421

But gone are the days when it was sufficient to take the simple view that blood-urea is solely

roused by beef-steaks and calmed by rationing, dammed up by renal failure and magnified by dehydration. Hsu and his colleagues3 have introduced a new dimension by describing a family with some members azotaemic because of selectively reduced renal urea clearance; their diet was conventional, they were not dehydrated, and all other standard measures of renal function were normal. This new aspect of urea-handling is not only of immense physiological interest but also of practical diagnostic importance too, one patient having had an unnecessary renal biopsy before the penny

THE LANCET

Uræmia, Azotæmia, Sharks, and Camels Richard Bright was fortunate in having a clinical chemist at his elbow: John Bostock, Edinburgh graduate and Liverpool-physician-turned-chemistat-Guy’s, discovered from specimens "promiscuously" obtained by Bright’s "intelligent and zealous pupils" that urinary urea was diminished in renal failure while at the same time serum contained "animal matter, possessing peculiar proper-

ties, which seemed

to

approach

those of

urea";1

analytical methods were not yet sufficiently sensitive to detect urea in the serum of healthy individuals. Thus urea retained in renal failure gave its name to the syndrome of uraemia, a symptom complex reflecting a biochemical disturbance far wider and more disabling than the effects of urea retention itself. Azotxmia due to selective urea retention, unlike the nitrogen retention of chronic renal failure, neither causes symptoms nor depresses the bonemarrow. Both a large protein intake and dehydration raise the blood-urea in the absence of renal disease. Increased protein intake rarely increases the blood-urea above 10 mmol/1, but curiosities, such as the cod-consuming patient of RICHARDS and Brownsmay maintain a blood-urea of 20 mmol/1 for years. It is a sobering reflection on the nature of the glomerular filtration membrane that the same blood-urea in response to 4 g protein/kg body weight in health or 0.55 g/kg in a patient with renal disease has such different metabolic consequences ; toxic products escape in the former, notwithstanding urea retention, but not in the latter. Severe dehydration may raise the bloodurea to 30 mmol/1 or more as a result of delayed tubular transport, concentration of body fluids, and reduced glomerular filtration in response to reduced plasma volume. 1. 2

R. Reports of Medical Cases; p. 83. London, Richards, P., Brown, C. L. Lancet, 1975, ii, 207.

Bright,

1827.

dropped. No grounds were found for suspecting decreased urea filtration; serum urea-binding proteins were considered and dismissed. Enhanced passive transport of urea also seemed most unlikely: if from the distal convoluted tubule and cortical collecting duct, then medullary solute concentration (on which urine concentration depends) would have been impaired, yet maximum urine concentration was in fact normal; if from the medullary collecting duct, then either the collecting-duct urea concentration must have been increased, which it was not, judged from the low urinary urea concentration during antidiuresis, or the rate of removal of urea from the medulla must have been increased, in which case, once again, medullary interstitial solute concentration would have been reduced with consequences for urine concentration. Active urea transport out of the medullary collecting duct could, however, explain the findings and has a precedent in other species,4sand so also could failure of active transport of urea into the proximal tubule, for which there is evidence in the rabbit.66 An inherited failure of active transport is inherently more likely than increased active transport. The question then arises whether a similar disorder of active urea transport might sometimes be acquired, notably during protein restriction. Both elasmobranchs and mammals8 have the facility substantially to reduce urea clearance: for sharks and their cousins, reabsorption of almost all the filtered urea is a way of life to maintain their osmotic ego in a hypertonic environment; for mammals, including man,9 this seems to be a homoeostatic response to reduce nitrogen intake. SCHMIDTNIELSEN’S camel wins the prize by reducing the fraction of filtered urea which is excreted from a 3. Hsu, C.

H., Kurtz, T. W., Massari, P. U., Ponze, S. A., Chang, B. S. New Engl. J. Med. 1978, 298, 117. 4. Truniger, B., Schmidt-Nielsen, B. Am. J. Physiol. 1964, 207, 971. 5. Lassiter, W. E. in Urea and the Kidney (edited by B. Schmidt-Nielsen and D. N. S. Kerr); p. 206. Amsterdam, 1970. 6. Kawamura, S., Kokko, J. P. J. clin. Invest. 1976, 58, 604. 7. Smith, H. W. Biol. Rev. 1936, 11, 49 8. Schmidt-Nielsen, B. Fedn Proc. 1977, 36, 2493. 9. Murdaugh, H. V., Schmidt-Nielsen, B., Doyle, E M., O’Dell, R. J. appl. Physiol. 1958, 13, 263.

422

normal 30-50% to a mere 1-3% during protein restriction.10 Do some men respond superhumanly to protein restriction by suppressing the same active transport process which is faulty in familial azot aemia? It may no longer be too far-fetched to speculate that rare cases of azotaemia during starvation," which have generated such earnest discussion in the past,12-15 might be explained as a touch of the shark-and-camel syndrome; sadly, more like the shark, because man is not very adept at turning urea nitrogen back into protein. 2.16

The

Biochemistry of Depression

THE biochemist treads

difficult terrain when he enters the realms of psychiatry. The certainty of objective tests (so often lacking in mental disorder) seemed to offer the basic sciences a great chance to make their mark; but the results have seldom satisfied expectations. Though there have been many apparent breakthroughs, time and again they have been like elephants’ footprints in the mud, making a large initial impression but quickly fading into the background. Evidence is accumulating of biochemical abnormalities in psychiatric disorder: the main difficulty lies in their interpretation. The correspondence in our columns which followed the report by BIRD and his colleaguesl of biochemical changes in schizophrenia illustrates the many interpretations2-4 that can be put upon apparently straightforward facts. Similar difficulties face the biochemist in his study of depression. When he detects an abnormal finding _in depressed patients, it may be a primary difference at the core of the illness, a secondary finding caused by change in mood and activity or by drug treatment, or an artefact associated with technique. Thus, abnormalities in depressed patients, such as raised plasma-cortisol, altered electrolytes,6 decreased cyclic A.M.P.,’ and reduced metabolites of monoamines on

(for example, 3-methoxy-4-hydroxyphenyl-ethylene 10.

Schmidt-Nielsen, B., Schmidt-Nielsen, K., Houpt, T. R., Jarnum S. A. Am. J. Physiol 1957, 188, 477. 11. Kumar, R., Steen, P., McGeown, M. G. Lancet, 1972, ii, 1005. 12. Dudley, H. ibid. p. 1255. 13. Walser, M. ibid. 1973, i, 49, 722. 14. McGeown, M. G., Neill, D. W., Steen, P., McMillin, W. P., Kumar, R ibid. p. 49. 15. Neill, D. W., McGeown, M. G. ibid. p. 722. 16. Varcoe, R., Halliday, D., Carson, E. R., Richards, P., Tavill, A. S. Clin. Sci. mol. Med. 1975, 48, 379. 1. Bird, E. D., Spokes, E. G., Barnes, J., MacKay, A. V. P., Iversen, L. L., Shepherd, M. Lancet, 1977, ii, 1157. 2. Perry, E. K., Blessed, G., Perry, R. H., Tomlinson, B. E. ibid. Jan. 7, 1978,

p. 35. J., Owen, F., Cross, A. J., Lofthouse, R., Longden, A. ibid. Jan, 7, 1978, p. 36. 4. Bird, E. D., Spokes, E. G., Barnes, J., MacKay, A. V. P., Iversen, L. L., Shepherd, M. ibid. Jan. 21, 1978, p. 156. 5. Gibbons, J. L., McHugh, P. R. J. psychiat. Res. 1962, 1, 162. 6. Coppen, A., Shaw, D. M. Br. med. J. 1963, ii, 1439. 7. Eccleston, D., Losse, R., Pullar, I. A., Sugden, R. F. Lancet, 1970, ii, 612. 3. Crow, T.

and

5-hydroxyindoleacetic acid9), may all consequence of the secondary features of depressive illness, such as reduced food intake, sleep disturbance, and psychomotor retardation, rather than primary abnormalities. The amine hypothesis of affective illness, developed from biochemical inquiries, is still the most favoured, but the uncertainties of interpretation are reflected in

glycol8 be

a

the criticismslo directed at even its vaguest form (that pathological mood changes are mediated through changes in one or more of the brain biogenic amines). It can be argued that if consistent biochemical abnormalities are found in patients when they are both ill and well, such abnormalities are less likely to be contaminated by secondary factors and may be of true importance. If such distinct changes could be identified they would be compatible with the view that depressive illness is genetically determined and becomes manifest only at certain times. To detect such abnormalities, however, and to demonstrate that they are specifically associated with depression-proneness in individual patients is a laborious task. A new report by BONHAM CARTER and her colleaguesll illustrates some of the difficulties. They found that a group of depressed patients awaiting modified leucotomy excreted less of an oral tyramine load as the sulphate conjugate in the first three hours after injection than did control subjects, although there were no significant differences in the subsequent three hours. Since the amounts of conjugate excreted by these patients had not

changed following leucotomy or one year later, though by this time 6 of the 16 patients were much improved, these workers argue that the patient-control differences may be related to a "bodily metabolic failure" in their patient group. Is this an elephant’s footprint or a real step forward? This is where the difficulties of interpretation begin. What are the factors that normally determine the rate at which tyramine from the gut is conjugated and excreted? Does free and conjugated even

tyramine

excretion show age and sex differences, and is it affected by gut motility, water intake, or antidepressant therapy? Urine volume, food intake, consumption of diuretic methylxanthines in tea and coffee, and bodily activity all have to be controlled, because they may be responsible for the different tyramine conjugation in the depressed patients. If all these secondary factors are excluded, it still needs to be determined whether the differences are specific to depression, before concluding that bodily metabolic failure is an intrinsic part of the depressive-illness syndrome. Patients with migraine excrete conjugated tyra8. Ebert, M. H., Post, R. M., Goodwin, F. K. ibid. 1972, ii, 766. 9. Papeschi, R., McClure, D. J. Archs gen. Psychiat. 1971, 25, 354. 10. Mendels, J., Frazer, A. ibid. 1974, 30, 447. 11. Bonham Carter, S., Sandler, M., Goodwin, B. L., Sepping, P. K. Br. J. Psychiat. 1978, 132, 125.

P., Bridges,

Uraemia, azotaemia, sharks, and camels.

421 But gone are the days when it was sufficient to take the simple view that blood-urea is solely roused by beef-steaks and calmed by rationing, da...
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