Acute Renal Failure in Lambs

Br. vet.

J.

(1974), 13°,475

ACUTE RENAL FAILURE IN LAMBS By

J.

A.

BENSON AND B.

M.

WILLIAMS

*

Veterinary Investigation Centres, Aberystwyth and ·Carmarthen

SUMMARY

An acute, fatal, renal disease of lambs is described, which is characterized by elevated blood urea, creatinine and leucine amino-peptidase levels. At postmortem examination the kidneys are pale and enlarged and the main pathological change is an acute nephrosis. Its association with nematodiriasis and anthelmintic treatment is discussed and it is suggested that renal ischaemia and dehydration due to nematodiriasis causes tubular damage and that the final insult in the form of anthelmintic treatment results in the production ofirreversible lesions. INTROD UCTION

Primary kidney disease is rare in sheep, but since the summer of 1963 a kidney disease in lambs has been recognized at the Aberystwyth Veterinary Investigation Centre . Clinically the disease can be described as acute renal failure and pathologically as a nephrosis. Because there are no records of similar cases in the United Kingdom this paper describes the clinical condition and deals with the incidence, biochemical and pathological features, and discusses the aetiological factors involved. METHODS

The histories were collected when the lambs were delivered to the laboratory, by interviewing the farmers and/or veterinary surgeons. Lambs which were submitted alive were examined clinically and blood samples were collected before the animals were bled out under barbiturate anaesthesia. Post-mortem examinations were performed without delay. Analyses using Boehringer and Soehne Test kits were carried out onjugular blood samples taken from live lambs and on heart blood samples taken from recently dead lambs. The urea content was calculated from the amount of ammonia released by the addition of urease. The ammonia was measured colorimetrically using phenol, sodium nitroprusside and sodium hypochlorite in alkaline solution. The creatinine level was measured colorimetrically after the addition of picric acid followed by sodium hydroxide to the supernatant liquid obtained by precipitating serum with trichloracetic acid. The leucine amino peptidase (leucine arylamidase) (LAP) levels were determined by the increase in optical density over a period of half an hour after addition of leucine p-nitranilide to the serum.

BRITISH VETERINARY JOURNAL, 130,5

The kidney tissue was fixed in 10 per cent buffered formol saline for histological examinations and blocks were embedded in paraffin wax for section cutting. The staining techniques were those described by Culling (1963) and included haematoxylin and eosin, van Gieson and periodic acid-Schiff (PAS). INCIDEN C E AND CLINICAL HISTORY

A total of 96 affected lambs, 33 living and 63 dead, was received between 1963 and 1970, 89 per cent in May and June (Table I). Two-thirds were between 8 and 12 weeks of age, with a range from 4 to 16 weeks. Most of the lambs were from lowland flocks and Suffolk/Welsh crosses predominated but this probably reflects local breeding practice rather than a breed sus..ceptibility, as affected lambs of other breeds and crosses including Cheviot, Clun, Dorset, Radnor, Romney and Speckled were also received. Welsh lambs TABLE I DISTRIBUTION OF CASES BY YEAR AND MONTH

April

196 3 1964 1965 1966 196 7 1968 1969 197 0 Totals

May

June

7 3

4

.4 43

42

I

2 10 2 4

II

August

3

2

I

2 6 8 7 10 4

5

July

5

2

from mountain pastures were rarely seen. The number of cases per flock at the time of receipt varied quite considerably. In about half of the flocks the number ofaffected lambs was four or less, but in a few flocks as many as 20 were involved. With a few exceptions the lambs had been dosed with anthelmintics between I and 2 I days prior to submission, either as a routine measure or because several of the flock were scouring. In some instances there was a second or third dose because previous treatment had not stopped the scour. There was no definite association with anyone anthelmintic; those known to be effective against Nematodirus were most popular and bephenium hydroxynaphthoate, methyridine, morantel tartrate, tetramisole hydrochloride, thiabendazole, phenothiazine/hexachlorethane and tetramisole hydrochloride/oxyclozanide had all been given. The doses used were said to be those recommended by the manufacturers. The usual complaint was that the lambs had become unthrifty after a period of scouring which often had continued despite anthelmintic treatment. Lambs that were delivered alive to the laboratory were usually found to be in poor condition with tucked up abdomens and soiled hindquarters. They appeared depressed, were anorexic and tenesmus was present in some cases. Rapid deterioration usually occurred with nervous signs appearing shortly before death.

PLATE I

Fig.

I.

Dilatio n of tubul es with fiattenino- of epithelia l cells. (H and E. )

Benson and Williams, Br. vet. ]. ( 1974), 13°, 5

ACUTE RENAL FAILURE IN LAMBS

477

RESULTS

Biochemical findings The results of the estimations of serum urea, creatinine and leucine aminopeptidase on all lambs from which it was possible to obtain a blood sample in 1969 and from 6 normal lambs are set out in Table II. The serum urea levels were consistently high; the average figure for 18 lambs was 424 mg/ lOo ml compared with an average of 30.6 mg/ lOo ml in normal lambs. Serum creatinine levels were also consistently higher than in normal lambs. Similarly, the leucine amino peptidase levels were elevated; four clinically affected lambs had average values of I 1'4 mU /ml compared with an average of 3.6 mU /ml in the normal lambs. TABLE II SE R UM U R EA, C R EATININE, AND LAP VALUES IN NORMAL AND AFFECTED LAMBS

Refermce No,

Urea mg/loo ml

Creatinine mg/loo ml

LAP mU/ml

37'5 31,8 30'0 22'5 3 1 ,8 30 '0

1'94 0,82 1'94 1'7 2 2,83 2'38

5,62 2'27 5'29 1'5 1 3'24 3'78

30 '6

I'g

Normal I

2 3 4 5 6 Average Affected

578 648 655 666a b 672a b 677 682 702a b 70 7 717 727 739 740 75 2a b

222 3 00 173 473 73 8 808 56 1 5 10 795 68 5 443 275 25 2 340 200 300 25 0 3 20

Average

424

3'55 8'25 3' 10 6'20

9'5 0 9'94

5'00 8'00 8,67 6'33 g'o

12 '42 13'90

6'45

11'4

Post-mortem examinations Lambs were usually in poor condition with little body fat present but in the more acute cases there had not been time for the fat deposits to become depleted, The most striking post-mortem feature was the colour and size of the kidneys, They were pale, enlarged and oedematous, Littlejohn et at. (1968) indicate that the kidney weight of a normal lamb is 0'45 per cent of the body weight at 8

BRITISH VETERI NARY JOURNAL, 130, 5

weeks. The weights of the kidneys from I I affected lambs (Table III ) show that these are up to twice the calculated weight. The capsule stripped readily from the underlying cortex, which was paler than normal and from which fluid could be expressed. There was some oedema of the renal pelvis but no calculi could be demonstrated. TABLE IIi ACT U AL A N D C AL C ULA T ED

( LITTLEJOHN

Lamb Reference

666a b

67 2a b

677 707 727 739 740 752a

b

et ai, 1968)

A ActWlI kid/ley wtight g

146 189 11 4 11 0 101 11 3 102 96 91 99 165

KID N EY WEIGHTS

B Calculated kidney weight g

OF AFFECTED

LAMBS

AlB

58 67 54 49 63 63 67'5 50 75 49' 5 63

Lesions were occasionally seen in other organs and included gastritis, enteritis and congestion of the liver and lungs. Small numbers of roundworms, predominantly Nematodirus, and varying numbers of tapeworms were found in the small intestine of some lambs and coccidial oocyst counts on large intestinal contents showed the wide variations usually expected in lambs.

Histopathological findings In all kidneys examined histologically the pathological changes found were similar. These were essentially degenerative as distinct from inflammatory, and were predominantly tubular and mainly confined to the convoluted tubules. J ubb & Kennedy (1963) consider these lesions to be typical of nephrosis. In some cases glomerular changes were virtually absent but in others some glomeruli were misshapen, with shrunken and vacuolated glomerular tufts and a number of small droplets present in the glomerular space. The most striking feature, however, was the marked dilatation of the tubules (Fig. I) ; in some of the distal convoluted tubules the dilatation had been so severe as to lead to rupture. The lining epithelial cells of the tubules were flattened and hyaline casts were present in the lumen of some tu buIes. Rarely was necrosis of the epithelial cells observed. The proximal convoluted tubules sometimes appeared normal but more often had a fine vacuolated appearance but in longer-standing cases dilatation was occasionally observed. PAS-positive granules were demonstrated in the cytoplasm of the tubular epithelial cells of two lambs only. Although the pathological changes were largely non-inflammatory in animals which had survived for longer periods there was some cellular reaction in the form of infiltration by lymphocytes, mononuclear and plasma cells and occasionally small numbers of polymorphs.

ACUTE RENAL FAILURE IN LAMBS

479

DISCUSSION

Renal failure is a clinical entity characterized by the ina bility of the kidney to maintain homeostasis. It is said to be acute if the process lasts days or weeks and chronic if it spans months or years. The chemical and pathological features of the disease in this series of cases are similar to those described in acute renal failure in m an by Brun & Munk (1957) and Black (1971 ). Acute renal failure can be precipitated by renal and extrarenal factors (Heptinstall, 1966). Renal factors include glomerulonephritis, acute tubular necrosis and cortical necrosis ; extrarenal factors include reduced blood supply to the kidney due to any cause and blockage of both ureters or pelvis simultaneously. Bentinck Smith (1 963) considers that blood urea levels will rise when there is a deficient blood flow to the kidney and that when the blood creatinine levels rise less than 25 per cent of the kidney is functional. In this series of cases the blood urea a nd creatinine levels were consistently high, indicating renal ischaemia and severe kidney damage. Schmidt & Schmidt (1967) suggest that urinary LAP levels might be used as a n index of tubular damage in man. Urine was not available from our lambs, but the blood levels of this enzyme in a selection were on average more than three times normal which, in the absence of liver lesions, would confirm impaired renal function. The vast majority of lambs had been dosed with anthelmintics during the three weeks prior to submission to the laboratory. Bell, Galvin & Turk (1962) and Jones, Leaver & Milne (1965) produced acute renal failure in sheep by dosing with 20 times the therapeutic dose of thiabendazole

60

x

Nematodiriasis Acute renol failu re

50

40 II>

"'~" 0

.D

:; 0

30

'0 d 2

20

10

1963

1967

1968

Year

Fig.

2.

Correlation of incidence of nematodiriais and ac ute renal failure in lambs.

BRITISH VETERINARY JOURNAL, 130 , 5

and 2-phenyl benzimadazole respectively. Although overdosing could be a factor it is unlikely that overdosing to this extent could have occured in MidWales. Furthermore Jones et at. (1965) found that a metabolite of the anthelmintic had crystallized in the collecting tubules of their animals but this was not a feature in the present series. In children diarrhoea, gastroenteritis or excessive dehydration may cause acute renal failure (Black, 1971 ). The lambs in this series of cases had all scoured and reference to Figure 2 shows that, with the exception of 1966, years of high nematodiriasis incidence were also years of a high incidence of acute renal failure. We suggest that a possible sequence of events is that the diarrhoea and/or dehydration causes an ischaemia of the kidney leading to tubular damage and that this damage is usually reversible. However the final insult of an anthelmintic dose leads to irreversible changes in an already damaged kidney and acute renal failure is the result. Quite clearly, the aetiology of acute renal failure in lambs is complex. This paper has recorded the occurrence of the condition and outlines some of the possible factors involved. Further investigations are required to determine their precise relationships with the disease as described. ACKNOWLEDGEMENT

We would like to thank Mr H. E. Roberts, Veterinary Investigation Officer Aberystwyth for all his help and encouragement and Mr D. M. Horwill Veterinary Investigation Centre, Gloucester for carrying out the biochemical estimations. REFERENCES

BELL, R. R., GALVIN, T. j. & TURK, R. D. (1962). Am. J. uet. Res. 23, 193. BENTINCK-SMITH, J. (1963). Clinical Biochemistry of Domestic Animals. Ed. C. E. Cornelius & j. j. Kaneko, New York: Academic Press. BLACK, D. A. (1971). Renal Disease, 3rd edn. London: Blackwell. BRUN, C. & MUNCK, 0. (1957). Lancet, 1,603. CULLING, C. F. A. (1963). Handbook of Histopathological Techniques, Butterworth. London: HEPTINSTALL, R. H. (1966). Pathology of the Kidney, p. 645, London: Churchill. JONES, L. P. H ., LEAVER, D. D. & MILNE, A. A. (1965). Res. uet. Sci. 6, 316. JUBB, K. F. V. & KENNEDY, P. C. (1963). Pathology of Domestic Animals, p. 257, New York: Academic Press. LITTLEJOHN, C. A., TUMBLESON, M. E., KOMER, E. G., WILSON, R. P. & BLOOMFIELD, R . A. (1968). Am. J. clin. Path. 2, 145. SCHMIDT, E. & SCHMIDT, F. W. (1967). Guide to Practical Enzyme D iagnosis, Manheim: Boehringer & Soehne.

(Accepted for publication

I I

September 1973)

Insuffisance renale aigue chez les agneaux (Benson et WilliaIDS) Res1UIle. Une maladie renale, aigue, mortelle est decrite chez les agneaux, qui est caracterisee par une elevation de l'uree sanguine, des taux de creatinine et de la leucine amino-peptidase. A l'examen post-mortem, les reins sont pales et hypertrophies et la principale modification pathologique est une nephrose aigue. Son association avec un traitement antinematodique provoquant une diarrhee et un traitement antihelmintique est discutee; et il est suggere que

ACUTE RENAL FAILURE IN LAMBS l'ischemie renale et la deshydratation resultant de la diarrhe provoquee par l'antinematodique entrainent une alteration tubulaire, et que l'atteinte finale se presentant so us forme de traitement antihelmintique provoque des lesions irreversibles. Akutes Versagen der Nierenfunktion bei Liinunern (Benson und Wlllialtls) Zusaltllllenfassung. Beschreibung einer akuten todlichen Nierenerkrankung bei Lammern, charakterisiert durch vermehrte Bluturea und erhohte Kreatinin- und Aminoleucin-peptidaseKonzentrationen. Bei der Sektion sind die Nieren blass und vergrossert; die hauptsachliche pathologische Veranderung ist eine akute Nephrose. Die Beziehung zu einer Nematodiriasis und antihelmintischer Therapie wird besprochen und die Moglichkeit eines Zusammenhangs der durch Nematodiriasis verursachten renalen Ischamie und Dehydration mit folgender Schadigung del' Tubuli und del' dann folgenden Attacke in Form der antihelmintischen Behandlung erortert im Hinblick auf dadurch verursachte irreversible Schaden. EI colapso renal agudo en los corderos (Benson y Wlllialtls) ResUltlen. Se describe una enfermedad renal aguna, fatal, de los cOl'deros, que se caracteriza pOI' niveles sanguineos elevados de creatina, leucina aminopeptidasa y urea. En el ezamen post-mortem, los rinones son palidos y estan dilatados y el cambio patologico principal consiste en nefrosis aguda, Se discute su asociacion con la nematodiriasis asi como el tratamien to antihelmintico, y se sugiere que la inquemia renal y la deshidratacion debidas a nematodiriasis causan dano tubular y que el insulto final, en la forma del tratamiento an tihelmintico, resulta en la produccion de lesiones irreversibles.