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Renal osteodystrophy chronic renal insufficiency GFR < 60 ml/min 1,25(OH) 2 D3 P VDR-binding VDR-number Ca PARATHORMON Ca sensitivity Osteitis fibrosa – high turnover Therap y Al P Vit D Ca PTH Diab Osteo- malaci a Adynamic bone Low turnover

Renal osteodystrophy chronic renal insufficiency – GFR < 60 ml/min 1,25(OH) 2 D3P VDR-binding VDR-number Ca PARATHORMON Ca sensitivity Osteitis fibrosa

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Renal osteodystrophychronic renal insufficiency – GFR < 60 ml/min

1,25(OH)2 D3 P

VDR-binding

VDR-number Ca

PARATHORMON

Ca sensitivity

Osteitis fibrosa – high turnover

Therapy

Al

P

Vit D

Ca

PTH

Diab

Osteo-malacia

Adynamic bone

Low turnover

ROD - natural history

• 176 patients, creatinin clearance: 50-15 ml/min

• Untreated

• No complaints

• Dg.: Bone biopsy

• 56%: Osteitis fibrosa

• 14%: Osteomalacia + osteitis fibrosa

• 5%: Adynamic bone

• 25%: Normal

Hamdy et al., BMJ, 1995

RENAL OSTEODYSTROPHY

• Disease of bone remodelling

- Abmormal structure

- Low mineral content

- Increased fracture risk

- Bone pain

- Proximal muscle weakness

• Accelerated atherosclerosis• Calciphylaxis

- Soft tissue calcification

- Calcification of small vessels, nerves

Ca - deposition

. Ca content

Plasma: 0,025%

Interstitial: 0,075%

Intracellular: 0,9 %

Bone 99%

calcium

R O D

Kidney

CRF

Macroangiopathy, coronaria sclerosis

Bone mineralization vs vascular calcification

• Bone density and vascular calcium content as measured by electron beam CT are inversely related.

• Proteins characteristic of bone are also present in arteries:

osteopontin, osteonectin, bone sialoprotein, matrix gla protein, osteocalcin

Se P, Ca x P product, PTH and mortality

0

0,2

0,4

0,6

0,8

1

1,2

1,4

6400 HD pts, age: 53 yrs, 30% Diabetic (Block et al., AJKD, 1998.)

Mo r

t al it

y , R

R

1,45- 1,76- 2,11- > 2,53 1,75 2,10 2,52

Se P (mmol/l)

p = 0,03

p < 0,0001

0

0,2

0,4

0,6

0,8

1

1,2

1,4

43- 53- 61- 73-52 60 72 132

Ca x P (mg2/dl2)

p<0,01

Mortality is increased if PTH < 65 pg/ml> 500 pg/ml

Calciphylaxis

ROD – therapy I

During therapy, awareness is necessary to avoid atherosclerosis progression.

Target values:

• Calcium: 2,1-2,39 mmol/l

• Foszfor: 1,13-1,8 mmol/l

• Ca x P: < 4 mmol2/l2

• PTH: GFR 15-60 ml/min: 65-100 (??) pg/ml Dialysis: 150-300 pg/ml

• 25(OH) D3: 30-50 ng/ml (75-125 nmol/l)

ROD: therapy II

Ca, P, PTH, 25(OH)D control q 3-6 months

GFR 60-30 ml/min: Phosphate restriction: 800-1000 mg/napCa CO3: 700-1400 mg/d (1-2 t)D vitamin: 400-800 IU/d

P Ca CO3 PTH > 65-80 pg/ml: Calcitriol 0,25 μg daily or every other day

GFR 30-15 ml/min: Increasing P, Ca CO3 Ca, Ca x P: Sevelamer, Paracalcitol,

Calcimimetics PTH > 100 pg/ml: Calcitriol 0,25 μg daily or every other day

ROD – therapy III

Applying current therapeutic approach, an increase in Ca x P product cannot be avoided in 10-15 % of patients.

What to do?

• Aluminum- and calcium free phosphate binders

• New vitamin D analogues that suppress PTH effectively but does not increase Ca- and phosphate absorption

• Calcimimetics

Aluminum- and Ca free phosphate binder: Sevelamer

Sevelamer: cross-bound(allylamin hydroclorid)polimer: Renagel®

Mechanism of action

Amine groups gain protons and bind phosphate by ion exchange and hidrogen bondage.

Indications:

Adynamic bone (ESRD: PTH < 150 ng/ml)Hypercalcemia (Ca > 2,55), high Ca x PSevere vascular / soft tissue calcification

Sevelamer inhibits vascular calcification in hemodialysis patients

Randomised study, sevelamer vs Ca-acetate, 200 patients

-40

-30

-20

-10

0

10

20

30

sevelamer

calcium

%

mg/dl

Ch

ange

0-5

2 m

onth

s

p=0,02

p<0,0001 p<0,0001

coronary Ca x P hyper- chol LDL score calcemia

p=0,04

Chertow GM et al.:Kidney Int. 2002 Jul;62(1):245-52.

CH2

OHHO

OH OH

CH3

OHHO

1,25(OH)2 D3 19-nor-1,25(OH)2 D2

Calcitriol Paracalcitol

Comparison of Paracalcitol and Calcitriol

Biologic action Effektivity vs Calcitriol

PTH suppression 1/3

Ca absorption 1/10

P absorption 1/10

Paracalcitol is three times more selective than calcitriol in terms of PTH suppression

Calcitriol resistant hyperparathyreosis treated by Paracalcitol

24 HD patients, PTH: 600-800 pg/ml, calcitriol dose: 3,2 µg/HD

Paracalcitol starting dose: {calcitriol dose} x 3

alap 6 hó 12 hó 16 hó

PTH pg/ml

750

500

250

7 4 2 1,5 Paracalcitol:µg / HD

(Llach et al. AJKD, 2001)

Calcimimetics

• Ca receptor: low affinity, non-specific

• Expression: parathyreoids, C cells, nephron, bone, brain

• Secunder hyperparathyroidism: low CaR expression

• Calcimimetics: increase Ca sensitivity of CaR

• Indications: primary- and secundary hyperparathyroidism

- Effects of 50-100 mg/d AMG 073 :

PTH Ca Ca x P

Decrease (%) 25-30 3-5 10-15

Calcimimetics in clinical practice

• Randomized, placebo controlled, 18 wk study, 78 HD patients• AMG 073: 20-50 mg/d vs placebo• Other therapy: Calcitriol: 64%, phosphate binder 87%• Baseline PTH: 623 pg/ml

p<0,001p<0,001

Invasive therapyIndications

- Symptoms: severe hypercalcemiasevere bone diseasecalciphylaxispruritusmyopathy

- PTH > 1000 pg/ml

Surgery: total parathyreoidectomy + autotransplantation

30-40 mg

> 500 mg

Ethanol / calcijex infiltration

• Water and sodium balance maintains normal tonicity of body fluids and normal effective circulating volume.

• Tonicity = effective osmolality resulting from the restriction of particles to a compartment. It determines the volume of a compartment.

• Effective circulating volume maintains normal perfusion of tissues.

• Control of sodium- and water balance is independent.

Water: 60%bodyWT

H2O No of particles constant

Extracellular: ECF20% Body Wt : ICF

Posm= 275-290 mOsm/kg

Eff Posm= 270-285 mOsm/kg

Na/K/ 2Cl

Regulation of water balance

Interplay of ADH and thirst

Regulation:

• tonicity ~ se Na.

tonicity: ADH + thirst

tonicity: no ADH, water diuresis

• effective volume: ADH + thirst

even in the presence of tonicity !

• Drugs

• Nausea, pain

Expected urine Osm during hyponatremia: 20-80 mOsm/kg

Water balanceIn (ml) Out (ml)

Water po: 1400 Urine: 1500

Food: 850 Skin: 500

Oxidation: 350 Respiration: 400

Stool: 200

Total: 2600 2600

[Na] ~ (Na content + K content) / TBW

2 x [Na] ~ Eff Posm

2 x [Na] x TBW = total effective osmoles

Regulation of sodium balance

Effective circulating volume

effective circulating volume: Angiotensin IIAldosteron Na conservation

ADH/Thirst

effective circulating volume: No Angiotensin IINo aldosteron NatriuresisANPBNP

Low effective circulating volume: high urine Osm

UNa < 10 mmol/l

Hyponatremia[Na] ~ (Na content + K content) / TBW

[Na] determines the volume of the ICF. Na content determines ECF.

Hyponatremia: [Na] < 136 mmol/l and low plasma Osm: Posm< 275 mOsm/kg

Low [Na] but plasma Osm not low:

Pseudohyponatremia: hyperproteinemia, hyperlipidemia Hyperglycemia: elevation of [glu] by 4 mmol/l will reduce [Na] by 1 mmol/l

Expected renal response: maximally dilute urine: Uosm 20-80 mOsm/kg

Normal kidneys can make 12 l electrolite free water / day.

Development of hyponatremia requires:

ADH

Renal failure- low GFR

Depletion of osmoles (min U-Osm: 20-80 mOsm/kg H2O)

Vurine = Excreted osmoles / Uosm

Causes of hyponatremiaECF

Low Not low

Primary Na loss Effective circulating volume

Urine Na Low Not low

< 10 mmol/l > 20 mmol/l

Heart failure SIADH:

Non-renal loss Urine K Liver cirrhosis CNS lesion

(burns, sweat) High Low Low albumin Lung cc, inf.

Remote diuretic i.e. edema states Drugs

Remote vomiting Vomit. Addison`s Low cortisol Post surgery

Diur. Hypothyroidism Nausea

Renal Na Reset osmostat

wasting

Drugs affecting ADH action

Stimulate secretion

nicotine

morphine

tricyclic antidepressants

vincristine

cyclophosphamide

Potentiate action

caffeine

aminophyllin

aspirin

NSAIDs

Inhibit

ethanol

haloperidol

carbamazepine

clonidine

glucocorticoids

Consequences of hyponatremia

• Cell swelling- cerebral edema

• Brain cells are the only ones that regulate their volume by changing the number of intracellular particles (osmolytes) - it takes several days to adapt.

• Acute (whithin 1-3 days) hyponatremia: symptomatic

Symptoms: nausea headache

lethargy, obtundation

seizures, permanent neurological deficits

death

Hyponatremia: therapy I

Acute symptomatic hyponatremia

• Stop water intake

• Rise se [Na] until symptoms stop or by 6 mmol/l whichever comes first.

• Use 3 % NaCl for replacement. 3 % NaCl = 30 g/l = 513 mmol/l

• To rise [Na] by 6 mmol/l in a 70 kg patient:

42 L TBW. Needs 42 x 6 = 252 mmol NaCl = 490 ml 3% NaCl

• Reduce rate of rise to 0,5 mmol/l/hr, limit daily rise to 12 mmol/l.

Hyponatremia: therapy II

Chronic, asymptomatic hyponatremia

• Beware of acute recognition of a chronic problem!

• Too fast rise of se[Na] will cause central pontine myelinolysis.

• Do not permit se[Na] to rise more than 0,5 mmol/l/hr and 12 mmol/l/day.

• Administration of KCl to treat hypokalemia will rise se[Na]: Na leaves cells as K enters. There is 13,5 mmol K+ in 10 ml 10% KCl.

• To determine the impact of urine excretion on se[Na], measure urinary Na + urinary K! Potassium in the urine eventually comes from cells. As K leaves the cell Na enters.

If (U[Na] + U[K ]) > se[Na] : se[Na] decreases

If (U[Na] + U[K ]) < se[Na] : se[Na] rises

Electrolite free water clearance = V [1 - (UNa + UK)/seNa]

Hyponatremia: therapy III

Hyponatremia and a contracted ECF volume

• Decifit of Na and water in ECF, surplus of water in ICF

• Goal: reexpand ECF by giving Na and move water out of cells.

• Do NOT give hypertonic saline!!

• 1 mmol NaCl / TBW will rise se[Na] by 1 mmol/l and expand ECF by 2%.

• For rapid expansion of ECF (shock) use iv solution isotonic to the patient!

If se[Na]=115 mmol/l: give 50-50% of 0,9% (155 mmol/l) and 0,45% (75 mmol/l) saline.

• For slow expansion of ECF may use 0,9% NaCl.

• Correction of ECF blocks ADH and induces water diuresis: danger of too rapid [Na] rise: may have to give aeqous vasopressin (desmopressin).

se[Na]=115 mmol/l, TBW= 40 L.

Infuse 2 L normal saline/10 h, diuresis: 1,2 l/ 10hr, urine (Na + K) = 40 mmol

Total osmoles = 40L x 230 mOsm/L = 9200 mOsm

New TBW = 40,8 L, New total osmoles = 9200+620-50=9780 mOsm

New seOsm= 9780 mOsm / 40,8L = 240 mOsm/L

New [Na] = 120 mmol/l

Rise of Na = 5 mmol/10 h = 0,5 mmol/h

Hyponatremia: therapy IV

Hyponatremia and expanded ECF volume

• Surplus Na and surplus water

• Limit intake of water and Na

• Augment urinary water- and Na+ loss by loop diuretic

• Replace part of Na+ loss if se[Na] rise < 0,5 mmol/h (use hypertonic solution)

• Beware of overexpansion of ECF

• Replace part of water loss if se[Na] rise > 0,5 mmol/h

• Replace K+ loss

Hypernatremia

Se Na > 144 mmol/l and Posm > 290 mOsm/kg

Expected response: maximal Uosm (> 1000 mOsm/kg), sg: 1025-1030

minimal urine volume (~ 0,5 l/day)

THIRST (provoked by 2% elevation of [Na])

Minimum urine volume= osmoles to be excreted / maximum achievable Uosm

Eg.: 800 mOsm to be excreted (urea, NaCl, NH4), max Uosm = 200 Osm/kg

Minimum urine volume: 4 L

Causes of hypernatremia

Expanded ECF Decreased body weight No change of BW

Na gain What is Uosm and U-vol? Water shift: e.g. iatrogenic seizures, rhabdomyolysis

U-vol.: min.Uosm: max.

Non renal water loss

Polyuria, Uosm: not maximal

Uosm > 300 mOsm/kg Uosm < 250 mOsm/kg

Osmotic diuresis Diuretics Rise of Uosm and decrease of

glucose U-vol post ADH? urea mannitol Yes No(UNa: 50 mmol/l

UK: 25-50 mmol/l) Central DI Nephrogenic DI

Diabetes insipidus

Diabetes insipidus: polyuria and polydipsia - there is no hypernatremia as long as patient has access to water.

Central diabetes insipidus

•Craniopharingeoma

•Metastasis

•Transsphenoidal surgery

•Head trauma

•Hypoxia

•Sarcoidosis

•Encephalitis, meningitis

•Cerebral aneurism

Nephrogenic diabetes insipidus

•Congenital

•Hypercalcemia

•Hypokalemia

•Lithium

•Amyloidosis

•Pyelonephritis

•Polycysitic kidneys

•Sjögren sy

Evaluation of polyuria

Water restriction test

Measure U-vol, Uosm and body weight hourly

Continue test until Uosm reaches a plateau or Posm reaches 295-300 mOsm/kg

Do not allow more than 3 % decrease of body weight.

Normal: U-vol to minimum, Uosm to 1000 mOsm/kg

Diabetes insipidus: no change in U-vol and Uosm

Primary polydipsia: decrease of U-vol, increase of Uosm ~ 600 mOsm/kg

Give 10 µg desmopressin nasally:

Central DI: Rising Uosm, decreasing U-vol

Nephrogenic DI: no change

Symptoms of hypernatremia

Cell shrinkage

Lethargy, weakness, irritability, twitching,

Intracranial hemorrhage, seizures, coma, death

Fever, nausea, vomiting

Labored respiration

Adaptation: accumulation of osmolytes in brain cells - takes several days

Therapy of hypovolemic hypernatremia• Estimate ECF volume contraction on clinical grounds: 10% deficit is just detectable, 30 % deficit causes shock.

• To replace ECF volume give 0,9 % saline.

• Stop ongoing water loss : ADH replacement in DI, look for osmotic agent

• Calculate water deficit: Desired TBW = present [Na] x TBW / desired [Na]

Add electrolite free water diuresis

• To replace water give water po or D5 iv or 0,45% saline.

• Rate of D5 should not exceed 300 ml/h.

• 0,45% saline will only be effective if U[Na] + U[K] > 75 mmol/l - give furosemide if necessary and replace water + K lost in urine.

• Rate of [Na] decrease should not exceed 0,5 mmol/h and 12 mmol / day

Therapy of diabetes insipidus

Therapy of central diabetes insipidus: 10-20 µg / d desmopressin (DDAVP) intranasally

Therapy of nephrogenic diabetes insipidus: salt restriction + thiazide diuretic, correction of potassium and calcium

Therapy of hypervolemic hypernatremia

Discontinue offending agent

Furosemide

Replace part of water

Replace potassium

In case of renal failure: dialysis