American Journal of Pathology, Vol. 139, No. 3, September 1991 Coprzght © American Association of Pathologit
Animal Model of Human Disease Hereditary Polycystic Kidney Disease Adult Polycystic Kidney Disease Associated with Renal Hypertension, Renal Osteodystrophy, and Uremic Enteritis in SPRD Rats
J. Kaspareit-Rittinghausen, F. Deerberg, and A. Wcislo From the Central Institute for Laboratory Animal Breeding, Hannover, Federal Republic of Germany
Biologic Features Polycystic kidney disease in man is a hereditary defect that exists in two basic types with different modes of genetic transmission and different age of onset of renal failure. Adult polycystic kidney disease (APKD) is an autosomal dominant condition that progresses to renal insufficiency between the fourth and sixth decades of life.' It accounts for 5% to 8% of renal failures in individuals admitted to renal transplantation and ranks third (behind glomerulonephritis and pyelonephritis) as a cause of end-stage kidney disease.2 Adult polycystic kidney disease in humans frequently is associated with liver cysts3 and intracranial aneurysms.4 Subarachnoid hemorrhage due to rupture of cerebral aneurysms is an important cause of death in patients suffering from APKD.4 In contrast, infantile polycystic kidney disease (IPKD) is a hereditary defect transmitted in an autosomal recessive pattern. This disease of newborns is fatal, with 75% of affected infants dying within the first 24 hours of life and 93% dying within the first year of life.5 Laboratory animal models of hereditary cystic kidney disease with known mode of genetic transmission have been described in different strains of mice6-9 and rabbits.10 In none of these models have signs of chronic renal failure such as renal osteodystrophy, uremic enteritis, and renal hypertension been reported.
Animal Model In 1986 male Han:SPRD rats with polycystic kidney disease (PKD) were observed in the breeding colony of this strain at the Central Institute for Laboratory Animal Breed-
ing. The offspring of one male with PKD was bred for establishment of a colony of this mutant. The colony has now been maintained for 11 generations. The observed ratio of phenotypes born from matings with rats both affected by PKD as well as from matings of healthy and diseased rats is consistent with that of an autosomal incomplete dominant trait transmitted by a single gene. In homozygous animals, the disease is fatal within the first 3 to 4 weeks of life. Clinically, affected homozygous rats show a markedly distended abdomen, apathy, and tremble. At necropsy, the kidneys are bilaterally extremely enlarged (kidney weight often accounts for more than 20% of body weight) and pale (Figure 1). Under the smooth renal surface, numerous cysts of different size are visible. Histologically, kidneys of 3- to 4-week-old rats contain large cysts that occupy the entire organ. All homozygous animals demonstrate severe dilation of the renal pelvis accompanied by atrophy of the renal papilla. Heterozygous males show signs of severe illness and die at about 6 months. They are apathetic, have a ruffled fur coat, and show signs of anemia such as pale mucous membranes and conjunctivae. Heterozygous females lack any clinical signs of illness at that point. At autopsy, kidneys of both sexes are rough, and numerous cysts are present in their parenchyma (Figure 2). Females, however, generally demonstrate smaller and fewer cysts when compared with males of the same age. Although cyst number and size are considerably increased in 10-month-old females compared with Publication sponsored by the Registry of Comparative Pathdogy, Armed Forces Institute of Pathology and supported by Grant RR-00301 from the Division of Research Resources, NIH, under the auspices of Universities Associated for Research and Education in Pathology, Inc., and by Hazelton Laboratones America, Inc. Address reprint requests to Dr. J. Kaspareit-Rittinghausen, Department of Toxicology, Squibb-von Heyden, Donaustaufer Str 378, 8400 Regensburg, Federal Republic of Germany.
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AJP September 1991, Vol. 139, No. 3
I I
I Figure 1. Macroscopic appearance ofpolycystic kidneys in a 3- to 4-week-old homozygous SPRD rat. Note that the polycystic kidneys occupy nearly the whole abdominal cavity.
Figure 3. Microscopic appearance of polvcvstic kidnevs in 6-month-old male heterozygous SPRD rats (HE, x 9).
6-month-old females, the degree of cyst formation observed in 6-month-old males is not reached by the older females, and they appear clinically healthy (unpublished). Further macroscopic findings in males are enlarged parathyroid glands, stiff tubelike aortae, and small white streaks in the walls of heart and stomach. Thickening of the walls of colon and cecum with intramural bleedings is frequent in 6-month-old heterozygous males.11 When examined histologically, the renal tissue of 6-month-old rats of both sexes and 1 0-month-old females is composed of irregular cysts (Figure 3) lined by a cuboidal or flat epithelium. Proximal and distal convoluted tubules as well as collecting tubules are uniformly involved. Cysts are embedded in a loose fibrous tissue and many contain purulent exudate or proteinaceous casts. The most important consequence of reduced kidney function is the development of renal osteodystrophy, with striking hyperplasia of the parathyroid glands and replacement of bone by fibrous tissue, in the great majority of heterozygous, 6-month-old males (Figures 4, 5). Metastatic calcification varies between different animals and involves basement membranes (Figure 6) of renal glomeruli and tubules, walls of aorta and other large vessels, walls of
fore- and glandular stomach, alveolar walls of the lungs, and heart muscle. Renal osteodystrophy does not occur in heterozygous 6-month-old females,11 but is present in a few 1 0-month-old female rats (unpublished). Foci of fibrosis of the heart are observed in one fourth of males with PKD in the walls of both ventricles and the septum. Polycystic kidney disease is accompanied by uremic enteritis in about 40% of males. They demonstrate marked edema and infiltration with polymorphonuclear granulocytes in the walls of cecum and colon, as well as numerous ulcers in both segments of large intestine.11 Blood urea nitrogen (BUN) values are presented in Table 1. They are markedly elevated in 6-month-old male rats, and only slightly raised in 6-month-old females.11 In accordance with the progression of PKD in 6- to 10month-old females, BUN is increased further in the older female rats (unpublished), but has still not reached BUN values estimated in 6-month-old males. Measurements of systolic blood pressure in rats with PKD aged 5.5 months (Table 2) show a marked increase in males. Although female rats have an average blood pressure of 1 19 mm Hg, it is increased to 167 mm Hg in males. Two thirds of the male rats with PKD show blood pressure values above 170 mm Hg.12
I
I
**. _S
w_V
I
Figure 2. Macroscopic appearance of polycystic kidneys in 6-month-old male heterozygous SPRD rats.
Figure 4. Secondary hyperparathyroidism in a 6-month-old heterozygous male rat (HE, X 15).
Polycystic Kidney Disease in the Rat 695 AJP September 1991, Vol. 139, No. 3
Table 1. Blood Urea Nitrogen Values (mg/100 ml) of Rats with PKD
Age
Sex Male controls Males with PKD
(months)
Female controls Females with PKD Female controls Females with PKD Figure 5. Renal osteodystropy with replacement of bone bvfibrous tissue in a 6-month-old heterozvgous male rat (HE, x 40).
Comparison with Human Disease Genetic transmission of the disease in rats is quite similar to human APKD. Both renal disorders are transmitted by a single gene as autosomal-dominant traits. In accordance with the onset of signs of illness in adult patients, PKD of heterozygous male SPRD rats also occurs in adult animals. In contrast to humans suffering from APKD, development of renal lesions and onset of uremia is retarded in female rats compared with males, indicating lower expressivity of the gene in females. Macroscopic and histologic appearance of kidneys in heterozygous rats with PKD closely resemble that of human beings. Cysts have been also described in humans with APKD in a variety of other locations, however, including liver, pancreas, lungs, spleen, ovaries, testis, epididymis, thyroid, uterus, broad ligament, and bladder.2 In none of these organs could comparable cystic changes be found in SPRD rats. They also lack cerebral aneurysms as observed in humans. Several complications of the primary disease are as-
x
SD
t test
1.90
19.46
217.32 137.45 P < 0.001 18.86 2.75
6 6
25.73 21.62
10
43.81
7.31 P < 0.001 3.14 35.20 P < 0.05
sociated with APKD in humans. Urinary tract infection, resulting in pyuria and bacteriuria, develops in 50% to 75% of all patients during the course of their illness.2 Purulent nephritis is also seen in the majority of rats with PKD. Renal hypertension is a further clinical feature of PKD that the rat model shares with its human counterpart, where it occurs in 70% to 75% of patients with APKD.2 Renal insufficiency due to loss of functional capacity accompanies APKD, just as do many other severe renal diseases. Uremia is a frequent terminal event in the clinical course of APKD in humans.5 Markedly increased BUN values leading to death in a state of uremic coma also characterize the final stage of PKD in heterozygous male rats. As could be expected from the delayed progression of renal cystic changes in females, they demonstrate only mild uremia. Uremia coincides partly with hemorrhagic and ulcerative colitis and typhlitis in heterozygous males. Comparable lesions located in cecum, colon, and rectum have also been described in humans with uremia.13'14 Advanced renal insufficiency resulting from any kind of severe chronic disease of the kidneys can be associated with renal osteodystrophy in humans.15 Renal osteodystrophy is observed in the great majority of males with PKD and accompanied by metastatic calcification of a variety of tissues that are identical to those affected by metastatic calcification in humans.15
Usefulness of the Model The SPRD mutant is the first model of inherited polycystic kidney disease observed in rats. In contrast to most of the Table 2. Systolic Blood Pressure (mmHg) in Rats with PKD Aged 5.5 Months
Sex
Figure 6. Metastatic cakification of tubular basement membranes in a polycystic kidney of a 6-month-old heterozygous male rat (HE, x40).
Male controls Males with PKD Female controls Females with PKD
x
SD
115.2 167.4 109.3 119.4
11.0 22.0 11.7 11.9
ttest
P < 0.001 P < 0.01
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Kaspareit-Rittinghausen, Deerberg, and Wcislo
AJP September 1991, Vol. 139, No. 3
mouse models, diseased heterozygous rats are able to survive for at least 6 months (males) or even considerably longer (females) and present the possibility of continuous studies on the course of PKD and of the complications associated with that disease. The model is suitable for research on the field of histogenesis of this important illness of humans from the earliest expression in utero to its terminal stages. Furthermore this rat model offers opportunity for studies concerning the relationship between structural renal alterations and symptoms of chronic renal failure such as renal osteodystrophy, uremia, uremic enteritis, and renal hypertension.
Availability Litters from matings of heterozygote with nonaffected SPRD rats for the establishment of satellite colonies of this SPRD mutant with hereditary PKD are available on request from the Central Institute for Laboratory Animal Breeding, Hannover, Federal Republic of Germany.
References 1. Furlow WL, Greene LF: Congenital polycystic kidney disease. Med Clin North Am 1966, 50:1111-1117 2. Danovitch GM: Clinical features and pathophysiology of polycystic kidney disease in man, Cystic Diseases of the Kidney, Perspectives in Nephrology and Hypertension, Vol 4. Edited by KD Gardner Jr. New York, Wiley, 1976, pp 125-150 3. Comfort MW, Gray HK, Dahlin DC, Whitesell FB Jr: Polycystic disease of the liver: A study of 24 cases. Gastroenterology 1952, 20:60-65 4. Grantham JJ: Polycystic renal disease. Strauss and Welt's Diseases of the Kidney, Vol 2. Edited by LE Early, CW
Gottschalk. Boston, Little, Brown and Co, 1979, pp 11231146 5. Daalgard OZ: Polycystic disease of the kidneys, Diseases of the Kidney, Vol 2. Edited by MB Straus, LG Welt. Boston, Little, Brown and Co, 1971, pp 907-937 6. Fry JL, Koch WE, Jenette JC, McFarland E, Fried FA, Mandell J: A genetically determined murine model of infantile polycystic kidney disease. J Urol 1985,134:828-833 7. Takahashi H, Ueyama Y, Hibino T, Kuwahara Y, Suzuki S, Hioki K, Tamaoki N: A new mouse model of genetically transmitted polycystic kidney disease. J Urol 1986, 135:1280-1283 8. Werder AA, Amos MA, Nielson AH, Wolfe GH: Comparative effects of germfree and ambient environments on the development of cystic disease in CFWWd mice. J Lab Clin Med 1984,103:399-407 9. Gialamas J, Hoger H, Adamiker D: Polycystische Nierenerkrankung bei infantilen Mausen. Z Versuchstierkd 1987, 30:217-222 10. Fox RR, Krinsky WL, Crary DD: Hereditary cortical renal cysts in the rabbit. J Hered 1971, 62:105-109 11. Kaspareit-Rittinghausen J, Rapp K, Deerberg F, Wcislo A, Messow C: Hereditary polycystic kidney disease associated with osteorenal syndrome in rats. Vet Pathol 1989, 26:195-201 12. Kaspareit-Rittinghausen J, Deerberg F, Rapp K, Wcislo A: Renal hypertension in rats with hereditary polycystic kidney disease. Z Versuchstierkd 1990, 33:201-204 13. Mason EE: Gastrointestinal lesions occurring in uremia. Ann Intern Med 1952, 37:96-105 14. Eknoyan G: Pathophysiology of chronic renal failure and uremic syndrome. In: Pathophysiology of the kidney. Edited by NA Kurtzmann, M Martinez-Maldanado. Springfield, CC Thomas Publisher, 1977, pp 843-880 15. Coburn JW, Slatopolsky E: Vitamin D, parathyroid hormone and renal osteodystrophy. In: The Kidney. Edited by BM Brenner, FC Rector. Philadelphia, WB Saunders, 1986, pp 1657-1731
Animal Model of Human Disease Hereditary Polycystic Kidney Disease Adult Polycystic Kidney Disease Associated with Renal Hypertension, Renal Osteodystrophy, and Uremic Enteritis in SPRD Rats
J. Kaspareit-Rittinghausen, F. Deerberg, and A. Wcislo From the Central Institute for Laboratory Animal Breeding, Hannover, Federal Republic of Germany
Biologic Features Polycystic kidney disease in man is a hereditary defect that exists in two basic types with different modes of genetic transmission and different age of onset of renal failure. Adult polycystic kidney disease (APKD) is an autosomal dominant condition that progresses to renal insufficiency between the fourth and sixth decades of life.' It accounts for 5% to 8% of renal failures in individuals admitted to renal transplantation and ranks third (behind glomerulonephritis and pyelonephritis) as a cause of end-stage kidney disease.2 Adult polycystic kidney disease in humans frequently is associated with liver cysts3 and intracranial aneurysms.4 Subarachnoid hemorrhage due to rupture of cerebral aneurysms is an important cause of death in patients suffering from APKD.4 In contrast, infantile polycystic kidney disease (IPKD) is a hereditary defect transmitted in an autosomal recessive pattern. This disease of newborns is fatal, with 75% of affected infants dying within the first 24 hours of life and 93% dying within the first year of life.5 Laboratory animal models of hereditary cystic kidney disease with known mode of genetic transmission have been described in different strains of mice6-9 and rabbits.10 In none of these models have signs of chronic renal failure such as renal osteodystrophy, uremic enteritis, and renal hypertension been reported.
Animal Model In 1986 male Han:SPRD rats with polycystic kidney disease (PKD) were observed in the breeding colony of this strain at the Central Institute for Laboratory Animal Breed-
ing. The offspring of one male with PKD was bred for establishment of a colony of this mutant. The colony has now been maintained for 11 generations. The observed ratio of phenotypes born from matings with rats both affected by PKD as well as from matings of healthy and diseased rats is consistent with that of an autosomal incomplete dominant trait transmitted by a single gene. In homozygous animals, the disease is fatal within the first 3 to 4 weeks of life. Clinically, affected homozygous rats show a markedly distended abdomen, apathy, and tremble. At necropsy, the kidneys are bilaterally extremely enlarged (kidney weight often accounts for more than 20% of body weight) and pale (Figure 1). Under the smooth renal surface, numerous cysts of different size are visible. Histologically, kidneys of 3- to 4-week-old rats contain large cysts that occupy the entire organ. All homozygous animals demonstrate severe dilation of the renal pelvis accompanied by atrophy of the renal papilla. Heterozygous males show signs of severe illness and die at about 6 months. They are apathetic, have a ruffled fur coat, and show signs of anemia such as pale mucous membranes and conjunctivae. Heterozygous females lack any clinical signs of illness at that point. At autopsy, kidneys of both sexes are rough, and numerous cysts are present in their parenchyma (Figure 2). Females, however, generally demonstrate smaller and fewer cysts when compared with males of the same age. Although cyst number and size are considerably increased in 10-month-old females compared with Publication sponsored by the Registry of Comparative Pathdogy, Armed Forces Institute of Pathology and supported by Grant RR-00301 from the Division of Research Resources, NIH, under the auspices of Universities Associated for Research and Education in Pathology, Inc., and by Hazelton Laboratones America, Inc. Address reprint requests to Dr. J. Kaspareit-Rittinghausen, Department of Toxicology, Squibb-von Heyden, Donaustaufer Str 378, 8400 Regensburg, Federal Republic of Germany.
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Kaspareit-Rittinghausen, Deerberg, and Wcislo
AJP September 1991, Vol. 139, No. 3
I I
I Figure 1. Macroscopic appearance ofpolycystic kidneys in a 3- to 4-week-old homozygous SPRD rat. Note that the polycystic kidneys occupy nearly the whole abdominal cavity.
Figure 3. Microscopic appearance of polvcvstic kidnevs in 6-month-old male heterozygous SPRD rats (HE, x 9).
6-month-old females, the degree of cyst formation observed in 6-month-old males is not reached by the older females, and they appear clinically healthy (unpublished). Further macroscopic findings in males are enlarged parathyroid glands, stiff tubelike aortae, and small white streaks in the walls of heart and stomach. Thickening of the walls of colon and cecum with intramural bleedings is frequent in 6-month-old heterozygous males.11 When examined histologically, the renal tissue of 6-month-old rats of both sexes and 1 0-month-old females is composed of irregular cysts (Figure 3) lined by a cuboidal or flat epithelium. Proximal and distal convoluted tubules as well as collecting tubules are uniformly involved. Cysts are embedded in a loose fibrous tissue and many contain purulent exudate or proteinaceous casts. The most important consequence of reduced kidney function is the development of renal osteodystrophy, with striking hyperplasia of the parathyroid glands and replacement of bone by fibrous tissue, in the great majority of heterozygous, 6-month-old males (Figures 4, 5). Metastatic calcification varies between different animals and involves basement membranes (Figure 6) of renal glomeruli and tubules, walls of aorta and other large vessels, walls of
fore- and glandular stomach, alveolar walls of the lungs, and heart muscle. Renal osteodystrophy does not occur in heterozygous 6-month-old females,11 but is present in a few 1 0-month-old female rats (unpublished). Foci of fibrosis of the heart are observed in one fourth of males with PKD in the walls of both ventricles and the septum. Polycystic kidney disease is accompanied by uremic enteritis in about 40% of males. They demonstrate marked edema and infiltration with polymorphonuclear granulocytes in the walls of cecum and colon, as well as numerous ulcers in both segments of large intestine.11 Blood urea nitrogen (BUN) values are presented in Table 1. They are markedly elevated in 6-month-old male rats, and only slightly raised in 6-month-old females.11 In accordance with the progression of PKD in 6- to 10month-old females, BUN is increased further in the older female rats (unpublished), but has still not reached BUN values estimated in 6-month-old males. Measurements of systolic blood pressure in rats with PKD aged 5.5 months (Table 2) show a marked increase in males. Although female rats have an average blood pressure of 1 19 mm Hg, it is increased to 167 mm Hg in males. Two thirds of the male rats with PKD show blood pressure values above 170 mm Hg.12
I
I
**. _S
w_V
I
Figure 2. Macroscopic appearance of polycystic kidneys in 6-month-old male heterozygous SPRD rats.
Figure 4. Secondary hyperparathyroidism in a 6-month-old heterozygous male rat (HE, X 15).
Polycystic Kidney Disease in the Rat 695 AJP September 1991, Vol. 139, No. 3
Table 1. Blood Urea Nitrogen Values (mg/100 ml) of Rats with PKD
Age
Sex Male controls Males with PKD
(months)
Female controls Females with PKD Female controls Females with PKD Figure 5. Renal osteodystropy with replacement of bone bvfibrous tissue in a 6-month-old heterozvgous male rat (HE, x 40).
Comparison with Human Disease Genetic transmission of the disease in rats is quite similar to human APKD. Both renal disorders are transmitted by a single gene as autosomal-dominant traits. In accordance with the onset of signs of illness in adult patients, PKD of heterozygous male SPRD rats also occurs in adult animals. In contrast to humans suffering from APKD, development of renal lesions and onset of uremia is retarded in female rats compared with males, indicating lower expressivity of the gene in females. Macroscopic and histologic appearance of kidneys in heterozygous rats with PKD closely resemble that of human beings. Cysts have been also described in humans with APKD in a variety of other locations, however, including liver, pancreas, lungs, spleen, ovaries, testis, epididymis, thyroid, uterus, broad ligament, and bladder.2 In none of these organs could comparable cystic changes be found in SPRD rats. They also lack cerebral aneurysms as observed in humans. Several complications of the primary disease are as-
x
SD
t test
1.90
19.46
217.32 137.45 P < 0.001 18.86 2.75
6 6
25.73 21.62
10
43.81
7.31 P < 0.001 3.14 35.20 P < 0.05
sociated with APKD in humans. Urinary tract infection, resulting in pyuria and bacteriuria, develops in 50% to 75% of all patients during the course of their illness.2 Purulent nephritis is also seen in the majority of rats with PKD. Renal hypertension is a further clinical feature of PKD that the rat model shares with its human counterpart, where it occurs in 70% to 75% of patients with APKD.2 Renal insufficiency due to loss of functional capacity accompanies APKD, just as do many other severe renal diseases. Uremia is a frequent terminal event in the clinical course of APKD in humans.5 Markedly increased BUN values leading to death in a state of uremic coma also characterize the final stage of PKD in heterozygous male rats. As could be expected from the delayed progression of renal cystic changes in females, they demonstrate only mild uremia. Uremia coincides partly with hemorrhagic and ulcerative colitis and typhlitis in heterozygous males. Comparable lesions located in cecum, colon, and rectum have also been described in humans with uremia.13'14 Advanced renal insufficiency resulting from any kind of severe chronic disease of the kidneys can be associated with renal osteodystrophy in humans.15 Renal osteodystrophy is observed in the great majority of males with PKD and accompanied by metastatic calcification of a variety of tissues that are identical to those affected by metastatic calcification in humans.15
Usefulness of the Model The SPRD mutant is the first model of inherited polycystic kidney disease observed in rats. In contrast to most of the Table 2. Systolic Blood Pressure (mmHg) in Rats with PKD Aged 5.5 Months
Sex
Figure 6. Metastatic cakification of tubular basement membranes in a polycystic kidney of a 6-month-old heterozygous male rat (HE, x40).
Male controls Males with PKD Female controls Females with PKD
x
SD
115.2 167.4 109.3 119.4
11.0 22.0 11.7 11.9
ttest
P < 0.001 P < 0.01
696
Kaspareit-Rittinghausen, Deerberg, and Wcislo
AJP September 1991, Vol. 139, No. 3
mouse models, diseased heterozygous rats are able to survive for at least 6 months (males) or even considerably longer (females) and present the possibility of continuous studies on the course of PKD and of the complications associated with that disease. The model is suitable for research on the field of histogenesis of this important illness of humans from the earliest expression in utero to its terminal stages. Furthermore this rat model offers opportunity for studies concerning the relationship between structural renal alterations and symptoms of chronic renal failure such as renal osteodystrophy, uremia, uremic enteritis, and renal hypertension.
Availability Litters from matings of heterozygote with nonaffected SPRD rats for the establishment of satellite colonies of this SPRD mutant with hereditary PKD are available on request from the Central Institute for Laboratory Animal Breeding, Hannover, Federal Republic of Germany.
References 1. Furlow WL, Greene LF: Congenital polycystic kidney disease. Med Clin North Am 1966, 50:1111-1117 2. Danovitch GM: Clinical features and pathophysiology of polycystic kidney disease in man, Cystic Diseases of the Kidney, Perspectives in Nephrology and Hypertension, Vol 4. Edited by KD Gardner Jr. New York, Wiley, 1976, pp 125-150 3. Comfort MW, Gray HK, Dahlin DC, Whitesell FB Jr: Polycystic disease of the liver: A study of 24 cases. Gastroenterology 1952, 20:60-65 4. Grantham JJ: Polycystic renal disease. Strauss and Welt's Diseases of the Kidney, Vol 2. Edited by LE Early, CW
Gottschalk. Boston, Little, Brown and Co, 1979, pp 11231146 5. Daalgard OZ: Polycystic disease of the kidneys, Diseases of the Kidney, Vol 2. Edited by MB Straus, LG Welt. Boston, Little, Brown and Co, 1971, pp 907-937 6. Fry JL, Koch WE, Jenette JC, McFarland E, Fried FA, Mandell J: A genetically determined murine model of infantile polycystic kidney disease. J Urol 1985,134:828-833 7. Takahashi H, Ueyama Y, Hibino T, Kuwahara Y, Suzuki S, Hioki K, Tamaoki N: A new mouse model of genetically transmitted polycystic kidney disease. J Urol 1986, 135:1280-1283 8. Werder AA, Amos MA, Nielson AH, Wolfe GH: Comparative effects of germfree and ambient environments on the development of cystic disease in CFWWd mice. J Lab Clin Med 1984,103:399-407 9. Gialamas J, Hoger H, Adamiker D: Polycystische Nierenerkrankung bei infantilen Mausen. Z Versuchstierkd 1987, 30:217-222 10. Fox RR, Krinsky WL, Crary DD: Hereditary cortical renal cysts in the rabbit. J Hered 1971, 62:105-109 11. Kaspareit-Rittinghausen J, Rapp K, Deerberg F, Wcislo A, Messow C: Hereditary polycystic kidney disease associated with osteorenal syndrome in rats. Vet Pathol 1989, 26:195-201 12. Kaspareit-Rittinghausen J, Deerberg F, Rapp K, Wcislo A: Renal hypertension in rats with hereditary polycystic kidney disease. Z Versuchstierkd 1990, 33:201-204 13. Mason EE: Gastrointestinal lesions occurring in uremia. Ann Intern Med 1952, 37:96-105 14. Eknoyan G: Pathophysiology of chronic renal failure and uremic syndrome. In: Pathophysiology of the kidney. Edited by NA Kurtzmann, M Martinez-Maldanado. Springfield, CC Thomas Publisher, 1977, pp 843-880 15. Coburn JW, Slatopolsky E: Vitamin D, parathyroid hormone and renal osteodystrophy. In: The Kidney. Edited by BM Brenner, FC Rector. Philadelphia, WB Saunders, 1986, pp 1657-1731
