Int Urol Nephrol (2012) 44:857–863 DOI 10.1007/s11255-011-9953-6
NEPHROLOGY – ORIGINAL PAPER
Persistence of hypercalciuria after successful surgical treatment for primary hyperparathyroidism Francisco Rodolfo Spivacow • Armando Luis Negri Elisa Elena del Valle • Erich Fradinger • Carolina Martinez • Ana Polonsky
•
Received: 30 December 2010 / Accepted: 23 March 2011 / Published online: 20 April 2011 Ó Springer Science+Business Media, B.V. 2011
Abstract Primary hyperparathyroidism (PHPT) causes hypercalciuria and stone disease in a subset of patients. Hypercalciuria typically normalizes after surgery, although the risk of stone formation may persist up to 10 years. There are few reports in the literature that show persistent hypercalciuria despite normalization of serum calcium after parathyroid surgery. We retrospectively analyzed 111 patients with PHPT from the osteoporosis, and stone clinics seen between 1999 and 2006. We selected only patients who had a complete metabolic profile that included 24-hour collections before and at least 3 months after parathyroidectomy. We excluded patients who had creatinine clearance \60 ml/min/ 1.73 m2. Fifty-four patients were selected for further analysis, 46 with baseline hypercalciuria and 8 with normocalciuria. Changes in filtered load of calcium and fractional excretion of calcium were evaluated before and after parathyroid surgery. Total and ionized calcium and phosphorus normalized in all patients after surgery (24 ± 19 months); fractional excretion of calcium decreased, but did not normalize. Hypercalciuria persisted after surgery in 30.7% (n = 12/39) of the women and 50% (n = 4/8) of
F. R. Spivacow A. L. Negri (&) E. E. del Valle E. Fradinger C. Martinez A. Polonsky Instituto de Investigaciones Metabo´licas, Universidad del Salvador, Libertad 836 1 piso, 1012 Buenos Aires, Argentina e-mail:
[email protected]
men. Of the patients in whom calciuria normalized after parathyroidectomy, 43.3% (n = 13/30) had kidney stones before surgery, whereas kidney stones were present in 87.5% (n = 14/16) in those in whom hypercalciuria persisted postsurgery. In hypercalciuric men and women before surgery in whom hypercalciuria persisted after surgery, fractional excretion of calcium was significantly higher than that in patients with normocalciuria. Conclusions: Persistently increased fractional excretion of calcium could explain the sustained increased risk of stone disease in patients with PHPT for many years after successful parathyroidectomy. Keywords Primary hyperparathyroidism Hypercalciuria Renal stones Surgery Fractional calcium excretion
Introduction Primary hyperparathyroidism (PHPT) is the second most frequent endocrine disease diagnosed by demonstrating persistent hypercalcemia together with elevated serum parathyroid hormone (PTH) concentrations [1]. The estimated incidence is 1 case per 1,000 men and 2–3 cases per 1,000 women [2]. PHPT causes hypercalciuria and stone disease in a subset of patients. Before the advent of routine serum calcium
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testing, urolithiasis developed in almost half the patients with PHPT [3]. In more recent series, this number has decreased dramatically to approximately 20% or less. In patients presenting with recurrent stone disease, the prevalence of PHPT ranges between 2 and 8% [4]; in our own series, it was 2.6% [5]. Patients with PHPT and stone disease frequently present with moderate to severe hypercalciuria with mild to moderate increase in serum calcium. To date, parathyroidectomy is the most effective treatment for symptomatic PHPT[6], with normalization of serum parameters in 95% of patients [7]. Hypercalciuria typically normalizes after surgery, although the risk of stone formation may persist up to 10 years [8]. There are few reports in the literature that show persistent hypercalciuria despite normalization of serum calcium after parathyroid surgery. Farias et al. [9, 10] found that after successful parathyroid surgery, hypercalciuria persisted in 60% of a small group of patients with PHPT and suggested disturbances in renal function as its cause. In a recent study resuming 40 years of experience, Parks et al. [11] mention that surgical cure of PHPT did not completely eradicate either hypercalciuria or hypophosphatemia suggesting that some of these patients have some additional mineral disorder. Thus, the aim of our study was to assess the changes in the metabolic profile before and after parathyroid surgery in a large group of patients with PHPT and to analyze those with persistent hypercalciuria.
Materials and methods We retrospectively analyzed 111 patients with PHPT from the osteoporosis, and stone clinics seen at the Metabolic Research Institute between 1999 and 2006. We selected only patients that had a complete metabolic profile that included 24-hour collections before and at least 3 months after parathyroidectomy. Surgery was indicated in symptomatic patients with PHPT; in asymptomatic patients, we followed criteria similar to those established in the proceedings of an International workshop on asymptomatic PHPT [12]. We excluded patients that had a corrected creatinine clearance \60 ml/min/1.73 m2. All study procedures were approved by the institutional review board of
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the Metabolic Research Institute (CODEI), and each study participant gave his written informed consent for the use of their clinical records for scientific purposes. Fifty-four patients were selected for further analysis, 46 with basal hypercalciuria (39 women mean age: 59.1 ± 10 years and 7 men mean age: 56.8 ± 11 years) and 8 with normocalciuria (7 women mean age: 54.2 ± 15 years and 1 man of 25 years). Kidney stones were present in 22 of the women (47.8%) and 7 of the men (87.5%). The histological study of the removed parathyroid glands showed mostly adenomas, 72% in women and 87.5% in men. We considered hypercalciuria a urinary calcium excretion [220 mg/24 h for women and [300 mg/24 h for men or [4 mg/Kg body weight in both sexes on a normal calcium diet (*1,000 mg/ day). Fasting morning, venous blood samples where obtained before breakfast and analyzed for creatinine, calcium, ionic calcium, phosphorus, and iPTH. A 24 hour, urine sample was obtained, followed by a 2-hour fasting urine sample collected by spontaneous voiding on the morning of the following day. Urine samples were analyzed for calcium, creatinine, sodium, and deoxypyridoline (DPD). Creatinine clearance (corrected for 1.73 m2 of body surface area), filtered load of calcium (FL Ca) = UF Ca 9 GFR, and fractional excretion of calcium (FE Ca) = U Ca/FL Ca were calculated from plasma and urinary samples (normal FE Ca for our normal population on a normal calcium diet is 0.019 ± 0.05 in women and 0.021 ± 0.04 in men). Serum ionized calcium was taken as ultrafiltrable calcium (UF Ca). Urinary calcium excretion corrected for 100 ml of glomerular filtrate (U Ca/100 ml GFR) was also calculated in order to compare patients with different GFR values. Serum ionized calcium was measured by ionselective electrode on a Roche Diagnostics AVL instrument without correcting for pH (normal values: 4.5–5.2 mg%). Serum and urine calcium and sodium were measured by ion-selective electrode (ISE) method using a Synchron CX3 automated analyzer (Beckman, Beckman Instruments inc., Brea, California, USA). Normal values for total serum calcium: 8.8–10.5 mg%. Creatinine (Jaffe) and phosphate (UV) were measured using CCX Spectrum automated analyzer (Abbott Labs, USA). Normal
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values for serum creatinine: females: 0.6–1.1 mg%; males 0.9–1.3 mg%. Normal values for phosphate: 2.7–4.5 mg%. Intact PTH was measured using Roche Elecsys PTH from Roche Diagnostics; normal values: 10-65 pg/ml. Deoxypyridoline (DPD) was measured by Elisa method (Metra Biosystems RR; normal values: females: 3–8 nM DPyr/mM Creat.and males: 2.3–5.4 nM DPyr/mM Creat).
normalized, 43.3% (n = 13/30) had kidney stones previously, whereas renal lithiasis was present in 87.5% (n = 14/16) among those in whom hypercalciuria persisted postsurgery. Both in hypercalciuric men and women before surgery in whom hypercalciuria persisted after surgery, FE Ca determinations were significantly higher than in those in whom calciuria normalized.
Statistical analysis
Discussion
Student’s unpaired t tests were used to compare PHPT patients with and without basal hypercalcuria, and all of the patients before and after surgery. The same test was used to compare hypercalciuric patients after surgery who corrected hypercalciuria and those with persistent hypercalciuria. Results were expressed as mean ± SD. In both cases, P B 0.05 was considered a significant.
PHPT is a well known cause for hypercalcemia, and one of the classic presenting symptoms in these patients is kidney stone disease [13]. Hypercalciuria has traditionally been thought as the primary risk factor for urinary stone disease in these patients, yet only a small proportion of them develop lithiasis. In the classical view, primary hyperparathyroidism produces excessive bone resorption resulting from hypersecretion of PTH. Intestinal absorption of calcium is frequently elevated, because of PTHdependent stimulation of renal synthesis of 1,25 (OH)2D. Broadus et al. have demonstrated that the higher the plasma levels of 1,25(OH)2D, the higher the absorption of calcium and the incidence of renal stones in patients with PHPT [14]. These effects (increased bone resorption and increased intestinal absorption) lead to increased serum calcium levels and increased filtered load of calcium. The presence of hypercalciuria in PHPT seems paradoxical, since the primary renal effect of PTH is to stimulate calcium reabsorption. Thus, for hypercalciuria to occur, the PTH-dependent augmentation of renal reabsorption of calcium should be overcome by an increase in renal filtered load and by a suppressive effect of hypercalcemia on calcium reabsorption. In the present series of patients with PHPT, those with renal stones are over represented because of a selection bias. We found that hypercalciuria before surgery was very frequent in these patients ([80%) and that the principal difference between hypercalciuric and normocalciuric patients was the higher fractional excretion of calcium in the former. After surgery, filtered load of calcium decreased in all of the patients but fractional excretion of calcium remained elevated in those with persistent hypercalciuria. Even in those that normalized calciuria, fractional excretion of calcium persisted at values
Results Before surgery, hypercalciuria was present in 39 of the women (84.8%), and in 7 of the men (87.5%) included. Table 1 shows the comparison of baseline biochemical profiles of hypercalciuric and normocalciuric patients with PHPT before surgery. There were no differences in urinary sodium excretion that could account for differences in calciuria. The only difference between groups was a significantly higher fractional excretion of calcium in the hypercalciuric group. Table 2 shows the biochemical profile of all of the patients before and 24 ± 19 months after surgery. Total serum calcium, serum ionized calcium and serum phosphorus were normalized after parathyroidectomy in the patients in whom their baseline values were abnormal. In only 2 patients, iPTH stayed slightly elevated, although the decrease was more than 70% postsurgery. Again, although fractional excretion of calcium decreased, it did not normalize. Hypercalciuria persisted after surgery in 30.7% (n = 12/39) of the women and 50% (n = 4/8) of men. Table 3 shows the metabolic profile after surgery of patients with normalized and persistent hypercalciuria. Among the patients whose calciuria
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Table 1 Comparison of baseline biochemical profiles of hypercalciuric and normocalciuric patients with PHPT before surgery Hypercalciuric women (n = 39)
Normocalciuric women (n = 7)
P
Hypercalciuric men (n = 7)
Normocalciuric man (n = 1)
Total Ca (mg/dl)
11.2 ± 1.0
11.4 ± 0.5
NS
11.1 ± 0.7
12
Ionized Ca (mg/dl)
5.70 ± 0.5
5.69 ± 0.5
NS
5.56 ± 0.32
6.0
Phosphate (mg/dl)
3.02 ± 0.39
3.0 ± 0.30
NS
2.56 ± 0.37
2.2
128.2 ± 65.4
120 ± 42.8
NS
130 ± 42
85.6
90.7 ± 21.8
82.3 ± 13.1
NS
81.4 ± 5.5
87.0
Urinary Ca (mg/24hs)
391.1 ± 117.0
187.5 ± 11.6
\0.01
453.3 ± 120.9
187
Urinary Na (mEq/24hs)
146.8 ± 49.8
120.1 ± 50.9
NS
167.2 ± 81.2
183
6.1 ± 1.9
3.17 ± 0.38
5.17 ± 1.36
3.12
iPTH (pg/ml) Cr Cl (ml/min)
Urinary Ca (mg/Kg)
\0.01
Urinary Ca/100 ml GFR
0.30 ± 0.10
0.16 ± 0.04
\0.01
0.39 ± 0.10
0.14
Ca/Cr 2 h urine
0.23 ± 0.11
0.09 ± 0.07
\0.01
0.23 ± 0.12
0.13
FL Ca (mg/min)
5.17 ± 1.29
4.66 ± 0.73
NS
4.52 ± 0.32
5,22
FE Ca (fraction)
0.054 ± 0.017
0.028 ± 0.006
0.070 ± 0.018
0.028
5.7 ± 2.6
4.85 ± 2.4
DPD (nMol/mMol Cr)
\0.05 NS
6.38 ± 1.2
4.1
iPTH Intact parathyroid hormone, Cr Cl Creatinine clearance, Ca Calcium, Na Sodium, FL Ca Filtered load of calcium, FE Ca Fractional excretion of calcium Table 2 Metabolic profile before and after surgery in all the patients with PHPT Women baseline (n = 46) Total Ca (mg/dl)
11.2 ± 0.9
Women postPTx (n = 46) 9.53 ± 0.37
P \0.001
Men baseline (n = 8) 11.2 ± 0.68
Men postPTx(n = 8)
9.8 ± 0.9
P \0.001
Ionized Ca (mg/dl)
5.6 ± 0.5
4.6 ± 0.3
\0.001
5.5 ± 0.3
4.8 ± 0.3
=0.001
Phosphate (mg/dl)
3.0 ± 0.37
3.8 ± 0.4
\0.001
2.67 ± 0.5
3.2 ± 0.3
=0.03
131.6 ± 65.4
42.0 ± 16
\0.001
134.0 ± 48.9
38.1 ± 18.6
\0.001
88.5 ± 19.6
86.3 ± 17
NS
84,5 ± 12,3
84,4 ± 13,6
NS
Urinary Ca (mg/24hs)
337.7 ± 131
189.2 ± 77
\0.001
447.6 ± 121
334 ± 166
0.143
Urinary Na (mEq/24hs)
138.2 ± 49
155.2 ± 59
NS
166.7 ± 62
148.5 ± 60
5.3 ± 2.0
2.9 ± 1.2
5.13 ± 1.4
3.79 ± 1.8
iPTH (pg/ml) Cr Cl (ml/min)
Urinary Ca (mg/Kg)
\0.001
NS 0.133
Urinary Ca/100 ml GFR
0.27 ± 0.10
0.15 ± 0.06
\0.001
0.36 ± 0.12
0.27 ± 0.15
NS
Ca/Cr 2 h urine
0.20 ± 0.12
0.09 ± 0.04
\0.001
0.14 ± 0.09
0.12 ± 0.04
NS
FL Ca (mg/min)
5.03 ± 1.1
4.02 ± 0.9
\0.001
4.66 ± 0.5
3.96 ± 0.4
=0,01
FE Ca (fraction)
0.047 ± 0.01
0.033 ± 0.01
\0.001
0.065 ± 0.02
0.056 ± 0.03
NS
7.1 ± 3.9
5.19 ± 2.8
6.0 ± 1.2
5.0 ± 2.2
NS
DPD (nMol/mMolCr)
NS
PTx: Parathyroidectomy, iPTH: Intact parathyroid hormone, Cr Cl: Creatinine clearance, Ca: Calcium, Na: Sodium, FL Ca: Filtered load of calcium, FE Ca: Fractional excretion of calcium
higher than those our normal population on a normal calcium diet. The persistence of hypercalciuria after the successful parathyroid surgery may not originate from excessive intestinal calcium absorption or bone resorption as filtered load of calcium normalized; it occurred because deficient renal reabsorption as fractional excretion continued elevated. As hypercalcemia was
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not present any more, it cannot explain the decreased calcium reabsortion and strongly suggest a renal tubular defect in calcium reabsorption as the cause of their hypercalciuria. This defect could be a primary renal tubular defect, as in patients with idiopathic renal hypercalciuria [15], as recurrent kidney stones were present more frequent before parathyroidectomy (PTx) in those with persistent hypercalciuria after
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Table 3 Comparison of biochemical profiles after PTx of hypercalciuric patients who normalized calciuria and those with persistent hypercalciuria Women who normalized calciuria (n = 27)
Women with persistent hypercalciuria (n = 12)
P
Men who Normalized calciuria (n = 3)
Men with persistent hypercalciuria (n = 4)
P
Total Ca (mg/dl)
9.47 ± 0.3
9.6 ± 0.3
NS
9.33 ± 0.7
10.32 ± 1.25
NS
Ionized Ca (mg/dl) Phosphate (mg/dl)
4.62 ± 0.3 3.8 ± 0.4
4.68 ± 0.2 3.81 ± 0.4
NS NS
4.84 ± 0.22 3.06 ± 0.56
4.92 ± 0.51 3.27 ± 0.34
NS NS
iPTH (pg/ml)
45.6 ± 18.8
36.5 ± 13.0
NS
44.7 ± 9.68
37.4 ± 27.8
NS
Cr Cl (ml/min)
87.0 ± 17.9
89.5 ± 17.7
NS
82.1 ± 13.2
83.4 ± 3.7
NS
153 ± 43.4
287.4 ± 52.5
\0.001
222 ± 121
472.58 ± 72.8
159.8 ± 63.8
154.3 ± 44.0
NS
136 ± 17.6
142.3 ± 67.9
Urinary Ca (mg/Kg)
2.36 ± 0.65
4.33 ± 1.24
\0.001
2.51 ± 1.4
5.37 ± 0.33
\0.001
Urinary Ca/100mlGFR
0.12 ± 0.04
0.22 ± 0.04
\0.001
0.19 ± 0.15
0.39 ± 0.05
\0.001
Urinary Ca (mg/24hs) Urinary Na (mEq/24hs)
\0.001 NS
Ca/Cr 2 h urine
0.07 ± 0.03
0.27 ± 0.141
\0.001
0.10 ± 0.02
0.15 ± 0.02
=0.01
FL Ca mg/min
4.03 ± 0.93
4.20 ± 0.91
NS
3.96 ± 0.47
4.11 ± 0.60
NS
0.027 ± 0.010
0.049 ± 0.011
0.040 ± 0.02
0.080 ± 0.011
FE Ca (fraction)
\0.001
\0.001
PTx: Parathyroidectomy, iPTH: Intact parathyroid hormone, Cr Cl: Creatinine clearance, Ca: Calcium, FL Ca: Filtered load of calcium, FE Ca: Fractional excretion of calcium
surgery. On the other hand, it could be that long standing hypercalcemic hyperparathyroidism could alter distal tubular function permanently. There are few reports in the literature about the changes that occur in the metabolic profile, as measured by 24-hour urine collections before and after parathyroid surgery. In one of these reports, Frøkjaer and Mollerup [16] noted that even after successful parathyroid surgery, 24-hour urine calcium remained increased in patients with history of renal stones compared to those that did not have a nephrolithiasis history. Before surgery, they found no difference in 24-hour urine calcium excretion in patients with PHPT with and without history of stones. In our series of patients, we had a similar finding of the patients who normalized calciuria, 43.3% had had kidney stones previously, whereas a history of renal lithiasis was present in 87.5% of those in whom hypercalciuria persisted postsurgery. In another study, Berger et al. [17] enrolled 54 patients that presented for parathyroid surgery and had a preoperative 24-hour urine collection; twentyseven of these patients had an additional postoperative urine profile. They observed no significant differences in 24-hour urine metabolic profiles or
serum calcium between patients with PHPT with and without history of urolithiasis. In the 27 patients that completed a second urine collection 2.5 months after parathyroid surgery, hypercalciuria decreased significantly, and they did not report patients with persistent hypercalciuria; however, only 3 of the 27 patients had a history of stones before surgery. Farias et al. [18] studied 10 patients with PHPT and found that hypercalciuria persisted in 6 of them after successful parathyroid surgery, using non-conventional criteria (urinary calcium/100 ml FG [0.11 and FE Ca[0.023 following a calcium-restricted diet during 5 days). They also studied the mechanisms responsible for this persistent hypercalciuria. They found a significant positive correlation between the fractional calcium reabsorption and the FPRNa, indicating that proximal tubular function was preserved and that the urinary calcium losses in the hypercalciuric PTx patients (h-PTx) occurred in the distal nephron. However, h-PTx patients had reduced renal plasma flow, renal blood flow, and GFR, as well as a high renal vascular resistance, which was even more evident after a calcium challenge. These findings led these authors to conclude that
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h-PTx patients had hypercalcemic nephropathy as the most probable cause for the alterations in distal calcium reabsorption and renal hemodynamics. In our patients, we only measured creatinine clearance, filtered load of calcium, and fractional excretion of calcium. We found that creatinine clearances pre- and postsurgery between h-PTx and n- PTx were not significantly different, but a significantly increased fractional excretion of calcium was present in h-PTx suggesting that these patients have a renal tubular defect in calcium reabsorption. This tubular defect could be preexistent to the PHPT, or it could be an acquired nephropathy due to sustained hypercalcemia during PHPT. The persistence of hypercalciuria due to an increased fractional calcium excretion could explain the increased stone risk patients with PTHx continue to have for years after surgery. In a large Danish study in more than 3,200 patients with PHPT, Vestergard and Mosekilde [19] found that the incidence of kidney stones remained significantly increased compared to patients who were followed conservatively without parathyroid surgery. These authors hypothesized that there must have been a selection bias because patients who underwent surgery may have had a more severe disease with a probable permanent kidney damage that was the cause for the persistent risk of kidney stones. Posen et al. [20] have shown that patients with primary hyperparathyroidism and renal stones may continue to produce stones after parathyroid surgery even though normocalcaemia has been established. In a study in more than 600 [8] patients presenting for parathyroid surgery, parathyroidectomy decreased the risk of kidney stones, but the risk did not return to that of the general population until 10 years after surgery. As expected, patients with a history of stones preoperatively were more likely to have stones events postoperatively. Despite this, other authors [21, 22] have not found increased risk of stone events in those who had parathyroid surgery and preoperative history of stone disease. Our study has several limitations. First, this was a retrospective study without a planed postsurgery scheme of controls at fixed intervals. This produced a wide range of postsurgery metabolic evaluation times that included patients in different phases of recovery after PTx. Second, we selected only patients that had a complete metabolic profile that included 24-hour collections before and at least 3 months
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postsurgery. This could have induced a selection bias as we could have repeated the controls more frequently in the patients with previous high urine calcium excretion. Third, filtered load of calcium was calculated assuming ionized calcium as UFCa; we did not account for calcium–ion complexes that also forms part of the UFCa. Finally, our speculation about hypercalcemic tubulopathy is not supported by the use of other markers of tubular injury. In conclusion in this series of patients with PTHP, hypercalciuria persists after surgery in 30.7% of women and 50% of men. Of the patients in whom calciuria normalized, 43.3% had kidney stones previously, whereas a history of renal lithiasis was present in 87.5% of those in whom hypercalciuria persisted postsurgery. Despite normalization of calcemia and filtered load of calcium, patients with persistent hypercalciuria have an increased fractional excretion of calcium suggesting that these patients have a renal tubular defect in calcium reabsorption. This persistently increased fractional excretion of calcium could explain the sustained increased risk of stone disease in patients for many years after successful parathyroid surgery.
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