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Archives de pédiatrie
Volume 24, n° 5S2
pages 593-595 (mai 2017)
Doi : 10.1016/S0929-693X(18)30023-X
Renal impairment in hypophosphatasia
Atteinte rénale des hypophosphatasies
 

J. Bacchetta
 Service de néphrologie rhumatologie dermatologie pédiatriques, centre de référence des maladies rénales rares, hôpital Femme-Mère-Enfant, 59, boulevard Pinel, 69677 Bron Cedex 
 faculté de médecine Lyon-Est, université de Lyon, INSERM U 1033, LYOS, prévention des maladies osseuses, 69008 Lyon, France 

*Corresponding author.
Summary

Renal impairment in hypophosphatasia (HPP) has been described but remains poorly understood: hypercalciuria, nephrocalcinosis and sometimes even chronic kidney failure secondary to chronic hypercalcemia/hypercalciuria or exposure to toxic agents. The objectives of this review are to describe the different renal lesions observed in HPP, and the therapeutic measures that can be applied (in particular, thiazide diuretics).

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Résumé

L’atteinte rénale des hypophosphatasies (HPP) existe, mais est, en réalité, peu connue : hypercalciurie, néphrocalcinose et parfois même insuffisance rénale chronique après hypercalcémie/hypercalc iurie ou après exposition à des toxiques. L’objectif de cette mise au point est d’envisager les différentes atteintes rénales possibles en cas d’HPP et les moyens de les prendre en charge (en particulier les diurétiques thiazidiques).

The full text of this article is available in PDF format.
Introduction

Renal impairment in HPP has been described but remains poorly understood: hypercalciuria, nephrocalcinosis and sometimes even chronic renal failure in a context of hypercalcemia/hypercalciuria or exposure to toxic agents (non-steroidal anti-inflammatory drugs, bisphosphonates). Renal impairment occurs in the early-onset severe cases of HPP as defined by Whyte et al., in patients with clinical signs emerging before age 6 months [1]. In a Japanese series of 52 patients with HPP, only three presented with renal calcifications although all of them presented with the lethal perinatal disease [2]. In the large American series of 173 children, renal impairment was unfortunately not evaluated [3].

With regard to pathophysiology, at least in the early infantile forms of the disease, skeletal mineralization is blocked by extracellular accumulation of inorganic pyrophosphate. This results in hypercalcemia (classically considered absorptive, but probably secondary to a disequilibrium between bone resorption and an abnormal bone mineralization), which may or may not be associated with hypercalciuria, during which parathyroid hormone (PTH) levels become low, in an adaptive manner [1]. In the HPP forms diagnosed later in life, the metabolic abnormalities are much milder; blood calcium, vitamin D and PTH levels are normal [1]. Patients nonetheless present with a tendency toward hyperphosphatemia with increased tubular phosphate reabsorption (increase in maximum rate of phosphate reabsorption, TmP/GFR) [4], whose exact mechanisms have yet to be elucidated [1]. The objective of this review is to consider the various potential renal impairments in the event of HPP and the resources for their management.

Literature review

Table 1 summarizes the publications on HPP that report on renal impairment and its management. The underlying mechanisms and courses are addressed in the publications publishing isolated clinical cases by Barcia et al. [5], Auron et al. [6], Baumgartner-Sigl et al. [7], Mohn et al. [8], Whyte et al. [4], and Cundy et al. [9].

Implications for practice

In practice, in the absence of any etiological treatment, the following conclusions may be drawn from the clinical cases:

1/ management should aim at decreasing intestinal calcium absorption (in particular, a low diet, including low calcium milk, Locasol®; limitation of endogenous 1,25-vitamin D production, corticosteroids) is sometimes effective in early onset HPP, but should be avoided as far as possible since there is a long-term risk of an additional negative effect on bone mineralization;

2/ treatment decreasing osteoclastic activity (in particular with calcitonin or bisphosphonates) may be of value for the management of hypercalcemia but should probably be restricted to settings of severe acute hypercalcemia ‘to get over the worst’, particularly since the role of bisphosphonates, due to the similarity of their chemical structure to that of inorganic pyrophosphate, has not been clearly established; moreover repeated use of bisphosphonates is contra-indicated in HPP;

3/ treatment with thiazide diuretics, which has the theoretical dual advantage of decreasing calciuria while promoting bone mineralization, may be of value in the event of hypercalciuria and/or nephrocalcinosis. Caution is, however, required due to the hypokaliemia that thiazide diuretics often induce (begin with low dose of hydrochlorothiazide with regular monitoring of serum electrolytes);

4/ in the presence of clinical rickets, before «blindly’ instituting therapy with calcium and vitamin D, it is necessary to conduct a complete calcium – phosphate – ALP panel to rule out HPP;

5/ there are rare cases of chronic renal failure in adults with moderate HPP, the pathophysiology of which is poorly understood, but with, however, potentially explanatory factors such as chronic use of nephrotoxic analgesics (particularly non-steroidal anti-inflammatory drugs for bone pain), progression of low level nephrocalcinosis, and an adverse effect of bisphosphonates (in this very particular genetic context).

Conclusion and prospects

In the future, long-term studies to generate additional data on renal impairment would be of value even though the latter is not the primary concern in patients with HPP [10].


Statements of interests

No interests.

No financial aid.

References

Whyte M.P. Hypophosphatasia – aetiology, nosology, pathogenesis, diagnosis and treatment Nat Rev Endocrinol 2016 ;  12 : 233-246 [cross-ref]
Taketani T., Onigata K., Kobayashi H., and al. Clinical and genetic aspects of hypophosphatasia in Japanese patients Arch Dis Child 2014 ;  99 : 211-215 [cross-ref]
Whyte M.P., Zhang F., Wenkert D., McAlister W.H., Mack K.E., Benigno M.C., and al. Hypophosphatasia: Validation and expansion of the clinical nosology for children from 25years experience with 173 pediatric patients Bone 2015 ;  75 : 229-239 [cross-ref]
Whyte M.P., Leelawattana R., Reinus W.R., and al. Acute Severe Hypercalcemia After Traumatic Fractures and Immobilization in Hypophosphatasia Complicated by Chronic Renal Failure J Clin Endocrinol Metab 2013 ;  98 : 4606-4612 [cross-ref]
Barcia J.P., Strife C.F., Langman C.B. Infantile hypophosphatasia: treatment options to control hypercalcemia, hypercalciuria, and chronic bone demineralization J Pediatr. 1997 ;  130 : 825-828 [inter-ref]
Auron A., Alon U.S. Resolution of medullary nephrocalcinosis in children with metabolic bone disorders Pediatr Nephrol 2005 ;  20 : 1143-1145 [cross-ref]
Baumgartner-Sigl S., Haberlandt E., Mumm S., choll-Bürgi S., Sergi C., Ryan L., and al. Pyridoxine-responsive seizures as the first symptom of infantile hypophosphatasia caused by two novel missense mutations (c.677T>C, p.M226T; c.1112C>T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene Bone 2007 ;  40 : 1655-1661 [cross-ref]
Mohn A., De Leonibus C., de Giorgis T., Mornet E., Chiarelli F. Hypophosphatasia in a child with widened anterior fontanelle: lessons learned from late diagnosis and incorrect treatment Acta Paediatr 2011 ;  100 : e43-e46
Cundy T., Michigami T., Tachikawa K., Dray M., Collins J.F., Paschalis E.P., and al. Reversible Deterioration in Hypophosphatasia Caused by Renal Failure With Bisphosphonate Treatment J Bone Miner Res 2015 ;  30 : 1726-1737 [cross-ref]
Whyte M.P., Rockman-Greenberg C., Ozono K., Riese R., Moseley S., Melian A., and al. Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia J Clin Endocrinol Metab 2016 ;  101 : 334-342 [cross-ref]



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