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Rainer Birck, Mark Newman, Claude Braun, Irmgard Neumann, Kyuichi Nemoto, Benito Yard, Rüdiger Waldherr, Fokko J. van der Woude, 15-Deoxyspergualin and cyclophosphamide, but not mycophenolate mofetil, prolong survival and attenuate renal disease in a murine model of ANCA-associated crescentic nephritis, Nephrology Dialysis Transplantation, Volume 21, Issue 1, January 2006, Pages 58–63, https://doi.org/10.1093/ndt/gfi070
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Abstract
Background. Here we compare the efficacy of cyclophosphamide (CYC) for treatment of crescentic nephritis (CGN) with the newer immunosuppressants 15-deoxyspergualin (DSG) and mycophenolate mofetil (MMF) in SCG/Kj mice, an inbred mouse strain that spontaneously develops CGN, systemic necrotizing vasculitis and antineutrophil cytoplasmic antibodies (ANCAs).
Methods. Mice were randomly assigned to intraperitoneal treatment with either DSG (2 mg/kg/day), CYC (50 mg/kg/week), MMF (60 or 100 mg/kg/day) or vehicle (VEH, dextrose 5% 0.3 ml/day) beginning at the 10th week of life. ANCA, blood urea nitrogen (BUN) and proteinuria were determined in all animals regularly, and survival was calculated. Renal histology was obtained in the 18th week of life in the MMF- or VEH-treated groups and in the 24th week in DSG- or CYC-treated animals.
Results. Mean survival in VEH-treated animals was 123 days. At that point, survival was 100% in the CYC- or DSG-treated animals (P<0.001). Survival in the MMF group (pooled data) was not significantly different from the VEH-treated animals [MMF, 117 days (95% CI 108–127)]. BUN (18th week, CYC 43±9 mg/dl and DSG 36±6 mg/dl vs VEH 73±28 mg/dl, P<0.001, MMF 66±26 mg/dl), 24 h proteinuria (18th week, CYC 0.4±0.2 mg and DSG 0.7±0.6 mg vs VEH 2.7±3 mg, P<0.001, MMF 2.2±3 mg) crescent formation (18th week, VEH 42±9%, MMF 39±11%; CYC 5±2% and DSG 22±7% vs VEH, P<0.05), glomerular immune complex deposition, and ANCA formation were significantly improved in CYC- and DSG- but not in MMF-treated animals when compared with controls.
Conclusion. DSG and CYC, but not MMF, prolong life, limit renal damage and prevent autoantibody formation in SCG/Kj mice.
Introduction
Antineutrophil cytoplasmic antibody (ANCA)-associated necrotizing crescentic glomerulonephritis (CGN) is the most common and one of the most aggressive variants of human CGN, leading almost invariably to irreversible renal failure without treatment [1]. The alkylating agent cyclophosphamide (CYC) in combination with steroids has been an efficient standard treatment in such patients in the past, but this regimen carries substantial drug-related morbidity and mortality [1]. Recently, newer immunosuppressive drugs combining comparable efficacy and improved tolerability have been developed.
15-Deoxyspergualin (DSG, generic name Gusperimus) is a synthetic analogue of spergualin, a natural product of the bacterium Bacillus laterosporus [2]. Although initially developed as an anti-cancer drug [3], strong immunosuppressive properties were soon discovered and studied in several animal models of transplantation [4] and autoimmune disease [5]. Hitherto, its mode of action has not been precisely identified but has been related to the inhibition of nuclear factor-κB activity through binding to members of heat shock protein 70 families [6,7]. Mycophenolate mofetil (MMF), the prodrug of mycophenolate acid (MPA), inhibits eukaryotic inosine 5′-monophosphate dehydrogenase, the rate-controlling enzyme of the de novo biosynthesis of guanosine triphosphate [8]. Since proliferation of activated T and B lymphocytes mainly depends on this pathway [9], MMF causes selective suppression of these cells. MMF has been found to exert potent immunosuppressive effects in kidney transplantation [10] as well as in non-transplant immune-mediated nephropathies [11] experimentally and clinically.
Both DSG and MMF may have the potential to treat CGN. The former has already been used in experimental anti-glomerular basement membrane (GBM) nephritis, successfully inhibiting antibody response and the development of renal [5] and pulmonary [12] disease manifestations when given during the induction phase of the disease. However, there are no data available regarding the therapeutic effectiveness of DSG in an animal model of CGN with already established disease. As regards MMF, virtually all experimental and clinical data stem from non-crescentic variants of glomerulonephritides [11] such as lupus nephritis, IgA nephropathy and membranous glomerulonephritis. Moreover, to the best of our knowledge, there are also no published data describing the use of MMF in an animal model of CGN. Thus, the efficacy of MMF in these most severe cases of glomerular inflammation remains to be established.
Spontaneous CGN-forming mice/Kinjoh (SCG/Kj) are an animal model of CGN and systemic vasculitis described initially by Kinjoh and Good in 1993 [13]. This recombinant inbred mice strain was established by selectively mating siblings of (BXSB/Mp × MRL/Mp-lpr/lpr) F1 hybrid mice, with the highest frequency of glomerular crescent formation in inbreeding the progeny for >40 generations. In contrast to its mother strains, female SCG/Kj mice are characterized by the presence of systemic necrotizing vasculitis with a more severe crescentic form of immune complex nephritis, earlier onset of proteinuria and reduced survival [13,16]. Moreover, ANCAs directed against myeloperoxidase develop as early as in the sixth week of life and are present in up to 80–100% of animals between weeks 12 and 24 [16]. Therefore, these mice have been proposed as a tool to investigate the efficacy of new treatment modalities in related forms of human CGN [13,15,16].
The aim of this study was to evaluate the efficacy of DSG and MMF in comparison with the standard immunosuppressant CYC with respect to survival, renal disease and antibody formation in SCG/Kj mice when given with therapeutic intention.
Methods
Animals
Female 6- to 8-week-old SCG/Kj mice were obtained from a colony at Nippon Kayaku Co. Ltd, Tokyo, Japan. This facility as well as the responsible person collaborated with Kinjoh in breeding the original cohort in 1993, and thereafter the breeding of these mice has been performed continuously only in this laboratory (Dr K. Nemoto, Nippon Kayaku Co. Ltd, Tokyo, Japan, personal communication). The mice were housed in a constant temperature room with a 12 h dark/12 h light cycle under specific pathogen-free conditions in groups of 5–6 animals per cage and were allowed standard laboratory chow and water ad libitum. Animal care and experimental procedures were conducted according to national and international laws and policies, and were permitted by local governmental authorities.
Experimental design
Mice were randomly assigned to intraperitoneal (i.p.) treatment with either DSG (2 mg/kg/day, n = 25), CYC (50 mg/kg/weekly, n = 25), MMF [60 (n = 12) or 100 (n = 13) mg/kg/day) or vehicle (VEH, dextrose 5%, daily, n = 25). DSG, MMF and CYC solutions were prepared daily in our pharmacy. Administration started in the 10th week of life at disease onset as indicated by significantly increased proteinuria (8th week, all animals: 0.3±0.13 mg/dl; 10th week, all animals: 0.6±0.9 mg/dl, P = 0.002 paired t-test) and progressing haematuria (8th week, all animals, 5%; 10th week, all animals, 14%) when compared with week 8, and lasted until mice died or were terminally ill. At week 10, crescent formation in up to 20% of female SCG/kj mice can be expected [13,16]. In the MMF groups, random serum samples (n = 3, week 14) were obtained 4 h after MMF administration and the levels of MPA, the active metabolite of MMF, were measured by EMIT assay (Dade Behring, Schwalbach, Germany). Serum levels of MPA ranged between 15 and 25 mg/ml. All mice were housed in metabolic cages to collect 24 h urine samples for quantitative determination of proteinuria and semi-quantitative determination of haematuria. Blood samples were obtained by puncture of the retroorbital venous plexus. Surviving animals were killed for renal histology in the 18th week of life in MMF- and VEH-treated groups. Since virtually all animals were alive in the DSG- and CYC-treated groups, it was decided to prolong the follow-up in these groups up to the 24th week of life.
Laboratory analysis
ANCA titre, blood urea nitrogen (BUN) and 24 h proteinuria were determined in all animals every 4 weeks. Quantitative urinary protein concentration was determined by the Coomassie blue G dye-binding assay with bovine serum albumin as standard. Renal function was assessed as BUN on serum samples using an enzymatic UV rate (Dimension, Dade Behring, Schwalbach, Germany). Haematuria was determined semi-quantitatively with commercially available standard urinary dipsticks (Combur-Test, Roche Mannheim, Germany) at the 8th and 10th week of life. Animals were considered to have relevant haematuria in the presence of scores ≥++.
Indirect immunofluorescence
Sera were analysed for the presence of cANCA, pANCA and antinuclear antibody (ANA) by indirect immunofluorescence (IIF) using a biochip containing formaldehyde- and ethanol-fixed human granulocytes as well as primate liver and Hep2 cells (Biochip MosaiK Euroimmun, Lübeck, Germany) as previously described [16]. Perinuclear ANCAs (pANCAs) were considered to be positive when IIF revealed a typical perinuclear immunofluorescence pattern on ethanol-fixed granulocytes at titres >1:16 combined with a shift to a cytoplasmic pattern on formaldehyde-fixed granulocytes as previously reported [16].
Renal histology
For standard light microscopy, renal tissue was fixed in neutral-buffered formaldehyde in saline and 3 mm paraffin-embedded sections were stained with haematoxylin–eosin and periodic acid–Schiff. Extracapillary proliferation was defined as the presence of two or more cell layers within the Bowmann's space and expressed as the percentage of crescents/glomeruli. For immunofluorescence microscopy, cryostat 4 mm kidney sections were incubated with fluorescein isothiocyanate (FITC)-conjugated anti-mouse IgG or FITC-conjugated antibodies against mouse complement factor C3. Immunofluorescence findings were recorded according to the intensity of fluorescence on a semi-quantitative scale of zero to three (− = none; ± = weakly positive; +, ++, +++ = intensities of positive staining). All renal tissue was analysed by the same researcher in a blind fashion.
Statistics
Results are expressed as means±SD. Since no significant differences were found in any parameter between both MMF groups, their values were pooled. BUN and proteinuria data were analysed using one-way analysis of variance employing Dunnett's method for multiple comparisons against a control group. For data assumed to be non-parametrically distributed, either McNemar's test for paired comparisons or Fisher's exact test for unpaired comparison were employed for dichotomized data (i.e. number of sera with ANCA titres >1:16) and the Kruskal–Wallis test for multiple comparisons of continuous data (i.e. crescent formation and immunofluorescence intensity). The log-rank test was used for survival analysis. Statistical significance was defined as P<0.05. The statistical software package StatsDirect 2.2.12 (StatsDirect Ltd, Cheshire, UK) was used.
Results
Effects on proteinuria
Proteinuria remained at baseline levels in CYC-treated animals during the whole study period. DSG delayed the onset of proteinuria up to the 18th week of life. At this time point, proteinuria in these two groups was significantly reduced when compared with controls. From week 20 onwards, proteinuria increased significantly in the DSG group when compared with CYC-treated animals. MMF did not reduce proteinuria when compared with VEH-treated animals (see Figure 1).
Effects on renal function
In CYC- or DSG-treated animals, renal function did not deteriorate up to week 18, as indicated by significantly lower BUN levels when compared with VEH-treated animals at that time (week 18, CYC 43±9 mg/dl, P = 0.0001; DSG 36±6 mg/dl, P = 0.0001; VEH 73±28 mg/dl). MMF did not reduce BUN levels when compared with VEH-treated animals (week 18, MMF 66±26 mg/dl).
Effects on ANCA
At 10 weeks of age, 38–56% of animals showed ANCA titres >1:16. CYC significantly depressed the number of sera positive for ANCA from 33% in the 10th week to 4% at week 14 (P = 0.0002) and kept titres below 5% during the complete experimental period. DSG did not reduce but significantly delayed further increase of ANCA titres when compared with VEH-treated animals (week 14, DSG 29%, VEH 86%, P = 0.0001; week 18, DSG 39%, VEH 88%, P = 0.03). MMF showed no clear-cut effect on ANCA titres (see Figure 2).
Effects on survival
Median survival time in VEH-treated animals was 123 days [95% confidence interval (CI) 112–134]. In contrast, at that time point, survival was 100% in CYC- and DSG-treated animals. Median survival in the MMF groups was not significantly different from the VEH-treated animals [MMF, 117 days (95% CI 96–134)]. Up to the 20th week of life, survival was equal in CYC- and DSG-treated mice. However, at week 24, survival was significantly prolonged in CYC-treated animals (P = 0.0075) (see Figure 3).
Renal histology
Crescent formation was significantly lower in CYC- and DSG-treated animals in the 24th week of life when compared with VEH-treated animals killed at the 18th week of life. The CYC group also showed a significantly decreased crescent formation when compared with DSG at the 24th week of life. The MMF group did not differ from VEH-treated animals at week 18 (see Table 1). Glomerular immunofluorescence findings revealed that CYC- and DSG- but not MMF-treated animals showed a significantly reduced immunofluorescence intensity with respect to both IgG and C3 when compared with VEH-treated mice (see Table 2).
. | VEH (n = 8) . | MMF (n = 13) . | CYC (n = 23) . | DSG (n = 16) . |
---|---|---|---|---|
Time | 18th week | 18th week | 24th week | 24th week |
No. of crescents (%) | 42±9 | 39±11 | 5±2*,§ | 22±7** |
. | VEH (n = 8) . | MMF (n = 13) . | CYC (n = 23) . | DSG (n = 16) . |
---|---|---|---|---|
Time | 18th week | 18th week | 24th week | 24th week |
No. of crescents (%) | 42±9 | 39±11 | 5±2*,§ | 22±7** |
The values represent the mean number of crescents in %±SD.
*P<0.01 CYC vs VEH, **P<0.05 DSG vs VEH, §P<0.05 CYC vs DSG, all Kruskal–Wallis test.
. | VEH (n = 8) . | MMF (n = 13) . | CYC (n = 23) . | DSG (n = 16) . |
---|---|---|---|---|
Time | 18th week | 18th week | 24th week | 24th week |
No. of crescents (%) | 42±9 | 39±11 | 5±2*,§ | 22±7** |
. | VEH (n = 8) . | MMF (n = 13) . | CYC (n = 23) . | DSG (n = 16) . |
---|---|---|---|---|
Time | 18th week | 18th week | 24th week | 24th week |
No. of crescents (%) | 42±9 | 39±11 | 5±2*,§ | 22±7** |
The values represent the mean number of crescents in %±SD.
*P<0.01 CYC vs VEH, **P<0.05 DSG vs VEH, §P<0.05 CYC vs DSG, all Kruskal–Wallis test.
. | VEH . | MMF . | CYC . | DSG . | ||||
---|---|---|---|---|---|---|---|---|
Time | 18th week | 18th week | 24th week | 24th week | ||||
Intensity scores | ||||||||
IgG | 2.2±0.41 | 2.3±0.52 | 0.7±0.26* | 1.3±0.52* | ||||
C3 | 1.5±0.55 | 1.5±0.55 | 0.5±0** | 0.9±0.2** |
. | VEH . | MMF . | CYC . | DSG . | ||||
---|---|---|---|---|---|---|---|---|
Time | 18th week | 18th week | 24th week | 24th week | ||||
Intensity scores | ||||||||
IgG | 2.2±0.41 | 2.3±0.52 | 0.7±0.26* | 1.3±0.52* | ||||
C3 | 1.5±0.55 | 1.5±0.55 | 0.5±0** | 0.9±0.2** |
The results from six randomly chosen animals from each group are given.
The values represent the mean intensity score±SD. *P<0.0001 CYC vs VEH, **P<0.05 DSG vs VEH, all Kruskal–Wallis test.
. | VEH . | MMF . | CYC . | DSG . | ||||
---|---|---|---|---|---|---|---|---|
Time | 18th week | 18th week | 24th week | 24th week | ||||
Intensity scores | ||||||||
IgG | 2.2±0.41 | 2.3±0.52 | 0.7±0.26* | 1.3±0.52* | ||||
C3 | 1.5±0.55 | 1.5±0.55 | 0.5±0** | 0.9±0.2** |
. | VEH . | MMF . | CYC . | DSG . | ||||
---|---|---|---|---|---|---|---|---|
Time | 18th week | 18th week | 24th week | 24th week | ||||
Intensity scores | ||||||||
IgG | 2.2±0.41 | 2.3±0.52 | 0.7±0.26* | 1.3±0.52* | ||||
C3 | 1.5±0.55 | 1.5±0.55 | 0.5±0** | 0.9±0.2** |
The results from six randomly chosen animals from each group are given.
The values represent the mean intensity score±SD. *P<0.0001 CYC vs VEH, **P<0.05 DSG vs VEH, all Kruskal–Wallis test.
Discussion
In this study, CYC or DSG, but not MMF, prolonged life, limited renal damage and prevented autoantibody formation in SCG/Kj mice.
The efficacy of CYC was not unexpected given its proven benefits in animal models of lupus nephritis [17–19]. Despite the widespread use of CYC in various forms of human proliferative nephritides [20], basic research trying to elucidate its mode of action in this setting seems sparse. CYC is believed to exert unselective cytostatic and immunosuppressive properties by covalently linking alkyl groups to DNA. However, on a cellular level, these effects are only incompletely understood. Strong inhibition of lymphocytes, mainly on proliferation and antibody formation of B cells, has been repeatedly described [21]. A more recent aspect of potential importance, particularly as far as crescentic nephritides are concerned, is the ability of CYC to downregulate the renal expression of monocyte chemoattractant protein-1 (MCP-1) [22], a chemokine which, in conjunction with its receptor chemokine receptor 2 (CCR2), has been shown to be crucial for the development of crescentic nephritis [23–25]. Despite its clinically well-established efficacy in various autoimmune diseases, the use of CYC-containing regimens is hampered by substantial side effects such as the development of unpredictable bone marrow suppression, malignancies or infections [1].
DSG was as effective as CYC with respect to survival and prevention of proteinuria up to the 18th week of life. DSG also delayed autoantibody production, but, in contrast to CYC-treated animals, ANCA levels were never completely suppressed. Beneficial effects of DSG have also been reported in experimental anti-GBM nephritis when given during the induction phase [5]. Moreover, LF15-1905, a derivative of DSG, has been found to be effective in both prevention and treatment of anti-GBM disease [5,12,26]. The inferior results of DSG when compared with CYC may be explained by the dosages used. Whereas a high dosage of CYC was employed in our setting, the amount of DSG given represents a rather low to moderate dosage. Okubo showed that DSG 6 mg/kg four times a week was as effective as CYC 15 mg/kg weekly in reversing established murine lupus nephritis [19]. Clinical experience is available for DSG and mainly stems from the renal transplant setting [27]. In non-transplant renal disease, however, clinical experience is limited. Hotta et al. recently described the antiproteinuric effects of DSG in a small number of patients with proliferative glomerulonephritides including crescentic variants [28]. Our group showed that DSG may induce remission in patients with refractory Wegener's granulomatosis without severe renal involvement. Improvement in renal function as well as decreasing proteinuria and haematuria were also noted [29]. The precise mode of action, however, remains obscure and not comparable with standard immunosuppressants. DSG has been shown to bind specifically to Hsc70, a member of the heat shock protein 70 families [6]. These proteins are important for many cellular processes, including protein folding and molecular chaperoning [30]. Similar to CYC, profound effects on B-lymphocyte maturation, differentiation, proliferation and antibody secretion have been described [7,19,31–33]. Some of these effects have been shown to be mediated by blocking nuclear translocation of the transcription factor NF-κB [7]. In contrast to CYC, where effects on lymphocytes can be long lasting, DSG leads to a reversible inhibition of lymphocyte proliferation and cytokine secretion [32]. DSG also affects monocytes/macrophages/antigen-presenting cells. Diminished expression of major histocompatibility complex (MHC) class II antigens [34], inhibition of proliferation and antigen processing/presentation as well as downregulation of MCP-1 have been observed [35,36].
MMF did not show any therapeutic effect on the course of disease in SCG/Kj mice. Neither survival, antibody formation nor renal disease manifestations were different from controls. Similar dosages of MMF have been successfully employed in murine lupus nephritis in the past [37–40]. However, most studies describing beneficial effects in proliferative nephritis models used MMF as a prophylactic measure [38–40]. When MMF was given at time points with already established glomerular disease, it either had no or only limited therapeutic effects [39,41]. Clinically, MMF has been shown to be efficacious in proliferative forms of glomerulonephritis [42,43]; its efficacy in crescentic variants, however, remains to be proven [44–46]. As regards animal models of CGN, to the best of our knowledge there are no data describing the use of MMF in such settings. Thus, our study provides the first data on the therapeutic potential of MMF in an animal model of CGN.
In conclusion, we could show that DSG and MMF are not comparable in their therapeutic efficacy in a murine model of CGN. DSG may have the potential to treat successfully these most severe forms of human glomerulonephritis. DSG appears to be a promising agent combining potent immunosuppression with a favourable side effect profile [28]. Clinical trials are warranted to establish the efficacy of DSG in human CGN.
This work was supported by a grant (project no. 59/98) from the Faculty for Clinical Medicine Mannheim of the University of Heidelberg.
Conflict of interest statement. RB received a research grant from Nippon Kayaku.
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Author notes
1Fifth Department of Medicine, University Hospital Mannheim, 2Nippon Kayaku Co. Ltd, Tokyo, Japan and 3Institute for Pathology, Heidelberg, Germany
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