Most Important Effects of Hyperhydration and DehydrationB. Causes of Dehydration

Factor VII deficiency

pH 7.4 PCO2

C. Most Important Effects of Hyperhydration and DehydrationB. Causes of Dehydration

134

Abnormalities of Potassium Balance

An abnormal potassium level results from a dis-order of K⁺balance or of its redistribution be-tween the intracellular and extracellular space.

An abnormal potassium balance occurs, for example, if potassium supply is inadequate (→

A 1). As intravenous infusion of K⁺initially en-ters into a compartment, namely plasma, that has a relatively low potassium content, too rapid K⁺administration can lead to dangerous hyper-kalemia even at K⁺deficiency. The secretion of K⁺in exchange for Na⁺in the distal tubules and collecting duct is the decisive step in the renal elimination of K⁺(→A 2; see also p. 104 ff.). Renal loss of K⁺occurs, for example, in hyperaldoster-onism (→p. 288) or if there is an increased avail-ability of Na⁺in the distal tubules (→p. 107 D).

Conversely, renal K⁺elimination is decreased if:

1) Na⁺reabsorption is impaired in the distal tu-bules, as in hypoaldosteronism; 2) diuretics act-ing on the connectact-ing tubule and collectact-ing duct have been administered; or 3) there is a de-creased supply of Na⁺(e.g., in renal failure). In al-kalosis fewer H⁺ions are secreted in the connect-ing tubule and collectconnect-ing duct and more K⁺is lost, while conversely acidosis decreases K⁺ se-cretion in the distal nephron. K⁺may also be lost via the gut (→A 3). In hyperaldosteronism or at increased delivery of Na⁺to the colon K⁺ may be lost in exchange for Na⁺. Significant amounts of K⁺may further be lost in sweat.

Even minor shifts of K⁺between intracellular and extracellular fluid may lead to massive changes in plasma K⁺concentration, because the K⁺content in cells is more than 30 times that in the extracellular space. Cellular loss of K⁺and hyperkalemia may result from cellular energy deficiency (→A 5), during severe physi-cal work (muscular K⁺loss), cell death (e.g., in hemolysis, myolysis), and in transfusion of stored blood (loss of K⁺from erythrocytes). Fur-thermore, hemolysis venopuncture can in-crease the K⁺concentration in the plasma and be mistaken for hyperkalemia.

In (extracellular) alkalosis the cells release H⁺in exchange for Na⁺(Na⁺/H⁺exchangers) and pump the Na⁺out again in exchange for K⁺(Na⁺/K⁺-ATPase) (→A 6). This K⁺uptake by the cells causes hypokalemia. Conversely, acidosis leads to hyperkalemia. Glucose stimu-lates the release of insulin that, by activating Na⁺/H⁺exchangers, Na⁺-K⁺-2 Cl^– cotransport-ers and Na⁺/K⁺-ATPase, stimulates the cellular

uptake of K⁺. In insulin deficiency or hypogly-cemia (when fasting), the cells lose K⁺. The ad-ministration of insulin in diabetic hyperglyce-mia (→p. 308 ff.) or food intake following star-vation may lead to dangerous hypokalemia be-cause the cells will be taking up K⁺.

Catecholamines promote the uptake of K⁺by the cells viaβ-receptors and the cellular release of K⁺from the cells viaα-receptors. At massive new formation of cells (e.g., at stimulated erythropoiesis) significant amounts of K⁺are accumulated in the newly formed cells. More-over, intoxication with K⁺ channel blockers (e.g., Ba²⁺) may lead to hypokalemia.

The effects of changed plasma K⁺ concentra-tion are mainly due to changes in the mem-brane potential. Hypokalemia hyperpolarizes, while hyperkalemia depolarizes the K⁺ equilib-rium potential, and thus the membrane poten-tial of selective cells. In this way hypokalemia reduces the excitability of nerve cells (hypore-flexia), skeletal muscles (adynamia), and smooth muscles (gut, bladder, etc.) (→A 6).

Consequences include the life-threatening in-testinal paralysis (→A 7). Conversely, hyperka-lemia can increase the excitability of the ner-vous system (hyperreflexia), smooth muscles (→A 7), and skeletal muscles (→p. 328).

In contrast, a decrease in K⁺concentration reduces the conductance of the K⁺channels, thus decreasing the hyperpolarizing effect of K⁺on the membrane potential. This promotes the heterotopic automaticity of the heart that may even trigger ventricular fibrillation (→p. 202 ff.). The reduction of K⁺conductance is also responsible for delayed repolarization of the Purkinje fibers. Hypokalemia often pro-duces a prominent U wave in the electrocardio-gram (ECG) (→A 6). Conversely, hyperkalemia increases the K⁺conductance, the action po-tential is shortened, and correspondingly also the ST segment in the ECG (→A 7).

K⁺deficiency promotes the cellular reten-tion of H⁺and its secretion in the distal tubules.

This results in an alkalosis (→p. 94). Converse-ly, K⁺excess leads to acidosis (→p. 96). Hypo-kalemia also causes polyuria (→p. 108) and can ultimately lead to irreversible tubular cell damage. Lastly, the release of a number of hor-mones is abnormal in K⁺deficiency (especially insulin [→p. 308] and aldosterone [→p. 288]).

5Kidney,SaltandWaterBalance

Plate5.18AbnormalitiesofPotassiumBalance

135 GFR

Na⁺ K⁺

H⁺ K⁺

K⁺

K⁺

K⁺

K⁺

Na⁺ Na⁺

Na⁺

Na⁺

Na⁺ H⁺

H⁺

H⁺

K⁺

K⁺ K⁺

K⁺

K⁺ 1

2

3

5

6 8

Na⁺ K⁺

2Cl^–

Na⁺ K⁺ 2Cl^–

Na⁺ 7

4

Heart:

Delayed repolarization Heterotopic automatism Neuromuscular excitability Urinary concentration Alkalosis

Hormone release Heart:

accelerated repolarization (shortened ST segment) Neuromuscular excitability Acidosis Hormone release

Hypokalemia Increased

supply

Insulin and energy deficiency

Hypoaldosteronism,

distal diuretics Reduced

renal elimination

Release of cellular potassium

U wave

Aldosterone

Alkalosis Renal loss of potassium

Intestinal loss

Deficient supply

Epinephrine (b) Insulin Diuretics,

salt-losing nephritis

Epinephrine(a)

Lumen Distal tubule Blood

Muscle work

Cell death Acidosis

Hyperkalemia

K⁺ equilibrium potential K⁺ conductance

K⁺ conductance

K⁺ uptake into cells K⁺ equilibrium

potential

Loss through perspiration A. Deranged Potassium Metabolism

136

Abnormalities of Magnesium Balance

Half of the bodyʼs magnesium is bound in bone, almost one-half is intracellular. Mg²⁺ concentra-tion in extracellular fluid is relatively low (ap-prox. 1 mmol/L) and the plasma concentration is not a reliable indicator for the Mg²⁺balance.

Mg²⁺binds to ATP and is essential for the activity of numerous enzymes. It acts in part antagonis-tically to Ca²⁺, which it can displace from its binding to proteins. In this way Mg²⁺can inhibit the release of neurotransmitters and thus inhib-it synaptic transmission. Intracellular Mg²⁺ in-hibits Ca²⁺-permeable neuronal NMDA chan-nels. Extracellular Mg²⁺stimulates the Ca²⁺ -sensing receptor and thus inhibits PTH release.

Magnesium deficiency occurs mainly when there is an inadequate supply or a loss via the gut (malabsorption; vomiting, diarrhea, fistulas, vitamin D deficiency, primary infantile hypo-magnesemia;→A 1; see also p. 164 ff.) or the kidneys. In the kidneys, paracellular Mg²⁺ trans-port requires claudin-16/paracellin-6, and transcellular Mg²⁺transport requires the Mg²⁺ channel TRPM6 (→p. 104). The driving force is provided by the cell membrane potential, which depends on the Na⁺/K⁺ATPase activity. The par-acellular reabsorption is driven by the transepi-thelial potential that is indirectly created by NaCl reabsorption (→A 2). The permeability of the tight junctions is reduced in hypercalcemia and acidosis. Ca²⁺further inhibits, via the Ca²⁺ sensing receptor, the Na⁺-K⁺-2 Cl⁻cotransport, causing a decrease in the transepithelial poten-tial and thus of Mg²⁺reabsorption. Magnesuria may further be the consequence of very rare ge-netic defects (→p. 104) such as Bartterʼs syn-drome (Na⁺-K⁺-2 Cl⁻cotransporter, Cl⁻channel or luminal K⁺channel), Gitelmanʼs syndrome (NaCl cotransporter), hypomagnesemia with secondary hypocalcemia (TRPM6), autosomal dominant renal hypomagnesemia with hyper-calciuria (claudin-16/paracellin-1), and autoso-mal dominant renal hypomagnesemia with hy-pocalciuria (Na⁺/K⁺ATPase).

The reabsorption of Mg²⁺is also reduced in salt-losing nephropathy, in osmotic diuresis (e.g., glycosuria in diabetes mellitus), and due to the effect of alcohol and loop diuretics. Hy-peraldosteronism leads to volume expansion and thus decreases Na⁺and Mg²⁺reabsorption in the proximal tubules and the ascending limb (→A 2). Mg²⁺may further be lost in sweat or during lactation.

Even when the Mg²⁺balance is in equilibri-um, shifts of Mg²⁺between the extracellular and intracellular spaces or bone can change the plasma concentration of Mg²⁺. Insulin stimu-lates the cellular uptake of both K⁺(→p. 134) and Mg²⁺(→A 3, A 7), and loss of Mg²⁺may oc-cur in diabetes mellitus or prolonged fasting.

Substitution of insulin or resumption of food in-take may then bring about hypomagnesemia.

Alkalosis or correction of acidosis similarly stim-ulates cellular Mg²⁺uptake, acidosis stimulates the cellular Mg²⁺release. Enhanced Mg²⁺uptake in bone is observed after parathyroidectomy.

In acute pancreatitis (→A 4) activated li-pases from the damaged pancreas split tri-glycerides (TGs) in the fat tissue. The liberated fatty acids (FAs) bind Mg²⁺and thus lower the plasma Mg²⁺concentration.

The effects of Mg²⁺deficiency include an in-creased neuromuscular excitability, hyperre-flexia, cramps, depression, and psychosis (→A 5). The cramps sometimes resemble those after damage to the basal ganglia (→p. 334 ff.).

Cardiovascular signs include tachycardia and arrhythmias, even ventricular fibrillation, and a rise in blood pressure. These symptoms are accentuated by hypocalcemia. Usually Mg²⁺ deficiency coexists with K⁺deficiency (com-mon causes;→p. 134) so that the symptoms of hypokalemia are accentuated.

Mg²⁺excess is caused by renal failure (→A 6).

If the glomerular filtration rate (GFR) drops be-low ca. 30 mL/min a decrease of filtration can no longer be compensated by decreased renal tub-ular reabsorption. The renal Mg²⁺reabsorption is enhanced in patients with a genetic defect of the Ca²⁺-sensing receptor (familial hypocalciu-ric hypercalcemia). Hypermagnesemia (without excess Mg²⁺) can also occur in diabetes mellitus (→A 7). Lastly, excessive supply of Mg²⁺(Mg²⁺ -containing infusions, parenteral feeding, or therapeutic Mg²⁺administration to reduce neu-romuscular excitability) can cause hypermag-nesemia.

The effects of Mg²⁺excess are impaired neu-romuscular excitability (hyporeflexia) that may even lead to respiratory arrest, disorders of car-diac action potential generation and prop-agation, vomiting, and constipation (→A 8).

5Kidney,SaltandWaterBalance

Plate5.19AbnormalitiesofMagnesiumBalance

137 Cl^–

FA^–

Mg(FA)2

Ca²⁺

Mg²⁺

Mg²⁺

Mg²⁺

Mg²⁺

Mg²⁺

Mg²⁺

Mg²⁺

Mg²⁺

Mg²⁺

Ca²⁺

Na⁺ K⁺ K⁺

1 2

3

4

5 6

7

8

H⁺

Ca²⁺

Renal retention

Excess supply

Cardiac arrhythmias Neuromuscular excitability Hyporeflexia

Constipation Vomiting

Tachycardia Arrhythmias Blood pressure

PTH

Uptake into cells

Deficient supply Malabsorption

Renal loss Pars ascendens

Hypomagnesemia Hypermagnesemia

Respiratory arrest GFR

Pancreatitis TG

Blood

Lipases Insulin

Intestinal loss

Uptake into cells Diabetes mellitus

Insulin

Hyperaldosteronism Salt-losing nephritis Loop diuretics Alcoholism Bartter’s syndrome Osmotic diuresis

Neuromuscular excitability

– Hyperreflexia

– Depression

– Cramps A. Deranged Magnesium Metabolism

Abnormalities of Calcium Balance

Ca²⁺regulates as“intracellular transmitter” (→

p. 6 ff) the electromechanical coupling, the re-lease of neurotransmitters (synaptic transmit-ters) and hormones, the secretory activity of exocrine glands as well as the activity of a num-ber of enzymes (e.g., glycogenolysis, phospholi-pase A, adenylylcyclase, phosphodiesterases) and of several ion channels, such as K⁺channels in the heart. Extracellular Ca²⁺stabilizes Na⁺ channels, reduces the permeability of the base-ment membranes and the tight junctions, plays a role in blood clotting, and stimulates the Ca²⁺ sensing receptor, which governs a variety of functions including PTH release, activity of the renal tubular Na⁺–K⁺–2 Cl⁻cotransporter, gas-tric acid secretion, and cell proliferation.

The regulation of the extracellular Ca²⁺ con-centration is, in the first instance, the task of PTH. It is released in hypocalcemia (and hypo-magnesemia) and its action increases the plas-ma concentration of Ca²⁺(→A 1, A 2). PTH stim-ulates the mobilization of calcium phosphate from bone, decreases the plasma concentration of phosphate and HCO₃⁻by inhibiting their re-nal tubular reabsorption, and stimulates the formation of calcitriol, which promotes the en-teric absorption of Ca²⁺and phosphate.

Hypocalcemia (→A 1) can be the result of re-duced PTH release (hypoparathyroidism) or ef-fect (pseudohypoparathyroidism). In addition, vitamin D deficiency can lead to hypocalcemia via a diminished formation of calcitriol (→p. 142). In renal failure phosphate elimina-tion by the kidney is reduced, the plasma phos-phate level rises, and calcium phosphos-phate is de-posited in the body (→p. 120). One of the con-sequences is hypocalcemia. Mg²⁺deficiency de-creases the PTH release and may thus similarly lead to hypocalcemia. A rare genetic defect of claudin-16/paracellin-1 impedes the paracellu-lar Ca²⁺reabsorption (→p. 106) and thus simi-larly causes hypocalcemia.

Even when the total Ca²⁺concentration in blood is normal, the concentration of the phys-iologically relevant ionized Ca²⁺may be re-duced because of increased formation of com-plexes with proteins (in alkalosis), bicarbonate (in metabolic alkalosis), phosphate (in renal failure, see above), and fatty acids (in acute pancreatitis;→p. 136, 172) (→A 3).

Hypercalcemia (→A 2) occurs in hyperpara-thyroidism and vitamin D excess. Malignant tu-mors may, even in the absence of skeletal me-tastases, produce bone-mobilizing hormones such as PTHrP (PTH related protein) or osteo-clast-activating factor (OAF). Bone minerals are mobilized on acute immobilization associ-ated with atrophy of inactivity. Increased (par-tially paracellular) enteric Ca²⁺absorption may result from an excessive supply of Ca²⁺and of al-kaline anions (milk-alkali syndrome). Several rare genetic defects lead to disorders of bone metabolism and hypercalcemia (→p. 132).

The clinically most significant effect of hy-pocalcemia is an increased excitability of mus-cles and nerves with the occurrence of invol-untary muscle spasms (tetany) and paresthe-sias (→A 4). The increased excitability results from a lowered threshold of Na⁺channels in hypocalcemia. In severe cases epileptic seiz-ures may occur (→p. 360). Hypocalcemia de-lays the activation of repolarizing cardiac K⁺ channels and thus lengthens the cardiac action potential, which is apparent from a prolonga-tion of the ST segment and QT interval in the ECG.

The effects of hypercalcemia (the condition is often asymptomatic) may include gastroin-testinal symptoms (activation of the Ca²⁺ recep-tor: nausea, vomiting, constipation), polyuria (inhibition of renal reabsorption due to closure of tight junctions and activation of the Ca²⁺ re-ceptor), increased thirst with polydipsia, and psychogenic disorders (→A 5). If present for long, nephrolithiasis may result. If total plasma Ca²⁺concentration is above 3.5 mmol/L (so-called hypercalcemia syndrome), coma, cardiac arrhythmias, and renal failure (mainly due to Ca²⁺deposition in renal tissue) occur. An im-portant indication of the presence of hypercal-cemia syndrome is precipitation of calcium phosphate in the locally alkaline cornea (through loss of CO2; cataract;“keratitis”). In the ECG the ST segment is shortened in line with accelerated activation of the repolarizing K⁺channels. Of great clinical significance in hy-percalcemia is the increased sensitivity of the heart to digitalis, as this effect is normally mediated via an increased cytosolic Ca²⁺ con-centration (→p. 196).

138

5Kidney,SaltandWaterBalance

Plate5.20AbnormalitiesofCalciumBalance

139

? 25-OH-D3

g_K⁺

25-OH-D3

g_Na⁺ g_K⁺

Prot^–

Prot^– FA^– HPO42–

H⁺ Ca²⁺

Ca²⁺

Ca²⁺

Ca²⁺

Ca²⁺

Ca²⁺

Ca²⁺

HPO42–

1 2

3 4

5

Polyuria, magnesiuria, constipation, indigestion, nausea Heart:

– Shortening of action potentials

– Increased digitalis sensitivity Nephrocalcinosis, keratitis Psychiatric disorders

Hypercalcemia

Hypocalcemia

Heart:

– Prolonging of action potentials Tetany, paresthesias

Alkali Inactivity Tumor cells

Renal retention PTH

Interleukin

Tight junctions, Ca²⁺receptor

Formation of complexes Lack of

mobilization Decreased

intestinal absorption

PTH

Alkalosis Precipitation

Calcitriol

D3 deficiency

renal HPORenal Ca²⁺4 loss,2– retention D3 excess

Calcitriol

Ca²⁺ bound A. Deranged Calcium Metabolism

Abnormalities of Phosphate Balance

Phosphate is part of a wide variety of com-pounds, including nucleotides (ATP, cAMP, cGMP, etc.), nucleic acids, creatine phosphate, intermediary substrates of carbohydrate me-tabolism (e.g., glucose phosphate), and phos-pholipids. Phosphorylation activates or inacti-vates many enzymes. Phosphate is an essential buffer in cells and in urine. It also plays a signif-icant role in the mineralization of bone.

PTH and calcitriol are critically important for the regulation of phosphate balance. When kidney function is normal, PTH reduces the plasma phosphate level by inhibiting renal re-absorption, but at the same time it promotes the mobilization of phosphate in bone. Calci-triol raises the plasma phosphate level by stim-ulating its enteric absorption and renal reab-sorption.

Abnormal phosphate metabolism can be caused by an uneven external balance (rela-tionship between enteric absorption and renal excretion) or by changes in distribution within the body (intracellular and extracellular spaces; bone).

Phosphate deficiency can be the result of duced enteric absorption, for example, the re-sult of inadequate supply in food (common in alcoholics), due to malabsorption, vitamin D deficiency, or chronic intake of phosphate-binding drugs (→A 1). Renal loss of phosphate occurs in hyperparathyroidism, vitamin D defi-ciency, certain transport defects in the proxi-mal tubules (phosphate diabetes, Fanconiʼs syndrome;→p. 104), and, to a lesser extent, in salt-losing nephritis, in expansion of the ex-tracellular space, during diuretic treatment, in osmotic diuresis (e.g., glucosuria of diabetes mellitus) and in glucocorticoid excess. Some tumors produce phosphatonins with phospha-turic action, such as PTHrP (PTH related pep-tide,→p. 104).

Phosphate excess can be caused by excessive oral phosphate intake, vitamin D intoxication (→p. 142), lack of PTH (hypoparathyroidism), decreased efficacy of PTH (pseudohypopara-thyroidism), or renal failure (→A 2).

The phosphate concentration is markedly higher in the cells than in the extracellular space (see also potassium;→p. 134). For this reason shifts between intracellular and

extra-cellular space play an important role in deter-mining the plasma phosphate level. Cellular phosphate uptake occurs when phosphate is utilized for metabolism (e.g., for the formation of glucose phosphate from free glucose). A dra-matically increased cellular uptake occurs after food intake following starvation and in alcohol-ics, after insulin administration in diabetic coma, and in severe alkalosis (→A 3). This re-sults in, at times marked, hypophosphatemia.

Conversely, phosphate is released from cells in acidosis, diabetic coma, and cell damage, such as severe hemolytic anemia (→A 4).

Hyperphosphatemia may occur as a result of its mobilization from bone (e.g., by tumor, skel-etal immobilization, hyperparathyroidism), unless its renal elimination is stimulated at the same time. In renal failure, skeletal demin-eralization, stimulated by hyperparathyroid-ism, contributes to the development of hyper-phosphatemia (→p. 142). Conversely, exces-sive bone mineralization (e.g., following para-thyroidectomy or treatment of rickets with vi-tamin D) may result in hypophosphatemia.

Effects of hypophosphatemia include myop-athy (muscular weakness, myolysis), heart fail-ure, respiratory failfail-ure, hemolysis, dysfunction of platelets and leukocytes, renal tubular le-sions, and nervous system dysfunction (e.g., weakness, sensoric and motoric disorders, con-fusion, coma). The abnormalities are explained mainly by a reduced energy metabolism in the cells (ATP). The decrease of 2,3-bisphospho-glycerate (2,3-BPG) in erythrocytes leads to a decreased oxygen release to the tissues. Skele-tal demineralization occurs in prolonged hypo-phosphatemia (osteomalacia;→p. 142).

Effects of hyperphosphatemia include pre-cipitation of calcium phosphate with the devel-opment of soft-tissue calcifications in tissues of low metabolic turnover (e.g., mucous bursae, joints, skin). Corresponding symptoms are itch-ing (pruritus), joint pain (arthritis), etc. Vascu-lar Ca²⁺precipitations lead to vascular calcifica-tion. The plasma Ca²⁺concentration falls and the release of PTH is stimulated. In renal failure a vicious circle develops (→p. 120 ff.).

140

5Kidney,SaltandWaterBalance

Plate5.21AbnormalitiesofPhosphateBalance

141 Glucose

Glucose phosphate

ATP etc.

2,3-BPG

H⁺

[Ca²⁺]·[HPO42–]

Ca²⁺

H⁺ HPO42–

HPO42–

Glucose

Glucose

1 2

3

4

5 6

HPO42–

HPO42–

HPO42–

HPO42–

HPO42–

HPO42–

Vitamin D3 deficiency Vitamin D3

supply

Renal retention

Acidosis Insulin deficiency

Increased supply and intestinal absorption

PTH Insulin

Alkalosis

Cellular uptake Renal loss

Inadequate supply, malabsorption

Osteomalacia

O2 affinity of hemoglobin Interleukin GFR

PTH

Glycolysis Urolithiasis

Arthritis

Pruritus

Glycolysis Hyperphosphatemia

Hypophosphatemia CaHPO4

precipitation

(30mL/min)

Calcitriol

Calcitriol

Cellular loss Bone demineralization Tumor cells Immobilization

Glucose phosphate Diuresis

Tumor Phosphatomine Vascular

calcification

Complexation

Muscle weakness, myolysis, heart failure, renal tubulus lesions, hemolysis, platelet function , leukocyte function , seizures, coma A. Deranged Phosphate Metabolism

Pathophysiology of Bone

Bone consists of connective tissue or bone ma-trix (including type I collagen [> 90%], thrombo-spondin, osteopontin, fibronektin, osteocalcin, proteoglykanes), minerals (alkaline salts of Ca²⁺, phosphate, Na⁺, CO32–, Mg²⁺, K⁺, and F⁻) and cells (osteocytes, osteoblasts, and osteoclasts).

Osteocytes are mechanosensitive and adjust the bone architecture to the mechanical re-quirements by influencing osteoblasts and os-teoclasts.

Osteoblasts develop under the influence of BMPs (bone morphogenetic proteins) from mesenchymal progenitor cells. BMPs stimulate through the transcription factor CBFA1 (cor binding factor A1) the expression of, among others, type I collagen, osteocalcin, osteopon-tin, and RANKL (receptor activator of NFκB li-gand). Osteoblasts are stimulated by growth factors (TGF-β, FGF, PDGF, IGF) and form alka-line phosphatase, which fosters the mineraliza-tion by cleaving pyrophosphate. The plasma concentration of alkaline phosphatase reflects the osteoblast activity (→A).

The osteoblasts release RANKL, a mediator that stimulates the formation of osteoclasts from hematopoietic progenitor cells. The devel-opment of osteoclasts is inhibited by RANKL-binding osteoprotegerin and is fostered by the antiapoptotic M‑CSF (macrophage colony-stim-ulating factor). The osteoclasts are inhibited by calcitonin. Osteoclasts degrade bone by proteol-ysis (proteinases such as kathepsin K) and by H⁺ secretion (H⁺ATPase, carbonic anhydrase II [Ca II], Cl⁻channel). The osteoclast activity is appa-rent from the plasma concentrations of type I collagen degradation products (peptides).

In children bone develops from cartilage, which is generated by chondrocytes. Those cells are under the control of parathyroid hor-mone (PTH), PTHrP (PTH-related peptide), FGF (fibroblast growth factor), growth hormone, glucocorticoids, and estrogens. High phosphate concentrations stimulate the apoptosis of chondrocytes.

Bone is constantly remodeled to meet the mechanical requirements. Following bone frac-tures, infections, and ischemia, dead bone is degraded, the blood supply improved by angio-genesis, and new bone is synthesized. Unstable

links stimulate the formation of connective tis-sue and of cartilage.

The regulation of bone structure and miner-alization is a function of mechanical use, plasma Ca²⁺and phosphate concentrations as well as of PTH and calcitriol.

The release of PTH is stimulated by hypocal-cemia (→p. 138) and inhibited by calcitriol (→B). PTH stimulates the remodeling of bone and increases the number of osteoblasts and (via RANKL and M‑CSF) of osteoclasts. Inter-mittent administration of PTH stimulates bone formation; continuous increase of PTH leads to bone resorption.

PTH further influences bone metabolism by stimulation of calcitriol (1,25(OH)₂D₃) forma-tion (→A 1,→p. 138): Exposure of the skin to UVB radiation stimulates the generation of vi-tamin D₃from 7-dehydrocholesterin. Vitamin D₃is converted to 25(OH)D₃in the liver and by the enzyme 1α-hydroxylase to the active hor-mone 1,25(OH)2D3mainly in the kidney. The enzyme is stimulated by PTH and growth hor-mone and inhibited by excess of Ca²⁺and phos-phate, by FGF23 and by KLOTHO (→p. 100).

1,25(OH)2D3is further produced in macrophag-es and lymphocytmacrophag-es, which synthmacrophag-esize the hor-mone irrespective of PTH and calcium phos-phate metabolism. Stimulation of macrophages (e.g., at sarcoidosis and tuberculosis) or lym-phocytes (e.g., lymphomas) thus leads to inade-quate formation of 1,25(OH)₂D₃. A vitamin D-24-hydroxylase inactivates 1,25(OH)₂D₃. Calci-triol stimulates via the vitamin D receptor (VDR) the formation of bone matrix proteins, osteocalcin, osteopontin, and RANKL. Calcitriol stimulates via RANKL and M‑CSF the formation of mature osteoclasts. Calcitriol thus stimulates both bone formation and bone resorption. The VDR is stimulated not only by 1,25(OH)2D3but also by excessive 25(OH)D₃concentrations.

Glucocorticoids inhibit the formation and action of calcitriol and thus foster bone resorp-tion. Insulin stimulates the formation of bone matrix. Estrogens (mainly estradiol) inhibit the apoptosis of osteoblasts and stimulate the apoptosis of osteoclasts. They inhibit via RANKL and M‑CSF the formation of mature os-teoclasts and thus the bone resorption. Thyroid hormones increase the bone remodeling. Bone 142

"

5Kidney,SaltandWaterBalance

Plate5.22PathophysiologyofBoneI

143 CO2 HCO3– H⁺

Paget’s disease

Hematopoetic progenitor cells

RANKL

Calcitonin

Type I collagen Apoptosis

Osteogenesis imperfecta

Hypo-phosphatasia

Osteoclasts Osteoblasts

M-CSF

Pyknodysostosis

Cathepsin K Mesenchymal

progenitor cells

Osteopetrosis BMP

Degradation PTH

P Pyrophosphate

CA II

Cl^–

Apoptosis Cleidocranial

dystrophy

CBFA1

FGF

Osteochondrodysplasia IGF

PTHrP Calcitriol

Chondrocytes

pH decrease bone formation bone degradation

low high

Estrogens

Mineralization Alkaline

phospatase Osteocalcin Osteopontin

Osteo-protegerin

Mechanic stress

Estrogens

PTH Glucocorticoids

Growth hormone

Insulin Growth factors:

TGFb, FGF, PDGF, IGF

Phosphate

Vitamin A

Bone

Cartilage

Glucocorticoids