ORIGINAL
ARTICLE
Parathyroidectomy Halts the Deterioration of Renal Function in Primary Hyperparathyroidism Francesco Tassone, Andrea Guarnieri, Elena Castellano, Claudia Baffoni, Roberto Attanasio, and Giorgio Borretta Divisions of Endocrinology and Metabolism (F.T., E.C., C.B., G.B.) and Nephrology (A.G.), Santa Croce and Carle Hospital, 12100 Cuneo, Italy; and Endocrinology Service (R.A.), Galeazzi Institute Instituto di Ricovero e Cura a Carattere Scientifico, 20161 Milan, Italy
Objective: Decreased renal function has been consistently included among factors prompting recommendation for surgery in primary hyperparathyroidism (PHPT). However, most retrospective studies addressing this issue did not show an improvement in renal function after parathyroidectomy (PTX). The aim of this study was to investigate changes in renal function after PTX in PHPT patients subdivided according to renal function at diagnosis. Design: This was a retrospective cross-sectional study. Patients and Methods: We studied 109 consecutive PHPT patients before and after PTX. Biochemical evaluation included fasting total and ionized serum calcium, phosphate, creatinine, immunoreactive intact PTH, and 25-hydroxyvitamin D3 levels. Glomerular filtration rate (GFR) was assessed with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Results: Mean (⫾ SD) CKD-EPI estimated GFR (eGFR) at diagnosis was 82.4 ⫾ 19.3 mL/min/1.73 m2 (median, 84.8 mL/min/1.73 m2; interquartile range, 68.5–94.2 mL/min/1.73 m2). Patients with eGFR equal to or higher than 60 mL/min/1.73 m2 (group 1, n ⫽ 95) were significantly younger than patients with eGFR lower than 60 mL/min/1.73 m2 (group 2, n ⫽ 14; P ⬍ .0003). After PTX, eGFR did not change in patients of group 2 (P ⫽ .509), whereas it was significantly reduced in patients of group 1 (P ⬍ .0002). The difference in eGFR between baseline and post-PTX values was correlated negatively with baseline serum creatinine (R ⫽ ⫺0.27; P ⫽ .0052) and positively with baseline CKD-EPI eGFR (R ⫽ 0.32; P ⫽ .00062). At multiple regression analysis, only systolic blood pressure and baseline CKD-EPI eGFR were independent predictors of GFR variation. Conclusion: Surgical cure of PHPT halts renal function deterioration in patients with coexisting renal disease. Our study thus supports the indication for surgery in patients with eGFR less than 60 mL/min/1.73 m2, as recommended by current guidelines. Moreover, our data show that presurgical renal function is a relevant predictor of renal function after PTX. (J Clin Endocrinol Metab 100: 3069 –3073, 2015)
R
enal impairment has consistently been regarded as an indication for surgery in primary hyperparathyroidism (PHPT) (1–5). Guidelines for the clinical management of asymptomatic PHPT, at present the most frequently diagnosed form of this disease, were recently updated and, similarly to previous releases, include renal function
among criteria for surgery, confirming the threshold of ⬍ 60 mL/min/1.73 m2 to define renal impairment. Elevations in serum PTH occur indeed below this glomerular filtration rate (GFR) threshold, and pathophysiological abnormalities associated with declining renal function may worsen the hyperparathyroid state (1).
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA Copyright © 2015 by the Endocrine Society Received April 29, 2015. Accepted June 11, 2015. First Published Online June 16, 2015
Abbreviations: BMI, body mass index; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration; DBP, diastolic blood pressure; eGFR, estimated GFR; GFR, glomerular filtration rate; 25(OH)D3, 25-hydroxyvitamin D3; PHPT, primary hyperparathyroidism; PTX, parathyroidectomy; SBP, systolic blood pressure.
doi: 10.1210/jc.2015-2132
J Clin Endocrinol Metab, August 2015, 100(8):3069 –3073
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Kidney is a classical target organ of PTH, and the association between PHPT and kidney damage has long been observed (2, 6 –9). Therefore, it has been assumed that the surgical cure of PHPT could preserve kidney function in these patients (2). However, most retrospective studies addressing this issue did not show an improvement in renal function after parathyroidectomy (PTX) (10 –17). Moreover, more recently randomized controlled trials conducted primarily in mild asymptomatic PHPT patients showed no effect of PTX on renal function (18 –21). However, it cannot be excluded that surgical cure of PHPT does prevent further impairment of renal function. In particular, we are not aware of studies investigating whether surgical correction of PHPT halts an existing renal impairment. Therefore, our study aimed to check changes in renal function after PTX in a large series of PHPT patients, with or without renal impairment at baseline evaluation. In addition, we tried to identify predictors of decline in renal function in these patients.
Patients and Methods Charts of patients with PHPT referred to our Division of Endocrinology at Santa Croce Hospital, Cuneo, Italy, from 1995 through 2012 and cured by PTX were retrospectively reviewed, retrieving age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), creatinine, PTH, total and ionized calcium levels, and 25-hydroxyvitamin D3 [25(OH)D3] levels.
Table 1.
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Inclusion criteria were: 1) complete family and personal medical history; 2) physical examination including body weight, BMI, and blood pressure; 3) fasting biochemical evaluation of general blood and urinary parameters, including total and ionized serum calcium, serum phosphate, serum creatinine, serum immunoreactive intact PTH, and serum 25(OH)D3; 4) plain radiograph of the abdomen and/or ultrasound scan of the kidneys; and 5) follow-up evaluation after curative PTX (ie, serum calcium levels in the normal range within 6 mo after PTX). All patients were white Caucasians of Italian origin. All evaluations were performed during a single hospitalization at the time of the diagnosis and subsequently at the follow-up visits. Patients gave informed consent to these investigations as part of their normal medical care both at diagnosis and follow-up. The Institutional Review Board of the Santa Croce e Carle Hospital approved this chart review study. PHPT was diagnosed by demonstrating persistent hypercalcemia in the presence of inappropriately normal or elevated PTH concentrations (3). The criteria used to define asymptomatic PHPT were in agreement with the summary statement by Bilezikian et al (3), based on the NIH Consensus Conference on asymptomatic PHPT of 1991 (4). None of the patients had hepatic or active thyroid dysfunction (TSH levels ⬍ 0.2 or ⬎ 4 U/mL represented exclusion criteria) or was on ergocalciferol supplementation. Also in the present study, patients affected by multiple endocrine neoplasia type 2 and hyperparathyroidismjaw tumor syndrome were excluded. The criteria for surgery were in accordance with guidelines applied at the time of the diagnosis (3–5). Approximately 80% of PHPT patients in our series are submitted to PTX, attaining normal calcium levels in 97% of cases. Serum total calcium, phosphate, and creatinine were analyzed by a standard autoanalyzer using colorimetric and enzymatic methods.
Clinical Data of the 109 PHPT Patients
n Age, y Sex (females/males), n BMI, kg/m2 Symptomatic/asymptomatic, n SBP, mm Hg DBP, mm Hg PTH, pg/mLa Calcium, mg/dL Ionized calcium, mmol/L Creatinine, mg/dL 25(OH)D3, ng/mL CKD-EPI-eGFR, mL/min/1.73 m2a Hypertension, % ACEi/ARB use, % Diabetes, % Follow-up period, ya
Whole Group
Group 1 (eGFR > 60 mL/min/1.73 m2)
Group 2 (eGFR < 60 mL/min/1.73 m2)
Pb
109 58.1 (11.4) 73/36 26.0 (4.8) 65/44 141.2 (19.3) 86.4 (9.5) 144 (99 –261) 11.4 (1.4) 1.51 (0.21) 0.89 (0.27) 32.3 (25.0) 84.8 (68.5–94.2) 46/109 (42.2) 17/109 (15.6) 9/109 (8.2) 2.15 (0.95–3.47)
95 56.6 (10.8) 65/30 25.9 (4.8) 56/95 140.3 (19.5) 86.2 (9.2) 140 (95–250) 11.4 (1.5) 1.5 (0.2) 0.82 (0.16) 31.7 (24.0) 86.8 (73.5–98.2) 38/95 (40) 15/95 (15.8) 8/95 (8.4) 2.11 (0.95–3.19)
14 68.4 (10.4) 8/6 26.4 (4.8) 9/14 148.3 (16.0) 87.9 (11.6) 248 (120 –597) 11.6 (1.3) 1.55 (0.22) 1.32 (0.45) 35.0 (30.9) 52.6 (48.7–57.0) 8/14 (57) 2/14 (14.3) 1/14 (7.1) 2.39 (1.27–3.7)
.000211 n.s. n.s. n.s. n.s. n.s. .000652 n.s. n.s. ⬍.00001c n.s. ⬍.00001c n.s. n.s. n.s. n.s.
Abbreviations: ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; n.s., not significant. Data are expressed as mean (SD) unless stated otherwise. a
Expressed as median (interquartile range).
b
Group with eGFR ⱖ 60 mL/min/1.73 m2 vs group with eGFR ⬍ 60 mL/min/1.73 m2.
c
Results expected due to the stratification criteria.
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doi: 10.1210/jc.2015-2132
Table 2.
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Pre- and Post-PTX Data in Patients Subdivided According to eGFR
Age, y BMI, kg/m2 SBP, mm Hg DBP, mm Hg PTH, pg/mLa Calcium, mg/dL Ionized calcium, mmol/L Creatinine, mg/dL 25(OH)D3, ng/mL CKD-EPI-eGFR, mL/min/1.73 m2
Group 1 (eGFR > 60 mL/min/1.73 m2) (n ⴝ 95)
Group 2 (eGFR < 60 mL/min/1.73 m2) (n ⴝ 14)
Pre-PTX
Post-PTX
Pre-PTX
Post-PTX
56.6 ⫾ 10.8 25.9 ⫾ 4.8 140.3 ⫾ 19.5 86.2 ⫾ 9.2 140 (95–250) 11.4 ⫾ 1.5 1.5 ⫾ 0.2 0.82 ⫾ 0.16 31.7 ⫾ 24.0 86.8 (73.5–98.2)
58.9 ⫾ 11.2 26.9 ⫾ 5.2 144.8 ⫾ 20.1 87.3 ⫾ 9.7 48 (34 – 66) 9.4 ⫾ 0.61 1.19 ⫾ 0.08 0.87 ⫾ 0.19 49.2 ⫾ 31.8 81.6 (69.5–91.6)
68.4 ⫾ 10.4 26.4 ⫾ 4.8 148.3 ⫾ 16.0 87.9 ⫾ 11.6 248 (120 –597) 11.6 ⫾ 1.3 1.55 ⫾ 0.22 1.32 ⫾ 0.45 35.0 ⫾ 30.9 52.6 (48.7–57)
70.8 ⫾ 11.0 27.1 ⫾ 5.76 141.5 ⫾ 23.8 87.5 ⫾ 10.3 57 ⫾ 35 9.16 ⫾ 0.63 1.16 ⫾ 0.08 1.41 ⫾ 0.60 33.5 ⫾ 25.7 50.2 (37.0 –53.0)
Data are expressed as mean ⫾ SD unless stated otherwise. a
Expressed as median and interquartile range.
Serum immunoreactive intact PTH was measured by a second-generation immunochemiluminometric assay (Diagnostic Products Corporation) with intra- and interassay coefficients of variation of 4.2–5.7 and 6.3– 8.8%, respectively. This assay reacts with long fragments of human PTH that represent up to 50% of PTH immunoreactivity in renal failure patients. Serum 25(OH)D3 levels were measured by RIA (Biosource Europe) with intra- and interassay coefficients of variation of 6.1–7.9 and 7.1– 8.2%, respectively. GFR was assessed with the following CKD-EPI creatinine equation (6): 141 ⴱ min(SCr/k, 1)␣ ⴱ max(SCr/k, 1)⫺1.209 ⴱ 0.993Age [ⴱ 1.018 if female] [ⴱ 1.159 if black], where SCr is serum creatinine (in mg/dL), k is 0.7 for females and 0.9 for males, ␣ is ⫺0.329 for females and ⫺0.411 for males, min is the minimum of SCr/k or 1, and max is the maximum of SCr/k or 1.
Statistical analysis Variables were tested for normal distribution; whenever confirmed, results are expressed as mean ⫾ SD, and otherwise they are given as median and interquartile range. Laboratory data were compared between groups using unpaired Student’s t test or Mann-Whitney U test for unpaired samples and paired Student’s t test or Wilcoxon’s test for paired samples, where appropriate (pre vs post PTX). Relationships between continuous variables were assessed using Spearman correlation coefficients. A subsequent multiple regression analysis was performed with the variables that had P ⬍ .20 in our a priori analysis (all variables entered model). Results were considered statistically significant for P ⬍ .05. All analyses were performed using Statistica (version 5.0 for Windows; StatSoft Inc).
Results We identified 109 patients that fulfilled the inclusion criteria (67% females), and 44 of them were classified as having asymptomatic PHPT. Clinical data of the whole group of patients are reported in Table 1.
Mean CKD-EPI eGFR was 82.4 ⫾ 19.3 mL/min/1.73 m (median, 84.8 mL/min/1.73 m2; interquartile range, 68.5–94.2 mL/min/1.73 m2). According to the threshold of 60 mL/min/1.73 m2, patients in the two groups (group 1 and 2 with eGFR higher or lower than threshold, respectively) did not differ as to gender, presence/absence of PHPT symptoms, percentage of nephrolithiasis, diabetes mellitus, and hypertension (Table 2), but patients of group 1 were significantly younger than patients of group 2 ( P ⬍ .0003). No perioperative complications such as bleeding or hematomas of hemodynamic importance were reported. Table 2 shows that after PTX, eGFR did not change in patients of group 2 (P ⫽ .509 by Wilcoxon test), whereas it was significantly reduced in patients of group 1 (P ⫽ .000177). The difference in eGFR between baseline and post-PTX values was correlated negatively with baseline serum creatinine (R ⫽ ⫺0.27; P ⫽ .0052) and positively with baseline CKD-EPI eGFR (R ⫽ 0.32; P ⫽ .00062). Borderline but not significant correlations were also observed with SBP (R ⫽ 0.155; P ⫽ .13), basal serum calcium levels (R ⫽ ⫺0.17; P ⫽ .085), and age (R ⫽ ⫺0.12; P ⬍ .199). Multiple linear regression was used to examine factors associated with variation of eGFR. The included indepen2
Table 3. Multiple Linear Regression Model of Independent Predictors of Variations in eGFR Pre- and Post-PTX in PHPT Independent Variables

P
Age, y SBP, mm Hg Serum calcium, mg/dL Serum creatinine, mg/dL Baseline CKD-EPI-eGFR, mL/min/1.73 m2
0.08 0.24 ⫺0.096 0.07 0.487
.054 .019 .314 .679 .025
Dependent variable ⫽ ⌬ eGFR. R2 of the model ⫽ 0.18.
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dent variables were age, SBP, baseline serum calcium levels, baseline serum creatinine, and baseline CKD-EPI eGFR. Only SBP and baseline CKD-EPI eGFR were independent predictors of GFR variation. The full regression model is presented in Table 3 (model F ⫽ 3.94; model R2 ⫽ 0.18; P ⬍ .00274).
Discussion The present study shows that PTX prevents further deterioration of renal function in PHPT patients with a coexisting renal impairment. Moreover, presurgical CKD-EPI eGFR is significantly and independently associated with the variation in GFR after PTX, as well as SBP. Guidelines on the management of asymptomatic PHPT (the predominant form of the disease in the last decade) reaffirmed renal impairment among surgical criteria. In the last two editions of this consensus, the threshold of 60 mL/min/1.73 m2 has been identified and confirmed to define renal impairment (1–3). Indeed, pathophysiological abnormalities associated with declining renal function below this level of GFR seem to influence negatively the course of the disease (7). However, some questions remain unresolved; first is the actual negative impact of PHPT on renal function, especially in the modern clinical presentation of the disease. In fact, in these mild forms, observational data are not very consistent, ie, there is no definite evidence that asymptomatic/mild PHPT has a negative impact on renal function. Moreover, and most importantly, it is not yet undoubtedly proven that curative PTX impacts positively on renal function (2). While browsing literature for evidence that surgical cure of PHPT is able to change the course of renal impairment, we found that most retrospective studies did not show any change in renal function (no matter if estimated with serum creatinine, creatinine clearance, or GFR) over periods of follow-up ranging from months to years (9 –17). More recently, several prospective randomized controlled trials randomized asymptomatic PHPT patients to observation or PTX (18 –21). Despite differences in the length of follow-up and in the evaluation of renal function, no effect on renal function was dependent on the treatment arm. So, definite data about a beneficial effect of PTX on existing renal disease are still lacking (2). To our knowledge, even if current guidelines recommend PTX in asymptomatic PHPT patients with eGFR lower than 60 mL/min/1.73 m2, there is indeed no evidence that curative PTX could be beneficial for renal function in PHPT patients with coexisting renal damage.
J Clin Endocrinol Metab, August 2015, 100(8):3069 –3073
Our data show for the first time that curative PTX in PHPT patients with a baseline eGFR ⬍ 60 mL/min/1.73 m2 could prevent further impairment of renal function. On the other hand, this is not the case in patients with a baseline GFR above 60 mL/min/1.73 m2. It might be speculated that in this latter group, the fate of renal function is not affected by surgical cure of PHPT. Due to the retrospective observational nature of the study, we cannot establish a direct cause-and-effect relationship between renal function and PTX; we can only raise several hypotheses. First, patients with a concomitant renal disease might be more prone to PHPT-mediated kidney damage. Cure of PHPT in these patients could thus halt further decline of renal function. Second, patients without renal impairment (ie, eGFR ⬎ 60 mL/min/1.73 m2) showed a decline in renal function after PTX, possibly not due to PHPT-related factors. However, it should be noted that known factors influencing renal function (namely, diabetes mellitus, hypertension, angiotensinconverting enzyme inhibitor/angiotensin receptor blocker therapy) were evenly distributed in both groups. Third, it might be possible that PHPT does not cause renal damage in all patients, but only in predisposed subjects that we are not able to identify a priori. In other words, only some PHPT patients are susceptible to PHPT kidney damage, and these patients would be the ones that could benefit from PTX. Lastly, we have to acknowledge that the equations used to estimate GFR are less reliable whenever GFR values are higher than 60 mL/min/1.73 m2 (6). This issue weakens our counterintuitive finding about GFR reduction after PTX in PHPT patients with normal renal function. In conclusion, even taking into account all the abovementioned limitations, our data show that surgical cure of PHPT halts renal function worsening in patients with concomitant renal disease, thus supporting current guidelines that recommend surgery for PHPT patients whose GFR is below 60 mL/min/1.73 m2. Moreover, our data also show that presurgical renal function is the most relevant predictor of renal function change after PTX.
Acknowledgments We are indebted to Mrs Michela Ghio for the contribution to data collection. Address all correspondence and requests for reprints to: Francesco Tassone, MD, PhD, Division of Endocrinology Diabetes and Metabolism, Santa Croce e Carle Hospital, 12100 Cuneo, Italy. E-mail: [email protected]. Disclosure Summary: The authors have nothing to disclose.
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doi: 10.1210/jc.2015-2132
References 1. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3561–3569. 2. Hendrickson CD, Castro Pereira DJ, Comi RJ. Renal impairment as a surgical indication in primary hyperparathyroidism: do the data support this recommendation? J Clin Endocrinol Metab. 2014; 99(8):2646 –2650. 3. Bilezikian JP, Potts JT Jr, Fuleihan Gel-H, et al. Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Bone Miner Res. 2002;17 (suppl 2):N2–N11. 4. NIH conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement. Ann Intern Med. 1991;114:593–597. 5. Bilezikian JP, Khan AA, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94(2):335–339. 6. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3:1–150. 7. Gianotti L, Tassone F, Cesario F, et al. A slight decrease in renal function further impairs bone mineral density in primary hyperparathyroidism. J Clin Endocrinol Metab. 2006;91(8):3011–3016. 8. Walker MD, Nickolas T, Kepley A, et al. Predictors of renal function in primary hyperparathyroidism. J Clin Endocrinol Metab. 2014; 99(5):1885–1892. 9. Valdemarsson S, Lindergård B, Tibblin S, Bergenfelz A. Increased biochemical markers of bone formation and resorption in primary hyperparathyroidism with special reference to patients with mild disease. J Intern Med. 1998;243(2):115–122. 10. Kristoffersson A, Backman C, Granqvist K, Järhult J. Pre- and postoperative evaluation of renal function with five different tests in patients with primary hyperparathyroidism. J Intern Med. 1990; 227(5):317–324.
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11. Jones DB, Jones JH, Lloyd HJ, Lucas PA, Wilkins WE, Walker DA. Changes in blood pressure and renal function after parathyroidectomy in primary hyperparathyroidism. Postgrad Med J. 1983; 59(692):350 –353. 12. Hedbäck G, Abrahamsson K, Odén A. The improvement of renal concentration capacity after surgery for primary hyperparathyroidism. Eur J Clin Invest. 2001;31(12):1048 –1053. 13. Salahudeen AK, Thomas TH, Sellars L, et al. Hypertension and renal dysfunction in primary hyperparathyroidism: effect of parathyroidectomy. Clin Sci (Lond). 1989;76(3):289 –296. 14. Ghose RR, Morgan WD. Improvement in renal function in primary hyperparathyroidism following parathyroidectomy. Postgrad Med J. 1981;57(663):28 –30. 15. Posen S, Clifton-Bligh P, Reeve TS, Wagstaffe C, Wilkinson M. Is parathyroidectomy of benefit in primary hyperparathyroidism? Q J Med. 1985;54(215):241–251. 16. Rowlands C, Zyada A, Zouwail S, Joshi H, Stechman MJ, ScottCoombes DM. Recurrent urolithiasis following parathyroidectomy for primary hyperparathyroidism. Ann R Coll Surg Engl. 2013; 95(7):523–528. 17. Falkheden T, Ohlsson L, Sjögren B. Renal function in primary hyperparathyroidism. A follow-up study two to eleven years after surgery comprising 139 patients. Scand J Urol Nephrol. 1980;14(2): 167–175. 18. Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Engl J Med. 1999;341(17):1249 –1255. 19. Rao DS, Phillips ER, Divine GW, Talpos GB. Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism. J Clin Endocrinol Metab. 2004;89(11):5415–5422. 20. Bollerslev J, Jansson S, Mollerup CL, et al. Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial. J Clin Endocrinol Metab. 2007;92(5):1687–1692. 21. Ambrogini E, Cetani F, Cianferotti L, et al. Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial. J Clin Endocrinol Metab. 2007;92(8): 3114 –3121.
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ARTICLE
Parathyroidectomy Halts the Deterioration of Renal Function in Primary Hyperparathyroidism Francesco Tassone, Andrea Guarnieri, Elena Castellano, Claudia Baffoni, Roberto Attanasio, and Giorgio Borretta Divisions of Endocrinology and Metabolism (F.T., E.C., C.B., G.B.) and Nephrology (A.G.), Santa Croce and Carle Hospital, 12100 Cuneo, Italy; and Endocrinology Service (R.A.), Galeazzi Institute Instituto di Ricovero e Cura a Carattere Scientifico, 20161 Milan, Italy
Objective: Decreased renal function has been consistently included among factors prompting recommendation for surgery in primary hyperparathyroidism (PHPT). However, most retrospective studies addressing this issue did not show an improvement in renal function after parathyroidectomy (PTX). The aim of this study was to investigate changes in renal function after PTX in PHPT patients subdivided according to renal function at diagnosis. Design: This was a retrospective cross-sectional study. Patients and Methods: We studied 109 consecutive PHPT patients before and after PTX. Biochemical evaluation included fasting total and ionized serum calcium, phosphate, creatinine, immunoreactive intact PTH, and 25-hydroxyvitamin D3 levels. Glomerular filtration rate (GFR) was assessed with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Results: Mean (⫾ SD) CKD-EPI estimated GFR (eGFR) at diagnosis was 82.4 ⫾ 19.3 mL/min/1.73 m2 (median, 84.8 mL/min/1.73 m2; interquartile range, 68.5–94.2 mL/min/1.73 m2). Patients with eGFR equal to or higher than 60 mL/min/1.73 m2 (group 1, n ⫽ 95) were significantly younger than patients with eGFR lower than 60 mL/min/1.73 m2 (group 2, n ⫽ 14; P ⬍ .0003). After PTX, eGFR did not change in patients of group 2 (P ⫽ .509), whereas it was significantly reduced in patients of group 1 (P ⬍ .0002). The difference in eGFR between baseline and post-PTX values was correlated negatively with baseline serum creatinine (R ⫽ ⫺0.27; P ⫽ .0052) and positively with baseline CKD-EPI eGFR (R ⫽ 0.32; P ⫽ .00062). At multiple regression analysis, only systolic blood pressure and baseline CKD-EPI eGFR were independent predictors of GFR variation. Conclusion: Surgical cure of PHPT halts renal function deterioration in patients with coexisting renal disease. Our study thus supports the indication for surgery in patients with eGFR less than 60 mL/min/1.73 m2, as recommended by current guidelines. Moreover, our data show that presurgical renal function is a relevant predictor of renal function after PTX. (J Clin Endocrinol Metab 100: 3069 –3073, 2015)
R
enal impairment has consistently been regarded as an indication for surgery in primary hyperparathyroidism (PHPT) (1–5). Guidelines for the clinical management of asymptomatic PHPT, at present the most frequently diagnosed form of this disease, were recently updated and, similarly to previous releases, include renal function
among criteria for surgery, confirming the threshold of ⬍ 60 mL/min/1.73 m2 to define renal impairment. Elevations in serum PTH occur indeed below this glomerular filtration rate (GFR) threshold, and pathophysiological abnormalities associated with declining renal function may worsen the hyperparathyroid state (1).
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA Copyright © 2015 by the Endocrine Society Received April 29, 2015. Accepted June 11, 2015. First Published Online June 16, 2015
Abbreviations: BMI, body mass index; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration; DBP, diastolic blood pressure; eGFR, estimated GFR; GFR, glomerular filtration rate; 25(OH)D3, 25-hydroxyvitamin D3; PHPT, primary hyperparathyroidism; PTX, parathyroidectomy; SBP, systolic blood pressure.
doi: 10.1210/jc.2015-2132
J Clin Endocrinol Metab, August 2015, 100(8):3069 –3073
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Kidney is a classical target organ of PTH, and the association between PHPT and kidney damage has long been observed (2, 6 –9). Therefore, it has been assumed that the surgical cure of PHPT could preserve kidney function in these patients (2). However, most retrospective studies addressing this issue did not show an improvement in renal function after parathyroidectomy (PTX) (10 –17). Moreover, more recently randomized controlled trials conducted primarily in mild asymptomatic PHPT patients showed no effect of PTX on renal function (18 –21). However, it cannot be excluded that surgical cure of PHPT does prevent further impairment of renal function. In particular, we are not aware of studies investigating whether surgical correction of PHPT halts an existing renal impairment. Therefore, our study aimed to check changes in renal function after PTX in a large series of PHPT patients, with or without renal impairment at baseline evaluation. In addition, we tried to identify predictors of decline in renal function in these patients.
Patients and Methods Charts of patients with PHPT referred to our Division of Endocrinology at Santa Croce Hospital, Cuneo, Italy, from 1995 through 2012 and cured by PTX were retrospectively reviewed, retrieving age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), creatinine, PTH, total and ionized calcium levels, and 25-hydroxyvitamin D3 [25(OH)D3] levels.
Table 1.
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Inclusion criteria were: 1) complete family and personal medical history; 2) physical examination including body weight, BMI, and blood pressure; 3) fasting biochemical evaluation of general blood and urinary parameters, including total and ionized serum calcium, serum phosphate, serum creatinine, serum immunoreactive intact PTH, and serum 25(OH)D3; 4) plain radiograph of the abdomen and/or ultrasound scan of the kidneys; and 5) follow-up evaluation after curative PTX (ie, serum calcium levels in the normal range within 6 mo after PTX). All patients were white Caucasians of Italian origin. All evaluations were performed during a single hospitalization at the time of the diagnosis and subsequently at the follow-up visits. Patients gave informed consent to these investigations as part of their normal medical care both at diagnosis and follow-up. The Institutional Review Board of the Santa Croce e Carle Hospital approved this chart review study. PHPT was diagnosed by demonstrating persistent hypercalcemia in the presence of inappropriately normal or elevated PTH concentrations (3). The criteria used to define asymptomatic PHPT were in agreement with the summary statement by Bilezikian et al (3), based on the NIH Consensus Conference on asymptomatic PHPT of 1991 (4). None of the patients had hepatic or active thyroid dysfunction (TSH levels ⬍ 0.2 or ⬎ 4 U/mL represented exclusion criteria) or was on ergocalciferol supplementation. Also in the present study, patients affected by multiple endocrine neoplasia type 2 and hyperparathyroidismjaw tumor syndrome were excluded. The criteria for surgery were in accordance with guidelines applied at the time of the diagnosis (3–5). Approximately 80% of PHPT patients in our series are submitted to PTX, attaining normal calcium levels in 97% of cases. Serum total calcium, phosphate, and creatinine were analyzed by a standard autoanalyzer using colorimetric and enzymatic methods.
Clinical Data of the 109 PHPT Patients
n Age, y Sex (females/males), n BMI, kg/m2 Symptomatic/asymptomatic, n SBP, mm Hg DBP, mm Hg PTH, pg/mLa Calcium, mg/dL Ionized calcium, mmol/L Creatinine, mg/dL 25(OH)D3, ng/mL CKD-EPI-eGFR, mL/min/1.73 m2a Hypertension, % ACEi/ARB use, % Diabetes, % Follow-up period, ya
Whole Group
Group 1 (eGFR > 60 mL/min/1.73 m2)
Group 2 (eGFR < 60 mL/min/1.73 m2)
Pb
109 58.1 (11.4) 73/36 26.0 (4.8) 65/44 141.2 (19.3) 86.4 (9.5) 144 (99 –261) 11.4 (1.4) 1.51 (0.21) 0.89 (0.27) 32.3 (25.0) 84.8 (68.5–94.2) 46/109 (42.2) 17/109 (15.6) 9/109 (8.2) 2.15 (0.95–3.47)
95 56.6 (10.8) 65/30 25.9 (4.8) 56/95 140.3 (19.5) 86.2 (9.2) 140 (95–250) 11.4 (1.5) 1.5 (0.2) 0.82 (0.16) 31.7 (24.0) 86.8 (73.5–98.2) 38/95 (40) 15/95 (15.8) 8/95 (8.4) 2.11 (0.95–3.19)
14 68.4 (10.4) 8/6 26.4 (4.8) 9/14 148.3 (16.0) 87.9 (11.6) 248 (120 –597) 11.6 (1.3) 1.55 (0.22) 1.32 (0.45) 35.0 (30.9) 52.6 (48.7–57.0) 8/14 (57) 2/14 (14.3) 1/14 (7.1) 2.39 (1.27–3.7)
.000211 n.s. n.s. n.s. n.s. n.s. .000652 n.s. n.s. ⬍.00001c n.s. ⬍.00001c n.s. n.s. n.s. n.s.
Abbreviations: ACEi/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; n.s., not significant. Data are expressed as mean (SD) unless stated otherwise. a
Expressed as median (interquartile range).
b
Group with eGFR ⱖ 60 mL/min/1.73 m2 vs group with eGFR ⬍ 60 mL/min/1.73 m2.
c
Results expected due to the stratification criteria.
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doi: 10.1210/jc.2015-2132
Table 2.
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Pre- and Post-PTX Data in Patients Subdivided According to eGFR
Age, y BMI, kg/m2 SBP, mm Hg DBP, mm Hg PTH, pg/mLa Calcium, mg/dL Ionized calcium, mmol/L Creatinine, mg/dL 25(OH)D3, ng/mL CKD-EPI-eGFR, mL/min/1.73 m2
Group 1 (eGFR > 60 mL/min/1.73 m2) (n ⴝ 95)
Group 2 (eGFR < 60 mL/min/1.73 m2) (n ⴝ 14)
Pre-PTX
Post-PTX
Pre-PTX
Post-PTX
56.6 ⫾ 10.8 25.9 ⫾ 4.8 140.3 ⫾ 19.5 86.2 ⫾ 9.2 140 (95–250) 11.4 ⫾ 1.5 1.5 ⫾ 0.2 0.82 ⫾ 0.16 31.7 ⫾ 24.0 86.8 (73.5–98.2)
58.9 ⫾ 11.2 26.9 ⫾ 5.2 144.8 ⫾ 20.1 87.3 ⫾ 9.7 48 (34 – 66) 9.4 ⫾ 0.61 1.19 ⫾ 0.08 0.87 ⫾ 0.19 49.2 ⫾ 31.8 81.6 (69.5–91.6)
68.4 ⫾ 10.4 26.4 ⫾ 4.8 148.3 ⫾ 16.0 87.9 ⫾ 11.6 248 (120 –597) 11.6 ⫾ 1.3 1.55 ⫾ 0.22 1.32 ⫾ 0.45 35.0 ⫾ 30.9 52.6 (48.7–57)
70.8 ⫾ 11.0 27.1 ⫾ 5.76 141.5 ⫾ 23.8 87.5 ⫾ 10.3 57 ⫾ 35 9.16 ⫾ 0.63 1.16 ⫾ 0.08 1.41 ⫾ 0.60 33.5 ⫾ 25.7 50.2 (37.0 –53.0)
Data are expressed as mean ⫾ SD unless stated otherwise. a
Expressed as median and interquartile range.
Serum immunoreactive intact PTH was measured by a second-generation immunochemiluminometric assay (Diagnostic Products Corporation) with intra- and interassay coefficients of variation of 4.2–5.7 and 6.3– 8.8%, respectively. This assay reacts with long fragments of human PTH that represent up to 50% of PTH immunoreactivity in renal failure patients. Serum 25(OH)D3 levels were measured by RIA (Biosource Europe) with intra- and interassay coefficients of variation of 6.1–7.9 and 7.1– 8.2%, respectively. GFR was assessed with the following CKD-EPI creatinine equation (6): 141 ⴱ min(SCr/k, 1)␣ ⴱ max(SCr/k, 1)⫺1.209 ⴱ 0.993Age [ⴱ 1.018 if female] [ⴱ 1.159 if black], where SCr is serum creatinine (in mg/dL), k is 0.7 for females and 0.9 for males, ␣ is ⫺0.329 for females and ⫺0.411 for males, min is the minimum of SCr/k or 1, and max is the maximum of SCr/k or 1.
Statistical analysis Variables were tested for normal distribution; whenever confirmed, results are expressed as mean ⫾ SD, and otherwise they are given as median and interquartile range. Laboratory data were compared between groups using unpaired Student’s t test or Mann-Whitney U test for unpaired samples and paired Student’s t test or Wilcoxon’s test for paired samples, where appropriate (pre vs post PTX). Relationships between continuous variables were assessed using Spearman correlation coefficients. A subsequent multiple regression analysis was performed with the variables that had P ⬍ .20 in our a priori analysis (all variables entered model). Results were considered statistically significant for P ⬍ .05. All analyses were performed using Statistica (version 5.0 for Windows; StatSoft Inc).
Results We identified 109 patients that fulfilled the inclusion criteria (67% females), and 44 of them were classified as having asymptomatic PHPT. Clinical data of the whole group of patients are reported in Table 1.
Mean CKD-EPI eGFR was 82.4 ⫾ 19.3 mL/min/1.73 m (median, 84.8 mL/min/1.73 m2; interquartile range, 68.5–94.2 mL/min/1.73 m2). According to the threshold of 60 mL/min/1.73 m2, patients in the two groups (group 1 and 2 with eGFR higher or lower than threshold, respectively) did not differ as to gender, presence/absence of PHPT symptoms, percentage of nephrolithiasis, diabetes mellitus, and hypertension (Table 2), but patients of group 1 were significantly younger than patients of group 2 ( P ⬍ .0003). No perioperative complications such as bleeding or hematomas of hemodynamic importance were reported. Table 2 shows that after PTX, eGFR did not change in patients of group 2 (P ⫽ .509 by Wilcoxon test), whereas it was significantly reduced in patients of group 1 (P ⫽ .000177). The difference in eGFR between baseline and post-PTX values was correlated negatively with baseline serum creatinine (R ⫽ ⫺0.27; P ⫽ .0052) and positively with baseline CKD-EPI eGFR (R ⫽ 0.32; P ⫽ .00062). Borderline but not significant correlations were also observed with SBP (R ⫽ 0.155; P ⫽ .13), basal serum calcium levels (R ⫽ ⫺0.17; P ⫽ .085), and age (R ⫽ ⫺0.12; P ⬍ .199). Multiple linear regression was used to examine factors associated with variation of eGFR. The included indepen2
Table 3. Multiple Linear Regression Model of Independent Predictors of Variations in eGFR Pre- and Post-PTX in PHPT Independent Variables

P
Age, y SBP, mm Hg Serum calcium, mg/dL Serum creatinine, mg/dL Baseline CKD-EPI-eGFR, mL/min/1.73 m2
0.08 0.24 ⫺0.096 0.07 0.487
.054 .019 .314 .679 .025
Dependent variable ⫽ ⌬ eGFR. R2 of the model ⫽ 0.18.
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Tassone et al
Parathyroidectomy and Renal Function in PHPT
dent variables were age, SBP, baseline serum calcium levels, baseline serum creatinine, and baseline CKD-EPI eGFR. Only SBP and baseline CKD-EPI eGFR were independent predictors of GFR variation. The full regression model is presented in Table 3 (model F ⫽ 3.94; model R2 ⫽ 0.18; P ⬍ .00274).
Discussion The present study shows that PTX prevents further deterioration of renal function in PHPT patients with a coexisting renal impairment. Moreover, presurgical CKD-EPI eGFR is significantly and independently associated with the variation in GFR after PTX, as well as SBP. Guidelines on the management of asymptomatic PHPT (the predominant form of the disease in the last decade) reaffirmed renal impairment among surgical criteria. In the last two editions of this consensus, the threshold of 60 mL/min/1.73 m2 has been identified and confirmed to define renal impairment (1–3). Indeed, pathophysiological abnormalities associated with declining renal function below this level of GFR seem to influence negatively the course of the disease (7). However, some questions remain unresolved; first is the actual negative impact of PHPT on renal function, especially in the modern clinical presentation of the disease. In fact, in these mild forms, observational data are not very consistent, ie, there is no definite evidence that asymptomatic/mild PHPT has a negative impact on renal function. Moreover, and most importantly, it is not yet undoubtedly proven that curative PTX impacts positively on renal function (2). While browsing literature for evidence that surgical cure of PHPT is able to change the course of renal impairment, we found that most retrospective studies did not show any change in renal function (no matter if estimated with serum creatinine, creatinine clearance, or GFR) over periods of follow-up ranging from months to years (9 –17). More recently, several prospective randomized controlled trials randomized asymptomatic PHPT patients to observation or PTX (18 –21). Despite differences in the length of follow-up and in the evaluation of renal function, no effect on renal function was dependent on the treatment arm. So, definite data about a beneficial effect of PTX on existing renal disease are still lacking (2). To our knowledge, even if current guidelines recommend PTX in asymptomatic PHPT patients with eGFR lower than 60 mL/min/1.73 m2, there is indeed no evidence that curative PTX could be beneficial for renal function in PHPT patients with coexisting renal damage.
J Clin Endocrinol Metab, August 2015, 100(8):3069 –3073
Our data show for the first time that curative PTX in PHPT patients with a baseline eGFR ⬍ 60 mL/min/1.73 m2 could prevent further impairment of renal function. On the other hand, this is not the case in patients with a baseline GFR above 60 mL/min/1.73 m2. It might be speculated that in this latter group, the fate of renal function is not affected by surgical cure of PHPT. Due to the retrospective observational nature of the study, we cannot establish a direct cause-and-effect relationship between renal function and PTX; we can only raise several hypotheses. First, patients with a concomitant renal disease might be more prone to PHPT-mediated kidney damage. Cure of PHPT in these patients could thus halt further decline of renal function. Second, patients without renal impairment (ie, eGFR ⬎ 60 mL/min/1.73 m2) showed a decline in renal function after PTX, possibly not due to PHPT-related factors. However, it should be noted that known factors influencing renal function (namely, diabetes mellitus, hypertension, angiotensinconverting enzyme inhibitor/angiotensin receptor blocker therapy) were evenly distributed in both groups. Third, it might be possible that PHPT does not cause renal damage in all patients, but only in predisposed subjects that we are not able to identify a priori. In other words, only some PHPT patients are susceptible to PHPT kidney damage, and these patients would be the ones that could benefit from PTX. Lastly, we have to acknowledge that the equations used to estimate GFR are less reliable whenever GFR values are higher than 60 mL/min/1.73 m2 (6). This issue weakens our counterintuitive finding about GFR reduction after PTX in PHPT patients with normal renal function. In conclusion, even taking into account all the abovementioned limitations, our data show that surgical cure of PHPT halts renal function worsening in patients with concomitant renal disease, thus supporting current guidelines that recommend surgery for PHPT patients whose GFR is below 60 mL/min/1.73 m2. Moreover, our data also show that presurgical renal function is the most relevant predictor of renal function change after PTX.
Acknowledgments We are indebted to Mrs Michela Ghio for the contribution to data collection. Address all correspondence and requests for reprints to: Francesco Tassone, MD, PhD, Division of Endocrinology Diabetes and Metabolism, Santa Croce e Carle Hospital, 12100 Cuneo, Italy. E-mail: [email protected]. Disclosure Summary: The authors have nothing to disclose.
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doi: 10.1210/jc.2015-2132
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