1
Pathophysiology of kidneys
– part I
Glomerular hemodynamics and GFR
Methods for measurement of GFR
Glomerular filtration membrane and its pathologic
changes
Proteinuria
Glomerular diseases
2
Blood supply & functions of the kidney
• blood flow through kidney ∼1200 ml/min, this represents ∼20-25% cardiac
output
― cortical flow >>> medullar flow
• arterio-venose difference in oxygen saturation of hemoglobin is very low
― given nearly 100% saturation of Hb with O2 in arterial blood, high Hb saturation in
venous blood proves that great perfusion serves primarily to regulation purposes and
not to nutrition !!!
• heart ∼35%, brain ∼50%, kidney ∼90%
• blood suply to kidney
• a. renalis → aa. interlobares → aa. arcuates → aa. interlobulares →
afferent arteriols → glomerular capillaries → efferent arteriols
― → peritubular capillary network (cortical nephrons)
― → vasa recta (juxtamedullar nephrons)
• regulation of
― extracellular volume
― tonicity and osmolarity
― acid-base balance
― nitrogen metabolism
― calcium and phosphate homeostasis
― hematocrit
3
Nephron – transport processes
• glomerular filtration
― driven by hydrostatic
and osmotic pressure
gradients (Starling
forces)
― limited by size of filtered
compounds (<65kDa)
and other criteria
• tubular reabsorption
― typical symports
• e.g. Na/Glc, Na/AAs, …
― saturable capacity
(transport maximum,
Tm)
• renal thresholds (e.g. Glc)
• tubular secretion
― active (ATP)
― secondary active
4
Requirements for a normal control of
homeostatic parameters by kidney
• sufficient kidney perfusion
― autoregulation vs. systemic effects
• sufficient volume of glomerular filtrate
― ultrafiltration of the plasma is the first step
in formation of urine
• ultrafiltrate is free of cells and proteins,
concentration of low molecular weight substances
is equla to plasma
― GFR is a crucial parameter of kidney function
• volume of glom. filtrate per min
― low range of normal interval ∼100
ml/min/1.73m2
― natural age-related decline (>40 yrs) 0.4 - 1.2
mL/min per year
• normal function of tubular epithelia
― tubular reabsorption of ∼99% of glom.
filtrate
• normal function of peritubular capillaries
― in both cortical and juxtamedullar nephrons
5
Two types of nephrons
• cortical nephrons (∼80%)
― outer 2/3 of cortex
― shorter tubules and loops of Henle
(LH)
― participates in reabsorption of
solutes, not in urine concentration
• loops of peritubular capillaries
― important for autoregulation
• tubulo-glomerular feedback
• juxtamedular nephrons
― inner 1/3 of cortex
― longer LH radiating deeply into the
osmotically concentrated medulla
― important for production of
concentrated urine
• capillaries - vasa recta (from efferent
arteriole) together with LH form
„counter-current“ concentration
system
• various diseases can affect
variably these two populations
and thus have deferent effects on
renal processes 6
Variable length of LH and capillaries
→ different function
7
Counter-current system in medulla
8
GLOMERULAR FILTRATION RATE
(GFR)
9
Determinants of GFR
• rate of ultrafiltration of plasma
to Bowman capsule is
determined:
― GFR = A × K × Pf
• depends on:
― A = a total area available for filtration
(∼100m2)
• number of glomeruli
― changes with loss of functional glomeruli
• effect of mesangial cells
― capable of contraction (a thus ↓ A)
― K = permeability of filtration membrane
• changed by diseases affecting structure
of glom. filtr. membrane (see further)
― Pf = effective ultrafiltration pressure
• Starling forces (see further)
10
Microcirculation – Starling forces
situation elsewhere in
microcirculation apart from
glomerulus
11
Glomerular filtration pressure
12
Glomerular capillaries – Starling forces
• net filtration pressure (Pf) in the renal corpuscle equals glomerular-capillary hydraulic pressure (PGC) minus
Bowman’s capsule hydraulic pressure (PBC) minus glomerular capillary oncotic pressure (πGC)
• contrary to common capillaries hydrost. pressure in the whole length of glom. capillary decreases minimally
(due to autoregulation), therefore filtration is about 100-times higher compared to other capillaries
• hydrostatic pressures
― PGC is high and constant ∼45 - 55mmHg
― PBC ∼10 - 15mmHg
• osmotic pressures
― πGC∼25 - 30mm Hg
― thanks to large filtration πGC increases along the capillary up to ∼35 mm Hg at which point pressures reach equilibrium
net filtration pressure Pf ∼35 mm Hg
13
Renal blood flow (RBF) and GFR
• RBF in a healthy man (and GFR too) are thanks to the autoregulation
quite stable
― all plasma volume circulate through kidney in approx. 20 min
― systemic pressure typically fluctuates
― however, RBF stays rather constant in the range of 80 – 180 mmHg due to
the autoregulation
― only after significant drop of syst. BP RBF falls
• → i schemia, tubular necrosis
• RBF vs. renal plasma flow (RPF)
― RBF ∼ 20-25% of CO (cortex >>> medulla)
• i.e. ∼1000 - 1200 ml/min
• rather high considering the weight of kidneys (∼350 g)
― RPF (hematocrit 0.45) ∼600 - 700 ml/min
• glom. filtration
― GFR ∼20 - 25% RPF → GFR ∼ 120 – 140 ml/min
― ratio GFR/RPF = filtration fraction (∼ 120/600 = ∼ 0.2)
― daily filtered ∼ 180 l, but 99% reabsorption → 1.5–1.8 l of urine/day
• GFR and RPF can be assessed by various methods based on clearance
― RPF (RBF) - PAH
― GFR – creatinin, inulin (experimental) etc. 14
Regulation of RBF
• autoregulation of RBF
― (1) myogenic reflex
• SMC of the aff. and eff. arterioles detect wall tension and modify their resistance
― (2) tubuloglomerular negative feedback
• juxtaglomerular apparatus – macula densa - changes of NaCl – renin release – local RAS (dosedependent
effect)
• other paracrine factors
― prostaglandins, adenosine and NO
• sympathetic nervous system
― NE from adrenergic nerve endings
and circulating E from adrenal
medulla mediate constriction of
afferent and efferent arterioles
(α1-receptors)
• drop of RBF and GFR
― NE stimulates release
of renin from granular
JG-cells (via β1-receptors)
and thus activation of
systemic RAAS
― NE ↑Na+-reabs.in prox. tubule
• systemic RAAS
15
Autoregulation of RBF vs. systemic interest
16
(1) Myogenic regulation (Bayliss effect)
(A) Increasing pressure causes vasoconstriction.(B) The BE is mediated by the smooth muscle
layer, independent of the inner layer of endothelial cells. (C) Proposed mechanism for stretchinduced
activation of stretch-activated receptors in vascular smooth muscle membranes.
17
(2) Tubulo-glomerular feedback
18
Juxtaglomerular apparatus (JGA)
• tubular and vascular component
― (1) tubular component
• specialised parts of distal tubule near afferent and efferent arterioles (macula densa)
• cells of macula densa are sensitive to NaCl and control production of renin in granular
cells of JGA
― (2) vascular component
• afferent and efferent arterioles
• extra-glomerular mesangium
• JGA granular cells are specialized
SMC producing and storing renin
― cells of macula densa do not have a
basal membrane – tight contact
with granular cells
• both vascular and tubular
components are innervated by SNS
― renal nerve stimulation increases
renin secretion by NE-induced
stimulation of beta-adrenergic
receptors
19
Detailní mechanismus TGF
• macula densa cells (at the junction of
ascending limb of loop of Henle and
distal convoluted tubules)
― presence of Na-K-2Cl symporter
• when ↑ NaCl content at macula densa cells
→- ↑ NaCl uptake → swelling of macula
densa cells → release of ATP
― stimulation of purinergic P2 receptors on
mesangial cells and afferent arteriole smooth
muscles
― alternatively ATP may be metabolised to
adenosine, which also causes vasoconstriction
here
• adenosine normally causes vasodilation in
other tissues !!!
• effect of increased NaCl content
― contraction of mesangial cells and
contraction of glom. arterioles
• reduction in effective filtration area
• decreases GFR and RBF
― NaCl content at macula densa also ↓
renin release
• effect of decreased NaCl content
― opposite 20
Other regulators of glom. hemodynamics
• sympathetic
nervous system
― sympathetic
innervation of
glom. arterioles
• 3-time denser in
afferent arteriole
• vasoactive
peptides
― receptors for
vasodilators
mainly in AA
• their
pharmacological
blockade (e.g. by
COX1 inhibitors)
can decrease GFR
without BP
change
21
Summary of regulatory mechanisms
22
Three major mechanisms governing
renin release
• (1) signals at the individual nephron
― decreased NaCl load at the macula densa
― decreased afferent arteriolar pressure
(probably mediated by a cellular stretch
mechanism)
• (2) signals involving the entire kidney
― beta1-adrenergic receptor stimulation at
the juxtaglomerular cells
― at the same time, negative-feedback
inhibition by AT ll at the JG cells
― other hormonal factors
• (3) local effectors
― prostaglandins E2 and I2
― nitric oxide
― adenosine
― dopamine
― arginine vasopressin
23
Systemic RAAS
• prorenin is converted to
active renin by a trypsinlike
activating enzyme
• renin enzymatically cleaves
AGT to form the
decapeptide AT I
― this step can be blocked
by renin inhibitors
• AT I is hydrolyzed to the
octapeptide AT II by
angiotensin- converting
enzyme (ACE)
― this step is blocked by ACE
inhibitors
• AT II acts at a specific
receptor
― this interaction can be
blocked by a variety of
peptide or non-peptide AT
II antagonists
24
Paracrine effects of AT II in the kidney
• AGT either circulates to the kidney from the site of production in the liver or is synthesized locally in
proximal tubular cells in the kidney
• renin is synthesized and released from the JG cells into the afferent arteriolar lumen or into the renal
interstitium
• AT I is generated in the afferent arteriole and is converted to AT II by ACE and acts on efferent arteriole
• AT II can also be filtered at the glomerulus and may subsequently act at the proximal tubular cells to
increase sodium reabsorption
• in the renal interstitium renin can cleave AGT to produce angiotensin peptides
― these peptides may act at vascular and tubular structures
25
The renal tissue localization of AT II receptors and
their physiologic action
• vasoconstriction occurs when AT II acts at
receptors in the arcuate and interlobular
arteries [1], the afferent [2] and efferent [3]
arterioles and the medullary vasa recta [7]
― AT II preferentially constricts the efferent arteriole,
thereby increasing glomerular filtration pressure
• AT II also acts on mesangial cell receptors [4]
to produce cellular contraction and reduce
glomerular filtration
• AT II receptors also are localized to the
proximal tubule [5] and the cortical thick
ascending LH cells [6] which cause sodium
reabsorption
• AT II receptors are expressed also elsewhere in
kidney - medullary interstitial cells [8] - but the
physiologic significance of these receptors is
still unknown
• in summary, AT II has three major effects all of
which result in sodium retention
― 1) arteriolar vasoconstriction
― 2) renal sodium retention
― 3) increased aldosterone biosynthesis
• these effects work together to maintain
arterial blood pressure as well as blood
volume
• AT II also stimulates the sympathetic nervous
system， particularly the thirst center in the
hypothalamus 26
Cellular action of AT II
• when ATII activates AT1 receptors in vascular cells the peptide initiates a
biphasic signalling response
― the initial phase comprises PLC-mediated break-down of the inositol
polyphospholipids to generate IP3 and DAG as well as to mobilize intracellular
calcium
― the second phase is characterized by a sustained accumulation of DAG, activation of
PKC, hydrolysis of phosphatidylcholine-mediated by PLD, and intracellular
alkalinization
27
RBF is regulated in conflicting manner
• during light to moderate decrease of systemic pressure by autoregulation
― the aim is to maintain renal perfusion, GFR a homeostasis
• during significant decrease (circulation emergency) perfusion of kidney drops in
“systemic interest”
― pre-renal azotemia
― eventually with morphological consequences (acute tubular necrosis)
28
Measurement of GFR
• GFR is a main parameter characterizing
kidney function
― however the volume of glomerular filtrate
produced per time unit is not directly
measurable
• it can be assessed precisely enough by
― (1) determining clearance of certain substances
fulfilling certain criteria (see further)
• endogenous substances – creatitinin, urea
• exogenous
― unlabeled tracer – inulin,
― radio-contrast - iohexol
― radioactive isotope – [51Cr] EDTA, [125I] iothalamate, [99Tcm] DTPA
― (2) estimation of GFR based on plasma levels of endogenous
substances by formula
• creatinin - Cockroft-Gault, MDRD, CKD-EPI, …
• other endogenous markers (freely filtred and completely degraded by tubular
cells)
― β2-microglobulin, cystatin C
29
Clearance
hyperbolic
relationship is
clinically important
• substances must fulfill following criteria
― LMW, freely filtered to urine, unbound
to plasma carriers
― not undergoing further degradation
― no tub. reabsorption nor secretion
― concentration in plasma and analogic
volume of glom. filtrate stable
― detection method is simple, cheap and
standardized
• concentrace in urine is proportional to
changes of GFR:
― [P] × GF = V × [U]
• clearance of substance X = volume of
plasma that is cleared of substance X
per unit time
― units: volume/time
― timed urine collection is necessary
• ideally 24 hrs, often shorter
30
Creatinin
• produced in muscles from creatin
• in kidneys 90% filtered, z 10% secreted to urine by
tubules
― the contribution of tubular secretion rises with
↓ filtration (↓ number of functional nephrons)
― i.e. the lower the GFR the less precise assessment
of GFR by Ccr, but still the best endogenous
marker of GFR
• there are possible technical problems with timed
urine collection
― suboptimal cooperation of patient
• concentration of S-creatinin directly related to
muscle mass (therefore depends on age and gender)
― plasma creatinin = 35 – 100 μmol/l, production
1.2mg/min
― usually corrected for body surface area (1.73m2), but
still there are discrepancies due to body composition
• 25-yrs old athlete vs. 60-yrs old obese man with the same
weight and body surface
• intra-individual fluctuation not more than 10 - 15%
― concentration rises after the strenuous physical
exercise and after intake of exogenous creatinin (meat)
• especially fried
31
Heterogenous GFR in individual nephrones
32
TUBULAR REABSORPTION AND
SECRETION
33
Tubular reabsorption and secretion
• complex processes (active and passive)
― epithelial cells of kidney tubules (and their hormonal control)
• reabsorption means transport from apical to basolateral side
• secretion is a transport from basolateral to apical side
• different parts of tubules have different function –
specialization of tubular segments
― nearly 90% complete
reabsorption in prox.
tubule by various forms
of transport
• ∼75% Na+ (and HCO3
-),
Cl- and H20
• ∼90% K+
― secretion of K+ in collecting
tubules, total amount depends
on Na+ concentration in
particular segment (aldosterone)
― distal tubule and collecting
duct are under the
influence of ADH & aldosterone 34
Types of transport
35
Reabsorption of Na+ (and HCO3
-)
36
Hormones affecting renal function
37
Hormones affecting renal function
38
Diuretics
• types
― inhibitors of
carboanhydrase
• ↑ osmotic
pressure of
filtrate
― loop diuretics
• inhibit NaCl
transport in
ascendent part of
LH
― thiazide diuretics
• inhibit NaCl
reabsorption in
the 1st segment
of DCT
― osmotic diuretics
― kalium sparing
diuretics
― combined
diuretics increase volume of urine (more exactly a proportion of
glomerular filtrate excreted as urine)
39
FILTRATION MEMBRANE
40
Properties of filtration membrane
• size-selectivity, i.e. limit of mol.
weight of filtered substances
― <7kDa freely
― 7-70kDa concentration dependent
― >70kDa not
• charge-selectivity
― negative charge (also for proteins
<70kDa)
41
Glomerular filtration barrier
42
Structure of glom. filtration membrane
• (1) endothelium
― fenestrae – filter ∼50-100nm ∅
• separation of blood cells
• (2) glom. basal membrane (GBM)
― network of glycoproteins (collagen type IV,
laminin, entactin, agrin, …) and
mucopolysacharides ∼300nm thick wit summary
negative charge
• size-selective separation of majority of plasma
proteins >70kDa (∼ 4nm ∅)
― hemoglobin (∼ 40kDa) yes
― myoglobin (∼ 17kDa) yes
― β2-mikroglobilin (12kDa) yes, but reabsorbed
― paraproteins (<70kDa) yes
• neg. charge – heparansulphate, hyaluronic and sialic
acid
― albumin (∼ 67kDa) mostly no/in limited extent yes
• (3) visceral epithelium of Bowmann capsule =
podocytes
― prim., sec. and tert. foot processes (pedicles)
― slit diaphragm (cell-cell junction)
• important contribution to size (as well as charge)
separation of proteins
• (4) mesangium
― indirectly affect filtration of proteins – mesangial
cells contract and ↑ filtration pressure
43
Podocytes – slit diaphragm
Johnstone DB and Holzman LB (2006) Clinical impact of research on the podocyte slit diaphragm. Nat Clin Pract
Neprol 2: 271–282 doi:10.1038/ncpneph0180 44
Proteins of slit diaphragm
• (1) basal domain – anchoring to GBM
― integrins, DG = dystroglycan
• (2) cytoskeleton - shape
― actin, myosin, synaptopodin, actinin
• (3) junction domain – slit diaphragm
― nephrin, Neph1, podocin, CD2AP = CD2-associated protein, ZO-1 = zona occludens-1 protein, densin,
FAT = mammalian homolog of Drosophila fat protocadherin
• (4) apical domain – neg. charge
― podocalyxin, podoplanin, podoendin, GLEPP-1 = glomerular epithelial protein-1, other proteins and
receptors (NHERF-2 = Na+/H+ exchanger regulatory factor-2, …)
45
Proteins in urine (1) - normal
• physiological presence of proteins in urine
― proteins produced by tubular cells
• Tamm-Horsfall protein (= uromodulin)
― glycoprotein produced by cells of asc. arm of LH
― unknown function (immunomodulation, protection against crystala or infection?)
― main component of hyaline casts
• uropontin
• IgA immunoglobulin
• nephrocalcin
― filtered but reabsorbed and degraded in tubule
• albumin (see further details)
• α2- a β2-microglobulins, enzymes, apoproteins,
peptide hormones, …
• sensitivity of routine dg. methods
ensures, that these proteins and
albumin fragments are not detected
• only clinically significant proteinuria
(>0.5 g protein) gives positive results 46
Human serum albumin (HSA) paradox
• HSA ∼65kDa
• the molecule contains ∼ 185 charged residues (Asp, Glu, Lys)
― their surface distribution and overall charge is variabile due to
multiple functions of albumin:
• transport (FFA, bilirubin, Ca, Mg, hormones, drugs, vitamins, …)
• buffer / AB balance
• enzymová activity (antioxidant, esterase)
• oncotic pressure
• AA pool
• handling of albumin by kidneys
― (1) limited filtration
• electrostatic repulsion of albumin was not always exp. proved
• this concept was dominantly base on the absence of
albumin in urine
― (2) tubular reabsorbtion
• endocytosis = degradation (→ AA and small fragments)
― (3) tubular degradation
47
Normal renal handling of albumin
(a) Albumin (represented by
green spheres) normally remains
within the capillaries of the
glomerular tuft, and does not
escape into the urinary
(Bowman's) space. (b) Fenestrae
within specialized endothelial
cells are covered by a negatively
charged glycocalyx. Podocytes
attach to the outermost aspect
of the GBM by foot processes,
between which are proteins
comprising the size barrier slit
diaphragm. (c) The albumin that
is physiologically filtered at the
level of glomerulus into the
urinary space is taken up by the
megalin/cubulin receptor lining
the brush border of proximal
tubular cells. Albumin is
internalized by vesicles, and
upon lysozyme action, the
resultant fragments are either
reabsorbed or secreted back into
the tubular lumen as albumin
fragments 48
Mechanism of proximal tubular reuptake
of albumin
• receptor-mediated endocytosis
― high capacity/low affinity
• the same mechanism is used elsewhere (e.g. absorption of
complex of vit. B12/intrinsic factor in ileum)
― endocytic complex
• megalin/cubilin – binding of albumin
― Imerslund-Graesbeck disease (mutation in cubilin gene) - proteinuria
― Fanconi syndrome (mutation in megalin genu) - proteinuria
• NHE3 – necessary for acidification of endosome/lysosome
― NHE3 KO animals - proteinuria
• ClC5 – interaction with cytoskeleton
― Dent’s disease (mutation in ClC5 gene) - proteinuria
• H-ATPase – necessary for acidification of
endosome/lysosome
49 50
Megalin/cubilin
51
Proteins in urine (2) - proteinuria
• (a) functional proteinuria
― appears occasionally as a result of altered glomerular hemodynamics (↑
hydrostat. pressure in capillaries), glomerular membrane intact
• orthostatic, exercise, fever, …
• non-selective proteinuria
• (b) glomerular proteinuria (often >1g/day)
― pre-renal – pathological increase of “small” proteins capable of passing to
glomerular filtrate
• e.g. hemolysis (α-β-dimers globin), rhabdomyolysis (myoglobin), paraproteins (leight
chains of Ig κ and λ (so called Bence-Jones protein)
― selective - intact lamina densa (loss of glycocalyx from the surface of
endothelia and podocytes)
• albuminuria, larger proteins retained
― non-selective – gross structural damage incl. lamina densa and podocytes
• (c) tubular proteinuria (often <1g/den)
― decreased reabsorption of small plasma proteins (mainly albumin and β2microglobulin
in urine)
• congenital (Dent’s disease (ClC5), Imerslund-Graesbeck disease (cubilin), Fanconi
syndrome (megalin) etc.)
• acquired (e.g. hypertension) 52
Pathogenesis of glomerular proteinuria
• congenital
― disorders of GBM
• e.g. Alport syndrome
(mutation in collagen gene)
― disorders of podocytes
(slit diaphragm)
• mutations in genes for nephrin, podocin, …
• acquired – affect any part of glomerulus
― immune mechanisms - typically glomerulonephritis
• circulating or in situ immune complexes (90 %)
― antigen: bacteria (β-hemolyt. Strepto-, Staphylo-, Pneumococci), parasites,
viruses, endotoxin, cell organelles (in SLE), drugs, …
― it depends on the size whether immune complexes remain in circulation (→
vasculitis), will be scavenged by phagocytizing cells or become deposited (owing to
large perfusion and fenestrated endothelia) in kidneys
• antibodies against GBM, anti-neutrophil or against glomerular cells (10
%)
― non-immune – ischemia, hyperfiltration, toxins, infection, …
• e.g. diabetes, hypertension, amyloidosis, HIV, ...
53
Importance of podocyte slit diaphragm
• (1) study of familiar forms of nephrotic syndrome
led to the identification of majority proteins of
slit diaphragm of podocytes
― nephrin (Finnish-type congenital nephrotic
syndrome, NPHS1)
• congenital. defect of development of pedicles and
slit diaphragm
• massive and potentially lethal proteinuria starting during the fetal period
• parenteral nutrition and peritoneal dialysis necessary till the transplantation
― in comparison Alport syndrome (collage IV) leads to only moderate proteinuria
― deletion of heparansulphate in mouse models do not lead to any proteinuria
― podocin (familiar steroid-resistant nephrotic syndrome, NPHS2)
• early postnatal proteinuria
― other syndromes with significant proteinuria (CD2AP, NEPH1, FAT, TRPC6, …)
• (2) it is possible to induce nephrotic syndrome experimentally by polyclonal antibodies
against slit diaphragm or by monoclonal ab. against nephrin, podocin, …
• (3) clinical importance
― glomerulopathies are dominant cause of proteinuria
• current classification of glomerulopathies based histopathologic
appearance (= non-specific)
― future (?} molecular-biologic classification
• diagnostics, prognosis, treatment (steroids y/n), benefit of transplantation
(family member/donor), …
54
Podocytes - foot-process effacement
• = “smoothening” of podocytes - universal
sign of damage to podocytes
• correlate with degree of proteinuria
(“chicken or egg”?)
• variable etiology of podocyte damage
― ROS (→ DNA damage, apoptosis, peroxidation of
lipids)
― AT II (→ apoptosis, hypertrophy, ↑ TGF-b, ↓
nephrin)
― MMPs (→ ↓ GBM, ↓ nephrin-Neph complex)
― mechanical stress (→ apoptosis, hypertrophy)
― growth factors (→ ↑ MMPs, GBM, …)
― hyperglycemia (→ ↓ neg. charged apical protein)
• loss of podocytes ⇒ proteinuria ⇒
glomerulosclerosis
― synechia between naked GBM and parietal
epithelium of Bowmann capsule → sclerotisation
(FSGS)
― podocytes do not regenerate
55
Consequences of glomerulopathies
resp. proteinuria
• extra-renal
― hemodynamics
• ↓ oncotic pressure (edema)
― composition of ECF
― dyslipidemia
― loss of substances bound to proteins
• hypovitaminoses
― nutrition
• intra-renal
― albumin in small concentration necessary
survival factor for tubular cells
― however, larger quantities of proteins in
tubules lead to inflammation and
interstitial sclerotisation
• perpetuation of renal damage!!!
56
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
57
Proteinuria results in the development of
glomerulosclerosis and fibrosis
58
GLOMERULOPATHIES
59
Glomerulus - cells
60
Classification of glomerular diseases
61
Classification of glomerular diseases
• unless exact etiology is known GN are
classified based on clinical-laboratoryhistologic
criteria
― kidney biopsy
• → light, immunofluorescent, electron
microscopy
• histologic classification of GN
dominantly focuses on the number of
affected glomeruli and predominantly
affected cell type
― focal (only some glomeruli affected)
― diffuse (mote than 80% of glomeruli)
― segmental (only certain structures)
― global (all cell types affected)
• and also degree of cellularity
― non-proliferative
― proliferative
• the exact cause of the majority of
glomerular disease unknown, therefore
etiologic classification does not exist
• clinically
― primary (affect only kidneys)
― secondary (renal manifestation of
systemic disease)
• autoimmune (SLE, IgA nephropathy, m. HenochSchonlein,
Goodpasteur syndrome etc.)
• vascular (vasculitis)
• metabolic (diabetes, amyloidosis)
• tumors (multiple myeloma)
• genetic
• but even this is ambiguous
(immunopathologic process responsible
for development of vast majority
glomerulonephritis is
predominantly systemic)
• according to time course
― acute
― chronic
62
63
General pathogenesis of acute GN
• formation of immune complexes
― in circulation or in situ
• complement activation
― formation of opsonins, chemotaxis,
glomerular cell lysis
• inflammatory infiltration by neutrophils
and macrophages
― protease degradation of cells and ECM
• healing
― growth factors – cell proliferation
― connective tissue (mesangium) – fibrosis
and sclerosis 64
General pathogenesis of GN
• glomerulus has only limited spectrum of reactions to damage
― inflammation
• proliferation of glomerular cells
• infiltration by other cells
• proteolytic destruction of filtration membrane
― proteinuria
― deposition of ECM
• fibrosis
• scarring
• sclerosis
― decrease of GFR
― histologic appearance depends
on which particular part of
glomerulus affected
• proliferative GN – mesangium
• membranous GN – GBM thickening
• sclerotising GN – capillaries and synechia
65
Clinical picture of GN
• nephritic syndrome
― gross damage to filtration
barrier (involving endothelium
and GBM) = oliguria
• activation of complement
― inflammation causes blockade of
filtration and hypertension due
to hypervolemia
― leak of red blood cells =
glomerular hematuria
― diff. dg. post-renal!
• macroscopic (visible by naked eye)
• microscopic (urine analysis)
― mild proteinuria in comparison
with nephrotic syndrome
• only as much protein as in the
given volume of blood leaking into
urine
• nephrotic syndrome
― damage to filtration barrier (involving
mainly podocytes)
• no activation of complement
― no blockade to filtration therefore no
hypertension
― large proteinuria dominates
• typically >3g/day
― as a result of hypoalbuminamia /
hyporoteinemia
• oncotic pressure decrease → edema
• infections
• hypocalcemia, hypovitaminosis, …
― protein loss becomes compensated by
liver, the non-selectivity of this
globally increased protein synthesis
explains
• dyslipidemia
― ↑ lipoproteins, ↓ plasma LPL
• hypercoagulation (risk of thrombosis) 66
Nephritic vs. nephrotic syndrome
• Both syndromes are caused by the formation of soluble complexes of
antigens after an insufficient clearing from the immune system
― nephrotic syndrome – no activation of complement
• soluble antigen/antibody complexes are deposited within the slit pores (between
opposing podocyte foot processes) or within the mesangial artery
― nephritic syndrome - activation of complement
• soluble antigen/antibody complexes are deposited sub-endothelial space
67 68
nephritic
nephrotic
69
Vrozené choroby ledvin
• polycystická choroba ledvin
(PKD)
― autosomálně dominantní
(ADPKD)
• mutace v genu PKD1 (ch. 16)v
85%, v 15% případů PKD2
• progresivně se rozvíjející
mnohočetné cysty
oboustranně v ledvinách
• hypertenze
• renální insuficience
• ~50% případů ESRD
― recesivní forma vzácná,
závažnější
70