Cautious clinical interpretation of preoperative Tc-^99m-Sestamibi localization scan among chronic kidney disease and transplanted patients

Highlights

• •Chronic kidney disease patients demonstrate a high rate of multiglandular disease.
• •Preoperative MIBI scans frequently yield false-positive results in renal patients.
• •MIBI localization scans demonstrate limited accuracy in CKD and transplant cohorts.
• •Surgical choices should favor bilateral exploration over imaging reliance.

Abstract

Introduction

Chronic kidney disease (CKD) patients and kidney transplant recipients are predisposed to developing hyperparathyroidism. Although CKD is typically associated with parathyroid hyperplasia, preoperative assessment may include a ^99mTc‑MIBI localization scan, performed selectively rather than routinely, which may demonstrate findings suggestive of a parathyroid adenoma. Diagnosing an adenoma potentially eliminates the need for four-gland exploration. However, the clinical meaning of pre-operative scans among renal patients remains unclear.

The study objectives are: Determine adenoma and hyperplasia prevalence in the study population and the pre-operative MIBI scan localization outcomes. Identify potential predictors for either adenoma or hyperplasia.

Materials and methods

Retrospective cohort study, with at least 6 months post-operative follow-up, based on laboratory, imaging, medical, and operative notes in referral medical center between 2012 and 2022.

Results

Among 871 parathyroidectomies, 59 patients had a relevant renal background and long-term follow-up. Of these, 31 (53%) had hyperplasia. Preoperative ^99m Tc-MIBI scan demonstrated positive localization for adenoma in 73% of patients. However, 22% were later diagnosed with hyperplasia (false positive), resulting in an effective localization rate of only 56.9%. The scan had 78.6% accuracy and positive and negative predictive values of 76.7% and 83.3%, respectively.

Hyperplasia was significantly associated with younger age (p = 0.009) and dialysis dependence (p = 0.007). Hyperplasia was correlated with relative subtle hypercalcemia (p = 0.015), significant higher phosphorus (p = 0.001), higher alkaline phosphatase (p < 0.001), and higher PTH levels (p = 0.004).

Discussion

Over half of CKD patients had hyperplasia. The majority of patients underwent a localization parathyroid MIBI scan. About 3/4 of scanned patients had positive adenoma localization, but only 3/4 were eventually operated on and cured as adenoma.

Conclusions

We demonstrate a limited benefit of MIBI scans in CKD and kidney transplant patients. We recommend either omitting the scan or performing bilateral neck exploration or at least two same-side parathyroid glands exploration to improve cure rates.

1. Introduction

Hyperparathyroidism (HPT) is a common endocrine disorder manifested by a parathyroid hormone (PTH) increase and an excess of serum calcium [1]. We divide the disorder into three categories according to the etiology; Primary hyperparathyroidism (PHPT) is caused by overproduction of PTH in the glands itself [1]. Secondary hyperparathyroidism (SHPT) is a condition in which a decrease in active vitamin D levels, hypocalcemia, and hyperphosphatemia trigger a feedback pathway that causes PTH overproduction in order to maintain normal serum calcium levels [2,3]. This condition is common among chronic kidney disease (CKD) and dialysis patients and is part of renal failure complications which may accelerates end-stage kidney disease and dialysis [4]. In most secondary HPT cases excretion increment is due to four glands hyperplasia [5,6]. Tertiary hyperparathyroidism (THPT) is a continuation of SHPT in which increased excretion of PTH can be seen even after the cause of SHPT has been treated. Various studies have shown that THPT can occur in 20–80% of kidney transplant patients within 12 months after transplantation [7,8]. In SHPT and THPT, we first attempt to conservatively balance calcium, phosphate, and vitamin D levels through medications (e.g. Calcimimetics family) and lifestyle changes [9,10]. In general, we wait until reaching a refractory stage before a surgical intervention [6,11].

Since primary hyperparathyroidism (PHPT) is by far the most common cause of hypercalcemia, the preoperative evaluation of both secondary and tertiary hyperparathyroidism is often influenced by the standard diagnostic approach used for PHPT. This includes preoperative imaging localization by ^99mTc-MIBI scan in addition to sonographic neck examination [5,6]. Notably, most patients are referred to specialized tertiary surgery clinics after the initial diagnostic workup has already been completed. Identifying an adenoma allows, potentially, to forego surgical bilateral four glands exploration. Some patients with secondary HPT and tertiary HPT may indeed have a single adenoma. However, the reliability of the pre-operative localization using Tc-^99m-Sestamibi scan among CKD and transplant patients is not clear [[12, [13], [14]].

Our primary research objectives: Determine adenoma and hyperplasia prevalence in the study population and the pre-operative ^99mTc-MIBI scan outcomes; true and false localization. Thereafter, identify potential predictors for either adenoma or hyperplasia among CKD and transplant patients.

2. Methods

2.1. Study design

This is a retrospective cohort study conducted at a tertiary referral medical center. Data was retrieved from medical records and included long-term follow-ups, imaging reports, blood test results, surgery, and pathology notes. The study was approved by the local institutional ethics committee (application number 0728–22-HMO) in accordance with the Declaration of Helsinki. Because this study involved retrospective, de-identified data, it was exempted from patients’ signed informed consent.

2.2. Study population

patients with a relevant renal background who underwent parathyroidectomy for hyperparathyroidism, between January 2012 and December 2022, at Hadassah Medical Center. The patients included in the study group had CKD grade 3 or higher, on dialysis, kidney transplant recipients [15]. Dialysis patients were defined as ESRD without calculating eGFR (irrelevant).

2.3. ^99mTc-MIBI protocol

SPECT/CT acquisition 15 minutes (early) and two hours (late) post ^99mTc MIBI administration

2.4. Surgical technique

In cases in which preoperative imaging localized a presumed parathyroid adenoma, patients underwent focused parathyroidectomy rather than routine bilateral neck exploration, irrespective of CKD or transplantation status. Intraoperative PTH monitoring was used to guide the procedure, with a reduction of at least 50% considered indicative of adequate gland excision. This approach represents the primary focus of the current investigation.

2.5. Definition of surgical success and failure

We avoided defining parathyroid adenoma resection success only by PTH drop during or immediately after the surgery. Moreover, we did not define surgical success based on a presumed surgical identification of a single enlarged gland. Instead, we defined surgical cure as a mandatory long-term PTH decrease and normal-range calcium of at least six months after the surgery. Conversely, surgical failure was defined by the recurrence of hypercalcemia and/or symptoms, a need for Calcimimetics or reoperation, together with elevated PTH values.

2.6. Normal laboratory values

Calcium (Ca) 8.3–10.6 mg/dL, Parathyroid hormone (PTH) 1.95–8.5 pmol/L, Phosphor (P) 2.4–5.1 mg/dL, Alkaline phosphatase (Alk-P) 46–116 U/L. We describe PTH levels both by implicating the absolute values, pmol/L, and by defining the deviation relatively to the upper normal range.

2.7. Statistics

Statistical analysis was performed by a certified statistician using SPSS software. The examination of the relationship between two categorical variables was done using the Chi-square test or Fisher's exact test. A comparison of quantitative variables between two groups was done using the non-parametric Mann-Whitney test. The non-parametric test was used due to the small sample size and the non-normal distribution of the variables. In order to simultaneously examine the effect of several independent variables on a dichotomous dependent variable, a multivariate model of logistic regression using the Forward stepwise likelihood ratio method was used. All statistical tests were two-tailed and a p-value of 0.05 or less was considered statistically significant.

3. Results

3.1. Study population (Fig. 1)

Fig. 1.

Parathyroid adenoma versus hyperplasia along the therapeutic timeline.

871 patients underwent parathyroidectomy; 61 (7%) had relevant renal background (average eGFR of 42.1) of whom 33 patients (54.1%) were women. Overall, 25 patients (41.0%) performed hemodialysis during their lifetime (average dialysis duration until surgery was 59.1 months), and 20 patients (32.8%) were on active dialysis at the time of surgery. The average age at surgery was 61.2 years (standard deviation 16.9 years). Thirteen patients (21.3%) had kidney transplantation performed on average 81.5 months prior to parathyroid surgery.

3.2. Preoperative laboratory

The average calcium, phosphorus, ALK-P and PTH levels were 10.47±1.43 mg/dL, 3.83±1.92mg/dL, 214.83±356.23 U/L and 76.41±82.8 pmol/L, respectively. Average PTH levels were 8.99 times above the normal upper limit.

3.3. Surgical treatment and outcome

Overall, 59 patients had a long-term follow-up (average, 50.5 months) of whom 31 (53%) had hyperplasia and 28 (47%) had adenoma (Fig. 2). The average post-surgical PTH level was 15.21 pmol/L, representing an average of 74.27% drop. The average calcium level on the first day following surgery was 9.02 mg/dL, and remained relatively stable, 8.92 mg/dL, on long-term follow-up (Table 1). The average admission time was 5.5 days. Fifteen patients (24.6%, valid 25.0%) suffered from hungry bone syndrome (HBS). Overall, one patient (1.6%) required blood products and two (3.3%) experienced temporary recurrent laryngeal nerve palsy.

Fig. 2.

Parathyroid adenoma and hyperplasia prevalence among patients with hyperparathyroidism and relevant renal background.

Table 1.

The surgical and postoperative course of the study participants.

	Valid (n = 61)	Mean (SD)
Baseline pre-operative PTH, pmol/L	61	76.41 (82.84)
Intraoperative PTH, pmol/L	61	15.21 (18.75)
Intraoperative PTH decline, %	61	74.27 (21.92)
3-month post-op PTH, times over UNL	31	2.01 (2.57)
≥6 months PTH post-op, times over UNL	54	3.13 (4.63)
Pre-op calcium, mg/dL*	61	10.47 (1.43)
POD-1 Ca, mg/dL	54	9.02 (1.32)
Most recent Ca, mg/dL	42	8.92 (0.97)
Duration of hospitalization, days	60	5.53 (6.51)
Daily calcium additives dosage at discharge, mg	60	3871.02 (4447.01)
Daily Alfacalcidol dosage at discharge, mcg	60	1.37 (2.19)
Daily vitamin D dosage at discharge, IU	5	2800.00 (4079.22)

Normal lab values: Calcium (Ca) 8.3–10.6 mg/dL, Parathyroid hormone (PTH) 1.95–8.5 pmol/L, Phosphor (P) 2.4–5.1 mg/dL, Alkaline phosphatase (Alk-P) 46–116 U/L.

PTH = Parathyroid hormone, OR = operating room, Post-op = Postoperative, UNL = Upper Normal Limit, POD-1 = Post-Operative Day – 1, IU = International Units.

3.4. Pre-operative 99mTc-MIBI scan accuracy (Fig. 3)

Fig. 3.

Parathyroid localization test accuracy.

A total of 44 patients (72%) with CKD or kidney transplantation performed (in addition to sonographic neck investigations) a parathyroid glands localization scintigraphy scan. Of whom 32 patients (73%) had a positive scan, hence they were considered to have a pre-surgical diagnosis of parathyroid adenoma. We scrutinized the scan results and compared them with the surgical findings and with long-term follow-up outcomes. Among the 32 patients with a positive localization test for adenoma, only 28 (87%) were operated as adenoma (the remaining 4 patients, 13%, had 4 glands hyperplasia during surgery), of whom only 23 patients (82%) were cured on long follow-up. When both the presumed localization rate and the long-term outcomes of patients undergoing focused parathyroidectomy were considered, the overall clinical utility of preoperative MIBI imaging was in only 56.9% of patients in the study cohort. Overall, of the 28 patients with confirmation of successful adenoma removal in a long-term follow-up, 23 had an accurate preoperative scan (True Positive), three did not perform a scan but were operated on and treated successfully as adenoma, and two patients had a false-negative scan (initially considered as hyperplasia and discovered to be adenoma during surgery) (Fig. 2). Accordingly, for patients who underwent pre-operative scan and were under long-term follow-up, we demonstrated a 78.57% accuracy level, 76.66% positive predictive value (PPV), and an 83.33% negative predictive value (NPV) (Fig. 3).

3.5. Pre-operative scan localization, subgroups analysis (Table 2)

Table 2.

Pre-operative scan localization subgroups analysis in accordance with dialysis and transplant status.

	Overall Pre-operative localization, n = 42	Dialysis ever, n = 11	No dialysis, n = 31	Kidney transplantation, n = 9	Non-transplant patients, n = 33
Sensitivity (True Positive rate)	92%	75%	95.2%	66.7%	95.4%
Specificity (True Negative rate)	58.8%	85.7%	40%	66.7%	54.5%
Positive predictive value	76.7%	75%	76.9%	50%	80.8%
Negative predictive value	83.3%	85.7%	80%	80%	85.7%
Accuracy	78.6%	81.8%	77.4%	66.7%	81.8%

Among patients who were never on dialysis, the test demonstrated 95.2% sensitivity but low specificity (40%). The PPV in this group was 76.9%, and the NPV was 80.0%. In comparison, patients with a history of dialysis showed lower sensitivity (75%) but higher specificity (85.7%), with a similar PPV and NPV, 75% and 85.7%, respectively. Kidney transplant recipients, tertiary HPT, (n = 9) demonstrated poorer scan performance with 66.7% sensitivity and 50% positive predictive value. Non-transplant patients (n = 33), showed higher sensitivity (95.5%) and PPV (80.8%). Notably, transplant recipients had a lower prevalence of adenoma (33.3%) compared to non-transplant patients (66.7%).

3.6. Pre-operative sonographic localization analysis

Among the 57 patients with available sonographic data, the sensitivity of pre-operative adenoma identification was 67.9% (95% CI: 47.7%–84.1%) and the specificity was 75.9% (95% CI: 56.5%–89.7%).

3.7. Pre-operative predictors for adenoma versus hyperplasia (Table 3)

Table 3.

Epidemiological predictors for the presence of adenoma versus hyperplasia among the study population.

	Overall long-term follow-up, n = 59 (%)		Adenoma n = 28 (%)	Hyperplasia n = 31 (%)	Significance.
Male	28 (47.5%)		13 (46.4%)	15 (48.4%)	0.880
Female	31 (52.5%)		15 (53.6%)	16 (51.6%)
Age at surgery, years (SD)	61.2 (16.9)		69.6 (11.0)	53.6 (18.3)	<0.001
Dialysis ever N (%)	Yes	25 (42.4%)	5 (17.8%)	20 (64.5%)	<0.001
	No	34 (57.6%)	23 (82.2%)	11 (35.5%)
Kidney transplant N (%)	Yes	13 (22%)	4 (14.3%)	9 (29%)	0.172
	No	46 (78%)	24 (85.7%)	22 (71%)
	Overall		Adenoma	Hyperplasia	Significance
	N=25, Mean (SD)		N= 5, Mean (SD)	N=20, Mean (SD)
Dialysis duration, months	59.08 (36.5)		29.80 (34.5)	66.4 (33.9)	0.035

SD; standard deviation.

Multivariate analysis demonstrated significantly more hyperplasia among younger patients (p = 0.009, adjusted OR=0.941, mean age 53.61 vs. 69.64 years) and among patients on dialysis (p = 0.007, Adjusted OR=6.046). 20 patients out of 25 patients on dialysis had hyperplasia. Longer time on dialysis was significantly associated with hyperplasia (p = 0.035, mean of 66.4 months in the hyperplasia group vs. 29.8 months in the adenoma group). The mean pre-operative PTH, phosphorus and alkaline phosphatase levels were significantly higher in hyperplasia (111.10 pmol/L vs. 42.00 pmol/L, p = 0.001, 4.85 mg/dL vs. 2.88 mg/dL, p < 0.001 and 322.04 U/L vs. 99.65 U/L, p = 0.004), respectively. On the other hand, average calcium levels were relatively lower in hyperplasia (10.07 mg/dL vs. 10.88 mg/d, p = 0.015).

3.8. Pre-operative predictors for hungry bone syndrome

Of the 60 patients with blood test results, 15 (25%) developed Hungry Bone Syndrome (HBS). All patients with HBS underwent bilateral neck exploration. 13 of the HBS patients had hyperplasia (out of 30 patients with hyperplasia, 43.3%), compared with only two patients with adenoma (out of 28 patients with adenoma, 7.1%). There is a clear association, even when considering the rate of bilateral exploration, between the development of HBS and hyperplasia (p = 0.002). It is important to emphasize that not all patients with hyperplasia (56.7%) develop HBS. Moreover, multivariate analysis demonstrates that the higher pre-operative PTH levels are (p = 0.002, adjusted OR=1.015) and the steeper the PTH drop is (86.27%vs. 71.37%, p = 0.001) the higher the risk for HBS.

4. Discussion

Patients with chronic kidney disease and patients following kidney transplant may develop secondary (SHPT) and tertiary (THPT) hyperparathyroidism as a complication of their underlying renal disease. We expect hyperplasia [5,6] in most SHPT and THPT, however, the pre-operative investigation is often influenced by the routine examinations performed for PHPT, which is a much more common condition. Therefore, some patients are having a localization attempt with a ^99mTc-MIBI scan. The clinical accuracy of the scan among this subgroup of patients is unclear. The current literature investigating scans among CKD patients emphases the identification of ectopic glands but does not address the differentiation between the presence of adenoma and hyperplasia for surgical planning [[12, [13], [14],16,17].

In our study, prolonged follow-up demonstrated that more than half of the CKD patients had hyperplasia. The majority of patients in our study (72%) underwent a localization parathyroid ^99mTc-MIBI scan, reflecting the routine investigation of PHPT, a condition that affects most (93%) hyper parathyroidism patients. About 3/4 of patients undergoing ^99mTc-MIBI scan had a positive adenoma localization, but only about 3/4 of them were eventually operated on and cured as adenoma. Overall, preoperative MIBI imaging benefited only 56.9% of patients in the study cohort, highlighting the limited value of this localization modality in this population. The rest were ultimately diagnosed as hyperplasia due to findings during surgery or long-term healing failure (false positives). Based on the data collected in the study, the MIBI scan demonstrated an accuracy level of 78.57%, a positive predictive value of only 76.66%, and a negative predictive value of 83.33%. As a routine, all our patients perform sonographic investigation prior to parathyroidectomy. Compared with MIBI scan, ultrasound demonstrated lower sensitivity and higher specificity for the detection of parathyroid adenoma. To note, sonographic examination also defines thyroid gland; either suspicious nodules (dictates needle aspiration) or non-suspicious nodules that may mimic parathyroid enlargement. We support our routine sonographic examination, considering the ease, cost and availability together with information regarding both parathyroid and thyroid glands.

The data emerging from our study shows that ^99mTc-MIBI scan has a limited value among CKD patients. Therefore, our recommendations are divided into two steps: a. It is advisable not to perform a ^99mTc-MIBI scan among CKD patients. b. In cases where a scan was already performed with a so-called positive adenoma localization, a high suspicious index for hyperplasia is required with a recommendation for either a bilateral neck exploration or at least a visual exploration of both ipsilateral parathyroid glands to exclude multi-gland disease. Furthermore, our recommendations are strengthened in young patients, patients on dialysis (specifically prolonged dialysis treatment), and pre-operative relatively subtle hypercalcemia, significant high phosphorus, high alkaline phosphate, and high PTH levels. Additionally, we demonstrate no difference in the rate of complications when bilateral exploration is performed. The high percentage of patients (77%) that underwent bilateral neck surgery, including most patients with presumed adenoma (60.7%) highlights the importance of clinical judgment even before data extraction.

Furthermore, we investigate whether the preoperative scan metrics are differently affected among secondary HPT (either on dialysis or never on dialysis treatment) and tertiary HPT patients. Among those second HPT patients never on dialysis, the test showed a high misclassification rate, with a PPV of 76.9% and an NPV of 80.0%, suggesting that nearly one in four patients was planned for a minimally invasive surgery based on incorrect localization. In contrast, dialysis patients had higher specificity and lower sensitivity (75.0%), with similar, relative insufficient, NPV (85.7%). Kidney transplant recipients showed even poorer test performance, only 50% of patients with a positive localization indeed had adenoma. Likely explanation is the lower prevalence of adenoma in this group, thus, transplant recipients are particularly vulnerable to false confidence in localization.

The average PTH levels dropped by 75% following surgery. In some patients, reduced PTH levels were still higher than the norm but were accompanied by normo-calcemia (average 8.92 mg/dL in long-term follow-up), disappearance of symptoms, and elimination of Calcimimetics treatment requirement. Note, that this could be explained by PTH half-life and hormone breakdown product clearance change in advanced CKD and dialysis [[18], [19], [20]]. Additionally, ongoing nephron injury and impaired PTH homeostasis, are prophesied in cases where kidney disease continues [21].

A quarter of our patients developed Hungry Bone Syndrome (HBS). This is a potentially life-threatening condition in which the bones absorb calcium in an increased manner after prolonged demineralization. We demonstrated a significant association between HBS, hyperplasia, and high pre-operative PTH levels consistent with previous research groups [[22], [23], [24]].

The main study limitations are the small study group and the study’s retrospective nature, which are expected when investigating a specific and unique subgroup of patients. The meticulous data extraction with an emphasis on the long follow-up duration (average follow-up time 51 months) has overcome this restraint.

Future research is needed, including exploring other pre-operative localization techniques, which are less frequently performed but demonstrated (not in CKD patients) promising results. For example, the 4DCT (need for high radiocontrast agent dose) [12] and the F18-Choline PET/CT test (using an expensive radioactive agent) which are better investigated in PHPT [25].

5. Conclusions

We reinforce that localization studies should be interpreted cautiously in this specific group of patients. We recommend either not performing a scan or executing bilateral neck exploration or at least two, same-side, parathyroid glands in order to achieve better cure outcomes with similar low complications rate.

Ethical consideration

The study was conducted following the approval by the institutional review board (application number 0728–22-HMO). The study was conducted according to the 2008 World Medical Association Declaration of Helsinki.

Consent to participate

A waver for informed consent was given.

Ethics approval and consent to participate

The study was conducted following the approval by the institutional review board. The study was conducted according to the 2008 World Medical Association Declaration of Helsinki. A waver for informed consent was given.

Consent for publication

Not applicable. The information / data is not identifiable.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Declaration of generative AI use

None.

Permission to reproduce material from other sources

The study (or part of it) was not presented or published in any form and is not under consideration for publication elsewhere.

All authors have seen and approved the final version of the manuscript. All authors fulfill the Committee on Publication Ethics requirements for authorship.

CRediT authorship contribution statement

Orel Elhadad: Writing – review & editing, Methodology, Data curation, Conceptualization. Ran Fisher: Writing – review & editing, Validation, Supervision, Project administration, Formal analysis, Conceptualization. Keren Tzukert: Writing – original draft, Supervision, Project administration, Conceptualization. Jeffrey Weinberger: Writing – original draft, Visualization, Project administration, Conceptualization. Haggi Mazeh: Writing – original draft, Validation, Supervision, Conceptualization. Nir Hirshoren: Writing – review & editing, Supervision, Methodology, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

All authors declare that they have no competing interests.