Papers

Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study

Charlotte L Mollerup, associate professor ^a, Peter Vestergaard, registrar ^b, Vibe Gedsø Frøkjær, registrar ^a, Leif Mosekilde, professor ^b, Peer Christiansen, consultant in surgery ^c, Mogens Blichert-Toft, professor emeritus ^a. 

^a Department of Endocrine and Breast Surgery, Copenhagen University Hospital, Rigshospitalet, DK 2100 Copenhagen, Denmark, ^b Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus Amtssygehus, DK 8000 Aarhus, Denmark, ^c Department of Surgery L, Aarhus University Hospital

Correspondence to: C L Mollerup molle{at}rh.dk

	Abstract

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Aim: To study the risk of renal stone episodes and risk factors for renal stones in primary hyperparathyroidism before and after surgery.
Design: Register based, controlled retrospective follow up study.
Setting: Tertiary hospitals in Denmark.
Participants: 674 consecutive patients with surgically verified primary hyperparathyroidism. Each patient was compared with three age- and sex-matched controls randomly drawn from the background population. Hospital admissions for renal stone disease were compared between patients and controls. Risk factors for renal stones among patients were assessed.
Main outcome measures: Number of renal stone episodes; comparison of hospital admissions for renal stones in patients and controls; assessment of risk factors for renal stones.
Results: Relative risk of a stone episode was 40 (95% confidence interval 31 to 53) before surgery and 16 (12 to 23) after surgery. Risk was increased 10 years before surgery, and became normal more than 10 years after surgery. Stone-free survival 20 years after surgery was 90.4% in patients and 98.7% in controls (risk difference 8.3%, 4.8% to 11.7%). Patients with preoperative stones had 27 times the risk of postoperative stone incidents than controls. Before surgery, males had more stone episodes than females and younger patients had more stone episodes than older patients. Neither parathyroid pathology, weight of removed tissue, plasma calcium levels, nor skeletal pathology (fractures) influenced the risk of renal stones. After surgery, younger age, preoperative stones and ureteral strictures were significant risk factors for stones.
Conclusions: The risk of renal stones is increased in primary hyperparathyroidism and decreases after surgery. The risk profile is normal 10 years after surgery. Preoperative stone events increase the risk of postoperative stones. Stone formers and non-stone formers had the same risk of skeletal complications.

What is already known on this topic Patients with primary hyperparathyroidism have an increased risk of renal stone events The extent to which parathyroid surgery reduces the risk of further stones is unclear What this study adds The risk of a new stone event was 8.3% higher in patients than in controls after surgery In patients with stone disease before operation the risk rate for a postoperative stone event was 27 times that in controls The risk of a renal stone event was higher than the risk among controls until more than 10 years after surgery

	Introduction

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Primary hyperparathyroidism is associated with increased risk of renal stones. As the clinical picture of primary hyperparathyroidism has shifted towards milder and even asymptomatic cases with the advent of biochemical screening, the prevalence of stone disease has declined from around 80% in early series to 7-20% in more recent series. ^{1 2}

It is generally accepted that parathyroidectomy reduces the risk of recurrent stone disease provided that normocalcaemia is obtained.³ However, a 30-50% risk of recurrence after an observation period of three to five years has been reported, ^{4 5} bringing into question the effect of parathyroidectomy in a substantial proportion of the patients.

The objective of this study was to investigate the whether the risk of renal stones is higher in patients with primary hyperparathyroidism before surgery than in the general population,; the extent to which patients with and without renal stones differ in variables such as age, sex, severity of disease, histopathology, and skeletal symptoms; and whether surgery decreases the future risk of stone disease.

	Methods

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The study was designed as a register based, controlled retrospective follow up study.

Patients
The cohort consisted of 674 consecutive white patients with surgically verified primary hyperparathyroidism treated at Aarhus University Hospital between 1979 and 1997, at Odense University Hospital between 1979 and 1990, and at Copenhagen University Hospital, Rigshospitalet, between 1991 and 1997. Of the 674 patients, 97% (653) were operated on within one year after the diagnosis was first registered. All patients included were normocalcaemic after surgery.

Controls
For each of the 674 patients, three white controls frequency matched for age (birth year), sex, and status were drawn from population lists of people residing in Denmark between 1 January 1979 and 31 December 1997. The status match regarded death or emigration. The follow up period of the controls was then divided into the period before and after this date.⁶

Outcome variables
For both patients and controls, all inpatient and outpatient discharge diagnoses concerning kidney or urinary tract stones (see bmj.com) between 1 January 1978 and 31 December 1997 were retrieved from the National Patient Register under the Danish National Board of Health.⁷ Only discharges in which renal stone disease was the main diagnosis were considered for statistical evaluation.

Furthermore, for both patients and controls, information on any fracture diagnosis or osteoporosis (ICD-8 code 723.09; ICD-10 codes M80.0-M81.9) was retrieved from the same source.

Data on serum calcium were retrieved from patients' files. All calcium values reported were measured the day before surgery.

Statistics
The Mann-Whitney test or the ² test for contingency tables were used to compare numbers where appropriate. Incidence rates were calculated as the number of participants with at least one stone-related admission divided by the observation time and were compared as incidence rate ratios by Mantel-Haenszel-type statistics. Differences between proportions were calculated by Fischer's exact test. Incidence rate ratios were compared by using Poisson regression. Risk factors were analysed by using logistic regression and Cox regression. Stone-free survival was determined from Kaplan-Meier plots.

	Results

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Women made up 74% of the cohort, of whom 90% (451) had parathyroid adenoma and 10% (50) had hyperplasia. The amount of removed tissue varied greatly. Male patients were younger and had larger adenomas and a higher incidence of stone disease than female patients (table).

View larger version (23K): [in this window] [in a new window]   Fig 1.   Renal stone events among patients compared with controls before and after parathyroid surgery. Bars indicate 95% confidence intervals; vertical line indicates time of surgery

Risk of stone disease and effect of parathyroid surgery
The incidence rate ratio of contact with hospital because of stone disease was 40 (95% confidence interval 31 to 53) before parathyroid surgery and 17 (12 to 24) after surgery (P<0.01]). The risk of stone disease was highest within the four years before and in the four years after surgery, with a peak in risk immediately before diagnosis and treatment (fig 1). As much as 10 years before the diagnosis of primary hyperparathyroidism, the risk of a stone event was significantly increased. From five to 10 years after surgery the risk of stone events remained at the same level as five to 10 years before surgery. However, more than 10 years after surgery the risk of stone events in patients did not differ from the risk among controls.

The stone-free survival after surgery was 98.7% in controls and 90.4% in patients 20 years after surgery, yielding a risk difference of 8.3% (4.8-11.7%) (fig 2).

View larger version (15K): [in this window] [in a new window]   Fig 2.   Stone-free survival after surgery

Patients with preoperative stones had 27 times the risk of postoperative stone incidents (incidence rate ratio 75.9; 45.8 to 125.5) of patients without preoperative stones (2.8; 1.5 to 5.5).

The risk of strictures of the ureters and hydronephrosis was higher in patients than in controls both before and after parathyroid surgery. All three patients with ureteral stricture or hydronephrosis before diagnosis also had urinary tract stones; one of the three patients diagnosed as having postoperative strictures or hydronephrosis did not have concomitant urinary tract stones.

Differences between stone formers and non-stone formers
Apart from a significantly lower age at diagnosis (53 (SD 16) years v 60 (15) years, P<0.01) and a higher proportion of men among patients with stones (35/167 (21%) v 23/506 (5%), P<0.01), no significant differences were evident in patients with and without renal stones. The groups did not differ in parathyroid pathology, weight of removed tissue, or plasma calcium concentrations. Skeletal complications in terms of fractures or a diagnosis of osteoporosis were similar in the two groups.

Risk factors for renal stones
Before surgery, men had more stone episodes than women (adjusted odds ratio 1.83; 1.11 to 3.00), and younger patients (<60 years) had more stone episodes than older patients (0.33; 0.20 to 0.54). Neither the weight of removed parathyroid tissue nor preoperative plasma calcium was related to the risk estimate. Also, after surgery younger patients had more stone episodes than older patients. Furthermore, a history of stones was associated with more stone episodes after surgery (adjusted hazard ratio 5.89; 3.04 to 11.41).

	Discussion

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Patients with primary hyperparathyroidism had a greater risk of renal stone disease even 10 years before the diagnosis was registered than did a population based control group matched for sex and age. This is in accordance with the higher risk of fractures observed in the same population 10 years before diagnosis.⁶ These findings suggest that the disease has started several years before diagnosis and emphasises the importance of early diagnosis and treatment. This view is further supported by the finding of a higher risk of stone events before diagnosis. Parathyroid adenomas were larger and preoperative serum calcium concentrations were higher in our patients than in other surgical series, ^{8 9} supporting the theory of a delay in diagnosis.

After surgical treatment of primary hyperparathyroidism, hospital admissions due to stone episodes were reduced. Without randomisation to surgery or no surgery, one cannot determine whether this reduction in stone episodes is caused by the treatment, by the natural course of the disease, or by the synchronisation effect induced by a possible Berkson's bias. In our study, the risk of new renal stone episodes before, as well as after, parathyroid surgery was lower with older age. However, the reduction of stone events after diagnosis and surgery was significantly higher than could be explained by the average increase in age during follow up, suggesting a treatment effect of around 8%. The risk of hospital admission because of stone disease returned to normal more than 10 years after surgery (fig 1).

Patients also had a higher risk of strictures of the ureters and of hydronephrosis than the controls both before and after surgery. This could indicate that stones caused anatomical damage to the urinary tract. These structural changes could increase the risk of having stones subsequently even though the biochemical abnormalities had been normalised by surgery.

Our data accord with recent studies that have shown that patients with primary hyperparathyroidism and renal stones may continue to produce stones after parathyroid surgery even though normocalcaemia has been established. ^{4 5} Patients with renal stones who have primary hyperparathyroidism have a higher renal calcium excretion than those without stones who have similar concentrations of plasma calcium.¹⁰ Finally, three years after parathyroidectomy, patients who continue to form stones have higher average renal calcium excretion than those without stones. This suggests again that idiopathic renal hypercalciuria could have a pathogenic role in patients with recurrent stone formation.¹¹

	Acknowledgments

Contributors: See bmj.com

	Footnotes

Funding: None.

Competing interests: None declared.

This is an abridged version; the full version is on bmj.com

	References

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(Accepted 21 May 2002)