Effect of Serum Parathyroid Hormone on Tacrolimus Therapy in Kidney Transplant Patients: A Possible Biomarker for a Tacrolimus Dosage Schedule

Abstract

The mechanism responsible for the decreased extra-renal CYP3A activity in chronic kidney disease (CKD) patients remains unknown. Using an animal model, we previously found that elevated levels of serum intact parathyroid hormone (iPTH) caused a reduced CYP3A activity. This retrospective observational study assessed the relationship between serum iPTH levels and the blood concentration or dosage of tacrolimus, a CYP3A substrate, after oral administration in kidney transplant patients. Thirty-four patients were enrolled who had kidney transplants between April 2014 and March 2016 and who had been administrated once- daily prolonged-release tacrolimus (Graceptor^®, Astellas Pharm Inc.). Among the 34 patients, 22 had taken a CYP3A inhibitor. These patients were excluded from the study. A significant positive correlation between serum iPTH and tacrolimus trough levels was found at 4 d before kidney transplantation in 12 patients who were not receiving potent CYP3A inhibitor. In addition, serum iPTH levels before transplantation could serve as a factor for the dose of tacrolimus up to 1 year after transplantation. Monitoring serum iPTH levels could predict the trough level for the initial administration of tacrolimus, and may serve as an index for the initial dose of tacrolimus in kidney transplantation patients.

INTRODUCTION

The number of organ transplant patients have increased in recent years. This is particularly true for kidney transplantations, which have reached about 1600 patients per year in Japan. For kidney engraftment, prophylaxis of rejection and/or graft-versus-host disease (GVHD) are important considerations. To address this issue, patients are frequently administered a calcineurin inhibitor such as tacrolimus or cyclosporine, even before transplantation. According to the annual progress report from the Japanese Renal Transplant Registry, 87% of recipients were administered tacrolimus in comparison with only 13% who were administered cyclospoline.¹⁾ On the other hand, a personalized administration plan based on therapeutic drug monitoring (TDM) is essential for tacrolimus administration because of its narrow therapeutic range and individual differences in the pharmacokinetics of tacrolimus.^2,3) Because it’s metabolic enzyme CYP3A activity affects the inter- or intra-individual differences in tacrolimus pharmacokinetics, it is important to understand the factors that affect CYP3A activity.

Simultaneously administered drug that is a inhibitor of CYP3A⁴⁾ or an allele mutation of CYP3A^5–7) are factors that can contribute to fluctuations in CYP3A activity. In addition, it has been reported that chronic kidney disease (CKD) also can affect extra-renal CYP3A activity.^8–10) In fact, it was reported that, not only renal clearance, but also extra-renal clearance is decreased in the case of CKD.^11–13) However, the mechanism responsible for the decreased CYP3A activity in CKD remains unknown.

We recently focused on the parathyroid hormone (PTH), one of the middle molecule uremic toxins, the serum level of which was increased by a decrease in kidney function, and examined the effect of PTH on the expression and activity of CYP3A. Using a secondary hyperparathyroidism (SHPT) model rat, primary rat hepatocytes and a human colon carcinoma cell line, Caco-2 cells, we found that serum PTH elevations caused the reduction in CYP3A expression in both the small intestine and liver, which resulted in a significant reduction in the activity of CYP3A and a marked increase in the area under the curve (AUC) of midazolam, a typical substrate of CYP3A. We also found that PTH down-regulated CYP3A mRNA expression via the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase C (PKC)/protein kinase A (PKA)/nuclear factor-kappaB (NF-κB) pathway after intracellular cAMP levels were elevated through the PTH receptor.¹⁴⁾

These findings led us to hypothesize that serum PTH levels would influence the pharmacokinetics of tacrolimus, and hence its dosage schedule in kidney transplant recipients. To investigate this hypothesis, we performed a retrospective observational study regarding the relationship between serum intact PTH (iPTH) and the blood concentration or dosage of tacrolimus orally administered from 4 d (initial dosing point) prior to kidney transplantation to 1 year after kidney transplantation.

PATIENTS AND METHODS

Background of Patients

Thirty-four patients were enrolled who had kidney transplants between April 2014 and March 2016 and who had been administrated once-daily prolonged-release tacrolimus (Graceptor^®, Astellas Pharm Inc., Japan). Among the 34 patients, 22 had taken a CYP3A inhibitor (Table 1). No patients who were taking CYP3A inducer were enrolled. These patients were excluded from the study (Fig. 1). This study was approved by the ethics committees of Japanese Red Cross Kumamoto Hospital (Approval number 259).

Table 1. Background of Enrolled 34 Patients

Patient No.	Age(’s)	Sex	Primary disease	Duration of dialysis (year)	Co-administered CYP3A4 inhibitor
1	50	Male	Chronic glomerulonephritis	24	—
2	30	Male	Unclear (CKD)	1	—
3	60	Female	Chronic glomerulonephritis	0.5	—
4	50	Male	IgA nephropathy	0	—
5	30	Male	Unclear (CKD)	7	—
6	60	Female	Unclear (CKD)	0	—
7	30	Female	Unclear (CKD)	0	—
8	40	Female	Polycystic kidney disease	0.3	—
9	50	Male	Unclear (CKD)	0.67	—
10	60	Male	Unclear (CKD)	1.5	—
11	30	Male	Unclear (CKD)	6	—
12	60	Male	IgA nephropathy	9	—
13	50	Male	Crescentic nephritis	3	Amlodipine
14	20	Male	IgA nephropathy	0	Nifedipine
15	50	Male	Diabetic nephropathy	0.33	Amlodipine
16	60	Female	IgA nephropathy	0	Nifedipine
17	50	Male	Diabetic nephropathy	0.25	Amlodipine
18	60	Male	Unclear (CKD)	0	Nifedipine
19	60	Female	Chronic glomerulonephritis	0	Amlodipine
20	40	Female	Unclear (CKD)	0.33	Amlodipine
21	20	Male	IgA nephropathy	0.6	Amlodipine
22	40	Female	Diabetic nephropathy	1	Nifedipine
23	60	Male	Chronic glomerulonephritis	0.25	Amlodipine, nifedipine
24	60	Male	IgA nephropathy	4.5	Azelnidipine
25	50	Female	Unclear (CKD)	0	Amlodipine, nifedipine
26	20	Male	IgA nephropathy	0.6	Amlodipine, atorvastatin
27	40	Male	Diabetic nephropathy	1	Amlodipine, nifedipine
28	20	Male	Crescentic nephritis	0.6	Nifedipine
29	50	Male	Diabetic nephropathy	0	Amlodipine
30	40	Male	IgA nephropathy	0.25	Amlodipine
31	60	Male	Chronic glomerulonephritis	6	Diltiazem, azelnidipine
32	40	Female	Unclear (CKD)	0	Amlodipine, azelnidipine
33	50	Male	Focal glomerulosclerosis	0	Nifedipine, atorvastatin
34	50	Male	IgA nephropathy	3	Nifedipine, azelnidipine

Fig. 1. Patient Screening and Enrollment

Methods

Administration of Graceptor^® (tacrolimus) was started 4 d before the operation at a dose of 0.15 mg/kg. Blood tacrolimus concentrations were measured by an electro-chemiluminescence immunoassay (ECLIA) method. After the administration of 0.15 mg/kg tacrolimus, we adjusted the tacrolimus dose based on the target AUC or trough concentration of tacrolimus. Blood tacrolimus levels in the patients were followed from 4 d before kidney transplantation to 1 year after kidney transplantation. Serum intact PTH levels was measured by electro chemiluminescence immunoassay (cobas 8000, Roche Inc., CA, U.S.A.).

Statistical Analyses

Correlations between two variables were calculated using Spearman’s correlation. Significant differences were identified using the paired t-test (Fig. 2) or unpaired Student t-test (Fig. 4 and Supplementary Fig. 1).

Fig. 2. Serum iPTH Changes in 12 Patients at Pre-operation (4 Days before Operation), Discharge (3–4 Weeks after the Operation) and 1 Year after the Operation

Each circle represents each patient’s serum iPTH level and each bar represents the mean value for each point. ** p < 0.01 vs. pre-operation.

RESULTS

Patients

Thirty-four patients who were recipients of kidney transplantation between April 2014 and March 2016 and were administrated prolonged-release tacrolimus (Graceptor^®, Astellas Pharm Inc.) once daily were the subjects of this study. Patient’s backgrounds are shown in Table 1. Among the 34 patients, 22 patients had received the CYP3A inhibitor (Table 1). To clarify the role of PTH on the pharmacokinetics of tacrolimus, we performed the analysis using 12 patients who had not been administered concomitant drugs that are the inhibitor of CYP3A (Fig. 1, Table 1).

Changes in Serum iPTH Levels before Kidney Transplantation to 1 Year after Kidney Transplantation

Figure 2 shows the serum iPTH levels at 4 d before the operation (pre-operation), discharge (3–4 weeks after operation) and 1 year after the operation. The high serum iPTH levels in patients before the operation (pre-operation, 333.1 ± 264.6 (mean ± standard deviation (S.D.)) pg/mL) were significantly reduced by kidney transplantation (discharge, 113.5 ± 80.3 pg/mL, p < 0.05 vs. pre-operation) and this reduced serum iPTH level remained reduced for up to 1 year after the operation (1 year after the operation, 112.5 ± 60.2 pg/mL, p < 0.01 vs. pre-operation).

Relationship between Serum iPTH Levels and Tacrolimus Trough Concentration before Kidney Transplantation

To investigate the relationship between serum iPTH levels and tacrolimus trough levels, we monitored the serum iPTH levels in patients before kidney transplantation. At this time point, serum iPTH levels in these subjects were increased, but with large deviations due to the difference in the patients’ background such as the causes of and the progression of renal failure and complications (Fig. 2, Table 1). Therefore, we examined the correlation between serum iPTH levels and trough levels after the first oral administration of tacrolimus at 4 d before kidney transplantation in 12 patients. A significant positive correlation between serum iPTH level and the initial trough level for tacrolimus was found in these 12 patients (initial tacrolimus trough concentration = 0.0046 × iPTH (before operation) + 2.4781, R² = 0.6967; p = 0.0003) (Fig. 3). This indicates that the tacrolimus trough level before transplantation was higher in patients with high serum iPTH levels as compared to patients with low iPTH values. These data suggest that CYP3A activity might be lower in patients with high serum iPTH levels, as was observed in the previous animal study, and that the initial trough level of tacrolimus could be predicted from serum iPTH levels before kidney transplantation.

Fig. 3. Correlation between Serum iPTH and Blood Tacrolimus Trough Concentration at 4 d before Transplantation

The patients who were not administrated a CYP3A inhibitor (n = 12) are shown.

Effect of Pre-operative Serum iPTH Level on the Post-operative Dose of Tacrolimus

We next divided the 12 patients into a high serum iPTH group (iPTH > 240 pg/mL, n = 7) and a low serum iPTH group (iPTH < 240 pg/mL, n = 5) before transplantation because “240” is the upper limit for the management target of serum iPTH in clinical guidelines in Japan.¹⁵⁾ We then monitored the maintenance doses of tacrolimus in each patient for a period of 1 year post-operation (Fig. 4). Since the target AUC or target trough concentration for tacrolimus decreases over time after operation (Fig. 4), the maintenance dose of tacrolimus in each group was gradually decreased. Up to 1 year after transplantation, the high serum iPTH group showed a significantly lower maintenance dose of tacrolimus as compared to the low serum iPTH group (Fig. 4). We further examined the correlation between serum iPTH levels and the maintenance dose of tacrolimus. As shown in Fig. 5A, a significant negative correlation (R² = 0.467; p = 0.01) was found between serum iPTH levels before transplantation and the tacrolimus dose at 1 year after transplantation. On the other hand, no significant correlation was found between serum iPTH levels at the point of discharge (3 or 4 weeks after the operation) and the tacrolimus dose at 1 year after transplantation (Fig. 5B, R² = 0.377; p = 0.055). In addition, no significant correlation was also found between serum iPTH levels at 1 year after transplantation and the tacrolimus dose at 1 year after transplantation (Fig. 5C, R² = 0.171; p = 0.118).

Fig. 4. Alteration in Tacrolimus Dose from Pre- to 1 Year after the Operation

Twelve patients were divided into (◆) low iPTH patients (<240, n = 5) and (■) high iPTH patients (> 240, n = 7) at the pre-operation. * p < 0.05 and ** p < 0.01 as compared with each point of high iPTH patients. Each bar represents the mean ± S.D.

Fig. 5. Correlation between Serum iPTH Levels at Pre-operation, 3–4 Weeks or 1 Year after Post-operation and Tacrolimus Dose at 1 Year after the Operation

(A) Correlation between serum iPTH levels at pre-operation and tacrolimus dose at 1 year after the operation. (B) Correlation between serum iPTH at 3–4 weeks after the operation and tacrolimus dose at 1 year after the operation. (C) Correlation between serum iPTH levels at 1 year after post-operation and tacrolimus dose at 1 year after the operation.

DISCUSSION

In patients with kidney transplants, tacrolimus is an important immunosuppressive agent that is indispensable for the successful engraftment of transplanted kidneys. However, the incorrect control of its blood concentration causes opportunistic infections accompanied by hyper-immunosuppression or renal dysfunction associated with an over-dosage, and conversely, constitutes a risk of causing rejection if the dose is low.¹⁶⁾ Therefore, in order to maintain a stable AUC and stable trough concentrations of tacrolimus in organ transplant patients, it is necessary to fully understand the factors that affect its pharmacokinetics.

In this retrospective observational study of the relationship between serum iPTH levels and the blood concentration or dosage of tacrolimus in kidney transplant patients, we obtained the following novel findings: 1) The initial tacrolimus trough concentration before kidney transplantation was positively correlated with serum iPTH levels in patients who were not taking CYP3A inhibitor. 2) The high iPTH group (> 240 pg/mL) showed a continuously lower dosage of tacrolimus compared to the low iPTH group (< 240 pg/mL) from before transplantation to 1 year after transplantation. 3) The maintenance dose of tacrolimus at 1 year after transplantation was dependent on the iPTH levels before transplantation. The finding of this study suggested that serum iPTH levels before transplantation could serve as a predictable factor for the tacrolimus trough concentration before transplantation. Therefore, the monitoring of serum iPTH levels before transplantation has the potential to determine not only the initial dose of tacrolimus before transplantation, but also the maintenance dose for at least 1 year after transplantation. In addition, it appears that no attention has been paid to iPTH levels in the field of TDM including tacrolimus. Thus, another significant aspect of the present study is that it clarifies the importance of monitoring serum iPTH levels, regarding TDM as a CYP3A substrate under CKD conditions.

It has been previously reported that CYP3A activity is decreased in patients with CKD.^8–10) In fact, among the drugs approved by the U.S. Food and Drug Administration (FDA) from 2003 to 2007, increased AUC was observed in around 30% of the non-renally cleared drugs in patients with CKD.¹⁷⁾ Regarding this decrease in extra-renal clearance with CKD, it is noteworthy that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in this process,^18–20) but details concerning this has remained unclear. Recently, we reported that PTH was involved in the decrease in CYP3A expression in both the small intestine and liver by CKD, based on the use of a disease model animal and cell systems. We specifically revealed the mechanism by which PTH activates the PI3K/PKC/PKA/NF-κB pathway by increasing intracellular cAMP levels, and that activated NF-κB suppressed CYP3A mRNA expression.¹⁴⁾

In this study, to investigate whether the decrease in CYP3A expression by iPTH observed in animal experiments was also observed in clinical practice in humans, blood tacrolimus concentrations or the dosage of tacrolimus was monitored in kidney transplant patients. Interestingly, we found a good positive correlation between the trough level of tacrolimus after the first administration and serum iPTH levels before transplantation in 12 patients who were not taking CYP3A inhibitor. These data are entirely consistent with results reported for animal experiments showing that iPTH reduced the expression of CYP3A in both the small intestine and liver, suggesting that iPTH may have a similar effect in humans. Although the initial dose (for example, 0.15 mg/kg) before transplantation is indicated in the package insert of tacrolimus, the trough levels of tacrolimus varied widely within the group of patients. The results obtained here suggest that serum iPTH levels before transplantation could serve as an index for the initial setting of the dose of tacrolimus in kidney transplant patients.

On the other hand, the maintenance dose of tacrolimus at 1 year after transplantation was negatively correlated with the serum iPTH levels before transplantation, but it did not significantly correlate with serum iPTH levels at 3 to 4 weeks or 1 year after transplantation. These results indicate iPTH that accumulates under CKD conditions might have a sustained effect to CYP3A activity, even after the transplantation, and continues to have an influence on the maintenance dose of tacrolimus. In addition, the findings indicate that the tacrolimus dose of the high iPTH group (> 240 pg/mL) was continuously lower than that for the low iPTH group (< 240 pg/mL) for periods of up to 1 year after transplantation. Although it will be necessary to investigate why the dose of tacrolimus was not reversed with the decrease in serum iPTH levels after transplantation, it may take a long period of time for the CYP3A activity to recover in these patients. Indeed, as serum Ca levels often continues to be high after transplantation,^21–23) the influence of a high pre-operative iPTH level may continue for a long period. In addition, it has also been reported that erythropoietin preparations used for treating anemia in dialysis patients also suppressed CYP3A4 via the NF-κB pathway.²⁴⁾ These data indicate that factors other than iPTH might also contribute to a decrease in CYP3A activity. Details regarding these observations could be clarified by increasing the number of patients in a future study.

Although the findings of this study indicate the existence of a positive correlation between serum iPTH levels and the tacrolimus trough concentration before renal transplantation, this did not reappear in the analysis using the entire starting group of patients (n = 34), which included 22 patients who were taking a CYP3A inhibitor (initial tacrolimus trough concentration = 0.0022 × iPTH (before operation) + 4.746, R² = 0.0293; p = 0.0614, Supplementary Fig. 1A). It is well known that the administration of a CYP3A inhibitor, such as voriconazole^25–27) or lansoprazole²⁸⁾ to renal transplant patients results in an increase in the concentration of tacrolimus in the blood. In fact, as shown in Supplementary Fig. 1B, the tacrolimus trough concentration was increased in parallel with the simultaneous increase in a drug that is a inhibitor of CYP3A4. Especially, in the two drugs co-administration group, a significant increase in the concentration of tacrolimus was observed as compared with the non-combination group. The present result reconfirms that the concomitant administration of CYP3A inhibitor can have a significant influence on tacrolimus levels in the blood, even under conditions associated with the accumulation of iPTH.

The present study has several limitations. This is a retrospective and observational study in which a limited number of patients who attend a single hospital was enrolled. Therefore, it would be desirable to conduct a prospective and multicenter study using a much larger number of patients to confirm the close relationship between serum iPTH levels and tacrolimus trough levels. In addition, it has been well recognized that genetic polymorphism is a factor that significantly affects the activity of CYP3A. Among the CYPs that metabolize tacrolimus, CYP3A5 has wild type *1 and mutant type *3 alleles, and it is known that the enzyme activity of CYP3A5 is decreased in the *3/*3 alleles.⁵⁾ In this study, a genetic polymorphism of CYP3A5 could not be identified and the involvement of genetic polymorphism is also a subject that should be examined in the future. Moreover, it is possible that PTH may affect the activity of the P-glycoprotein,²⁰⁾ and hence contribute to the fluctuations in the blood levels and doses of tacrolimus because tacrolimus is a typical substrate for the P-glycoprotein. However, our previous study using animal and cell systems showed that PTH did not have a significant influence on P-glycoprotein expression in both the small intestine and liver of animal model. Thus, it seems that P-glycoprotein does not contribute to the fluctuations in tacrolimus trough levels at the time of the initial dose.

In the current used renal replacement therapy, it is becoming more common to choose either dialysis or transplantation earlier compared to before. In fact, there are many patients who have had a kidney transplant without ever experiencing dialysis.¹⁾ It was also reported that a shorter dialysis period leads to a longer engraftment period for a transplanted kidney.^29,30) This suggests that the number of renal transplant patients will likely increase in the future. Regarding the engraftment and survival rate of a transplanted kidney, it is essential to control the blood concentration of tacrolimus by TDM. Based on this study, our data suggested that serum iPTH levels are a factor in determining the dose of tacrolimus to be administered before kidney transplantation.

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (KAKENHI 16H05114).

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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