- Email: [email protected]
Influence of dialysis modalities on patients undergoing parathyroidectomy for renal hyperparathyroidism
Formosan Journal of Surgery (2015) 48, 151e156
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.e-fjs.com
ORIGINAL ARTICLE
Influence of dialysis modalities on patients undergoing parathyroidectomy for renal hyperparathyroidism Kung-Chen Ho a,b, Jie-Jen Lee a,b,c, Tsang-Pai Liu a,b,c, Po-Sheng Yang a,b, Shih-Ping Cheng a,b,* a
Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan Mackay Medical College, Taipei, Taiwan c Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan b
Received 10 May 2015; received in revised form 24 June 2015; accepted 22 July 2015
Available online 28 September 2015
KEYWORDS dialysis; hyperparathyroidism; parathyroidectomy
Summary Background/Introduction: Dialysis modalities may influence parathyroid hormone (PTH) levels and renal osteodystrophy patterns. To date, no study has compared the effects of dialysis modality on surgical patients with renal hyperparathyroidism. Purpose/Aim: This study evaluated the influence of different dialysis modalities on perioperative features among patients undergoing parathyroidectomy. Methods: Overall, 386 patients who underwent initial parathyroidectomy for renal hyperparathyroidism were recruited. Biochemical data and relevant symptoms were compared between hemodialysis and peritoneal dialysis patients. Results: Compared with the hemodialysis patients, the 40 (10%) peritoneal dialysis patients were younger (p Z 0.002) and had a shorter duration of dialysis (p < 0.001). The peritoneal dialysis patients had lower hemoglobin (p Z 0.006), albumin (p Z 0.040), and intact PTH levels (p Z 0.039) prior to surgery but had higher serum aluminum levels (p Z 0.039). During followup, the peritoneal dialysis patients tended to have higher calciumephosphorus product levels and more severe residual symptoms of bone pain (p Z 0.080), mood swings (p Z 0.053), and pruritus (p Z 0.094). Conclusion: Patients on different dialysis modalities had similar decreases in intact PTH and alkaline phosphatase levels after surgery. However, the peritoneal dialysis patients had higher postoperative calciumephosphorus product levels and more severe residual symptoms. Copyright ª 2015, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.
Conflicts of interest: The authors have no conflicts of interest to declare. * Corresponding author. Department of Surgery, MacKay Memorial Hospital, 92, Chung-Shan North Road, Section 2, Taipei 10449, Taiwan. E-mail address: [email protected] (S.-P. Cheng). http://dx.doi.org/10.1016/j.fjs.2015.07.002 1682-606X/Copyright ª 2015, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.
152
1. Introduction Mineral dysfunction and hyperparathyroidism are common complications of end-stage renal disease (ESRD). The prevalence of renal hyperparathyroidism among dialysis populations ranges from 12% to 54%.1 Elevated levels of parathyroid hormone (PTH) are associated with several inflammatory markers.2 For patients with severe uncontrollable hyperparathyroidism, parathyroidectomy may improve overall survival,3 bone mineral density (BMD),4 and quality of life as well as alleviate symptoms5 and fracture nonunion.6 In the United States, the rate of parathyroidectomy declined between 1988 and 1998 but increased thereafter, despite advances in medical treatment.7 For patients requiring renal replacement therapy, no clear survival benefit exists for hemodialysis or peritoneal dialysis.8 Nonetheless, dialysis modalities significantly influence hemoglobin, ferritin, albumin, cholesterol, and PTH levels.9 Some studies have shown that the prevalence of adynamic bone disease is consistently higher in peritoneal dialysis patients than in hemodialysis patients.10 To our knowledge, no study has compared the effects of dialysis modality on surgical patients with renal hyperparathyroidism. This study evaluated the influence of different dialysis modalities on perioperative features among patients undergoing parathyroidectomy for renal hyperparathyroidism.
K.-C. Ho et al. the decision was at the discretion of the operating surgeon. After parathyroidectomy, persistent disease was defined as any measurement of an intact PTH level >300 pg/mL in the postoperative 6 months. Recurrence was defined as any measurement of an intact PTH level >300 pg/mL beyond 6 months after surgery.11 After August 2008, the Parathyroidectomy Assessment of Symptoms (PAS) questionnaire was used to assess relevant symptoms preoperatively and 6e12 months after the surgery. The PAS scoring system addresses 13 parameters: pain in the bones, feeling tired easily, mood swings, feeling “blue” or depressed, pain in the abdomen, feeling weak, feeling irritable, pain in the joints, being forgetful, difficulty getting out of a chair or car, headaches, itchy skin, and being thirsty.15 Each item was scored on a 100-point visual analog scale, and the PAS score was calculated as the sum of all 13 answers (range, 0e1300). The reliability and validity of the Taiwan Chinese-translated version were established in our previous study.5 Data were analyzed using STATA 12.0 (Stata Corp., College Station, TX, USA) and are reported as the mean standard deviation. Natural log or square root transformations were performed when necessary to normalize skewed distributions. Categorical data were compared using Fisher’s exact test or the Chi-square test, as appropriate. A paired or unpaired Student t test was used to evaluate differences between groups. All statistical tests were two-sided, and statistical significance was determined as p < 0.05.
2. Methods 3. Results From January 2004 to December 2014, 389 consecutive ESRD patients underwent initial parathyroidectomy for renal hyperparathyroidism at a tertiary care center. Three patients younger than 20 years were excluded. Overall, 386 patients who had biochemically confirmed renal hyperparathyroidism comprised the study population. The indication for parathyroidectomy was severe hyperparathyroidism associated with hypercalcemia and/or hyperphosphatemia that was refractory to medical therapy.11 Serum calcium, phosphate, total alkaline phosphatase, albumin, and intact PTH levels (1e84) were regularly monitored preoperatively and during follow-up.12 Most referring dialysis centers examined electrolytes on a monthly basis and alkaline phosphatase and PTH levels at 3month intervals. When the serum albumin level was <4.0 g/ dL, serum calcium levels were corrected using the following formula: corrected calcium (mg/dL) Z measured total calcium (mg/dL) þ 0.8 [4.0 serum albumin (g/dL)]. (1) BMD at the lumbar spine and hip was measured using dual-energy X-ray absorptiometry. After August 2008, the serum aluminum level was determined preoperatively and/ or within 1 week after surgery.13 All operations were performed or supervised by boardcertified endocrine surgeons. Bilateral cervical exploration was followed by subtotal parathyroidectomy or total parathyroidectomy with or without autotransplantation14;
Of the 386 patients, 346 (90%) were on regular hemodialysis and 40 (10%) were on regular peritoneal dialysis. The peritoneal dialysis patients were significantly younger and had a shorter duration of dialysis compared with the hemodialysis patients (Table 1). The mean duration of dialysis prior to surgery was 9.9 4.9 years and 6.3 3.9 years for the hemodialysis patients and peritoneal dialysis patients, respectively. The peritoneal dialysis patients had lower hemoglobin, albumin, and intact PTH levels compared with the hemodialysis patients. Prior to parathyroidectomy, no differences existed in serum calcium, phosphorus, and alkaline phosphatase levels between the groups. Serum aluminum levels were significantly higher among the peritoneal dialysis patients than among the hemodialysis patients (17.0 11.1 mg/L vs. 13.1 6.7 mg/L, p Z 0.039). The majority of patients underwent total parathyroidectomy and autotransplantation (Table 2). Overall, 89 (26%) hemodialysis patients underwent concurrent thyroidectomy for benign goiter (n Z 73), thyroiditis (n Z 3), or papillary thyroid cancer (n Z 13). Six peritoneal dialysis patients underwent concurrent thyroidectomy for benign goiter. The average postoperative hospital stay was 5.0 3.6 days (range, 2e42 days). Both groups showed similar postoperative recovery. Persistent disease was observed in 46 (12%) patients. The dialysis modality did not influence the prevalence of persistent disease. In both groups, serum calcium, phosphorus, alkaline phosphatase, and intact PTH levels decreased significantly
Dialysis modalities and parathyroidectomy Table 1
153
Characteristics of 386 patients with renal hyperparathyroidism.
Age (y) Female (n) Duration of dialysis (y) Body weight (kg) Body mass index (kg/m2) Preop bone mineral density (T score) Preop bone mineral density (Z score) Preop hemoglobin (g/dL) Preop albumin (g/dL) Preop corrected calcium (mg/dL) Preop phosphorus (mg/dL) Calciumephosphorus product (mg2/dL2) Preop alkaline phosphatase (IU/L) Preop parathyroid hormone (pg/mL)
Hemodialysis (n Z 346)
Peritoneal dialysis (n Z 40)
p
55 11 212 (61) 9.9 4.9 60 13 23.5 4.0 1.6 1.4 0.6 1.1 11.0 1.7 4.2 0.5 10.6 0.9 6.0 1.3 64.1 14.5 304 288 1384 430
50 10 22 (55) 6.3 3.9 63 13 24.3 3.8 1.1 1.5 0.4 1.3 10.2 1.9 4.0 0.4 10.7 0.9 6.4 1.6 68.0 13.6 275 329 1238 313
0.002 0.442 <0.001a 0.152b 0.326b 0.087 0.598 0.006b 0.040 0.584 0.118a 0.120 0.196b 0.039
Data are presented as n (%) or mean standard deviation. Preop Z preoperative. a Analysis after square root transformation. b Analysis after logarithmic transformation.
Table 2
Perioperative features in patients undergoing parathyroidectomy for renal hyperparathyroidism.
Subtotal parathyroidectomy Concurrent thyroidectomy Removed parathyroid weight (mg) Length of postoperative stay (d) Persistent disease
Hemodialysis (n Z 346)
Peritoneal dialysis (n Z 40)
p
119 (34) 89 (26) 3152 2446 5.0 3.7 42 (12)
11 (28) 6 (15) 2740 1689 4.3 2.6 4 (10)
0.382 0.175 0.292a 0.088a > 0.99
Data are presented as n (%) or mean standard deviation. a Analysis after logarithmic transformation.
after 1 month of parathyroidectomy. During follow-up, intact PTH (Figure 1) and alkaline phosphatase (Figure 2) levels were comparable between the groups. Serum calciumephosphorus product levels were comparable between the groups prior to surgery and were higher among the peritoneal dialysis patients at 1 month postoperatively
(p Z 0.001; Figure 3). The difference did not reach statistical significance at 6 (p Z 0.082) and 12 months postoperatively (p Z 0.342). During a mean follow-up of 3.7 years, 10 (3%) patients developed recurrent hyperparathyroidism. All recurrences occurred beyond 1 year after surgery.
Figure 1 Mean intact parathyroid hormone (PTH) levels after parathyroidectomy in patients on hemodialysis (HD) or peritoneal dialysis (PD) over time. Error bars indicate standard deviations. *p < 0.05.
Figure 2 Mean total alkaline phosphatase levels after parathyroidectomy in patients on hemodialysis (HD) or peritoneal dialysis (PD) over time. Error bars indicate standard deviations.
154
K.-C. Ho et al.
4. Discussion
Figure 3 Mean serum calciumephosphorus product levels after parathyroidectomy in patients on hemodialysis (HD) or peritoneal dialysis (PD) over time. Error bars indicate standard deviations. *p < 0.05.
Preoperatively, no differences existed in the 13 PAS symptom items between the groups (Figure 4). After parathyroidectomy, peritoneal dialysis patients tended to have more severe residual symptoms in three aspects compared with hemodialysis patients (Figure 5): pain in the bones (p Z 0.080), mood swings (p Z 0.053), and itchy skin (p Z 0.094). The scores for difficulty getting out of a chair or car were similar between the groups (p Z 0.337). For hemodialysis patients, a decrease in symptom severity was observed in almost all aspects including bone pain (p Z 0.027), mood swings (p Z 0.047), itchy skin (p < 0.001), and difficulty getting out of a chair or car (p Z 0.006). By contrast, peritoneal dialysis patients did not experience decreases in bone pain (p Z 0.224), mood swings (p Z 0.546), and itchy skin (p Z 0.702).
We demonstrated that peritoneal dialysis patients who underwent parathyroidectomy for renal hyperparathyroidism had a shorter duration of dialysis and lower preoperative intact PTH levels compared with hemodialysis patients. Nonetheless, after surgery, the peritoneal dialysis patients had higher calciumephosphorus product levels in the short term and a tendency toward more severe residual symptoms compared with the hemodialysis patients. As expected, we found that the surgical patients on peritoneal dialysis were significantly younger. Peritoneal dialysis is a feasible and safe option for elderly patients with ESRD,16 but old age is associated with the adverse outcomes of peritoneal dialysis-related peritonitis.17 This is in keeping with the experience of other researchers. In general, elderly patients and patients with peripheral vascular disease, cerebrovascular disease, malignancy, and multiple comorbidities are less likely to receive peritoneal dialysis.18 In Taiwan, younger patients who received peritoneal dialysis had more favorable survival than patients who received hemodialysis.19 By contrast, among ESRD patients with cardiovascular disease or diabetes mellitus, peritoneal dialysis may be associated with poor survival.20 In the present study, the peritoneal dialysis patients underwent parathyroidectomy after a shorter duration of dialysis and at a lower PTH level. Although this finding may suggest treatment and referral bias, higher serum aluminum levels in these patients suggest that more peritoneal dialysis patients fail to be adequately treated with calcium-based phosphate binders. Data from the National Health Insurance Research Database showed that peritoneal dialysis patients had a higher incidence rate of parathyroidectomy (hazard ratio, 1.657) compared with hemodialysis patients.21 The PTH level is not the only factor in surgical referral. For patients who changed from
Figure 4 Preoperative Parathyroidectomy Assessment of Symptoms (PAS) scores in hyperparathyroidism patients on hemodialysis (HD) or peritoneal dialysis (PD). Error bars represent 95% confidence intervals.
Dialysis modalities and parathyroidectomy
155
Figure 5 Postoperative Parathyroidectomy Assessment of Symptoms (PAS) scores in hyperparathyroidism patients on hemodialysis (HD) or peritoneal dialysis (PD). Error bars represent 95% confidence intervals.
peritoneal dialysis to hemodialysis, a progressive rise in PTH levels was observed.9 Higher PTH levels may be associated with a higher risk of high-turnover bone disease. This may partially explain why in Taiwan, hemodialysis patients had a greater risk of hip fracture compared with peritoneal dialysis patients.22 In our study, peritoneal dialysis patients tended to have higher preoperative BMD than hemodialysis patients, although the difference was not statistically significant. The perioperative course was similar for the two groups. Parathyroidectomy was associated with higher short-term, and lower long-term, mortality rates in ESRD patients.23 Short-term relative mortality risks did not differ appreciably by dialysis modality. In both groups, intact PTH and alkaline phosphatase levels decreased significantly after surgery. Nevertheless, peritoneal dialysis patients had higher postoperative calciumephosphorus product levels and more severe residual symptoms compared with hemodialysis patients. The observation may result from higher serum aluminum levels. We clearly demonstrated that a high serum aluminum level was associated with reduced symptom improvement in patients undergoing parathyroidectomy.13 In this study, a marked difference was observed in mood swings (p Z 0.053). A plausible explanation is that peritoneal dialysis patients had lower levels of 25-hydroxyvitamin D compared with hemodialysis patients.24 Research has suggested a role of vitamin D in mood disorders. A limitation of our study is that serum levels of 25-hydroxyvitamin D were not determined in our patients. The role of vitamin D deficiency requires further investigation. Pruritus was the most prominent symptom prior to parathyroidectomy. Consistent with our previous finding,5 the mean score of itching significantly dropped from 51 30 to 31 29 (p < 0.001) in hemodialysis patients. Nonetheless, the itching score of peritoneal dialysis
patients did not change significantly (from 52 26 to 48 32, p Z 0.702). This phenomenon may be attributed to higher calciumephosphorus product levels in the peritoneal dialysis group than in the dialysis group, because histological studies have shown more calcium depositions in skin basal and spinous cells among patients with uremic pruritus.25 A high calciumephosphorus product level increases the risk of soft tissue and vascular calcification. ESRD patients have higher odds of having pruritus if the calciumephosphorus product level is high, and pruritus is associated with poor outcomes and higher mortality risk.26 Another possibility is that peritoneal dialysis patients had higher serum aluminum levels. As shown in our previous study, a high serum aluminum level was associated with reduced symptom alleviation.13 Data from the Taiwan National Health Insurance Research Database suggest that ESRD patients with secondary hyperparathyroidism have a greater risk of developing thyroid cancer.27 For a substantial minority of these patients, benign and malignant thyroid disease warranted surgical treatment at the time of parathyroidectomy. In this study, 95 (25%) patients had concurrent thyroid operations, including 13 patients for papillary thyroid cancer. The presence of thyroid neoplasms in our patients seems higher than that in the general population. The underlying mechanisms were unclear, but a negative association between PTH levels and some thyroid-disrupting agents (perchlorate, nitrate, and thiocyanate) has been reported.28 At our institute, surgeon-performed neck ultrasound is routinely conducted prior to the surgery.29 A comprehensive thyroid evaluation of patients referred for parathyroidectomy is recommended.30 This study has several limitations. First, the study has a retrospective and nonrandomized design. The number of peritoneal dialysis patients was relatively small. Consequently, large variations and nonsignificant differences may
156 occur between pre- and postoperative PAS scores in this patient group. A recent large series from Tainan showed that 82 (9%) of 888 ESRD patients undergoing parathyroidectomy were on peritoneal dialysis.31 Differences between dialysis modalities would be more pronounced in a larger cohort of patients. In addition, our study was limited by its relatively short follow-up period, which restricts the ability to make meaningful conclusions regarding recurrence. In conclusion, our study showed that patients on hemodialysis or peritoneal dialysis had similar decreases in intact PTH and alkaline phosphatase levels after surgery. However, dialysis modalities may influence postoperative calciumephosphorus product levels and hyperparathyroidismassociated symptoms.
References 1. Hedgeman E, Lipworth L, Lowe K, Saran R, Do T, Fryzek J. International burden of chronic kidney disease and secondary hyperparathyroidism: a systematic review of the literature and available data. Int J Nephrol. 2015;2015:184321. 2. Cheng SP, Liu CL, Liu TP, Hsu YC, Lee JJ. Association between parathyroid hormone levels and inflammatory markers among US adults. Mediators Inflamm. 2014;2014:709024. 3. Goldenstein PT, Elias RM, Pires de Freitas do Carmo L, et al. Parathyroidectomy improves survival in patients with severe hyperparathyroidism: a comparative study. PLoS One. 2013;8: e68870. 4. Yamanouchi M, Ubara Y, Hayami N, et al. Bone mineral density 5 years after parathyroidectomy in hemodialysis patients with secondary hyperparathyroidism. Clin Nephrol. 2013;79: 380e386. 5. Cheng SP, Lee JJ, Liu TP, et al. Parathyroidectomy improves symptomatology and quality of life in patients with secondary hyperparathyroidism. Surgery. 2014;155:320e328. 6. Lee F, Lee JJ, Liu TP, Cheng SP. Parathyroidectomy improves fracture nonunion in hyperparathyroidism. Am Surg. 2015;81: E36eE37. 7. Foley RN, Li S, Liu J, Gilbertson DT, Chen SC, Collins AJ. The fall and rise of parathyroidectomy in U.S. hemodialysis patients, 1992 to 2002. J Am Soc Nephrol. 2005;16:210e218. 8. Quinn RR, Hux JE, Oliver MJ, Austin PC, Tonelli M, Laupacis A. Selection bias explains apparent differential mortality between dialysis modalities. J Am Soc Nephrol. 2011;22: 1534e1542. 9. Rao R, Ansell D, Gilg JA, Davies SJ, Lamb EJ, Tomson CR. Effect of change in renal replacement therapy modality on laboratory variables: a cohort study from the UK Renal Registry. Nephrol Dial Transplant. 2009;24:2877e2882. 10. Moe SM. Management of renal osteodystrophy in peritoneal dialysis patients. Perit Dial Int. 2004;24:209e216. 11. Cheng SP, Yang TL, Lee JJ, et al. Gender differences among patients with secondary hyperparathyroidism undergoing parathyroidectomy. J Surg Res. 2011;168:82e87. 12. Chen HH, Lin CJ, Wu CJ, et al. Chemical ablation of recurrent and persistent secondary hyperparathyroidism after subtotal parathyroidectomy. Ann Surg. 2011;253:786e790. 13. Cheng SP, Lee JJ, Liu TP, Chen HH, Wu CJ, Liu CL. Aluminum overload hampers symptom improvement following
K.-C. Ho et al.
14.
15.
16. 17.
18.
19.
20.
21.
22.
23.
24.
25.
26. 27.
28.
29.
30.
31.
parathyroidectomy for secondary hyperparathyroidism. World J Surg. 2014;38:2838e2844. Cheng SP, Liu CL, Chen HH, Lee JJ, Liu TP, Yang TL. Prolonged hospital stay after parathyroidectomy for secondary hyperparathyroidism. World J Surg. 2009;33:72e79. Pasieka JL, Parsons LL. A prospective surgical outcome study assessing the impact of parathyroidectomy on symptoms in patients with secondary and tertiary hyperparathyroidism. Surgery. 2000;128:531e539. Ng XY, Liu CL, Liu TP, et al. Surgical outcome of peritoneal dialysis in elderly patients. Int J Gerontol. 2009;3:143e148. Tsai CC, Lee JJ, Liu TP, et al. Effects of age and diabetes mellitus on clinical outcomes in patients with peritoneal dialysis-related peritonitis. Surg Infect (Larchmt). 2013;14: 540e546. van de Luijtgaarden MW, Noordzij M, Stel VS, et al. Effects of comorbid and demographic factors on dialysis modality choice and related patient survival in Europe. Nephrol Dial Transplant. 2011;26:2940e2947. Chang YK, Hsu CC, Hwang SJ, et al. A comparative assessment of survival between propensity score-matched patients with peritoneal dialysis and hemodialysis in Taiwan. Medicine (Baltimore). 2012;91:144e151. Wang IK, Kung PT, Kuo WY, et al. Impact of dialysis modality on the survival of end-stage renal disease patients with or without cardiovascular disease. J Nephrol. 2013;26:331e341. Chuang CH, Wang JJ, Weng SF, et al. Epidemiology and mortality among dialysis patients with parathyroidectomy: Taiwan National Cohort Study. J Nephrol. 2013;26:1143e1150. Chen YJ, Kung PT, Wang YH, et al. Greater risk of hip fracture in hemodialysis than in peritoneal dialysis. Osteoporos Int. 2014;25:1513e1518. Kestenbaum B, Andress DL, Schwartz SM, et al. Survival following parathyroidectomy among United States dialysis patients. Kidney Int. 2004;66:2010e2016. Gracia-Iguacel C, Gallar P, Qureshi AR, et al. Vitamin D deficiency in dialysis patients: effect of dialysis modality and implications on outcome. J Ren Nutr. 2010;20:359e367. Momose A, Kudo S, Sato M, et al. Calcium ions are abnormally distributed in the skin of haemodialysis patients with uraemic pruritus. Nephrol Dial Transplant. 2004;19:2061e2066. Wikstrom B. Itchy skinda clinical problem for haemodialysis patients. Nephrol Dial Transplant. 2007;22:v3e7. Lin SY, Lin WM, Lin CL, et al. The relationship between secondary hyperparathyroidism and thyroid cancer in end stage renal disease: a population based cohort study. Eur J Intern Med. 2014;25:276e280. Ko WC, Liu CL, Lee JJ, et al. Negative association between serum parathyroid hormone levels and urinary perchlorate, nitrate, and thiocyanate concentrations in U.S. adults: the National Health and Nutrition Examination Survey 2005e2006. PLoS One. 2014;9:e115245. Cheng SP, Lee JJ, Liu TP, Lee KS, Liu CL. Preoperative ultrasonography assessment of vocal cord movement during thyroid and parathyroid surgery. World J Surg. 2012;36:2509e2515. Sloan DA, Davenport DL, Eldridge RJ, Lee CY. Surgeon-driven thyroid interrogation of patients presenting with primary hyperparathyroidism. J Am Coll Surg. 2014;218:674e683. Hsu YC, Hung CJ. Intramuscular and subcutaneous forearm parathyroid autograft hyperplasia in renal dialysis patients: a retrospective cohort study. Surgery. 2015 Jun 5. pii: S00396060(15)00351-7. http://dx.doi.org/10.1016/j.surg.2015.04. 027. [Epub ahead of print].
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.e-fjs.com
ORIGINAL ARTICLE
Influence of dialysis modalities on patients undergoing parathyroidectomy for renal hyperparathyroidism Kung-Chen Ho a,b, Jie-Jen Lee a,b,c, Tsang-Pai Liu a,b,c, Po-Sheng Yang a,b, Shih-Ping Cheng a,b,* a
Department of Surgery, MacKay Memorial Hospital, Taipei, Taiwan Mackay Medical College, Taipei, Taiwan c Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan b
Received 10 May 2015; received in revised form 24 June 2015; accepted 22 July 2015
Available online 28 September 2015
KEYWORDS dialysis; hyperparathyroidism; parathyroidectomy
Summary Background/Introduction: Dialysis modalities may influence parathyroid hormone (PTH) levels and renal osteodystrophy patterns. To date, no study has compared the effects of dialysis modality on surgical patients with renal hyperparathyroidism. Purpose/Aim: This study evaluated the influence of different dialysis modalities on perioperative features among patients undergoing parathyroidectomy. Methods: Overall, 386 patients who underwent initial parathyroidectomy for renal hyperparathyroidism were recruited. Biochemical data and relevant symptoms were compared between hemodialysis and peritoneal dialysis patients. Results: Compared with the hemodialysis patients, the 40 (10%) peritoneal dialysis patients were younger (p Z 0.002) and had a shorter duration of dialysis (p < 0.001). The peritoneal dialysis patients had lower hemoglobin (p Z 0.006), albumin (p Z 0.040), and intact PTH levels (p Z 0.039) prior to surgery but had higher serum aluminum levels (p Z 0.039). During followup, the peritoneal dialysis patients tended to have higher calciumephosphorus product levels and more severe residual symptoms of bone pain (p Z 0.080), mood swings (p Z 0.053), and pruritus (p Z 0.094). Conclusion: Patients on different dialysis modalities had similar decreases in intact PTH and alkaline phosphatase levels after surgery. However, the peritoneal dialysis patients had higher postoperative calciumephosphorus product levels and more severe residual symptoms. Copyright ª 2015, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.
Conflicts of interest: The authors have no conflicts of interest to declare. * Corresponding author. Department of Surgery, MacKay Memorial Hospital, 92, Chung-Shan North Road, Section 2, Taipei 10449, Taiwan. E-mail address: [email protected] (S.-P. Cheng). http://dx.doi.org/10.1016/j.fjs.2015.07.002 1682-606X/Copyright ª 2015, Taiwan Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.
152
1. Introduction Mineral dysfunction and hyperparathyroidism are common complications of end-stage renal disease (ESRD). The prevalence of renal hyperparathyroidism among dialysis populations ranges from 12% to 54%.1 Elevated levels of parathyroid hormone (PTH) are associated with several inflammatory markers.2 For patients with severe uncontrollable hyperparathyroidism, parathyroidectomy may improve overall survival,3 bone mineral density (BMD),4 and quality of life as well as alleviate symptoms5 and fracture nonunion.6 In the United States, the rate of parathyroidectomy declined between 1988 and 1998 but increased thereafter, despite advances in medical treatment.7 For patients requiring renal replacement therapy, no clear survival benefit exists for hemodialysis or peritoneal dialysis.8 Nonetheless, dialysis modalities significantly influence hemoglobin, ferritin, albumin, cholesterol, and PTH levels.9 Some studies have shown that the prevalence of adynamic bone disease is consistently higher in peritoneal dialysis patients than in hemodialysis patients.10 To our knowledge, no study has compared the effects of dialysis modality on surgical patients with renal hyperparathyroidism. This study evaluated the influence of different dialysis modalities on perioperative features among patients undergoing parathyroidectomy for renal hyperparathyroidism.
K.-C. Ho et al. the decision was at the discretion of the operating surgeon. After parathyroidectomy, persistent disease was defined as any measurement of an intact PTH level >300 pg/mL in the postoperative 6 months. Recurrence was defined as any measurement of an intact PTH level >300 pg/mL beyond 6 months after surgery.11 After August 2008, the Parathyroidectomy Assessment of Symptoms (PAS) questionnaire was used to assess relevant symptoms preoperatively and 6e12 months after the surgery. The PAS scoring system addresses 13 parameters: pain in the bones, feeling tired easily, mood swings, feeling “blue” or depressed, pain in the abdomen, feeling weak, feeling irritable, pain in the joints, being forgetful, difficulty getting out of a chair or car, headaches, itchy skin, and being thirsty.15 Each item was scored on a 100-point visual analog scale, and the PAS score was calculated as the sum of all 13 answers (range, 0e1300). The reliability and validity of the Taiwan Chinese-translated version were established in our previous study.5 Data were analyzed using STATA 12.0 (Stata Corp., College Station, TX, USA) and are reported as the mean standard deviation. Natural log or square root transformations were performed when necessary to normalize skewed distributions. Categorical data were compared using Fisher’s exact test or the Chi-square test, as appropriate. A paired or unpaired Student t test was used to evaluate differences between groups. All statistical tests were two-sided, and statistical significance was determined as p < 0.05.
2. Methods 3. Results From January 2004 to December 2014, 389 consecutive ESRD patients underwent initial parathyroidectomy for renal hyperparathyroidism at a tertiary care center. Three patients younger than 20 years were excluded. Overall, 386 patients who had biochemically confirmed renal hyperparathyroidism comprised the study population. The indication for parathyroidectomy was severe hyperparathyroidism associated with hypercalcemia and/or hyperphosphatemia that was refractory to medical therapy.11 Serum calcium, phosphate, total alkaline phosphatase, albumin, and intact PTH levels (1e84) were regularly monitored preoperatively and during follow-up.12 Most referring dialysis centers examined electrolytes on a monthly basis and alkaline phosphatase and PTH levels at 3month intervals. When the serum albumin level was <4.0 g/ dL, serum calcium levels were corrected using the following formula: corrected calcium (mg/dL) Z measured total calcium (mg/dL) þ 0.8 [4.0 serum albumin (g/dL)]. (1) BMD at the lumbar spine and hip was measured using dual-energy X-ray absorptiometry. After August 2008, the serum aluminum level was determined preoperatively and/ or within 1 week after surgery.13 All operations were performed or supervised by boardcertified endocrine surgeons. Bilateral cervical exploration was followed by subtotal parathyroidectomy or total parathyroidectomy with or without autotransplantation14;
Of the 386 patients, 346 (90%) were on regular hemodialysis and 40 (10%) were on regular peritoneal dialysis. The peritoneal dialysis patients were significantly younger and had a shorter duration of dialysis compared with the hemodialysis patients (Table 1). The mean duration of dialysis prior to surgery was 9.9 4.9 years and 6.3 3.9 years for the hemodialysis patients and peritoneal dialysis patients, respectively. The peritoneal dialysis patients had lower hemoglobin, albumin, and intact PTH levels compared with the hemodialysis patients. Prior to parathyroidectomy, no differences existed in serum calcium, phosphorus, and alkaline phosphatase levels between the groups. Serum aluminum levels were significantly higher among the peritoneal dialysis patients than among the hemodialysis patients (17.0 11.1 mg/L vs. 13.1 6.7 mg/L, p Z 0.039). The majority of patients underwent total parathyroidectomy and autotransplantation (Table 2). Overall, 89 (26%) hemodialysis patients underwent concurrent thyroidectomy for benign goiter (n Z 73), thyroiditis (n Z 3), or papillary thyroid cancer (n Z 13). Six peritoneal dialysis patients underwent concurrent thyroidectomy for benign goiter. The average postoperative hospital stay was 5.0 3.6 days (range, 2e42 days). Both groups showed similar postoperative recovery. Persistent disease was observed in 46 (12%) patients. The dialysis modality did not influence the prevalence of persistent disease. In both groups, serum calcium, phosphorus, alkaline phosphatase, and intact PTH levels decreased significantly
Dialysis modalities and parathyroidectomy Table 1
153
Characteristics of 386 patients with renal hyperparathyroidism.
Age (y) Female (n) Duration of dialysis (y) Body weight (kg) Body mass index (kg/m2) Preop bone mineral density (T score) Preop bone mineral density (Z score) Preop hemoglobin (g/dL) Preop albumin (g/dL) Preop corrected calcium (mg/dL) Preop phosphorus (mg/dL) Calciumephosphorus product (mg2/dL2) Preop alkaline phosphatase (IU/L) Preop parathyroid hormone (pg/mL)
Hemodialysis (n Z 346)
Peritoneal dialysis (n Z 40)
p
55 11 212 (61) 9.9 4.9 60 13 23.5 4.0 1.6 1.4 0.6 1.1 11.0 1.7 4.2 0.5 10.6 0.9 6.0 1.3 64.1 14.5 304 288 1384 430
50 10 22 (55) 6.3 3.9 63 13 24.3 3.8 1.1 1.5 0.4 1.3 10.2 1.9 4.0 0.4 10.7 0.9 6.4 1.6 68.0 13.6 275 329 1238 313
0.002 0.442 <0.001a 0.152b 0.326b 0.087 0.598 0.006b 0.040 0.584 0.118a 0.120 0.196b 0.039
Data are presented as n (%) or mean standard deviation. Preop Z preoperative. a Analysis after square root transformation. b Analysis after logarithmic transformation.
Table 2
Perioperative features in patients undergoing parathyroidectomy for renal hyperparathyroidism.
Subtotal parathyroidectomy Concurrent thyroidectomy Removed parathyroid weight (mg) Length of postoperative stay (d) Persistent disease
Hemodialysis (n Z 346)
Peritoneal dialysis (n Z 40)
p
119 (34) 89 (26) 3152 2446 5.0 3.7 42 (12)
11 (28) 6 (15) 2740 1689 4.3 2.6 4 (10)
0.382 0.175 0.292a 0.088a > 0.99
Data are presented as n (%) or mean standard deviation. a Analysis after logarithmic transformation.
after 1 month of parathyroidectomy. During follow-up, intact PTH (Figure 1) and alkaline phosphatase (Figure 2) levels were comparable between the groups. Serum calciumephosphorus product levels were comparable between the groups prior to surgery and were higher among the peritoneal dialysis patients at 1 month postoperatively
(p Z 0.001; Figure 3). The difference did not reach statistical significance at 6 (p Z 0.082) and 12 months postoperatively (p Z 0.342). During a mean follow-up of 3.7 years, 10 (3%) patients developed recurrent hyperparathyroidism. All recurrences occurred beyond 1 year after surgery.
Figure 1 Mean intact parathyroid hormone (PTH) levels after parathyroidectomy in patients on hemodialysis (HD) or peritoneal dialysis (PD) over time. Error bars indicate standard deviations. *p < 0.05.
Figure 2 Mean total alkaline phosphatase levels after parathyroidectomy in patients on hemodialysis (HD) or peritoneal dialysis (PD) over time. Error bars indicate standard deviations.
154
K.-C. Ho et al.
4. Discussion
Figure 3 Mean serum calciumephosphorus product levels after parathyroidectomy in patients on hemodialysis (HD) or peritoneal dialysis (PD) over time. Error bars indicate standard deviations. *p < 0.05.
Preoperatively, no differences existed in the 13 PAS symptom items between the groups (Figure 4). After parathyroidectomy, peritoneal dialysis patients tended to have more severe residual symptoms in three aspects compared with hemodialysis patients (Figure 5): pain in the bones (p Z 0.080), mood swings (p Z 0.053), and itchy skin (p Z 0.094). The scores for difficulty getting out of a chair or car were similar between the groups (p Z 0.337). For hemodialysis patients, a decrease in symptom severity was observed in almost all aspects including bone pain (p Z 0.027), mood swings (p Z 0.047), itchy skin (p < 0.001), and difficulty getting out of a chair or car (p Z 0.006). By contrast, peritoneal dialysis patients did not experience decreases in bone pain (p Z 0.224), mood swings (p Z 0.546), and itchy skin (p Z 0.702).
We demonstrated that peritoneal dialysis patients who underwent parathyroidectomy for renal hyperparathyroidism had a shorter duration of dialysis and lower preoperative intact PTH levels compared with hemodialysis patients. Nonetheless, after surgery, the peritoneal dialysis patients had higher calciumephosphorus product levels in the short term and a tendency toward more severe residual symptoms compared with the hemodialysis patients. As expected, we found that the surgical patients on peritoneal dialysis were significantly younger. Peritoneal dialysis is a feasible and safe option for elderly patients with ESRD,16 but old age is associated with the adverse outcomes of peritoneal dialysis-related peritonitis.17 This is in keeping with the experience of other researchers. In general, elderly patients and patients with peripheral vascular disease, cerebrovascular disease, malignancy, and multiple comorbidities are less likely to receive peritoneal dialysis.18 In Taiwan, younger patients who received peritoneal dialysis had more favorable survival than patients who received hemodialysis.19 By contrast, among ESRD patients with cardiovascular disease or diabetes mellitus, peritoneal dialysis may be associated with poor survival.20 In the present study, the peritoneal dialysis patients underwent parathyroidectomy after a shorter duration of dialysis and at a lower PTH level. Although this finding may suggest treatment and referral bias, higher serum aluminum levels in these patients suggest that more peritoneal dialysis patients fail to be adequately treated with calcium-based phosphate binders. Data from the National Health Insurance Research Database showed that peritoneal dialysis patients had a higher incidence rate of parathyroidectomy (hazard ratio, 1.657) compared with hemodialysis patients.21 The PTH level is not the only factor in surgical referral. For patients who changed from
Figure 4 Preoperative Parathyroidectomy Assessment of Symptoms (PAS) scores in hyperparathyroidism patients on hemodialysis (HD) or peritoneal dialysis (PD). Error bars represent 95% confidence intervals.
Dialysis modalities and parathyroidectomy
155
Figure 5 Postoperative Parathyroidectomy Assessment of Symptoms (PAS) scores in hyperparathyroidism patients on hemodialysis (HD) or peritoneal dialysis (PD). Error bars represent 95% confidence intervals.
peritoneal dialysis to hemodialysis, a progressive rise in PTH levels was observed.9 Higher PTH levels may be associated with a higher risk of high-turnover bone disease. This may partially explain why in Taiwan, hemodialysis patients had a greater risk of hip fracture compared with peritoneal dialysis patients.22 In our study, peritoneal dialysis patients tended to have higher preoperative BMD than hemodialysis patients, although the difference was not statistically significant. The perioperative course was similar for the two groups. Parathyroidectomy was associated with higher short-term, and lower long-term, mortality rates in ESRD patients.23 Short-term relative mortality risks did not differ appreciably by dialysis modality. In both groups, intact PTH and alkaline phosphatase levels decreased significantly after surgery. Nevertheless, peritoneal dialysis patients had higher postoperative calciumephosphorus product levels and more severe residual symptoms compared with hemodialysis patients. The observation may result from higher serum aluminum levels. We clearly demonstrated that a high serum aluminum level was associated with reduced symptom improvement in patients undergoing parathyroidectomy.13 In this study, a marked difference was observed in mood swings (p Z 0.053). A plausible explanation is that peritoneal dialysis patients had lower levels of 25-hydroxyvitamin D compared with hemodialysis patients.24 Research has suggested a role of vitamin D in mood disorders. A limitation of our study is that serum levels of 25-hydroxyvitamin D were not determined in our patients. The role of vitamin D deficiency requires further investigation. Pruritus was the most prominent symptom prior to parathyroidectomy. Consistent with our previous finding,5 the mean score of itching significantly dropped from 51 30 to 31 29 (p < 0.001) in hemodialysis patients. Nonetheless, the itching score of peritoneal dialysis
patients did not change significantly (from 52 26 to 48 32, p Z 0.702). This phenomenon may be attributed to higher calciumephosphorus product levels in the peritoneal dialysis group than in the dialysis group, because histological studies have shown more calcium depositions in skin basal and spinous cells among patients with uremic pruritus.25 A high calciumephosphorus product level increases the risk of soft tissue and vascular calcification. ESRD patients have higher odds of having pruritus if the calciumephosphorus product level is high, and pruritus is associated with poor outcomes and higher mortality risk.26 Another possibility is that peritoneal dialysis patients had higher serum aluminum levels. As shown in our previous study, a high serum aluminum level was associated with reduced symptom alleviation.13 Data from the Taiwan National Health Insurance Research Database suggest that ESRD patients with secondary hyperparathyroidism have a greater risk of developing thyroid cancer.27 For a substantial minority of these patients, benign and malignant thyroid disease warranted surgical treatment at the time of parathyroidectomy. In this study, 95 (25%) patients had concurrent thyroid operations, including 13 patients for papillary thyroid cancer. The presence of thyroid neoplasms in our patients seems higher than that in the general population. The underlying mechanisms were unclear, but a negative association between PTH levels and some thyroid-disrupting agents (perchlorate, nitrate, and thiocyanate) has been reported.28 At our institute, surgeon-performed neck ultrasound is routinely conducted prior to the surgery.29 A comprehensive thyroid evaluation of patients referred for parathyroidectomy is recommended.30 This study has several limitations. First, the study has a retrospective and nonrandomized design. The number of peritoneal dialysis patients was relatively small. Consequently, large variations and nonsignificant differences may
156 occur between pre- and postoperative PAS scores in this patient group. A recent large series from Tainan showed that 82 (9%) of 888 ESRD patients undergoing parathyroidectomy were on peritoneal dialysis.31 Differences between dialysis modalities would be more pronounced in a larger cohort of patients. In addition, our study was limited by its relatively short follow-up period, which restricts the ability to make meaningful conclusions regarding recurrence. In conclusion, our study showed that patients on hemodialysis or peritoneal dialysis had similar decreases in intact PTH and alkaline phosphatase levels after surgery. However, dialysis modalities may influence postoperative calciumephosphorus product levels and hyperparathyroidismassociated symptoms.
References 1. Hedgeman E, Lipworth L, Lowe K, Saran R, Do T, Fryzek J. International burden of chronic kidney disease and secondary hyperparathyroidism: a systematic review of the literature and available data. Int J Nephrol. 2015;2015:184321. 2. Cheng SP, Liu CL, Liu TP, Hsu YC, Lee JJ. Association between parathyroid hormone levels and inflammatory markers among US adults. Mediators Inflamm. 2014;2014:709024. 3. Goldenstein PT, Elias RM, Pires de Freitas do Carmo L, et al. Parathyroidectomy improves survival in patients with severe hyperparathyroidism: a comparative study. PLoS One. 2013;8: e68870. 4. Yamanouchi M, Ubara Y, Hayami N, et al. Bone mineral density 5 years after parathyroidectomy in hemodialysis patients with secondary hyperparathyroidism. Clin Nephrol. 2013;79: 380e386. 5. Cheng SP, Lee JJ, Liu TP, et al. Parathyroidectomy improves symptomatology and quality of life in patients with secondary hyperparathyroidism. Surgery. 2014;155:320e328. 6. Lee F, Lee JJ, Liu TP, Cheng SP. Parathyroidectomy improves fracture nonunion in hyperparathyroidism. Am Surg. 2015;81: E36eE37. 7. Foley RN, Li S, Liu J, Gilbertson DT, Chen SC, Collins AJ. The fall and rise of parathyroidectomy in U.S. hemodialysis patients, 1992 to 2002. J Am Soc Nephrol. 2005;16:210e218. 8. Quinn RR, Hux JE, Oliver MJ, Austin PC, Tonelli M, Laupacis A. Selection bias explains apparent differential mortality between dialysis modalities. J Am Soc Nephrol. 2011;22: 1534e1542. 9. Rao R, Ansell D, Gilg JA, Davies SJ, Lamb EJ, Tomson CR. Effect of change in renal replacement therapy modality on laboratory variables: a cohort study from the UK Renal Registry. Nephrol Dial Transplant. 2009;24:2877e2882. 10. Moe SM. Management of renal osteodystrophy in peritoneal dialysis patients. Perit Dial Int. 2004;24:209e216. 11. Cheng SP, Yang TL, Lee JJ, et al. Gender differences among patients with secondary hyperparathyroidism undergoing parathyroidectomy. J Surg Res. 2011;168:82e87. 12. Chen HH, Lin CJ, Wu CJ, et al. Chemical ablation of recurrent and persistent secondary hyperparathyroidism after subtotal parathyroidectomy. Ann Surg. 2011;253:786e790. 13. Cheng SP, Lee JJ, Liu TP, Chen HH, Wu CJ, Liu CL. Aluminum overload hampers symptom improvement following
K.-C. Ho et al.
14.
15.
16. 17.
18.
19.
20.
21.
22.
23.
24.
25.
26. 27.
28.
29.
30.
31.
parathyroidectomy for secondary hyperparathyroidism. World J Surg. 2014;38:2838e2844. Cheng SP, Liu CL, Chen HH, Lee JJ, Liu TP, Yang TL. Prolonged hospital stay after parathyroidectomy for secondary hyperparathyroidism. World J Surg. 2009;33:72e79. Pasieka JL, Parsons LL. A prospective surgical outcome study assessing the impact of parathyroidectomy on symptoms in patients with secondary and tertiary hyperparathyroidism. Surgery. 2000;128:531e539. Ng XY, Liu CL, Liu TP, et al. Surgical outcome of peritoneal dialysis in elderly patients. Int J Gerontol. 2009;3:143e148. Tsai CC, Lee JJ, Liu TP, et al. Effects of age and diabetes mellitus on clinical outcomes in patients with peritoneal dialysis-related peritonitis. Surg Infect (Larchmt). 2013;14: 540e546. van de Luijtgaarden MW, Noordzij M, Stel VS, et al. Effects of comorbid and demographic factors on dialysis modality choice and related patient survival in Europe. Nephrol Dial Transplant. 2011;26:2940e2947. Chang YK, Hsu CC, Hwang SJ, et al. A comparative assessment of survival between propensity score-matched patients with peritoneal dialysis and hemodialysis in Taiwan. Medicine (Baltimore). 2012;91:144e151. Wang IK, Kung PT, Kuo WY, et al. Impact of dialysis modality on the survival of end-stage renal disease patients with or without cardiovascular disease. J Nephrol. 2013;26:331e341. Chuang CH, Wang JJ, Weng SF, et al. Epidemiology and mortality among dialysis patients with parathyroidectomy: Taiwan National Cohort Study. J Nephrol. 2013;26:1143e1150. Chen YJ, Kung PT, Wang YH, et al. Greater risk of hip fracture in hemodialysis than in peritoneal dialysis. Osteoporos Int. 2014;25:1513e1518. Kestenbaum B, Andress DL, Schwartz SM, et al. Survival following parathyroidectomy among United States dialysis patients. Kidney Int. 2004;66:2010e2016. Gracia-Iguacel C, Gallar P, Qureshi AR, et al. Vitamin D deficiency in dialysis patients: effect of dialysis modality and implications on outcome. J Ren Nutr. 2010;20:359e367. Momose A, Kudo S, Sato M, et al. Calcium ions are abnormally distributed in the skin of haemodialysis patients with uraemic pruritus. Nephrol Dial Transplant. 2004;19:2061e2066. Wikstrom B. Itchy skinda clinical problem for haemodialysis patients. Nephrol Dial Transplant. 2007;22:v3e7. Lin SY, Lin WM, Lin CL, et al. The relationship between secondary hyperparathyroidism and thyroid cancer in end stage renal disease: a population based cohort study. Eur J Intern Med. 2014;25:276e280. Ko WC, Liu CL, Lee JJ, et al. Negative association between serum parathyroid hormone levels and urinary perchlorate, nitrate, and thiocyanate concentrations in U.S. adults: the National Health and Nutrition Examination Survey 2005e2006. PLoS One. 2014;9:e115245. Cheng SP, Lee JJ, Liu TP, Lee KS, Liu CL. Preoperative ultrasonography assessment of vocal cord movement during thyroid and parathyroid surgery. World J Surg. 2012;36:2509e2515. Sloan DA, Davenport DL, Eldridge RJ, Lee CY. Surgeon-driven thyroid interrogation of patients presenting with primary hyperparathyroidism. J Am Coll Surg. 2014;218:674e683. Hsu YC, Hung CJ. Intramuscular and subcutaneous forearm parathyroid autograft hyperplasia in renal dialysis patients: a retrospective cohort study. Surgery. 2015 Jun 5. pii: S00396060(15)00351-7. http://dx.doi.org/10.1016/j.surg.2015.04. 027. [Epub ahead of print].