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ISCHÆMIA IN TRANSPLANTED KIDNEYS
498 The modified instrument has proved entirely satisfactory, and has been in sole use for over six months; the original blade is still intact. I should like to thank Mr. R. W. Cox and the staff at the Manchester branch of Allen & Hanburys (Surgical Engineering), Ltd., for their help and advice. Pharmaceutical Department, Victoria Memorial Jewish Hospital, A. J. Ross. Manchester, 8.
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ISCHÆMIA IN TRANSPLANTED KIDNEYS SIR,-Dr. Swales and Mr. Naunton Morgan (July 31) attempt to distinguish in dogs between the effect of a short period of renal ischaemia and a longer period during which the animal is the recipient of a renal transplant. They draw attention to the hypotensive effect of-the renal medulla of the transplanted kidney in masking in the recipient any rise of blood-pressure, which they reasonably infer would have occurred otherwise. A short period of renal ischxmia accompanies a fairly immediate or early transplantation, when the effects of clamping of the renal pedicle in the process of nephrectomy has been followed by a quick return of the renal circulation. A longer period implies a more prolonged renal ischxmia; and in man these authors found a period of anuria accompanied by microscopical changes resembling tubular necrosis in biopsy specimens from the kidney. In normotensive subjects in whom possible protective reactions against hypertensive stimuli had not been perfected, there were pronounced rises in blood-pressure. Translating the effect in dogs from clamping the renal artery, and by using the angiotensin-tyramine reaction, they have shown that the explanation of all the changes could be traceable to renin, presence of which the test revealed. In this connection it is important to contrast Balint’s findings1 of the effect of clamping the renal pedicle temporarily: 5 days later, those animals under light morphine anaesthesia developed severe azotxmia and died in 14 days with renal changes of interspread tubular necrosis; but those animals in whom the operation was conducted under deep chloralose anaesthesia survived without displaying any clinical signs of azotaemia. It was noted that the renal blood-flow (R.B.F.) fell to 50% of normal; but filtration was chiefly affected, the glomerular filtration-rate (G.F.R.) falling to 10% of normal. In earlier and parallel experiments Franklin and I2 had shown that stimulation by intermittent sinusoidal current of the renal nerves investing the renal artery produced severe cortical renal ischaemia with diversion of blood-flow to the medulla, and eventually caused cortical necrosis. This had never been demonstrated previously; but remarkable also was the fact that, if the animal was not immediately killed, in 2-3 hours the opposite kidney developed striking pallor indicating a release of vasoconstrictor material (quite possibly renin) from the experimental kidney. Balint’s findings make it clear that renal ischaemia was not the major determining factor of the cortical necrosis in these experiments, and that stimulation of the renal arteries’ nervous investment is of considerable astiological significance-this has important therapeutic applications in concealed accidental hxmorrhage where anuria can supervene when the blood-loss is insufficient to account for it,3 and which can be overcome by " denervation of the kidney in the early oliguric stages by conduction anaesthesia reaching the llth dorsal nerve supplying the kidney.4 But " even total transplantation may not produce absolute denervation, for some intact renal reflex arcs may remain since several small hilar ganglia would be distal to the line of vascular division and suture 11.5 In transplanting the kidney it necessarily follows that " denervation " cannot be postulated as excluding nervous control of the renal autoregulatory
especially since this control is abolished by smoothmuscle-paralysing agents (an attempt to transfer the emphasis to myogenic control). Recent proof of afferent arteriolar diameter changes during autoregulation in the dog’s kidney has been provided by Silver and Silver 6 who also regard this as myogenic ", whereas the Trueta mechanism nervously imposed by causing a spasm of the intralobular artery from the cortex towards the medulla could equally affect the closure of the afferent arteriolar vessels, whilst allowing for the opening of the juxtamedullary circulation.’7 That under normal physiological conditions there is a conprocesses,
"
siderable variation in the intrarenal blood-distribution has been shown by Thorburn et al. by the use of 85Kr y rays that are measurable externally. It was found that 80% of the radioactivity was distributed initially to the cortex, 16% to the outer medulla, 2% to the inner medulla, and 2% to the hilar and perirenal fat. Since then Pilkington 9 has shown that after mannitol and acetylcholine (50-80 limoles per minute) there were differences in response between the cortical and medullary flow, both of which were increased (the medullary flow proportionately more); and while noradrenaline (3-8-9-0 timoles per minute) decreased cortical flow, medullary flow did not change significantly.9 These data provide evidence of an initial difference in the distribution of the renal circulation, whilst they further emphasise that under experimental conditions there is an exaggeration of this difference, with the medullary flow becoming the greater. It is the opening of this juxtamedullary circulation that could explain the reduced G.F.R. in face of the far less reduced R.B.F. In this connection there is considerable support from the finding of Ljungqvist, who has demonstrated in the juxtamedullary zone a continuous arteriole with an incompletely visualised glomerular tuft; the arteriole splits into medullary arterioles, thereby allowing for an unfiltered blood-flow.1o In summary it is deducible that the autoregulation of the kidney is under a neurogenic control that can be considerably disorganised by overriding sympathetic nervous influences causing severe renal ischaemia, cortical necrosis, and renin release. These overriding impulses may be blocked by chloralose anaesthesia (Balint), or conduction anaesthesia reaching the nerve of supply to the kidney (the llth dorsal)a set of circumstances that the earlier experiments of Franklin and myself had clearly indicated. JOHN SOPHIAN. Worthing, Sussex. X2 TESTS AND SMOKING DURING PREGNANCY SirI would like to return to the question of whether Dr. Ravenholt’s data 11 demonstrate a significant negative correlation between the number of cigarettes smoked by women during pregnancy and the proportion of males among their liveborn offspring. After searching the statistical cookery books the best recipe he can produce (July 31) gives him a P of 0-04. The following data of mothers’ smoking habits during pregnancy by Macmahon et aI., 12 from a much larger investigation, indicate that Dr. Ravenholt’s 1 in 24 chance has not come off:
"
1. Bálint, P. in Acute Renal Failure (edited by S. Shaldon and G. C. Cook); p. 7. Oxford, 1964. 2. Sophian J. Excerpta med. sect. 10, 1958, 2, 1. 3. Parsons, F. M. Proc. R. Soc. Med. 1963, 56, 111. 4. Feeney, J. K. Ir. J. med. Sci. 1955, p. 195. 5. Carrel, A., Guthrie, C. C. J. Am. med. Ass. 1906, 47, 1648; cited by Mitchell, G. A. G. in Anatomy of the Autonomic Nervous System
London, 1953.
Clearly, there is nothing
in it. Dr. Ravenholt’s numbers are small. Department of Social and Occupational Medicine, Welsh National School of Medicine, C. R. LOWE. Cardiff.
too
Silver, S. B., Silver, A. S. J. invest. Urol. 1965, 2, 474. Sophian, J. Lancet, 1962, ii, 561; Int. Congr. Nephrol. 1963; p. 222. Thorburn, G. D., Kopald, H. H., Herd, A., Hollenberg, M., O’Morchoe, C. C., Barger, A. C. Circulation Res. 1963, 13, 290. 9. Pilkington, L. A., Binder, R., de Haas, J. C. M., Pitts, R. F. Am. J. Physiol. 1965, 208, 1107. 10. Ljungqvist, A. Nephron, 1964, 1, 329. 11. Ravenholt, R. T., Levinski, M. J. Lancet, 1965, i, 961. 12. Macmahon, B., Alpert, M., Salba, E. J. Am. J. Epidemiol. (in the press). 6. 7. 8.
-
ISCHÆMIA IN TRANSPLANTED KIDNEYS SIR,-Dr. Swales and Mr. Naunton Morgan (July 31) attempt to distinguish in dogs between the effect of a short period of renal ischaemia and a longer period during which the animal is the recipient of a renal transplant. They draw attention to the hypotensive effect of-the renal medulla of the transplanted kidney in masking in the recipient any rise of blood-pressure, which they reasonably infer would have occurred otherwise. A short period of renal ischxmia accompanies a fairly immediate or early transplantation, when the effects of clamping of the renal pedicle in the process of nephrectomy has been followed by a quick return of the renal circulation. A longer period implies a more prolonged renal ischxmia; and in man these authors found a period of anuria accompanied by microscopical changes resembling tubular necrosis in biopsy specimens from the kidney. In normotensive subjects in whom possible protective reactions against hypertensive stimuli had not been perfected, there were pronounced rises in blood-pressure. Translating the effect in dogs from clamping the renal artery, and by using the angiotensin-tyramine reaction, they have shown that the explanation of all the changes could be traceable to renin, presence of which the test revealed. In this connection it is important to contrast Balint’s findings1 of the effect of clamping the renal pedicle temporarily: 5 days later, those animals under light morphine anaesthesia developed severe azotxmia and died in 14 days with renal changes of interspread tubular necrosis; but those animals in whom the operation was conducted under deep chloralose anaesthesia survived without displaying any clinical signs of azotaemia. It was noted that the renal blood-flow (R.B.F.) fell to 50% of normal; but filtration was chiefly affected, the glomerular filtration-rate (G.F.R.) falling to 10% of normal. In earlier and parallel experiments Franklin and I2 had shown that stimulation by intermittent sinusoidal current of the renal nerves investing the renal artery produced severe cortical renal ischaemia with diversion of blood-flow to the medulla, and eventually caused cortical necrosis. This had never been demonstrated previously; but remarkable also was the fact that, if the animal was not immediately killed, in 2-3 hours the opposite kidney developed striking pallor indicating a release of vasoconstrictor material (quite possibly renin) from the experimental kidney. Balint’s findings make it clear that renal ischaemia was not the major determining factor of the cortical necrosis in these experiments, and that stimulation of the renal arteries’ nervous investment is of considerable astiological significance-this has important therapeutic applications in concealed accidental hxmorrhage where anuria can supervene when the blood-loss is insufficient to account for it,3 and which can be overcome by " denervation of the kidney in the early oliguric stages by conduction anaesthesia reaching the llth dorsal nerve supplying the kidney.4 But " even total transplantation may not produce absolute denervation, for some intact renal reflex arcs may remain since several small hilar ganglia would be distal to the line of vascular division and suture 11.5 In transplanting the kidney it necessarily follows that " denervation " cannot be postulated as excluding nervous control of the renal autoregulatory
especially since this control is abolished by smoothmuscle-paralysing agents (an attempt to transfer the emphasis to myogenic control). Recent proof of afferent arteriolar diameter changes during autoregulation in the dog’s kidney has been provided by Silver and Silver 6 who also regard this as myogenic ", whereas the Trueta mechanism nervously imposed by causing a spasm of the intralobular artery from the cortex towards the medulla could equally affect the closure of the afferent arteriolar vessels, whilst allowing for the opening of the juxtamedullary circulation.’7 That under normal physiological conditions there is a conprocesses,
"
siderable variation in the intrarenal blood-distribution has been shown by Thorburn et al. by the use of 85Kr y rays that are measurable externally. It was found that 80% of the radioactivity was distributed initially to the cortex, 16% to the outer medulla, 2% to the inner medulla, and 2% to the hilar and perirenal fat. Since then Pilkington 9 has shown that after mannitol and acetylcholine (50-80 limoles per minute) there were differences in response between the cortical and medullary flow, both of which were increased (the medullary flow proportionately more); and while noradrenaline (3-8-9-0 timoles per minute) decreased cortical flow, medullary flow did not change significantly.9 These data provide evidence of an initial difference in the distribution of the renal circulation, whilst they further emphasise that under experimental conditions there is an exaggeration of this difference, with the medullary flow becoming the greater. It is the opening of this juxtamedullary circulation that could explain the reduced G.F.R. in face of the far less reduced R.B.F. In this connection there is considerable support from the finding of Ljungqvist, who has demonstrated in the juxtamedullary zone a continuous arteriole with an incompletely visualised glomerular tuft; the arteriole splits into medullary arterioles, thereby allowing for an unfiltered blood-flow.1o In summary it is deducible that the autoregulation of the kidney is under a neurogenic control that can be considerably disorganised by overriding sympathetic nervous influences causing severe renal ischaemia, cortical necrosis, and renin release. These overriding impulses may be blocked by chloralose anaesthesia (Balint), or conduction anaesthesia reaching the nerve of supply to the kidney (the llth dorsal)a set of circumstances that the earlier experiments of Franklin and myself had clearly indicated. JOHN SOPHIAN. Worthing, Sussex. X2 TESTS AND SMOKING DURING PREGNANCY SirI would like to return to the question of whether Dr. Ravenholt’s data 11 demonstrate a significant negative correlation between the number of cigarettes smoked by women during pregnancy and the proportion of males among their liveborn offspring. After searching the statistical cookery books the best recipe he can produce (July 31) gives him a P of 0-04. The following data of mothers’ smoking habits during pregnancy by Macmahon et aI., 12 from a much larger investigation, indicate that Dr. Ravenholt’s 1 in 24 chance has not come off:
"
1. Bálint, P. in Acute Renal Failure (edited by S. Shaldon and G. C. Cook); p. 7. Oxford, 1964. 2. Sophian J. Excerpta med. sect. 10, 1958, 2, 1. 3. Parsons, F. M. Proc. R. Soc. Med. 1963, 56, 111. 4. Feeney, J. K. Ir. J. med. Sci. 1955, p. 195. 5. Carrel, A., Guthrie, C. C. J. Am. med. Ass. 1906, 47, 1648; cited by Mitchell, G. A. G. in Anatomy of the Autonomic Nervous System
London, 1953.
Clearly, there is nothing
in it. Dr. Ravenholt’s numbers are small. Department of Social and Occupational Medicine, Welsh National School of Medicine, C. R. LOWE. Cardiff.
too
Silver, S. B., Silver, A. S. J. invest. Urol. 1965, 2, 474. Sophian, J. Lancet, 1962, ii, 561; Int. Congr. Nephrol. 1963; p. 222. Thorburn, G. D., Kopald, H. H., Herd, A., Hollenberg, M., O’Morchoe, C. C., Barger, A. C. Circulation Res. 1963, 13, 290. 9. Pilkington, L. A., Binder, R., de Haas, J. C. M., Pitts, R. F. Am. J. Physiol. 1965, 208, 1107. 10. Ljungqvist, A. Nephron, 1964, 1, 329. 11. Ravenholt, R. T., Levinski, M. J. Lancet, 1965, i, 961. 12. Macmahon, B., Alpert, M., Salba, E. J. Am. J. Epidemiol. (in the press). 6. 7. 8.