Nephrol Dial Transplant (2015) 30: 2027–2033 doi: 10.1093/ndt/gfv334 Advance Access publication 15 September 2015
The effect of parathyroidectomy on patient survival in secondary hyperparathyroidism Kerstin M. Ivarsson1, Shahriar Akaberi2, Elin Isaksson3, Eva Reihnér4, Rebecca Rylance5, Karl-Göran Prütz6, Naomi Clyne2 and Martin Almquist7 1
Department of Nephrology, Clinical Sciences Lund, Skåne, Sweden, 2Department of Nephrology and Transplantation, Skane University Hospital
Lund, Skåne, Sweden, 3VO Urology, Division 4, Malmö, Sweden, 4Department of Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden, 5National Registry Centre, Skane University Hospital Lund, Skåne, Sweden, 6Department of Internal Medicine, Helsingborg Hospital, Helsingborg, Sweden and 7Department of Surgery Section of Endocrine and Sarcoma, Skane University Hospital, Lund, Skåne, Sweden
Correspondence and offprint requests to: Kerstin Ivarsson; E-mail: [email protected]
Background. Secondary hyperparathyroidism is a common condition in patients with end-stage renal disease and is associated with osteoporosis and cardiovascular disease. Despite improved medical treatment, parathyroidectomy (PTX) is still necessary for many patients on renal replacement therapy. The aim of this study was to evaluate the effect of PTX on patient survival. Methods. A nested index-referent study was performed within the Swedish Renal Registry (SRR). Patients on maintenance dialysis and transplantation at the time of PTX were analysed separately. The PTX patients in each of these strata were matched for age, sex and underlying renal diseases with up to five referent patients who had not undergone PTX. To calculate survival time and hazard ratios, indexes and referents were assigned the calendar date (d) of the PTX of the index patient. The risk of death after PTX was calculated using crude and adjusted Cox proportional hazards regressions. Results. There were 20 056 patients in the SRR between 1991 and 2009. Of these, 579 (423 on dialysis and 156 with a renal transplant at d) incident patients with PTX were matched with 1234/892 non-PTX patients. The adjusted relative risk of death was a hazard ratio (HR) of 0.80 [95% confidence interval (CI) 0.65–0.99] for dialysis patients at d who had undergone PTX compared with matched patients who had not. Corresponding results for the patients with a renal allograft at d were an HR of 1.10 (95% CI 0.71–1.70). Conclusions. PTX was associated with improved survival in patients on maintenance dialysis but not in patients with renal allograft. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Keywords: dialysis, epidemiology, hyperparathyroidism, kidney transplantation, PTH, survival analysis
INTRODUCTION Secondary hyperparathyroidism (sHPT) is common among patients with end-stage renal disease (ESRD) [1], and it often persists after successful renal transplantation [2]. sHPT is associated with high-turnover bone disease [3], interstitial and vascular calcifications [4] and cardiovascular morbidity [5] and mortality [6]. It can contribute to calcification of the allograft and thereby worsen the transplant function [7]. Despite improvements in medical therapy, such as the introduction of calcimimetics, surgical parathyroidectomy (PTX) is often necessary [8]. PTX has been shown to reduce cardiovascular calcification [9] and to have a positive impact on blood pressure [10], anaemia and serum lipids [11]. Improvements in bone density [12] and bone pain [13] have also been reported, although PTX can be associated with significant morbidity [14] and even mortality [15]. PTX has been shown to improve long-term survival in dialysis patients in some [16–21], but not all [22, 23], previous studies. However, none of these studies included transplanted patients. Furthermore, three of them were performed before the introduction of calcimimetics [17, 18, 22] and five of them were limited by small numbers of PTX patients [16, 19, 20, 22, 23]. A randomized trial is unlikely to be performed to compare PTX with medical treatment alone, due to the low rate of PTX [18, 24–27]. Hence, there is a rationale for observational cohort studies on the outcome of PTX for patients with sHPT. 2027
ORIGINAL ARTICLE
A B S T R AC T
The aim of this study was to investigate the effect of PTX on mortality in patients receiving renal replacement therapy (RRT), comprising both transplanted patients and dialysis patients, in a nationwide, population-based cohort. M AT E R I A L S A N D M E T H O D S
ORIGINAL ARTICLE
Study cohort This study was performed and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology statement [28]. It is a matched index-referent study within a cohort consisting of all patients in the Swedish Renal Registry (SRR) between 1 January 1991 and 31 December 2009. Registration in the SRR is mandatory for all patients at the start of RRT. All Swedish dialysis and renal transplantation units are affiliated with the SRR, which has a coverage of almost 100% [29]. Ascertaining PTX, comorbidity and death The date of PTX, defined as total or subtotal PTX, and diagnosis at hospital discharge were retrieved by linking the SRR to the Swedish Inpatient Registry. The dates for PTX in the Swedish Inpatient Registry were compared with information from the Scandinavian Quality Registry for Thyroid, Parathyroid and Adrenal Surgery, which has registered thyroid and parathyroid operations since 2004. Approximately 90% of the units performing this surgery in Sweden report to this registry [30]. Discharge diagnoses in International Classification of Diseases, 7th-9th revision codes were translated into ICD10 by using conversion tables from the Swedish National Board of Health and Welfare [31]. Discharge diagnoses were then used to construct comorbidity groups according to Charlson et al. [32], with the help of an algorithm described by Quan et al. [33]. The Swedish Inpatient Registry has had a national coverage of nearly 100% since 1987 and has high validity [34, 35]. The physician in charge of the patient enters the date and cause of death into the SRR. Matching The patients who had undergone PTX after being entered into the SRR were divided into two patient groups: those on maintenance dialysis treatment and those with a functioning renal allograft at the time of PTX. The patients in the two groups were randomly matched with between one and five patients who had not undergone PTX. The matching criteria were birth year in 10-year categories, sex and cause of ESRD in categories (autosomal dominant polycystic kidney disease, diabetes mellitus, glomerulonephritis, nephrosclerosis, pyelonephritis and other/unknown). In order to calculate survival time, index and referent patients were assigned the calendar date of PTX of the index patient, hereafter referred to as d. The matched reference patient was required to be alive on this date and to have the same form of RRT at d, i.e. dialysis or a functioning renal transplant. Statistical analysis Means and SDs were calculated for continuous variables and numbers and column percentages were calculated for categorical variables. Patients were censored at death or at end of
2028
follow-up, 31 December 2009. Crude and adjusted Cox proportional hazards regression models were used to compare hazard ratios (HRs) with 95% confidence intervals (CIs) for death between PTX and non-PTX patients in the matched sets, using as the timescale time from d to censoring. Cox regressions were performed for the PTX and matched non-PTX patients among patients on dialysis and patients with a functioning allograft, respectively. In the adjusted analysis of patients on dialysis, total time in RRT before d and Charlson comorbidity score at d were entered as continuous covariates. Renal transplant during the study period (yes versus no), treatment region (South, South-east, West, Uppsala/Örebro, North and abroad) versus Stockholm region and the first RRT modality, peritoneal dialysis or renal transplantation compared with haemodialysis after entry in the SRR were entered as categorical covariates. In the adjusted analysis of patients with functioning renal allograft at d, total time in RRT before d and Charlson comorbidity score at d were entered as continuous covariates. Treatment region (South, South-east, West, Uppsala/Örebro, North and abroad) versus Stockholm region was entered as a categorical covariate. Unadjusted Kaplan–Meier survival estimate curves were calculated from d, censored for end of follow-up at 31 December 2009, for PTX and non-PTX patients with dialysis and renal transplant at d, respectively. We analysed survival after PTX in unadjusted and adjusted models for dialysis patients starting RRT before 1 January 2004 and after 31 December 2003 separately, i.e. before and after the year of introduction of calcimimetics. Cox regressions were performed separately for men and women. Using analysis of variance, we tested the interaction between renal transplantation and PTX with survival time as the dependent variable. Results with a P-value
The effect of parathyroidectomy on patient survival in secondary hyperparathyroidism Kerstin M. Ivarsson1, Shahriar Akaberi2, Elin Isaksson3, Eva Reihnér4, Rebecca Rylance5, Karl-Göran Prütz6, Naomi Clyne2 and Martin Almquist7 1
Department of Nephrology, Clinical Sciences Lund, Skåne, Sweden, 2Department of Nephrology and Transplantation, Skane University Hospital
Lund, Skåne, Sweden, 3VO Urology, Division 4, Malmö, Sweden, 4Department of Molecular Medicine and Surgery, Karolinska University Hospital, Stockholm, Sweden, 5National Registry Centre, Skane University Hospital Lund, Skåne, Sweden, 6Department of Internal Medicine, Helsingborg Hospital, Helsingborg, Sweden and 7Department of Surgery Section of Endocrine and Sarcoma, Skane University Hospital, Lund, Skåne, Sweden
Correspondence and offprint requests to: Kerstin Ivarsson; E-mail: [email protected]
Background. Secondary hyperparathyroidism is a common condition in patients with end-stage renal disease and is associated with osteoporosis and cardiovascular disease. Despite improved medical treatment, parathyroidectomy (PTX) is still necessary for many patients on renal replacement therapy. The aim of this study was to evaluate the effect of PTX on patient survival. Methods. A nested index-referent study was performed within the Swedish Renal Registry (SRR). Patients on maintenance dialysis and transplantation at the time of PTX were analysed separately. The PTX patients in each of these strata were matched for age, sex and underlying renal diseases with up to five referent patients who had not undergone PTX. To calculate survival time and hazard ratios, indexes and referents were assigned the calendar date (d) of the PTX of the index patient. The risk of death after PTX was calculated using crude and adjusted Cox proportional hazards regressions. Results. There were 20 056 patients in the SRR between 1991 and 2009. Of these, 579 (423 on dialysis and 156 with a renal transplant at d) incident patients with PTX were matched with 1234/892 non-PTX patients. The adjusted relative risk of death was a hazard ratio (HR) of 0.80 [95% confidence interval (CI) 0.65–0.99] for dialysis patients at d who had undergone PTX compared with matched patients who had not. Corresponding results for the patients with a renal allograft at d were an HR of 1.10 (95% CI 0.71–1.70). Conclusions. PTX was associated with improved survival in patients on maintenance dialysis but not in patients with renal allograft. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
Keywords: dialysis, epidemiology, hyperparathyroidism, kidney transplantation, PTH, survival analysis
INTRODUCTION Secondary hyperparathyroidism (sHPT) is common among patients with end-stage renal disease (ESRD) [1], and it often persists after successful renal transplantation [2]. sHPT is associated with high-turnover bone disease [3], interstitial and vascular calcifications [4] and cardiovascular morbidity [5] and mortality [6]. It can contribute to calcification of the allograft and thereby worsen the transplant function [7]. Despite improvements in medical therapy, such as the introduction of calcimimetics, surgical parathyroidectomy (PTX) is often necessary [8]. PTX has been shown to reduce cardiovascular calcification [9] and to have a positive impact on blood pressure [10], anaemia and serum lipids [11]. Improvements in bone density [12] and bone pain [13] have also been reported, although PTX can be associated with significant morbidity [14] and even mortality [15]. PTX has been shown to improve long-term survival in dialysis patients in some [16–21], but not all [22, 23], previous studies. However, none of these studies included transplanted patients. Furthermore, three of them were performed before the introduction of calcimimetics [17, 18, 22] and five of them were limited by small numbers of PTX patients [16, 19, 20, 22, 23]. A randomized trial is unlikely to be performed to compare PTX with medical treatment alone, due to the low rate of PTX [18, 24–27]. Hence, there is a rationale for observational cohort studies on the outcome of PTX for patients with sHPT. 2027
ORIGINAL ARTICLE
A B S T R AC T
The aim of this study was to investigate the effect of PTX on mortality in patients receiving renal replacement therapy (RRT), comprising both transplanted patients and dialysis patients, in a nationwide, population-based cohort. M AT E R I A L S A N D M E T H O D S
ORIGINAL ARTICLE
Study cohort This study was performed and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology statement [28]. It is a matched index-referent study within a cohort consisting of all patients in the Swedish Renal Registry (SRR) between 1 January 1991 and 31 December 2009. Registration in the SRR is mandatory for all patients at the start of RRT. All Swedish dialysis and renal transplantation units are affiliated with the SRR, which has a coverage of almost 100% [29]. Ascertaining PTX, comorbidity and death The date of PTX, defined as total or subtotal PTX, and diagnosis at hospital discharge were retrieved by linking the SRR to the Swedish Inpatient Registry. The dates for PTX in the Swedish Inpatient Registry were compared with information from the Scandinavian Quality Registry for Thyroid, Parathyroid and Adrenal Surgery, which has registered thyroid and parathyroid operations since 2004. Approximately 90% of the units performing this surgery in Sweden report to this registry [30]. Discharge diagnoses in International Classification of Diseases, 7th-9th revision codes were translated into ICD10 by using conversion tables from the Swedish National Board of Health and Welfare [31]. Discharge diagnoses were then used to construct comorbidity groups according to Charlson et al. [32], with the help of an algorithm described by Quan et al. [33]. The Swedish Inpatient Registry has had a national coverage of nearly 100% since 1987 and has high validity [34, 35]. The physician in charge of the patient enters the date and cause of death into the SRR. Matching The patients who had undergone PTX after being entered into the SRR were divided into two patient groups: those on maintenance dialysis treatment and those with a functioning renal allograft at the time of PTX. The patients in the two groups were randomly matched with between one and five patients who had not undergone PTX. The matching criteria were birth year in 10-year categories, sex and cause of ESRD in categories (autosomal dominant polycystic kidney disease, diabetes mellitus, glomerulonephritis, nephrosclerosis, pyelonephritis and other/unknown). In order to calculate survival time, index and referent patients were assigned the calendar date of PTX of the index patient, hereafter referred to as d. The matched reference patient was required to be alive on this date and to have the same form of RRT at d, i.e. dialysis or a functioning renal transplant. Statistical analysis Means and SDs were calculated for continuous variables and numbers and column percentages were calculated for categorical variables. Patients were censored at death or at end of
2028
follow-up, 31 December 2009. Crude and adjusted Cox proportional hazards regression models were used to compare hazard ratios (HRs) with 95% confidence intervals (CIs) for death between PTX and non-PTX patients in the matched sets, using as the timescale time from d to censoring. Cox regressions were performed for the PTX and matched non-PTX patients among patients on dialysis and patients with a functioning allograft, respectively. In the adjusted analysis of patients on dialysis, total time in RRT before d and Charlson comorbidity score at d were entered as continuous covariates. Renal transplant during the study period (yes versus no), treatment region (South, South-east, West, Uppsala/Örebro, North and abroad) versus Stockholm region and the first RRT modality, peritoneal dialysis or renal transplantation compared with haemodialysis after entry in the SRR were entered as categorical covariates. In the adjusted analysis of patients with functioning renal allograft at d, total time in RRT before d and Charlson comorbidity score at d were entered as continuous covariates. Treatment region (South, South-east, West, Uppsala/Örebro, North and abroad) versus Stockholm region was entered as a categorical covariate. Unadjusted Kaplan–Meier survival estimate curves were calculated from d, censored for end of follow-up at 31 December 2009, for PTX and non-PTX patients with dialysis and renal transplant at d, respectively. We analysed survival after PTX in unadjusted and adjusted models for dialysis patients starting RRT before 1 January 2004 and after 31 December 2003 separately, i.e. before and after the year of introduction of calcimimetics. Cox regressions were performed separately for men and women. Using analysis of variance, we tested the interaction between renal transplantation and PTX with survival time as the dependent variable. Results with a P-value
