1319 DISCUSSION

Use of the prosthesis has eliminated the permanent communication between the skin and the peritoneal cavity required for the Deane prosthesis and the Tenckhoff catheter. Patients are free of dressing and of abdominal tubes and bags. Possibly, the use of this new implement will diminish the incidence of

Fig. 2-Plate part of prosthesis supported by subcutaneous fat and covered by skin.

plate of the prosthesis. The aponeurosis and the peritoneum are incised on the midline and the tube of the device is placed into the peritoneal cavity. The peritoneum is sutured with a continuous running silk suture and the knot is closed around the neck of the prosthesis. The aponeurosis is closed with an interrupted silk suture.

for the

One of them is also closed around the neck of the device. The plate part is supported by the subcutaneous tissue (fig. 2) which is closed with catgut, and finally the skin is also closed. 1 week after the operation, peritoneal dialysis can be started. The patient is supine, and a commercially available catheter is used. After antisepsis and under local anaesthesia the skin is pierced with the stylet, near the external border of the plate, and then the catheter is introduced into the prosthesis. Sometimes the tube may be obstructed by a weak omental wrapping on the distal tip of the prosthesis. It can be easily overcome by pushing with the blunted tip of the catheter, which is finally placed in the pelvic gutter, and then dialysis can be started. Commercially available solution (’Dianeal’) was used, and patients were included in a 12-hour twice-weekly dialysis schedule. At the end of dialysis, the catheter is withdrawn and the pierced skin is dressed for 24 hours. RESULTS

The three patients have received a total of SO peritoneal dialyses. All six prostheses are still in situ (table), and the patients are still on peritoneal dialysis. The prostheses are acceptable to the patients and none of them experienced discomfort in the intervals between dialysis. Local fibrosis was prevented by weekly intradermic infiltrations of triamcinolone. No cases of peritonitis were seen. Patient A had a wound infection because of very poor personal hygiene; this was cured by local treatment. DETAILS OF

50 PERITONEAL

DIALYSES

WITH SIX PROSTHESES IN

THREE CHRONIC URÆMIC PATIENTS

peritonitis. Surgical implantation is simple. Alternate use of the two sites helps skin healing, which is relevant in case of local wound infection. Moreover, the plate of the device can be moved part freely under the and can be skin, punctures performed at different Introduction of the points. commercially available catheter into the peritoneal cavity is easy and safe. The standard percutaneous technique requires the dangerous use of the stylet to pierce the peritoneum, with the risk of bladder or bowel perforation, risks which are higher in the unconscious patient or even in the awake patient with a flabby abdominal wall. We have eliminated the use of indwelling catheter with limited lifetime. There is no need to leave dialysate in the peritoneal cavity at the end of each dialysis to prevent clotting and omental adhesions. On the contrary, we think that light omental wrapping on the distal tip of the prosthesis is beneficial, preventing leakages and hermetically sealing the peritoneal cavity.

Requests for reprints should be addressed Unit, Central Emek Hospital, Afula, Israel.

to

L.

G.,

Renal

REFERENCES

Lankish, P. G., Tonnis, H. J., Fernandez-Redo, E., Girndt, J., Kramer, P., Quellhorst, E., Sheller, F. Br. med. J. 1973, i, 712. 2. Rae, A., Pendray, M. J. Am. med. Ass. 1973, 228, 937. 3. Tenckhoff, H., Curtis, F. K. Trans. Am. Soc. artif. intern. Organs, 1970, 16, 90. 4. Brewer, T. E., Caldwell, F. T., Patterson, R. M., Flanigan, W. J. J. Am. med. Ass. 1972, 219, 1011. 1.

Hypothesis ROLE OF PROSTAGLANDINS IN THE PATHOGENESIS OF ACUTE RENAL FAILURE DONALD E. OKEN

Department of Medicine, Peter Bent Brigham Hospital, 721 Huntington Avenue, Boston, Massachusetts 02115, U.S.A. It is suggested that impaired glomerular infiltration in acute renal failure may be due, if only in part, to the derangement of a normal local feedback mechanism involving prostaglandins. According to this hypothesis, prostaglandins made in the medulla normally enter the loop of Henle and thus are present in distal tubule fluid reaching the macula densa. In the absence of direct vascular channels connecting the renal medulla with the outer cortex, this may be the only route by which medullary prostaglandins can reach the cortex without being destroyed by dehydrogenases. Under most circumstances in which renal perfusion and glomerular filtration fall, flow through Henle’s loop con-

Summary

1320

tinues, albeit at a reduced rate. This slowed flow through the loop and augmented prostaglandin release combine to produce a high concentration of prostaglandin in fluid leaving the medulla which, acting on the macula densa, counteracts the vasoconstrictor stimulus. If, however, filtration stops completely because of overwhelming vasoconstriction, flow along the loop also stops and prostaglandins no longer reach the macula densa. Thus, the prostaglandin feedback loop would be opened, constrictor mechanisms remain unchecked, and filtration failure perpetuated. It is proposed that such a self-perpetuating mechanism might operate in acute renal failure. INTRODUCTION

ACUTE renal failure

usually occurs after an episode of shock, haemolysis, sepsis, or trauma. The syndrome is often recognised after the initiating cause has already been successfully treated and persists for as long as 3 or more weeks afterwards. Renal micropuncture studies over the past 10 years have shown that experimental acute renal failure of diverse aetiology is directly attributable to a near cessation of glomerular filtration.’ However, tubular leakage has been described as the prime pathogenic low-dose

mercuric-chloride poisoning,2,3 although importance of such leakage is questionable.4 Filtration failure apparently persists throughout the course of renal failure, despite measures which assure normal or increased plasma volume, total-body water, and cardiac output. At the onset of recovery from myoglobinuric acute renal failure, filtration in individual nephrons of a given kidney was either almost non-existent or essentially normal, the wholekidney inulin clearance correlating directly with the proportion of nephrons in which filtration was restored.5 Nephrons with normal glomerular filtration-rates (G.F.R.) lay next to nephrons almost devoid of filtrate, and it is difficult to see how any circulating factor might, by itself, affect adjacent nephrons so differently. Thus, it was suggested that filtration failure reflects a local phenomenon.5 Having excluded increased tubular pressure as the direct cause

event

in

the

of impaired filtration in most experimental models.’ it must be assumed that intraglomerular capillary pressure is too low for filtration to continue, that glomerular permeability is grossly reduced, or that both factors are involved. GLOMERULAR PERMEABILITY IN RENAL FAILURE

Glomerular permeability has been generally assumed be normal in acute renal failure, since the glomerulus shows only minor anatomical changes on electron microscopy and afferent arteriolar constriction alone could theoretically account for any haemodynamic and filtration abnormalities observed. However, renal cortical blood-flow in mercury-induced, post-ischaemic, and myohaemoglobinuric acute renal failure is not always subnormal, despite maximum suppression of G.F.R.6 Indeed, jaenike reported supernormal blood-flow in a study of rats with methaemoglobin-induced renal failure,’ and occasional cases of acute renal failure in man have been reported not to

to

demonstrate renal cortical ischæmia.8,9 This maintenance of normal blood-flow despite filtration failure might, then, signify abnormal permeability of the glomerular membrane, but it by no means rules out a vascular aetiology for filtration failure; afferent arteriolar constriction may greatly lower glomerular capillary pressure without reducing blood-flow, so long as the resistance of the postglomerular vasculature decreases correspondingly. But how might such hæmodynamic readjustment or altered glomerular permeability be mediated? Flores et al.10 proposed that swelling of interstitial and endothelial cells or the aggregation of blood elements is at least partly responsible for the diminished blood-flow and failed filtration in renal failure pro-

duced by

prolonged renal-artery clamping. Wardle al.,l1 finding altered fibrinogen catabolism and fibrin-degradation products in the urine of rats with glycerol-induced, myohaemoglobinuric acute renal failure, have suggested that intravascular coagulation also may impair renal blood-flow by mechanical means; et

Clarkson et a1,l2 drew a similar conclusion from studies of kidney samples from patients with renal failure. We have found, however, that long-term saline-solution loading almost completely protects rats from myohaemoglobinuric acute renal failure ’11 the model studied by Wardle. Furthermore, animals recovering from glycerol-induced renal failure are resistant to a second challenge with either mercuric chloride or glycerol.14 The way in which either of these manoeuvres might influence cell swelling or fibrin deposition is not known. More directly, renal cortical blood-flow, measured by implanted platinum electrodes,1s returns to a nearly normal value soon after release of the clamping procedure used by Flores et al." Furthermore, Tanner et ap6 found intratubular pressures equal to normal filtration pressure in this model of acute renal failure, a finding which, coupled with the finding of a well-maintained cortical blood-now,15 clearly indicates that preglomerular resistance was not greatly increased by either mechanical or vasomotor factors in that particular model of renal failure. Rather, acute renal failure induced in this way is different from most other types studied to date and seems to be directly attributable to tubule obstruction. Most other models of the syndrome produce low intratubular pressures, as stated above, a finding which accords with the low renal venous wedge pressures recorded in human renal failure." We are, then, still left with the likelihood that most forms of acute renal failure are the result of altered renovascular resistance or abnormally low glomerular permeability. RENOVASCULAR RESISTANCE

Renovascular resistance is controlled by myogenic receptors interacting with neural influences, circulating catecholamines, the renin system, prostaglandins, and, possibly, the kinins. A constrictor effect of renal- .

stimulation, circulating catecholamines, or angiotensin is offset by prostaglandin release by the normal kidney,t8 and the constrictor agonists augment arteriolar resistance if prostaglandin synthesis is reduced by indomethacin.19 The prostaglandins

nerve

1321

competitively inhibit angiotensin generation,2° modulate neurotransmission,l8 regulate intrarenal distribution of blood-flow by an apparently direct action,21 and induce other effects which might influence the development of acute renal failure. Because of these interactions, it seems likely that more than one factor may be involved in the haemodynamic aberrations observed, and each factor needs to be considered in the light of possible interplay with the others. RENIN-ANGI,OTENSIN SYSTEM

widely believed that the renin-angiotensin system plays a key part in the haemodynamic aberraIt is

, .

Several laboratories tions of acute renal failure. have now demonstrated feedback between electrolyte transport in the distal tubule and glomerular filtration in the normal kidney,22 and such a mechanism has been postulated as the immediate cause of acute renal failure. 23 According to this postulate, impaired sodium transport across injured proximal tubules presents an increased load (? concentration) of sodium to the macula densa with subsequent local renin release and active afferent arteriolar constriction. While the " macula densa mechanism " may operate under physiological conditions, some workershave demonstrated that virtually no filtrate is formed by most nephrons of kidneys with acute renal failure to provide perfusate for the macula densa. Witty et al., however, demonstrated that renin release at the afferent arteriole is also modified by a baroreceptor mechanism independent of filtration 240 and this mechanism should still be operable even in the presence of renal failure. Perhaps the strongest circumstantial evidence supporting the renin concept derives from the finding that rats given 1% saline solution in place of tap-water for a month are highly resistant to all forms of experimental acute renal failure used in this laboratory,13 except the renalartery-clamp model (unpublished data). Such rats have very low plasma and renal renin titres, and it is tempting to suggest that this renin depletion is responsible for the protection observed. However, Kilcoyne and Cannon 25 found that sodium balance also modifies the constrictor effect of noradrenaline, and renal prostaglandin release is reported to be inversely related to plasma-renin-activity.26 Thus, the prophylactic effect of long-term salt loading might be produced, at least in part, by reduced sensitivity to noradrenaline or augmented prostaglandin synthesis in addition to renin depletion. Plasma and renal renin titres are normal or high in animals that have recently recovered from renal failure, yet these animals also are refractory to the development of renal insufl’ICiency 14 Evidently, renin depletion is not essential for protection, and this finding seems to argue against the renin system being the only factor involved in the pathogenesis of acute renal

failure. RENAL PROSTAGLANDINS

As described above, the release of prostaglandins by the normal kidney has been shown repeatedly to antagonise the renal cortical vasoconstriction caused by angiotensin, sympathetic-nerve stimulation,

noradrenaline in various species. Why, then, do renal prostaglandins not similarly prevent the sustained vasoconstriction which typifies acute renal failure? There is evidence that renal prostaglandins are synthesised in the medulla 27 but have potent effects on the cortical circulation. Only small amounts seem to be produced in the cortex,28 which is very rich in 15-hydroxydehydrogenase, the major metabolising enzyme for prostaglandins.29 There are no vascular channels directly connecting the medulla with the mid and outer cortex of the kidney, and it seems unlikely that the prostaglandins reach the cortex by diffusion because of the rapidity with which they act and the likelihood that they would be degraded by cortical dehydrogenases en route. Henle’s loop does lead directly from the medulla to the cortical segment, however, and it is at least reasonable to -suggest that this may be the pathway through which prostaglandins synthesised in the renal medulla -travel without being enzymatically degraded. If prostaglandins enter the ascending or descending limb of Henle’s loop in the normal kidney, they would then be present in distal tubule fluid bathing the macula densa-the presumed site of glomerular arteriolar regulation. Indeed, evidence suggests that renal prostaglandins enter the urine at some distal site,3° -which might include the loop of Henle. If this postulate is correct, an increased prostaglandin release by the normal kidney during a period of renal ischxmia, coupled with a slower flow through the loop of Henle, could greatly increase the concentration of prostaglandins in fluid reaching the macula densa and help to maintain normal glomerular filtration. This feedback system could operate in the normal kidney regardless of the proportion of long loops of Henle, since even the outer medulla bathing .the short loops of Henle contains significant amounts of prostaglandin 31 In 1970 Fine 32 suggested that depletion of renal prostaglandin might be responsible for the genesis of acute renal failure, even before the ability of prostaglandins to counteract renal vasoconstriction was established. Gerhard and Mulrow 33 reported low renal concentrations of prostaglandin A in rats in which acute renal failure had been induced by glycerol 24 hours earlier. The reduction in prostaglandin concentration correlated well with the degree of renal insufficiency induced. However, since indomethacin lowered prostaglandin A titres even further without affecting the severity of renal failure, Gerhard and Mulrow suggested that reduced renal prostaglandin A content in acute renal failure is secondary to damage and does not itself influence the severity of renal failure. Torres et al.,34 by contrast, found that the concentration of prostaglandin was increased in kidneys of rats and rabbits with glycerol or mercuric-chloride induced acute renal failure. Regardless of the renal medullary prostaglandin content, however, the cessation of glomerular filtration in acute renal failure would effectively stop flow through Henle’s loop and thus eliminate the pathway through which I suggest prostaglandins might exert In a previous study their autoregulatory function. of low-dose mercury poisoning, nephrons which were filtering virtually no fluid but had minimally increased intratubular pressure began to filter at a rate of some

or

1322

80% of normal once flow had been induced by injecting isotonic saline solution into their proximal tubules at physiological hydrostatic pressure. A I

feedback system between tubule flow and filtration was postulated but was not pursued further, and other models of acute renal failure have not yet been examined in this light. Whether restoration of flow in such tubules caused the return of glomerular filtration as a result of the resumed delivery of prostaglandins to the macula densa or of other factors must be investigated. The finding is, however, in keeping with my present hypothesis of a complex tubular/ glomerular feedback mechanism which may be associated with neural factors, the renin-angiotensin system, and the availability of prostaglandins reaching the glomerular vascular pole in acute renal failure. Whether such action might be mediated through a vasomotor mechanism, change in glomerular permeability, or both remains to be determined. This work was supported by grant AM-08695 from the National Institutes of Health. REFERENCES

6. Mende, C. W., Taraba, I., Oken, D. E. Clin. Res. 1972, 20, 602. 7. Jaenike, J. R. J. clin. Invest. 1967, 46, 378. 8. Reubi, F. C., Gürtler, R., Gossweiler, N. Proc. Soc. exp. Biol. Med. 9. 10. 11. 12.

13. 14.

15. 16. 17.

199. 18. 19. 20. 21. 22. 23. 24.

25. 26. 27.

28.

Oken, D. E. in Progress in Biochemistry and Pharmacology (edited by K. D. G. Edwards); p. 219. Basel, 1972. 2. Bank, N., Mutz, B. F., Aynedjian, H. S. J. clin. Invest. 1967, 46, 1.

29. 30.

695.

Steinhausen, M., Eisenbach, G. M., Helmstadter, V. Pflügers Arch. ges. Physiol. 1969, 311, 1. 4. Oken, D. E. Am. J. Med. 1975, 58, 77. 5. Oken, D. E., DiBona, G. F., McDonald, F. D. J. clin. Invest. 1970, 49, 730. 3.

Reviews of Books A Textbook of Health Education 2nd ed. A. J. DALZELL-WARD, Health Education Council. London : Tavistock.

1975.

Pp. 328.

S5.50

(paperback

S2.75). Health and Social Education MAY V. LEA. London: Heinemann Educational. Pp. 164. E3.80 (paperback E1.90).

1975.

CONFUSION about the legitimate goals of medical and educational institutions and the methods by which they may be achieved is greatest when we come to health education-an amalgam of both disciplines. What should be taught, and how ? How far may we go in trying to change the behaviour of people to make them healthier ? How much public money can we justify for health education ? How do we reach high-risk groups, such as the socially underprivileged with their higher rates of mortality, morbidity, and illegitimacy ? In the absence of satisfying answers to these questions, people polarise-some become enthusiastic believers in health education while others, including open-minded sceptics, are labelled as infidels. With so many hazards and so much confusion, anyone writing on health education deserves an award for bravery. Dr Dalzell-Ward’s textbook for trainee teachers and health educators reflects his experience and his grasp of many of the issues, including new educational techniques. The book concentrates on those forms of health education which are directed towards prevention of illness at different stages throughout life, but there are also sections on the structure of the N.H.S. and on the wider issues of community responsibility and the political implications of health legislation. A very short section raises the question of the evaluation of different forms of health education-a form of self-criticism

1962, 111, 760. Walker, J. G., Silva, H., Lawson, T. R., Ryder, J. A., Shaldon, S. ibid. 1963, 112, 932. Flores, J., DiBona, D. R., Beck, C. H., Leaf, A. J. clin. Invest. 1972, 51, 118. Wardle, E. N. Thromb. Diath. hœmorrh. 1973, 29, 579. Clarkson, A. R., MacDonald, M. K., Fuster, V., Cash, J. D., Robson, J. S. Q. Jl Med. 1970, 39, 585. Thiel, G., McDonald, F. D., Oken, D. E. Nephron, 1970, 7, 67. Oken, D. E., Mende, C. W., Taraba, I., Flamenbaum, W. ibid. (in the press). Zarlengo, M. D., Oken, D. E. Clin. Res. (in the press). Tanner, G. A., Sloan, K. L., Sophasan, S. Kidney Int. 1973, 4, 377. Brun, C., Crone, C., Davidsen, H. G., Fabricius, J., Hansen, A. T., Lassen, N. A., Munck, O. Proc. Soc. exp. Biol. (N.Y.) 1956, 91,

31. 32. 33. 34.

Lonigro, A. J., Terragno, N. A., Malik, K. U., McGiff, J. C. Prostaglandins, 1973, 3, 595. Hedqvist, P. Acta physiol. scand. 1970, 345, suppl. p. 1. Kotchen, T. A., Miller, M. C. Am. J. Physiol. 1974, 226, 314. Herbaczynska, C. E., Vane, K., Jr. Circulation Res. 1973, 33, 428. Schnermann, J., Wright, F. S., Davis, J. M., Stackelberg, W. V., Grill, G. Pflügers Arch. Eur. J. Physiol. 1970, 318, 147. Thurau, K. Anæsthesiologie und Wiederbelebung, 1970, 49, 1. Witty, R. T., David, J. O., Johnson, J. A., Prewitt, R. L. Am. J. Physiol. 1971, 221, 1666. Kilcoyne, M. M., Cannon, P. J. ibid. 1966, 210, 1231. Bunag, R. D., Page, I. H., McCubbin, J. W. ibid. 1966, 211, 1383. Lee, J. B., Crowshaw, K., Takman, B. H., Attrep, K. A. Biochem. J. 1967, 105, 1251. Anggård, E., Bohman, S. O., Griffin, J. E., Larsson, C., Maunsbach, A. B. Acta physiol. scand. 1972, 84, 231. Anggård, E., Larsson, C., Samuelsson, B. ibid. 1971, 81, 396. Williams, M. W., Wilson, T. W., Oates, J. A., Nies, A. S., Frolich, J. C. J. clin. Invest. 1974, 53, 85a. van Dorp, D. Ann. N.Y. Acad. Sci. 1971, 180, 181. Fine, L. G. Israeli J. med. Sci. 1970, 6, 346. Gerhard, H., Mulrow, P. J. Clin. Res. 1974, 22, 528A. Torres, V. E., Romero, J. C., Strong, C. G., Wilson, D. M., Walker, V. R. Prostaglandins, 1974, 8, 353.

for which neither medicine nor education have robust reputations, but which in the context of modern economic realities is becoming very important. The book gives copious references, is well written, and should serve as a good reference book for its intended readers. May Lea has written a shorter book for the same readership but in a racy, sometimes breathless, style. Man is his own worst enemy, polluting and overpopulating his world to destruction, spoiling his teeth and feet, and doing many other evils at great pace. The subjects covered, including abortion, teenage sex, and drugs, are all topical. At times the reader may wonder quite what the line of argument has to do with the main theme of the book, because a considerable time is spent justifying counterculture mores. At other times he may feel starved for facts and rather too well fed on the author’s anecdotes and opinions. However, the author concludes usefully with a clear and concise appendix of ways in which health education may be integrated into the curricula of English and Scottish schools. Despite the unattractive style, it is encouraging to find a book which brings enthusiasm and a fresh perspective to this subject. Both books, however, leave the impression that health education has taken on too much. This may stem from contemporary concepts of health which are too idealistic and impractical. The best hope for health education may lie in the development of less ambitious programmes directed to high-risk groups for specific purposes (e.g., the prevention of cigarette smoking among poorer children) which may be simply evaluated and, if effective, be seen to be so. But if we enthusiastically expect health education to be the magic which will prevent all illness, without disturbing underlying life-styles or system of values too much, or if we try to relegate it to the status of arithmetic in a universal education, we will probably be wrong. These two books may help train educators to teach about health properly, and to evaluate their own successes and failures critically.