1
Pathophysiology of kidneys
– part II
Acute renal failure
Acute tubular necrosis
Chronic kidney disease
Chronic renal insufficiency
Chronic renal failure
2
Terminology – renal failure (RF)
• situation when kidneys are not able to
― a) excrete waste products of protein catabolism (nitrogen-containing compounds) metabolism
― b) maintain volume and electrolyte homeostasis and AB balance
• under the basal conditions with normal protein (min 0.5g/kg/day) and energy intake
• azotemia = increased concentration of non-protein nitrogen-containing compounds
(creatinin, blood urea nitrogen, BUN)
― accompanies RF (diagnostic sign), feature of uremic syndrome
• uremia („urine in blood“) = cluster of clinical abnormalities (uremic syndrome) due to RF
• causes of RF:
― suddenly in subject without pre-existing renal pathology = acute RF (ARF, situation 1 in figure below)
• synonym acute kidney injury (AKI)
― as a consequence of a chronic renal disease with progressive loss of renal function = chronic RF (situation 3 in
figure below)
• synonym end-stage renal disease (ESRD)
• etiology
― 1) pre-renal
― 2) renal
― 3) post-renal
• 70% patients with ARF/AKI develop ac. tubular necrosis
3
Terminology – renal insufficiency
• situation when kidneys
are able to maintain
homeostasis under the
basal conditions, but not
under the stress, e.g.:
― infection
― surgery
― excess intake of protein,
fluid or electrolytes
• typically product of
chronic kidney disease
(CKD)
― CKD (stages 1 - 5)
defined (disregard of
etiology) solely based on
GFR (see table)
• renal insufficiency
corresponds to stages 3 - 4
• renal failure to stage 5
4
Autoregulation of renal blood flow and GFR
GFR ∼120ml/min/1.73m2
5
Mechanisms involved in (auto)regulation
6
Relationship between serum creatinin and GFR
• no significant changes of GFR with loss of up to
50% of functional glomeruli
― non-linear relationship of [Cr] and GFR
• with progressive renal disease (another ∼50% of
the remaining capacity) initial GFR decline is not
accompanied by rise of [Cr]
― with more pronounced GFR decline serum Cr levels rise
more steeply
― only then have Cr serum levels diagnostic value
• estimated GFR (eGFR)
― calculation of GFR using serum Cr, age and body weight
• Cockroft-Gault and other formulas → mathematical
expression of hyperbolic relationship
7
ACUTE RENAL FAILURE (ARF)
[NEWLY ACUTE KIDNEY INJURY]
(AKI)
8
Who is in immediate risk of ARF
• most episodes of AKI occur in the hospital !!!
― mortality rates ranging from 36% to as high as 86%
(depends on the setting in which AKI is acquired, the age
of the patient, and the acuity of the illness)
• 5–20% of critically ill patients experience an
episode of acute renal failure during the course of
their illness, in many cases accompanied by
multiorgan dysfunction syndrome (MODS)
• recognition of risk patients
― patients after extensive surgery
― heart operations (extracorporeal circulation)
― septic shock
― but also less critically ill patients with
• pre-existing kidney disease (serum creatinine >180 μmol/l)
• multiple comorbidities (heart and liver!)
― renovascular disease has been found in 34% of elderly people with
heart failure!
• those treated with NSAID, ACEI or ARBs
• prevention of progression of pre-renal ARF into the
renal form
― acute tubular necrosis
• maintenance of sufficient renal perfusion
― isovolemia, cardiac output, normal BP
― attention to administering potential nephrotoxins
9
Etiology and pathogenesis of ARF
• acute and rapidly progressive
(within hours) decrease of
glomerular filtration and
excretion in both kidneys ,
although the process may be
reversible
― oliguria < 500 ml/day
― anuria < 100 ml/day
― however rarely It may be caused by
different clinical conditions
• etiology
― pre-renal azotemia
― renal azotemia
― post-renal azotemia
• pathogenesis
― decreased blood flow through
glomeruli
― loos of filtration area
― increased pressure in tubules or
Bowman capsule
10
Specific etiology of ARF – pre-renal
• most common type of AFR
caused by impaired renal
blood flow below the range
of autoregulation
― GFR declines because of the
decrease in filtration pressure
― ARF may superimpose on
chronic renal condition under
the sudden stress
• failure to restore normal
blood perfusion through
kidneys may cause acute
tubular necrosis (ATN)
― therefore progress to a renal
form of ARF
11
Specific etiology of ARF – pre-renal
• acute heart failure &
cardiogenic shock
― acute myocardial infarction
― arrhythmias with low cardiac
output
― pericardial tamponade
• intravascular volume depletion
and hypotension
― hemorrhage
― gastrointestinal, renal, and dermal
losses (burns)
• decreased effective
intravascular volume
― congestive heart failure
― cirrhosis (ascites)
― peritonitis
• systemic vasodilation/renal
vasoconstriction
― sepsis
― hepatorenal syndrome
― inappropriate anti-hypertensive
therapy
12
Hepatorenal syndrome
• development of ARF in
patients with advanced
chronic liver disease who
have portal hypertension
and ascites
― at least 40% of patients
with cirrhosis will develop
HRS during the natural
history of their disease
• pathogenesis
― hypovolemia
• congestion in GIT due to
portal hypertension
• ascites
• bleeding
― decreased RBF in generally
hyperkinetic circulation
(typical liver failure)
• drop of BP due to peripheral
vasodilation lead to
constriction of afferent
arterioles (mediated by
sympathetic innervation) and
subsequent ischemia of renal
cortex
13
Circulation abnormalities in liver cirrhosis
14
Specific etiology of ARF – renal
• large-vessel renal vascular disease
• renal artery thrombosis or embolism
• renal artery stenosis
• thrombosis of renal veins
• small-vessel renal vascular disease
― vasculitis
― hemolytic-uremic syndrome
― others
• malignant hypertension, scleroderma, preeclampsia, sickle cell anemia,
hypercalcemia, transplant rejection
• impaired renal blood flow
― ↓ post-glomerular resistance (ACEs, ARBs)
― ↑ pre-glomerular resistance (NSAIDs)
― radiocontrast agents
• glomerular diseases
― acute glomerulonephritis
• acute tubular necrosis
― ischemia
― toxins
― obstruction (hemolysis, rhabdomyolysis, paraprotein)
• ac. interstitial diseases
― toxo-alergic
― infection
― idiopatic
15 Rick G. Schnellmann & Katrina J. Kelly
Renal nephrotoxic ARF
16
Acute tubular necrosis (ATN)
• etiology
― ischemia
• generates toxic oxygen free readicals and
inflammatory mediators that cause swelling, injury,
and necrosis
― toxic
• drugs
― antibiotics, antiviral, antifungal, cytostatics
• radiocontrast nephropathy
• environmental toxins? (heavy metals such as
mercury, arsenic)
• reasons for high vulnerability of tubules to
ischemia and toxins
― lower perfusion of medulla compared to cortex,
worse energetics
― local increase of concentration of toxins during
reabsorption of water
― additional increase of concentration of toxins by
their secretion
― intracellular toxicity due to their reabsorption
― change of toxicity in low urine pH
• final effect mediated not only by necrosis
but also by apoptosis
17
Pathogenesis of ATN
18
Mechanisms of oliguria in ATN
19
Pattern of tubular damage in ATN
• ATN caused by nephrotoxins is usually uniform and limited to proximal tubules
• ischemic ATN tends to be patchy and may be distributed along any part of the
nephron
20
Reversibility of ATN
• tubular epithelia
regenerates but it
takes time and
additional damage
can be caused by
reperfusion injuty
21
Formation of casts in ATN
22
Tubular changes in ATN pathophysiology
• morphological changes
occur in the proximal
tubules, including loss of
polarity, loss of the brush
border, and redistribution of
integrins and
sodium/potassium ATPase
to the apical surface.
Calcium and reactive oxygen
species also have roles in
these morphological
changes, in addition to
subsequent cell death
resulting from necrosis and
apoptosis. Both viable and
non-viable cells are shed
into the tubular lumen,
resulting in the formation of
casts and luminal
obstruction and contributing
to the reduction in the GFR
23
Hemolytic-uremic syndrome (HUS)
• is a disorder that usually occurs when an
infection in the digestive system (but also
other causes) produces toxic substances
that destroy red blood cells
― hemolytic anemia → hemoglobinuria →
precipitation of hemoglobin in tubules causes
kidney injury
― also thrombocytopenia → bleeding
• etiology
― gastrointestinal infections
• E. coli
• Shigellosis dysentery
• Salmonellosis
― non-gastrointestinal infections
• Pneumococcus infection
― iatrogenic (drugs)
• HUS is most common in children
― the most common cause of ARF in children
• HUS is more complicated in adults.
― similar to thrombotic thrombocytopenic
purpura (TTP)
24
Specific etiology of ARF – post-renal
• obstruction of the urinary tract below the kidneys
for fluid outflow leading to waste product
accumulation
• bilateral
• unilateral in solitary kidney or with reflex anuria in
contralateral unaffected kidney
― due to the pain during the renal colic
― nephrolithiasis
― benign prostate hypertrophy
― tumors (prostate, urinary bladder,
intestine, ovary…)
― retroperitoneal fibrosis or hematoma
― neurogenic dysfunction of bladder
• consequences (apart from ARF)
― already after the relatively short obstruction →
↑pressure above obstruction → dilation of renal pelvis
and calices → hydronephrosis → reflux
nephropathy → infection → kidney atrophy
― post-obstruktive profuse
diuresis (>4l/day)
― hyperkalemic hyperchloremic
renal tubular acidosis
25
Summary of etiology of ARF
26
Summary of pathogenic mechanisms of ARF
27
Homeostatic abnormalities during ARF
• development during several days but generally
quite fast!
• ↑ serum creatinin and BUN
― however BUN reflects more factors (GFR , protein
catabolism, nutrition) than creatinin
• changes of Purea/Pcreat ratio
― normally ∼40-100:1
• urea reabsorbed in prox. tubule while creatinin not
• cam be normal in post-renal ARF
― in pre-renal ARF often >100:1
• increased reabsorption in hypovolemia
― in renal ARF often <40:1
• tubule damage and decreased reabsorption
• plasma concentration of K+
• see later for more detail
― ↑ during oliguria phase
― ↓ during polyuric phase
• conc. of Na+
― normal, ↑ or ↓ = depends on volemia
• metabolic acidosis (high anion gap)
• water retention (+ metabolic water ∼500ml/day)
28
Phases of ARF
• reduction in renal blood flow causes a reduction in GFR
― variety of cellular and vascular adaptations maintain renal
epithelial cell integrity during this phase
• initiation phase occurs when a further reduction in renal
blood flow results in cellular injury, particularly the renal
tubular epithelial cells, and a continued decline in GFR
• vascular and inflammatory processes that contribute to
further cell injury and a further decline in GFR usher in the
proposed extension phase
• during the maintenance phase, GFR reaches a stable nadir
as cellular repair processes are initiated in order to
maintain and re-establish organ integrity
• recovery phase is marked by a return of normal cell and
organ function that results in an improvement in GFR
29
Risks associated with ARF
• major risks during the oliguric stage of ARF
― hyperkalemiaa (>7mmol/l)
• arrhythmias, heart arrest
― hypervolemia (hyperhydration)
― isoosmolar
― later hypoosmolar due to dilution
• hyponatremia → brain edema → increased intracranial pressure → brain ischemia and hypoxia →
subjective symptoms (head pain, nausea, vomiting) → disorder of consciousness
• volume and pressure overload of the heart
• congestion or even pulmonary edema
• indication to acute hemodialysis
― absolute
• hyperkalemia (>6.5mmol/l)
• metabolic acidosis
• hypervolemia
• uremia
― see in more detail later
― relative
• progressive hyperazotemia (creatinin >500 μmol/l, urea >35mmol/l)
• hypercalcemia (> 4mmol/l), hyperuricemia
• prolonged oliguria (>3 days)
30
Urine analysis in ARFL
• concentration of Na+ in urine:
― pre-renal azotemia, acute GN or altered vascular resistance - tubules functioning and reabsorb Na+ from lower
amount of filtrate (Na+ in urine < 20 mmol/l)
― damage of tubules and post-renal azotemia: Na+ in urine > 40 mmol/l)
• fractional excretion of Na+
― FE-Na+ = U-Na/S-Na, normally < 1 %
• osmotic concentration of urine
― pre-renal azotemia: > 500 mOsm/kg
― tubular damage: < 350 mOsm/kg
31
CHRONIC KIDNEY DISEASE AND RENAL
INSUFFICIENCY
32
Chronic kidney disease (CKD)
• progressive, typically many years
lasting decline of renal function
― no matter of the etiology CKD
defined solely based on degree of
GFR decline
• basically any kind of progressive
kidney disease can by the cause
― 50% - any form of GN
― 20% - diabetic nephropathy
― 30% - others
• ischemic kidney disease
• tubulointerstitial nephritis
• polycystic kidney disease
• myeloma
• hereditary nephritides
• vascular nephrosclerosis
• others
33
Pathogenesis of CKD – perpetual damage
• an initial glomerular insult is responsible for alterations of glomerular cell
functions, leading to glomerulosclerosis and thus reduction in nephron
number
― however, symptoms appear only after the loss >75% nephrons
• this induces an increase in glomerular capillary pressure and/or glomerular
volume in residual nephrons, which have to adapt (functionally and
morphologically) to sustain higher workload and became damaged later, i.e.
further glomerular damage
― higher glomerular pressure favors proteinuria
• reduced nephron number is also associated with tubular dysfunction
― tubular dysfunction is responsible for interstitial fibrosis and destruction of
peritubular capillaries, which leads to tubular destruction
― destruction of interstitial capillaries may also increase glomerular capillary pressure
and thus enhance glomerular damage
― similarly, glomerulosclerosis damages glomerular capillaries and enhances tubular
hypoxia
― proteinuria enhances tubular dysfunction and thus interstitial fibrosis
• along this process GFR decreases, later on renal insufficiency and event. failure
develop
• CKD is associated with high cardiovascular mortality
― several times higher of that in non-CKD population 34
Pathogenesis of CKD – perpetual damage
35
Mean decline in GFR depends on proteinuria
• mean decline in GFR (mL/min)
over a 36-month period in
groups with four different
mean baseline 24-hour urine
protein levels in non-diabetic
patients with chronic renal
failure in the MDRD study
― compared in each of these four
groups are the
• normal blood pressure group
(dashed line; 140/90 mm Hg;
102-107 mm Hg MAP)
• intensive control group (solid
line; 125/75 mm Hg; 92 mm Hg
MAP)
Progressive renal and cardiovascular
disease: Optimal treatment strategies
Matthew R Weir
36
Progressive nature of CKD
• damage and of nephrons caused by initial specific process
• damage and loss of nephrons caused by overload of residual nephrons (a further
non-specific process)
• damage and loss of nephrons caused by reno-parenchymal secondary arterial
hypertension
― i.e. after the loss of critical number of nephrons caused by initial disease, further
progression of CKD becomes independent in the primary pathological process
• factors determining the rate of progression
― non-modifiable risk factors
• primary disease
• age, gender, ethnicity, genetics
― modifiable risk factors
• proteinuria
• art. hypertension
• glycemic
• hyperlipidemia
• obesity
• hyperuricemia
• smoking
37
Dynamics of CKD associated abnormalities
and their relationship to GFR
• ↓ of GFR by ∼¼ do not causes changes of internal environment of the body (renal
functional reserve)
― functional adaptation of tubules to decreased GFR
• in the stage of ¼ - ¾ decrease of physiological GFR (= renal insufficiency)
― gradual failure of tubular adaptation to ↓GFR and rise of plasma concentration of waste products
• creatinin, BUN
• uric acid
• uremic toxins ?
• in the stage < ¾ of initial GFR kidney failure
with full blown sumptoms of uremia
― changes similar to ARF
• azotemia
• hyperkalemia
• hypervolemia
― and on top of that
• anemia
• bone disease
• hypertension
• polyneuropathies
38
Functional adaptation of residual nephrons
• allows to maintain homeostasis even if GFR is substantially decreased
― modification of intensity of tubular transport processes, mainly maintenance of
normal sodium, potassium and water balance (↓ tubular reabsorption or ↑ tubular
secretion)
• it is useful to measure fractional excretion (FE) of compounds (i.e. percentage of the given
compound filtered by the kidney which is excreted in the urine)
• ↓ tubular reabsorption of sodium and water
― normal reabsorption of Na ∼99%
― when ↓ GFR then ↓ reabsorption from filtered volume
• although for normal excretion of Na GFR 4ml/min would be sufficient
― mechanisms ???
• ANP, prostaglandins
• ↓ tubular reabsorption of phosphate
― normal renal excretion of phosphates ∼10-20% of filtered amount
― when ↓ GFR then ↓ reabsorption from filtered volume, i.e. excretion ∼40% - 100%
• if not sufficient → hyperphosphatemia
• ↑ secretion of potassium
― mechanisms maintaining homeostasis of K+ until very low GFR
• hyperkalemia develops only after extreme fall of renal function
― secretion via extra-renal ways (GIT) contributes to the potassium balance
39
Abnormalities of hormones and metabolism
• altered concentrations of many
hormones in CKD influence
function of many systems
― ↓ formation/activity
• 1, 25-dihydroxycholecalcipherol
― contributes to MBD (esp.
osteomalacia)
• erythropoietin
― untreated anemia places patients at
risk for
• cardiovascular events (hypoxia)
• more rapid progression of CKD
• significantly decreased quality of
life
• prostaglandins
― ↑ formation/activity
• angiotensinogen
― contributes to CVD morbidity and
mortality
• parathormone
― contributes to MBD (esp.
osteodystrophy)
• metabolic abnormalities in CKD/CHRI
― metabolism of proteins and amino acids
• malnutrition in proteinuria and decreased
dietary intake of protein (necessary though)
• increased protein catabolism in muscle
• changes of intracellular AA concentrations in
tissues as well as in plasma (↓essential, ↑non-
essential)
― saccharide metabolism (insulin resistance)
• fasting hyperglycemia in 30 % h of CKD patients
• impaired glucose tolerance in oGTT in 60%
• ↑ plasma insulin due to peripheral resistance
(post-receptor defect)
― moreover secretion of insulin stimulated also by
↑K+ (insulin promotes transport of K+ into cells)
― lipid metabolism - hyperlipidemias
• present in ∼70% of CKD patients
• pathogenesis of secondary hyperlipidemia is
complex
― ↓ catabolism (↓LPL) and ↑ liver synthesis of
lipoproteins
• ↑ VLDL, LDL and TAG, ↓ HDL
40
Anemia in CKD
• The cause of anemia in patients with CKD is
multifactorial. The most well-known cause is
inadequate erythropoietin (EPO) production
― EPO is produced in the peritubular capillary
endothelial cells in the kidney relying on a feedback
mechanism measuring total oxygen carrying
capacity
• subsequent production of hypoxia inducible
factor (HIF)
― EPO then binds to receptors on erythroid
progenitor cells in the bone marrow(BFU-E and
CFU-E). With EPO present, these erythroid
progenitors differentiate into reticulocytes and
red blood cells (RBCs)
― The absence of EPO leads to pre-programmed
apoptosis mediated by the Fas antigen
• There are other factors in chronic kidney
disease which contribute to anemia. Acute and
chronic inflammatory conditions have a
significant impact on anemia in the CKD
population by pro-inflammatory cytokines
decreasing EPO production and inducing
apoptosis in CFU-E.
― inflammatory cytokines have also been found to
induce the production of hepcidin, a recently
discovered peptide generated in the liver, which
interferes with RBC production by decreasing iron
availability for incorporation into erythroblasts.
• Red blood cells also have a decreased life span
in patients with CKD
• Uremic toxins have been implicated as
contributing to apoptosis as the anemia will
often improve after initiation of dialysis
41
MINERAL BONE DISEASE (MBD) IN
CKD
42
Terminology
• osteoporosis ("porous bones“)
― the bone mineral density (BMD) is reduced, bone
microarchitecture deteriorates, and the amount and
variety of proteins in bone are altered
― an increased risk of fracture
― causes: old age, inactivity, menopause
• ↓ sex steroids (esp. estrogens) → ↓synthesis of
collagen (prevent mineralization)
• osteomalacia
― softening of the bones caused by defective bone
mineralization secondary to inadequate amounts of
available phosphorus and/or calcium
― causes: hypovitaminosis D or hypophosphatemia
• lack of calcium or phosphate in the body
― calcium : phosphate ratio prevents mineralization
• ↓vitamin D → hypocalcaemia → ↑ PTH → ↑
calcaemia but ↓ phosphataemia
• osteodystrophy
― bone mineralization deficiency associated with
either high or low bone turnover as a consequence
of hyperparathyroidism
• primary HPTH: ↑ PTH → ↑ calcemia but ↓
phosphatemia
• secondary (renaln osteodystrophy): ↑ phosfatemia →
↓calcemia → ↑ PTH
― in advanced stage accompanied by osteitis fibrosa
43
Hyperphosphatemia/hypocalcemia in CKD
• abnormal metabolisms of Ca, phosphorus,
PTH and vitamin D in CKD
• ↓ excretion of phosphorus in kidney when ↓
GFR leads to hyperphosphatemia and
― a) ↓ ionized Ca, hypocalcaemia stimulate
production of PTH
• altered calcium : phosphate product leads to
calcium phospate precipitation and extraosseal
calcifications
― b) inhibition of 1α-hydroxylase in proximal
tubular cells and ↓production of active D vit.
• impaired intestinal absorption of Ca in GIT
aggravates hypocalcaemia and this way to another
↑ of PTH
― c) blockade of inhibitory action of vit. D on
parathyroid bodies
• less vit. D binds to VDR receptors in parathyroid
bodies , ↓ inhibition of transkription of the PTH
gene and ↑secretion of PTH
― d) direct stimulatory effect on parathyroid
bodies
• development of secondary
hyperparathyroidism
44
Pathophysiology of secondary
hyperparathyroidism in CKD
• consequence of phosphate retention and
reduced renal production of active
vitamin D, resulting in
hyperphosphatemia and hypocalcemia.
With GFR <70 mL/min, renal excretion of
phosphate can no longer keep pace with
GIT absorption, and phosphorus
retention occurs. Hyperphosphatemia
inhibits the renal 1–alpha-hydroxylase, so
that production of active 1,25 dihydroxy
vitamin D3 by the kidney is reduced.
Vitamin D deficiency then leads to
hypocalcemia as a consequence of
defective gastrointestinal calcium
absorption and skeletal resistance to the
calcemic effect of PTH. The serum-ionized
calcium is the most important factor
regulating PTH secretion. The effects of
calcium on parathyroid cells are mediated
by a membrane-bound calcium-sensing
receptor (CaR). Low serum calcium leads
to an increase in PTH . In contrast, active
vitamin D modulates PTH production in
the parathyroid by binding to the
cytoplasmic vitamin D receptor (VDR).
The vitamin D-VDR complex binds to the
PTH promoter and inhibits the
transcription of PTH mRNA. Thus, vitamin
D deficiency will lead to increased
production of PTH message. A chronic
decrease in vitamin D levels also leads to
parathyroid cell proliferation and gland
hyperplasia.
45
Renal osteopathy
• synonym mineral bone disease (CKD-
MBD)
• adverse complication of advanced CKD
• main features
― abnormal mineral metabolism
― increased bone fragility and impaired
linear bone growth
• fractures, pain, limited mobility
― soft tissue, vascular and valvular
calcification
• arterial calcification is an active process similar
to bone formation with participation of
multiple factors (osteopontin, osteoprotegerin,
RANKL, RANK, FGF23 and fetuin A)
• MBD consists of a mixture of bone
abnormalities
― osteodystrophy (+ osteitis fibrosa cystica)
― osteomalacia
― osteoporosis
46
CV consequences of CKD-MBD
• causal abnormalities
― arterial hypertension (90%)
― hyperlipidemia, diabetes
― sec. anemia (anemic hypoxia)
― hyperhydration (volume overload)
― calcification (arteries and valves)
― uremic toxins
― others
• oxidative stress, hypofibrinolysis
(= thrombophilia), homocystein
• manifestation
― LV hypertrophy
― CAD
• compared to non-CKD patients ↑ media thickness, ↓ lumen
diametr and more calcification, due to uremic neuropathy
quite often „silent ischemia“
― arrhythmias
• due to hyperhydration and electrolyte dysbalances , event.
pericarditis and CAD (+ myocardial ischemia during
hypotension in dialysis)
• consequences
― cardio-renal resp. reno-cardiac syndrome
• pre-existing heart disease worsens CKD prognosis and vice
versa
47
Pathogenesis of vascular calcification
• Normally, mesenchymal stem cells
differentiate into adipocytes,
osteoblasts, chondrocytes, and vascular
smooth muscle cells (VSMCs). In the
setting of chronic kidney disease (CKD),
diabetes, aging, inflammation and
multiple other toxins, these VSMCs can
de-differentiate or transform into
chondrocyte/osteoblast-like cells by
upregulation of transcription factors
such as Runx2 and Msx2. These
transcription factors are critical for
normal bone development and thus their
upregulation in VSMCs is indicative of a
phenotypic switch. These
osteo/chondrocytic-like VSMCs then
become calcified in a process similar to
bone formation. These cells lay down
collagen and non-collagenous proteins in
the intima or media and incorporate
calcium and phosphorus into matrix
vesicles to initiate mineralization and
further grow the mineral into
hydroxyapatite. Ultimately, whether an
artery calcifies or not depends on the
strength of the army of inhibitors
standing by in the circulation (fetuin-A)
and in the arteries
• MGP = matrix gla protein; OP =
osteopontin; PPi = pyrophosphate
48
Reno-cardiac syndrome
49
Pathophysiological
interactions between heart
and kidney (= reno-cardiac
syndrome )
CKD contributing to decreased cardiac
function, cardiac hypertrophy, or
increased risk of adverse cardiovascular
events)
BMI = body mass index; EPO =
erythropoietin; LDL = low-density
lipoprotein
Ronco C et al, JACC 2008 50
CHRONIC KIDNEY FAILURE
51
Chron. renal failure = CKD stage 5 = ESRD
• appearance of small, irregular
shape, scarred, shrunken
kidney with granular surface
• full blown symptoms of uremia
• it is necessary to
― treat conservatively but
aggressively (only symptomatic
though)
• ↓ fluid intake
• ↓ Na+, K+ intake
• ↓ protein intake
• complications
― anemia, MBD, hypertension,
infections, …
• modification of drug dosage!!
― kidney replacement therapy
• dialysis
• transplantation
― etiology of the most common
CKD causes progressing to ESRD
52
Uremic
symptoms
53
Hypercalemia
• 98% K+ in ICF
― 35-50x more than in ECF (3.8 – 5.5 mmol/l)
― Na+/K+ ATPase
• higher permeability of membrane for K+ that other
cations
― contribution to the resting membrane potential
• passive K flow from the cell along the conc. gradient
limited by intracellular anoints
― changes of kalemia in ECF are slowly reflected in ICF too
• disorders of K balance in organism:
• ↑ dietary intake with intact kidneys is not a problem
• decreased K excretion in renal insufficiency and ESRD
• disorders of distribution – multiple factors influence K
distribution between ECF and ICF:
― disruption of cells/ hemolysis
― osmolality
― acidosis
• regulation of [K+] in ECF
― (1) redistribution of K+ (from ECF to ICF)
• pH, insulin, adrenalin
― (2) renal excretion
• aldosterone, [K+]
2 K+
ATP
3 Na+
2 K+
ATP
3 Na+
2 K+
ATP
3 Na+
K+
Na+
intersticium buňka distálního tubulu lumen
a sběracího kanálku
ALDOSTERON
nadledvina
angiotensin II
K+
adrenalin
inzulin
54
Effect of hyperkalemia on heart
• effect depends on the magnitude of change
(= how much) and speed of change (= how
fast)!!!!
― therefore there are significant differences
between acute and chronic renal failure
• hyperkalemia
― ↑ excitability by moving the resting membrane
potential closer to the threshold
• passive K flow from the cell along the conc. gradient
limited by intracellular anoints is diminished by ↑[ K+]
in ECF, retention of K+ in ICF and depolarisation
― initially also quicker repolarization (phase 3)
• activating substrate effect on Na+/K+ ATP-ase (↑
availability of K+ for exchange)
― later when ↑↑ [K+] inhibition of repolarization
• too low concentration gradient
― finally when ↑↑↑ [K+] cardiac arrest
• inhibitory effect on Na+/K+ ATP-ase (it cannot pump
against extremely high concentration of K+ in ICT)
• too close shift of resting m. potential to threshold
disables opening (voltage gated) of Na+ channels
55
Hyperkalemia (K+ >5.5 mmol/l)
• affected all types of muscles
― skeletal
― smooth
― myocardium
• signs
― arrhythmia (ECG):
• < 7 mmol/l
― spiked T waves
― widened QRS
― prolonged PR interval
― flattened P waves
• > 7 mmol/l
― lowered voltage
― bradycardia
• > 8 mmol/l
― „sinusoidal“ shape of QRS
― idioventricular rhythm
― ventricular fibrillation, arrest
― paresthesias, weak reflexes,
paresis and obstipation
56
RENAL REPLACEMENT THERAPY -
METHODS
57
Principle of hemodialysis
• for the first time in 1943 in
Netherlands
• 3 main physical principles
― diffusion and ultrafiltration of solutes
across a semipermeable membrane
― counter current flow where the dialysate
is flowing in the opposite direction to
blood flow in the extracorporeal circuit
• standard regimen
― three times a week, 3–4 hours per
treatment schedule
• dialysis solution
― urea, creatinin, potassium and
phosphate diffuse into the dialysis
solution (high in blood, low in solution)
― concentrations of sodium and chloride
are similar to those in plasma to prevent
loss
― sodium bicarbonate is added in a higher
concentration than plasma to correct
blood acidity
― glucose is also added to balance
glycaemia and prevent hypoglycemia 58
Blood stream access
• temporary – useful for
limited number of
procedures
― two-way catheter
• v. subclavia, v. jugularis, v.
femoralis
― risks: bleeding,
thrombosis, stenosis,
infection
• permanent – in patients
in regular HD program
― arterio-venous fistule
• between a. radialis and v.
cephalica
― synthetic graft
59
HD side-effects and complications
• hypotension
― most often, nearly 30% of dialyses
• leg-cramps, nausea and headaches
― second most common complication
― due to volume depletion during ultrafiltration or ion
dysbalance
• disequilibrium syndrome
― u acute HD with high pre-dialysis BUN and too fast HD
• sudden drop of BUN is not reflected with urea decrees in CSF
• ↑ CSF osmolality causes intracranial hypertension and brain
edema
― metabolic acidosis also contributes
• during HD plasma bicarbonate (HCO3
– ) level rapidly increases, but
bicarbonate cannot readily pass across the BBB, whereas carbon
dioxide (CO2 ) diffuses rapidly. The initial increased passage of
carbon dioxide into the CSF and brain leads to a reduction in pH
(Henderson-Hasselbach equation), and intracellular acidosis
results in the breakdown of intracellular proteins to create
idiogenic osmoles that create an osmotic gradient for water
movement into the brain
― stop of HD and anti-edematous therapy
• infection (esp. endocarditis and osteomyelitis)
• long term (neuropathies, amyloidosis) 60
HD vs. peritoneal dialysis
61
Kidney transplantation
• necessity to obtain donor kidney
― cadaverous
― from living donor (often relative)
• immunological compatibility
― risk of rejection
• hyper-acute
• acute
• chronic
― risks associated with
immunosuppressive therapy
62