HEPARIN IN DELAYED TRANSPLANT FUNCTION

1178

centrilobular necrosis could have been associated with poor early perfusion of the liver and may have been responsible for the hoemorrhagic state in four animals and liver failure in two of the others. This initial poor perfusion was not related to the operative ischasmic period, which was between 30 and 40 minutes in all experiments. This length of ischxmia is well tolerated by pigs with allografted livers. Human fibrinogen appeared to prevent bleeding; and early liver failure did not occur in the last experiment, in which the microscopical changes in the liver were similar to those described in canine liver allografts. 20 Further experiments are planned to determine whether more intensive immunosuppression might inhibit the cellular manifestations of rejection. If rejection were avoided it has yet to be shown whether a primate’s health can be maintained with the hepatic metabolism of a pig. We thank Dr. R. D. Keynes and the staff of the Agricultural Research Council, Babraham, for the experimental facilities and Dr. G. A. Gresham who helped us with blood-transfusion in the baboons.

R. Y. CALNE Cantab., M.S. Lond., F.R.C.S. H. J. O. WHITE M.A., M.CHIR. Cantab., F.R.C.S. B. M. HERBERTSON M.A. Cantab., M.D. Durh., M.C.PATH. P. R. MILLARD M.A.

M.B.

Lond.

D. R. DAVIS University Departments of Surgery and Pathology and Department of Anæsthesia,

Addenbrooke’s Hospital,

Cambridge

J. R. SALAMAN Cantab., F.R.C.S. R. SAMUEL J. M.B. Lond., F.F.A. R.C.S.

M.A., M.B.

HEPARIN IN DELAYED TRANSPLANT FUNCTION Five cases of cadaveric renal transplantaSum ary tion are reported in which improvement in transplant function followed systemic heparin therapy. It is suggested that the heparin may have been partially responsible for the improved renal function by dispersing platelet aggregates in glornerular capillaries. INTRODUCTION

SEVERAL workers have described the histological changes in renal transplants before, during, and after episodes of rejection.21 Porter 22 described a variety of microscopic appearances during and after rejection at differing intervals after transplantation. In some renal-biopsy specimens taken 11 or more days after transplantation, evidence of cellular infiltration was scanty or absent. There may be other changes, namely fibrinoid necrosis of arteriolar walls and platelet aggregates within the glomerular capillaries. Kincaid-Smith,21 reporting on renal biopsies in cases of acute rejection, described capillary-loop lesions which closely resemble those seen in thrombotic thrombocytopenic purpura. Mowbray et al. 23 stated that 51Crlabelled platelets disappeared from the general circulation during rejection episodes and accumulated in the transplanted kidney. They also showed that if the platelets seen

20. McBride, R. A., Brownell Wheeler, H., Smith, L. L., Moore, F. D., Dammin, G. J. Am. J. Path. 1962, 41, 501. 21. Kincaid-Smith, P. Lancet, 1967, ii, 849. 22. Porter, K. A. Br. med. Bull. 1965, 21, 171. 23. Mowbray, J. F., Ellis, E., Ackerman, J. R. Int. Congr. Transplantation Soc.

Paris, 1967.

released by adequate treatment of the rejection episode their survival-time was normal. Mathew et al.24 have attempted to monitor these changes by doing serial platelet-counts. Adenosine diphosphate (A.D.P.) causes platelet aggregation in vitro, and Hansson 25 studied the effects of intra-arterial A.D.P. on the normothermic perfusion of cat kidneys. He demonstrated a fall in plateletcount in the venous blood draining the kidney. Subsequent histology showed the glomerular capillaries to be full of platelet aggregates. He suggested that this might interfere with glomerular and tubular function without necessarily impairing the nutrition of the kidney. It is possible that some of the functional changes in kidney allografts during rejection may be produced in this way. The localisation of platelet thrombi during a rejection episode may be related to gamma-globulin deposits on the vascular endothelium.26 Prompt and vigorous treatment of a rejection episode with adequate doses of immunosuppressive agents often causes the arteriolar and glomerular thrombi to disappear within 2 days.21 There may or may not be residual endothelial damage.26 Mowbray et al. 23 and Saker et all have attempted to clear platelet thrombi using a variety of other drugs including phenylbutazone, sulphinpyrazone, and streptokinase. Rejection in a functioning kidney transplant is relatively were

diagnose clinically. In a non-functioning or poorly functioning transplant rejection is more difficult to recognise. This is particularly so when the transplanted kidney suffers from ischxmic tubular necrosis. A fall in platelet-count and plasma-fibrinogen level may be useful here as in other situations involving intravascular microcoagulation.28 29 In this connection it seems (Dr. M. L. N. Willoughby, personal communication) that platelet-counts performed on sequestrene blood-samples are less reliable than those obtained by finger prick and counted by the easy to

method of Brecher and Cronkite.3o In the Cambridge series of transplants of cadaveric

kidneys,31

most

transplants developed postoperative

tubular necrosis which necessitated continuing haemodialysis for periods of up to 2 weeks. I describe here improvement in transplant function in five cases of cadaveric renal transplantation after heparin administration. Routine heparinisation in the dialysis circuit is used in this centre during any haemodialysis in the first 2 postoperative weeks. Systemic heparinisation has been necessary in some patients for other medical reasons including deep-vein thrombosis and clotting of shunts. The five cases reported here received systemic heparin and subsequent improvement in urinary output was noted. All five patients were given routine immunosuppressive therapy 32 which was increased during a rejection episode as follows: Steroids.-Prednisolone increased

to

200 mg.

daily

for 3

days, thereafter decreased by 25 mg. every other day. Azathioprine.-To the maximum tolerated dose depending urine output and total white-cell count. Actinomycin C.-200 g. daily intravenously for 3 days. Four patients had a creatinine clearance of less than 5 ml.

on

24. 25. 26. 27. 28. 29. 30. 31. 32.

Mathew, T. H., Kincaid-Smith, P., Marshall, V. C., Eremin, J. ibid. Hansson, L. Acta chir. scand. 1965, suppl. 345, p. 35. Porter, K. A. J. clin. Path. 1967, 20, suppl. p. 518. Saker, B., Kincaid-Smith, P., Hirsh, J., Mathew, T. H., Eremin, J., Marshall, V. C. Unpublished. Cited by P. Kincaid-Smith, footnote 1. Mirskey, C., Johnson, A. J., Kleiner, G. J., Wohl, H. Br. J. Hœm. 1967, 13, 528. Willoughby, M. L. N. J. Obstet. Gynœc. 1966, 73, 940. Brecher, G., Cronkite, E. P. J. appl. Physiol. 1950, 3, 365. Calne, R. Y. et al. Unpublished. Calne, R. Y. Renal Transplantation. London, 1966.

1179

The other patient had per minute. had a bilateral nephrectomy.

previously

CASE-REPORTS

Case1

27-year-old Coloured woman. Rejection episodes diagnosed on the 4th and 10th postoperative days and treated as above without any significant changes in urinary output. A percutaneous renal biopsy performed on the 27th day showed " recent necrosis of a few tubular cells and slight neutrophil and mononuclear cell infiltration. Most of the glomeruli showed no important changes but in two, the glomerular tufts had undergone necrosis. Two small arteries showed no important abnormalities ". Possible explanations for these changes were thought to be infection or focal ischaemia. Intermittent hxmodialysis was continued until the 31st day when her Scribner shunt clotted. Systemic heparinisation (5000 units, 4 hourly) was commenced. Urinary output on the 31st day was 840 ml. containing 2 g. urea and on the 32nd day was 6-5 litres containing 77 g. urea (fig. 1). Rejection was diagnosed clinically on day 41, A

were

and this

was

treated in the usual way. 13 months after

transplantation, this patient’s creatinine clearance is 120 ml. per minute with a plasma-creatinine of 0-9 mg. per 100 ml.

Fig. 2-Case 5: progress during the period preceding and after heparin Case 2 therapy. A 48-year-old male. A rejection episode was diagnosed and treated on the 6th postoperative day. The urinary volcontaining 16-8 g. urea was passed. 17 monchs after transume at this time was 80 ml. per day. On the 12 postoperative plantation plasma-creatinine is 1-9 mg. per 100 ml. with a day when the urinary volume was 120 ml. the patient’s Scribner creatinine clearance of 88 ml. per minute. shunt clotted and systemic heparin (2000 units, 2-hourly) was Case 4 commenced. There was no increase in urinary volume until A 40-year-old male. This patient was dialysed by means of the 17th day when an output of 1200 ml. was passed with an internal arteriovenous shunt (Brescia-Cimino). Using this 11.1g. urea. 13 months after transplantation, plasmashunt on regional heparinisation the patient’s clotting-time had creatinine varies between 1-0-1-3 mg. per 100 ml. to be prolonged beyond our usual level to avoid clotting of the Case 3 dialyser. Hmmodialysis was necessary until the 14th postA 42-year-old male. Systemic heparinisation (5000 units, operative day when the urine volume was 950 ml., containing 4 hourly) was begun on the 2nd day postoperatively for a deep7 g. urea. During the dialysis on this day the patient’s clottingvein thrombosis when the urine volume was 460 ml. containing time was maintained in excess of 1 hour. On the next day the 1-6 g. urea. On the 4th postoperative day 1650 ml. of urine urinary output was 2400 ml. containing 14-6 g. urea. The present urinary volume 20 days postoperatively is 2500 ml. with 32-2 g. urea. Case 5

A 24-year-old male on whom a bilateral nephrectomy was performed 10 weeks before transplantation. After the transplant, the to rise above 800 ml. A renal biopsy on the 34th day showed " moderate mononuclear cell and neutrophil polymorph infiltrate. Interlobular arteries and glomerular arterioles appeared normal. No gross abnormality was noted in the glomeruli or tubules ". Standard rejection therapy was given with no improvement in urinary volume. Systemic heparin (4000 units, 4 hourly) was given on the 46th day for a clotted Scribner shunt. On the 48th day urinary volume was 1770 ml. containing 26-7 g. urea (fig. 2). The present urine volume is 2680 ml. with 33-2 g. urea 87 days after transplantation.

urinary volume failed per

day.

DISCUSSION

Fig. 1-Case

1: progress

during the period preceding and after heparin therapy.

An increase in urinary output was noted in five patients who were all systemically heparinsed at a time when renal function was poor after cadaveric renal transplantation. This increase happened with-

1180

in 48 hours in all but one of the patients. The fact that this patient received a smaller dose of heparin than the others may be of significance. Case 3 is also of interest. The total ischaemia-time for the transplanted kidney was 185 minutes of which 78 minutes was " warm time ". In the Cambridge series it is unusual in kidneys with ischaemia-times of this order for diuresis to happen before 2 weeks postoperatively. None of these patients were thought to be rejecting at the time when heparin therapy was started. Most of the criteria of rejection are absent in patients in whom adequate transplant function has never been attained. In the two patients in whom biopsy reports are available, it was impossible to state that the changes present were specifically those of rejection, since infection or vascular insufficiency may have modified the microscopic appearIt is hoped that accurate platelet-counts and ances. estimation of plasma-fibrinogen levels may provide more information on the value of systemic heparin on renal transplant function. One cannot conclude from this data that heparin was responsible for improvement in renal function. A possible correlation, however, is suggested which would accord with the platelet observations already mentioned. I thank Prof. R. Y. Calne for permission to present details of patients under his care and for his guidance in the preparation of this report, Dr. D. B. Evans, Dr. P. R. Millard, and Dr. B. M. Herbertson for their interest and help, and Mrs. J. Small for preparing the typescript. Department of Surgery, of Cambridge, Addenbroke’s Hospital, Trumpington Street, Cambridge

University

ROBERT MCMILLAN M.B.

Glasg.

Hypothesis INTRAVASCULAR COAGULATION AND HYALINE-MEMBRANE DISEASE OF THE NEWBORN It is suggested that in hyaline-membrane disease the underlying cause is disseminated intravascular coagulation. Maternal events such as toxaemia, cxsarian section, and diabetes, especially where clotting is involved, can prove lethal to the infant. This hypothesis leads to a number of riders involving clotting factors and the prevention of hyaline-membrane disease in the at-risk infant by treatment with heparin.

Sum ary

INTRODUCTION

RESPIRATORY distress of the newborn is a common and often lethal condition. In the presence of pneumothorax or diaphragmatic hernia, the explanation and treatment of the distress seem almost obvious. However, when a well-formed infant progresses from normal respiration with fully expanded well-aerated lungs to an increasingly rapid respiratory-rate with atelectatic, congested, hyalinemembrane-ridden, non-functional lungs, one notes such seemingly unrelated antecedents as prematurity, cxsarean section, maternal diabetes, or toxxmia, and gives supportive treatment. We suggest here a possible setiological mechanism for this variety of respiratory distress of the newborn, and suggest an entirely new approach to treatment.

brief, we suggest that disseminated intravascular coagulation (D.I.C.) is the underlying cause of hyalineIn

membrane disease is:

(H.M.D.). A model of the critical

events

Antecedent Associations From the model it followsthat maternal conditions which compromise the placenta, especially events which involve clotting, initiate a complex set of circumstances which can be lethal for the foetus or liveborn infant. Toxaemia.-The toxaemias of pregnancy demonstrate the most obvious association between D.I.c. and H.M.D. Thrombi are frequently found in small vessels in nearly all of the maternal visceral organs. Haemorrhagic manifestations, thrombocytopenia, and clotting-factor deficiencies are also frequently associated with pre-eclampsia and eclampsia. These aberrations of clotting physiology may- be transmitted to the foetus when the placenta becomes involved. For example, abruptio placenta in toxsemia is associated with infarction, intervillous thrombosis, fibrin deposits in the walls of decidual vessels, and retroplacental blood-clot. With this extensive involvement of the placenta it seems quite possible that the foetus receives several maternal/foetal transfusions of tissue thromboplastin in sufficient amounts to initiate a widespread intravascular coagulation catastrophe in the fcetus. Ceesarean section.-H.M.D. may follow from the obstetrical complications leading to cxsarean-section,2 but an independent association is conceivable. For example, an inadvertent incision of the placenta could easily result in a foetal infusion of thromboplastin-rich placental tissue fluid which in turn could set off a foetal intravascular coagulation episode. The small foetus deficient in fibrinolytic enzymes,3 or unable to synthesise enough of them, could be compromised by an infusion of sufficient size. Prematurity.-The strong association between H.M.D. and immaturity with or without maternal complication4 is no doubt related to the biochemical immaturity of the 1.

McKay,

D. G. Disseminated Intravascular

Coagulation. New York,

1965.

Swyer, P. R., Levison, H. Can. med. Ass. J. 1965, 93, 335. Ambrus, C. M., Weintraub, D. H., Niswander, K. R., Ambrus, J. L. Pediatrics, Springfield, 1965, 35, 91. 4. Fujikura, T., Froehlien, L. A. Am. J. Obstet. Gynec. 1966, 95, 572. 2. 3.