Michael S Goligorsky Wilfred Lieberthal

Kidney Function Restoration Program

Curing Kidney Disease Forever

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Acute renal failure (ARF) is a syndrome characterized by an abrupt and reversible kidney dysfunction. The spectrum of inciting factors is broad: from ischemic and nephrotoxic agents to a variety of endotoxemic states and syndrome of multiple organ failure. The pathophysiology of ARF includes vascular, glomerular and tubular dysfunction which, depending on the actual offending stimulus, vary in the severity and time of appearance. Hemodynamic compromise prevails in cases when noxious stimuli are related to hypotension and septicemia, leading to renal hypoperfusion with secondary tubular changes (described in Chapter 13). Nephrotoxic offenders usually result in primary tubular epithelial cell injury, though endothelial cell dysfunction can also occur, leading to the eventual cessation of glomerular filtration. This latter effect is a consequence of the combined action of tubular obstruction and activation of tubuloglomerular feedback mechanism. In the following pages we shall review the existing concepts on the phenomenology of ARF including the mechanisms of decreased renal perfusion and failure of glomerular filtration, vasoconstriction of renal arterioles, how formed elements gain access to the renal parenchyma, and what the sequelae are of such an invasion by primed leukocytes.

FIGURE 14-1

Pathophysiology of ischemic and toxic acute renal failure (ARF). The severe reduction in glomerular filtration rate (GFR) associated with established ischemic or toxic renal injury is due to the combined effects of alterations in intrarenal hemody-namics and tubular injury. The hemodynamic alterations associated with ARF include afferent arterio-lar constriction and mesangial contraction, both of which directly reduce GFR. Tubular injury reduces GFR by causing tubular obstruction and by allowing backleak of glomerular filtrate. Abnormalities in tubular reabsorption of solute may contribute to intrarenal vasoconstriction by activating the tubu-loglomerular (TG) feedback system. GPF—glomerular plasmaflow; P—glomerular pressure; Kf— glomerular ultrafiltration coefficient.

Angiotensin II Endothelin Thromboxane Adenosine Leukotrienes Platelet-activating factor

Angiotensin II Endothelin Thromboxane Adenosine Leukotrienes Platelet-activating factor

Ischemic or toxic injury to the kidney

Imbalance in vasoactive hormones causing persistent intrarenal vasoconstriction

Persistent medullary hypoxia

FIGURE 14-2

Vasoactive hormones that may be responsible for the hemodynamic abnormalities in acute tubule necrosis (ATN). A persistent reduction in renal blood flow has been demonstrated in both animal models of acute renal failure (ARF) and in humans with ATN. The mechanisms responsible for the hemodynamic alterations in ARF involve an increase in the intrarenal activity of vasoconstrictors and a deficiency of important vasodilators. A number 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 some extent 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 renal hypoperfusion associated with ARF. This imbalance in intrarenal vasoactive hormones favoring vasoconstriction causes persistent intrarenal hypoxia, thereby exacerbating tubular injury and protracting the course of ARF.

Glomerular basement membrane

Glomerular capillary endothelial cells

Glomerular epithelial cells

Mesangial cell contraction Angiotensin II Endothelin-1 Thromboxane Sympathetic nerves

Mesangial cell contraction Angiotensin II Endothelin-1 Thromboxane Sympathetic nerves

Glomerular basement membrane

Glomerular capillary endothelial cells

Glomerular epithelial cells

Mesangial cell relaxation Prostacyclin EDNO

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 relationship between glomerular capillary loops and the mesangium. The mesangium is surrounded by capillary loops. Mesangial cells (M) are specialized pericytes with contractile elements that can respond to vasoactive hormones. Contraction of mesangium can close and prevent perfusion of anatomically associated glomerular capillary loops. This decreases the surface area available for glomerular filtration and reduces the glomerular ultrafiltration coefficient.

FIGURE 14-4

A, The topography of juxtaglomerular apparatus (JGA), including macula densa cells (MD), extraglomerular mesangial cells (EMC), and afferent arteriolar smooth muscle cells (SMC). Insets schematically illustrate, B, the structure of JGA; C, the flow of information within 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.)

The normal tubuloglomerular (TG) feedback mechanism

3. Renin is released from specialized cells of JGA and the intrarenal renin angiotensin system generates release of angiotensin II locally.

2. The composition of filtrate passing the macula densa is altered and stimulates the JGA.

3. Renin is released from specialized cells of JGA and the intrarenal renin angiotensin system generates release of angiotensin II locally.

1. SNGFR increases

causing increase

in delivery of solute

to the distal nephron.

2. The composition of filtrate passing the macula densa is altered and stimulates the JGA.

Role of TG feedback in ARF

Role of TG feedback in ARF

FIGURE 14-5

The tubuloglomerular (TG) feedback mechanism. A, Normal TG feedback. In the normal kidney, the TG feedback mechanism is a sensitive device for the regulation of the single nephron glomerular filtration rate (SNGFR). Step 1: An increase in SNGFR increases the amount of sodium chloride (NaCl) delivered to the juxtaglomerular apparatus (JGA) of the nephron. Step 2: The resultant change in the composition of the filtrate is sensed by the macula densa cells and initiates activation of the JGA. Step 3: The JGA releases renin, which results in the local and systemic generation of angiotensin II. Step 4: Angiotensin II induces vasocontriction of the glomerular arterioles and contraction of the mesangial cells. These events return SNGFR back toward basal levels. B, TG feedback in ARF. Step 1: Ischemic or toxic injury to renal tubules leads to impaired reabsorption of NaCl by injured tubular segments proximal to the JGA. Step 2: The composition of the filtrate passing the macula densa is altered and activates the JGA. Step 3: Angiotensin II is released locally. Step 4: SNGFR is reduced below normal levels. It is likely that vasoconstrictors other than angiotensin II, as well as vasodilator hormones (such as PGI2 and nitric oxide) are also involved in modulating TG feedback. Abnormalities in these vasoactive hormones in ARF may contribute to alterations in TG feedback in ARF.

Osswald's Hypothesis

Osswald's Hypothesis

Nerve endings

FIGURE 14-6

Metabolic basis for the adenosine hypothesis. A, Osswald's hypothesis on the role of adenosine in tubuloglomerular feedback. B, Adenosine metabolism: production and disposal via the salvage and degradation pathways. (A, Modified from Osswald et al. [2]; with permission.)

Adenosine nucleotide metabolism

Adenosine nucleotide metabolism

^ Transporter

Phosphorylation or degradation

ATP AMP

Adenosine juj^ Inosine~jzz^>

Degradation pathway

Hypo-xanthine

^ Transporter

Phosphorylation or degradation

ATP AMP

Adenosine juj^ Inosine~jzz^>

Salvage pathway

Degradation pathway

Hypo-xanthine

Uri ic acid

Xanthine

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I I I I I I I I I I I I I I I I I I 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Volume collected, mL

Elevated concentration of adenosine, inosine, and hypoxanthine in the dog kidney and urine after renal artery occlusion. (Modified from Miller et al. [3]; with permission.)

FIGURE 14-8

Endothelin (ET) is a potent renal vasoconstrictor. Endothelin (ET) is a 21 amino acid peptide of which three isoforms—ET-1, ET-2 and ET-3—have been described, all of which have been shown to be present in renal tissue. However, only the effects of ET-1 on the kidney have been clearly elucidated. ET-1 is the most potent vasoconstrictor known. Infusion of ET-1 into the kidney induces profound and long lasting vasoconstriction of the renal circulation. A, The appearance of the rat kidney during the infusion of ET-1 into the inferior branch of the main renal artery. The lower pole of the kidney perfused by this vessel is profoundly vasoconstricted and hypoperfused. B, Schematic illustration of function in separate populations of glomeruli within the same kidney. The entire kidney underwent 25 minutes of ischemia 48 hours before micropuncture. Glomeruli I are nephrons not exposed to endothelin antibody; Glomeruli II are nephrons that received infusion with antibody through the inferior branch of the main renal artery. SNGFR—sin-gle nephron glomerular filtration rate; PFR—glomerular renal plasma flow rate. (From Kon et al. [4]; with permission.)

Pre-proendothelin-1

Pre-proendothelin-1

FIGURE 14-9

Biosynthesis of mature endothelin-1 (ET-1). The mature ET-1 peptide is produced by a series of biochemical steps. The precursor of active ET is pre-pro ET, which is cleaved by dibasic pair-specific endopeptidases and carboxypeptidases to yield a 39-amino acid intermediate termed big ET-1. Big ET-1, which has little vasoconstrictor activity, is then converted to the mature 21-amino acid ET by a specific endopeptidase, the endothelin-converting enzyme (ECE). ECE is localized to the plasma membrane of endothelial cells. The arrows indicate sites of cleavage of pre-pro ET and big ET.

Plasma

Mature ET

Endothelium

Mature ET

Vascular smooth muscle

Mature ET

Endothelium

Mature ET

Vasoconstriction

Vasodilation

Vasoconstriction

Vasodilation

FIGURE 14-10

Regulation of endothelin (ET) action; the role of the ET receptors. Pre-pro ET is produced and converted to big ET. Big ET is converted to mature, active ET by endothe-lin-converting enzyme (ECE) present on the endothelial cell membrane. Mature ET secreted onto the basolateral aspect of the endothelial cell binds to two ET receptors (ETa and ETb); both are present on vascular smooth muscle (VSM) cells. Interaction of ET with predominantly expressed ETa receptors on VSM cells induces vasoconstriction. ETB receptors are predominantly located on the plasma membrane of endothelial cells. Interaction of ET-1 with these endothelial ETB receptors stimulates production of nitric oxide (NO) and prosta-cyclin by endothelial cells. The production of these two vasodilators serves to counterbalance the intense vasoconstrictor activity of ET-1. PGI2—prostaglandin I2.

10-

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8-

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6-

b

m

4-

N

2-

0

150—

120—

id

90-

GF

60

30-

Basal 24h control

Ischemia e

Basal 24h control

Ischemia e

Basal 24h control

Posttreatment days

Endothelin-1 (ET-1) receptor blockade ameliorates severe ischemic acute renal failure (ARF) in rats. The effect of an ETA receptor antagonist (BQ123) on the course of severe postischemic ARF was examined in rats. BQ123 (light bars) or its vehicle (dark bars) was administered 24 hours after the ischemic insult and the rats were followed for 14 days. A, Survival. All rats that received the vehicle were dead by the 3rd day after ischemic injury. In contrast, all rats that received BQ123 post-ischemia survived for 4 days and 75% recovered fully. B, Glomerular filtration rate (GFR). In both groups of rats GFR was extremely low (2% of basal levels) 24 hours after ischemia. In BQ123-treated rats there was a gradual increase in GFR that reached control levels by the 14th day after ischemia. C, Serum potassium. Serum potassium increased in both groups but reached significantly higher levels in vehicle-treated compared to the BQ123-treated rats by the second day. The severe hyperkalemia likely contributed to the subsequent death of the vehicle treated rats. In BQ123-treated animals the potassium fell progressively after the second day and reached normal levels by the fourth day after ischemia. (Adapted from Gellai et al. [5]; with permission.)

NSAID

PGF,

Lipid Membrane

Lipid Membrane

Arachidonic acid

Phospholipase A2

Arachidonic acid

PGF,

Cycloxygenase

Prostaglandin intermediates

Thromboxane

JxA,

PGE,

Production of prostaglandins. Arachidonic acid is released from the plasma membrane by phospholipase A2. The enzyme cycloxygenase catalyses the conversion of arachidonate to two prostanoid intermediates (PGH2 and PGG2). These are converted by specific enzymes into a number of different prostanoids as well as thromboxane (TXA2). The predominant prostaglandin produced varies with the cell type. In endothelial cells prostacyclin (PGI2) (in the circle) is the major metabolite of cycloxygenase activity. Prostacyclin, a potent vasodilator, is involved in the regulation of vascular tone. TXA2 is not produced in endothelial cells of normal kidneys but may be produced in increased amounts and contribute to the pathophysiology of some forms of acute renal failure (eg, cyclosporine A-induced nephrotoxicity). The production of all prostanoids and TXA2 is blocked by nonsteroidal anti-inflammatory agents (NSAIDs), which inhibit cycloxygenase activity.

FIGURE 14-13

Endothelin (ET) receptor blockade ameliorates acute cyclosporine-induced nephrotoxicity. Cyclosporine A (CSA) was administered intravenously to rats. Then, an ET receptor anatgonist was infused directly into the right renal artery. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were reduced by the CSA in the left kidney. The ET receptor antagonist protected GFR and RPF from the effects of CSA on the right side. Thus, ET contributes to the intrarenal vasoconstriction and reduction in GFR associated with acute CSA nephrotoxicity. (From Fogo et al. [6]; with permission.)

Normal basal state

Circulating levels of vasoconstrictors: Low

Afferent arteriolar tone normal

Intrarenal levels of prostacyclin: Low

Afferent arteriolar tone normal

Intraglomerular A P normal

GFR normal

Intraglomerular A P normal

GFR normal

Intravascular volume depletion

Circulating levels of vasoconstrictors: High

_ Afferent arteriolar tone normal or mildly reduced

Intrarenal levels of prostacyclin: High

Intraglomerular A P normal or mildly reduced

normal or mildly reduced

Intraglomerular A P normal or mildly reduced

normal or mildly reduced

Intravascular volume depletion and NSAID administration

Circulating levels of vasoconstrictors: High

Afferent arteriolar tone severely increased

Intrarenal levels of prostacyclin: Low

Afferent arteriolar tone severely increased

Intraglomerular A P severely reduced

GFR severely reduced

Intraglomerular A P severely reduced

GFR severely reduced

FIGURE 14-14

Prostacyclin is important in maintaining renal blood flow (RBF) and glomerular filtration rate (GFR) in "prerenal" states. A, When intravascular volume is normal, prostacyclin production in the endothelial cells of the kidney is low and prostacyclin plays little or no role in control of vascular tone. B, The reduction in absolute or "effective" arterial blood volume associated with all prerenal states leads to an increase in the circulating levels of a number of of vasoconstrictors, including angiotensin II, catecholamines, and vasopressin. The increase in vasoconstrictors stimulates phospholipase A2 and prostacyclin production in renal endothelial cells. This increase in prostacyclin production partially counteracts the effects of the circulating vasoconstrictors and plays a critical role in maintaining normal or nearly normal RBF and GFR in prerenal states. C, The effect of cycloxygenase inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) in pre-renal states. Inhibition of prostacyclin production in the presence of intravascular volume depletion results in unopposed action of prevailing vasoconstrictors and results in severe intrarenal vascasoconstric-tion. NSAIDs can precipitate severe acute renal failure in these situations.

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