J Am Soc Nephrol 12: 1242–1248, 2001 Parathyroidectomy in Patients on Renal Replacement Therapy: An Epidemiologic Study

FABIO MALBERTI, DANIELE MARCELLI, FERRUCCIO CONTE, AURELIO LIMIDO, DONATELLA SPOTTI, and FRANCESCO LOCATELLI Registro Lombardo Dialisi e Trapianto, Milano, .

Abstract. Secondary hyperparathyroidism is a frequent com- 1000 patient-years in patients who had been on RRT for Ͻ5yr plication of long-term dialysis treatment, and despite recent to 30 per 1000 patient-years in those receiving RRT for Ͼ10 advances in medical therapy, surgical parathyroidectomy yr. The Cox regression models showed that the relative risk for (PTx) is necessary in a considerable number of uremic patients. PTx was significantly higher in women and lower in elderly A prevalence of PTx of 22% was reported in Europe in 1988 and diabetic patients. The relative risk for PTx (adjusted for in patients on dialysis from 10 to 15 yr, but no large-scale gender, age, and nephropathy) was higher in the patients on epidemiologic study has been published since then. The aim of peritoneal dialysis than in those on hemodialysis and decreased the study was to evaluate the prevalence, incidence, and risk after transplantation. During the course of a follow-up of 7 yr, factors for PTx in patients on renal replacement therapy (RRT) the incidence of PTx in patients who started RRT between in and to determine whether the incidence has 1990 and 1992 was no different from that observed in patients changed over time. The study involved 14,180 patients in- who started RRT between 1983 and 1985. In conclusion, the cluded in the Lombardy Registry of Dialysis and Transplanta- prevalence and incidence of PTx in patients receiving RRT in tion who received RRT for end-stage renal disease (ESRD) Lombardy is lower than that in Europe and Italy as a whole, as between 1983 and 1996. Cox-proportional hazards regression reported by the 1988 European Dialysis and Transplantation models were used to evaluate the risk factors of PTx, the Association Registry; its frequency has not changed signifi- explanatory covariates being age on admission to RRT, gender, cantly during the past few years. The need for PTx decreases underlying renal disease (nondiabetic or diabetic nephropathy), markedly after successful transplantation. The epidemiologic and dialysis modality (peritoneal dialysis or hemodialysis). finding that the rate of PTx is greater in women, young pa- The prevalence of PTx in the 7371 ERSD patients who were tients, and individuals who do not have diabetes suggests the alive on December 31, 1996, was 5.5% and increased with the need for a more aggressive medical treatment of secondary duration of RRT (9.2% after 10 to 15 yr, 20.8% after 16 to 20 hyperparathyroidism particularly in such patients. yr). Similarly, the incidence of PTx increased from 3.3 per

Secondary hyperparathyroidism is a frequent complication in patient-years during the first 2 to 3 yr of dialysis but more than patients with chronic renal failure and generally is managed by 40 per 1000 patient-years in the patients who had spent 10 yr controlling hyperphosphatemia, normalizing serum calcium or more on maintenance dialysis (1). PTx was performed much levels, and administering vitamin D analogs. However, medi- less frequently in patients with diabetic nephropathy, and its cal therapy is not always successful and parathyroidectomy use decreased markedly after successful transplantation (1). In (PTx) is necessary in a considerable number of patients who 1988, the EDTA Registry reported that the mean prevalence of are on maintenance dialysis or who have received a renal graft. PTx among all RRT patients had increased in comparison with In 1982, the European Dialysis and Transplantation Associa- 1982 because of the larger number of long-term survivors; tion (EDTA) Registry reported that the overall incidence of a however, its mean annual incidence was similar in the periods first PTx in patients who are on renal replacement therapy 1983 to 1985 and 1986 to 1988 (2). (RRT) in Europe was 12.1 per 1000 patient-years, with a No epidemiologic study of a large number of uremic prevalence of 42.1 per 1000 patients alive at the end of that patients has been published during the past few years, but it year (1). The incidence of PTx was approximately 5 per 1000 seems reasonable to expect that the number of patients who require PTx has decreased in line with the better control of secondary hyperthyroidism obtained as a result of advances Received April 5, 2000. Accepted October 25, 2000. in the monitoring and management of dialysis patients and Correspondence to Dr. Fabio Malberti, Servizio Dialisi, I-26900 Lodi, Italy. of the introduction of new therapeutic approaches, such as Phone: ϩ39-0371-372731; Fax: ϩ39-0371-372105; E-mail: nefrodialisilodi@ pmp.it the diffusion of calcium carbonate or acetate as phosphate binders (3–6), the administration of intermittent high-dose 1046-6673/1206-1242 Journal of the American Society of Nephrology active vitamin D metabolites, and the use of intravenous Copyright © 2001 by the American Society of Nephrology calcitriol (7–13). The aim of this study was to evaluate the J Am Soc Nephrol 12: 1242–1248, 2001 Parathyroidectomy in Uremic Patients 1243 prevalence, incidence, and risk factors for PTx in patients on mmol/L in 39% of the centers (23% in 1990); 20% of the centers used RRT in Lombardy and to determine whether the incidence a dialysate calcium of 1.25 mmol/L when the patients developed has changed over time. hypercalcemia or received high-dose calcitriol. The present analysis of the incidence of PTx considered the 11,351 Materials and Methods patients who started RRT at an age of more than 18 yr between Patients and Data Collection January 1, 1983, and December 31, 1996, and who survived for more than 1 mo. The patients who underwent PTx before starting RRT or The data used for this analysis were based on the 14,180 patients for whom no PTx data were available were excluded (n ϭ 560). To who were included in the Lombardy Registry of Dialysis and Trans- determine whether the incidence has changed over time, we compared plantation and who received RRT for end-stage renal disease (ESRD) the 1573 patients who started RRT between January 1, 1983, and in one of Lombardy’s 44 DIALYSIS Units between January 1, 1983, December 31, 1985 (group A), and the 2470 patients who started RRT and December 31, 1996. This registry was begun in 1982 under the between January 1, 1990, and December 31, 1992 (group B). aegis of the Lombardy Regional Section of the Italian Society of Nephrology and the Regional Health Department, with the data being collected at the end of each year (100% center response rate); a Statistical Analyses detailed study concerning the 1983 to 1992 dialysis and transplanta- Cox proportional hazard regression models (15) were used to test tion results has been published (14). The registry tracks the modality the statistical relationship between PTx and the possible risk factors of treatment and outcomes (mortality, hospitalization, PTx, surgery for secondary hyperparathyroidism: age on admission to RRT, gender, for carpal tunnel syndrome, etc.) of the ESRD patients who were alive underlying renal disease (diabetic or nondiabetic nephropathy), and as of January 1, 1983, and the new patients starting dialysis from the initial dialysis modality (peritoneal or hemodialysis). PTx was con- same date. sidered as the end point, whereas patient death, transfer to a dialysis The occurrence of PTx has been included in the annual question- unit outside Lombardy, renal transplantation, and the end of PTx-free naire relating to each patient since 1983. The criteria for performing follow-up (December 31, 1996) were regarded as censored informa- PTx were the documentation of severe secondary hyperparathyroid- tion. Furthermore, to evaluate the effect of transplantation on the ism (parathyroid hormone [PTH] levels markedly increased) associ- relative risk for PTx (only five patients received a transplantation as ated with any of the following: persistent hypercalcemia, extraskeletal their initial RRT), we applied Cox proportional hazard regression calcifications, calciphylaxis, persistently elevated serum calcium- models to the restricted subgroup of 6559 patients who survived on phosphorous product, bone fractures, or progressive worsening of RRT for more than 2 yr without undergoing PTx. The modality of hyperparathyroidism despite vitamin D therapy. Information on vita- treatment after 2 yr of RRT was considered as a covariate. The min D therapy and use of phosphate binders was included in the follow-up period for the calculation of the incidence rate of PTx was annual questionnaire from 1983 to 1987. The proportion of patients censored as of December 31, 1990 (group A), or December 31, 1996 who were treated with vitamin D increased from 51% in 1983 (cal- (group B). citriol, 33.1%; calcifediol, 13.1%; dihydrotachysterol, 4.8%; n ϭ The calculations relating to the Cox proportional hazard regression 2963) to 52.7% in 1987 (calcitriol, 45.5%; calcifediol, 7.2%; n ϭ models and the other descriptive statistical analyses were made with 3089). Aluminum hydroxide was given to 89.2% and 83.5% of the the use of version 7.5 of the SPSS software package (SPSS Inc., patients in 1983 and 1987, respectively; the dosage was Ͼ2 g/d in Chicago, IL). The contributions of the covariates toward explaining 51.9% of the patients in 1983 compared with 29.9% of the patients in the dependent variable were assessed by means of a two-tailed like- 1987. Calcium salts, as phosphate binders, were given to 34.7% and lihood ratio test; P Ͻ 0.05 was considered significant. 67.8% of the patients in 1983 and 1987, respectively. The dose of Ͼ calcium (as elemental calcium) was 1 g/d in 21.2% and 47% of the Results patients in 1983 and 1987, respectively. Target levels of serum cal- Information concerning a first PTx was available in 97% of cium, phosphate, and PTH, as reported by a questionnaire submitted to each dialysis center in 1996, are reported in Table 1. Pulse therapy the updated records relating to 13,755 patients, of whom 618 with oral or intravenous calcitriol was started when PTH was Ͼ250 (4.5%: 307 males, 311 females) actually underwent PTx; only pg/ml in 27% of the centers, when Ͼ500 pg/ml in 66%, and when 3 of these patients were diabetic. Seventy-eight patients under- Ͼ750 pg/ml in 7%. The usual dialysate calcium concentration was went PTx between 1972 and 1982, and 540 underwent PTx 1.75 mmol/L in 41% of the centers in 1996 (72% in 1990) and 1.5 between 1983 and 1996. The annual number of operations

Table 1. Serum calcium, phosphorus, and intact PTH considered ideal for dialysis patients in Lombardy dialysis centers (n ϭ 44)

Laboratory Test Range of Serum Level

Calcium (mg/dl) 9–9.5 9.5–10 10–10.5 10.5–11 centers (%) 5 31 56 8 Phosphorus (mg/dl) Ͻ4.5 4.5–5.5 5.5–6.5 centers (%) 33 67 0 PTHa (pg/ml) Ͻ60 60–120 120–250 250–500 centers (%) 5 19 75 1

a PTH, parathyroid hormone. 1244 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 1242–1248, 2001

Table 2. Parathyroidectomies per 1000 patients who were alive on December 31, 1996, by duration of RRTa

Duration Dialysis Transplantation Total of RRT (No. Patients) (No. Patients) (No. Patients)

Ͻ5 yr 9.1 (3109) 7.5 (401) 8.8 (3510) 5–10 yr 51.9 (1079) 13.9 (645) 37.7 (1724) 10–15 yr 133.6 (554) 35.5 (394) 92.8 (948) Ͼ15 yr 281.6 (632) 83.5 (374) 208 (1006) Total 62.5 (5374) 31.4 (1814) 54.6 (7188)

a RRT, renal replacement therapy. ranged from 24 in 1984 to 74 in 1996; 393 (5.46%) of the 7188 ESRD patients who were alive on December 31, 1996, had undergone PTx. The rate of patients who underwent PTx increased in relation to the time spent on RRT (Table 2). Among the 10,591 patients who started RRT between 1983 Figure 1. Kaplan-Meyer survival curve of patients who began renal and 1996 (6240 males [58.9%] and 4351 females [41.1%]), the replacement therapy (RRT) in Lombardy between 1983 and 1996, overall proportion of patients who underwent PTx was 1.74% using parathyroidectomy (PTx) as the end point. The patients were (n ϭ 184). The mean annual incidence of first PTx was 5.28 censored at the time of death, transfer out of Lombardy, or end of per 1000 patient-years (3.3 per 1000 patient-years in the pa- follow-up (December 31, 1996). tients who had been on RRT for Ͻ5 yr, 11.6 in those who had been treated for 5 to 10 yr, and 30 in those who had been treated for more than 10 yr). The mean age of patients who 99% after 2 yr of follow-up and decreased to 93% after 10 yr underwent PTx was 49.9 Ϯ 12 yr (range, 19 to 84 yr), and the of follow-up and 90% after 12 yr of follow-up. Cox’s propor- average duration of RRT was 66 Ϯ 43 mo. None was diabetic, tional hazard model showed that the relative risk (RR) for PTx 60.5% were females, and 65.2% received hemodialysis (34.8% was significantly higher in women than in men and lower in peritoneal dialysis) as the first treatment modality. The propor- elderly patients and in patients with diabetic nephropathy (Ta- tion of females and young patients was greater in the group of ble 4, Figure 2). The RR for PTx (adjusted for gender, age, and patients who underwent PTx than in the group of patients who nephropathy) was higher in the patients on peritoneal dialysis did not (Table 3). PTx was performed less frequently in elderly than in those on hemodialysis and decreased after transplanta- (13 of 4237 patients [0.3%]) than in young patients (171 of tion (Table 4). 6354 patients [2.7%]). Two yr after admission to RRT, 6559 patients had not Figure 1 shows the Kaplan-Meier cumulative survival curve undergone PTx: 4236 were on hemodialysis, 1647 were on of the patients who were admitted to RRT between 1983 and peritoneal dialysis, and 676 were not receiving dialysis because 1996. The cumulative survival without PTx was approximately of a functioning renal graft. During the follow-up, only 4

Table 3. Patient distribution by gender, nephropathy (diabetic and nondiabetic), age on admission to RRT, and first treatment modality (hemodialysis and peritoneal dialysis) in PTx and non-PTx patients who began RRT between 1983 and 1996a

PTx (n ϭ 184) Non-PTx (n ϭ 10,407) Parameter P Value N% N %

Males 73 39.5 6130 59.0 Ͻ0.001 Females 111 60.5 4277 41.0 Ͻ0.001 Diabetic nephropathy 0 0 1249 12.0 Ͻ0.001 Nondiabetic nephropathy 184 100 9158 88.0 Ͻ0.001 18–54 yr 115 62.5 3224 31.0 Ͻ0.001 55–64 yr 56 30.5 2959 28.5 NS Ͼ64 yr 13 7.0 4224 40.5 Ͻ0.001 Hemodialysis 120 65.4 6975 67.0 NS Peritoneal dialysis 64 34.6 3432 33.0 NS

a PTx, parathyroidectomy. J Am Soc Nephrol 12: 1242–1248, 2001 Parathyroidectomy in Uremic Patients 1245

Table 5. Patient distribution by gender, age on admission to RRT, nephropathy (D/ND), first treatment modality (HD and PD), and duration of RRT in patients who began RRT between 1983 and 1985 (group A) and between 1990 and 1992 (group B)a

Group A Group B Parameter (n ϭ 1573) (n ϭ 2470) P % % Value

Male/female 58.4/61.6 58/62 NS 18–54 yr 43.7 28.5 Ͻ0.001 55–64 yr 31.3 30.1 NS Ͼ64 yr 25.0 41.4 Ͻ0.001 D/ND 10.2/89.8 11.4/88.6 NS HD/PD 65.5/34.5 66.3/33.7 NS

a D/ND, diabetic/nondiabetic. Figure 2. Kaplan-Meyer gender-related and age-related survival curves of patients who began RRT in Lombardy between 1983 and 1996, using PTx as the end point (patients censored upon death, transfer out of Lombardy, or end of follow-up). The patients were divided into three age groups on the basis of their age on admission to RRT.

Table 4. RR for PTx by demographic and treatment modality (peritoneal dialysis, hemodialysis, and transplantation) according to Cox’s main effect model in patients who began RRT between 1983 and 1996 (n ϭ 10,591)a

Variable Reference RR (95% CI) P Value

Female gender Male 2.28 (1.68–3.08) Ͻ0.001 Age 55–64 yrb Age 18–54 yr 0.83 (0.59–1.15) NS Age Ͼ64 yrb Age 18–54 yr 0.23 (0.12–0.45) Ͻ0.001 Diabetic Nondiabetic 0.09 (0.12–0.64) Ͻ0.01 nephropathy nephropathy PD HD 1.62 (1.17–2.25) Ͻ0.003 Figure 3. Comparison of the Kaplan-Meyer survival curves of the PDc HDc 1.70 (1.16–2.48) Ͻ0.006 patients who began RRT at Lombardy between 1983 and 1985 and those who began RRT between 1990 and 1992, using PTx as the end Transplantationc HDc 0.15 (0.05–0.39) Ͻ0.001 point. a RR, relative risk; CI, confidence interval; PD, peritoneal dialysis; HD, hemodialysis. b Age on admission to RRT. PTx and who were admitted to RRT between 1990 and 1992 c ϭ Treatment modality after 2 yr of RRT (HD, n 4236; PD, was not different from that of the patients who were admitted n ϭ 1647; transplantation, n ϭ 676). to RRT between 1983 and 1985 (Figure 3): 30 (1.21%) versus 17 (1.08%). The mean annual incidence of a first PTx was 2.55 and 3.32 per 1000 patient-years, respectively. The Cox regres- (0.6%) of the 676 transplanted patients underwent PTx, as sion model showed that significant (P Ͻ 0.001) risk factors for compared with 105 (2.4%) on hemodialysis and 37 (2.2%) on PTx were gender (females: RR, 2.59; P Ͻ 0.003) and young peritoneal dialysis. The number of PTx per 1000 patient-years age (18 to 54 yr) on admission to RRT (patients aged Ͼ64 yr: was lower in the patients who had received a transplant (0.9) RR, 0.35; P Ͻ 0.04 versus age 18 to 54); the year of admission than in those who were receiving peritoneal dialysis (5.62) or to RRT (1983 to 1985 versus 1990 to 1992), nephropathy, and hemodialysis (4.69). first treatment modality (hemodialysis or peritoneal dialysis) The demographic and clinical data of group A and group B were not significant risk factors. incident patient cohorts are shown in Table 5. The only differ- ence in the baseline characteristics of the two groups was the Discussion greater proportion of elderly patients in group B. During a In 1988, the EDTA Registry reported an increase in the follow-up of 7 yr, the proportion of patients who underwent mean proportion of uremic patients who were treated with PTx 1246 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 1242–1248, 2001 in comparison with 1982 (2). No epidemiologic study of a expectancy of approximately 4 yr and a cumulative survival large number of ESRD patients has been published since, so rate of 39% and 13% after 4 and 8 yr of RRT, respectively (23). the present study is an attempt to reevaluate the magnitude of Anyway, the lower survival rate does not explain the lower the problem. proportion of PTx observed in older patients during the fol- The proportion of patients who underwent PTx in Lombardy low-up period. Elderly patients on RRT have been reported to was 54.6 per 1000 patients who were alive and on RRT at the have lower PTH levels than younger patients (24). However, as end of 1996, an overall prevalence that is similar to that in we did not collect data on PTH levels, we cannot clarify Europe as reported by the EDTA Registry in 1988 (2); more- whether the lower incidence of PTx in elderly patients was over, our study confirmed previous reports that indicated that because hyperparathyroidism was less severe or surgery was the rate of PTx rises with increasing time on dialysis (1,2,13). less indicated. Elderly patients more frequently have comor- However, when the patients were stratified on the basis of the bidities that may discourage a surgical operation, although the duration of RRT, the proportion of patients who underwent cure rate, morbidity, and mortality have been reported to be PTx in Lombardy was nearly 50% lower than that reported in similar in elderly and young patients who undergo PTx for Europe and in Italy in 1988 (2). The overall annual incidence primary and secondary hyperparathyroidism (25). rate of first PTx in patients who were admitted to RRT in PTx rarely is performed in Lombardy patients with diabetic Lombardy between 1983 and 1996 was 5.28 per 1000 patient- nephropathy. Patients with diabetes mellitus and normal renal years, once again lower than the annual rates reported by the function have a reduced bone mass, a low bone formation rate, EDTA Registry in 1988 (2) and by the Okinawa Dialysis Study and lower PTH levels than age-matched normal subjects (26), Registry (16); the incidence adjusted for time on RRT (3.3 per and it has been reported that patients who have diabetes and 1000 patient-years in the patients who were on RRT for Ͻ 5yr who are on dialysis have lower PTH levels and a lower bone and 30 per 1000 patient-years in those who were treated for formation rate than individuals who do not have diabetes (27). Ͼ10 yr) was accordingly 30 to 50% lower than the rates Hyperglycemia and insulin deficiency inhibit PTH release (28) reported by the EDTA (2,17) and Fournier et al. (18). The and seem to make patients who have diabetes and who are on reduced need for PTx in our patients can be explained by the dialysis more subject to low bone turnover states; therefore, it improvements in the monitoring and management of dialysis is not surprising that high-turnover bone disorders are uncom- patients that haven taken place over the last few years. Ap- mon in patients who have diabetes and who are on dialysis proximately 50% of the patients who were undergoing chronic (28,29). dialysis in Lombardy (n ϭ 2963) were already receiving active As reported previously in other studies (1,2), our study vitamin D metabolites in 1983 (33% calcitriol, 13% calcidiol), shows that the need for PTx in ESRD patients decreases and it has been shown elsewhere that the introduction of markedly after successful transplantation. The incidence rate of therapy with active vitamin D compounds significantly de- patients who had received a transplantation in Lombardy was creased the need for PTx in comparison with the pre-vitamin D 0.9 per 1000 patient-years, a rate much lower than that reported period (16). However, it is surprising that there was no further in Europe and in Italy by the EDTA Registry in 1988 (2 to 4 decrease in the need for PTx in our dialysis population in more per 1000 patient-years) (2). recent years: the incidence rate of PTx during 7 yr of follow-up We found a higher frequency of PTx in patients who were was not different between the patients who were admitted to treated with peritoneal dialysis than in those who were on RRT between 1983 and 1985 and those who began RRT hemodialysis. Unfortunately, as we did not collect data on PTH between 1990 and 1992. In addition to the widespread use of levels either at the beginning of RRT or during the follow-up, active vitamin D metabolites and calcium salts since the early we cannot be sure that the two groups of patients were homo- 1980s, this probably is due to the adequate control of serum geneous in terms of the severity of the secondary hyperpara- calcium and phosphate levels (19,20). thyroidism. Our results concerning the effect of treatment Our study shows that gender and a young age on admission modality on the outcome of secondary hyperparathyroidism to RRT are relevant risk factors for PTx. The risk for PTx is therefore should be evaluated with caution. It has been reported twice as high in women, and this, together with the evidence that osteitis fibrosa is more frequent in patients who are on that women are affected by primary hyperparathyroidism twice hemodialysis than in those who are on peritoneal dialysis as often as men (21), suggests that women may be more (30–32), but the former also had a younger age, a longer period susceptible to parathyroid gland hyperactivity. Furthermore, on dialysis treatment, and a lower incidence of diabetic ne- the abnormal ovarian function frequently observed in uremic phropathy (30–32). In one group of RRT patients who were women (22) may be a predisposing factor for increased bone followed up for 1 yr, it was found that secondary hyperpara- resorption and thus contribute to the aggravation of osteitis thyroidism was similarly controlled regardless of whether they fibrosa. were receiving peritoneal dialysis or hemodialysis (33). It Only a few elderly patients underwent PTx. The low abso- therefore is likely that factors other than treatment modality per lute number of PTx in elderly patients can be explained by the se (peritoneal dialysis or hemodialysis) play a major role in the fact that severe secondary hyperparathyroidism is a complica- progression of secondary hyperparathyroidism. tion of long survivors on RRT, and the survival rate of elderly In conclusion, our study shows that the prevalence and patients on RRT is low. We previously reported that patients incidence of PTx in Lombardy patients who were on RRT is aged 65 to 69 yr on admission to RRT in Lombardy have a life lower than that reported in Europe and in Italy by the EDTA J Am Soc Nephrol 12: 1242–1248, 2001 Parathyroidectomy in Uremic Patients 1247

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