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ScienceDirect www.sciencedirect.com Annales d’Endocrinologie 76 (2015) 116–119
Journées Klotz 2015
Primary hyperparathyroidism and nephrolithiasis Hyperparathyroïdie primaire et lithiases Peter Vestergaard Departments of Clinical Medicine and Endocrinology, Aalborg University Hospital, Medicinerhuset, Mølleparkvej 4, 9100 Aalborg, Denmark
Abstract Calcifications in the kidneys may occur in the parenchyma (nephrocalcinosis), pelvis renis (nephrolithiasis) or ureters (ureterolithiasis). Several factors may protect against stone formation or promote precipitation of stones. Most stones contain calcium, and the hypercalciuria seen in primary hyperparathyroidism is a contributing factor to stone formation in the kidneys and urinary tract. In early case series, renal stone formation was frequent, whereas the proportion of patients with symptomatic renal stones has declined in recent years. However, a substantial proportion of patients presents with asymptomatic nephrocalcinosis or nephrolithiasis. Before diagnosis and treatment of primary hyperparathyroidism, renal stone events are more frequent than in the general population. However, even after surgical cure, an increased rate of renal stone events may be seen. This may to some extent be the result of stones or calcifications already present at the time of diagnosis or sequelae to prior stones such as infections or ureter strictures. © 2015 Elsevier Masson SAS. All rights reserved. Keywords: Nephrolithiasis; Nephrocalcinosis; Hyperparathyroidism
Résumé Les calcifications rénales peuvent survenir au sein du parenchyme (néphrocalcinose), des cavités rénales (néphrolithiases) ou dans les uretères (urétérolithiases). Plusieurs facteurs sont susceptibles de protéger contre la formation de calculs, d’autres contribuent à leur constitution. La plupart des lithiases ont un contenu calcique, et l’hypercalciurie observée dans l’hyperparathyroïdie est un facteur prédisposant à la formation de calculs des reins et du tractus urinaire. Dans les séries initiales d’hyperparathyroïdies, la constitution de calculs rénaux était fréquente, mais la proportion de patients souffrant de lithiases rénales symptomatiques s’est maintenant réduite. Cependant, un nombre significatif de patients présente une néphrocalcinose et des lithiases rénales asymptomatiques. Avant que ne soit établi le diagnostic et débuté le traitement de l’hyperparathyroïdie primaire, les évènements lithiasiques rénaux sont plus fréquents que dans la population générale. Cependant même après la cure chirurgicale de l’hyperparathyroïdie, persiste encore un risque accru de survenue de lithiases. Dans une certaine mesure, ceci peut résulter de lithiases ou de calcifications déjà présentes au moment du diagnostic, ou apparaître comme les séquelles de lithiases antérieures, liées par exemple à l’infection ou à des rétrécissements urétéraux. © 2015 Elsevier Masson SAS. Tous droits réservés. Mots clés : Lithiases rénales ; Néphrocalcinose ; Hyperparathyroïdie
1. Introduction Many factors may contribute to stone formation in the renal pelvis (nephrolithiasis) or ureters (ureterolithiasis) or to calcifications in the kidney parenchyma (nephrocalcinosis). However, protective factors also exist [1]. Most stones are calcium containing. This narrative review will focus on calcifications in the kidney parenchyma (nephrocalcinosis), renal pelvis E-mail address: [email protected] http://dx.doi.org/10.1016/j.ando.2015.03.002 0003-4266/© 2015 Elsevier Masson SAS. All rights reserved.
(nephrolithiasis) and ureters. The main factor behind the calcifications is believed to be the increased calcium excretion in the urine [2]. However, other factors may also contribute such as dehydration brought about be nausea and the osmotic diuretic effect of the high calcium levels. 2. Basal physiology Fig. 1 shows the normal calcium fluxes and an example of primary hyperparathyroidism. Usually calcium is absorbed in
P. Vestergaard / Annales d’Endocrinologie 76 (2015) 116–119
117
Fig. 1. Example of calcium flux in a normal person and in primary hyperparathyroidism; ECV: extracellular volume. A. Normal individual. B. Primary hyperparathyroidism.
the intestine, deposited and resorbed from the skeleton and filtered in the glomerulus in the kidney. A large re-absorption of calcium takes place in the kidney (see Table 1 for a hypothetical example). In primary hyperparathyroidism, more calcium is reabsorbed from the skeleton through the effects of parathyroid hormone (PTH) on the osteoclasts. However, an increased calcium absorption in the intestine may also play a role as PTH activates the one-alpha-hydroxylase enzyme, which increases the levels of activated vitamin D (1,25-dihydroxy-vitamin D), which in turn may increase intestinal calcium absorption thus further contributing to the calcium load in the kidney. In the kidney, PTH may increase calcium re-absorption, but as PTH only works in parts of the tubuli, e.g. through stimulation of TRPv5
in the distal tubulus [1], the increased filtration of calcium in the glomerulus may overpower the capacity for calcium absorption further downstream in the tubuli leading to an increased net excretion although the calcium/creatinine clearance ratio if increased (Table 1). Under normal circumstances, total plasma calcium is around 2.20–2.55 mol/l with an ionised plasma calcium of 1.18–1.32 mmol/l. This is because approximately 50% of the total calcium is “free”. Calcium is filtered in the glomerulus as other ions. At a glomerular filtration of 90 ml/min and a “free” ionised plasma calcium of 1.20 mmol/l. The filtration is thus 155.5 mmol of calcium per day (or 6221 mg). With an excretion of 4%, the total daily excretion is around 249 mg in the urine (Fig. 1). The normal urine calcium excretion is around
118
P. Vestergaard / Annales d’Endocrinologie 76 (2015) 116–119
Table 1 Hypothetical example of renal handling of calcium under normal circumstances, in primary hyperparathyroidism (PHPT), and in patients with familial hypocalciuric hypercalcemia (FHH).
interesting as patients with primary hyperparathyroidism may tend to weigh more than the general population [10].
Parameter
3. Epidemiology
Plasma total calcium (mmol/l) Plasma filtrable (ionised) calcium (mmol/l) GFR (ml/min) dU creatinine/plasma creatinine Filtered calcium (mmol/day) Fractional absorption in proximal tubulus (%) Fractional absorption in thick ascending loop (%) Fractional absorption in distal tubulus (%) Net excreted calcium (mmol/day) Net excreted calcium (mg/day) Calcium/creatinine clearance
Normal 2.25 1.20
PHPT 2.80 1.42
FHH 2.80 1.42
90 130 156 65
90 130 184 60
90 130 184 68
25
26
24
6
7
7
6.2 249 0.02
12.9 515 0.035
1.8 74 0.005
dU: daily urine; GFR: glomerulus filtration rate. The table is based on modifications of references [3] and [4].
2–9 mmol/day (or 80–360 mg). This may be increased by a five-fold factor (especially for the lower values), i.e. to around 400–1000 mg per day. This is brought about by lower re-absorption and higher urine output. In moderate primary hyperparathyroidism with a total plasma calcium of 2.80 mmol/l, the free filtrable plasma calcium is 1.42 mmol/l. With a GFR of 90 ml/min, the filtration would be 90 × 60 × 24 × 1.42/1000 = 184 mmol/day. However, with a loss of 7% (versus usually 1–4%), the excretion would be 12.9 mmol/day (or 515 mg/day) [3,4]. PTH increases the re-absorption of calcium and the excretion of phosphate in the kidney. The increased phosphate load may thus tip the crystallinasation balance, leading to the formation of crystals in the urine if this is concentrated say from dehydration. Usually ectopic calcifications are prevented in PHPT as phosphate is low despite high calcium. The calciumphosphate product at which calcifications occur may be between 4.7–6 (mmol/l)2 [5,6]. If the plasma total calcium is between 2.2 and 2.55 and the plasma phosphate is between 0.7–1.5 mmol/l in normal subjects, then under normal conditions the maximal calcium-phosphate product would be 2.55 × 1.5 = 3.83, i.e. far from the precipitation limit. Even in extreme PHPT with plasma total calcium of 4.00 mmol/l, plasma phosphate would usually be around 0.7–1, i.e. the calcium-phosphate product would be in the range of 2.8–4, i.e. still “safe”, although calcifications have been seen even at lower calcium-phosphate product levels [7,8]. In PHPT, however, phosphate may be concentrated locally and thus lead to precipitations. Other factors such as oxalate, magnesium, sodium, various proteins, pH, bacteria in the urine, and concentration of the urine may also contribute as in other cases of renal stone events [1]. Recent studies have pointed at an effect of obesity on risk of hypercalciuria and renal stones in primary hyperparathyroidism [9]. This relationship may be particularly
The prevalence of renal stones in primary hyperparathyroidism has declined from as much as 80% in early series to between 7 and 20% in more recent series [11,12]. However, these estimates are based on clinical stone events – which in the early series earned the disease its eponym of “stones, bones, abdominal groans, thrones and psychiatric moans”. In more recent series, where systematic screening of patients presenting with largely asymptomatic primary hyperparathyroidism has been performed, a prevalence of 25% (95% CI: 19–31%) of either nephrocalcinosis (10%) or nephrolithiasis (15% of all patients evaluated for primary hyperparathyroidism) has been observed [13]. As expected, calcium excretion was higher in patients with calcifications than in those without [13], but otherwise no correlations was present with plasma calcium, plasma phosphate, plasma 25-hydroxy-vitamin D, plasma 1,25-dihydroxy-vitamin D. No reduction in renal function was seen in the patients with renal calcifications [13]. The absence of a relationship with biochemical parameters underlines the importance of fluxes of calcium and parameters of renal calcium handling not necessarily mirrored in plasma levels of calcium. An increased risk of clinical renal stone events may be seen as early as 10 years before the diagnosis of primary hyperparathyroidism is made [14]. This indicates that the disease may have been present many years prior to its diagnosis. A significant increase in the presence of renal stone events is seen in the time leading up to the diagnosis of primary hyperparathyroidism [14]. However, this is biased by the fact that the renal stone events lead to the disease being diagnosed (a form of “Berkson Bias”). After surgical cure, the risk of recurrent clinical renal stone events taper only gradually [14], possibly as a consequence of stones left over from before the diagnosis, infections, ureter stenoses, etc. Although the disease of primary hyperparathyroidism is cured, damage left from it may thus still impact the occurrence of new stone events. 4. Treatment The treatment of renal stone events follows current guidelines for management of renal stones in general. Current guidelines emphasize surgical treatment for primary hyperparathyroidism in the presence of renal stones [15]. Current evidence only suggests a gradual decrease in renal stone events after surgery [14]. Actually, surgery does not reduce the risk of renal stones compared to non-surgically managed cases [16] – as mentioned probably related to damage done by the disease not necessarily corrected by surgery such as ureter strictures and leftover renal stones. It should be mentioned that the study cited [16] was done on patients with relatively high plasma calcium levels as compared to the often asymptomatic patients of current series. The treatment may thus be tailored in individual cases.
P. Vestergaard / Annales d’Endocrinologie 76 (2015) 116–119
Disclosure of interest The author declares that he has no conflicts of interest concerning this article. References [1] Friedman P, Bushinsky DA. Renal tubular physiology of calcium excretion. In: Rosen C, editor. Primer on the metabolic bone disease and disorders of mineral metabolism. ASBMR; 2013. p. 845–50. [2] Peacock M. Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum. J Bone Miner Res 2002;17(Suppl. 2):N87–94. [3] Kristiansen JH, Brøchner-Mortensen J, Pedersen KO. Renal tubular reabsorption of calcium in familial hypocalciuric hypercalcaemia. Acta Endocrinol (Copenh) 1986;112:541–6. [4] Kristiansen JH, Brøchner-Mortensen J, Pedersen KO, et al. Renal tubular reabsorption of calcium and sodium in primary hyperparathyroidism. Acta Endocrinol (Copenh) 1990;123:194–202. [5] Hebert LA, Lemann JJ, Petersen JR, et al. Studies of the mechanism by which phosphate infusion lowers serum calcium concentration. J Clin Invest 1966;45:1886–94. [6] Herbert L, Miller H, Richardson G. Chronic renal disease, secondary parathyroid hyperplasia, decalcification of bone and metastatic calcification. J Pathol Bacteriol 1941;53:161–82. [7] McLean F, Hinrichs M. The formation and behaviour of colloidal calciumphosphate in the blood. Am J Physiol 1938;121:580–94.
119
[8] Logan M. Recent advances in the chemistry of calcification. Physiol Rev 1940;20:522–60. [9] Tran H, Grange JS, Adams-Huet B, et al. The impact of obesity on the presentation of primary hyperparathyroidism. J Clin Endocrinol Metab 2014;99:2359–64. [10] Grey A, Evans M, Stapleton J, et al. Body weight and bone mineral density in postmenopausal women with primary hyperparathyroidism. Ann Intern Med 1994;121:745–9. [11] Klugman V, Favus M, Pak C. Nephrolithiasis in primary hyperparathyroidism. In: Rosen C, Bilezikian J, Marcus R, Levine M, editors. The parathyroids – basic and clinical concepts. New York: Raven; 1994. p. 505–17. [12] Silverberg SJ, Shane E, Jacobs TP, et al. Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am J Med 1990;89: 327–34. [13] Starup-Linde J, Waldhauer E, Rolighed L, et al. Renal stones and calcifications in patients with primary hyperparathyroidism: associations with biochemical variables. Eur J Endocrinol 2012;166:1093–100. [14] Mollerup C, Vestergaard P, Frøkjær V, et al. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. BMJ 2002;325:807–12. [15] Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop; 2014. [16] Vestergaard P, Mosekilde L. Cohort study on the effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism. BMJ 2003;327:530–5.
ScienceDirect www.sciencedirect.com Annales d’Endocrinologie 76 (2015) 116–119
Journées Klotz 2015
Primary hyperparathyroidism and nephrolithiasis Hyperparathyroïdie primaire et lithiases Peter Vestergaard Departments of Clinical Medicine and Endocrinology, Aalborg University Hospital, Medicinerhuset, Mølleparkvej 4, 9100 Aalborg, Denmark
Abstract Calcifications in the kidneys may occur in the parenchyma (nephrocalcinosis), pelvis renis (nephrolithiasis) or ureters (ureterolithiasis). Several factors may protect against stone formation or promote precipitation of stones. Most stones contain calcium, and the hypercalciuria seen in primary hyperparathyroidism is a contributing factor to stone formation in the kidneys and urinary tract. In early case series, renal stone formation was frequent, whereas the proportion of patients with symptomatic renal stones has declined in recent years. However, a substantial proportion of patients presents with asymptomatic nephrocalcinosis or nephrolithiasis. Before diagnosis and treatment of primary hyperparathyroidism, renal stone events are more frequent than in the general population. However, even after surgical cure, an increased rate of renal stone events may be seen. This may to some extent be the result of stones or calcifications already present at the time of diagnosis or sequelae to prior stones such as infections or ureter strictures. © 2015 Elsevier Masson SAS. All rights reserved. Keywords: Nephrolithiasis; Nephrocalcinosis; Hyperparathyroidism
Résumé Les calcifications rénales peuvent survenir au sein du parenchyme (néphrocalcinose), des cavités rénales (néphrolithiases) ou dans les uretères (urétérolithiases). Plusieurs facteurs sont susceptibles de protéger contre la formation de calculs, d’autres contribuent à leur constitution. La plupart des lithiases ont un contenu calcique, et l’hypercalciurie observée dans l’hyperparathyroïdie est un facteur prédisposant à la formation de calculs des reins et du tractus urinaire. Dans les séries initiales d’hyperparathyroïdies, la constitution de calculs rénaux était fréquente, mais la proportion de patients souffrant de lithiases rénales symptomatiques s’est maintenant réduite. Cependant, un nombre significatif de patients présente une néphrocalcinose et des lithiases rénales asymptomatiques. Avant que ne soit établi le diagnostic et débuté le traitement de l’hyperparathyroïdie primaire, les évènements lithiasiques rénaux sont plus fréquents que dans la population générale. Cependant même après la cure chirurgicale de l’hyperparathyroïdie, persiste encore un risque accru de survenue de lithiases. Dans une certaine mesure, ceci peut résulter de lithiases ou de calcifications déjà présentes au moment du diagnostic, ou apparaître comme les séquelles de lithiases antérieures, liées par exemple à l’infection ou à des rétrécissements urétéraux. © 2015 Elsevier Masson SAS. Tous droits réservés. Mots clés : Lithiases rénales ; Néphrocalcinose ; Hyperparathyroïdie
1. Introduction Many factors may contribute to stone formation in the renal pelvis (nephrolithiasis) or ureters (ureterolithiasis) or to calcifications in the kidney parenchyma (nephrocalcinosis). However, protective factors also exist [1]. Most stones are calcium containing. This narrative review will focus on calcifications in the kidney parenchyma (nephrocalcinosis), renal pelvis E-mail address: [email protected] http://dx.doi.org/10.1016/j.ando.2015.03.002 0003-4266/© 2015 Elsevier Masson SAS. All rights reserved.
(nephrolithiasis) and ureters. The main factor behind the calcifications is believed to be the increased calcium excretion in the urine [2]. However, other factors may also contribute such as dehydration brought about be nausea and the osmotic diuretic effect of the high calcium levels. 2. Basal physiology Fig. 1 shows the normal calcium fluxes and an example of primary hyperparathyroidism. Usually calcium is absorbed in
P. Vestergaard / Annales d’Endocrinologie 76 (2015) 116–119
117
Fig. 1. Example of calcium flux in a normal person and in primary hyperparathyroidism; ECV: extracellular volume. A. Normal individual. B. Primary hyperparathyroidism.
the intestine, deposited and resorbed from the skeleton and filtered in the glomerulus in the kidney. A large re-absorption of calcium takes place in the kidney (see Table 1 for a hypothetical example). In primary hyperparathyroidism, more calcium is reabsorbed from the skeleton through the effects of parathyroid hormone (PTH) on the osteoclasts. However, an increased calcium absorption in the intestine may also play a role as PTH activates the one-alpha-hydroxylase enzyme, which increases the levels of activated vitamin D (1,25-dihydroxy-vitamin D), which in turn may increase intestinal calcium absorption thus further contributing to the calcium load in the kidney. In the kidney, PTH may increase calcium re-absorption, but as PTH only works in parts of the tubuli, e.g. through stimulation of TRPv5
in the distal tubulus [1], the increased filtration of calcium in the glomerulus may overpower the capacity for calcium absorption further downstream in the tubuli leading to an increased net excretion although the calcium/creatinine clearance ratio if increased (Table 1). Under normal circumstances, total plasma calcium is around 2.20–2.55 mol/l with an ionised plasma calcium of 1.18–1.32 mmol/l. This is because approximately 50% of the total calcium is “free”. Calcium is filtered in the glomerulus as other ions. At a glomerular filtration of 90 ml/min and a “free” ionised plasma calcium of 1.20 mmol/l. The filtration is thus 155.5 mmol of calcium per day (or 6221 mg). With an excretion of 4%, the total daily excretion is around 249 mg in the urine (Fig. 1). The normal urine calcium excretion is around
118
P. Vestergaard / Annales d’Endocrinologie 76 (2015) 116–119
Table 1 Hypothetical example of renal handling of calcium under normal circumstances, in primary hyperparathyroidism (PHPT), and in patients with familial hypocalciuric hypercalcemia (FHH).
interesting as patients with primary hyperparathyroidism may tend to weigh more than the general population [10].
Parameter
3. Epidemiology
Plasma total calcium (mmol/l) Plasma filtrable (ionised) calcium (mmol/l) GFR (ml/min) dU creatinine/plasma creatinine Filtered calcium (mmol/day) Fractional absorption in proximal tubulus (%) Fractional absorption in thick ascending loop (%) Fractional absorption in distal tubulus (%) Net excreted calcium (mmol/day) Net excreted calcium (mg/day) Calcium/creatinine clearance
Normal 2.25 1.20
PHPT 2.80 1.42
FHH 2.80 1.42
90 130 156 65
90 130 184 60
90 130 184 68
25
26
24
6
7
7
6.2 249 0.02
12.9 515 0.035
1.8 74 0.005
dU: daily urine; GFR: glomerulus filtration rate. The table is based on modifications of references [3] and [4].
2–9 mmol/day (or 80–360 mg). This may be increased by a five-fold factor (especially for the lower values), i.e. to around 400–1000 mg per day. This is brought about by lower re-absorption and higher urine output. In moderate primary hyperparathyroidism with a total plasma calcium of 2.80 mmol/l, the free filtrable plasma calcium is 1.42 mmol/l. With a GFR of 90 ml/min, the filtration would be 90 × 60 × 24 × 1.42/1000 = 184 mmol/day. However, with a loss of 7% (versus usually 1–4%), the excretion would be 12.9 mmol/day (or 515 mg/day) [3,4]. PTH increases the re-absorption of calcium and the excretion of phosphate in the kidney. The increased phosphate load may thus tip the crystallinasation balance, leading to the formation of crystals in the urine if this is concentrated say from dehydration. Usually ectopic calcifications are prevented in PHPT as phosphate is low despite high calcium. The calciumphosphate product at which calcifications occur may be between 4.7–6 (mmol/l)2 [5,6]. If the plasma total calcium is between 2.2 and 2.55 and the plasma phosphate is between 0.7–1.5 mmol/l in normal subjects, then under normal conditions the maximal calcium-phosphate product would be 2.55 × 1.5 = 3.83, i.e. far from the precipitation limit. Even in extreme PHPT with plasma total calcium of 4.00 mmol/l, plasma phosphate would usually be around 0.7–1, i.e. the calcium-phosphate product would be in the range of 2.8–4, i.e. still “safe”, although calcifications have been seen even at lower calcium-phosphate product levels [7,8]. In PHPT, however, phosphate may be concentrated locally and thus lead to precipitations. Other factors such as oxalate, magnesium, sodium, various proteins, pH, bacteria in the urine, and concentration of the urine may also contribute as in other cases of renal stone events [1]. Recent studies have pointed at an effect of obesity on risk of hypercalciuria and renal stones in primary hyperparathyroidism [9]. This relationship may be particularly
The prevalence of renal stones in primary hyperparathyroidism has declined from as much as 80% in early series to between 7 and 20% in more recent series [11,12]. However, these estimates are based on clinical stone events – which in the early series earned the disease its eponym of “stones, bones, abdominal groans, thrones and psychiatric moans”. In more recent series, where systematic screening of patients presenting with largely asymptomatic primary hyperparathyroidism has been performed, a prevalence of 25% (95% CI: 19–31%) of either nephrocalcinosis (10%) or nephrolithiasis (15% of all patients evaluated for primary hyperparathyroidism) has been observed [13]. As expected, calcium excretion was higher in patients with calcifications than in those without [13], but otherwise no correlations was present with plasma calcium, plasma phosphate, plasma 25-hydroxy-vitamin D, plasma 1,25-dihydroxy-vitamin D. No reduction in renal function was seen in the patients with renal calcifications [13]. The absence of a relationship with biochemical parameters underlines the importance of fluxes of calcium and parameters of renal calcium handling not necessarily mirrored in plasma levels of calcium. An increased risk of clinical renal stone events may be seen as early as 10 years before the diagnosis of primary hyperparathyroidism is made [14]. This indicates that the disease may have been present many years prior to its diagnosis. A significant increase in the presence of renal stone events is seen in the time leading up to the diagnosis of primary hyperparathyroidism [14]. However, this is biased by the fact that the renal stone events lead to the disease being diagnosed (a form of “Berkson Bias”). After surgical cure, the risk of recurrent clinical renal stone events taper only gradually [14], possibly as a consequence of stones left over from before the diagnosis, infections, ureter stenoses, etc. Although the disease of primary hyperparathyroidism is cured, damage left from it may thus still impact the occurrence of new stone events. 4. Treatment The treatment of renal stone events follows current guidelines for management of renal stones in general. Current guidelines emphasize surgical treatment for primary hyperparathyroidism in the presence of renal stones [15]. Current evidence only suggests a gradual decrease in renal stone events after surgery [14]. Actually, surgery does not reduce the risk of renal stones compared to non-surgically managed cases [16] – as mentioned probably related to damage done by the disease not necessarily corrected by surgery such as ureter strictures and leftover renal stones. It should be mentioned that the study cited [16] was done on patients with relatively high plasma calcium levels as compared to the often asymptomatic patients of current series. The treatment may thus be tailored in individual cases.
P. Vestergaard / Annales d’Endocrinologie 76 (2015) 116–119
Disclosure of interest The author declares that he has no conflicts of interest concerning this article. References [1] Friedman P, Bushinsky DA. Renal tubular physiology of calcium excretion. In: Rosen C, editor. Primer on the metabolic bone disease and disorders of mineral metabolism. ASBMR; 2013. p. 845–50. [2] Peacock M. Primary hyperparathyroidism and the kidney: biochemical and clinical spectrum. J Bone Miner Res 2002;17(Suppl. 2):N87–94. [3] Kristiansen JH, Brøchner-Mortensen J, Pedersen KO. Renal tubular reabsorption of calcium in familial hypocalciuric hypercalcaemia. Acta Endocrinol (Copenh) 1986;112:541–6. [4] Kristiansen JH, Brøchner-Mortensen J, Pedersen KO, et al. Renal tubular reabsorption of calcium and sodium in primary hyperparathyroidism. Acta Endocrinol (Copenh) 1990;123:194–202. [5] Hebert LA, Lemann JJ, Petersen JR, et al. Studies of the mechanism by which phosphate infusion lowers serum calcium concentration. J Clin Invest 1966;45:1886–94. [6] Herbert L, Miller H, Richardson G. Chronic renal disease, secondary parathyroid hyperplasia, decalcification of bone and metastatic calcification. J Pathol Bacteriol 1941;53:161–82. [7] McLean F, Hinrichs M. The formation and behaviour of colloidal calciumphosphate in the blood. Am J Physiol 1938;121:580–94.
119
[8] Logan M. Recent advances in the chemistry of calcification. Physiol Rev 1940;20:522–60. [9] Tran H, Grange JS, Adams-Huet B, et al. The impact of obesity on the presentation of primary hyperparathyroidism. J Clin Endocrinol Metab 2014;99:2359–64. [10] Grey A, Evans M, Stapleton J, et al. Body weight and bone mineral density in postmenopausal women with primary hyperparathyroidism. Ann Intern Med 1994;121:745–9. [11] Klugman V, Favus M, Pak C. Nephrolithiasis in primary hyperparathyroidism. In: Rosen C, Bilezikian J, Marcus R, Levine M, editors. The parathyroids – basic and clinical concepts. New York: Raven; 1994. p. 505–17. [12] Silverberg SJ, Shane E, Jacobs TP, et al. Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am J Med 1990;89: 327–34. [13] Starup-Linde J, Waldhauer E, Rolighed L, et al. Renal stones and calcifications in patients with primary hyperparathyroidism: associations with biochemical variables. Eur J Endocrinol 2012;166:1093–100. [14] Mollerup C, Vestergaard P, Frøkjær V, et al. Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study. BMJ 2002;325:807–12. [15] Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop; 2014. [16] Vestergaard P, Mosekilde L. Cohort study on the effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism. BMJ 2003;327:530–5.
