Physician-induced hypocalcaemia, nephrocalcinosis, and incomplete distal renal tubular acidosis

(Section Editor: K. Kühn)

Marina Brindzjuk, Götz Krupp, Ute Kettritz and Friedrich C. Luft

Department of Medicine-Nephrology and Department of Radiology, Klinikum-Buch and the Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin, Germany

Introduction

Nephrocalcinosis has diverse aetiologies and is generally associated with hypercalcaemia, hypercalciuria, or distal renal tubular acidosis [1]. We recently encountered a patient referred because of renal stone disease. We were surprised to observe hypocalcaemia and normal arterial blood gases and serum electrolytes. The nephrocalcinosis proved iatrogenic and provided some clinical lessons as well as a therapeutic dilemma.

Case

A 50-year-old woman was referred for inpatient evaluation of a kidney stone. She had never had a kidney stone before. She felt well and had no complaints. Thirty years earlier, she had undergone thyroid surgery for hyperthyroidism. Since then, she had received ‘hormone’ tablets from her family physician. In 1972, a urinary tract infection was treated uneventfully. On examination, she was mildly hypertensive (165/90 mmHg). Her physical examination, including conjunctivae, musculoskeletal system, and skin were entirely normal. The creatinine was 117 µmol/l. The electrolytes were Na 141, Cl 101, K 4.9 and HCO3 25 mmol/l. The pH was 7.40, pO2 95, pCO2 40 mmHg. The calcium was 2.05 and the phosphorus 1.56 mmol/l. Serum albumin (40 g/l) and total proteins (70 g/l) were normal; no paraproteins were present. The electrocardiogram showed a normal QTc interval. The urine was normal. The urine pH ranged between 6.5 and 7.0 for the entire hospital stay. A plain roentgenogram of the abdomen was unremarkable with the exception of several calcified lymph nodes (not shown). A renal ultrasound showed a slightly reduced renal cortex with normal papillae. The medullary area suggested nephrocalcinosis (Figure 1aGo), which was confirmed by a CT scan (Figure 1bGo).



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Fig. 1. (a) Sonogram of the left kidney demonstrating hyperechogenic areas in the medulla typical of nephrocalcinosis. (b) Non-contrast CT scan showing dense rings in the medulla of both kidneys, indicating medullary nephrocalcinosis.

 
Special tests revealed that the creatinine clearance was 82 ml/min. The electrolyte excretion was Na 197, Cl 181, K 61, Ca 5.1 mmol/24 h. The citrate and oxalate excretions were 53 and 35 mg/24 h respectively. Urine net charge, that is NH4=(Cl-Na-K)+80 revealed a value of 2.7 mmol/24 h. The transtubular gradient for potassium (K urine/K serum)/UOsm/ POsm) was 4. Parathyroid hormone (PTH) in serum was undetectable, the serum calcidiol concentration was 73 nmol/l, and the calcitriol concentration was 58 pmol/l. A short oral ammonium chloride loading test was performed sufficient to lower the arterial pH to 7.29. This procedure yielded a pCO2 40 mmHg, Na 141, Cl 110, K 4.0 and HCO3 19 mmol/l. Under these conditions, the urine pH was 6.5 and the urine net charge (net charge=urine (Cl-Na-K) did not become negative. Had ammonium been excreted in the urine in appropriate amounts, we would have expected urine Cl to exceed the sum of urine Na and urine K.

A detailed discussion with the patient's physician revealed that her parathyroid glands had been extirpated along with her thyroid gland 30 years earlier. Although she had no symptoms of hypocalcaemia, she received vitamin D replacement therapy, most recently with oral calcitriol.

Comment

This patient had surgical hypoparathyroidism; thyroid operations remain the commonest cause for this condition. Hypoalbuminaemia, hypomagnesaemia, or disturbed phosphate concentrations may cause hypocalcaemia, but obviously were not relevant in our patient [1]. The history of prior thyroid surgery and the absent serum PTH concentrations secured the diagnosis. She had been given vitamin D over a period of years, which had increased her oral calcium absorption and renal calcium excretion, with little effect on her low serum calcium concentration. In the absence of PTH, calcium absorption along the nephron was lower than usual, accounting for her relatively generous hypercalciuria in the face of hypocalcaemia.

The discovery of the calcium-sensing receptor has greatly increased our understanding of calcium homeostasis [2]. The receptor is expressed in many tissues, including parathyroid glands, kidneys, bone marrow, breast, gastrin-secreting cells in the stomach, and elsewhere. In the parathyroids, the sensor reacts to a fall in serum calcium to signal a potent release of PTH. The sensor sets the PTH-release threshold. In the kidney, the calcium-sensing receptor is important in regulating urinary calcium excretion. Under hypercalcaemia, the receptor signals the generation of arachidonic acid metabolites (which may be 20-HETE) that then inhibit the potassium channel in the luminal membrane [3]. This mechanism explains the volume loss associated with hypercalcaemia. Mutations of the calcium-sensing receptor are of great interest. An inactivating mutation resets the receptor's activity so that a higher than normal serum calcium is necessary to release PTH. Affected persons have hypercalcaemia with PTH values that are within the normal range, but have a urinary calcium excretion that is lower than normal [4]. In the kidney, the inactivating mutation leads to an increased tubular calcium and magnesium reabsorption [5]. Homozygous persons have severe hypercalcaemia in infancy. Interestingly a mirror image to this condition exists in which affected persons have familial hypocalcaemia. In such cases, an activating mutation in the calcium-sensing receptor results in lower than normal serum calcium concentrations causing the release of PTH. The urinary calcium excretion is normal or elevated [6]. Several reports indicate that hypoparathyroidism because of an activating calcium-sensing receptor mutation can be associated with nephrocalcinosis [7].

A major recent breakthrough in completing the molecular details of calcium homeostasis in the kidney is the identification of an epithelial Ca2+ channel, termed ECaC [8]. ECaC is present in kidney, small intestine, and placenta. The channel should be a prime target for hormonal control of active calcium flux from the intestinal lumen or urine space to the blood compartment. ECaC is located in the apical domain of the connecting tubule [9]. The regulation of the channel is currently being investigated so we cannot speculate on any role for ECaC in our patient's clinical picture.

We were interested in the presence of nephrocalcinosis in this patient. Radiologically apparent nephrocalcinosis occurs in several hypercalcaemic disorders, including primary hyperparathyroidism, vitamin D intoxication, sarcoidosis, and the milk–alkali syndrome [10]. However, our patient had hypocalcaemia rather than hypercalcaemia. Distal renal tubular acidosis, either complete or incomplete can cause nephrocalcinosis [1]. For that reason, urinary calcium and citrate were measured. The urinary calcium excretion was high-normal for a woman; certainly inappropriately high for someone with hypocalcaemia. The urinary citrate was low, a common feature in distal renal tubular acidosis, which contributes to nephrocalcinosis and stone formation. The serum potassium concentration in our patient was considerably higher than that generally seen in distal renal tubular acidosis. Urinary net charge was determined and gave a positive value strongly suggesting the presence of a defect in the excretion of NH4 [11]. The transtubular potassium gradient was also inappropriately low in our patient. In the face of a potassium approaching 5 mmol/l a gradient of 8 would have been expected, while only 4 was measured. An aldosterone level would have been helpful to interpret the transtubular potassium gradient, since hypomineralocorticoidism may also be associated with hypercalciuria. However, our patient had no features of Addison's disease. To secure the diagnosis of incomplete RTA, a short ammonium chloride loading test was done. In the face of systemic acidosis, our patient could not acidify her urine, corroborating the inability of excreting hydrogen ions against a gradient appropriately.

A selective defect in net acid excretion is observed in genetically transmitted diseases, autoimmune diseases, drug or toxic nephropathies, tubulointerstitial diseases, and miscellaneous causes such as hepatic cirrhosis and the empty sella syndrome [1]. None of these explanations was appropriate in our patient. Nephrocalcinosis is associated with a selective defect in net acid excretion. However, the ‘text-book’ causes of primary hyperparathyroidism, hyperthyroidism, hereditary causes, hyperoxaluria, medullary sponge kidney, Fabry's disease, and Wilson's disease were not operative here [1]. Vitamin D intoxication can cause nephrocalcinosis and is generally a feature of the milk–alkali syndrome. Our patient was not intoxicated with vitamin D in the usual sense, as her serum values indicate. However, in the face of total hypoparathyroidism, she was faced with obligate relative hypercalciuria, irrespective of her serum calcium concentration. We suggest that her vitamin D therapy was the cause or contributed to her nephrocalcinosis and tubulo-interstitial nephritis.

Our therapeutic options are relatively limited. Conceivably, discontinuing the patient's vitamin D preparation could result in symptomatic hypocalcaemia, although she has not yet reported such symptoms. We have initiated thiazide diuretic therapy to minimize her urinary calcium excretion. Potassium citrate should decrease stone development in this patient, although she has difficulty in establishing a urinary potassium gradient and could develop hyperkalaemia. In addition, were she to develop metabolic alkalosis, symptomatic hypocalcaemia could result. Aside from the association with an activating mutation in the calcium-sensing receptor, we are not aware of any other reports describing hypoparathyroidism as a cause of nephrocalcinosis and stone disease.

Teaching point

Chronic vitamin D therapy has become not only one of the commonest causes of hypercalcaemia, but also may cause nephrocalcinosis, even if the serum calcium concentration is not elevated. Nephrocalcinosis can occur even in patients with hypocalcaemia. The incomplete RTA may have been related to nephrocalcinosis, vitamin D, or both.

Notes

Supported by an educational grant from

Correspondence and offprint requests to: Friedrich C. Luft MD, Charité Campus-Buch, Franz Volhard Clinic, Wiltberg Str. 50, 13125 Berlin, Germany. Back

References

  1. DuBose TD, Cogan MG, Rector FC. Acid–base disorders. In: Brenner BM, Rector FC (eds), The Kidney. Saunders, Philadelphia, 1996; 929–998
  2. Brown EM, Hebert SC. Calcium-receptor-regulated parathyroid and renal function. Bone1997; 20: 303–309[ISI][Medline]
  3. Wang WH, Lu M, Hebert SC. Cytochrome p-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL. Am J Physiol1996; 271: C103–111[Abstract/Free Full Text]
  4. Pearce SH, Bai M, Quinn SJ, Kifor O, Brown EM, Thakker RV. Functional characterization of calcium-sensing receptor mutations expressed in human embryonic kidney cells. J Clin Invest1996; 98: 1860–1866[Abstract/Free Full Text]
  5. Bai M, Pearce SHS, Kifor O. In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia. J Clin Invest1997; 99: 88[Abstract/Free Full Text]
  6. Pollak MR, Brown EM, Estep HL et al. Autosomal dominant hypocalcemia caused by a Ca2+-sensing receptor gene mutation. Nat Genet1994; 8: 303–307[ISI][Medline]
  7. De Luca F, Baron J. Molecular biology and clinical importance of the Ca(2+)-sensing receptor. Curr Opin Pediatr1998; 10: 435–440[Medline]
  8. Hoenderop JGJ, van der Kemp AWCM, Hartog A et al. Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem1999; 274: 8375–8378[Abstract/Free Full Text]
  9. Hoenderop JGJ, Hartog A, Stuiver M, Doucet A, Willems PHGM, Bindels RJM. Localization of the epithelial Ca2+ channel in rabbit kidney and intestine. J Am Soc Nephrol (in press)
  10. Sutton RAL. Clinical aspects of nephrocalcinosis. In: Bichler KH, Strohmaier WL (eds), Nephrocalcinosis, Calcium Antagonists, and Kidney. Springer-Verlag, Berlin, 1988; 105–112
  11. Kamel KS, Halperin ML, Faber MD, Steigerwalt SP, Heilig CW, Narins RG. Disorders of potassium balance. In: Brenner BM, Rector FC (eds), The Kidney. Saunders, Philadelphia, 1996; 999–1037




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