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Renal Division, Department of Clinical Medicine, Faculty of Medicine, University of São Paulo, São Paulo, Brazil.
Correspondence to Dr. Roberto Zatz, Laboratório de Fisiopatologia Renal, Av. Dr. Arnaldo, 455, 3-s/3342, 01246-903 São Paulo SP, Brazil. Phone: 55 11 3068 9428; Fax: 55 11 883 1693; E-mail: rzatz{at}ibm.net
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Two recent studies from this laboratory have shown that inhibition of the inflammatory process associated with the 5/6 renal ablation (NX) model can markedly retard the development of renal injury. In the first of these studies (16), NX rats were treated with a novel anti-inflammatory drug devoid of gastrointestinal toxicity, nitroflurbiprofen, which inhibited the biosynthesis of cyclooxygenase derivatives. In the second study (5), NX rats received mycophenolate mofetil (MMF), a lymphocyte inhibitor largely used in recent years to prevent allograft rejection. Lymphocyte and macrophage infiltration, as well as tubulointerstitial cell proliferation, were all attenuated by MMF treatment. In both studies, glomerular and interstitial injury were ameliorated, despite persistence of glomerular hypertension.
Considering the individual renoprotective efficacy of MMF and renin-angiotensin suppressors and the fact that these agents act at distinct steps of the cascade leading to end-stage renal disease, we investigated whether simultaneous treatment with MMF and the AIIRa losartan potassium affords better renal protection than monotherapy with either drug alone. To test this hypothesis, combined MMF/losartan therapy was instituted in NX rats 1 mo after surgery. Since NX rats already exhibit substantial renal injury at this time, their condition resembles more closely that observed in clinical practice than treatment initiated immediately after NX.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thirty days after NX, the tail-cuff pressure (TCP) was measured by an indirect method (17). The animals were then placed in metabolic cages for determination of 24-h urinary albumin excretion rate (UalbV). Twenty-one NX rats (16% of total) failing to develop hypertension (defined as TCP >130 mmHg) or albuminuria (UalbV >20 mg/d) were excluded from the protocol. (In every case this was due to insufficient removal of renal parenchyma.) The kidneys of 17 rats were then perfusion-fixed with Duboscq-Brazil solution (0.45% picric acid in a mixture of ethanol, formaldehyde, and acetic acid) after a brief saline washout, and prepared for light microscopic and immunohistochemical analysis as described below. This group, designated NXpre, was used to evaluate the extent of renal injury at 30 d of NX and served to assess the beneficial effects of treatments started thereafter. The remaining NX rats were then distributed among four experimental groups: NX+V (n = 25), NX rats receiving inert vehicle as described; NX+M (n = 22), NX rats receiving MMF as described above; NX+L (n = 22), NX rats receiving losartan, as described above; NX+L+M (n = 24), rats given simultaneous MMF and losartan treatments. The concentration of losartan in the drinking water was adjusted to compensate for variations in daily water intake and to ensure that both group NX+L and group NX+L+M received the same dosage. A group of S rats (n = 25) was also studied. The distribution of rats into the four NX groups was performed in such a way as to ensure that both mean TCP and albumin excretion rates were similar among groups. The mean initial BP values (in mmHg) for the NX groups were 166 ± 4 (group NX+V), 162 ± 6 (group NX+M), 165 ± 6 (group NX+L), and 164 ± 6 (group NX+L+M). Mean albuminuria values (in mg/d) were 68 ± 4 (group NX+V), 69 ± 9 (group NX+M), 65 ± 8 (group NX+L), and 66 ± 8 (group NX+L+M). None of these differences reached statistical significance.
Renal Hemodynamic Studies
Thirty days after treatments were initiated (60 d after NX), eight S rats,
eight rats of group NX+V, eight of group NX+M, seven of group NX+L, and eight
of group NX+L+M were subjected to renal hemodynamic studies after anesthesia
with inactin, 100 mg/kg intraperitoneally, and placed on a
temperature-regulated surgical table. The femoral artery was cannulated with
PE-50 tubing for baseline hematocrit determination and subsequent collection
of blood samples, and for continuous monitoring of mean arterial pressure with
a P23Db Statham pressure transducer connected to a computerized data
acquisition system (Dataq Instruments, Akron, OH). Surgical fluid losses were
compensated by an intravenous infusion of homologous rat plasma
(18). Saline solution
containing 14C-tagged inulin (0.3 µCi/ml) was infused at 1.5
ml/h. The left kidney was freed from the adrenal gland and perirenal fat,
immobilized with a lucite holder, and continuously bathed with isotonic
saline. After about 2.5 h of anesthesia, urine was collected from the left
ureter during 20 to 30 min for measurement of flow rate and inulin
concentration. Hydraulic pressures in superficial glomeruli
(PGC), tubules (PT), and efferent
arterioles (PE) were measured with a servo-nulling device
(model V; Instrumentation for Physiology and Medicine, San Diego, CA).
Whole-kidney filtration fraction (FF) was determined by the simultaneous
collection of blood samples from the femoral artery and renal vein, with
measurement of the respective 14C activities and calculation of
renal inulin extraction. Blood samples were obtained from the left renal vein
with a sharpened glass micropipette, 40 to 45 µm outer diameter. Plasma and
urine 14C activities were determined in a scintillation counter
(Beckman Instruments, Shiller Park, IL). Renal plasma flow (RPF) was
calculated as RPF = GFR/FF. Renal vascular resistance (RVR) was estimated by
the expression RVR = MAP x (1 - Hct)/RPF, where MAP and Hct represent
mean arterial pressure and arterial hematocrit, respectively.
Long-Term Studies
Seventeen S rats, 17 rats from group NX+V, 14 from group NX+M, 15 of group
NX+L, and 16 from group NX+L+M were followed until 120 d after surgery (90 d
of treatment), with monthly determination of TCP
(17) and UalbV
(19). At the end of the study
period, rats were anesthetized with sodium pentobarbital, 50 mg/kg
intraperitoneally, and a blood sample was collected from the abdominal aorta
for blood cell counting. The renal tissue was then perfusion-fixed with
Duboscq-Brazil solution after washout with saline and prepared for morphologic
analysis as described below.
Preparation of Renal Tissue for Morphologic Analysis
The renal tissue was perfusion-fixed by in situ perfusion at the
measured arterial pressure with Duboscq-Brazil solution after a brief saline
washout. After fixation, the renal tissue was weighed, and two midcoronal
sections were post-fixed in buffered 10% formaldehyde solution. The material
was then embedded in paraffin for assessment of glomerular and renal cortical
interstitial injury, as well as for immunohistochemical identification of
macrophages.
Histomorphometry
Sections 2- to 3-µm thick were stained with periodic acid-Schiff
reaction and by the Masson trichrome technique. All morphometric evaluations
were performed in a blinded manner by a single observer. The average
glomerular tuft volume (VG) at 30 d of treatment (60 d of
NX) was estimated by point counting
(20), after light microscopic
examination at a final magnification of x 100 under a 176-point ocular
grid. The corresponding microscopic field covered an area of 206,700
µm2. The mean glomerular cross-sectional area
(AG) was determined for each rat by averaging individual
values for at least 50 consecutively sampled glomerular tuft profiles.
Individual glomerular values were calculated by counting points falling within
the glomerular area. VG was then calculated as:
VG = 1.25 x (AG)3/2
(21).
The extent of GS was evaluated by attributing a score to each glomerulus according to the apparent extent of the tuft area affected by the sclerotic injury, as follows: 0, intact glomeruli; 1, lesions affecting 10% or less of the tuft area; 2, lesions affecting 11 to 20% of the tuft area; 3, lesions affecting 21 to 30% of the tuft area; 4, lesions affecting 31 to 40% of the tuft area; 5, lesions affecting 41 to 50% of the tuft area; 6, lesions affecting 51 to 60% of the tuft area; 7, lesions affecting 61 to 70% of the tuft area; 8, lesions affecting 71 to 80% of the tuft area; 9, lesions affecting 81 to 90% of the tuft area; and 10, lesions exceeding 90% of the glomerular tuft area. In addition, glomeruli exhibiting severe tuft atrophy (>70% volume reduction), cystic dilation of the urinary space, and periglomerular inflammation, according to the recent description of Kriz et al. (22), were also attributed a score of 10. A GS index (GSI) was calculated for each rat as the weighted average of all individual glomerular scores thus obtained, multiplied by 100. At least 120 glomeruli were examined for each rat. The reproducibility of the scoring method was assessed in a blinded manner by having the same observer examine, on two separate occasions, 18 kidneys with widely variable extents of glomerular injury. The two average GSI values thus obtained agreed within 1%, while the correlation coefficient between the two sets of GSI values was 0.995. To evaluate the extent of renal interstitial expansion, the fraction of renal cortex occupied by interstitial tissue staining positively for extracellular matrix components was quantitatively evaluated in Masson-stained sections by a point counting technique (23) in 25 consecutive microscopic fields, at a final magnification of x 100 under a 176-point grid.
Immunohistochemical Analysis
Macrophages were detected in 4-µm-thick, paraffin-embedded renal
sections. Sections were mounted on glass slides coated with 2% gelatin,
deparaffinized in xylene, and rehydrated through graded ethanol and in
deionized water in the final step. Sections were then subjected to microwave
irradiation in citrate buffer to enhance antigen retrieval, and preincubated
with 5% normal rabbit serum in Trisbuffered saline or in phosphate-buffered
saline to prevent nonspecific protein binding.
Optimal working dilutions of the primary antibody were determined previously by titration experiments. Negative control experiments for the ED-1 antigen were performed by omitting the incubation with the primary antibody.
For specific immunostaining of macrophages, a monoclonal mouse anti-rat ED-1 antibody (Serotec, Oxford, United Kingdom) was used. The incubations were carried out overnight at 4°C in a humidified chamber. After washing, the sections were incubated with rabbit anti-mouse immunoglobulins with low affinity for rat Ig (Dako, Glostrup, Denmark). To complete the sandwich technique, incubation with a soluble complex of alkaline phosphatase anti-alkaline phosphatase (APAAP; Dako) was performed. The last two steps were repeated to enhance the intensity of the reaction product. Finally, the slides were developed with a fast-red dye solution, counterstained with Mayer's hemalaum solution (Merck, Darmstadt, Germany), and covered with Kaiser's glycerin-gelatin (Merck).
The extent of ED-1-positive cell infiltration was evaluated in a blinded manner at x250 magnification and expressed as cells/mm2. For each section, 25 microscopic fields, each corresponding to an area of 0.06 mm2, were examined.
Statistical Analyses
One-way ANOVA with pairwise comparisons according to the Newmann-Keuls
formulation was used in this study
(24). P values of
0.05 were considered significant. GSI behaved as a continuous variable
with non-normal distribution. An approximately Gaussian distribution was
obtained in all groups by performing log transformation of the data. Albumin
excretion rates behaved in the same manner, also requiring log transformation
before statistical analysis.
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Results |
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Long-Term Studies
Renal and systemic parameters obtained at 120 d after NX (90 d of
treatment) are given in Table
2. Despite drug treatment, all NX groups exhibited an increase in
body weight compared with values measured 30 d after NX (group
NXpre). However, growth was limited in all NX groups compared with
S rats. Average food intake (g/d) was similar among the six groups studied.
The increase in perfused kidney weight was similar among NX groups 120 d after
NX. Systemic hypertension, evaluated by TCP, was considerably worsened in
untreated NX+V rats compared with pretreatment values. Treatment with MMF
lowered TCP to levels not significantly different from those observed before
treatments were started, but still markedly elevated compared with S values.
Losartan treatment also prevented the progression of systemic hypertension,
although TCP remained at hypertensive levels in group NX+L. In rats receiving
the combined MMF/losartan treatment, TCP regressed to levels inferior to those
measured before treatment, and was not significantly different from those
obtained in S rats. Albumin excretion rate (UalbV) was markedly
increased in untreated NX+V rats, reaching values twice as high as those
obtained before treatment. MMF treatment promoted a slight and not
statistically significant attenuation of albuminuria compared with NX+V. In
losartan-treated rats, albuminuria remained at levels nearly identical to
those obtained before treatments were started. In rats receiving combined
MMF/losartan treatment, albuminuria was numerically lower than in group
NXpre. Blood leukocyte counts (xmm-3) were 6.1
± 0.3 (group S), 7.7 ± 0.5 (group NX+V), 7.7 ± 0.3 (group
NX+M), 6.7 ± 0.4 (group NX+L), and 6.4 ± 0.7 (group NX+L+M).
Differences between groups were not statistically significant. No
abnormalities in red blood cell or platelet count were observed in any of the
groups.
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The results of the histologic and immunohistochemical analyses of the renal tissue performed at 30 and 120 d of NX are represented in Figures 1, 2, 3, 4, 5. Glomerular segmental sclerotic lesions, such as represented in Figure 1, were evident at 30 d of NX (group NXpre), with GSI (Figure 2A) reaching values almost 10-fold higher than in S. Most glomerular lesions were mild, occupying <20% of the tuft area, while only 2.4 ± 1.2% of the affected glomeruli received scores greater than 4 (Figure 3). No glomerular atrophy (22) was seen at this stage.
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Ninety days later (120 d after NX), considerable progression of glomerular injury had occurred. In untreated NX+V rats, GSI attained values almost 14-fold as high as in NXpre and 150-fold higher than S (Figure 2A). The profile of glomerular scores (Figure 3) was shifted to the right compared with NXpre: 26.2 ± 4.1% of injured glomeruli exhibited scores of 4 or higher, indicating progression not only of the intensity, but also of the severity of injury. Glomeruli showing tuft atrophy and cystic dilation of Bowman's space (Figure 4) represented 2.2 ± 0.4% of all injured glomeruli. Treatment with MMF significantly attenuated the progression of glomerular injury (Figure 2A), reducing GSI by approximately 30%. However, the profile of glomerular scores remained clearly shifted to the right, 18.6 ± 6.2% of injured glomeruli receiving scores 4 or higher (Figure 3). In addition, MMF treatment reduced the frequency of atrophic glomeruli, which represented 0.6 ± 0.2% of injured glomeruli in group NX+M (Figure 3). In rats receiving losartan monotherapy, GSI (Figure 2A) was strongly reduced compared with untreated NX+V rats. The shift to the right of the glomerular score distribution was also attenuated (Figure 3), 11.5 ± 3.7% of injured glomeruli exhibiting scores greater than 4. Atrophic glomeruli were still observed (0.8 ± 0.3% of injured glomeruli). Combined losartan/MMF treatment reduced GSI (Figure 2A) to levels similar to those verified in NXpre. The profile of distribution of the glomerular scores approached that observed in group NXpre (Figure 3), since only 2.6 ± 1.0% of glomeruli were attributed scores 4 or higher, indicating arrest of glomerular sclerotic injury in this group. In addition, atrophic glomeruli were entirely absent in these animals.
Interstitial expansion was also a prominent component of renal injury after renal NX (Figure 2B). In group NXpre (30 d after NX), the percent interstitial area was increased compared to group S. Interstitial fibrosis was markedly aggravated 120 d after NX in untreated rats. MMF treatment attenuated the progression of interstitial expansion. Losartan treatment was less effective at the interstitium than at the glomeruli, conferring only slightly better interstitial protection than MMF monotherapy. By contrast, the progression of interstitial fibrosis was effectively arrested in rats receiving combined MMF/losartan therapy, in which the percent interstitial area was nearly identical to the pretreatment value.
Thirty days after NX, the macrophage infiltration in the renal tissue, assessed by the density of ED-1-positive cells, was more than doubled compared with S values (Figure 5). Macrophage infiltration was aggravated in untreated NX+V rats 120 d after NX. MMF treatment returned macrophage infiltration to levels only slightly and not significantly higher than in NXpre. A reduction of similar magnitude was obtained in losartan-treated NX rats. Combined MMF/losartan treatment exerted a better anti-inflammatory effect than any of the individual treatments, reducing the renal macrophage density to levels numerically lower than in the NXpre group.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MMF treatment prevented the aggravation of systemic hypertension after 120 d of NX (90 d of treatment) and attenuated glomerular hypertension at 60 d of NX. In addition, MMF limited the intensity of macrophage infiltration at 120 d of NX. This mixed hemodynamic/anti-inflammatory effect was associated with a significant attenuation of long-term renal injury, compared with untreated NX+V rats. However, GSI and the percent interstitial area were still markedly increased in MMF-treated rats compared with pretreatment values. This finding is in apparent contrast to previous data obtained in this laboratory (5) and elsewhere (8), which indicated strong attenuation of progressive renal injury in MMF-treated NX rats. It must be noted, however, that in those studies MMF treatment was initiated soon after NX, while in the present study MMF was started only 30 d after NX, when renal injury was already evident. Thus, MMF appears to require early institution of therapy to exert maximal protection in the NX model, perhaps because of a preferential effect on early and short-lived events in the course of the attending nephropathy. Previous studies of this laboratory (5) and elsewhere (3,4) showed a surge of tubulointerstitial cell proliferation in the first week after NX, which receded gradually and nearly disappeared after 2 mo. We also showed an intense interstitial lymphocyte infiltration at 1 wk of NX (5), while others reported a dramatic increase in the expression of intercellular adhesion molecules at 4 wk, but not at 8 wk, after NX (8). It also must be noted that rats failing to develop hypertension or albuminuria at 30 d after NX were excluded from the protocol. Thus, we dealt in this study with a rather aggressive nephropathy, hence less responsive to pharmacologic intervention than in previous studies.
Losartan treatment limited BP to pretreatment values, while strongly attenuating the particularly severe manifestations of renal injury observed in untreated NX rats. In addition, the GSI profile was shifted to the left, indicating less extensive glomerular damage. These beneficial effects may be at least partly explained by a hemodynamic effect, since PGC was lowered by 24 mmHg relative to NX+V rats. Additional benefit may have derived from blockade of nonhemodynamic effects of AngII such as enhanced proliferation of mesangial cells (12), myofibroblasts (13), and T cells (27), as well as overexpression of adhesion molecules (28). Abnormal renal interstitial production of AngII may occur in the NX model (29), while AngII blockade was shown to diminish the renal expression of transforming growth factor-ß (30) and platelet-derived growth factor (31), as well as the infiltration and proliferation of macrophages and myofibroblasts (13). Despite this favorable association of hemodynamic and nonhemodynamic mechanisms, the protective effect of losartan treatment was incomplete. Globally sclerotic and atrophic glomeruli were still detected in the NX+L group (two losartan-treated rats had developed terminal renal failure at 120 d), indicating the persistence of progressive renal injury in these animals. Late institution of treatment must have contributed to limit the renoprotective effect of losartan compared to early treatment, as observed in previous studies (32, 33, 34). Residual injury in group NX+L may have been mediated by persistent glomerular hypertension (PGC remained 6 mmHg higher in this group than in S rats) and hypertrophy (which was only slightly attenuated by treatment). In addition, macrophage infiltration was only partially limited by losartan monotherapy, suggesting that AngII-unrelated inflammatory phenomena may also have favored the progression of renal injury.
Combined losartan/MMF therapy was associated with actual reversal of systemic hypertension and albuminuria, as well as arrest of macrophage infiltration, GS, and interstitial injury, which remained at levels similar to those obtained 30 d after NX. The distribution of glomerular scores was very similar to that observed before treatment, only 2.6 ± 0.6% of injured glomeruli exhibiting scores of 4 or higher. In addition, the frequency of severely sclerosed or atrophic glomeruli was brought to zero in this group, indicating nearly complete arrest of renal injury. This effect cannot be explained by a more effective action of combined therapy on glomerular hemodynamics, since PGC was lowered to a similar extent in rats treated with losartan alone. Since the anti-inflammatory effect of MMF per se must have been the same as in rats treated with MMF alone, the greater efficacy of combined therapy suggests a synergistic drug interaction. Although both losartan and MMF exert hemodynamic and nonhemodynamic renal effects, they most likely act on distinct steps in the sequence of events leading to glomerular scarring. Simultaneous targeting of differing pathogenic mechanisms by combined therapy can thus promote a more effective interruption of this process. Of note, a recent study (35) has shown that simultaneous treatment of NX rats with tacrolimus and candesartan exerted a more effective renal protection than either drug alone. In addition, Remuzzi and associates (36) have recently reported preliminary observations similar to those described in the present study, showing superiority of early combined therapy with MMF and an angiotensin-converting enzyme inhibitor over the respective monotherapies. As a whole, these recent observations and the present study hold out the possibility of a more efficient action to arrest the progression of human disease toward end-stage renal failure.
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Acknowledgments |
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