Renal osteodystrophy
chronic renal insufficiency – GFR < 60 ml/min
1,25(OH)2 D3
VDR-binding
VDR-number
Ca
Ca sensitivity
PARATHORMON
Osteitis fibrosa
– high turnover
Therapy
P
Ca
Al
PTH
P
Diab
Vit D
Adynamic
bone
Osteomalacia
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
calcium
.
CRF
ROD
Ca content
Plasma:
0,025%
Interstitial:
0,075%
Intracellular:
0,9 %
Bone
99%
Kidney
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
6400 HD pts, age: 53 yrs, 30% Diabetic (Block et al., AJKD, 1998.)
p < 0,0001
1,4
p = 0,03
1,2
1,2
1
1
0,8
0,8
0,6
0,6
0,4
0,4
0,2
0,2
0
0
1,451,75
1,76- 2,11- > 2,53
2,10 2,52
Se P (mmol/l)
p<0,01
1,4
4352
Mortality is increased if PTH
53617360
72
132
Ca x P (mg2/dl2)
< 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/nap
Ca CO3: 700-1400 mg/d (1-2 t)
D vitamin: 400-800 IU/d
 P   Ca CO3
PTH > 65-80 pg/ml:
GFR 30-15 ml/min:
PTH > 100 pg/ml:
Calcitriol 0,25 μg daily or every other day
Increasing P,   Ca CO3
 Ca,  Ca x P: Sevelamer, Paracalcitol,
Calcimimetics
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 P
Severe vascular / soft tissue calcification
Sevelamer inhibits vascular calcification in
hemodialysis patients
Randomised study, sevelamer vs Ca-acetate, 200 patients
Change 0-52 months
% 30
p=0,02
p=0,04
20
sevelamer
10
p<0,0001 p<0,0001 calcium
0
-10
-20
-30
mg/dl
-40 coronary
score
Ca x P
hypercalcemia
Chertow GM et al.:Kidney Int. 2002 Jul;62(1):245-52.
chol
LDL
CH3
OH
OH
CH2
HO
1,25(OH)2 D3
Calcitriol
OH
HO
OH
19-nor-1,25(OH)2 D2
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
PTH pg/ml
750
500
250
7
alap
(Llach et al. AJKD, 2001)
4
6 hó
2
1,5
12 hó
16 hó
Paracalcitol:
µg / HD
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 :
Decrease (%)
PTH
Ca
Ca x P
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<0,001
p<0,001
Invasive therapy
Indications
30-40 mg
> 500 mg
- Symptoms:
severe hypercalcemia
severe bone disease
calciphylaxis
pruritus
myopathy
- PTH
> 1000 pg/ml
Surgery: total parathyreoidectomy +
autotransplantation
Ethanol / calcijex infiltration
Water: 60%bodyWT
Posm= 275-290 mOsm/kg
Eff Posm= 270-285 mOsm/kg
Extracellular: ECF
20% Body Wt
H2O
No of
particles
constant
: ICF
• 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.
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 balance
In (ml)
Water po:
Out (ml)
1400
Urine:
1500
Food:
850
Skin:
500
Oxidation:
350
Respiration:
400
Stool:
200
Total:
2600
[Na] ~ (Na content + K content) / TBW
2 x [Na] ~ Eff Posm
2 x [Na] x TBW = total effective osmoles
2600
Regulation of sodium balance
Effective circulating volume
effective circulating volume:
Angiotensin II
Aldosteron
Na conservation
ADH/Thirst
effective circulating volume:
No Angiotensin II
No aldosteron
ANP
BNP
Natriuresis
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 hyponatremia
ECF
Low
Not low
Effective circulating volume
Primary Na loss
Urine Na
< 10 mmol/l
Low
> 20 mmol/l
Heart failure
Non-renal loss
(burns, sweat)
Not low
Urine K
High
Low
Remote diuretic
Remote vomiting Vomit.
Diur.
Renal Na
wasting
Addison`s
SIADH:
Liver cirrhosis
CNS lesion
Low albumin
Lung cc, inf.
i.e. edema states
Drugs
Low cortisol
Post surgery
Hypothyroidism
Nausea
Reset osmostat
Drugs affecting ADH action
Stimulate secretion
Potentiate action
Inhibit
nicotine
caffeine
ethanol
morphine
aminophyllin
haloperidol
tricyclic antidepressants
aspirin
carbamazepine
vincristine
NSAIDs
clonidine
cyclophosphamide
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
Na gain
e.g. iatrogenic
U-vol.: min.
Uosm: max.
Non renal
water loss
Decreased body weight
No change of BW
What is Uosm and U-vol?
Water shift:
seizures, rhabdomyolysis
Polyuria, Uosm: not maximal
Uosm > 300 mOsm/kg
Osmotic diuresis
glucose
urea
mannitol
(UNa: 50 mmol/l
UK: 25-50 mmol/l)
Diuretics
Uosm < 250 mOsm/kg
Rise of Uosm and decrease of
U-vol post ADH?
Yes
No
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
Nephrogenic diabetes insipidus
•Craniopharingeoma
•Congenital
•Metastasis
•Hypercalcemia
•Transsphenoidal surgery
•Hypokalemia
•Head trauma
•Lithium
•Hypoxia
•Amyloidosis
•Sarcoidosis
•Pyelonephritis
•Encephalitis, meningitis
•Polycysitic kidneys
•Cerebral aneurism
•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