Path. vet. 2: 37-48 (1965)

From the Veterinary Diagnostic Section, Ruakura Agricultural Research Centre Hamilton, New Zealand

Bilateral Renal Hypoplasia of the Pig D. 0. CORDES and D. C. DODD

Many renal malformations such as renal agenesis and hypoplasia (which are different degrees of the same condition), persistent foetal lobation, fusion, ectopia, cysts, tumours, duplication of the ureters and double pelvis have been described in mammals. Bilateral agenesis and hypoplasia have been described in man (ANDERSON~) and pigs (STENIUS~~; COHRS~) whilst bilateral renal cortical hypoplasia has been reported in the cocker spaniel dog (KRooK~). unilateral renal agenesis is generally considered to be more common than bilateral and occurs more frequently on the left side in the human male2 and the dog (MCFARLAND and DENIZ~), whilst it is more frequent on the right side in the cat (MACKand MCGLOTHIN~; BERG^ ; PIERSON and GROLLMAN~). Unilateral renal agenesis is also described in the horse, sheep, ox, goat, rabbit and rat4. In a strain of rats, absence of both kidneys in some and unilateral absence or bilateral hypoplasia in others has been reported (MORGANS). These conditions have usually been described in the general terms of agenesis or hypoplasia but more critical analysis should indicate which of the three embryonic tissues, wscular mesenchyme, nephrogenic mesenchyme, or mesonephric mesenchyme is primarily responsible for the defect. Renal hypoplasia of the pig is stated to be “not rare” by COHRS~ whose only reference is to STENIUS’S reportlo. The latter author described a bilateral renal cortical hypoplasia in six clinically normal pigs in which each kidney was smaller than normal and grey-white with a capsule which stripped easily leaving a surface of rough texture. The cortex was narrower than normal and it was poorly demarcated from term) were the medulla. Isolated cysts up to the size of a pea (STENIUS’S present in the cortex and medulla. I n the outer cortex, glomeruli were fewer and smaller than normal and many showed periglomerular

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fibrosis and hyalinization of the glomerular tuft. In some regions, convoluted tubules were cystic and tubular casts were occasionally present. Fibrous tissue was dense within the cortex but less was present in the cortico-medullary area. There were few medullary rays. The only change in the medulla was fibrous tissue deposition. This report describes the occurrence of congenita1 bilateral renal hypoplasia in a pig herd and suggests a possible mode of inheritance and pathogenesis of the abnormality.

Case Material and Clinical Signs Renal hypoplasia was observed in 19 piglets. Twelve of these were born dead or died within two days of birth. Survival times for the remainder were 11, 14, 21, 25, 26, 66 and 69 days. Clinical signs exhibited by these older pigs included lethargy, shivering, anorexia, diarrhoea, slow rate of growth and sometimes loss of weight. Death, presumed due to renal insufficiency, occurred naturally except for the oldest survivor (69 days) which was destroyed owing to inappetence and inability to thrive. The 19 affected piglets were born in eight litters and were all sired by one boar of the Large White breed. The eight sows concerned were Large White or Large White Berkshire crosses, and were themselves all sired by another Large White boar. The eight litters at birth comprised 46 males, of which 12 proved to be affected and 27 females of which 7 were affected; the overall incidence being 19 pigs with renal hypoplasia out of 73 born (dead or alive), i.e. 26%. Post mortem examination of numerous littermates of affected pigs revealed no renal abnormality. Gestation lengths in all cases, and birth weights generally were normal. A gross examination was made of the kidneys of many of the surviving piglets when they were slaughtered for meat at live weights of between 30 and 150 pounds; all were normal. Renal hypoplasia was found in 5.65% of all pigs sired by the boar in question. Abb. 1. Zwei neugeborene Ferkel. Rechts: normal. Links: Hypoplasie der Nieren. Der Pfeil zeigt auf die vesikulare Struktur, in der ein Nierenkelch zu sehen ist. Abb. 2. Zwei neugeborene Ferkel. Rechts: normal. Links: Renale Hypoplasie. 1. Nebenniere. 2. Niere. 3. Ureter. 4. Nierenkelche.

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Fig. 1. Two newborn pigs. Right: Normal. Left: Renal hypoplasia. The arrow points to the vesicular structure in which a calyx can be seen. Fig. 2. Two newborn pigs. Right: Normal. Lef: Renal hypoplasia. 1. Adrenal Gland. 2 . Kidney. 3. Ureter. 4. Renal calyces.

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Gross Pathology of the Kidney 1. Neonatal Deaths (within two days of birth) In this age group there were twelve piglets withabnormal kidneys. Renal hypoplasia was bilateral in all cases and in most there was no appreciable difference in size between the pair. In all cases the ureters could be traced from the urinary bladder as far as the renal calyces (Figs. 1 and 2). All kidneys were in the normal position. In two piglets in this group the most extreme degree of renal hypoplasia was observed. No renal cortical or medullary tissue was found and the ureters began in a small, colourless thin-walled, cyst-like structure 2 to 3 mm in diameter. Within this could be seen three or four fine white strands which were probably renal calyces, radiating from the ureter. A less extreme condition seen in two cases is shown in Figure 2, where a small pink crest covered the lateral edge of similar cyst-like structures. In the remaining eight piglets of this group, the kidneys were pale brown-yellow and thinner and flatter than normal. The capsule stripped normally, exposing a rough surface. The cut surface was the same colour as the capsular and many pinpoint colourless spots were evenly distributed through the parenchyma.

2. Subsequent Deaths (11 to 69 days of age) There were seven piglets with renal hypoplasia in this group. Deaths occurred at 11, 14, 21, 25,26 and 66 days of age and one was destroyed when it was 69 days old. In all these piglets the kidneys were in at least one dimension (length, breadth or thickness) obviously much smaller than normal. In one case there was persistence of the foetal lobation whilst in another, one kidney was composed of two main lobes (Figs. 3 and 4). Blocks of kidney tissue, cut transversely to include the hilus, medulla and cortex, were taken from the majority of abnormal kidneys and preserved in 10% neutral formalin. Where very little kidney tissue was present, blocks included the sublumbar tissue in addition to the vestigial kidneys. No suitable samples were obtained from the cases of the most extreme degree of hypoplasia. Wax embedded tissue sections were stained by haematoxylin and eosin. Selected sections were stained by the van Gieson method for collagen.

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Fig. 3. Sixty-six days old pig. The right kidney is composed of a small anterior and a larger posterior lobe. The left kidney lies posterior to the elongated left adrenal. Abb. 3. 66 Tage altes Ferkel. Die rechte Niere besteht aus einem kleinen Vorderund einem grosseren Hinterlappen. Die linke Niere liegt hinter der verlangerten linken Nebenniere. 3 Path. vet., Vol. 2, No. 1 (1965)

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Fig. 4. Sixty-nine days old pig. Persistent foetal lobulation as part of the renal hypoplasia syndrome. Abb. 4. 69 "age altes Ferkel. Persistenz der fetalen Lappung als Teil des renalen Hypoplasie Syndroms. Abb. 5. Mikroskopisches Bild der nephrogenen Zone und der Nierenrinde eines normalen neugeborenen Ferkels. HE-Farbung. Abb. 6. Querschnitt der in Abb. 2 dargestellten hypoplastischen Niere. Sparliche Entwicklung der nephrogenen Zone. Ein Nierencalix befindet sich im linken Mittelfeld. Van Gieson-Farbung.

b

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5

Fig. 5. Photomicrograph of the nephrogenic zone and renal cortex of a newborn normal pig. H. & E. Fig. 6. Cross-section of a hypoplastic kidney depicted in Fig. 2. Poor development of the nephrogenic zone. A renal calyx is present in the left central area. Van Gieson.

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Histopathology of the Kidney The histological structure of kidneys of pigs with renal hypoplasia was compared with that of grossly normal kidneys of pigs of the same age. Some of the normal kidneys came from pigs of the same litters as those with renal hypoplasia.

The Normal Kidney of a Newborn Piglet In H. & E.-stained sections of the normal kidney the nephrogenic zone was readily seen as a dark blue crest within the renal cortex against the renal capsule (Fig. 5). Within this zone the cell nuclei were small, dark and densely packed. A progressive lightening of the staining reaction occurred as the nephrogenic zone merged with the rest of the renal cortex. The most distal part of the nephrogenic zone was composed of several layers of cells which gave rise on one side to renal capsule and on the other to the proximal tubules. The renal capsule was composed of collagenous fibrous tissue and varied in thickness. Many capillaries, some of which had a wide diameter, were seen in the nephrogenic zone. Collecting tubules, adjacent to the layer of proximal tubules were seen within the nephrogenic zone and were separated from the capsule by three to five mesenchymal cells. The width of the nephrogenic zone was notably uniform within kidneys but varied considerably between kidneys. The glomeruli tended to be small near the nephrogenic zone and to become progressively larger the nearer they were to the medulla. Collagen, which was abundant in the capsule and the renal medulla and around blood vessels in the cortex, occurred as fine strands between some tubules of the medullary rays. Very little collagen was seen elsewhere. The Hypoplastic Kidney

I . Neonatal Deaths In general, abnormal kidneys had a thinner renal capsule and a narrower nephrogenic zone. This zone was present in all kidneys but in addition to being generally narrower than normal, was of very variable width. In some kidneys it was absent over much of the section.

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Fig. 7. The nephrogenic zone of a 0.3 cm long kidney of a newborn affected pig. Formation of S-tubules and glomeruli is poor. A: Cross-section of a dilated distal convoluted tubule. H. & E. Abb. 7. Nephrogene Zone einer 0,3 cm langen Niere eines neugeborenen in Mitleidenschaft gezogenen Ferkels. Die Ausbildung S-formiger Harnkanalchen und der Glomeruli ist kiimmerlich. A: Querschnitt eines erweiterten, distalen Tubulus contortus. HE-Farbung.

Two piglets were said previously to have narrow crests of renal tissue. In a section of a kidney of one of them there were only six recognisable glomeruli, whilst in the other pig there were 18 glomeruli in a similar section (Fig. 6). All parts of the tubular system with the exception of collecting tubules were recognised (Fig. 7). In kidneys with slightly lesser degrees of hypoplasia, collecting tubules were also present. As the degree of hypoplasia decreased, collecting tubules were found in increasing numbers in the medulla. The development of medullary rays was also closely associated with the degree of hypoplasia; the less affected the kidney the more the rays appeared.

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In all sections hyalinisation of part of glomerular tufts was seen even in some of those adjacent to the nephrogenic zone. Swelling and cytoplasmic vacuolation beginning at the base of the cells was present in some of the convoluted tubules.

2.SabseqHent Death The histologic picture presented by this group of kidneys was in general similar to those previously described. Medullary ray formation was again poor or absent and many dilated distal convoluted tubules were seen.

Discussion According to A R E Ythe ~ mammal during intra-uterine life relies mainly on the placenta to excrete its waste metabolic products. Nevertheless urine is produced slowly by the kidneys and at birth the bladder is normally full of urine. The post-natal survival of piglets with inadequate renal tissue probably depends on several factors, of which preparturient demand on renal function and postparturient growth rate and diet may be the most important. There is a general impression that unilateral renal hypoplasia is more common than bilateral. Whilst one functional kidney allows survival of the animal, severe bilateral renal hypoplasia is incompatible with life and it is probable that most animals with this lesion die in the immediate post-natal period. Probably only a small proportion of all animals dying in this period are submitted to a routine necropsy examination and for this reason the proportion with bilateral renal hypoplasia may be greater than has been recorded. A study of the case history of the pigs of this report shows that 26% of pigs of affected litters had the disease, and that the disease occurred when a certain boar was mated to eight sows who had a common sire. This is taken to be strong evidence for the presence of a single recessive gene inherited in a simple Mendelian manner. If this is true then the disease should be manifest in the homozygotes (25%) whilst the heterozygotes (50%) would be carriers with normal kidneys. Further genetic study of this problem is planned. For a complete description of renal development the reader is The facts pertinent to this discussion are: 1. The referred to AREY~. collecting tubules are derived from the ureteric bud of the meso-

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nephric duct. 2. The renal cortex by contrast arises from the caudal end of the nephrogenic cord. 3. The presence of a collecting tubule adjacent to the nephrogenic mesenchyme is a necessary stimulus for nephron formation. Excretory primordia about the end of the collecting tubule commence to grow and form tubular structures, which by twisting, come to form S-shaped tubules. One limb of the S surrounds a vascular glomerulus thereby forming the Bowman’s capsule. The other end of the S becomes elongated to form the various parts of the nephron which connect with the collecting tubule. S T E N I U Swas ~ ~ of the opinion that the hypoplasia which he described was primarily caused by excessive fibrous tissue in the medulla. He postulated that this fibrous tissue restricted blood supply and consequently the growth of nephrons. The present study does not support such a view and the evidence as presented shows that it was a failure of development of collecting tubules either complete or partial and the consequent lack of stimulus to nephron development that was the cause of the hypoplasia. That is to say there was a primary defect in mesonephric mesenchyme. In several of the sections there was undoubtedly a relative increase in the proportion of fibrous to tubular tissue but in no case was it considered that the increase was absolute. Sammaty Bilateral renal hypoplasia of the pig is described and is compared with a previous description. The defect was observed in 19 piglets out of a total of 73 born in eight litters, sired by one Large White boar. Twelve affected piglets died at or soon after birth and 7 died between the ages of 11 and 69 days. Inheritance by a simple autosomal recessive factor is suggested by the evidence. Grossly the condition was characterized by varying degrees of hypoplasia and persistence of foetal lobulation. Microscopically, the dominant feature was the poor development of the collecting tubule system, It is concluded that the basic defect is a failure of development of mesonephric mesenchyme.

Zmammenfaswng Eine doppelseitige Nierenhypoplasie des Schweines wird geschildert und mit einer vorhergehenden Beschreibung verglichen. Der Defekt wurde bei 19 von insgesamt 73 in 8Wiirfen geborenen und von einem ctLarge-White))-Ebergezeugten Ferkeln beobachtet. Zwolf der betroffenen Ferkel starben wahrend bzw. kurz nach der Geburt. Die restlichen sieben starben im Alter von 11 bis 69 Tagen. Als Ursache wird Vererbung durch einen einfachen, rezessiven autosomalen Faktor vermutet.

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Makroskopisch sind die Veranderungen durch unterschiedlich ausgepragte Hypoplasie sowie Persistenz der fetalen Lappung gekennzeichnet. Mikroskopisch besteht das dominierende Merkmal in einer Unterentwicklung des Sammelrohrsystems. Es wird angenommen, dass der grundlegende Defekt in einer Fehlentwicklung des Urnierenmesenchyms besteht.

Acknowledgments The authors would like to thank Dr. A.H. CARTER, Geneticist, of the Centre for examining the pedigrees of the pigs and advising on the probable inheritance of this condition. and Miss L. BROCKis gratefully The technical assistance of Mr. B. YOUNG for the photographic acknowledged. Thanks are due to Mr. D.B. MACQUEEN illustrations.

References 1. AREY,L.B. : Developmental Anatomy. 5th edit. (W.B. Saunders, Philadelphia 1947). 2. ANDERSON, W.A.D.: Pathology. 2nd edit. (C.V. Mosby, St. Louis 1953). 3. BERG,R. VON: Agenesis renis unilateralis bei einer Katze. Anat. An?. 109: 3 6 4 0 (1961). 4. COHRS,P. : NIEBERLE and COHRS.Lehrbuch der speziellen pathologischen Anatomie der Haustiere, 4. Aufl. (Jena, Gustav Fischer, 1961). 5. KROOK,L.: The pathology of renal cortical hypoplasia in the dog. Nord. Vet. Med. 7: 161-176 (1957). L.Z. and DENIZ,E.: Unilateral renal agenesis with ipsilateral 6. MCFARLAND, cryporchidism and perineal hypospadias in a dog. J. amer. vet. naed, Ass. 139: 1099-1100 (1961). 7. MACK,C. 0. and MCGLOTHIN, J. H.: Renal agenesis in the female cat. Anat. Rec. 105: 445-450 (1949). 8. MORGAN, W. C.: Inherited congenital kidney absence in an inbred strain of rats. Anat. Rec. 115: 635-639 (1953). 9. PIERSON,DELORES, L. and GROLLMAN, S.S.: Absence of one kidney and abnormal development of the uterus in the domestic cat. Acta anat. 40: 385-390 (1960). 10. STENIUS,P.I. : Uber eine unter dem Bilde einer Schrumpfniere verlaufende schwere Hypoplasie der Nierenrinde beim Schwein. DtJcb. tierarZtl. Wschr. 45: 289-292 (1937). Author’s address: Mr. D. 0. Cono~s,Ruakura Agricultural Research Centre, Hornifton (New Zealand).