ACUTE AND CHRONIC RENAL FAILURE
VLA
December 5, 2017
EXTRACELLULAR VESICLES
 Extracellular vesicles are cell-derived membrane particles ranging from 30 to
5,000 nm in size, including exosomes, microvesicles, and apoptotic bodies.
 They are released under physiological conditions, but also upon cellular activation,
senescence, and apoptosis.
 They play an important role in intercellular communication. Their release may also
maintain cellular integrity by ridding the cell of damaging substances.
 They can modify mechanisms important in the pathophysiology of kidney diseases,
such as thrombosis, angiogenesis, tissue regeneration, immune modulation, and
inflammation.
 In kidney diseases, extracellular vesicles may be utilized as biomarkers, as they are
detected in both blood and urine.
 They may contribute to the pathophysiology of renal disease while also having
beneficial effects associated with tissue repair. Because of their role in the
promotion of thrombosis, inflammation, and immune-mediated disease, they
could be the target of drug therapy, whereas their favorable effects could be
utilized therapeutically in acute and chronic kidney injury.
Pediatr Nephrol. 2017 Nov 27. doi: 10.1007/s00467-017-3816-z.
ESCRT – endosomal sorting complex required for
transport
Pediatr Nephrol. 2017 Nov 27. doi: 10.1007/s00467-017-3816-z.
Pediatr Nephrol. 2017 Nov 27. doi: 10.1007/s00467-017-3816-z.
EXTRACELLULAR VESICLES- FUNCTION
 During physiological and pathological processes, EVs are released
and partake in cellular communication affecting processes such
as coagulation and thrombosis, angiogenesis, immune
modulation and inflammation.
 Glomerular endothelial cell-derived microvesicles exposing the
kinin B1 receptor and interleukin 8 (IL-8) on their surface attracted
neutrophils.
 Proximal tubular cells cultured in the presence of fenoldopam (a
dopamine receptor agonist) released exosomes that reduced the
production of reactive oxygen species in distal tubule and
collecting duct cells, indicating the transfer of an antiinflammatory
response.
Pediatr Nephrol. 2017 Nov 27. doi: 10.1007/s00467-017-3816-z.
EVS
 The prothrombotic, proinflammatory, and immunomodulatory properties
associated with EVs, described above, may all contribute to and
maintain tissue damage in the kidney and urinary tract during the
development of AKI, glomerular and tubular diseases, infections, and
chronic renal failure in addition to numerous other conditions affecting
the kidney.
 Studies on the role of EVs in AKI have mostly been carried out in patients
with sepsis, burns or other forms of acute tubular injury .
Pediatr Nephrol. 2017 Nov 27. doi: 10.1007/s00467-017-3816-z.
EVS
 Their contribution to the induction and progression of renal
diseases may lead to the development of treatments geared
toward temporary reduction of EVs systemically in the circulation,
or locally in the kidney and urinary tract. Treatments that reduce
the release or uptake of EVs need to take into account the notion
that EVs may also be cytoprotective, as their release and the
removal of unwanted or damaging substances from their parent
cells may maintain cellular integrity. EVs may have potentially
beneficial properties associated with tubular regeneration and
the induction of angiogenesis. The therapeutic potential and
nephroprotective effects of EVs, owing to their capacity to shuttle
proteins, lipids, and genetic cargo to recipient cells, are being
explored in preclinical studies, which may lead to clinical trials in
the future.
Pediatr Nephrol. 2017 Nov 27. doi: 10.1007/s00467-017-3816-z.
RENAL FAILURE
 is a situation in which the kidneys fail to function
adequately. It is divided in acute and chronic forms;
either form may be due to a large number of other
medical problems.
 Biochemically, it is typically detected by an decreased
creatinine clearance
 Pathophysiologically, it is decrease in the glomerular
filtration rate.
 When the kidneys malfunction, problems frequently
encountered are abnormal fluid levels in the body,
deranged acid levels, abnormal levels of potassium,
calcium, phosphate, and (in the longer term) anemia.
 Long-term kidney problems have significant repercussions
on other diseases, such as cardiovascular disease.
ACUTE RENAL FAILURE: ETIOLOGY
 Prerenal:
 CV and volume depletion
 Drug-induced or related (NSAIDs, ACEIs,
diuretics)
 Intrarenal:
 Inflammatory disease: Vasculitis, glomerulonephritis,
drug-induced
 Acute tubular necrosis
 Postrenal: Obstruction, Cancer,
congenital abnormalities
ACUTE RENAL FAILURE
Pre-renal (causes in the blood supply):
 hypovolemia (decreased blood volume),
usually from shock or dehydration and
fluid loss or excessive diuretics use.
 hepatorenal syndrome in which renal
perfusion is compromised in liver failure
 vascular problems, such as atheroembolic
disease and renal vein thrombosis (which
can occur as a complication of the
nephrotic syndrome)
ACUTE RENAL FAILURE
Renal (damage to the kidney itself):
 infection usually sepsis (systemic inflammation due to
infection),rarely of the kidney itself, termed pyelonephritis
 toxins or medication (e.g. some NSAIDs, aminoglycoside
antibiotics, iodinated contrast, lithium)
 rhabdomyolysis (breakdown of muscle tissue) - the resultant
release of myoglobin in the blood affects the kidney; it can be
caused by injury (especially crush injury and extensive blunt
trauma), drugs
 hemolysis - the hemoglobin damages the tubules; it may be
caused by various conditions such as sickle-cell disease, and
lupus erythematosus
 multiple myeloma, either due to hypercalcemia or "cast
nephropathy" (multiple myeloma can also cause chronic renal
failure by a different mechanism)
 acute glomerulonephritis which may be due to a variety of
causes, such as anti glomerular basement membrane
disease/Goodpasture's syndrome, Wegener's granulomatosis or
acute lupus nephritis with systemic lupus erythematosus
ACUTE RENAL FAILURE
Post-renal (obstructive causes in the urinary
tract) due to:
 medication interfering with normal
bladder emptying.
 benign prostatic hypertrophy or prostate
cancer.
 kidney stones.
 due to abdominal malignancy (e.g.
ovarian cancer, colorectal cancer).
 obstructed urinary catheter.
ACUTE RENAL FAILURE: PATHOGENESIS
 Acute tubular necrosis (ATN):
 Tubular cell sloughing
 Reversibility/Irreversibility: dependent
on time of intervention
 ATN Pathogenesis
 Tubular occlusion theory and cast
formation
 Vascular hypoperfusion theory:
Afferent vasoconstriction with efferent
vasodilation
 Role of renal mediators?
ACUTE RENAL FAILURE: CLINICAL PRESENTATION
 Heterogeneous group of disorders
characterized by rapid deterioration
in renal function (decreased GFR)
 Rapid elevation of urea in blood and
serum creatinine
 Oliguria: variable
 Other: hematuria, proteinuria, edema,
hypertension
ACUTE RENAL FAILURE:
EARLY CLINICAL MANIFESTATIONS
 Symptoms depend on degree and cause of
renal failure
 Initial Symptoms: Fatigue and malaise:
 Loss of excretory capacity and accumulation of
water, electrolytes and nitrogenous wastes
 Prerenal azotemia: Elevated BUN/SrCr (20-30:1) with
normal SrCr
 Urinalysis: No casts detected
 Maximal urinary concentration: 1500 mosm/L
 Fractional Na excretion (99%)
 May progress to ATN without proper treatment
ACUTE RENAL FAILURE:
LATER CLINICAL MANIFESTATIONS
 Later Symptoms (frank ATN): dyspnea,
orthopnea, heart (sound S3), edema
 Normal BUN/SrCr, progressive elevation of
SrCr
 Casts (protein, RBC, epithelial cells)
 Urine osmolality
 Fractional excretion of Na (as low as 1%)
CHRONIC RENAL FAILURE-ETIOLOGY
 Diabetes mellitus (28%)
 Hypertension (25%)
 Glomerulonephritis (21%)
 Polycystic kidney disease (4%)
 Other (23%): Obstruction,
infection, etc.
PATHOGENESIS OF CHRONIC RENAL
FAILURE
 Chronic vs Acute renal failure
pathogenesis:
 Acute: tubular cell death and regeneration
(reversible)
 Chronic: Irreversible nephron loss
 Glomerular Hyperfiltration:
 Compensatory mechanism with increased
nephron GFR:
 Pre-disposition to glomerular sclerosis
 Azotemia at 30-35% GFR
 Uremia: <20% normal excretory
capacity
CHRONIC KIDNEY DISEASE
 is a progressive loss of renal function over a period
of months or years through five stages. Each stage
is a progression through an abnormally low and
progressively worse glomerular filtration rate, which
is usually determined indirectly by the creatinine
level in blood serum.
 Stage 1 CKD is mildly diminished renal function,
with few overt symptoms.
 Stage 5 CKD is a severe illness and requires some
form of renal replacement therapy (dialysis or
renal transplant). Stage 5 CKD is also called endstage
renal disease (ESRD).
PATHOGENESIS OF UREMIA
 Retention of nitrogenous wastes
 Increased intracellular Na and water
 Decreased intracellular K
 Increased levels of bioactive substances
normally cleared by kidneys (hormones)
 Decreased levels of hormones and other
mediators produced by the kidney
 Decreased basal body temperature
 Diminished lipoprotein lipase activity
CHRONIC RENAL FAILURE: CLINICAL MANIFESTATIONS
 Sodium and water retention
 Hyperkalemia
 Metabolic Acidosis
 Mineral and Bone metabolism Disorders
 Cardiovascular and Pulmonary Disorders
 Hematologic Abnormalities
 Neuromuscular Abnormalities
 Gastrointestinal Abnormalities
 Endocrine Abnormalities
 Dermatologic Abnormalities
CHRONIC RENAL FAILURE:
SODIUM AND VOLUME BALANCE
 Sodium and water retention:
 CHF, Hypertension, ascites, edema
 Enhanced sensitivity to extra-renal
sodium and water loss
 vomiting, diarrhea, fever, sweating
 Symptoms: dry mouth, dizziness,
tachycardia, etc.
CHRONIC RENAL FAILURE: POTASSIUM BALANCE
 Hyperkalemia (GFR below 5 mL/min)
 GFRs >5 mL/min: compensatory aldosteronemediated
K+ transport in the DTCs
 K-sparing diuretics, ACEis, beta-blockers
impair Aldosterone-mediated actions
 Exacerbation of hyperkalemia:
 Exogenous factors: K-rich diet, etc.
 Endogenous factors: infection, trauma, etc.
CHRONIC RENAL FAILURE:
POTASSIUM BALANCE AND DIABETES
 Diabetics (major cause of
CRF):
 Hyporeninemic
hypoaldosteronism
 Lack of renin - decreased
angiotensin II - impaired
aldosterone secretion - loss of
compensation for low GFR
CHRONIC RENAL FAILURE: METABOLIC
ACIDOSIS
Decreased acid excretion and
ability to maintain physiologic
buffering capacity:
 GFR > 20 mL/min: transient
moderate acidosis
 Increased susceptibility to acidosis
CHRONIC RENAL FAILURE:
MINERAL AND BONE DISEASES
Bone disease from:
 Decreased Ca++ absorption from the
gut (decreased calcitriol- osteomalacia
in adults)
 Over-production of PTH (decreased
plasmatic calcium) –renal
osteodystrophy
 Chronic metabolic acidosis (increased
ionised calcium fraction)
CHRONIC RENAL FAILURE:
CARDIOVASCULAR AND PULMONARY ABNORMALITIES
 Volume and salt overload
 CHF and pulmonary edema
 Hypertension
 Hyperreninemia: Hypertension
 Pericarditis: Remic toxin accumulation
 Accelerated atherosclerosis: linked to
factors above and metabolic
abnormalities (Ca alterations,
hyperlipidemia)
CHRONIC RENAL FAILURE:
HEMATOLOGICAL ABNORMALITIES
 Anemia: lack of erythropoietin
production
 Bone marrow suppression:
 uremic poisons: leukocyte suppression -
infection
 bone marrow fibrosis: elevated PTH an
aluminum toxicity from dialysis
 Increased bruising, blood loss (surgery)
and hemorrhage
 Lab Abnormalities: Prolonged bleeding
time, abnormal platelet aggregation
CHRONIC RENAL FAILURE:
NEUROMUSCULAR ABNORMALITES
 CNS Abnormalities:
 Mild-Moderate: Sleep disorders, impaired
concentration and memory, irritability
 Severe: Asterixis, myoclonus, stupor,
seizures and coma
 Peripheral neuropathies:
 “restless legs” syndrome
 Hemodialysis-related neuropathies
CHRONIC RENAL FAILURE:
GASTROINTESTINAL ABNORMALITIES
 Peptic ulcer disease: secondary
hyperparathyrodism?
 Uremic gastroenteritis: mucosal
alterations
 Uremic fetor: bad breath (ammonia)
 Non-Specific abnormalities:
 anorexia, nausea, vomiting,
diverticulosis, hiccoughs
CHRONIC RENAL FAILURE:
ENDOCRINE ABNORMALITIES
 Insulin: Prolonged half-life due to
reduced clearance (metabolism)
 Amenorrhea and pregnancy
failure: low estrogen levels
 Impotence, oligospermia and
germinal cell dysplasia: Low
testosterone levels
CHRONIC RENAL FAILURE:
DERMATOLOGIC ABNORMALITIES
 Pallor: anemia
 Skin color changes: accumulation of
pigments
 Ecchymoses and hematomas: clotting
abnormalities
 Pruritus and Excoriations: Ca deposits
from secondary hyperparathyroidism
FIBROSIS OF THE KIDNEY
 Sustained inflammation and repeated cycles of kidney
injury/repair (or incomplete recovery) leads to tubular atrophy,
progressive fibrosis, functional decline and, ultimately, organ
failure.
 Episodic acute injury (AKI) to the proximal tubular epithelium is a
major factor in the transition to chronic kidney disease (CKD)
patients who survive AKI have an increased risk of development of
CKD.
 Excessive accumulation of extracellular matrix (ECM; e.g., the
fibrillar collagens, fibronectin) in the glomerular, interstitial and
vascular compartments is accompanied by a significant decline
in glomerular filtration rate and impaired epithelial regeneration.
FIBROSIS OF THE KIDNEY
 Interstitial fibrosis is both a pathophysiologic hallmark feature and
prognostic biomarker of end-stage renal disease (ESRD).
 The primary sources of ECM synthesis during interstitial fibrogenesis
are activated fibroblasts or myofibroblasts. Although controversial
in origin, recent biomarker analysis and lineage-tracing studies
suggest that this cell type-predictor of disease progression likely
derives from FoxD1+ mesenchymal precursors (i.e., vascular
pericytes and tissue-resident fibroblasts) with perhaps minor
varying contributions from endothelial cells, completely or partially
transdifferentiated tubular epithelia, and bone marrow fibrocytes.
 The persistence of such activated fibroblasts is a critical factor in
the initiation and development of renal disease where they likely
participate in the silent scarring phase prior to development of
significant organ dysfunction.
SCHEMATIC PRESENTATION OF THE RELEASE
AND UPTAKE OF EXTRACELLULAR VESICLES
 a Exosomes are released from late endosomes termed
multivesicular bodies bearing intraluminal vesicles (ILVs)
intracellularly. When the multivesicular bodies fuse with the
plasma membrane and empty their contents, ILVs are released
and are termed exosomes once they are extracellular. Exosomes
are the smallest extracellular vesicles.
 b Microvesicles are shed directly from the plasma membrane,
thereby carrying membrane markers of the parent cell.
Microvesicle formation is calcium-dependent and associated with
loss of membrane asymmetry and disruption of the cellular
cytoskeleton.
 c Extracellular vesicle uptake by target cells may occur via fusion
of the vesicle membrane with the cell membrane or by
endocytosis. The vesicle may also transduce an intracellular signal
by ligand binding to a receptor on the recipient cell.
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