Persistent Hyperparathyroidism: A Reality Calling for Additional Evidence

Abstract

Related Article, p. 270 Related Article, p. 270 In this issue of AJKD, Wang et al1Wang A.X. Liu S. Montez-Rath M.E. Chertow G.M. Lenihan C.R. Parathyroidectomy and cinacalcet use in Medicare-insured kidney transplant recipients.Am J Kidney Dis. 2023; 81: 270-280https://doi.org/10.1053/j.ajkd.2022.07.015Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar report on the incidence, trends, and consequences of treatment of posttransplant hyperparathyroidism in a nationwide registry encompassing 30,127 Medicare-insured US patients who received a first kidney transplant. The 2 treatments of interest were cinacalcet use and parathyroidectomy in the first 3 years following kidney transplantation. The authors report that cinacalcet use was common (18%) and increased by 20% from 2007 to 2013, with treatment most often initiated early in the posttransplant course (a median of 6.8 weeks). In contrast, surgical parathyroidectomies were much less common (1.8%), did not increase in frequency, and were typically performed >12 months posttransplant. These findings confirm that hyperparathyroidism is a common complication after kidney transplantation—and that its incidence is increasing. The latter likely reflects a shift toward medical therapy first in controlling secondary hyperparathyroidism in patients with late-stage chronic kidney disease, including those on the kidney transplant waiting list.2Tentori F. Wang M. Bieber B.A. et al.Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study.Clin J Am Soc Nephrol. 2015; 10: 98-109https://doi.org/10.2215/CJN.12941213Crossref PubMed Scopus (200) Google Scholar One-third of the patients enrolled in the study by Wang et al had been treated with cinacalcet prior to kidney transplantation. These patients are at risk for rebound hyperparathyroidism when calcimimetic therapy is discontinued at the time of transplantation,3Evenepoel P. Sprangers B. Lerut E. et al.Mineral metabolism in renal transplant recipients discontinuing cinacalcet at the time of transplantation: a prospective observational study.Clin Transplant. 2012; 26: 393-402https://doi.org/10.1111/j.1399-0012.2011.01524.xCrossref PubMed Scopus (29) Google Scholar especially when exposure time is short. Although it is reassuring to observe that in a substantial subset of patients in the study from Wang et al, cinacalcet withdrawal at time of transplantation was without complications, there remains a clear window of opportunity for better control of secondary hyperparathyroidism pre-transplant. The clinical consequences of hyperparathyroidism posttransplant remain uncertain. Observational studies indicate unfavorable outcomes, with increased risk of fracture,4Perrin P. Caillard S. Javier R.M. et al.Persistent hyperparathyroidism is a major risk factor for fractures in the five years after kidney transplantation.Am J Transplant. 2013; 13: 2653-2663https://doi.org/10.1111/ajt.12425Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar cardiovascular disease,5Pihlstrøm H. Dahle D.O. Mjøen G. et al.Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism.Transplantation. 2015; 99: 351-359https://doi.org/10.1097/TP.0000000000000583Crossref PubMed Scopus (81) Google Scholar and kidney graft loss,5Pihlstrøm H. Dahle D.O. Mjøen G. et al.Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism.Transplantation. 2015; 99: 351-359https://doi.org/10.1097/TP.0000000000000583Crossref PubMed Scopus (81) Google Scholar but intervention studies are limited and, so far, yielded unequivocal results.6Trillini M. Cortinovis M. Ruggenenti P. et al.Paricalcitol for secondary hyperparathyroidism in renal transplantation.J Am Soc Nephrol. 2015; 26: 1205-1214https://doi.org/10.1681/ASN.2013111185Crossref PubMed Scopus (50) Google Scholar,7Evenepoel P. Cooper K. Holdaas H. et al.A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism.Am J Transplant. 2014; 14: 2545-2555https://doi.org/10.1111/ajt.12911Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar A first question to be tackled in kidney transplant recipients presenting with hyperparathyroidism is whom to treat? Clearly, it is important to discriminate persistent (or tertiary) from secondary hyperparathyroidism when considering treatment posttransplant, as the first is likely a maladaptive condition, while the latter can be considered a beneficial adaption to maintain normocalcemia and normophosphatemia in the face of kidney graft dysfunction. To complicate matters further, the phenotype of persistent hyperparathyroidism posttransplant often mimics familial hypocalciuric hypercalcemia, with lower levels of calciuria than what is typically seen for primary hyperparathyroidism.8Marx S.J. Familial hypocalciuric hypercalcemia as an atypical form of primary hyperparathyroidism.J Bone Miner Res. 2018; 33: 27-31https://doi.org/10.1002/jbmr.3339Crossref PubMed Scopus (23) Google Scholar Pathophysiological mechanisms underlying this atypical presentation remain to be defined, but both calcium-sensing receptor dysfunction and skeletal parathyroid hormone (PTH) resistance may be hypothesized to be involved. According to a recent bone biopsy study, the majority of kidney transplant recipients have normal bone turnover at 1 year posttransplant, and hyperparathyroidism with hypercalcemia is not necessarily indicative of high bone turnover, as was also found in previous reports.9Borchhardt K. Sulzbacher I. Benesch T. et al.Low-turnover bone disease in hypercalcemic hyperparathyroidism after kidney transplantation.Am J Transplant. 2007; 7: 2515-2521https://doi.org/10.1111/j.1600-6143.2007.01950.xAbstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar,10Jørgensen H.S. Behets G. Bammens B. et al.Patterns of renal osteodystrophy 1 year after kidney transplantation.Nephrol Dial Transplant. 2021; 36: 2130-2139https://doi.org/10.1093/ndt/gfab239Crossref PubMed Scopus (7) Google Scholar In clinical practice, we want to identify patients with negative effects of PTH on target organs—such as high bone turnover with risk of bone demineralization, or excessive calciuria with risk of kidney stones and nephrocalcinosis. To that end, besides routine mineral metabolism parameters, bone turnover markers and the calcium to creatinine clearance ratio may be of help. As the positive predictive value of bone turnover markers for high bone turnover is rather disappointing,11Jørgensen H.S. Behets G. Viaene L. et al.Diagnostic accuracy of noninvasive bone turnover markers in renal osteodystrophy.Am J Kidney Dis. 2022; 79: 667-676.e1https://doi.org/10.1053/j.ajkd.2021.07.027Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar,12Keronen S.M. Martola L.A.L. Finne P. et al.Clinical prediction of high-turnover bone disease after kidney transplantation.Calcif Tissue Int. 2022; 110: 324-333https://doi.org/10.1007/s00223-021-00917-1Crossref PubMed Scopus (1) Google Scholar the threshold for performing a bone biopsy in a patient with hyperparathyroidism and elevated bone biomarkers prior to referral for a parathyroidectomy should be low. Having identified patients with maladaptive hyperparathyroidism, we should next consider how to treat. Lack of hard outcome trials precludes formal treatment recommendations, and so, benefits and risks of calcimimetics versus parathyroidectomy should be considered, in order to define the best treatment option at the individual level (Table 1). Cinacalcet has been shown to normalize mineral metabolism parameters posttransplant, but its effect on bone mineral density is limited.7Evenepoel P. Cooper K. Holdaas H. et al.A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism.Am J Transplant. 2014; 14: 2545-2555https://doi.org/10.1111/ajt.12911Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar In a small randomized study comparing parathyroidectomy with cinacalcet for treating hypercalcemia in kidney allograft recipients, subtotal parathyroidectomy induced greater reductions in PTH and calcium and was associated with a significant increase in femoral neck bone mineral density.13Cruzado J.M. Moreno P. Torregrosa J.V. et al.A randomized study comparing parathyroidectomy with cinacalcet for treating hypercalcemia in kidney allograft recipients with hyperparathyroidism.J Am Soc Nephrol. 2016; 27: 2487-2494https://doi.org/10.1681/ASN.2015060622Crossref PubMed Scopus (90) Google ScholarTable 1Considerations for Medical Versus Surgical Treatment of Persistent Hyperparathyroidism After Kidney TransplantationCalcimimeticsParathyroidectomyBenefits and RisksAdvantagesNoninvasive; can be withdrawnRadical treatment; proven skeletal benefitDisadvantagesTolerability not assured; adherence not assured; treatment duration unknownInvasive; peri- and postsurgical risks; initial costEffect ParametersParathyroid hormoneReduced (by 25%)NormalizedCalciumNormalized (for 70%); low risk of hypocalcemiaNormalized (for 100%); high risk of hypocalcemiaPhosphateNormalizedNormalizedBone turnover markersNo change/initial increaseDecreaseBone mineral densityNo changeSubstantial gainVascular calcificationNo changeNo changeKidney functionNo reductionPossible reduction Open table in a new tab Any intervention carries inherent risks. In the study by Wang et al, 1 in 4 patients (25%) were hospitalized within 90 days of parathyroidectomy and a similar number (28%) after their first prescription of cinacalcet. To counter the earlier initiation of cinacalcet (at a median of 6.8 weeks) compared to parathyroidectomy (at a median of 13.9 months), a sensitivity analysis was performed restricting to patients starting therapy >12 months posttransplant. In this analysis, hospitalizations were more common following a parathyroidectomy (24%) than after cinacalcet prescription (15%). The most feared complications of PTH suppressive therapy are hypocalcemia and kidney dysfunction. Hypocalcemia results from decreased skeletal calcium efflux and even, in the case of hungry bone syndrome, from net skeletal calcium influx. The timing, severity, and duration of hypocalcemia relate directly to the dynamics of the PTH signaling changes and degree of bone mineralization defect at baseline. Thus, not surprisingly, the hypocalcemia following (sub)total parathyroidectomy differs from that following calcimimetic therapy: by occurring earlier (acutely) and being more pronounced, often symptomatic, and of longer duration. Accordingly, in the study by Wang et al, the risk of hypocalcemia was clearly higher after parathyroidectomy than after cinacalcet initiation (44% vs 2%). Kidney graft dysfunction has been reported following parathyroidectomy and calcimimetic therapy in some, but not all, case series—and likely has a hemodynamic origin.14Evenepoel P. Claes K. Kuypers D. et al.Impact of parathyroidectomy on renal graft function, blood pressure and serum lipids in kidney transplant recipients: a single centre study.Nephrol Dial Transplant. 2005; 20: 1714-1720https://doi.org/10.1093/ndt/gfh892Crossref PubMed Scopus (117) Google Scholar Wang et al report a similar risk of acute kidney injury necessitating admission with both treatment options (7.8% vs 10.8%). These absolute risks are hard to interpret without knowledge of the baseline risk. A recent meta-analysis is reassuring, as it demonstrated no sustained kidney dysfunction with either therapy.15Frey S. Goronflot T. Kerleau C. et al.Parathyroidectomy or cinacalcet: do we still not know the best option for graft function in kidney-transplanted patients? A meta-analysis.Surgery. 2021; 170: 727-735https://doi.org/10.1016/j.surg.2021.02.048Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Whereas a successful parathyroidectomy offers a permanent solution,9Borchhardt K. Sulzbacher I. Benesch T. et al.Low-turnover bone disease in hypercalcemic hyperparathyroidism after kidney transplantation.Am J Transplant. 2007; 7: 2515-2521https://doi.org/10.1111/j.1600-6143.2007.01950.xAbstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar,10Jørgensen H.S. Behets G. Bammens B. et al.Patterns of renal osteodystrophy 1 year after kidney transplantation.Nephrol Dial Transplant. 2021; 36: 2130-2139https://doi.org/10.1093/ndt/gfab239Crossref PubMed Scopus (7) Google Scholar the effect of cinacalcet is only for the duration of the treatment, with a risk of rebound hyperparathyroidism after discontinuation.8Marx S.J. Familial hypocalciuric hypercalcemia as an atypical form of primary hyperparathyroidism.J Bone Miner Res. 2018; 33: 27-31https://doi.org/10.1002/jbmr.3339Crossref PubMed Scopus (23) Google Scholar Although some degree of spontaneous resolution of hyperparathyroidism is expected posttransplant, the prevalence seems fairly stable from 1 year posttransplant and onward.11Jørgensen H.S. Behets G. Viaene L. et al.Diagnostic accuracy of noninvasive bone turnover markers in renal osteodystrophy.Am J Kidney Dis. 2022; 79: 667-676.e1https://doi.org/10.1053/j.ajkd.2021.07.027Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Thus, the duration of treatment with cinacalcet may well be indefinite. From a health economic perspective, this is relevant, as it has been calculated that surgery would be more cost-effective if cinacalcet duration reached 14 months.9Borchhardt K. Sulzbacher I. Benesch T. et al.Low-turnover bone disease in hypercalcemic hyperparathyroidism after kidney transplantation.Am J Transplant. 2007; 7: 2515-2521https://doi.org/10.1111/j.1600-6143.2007.01950.xAbstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar To conclude, the study by Wang et al provides helpful information regarding the current clinical practice of treating hyperparathyroidism after kidney transplantation. A main limitation is the lack of biochemical data on the prevalence and severity of mineral metabolism disturbances and indications for initiation of, and choice of, therapy. The consequences of persistent hyperparathyroidism in the posttransplant period still need to be defined, and this information is a prerequisite to establishing both treatment indications and targets for therapy. Considering the increasing utility of calcimimetics posttransplant, studies are urgently needed to determine whether they are safe and efficient in the early posttransplant period, whether treatment can be withdrawn or should continue indefinitely, and, most importantly, whether treatment benefits the patient by reducing the risk of fractures and cardiovascular events or improving kidney graft and overall survival. Hanne Skou Jørgensen, MD, PhD, and Pieter Evenepoel, MD, PhD. None. The authors declare that they have no relevant financial interests. Received September 28, 2022, in response to an invitation from the journal. Accepted October 3, 2022, after editorial review by an Associate Editor and a Deputy Editor. Parathyroidectomy and Cinacalcet Use in Medicare-Insured Kidney Transplant RecipientsAmerican Journal of Kidney DiseasesVol. 81Issue 3PreviewPosttransplant hyperparathyroidism is common, and treatment practices are poorly characterized. The goal of this study was to examine the incidence, associations, and outcomes of posttransplant parathyroidectomy and calcimimetic use in a cohort of Medicare-insured US kidney transplant recipients. Full-Text PDF