Temporal trends and risk factors for parathyroidectomy in the Swedish dialysis and transplant population – a nationwide, population-based study 1991 – 2009

Background Many patients on renal replacement therapy (RRT) require parathyroidectomy (PTX). Trends and current rates of PTX on a national level are not known. Furthermore, it is not completely clear which factors influence rates of PTX. Thus, our aim was to investigate the incidence, regional distribution and factors associated with PTX as well as possible temporal changes, in the Swedish RRT population. Methods From the Swedish Renal Registry we extracted data on 20 015 patients on RRT between 1991 and 2009. In these, 679 incident PTX (3.4%) were identified by linkage with the National Inpatient Registry, and the Scandinavian Quality Registry for Thyroid Parathyroid and Adrenal Surgery. Poisson models were used to estimate rates per calendar year, adjusted for risk factors such as gender, age, time with renal transplant, and underlying cause of renal disease. Results The PTX rate was 8.8/1 000 person-years. There was a significant increase 2001–2004 after which the rate fell, as compared with year 2000. Female gender, non-diabetic cause of renal disease and age between 40–55 were all associated with an increased frequency of PTX. Conclusion The rise in PTX rates after year 2000 might reflect increasing awareness of the potential benefits of PTX. The introduction of calcimimetics and paricalcitol might explain the decreased rate after 2005.

Previous studies reported wide variations in incidence of PTX over time [1][2][3]5] Younger age, female gender, absence of diabetes, longer time on dialysis [1,2,4,5] and lack of transplant [4] were all associated with an increased risk of PTX. However, as far as we know, no study has as yet investigated risk factors and rates of PTX in a country's entire population of patients on renal replacement therapy (RRT), comprising peritoneal, hemodialysis and transplant patients, after the introduction of current medical therapy for sHPT. Our aim was to investigate the incidence, regional distribution and factors associated with PTX as well as possible temporal changes, in the Swedish dialysis and transplant population.

Methods
This study included data from three prospective, population based, national registries. The Swedish Renal Registry, SRR [6], provided the patient cohort, whereas PTXs were identified in the Swedish National Inpatient Registry (SNIR), run by the Swedish National Board of Health and Welfare [7] and the Scandinavian Quality Register for Thyroid Parathyroid and Adrenal Surgery (SQRTPA), [8].

Ethical approval
The study was approved by the Regional Ethics Committee of Lund, DNR 2010/483.

Patient cohort
All patients included in the SRR between 1 st Jan 1991 and 31 st dec 2009 (n = 20,056) were eligible for the present study. The SRR is a national web-based quality registry for patients on maintenance RRT [9].
Out of 20,056 eligible patients, we excluded 13 patients due to errors in reporting. Thus, the patient cohort consisted of 20,043 patients.
The pharmaceutical company Amgen (Solna, Sweden) provided aggregate data on the sales of cinacalcet (Mim-para®) per calendar year in Sweden.

Parathyroidectomy data
PTX was identified through linkage between the SRR cohort and SNIR, and between the SRR and the (SQRTPA), by using the national personal identification number.
SNIR has been validated, with overall good to excellent results regarding accuracy of coding [10].
A total of 954 PTX were identified by the following in-hospital codes within the admission data: extirpation of parathyroid gland, BBA30 or 0851, subtotal parathyroidectomy, BBA40 or 0852, total parathyroidectomy, BBA50 or 0853, implantation or transplantation of parathyroid gland, BBA70 or 0870, and any other operation on parathyroid gland, BBA99 or 0898.
SQRTPA was launched in 2004 and the coverage 2010 was 90%. In general, less than five percent of patients were not registered or incorrectly registered. In this registry, 128 PTX were identified. Of these, 126 were also found among the hospital admission data. A total of 956 PTX were identified. We defined an incident PTX as the first PTX occurring after registration in the SRR. Out of the 956 PTX, 229 were performed before registration in the SRR. Of the remaining 727 PTX, 41 were in patients with two operations, and 7 in patients with three operations, during the study period. Thus we found a total of 679 incident PTX.

Determination of time-at-risk and follow-up
Start date was defined as date of registration in the SRR. Patients were censored at death, at PTX, when lost to follow-up, or at end of study. To be able to correct for the impact of renal transplantation on the risk for PTX, we used time spent with functioning transplant prior to censoring as a time-dependent covariate. The cumulative sum of time spent with a functioning transplant in all transplant episodes was calculated. The term zero time with a functioning graft was used for patients who never received a transplant or in whom the transplant failed to

Results
Patient characteristics at baseline are shown in Table 1. A total of 679 PTX were identified in 20,015 patients (3.4%).
The mean follow-up (SD) time for the whole cohort was 3.9 (4.1) years. The overall unadjusted PTX rate in 77,624 person-years of follow-up was 8.8 incident PTX per 1000 person-years at risk (95% CI: 8.1-9.4), Table 2.
After adjustment, female gender, age group 40-55 years as compared with other age groups, and non-diabetic cause of end-stage renal disease were all associated with an increased risk for PTX, Table 3. Cumulative time with functioning renal transplant (more than one but less than three years, and more than three years as compared with zero time with functioning graft) was inversely associated with risk of PTX in the adjusted analysis, Table 3. There were few events and person-years in the first two years the SNR was operating, 1991 and 1992, hence incidence rate ratios for those years had wide confidence intervals. In the adjusted model there were no statistically significant differences in the PTX rate from 1993 to 2000 using year 2000 as a reference year, Table 4. The PTX rate was significantly higher in the years 2001 through 2004. In the subsequent years following year 2005, there was a decrease in the PTX rate, although this change did not reach statistical significance as compared with the reference year 2000, Figure 1, Table 4. Aggregate data on the sales of cinacalcet seemed to match the decreasing rate of PTX, Figure 2.

Discussion
In the present study, risk factors for PTX were female gender, age 40-55 years, and non-diabetic cause of renal disease. In the adjusted model, having had a functioning renal graft for less than one year was also associated with increased risk of PTX, whereas having had a functioning renal graft for more than one year was associated with decreased risk, compared with zero time with functioning graft.
The increased risk of PTX in women, patients in younger middle age and non-diabetics is congruent with results from previous studies [1][2][3][4]. The regional distribution of PTX was heterogeneous with the lowest rate in the Northern region. We believe, as was also suggested by previous authors, that lower access to specialist nephrology might account for these regional differences [2]. Having had a functioning renal transplant for more than a year was associated with a decreased risk of PTX in the adjusted analysis. This is to be expected, given that renal transplantation usually ameliorates sHPT [11].
We found no significant differences in the PTX inci- There are several possible explanations for this reported diversity in PTX rates. Firstly, the studies cover a large span of time from 1971 to 2007 with different observational and comparison periods. Secondly, the patient cohorts studied are heterogenous, often comprising subgroups of RRT patients [1][2][3][4].
Our study comprises all RRT patients in Sweden and covers the period before and after key publications on the consequences of sHPT on mortality and cardiovascular risk [13][14][15][16] and after the publication of the KDOQI guidelines for PTX [17].   A limitation of the present study is the lack of biochemical data, such as levels of parathyroid hormone, and of information on medical treatment. Strengths include the high quality of the Swedish Renal Registry, with an almost 100% nation wide coverage and a data reporting incidence of 95% [6]. In addition, our follow-up period comprises different eras of treatment availability and modality. The fact that this study is based on an entire population with a wide geographical distribution within the country is to our knowledge a unique situation. We also believe that external validity was increased by including all patients on RRT, irrespective of treatment modality. The linkage of three nation-wide registries with broad and accurate coverage further adds to the validity of the present results.

Conclusion
PTX rates differed over time in Swedish patients on RRT. This might reflect increasing awareness of the potential benefits of treating sHPT, and it is possible that the fall in rates from 2005 was caused by the introduction of calcimimetics. Female gender, non-diabetic cause of renal disease and age group 40-45 compared with younger and older patients, and cumulative time with functioning graft less than one year were all associated with higher risk for PTX.