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NDT Advance Access originally published online on February 22, 2006
Nephrology Dialysis Transplantation 2006 21(5):1434-1438; doi:10.1093/ndt/gfl046
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Teaching Point
(Section Editor A. Meyrier)

Hypercalcaemia in a patient with membraneous nephropathy

Sonya Poulin1, Jean-Hugues Brossard2, Réal Noël1 and Paul Isenring1

1 From the Nephrology Group, L'Hôtel-Dieu de Québec Institution, Department of Medicine, Faculty of Medicine, Laval University, Québec G1R 2J6 and 2 From the Endocrinology Group, Saint-Luc Hospital, Department of Medicine, Faculty of Medicine, Montreal University, Montreal H2X 3J4, Canada

Correspondence should be addressed to: Paul Isenring, MD, PhD, Hôpital L’Hôtel-Dieu de Québec, Service de Néphrologie, 11 Côte du Palais, Québec (QC), G1R 2J6, Canada. Email: paul.isenring{at}crhdq.ulaval.ca

Keywords: Graves' disease; hypercalcaemia; parathyroid hormone; renal failure; sarcoidosis; vitamin D metabolites



   Introduction
Top
 Introduction
Case
 Discussion
 Teaching points
 References
 
We report the case of a man who was investigated at the age of 23 for hypercalcaemia. This disorder not only occurred in the setting of multiple diseases that can alter calcium balance, but also in the setting of unique nosological associations. The case presented here was therefore, a challenging problem to solve and it proved to be a great learning opportunity.



   Case
Top
 Introduction
 Case
Discussion
 Teaching points
 References
 
At 23 years of age, in May 2001, a Caucasian male consulted his family doctor for asthenia, weight loss, hand tremor, palpitations, polyuria, polydipsia, gynaecomastia and galactorrhoea, all of which developed progressively over a few months. At the time of consultation, he was on nifedipine, metoprolol, pravastatin and aspirin. His past medical history included a membraneous nephropathy that was diagnosed at the age of 15 (November 1992) and which was complicated by chronic, non-progressive renal failure, persistent proteinuria between 5–10 g per day and high blood pressure. The inquiry was otherwise negative and the patient denied using any non-prescription drugs, vitamin supplements, isotretinoin or lithium salts. A physical examination in May 2001 revealed a blood pressure of 154/92 mmHg, a heart rate of 100/min, a slightly enlarged thyroid gland and mild bilateral gynaecomastia. For the rest, the secondary sexual characters were normal, there was no ankle oedema, and the patient's weight and height were 57 kg and 170 cm, respectively.

Initial work-ups in May 2001 showed the following results: serum electrolytes normal, serum albumin 27 g/l, serum Ca corrected for albuminaemia 2.87 mM (11.5 mg/dl) (Serum Ca was corrected according to the following formula: corrected serum Ca = [Actual Serum Ca] + [(40 g/l – actual albumin) x 0.22]), serum phosphate 1.72 mM (5.33 mg/dl), alkaline phosphatase 96 U/l (normal = 56–136), serum creatinine 261 µM (2.9 mg/dl), serum HCO3 20 mM, serum PTH 5 pg/ml (normal = 13–60), serum TSH 0.01 µU/ml (normal = 0.50–5.70), serum free thyroxin (T4) 3.38 µg/dl (normal = 0.61–1.38), 24 h proteinuria 10.5 g, 24 h calciuria 9.6 mmol (384 mg), creatinine clearance 35 ml/min/1.73 m2 and fractional tubular phosphate reabsorption 92%. A chest X-ray was also abnormal, revealing large hilar adenopathies but no other abnormalities (Figure 1A and B). Interestingly, a review of the medical chart showed that in July 2000, serum Ca was high-normal and serum TSH low at 0.16 µU/ml (without anyone noticing), and that four years earlier, serum PTH was 67 pg/ml.


Figure 1
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  		Fig. 1. Results of an investigation for hilar adenopathies. (A) and (B) Plain chest X-rays showing the hilar masses, (C) Radioactive 67Ga scintiscan showing abnormal uptake of tracer in the hilar and mediastinal regions and (D) Biopsy of an enlarged lymph node showing non-caseating granulomatous lesions.

 
Additional tests were carried out to investigate the hilar adenopathies. Serum 25-(OH)D3 and 1,25-(OH)2D3, measured less than one week after the initial consultation and before steroid administration, were found to be abnormally normal at 24 ng/ml (normal = 10–34) and 51 pg/ml (normal = 17–60), respectively. The thoracic tomodensitometry confirmed the presence of large hilar adenopathies and absence of parenchymal lesions. A pancorporal 67Ga scintiscan was also abnormal, revealing tracer accumulation confined to the hilar region of the thorax (Figure 1C). Eventually, lymph nodes excised by mediastinoscopy were found to contain typical non-caseating epithelioid, mycobacteria-free granulomas (Figure 1D).

Because of galactorrhoea, a more extensive endocrine work-up was also ordered. Blood tests showed the following results: thyroid stimulating immunoglobulins 12.2 µU/ml (normal <9.0), {alpha}-foetoprotein normal, human chorionic gonadotropin normal, oestradiol 49.3 pg/ml (normal = 4.6–46.9), testosterone 11.0 ng/ml (normal = 1.3–10.6), FSH 9.1 mIU/ml (normal = 1.3–19.3), LH 19.3 mIU/ml (normal = 1.2–8.6) and prolactin (PRL) 13 ng/ml (normal = 3–13). Nuclear medicine studies revealed abnormalities as well with a 24 h thyroid 131I uptake of 35% and intense thyroid accumulation of 99Tc on a scintiscan.

During the course of these investigations, corrected serum Ca rose to a maximum of 3.11 mM (12.4 mg/dl). Early on, the dose of ß-blocker was increased and the patient was treated with prednisone 20 mg qd. Eventually propylthiouracil was introduced, after seeking the advice of an endocrinologist. With this regimen, serum Ca and free T4 normalized rapidly, and gynaecomastia, galactorrhoea and the intrathoracic adenopathies disappeared after a few weeks.



   Discussion
Top
 Introduction
 Case
 Discussion
Teaching points
 References
 
What diseases developed in this young man who had been diagnosed with membraneous nephropathy eight to nine years earlier?
One of the diseases was pulmonary sarcoidosis. It was at stage I, implying that the granulomatous lesions were confined to the hilar and/or mediastinal regions of the thorax [1]. The other disease was Graves’ thyrotoxicosis [2]. It was quite severe with free T4 serum levels that were 3–4 times above normal. Both entities had probably developed over several months and accounted for most of the clinical abnormalities that were noted at presentation, including hypercalcaemia and gynaecomastia.

Was renal failure a predisposing factor for the development of hypercalcaemia?
Two sets of conditions should be satisfied for hypercalcaemia to occur in any individuals. First, the rate at which Ca enters the extracellular fluid space, generally from the intestinal lumen or bone, must be increased, and second, a defect in renal Ca excretion, due to a decrease in glomerular filtration rate or increase in fractional tubular Ca reabsorption, must also be present. In this patient, we hypothesize that a creatinine clearance of 35 ml/min/1.73 m2 [3,4] and/or a T4-mediated increase in Na/Ca exchange along the distal tubules of his remnant nephrons corresponded to one such requirement for the development of hypercalcaemia [5–7].

How should one interpret urinary Ca excretion rates and fractional tubular phosphate reabsorption values in chronic renal failure?
These indices should decrease as chronic renal failure progresses [3,4,8–10]. Here, however, urinary Ca was abnormally high for a patient who was not on Ca or vitamin supplements, and fractional tubular reabsorption values were also in the high range. These results confirm that Ca was probably entering the extracellular fluid space at high rates and would be consistent with low PTH activity from decreased PTH production.

How should one interpret serum 25-(OH)D3 and 1,25-(OH)2D3 levels in this particular setting?
Normal serum 25-(OH)D3 levels indicate that the patient had not been ingesting 1,25-(OH)2D3 precursors surreptitiously at least one week before measurement. Surprisingly, however, serum 1,25-(OH)2D3 levels were at the upper limit despite the presence of chronic renal failure, which is associated with decreased 1,25-(OH)2D3 production, despite the nephrotic proteinuria, which leads to urinary loss of vitamin D-binding protein-bound 25-(OH)D3 and 1,25-(OH)2D3, and despite hypoparathyroidism and hypercalcaemia, both of which are associated with decreased renal 25-(OH)D3 1{alpha}-hydroxylase activity [11–14]. Hence, this hormone must have been produced in abnormally high quantities by an extrarenal source or the patient had been ingesting 1,25-(OH)2D3 supplements. The former possibility is much more likely, based on the identification of granulomatous lesions that can produce 25-(OH)D3 1{alpha}-hydroxylase [1].

Should vitamin D metabolites be measured in all cases of hypercalcaemia?
This presentation illustrates the importance of a systematic approach in the evaluation of hypercalcaemic disorders and, perhaps, of obtaining vitamin D measurements for all patients in whom elevated serum Ca levels are associated with suppressed PTH levels. If an X-ray had not been ordered, or if sarcoidosis had not affected the lungs as can be seen occasionally [1], an important diagnosis would have been missed without such measurements. For a number of years, in fact, we have been using a classification of hypercalcaemia-inducing disorders based not only on PTH measurements but on vitamin D measurements as well, to subdivide the low PTH group into vitamin D-related or vitamin D-unrelated aetiologies (Table 1). We find that this classification is more useful clinically and relevant pathophysiologically than the traditional aetiological categorizations that are generally based on the nosological banners of ‘malignancies’, ‘endocrinopathies’ and so on [15].


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  		Table 1. Predisposing factors and aetiologies for hypercalcaemia

 
What was the pathophysiology of hypercalcaemia in this case?
In thyrotoxicosis, high-normal serum Ca levels are commonly encountered and probably due to increased bone turnover rates coupled with the tubular excretion defect that was discussed earlier [5–7,14]. In sarcoidosis, hypercalcaemia can also develop, but probably as a result of a 1,25-(OH)2D3-induced increase in bone resorption coupled with a 1,25-(OH)2D3-induced increase in intestinal absorption [1,16,17]. Here, importantly, 1,25-(OH)2D3 serum levels were normal to high-normal, suggesting that the main source of excess Ca entering the extracellular fluid space was the bone, due to symptomatic Graves’ disease and sarcoidosis. The absence of a decrease in serum 1,25-(OH)2D3, as should have occurred in hyperthyroidism [14], as well as the presence of chronic renal failure appeared to have played a contributory role by maintaining Ca absorption at an inappropriately normal level and by preventing higher levels of net Ca excretion.

What caused the endocrine abnormalities?
Gynaecomastia is not unusual in thyrotoxicosis because of the stimulatory effect of thyroid hormones on sex hormone binding globulin production, an effect through which total oestradiol and testosterone increases, but testosterone bioavailability decreases [2,18]. This hormonal profile, which is also associated with a compensatory rise in LH levels, greatly resembles the one that was observed in our patient. Gynaecomastia can also occur in the setting of chronic renal failure or neurosarcoidosis but PRL levels are usually higher than those reported here because of a decrease in the hormone's clearance by the kidney or an increase in its production by the central nervous system [1,2,12].

Were there any specific disease associations in this case?
Both sarcoidosis and Graves’ disease have been occasionally associated with membraneous nephropathy and in some cases, the thyroid disorder has even been suspected of inducing the renal lesion [19–21]. For example, Sato et al. [21] have described a patient in whom Graves’ disease and a nephrotic syndrome developed concomitantly, and in whom a renal biopsy revealed membraneous electron-dense deposits composed of thyroid antigen-mediated immune complexes. In contrast to the association "membraneous nephropathy-sarcoidosis" or "membraneous nephropathy-Graves' disease," the association sarcoidosis-Graves’ disease appears to be much more common. In this regard, recent studies have shown that circulating thyroid autoantibodies are common in sarcoidosis, whether a clinical thyroid disorder is manifest or not [22]. Such observations raise the possibility that thyroid autoantibodies may not only be involved in the pathogenesis of certain forms of membraneous nephropathy, but in that of sarcoidosis as well.

How may steroids have acted in this case and what could be prescribed for the long term?
Steroids reduced the adenopathies in size by treating the granulomatous reaction and alleviated the hyperthyroid state by inhibiting T4-to-T3 peripheral conversion [1,2,15]. They therefore decreased hypercalcaemia secondarily, and also inhibited the activity of 25-(OH)D3 1{alpha}-hydroxylase directly [1]. If hypercalcaemia had reappeared or become steroid-dependent, a biphosphonate could have been introduced to reduce osteoclastic activity and increase Ca transfer into the bone, thereby preserving skeletal integrity and acting as a steroid-sparing agent [1].



   Teaching points
Top
 Introduction
 Case
 Discussion
 Teaching points
References
 
In conclusion, we feel that this case demonstrates the importance of serum vitamin D measurements in the evaluation of hypercalcaemia associated with suppressed PTH levels, and that the manner in which it was investigated should represent an incentive to adopt a new and more relevant classification of hypercalcaemia-inducing disorders.

Conflict of interest statement: None declared.



   References
Top
 Introduction
 Case
 Discussion
 Teaching points
 References
 

  1. Cox CE, Davis-Allen A, Judson MA. Sarcoidosis. Med Clin North Am 2005; 89: 817–828[CrossRef][Web of Science][Medline]
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  7. Peng JB, Brown EM, Hediger MA. Apical entry channels in calcium-transporting epithelia. News Physiol Sci 2003; 18: 158–163[Abstract/Free Full Text]
  8. Slatopolsky E, Gradowska L, Kashemsant C, Keltner R, Manley C, Bricker NS. The control of phosphate excretion in uraemia. J Clin Invest 1966; 45: 672–677[Web of Science][Medline]
  9. Bricker NS. The biologic control system for phosphate in health and its modifications in chronic renal disease [review]. Contrib Nephrol 1980; 20: 46–55[Medline]
  10. Elhalel MD, Wald H, Rubinger D et al. Regulation of NaPi-IIa mRNA and transporter protein in chronic renal failure: role of parathyroid hormone (PTH) and dietary phosphate (Pi). Pflugers Arch 2004; 449: 265–270[Web of Science][Medline]
  11. Breslau NA. Normal and abnormal regulation of 1,25-(OH)2D synthesis. Am J Med Sci 1988; 296: 417–425[Web of Science][Medline]
  12. Leavey SF, Weitzel WF. Endocrine abnormalities in chronic renal failure. Endocrinol Metab Clin North Am 2002; 31: 107–119[CrossRef][Web of Science][Medline]
  13. Grymonprez A, Proesmans W, Van Dyck M, Jans I, Goos G, Bouillon R. Vitamin D metabolites in childhood nephrotic syndrome. Pediatr Nephrol 1995; 9: 278–281[CrossRef][Web of Science][Medline]
  14. Iqbal AA, Burgess EH, Gallina DL, Nanes MS, Cook CB. Hypercalcaemia in hyperthyroidism: patterns of serum calcium, parathyroid hormone, and 1,25-dihydroxyvitamin D3 levels during management of thyrotoxicosis. Endocr Pract 2003; 9: 517–521[Medline]
  15. Bilezikian JP. Aetiologies and therapy of hypercalcaemia. Endocrinol Metab Clin North Am 1989; 18: 389–414[Web of Science][Medline]
  16. Meyrier A, Valeyre D, Bouillon R, Paillard F, Battesti JP, Georges R. Different mechanisms of hypercalciuria in sarcoidosis. Correlations with disease extension and activity. Ann N Y Acad Sci 1986; 465:575–586[Web of Science][Medline]
  17. Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med 1981; 305: 440–443[Web of Science][Medline]
  18. Abalovich M, Levalle O, Hermes R et al. Hypothalamic-pituitary-testicular axis and seminal parameters in hyperthyroid males. Thyroid 1999; 9: 857–863[Web of Science][Medline]
  19. Toda T. Kimoto S. Nishio Y. Ehara T. Sasaki S. Sarcoidosis with membranous glomerulonephritis and granulomatous nephritis. Intern Med 1999; 38: 882–886[Web of Science][Medline]
  20. Becker BA, Fenves AZ, Breslau NA. Membranous glomerulonephritis associated with Graves' disease. Am J Kidney Dis 1999; 33: 369–373[Medline]
  21. Sato Y, Sasaki M, Kan R et al. Thyroid antigen-mediated glomerulonephritis in Graves' disease. Clin Nephrol 1989; 31: 49–52[Medline]
  22. Papadopoulos KI, Hornblad Y, Liljebladh H, Hallengren B. High frequency of endocrine autoimmunity in patients with sarcoidosis. Eur J Endocrinol 1996; 134: 331–336[Abstract/Free Full Text]
Received for publication: 23.11.05
Accepted in revised form: 25. 1.06


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