Differenzialdiagnose Hyper- und Hypocalcämie

M. Dominik AlscherRobert-Bosch-KrankenhausStuttgartdominik.alscher@rbk.de

mailto:dominik.alscher@rbk.demailto:dominik.alscher@rbk.de

Agenda

• Calciumhaushalt

• Vitamin D

• PTH

• Renale Mechanismen

• Hypercalcämie

• Hypocalcämie

of vitamin D had been isolated, chemically identified, and syn-thesized (15, 16). This compound, 25-hydroxyvitamin D3[25(OH)D3], is now currently monitored in serum to indicate thevitamin D status of patients, as discussed below. However,25(OH)D3 itself is metabolically inactive and must be modifiedbefore function. The final active hormone derived from vitaminD was isolated and identified in 1971, and its structure wasdeduced as 1!,25-dihydroxyvitamin D3 [1,25(OH)2D3] (17) andconfirmed by synthesis (18). The pathway that vitamin D mustfollow is illustrated in Figure 2 and forms the basis of the vitaminD endocrine system. For !2 decades, there was consistent re-visitation of the concept that more than one hormone was derivedfrom vitamin D, and !33 metabolites of vitamin D were identi-fied (19). However, it soon became clear that all metabolites wereeither less active or rapidly cleared and were thus intermediatesin the degradation of this important molecule. The most impor-tant of these metabolites are 24,25-dihydroxyvitamin D3 and1!,24(R),25-trihydroxyvitamin D3 produced by the enzymeCYP24, which is induced by the vitamin D hormone itself (20).

Much is known about the enzymes that produce 1,25(OH)2D3and their regulation, but a great deal remains to be learned (20).Two enzymes are thought to function in the 25-hydroxylationstep. They are not exclusively hepatic but are largely functionallyactive in the liver. The mitochondrial enzyme, which is not spe-cific for vitamin D, has been cloned and a knockout mouse strainhas been prepared, without any apparent effect on vitamin Dmetabolism, which suggests that there is an alternate 25-hydroxylase (21). A microsomal hydroxylase was recentlycloned and could represent the missing enzyme (22). The25(OH)D3 1!-hydroxylase was cloned by 3 different laborato-ries (reviewed in ref 20), and the sites of vitamin D-dependent

rickets type I were identified in several studies (20). Very im-portant was the generation of 1!-hydroxylase knockout mice,which exhibit a phenotype virtually identical to the human vita-min D-dependent rickets type I phenotype. Therefore, the en-zymes that activate vitamin D have been identified.

Of major metabolic importance is the mode of disposal ofvitamin D and its hormonal forms. The cytochrome P-450 en-zyme now called CYP24 was isolated in pure form by Ohyamaand Okuda (23) and the complementary DNA and gene werecloned, which yielded a 24-hydroxylase-null mutant (reviewedin 20). No significant phenotype resulted except for a large ac-cumulation of 1,25(OH)2D3 in the circulation, which producedsecondary effects on cartilaginous growth (20, 24). CYP24 is anextremely active enzyme, but the gene remains silent in vitaminD deficiency; it is induced by the hormonal form of vitamin Ditself. Therefore, pulses of the vitamin D hormone program itsown death through induction of the 24-hydroxylase. The 24-hydroxylase is able to metabolize vitamin D to its excretionproduct calcitroic acid (20). 25(OH)D3 can also be degradedthrough this pathway. 24-Hydroxylase and its regulation areimportant factors in the determination of the circulating concen-trations of the hormonal form of vitamin D.

PHYSIOLOGIC FUNCTIONS OF VITAMIN D

A diagrammatic explanation of the role of the vitamin D hor-mone in mineralizing the skeleton and preventing hypocalcemictetany is presented in Figure 3 (20). Plasma calcium concentra-tions are maintained at a very constant level, and this level issupersaturating with respect to bone mineral. If the plasma be-comes less than saturated with respect to calcium and phosphate,then mineralization fails, which results in rickets among childrenand osteomalacia among adults (24). The vitamin D hormonefunctions to increase serum calcium concentrations through 3separate activities. First, it is the only hormone known to inducethe proteins involved in active intestinal calcium absorption.Furthermore, it stimulates active intestinal absorption of phos-phate. Second, blood calcium concentrations remain in the nor-mal range even when an animal is placed on a no-calcium diet.Therefore, an animal must possess the ability to mobilize calciumin the absence of calcium coming from the environment, ie,

FIGURE 1. Structure of vitamin D3, or cholecalciferol, and its numberingsystem.

FIGURE 2. Metabolic activation of vitamin D3 to its hormonal form,1,25(OH)2D3.

FIGURE 3. Diagrammatic representation of the role of the vitamin Dhormone and the parathyroid hormone (PTH) in increasing plasma calciumconcentrations to prevent hypocalcemic tetany (neuromuscular) and to pro-vide for mineralization of the skeleton.

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through enterocytes. Two mechanisms play a role in increasingblood calcium concentrations, especially in the absence of intes-tinal calcium absorption. Vitamin D hormone stimulates osteo-blasts to produce receptor activator nuclear factor-!B ligand(RANKL) (25). RANKL then stimulates osteoclastogenesis andactivates resting osteoclasts for bone resorption (25). Therefore,the vitamin D hormone plays an important role in allowing in-dividuals to mobilize calcium from bone when it is absent fromthe diet. It is very important to note, however, that in vivo bothvitamin D and parathyroid hormone are required for this mobi-lization event (26, 27). Therefore, 2 keys are required, similar toa safety deposit box. Third, the distal renal tubule is responsiblefor reabsorption of the last 1% of the filtered load of calcium, andthe 2 hormones interact to stimulate the reabsorption of this last1% of the filtered load (28). Because 7 g of calcium are filteredevery day among humans, this represents a major contribution tothe calcium pool. Again, both parathyroid hormone and the vi-tamin D hormone are required. Calcium physiologic processesare such that a single low concentration of the vitamin D hormonestimulates enterocytes to absorb calcium and phosphate. If theplasma calcium concentration fails to respond, then the parathy-roid glands continue to secrete parathyroid hormone, which in-creases production of the vitamin D hormone to mobilize bonecalcium (acting with parathyroid hormone). Under normal cir-cumstances, environmental calcium is used first; if environmen-tal calcium is absent, then internal stores are used.

VITAMIN D ENDOCRINE SYSTEM

A diagrammatic representation of the endocrine regulation ofcalcium concentrations in the plasma and the vitamin D endo-crine system is presented in Figure 4. Calcium-sensing proteinsthat sense plasma calcium concentrations are found in the para-thyroid gland (29, 30). When calcium concentrations decreasebelow normal, even slightly, then these transmembrane proteins,coupled to a G protein system, stimulate the secretion of para-thyroid hormone. Parathyroid hormone then proceeds to the os-teoblasts and to the proximal convoluted tubule cells withinseconds. Most importantly, in the convoluted tubule cells that

serve as the endocrine gland for the vitamin D hormone, 1"-hydroxylase concentrations are markedly elevated (30, 31). Thissignals the vitamin D hormone, which by itself stimulates intes-tinal absorption of calcium or together with parathyroid hor-mone, at higher concentrations, stimulates mobilization of bonecalcium and renal reabsorption of calcium. The increase in serumcalcium concentrations exceeds the set point of the calcium-sensing system, shutting down the parathyroid gland-inducedcascade of events. If the plasma calcium concentrations over-shoot, then the C-cells of the thyroid gland secrete the 32-aminoacid peptide calcitonin, which blocks bone calcium mobilization(32). Calcitonin also stimulates the renal 1"-hydroxylase to pro-vide the vitamin D hormone for noncalcemic needs under nor-mocalcemic conditions (33). The molecular mechanisms havenot been entirely determined, except for the vitamin D hormoneinduction of 24-hydroxylase (CYP24).

An important aspect of the vitamin D endocrine system is thatdietary calcium is favored to support serum calcium concentra-tions under normal conditions but, when this fails, the systemmediates calcium mobilization from bone and reabsorption in thekidney to satisfy the needs of the organism. This results in loss ofcalcium from the skeleton and can ultimately lead to osteoporo-sis. Another important aspect is that, except for stimulating min-eralization of the skeleton, the vitamin D hormone has not beenfound to be anabolic on bone by itself.

MOLECULAR MECHANISMS OF VITAMIN D ACTIONS

The vitamin D hormone functions through a single vitamin Dreceptor (VDR), which has been cloned for several species in-cluding humans, rats, and chickens. It is a member of the class IIsteroid hormones, being closely related to the retinoic acid re-ceptor and the thyroid hormone receptor (reviewed in ref 20). It,like other receptors, has a DNA-binding domain called theC-domain, a ligand-binding domain called the E-domain, and anF-domain, which is one of the activating domains. Despite manystatements to the contrary in the literature, a single receptorappears to mediate all of the functions of vitamin D, whichcomplicates the preparation of analogs for one specific functionrather than another. The human receptor is a 427-amino acidpeptide, whereas the rat receptor contains 423 amino acids andthe chicken receptor contains 451 amino acids. This receptor actsthrough vitamin D-responsive elements (VDREs), which areusually found within 1 kilobase of the start site of the target gene.The VDREs, which are shown in Figure 5, are repeat sequences

FIGURE 4. Diagrammatic representation of the vitamin D endocrinesystem. Red arrows indicate suppression; black arrows indicate stimulation.Serum calcium concentrations are represented by a thermometer. Low serumcalcium concentrations are detected by a calcium sensor in the parathyroidgland, which initiates synthesis and secretion of parathyroid hormone. Thecalcium sensor for high concentrations is in the C cells of the thyroid glandand initiates secretion of calcitonin (CT).

FIGURE 5. Partial list of VDREs found in the promoter regions of targetgenes. Most prominent is the VDRE found in the 24-hydroxylase (CYP24)promoter.

FUNCTIONS OF VITAMIN D 1691S

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VD, Ca, Ph

Antiproliferation und Differenzierung Inhibition von Renin/Angiotensin II

Herz-Kreislauf-System

Vitamin-D-Rezeptor-Aktivatoren zeigen klassische und nicht-klassische Wirkungen

Nebenschilddrüsen

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Immunsystem

Inhibition PTH-Synthese und PTH-Sekretion, Kontrolle der Hyperplasie

Calcium- und Phosphatreabsorption

Calcium- und Phosphatresorption

Calcium- und Phosphatresorption

Insulin-Synthese und -Sekretion

Immunmodulatorische Effekte in den T-Zellen, B-Zellen, Makrophagen,

Monozyten und Lymphozyten

Brown AJ et al. Am J Physiol 1999; 277:F157-F175

Holick M. N Engl J Med 2007;357:266-281

Non-skeletal

of 6 nucleotides separated by 3 nonspecified bases. It is now clearthat the 5' arm of this sequence binds the retinoic acid X receptorand the 3' arm binds the VDR. Of all of the genes identified todate, the most powerfully regulated is the CYP24 or 24-hydroxylase enzyme, which is responsible for the degradation ofvitamin D (20). The programming of its own destruction is thusan important aspect of this endocrine system, which uses one ofthe most potent ligands known.

A diagram that describes how the VDR with its ligand affectsthe transcription of target genes is presented in Figure 6. Al-though there is little evidence for a co-repressor, we think thatco-repressors will eventually be found for the VDR. When theVDR interacts with the ligand, the repressor is no longer able tobind to the receptor, and the receptor changes conformation.Together with the required RXR, the VDR forms a heterodimerat the VDREs (20). At the same time, it binds several otherproteins required in the transcription complex and, most impor-tantly, acquires an activator (20). To date, at least 3 coactivatorshave been identified, ie, SARC1, -2, and -3 (34) and DRIP205(35). There may be additional coactivators, and there may beselectivity among the coactivators with respect to which gene isbeing expressed. Much attention is being focused on this aspectfor selective regulation of target genes. Once the complex isformed, the DNA bends (36), phosphorylation on serine-205occurs (37), and transcription is either initiated or suppressed,depending on the gene. To date, it is unclear whether the phos-phorylation plays a functional role in transcription.

FUNCTIONS OF VITAMIN D UNRELATED TOCALCIUM

One of the most important findings after discovery of thereceptor was that the receptor appeared not only in the target cellsof enterocytes, osteoblasts, and distal renal tubule cells but also

in parathyroid gland cells, skin keratinocytes, promyelocytes,lymphocytes, colon cells, pituitary gland cells, and ovarian cells(20). The expression of VDRs in these cells and not in skeletalmuscle, heart muscle, and liver suggests that they must serve afunction there (20). Although VDRs have been reported in liver,heart, and skeletal muscle (38–42), we and other groups failed toconfirm those reports, with the use of specific monoclonal anti-bodies and other methods (43, 44). This led to the investigationand discovery of functions of vitamin D not previously appreci-ated, which takes the vitamin D system beyond bone.

An important discovery was made by Suda et al (25), whodemonstrated that the vitamin D hormone plays an important rolein the terminal differentiation of promyelocytes to monocytes,which are precursors of the giant osteoclasts. Those authors alsofound that, when the cells differentiated into a functional cellline, growth ceased. This function did not involve calcium andphosphorus and was later shown to be fundamental to vitaminD-induced production of osteoclasts through the RANKL system(for review, see reference 25).

Of great importance is the finding of the VDR in the parathy-roid glands. We now know, through the treatment of renal os-teodystrophy with the vitamin D hormone and its analogs, that anessential site for this therapy is the VDR in the parathyroid glands(20). An important function of the vitamin D hormone is to keepthe production of the preproparathyroid gene under control andreasonably suppressed (20, 45). Furthermore, the vitamin D hor-mone, through its receptor, in some way functions to preventproliferation of parathyroid gland cells. Therefore, an importantfunction of the vitamin D hormone among normal subjects is tomaintain normal parathyroid status. Among patients with renalfailure, the site of production of the vitamin D hormone is de-stroyed and the parathyroid gland becomes vitamin D deficient;in the presence of adequate amounts of calcium in the circulation,

FIGURE 6. Diagrammatic representation of the known molecular events in the regulation of gene expression by the vitamin D hormone, 1,25(OH)2D3,acting through its receptor, VDR. The result of regulation may be either suppression or activation. RXR, retinoid X receptor; DRE, VDRE (see Figure 5); TFIIB,transcription factor IIB; TFIID, transcription factor IID; RNAP, RNA polymerase.

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(PSD-95, Discs-large and ZO-1) binding motif that interactswith several PDZ proteins.16,17 PDZ domains, first describedin the early 1990s, comprise 80–100 residues distributed in sixb strands and two a helices. They bind to the carboxyl-terminal tail (PDZ-binding motif) of the correspondingligand (for review, see Nourry et al.18). A conserved sequencebetween the bA and bB strands of the PDZ domain (GLGF)provides a hydrophobic pocket for ligand binding. Amongthe PDZ proteins that interact with NaPi-IIa are the Na/H-exchanger regulatory factors NHERF1 (EBP50) and NHERF2(E3KARP) as well as PDZK1 (NHERF3), PDZK2 (IKEPP,NHERF4), and Shank2E.16,17

NHERF1 and NHERF2 are two related proteins eachcontaining two PDZ domains and a C-terminal Merlin-Ezin-Radixin-Moesin-binding domain.19–21 They are expressed inthe apical/subapical domain of murine proximal tubules,respectively.16,22 NaPi-IIa binds to the first PDZ domain onboth proteins.16 Renal proximal cells (opossum kidney cells)transfected with dominant-negative NHERF1 constructs23

and young NHERF1!/! animals24 show a reduced amount ofNaPi-IIa at the BBM. In animals, this reduction associateswith urinary loss of Pi, a phenotype that reverts with age.

25

These findings suggest that NHERF1 contributes to stabilize

NaPi-IIa at the BBM. This stabilization depends on theMerlin-Ezin-Radixin-Moesin-binding domain,23 which med-iates binding to the actin-associated protein Ezrin. Incontrast to the effect on NaPi-IIa, deficiency in NHERF1does not affect the expression of NHE3.24

PDZK1 and PDZK2 are related proteins, also expressed inmurine proximal tubules, each containing four PDZdomains. In both cases, NaPi-IIa binds to the third PDZdomain.16,26 Opossum kidney cells transfected with adominant-negative PDZK1 construct show reduced levels ofNaPi-IIa at the BBM.23 Although NaPi-IIa expression isunaffected in normally fed PDZK1!/! mice, its abundancedecreases when the animals are fed a high Pi-diet.

27 Thus, inextreme dietary conditions PDZK1 may contribute tostabilize NaPi-IIa at the BBM.

Shank2E is an epithelial-specific isoform of Shank2. Thethree members of the Shank family share a similar domainstructure consisting of six N-terminal ankyrin repeatsfollowed by an SH3 domain, a PDZ domain, and aproline-rich region.28 In rats, Shank2E is expressed at theBBM of proximal tubules and, as for the other PDZ proteins,association with NaPi-IIa requires the C-terminal TRL motifof the cotransporter.17 Shank2 can bind dynamin,29 a

Glomerular filtrate

1. Apical expression of NaPi-IIadepends on PDZ-mediatedinteractions

4. NaPi-lla internalizedvia clathrin coated pits.Internalization dependson a dibasic KR motif inthe last intracellualr loopof NaPi-IIa

5. NaPi-lla transportedto endosome in clathrin-coated vesicles

6. Endocytosed NaPi-IIatargeted to lysomes fordegradation. Microtubule-dependent step

2. Binding of PTH toapical receptors activatesPLC/PKC cascadeleading to NaPi-lladownregulation.

3. Activation of PLCby PTH receptors isdependent onNHERF1

2. Binding of PTHto basolateralreceptors activatesPKA cascadeleading to NaPi-lladownregualtion.

ERKPLC

PKC

PKA

PTH

PTH

Lysosome

Endosome

Blood

Figure 2 | The downregulation of NaPi-Iia. Schematic representation of the sequence of steps involved in PTH-induced downregulation ofNaPi-IIa in an epithelial proximal tubule cell. Apical and basolateral membranes are separated by tight junctions (orange), to establish twocompartments for hormonal access.

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regulation depends on its shuttling to/from the BBM. Thiscontrasts with many other transporters, which activity ismodulated by modification of the transport protein itself(e.g. phosphorylation, dimerization etc). This means that thebody’s requirements for a higher Pi reabsorption (i.e. afterlow Pi-diet) are met by increasing the expression of NaPi-IIa7,11,12 and NaPi-IIc4 at the BBM. For NaPi-IIa, acuteupregulation is independent of changes in transcription ortranslation. Therefore, the increased expression of NaPi-IIamust be owing to either the stabilization of the transporter atthe BBM or to an increased rate of insertion at themembrane. Experimental data supports this dual mechanism.Thus, dietary-induced upregulation depends on the presenceof scaffolding proteins,13 suggesting a stabilization action,and on the microtubule network,11 suggesting an increasedrate of insertion. This latter mechanism requires the presenceof an intracellular pool of NaPi-IIa ready to be shuttled to themembrane. Immunostainings of kidneys from rats fedacutely a low Pi-diet have indeed revealed the presence ofNaPi-IIa in the Golgi apparatus, although this pool is notdetected with all immunostaining protocols.11

In contrast, reduced reabsorption of Pi (i.e. upon PTHrelease or high Pi-diet) is achieved via downregulation ofNaPi-IIa8,11,14 and NaPi-IIc9 at the BBM. PTH-induceddownregulation of NaPi-IIa has been extensively studied andthe identifiable steps are summarized in Figure 2. Becauseendocytosed cotransporters do not recycle to the BBM butinstead are degraded in lysosomes, recovery of NaPi-IIa basallevels upon PTH removal depends on de novo synthesis. It istherefore clear that apical retention/removal of NaPi-IIa mustbe a regulated process, beyond the control of proteinturnover. We will now describe in detail the steps summar-ized in Figure 2, integrating what is known about themechanisms that regulate NaPi-IIa expression with the role ofprotein complexes.

Regulation of apical expression (step 1)Apical expression of NaPi-IIa is dependent on its last threeresidues (TRL, see Figure 4a). Truncation of these residuesleads to intracellular accumulation of the cotransporter,suggesting an impaired sorting and/or stability of themutated protein.15 The TRL sequence represents a PDZ

2−−

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+3Na

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ATP

ADP

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Driven by ATPhydrolysis, the NaK-ATPase maintainsintracellularelectronegativity by removing accumulated Na+ ions in exchange for K+ ions.

Basolateral exit of Pi is via an unknown pathway.Pi then diffuses into blood.

Glomerular filtrate

Blood

Electroneutral NaPi-IIc couples 2 Na+ ions to the uphill transport of one divalent Pi.No net charge transfer occurs.

Electrogenic NaPi-IIa couples 3 Na+ ions to uphill movement of one divalent Pi per transport cycle. One net charge istranslocated.

?

IIa IIc

Pi+Na

Pi

Figure 1 | Energetics of Pi reabsorption. In the BBM of proximal tubule epithelia, two Naþ -coupled transporters, designated as NaPi-IIa

and NaPi-IIc, mediate apical uptake of Pi from the glomerular filtrate. Both are secondary active and drive Pi inward using the electro-chemical free energy difference across the membrane for Naþ ions. NaPi-IIa is electrogenic and NaPi-IIc is electroneutral. With a typicaltransmembrane Naþ concentration ratio of 10:1, the theoretical Pi concentrating capacity of NaPi-IIc is B100:1, whereas that for NaPi-IIais B10 000:1 because of its 3:1 Naþ :Pi stoichiometry and the additional driving force contributed by the transmembrane potential difference.

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guanosine triphosphatase that mediates fission of endocyticvesicles.30 Thus, Shank2E may connect NaPi-IIa with theendocytic machinery.

PTH signaling (steps 2–4)In the proximal tubule, PTH binds to apical and basolateralreceptors. Stimulation of either receptor leads to an increasein urinary excretion of Pi as consequence of the reduction ofNaPi-IIa in the BBM.31 Apical application of PTH to isolatedproximal tubules activates preferentially the phospholipaseC/protein kinase C (PKC) pathway, whereas basolateralapplication leads to activation of cyclic adenosine mono-phosphate (cAMP)/protein kinase A (PKA) signaling.31 Themolecular explanation for this dual response may relay on thepresence (apical) or absence (basolateral) of NHERF. Thus, ithas been shown that NHERF associates with both the PTHreceptor and the phospholipase Cb1.32 The consequence ofthis intermolecular association is the preferential activationof phospholipase C upon binding of PTH to apical receptors.In accordance with this mechanism, both 1–34 PTH (afragment that activates PKA and PKC) and 3–34 PTH (afragment that activates only PKC) fail to activate phospho-lipase C in kidney slices from NHERF1!/! mice.33 Despitethe heterogeneity of their initial steps, apical, and basolateralPTH receptors use common downstream effectors. Mitogen-activated protein kinase-kinase 1/2 inhibitors partially orfully prevent the effect of both cascades, suggesting that thePKC and PKA pathways coactivate extracellular signal-regulated protein kinase 1/2.34 Interestingly, NHERF1 playsa very different role in the regulation of NHE3, where acts asa scaffold for PKA via association with the cAMP-kinaseassociated protein Ezrin.35 Then, PKA phosphorylates (andinhibits) NHE3 without initial changes in the expression ofNHE3 in the BBM.36 cAMP-induced inhibition of NHE3 canbe reproduced with cAMP analogs that activate exchangeprotein directly activated by cAMP (EPAC1), whereas NaPi-IIa is downregulated by PKA- but not by EPAC1-activatinganalogs.37

PTH-induced endocytosis of NaPi-IIa (steps 5 and 6)Binding of PTH leads to the axial movement of NaPi-IIaalong the microvilli and finally to its endocytosis from themicrovillar clefts.38,39 NaPi-IIa colocalizes with insulin uponPTH administration, suggesting its internalization viareceptor-mediated endocytosis.40 This is further supportedby the finding that NaPi-IIa endocytosis is prevented in micewith kidney-specific megalin deficiency and in receptor-associate-protein-deficient mice.41 The immunostainingsshown in Figure 3 illustrate the route followed by NaPi-IIain response to PTH.40 Endocytosis takes place via clathrin-coated pits and it is detected shortly upon PTH administra-tion. Later on, NaPi-IIa is observed in clathrin-coated pitsand in endosomes (early endosome-associated protein 1(EEA1) positive). Finally, the cotransporter is targeted to lateendosomes/lysosomes (lgp120 positive). Endocytosis associ-ates with microtubule rearrangement, owing to the formation

of apical to basolateral oriented bundles.42 Prevention ofmicrotubular rearrangement or microtubular depolymeriza-tion causes the delay of intracellular depletion of NaPi-IIa(i.e. lysosomal degradation), although it does not affect itsdownregulation (i.e. endocytosis).

Clathrin-mediated internalization of many proteins de-pends on discrete intracellular sequences, among themtyrosine (Y)- and dileucine (LL)-based motifs. These motifslink the protein to be endocytosed to the adaptor proteinAP2 which in turn binds to clathrin (for review, seeRobinson43). AP2 is a heterotetramer consisting of a, b2,m2, and s2 subunits. Y-based motifs bind to the m subunitwhereas LL-based motifs interact with the b subunit. NaPi-IIa contains several putative Y- or LL-motifs (GY402FAM,Y509RWF, LL101, LL374, and LI590) and two diacidic sequences(EE81 and EE616) that can control lysosomal targeting.Mutations of these motifs did not affect the PTH-inducedretrieval of NaPi-IIa.44 Instead, a dibasic sequence (KR)within the last intracellular loop (Figure 4a) is required forPTH sensitivity.45 These two positively charged residues arereplaced by uncharged residues (NI) in the PTH-insensitiveNaPi-IIb isoform. Swapping the specific residues inverts thePTH sensitivity of the protein. The KR-containing loop, butnot a mutant with the KR sequence replaced by NI, interactswith PEX19.46 In opossum kidney cells, NaPi-IIa endocytosisis accelerated upon transfection of PEX19, suggesting a roleof this protein in the internalization of the cotransporter.46

NHERF1 and PDZK1 remain attached to the BBM uponPTH administration; Deliot et al.,47 in preparation. Thissuggests the disassembly of protein complexes beforeinternalization of NaPi-IIa. In opossum kidney cells, theamount of NaPi-IIa that coimmunoprecipitates with

Clathrin EEA1 LgP 120

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Figure 3 | Immunohistochemical evidence for NaPi-IIa down-regulation. Immunofluorescence of kidney slices incubated in theabsence or presence (5, 15, and 60min) of PTH. Samples wereco-stained with antibodies against NaPi-IIa (green) and eitherclathrin, EEA1, or lgp120 (red) antibodies.

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NHERF1 is reduced upon PTH treatment.47 Thus, PTH maynegatively regulate the association between NaPi-IIa andNHERF1/PDZK1. PDZ-based interactions can be regulatedby phosphorylation of either the PDZ-binding motif or thecorresponding PDZ-domain. Studies using cell culturemodels have demonstrated that NHERF1 is constitutivelyphosphorylated, and the residues responsible for constitutiveand regulated phosphorylation have been identified.48–50

NHERF1 is also constitutively phosphorylated in mousekidney.47 Moreover, PTH, or pharmacological activation ofPKA and PKC induces phosphorylation of NHERF1, but notof NaPi-IIa. PDZK1 is also constitutively phosphorylated inkidney, and similar to NHERF1, PTH, or activation of

kinases, leads to an increase in its phosphorylation state(N. Déliot, N Hernando, unpublished experiments). Thus,we can hypothesize that phosphorylation of the PDZ-proteinsdestabilizes their association with NaPi-IIa. According to arecent report, PDZK1 is phosphorylated by PKA in Ser509and this modification is required for upregulation of thescavenger receptor class B type I.51

Like PTH, a high Pi-diet also induces downregulation ofNaPi-IIa.7,8,11,12 Although this process has not been studiedin the same detail as the PTH effect, endocytosedcotransporters are also degraded in lysosomes.8,12 Thus,PTH and Pi-diet may lead to similar cellular responses.Expression of NHERF1 and PDZK1 remain unaffected upon

Control NaPi-IIb

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b

Figure 4 | The NaPi-II protein. (a) Topological map of NaPi-IIa. This scheme is based on prediction algorithms and experimental data. TheNaPi-IIa monomer comprises twelve a-helical segments, four of which (yellow) have been confirmed by in vitro translation assays to spanthe membrane.67 substituted cysteine accessibility method (see text) has revealed sites accessible from the external,69,70,72–74 (blue) andinternal71 (green) sides of the membrane, respectively. Two reentrant regions in each half of the protein, which comprise putative a-helicalsegments 3–4 and 8–9 (boxed) and the preceding linkers, contain identical residues (pink). They are proposed to form the substratetranslocation pathway.75 A disulfide bridge in the large extracellular loop links the two halves of the protein. Regulatory sites include theK-R motif45 (orange), important for PTH-induced internalization, located at the cytosolic end of a-helical domain 1115 and the triglyceride-richlipoproteins motif (violet) at the end of the C-terminal tail, involved in PDZ interactions.15 The large extracellular linker region contains twoN-glycosylation sites (black). Three sites were found critical for NaPi-IIa electrogenicity in the linker between a-helical segments 4–5 (red).5

(b) Evidence for NaPi-II dimers in the plasma membrane. Freeze fracture micrographs of the P face of the oocyte plasma membrane show a lowdensity of endogenous particles in a control oocyte (left) and an increased particle density in an oocyte expressing the flounder renal/intestinalNaPi-IIb (center). Scale bar for both images: 200 nm. P Face¼protoplasmic face, ES¼ extracellular space; Cyt¼ cytosol. Statistical analysis ofparticle diameter (right) suggests a homodimeric complex for NaPi-IIb proteins based on freeze-fracture analysis of other membrane proteins.86

Images and analysis courtesy of S. Eskandari, Biological Sciences Department, California State Polytechnic University, Pomona, CA, USA.

1552 Kidney International (2006) 70, 1548–1559

rev iew IC Forster et al.: Renal phosphate handling

Proximal tubular handling of phosphate: A molecular perspective. KI 2006, 70: 1548

PTH in maintaining the Ca2þ balance. In addition,mutations in the Ca2þ -sensing receptor, which couples theplasma Ca2þ levels to the production and secretion of PTHfrom the thyroid glands, were identified in patients with

familial hypocalciuric hypercalcemia, neonatal severe hyper-parathyroidism (inactivating mutations),1 and autosomal-dominant hypocalcemia (activating mutations).2 From theclinical symptoms of these PTH-related disorders, includinghypo- or hypercalciuria and renal stone formation, it isevident that renal Ca2þ handling is also affected. PTHreceptors have been detected throughout the nephronincluding DCT and CNT, thus enabling the body to directlycontrol active Ca2þ reabsorption in the kidney via PTH.3 Inaddition, genetic ablation of Ca2þ -sensing receptor resultedin hyperparathyroidism and hypercalcemia, accompanied byan upregulation of TRPV5 and TRPV6 in the kidney andintestine, respectively (Table 1).4 To understand the mole-cular regulation of the Ca2þ transport proteins by PTH,parathyroidectomy was performed in rats.5 The effectivenessof this treatment was evident from the marked reduction ofPTH levels and hyperphosphatemia, a well-known symptomin hypoparathyroidism. Moreover, parathyroidectomy redu-ced the expression of TRPV5, calbindin-D28K, and NCX1.This decline in expression of the renal Ca2þ transportproteins resulted in decreased active Ca2þ reabsorption andthe development of hypocalcemia. PTH supplementation inthese parathyroidectomized rats resulted in normalization ofthe renal Ca2þ transport protein expression levels andincreased the plasma Ca2þ concentration.5 In addition, theregulation by PTH was investigated in primary cultures ofrabbit CNT and cortical collecting duct (CCD) cells.5 PTH

TRPV5

Ca2+Ca2+

Ca2+

Calbindin-D28K Na+NCX1

PMCA1b

PTH

Basolateral

Estrogen Vitamin D

ER

Apical

+

Figure 1 | Transcellular Ca2þ reabsorption in the kidney.Integrated model of active transcellular Ca2þ reabsorption in thekidney that consists of TRPV5 as the apical entry gate for Ca2þ ,calbindin-D28K as an intracellular ferry protein for Ca

2þ and, NCX1and PMCA1b as Ca2þ extrusion systems across the basolateralmembrane to the blood compartment. See text for details.

Table 1 | Coordinated regulation of the Ca2+ transport proteins

Kidney Intestine

TRPV5 Calbindin-D28K NCX1 PMCA1b TRPV6 Calbindin-D9K PMCA1b Reference

PTHCaSRa m NM NM NM m NM NM 4Parathyroidectomy k k k = NM NM NM 5Parathyroidectomy+PTH replacement therapy m m m = NM NM NM 5PTH supplementation m m m m NM NM NM 5

EstrogensEstrogen receptor-a"/" k k k k k = = 3Ovariectomy = = = = NM NM NM 3Ovariectomy+replacement therapy m m/= m/= m/= m m/ = m/= 3Estrogen supplementation in 1a-OHase"/" m = = = m NM NM 3Estrogen supplementation in ovariectomized VDR"/" m = = = m = = 3

Vitamin DVitamin D deficiency k NM NM NM NM NM NM 31a-OHase"/" k k k = NM NM NM 14/3VDR"/" k = = = k k = 151,25(OH)2D3 supplementation in vitamin D deficiency m m NM NM NM NM NM 3

Ca2+

Ca2+ supplementation in 1a-OHase"/" m m m m NM NM NM 3

MiscellaneousTRPV5"/" ND k k = m m m 16

Overview of the different studies investigating the expression of the Ca2+ transport proteins in the kidney and intestine. Genetic ablation, dietary, and hormonal Ca2+

alterations demonstrated a concomitant regulation in expression of the renal and intestinal Ca2+ transport proteins.m, upregulation; k, downregulation; =, no change in expression; NM, not measured; ND not detectable; PTH, parathyroid hormone; CaSR, Ca2+-sensing receptor; 1a-OHase,25-hydroxyvitamin D3-1a-hydroxylase.aGenetic ablation of the CaSR resulted in a severe hyperparathyroidism. See text for details.

Kidney International (2006) 69, 650–654 651

TT Lambers et al.: Coordinated control of renal Ca2þ handling min i rev iew

Kidney International (2006) 69, 650

Das Mnemotechnische Kunstwort „vitamins trap“ (Vitaminfalle) kann für das

Erinnern der Differentialdiagnose nützlich sein (Pont 1989):

V Vitamine A und DI ImmobilisationT ThyreotoxikoseA Addison-ErkrankungM Milch-Alkali-SyndromI inflammatorische DarmerkrankungN NeoplasienS SarkoidoseT Thiazide und andere MedikamenteR RhabdomyolyseA AIDSP Paget-Krankheit, parenterale Ernährung, Parathyreoideaerkrankungen.

Ursachen der HyperkalzämieUrsachen der HyperkalzämieHäufig • Primärer Hyperparathyreoidismus (HPT)

• Hyperkalzämie bei TumorenGelegentlich • Thyreotoxikose

• Sarkoidose• Vitamin-D-Intoxikation• Immobilisierung• Calcium-Alkali-Syndrom• Benigne familiäre hypokalzurische Hyperkalzämie• Tertiärer HPT• Thiazide

Selten •Weitere granulomatöse Erkrankungen• Theophyllinintoxikation•Massive Mammahyperplasie• Idiopathische infantile Hyperkalzämie• Lithiumintoxikationen• NNR-Insuffizienz• Vitamin-A-Intoxikation•Malignes neuroleptisches Syndrom• Aluminiumintoxikation• Sepsis• AIDS• Aspirinintoxikation•Morbus Paget mit Frakturen• Hypothyreose• Nach ANV durch Rhabdomyolyse• Varianten des Milch-Alkali-Syndroms („Kreidefresser“)• Aufnahme von hypertonischem Meerwasser

Vorgehen Hyper-

kalzämie

Messung des Serum-Kalzium:Falls erhöht Ionisiertes Ca++

Klinische Routine:Anamnese, körperliche Untersuchung, Röntgen-Thorax, Sono, Labor (AP, Eiweiß, El´pho.)

Neoplasie/ Plasmozytom, Sarkoidose Kein fassbarer Befund

PTH-BestimmungHyperparathyreoidismus

Lithiumintoxikation

PTHrP-BestimmungNeoplasie

Vitamin-D2-BestimmungVitamin-D-Intoxikation

Vitamin-D3-Bestimmung

Vitamin-D-IntoxikationGranulomatöse

ErkrankungLymphom

ImmobilisationM. Paget

Thyreotoxikose

PTH:

PTHrP:

VD2

VD3

PTH:

PTHrP:

VD3

ment must be involved. Cell/matrix recognition is medi-ated by integrins. These !/" heterodimers consist of longextracellular and relatively short intracellular domains thatfunction not only to attach cells to extracellular matrix butalso to transmit matrix-derived signals to the cell’s inte-rior. We have discovered that the !v family of integrinsare differentially expressed by osteoclasts during theirmaturation and that two members, namely !v"3 and!v"5, are functional in these cells. !v"5, but not !v"3appears on marrow macrophages maintained in the solepresence of M-CSF.66 With exposure to RANKL and as-sumption of the osteoclast phenotype, !v"5 disappearsto be replaced by !v"3.67 Interestingly, !v"5 deficiencyaccelerates bone loss in the estrogenopryvic68 statewhereas oophorectomized animals lacking !v"3 are pro-

tected.69 Thus, !v"3 presents as a candidate anti-re-sorptive therapeutic target and in fact, small moleculeinhibitors of the integrin are in clinical trial for treatment ofosteoporosis.70–72

The !v family of integrins recognizes the amino acidmotif Arg-Gly-Asp (RGD), resident in a number of bonematrix proteins such as osteopontin and bone sialopro-tein. Occupancy by these ligands activates the integrinby changing its conformation.73 This event, known asoutside-in signaling, induces a number of intracellularevents, one of the most prominent being organization ofthe actin cytoskeleton.

!v"3 is also modulated by an inside-out mechanismthat is stimulated by intracellular events, such as thosestimulated by M-CSF occupancy of its receptor c-fms.45

C-fms autophosphorylation of Tyr697 activates the inte-grin by signals that alter the conformation of its cytoplas-mic domain.45 In fact, !v"3 and c-fms enjoy a collabo-rative relationship during osteoclastogenesis. Thisrelationship is illustrated by the capacity of high-doseM-CSF to rescue the retarded osteoclast differentiation,in a c-Fos- and ERK1/2-dependent manner that occurson "3 integrin subunit deletion.45 ERK seems to regulatethe osteoclast by two distinct pathways. Short-term acti-vation of the MAP kinase stimulates proliferation of theresorptive cell’s precursors whereas prolonged ERK ac-tivation prompts its nuclear translocation where it inducesexpression of early immediate genes, such as c-Fos,essential to osteoclast differentiation.45 The paradox ofarrested osteoclast differentiation of !v"3-deficient pre-cursors in vitro in face of a 3.5-fold increase in vivo ofmature osteoclasts in mice lacking the integrin may beexplained by the abundant M-CSF present in the marrowof the mutant animals.45,66 Although exposure of !v"3-deficient osteoclasts to high-dose M-CSF rescues oste-oclastogenesis and cytoskeletal organization, the integrinis necessary for the cell’s capacity to resorb bone.45

Because !v"3 is the principal integrin expressed byosteoclasts and competitive ligands arrest bone resorp-tion in vitro,70 we deleted the "3 integrin subunit inmice.66 Mice lacking !v"3 generate osteoclasts incapa-ble of optimal resorptive activity as their ruffled mem-branes and actin rings are abnormal in vivo.66 The de-ranged cytoskeleton of the mutant osteoclasts is alsomanifest by failure of the cell to spread in vitro66 (Figure4). In consequence, "3!/! mice progressively increasebone mass with age. Interestingly, !v"3 also regulatesosteoclast longevity. The unoccupied integrin transmits apositive death signal mediated via caspase 8, and, there-fore, resorptive cells lacking !v"3 actually survive longerthan wild type.74

The osteoclast functions in a cyclical manner, firstmigrating to a bone resorptive site to which it attaches. Itdegrades the underlying bone, detaches, and reinitiatesthe cycle. During matrix attachment, !v"3 is predomi-nantly in its inactive conformation and resident in podo-somes, which in turn reside in the actin ring.65 Podo-somes are dynamic, adhesive dot-like structuresconsisting of an actin core surrounded by the integrinand associated cytoskeletal proteins such as vinculin,!-actinin, and talin. Thus, the signals mediating matrix

Figure 3. Formation of the osteoclast ruffled membrane. The unattachedosteoclast contains numerous acidified vesicles bearing H"ATPases (protonpumps) illustrated as spikes. On attachment to bone, matrix-derived signalspolarize the acidified vesicles to the bone-apposed plasma membrane intowhich they insert under the aegis of Rab3D. Insertion of the vesicles into theplasma membrane greatly increases its complexity and delivers theH"ATPases to the resorptive microenvironment.

Osteoclasts in Health and Disease 431AJP February 2007, Vol. 170, No. 2

Formation of the osteoclast ruffled membrane. The unat tached osteoclast contains numerous acidified vesicles bearing H+-AT P a s e s ( p r o t o n p u m p s ) i l l u s t r a t e d a s s p i k e s . O n attachment to bone, matrix-derived signals polarize the acidified vesicles to the bone-apposed plasma membrane into which they insert under the aegis of Rab3D. Insertion of the vesicles into the plasma membrane greatly increases its complexity and delivers the H+-ATPases to the resorptive microenvironment.

Osteoclasts: What Do They Do and How Do They Do It?

The American Journal of Pathology,170, 2007

Anterior Planar Image of the Neck and Chest of a Patient with Primary Hyperparathyroidism Obtained with Technetium-99m Sestamibi, Showing a Parathyroid Adenoma in the Mediastinum.

Marx S. N Engl J Med 2000;343:1863-1875

sium, 4.2 mEq/L (4.2 mmol/L); chloride, 86 mEq/L (86mmol/L); phosphorus, 4.4 mg/dL (1.42 mmol/L); albumin,4.1 g/dL (41 g/L); and urea nitrogen, 79.4 mg/dL (28.3mmol/L). Electrocardiography showed sinus bradycardia at50 beats/min and first-degree atrioventricular block with aPR interval of 280 milliseconds. The corrected QT (QTc)interval was within the normal range at 0.39 seconds. Ab-dominal computed tomography did not show notable abnor-malities other than mild calcification of the abdominal aorta.Echocardiography showed favorable cardiac function (leftventricular ejection fraction, 78%) and collapse of the infe-rior vena cava. Tests conducted by the patient’s generalphysician indicated a serum creatinine level of 0.9 mg/dL(80 !mol/L) and eGFR of 64 mL/min/1.73 m2 (1.07 mL/s/1.73 m2) 2 years before admission.

The patient presented with volume depletion, decreasedkidney function, hypercalcemia, hypermagnesemia, and met-abolic alkalosis. Her daily medications included 1.0 !g ofalfacalcidol and 6.0 g of magnesium oxide, and these werediscontinued upon presentation because it was believed to bethe primary cause of the electrolyte disorders. She wasinitially managed with 3,000 mL of saline solution and 20mg of furosemide administered intravenously daily. Hemo-dynamics stabilized and diuresis was achieved with a dailyurinary volume of 2,000 to 3,300 mL. The patient showedrapid recovery of consciousness and other symptoms, withimprovement in electrolyte disorders and kidney function(Fig 1). Electrolyte levels returned to their normal rangewithin 1 week and kidney function improved, with a serumcreatinine level of 1.10 mg/dL (97.2 !mol/L) and eGFR of50 mL/min/1.73 m2 (0.83 mL/s/1.73 m2) at the time ofdischarge (hospital day 14).

Additional InvestigationsOn further review of the patient’s oral medication history,

we found that she had begun using 1.5 g/d of magnesium

oxide for chronic constipation 4 years before admission andhad gradually increased the dosage. One month beforeadmission, she increased the dosage from 3.0 to 6.0 g/dbecause of persistent constipation. In addition, after experi-encing a compression fracture of the lumbar spine 2 yearsbefore admission, she had started using 1.0 !g/d of alfacal-cidol orally. Despite weakness and decreased appetite, thepatient continued to use these drugs. She had not usedcalcium-containing drugs or supplements and only occasion-ally consumed milk or yogurt.

DiagnosisCalcium-alkali syndrome and hypermagnesemia caused

by administration of vitamin D and magnesium oxide.

Clinical Follow-upKidney function remained stable without recurrence of elec-

trolyte or acid-base disorders during follow-up. The patient hada serum creatinine level of 1.0 mg/dL (88.4 !mol/L) and eGFRof 56 mL/min/1.73 m2 (0.93 mL/s/1.73 m2) 6 months afterdischarge.

DISCUSSIONThe pathophysiological mechanism of calcium-

alkali syndrome is complex and involves severalinterrelated factors. Increased intestinal absorp-tion of calcium, decreased urinary calcium excre-tion, and decreased kidney function can initiateand maintain hypercalcemia.9,10 Hypercalcemiacan reduce kidney function through vasoconstric-tion that decreases renal blood flow and GFR,increased sodium and free water excretion, andnausea and vomiting that induce volume deple-tion.11,12 Ingestion of an alkali, increased renaltubular bicarbonate reabsorption from volumedepletion, direct tubular effects of calcium,13 andsuppression of parathyroid hormone in responseto hypercalcemia14 can produce and maintainmetabolic alkalosis. Once established, hypercal-cemia, alkalosis, and decreased kidney functionpromote and maintain a self-perpetuating cycle.Calcium-alkali syndrome can occur wheneveralkalosis and a calcium load coexist, and exces-sive intake of calcium carbonate, which is both acalcium and an alkali source, is the leading causeof modern cases of calcium-alkali syndrome.

The patient in this case was using activatedvitamin D (alfacalcidol, 1.0 !g/d) and an excessof magnesium oxide (6.0 g/d, 3 times the normaldose), but neither calcium-containing drugs norsupplements. Magnesium oxide acts as an ant-acid in the stomach and is converted in theintestinal tract to magnesium carbonate and mag-

Figure 1. Serum creatinine (Cr), calcium (Ca), andmagnesium (Mg) levels during the course of hospitaliza-tion. Note that all 3 values decreased after discontinuationof medication and administration of saline solution andloop diuretics. Conversion factors for units: serum Cr inmg/dL to !mol/L, !88.4; serum Ca in mg/dL to mmol/L,!0.2495; serum Mg in mg/dL to mmol/L, !0.4114.

Hanada et al712

Calcium-Alkali Syndrome Due to Vitamin D Administration and Magnesium Oxide Administration.American Journal of Kidney Diseases, Vol 53, No 4 (April), 2009: pp 711-714

Serum creatinine (Cr), calcium (Ca), and magnesium (Mg) levels during the course of hospitalization Note that all 3 values decreased after dis-continuation of medication and administration of saline solution and loop diuretics.

Hypocalcemia: A Pervasive Metabolic Abnormality in the Critically Ill

Patients admitted to medical, surgical, trauma, neurosurgical, burn, respiratory, and coronary intensive care units [ICUs]; group A; n = 99).

Results were compared with the frequency and degree of hypocalcemia in non-critically ill ICU patients (initially admitted to an ICU but discharged within 48 hours; group B; n = 50)

or hospitalized non-ICU patients (group C; n = 50).

Incidences of hypoca|cemia (ionized calcium [Ca] < 1.16 mmol/L [less than normal]) were 88%, 66%, and 26% for groups A, B, and C, respectively (P < 0.001).

The occurrence of hypocalcemia correlated with both Acute Physiology and Chronic Health Evaluation il score (r = -0.39; P < 0.001) and patient mortality (eg, hazard ratio for death 1.65 for ca decrements of 0.1 mmol/L; P < 0.002). Hypomagnesemia, number of blood transfusions, and presence of acute renal failure were each associated with depressed Ca levels.

American Journal of Kidney Diseases, Vo137, No 4 (April), 2001: pp 689-698

692

P r e v a l a n c e

1

ZIVlN ET AL

c

0 z ~

A d m i s s i o n Diagnos i s

0.0001; Fig 3). A 28% mortality rate was ob- served (28 of 99 patients) in group A. Con- versely, there were no deaths in groups B or C. Figure 4 contrasts mortality distribution based on ranges of ionized Ca concentrations. The greatest mortality was observed with Ca levels in the 0.9- to 1.1-mmol/L range.

When modeling Ca level as a continuous time- dependent covariate, the univariate regression model yielded a hazard ratio (HR) for mortality of 1.65 (95% confidence interval [CI], 0.19 to 2.28; P = 0.002) for decreases in Ca level of 0.10 mmol/L. The magnitude of univariate asso- ciation between either hypocalcemia versus death

Fig 1. Percentage of hy- pocalcemic patients accord- ing to admission diagnoses.

or APACHE II score versus death was not quali- tatively changed after adjusting for eithe r pres- ence of ARF or history of hypertension, diabetes, chronic lung disease, or coronary artery disease. No patient with congestive heart failure died in this review. Bacteremia was not significantly associated with mortality and did not diminish the association between Ca level and death.

When Ca level was modeled as a dichotomous time-dependent covariate (Ca < 1.16 mmol/L versus -> 1.16 mmol/L), the HR for mortality was greater among hypocalcemic versus normo- calcemic patients, but the difference was not statistically significant (HR = 2.7; 95% CI, 0.8

7 0 % -

6 0 % -

5 0 % "

4 0 % -

3 0 % -

2 0 % -

1 0 % -

Fig 2. Percentage of dis- tribution of nadir ionized Ca 0%- levels for patients in groups A (11), B (m), and C (E2). ca _> 1.28 Ca: 1.16-1.27 Ca: 1.10-1.15 Ca: 0.90-1.09 Ca < 0.90

American Journal of Kidney Diseases, Vo137, No 4 (April), 2001: pp 689-698

Hypocalcämie und unterschiedliche Phosphatspiegel

Osteoblastische Metastasen.Akute Pankreatitis.„hungry bone syndrome“.Medikamente.Schwerste Krankheitszustände.„toxic shock syndrome“.

Zu Hypokalzämie führende StörungenMit Hyperphosphatämie einhergehende Erkrankungen• PTH-Mangel:

• Kongenital.• Erworben: Parathyreopriv (J131-Therapie), infiltrativ (Hämochromatose, Wilson, Sarkoidose),

chronische Hypomagnesiämie, idiopathisch.• PTH-Resistenz:

• Pseudohypoparathyreodismus Typ I.• Pseudohypoparathyreodismus Typ II.• Chronische Hypomagnesiämie.

• PTH-unabhängig:• Endogener Phosphatstau: Niereninsuffizienz, Hämolyse, Rhabdomyolyse, Tumorlysesyndrom.• Exogene Phosphatüberladung, Phosphathaltige Einläufe, Phosphorverbrennungen.

•Mit Hypophosphatämie einhergehende Erkrankungen: Vitamin-D-Mangel• Inadäquate Synthese, diätetischer Mangel:

• Malabsorption.• Gastrektomie.• Dünndarmerkrankungen.• Pankreasinsuffizienz.• Cholestyramin.

• Verminderte 25α-Hydroxylierung in der Leber:• Chronisch biliäre Erkrankungen.• Vermehrter Katabolismus: Phenobarbital, Diphenylhydantoin, Glutethimid.

• Resistenz gegen Vitamin D:• Vitamin-D-abhängige Rachitis Typ I.• Vitamin-D-abhängige Rachitis Typ II.

Vorgehen Hypokalzämie

Messung des Serum-Kalzium:Falls vermindert Ionisiertes Ca++

Magnesiumbestimmung

Abklärung Hypomagnesiämie

Phosphat + PTH-Bestimmung

PTH-Bestimmung

Phosphat

Hypo-para-

thyreoidismus

Phosphat

PTH:

PTH: + Ph

Mg++ Mg++

Vitamin-D-Mangel

Abklärung Vit.D-StatusKlinik

Pseudo-hypoparathyreodism

us

- Pathophysiologie des sekundären Hyperparathyreoidismus -

GFR

Ca x HP04

Weichteil-verkalkungen

1α-Hydroxylase

1,25(OH)2D3 = Calcitriol

Ca++

PTH

P04

Parenchym

25(OH)2D3

Calcium-Phosphat-Haushalt bei Niereninsuffizienz

Agenda

• Calciumhaushalt

• Vitamin D

• PTH

• Renale Mechanismen

• Hypercalcämie

• Hypocalcämie