1909 starling: „the kidney presents in the highest degree the phenomenon of sensibility… must be...
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1909 Starling: „The Kidney presents in the highest degree the phenomenon of sensibility… must be
endowed with intelligence.”
1957 Homer-Smith: … only a passive agent operating blinly and automatically according to the dictates of
receptor- effector systems located elsewhere in the body
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Acute Renal Failure (ARF)
(an abrupt reduction in renal function)
GFR
Oliguric: urine output <500ml/day (70-80%)
Non-oliguric: urine output >500 ml/day (20-30%)
Changes inblood biochemistry
( accumulation of metabolic waste products;
creatinin , urea , „azotemia”
hyperkalemia, oedema, metabolic acidosis etc.)
By the site of the abnormality
Prerenal
ARF or azotemia
Postrenal
ARF or azotemia
Renal(parenchimal)
ARF or azotemia(Acute tubular necrosis =ATNoften used interchangeably with ARF
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Causes of Prerenal Azotemia
HypovolemiaHemorrhageGastrointestinal lossesThird space
PancreatitisBurnsPeritonitisTraumatized tissue
Diuretic abuseImpaired cardiac function
Congestive heart failureMyocardial infarctionPericardial tamponadeAcute pulmonary embolism
Peripheral vasodilatationBacteremiaAntihypertensive medications
Increased renal vascular resistanceAnesthesiaSurgical operationHepatorenal syndrome
Renal vascular obstruction, bilateralEmbolismThrombosis
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Causes of Postrenal Azotemia
Obstruction of ureters, bilateralExtraureteral
Tumor: cervix, prostate, endometriosisPeriureteral fibrosisAccidental ureteral ligation during pelvic
operation
IntraureteralSulfonamide and uric acid crystalsBlood clotsPyogenic debrisStonesEdemaPapillary necrosis
Bladder neck obstruction Prostatic hypertrophy Bladder carcinoma Bladder infection Functional: neuropathy or ganglionic
blocking agents
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Specific Etiologies of Acute Renal Failure /1
I. HemodynamicSystemic disorders
Major traumaMassive hemorrhageCrush syndromeSpetic shockTransfusion reactionsPregnancy: postpartum hemorrhagePostoperative, particularly cardiac, aortic, and biliary surgery
Major blood vessel diseaseRenal artery thrombosis, embolism, or stenosisBilateral renal vein thrombosis
Diseases of glomeruli and small blood vesselsAcute poststreptococcal glomerulonephritisSystemic lupus erythematosusPolyarteritis nodosaSchönlein-Henoch purpuraSubacute bacterial endocarditisSerum sicknessGoodpasture’s syndromeMalignant hypertensionHemolytic-uremic syndromeDrug-related vasculitisPregnancy: abruptio placentae; abortion with and without
Gram-negative sepsis;Rapidly progressive glomerulonephritis, unknown etiology
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II. NephrotoxinsExogenous
Heavy metals: mercury, arsenic, lead, bismuth, uranium, cadmiumCarbon tetrachlorideOther organic solventsX-ray contrast mediaPesticidesFungicidesAntibiotics: aminoglycosides, penicillins, tetracyclines, amphotericinOther drugs and chemical agents: diphenylhydantoin, phenylbtazone
EndogenousCalcium (hypercalcemia)Uric acid (hyperuricemia and hyperuricosuria)Myoglobin (rhabdomyolysis)Hemoglobin (hemolysis)
Specific Etiologies of Acute Renal Failure /2
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Initiation of ARF(hours-days)
Course of parenchymal ARF
Recovery(weeks-months)
Maintenance of ARF(days-weeks)
hemo-dynamic event
toxic effect
vascular alterations
tubular alterations
partial total
glomerular capillary permeability
tubular obstruction
backleakage of filtrate
changes in resistances
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Initiation of ARF (experiments and observations)
1. Hemodynamic events- transitorical renal arterial occlusion ARF- intrarenal arterial infusion of vasoconsrictors ARF- inhibitors of prostaglandin synthesis incidence and
severity of ARF - in ARF: renin-angiotensin
Conclusion:During the initiation af ARF the RBF generally is decreased, later on RBF increased or normalized, but GFR still remains low.
2. Toxic effects: (experiments and life)- antibiotics (aminoglycosides, cephalosporins, colistin)- iodine-containing x-ray contrast- heavy metals (lead, arsenic, cadmium, mercury, uranium,
bismuth)- organic solvent (carbon tetrachloride)- ethylene glycol (antifreeze)- anesthesics (methoxyflurane, enflurane)- cyclosporin
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Efferent Arteriolar Dilatation
Afferent Arteriolar Constriction
Efferent Arteriole
Afferent Arteriole
RBF
GFR
A.,
B.,
RBF
GFR
RBF
GFR
C., Diminished Glomerular Permeability
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Changes in Endothelial Fenestration of Glomerular Capillary during ARF Induced
by Ischemia
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Changes in Podocytes’ Foot Processes of Glomerular Capillary during ARF
Induced by Ischemia
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Ischaemia
Possible Role of Renin Angiotensin System in the Development of ARF
Decrease of GFR Tubular lesion
Na+ concentration in distal tube and at
macula densa
Afferens arteriolar
resistance
TGF
Angiotensin II Renin secretion
in juxtaglomerular cells
glomerular permeability
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0
10
20
En
dot
hel
in C
once
ntr
atio
n (
pg
/ml)
Acute Renal Failure
Recovery
Figure: Plasma endothelin concentration during Acute Renal Failure and Recovery. The hatched area represents the normal range. Open circles denote patients who survived, and triangles patients who died
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Acute Renal Failure induced by uranyl nitrate (micropuncture studies at 48h)
Pre-UN Post-UN
Renal blood flow, ml/minUrine flow, ml/minGFR, ml/minBUN, mg%Nephron GFR, ml/minIntra-tubular pressure, mmHgTransit time, sec
1740.123513891624
2040.02*0.20*120*57*1624
* p < 0.001 or less.
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1 week after release of obstruction
22-26 hrs after release of obstruction
1-3 hrs after release of obstruction
Proximal tubular pressure before renal arterial obstruction
Proximal tubular pressure mmHg
% o
f tu
bule
s
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120
100
80
60
40
20
0
(3 H)
inul
in r
ecov
ery
%
Controln=14
UNn=17
Figure: Comparison of the urinary recovery of 3H-inulin injected into the proximal tubule of control and uranyl nitrate-treated dogs
Acute Renal Failure induced by uranyl nitrate (micropuncture studies at 48h)
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Nephrons disected from a human kidney during ARF
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Tubular obstruction
Acute Renal Failure
Normal
Decreased Glomerular Filtration Pressure
Increased Intratubular
Pressure
Obstruction
GFR
Efferent Arteriole
Afferent Arteriole
H2O and Electrolytes
H2O and Electrolytes
GFR
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Backleakage of Filtrate
Acute Renal Failure
Normal
Efferent Arteriole
Afferent Arteriole
H2O and Electrolytes
H2O and Electrolytes
GFR
Inulin
Efferent Arteriole
Afferent Arteriole
H2O and Electrolytes
Inulin
SNGFR
Inulin
Inulin
GFRH2O and Electrolytes
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nephrotoxins ischemia
Protective mechanism against lipid peroxidation
Protein synthesis
Membrane integrity
Cytoplasmic embranes Mithocondrial inner membrane
Permeability Energy productionTransport
IntracellularATP , Na+ , K+ , H+ ,
Ca++
Free radicals , proteolysis
Swelling of cells
Necrosis
Interactions of nephrotoxins or ischemia with tubular cell integrity and function.
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Comparison of balance of oxygen delivery and oxygen consumption in several organs
Region ororgan
O2 delivery
Blood flow rate
O2 consump-
tion O2 consumption/O2 delivery
%ml/min/100g
Hepato-portalKidneyOuter medullaBrainSkinSkeletal muscleHeart
11.684.07.6
10.82.60.5
16.8
58420190 54 13 2.7 84
2.2 6.8 6.0 3.7
0.38 0.18
11.0
188
7934153465
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The hypothetical role of the medullary thick ascending limb of Henle’s loop (mTAL) in
the pathophysiology of ischemic ARF
Ischemia toxin
RBF GFR tubular heterogeneity
mTAL ischemia
mTAL damage
continue high O2 demand
backleak
if SNGFR0 if SNGFR=0
transport
mTAL structure protected
(PG, diuretics)
obstruction tubuloglomerular feedback
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Injury to the mTAL in experimental renal ischemia
1, Controlled hemorrhagic hypotension (Bp:30-40 mmHg)
produces focal mTAL damage associated decreased urinary
concentrating ability before renal failure can be demostrated.
2, Recent observations show a selective decreasein the
Na-K-ATPase in the outer medulla as compared to the cortex
during ischemic injury.
3, mTAL injury associated with compldete arterial occlusion is
much less advanced than that of hypoxia imposed during
isolated perfusion.
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AVE
Oliguric
1960’s: ~ 98-100%
1990’s: ~ 30-80%
Nonoliguric
~ 2-0 %
~ 20-70 %
Lab and Clin Complications in Oliguric and Nonoliguric ARF
Oliguric
(n=38)
Nonoliguric
(n=54)
Maximum BUN 41±2 (114±5 mg/dl) 34±2 (95 ±5mg/dl)(mmol/l)
Max. creatinine 796 ±44 (9 ±0.5 mg/dl) 530±26 (6 ±0.3 mg/dl)(µmol/l)Hospitalization (days) 31±3 22 ± 2
Required dialysis 84% 28%Complications
Gastroinestinal hemorrhage 39% 19% Infection 42% 20% Metabolic acidosis 45% 20%
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100
80
60
40
20
0
% A
RF
MO
RT
AL
ITY
Oliguric
Nonoliguric
Hou et al
(n= 129)
Frankel et al
(n= 64)
Rasmussen et al
(n= 143)
Mortality rates of oliguric and nonoliguric acute renal failure.
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Possible explanations for nonoliguric ARF
1, In some healthy nephronns there are still filtration but
there is almost no reabsorption.
2, Decreased medullary osmotic concentration
decreased reabsorption of H2O