J Nephrol (2023). https://doi.org/10.1007/s40620-023-01815-5

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