Acute renal failure

ment of chronic renal failure have tended to divert interest from the clini¬ cal aspects of acute renal failure, a subject which for some years has been the "Cinderella" of nephrology. More recently, interest has been rekindled by various workers attempting to de¬ fine the pathophysiology of ARF, and by the growing suspicion that, somehow, dialysis has failed to make its expected impact on mortality from this condition.1 When, under the auspices of the National Institutes of Health, a conference on ARF was held in New York in May 1973, it became obvious that prognosis is hardly im¬ proved from what it was 20 years ago, and that many questions remain to be answered. Semantic problems and failure of definition have contributed to the con¬ fusion surrounding this subject. Acute, potentially reversible renal failure is that condition characterized by oli¬ guria, uremia and poor urinary con¬ centration which may follow shock, sepsis, trauma or the administration of certain nephrotoxic drugs. For the pur¬ poses of this paper, the term ARF does not encompass oliguria and uremia due to dehydration and hypo¬ volemia, or that due to lower urinary tract obstruction, although both of these conditions may progress to produce intrinsic renal damage. As defined, then, ARF has been recog¬ nized for many years, and was ori-

in New York in May 1973, it became obvious that prognosis is hardly im¬ proved from what it was 20 years ago, and that many questions remain to be answered.
Semantic problems and failure of definition have contributed to the con¬ fusion surrounding this subject. Acute, potentially reversible renal failure is that condition characterized by oli¬ guria, uremia and poor urinary con¬ centration which may follow shock, sepsis, trauma or the administration of certain nephrotoxic drugs. For the pur¬ poses of this paper, the term ARF does not encompass oliguria and uremia due to dehydration and hypo¬ volemia, or that due to lower urinary tract obstruction, although both of these conditions may progress to produce intrinsic renal damage. As defined, then, ARF has been recog¬ nized for many years, and was ori-.Chief of Medicine, Victoria Hospital, London, Ont. Reprint requests to: Dr. A. L. Linton, Victoria Hospital, London, Ont. N6A 4G5 ginally thought to be the functional result of tubular obstruction with cel¬ lular debris; this concept was based upon the observation of such changes at autopsy. It is now clear that the pathological changes of "acute tubular necrosis" do not necessarily occur in ARF,2 and micropuncture studies have shown that neither tubular obstruction nor passive back-diffusion of glomerular filtrate accounts for the oliguria.3 Perhaps the major stimulus to fur¬ ther study of ARF has been the ob¬ servation that despite improvements in dialysis techniques and in medical and surgical management of the critically ili patient, the mortality rate in patients with ARF remains around 50% ,M'5 not significantly lower than 20 years ago.6 Studies during the Vietnam con¬ flict revealed that despite the excellent results of improved overall manage¬ ment of combat casualties, the onset of ARF was a grave prognostic sign, and they emphasized that prevention remains very much better than at¬ tempted cure.7 Attempts to identify the cause of the persistingly high mortality in ARF have produced some informa¬ tion. There seems little doubt that there has been a shift in the spectrum of patients referred to renal units, in that patients who might previously have de¬ veloped mild degrees of ARF are now saved from this by better management, while many critically ili patients are now kept alive long enough to develop severe ARF. 4 As examples, patients re¬ ferred with acute renal failure in 1960 were often young adults in whom the condition was due to obstetric causes or followed trauma; now the typical patient seems to be over 60 years of age, to have developed renal failure following heroic vascular surgery, and to have many complications, particu¬ larly cardiovascular and infective. Ad¬ Attempts to improve survival by modification of the long-established treatment regimen of fluid and dietary control and dialysis have not so far yielded great benefit. Very frequent dialysis might have been expected to help by maintaining the patient more nearly normal in a biochemical sense, but only one study, by Kleinknecht et al* has demonstrated any such bene¬ fit, and that only in reduction in mor¬ tality from gastrointestinal hemorrhage. Alterations in dietary restrictions aimed at better nutrition of patients in the acute phase of ARF are also under study, and some evidence sug¬ gests that the use of intravenous es¬ sential amino acids and hypertonic glucose may reduce mortality.9 While such improvements are en¬ couraging, prophylaxis is a more worthwhile aim than improved therapy. Better understanding of fluid and electrolyte management has undoubtedly contributed to reduction in incidence of ARF in less severely ili patients,10 but specific prophylactic measures will only be developed when the pathophy¬ siology of the condition is understood.
Elucidation of the mechanism of production of ARF is further com¬ plicated by the probability that there are two distinct varieties of the con¬ dition. Oliver, MacDowell and Tracy11 originally distinguished, on histologic grounds, "toxic" and "circulatory" types of ARF, and other authors have recently supported the view that these two types may be produced by dif¬ ferent pathological mechanisms.1*'13 In clinical practice the toxic variety of ARF probably occurs most often after the administration of various nephro¬ toxic antibiotics. In animals it has been shown that renal damage induced by antibiotics such as cephaloridine differs histologically from circulatory types of ARF. It also appears that furosemide given along with the antibiotic increases the degree of renal failure both biochemically and histologi¬ cally.13 '14 This observation suggests that caution should be exercised in the use of potentially nephrotoxic antibiotics and diuretics. This very frequently pre¬ scribed combination of drugs may well be contributing to the incidence of ARF in those very complex cases where it is usually impossible to iden¬ tify any single cause for the renal failure.15 Further evidence that toxic and circulatory renal failure differ comes from the observation in rats that furosemide given before nephro¬ toxic doses of antibiotics protects against subsequent damage, but in the circulatory type of ARF induced by glycerol, pretreatment with furosemide increases the degree of damage.13 The means by which nephrotoxic substances produce renal impairment remains quite unknown. Studies on cephalo¬ ridine have demonstrated the presence of the drug in the renal medullary interstitium and in the cells of the proximal tubule; it seems likely that the nephrotoxicity is a local effect unrelated to circulatory disturbance in the kidney.
The mechanism of "circulatory" ARF likewise remains controversial. Accumulating evidence from micropuncture studies has totally failed to support the older theories which invoked the presence of tubular obstruction and/or passive back-diffusion of glomerular filtrate to explain the oliguria and consequent uremia.16 Studies both in ani¬ mals and the human now suggest that the basic disturbance in "circulatory" ARF involves vasomotor disturbances at the glomerular level.17"19 In most studies reported, renal blood flow of subjects with ARF has been found to be markedly reduced;20 renal cortical blood flow is often so greatly reduced as to cause failure of glomerular fil¬ tration.19 It has been postulated that vasoconstriction of the afferent arterioles to the glomeruli would so reduce filtration pressure as to cause oliguria even in the presence of continuing, though reduced, renal blood flow.16 It is of interest that such a hypothesis was proposed early in this century,21 but has had to wait until now for concrete support. While it is likely that reduc¬ tion in cortical blood flow and pre¬ glomerular vasoconstriction constitute the primary disturbances in circulatory ARF, it is necessary then to consider how these changes are brought about. Strong circumstantial evidence exists to implicate the renin/angiotensin sys¬ tem in the genesis of ARF, although the word "circumstantial" must be stressed. Since renin is produced at the juxtaglomerular apparatus, it would appear to be admirably sited to regulate directly the preglomerular arteriolar calibre, and if produced in excessive amounts might well create the pathophysiological state postulated in ARF.

At the clinical level it has been
shown that peripheral plasma renin levels are usually raised during the early stages of ARF, and patients with pre-existing high plasma renin levels seem more susceptible to ARF.22 In experimental models, plasma renin ac¬ tivity rises during the early stages of glycerol-induced ARF (analogous to "circulatory" ARF in man), but does not rise in renal failure induced by cephaloridine ("toxic" ARF).12 Infusion of large amounts of angiotensin II produces acute renal failure in rabbits, but less predictably in rats, illustrating again the inherent problems of relating animals to man.23 Failure to prevent ARF in animals by immunization against renin24 or angiotensin II25 sug¬ gests that angiotensin II formed in the peripheral circulation is not responsible for the production of ARF, but does not invalidate the possibility of local release of renin at the juxtaglomerular apparatus acting directly at the glo¬ merular vascular pole. This latter pos¬ sibility is supported by the observation that long-term salt-loading (which depletes intrarenal renin) protects rats against ARF, while comparable pro¬ tection is not afforded by acute volume expansion, which depresses peripheral, but not renal parenchymal renin levels.26 Definite proof of a role for intra¬ renal renin in ARF is still lacking and other mechanisms have to be con¬ sidered. Fung and Thomson27 in Win¬ nipeg have shown that infusion of norepinephrine into one renal artery of a dog can produce prolonged hemo¬ dynamic and functional renal abnor¬ malities resembling human ARF. They have demonstrated that prior renal denervation and post-insult phenoxyben¬ zamine confer considerable protection against glycerol-induced renal failure in the rat, suggesting that enhanced sympathetic activity may play a part in the pathogenesis of ARF. Against this, however, is the observation that ARF occurs in transplanted (denervated) kidneys, and these authors have been unable to demonstrate improve¬ ment in intrarenal hemodynamics fol¬ lowing a-adrenergic blockade in norepinephrine-induced ARF.28 Even if a vasoactive substance can be identified as the cause of the original hemodynamic disturbance of ARF, it is difficult to envisage any such sub¬ stance maintaining preglomerular vaso¬ constriction for the period of days or weeks that may elapse before the diuretic phase of human ARF ensues. One possible mechanism was suggested by Flores et al29 who produced some evidence that ischemia initiated by vasoconstriction might be perpetuated by cell swelling. They suggest that such swelling is due to failure of ischemic cells to extrude sodium nor¬ mally, and that subsequent renal dys¬ function may be prevented by infusion of hyperosmotic mannitol . there is also some clinical evidence for this.30 Another attractive theory to explain the duration of ARF is that initial vaso¬ constriction leads to coagulation within the glomeruli; Clarkson et aP1 have demonstrated marked deposition of fibrin and platelets within glomeruli of patients in the oliguric phase of ARF.
The New York conference did not resolve the enigma of acute renal fail¬ ure. There was general agreement that improvements in therapy, or better still, prevention, will stem from an under¬ standing of basic mechanisms, and at present the favoured hypothesis would be that initial preglomerular vasocon¬ striction is perpetuated possibly by coagulation or cell swelling. The need for meticulous fluid and electrolyte management of patients at risk re¬ mains, and prophylactic dialysis with intravenous feeding of essential amino acids deserves further study. Mannitol may still be worthy of trial in the early stages of ARF, since there is clinical evidence that it may abort the condition if given within 48 hours the renal insult. There is no convincing evidence that the widely used furosemide in high doses confers any benefit; in studies in man and animals Muth32 could not demonstrate any therapeutic benefit in ARF. Indeed, furosemide may be harmful, either by a direct nephrotoxic effect of its own, or by potentiating the nephrotoxic ac¬ tions of other drugs.
It is obvious that acute renal failure continues to present an additional hazard in patients already at risk from trauma, surgery or infection. The principles governing management can be simply stated as follows: 1 There is little evidence to support the use of high-dose furosemide, although some workers feel that this requires further evaluation and may be worth a trial. 6. Consider advisability of establishing frequent dialysis (possibly daily) to allow continued high protein, high calorie diet. 7. Avoid blood transfusion if possible, but be aware of the risk of alimentary bleeding. 8. Avoid prophylactic antibiotics, but continuously monitor for infections, bearing in mind that such patients are susceptible to infection with unusual organisms such as the bacteroides group; anaerobic blood cultures are necessary. 9. Remember that all drugs which are excreted by the kidney will be retained in ARF. Dosages of drugs such as digoxin, sedatives and antibiotics should be suitably reduced, and controlled by blood level estimations. It is to be hoped that better understanding of the pathogenesis of acute renal failure will soon lead to specific measures to prevent its development. The Associate Editor's duties include communicating with contributors and reviewers of scientific and other articles; preparing editorials, and supervising the editing of manuscripts. A knowledge of French would be an asset. This is a full-time appointment; location Ottawa; duties to commence in the autumn of 1974.
Initial salary will be dependent on experience and qualifications and in accordance with The Canadian Medical Association scale of pay which includes a liberal range of pension and fringe benefits.
Candidates are asked to apply in writing, giving full particulars of education and experience in practice and in writing, to: The Editor, THE