Divisions of 1 Developmental Biology and 2 Pathology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039; and 3 Centre for Inflammatory Diseases, Monash Medical Centre, Department of Medicine, Monash University, Clayton 3168, Melbourne, Australia
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ABSTRACT |
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First published August 21, 2001;
00.1152/ajprenal.0002.2001. Crescentic forms of glomerulonephritis
are characterized by the accumulation of fibrin and cells in Bowman's
space and are associated with a rapid loss of renal function.
Accumulation of fibrin in the glomerular tufts is thought to promote
macrophage infiltration and glomerular injury. To directly explore the
role of fibrin(ogen) in the development of crescentic
glomerulonephritis, antiglomerular basement membrane nephritis was
induced in fibrinogen-deficient and control mice. Glomeruli from
control mice developed severe disease including fibrin deposits,
inflammatory cell accumulation, and crescent formation (46.3 ± 7.3% of glomeruli). Fibrinogen-deficient mice developed significantly
milder disease with fewer glomerular crescents (24.0 ± 4.7% of
glomeruli; P < 0.03). Glomerular macrophage accumulation was diminished in fibrinogen-deficient mice (0.9 ± 0.4 macrophages/glomerular cross section) relative to control mice
(3.9 ± 1.4 macrophages/glomerular cross section;
P < 0.03). Finally, renal function as assessed by
serum creatinine was better maintained in fibrinogen-deficient mice.
These results indicate that although fibrin(ogen) is not essential for
the development of glomerular crescents, it contributes significantly
to the pathogenesis of crescentic glomerulonephritis by promoting
glomerular macrophage accumulation and impairing filtration.
knockout; immune-mediated response
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INTRODUCTION |
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CRESCENTIC GLOMERULONEPHRITIS (GN) is usually associated with severe, rapid-onset renal injury and a poor clinical prognosis. Immune-initiated injury within glomerular capillaries and mesangium promotes leukocyte recruitment, inflammatory glomerular injury, local fibrin deposition, increased permeability of the glomerular filtration barrier, and infiltration of inflammatory cells into Bowman's space. The combined impact of macrophage accumulation and epithelial proliferation in Bowman's space results in the formation of cellular crescents.
Crescentic GN has many of the features of a delayed-type hypersensitivity (DTH) response (23) including prominent glomerular fibrin deposition (17) and infiltration of macrophages (2) and CD4+ T cells (29). Studies using animal models have indicated that T cells are essential to the development of crescentic GN (13, 37) with predominantly T helper type 1 (Th1)-biased immune responses resulting in crescent formation (14, 15). This suggests that Th1-directed, cell-mediated effector mechanisms such as DTH in association with coagulation-pathway activation play a central role in the development of crescentic glomerular damage.
Accumulation of glomerular fibrin and upregulation of glomerular procoagulant activity are consistent features of proliferative and crescentic forms of GN (6, 38). Fibrin and/or fibrin degradation products (FDPs) may promote the development of crescentic GN through several mechanisms. First, the deposition of fibrin and/or fibrin-platelet microthrombi within glomerular capillaries may compromise filtration across the glomerular basement membrane (GBM), ultrafiltrate flow through Bowman's space, and glomerular blood flow. Second, fibrin is apparently chemotactic for macrophages in Bowman's space (11) and may provide a supportive matrix for inflammatory and epithelial cell migration and proliferation. Furthermore, FDPs are chemotactic for leukocytes (10, 27, 28) and may also influence macrophage accumulation in the glomerular tuft and Bowman's space. Studies with anticoagulants and fibrinolytic agents including heparin, warfarin, tissue-type plasminogen activator (tPA), and hirudin, have demonstrated that partial inhibition of glomerular fibrin deposition protects against the formation of crescents in experimental animals (3, 7, 40). Finally, fibrin is reported to be an important mediator of injury in cutaneous DTH responses (5) with a direct role in macrophage recruitment (12).
Perhaps the most provocative findings that support a significant role of fibrin in GN are derived from studies of renal disease in mice and rabbits with either genetic or drug-induced deficits in selected hemostatic factors. Elimination of key fibrinolytic system components in mice including plasminogen activator or plasminogen significantly increased glomerular fibrin, periodic acid Shiff (PAS)-positive material, macrophages, and the propensity to form crescents in an anti-GBM-induced model of GN (18). In addition, matrix metalloproteinase-9-deficient mice were recently shown to be more susceptible to anti-GBM GN due to accumulated fibrin in the glomeruli (21). In contrast, diminishing fibrinogen levels in rabbits with a snake venom component, ancrod, were shown to protect renal function, reduce glomerular inflammatory infiltrates into Bowman's space, and decrease crescent formation (22, 32, 34). However, because ancrod results in an incomplete and temporary reduction of circulating fibrinogen (25) and may increase the formation of circulating biologically active FDPs (8), there remains significant uncertainty regarding the importance of fibrin(ogen) in promoting crescentic GN. Recent studies of anti-GBM-induced GN in thrombin receptor [protease activator receptor-1 (PAR-1)]-deficient mice suggest that PAR-1 deficiency may protect against renal inflammation and crescentic GN in a manner that is at least partially independent of fibrin deposition (7).
The availability of fibrinogen-deficient (Fib/
) mice provides the
means to directly evaluate the contribution of fibrin to
immune-associated glomerular injury. Fatal perinatal hemorrhagic events
occur in a fraction of these mice, but mice surviving the neonatal
period generally live as long as littermate control mice (31) with no sign of spontaneous renal pathology.
Furthermore, unlike animals treated with ancrod, these animals have an
absolute and lifelong fibrinogen deficiency. In this report,
anti-GBM-induced GN was compared in Fib
/
and control (Fib+/
) mice
to directly determine whether fibrin(ogen) and/or FDPs are important
determinants of crescentic GN. We report that Fib
/
mice maintained
lower serum creatinine levels and developed significantly less
glomerular macrophages, PAS-positive material, and crescentic lesions
than control mice. However, the absence of fibrin(ogen) did not
completely block the progression of GN, and despite the absence of
fibrin in glomerular tufts and Bowman's space, glomerular crescents
were observed in Fib
/
mice.
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MATERIALS AND METHODS |
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Induction of GN and tissue collection.
Fib/
mice with a C57/BL6-inbred background were generated and
genotyped as previously described (31). Mice were between 8 and 12 wk of age at the initiation of experiments, and all
experiments were performed with female mice. Mice were presensitized
with 2 mg of sheep globulin in 200 µl of Freund's complete adjuvant (Difco Laboratories, Detroit, MI) injected subcutaneously in each flank. Ten days after presensitization, the mice (n = 26 Fib+/
and 20 Fib
/
) were injected with sheep anti-mouse GBM (5 mg iv) prepared as previously described (36). Mice dying
acutely from a shocklike syndrome (equal numbers in each group) were
excluded from the study (death within 2 h of anti-GBM injection, 5 Fib+/
mice and 4 Fib
/
mice; deaths between 1 and 4 days after
injection, 6 Fib+/
mice and 5 Fib
/
mice). Acute deaths from
hypersensitivity reactions are a feature of presensitized mouse models
of anti-GBM GN and are not associated with renal pathology, increased
proteinuria, or serum creatinine levels (unpublished observations).
Mice surviving these early periods were included in the study and
showed no evidence of the histological features of acute tubular
necrosis. Nine days after disease initiation, mice were placed in
metabolic cages to collect urine over a 24-h period. After 10 days,
blood was collected from each mouse via the retro-orbital plexus. Mice
were anesthetized, and one kidney was collected from each mouse for frozen sectioning. The other kidney was fixed in 10% neutral buffered formalin (Sigma Chemical, St. Louis, MO), processed into paraffin, and
embedded for sectioning.
Histological analysis. Paraffin-embedded sections (4 µm) were cut and routinely stained with hematoxylin and eosin, PAS, and silver trichrome (Jones) stains. Glomerular cellularity was assessed by counting cells in at least 20 random equatorial glomerular cross sections (gcs) per animal. The presence of crescents (defined as the presence of three or more cell layers in Bowman's space) was assessed in at least 60 random glomeruli and was expressed as a percentage of all glomeruli counted per animal. PAS-stained sections were scored without knowledge of mouse genotype using a semiquantitative scale according to the content of PAS-positive material [as previously described (18)]. Briefly, glomeruli with no PAS-positive material were scored as 0, up to one-third of the cross-sectional area of the glomerulus that stained positive scored as 1, one-third to two-thirds involvement scored as 2, and greater than two-thirds involvement scored as 3. A minimum of 20 glomeruli were scored per animal.
Immunohistochemical staining for fibrin was performed on paraffin sections with rabbit anti-mouse fibrinogen antisera and detection was achieved with a Vectastain ABC kit and diaminobenzidine (DAB) substrate (Sigma). Macrophages were detected with rat anti-mouse CD11b (M1/70, Pharmingen, San Diego, CA), anti-rat Ig conjugated to horseradish peroxidase, and DAB substrate. Macrophages were quantitated by counting the number of CD11b-positive cells per glomerulus. At least 20 glomeruli per animal were counted. Glomeruli of mice not treated with anti-GBM antibodies rarely contained CD11b-positive cells.Assessment of renal function. Serum creatinine was assessed by the alkaline picric acid method with a creatinine kit (Sigma). Proteinuria was measured using the Bradford assay on urine samples that had been collected over 24 h (4).
Detection of circulating anti-sheep globulin antibodies. Anti-sheep globulin antibodies were measured by ELISA according to a previously published protocol (14). Briefly, 96-well plates were coated with normal sheep globulin (prepared as described in Ref. 36), washed, and blocked with BSA. Plasma samples or known concentrations of mouse anti-sheep IgG (cross reactive with sheep IgG; Pierce, Rockford, IL) were added. Bound Ig was detected with biotinylated rabbit anti-mouse Ig (Vector Laboratories, Burlingame, CA), a Vectastain ABC kit (Vector), and 2,2'-azinobis-(3-ethylbenzthiazoline sulfonic acid) substrate (Boehringer Mannheim, Indianapolis, IN), and plates were read at 405 nm. In addition, IgG subtype analysis was performed by ELISA on anti-sheep-specific Ig from plasma as previously described (19).
Statistics. Results are expressed as means ± SE except where indicated. Data were analyzed by a Mann-Whitney U-test for pairwise comparisons and ANOVA for multiple comparisons.
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RESULTS |
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Fibrinogen is a determinant of kidney disease and survival.
To directly test the prevailing hypothesis that fibrin deposition
within glomeruli is an important factor in the development of
crescentic GN, cohorts of Fib+/ and Fib
/
mice were immunized with
sheep globulin and subsequently challenged with sheep anti-mouse GBM
antibodies. Fib
/
mice have a targeted deletion within the gene
encoding the A
chain of fibrinogen and have no circulating fibrinogen. Heterozygous (Fib+/
) mice, used as controls in this study, have a fibrinogen level that is 70% of wild-type mice (because synthesis of the B
chain appears to limit the rate of fibrinogen production in wild-type animals) and demonstrate no phenotypic differences to wild-type mice (31). The mice were
monitored for short-term survival and killed for microscopic analysis
of kidney pathology 10 days after disease induction. Significant mortality was associated with induction of kidney disease in mice of
both genotypes, but Fib+/
mice experienced the highest number of
fatalities. Of 15 Fib+/
mice in which disease was induced, 5 mice
died before day 10 (1 mouse at day 6, 2 mice at
day 7, and 2 mice at day 8), and 1 moribund mouse
was killed at day 8 upon the advice of a veterinarian
unaware of mouse genotype. Nine Fib+/
mice survived to day
10, although 2 were moribund. In contrast, of 11 Fib
/
mice in
which disease was induced, 2 were killed due to morbidity (1 each on
days 8 and 9) and the 9 remaining mice appeared
healthy through day 10. Morbidity and mortality (combined)
were significantly higher in Fib+/
mice (8/15, 53%) than in Fib
/
mice (2/11, 18%; P < 0.03,
2
analysis). The survival advantage observed in fibrinogen-deficient mice
relative to fibrinogen-expressing animals was accompanied by
significantly diminished kidney disease (discussed as follows).
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Assessment of glomerular deposition of PAS-positive material.
Glomeruli were graded on a scale of 0-3 for PAS-positive material
accumulation, where a score of 0 indicates no increase in glomerular
deposits and 3 indicates maximal accumulation of PAS-positive material.
Accumulation of PAS-positive material, which is likely to include cell
debris, plasma proteins, Ig deposits, and fibrin, was significantly
higher in control mice [2.28 ± 0.18 (arbitrary units);
n = 11] compared with Fib/
mice (1.55 ± 0.19; n = 6; P < 0.03). This
difference probably reflects the absence of fibrin deposits in Fib
/
mice and the increased cellular necrosis in Fib+/
mice. Accumulation
of PAS-positive material was largely associated with mesangial cells
within the glomerular tuft of both genotypes. In addition, accumulation
of PAS-positive material was also seen in the capillary loops of
Fib+/
mice but was less common in Fib
/
mice, which suggests that
fibrin deposits contribute to intraluminal thrombosis and capillary
loop obliteration in Fib+/
mice.
Detection of circulating anti-sheep globulin antibodies.
To demonstrate that equivalent systemic immune responses were generated
in Fib/
and control mice, circulating antibodies to sheep/goat IgG
were measured in serum samples via ELISA. Increased levels of
circulating antibodies to sheep IgG were detected in both Fib+/
mice
(25.6 ± 4.9 µg/ml; n = 8) and Fib
/
mice
(35.2 ± 6.2 µg/ml; n = 8) after induction of GN
compared with untreated mice (1.0 ± 0.2 µg/ml;
n = 5). IgG isotype analysis indicated that similar
ratios of anti-sheep-specific IgG subtypes were present in both
genotypes of mice after GN induction [as measured in OD405 units (means ± SE): total IgG: Fib+/
, 2.86 ± 0.22;
Fib
/
, 2.42 ± 0.21; IgG1: Fib+/
, 2.62 ± 0.18;
Fib
/
, 2.12 ± 0.2; IgG2a: Fib+/
, 1.04 ± 0.38;
Fib
/
, 0.93 ± 0.22; IgG2b: Fib+/
, 1.82 ± 0.36;
Fib
/
, 1.59 ± 0.27; IgG3: Fib+/
, 1.46 ± 0.49;
Fib
/
, 1.33 ± 0.34]. Given that there were no significant
differences between the titers of circulating specific antibodies or
the IgG isotypes in Fib+/
or Fib
/
mice, the difference in
severity of GN observed in mice of each genotype does not appear to be a consequence of differences in specific immune responses.
Assessment of renal function.
Consistent with microscopically evident severe renal disease, serum
creatinine levels were significantly higher in Fib+/ mice (67.1 ± 8.5 µM) than in Fib
/
mice (43.0 ± 2.5 µM;
P < 0.03; Fig. 4). These
values were elevated above the baseline creatinine value of 23.6 ± 2.9 µM, which was not different for Fib+/
or Fib
/
mice. Both
Fib+/
and Fib
/
mice developed proteinuria that was significantly
higher than baseline levels. Proteinuria was more pronounced in
Fib
/
mice but was not significantly different from Fib+/
mice
(baseline, 1.1 ± 0.5 mg/24 h; Fib
/
, 10.9 ± 7.5 mg/24 h;
Fib+/
, 5.5 ± 2.1 mg/24 h; P = 0.09, Fib
/
vs. Fib+/
, means ± SD). Decreased total urine volume in Fib+/
mice (Fib+/
, 2.6 ± 1.0 ml/24 h; Fib
/
, 3.9 ± 0.7 ml/24
h) along with histological evidence of glomerular thrombi may indicate
that renal filtration was impaired and may account for lower
proteinuria values over a 24-h period despite more severe disease.
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DISCUSSION |
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These studies are the first to examine the development of
crescentic GN in the complete absence of either fibrin(ogen) or FDPs
and show that fibrin(ogen) is an important factor in the development of
crescents and glomerular injury. Fib/
mice developed milder GN
relative to control mice with fewer necrotic glomeruli, diminished
macrophage infiltration, and a reduction in the number of glomerular
crescents. Although both groups of mice developed similar systemic
immune responses to the nephritogenic antigen, it appears that the
accumulation of fibrin within the glomerular tuft and Bowman's capsule
of fibrinogen-expressing mice greatly exacerbates capillary damage
leading to glomerular necrosis and an increased propensity toward
crescent formation. These studies indicate that although fibrin(ogen)
is an important mediator of advanced renal disease in mice, it is not
strictly required for either the induction of GN or crescent formation.
Glomerular procoagulant activity is elevated in crescentic GN, and the activation of the coagulation and fibrinolytic systems have been shown to contribute to disease progression (9, 35). Upregulation of tissue-factor activity leading to thrombin-mediated platelet activation, fibrin polymer formation, and the deposition of platelet-rich thrombi would be expected to promote glomerular damage and local inflammation. Consistent with this view, it has recently been demonstrated that administration of the specific thrombin inhibitor hirudin is highly protective against severe crescentic GN in mice (7). This effect was found to be at least partly due to signaling through the thrombin receptor PAR-1. However, it is likely that thrombin promotes GN through several of its known substrates, which include three G protein-coupled protease-activated receptors (PAR-1, -3, and -4); coagulation factors XI, VIII, V, and XIII, and fibrinogen; and the modulators of coagulation and fibrinolysis, protein C and thrombin-activated fibrinolysis inhibitor. The relative importance of individual targets of thrombin-mediated proteolysis in renal disease and the mechanistic details linking these substrates to severe GN remain to be fully defined.
One mechanism by which thrombin may promote the progression of GN is
local proteolytic activation of PARs on endothelial cells, which
results in adhesive changes that increase leukocyte and platelet
deposition in glomerular vasculature. The subsequent release of
proinflammatory and procoagulant factors may drive both
inflammatory-cell infiltration and basement-membrane disruption leading
to advanced renal disease. Thrombin may also promote progression of GN
through the conversion of fibrinogen to insoluble fibrin deposits
within immunologically damaged glomerular capillaries. In this model,
fibrin may promote crescentic disease by providing a supportive matrix
for leukocyte adhesion and cell migration into Bowman's space. In
addition, the accumulation of fibrin-rich thrombi within glomerular
capillaries may cause occlusion and contribute to local mesangial and
endothelial cell ischemia and subsequent necrosis. The
distinctly increased macrophage recruitment, glomerular necrosis, and
acellularity observed in Fib+/ mice relative to Fib
/
animals
would be consistent with these concepts. Taken together with earlier
findings, the studies presented here indicate that multiple targets of
thrombin-mediated proteolysis are important to the progression of GN
and suggest that the conversion of fibrinogen to fibrin contributes
significantly to the pathology of GN.
Fibrin is a consistent and prominent feature in humans and experimental
animals with severe crescentic forms of GN. Depletion of circulating
fibrinogen with ancrod in rabbits with experimentally induced GN
results in significant protection against crescent formation and loss
of renal function (22, 34). Macrophage infiltration into
the glomerular tuft was not affected, but migration into Bowman's
space did not occur in fibrin(ogen)-depleted animals, and subsequent
crescent formation was markedly reduced (11). However,
because ancrod treatment leads to incomplete and temporary fibrinogen
depletion and may increase the circulating levels of fibrinogen-cleavage products (25), it may not provide a
complete picture of the contribution of fibrin(ogen) to this disease.
The usage of Fib/
mice overcomes these potential pitfalls. In the current studies, we have definitively shown that macrophage recruitment into the glomerular tuft and Bowman's space is markedly reduced in the
complete absence of fibrin, fibrinogen, and FDPs. However, the
accumulation of some glomerular macrophages in mice completely lacking
fibrinogen illustrates that neither soluble fibrinogen nor the local
formation of fibrin matrices is essential for glomerular inflammatory
infiltrates to develop. Similarly, crescent formation was significantly
reduced but not absent in Fib
/
mice, which indicates that the
presence of fibrin(ogen) contributes to but is not essential for the
formation of glomerular crescents.
Consistent with the histopathology of the kidneys of these mice,
Fib/
mice had lower plasma creatinine levels, which indicates preservation of glomerular filtration and reduced disease severity compared with control mice. Proteinuria, an indicator of the disruption of the glomerular filtration barrier, showed a trend toward increased levels in Fib
/
mice although these levels were not statistically different from those in Fib+/
mice (P = 0.09). This
finding is consistent with studies in ancrod-treated rabbits where
fibrinogen depletion preserved glomerular filtration and allowed
greater protein leakage through damaged glomerular capillaries
(33).
Although these studies firmly establish that fibrinogen is important in
GN in vivo, a still-unresolved question involves the relative importance of soluble fibrinogen, insoluble fibrin polymers, and FDPs in renal disease progression. Interestingly, each of these
fibrinogen-derived species could influence GN in ways that are not
mutually exclusive. Soluble fibrinogen has many functional properties
that might promote glomerular damage and inflammation including the
ability to support cell-cell adhesion through integrin (e.g.,
IIb
3,
v
3,
5
1, and
M
2)
and nonintegrin (e.g., intracellular adhesion molecule-1) receptors
(16, 20, 30, 39). As a dimeric molecule, fibrinogen could
support the stable adhesion of leukocytes to glomerular endothelium
and/or adherent platelets by acting as a "molecular bridge" between
specific receptors on opposing cells. In this regard, it is notable
that fibrinogen has been reported to be important in transendothelial
leukocyte migration (1). The formation of fibrin polymers
within the glomerular tuft or Bowman's space could also significantly
contribute to renal disease. The local deposition of an insoluble
fibrin matrix could stabilize leukocyte and platelet adhesion within damaged capillaries and result in both inflammation and vasoocclusion. Fibrin matrices may stimulate or support the proliferative changes that
result in crescent formation. Finally, FDPs have been reported to have
chemoattractant and inflammation-modulating activities (24,
26), and these proteolytic derivatives of fibrin might influence
glomerular disease. The possible participation of FDPs in GN has not
been excluded based on the present studies, but clearly crescentic
glomerular pathologies can occur in the complete absence of FDPs.
Furthermore, the recent finding that plasminogen deficiency
dramatically increases the severity of GN relative to control animals
would argue that at least plasmin-generated FDPs are not crucial for
the development of crescentic renal disease.
In summary, this study provides definitive evidence that fibrin(ogen)
contributes to the development of crescentic GN and supports the
general hypothesis that multiple hemostatic factors including tissue
factor, prothrombin, plasminogen activator, and plasminogen strongly
influence the progression of renal disease. The availability of a
substantial number of viable mouse lines with specific hemostatic
defects (e.g., P-selectin, vWF, PARs, GPIb, integrin subunits
IIb and
3, G
q, and coagulation factors IX, VIII, and XI) provides an opportunity to define in greater detail
the impact of selected hemostatic factors on glomerular disorders. A
more detailed understanding of the role and interplay of hemostatic
factors in GN might suggest new therapeutic targets and adjunct
therapies that might limit or reverse glomerular disease progression.
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ACKNOWLEDGEMENTS |
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The authors gratefully acknowledge the assistance of J. H. Kiser with genotyping and A. Emley with photography.
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FOOTNOTES |
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This work was supported by an award from the American Heart Association, Ohio Valley Affiliate (to A. F. Drew), National Heart, Lung, and Blood Institute Grants HL-47826 and HL-63194 (to J. L. Degen), and the National Health and Medical Research Council of Australia (to P. G. Tipping).
Address for reprint requests and other correspondence: J. L. Degen, Children's Hospital Research Foundation, Children's Hospital Medical Center, IDR-NRB Rm. 2042, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (E-mail: degenjl{at}chmcc.org).
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.
First published August 21, 2001;00.1152/ajprenal.0002.2001
Received 5 January 2001; accepted in final form 23 July 2001.
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