Super-high levels of serum intact-parathyroid hormone and bone turnover markers descended with recuperating allograft function and a short-term high-dose methylprednisolone during preoperative period of renal transplantation: a retrospective cohort study

Introduction

End-stage renal disease (ESRD) is often combined with mineral and bone metabolism derangement, secondary hyperparathyroidism, multiple renal osteodystrophy and angiostenosis, known as chronic kidney disease-mineral and bone disorder (CKD-MBD) (1,2). Patients with maintenance dialysis (CKD-G5D) often have a super-high level of intact-parathyroid hormone (iPTH) and biochemical bone turnover markers (BTMs) (3-6). This situation may cause a higher incidence of osteoporosis, fracture, osteonecrosis, and renal osteodystrophy, and may lead to deteriorated quality of life and increased risk of mortality for ESRD patients (7,8). The super-high iPTH level is the central feature of CKD-MBD, and the increased BTMs could lead to osteolytic osteopathy, which is correlated with hyperparathyroidism.

Serum BTMs, as markers that can be detected non-invasively, have been used in clinical research to evaluate bone turnover, predict fracture risk, and monitor the osteoporosis treatment response (9,10). Among the BTMs, serum C-terminal telopeptide of type I collagen (CTX-I; a bone resorption marker) and procollagen type 1N-terminal propeptide (P1NP; a bone formation marker) have been recommended by the International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry (IFCC) Bone Marker Standards Working Group for clinical use (11,12).

CKD-MBD is important influence factor for ESRD patient survival quality. IPTH and BTMs are the leading factors resulting in and compounding or aggravating mineral abnormality and bone disorder. How to reduce iPTH levels in CKD-G5D patients has always been a difficult problem closely monitored by kidney disease clinicians. Many reports have highlighted the relationship between the BTMs, iPTH, and osteocalcin (OC) in long-term follow up after kidney transplantation (KT). Currently, these targets (BTMs, iPTH) cannot be improved by the existing equipment and technique of dialysis. However, bone loss after KT has been shown to vary at different timepoints (9,13). It is currently unclear which post-KT changes in CKD-G5D patients result in super-increased iPTH and BTMs levels. It is necessary to discover a way to resolve the difficult situation of CKD-MBD. If the underlying relationship between iPTH and BTMs levels in the perioperative period is identified, measures can be taken to improve the life quality of CKD-MBD patients and reduce the risk of mortality in ESRD patients.

This study retrospectively investigated the immediate changes of iPTH and BTMs levels before and after KT, explored the effect of allograft function rapid recovery and high-dose glucocorticoids on serum iPTH and BTMs levels, and attempted to discover a way to resolve the difficult situation of CKD-MBD. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-398/rc).

Methods

Participants

This was a retrospective cohort study. Between April 2018 and August 2021, 346 KT recipients were enrolled consecutively from the Kidney Disease Center, The First Affiliated Hospital, Zhejiang University, School of Medicine. Before KT, these patients had been undergoing dialysis (peritoneal dialysis or hemodialysis) for at least three months, and all of them had been matched with a donor kidney, consented to the KT operation, methylprednisolone (MP) pulse therapy and the other antirejection therapy, and had agreed to undergo biochemical BTMs and the other biochemical indicator assessment. The exclusion criteria were a dialysis duration of less than three months before operation, primary hyperparathyroidism, previous parathyroidectomy, undergoing diphosphonate therapy, and lacking adequate laboratory data. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (Medical Ethical Committee, No. IIT20221208A) and written informed consent was taken from all the patients.

Treatment and groups

All renal recipients accepted a short-term high-dose MP intravenous injection on the operative day and preoperative first day at a dose of: 10 mg/kg/d and a follow-up 5 mg/kg/d for 2 days, and from the fifth postoperative day, oral prednisone was continued at 10 mg/kg/d and decreased every day to 10–15 mg/day. Meanwhile, oral mycophenolate was given on the operative day and oral tacrolimus was administered postoperatively to prevent allograft rejection.

On the fifth postoperative day, allograft functions were evaluated by the estimated glomerular filtration rate (eGFR; creatinine-based eGFR) and use of eGFR to confirm CKD staging (14). All recipients were divided into different groups according to the CKD staging: CKD-II (eGFR 60–90 mL/min/1.73 m²), CKD-III (eGFR 30–59 mL/min/1.73 m²), CKD-IV (eGFR 15–29 mL/min/1.73 m²), and CKD-V (eGFR <15 mL/min/1.73 m²) groups.

Biochemical examinations

Before surgery and on the postoperative fifth day, fasting blood samples were collected at 7:00–8:30 am and detected within 24 hours of admission. Serum beta C-terminal crosslinking telopeptide of type I collagen (β-CTX), type 1N-terminal propeptide (P1NP) (total P1NP), OC, and iPTH were measured using an electro-chemiluminescence immunoassay analyzer (Roche Diagnostics GmbH, Mannheim, Germany). The serum C-terminal telopeptide of type I collagen (CTX-I; a bone resorption marker) and P1NP (a bone formation marker) recommended by the IOF and the IFCC Bone Marker Standards Working Group for clinical use (15,16). The CTX is mainly measured by electrochemiluminescence immunoassay analyzer (ECLIA) using the β-CrossLaps kit (Roche Diagnostics) (11). As bone ages, α-aspartic amino acid converts to β-aspartic acid, so detecting β-CTX is indicative of resorption of matured bone (12). Serum creatinine, total calcium (serum calcium), phosphate, and albumin, among others, were measured by photometric assays in vitro using an automated clinical chemistry analyzer (Olympus Diagnostica GmbH, Hamburg, Germany).

Data collection

The following clinical data of the participants were collected at baseline and postoperatively: gender, age, Kinsfolk renal, peritoneal dialysis or hemodialysis, dialysis duration, and the biomarkers such as eGFR, serum albumin, hemoglobin, serum total calcium, serum phosphates, serum total alkaline phosphatase (TAP), 25(OH)D3, iPTH, β-CTX, P1NP, OC, parathyroid hyperplasia, and extraosseous calcification.

Statistical analysis

Categorical variables were expressed as absolute numbers with percentages. The percentage data were compared by chi-square test. The median (interquartile range) values were presented by the Explore Test for non-normally distributed variables and the absolute changes from preoperative value to postoperative value in β-CTX, P1NP, OC, and iPTH concentrations were compared, and the interclass data were evaluated by nonparametric tests using the Kruskal-Wallis test for K independent samples. Continuous variables were presented as mean standard deviation (SD) for normally distributed variables (at each group) and the differences were compared by an independent samples t-test. The correlation of BTMs and influencing factors were analyzed by Spearman’s correlation analysis and or linear regression analysis. A P value less than 0.05 was considered statistically significant, and SPSS statistical software for Windows (version 22; IBM Corp., Armonk, NY, USA) was used for statistical analysis. Graphs were made using GraphPad Prism for Windows version 8.0.2 (GraphPad Software, La Jolla, CA, USA).

Results

Baseline characteristics

A total of 346 KT recipients were enrolled in this study. The baseline data before operation are displayed in Table 1; the serum phosphates, iPTH, β-CTX, P1NP, and OC levels exceeded normal reference values (Table 1). Spearman correlation analysis showed that β-CTX was significantly correlated with P1NP (r=0.592, P<0.001) and OC (r=0.473, P<0.001). P1NP correlated with OC (r=0.449, P<0.001). β-CTX, P1NP and OC all correlated with iPTH (r=0.399, P<0.001; r=0.320, P<0.001; and r=0.464, P<0.001, respectively).

BTMs levels and absolute changes

The serum levels of P1NP, OC, β-CTX, and iPTH had significantly decreased on the postoperative fifth day in all recipients. The changes of P1NP levels [−95.8 (−84.0 to −2.4) ng/mL] (−99.6%, P=0.001), OC levels [−88.0 (−96.9 to −42.9) ng/mL) (−94.8%, P=0.001), β-CTX levels [−62.3 (−73.6 to 0) pg/mL] (−60.8%, P<0.001), and iPTH levels [−57.6 (−15.6 to 11.9) pg/mL] (−66.7%, P<0.001) were significant (Table 2). The changes of P1NP levels and the OC levels were greater than that of the β-CTX levels (P<0.001, Table 2), whereas the changes of iPTH levels were comparable to those of the β-CTX levels (P=0.462, Table 2).

BTMs in allograft groups

At the postoperative fifth day, the allograft function reverted to CKD-II [134 (38.7%)], CKD-III [137 (39.6%)], CKD-IV [24 (6.9%)], and remained CKD-V [51 (14.7%)]. Before surgery, the β-CTX, iPTH, P1NP, and OC levels were not statistically different in all groups. After the postoperative fifth day, these BTMs levels were increased in the CKD-IV and CKD-V groups compared with the CKD-II group. The changes of P1NP and OC levels were more patent than the β-CTX and iPTH levels in every allograft group (P<0.001). The changes of β-CTX and iPTH levels decreased along with renal function fall-off, up to the CKD-V group, the β-CTX level [−0.7 (−43.15 to 0) pg/mL] (+15.7%, P=0.61) and the iPTH level [−25.54 (225.24 to 17.79) pg/mL] (−22.8%, P=0.36), compared to the CKD-II group, P<0.001 (Table 3, Figure 1).

Figure 1 After the post-operative fifth day, the changes of P1NP and OC reflected that every allograft CKD group had attained patency, and the changes of β-CTX and iPTH levels were lower in every CKD group, especially the CKD-V group. (A) In the CKD-II group, the rates of decrease in P1NP and OC were more pronounced than those of β-CTX and iPTH (P=0.001); (B) in the CKD-III group, the rates of decrease of P1NP and OC were more pronounced than those of β-CTX and iPTH (P=0.001); (C) in the CKD-IV group, the rates of decrease of P1NP and OC were more pronounced than those of β-CTX and iPTH (P=0.001); (D) in the CKD-V group, the rates of decrease of P1NP and OC were more pronounced than those of β-CTX and iPTH (P=0.001). β-CTX, beta C-terminal crosslinking telopeptide of type I collagen; iPTH, intact-parathyroid hormone; OC, osteocalcin; CKD, chronic kidney disease; P1NP, type 1N-terminal propeptide; BTM, bone turnover marker.

Spearman correlation analysis showed that after operation, β-CTX significantly correlated with serum iPTH (r=0.413, P=0.001); P1NP correlated with iPTH (r=0.459, P<0.001); OC correlated with iPTH (r=0.482, P=0.001), and the iPTH correlated with the eGFR (r=−0.474, P<0.001).

Influencing factors for iPTH

Linear regression analysis showed that the iPTH levels correlated with the dialysis duration levels and parathyroid hyperplasia before operation (P<0.001, P=0.013, respectively, Table 4). After surgery, the iPTH levels correlated with parathyroid hyperplasia and eGFR (P<0.001, P<0.001, respectively, Table 4).

Discussion

In this study, KT recipients had super-high levels of serum BTMs before surgery in maintenance dialysis state, these BTMs related with each other, and all participants had highly elevated levels of iPTH. These results are consistent with those of previous reports (9,10,12,13). Parathyroid hormone (PTH) is basic single-stranded polypeptide hormone that is secreted by parathyroid chief cells, with a 9,500 dalton molecular weight (13). To date, it has not been possible to remove PTH by peritoneal dialysis and hemodialysis in uremia patients, so super-high levels of iPTH have resulted in the excess increase of BTMs, causing bone metabolism derangement (9,10,12,13).

In this study, along with allograft function recovery, serum iPTH and BTMs levels quickly descended. These results confirmed that increased PTH might be cleared by normal renal function, and heightened BTMs correlated with PTH might be improved (13,17).

Our findings indicated that if the technique of peritoneal dialysis and hemodialysis could remove the major cause of CKD-MBD, iPTH, metabolic bone disorders might improve, and the survival quality of ESRD patients would be enhanced. Although KT recipients had overcome the effects of secondary hyperparathyroidism (SHPT)—the leading cause of CKD-MBD in the maintenance dialysis period, they were prone to being affected by the tertiary hyperparathyroidism after transplant, which induced hypercalcinemia. osteoporosis, fracture, angiostenosis, or led to some recipients having to undergo parathyroidectomy. Future research should include correlation study about tertiary hyperparathyroidism after KT (18).

In this study, the levels of osteoblast markers P1NP and OC rapidly decreased on the postoperative fifth day, not only in the CKD-II and CKD-III groups, but also in the CKD-IV and CKD-V groups, and their changes were greater than those of β-CTX and iPTH. This indicated that rapid decreases in P1NP and OC during the preoperative period were not affected by the allograft function (12,19), which might be the action of the short-term high-dose MP for osteoblasts (20). Through the inhibition of osteoblast activity, MP can lead to a decrease of bone formation markers (20,21). The survival rate of the recipient depends on survival rate of the graft, so the improved graft survival may help patients improve their quality of life (22). Previous research by Sablik et al. found that the addition of MP to intravenous immunoglobulins can significantly improve the graft survival in KT patients (23). At the same time, the changes of osteoclast marker β-CTX correlated with iPTH; their rate of decline were decremented alone with allograft eGFR, demonstrating that short-term high-dose MP did not inhibit osteoclast activity during the KT perioperative period.

Previously, arterial spin labeling and blood oxygen level-dependent imaging was used to evaluate the effectiveness of renal transplantation function due to their non-invasive nature (24). Since the patients who underwent KT in this study had already provided blood samples in clinical practice, our study analyzed the existing blood samples, minimizing secondary trauma to the patients.

Limitations

A limitation of this study is that it was a single-center study. Moreover, the effect of allograft function and high-dose glucocorticoids on BTMs were not studied by setting a KT-only group and a group using high-dose glucocorticoids, which should be added into future studies.

Conclusions

The super-high levels of iPTH and BTMs rapidly descended with recuperating allograft function during the short-term, indicating that improving current dialysis equipment to regulate iPTH could more efficiently decrease BMTs and improve CKD-MBD. That the osteogenesis markers P1NP and OC levels still decreased in CKD-V group indicated that short-term high-dose glucocorticoids during kidney grafting in the perioperative period might increase the inhibition of osteoblast activity.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-398/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-398/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-398/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-398/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (Medical Ethical Committee, No. IIT20221208A) and written informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Jones)