REVERSIBLE RENAL CONCENTRATING DEFECT IN SHOCK

372

Hypothesis REVERSIBLE RENAL CONCENTRATING DEFECT IN SHOCK ROBERT WHANG

MARTIN BRANDFONBRENER

Departments of Medicine, Indiana University School of Medicine, Northwestern University School of Medicine, and Veterans Administration

Hospital, Indianapolis,

Indiana

The loss of renal

concentrating

power shock is reversible upon correction of the shock state. Shock resulting from acute hypovolæmia leads to the following sequence of events: (1) diminished renal blood-flow; (2) decreased superficial cortical nephron perfusion; (3) continued juxtamedullary nephron perfusion; (4) enhanced proximal reabsorption of Na, Cl, and H2O; (5) decreased delivery of these ions to the ascending limb, which results in diminished hypertonicity of the medullary interstitium. This hypotonicity is worsened by the " washout " effect on the interstitial hypertonicity caused by continued perfusion of the

Summary in

hæmorrhagic

4. Chalmers, R. A., Watts, R. W. E.

Analyst. Lond. 1972, 97, 958. 5. Lawson, A., Chalmers, R. A., Watts, R. W. E. Biomed. Mass 6. 7. 8. 9. 10. 11.

12. 13.

14.

15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Spectrom. 1974, 1, 199. Chalmers, R. A., Lawson, A. Chem. Brit. (in the press). Healy, M. J. R., Chalmers, R. A., Watts, R. W. E. J. Chromatog. 1973, 87, 365. Richards, B. W., Sylvester, P. E., Hodgson, S. J. J. ment. Defic. Res. 1965, 9, 210. Chalmers, R. A., Watts, R. W. E. Clin. Chim. Acta, 1974, 55, 281. Perry, T. L., Hansen, S., Diamond, S., Melancon, S. B., Lesk, D. ibid. 1971, 31, 181. Perry, T. L., Hansen, S., Lesk, D. in Organic Acidurias (edited by J. Stern and C. Toothill); p. 99. Edinburgh, 1972. Oberholzer, V. G., Levin, B., Burgess, E. A., Young, W. F. Archs Dis. Childh. 1967, 42, 492. Chalmers, R. A., Lawson, A., Watts, R. W. E. Clin. chim. Acta, 1974, 52, 43. Levin, B., Oberholzer, V. G., Burgess, E. A. in Organic Acidurias (edited by J. Stern and C. Toothill); p. 9. Edinburgh, 1972. McKusick, V. A. Mendelian Inheritance in Man: catalogues of autosomal dominant, autosomal recessive, and X-linked phenotypes. Baltimore, 1971. Westall, R. G., Cahill, R., Sylvester, P. E. J. ment. Defic. Res. 1970, 14, 347. Levy, H. L., Mudd, H. L., Schulman, J. D., Dreyfus, P. M., Abeles, R. H. Am. J. Med. 1970, 48, 390. Schärer, K. in Organic Acidurias (edited by J. Stern and C. Toothill); p. 46. Edinburgh, 1972. Przyrembel, H., Bachmann, D., Lombeck, I., Becker, K., Wendel, U., Wadman, S. K., Bremer, H. J. Clin. chim. Acta (in the press). Tilden, J. T., Comblath, M. J. clin. Invest. 1972, 51, 493. Daum, R. S., Lamm, P. H., Mamer, O. A., Scriver, C. R. Lancet, 1971, ii, 1289. Daum, R. S., Scriver, C. R., Mamer, O. A., Delvin, E., Lamm, P. H., Goldman, H. Pediat. Res. 1973, 7, 149. Hillman, R. E., Keating, J. P. Pediatrics, Springfield, 1974, 53, 221. Hsia, D. Y.-Y., Lilljeqvist, A.-Ch., Rosenberg, L. O. ibid. 1970, 46, 497.

25. 26. 27. 28.

29. 30. 31. 32. 33.

34.

Kang, E. S., Snodgrass, P. J., Gerald, P. S. Pediat. Res. 1972, 6, 875. Smith, A. J., Strang, L. B. Archs Dis. Childh. 1958, 33, 109. Efron, M. L. New Engl. J. Med. 1965, 272, 1058, 1107. Hooft, C., Timmermans, J., Snoeck, J., Antener, I., Oyaert, W., van der-Hende, C. H. Ann. Pediat. 1965, 205, 73. Eldjarn, L., Stokke, O., Jellum, E. in Organic Acidurias (edited by J. Stern and C. Toothill); p. 113. Edinburgh, 1972. Brunette, M. G., Delvin, E., Hazel, B., Scriver, C. R. Pediatrics, Springfield, 1972, 50, 702. Scriver, C. R., Rosenberg, L. E. Amino Acid Metabolism and its Disorders; p. 443. Philadelphia, 1973. Kennaway, N. G., Buist, N. R. N. Pediat. Res. 1971, 5, 287. Yoshida, T., Tada, K., Honda, Y., Arakawa, T. Tohoku J. exp. Med. 1971, 104, 305. Raine, D. N. Br. med. J. 1972, ii, 329.

which results in (6) diminished renal concentrating capacity due to elimination of medullary hypertonicity. Replenishing blood-loss

juxtamedullary

vasa recta

"

correcting the hypovolæmic state " regenerates hypertonic renal medullary interstitium by (a) diminishing, proximal reabsorption and allowing presentation of greater quantities of Na and Cl to the ascending-limb "pump", (b) restoring superficial cortical nephron perfusion, thereby decreasing juxtamedullary perfusion and in this manner eliminating medullary "washout". and the

DEMONSTRATION of renal cortical hypoperfusion in states of hasmorrhagic shock, evidence of efflux of sodium from kidneys during shock, and avid proximal reabsorption of Na and Cl (with presumed decreased delivery of these ions to the Na and/or Cl pump in the ascending limb of Henle’s loop) form the basis for our hypothesis. We hypothesise that diminution of renal medullary hypertonicity results during shock; and that restoration of circulating volume reverses the abnormal stimuli which cause diminished renal interstitial osmolality, thus restoring renal concen-

trating

power. Trueta et al. in 1947 described the cortical and juxtamedullary nephron populations and the relation of cortical ischaemia to. a variety of states including

haemorrhagic shock.1 Recent evidence re-emphasises the partitioning of renal blood-flow2 and supports the idea that the cortical nephrons suffer from ischxmia during hasmorrhagic shock.3-7 In contrast to the superficial cortical ischaamia, perfusion of the deeper juxtamedullary glomeruli persists and may explain the loss of renal concentrating ability in shock. There are distinct differences between the morphology of superficial cortical nephrons and of the more deeply embedded juxtamedullary nephrons. Superficial cortical glomeruli are smaller, as is the efferent arteriole, and the post-glomerular vasculature, instead of breaking into capillary network, forms the vasa recta which take on a hairpin configuration. Another difference between the two types of nephrons is that the juxtamedullary nephrons have long loops which course into the deeper medullary interstitium, whereas superficial cortical nephrons are devoid of these long loops. Still another difference is that superficial cortical glomeruli outnumber the juxtamedullary nephrons by ratio of 6 or 7 to 1. How might cortical ischaemia with persistent medullary perfusion account for diminution in the concentrating ability of the kidney following haemorrhagic shock ? There is increased proximal tubular reabsorption of both sodium and water from the glomerular filtrate in response to volume depletion.s A likely consequence of enhanced proximal reabsorption of sodium chloride and water is inadequate delivery of sodium and chloride to the " pump " in the ascending limb of Henle’s loop 910 . This results in diminished hypertonicity of the medullary interstitium and production of hypo-osmolar urine despite antidiuretic hormone ac2ivi y 11 Another possibility involves the continued perfusion of the juxtamedullary vasa recta during the period of haemorrhagic shock, resulting in a "washa

373

out" of the medullary osmotic gradient.

Previous the view that support experimental sodium is being " washed out " from the medullary interstitium during haemorrhagic shock.12.13 This mechanism also leads to reduction in medullary interstitial tonicity. The net result of both enhanced sodium reabsorption and medullary sodium proximal " washout" during shock could be reduction of renal concentrating ability. This proposed mechanism is summarised in the accompanying figure. A third possibility to account for the acute loss of renal concentrating ability is the increased noradrenaline (norepinephrine) levels found in hxmorrhagic shock 14 Pressor amines have an inhibitory action on antidiuretic-hormone activity 14 Fischer’s observations indicated that in volunteers the response to vasopressin infusion-that is, the induction of a negative free water clearance-was significantly diminished by noradrenaline infusion.15 Reversal of the defect in renal concentrating power with correction of haemorrhagic shock results from retracing of the pathways depicted in the figure. According to our hypothesis, restoration of bloodvolume diminishes avid proximal reabsorption of sodium and chloride, allowing increased delivery of these ions to the ascending limb of Henle’s loop. With correction of shock there is redirection and observations

URINARY OSMOLALITY BEFORE AND AFTER SHOCK AND REINFUSION OF SHED BLOOD

I

(control) vs. II (1 hr.): Study A P = 0’05-0-025. Study B P = 0’025-0’02.

I

vs. 111 (2 P = 0,025-0,02. Not significant.

(control)

hr.):

restoration of blood-flow to the previously ischasmic superficial cortical nephrons. These nephrons are essentially devoid of long loops. Thus there is blunting of the "washout" effect on the sodium chloride, and on the urea content of the medullary interstitium. This results in restoration of medullary interstitial

hypertonicity. Preliminary

observations in our laboratories supthe view that a period of heemorrhagic shock port results in impaired renal concentrating ability which is reversed by reinfusion of shed blood (see accom-

panying table). Dogs shock in

two

The

dogs

were

subjected

to

hxmorrhagic

ways: Group A was bled to a mean arterial pressure (M.A.P.) of 50 mm. Hg which was held for 90 minutes; further bleeding was carried out to lower M.A.P. to 30 mm. Hg which was held for 30 minutes followed by reinfusion of the shed blood. Group B was submitted to a less severe shocking procedure. These dogs were bled to an M.A.P. of 50 mm. Hg which was held for 90 minutes followed by reinfusion of the shed blood. were anuric during the hypotensive The initial urine osmolality 1 hour after reinperiod. fusion was statistically significantly lower than the previous control urine osmolality. 2 hours after reinfusion of shed blood, urine osmolality was not statistically different from control values. Following shock, urine osmolality returned to control levels sooner in the less severely shocked group-B dogs. We interpret these data as meaning that hasmorrhagic shock in the dog is associated with a reversible loss of renal concentrating capacity. Replenishment of blood-volume reverses this defect.

Further studies necessary to validate this hypothesis include chemical analysis of renal medullary tissue demonstrating decreased Na, Cl, K, and urea associated with shock. Restoration of normal quantities of these principal constituents of renal medullary interstitial osmolality correction of shock by reinfusion of the y shed blood would further strengthen this

We thank Mrs Dorothy O’Connell preparation of this manuscript.

for assistance in the

Requests for reprints should be addressed to R. Administration Hospital, 1481 West 10th Street, Indiana 46202, U.S.A. Possible mechanisms of

acute

impairment

centrating mechanism in shock.

of renal

con-

W., Veterans Indianapolis,

374

severely disabled-here defined as those with minimal and possibly also without speech. Several of the systems described are in commercial production. Separate chapters discuss the concept, development, and prescription of electromechanical aids with brief details, not previously available in a single volume, of at least seven typewriters and environment control systems. Those engaged in the development of such aids will also be interested to read of controls produced by movement of the head, tongue, and lips, by the spoken word, by electromygraphic potentials, and through keyboards adapted to the

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Resistance in Antimicrobial

Therapy

E. J. L. LowBURY, F.R.C.PATH., M.R.C. Industrial Injuries and Burns Unit, and G. A. J. AYLIFFE, M.R.C.PATH., Hospital Infection Research Laboratory. Springfield, Illinois: Charles C. Thomas. 1974. Pp. 211. 516.75.

groups of antimicrobial agents appear, one thing to be certain-sooner rather than later, resistant organisms will appear. In the late 1940s Mary Barber noted the increasing frequency of staphylococci resistant to penicillin, and a similar picture has emerged with other antibiotics. To gain a better understanding of how and why this occurs has been the task of Dr Lowbury and Dr Ayliffe. They approach this task by examining the As

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Aids for the

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by KEITH COPELAND, biophysics department, University College London. London: Sector Publishing. 1974. Pp. 152. S4.20. Edited

THE fringe of rehabilitation medicine often seems to be inhabited by disappointed engineers and their medical friends persuaded that an instant application of technology will change the life-style of the disabled. These people have usually failed to realise that it is very much more difficult to identify the true needs and potential of the disabled than to provide them with complex hardware. For all such workers this small book is required reading; it will also be a welcome stimulus to bioengineers, administrators, and others who provide facilities for the disabled. In eighteen short chapters authors from many countries describe successful electromechanical systems that provide environment control or the ability to communicate for PROF.

1. 2. 3. 4.

5. 6. 7.

8.

9. 10. 11.

12. 13. 14.

15.

WHANG, PROF. BRANDFONBRENER: REFERENCES Trueta, J., Barclay, A. E., Franklin, K. J., Daniel, P. M., Prichard, M. L. Studies of the Renal Circulation. Springfield, Illinois, 1947. Barger, A. C., Herd, J. A. New Engl. J. Med. 1971, 284, 482. Carriere, S., Daigneault, B. J. clin. Invest. 1970, 49, 2205. Grandchamp, A., Veyrat, R., Rosset, E., Scherrer, J. R., Truniger, B. ibid. 1971, 50, 970. Powers, S. R., Jr. J. Trauma, 1970, 10, 554. Rosen, S. M. Int. Anesthesiol. Clin. 1969, 7, 861. Stahl, W. M., Stone, A. M. in Body Fluid Replacement in the Surgical Patient (edited by C. L. Fox, Jr., and G. G. Nahas). New York, 1970. Weiner, M. W., Weinman, E. J., Kashgarian, M., Hayslett, J. P. J. clin. Invest. 1971, 50, 1379. Rocha, A. S., Kokko, J. P. ibid. 1973, 52, 612. Wallin, J. D., Barratt, L. J., Rector, F. C., Jr., Seldin, D. W. Kidney Int. 1973, 3, 282. Share, L. Endocrinology, 1967, 81, 1140. Kramer, K. in Shock: Pathogenesis and Therapy (edited by K. D. Bock); p. 134, Berlin, 1962. Selkurt, E. E. ibid. p. 145. Chien, S. Physiol. Rev. 1967, 47, 214. Fischer, D. A. J. clin. Invest. 1968, 47, 540.

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