14

Pathophysiology of Ischemic Acute Renal Failure

Acute renal failure (ARF) is a syndrome characterized by anabrupt and reversible kidney dysfunction. The spectrum ofinciting factors is broad: from ischemic and nephrotoxic agents

to a variety of endotoxemic states and syndrome of multiple organfailure. The pathophysiology of ARF includes vascular, glomerularand tubular dysfunction which, depending on the actual offendingstimulus, vary in the severity and time of appearance. Hemodynamiccompromise prevails in cases when noxious stimuli are related tohypotension and septicemia, leading to renal hypoperfusion with sec-ondary tubular changes (described in Chapter 13). Nephrotoxicoffenders usually result in primary tubular epithelial cell injury,though endothelial cell dysfunction can also occur, leading to theeventual cessation of glomerular filtration. This latter effect is a con-sequence of the combined action of tubular obstruction and activationof tubuloglomerular feedback mechanism. In the following pages weshall review the existing concepts on the phenomenology of ARFincluding the mechanisms of decreased renal perfusion and failure ofglomerular filtration, vasoconstriction of renal arterioles, how formedelements gain access to the renal parenchyma, and what the sequelaeare of such an invasion by primed leukocytes.

Michael S. GoligorskyWilfred Lieberthal

C H A P T E R

14.2 Acute Renal Failure

FIGURE 14-1

Pathophysiology of ischemic and toxic acute renalfailure (ARF). The severe reduction in glomerular filtration rate (GFR) associated with establishedischemic or toxic renal injury is due to the com-bined effects of alterations in intrarenal hemody-namics and tubular injury. The hemodynamic alter-ations associated with ARF include afferent arterio-lar constriction and mesangial contraction, both of

Vasoactive Hormones

Reduced GPF and P

Afferent arteriolarvasoconstriction

Mesangialcontraction

Reduced tubularreabsorption of NaCl

Backleak of glomerular filtrate

Tubular obstruction

Reduced glomerularfiltration surface areaavailable for filtration

and a fall in Kf

Increased delivery ofNaCl to distal nephron

(macula densa) andactivation of TG feedback

Backleak of urea, creatinine,

and reduction in"effective GFR"

Compromises patencyof renal tubules and

prevents the recoveryof renal function

Hemodynamic changesTubular injury and

dysfunction

Ischemic or toxic insult

Ischemic or toxic injuryto the kidney

Increase in vasoconstrictors

Deficiency ofvasodilators

Imbalance in vasoactive hormonescausing persistent intrarenalvasoconstriction

Angiotensin IIEndothelinThromboxaneAdenosineLeukotrienesPlatelet-activating factor

PGI2

EDNO

Persistent medullary hypoxia

FIGURE 14-2

Vasoactive hormones that may be responsible for the hemodynamic abnormalities in acutetubule necrosis (ATN). A persistent reduction in renal blood flow has been demonstratedin both animal models of acute renal failure (ARF) and in humans with ATN. The mecha-nisms responsible for the hemodynamic alterations in ARF involve an increase in theintrarenal activity of vasoconstrictors and a deficiency of important vasodilators. A num-ber of vasoconstrictors have been implicated in the reduction in renal blood flow in ARF.The importance of individual vasoconstrictor hormones in ARF probably varies to someextent with the cause of the renal injury. A deficiency of vasodilators such as endothelium-derived nitric oxide (EDNO) and/or prostaglandin I2 (PGI2) also contributes to the renalhypoperfusion associated with ARF. This imbalance in intrarenal vasoactive hormonesfavoring vasoconstriction causes persistent intrarenal hypoxia, thereby exacerbating tubu-lar injury and protracting the course of ARF.

which directly reduce GFR. Tubular injury reducesGFR by causing tubular obstruction and by allow-ing backleak of glomerular filtrate. Abnormalities intubular reabsorption of solute may contribute tointrarenal vasoconstriction by activating the tubu-loglomerular (TG) feedback system. GPF—glomeru-lar plasmaflow; P—glomerular pressure; Kf—glomerular ultrafiltration coefficient.

14.3Pathophysiology of Ischemic Acute Renal Failure

Mesangial cell contractionAngiotensin IIEndothelin–1Thromboxane

Sympathetic nerves

Mesangial cell relaxationProstacyclin

EDNO

Glomerular epithelial cellsM

M

Glomerular capillaryendothelial cells

Glomerular basement membrane

Afferent arteriole

Periportalcell

Macula densacells

Extraglomerularmesangial cells

Glomerus

A

EA

D

AA

PPC

EMC GMCG

MD

ChlorideAdenosinePGE2AngiotensinNitric oxideOsmolarityUnknown?

EA

AA

SMC+GC

PPC

EMC GMCG

MD

C

EA

B

AA

PPC

EMC GMCG

MD

FIGURE 14-3

The mesangium regulates single-nephron glomerular filtration rate(SNGFR) by altering the glomerular ultrafiltration coefficient (Kf).This schematic diagram demonstrates the anatomic relationshipbetween glomerular capillary loops and the mesangium. Themesangium is surrounded by capillary loops. Mesangial cells (M)are specialized pericytes with contractile elements that can respondto vasoactive hormones. Contraction of mesangium can close andprevent perfusion of anatomically associated glomerular capillaryloops. This decreases the surface area available for glomerular fil-tration and reduces the glomerular ultrafiltration coefficient.

FIGURE 14-4

A, The topography of juxtaglomerular apparatus (JGA), includingmacula densa cells (MD), extraglomerular mesangial cells (EMC),and afferent arteriolar smooth muscle cells (SMC). Insets schemati-cally illustrate, B, the structure of JGA; C, the flow of informationwithin the JGA; and D, the putative messengers of tubuloglomeru-lar feedback responses. AA—afferent arteriole; PPC—peripolar cell;EA—efferent arteriole; GMC—glomerular mesangial cells.(Modified from Goligorsky et al. [1]; with permission.)