Developmental renal diseases of humans are relatively common. These include autosomal-recessive polycystic kidney disease (ARPKD), autosomal-dominant polycystic kidney disease (ADPKD), glomerulocystic kidney disease, renal dysplasia, familial nephronophthisis/medullary cystic disease, and medullary sponge kidney, among others1, 2, 3, 4 and 5. Cysts are the most common renal defect diagnosed in perinatal autopsies and stillborn fetuses6. ADPKD is the most common cystic renal disease and occurs in 
1 in 1000 live births6. Most cystic renal diseases can eventually lead to chronic renal failure, although clinical severity and time course are highly variable2,7, 8, 9 and 10. Cystic kidney diseases are associated with other serious conditions including hypertension, extra-renal malformations, aneurysms, and cardiac defects11, 12 and 13.
Kidney morphogenesis is a complicated process relying on exquisitely regulated communication between the branching ureteric bud and metanephric mesenchyme7,8,14,15. Many genes are involved in renal development, and mutations result in disease expression ranging in phenotypic severity from the subclinical to the embryonically lethal6,16. Renal dysmorphogenesis commonly results in cyst formation, and this family of diseases displays many overlapping clinical and morphologic features that can make precise diagnosis difficult without genetic testing1. In addition to kidney manifestations, ARPKD and ADPKD are associated with liver lesions including hepatic cysts, biliary dysgenesis, chronic cholangitis, and portal fibrosis1.
The New Zealand White (NZW) rabbit (Oryctolagus cuniculus) is commonly used in biomedical research, especially for renal and cardiovascular studies. The kidney of O. cuniculus has several unique functional and structural qualities17. Unlike other species, the rabbit is absolutely dependent on the kidney for proper calcium osmoregulation18,19. The renal fractional excretion of calcium in the rabbit is 45%, versus <2% in other mammals, which eliminate excess calcium through the intestinal tract19,20. Healthy rabbits maintain high serum calcium levels when compared to other species. Normal serum calcium levels in the rabbit are 11–14 mg/dL, and the upper limit of the normal reference range used in some laboratories is 16 mg/dL21. Calcium is constitutively absorbed from the rabbit gut, and dietary intake significantly influences serum levels in this species19,22. Because rabbits absorb calcium constitutively and are dependent on properly functioning kidneys for excretion, rabbits with kidney disease or those fed diets containing excessive calcium often develop hypercalcemia22,23,24,25. A common sequel to hypercalcemia in rabbits is metastatic mineralization of blood vessels and other soft tissues26,27. In muscular arteries, mineral deposits and scavenger cells aggregate in the tunica media, with disruption and degeneration of smooth muscle fibers resembling Mönckeberg's medial calcific sclerosis28.
In contrast to humans, few cases of renal cystic diseases have been reported in the rabbit. Heritable renal cysts attributed to an autosomal-recessive mutation with incomplete penetrance were described in the IIIvo rabbit strain29. These simple renal cysts of tubular origin were not associated with clinical signs or biochemical abnormalities referable to renal failure29. Experimentally, NZW rabbits given a single injection of long-acting corticosteroids on the day of birth developed cystic renal lesions and other defects including runting, muscular atrophy, and alopecia30. Renal cysts attributed to urinary obstruction were described in a case of idiopathic hypercalcemia in an NZW rabbit23. To our knowledge, there are no reports of spontaneous, clinically significant cystic renal disease in unrelated rabbits.
We present in this report a retrospective analysis of cystic kidney disease with common microscopic features in unrelated laboratory NZW rabbits, for which we propose the name polycystic kidney syndrome (PKS). PKS is associated with hypercalcemia and metastatic mineralization of muscular arteries and other soft tissues. Clinical signs and renal lesions in these rabbits are consistent with developmental human cystic kidney diseases. Idiopathic hypercalcemia is relatively common in New Zealand White rabbits, and it is possible that PKS contributes to this high prevalence. Familiarity with PKS may allow investigators to avoid confounding of results in renal and cardiovascular research by removing affected rabbits from animal studies. Laboratory animal production facilities may identify affected rabbits and remove carriers from the breeding pool. Finally, molecular and genetic characterization of this syndrome in rabbits may provide an important new small animal model of developmental cystic kidney disease of humans.
METHODS
Animal sources and husbandry
Experimental and control rabbits were acquired from multiple commercial sources including Hare (Hewitt, NJ, USA), Millbrook Breeding Labs (Amherst, MA, USA), and Covance (Denver, PA, USA). Animals were assigned identification numbers upon arrival at the Massachusetts Institute of Technology (MIT), and a separate Division of Comparative Medicine, Comparative Pathology Laboratory, diagnostic accession number at the time of necropsy Table 1. All animals included in this study were maintained at MIT except cases #92–1438 and 01–2554, which arrived for post-mortem evaluation from other institutions. Animals tested negative for a panel of important rabbit pathogens including Encephalitozoon cuniculi, and were housed singly in cages with slotted floors in an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC)-accredited facility. The environment was controlled for temperature, relative humidity, light/dark cycle, and ventilation. Animals received water and a commercial rabbit chow (Purina laboratory rabbit diet 5321 before 1995 and diet HF 5326 after 1995; Ralston Purina Co., St. Louis, MO, USA) ad libitum.
Table 1 - Summary of animal age, gender, and serum biochemical data in rabbits with polycystic kidney syndrome, other renal diseases, or normal age-matched controls.
Full table Case selection
Records from 1986–2002 in the MIT Division of Comparative Medicine, Comparative Pathology Laboratory, archives were reviewed. Included in this study were animals that had kidney lesions meeting the criteria of PKS, animals with other significant kidney lesions and corroborating serum chemistry data, and age-matched control animals without kidney lesions and for which serum chemistry data were available. Necropsies and initial histopathology were performed at MIT, and serum was sent to commercial veterinary reference laboratories for chemical analysis. Hematoxylin and eosin (H&E) stained kidney sections were reviewed for this study by a comparative pathologist without knowledge of case histories. Based on this histopathologic review, cases were assigned to one of three groups: (1) renal lesions consistent with PKS; (2) significant renal lesions not consistent with PKS and for which serum chemistry data were available; and (3) no signficant renal lesions, also with serum chemistry reports.
Special stains and immunohistochemistry
Formalin-fixed, paraffin-embedded tissues were retrieved, cut at 5 
, and stained with H&E, Masson's trichrome, Congo red, periodic-acid Schiff (PAS), or von Kossa. Microwave antigen–retrieved tissue sections were analyzed for lectin binding by biotinylated Dolichos biflorus (Sigma, St. Louis, MO, USA), or by immunohistochemistry using primary mouse antibodies against pan-cytokeratin (AE1/AE3; Dako, Carpinteria, CA, USA), rabbit immunoglobulins (Dako), or vimentin (Dako), followed by biotinylated anti-mouse immunoglobulin IgG, using a previously described protocol31.
Electron microscopy
Formalin-fixed kidney tissue was evaluated by transmission electron microscopy (glutaraldehyde-fixed specimens were not available). Tissues representing renal cortex, corticomedullary junction, and medulla were post-fixed in osmium tetroxide and processed by standard techniques as previously described32.
Statistical analysis
Statistical analyses of rabbit serum chemistry values between groups were performed by one-way analysis of variance (ANOVA) followed by Dunnett's post-test using Instat 3.0 software (GraphPad, Inc., San Diego, CA, USA). Comparisons of gender and clinical signs between groups were assessed by Fischer exact test.
RESULTS
Case selection
Review of records archived from 1986–2002 yielded 335 total rabbit records. Of those, 132 cases were eliminated because no renal histopathology was performed. Of the 203 cases in which kidney tissues were evaluated by histopathology, there were 63 with reported lesions. From these 63 cases we identified 7 cases of PKS which we defined by the following 3 criteria: (1) cysts or microcysts derived from tubules, glomeruli, or both; (2) loose mesenchymal expansion of cortical and/or medullary interstitium; and (3) irregular thickening, thinning, and splitting of tubular and/or glomerular basement membranes. Additionally, we identified 3 cases with available serum chemistry data and significant renal lesions inconsistent with PKS. The remaining 53 cases were not evaluated further because renal lesions were mild or serum chemistry data were unavailable. Thus, histopathologic assessment of kidneys from 203 rabbits revealed 7 cases of PKS (3.4%). Ten control cases were chosen based on age-matching criteria, absence of renal lesions, and availability of serum chemistry data.
Clinical presentation
Rabbits with PKS were significantly more likely to have a clinical history of weight loss and/or anorexia than unaffected controls (P = 0.015). However, anorexia and/or weight loss were equally common in rabbits with PKS and those with other significant renal diseases (P = 1.0). Additional clinical signs recorded from some rabbits with PKS included hematuria, lethargy, and pale mucous membranes. One animal, case #92–1438, had a history of polyuria and polydypsia progressing to oliguria and unthriftiness. Rabbits with PKS first demonstrated clinical signs at 2.9 (
1.3) years of age. Euthanasia was performed most commonly in both PKS and other renal disease groups due to serious illness. Gender did not appear to influence the risk for PKS when compared to healthy controls (P = 1.0) or other renal diseases (P = 0.18); however, the preponderance of females in our overall study population made gender comparisons difficult Table 1.
Serum chemistry
Rabbits with PKS had significant hypercalcemia (18.4 3.9 mg/dL vs. 13.4 1.2 in control; P < 0.01; Table 1). Hypercreatinemia was also associated with PKS (3.5 2.0 mg/dL vs. 1.5 0.4 in control; P < 0.01). Rabbits with PKS also exhibited higher serum albumin than control animals, although levels in both groups remained within the normal reference range for the species Table 133. Blood urea nitrogen (BUN) was inconsistently elevated in rabbits with PKS; however, BUN is an insensitive measure of renal disease in rabbits due to circadian fluctuations, cecal microflora urea metabolism, and other factors34, 35, 36 and 37. Mean serum phosphorus in rabbits with PKS was below the lower reference limit, and lower than control rabbits, although the difference between groups did not reach statistical significance Table 133. One rabbit with PKS (#92–1438) exhibited markedly increased levels of serum sodium (200 mEq/L), potassium (10.9 mEq/L), and chloride (139 mEq/L)33. Urinalysis data were not available.
Gross lesions
Lesions identified at necropsy were highly variable among rabbits with PKS. In many instances there were no reported gross lesions other than decreased body fat. Some rabbits exhibited variation in size between kidneys that was sometimes marked. There was one case of unilateral hydroureter with confirmed obstruction by a urolith; however, the absence of severe hydronephrosis in the ipsilateral kidney suggested that the ureteral obstruction was incomplete or occurred shortly before euthanasia. Although urinary calculi with renal grit Figure 1 and urocystic stones were common in the kidneys and bladder, respectively, hydronephrosis and hydroureter were rare. Because of the high fractional excretion of calcium in the kidney and production of alkaline urine, calcium carbonate crystals are normally present in the rabbit urinary bladder. Grossly visible renal cysts were infrequently reported, but when present were invariably confined to the cortex and were usually <2 mm diameter. In some cases, pinpoint surface depressions were identified following removal of the renal capsule, and cortical microcysts were barely evident on cut surface Figure 1. In other organs, vascular mineralization resulting in rigid "pipestem" arteries was a frequent finding in rabbits with PKS and hypercalcemia. Gross liver lesions were not reported.
Figure 1.
Gross renal lesions, polycystic kidney syndrome (PKS). Pinpoint surface lesions (arrows) noted after removal of the renal capsule (A). Cortical mineral deposits (white arrow) and microcysts (black arrow) at low (B) and high (C) magnification.
Full figure and legend (36K)Histopathology
Microscopic lesions in rabbits with PKS were highly variable between animals, and even between segments of the same kidney when compared with normal control animals (Figure 2a and B). Inclusion in this group, however, required that kidneys from all rabbits with PKS meet our 3 defining histologic criteria described above (Figure 2c–E). Animals with glomerular cysts exhibited clear dilation of Bowman's spaces up to 1 mm diameter with shrinkage, atrophy, and clefting of the tuft, but glomerular fibrosis was not marked. Bowman's capsules were irregularly thickened and split and sometimes lined by plump cuboidal parietal epithelium. Dilation of convoluted tubules and/or collecting ducts was variable, with attenuation of epithelium in larger cysts. Tubular lumens contained sloughed epithelium, cellular debris, and rare protein or waxy casts. Tubular mineralization was most apparent in distal convoluted tubules. Segmentally, cortical tubules were shrunken, lost, or disorganized. Mesenchymal expansion of interstitium was characterized by a mild-to-moderate infiltrate of fibroblasts and rare macrophages, irregular collagen formation in a loose amorphous-to-fibrillar matrix, and widening of the space between residual tubules. Some rabbits had multifocal, mild-to-moderate, interstitial nephritis characterized by infiltrates of mononuclear cells, usually most prominent near arcuate vessels. In the medulla, loose amorphous expansion of interstitium and decreased numbers of loops of Henle and collecting tubules and ducts were the most common abnormalities. Renal pelvicalyces and proximal ureters were mildly dilated or within normal limits except in the single case of ureteral obstruction. Muscular arteries in the kidney and elsewhere were disrupted by fine mineral deposits with myofiber degeneration and infiltration of phagocytes in the tunica media of rabbits with hypercalcemia Figure 2f. Otherwise, renal vessels were normal except for occasional mild perivascular fibrosis; thrombosis was not detected grossly or histologically. In the liver there was mild but consistent chronic portal hepatitis characterized by small aggregates of mononuclear leukocytes with a few granulocytes in rabbits with PKS Figure 2g. Additionally, there was mild-to-moderate bile duct duplication, ductular epithelial hyperplasia and/or dysplasia with occasional pseudostratification, and minimal pericholangiolar fibrosis Figure 2h.
Figure 2.
Histopathology of polycystic kidney syndrome (PKS). Normal rabbit kidney (A) versus segmentally variable lesions in kidney with PKS (B). Three polycystic kidney syndrome–defining criteria: (1) cystic or microcystic lesions affecting tubules, glomeruli, or both (C); (2) loose mesenchymal expansion of interstitium (D); and (3) irregular thickening (arrow), thinning, and/or splitting of basement membranes (E). Mineralization with artifactual fissure (arrow) in tunica media of muscular artery resembling Mönckeberg's medial calcific sclerosis (F). Hepatic lesions associated with PKS including mild chronic cholangitis and pericholangitis (G) and cholangiodysplasia and fibrosis (H). H&E, hematoxylin & eosin; bar = 500 (A, B), 100 (C, H), 250 (D), or 50 (E, F, G).
Rabbits with significant non-PKS renal lesions and biochemical evidence of renal failure included two animals with obstructive ureteral urolithiasis resulting in classic hydronephrosis characterized by marked renal pelvicalyceal dilation with compression atrophy of medullary and deep cortical structures and dilation of persistent collecting ducts. The other case involved signficant bilateral kidney effacement by a metastatic uterine adenocarcinoma. We identified a rabbit with evidence of multifocal renal thrombosis characterized by radial streaks of dense cortical fibrosis with mild mononuclear inflammation, tissue contraction caused by loss of affected pyramid glomeruli and tubules, and depression of the overlying capsule. We excluded this case from our study, however, as there was no clinical or biochemical evidence of renal insufficiency. Finally, we identified one animal with a 5-mm diameter solitary renal cortical cyst of presumptive tubular origin, consistent with previous reports in the IIIvo rabbit strain, also with no evidence of functional impairment29.
Special stains, lectin binding, and immunohistochemistry
PAS stain of polycystic kidneys highlighted the irregular thickening, thinning, and splitting of basment membranes observed in H&E-stained sections Figure 3a. Von Kossa stain confirmed the basophilic crystalline deposits in distal convoluted tubules and vessels observed in H&E-stained sections to be mineral, consistent with dystrophic or metastatic calcification Figure 3b. Masson's trichrome stain highlighted irregular collagen deposits in pale-staining, loose, amorphous-to-fibrillar interstitial matrix Figure 3c. Absence of congophilia in Congo red–stained sections confirmed that the expanded matrix was not amyloid Figure 3d. Compared with normal control Figure 4a, Dolichos biflorus lectin binding to N-acetylgalactosamine on collecting duct epithelium demonstrated loss of collecting ducts in affected rabbit kidneys, sometimes with irregular patchy labeling of interstitium in areas of degenerating collecting ducts, presumably caused by diffusion of residual glycoconjugate molecules Figure 4b. Cytokeratin staining labeled many but not all microcystic ducts and tubules, indicating involvement of both the convoluted and collecting tubular systems Figure 4c. Vimentin immunohistochemistry highlighted the infiltration of fibroblasts in expanded interstitial areas Figure 4d. An unexpected finding was the marked expression of vimentin in the epithelium of convoluted and/or collecting tubules in affected but not normal rabbit kidneys, suggesting dedifferentiation of tubular epithelial cells or failure of complete epithelial lineage commitment during organogenesis (Figure 4e and F). No abnormal immunoglobulin deposits consistent with immune-mediated disease were detected by immunohistochemistry (data not shown).
Figure 3.
Histochemical analysis of polycystic kidney syndrome (PKS). Periodic-acid Schiff (PAS) stain highlights irregular thickening and splitting of glomerular and tubular basement membranes (A). Von Kossa stain illustrates selective mineralization of distal convoluted tubules (B). Masson's trichrome stain demonstrating irregular loose and dense (arrow) fibrocollagenous expansion of interstitial stroma (C). Absence of congophilia in Congo red–stained section rules out amyloid deposition as the cause of mesenchymal expansion (D); note small mononuclear leukocyte aggregate in arcuate perivascular region (arrow). Bar = 50 (A), 100 (B), or 250 (C, D).
Figure 4.
Lectin-binding and immunohistochemical analysis of polycystic kidney syndrome (PKS).Dolichos biflorus lectin labels linearly arrayed collecting ducts in normal rabbit kidney (A); ducts in rabbit with PKS (B) are disorganized and decreased in number with diffuse pools of pale staining in regions of active ductular atrophy (arrows). Mixed presence and absence of cytokeratin labeling among dilated tubules suggests involvement of both convoluted and collecting tubuloductular systems (C). Increased vimentin-expressing mesenchymal cells in regions of expanded interstitium (D). Vimentin is expressed in blood vessels and glomerular mesangium, but not tubules, of normal rabbit (E). Aberrent expression of vimentin in many tubules and ducts (arrows) in rabbit with PKS (F). Diaminobenzidine label, Gill's hematoxylin counterstain. Bar = 500 (A–D) or 100 (E, F).
Electron microscopy
Transmission electron microscopy confirmed atrophy and clefting of tufts in glomerulocystic lesions, as well as periglomerular interstitial edema Figure 5a. Thickening and splitting of glomerular basement membranes was largely restricted to Bowman's capsule, with relative sparing of the endothelial-podocyte basement membrane complex in the tuft Figure 5b. Tubular basement membranes were variably thinned or thickened, split, and sometimes intercalated with collagen fibrils and/or microtubule-like bodies Figure 5c. Interstitial cellularity and matrix were highly variable, ranging from early tubular degeneration with fibroblast expansion Figure 5d, to marked tubular atrophy with fibroblastic replacement Figure 5d, to hypocellular regions comprised almost entirely of irregular bundles of collagen in a loose proteinaceous-to-fibrillar stroma Figure 5f.
Figure 5.
Transmission electron microscopy, polycystic kidney disease (PKS). Glomerular atrophy (black arrow) and dilation of Bowman's space accompanied by periglomerular edema (white arrow; A). Irregular thickening of Bowman's capsule with intercalated collagen fibrils (black arrow); contrasted with more normal glomerular endothelial-podocyte basement membrane complex (white arrow; B). Tubular basement membrane alterations include thinning and splitting with intercalation of microtubule-like structures (black arrow) and marked amorphous thickening (white arrow; C). Early fibrocollagenous expansion of cortical interstitium; note degenerating tubule (arrow) with condensation of cytoplasm and loss of well-defined organelles (D). Fibroblast hyperplasia in region of tubular atrophy (dark arrow); note relative sparing of blood vessel (white arrow; E). Interstitial hypocellularity with irregular collagen bundles (arrow) in a loose proteinaceous and fibrillar matrix (F). Bar 20 (A, D), 5 (B, F), or 10 (C, E).
DISCUSSION
We describe in this report a group of laboratory New Zealand White rabbits with renal abnormalities resembling human polycystic kidney diseases. This study was prompted by the unexpected finding of dysmorphogenic and cystic renal lesions in a rabbit submitted for necropsy because of calcified arteries encountered during an experimental surgical procedure. Lesions were variable, but always exhibited the 3 syndrome-defining criteria described in Methods. We have proposed the term polycystic kidney syndrome (PKS) for this disease entity in rabbits pending elucidation of the underlying cause(s). In most instances disease was bilateral but asymmetrical and segmentally variable. PKS was strongly associated with hypercalcemia and metastatic mineralization of muscular arteries and other soft tissues. We identified PKS in 3% of renal tissue specimens from our archives, suggesting that PKS may be a significant contributor to the high prevalence hypercalcemia in this breed19,21, 22 and 23.
Features of PKS in New Zealand White rabbits that resembled human ADPKD include involvement of the entire nephron, variable penetrance and clinical expression, onset of signs in maturity, and a relatively high prevalence4,38,39. On the other hand, some features of PKS more closely resembled human ARPKD, including the small and somewhat uniform size of renal cysts, and liver lesions characterized by mild cholangiodysplasia, fibrosis, and pericholangitis without hepatic cysts1,4,13,38, 39 and 40. Together, the mixed spectrum of lesions in rabbits with PKS mirrors the overlapping presentation of cystic kidney diseases in humans, and highlights the need for further molecular and genetic characterization6,41,42. Additionally, some diagnostic criteria of PKS are shared with nephrosclerosis (e.g., interstitial fibrosis and basement membrane alterations), and further study will be required to determine the potential role of renal hypertension as an inducer or potentiator of cystic nephropathy in the rabbit.
ADPKD occurs with mutations to either PKD1, PKD2, or, rarely, PKD343. The primary PKD gene products, polycystin-1 and polycystin-2 interact to form a calcium-selective cation channel44. To date, the subcellular localization and role of these proteins in the development of ADPKD have not been completely elucidated. Although the hypercalcemia in rabbits with PKS may be entirely attributable to renal failure, it is also possible that mutations of the genes responsible for intracellular calcium regulation in key cell populations may contribute to overall serum increases of this electrolyte.
The clinical signs most commonly observed in rabbits with PKS were anorexia and weight loss. Signs more specific to renal failure, including polydypsia and polyuria progressing to oliguria, were not generally recorded. This may be largely due to management and husbandry practices in modern animal care facilities. Conventionally reared laboratory rabbits often have automatic watering systems and are not maintained in metabolism cages for the quantitation of daily urinary output. In such settings it is not surprising that changes in water intake and urination would go unnoticed. Interestingly, the only rabbit with PKS in our study that was not raised with an automated watering system was noted to have polydypsia. Another reason why this syndrome may go unnoticed in a research environment is because observable signs first appear at 2 to 3 years of age. Research studies involving rabbits are often terminated before that time. Many of the rabbits with PKS were older rabbits used to produce polyclonal antibodies. However, antibody production per se did not increase the risk of PKS, as most of the unaffected age-matched controls in this study were also used to generate polyclonal antibodies.
Polycystic kidney disease has been reported in a variety of animals including mice, ferrets, rats, Persian cats, and dogs5,45, 46, 47, 48, 49, 50 and 51. Indeed, the striking resemblance of PKS to certain forms of canine familial nephropathy provides further evidence of the likely heritable nature of this condition in rabbits52. The use of these animals as models of human polycystic kidney diseases varies from extensive, in the case of the mouse and the rat, to rare, in the case of the dog, ferret, and cat. The rabbit compares favorably to rodent species as a model for human polycystic kidney disease. Rabbit PKS lesions and progression closely resemble human cystic kidney diseases. Additionally, NZW rabbits represent a readily available, docile, well-characterized research animal for which a wide array of laboratory reagents is available.
CONCLUSION
Identification of rabbits with PKS is significant for 3 reasons. First, PKS may confound research results relying on the NZW rabbit, particularly studies of the cardiovascular and urinary systems, and affected animals should be identified and removed. Second, careful screening may allow commercial rabbitries to remove animals with PKS from the breeding pool. Finally, prospective studies with molecular and genetic characterization of this syndrome may produce a valuable new small animal model of human cystic kidney diseases.
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Acknowledgments
This work was supported in part by National Institutes of Health T32-RR07036 to J.G.F. We thank Kathleen Cormier and the DCM Histology Laboratory for excellent tissue preparations, Nicki Watson for electron microscopy, Bobi Young for administrative assistance, and Dr. Amy Hancock for help with case selection. We are especially indebted to Helmut Rennke, M.D., for slide review and consultation on the pathology of human cystic kidney diseases.
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