Secondary hyperparathyroidism is a frequent complication in patients with chronic renal failure and generally is managed by controlling hyperphosphatemia, normalizing serum calcium levels, and administering vitamin D analogs. However, medical therapy is not always successful and parathyroidectomy (PTx) is necessary in a considerable number of patients who are on maintenance dialysis or who have received a renal graft. In 1982, the European Dialysis and Transplantation Association (EDTA) Registry reported that the overall incidence of a first PTx in patients who are on renal replacement therapy (RRT) in Europe was 12.1 per 1000 patient-years, with a prevalence of 42.1 per 1000 patients alive at the end of that year (1). The incidence of PTx was approximately 5 per 1000 patient-years during the first 2 to 3 yr of dialysis but more than 40 per 1000 patient-years in the patients who had spent 10 yr or more on maintenance dialysis (1). PTx was performed much less frequently in patients with diabetic nephropathy, and its use decreased markedly after successful transplantation (1). In 1988, the EDTA Registry reported that the mean prevalence of PTx among all RRT patients had increased in comparison with 1982 because of the larger number of long-term survivors; however, its mean annual incidence was similar in the periods 1983 to 1985 and 1986 to 1988 (2).
No epidemiologic study of a large number of uremic patients has been published during the past few years, but it 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 in the monitoring and management of dialysis patients and of the introduction of new therapeutic approaches, such as the diffusion of calcium carbonate or acetate as phosphate binders (3,4,5,6), the administration of intermittent high-dose active vitamin D metabolites, and the use of intravenous calcitriol (7,8,9,10,11,12,13). The aim of this study was to evaluate the prevalence, incidence, and risk factors for PTx in patients on RRT in Lombardy and to determine whether the incidence has changed over time.
Materials and Methods
Patients and Data Collection
The data used for this analysis were based on the 14,180 patients who were included in the Lombardy Registry of Dialysis and Transplantation and who received RRT for end-stage renal disease (ESRD) in one of Lombardy's 44 DIALYSIS Units between January 1, 1983, and December 31, 1996. This registry was begun in 1982 under the 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 detailed study concerning the 1983 to 1992 dialysis and transplantation results has been published (14). The registry tracks the modality of treatment and outcomes (mortality, hospitalization, PTx, surgery for carpal tunnel syndrome, etc.) of the ESRD patients who were alive as of January 1, 1983, and the new patients starting dialysis from the same date.
The occurrence of PTx has been included in the annual questionnaire relating to each patient since 1983. The criteria for performing PTx were the documentation of severe secondary hyperparathyroidism (parathyroid hormone [PTH] levels markedly increased) associated with any of the following: persistent hypercalcemia, extraskeletal calcifications, calciphylaxis, persistently elevated serum calcium-phosphorous product, bone fractures, or progressive worsening of hyperparathyroidism despite vitamin D therapy. Information on vitamin D therapy and use of phosphate binders was included in the annual questionnaire from 1983 to 1987. The proportion of patients who were treated with vitamin D increased from 51% in 1983 (calcitriol, 33.1%; calcifediol, 13.1%; dihydrotachysterol, 4.8%; n = 2963) to 52.7% in 1987 (calcitriol, 45.5%; calcifediol, 7.2%; n = 3089). Aluminum hydroxide was given to 89.2% and 83.5% of the patients in 1983 and 1987, respectively; the dosage was >2 g/d in 51.9% of the patients in 1983 compared with 29.9% of the patients in 1987. Calcium salts, as phosphate binders, were given to 34.7% and 67.8% of the patients in 1983 and 1987, respectively. The dose of calcium (as elemental calcium) was >1 g/d in 21.2% and 47% of the patients in 1983 and 1987, respectively. Target levels of serum calcium, phosphate, and PTH, as reported by a questionnaire submitted to each dialysis center in 1996, are reported in Table 1. Pulse therapy with oral or intravenous calcitriol was started when PTH was >250 pg/ml in 27% of the centers, when >500 pg/ml in 66%, and when >750 pg/ml in 7%. The usual dialysate calcium concentration was 1.75 mmol/L in 41% of the centers in 1996 (72% in 1990) and 1.5 mmol/L in 39% of the centers (23% in 1990); 20% of the centers used a dialysate calcium of 1.25 mmol/L when the patients developed hypercalcemia or received high-dose calcitriol.
The present analysis of the incidence of PTx considered the 11,351 patients who started RRT at an age of more than 18 yr between January 1, 1983, and December 31, 1996, and who survived for more than 1 mo. The patients who underwent PTx before starting RRT or for whom no PTx data were available were excluded (n = 560). To determine whether the incidence has changed over time, we compared the 1573 patients who started RRT between January 1, 1983, and December 31, 1985 (group A), and the 2470 patients who started RRT between January 1, 1990, and December 31, 1992 (group B).
Cox proportional hazard regression models (15) were used to test the statistical relationship between PTx and the possible risk factors for secondary hyperparathyroidism: age on admission to RRT, gender, underlying renal disease (diabetic or nondiabetic nephropathy), and initial dialysis modality (peritoneal or hemodialysis). PTx was considered as the end point, whereas patient death, transfer to a dialysis unit outside Lombardy, renal transplantation, and the end of PTx-free follow-up (December 31, 1996) were regarded as censored information. Furthermore, to evaluate the effect of transplantation on the relative risk for PTx (only five patients received a transplantation as their initial RRT), we applied Cox proportional hazard regression models to the restricted subgroup of 6559 patients who survived on RRT for more than 2 yr without undergoing PTx. The modality of treatment after 2 yr of RRT was considered as a covariate. The follow-up period for the calculation of the incidence rate of PTx was censored as of December 31, 1990 (group A), or December 31, 1996 (group B).
The calculations relating to the Cox proportional hazard regression models and the other descriptive statistical analyses were made with the use of version 7.5 of the SPSS software package (SPSS Inc., Chicago, IL). The contributions of the covariates toward explaining the dependent variable were assessed by means of a two-tailed likelihood ratio test; P < 0.05 was considered significant.
Information concerning a first PTx was available in 97% of the updated records relating to 13,755 patients, of whom 618 (4.5%: 307 males, 311 females) actually underwent PTx; only 3 of these patients were diabetic. Seventy-eight patients underwent PTx between 1972 and 1982, and 540 underwent PTx between 1983 and 1996. The annual number of operations 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 and 1996 (6240 males [58.9%] and 4351 females [41.1%]), the overall proportion of patients who underwent PTx was 1.74% (n = 184). The mean annual incidence of first PTx was 5.28 per 1000 patient-years (3.3 per 1000 patient-years in the patients who had been on RRT for <5 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 underwent PTx was 49.9 ± 12 yr (range, 19 to 84 yr), and the average duration of RRT was 66 ± 43 mo. None was diabetic, 60.5% were females, and 65.2% received hemodialysis (34.8% peritoneal dialysis) as the first treatment modality. The proportion of females and young patients was greater in the group of patients who underwent PTx than in the group of patients who did not (Table 3). PTx was performed less frequently in elderly (13 of 4237 patients [0.3%]) than in young patients (171 of 6354 patients [2.7%]).
Figure 1 shows the Kaplan-Meier cumulative survival curve of the patients who were admitted to RRT between 1983 and 1996. The cumulative survival without PTx was approximately 99% after 2 yr of follow-up and decreased to 93% after 10 yr of follow-up and 90% after 12 yr of follow-up. Cox's proportional hazard model showed that the relative risk (RR) for PTx was significantly higher in women than in men and lower in elderly patients and in patients with diabetic nephropathy (Table 4, Figure 2). The RR for PTx (adjusted for gender, age, and nephropathy) was higher in the patients on peritoneal dialysis than in those on hemodialysis and decreased after transplantation (Table 4).
Two yr after admission to RRT, 6559 patients had not undergone PTx: 4236 were on hemodialysis, 1647 were on peritoneal dialysis, and 676 were not receiving dialysis because of a functioning renal graft. During the follow-up, only 4 (0.6%) of the 676 transplanted patients underwent PTx, as compared with 105 (2.4%) on hemodialysis and 37 (2.2%) on peritoneal dialysis. The number of PTx per 1000 patient-years was lower in the patients who had received a transplant (0.9) than in those who were receiving peritoneal dialysis (5.62) or hemodialysis (4.69).
The demographic and clinical data of group A and group B incident patient cohorts are shown in Table 5. The only difference in the baseline characteristics of the two groups was the greater proportion of elderly patients in group B. During a follow-up of 7 yr, the proportion of patients who underwent PTx and who were admitted to RRT between 1990 and 1992 was not different from that of the patients who were admitted 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 regression model showed that significant (P < 0.001) risk factors for PTx were gender (females: RR, 2.59; P < 0.003) and young age (18 to 54 yr) on admission to RRT (patients aged >64 yr: RR, 0.35; P < 0.04 versus age 18 to 54); the year of admission to RRT (1983 to 1985 versus 1990 to 1992), nephropathy, and first treatment modality (hemodialysis or peritoneal dialysis) were not significant risk factors.
In 1988, the EDTA Registry reported an increase in the mean proportion of uremic patients who were treated with PTx in comparison with 1982 (2). No epidemiologic study of a large number of ESRD patients has been published since, so the present study is an attempt to reevaluate the magnitude of the problem.
The proportion of patients who underwent PTx in Lombardy was 54.6 per 1000 patients who were alive and on RRT at the end of 1996, an overall prevalence that is similar to that in Europe as reported by the EDTA Registry in 1988 (2); moreover, our study confirmed previous reports that indicated that the rate of PTx rises with increasing time on dialysis (1,2,13). However, when the patients were stratified on the basis of the duration of RRT, the proportion of patients who underwent PTx in Lombardy was nearly 50% lower than that reported in Europe and in Italy in 1988 (2). The overall annual incidence rate of first PTx in patients who were admitted to RRT in Lombardy between 1983 and 1996 was 5.28 per 1000 patient-years, once again lower than the annual rates reported by the EDTA Registry in 1988 (2) and by the Okinawa Dialysis Study Registry (16); the incidence adjusted for time on RRT (3.3 per 1000 patient-years in the patients who were on RRT for < 5 yr and 30 per 1000 patient-years in those who were treated for > 10 yr) was accordingly 30 to 50% lower than the rates reported by the EDTA (2,17) and Fournier et al. (18). The reduced need for PTx in our patients can be explained by the improvements in the monitoring and management of dialysis patients that haven taken place over the last few years. Approximately 50% of the patients who were undergoing chronic dialysis in Lombardy (n = 2963) were already receiving active vitamin D metabolites in 1983 (33% calcitriol, 13% calcidiol), and it has been shown elsewhere that the introduction of therapy with active vitamin D compounds significantly decreased the need for PTx in comparison with the pre-vitamin D period (16). However, it is surprising that there was no further decrease in the need for PTx in our dialysis population in more recent years: the incidence rate of PTx during 7 yr of follow-up was not different between the patients who were admitted to RRT between 1983 and 1985 and those who began RRT between 1990 and 1992. In addition to the widespread use of active vitamin D metabolites and calcium salts since the early 1980s, this probably is due to the adequate control of serum calcium and phosphate levels (19,20).
Our study shows that gender and a young age on admission to RRT are relevant risk factors for PTx. The risk for PTx is twice as high in women, and this, together with the evidence that women are affected by primary hyperparathyroidism twice as often as men (21), suggests that women may be more susceptible to parathyroid gland hyperactivity. Furthermore, the abnormal ovarian function frequently observed in uremic women (22) may be a predisposing factor for increased bone resorption and thus contribute to the aggravation of osteitis fibrosa.
Only a few elderly patients underwent PTx. The low absolute number of PTx in elderly patients can be explained by the fact that severe secondary hyperparathyroidism is a complication of long survivors on RRT, and the survival rate of elderly patients on RRT is low. We previously reported that patients aged 65 to 69 yr on admission to RRT in Lombardy have a life expectancy of approximately 4 yr and a cumulative survival rate of 39% and 13% after 4 and 8 yr of RRT, respectively (23). Anyway, the lower survival rate does not explain the lower proportion of PTx observed in older patients during the follow-up period. Elderly patients on RRT have been reported to have lower PTH levels than younger patients (24). However, as we did not collect data on PTH levels, we cannot clarify whether the lower incidence of PTx in elderly patients was because hyperparathyroidism was less severe or surgery was less indicated. Elderly patients more frequently have comorbidities that may discourage a surgical operation, although the cure rate, morbidity, and mortality have been reported to be similar in elderly and young patients who undergo PTx for primary and secondary hyperparathyroidism (25).
PTx rarely is performed in Lombardy patients with diabetic nephropathy. Patients with diabetes mellitus and normal renal function have a reduced bone mass, a low bone formation rate, and lower PTH levels than age-matched normal subjects (26), and it has been reported that patients who have diabetes and who are on dialysis have lower PTH levels and a lower bone formation rate than individuals who do not have diabetes (27). Hyperglycemia and insulin deficiency inhibit PTH release (28) and seem to make patients who have diabetes and who are on dialysis more subject to low bone turnover states; therefore, it is not surprising that high-turnover bone disorders are uncommon in patients who have diabetes and who are on dialysis (28,29).
As reported previously in other studies (1,2), our study shows that the need for PTx in ESRD patients decreases markedly after successful transplantation. The incidence rate of patients who had received a transplantation in Lombardy was 0.9 per 1000 patient-years, a rate much lower than that reported in Europe and in Italy by the EDTA Registry in 1988 (2 to 4 per 1000 patient-years) (2).
We found a higher frequency of PTx in patients who were treated with peritoneal dialysis than in those who were on hemodialysis. Unfortunately, as we did not collect data on PTH levels either at the beginning of RRT or during the follow-up, we cannot be sure that the two groups of patients were homogeneous in terms of the severity of the secondary hyperparathyroidism. Our results concerning the effect of treatment modality on the outcome of secondary hyperparathyroidism therefore should be evaluated with caution. It has been reported that osteitis fibrosa is more frequent in patients who are on hemodialysis than in those who are on peritoneal dialysis (30,31,32), but the former also had a younger age, a longer period on dialysis treatment, and a lower incidence of diabetic nephropathy (30,31,32). In one group of RRT patients who were followed up for 1 yr, it was found that secondary hyperparathyroidism was similarly controlled regardless of whether they were receiving peritoneal dialysis or hemodialysis (33). It therefore is likely that factors other than treatment modality per se (peritoneal dialysis or hemodialysis) play a major role in the progression of secondary hyperparathyroidism.
In conclusion, our study shows that the prevalence and incidence of PTx in Lombardy patients who were on RRT is lower than that reported in Europe and in Italy by the EDTA Registry in 1988. The epidemiologic finding that the rate of PTx is greater in women, young patients, and individuals who do not have diabetes has practical clinical implications insofar as it suggests that secondary hyperparathyroidism in such patients should receive a more aggressive medical treatment.
Participating Researchers and Centers: D. Marchesi and G. Remuzzi (Bergamo); P. Faranna (Trescore Balneario); G. Alongi and M. Lorenz (Zingonia); P. Ondei and L. Rusconi (Ponte S. Pietro); M. Massazza and M. Borghi (Treviglio); A. Strada and R. Maiorca (Brescia); S. Bove and F. Brandi (Brescia Umberto I); A. Testori (Desenzano); M. Brognoli and M. Usberti (Leno); R. Broccoli (Esine); F. Cossandi and S. De Marinis (Chiari); M. Fraticelli and C. Grillo-(Como); C. Romano and F. Pecchini (Cremona); V. Ogliari and M. Mileti (Crema); G. Pontoriero, L. Del Vecchio, and F. Locatelli (Lecco); F. Malberti and E. Imbasciati (Lodi); P. Botti and R. Tarchini (Mantova); A. Perego and G. Civati (Milano-Niguarda); G.C. Ambroso and C. Ponticelli (Milano-Croff); L. Luciani and G. D'Amico (Milano-S. Carlo); S. Bertoli and G. Barbiano di Belgioioso (Milano-Sacco); D. Spotti and G. Bianchi (Milano-San Raffaele); A. Baretta and D. Brancaccio (Milano-S. Paolo); A. Edefonti and F. Sereni (Milano-ICP); M. Beccari and G. Sorgato (Milano-FBF); M. Vigano[Combining Grave Accent] and B. Redaelli (Monza); A. Manfredi and R. Marangoni (Bollate); F. Conte and A. Sessa (Vimercate); O. Bracchi and S. Sforzini (Cernusco SN); M. Saruggia and G. Buccianti (Cinisello Balsamo); G. Bonforte and M. Surian (Desio); G. Renzetti and A. Colombo (Legnano); E. Orazi and C. Grassi (Melegnano); G. Pisano and C. Novi (Magenta); M. Doria and A. Frontini (S. Donato Milanese); A. Dal Canton (Pavia-S. Matteo); G. Villa and A. Salvadeo (Pavia-Cl. Lavoro); M. Nai and R. Bellazzi (Vigevano); W. Bazzini and C. Barbieri (Voghera); F. Sama[Combining Grave Accent] and L. Pedrini (Sondrio); O. Amatruda and L. Gastaldi (Varese); A. Limido and P. Cantu[Combining Grave Accent] (Gallarate); P. Scalia and C. Grossi (Tradate); and L. Brambilla Pisoni and A. Giangrande (Busto Arsizio).
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