Second Revised Edition. - OPUS 4 ?· Observations in men with idiopathic recurrent calcium urolithiasis…

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1

Research

Title:

Low magnesium in food is an abettor of calcium and magnesium accumulation in renal tissue, and

dyslipidemia? Observations in men with idiopathic recurrent calcium urolithiasis responding to a low

magnesium containing test meal with different degree of unrecovered magnesium in urine, and male

rats fed a magnesium-deficient diet. With a re-appraisal of kidney calcification and stone

pathophysiology. Second Revised Edition.

Author:

Paul Otto Schwille

Institutions:

Mineral Metabolism and Endocrine Research Laboratory, Departments of Surgery and Urology,

University of Erlangen-Nrnberg, Germany

Running head: Magnesium status and renal calcium stone formation.

Key words: Low food magnesium, abettor, magnesium retention, calcium urolithiasis of humans,

dyslipidemia, nephrocalcinosis of rats,

Address for correspondence:

Paul O. Schwille, M.D.

5, Finkenweg,

D-91080 Uttenreuth, Germany

Phone: +49-9131-59790,

Fax: +49-9131-533331,

E-mail: p.o.schwille@web.de

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Preface

Since completion oft the 1st online publication (Key Words: Low food magnesium, abettor;

http://www.opus.ub.uni-erlangen.de/opus/volltexte/2012/3603/) additional literature references were

identified fitting into the concept of IRCU as a magnesium-deficiency related disorder of calcium-

overloaded cells. Therefore, in this 2nd edition and adherent APPENDIX the number of citations and

text were enlarged and several additional figures included, together nourishing the idea that IRCU is

an outgrow of a primary pathology of blood vasculature.

Abstract

Background: The role of Mg in pathophysiology of IRCU is incompletely understood and would

benefit from animal models. Aims: To elucidate whether 1) Mg nutrition in IRCU impacts on minerals

and lipids in blood, minerals in urine, 2) dietary Mg deficiency of rats can serve as model for renal Ca

and Mg accumulation. Procedures: 1. Adult male patients (clinical trial 1; n = 88) underwent a

standardized laboratory program (urine and blood collections, intake of a TM with low Mg (type 1);

from Mg retention, viz. Mg not appearing in urine, and stratification Mg retention 50% (H) or

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Introduction

Intrarenal accumulation of calcium (Ca) and deposition as Ca phosphate (CaPi) can present as

nephrocalcinosis (NC) in humans and rats, in the latter species mostly caused by dietary magnesium

(Mg) deficit [1-6]. Nutritional Mg deficit also has been observed in survey-like studies of idiopathic

recurrent Ca urolithiasis (IRCU) of humans [7-9], a disease without clinically detectable NC, but

studies linking Ca stone formation and food Mg deficit more directly are not available. This situation

is somewhat surprising, considering that the idea of a link between Ca urolithiasis and Mg metabolism

is old [10], that in IRCU of males aged around 30 years a decrease of Mg in serum and erythrocytes

has been documented [11] and, more generally, Ca stone formation occurs on the basis of pre-existing

CaPi containing renal interstitial plaques (so-called Randalls plaques) [12, 13] that is reduced by Mg

supply with food [14]. An increasing renal cortico-medullary-papillary Ca gradient is characteristic for

both humans with IRCU [15] and the Mg-deficient rat [2, 4]; a similar but less expressed tissue Mg

gradient was reported for the rat model [4], whereas in IRCU robust data for renal Mg are lacking

(according to Pub-Med search).

Better understanding of the possible role played by low dietary Mg and other components of diet in

regulation of renal tissue Ca, Mg and other minerals in IRCU is further complicated by

overconsumption of lipids [16, 17] and the unknown role of lipids in pathogenesis of crystals and

stones [18, 19]. In rats fed a diet rich in cholesterol (CH) and triglycerides (TGL) but normal with

respect to Mg content, an increased renal cortico-medullary-papillary gradient of Mg and Ca not only

is preserved but even exaggerated, NC and CaPi stones form and document that both pathologies can

co-exist [2, 20]. On the other hand, IRCU patients reduce stone recurrence once Mg supplementation

of food has been instituted [14, 21], despite only marginal inhibitory effects of urinary Mg upon

crystallization of urinary Ca and oxalate (Ox) to CaOx [22], implying that once ambient Mg declines

the kidney tissue needs repletion of Mg stores, are formation of plaques and stones [13] to remain

under control, a task solved via inhibition of CaPi crystal maturation towards less soluble

hydroxyapatite (HAP) [23, 24]. As markers of disturbed mineral and bone metabolism in IRCU fasting

magnesiuria and magnesiemia were proposed [11, 25], but the gain of information for Mg in IRCU

pathophysiology remained limited. From these background informations we inferred that improved

knowledge of interplay of low Mg nutrition that leads to Mg "hunger", levels of blood lipids, renal

function and Mg appearing in simultaneously produced urine is indispensable, and should at best be

made transparent by means of a non-invasive laboratory procedure.

Among available methodologies quantitation of Mg hunger appeared to meet these requirements:

Assessment of the fraction Mg that is orally ingested as component of a test meal (TM) but not

recovered in postprandial urine ("retained" by the body) [26]. Because intestinal Mg absorption is

normal in normo- and hypercalciuric IRCU [27, 28], this kind of testing Mg status [26] might bring to

light low Mg status and possible association with so far etiologically inexplicable aspects of IRCU;

among the more prominent of the latter are changes of reactive oxidative species (ROS) [29, 30],

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sodium (Na) retention [31] and rise of blood pressure [8], together potentially acting as momentum of

all stone-forming processes (ASFP). To broaden the basis of the role of nutritional Mg in research of

IRCU etiology, rats were rendered Mg-deficient by dietary means, with post mortem analysis of Mg in

urine, blood, kidney and bone (the bodys major Mg storage site).

The present tripartite work, comprising two clinical trials and one experiment with rats, addresses

several questions: 1) Is there an IRCU subset detectable showing a high degree of Mg retention from a

TM containing very low Mg; if yes, is there alteration of Ca-uria, urine volume and saturation with

stone-forming salts, blood lipids and signs of oxidant/antioxidant imbalance? 2) When probing Mg

hunger in IRCU by intake of a TM with either definitively low or only marginally low Mg content,

does Mg retention deviate from non-stone-forming controls, depending on the amount of Mg ingested;

if yes, is variation of Mg retention a harbinger also of alteration of Ca and Na retention? 3) Is feeding

rats a low Mg diet followed by alteration of Mg, Ca, Pi in kidney, aorta, bone, as well as lipids in

blood, and signs of ROS excess? Because IRCU is a disorder with increasing incidence and prevalence

in Europe [32, 33] and abroad [34, 35], causing enormous financial burden to health-care providing

institutions, the observed data may be helpful for designing future projects.

Material and methods

1. Clinical studies, participants, procedures

The procedures described in the following were approved by the Ethics Committee of the University

of Erlangen Medical School; in addition, informed consent was obtained from all participants upon

prior written information about the necessity of examination under standardized laboratory conditions

at a fixed date and communication of program details [36, 37], including suspension of any medication

during the preceding two weeks. Other essentials of this program for outpatients were: collection of

24h urine on the day preceding examination while eating usual home food, withdrawal of fasting

venous blood, enhancement of diuresis (by drinking twice 200 ml deionized water), collection of 2h

fasting urine, intake of a test meal (TM), collection of 3h postprandial urine. The synthetic

carbohydrate-rich TM (Vivonex, Friesche Vlag, MA Leeuwarden, The Netherlands) was prepared to

deliver in 80 g dry weight: 1256 kJ (as glucose oligomers 67.9 g, fat 440 mg, amino acids 6.18 g), the

minerals (mM) calcium 25, Mg (two versions: one with 1.1 mM, designated very low Mg (VLMg),

another with 2.8 mM, designated low Mg (LMg)), Na (two versions: one with 19.5 mM, designated

normal Na (NNa), another with 6.1 mM, designated low-normal Na (LNa)); potassium 9.2, Pi (as

phosphorus) 5.4 were identical in both TM types. The meals (molar Ca/Pi 4.6) were taken as a

suspension in 300 ml deionized water (approx. 500 mOsm l-1). Two trials (one cross-sectional, one

controlled) were performed.

Trial 1: From the available database with inclusion of several blood lipids 88 male IRCU patients, age

21 68 years, without overt NC from any cause, especially mild primary hyperparathyroidism (cases

with normo- or hypercalciuria but normal intact serum parathyroid hormone (PTH)), were recruited.

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On the day of laboratory examination ASFP was scored for the two preceding