Natriuretic peptides and acute renal failure
David L. Vesely
Departments of Medicine, Physiology, and Biophysics, University of South
Florida Cardiac Hormone Center, and James A. Haley Veterans Medical Center,
Tampa, Florida 33612
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ABSTRACT
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Atrial natriuretic peptides (ANPs) are a family of peptide hormones, e.g.,
ANP, long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide
synthesized by the ANP gene. Brain natriuretic peptide (BNP) and C-type
natriuretic peptide are also members of this family but are synthesized by
separate genes. Within the kidney, the ANP prohormone's posttranslational
processing is different from that of other tissues, resulting in an additional
four amino acids added to the NH2 terminus of ANP (e.g.,
urodilatin). Each of these natriuretic and diuretic peptides increases within
the circulation with acute renal failure (ARF). Renal transplantation but not
hemodialysis returns their circulating concentrations to those of healthy
individuals. BNP and adrenomedullin, a 52-amino acid natriuretic peptide, have
beneficial effects on glomerular hypertrophy and glomerular injury but do not
improve tubular injury (i.e., acute tubular necrosis). Vessel dilator
ameliorates acute tubular necrosis with regeneration of the brush borders of
proximal tubules. Vessel dilator decreases mortality in ARF from 88 to 14% at
day 6 of ARF, even when given 2 days after renal failure has been
established.
adrenomedullin; atrial natriuretic peptide prohormone; acute tubular necrosis; transplantation; hemodialysis
ACUTE RENAL FAILURE (ARF) develops in 25% of all patients
sent to tertiary-care hospitals
(125). In 60% of patients,
the underlying cause is a renal insult [i.e., acute tubular necrosis (ATN)]
(39,
125). In the mid-1940s, when
dialysis was introduced, the mortality from severe ARF was
50%
(39). This poor prognosis has
not improved, and mortality now remains in the 4080% range in oliguiric
ARF patients (4,
9,
22,
38,
39,
90,
125). The occurrence of ARF
in the hospital increases the relative risk of dying by 6.2-fold and the
length of hospitalization by 10 days
(77). Thus ARF not only occurs
with a high frequency but is also associated with high morbidity and
mortality.
The present review will concentrate on the atrial natriuretic peptides
(ANPs), adrenomedullin (ADM), and urodilatin, their pathophysiological changes
with ARF, and their potential for the treatment of ARF. There are several
excellent reviews on the biochemistry and molecular biology
(28,
32,
56,
69,
73,
83,
106) and the physiology
(7,
10,
36,
43,
54,
84,
86,
105,
119) of these natriuretic
peptides so these aspects will not be reviewed in detail in the present
review.
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ANPs
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ANPs consist of a family of peptides that are synthesized by three
different genes (28,
32,
56,
73,
83) and then stored as three
different prohormones [i.e., 126-amino acid (aa) ANP, 108-aa brain natriuretic
peptide (BNP), and 126-aa C-type natriuretic peptide (CNP) prohormones]
(56,
104). In healthy adults, the
ANP prohormone's main site of synthesis is the atrial myocyte, but it is also
synthesized in a variety of other tissues, including the kidney
(31,
116). The sites of synthesis
of the ANPs in the approximate order in which they contribute to the synthesis
are listed in Table 1.
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Table 1. Site(s) of synthesis, molecular weight, and hemodynamic and natriuretic
properties of natriuretic peptides
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Peptide Hormones Originating From the ANP Prohormone
Within the 126-aa ANP prohormone are four peptide hormones
(Fig. 1), with blood
pressure-lowering, natriuretic, diuretic, and/or kaliuretic (i.e.,
potassium-excreting) properties in both animals
(8,
25,
26,
35,
37,
61,
113,
118,
127) and humans
(109112).
These peptide hormones, numbered by their aa sequences beginning at the
NH2-terminal end of the ANP prohormone, consist of the first 30 aa
of the prohormone [i.e., proANP-(130); long-acting natriuretic peptide
(LANP)], aa 3167 [i.e., proANP-(3167); vessel dilator], aa
7998 [proANP-(7998); kaliuretic peptide], and aa 99126
(ANP) (Fig. 1). Each of these
four peptide hormones circulates in healthy humans, with LANP and vessel
dilator concentrations in plasma being 15- to 20-fold higher than ANP and
100-fold higher than BNP (24,
29,
30,
41,
114,
123). More than one peptide
hormone originating from the same prohormone is common with respect to the
synthesis of hormones (104).
ACTH, for example, is derived from a prohormone that contains four known
peptide hormones (104). The
BNP and CNP genes, on the other hand, appear to each synthesize only one
peptide hormone within their respective prohormones, i.e., BNP and CNP
(7,
28,
32,
54,
55,
73). The natriuretic effects
of LANP, kaliuretic peptide, and vessel dilator have different mechanism(s) of
action from ANP, in that they inhibit renal
Na+-K+-ATPase secondarily to their ability to enhance
the synthesis of prostaglandin E2, which ANP does not do
(18,
35). The effects of ANP, BNP,
and CNP in the kidney are thought to be mediated by cGMP
(10,
36,
84,
104).

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Fig. 1. Structure of the atrial natriuretic peptide prohormone (proANP) gene. Four
peptide hormones [e.g., atrial natriuretic peptide (ANP), long-acting
natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide] are
synthesized by this gene. Each of these peptide hormones has biological
effects, e.g., natriuresis and diuresis, mediated via the kidney
(8,
25,
26,
35,
37,
61,
113,
118,
127). LANH, long-acting
natriuretic hormone (a different nomenclature for LANP); a.a., amino acids.
Reprinted by permission (Pearson Education, Inc., 1992)
(104).
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ANP has been found to be a potent in vivo and in vitro inhibitor of
aldosterone secretion via a direct effect on the adrenal
(5,
14,
17,
23,
33,
51,
59) and indirectly through
inhibition of renin release from the kidney
(14,
53,
59,
103). Kaliuretic peptide and
long-acting natriuretic peptide are also potent inhibitors of the circulating
concentrations of aldosterone in healthy humans
(108). Kaliuretic peptide and
LANP effects on decreasing plasma aldosterone levels last for at least 3 h
after their infusions have stopped, whereas ANP no longer has any effect on
plasma aldosterone concentrations within 30 min of cessation of its infusion
(108). Vessel dilator does
not appear to have direct effects on aldosterone synthesis but is a potent
inhibitor (66%) of plasma renin activity
(117). The site of synthesis,
molecular weight, and hemodynamic effects of each of the natriuretic peptides
in humans is summarized in Table
1. ANP, LANP, and vessel dilator cause a significant diuresis and
natriuresis in healthy humans
(112). Kaliuretic peptide
does not cause a significant natriuresis in healthy humans, but when infused
in humans with congestive heart failure it causes a significant natriuresis
(70).
Urodilatin. ANP prohormone posttranslational processing is
different within the kidney from that which occurs in the heart, resulting in
an additional four amino acids added to the NH2 terminus of ANP
[i.e., proANP-(95126); urodilatin]
(56,
69,
93)
(Fig. 2). The rest of the amino
acids in urodilatin are identical and in the same sequence as those in ANP
(Fig. 2). Urodilatin and ANP
have identical ring structures formed with cysteine-to-cysteine bonding
(Fig. 2). Urodilatin is not
formed in the heart or in other tissues except the kidney. This peptide
hormone is synthesized by the same gene that synthesizes ANP, but in the
kidney, as opposed to all other tissues that have been investigated, the ANP
prohormone is processed differently, resulting in the formation of urodilatin
rather than ANP (56,
69,
93). Urodilatin circulates in
very low concentrations (i.e., 912 pg/ml)
(115). Infusion of ANP
increases the circulating concentration of urodilatin, suggesting that some of
ANP's effects may be mediated by urodilatin
(115). Infusion of LANP,
vessel dilator, and kaliuretic peptide, on the other hand, do not affect the
circulating concentration of urodilatin in healthy humans
(115).

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Fig. 2. Amino acid sequences of the natriuretic peptides. Each of the sequences are
the human sequences except for Dendroaspis natriuretic peptide (DNP),
whose sequence is only known in the snake. The brackets illustrate the
location of cystine bridges that help to form a ring structure in a number of
these peptides. BNP, brain natriuretic peptide; CNP, C-type natriuretic
peptide.
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BNP and CNP
BNP. BNP has similar diuretic and natriuretic effects and a short
half-life as ANP (98). BNP's
half-life is 100-fold shorter than the half-lives of vessel dilator and LANP
(1,
54,
98,
99,
104). BNP has remarkable
sequence homology to ANP, with only four amino acids being different in the
17-aa ring structure common to both peptides
(Fig. 2)
(54,
55,
73,
83,
84,
98). Although BNP was named
(98) for where it was first
isolated (i.e., porcine brain), the main source of its synthesis and secretion
is the heart (Table 1)
(36,
54,
56,
84,
101). As with ANP, the
highest levels of BNP are found in the atria of the heart
(36,
101). BNP levels in the
atria, however, are <1% of ANP levels
(101). The immunoreactive
level of BNP within the ventricles is only 1% of BNP's concentration within
the atria (101). BNP,
however, has been termed a "ventricular" peptide based on
ventricular BNP mRNA levels being similar to those in the atria, and the
ventricles are much larger than the atria
(69).
The 108-aa BNP prohormone is processed within the heart to yield a
biologically functioning BNP consisting of aa 77108 of the BNP
prohormone and the NH2 terminus of the BNP prohormone (aa
176 of prohormone), both of which circulate
(54). The circulating
concentration of BNP is <20% that of ANP
(36). The sequence homology of
BNP differs appreciably across species (both in size and amino acid sequence)
(28,
54,
68,
73,
101). BNP's marked sequence
variability explains, in part, the variations in its biological activity in
different species. The peptide hormones from the ANP prohormone, on the other
hand, have remarkable homology across different species
(28,
32,
73,
104). Mice overexpressing the
BNP gene, where the circulating concentration of BNP is 10- to 100-fold higher
than in healthy mice, have less glomerular hypertrophy and mesangial expansion
with intraglomerular cells than healthy mice 16 wk after both received renal
ablation (45). This mouse
model of subtotal renal ablation, however, also has significantly increased
ANP concentrations (74,
102,
128), which may also have
contributed to the effects attributed to BNP in the BNP gene-overexpressing
mice (45).
CNP. CNP has remarkable similarity to ANP in its amino acid
sequence but lacks the COOH-terminal tail of ANP
(Fig. 2)
(6,
7,
99). CNP is present within the
human kidney (62,
100) and has been found to
have little effect on renal vasoconstriction
(126). Although CNP has been
reported to have natriuretic effects in some animals, when infused in humans
at physiological concentrations and in concentrations that reached 4- to
10-fold above those observed in disease states, CNP did not affect renal
function (6). Thus in healthy
humans CNP had no effect on renal hemodynamics, systemic hemodynamics,
intrarenal sodium handling, sodium excretion, or plasma levels of renin and
aldosterone (6). In another
study of infusion of CNP in healthy humans, CNP increased 60-fold in plasma
and there were no significant hemodynamic or natriuretic effects
(40). The authors of this
study concluded that it is unlikely that CNP has any endocrine role in
circulatory physiology (40).
There is one study in humans where infusion of CNP to increase CNP plasma
levels 550-fold caused a 1.5-fold increase in urinary volume and sodium
excretion (42). With this very
high plasma concentration of CNP, both ANP and BNP also increased 2.4-fold
(42), which may have been the
cause of the natriuresis and diuresis observed. Each of these studies suggests
that CNP does not contribute physiologically to any natriuresis or diuresis in
humans (6,
40,
42).
ADM
ADM, a 52-aa peptide originally isolated from an extract of a
pheochromocytoma (48), also
has biological properties nearly identical to those of the ANPs
(Table 1)
(43,
48,
86). Infusion of ADM lowers
blood pressure and produces a diuresis and natriuresis
(43,
48,
86). ANP but not LANP, vessel
dilator, or kaliuretic hormone increases the circulating concentration of ADM
three- to fourfold, suggesting that some of the reported effects of ANP may be
mediated via ADM (107).
However, the natriuresis and diuresis secondary to ANP in the above
investigation were much larger than has ever been observed with ADM
(107), suggesting that ADM
does not mediate all of the natriuretic and diuretic effects of ANP. ADM is
not produced in the atrium of the heart and therefore is not one of the ANPs
per se as these peptides were so named because they are synthesized in the
atrium of the heart (Table 1).
ADM is a larger peptide than any of the ANPs, with its main site of synthesis
being in the adrenal, but isolated renal cells also have the ability to
synthesize ADM secondarily to stimulation by vasopressin via V2
receptors (Table 1)
(88). Because vasopressin
[antidiuretic hormone (ADH)] inhibits a diuresis, these findings are opposed
to findings that ADM causes a diuresis
(43,
48,
86).
Dendroaspis Natriuretic Peptide
Dendroaspis natriuretic peptide (DNP) is the newest of the
natriuretic peptides. This peptide was isolated from the venom of the green
mamba, Dendroaspis angusticeps
(94). The venom also contains
several polypeptide toxins that block cholinergenic receptors to cause
paralysis (94). DNP-like
peptide has been reported to be present in human plasma and in heart atria
(91). In plasma, DNP's
concentration is very low, i.e., 6 pg/ml, which is one-half of 1% of the
circulating ANPs (91). This
peptide has a 17-aa disulfide ring structure similar to ANP, BNP, and CNP
(Fig. 2) and causes a
natriuresis and diuresis in dogs
(58). Infusion of DNP does not
cause any significant change in the circulating levels of ANP, BNP, or CNP
(58).
Richards et al. (81) have
questioned whether DNP actually exists in humans and mammals because it has
not been characterized by HPLC linked to immunoassay, followed by purification
and analysis to establish the human amino acid sequence as has been done with
the above natriuretic peptides. The gene for DNP has not been cloned in the
snake or in any mammal as has been done for each of the other natriuretic
peptides (81). Richards et al.
suggest that DNP may be "snake BNP" because BNP varies markedly in
amino acid sequence among species (and the BNP sequence in this snake is
unknown). The peptides from the ANP prohormone are markedly conserved among
species (36,
104), and one would not
suspect that DNP is one of these peptides as their amino acid sequences are
markedly different from DNP. Further experimentation with the above studies
suggested by Richards et al.
(81) should give us more
insight with respect to this interesting peptide.
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IMMUNOCYTOCHEMICAL LOCALIZATION AT ANPs IN THE KIDNEY
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The kidney is a prime target organ (along with vasculature) of the
physiological effects of ANPs
(10,
56,
104). Immunohistochemical
studies have localized ANP, vessel dilator, and LANP to the sub-brush border
of the pars convuluta and pars recta of the proximal tubules of animal
(79) and human
(85) kidneys
(Fig. 3). Immunofluorescent
studies reveal that each of these peptides has a strong inclination for the
perinuclear region in both the proximal and distal tubules
(79,
85). Immunohistochemical
studies localize urodilatin to the distal tubule, with no evidence of
urodilatin in the proximal tubule
(85). ANP mRNA studies have
confirmed that ANP prohormone is synthesized in the kidney
(34,
76,
97,
102). The amount of ANP
prohormone present in the kidney, however, is only one one-ninetieth of that
produced in the atria of the heart
(104). These studies taken
together suggest that because urodilatin
(93) is found mainly in the
distal nephron (82,
85) and because it is part of
the ANP prohormone (104),
synthesis of the ANP prohormone may take place in the distal nephron
(82,
85). The ANP prohormone gene
is present and can be expressed in the kidney
(34,
76,
97,
102). The gene is upregulated
within the kidney in early renal failure in diabetic animals
(34) and in the remnant kidney
of rats with
reduced renal mass
(102).

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Fig. 3. Vessel dilator immunoperoxidase staining in the rat kidney reveals strong
staining of the sub-brush border of proximal convoluted tubules (arrowheads in
A and B), including a proximal tubule (A)
originating directly from the top left portion of the glomerulus. The
interstitial artery (C) had strong proANP-(3167) staining of
the elastica with moderate staining of endothelial cells (arrow) and media
(*). The distal tubules and collecting ducts (arrows in A and
B) had weak staining with no demonstrable staining in some of the
collecting duct cells. Magnification: x940. Reprinted by permission
(Blackwell Publishing, Ltd., 1992)
(79).
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INFLUENCE OF ARF ON THE CIRCULATING CONCENTRATION OF ANPs
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Each of the ANPs from the ANP prohormone
(30,
41,
50,
70,
114,
123,
124), BNP
(13,
16,
21,
54,
55), and CNP
(7,
40,
42) increases in the
circulation in salt- and water-retaining states such as congestive heart
failure and renal failure compared with their concentrations in healthy
individuals. Thus in salt- and water-retaining states there is no decrease in
production of these natriuretic and diuretic peptides, but rather there is
increased production (mainly from the ventricle of the heart)
(32,
76) in an apparent attempt to
overcome the salt and water retention via their natriuretic and diuretic
properties (123). The disease
state associated with the highest circulating concentrations of ANPs is renal
failure (29,
30,
89,
122,
124). One would suspect that
ANPs are higher in renal failure vs. class IV congestive heart failure
patients because of the added pathophysiology of decreased degradation of
these peptides with the decreased functioning of renal parenchyma
(124). However, Franz et al.
(30) have shown that there is
an increased excretion of ANPs in renal failure and that the increase in
vessel dilator excretion occurs even before serum creatinine levels begin to
rise. The circulating concentrations of ANPs in chronic renal failure (CRF)
appear to reflect volume status
(50,
66,
80,
124). Despite increased
circulating ANPs in sodium-retaining disease states, the kidney retains sodium
and is hyporesponsive to ANP, LANP, and BNP
(11,
54,
77,
109). The mechanism for the
attenuated renal response to these natriuretic peptides is multifactoral and
includes renal hypoperfusion and activation of the
renin-angiotensin-aldosterone and sympathetic nervous systems
(10,
36,
65).
Hemodialysis
ANPs. These peptides have been suggested as possible indicators of
when to perform dialysis in persons with CRF
(50,
66,
80,
89,
124). However, other data
suggest that ANPs are not useful in predicting when hemodialysis is necessary
(29). Hemodialysis lowers the
circulating concentration of ANP by 3442%, with the amount of decrease
appearing to be related to the volume status of the patients
(50,
121,
124). Hemodialysis does not
decrease the circulating concentrations of vessel dilator and LANP
(124). Part of the reason for
the difference in the effects of hemodialysis on ANPs is that <1.5% of
vessel dilator and LANP crosses the dialysis membrane compared with
1525% of ANP crossing hemodialysis membranes
(124). Hemodialysis using
cellulose-triacete dialyzers reduces plasma levels of these peptides in ARF
more than hemodialysis therapy with polysulfone dialyzers
(29).
BNP. Hemodialysis has been reported to both lower
(55) and have no effect on
circulating BNP levels (49).
Before dialysis in persons with CRF, plasma BNP levels have no relationship to
serum creatinine or mean blood pressure
(55). In those CRF patients in
whom plasma BNP levels decrease with dialysis, this decrease correlates with
the degree of postural blood pressure drop, but there is no correlation with
the fall in serum creatinine
(55). In none of the studies
of BNP and dialysis (13,
21,
49,
55) has BNP ever returned to
its circulating concentration in healthy individuals. With volume repletion
after hemodialysis, there is an exaggerated release of ANP, but changes in BNP
are small and without any correlation with either atrial or ventricular volume
(21).
Renal Transplantation
Successful transplantation of functioning kidneys decreases the markedly
elevated circulating levels of ANPs in persons with ARF to those in healthy
individuals (75,
78). Nonfunctioning renal
allografts continue to have elevated circulating concentrations of ANPs
(78). Postrenal transplantion,
it takes 7 days for ANP and 10 days for vessel dilator to return to normal
(75). This suggests that the
allograft kidney does not fully function immediately with respect to clearing
these peptides. The half-life of ANP in healthy persons is only 2.53.5
min (1,
104). If the transplanted
kidneys began to function immediately, one would have expected the circulating
concentration of ANP to have decreased to the normal range within 24 h (i.e.,
360 half-lives). Vessel dilator has a 20-fold longer half-life compared with
that of ANP (1,
104), which may explain why
it takes 3 more days for this peptide hormone to normalize in the circulation
after successful renal transplantation. If one gives ANP (via infusion) at the
time of renal transplantion, this does not appear to have any beneficial
effect on the outcome of the renal allograft
(87).
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PROTECTIVE AND THERAPEUTIC EFFECTS OF ANPs IN ARF
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ANP and Urodilatin
Several of the atrial peptides have been investigated as possible
treatment(s) of ARF. ANP had encouraging results in early studies of ARF in
animals (20,
57). The infusion of ANP
(20,
57,
60,
66,
68,
71,
74,
77,
90,
95) or urodilatin
(63,
92,
96) in rat models of ischemic
ARF attenuated renal tissue damage and preserved glomerular filtration rate
(GFR). Nakamoto et al. (68)
and Shaw et al. (95) were able
to shorten the course of renal artery cross-clamping-induced ARF in rats with
ANP. Conger et al. (20) found
a marked improvement in GFR in a rat renal artery clamp model when ANP-III
(0.2
µg·kg1·min1)
was given intravenously immediately after clamp release in combination with
dopamine sufficient to maintain mean arterial pressure above 100 mmHg. In the
rat, ANP had no effect on GFR when given intravenously
(56) but did have an effect on
GFR when given directly into the renal artery for 4 h
(95). The inability of ANP to
increase GFR when given intravenously could be restored if dopamine were given
simultaneously (20). In the
dog, the improvement in renal perfusion only lasted for a short period after a
180-min infusion of ANP (71).
When ANP was given by intra-arotic bolus on days 1 and 2
after the above-mentioned infusion, there was not any significant improvement
in renal perfusion on those days
(71). Thus in animals the
improvement in renal failure with ANP was only of short duration and depended
on whether ANP was given intravenously or directly into the artery
(20,
56,
71).
The administration of 0.2 µg of ANP·kg body
wt1·min1 for
24 h to humans with ARF revealed that ANP did not cause significant
improvement and did not reduce the need for dialysis or reduce mortality
(3). ANP infusions were
associated with decreased survival in the nonoliguric ARF subjects, who
represented 75% of the subjects
(3). The usefulness of ANP for
treatment is hampered by its short half-life of 2.5 min
(1,
104) and by its very short
duration of action (20,
57,
59,
61,
77,
112). Of 504 ARF patients
treated with ANP, 46% developed hypotension, which would further limit its
usefulness in ARF (3). Use of
several of the ANPs investigated to treat ARF has each resulted in severe
hypotension and bradycardia (3,
47). In addition to ANP
resulting in 46% of renal failure patients becoming hypotensive
(3), urodilatin has also been
associated with severe hypotension and bradycardia, when given as a potential
treatment of congestive heart failure
(47). ANP is now considered
more harmful than helpful with respect to the treatment of ARF
(11). ANP has also been
investigated in humans with CRF to determine whether it could prevent
radiocontrast-induced nephropathy, one cause of hospital-acquired ARF
(52). When ANP was given
before and during a radiocontrast study in 247 patients, no beneficial effect
was found (52). Urodilatin has
been suggested as a possible treatment of renal failure
(63,
92,
96), but in double-blind
trials in ARF patients urodilatin was found to have no beneficial effect
(63).
Vessel Dilator
Vessel dilator appears to be one of the ANPs with promising therapeutic
potential in the treatment of ARF. Vessel dilator (0.3
µg·kg1·min1
via ip pump) decreases blood urea nitrogen and serum creatinine from 162
± 4 and 8.17 ± 0.5 mg/dl, respectively, to 53 ± 17 and
0.98 ± 0.12 mg/dl in ARF animals in which ARF was established for 2
days (after vascular clamping) before vessel dilator was given
(19). At day 6 of
ARF, mortality decreased to 14% with vessel dilator from 88% without vessel
dilator (19). The ARF animals
that did not receive vessel dilator had moderate (i.e., 2575% of all
tubules involved) to severe (i.e., >75% of all tubules necrotic) ATN by
day 8 after the ischemic event
(Fig. 4B). As shown in
Fig. 4B, the tubules
of the animals were almost completely destroyed. The destruction of the
tubules included both the proximal and distal tubules, with the proximal
tubules being more severely affected (Fig.
4B). The glomerulus of the ARF animals was spared
compared with the renal tubules, with the glomerulus appearing to be normal in
the ARF animals (Fig. 4, A and
B).

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Fig. 4. Renal histology of a normal Sprague-Dawley rat (A) with intact
proximal tubular brush border (arrowhead). B: acute renal failure
(ARF) rat at day 8 with marked tubular necrosis (open triangle) and
without intact brush border present (>75% of tubules are necrotic). The
glomerulus (x) appears to be normal. C: ARF rat treated with vessel
dilator from days 25 of ARF with kidney examined after day
8 of ARF reveals brush border to be present in proximal tubule
(arrowhead). No tubules are necrotic in this ARF animal treated with vessel
dilator. The glomerulus (x) is intact. Magnification of hematoxylin and eosin:
x426 (A and C) and x320 (B). Reprinted
from Ref. 19.
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The addition of vessel dilator after renal failure had been present for 2
days resulted in a marked improvement in renal histology, with scores ranging
from 0 (i.e., no tubular necrosis) to 1+ (i.e., <5% of the tubules
involved) (19). When the
kidneys were examined at day 8 of renal failure, the brush borders of
the proximal tubules in the ARF animals treated with vessel dilator were
present (Fig. 4C),
which was similar with respect to the proximal tubules in healthy animals
(Fig. 4A). In the ARF
animals not treated with vessel dilator, the brush borders of the tubules were
destroyed (Fig. 4B).
The glomeruli of vessel dilator-treated ARF animals also appeared normal
(Fig. 4C). It should
be pointed out that the animals treated with vessel dilator did have severe
renal failure before vessel dilator was begun on the second day of renal
failure (19). It is also
important to note that the animals treated with vessel dilator that had a
significant increase in survival had nonoliguric renal failure
(19). As noted above,
nonoliguric renal failure subjects treated with ANP had a decreased survival
rate, and it was nonoliguric renal failure subjects who did not respond to ANP
(3). Vessel dilator, LANP, and
kaliuretic peptide, as opposed to ANP, BNP, and urodilatin, have never caused
a hypotensive episode when given to either healthy animals or humans
(61,
111,
112) or when given to humans
with sodium and water retention
(70,
109,
110).
The ability of vessel dilator to reverse ischemic ARF is consistent with
the important concept, based on experiments at the cellular level and in
humans with ATN, that the pathophysiology of ischemic ARF is due to a
sublethal and reversible injury to renal tubular cells
(9,
64). This reversible injury is
now thought to contribute more predominately to renal tubular dysfunction than
permanent tubular cell necrosis
(9,
64). Pathological similarities
between humans and rats with ischemic ATN are that the injury is to the
proximal brush border, with a predilection for the most severe injury to occur
in the proximal straight (S3 segments) tubules
(64). As outlined above, it
was the proximal tubule brush borders that were mainly regenerated by vessel
dilator even when given 2 days after ischemic ATN
(19). Part of the improvement
by using vessel dilator may be due to its ability to cause intrarenal
vasodilation because it is a strong vasodilator
(113). The reason vessel
dilator has greater benefical effects than ANP, BNP, CNP, and urodilatin in
ARF appears due, at least in part, to its ability to cause the endogenous
synthesis of renoprotective PGE2, which ANP, BNP, CNP, and
urodilatin do not have (18,
35).
Prostaglandins have renoprotective effects in ARF
(2,
46,
121). An indication that
PGE2 is renoprotective (by maintaining glomerular hemodynamics) is
the observation that cyclooxygenase inhibitors in congestive heart failure and
volume depletion states augment the reduction in renal blood flow and GFR
(27,
120). With respect to the
mechanism of the protective effects of prostaglandins in ARF, after ischemic
injury there is a dramatic decrease in perfusion in the outer medulla
(44), a region of renal tissue
that normally operates "on the verge of ischemia"
(12). Prostaglandins have a
favorable effect on blood flow distribution to this region
(67). In addition,
prostaglandins have distinct cytoprotective effects and improve microvascular
permeability in ischemic ARF
(15,
46). Prostaglandins are not
stored in the kidney but rather have to be synthesized acutely secondarily to
a stimulating agent such as vessel dilator
(18,
35) for prostaglandins to have
a positive beneficial effect in renal failure.
ADM
There is evidence that ADM is renoprotective in Dahl salt-sensitive rats in
that when they were perfused for 7 days, their glomerular injury score was 54%
less (P < 0.05) than in untreated Dahl salt-sensitive rats
(72). The ADM-treated
salt-sensitive rats, however, had considerably more (P < 0.01)
glomerular sclerosis and anteriolar sclerosis and atrophic tubules after
treatment than the control Dahl salt-resistant rats
(72).
CNP
CNP increases in the circulation in ARF
(42), but its effects in ARF
are unknown. As above, CNP has no natriuretic effects in healthy humans
(6,
40,
42).
DNP
DNP has been evaluated in persons with end-stage renal disease on dialysis
and was found not to correlate (P = 0.62) with the echocardiographic
left ventricular mass index, whereas ANP and BNP did correlate with the left
ventricular mass index of these end-stage renal patients
(16). DNP has not been
investigated with respect to its possible therapeutic effects in renal
failure.
 |
SUMMARY AND FUTURE DIRECTIONS
|
---|
ANPs are both synthesized
(34,
76,
102), and have some of their
most potent biological effects, e.g., natriuresis and diuresis, within the
kidney (8,
25,
26,
35,
37,
61,
118,
127). Vessel dilator, via its
ability to ameliorate ARF and enhance tubule regeneration in ATN
(19), may prove useful in the
future in the treatment of ARF. BNP and ADM, with their effects in glomerular
hypertrophy (45) and
glomerular injury (72),
respectively, may be useful in the treatment of renal glomerular diseases.
Because BNP, ANP, and ADM do not appear to help tubular diseases such as ATN,
the major cause of ARF (39,
125), their therapeutic
potential in ATN appears limited. Future studies with these peptide hormones
in humans with ARF and/or glomerular diseases are necessary to determine
whether the findings in animal models of ARF are applicable to the treatment
of humans with ARF.
 |
DISCLOSURES
|
---|
This work was supported in part by grants from the National Institutes of
Health, a Merit Award from the U.S. Department of Veteran Affairs, and a
Grant-in-Aid from the American Heart Association, Florida-Puerto Rico
Affiliate.
 |
ACKNOWLEDGMENTS
|
---|
The author thanks Charlene Pennington for secretarial assistance and the
numerous coinvestigators without whom all of the investigations reported
herein could not have been completed.
 |
FOOTNOTES
|
---|
Address for reprint requests and other correspondence: D. L. Vesely, USF
Cardiac Hormone Ctr., 13000 Bruce B. Downs Blvd., Tampa, FL 33612 (E-mail:
david.vesely{at}med.va.gov).
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to
indicate this fact.
 |
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