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- PATIENTS AND METHODS
The kidney chiefly maintains homeostasis of water, electrolytes, and other solutions. When kidney function is reduced, mineral metabolism is disrupted. Mineral and bone disorder in patients with chronic kidney disease associates with increased cardiovascular risk and mortality; however, management of chronic kidney disease–mineral and bone disorder in predialysis patients remains controversial. This study investigates the association between parathyroid enlargement at dialysis initiation and hyperparathyroidism management in dialysis patients. We enrolled 72 patients at dialysis initiation in this study. Using parathyroid sonography, we categorized patients based on presence (detected group; N = 18) or absence (undetected group; N = 54) of enlarged parathyroid glands and assessed the clinical characteristics and laboratory findings. A literature review of ultrasound evaluations of secondary hyperparathyroidism was conducted. Ultrasonography revealed enlarged parathyroid glands in 18 patients (25%). Serum intact parathyroid hormone levels were high in patients with enlarged parathyroid glands; however, of the 29 patients with intact parathyroid hormone levels <240 pg/mL, four had enlarged parathyroid glands. Eight of the 29 patients with serum phosphorus and calcium levels within the optimal range had enlarged parathyroid glands. Twenty of these 29 patients were followed up at 38 ± 17 months (at least 3 months): enlarged parathyroid glands were detected in 6. During follow-up, serum intact parathyroid hormone levels were significantly higher in the detected group compared with the undetected. In conclusion, enlarged parathyroid glands are frequently detected at dialysis initiation, potentially predicting the persistence of secondary hyperparathyroidism and the need for strict management.
One of the main functions of the kidney is to maintain homeostasis of minerals. When kidney function is reduced, mineral metabolism is disrupted. Chronic kidney disease–mineral and bone disorder (CKD–MBD) is a serious complication associated with increased cardiovascular mortality in dialysis patients (1). The Japanese Society for Dialysis Therapy released the Clinical Practice Guideline for the Management of Secondary Hyperparathyroidism in Chronic Dialysis Patients in 2006 (2). This guideline prioritizes control of serum phosphorus and calcium levels over management of parathyroid hormone (PTH) levels on the basis of its impact on mortality. High cardiovascular and noncardiovascular mortality rates are reported at dialysis initiation (3). Furthermore, in predialysis patients, studies report an association between serum phosphorus levels and cardiovascular risk and mortality (4–6). However, management of CKD–MBD in predialysis patients remains controversial because insufficient evidence exists on hyperparathyroidism management in such patients. Although serum phosphorus and calcium levels are relatively stable across a spectrum of glomerular filtration rates (GFR), PTH increases at GFR <60 mL/min per 1.73 m2(7,8). Prevalence of enlarged parathyroid glands is positively related to dialysis duration: two studies report detection of enlarged parathyroid glands in small numbers of patients who underwent dialysis for <3 years. However, few reports evaluated parathyroid glands at dialysis initiation (9,10). This study investigated the association between parathyroid enlargement at dialysis initiation and hyperparathyroidism management in dialysis patients.
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- PATIENTS AND METHODS
Ultrasonography revealed parathyroid gland enlargement in 18 patients (25%): a single parathyroid gland was enlarged in nine patients, two glands in seven, and three glands in two. At dialysis initiation, age, gender, diabetes mellitus, estimated GFR, serum phosphorus and calcium levels, and ALP were comparable between the detected and undetected groups. Serum intact PTH levels were significantly higher in the detected group than in the undetected (Table 1). Of the 29 patients with intact PTH levels <240 pg/mL, four had enlarged parathyroid glands. Corrected PTH levels were higher in the detected group than in the undetected, and seven of the 33 patients with corrected PTH levels <240 pg/mL had enlarged parathyroid glands.
Table 1. Clinical and biochemical characteristics of patients with or without enlarged parathyroid glands at dialysis initiation
| ||All subjects||Detected subjects||Undetected subjects|
|Number of patients (%)||72 (100)||18 (25)||9||9||54 (75)|
|Age (years)||62 ± 13||62 ± 15||57 ± 17||67 ± 11||63 ± 13|
|Diabetes (%)||38 (53)||10 (56)||6 (67)||4 (44)||28 (52)|
|Medication (%)|| || || || || |
| Calcium carbonate||29 (40)||8 (44)||6 (67)||2 (22)||21 (39)|
| Active vitamin D||14 (19)||3 (17)||2 (22)||1 (11)||11 (20)|
|Laboratory|| || || || || |
| Hemoglobin (g/dL)||8.8 ± 1.7||8.6 ± 1.9||7.9 ± 2.0||9.3 ± 1.5||8.8 ± 1.6|
| Albumin (g/dL)||3.3 ± 0.5||3.3 ± 0.6||3.3 ± 0.7||3.3 ± 0.4||3.3 ± 0.5|
| Phosphorus (mg/dL)||5.8 ± 2.0||6.4 ± 2.5||7.2 ± 3.3||5.6 ± 1.1||5.6 ± 1.8|
| Calcium (mg/dL)||8.2 ± 1.1||8.0 ± 1.4||7.9 ± 1.7||8.2 ± 1.1||8.3 ± 1.0|
| iPTH (pg/mL)||406 ± 332||566 ± 367*||664 ± 360*||468 ± 368||353 ± 305|
| ALP (IU/L)||291 ± 160||274 ± 148||290 ± 200||254 ± 60||297 ± 165|
| Ca × P product (mg/dL) (2)||46.0 ± 12.4||48.7 ± 11.7||52.0 ± 12.9||45.3 ± 9.9||45.1 ± 12.6|
| eGFR(mL/min/1.73 m2)||4.35 ± 1.40||3.96 ± 1.30||3.38 ± 1.24||4.53 ± 1.14||4.48 ± 1.41|
Maximum longitudinal diameter and total volume of the enlarged glands was 6.7 ± 2.3 mm and 111 ± 103 mm3, respectively, in patients with a single enlarged parathyroid gland, and 7.0 ± 2.3 mm and 99 ± 71 mm3, respectively, in those with multiple enlarged parathyroid glands. There were no significant differences in serum phosphorus (7.2 ± 3.3 mg/dL vs. 5.6 ± 1.1 mg/dL); serum calcium corrected for albumin (cCa; 7.9 ± 1.7 mg/dL vs. 8.2 ± 1.1 mg/dL); intact PTH (664 ± 330 pg/dL vs. 468 ± 368 pg/dL); corrected PTH (297 ± 234 pg/dL vs. 221 ± 249 pg/dL); or ALP (290 ± 220 IU/L vs. 254 ± 60 IU/L) levels between patients with single or multiple enlarged parathyroid glands.
Eight (28%) of the 29 patients with serum phosphorus and calcium levels within the optimal range (phosphorus: 3.5–6.0 mg/dL; calcium: 8.4–10.0 mg/dL) at dialysis initiation had enlarged parathyroid glands (Fig. 1). Twenty of these 29 patients were followed up at 38 ± 17 months (at least 3 months) after dialysis initiation: enlarged parathyroid glands were detected in six (30%) of these 20 patients. Although serum phosphorus and cCa levels and medication use (phosphate binder and active vitamin D) were comparable during follow-up, serum intact and corrected PTH levels during follow-up were significantly higher in the detected group than in the undetected. Corrected PTH levels decreased from 517 ± 340 to 388 ± 268 pg/dL in patients with enlarged parathyroid glands and decreased from 299 ± 170 to 195 ± 93 pg/dL in those without (Fig. 2). Percutaneous ethanol injection therapy was performed in two patients with enlarged parathyroid glands at dialysis initiation, while cinacalcet treatment was performed in one patient with enlarged parathyroid gland and two without. The serum PTH levels of these treated patients decreased, but only one patient achieved the optimal PTH level, who had been treated by cinacalcet without enlarged parathyroid glands.
Figure 1. Comparison of serum phosphorus and corrected calcium levels in patients with or without enlarged parathyroid glands. In patients with serum phosphorus and calcium levels within the optimal range (serum phosphorus: 3.5–6.0 mg/dL; serum calcium: 8.4–10.0 mg/dL), eight patients had enlarged parathyroid glands (square), while 21 did not (circle).
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Figure 2. Corrected parathyroid hormone levels at dialysis initiation (baseline) and follow-up in patients with (square) and without (circle) enlarged parathyroid glands. Serum corrected parathyroid hormone levels decreased in patients with and without enlarged parathyroid glands by 34 ± 24% and 28 ± 40%, respectively. At final follow-up (after mean 38 months), corrected parathyroid hormone levels >240 pg/mL were evident in 50% (N = 6) of patients with enlarged parathyroid glands and in 21% (N = 14) of those without enlarged parathyroid glands.
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- PATIENTS AND METHODS
Ultrasonography of the parathyroid glands is a useful noninvasive method for evaluating SHPT. Many studies report that ultrasonography is very sensitive for detecting parathyroid glands and is associated with the findings of surgically resected specimens (2,9,10,13). Moreover, the parathyroid gland size is reportedly a useful factor in predicting the gland's response to active vitamin D therapy. However, only few studies have evaluated sonography of parathyroid enlargement at dialysis initiation.
Ultrasonography showed enlarged parathyroid glands in 18 (25%) of the 72 patients at dialysis initiation. We found only three reports describing the frequency of enlarged parathyroid glands in patients with CKD before and at initiation of dialysis (Table 2) (14–16). These studies involved relatively small patient numbers and did not consider serum phosphorus and calcium levels, which influence serum intact PTH levels. In our study, enlarged parathyroid glands were surprisingly detected in patients with serum phosphorus and calcium levels within the optimal range and with corrected PTH levels <240 pg/mL. Measurement of corrected PTH is recommended in HD patients because PTH secretion increases rapidly in response to decreasing serum calcium levels (11). Elevated PTH with hypocalcemia reflects the appropriate physiological response to decreased serum calcium: measurement of PTH in patients with abnormal serum calcium levels may not predict hyperparathyroidism severity. On the other hand, elevated PTH with hypercalcemia indicates the presence of adenoma or primary hyperparathyroidism, but there were no such cases in our study.
Table 2. Summary of studies assessing parathyroid glands in ultrasonography before and at dialysis initiation
|Study, year||Reported frequency||Intact PTH (pg/mL; mean ± SD)||Population|
|All subjects||Detected subjects||Undetected subjects|
|Ours, 2012||18/72 (25%)||406||566 ± 367||353 ± 305||At dialysis initiation|
|Etoh, 2004 (14)||6/47 (12%)||293†||502 ± 98||263 ± 27||Nondiabetic, at dialysis initiation|
|Yamanaka, 2004 (15)||5/31 (16%)||277||272 ± 200||278 ± 221||At dialysis initiation|
|Hamada, 2003 (16)||5/12 (42%)||484†||930 ± 781||166 ± 112||Before and at dialysis initiation|
Serum PTH levels were significantly correlated to the serum levels of calcium (R = −0.49, P = 0.01) and phosphate (R = 0.41, P = 0.01) in our study. Lower calcium levels and higher phosphate levels tend to be seen in patients with enlarged parathyroid glands (Table 1). Low calcium levels and chronic retention of phosphate due to reduced kidney functions stimulate secretion of PTH and induce parathyroid enlargement (17,18). Therefore, low serum calcium levels and high phosphate levels are predicted in patients with enlarged parathyroid glands. However, high PTH levels do not always mean low calcium or high phosphate levels in predialysis CKD patients, because PTH levels increase before decrease in calcium levels and increase in phosphate levels (7,8,19). Fibroblastic growth factor 23 (FGF-23) and PTH induce phosphate excretion in urine and compensate for phosphate retention. Similarly, high PTH levels induce bone absorption and compensate for the impaired vitamin D activation and calcium malabsorption from the intestines. Although serum ALP levels in patients with diabetes were lower than in those without diabetes, we did not exclude the diabetic patients because the prevalence of diabetes has no difference in detected subjects and undetected subjects (Table 1), and the number of patients in our study was not so large to exclude them. Although the PTH levels were significantly correlated to the ALP levels (R = 0.43, P = 0.01), the ALP levels did not show any difference between the detected and undetected groups. This is probably because of the small number of patients and different degrees of skeletal responses to PTH (20).
Follow-up of patients with serum phosphorus and calcium levels within the optimal range revealed that parathyroid gland enlargement at dialysis initiation predicts elevation of PTH levels. Dialysis duration and PTH levels at dialysis initiation are reportedly independent risk factors for SHPT (21); to these, parathyroid enlargement at dialysis initiation needs to be added. As elevated PTH levels influence not only mineral and bone disorders but also anemia, immunity, and the cardiovascular system (22,23), control of serum PTH levels in dialysis patients is essential. Early administration of a phosphate binder, with or without vitamin D, was reported to effectively suppress serum PTH levels in patients starting HD, but parathyroid glands >10 mm in diameter are considered to be resistant to active vitamin D therapy in HD patients (24,25). Both calcium-sensing receptors and vitamin D receptors could be downregulated in such parathyroid glands. Once enlarged parathyroid glands are detected, early treatment for hyperparathyroidism is necessary to avoid resistance and treatment failure.
Taniguchi et al. reported that both oral and intravenous calcitriol could reduce the serum PTH levels in HD patients, but only intravenous calcitriol successfully suppressed the increase of parathyroid gland volume (26). Unfortunately, in our study, 10 of the 20 patients received active vitamin D therapy and only one of them received intravenous vitamin D. The size of enlarged parathyroid glands was increasing in three cases and decreasing in three cases. Two of the former three cases and one of the latter three cases received vitamin D therapy. To suppress the development of SHPT, early prediction of parathyroid gland enlargement and early start of intravenous vitamin D therapy may be needed. We would like to examine the change in the size of enlarged parathyroid glands after dialysis initiation in a future, larger study.
Limitations of our study included accurate diagnosis of enlarged parathyroid glands. Because even enlarged parathyroid glands are relatively small, training and proficiency in ultrasonography are important for accurate diagnosis. However, ultrasonography is noninvasive, low-cost, and sensitive compared with other imaging modalities such as computed tomography, MRI, and 99mTc-labeled hexakis-2-methoxyisobutylisonitrile scanning (27,28).