Scand J Urol Nephrol 11: 173-177, 1977

THE EFFECT OF CHLORPROMAZINE AND HEPARIN PRETREATMENT ON KIDNEY VIABILITY AND FUNCTION AFTER WARM ISCHAEMIC DAMAGE T . Bilde, J. I . Dahlager, S. Asnaes and D. Jaglicic

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From the Surgical Department D and Medical Department P . Rigshospitalet, University Hospital of Copenhagen, Copenhagen and Department of Pathology, Bispebjerg Hospital, Copenhagen, Denmark

(Submitted for publication May 19, 1976)

Abstract. The influence of chlorpromazine and heparin pretreatment on kidney function and histology has been investigated in rabbit kidneys damaged by warm ischae-

mia. Three experimental groups were investigated. One in which animals were pretreated with heparin, one group pretreated with heparin and chlorpromazine, and one group without pretreatment. The left renal artery was temporarily clamped for 3 hours and the kidneys recirculated. After 2-3 weeks a delayed contralateral nephrectomy was made, and after another 2-3 weeks all kidneys were studied histologically. Kidney function was measured by determination of serum-creatinine. The experiments showed, that all animals survived with impaired renal function. Pretreatment with chlorpromazine and heparin did not affect the final results. Severity of the ischaemic damage, histologically evaluated was the same in all groups. Temporary interruption of kidney circulation entails impairment of renal function. An earlier study considers the relationship between the duration of temprary clamping of the renal artery and renal function after reestablishment of circulation (Bilde, Dahlager, Asnaes & Jaglicic ((I, to be published). After two hours clamping renal function was markedly impaired, but 14 days after reestablishment of circulation, renal function, as reflected by serum-creatinine values, was normal. Subsequent histological appearances were also normal. After 3 hours clamping, 9 of 10 animals died in uremia and severe ischaemic damage of the kidneys was observed. When animals were pretreated with chlorpromazine before clamping 6 of 10 animals survived 3 hours clamping of the renal artery, and renal function improved over the period of the study but was never fully restored

(Bilde, Dahlager, Asnaes & Jaglicic ( 6 , to be published). Chlorpromazine pretreatment was also associated with an earlier resumption of renal function. These experiments were made on rabbits in which the right kidney was removed before applying warm ischaemia to the left kidney. The present study examines the extent to which the left kidney after arterial clamping of 3 hours can resume function in animals in which a delayed contralateral nephrectomy was performed. The influence of chlorpromazine and heparin pretreatment on the final function and histology was also investigated in the same model.

MATERIAL A N D METHODS 29 female white Danish landrace rabbits, of average weight 2.7 kg, were used.

Operative method

The method has been described previously in detail (Bilde et al., a and b , to be published). The left renal artery was clamped for 3 hours, and renal circulation was thereafter re-established. Renal recirculation was controlled by renography to exclude arterial thrombosis and the abdomen was closed. Two to three weeks later the right kidney was removed through a lateral incision, after the renography had shown function of the left kidney (Dahlager & Bilde, u , to be published). Serum-creatinine was determined preoperatively, and 2 , 4 , 6 and 14 days after the temporary clamping, and with the same intervals after right nephrectomy. After 25-28 days the animals were anaesthetized, the kidneys were removed and the animals sacrificed. Kidneys were fixed in neutral formalin, tissue was taken

174

T . Bilde et al.

Table I. Serum-creatinine in the different groups mmolll. Mean ?S.D.

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Pretreatment . . .

None

Hours of ischaemia 3 Days after clamping 0.12f0.02 0 2 0.1520.02 4 0.15f0.02 0.14?0.02 6 0.13f0.02 14 Davs after nephrectomy 0.3 1 f 0 . 14 2 0.32f0.10 4 0.3020. I1 6 0.31f0.12 14

Heparin

Chlorpromazine & heparin

Heparin (one-sided nephrectomy)

3

3

0

0.11 f0.03 0.14f0.02 0.14_+0.01 0.13f0.02 0.1220.02

0.10f0.02 0.15*0.03 0.14f0.03 0.13f0.02

0.12*0.02

0.2620.16 0.28f0.15 0.2920.14 0.27rtO. 14

0.32f0.18 0.30fO. 14 0.28f0.14 0.27fO. I5

0.16f0.03 0.16f0.05 0.16f0.03 0.13f0.02

and embedded in paraffin, and sections were stained by the haematoxylin and eosin, Van Gieson and PAS method. The changes were semiquantitatively classified. Consequences of ischaemic damage Severe. Marked cicatricial changes in the cortex and medulla with fibrosis, hyalinization of glomeruli and dilatation of tubuli. Moderate. Less extensive diffuse scaring without glomerular changes, with less marked tubular change. Interstitial focal fibrosis, and lymphocyte infiltration. Mild. Mild diffuse fibrosis with dilatation of proximal tubules. Sporadic lymphocyte infiltration in the interstitium with or without oedema. Four experimental groups were studied. The first group of animals (9 experiments) were not pretreated. The second group (10 experiments) were given 500 i.e./kg heparin i.v. before the induction of ischaemia. The third group (10 experiments) was pretreated with heparin (the same dosage as in group 2) and with chlorpromazine N.F.N. (3.5 mg/kg i.v.) 15 min before clamping of the renal artery. A control group contained six heparinized animals subjected to transperitoneal left nephrectomy with abdominal closure after 3 hours to mimic the operative trauma in the experimental groups. This group is described in detail previously (Bilde et al. a to be published), and is included for the sake of comparisqn.

RESULTS All animals survived the experimental procedures. Serum-creatinine determinations in the three groups are shown in Table I. Fig. 1 shows the course after temporary clamping at the time of right nephrectomy. The control group is also represented in the figure. The values in the four groups are not statistically different. Serum-creatinine showed for all groups a significant increase (pO.I) and there was no significant difference between the g r o u p s (p>O. I ) . Table I1 gives the results of the histological studies. Most kidneys disclosed moderate or severe changes (Fig. 3), but occasional normal sections Serum -creoiinine rnrnol/l 1

0.20 0 15010-

0 050

0

2

6

14

Days after occlusion NO pretreatment

Chlorprornazinc

.

Heparinc

0 Control oncsidcd nephrectomy

Fig. 1 . Serum-creatinine after 3 hours of clamping of the left renal artery in groups pretreated with heparin and chlorpromazine, and in a control group not pretreated, but with contralateral nephrectomy.

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Chlorpromazine and heparin pretreatment on kidney viability

Table 11. Histological findings in the experimental groups. Consequences of ischaemia

Serum -creallnlna mmoI/I

Histological findings

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030-

0 20-

010-

0

0

2

L

6

14

Days after nephrectomy N O Pretreatment

Chlorpromazine

+

ticparine Hcparine

I

SD

Fig. 2. Serum-creatinine after right nephrectomy in the three groups described in Fig. I .

were seen (Fig. 4). No difference was observed between sections from treated and not treated kidneys. The histological changes were of the same type in all groups. Kidneys regaining normal function, i.e. serum-creatinine below 0.18 mmol/l, were compared with more damaged kidneys. Fischer’s fourfold test showed good correlation (P

The effect of chlorpromazine and heparin pretreatment on kidney viability and function after warm ischaemic damage.

Scand J Urol Nephrol 11: 173-177, 1977 THE EFFECT OF CHLORPROMAZINE AND HEPARIN PRETREATMENT ON KIDNEY VIABILITY AND FUNCTION AFTER WARM ISCHAEMIC DA...
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