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

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

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

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

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

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

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

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

Efferent Arteriolar Dilatation

Afferent Arteriolar Constriction

Efferent Arteriole

Afferent Arteriole

RBF

GFR

A.,

B.,

RBF

GFR

RBF

GFR

C., Diminished Glomerular Permeability

Changes in Endothelial Fenestration of Glomerular Capillary during ARF Induced

by Ischemia

Changes in Podocytes’ Foot Processes of Glomerular Capillary during ARF

Induced by Ischemia

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

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

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.

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

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)

Nephrons disected from a human kidney during ARF

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

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

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.

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

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

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.

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%

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.

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