Kidney Diseases - VOLUME ONE - Chapter 17

8/14/2019 Kidney Diseases - VOLUME ONE - Chapter 17

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17.3Molecular Responses and Growth Factors

Growth Factors in Acute Renal Failure

GROWTH FACTORSIN ACUTE RENAL FAILURE

EGF

Ischemic and toxic

IGF-I

Ischemic and toxic

Pretreatment and established ARF

HGF

Ischemic and toxic

Established ARF

ARFacute renal failure; EGFepidermal growth factor; HGFhepatocyte growthfactor; IGF-Iinsulin-like growth factor.

FIGURE 17-3

At least three growth factors have now been demonstrated to beuseful as therapeutic agents in animal models of acute renal failure

(ARF). These include epidermal growth factor (EGF), insulin-like

growth factor I (IGF-I) and hepatocyte growth factor (HGF). All

have efficacy in ischemia models and in a variety of toxic models

of ARF. In add ition, both IGF-I and H GF are beneficial when ther-

apy is delayed and ARF is established after a n ischemic insult.

IGF-I has the additional advantage in that it also ameliorates the

course of renal failure when given prophylactically before an acute

ischemic insult.

DCT

CTAL

PCT

OMCD

Prepro-EGFmRNA

MTAL

IMCD

FIGURE 17-4Expression o f messenger RNA (mRN A) for preproepidermal

growth factor (EGF) in kidney. This schematic depicts the localiza-

tion of mRNA for prepro-EGF under basal states in kidney.

Prepro-EGF mRNA is localized to the medullary th ick ascending

limbs (MTAL) and distal convoluted tubules (DCT).

Immunohistochemical studies demonstrate that under basal condi-

tions the peptide is located on the luminal membrane with the

active peptide actually residing within the tubule lumen. It is specu-

lated that, during pathologic states, preformed EGF is either trans-

ported or routed to the basolateral membrane or can enter the

interstitium via backleak. After a toxic or ischemic insult, expres-

sion of EGF is rapidly suppressed and can remain low for a long

time. Likewise, total renal content and renal excretion of EGF

decreases. CTALcortical thick ascending limb; IMCDinner

medullary collecting duct; O MCDouter medullary collectingduct; and PCTproximal convoluted tubule.


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17.6 Acute Renal Failure

DCT

CTAL

PCT

OMCD

IGF-1mRNA

MTAL

IMCD

GLOM

FIGURE 17-8

Expression of mRN A for insulin-like growth factor I (IGF-I).

Under basal conditions, a variety of nephron segments can produce

IGF-I. Glomeruli (GLOM), medullary an d cort ical thick ascending

limbs (MTAL/CTAL), and collecting ducts (O MCD, IMCD) are all

reported to produce IGF-I. Within hours of an acute ischemic renal

insult, the expression of IGF-I decreases; however, 2 to 3 days after

the insult, wh en there is intense regeneration, there is an increase in

the expression of IGF-I in the regenerative cells. In addition,

extratub ule cells, predominantly ma crophages, express IGF-I in the

regenerative period. This suggests that IGF-I works by bo th

autocrine and paracrine mechanisms during the regenerative

process. DCT/PCTdistal/proximal convoluted tubu le.

DCT

CTAL

PCT

OMCD

IGF-receptorbinding

MTAL

IMCD

GLOM

FIGURE 17-9

Receptor binding for insulin-like growth factor I (IGF-I).

IGF-I binding sites are conspicuous throughout the normal

kidney. Binding is higher in the structu res of the inn er medulla

than in the cort ex. After an acute ischemic insult, there is a

marked increase in IGF-I binding throughout the kidney. The

increase appears to be greatest in th e regenerative zones, which

include structures of the cortex and outer medulla. These find-

ings suggest an impor tant trop hic effect of IGF-I in the setting

of acute renal injury. CTAL/MTALcortical/medullary thick

ascending loop; D CT/PCTdistal/proximal convolut ed tub ule;

GLOMglomerulus; OMCD/IMCDouter/inner medullary col-

lecting duct.


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PI3-kinasesignaling

SOS

SOS

Grb2

Grb2

C3G

Phosphotyrosine

dephosphorylation

MEKs

IRS-1/ IRS-2

Crk II

P110

Othersubstrates

Raf-1

ERKs

EGF-R

MBP

TF

Growth,differentiation

Akt

BAD

Cell survival

p85

SHC

Ras

SYP

Geneexpression

IGF-IR

IGF-I

nck

S6-kinase

FIGURE 17-10

Diagram of intr acellular signaling pathways

mediated by the insulin-like growth factor I

(IGF-IR) receptor. IGF-IR when bound to

IGF-I undergoes autophosphorylation on its

tyrosine residues. This enhances its intrinsic

tyrosine kinase activity and phosphorylatesmultiple substrat es, including insulin r ecep-

tor substrate 1 (IRS-1), IRS-2, and Src

homology/collagen (SHC). IRS-1 upon

phosphorylation associates with the p85

subunit of the PI3-kinase (PI3K) and p hos-

phorylates PI3-kinase. PI3K upon phospho-

rylation converts phosphoinositide-3 phos-

phate (PI-3P) into PI-3,4-P2, which in turn

activates a serine-thronine kinase Akt (pro -

tein kinase B). Activated Akt kinase phos-

phorylates the proapoptotic factor Bad on a

serine residue, resulting in its dissociation

from B-cell lymphoma-X (Bcl-XL) . The

released Bcl-XL is then capable of suppr ess-

ing cell death pathways that involve theactivity of apoptosis protease activating fac-

tor (Apaf-1), cytochrome C, a nd caspases.

A number of growth factors, including

platelet-derived growth factor (PDGF) and

IGF 1 pr omotes cell survival. Activation of

the PI3K cascade is one of the mechanisms

by which growth factors mediate cell sur-

vival. Phosphorylated IRS-1 also associates

with growth factor receptor bound protein

2 (Grb2), which bind son of sevenless (Sos)

and activates the ras-raf-mitogen activated

protein (ras/raf-MAP) kinase cascade. SHC

also binds Grb2/Sos and activates the

ras/raf-MAP kinase cascade. Other sub -

strates for IGF-I are phosphotyrosine phos-phatases and SH2 domain containing tyro-

sine phosphatase (Syp). Figure 17 -7 has

details on the other signaling pathways in

this figure. MBPmyelin basic protein;

nckan adaptor protein composed of SH2

and SH3 domains; TFtranscription factor.


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RATIONALE FOR INSULIN-LIKE GROWTHFACTOR I (IGF-I) IN ACUTE RENAL FAILURE

FIGURE 17-19

Reported t herapeutic trials of insulin-like growth factor (IGF-I)in humans. Based on the compelling animal data and the fact

that there are clearly identified disease states involving both

over- and und erexpression o f IGF-I, this is the first grow th fac-

tor that has been used in clinical trials for kidn ey disease. Listed

above are a variety of studies of the effects of IGF-I in humans.

This peptide has n ow b een examined in several pub lished studies

of both acute and chronic renal failure. Additional studies are

currently in pr ogress.

In the area of acute renal failure there are now two reported tri-als of IGF-I. In the initial study IGF-I or p lacebo was adm inistered

to patients undergoing surgery involving the suprarenal aorta or

the renal art eries. This group w as selected as it best simulated the

work that had been reported in animal trials of ischemic acute

renal injury. Fifty-four patients were randomized in a doub le-blind,

placebo-contr olled trial of IGF-I to p revent the acute d ecline in

renal function frequently associated with this type of sur gery. The

primary end-point in this study was the incidence of renal dysfunc-

tion, defined as a reduction of the glomerular filtration rate as

compared with a preoperat ive baseline, at each of three measure-

ments obtained during the 3 postoperative days. Mod ern surgical

techniques have decreased the incidence of acute renal failure to

such a low level, even in this high-risk group, so as to make it

impractical to perform a single center trial with enough power to

obtain differences in clinically importa nt end-points. Thus, thistrial was intended only to offer proof of concept that IGF-I is

useful for pa tients with a cute renal injuries.

*

35

30

25

20

15

10

5

0

Renaldysfunction,%

Placebo IGF-I

Treatment groups

*P


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Growth hormoneresistant short stature

Laron-type dwarfism

Anabolic agent in catabolic statesAIDS(Protein wasting malnutrit ion)

Burns

FIGURE 17-22

Advantages of insulin-like growth factor (IGF-I) in the treatment of

acute renal failure. The limited data obtained to date on the use of

IGF-I for acute renal failure demonstrate that the peptide is well-

tolerated and may be useful in selected patient populations.

Additional human trials are ongoing including use in the settings of

renal transplantation and chronic renal failure.

Corticosteroid therapy

Postoperative state

Insulin-dependent and noninsulin-dependent diabetes mellitus

Acute renal failure

Chronic renal failure

LACK OF EFFECT OF RECOMBINANT

FIGURE 17-23

Limitations in the use of growth factors to treat acute renal failure

(ARF). The disappointing results of several recent clinical trials of

ARF therapy reflect the fact that our understanding of its pathophysi-

ology is still limited. Screening compounds using animal models may

be irrelevant. Most laboratories use relatively young animals, even

though ARF frequently affects older humans, whose organ regenera-

tive capacity may be limited. In addition, our laboratory models are

usually based on a single insult, whereas many of our patients suffer

repeated or multiple insults. Until we gain a better understanding of

the basic pathogenic mechanisms of ARF, studies in human patients

are likely to be frustrating.

Future Directions

HUMAN IGF-I IN PATIENTSWITH ARF*

Mult icenter, double-blind, randomized,placebo-controlled

ARFsecondary tosurgery, trauma,hypertensivenephropathy, sep-sis, or drugs

Treated within thefirst 6 days for 14days

Evaluated renal func-tion and mortality

1 Hour

(6 h)

(6 h)

1 Day

2 Days

5 Days

References

Bardella et al. [5]

Ouellette et al. [6]

Bonventreet al. [7]

Witzgall et al. [8]

Safirstein et al. [9]

Goeset al. [10]

Singh et al. [11]

Soifer et al. [12]

Firth and Ratcliffe [13]

*No difference between the groups were observed in final values or changes in values for glomerular fi lt ration

FIGURE 17-24

A list of genes

whose expr ession

is induced atvarious time points

by ischemic renal

injury. The molecu-

lar response of

the kidney to an

ischemic insult is

complex and is

the subject of

investigations b y

several labo rator ies.

(Continued on

next page)

(Table continued on next page)


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Well-tolerated

Safe in short-term studies

Experience with diseases of

overexpression and under-expression

Did not worsen outcomes

IGF-Iinsulin-like growthfactor.

I N ACUTERENALFAILURE

Lack of basic knowledgeof the pathophysiologyof ARF

No screening system forcompounds to treatARF

Animal models may notbe relevant

Animal studies have notpredicted results inhuman trials

Difficulty of identifyingappropriate target pop-ulations

GROWTH FACTOR LIMITATIONS

FIGURE 17-24 (Continued)

Several genes have already been identified to be

induced or down-regulated after ischemia and reper-

fusion. This table lists genes whose expression is

altered as a result of ischemic injury. It is not clear at

present if the varied expression of t hese genes plays a

role in cell injury, survival, or proliferation.


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Kidney Diseases - VOLUME ONE - Chapter 17

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