J Clin Pathol: first published as 10.1136/jcp.21.5.541 on 1 September 1968. Downloaded from J. clin. Path. (1968), 21, 541-554 Biochemical consequences of chronic renal failure: A review M. R. WILLS From the Department of Chemical Pathology, Royal Free Hospital, London The biochemical consequences of chronic renal UREA AND OTHER ORGANIC METABOLIC PRODUCTS failure involve a disturbance in one of the funda- mental mechanisms of the body's self-regulatory At their onset renal diseases may affect primarily control systems. The concept of self-regulation in the functions of either the glomerulus or the renal biological systems is both old and well established. tubules, but in the latter stages of chronic renal The idea held by Hippocrates that disease was damage the functional mass of the kidney is reduced cured by natural powers, by a 'vis medicatrix and there is progression to renal insufficiency naturae', implied the existence of systems ready to affecting all aspects of renal function, usually called cooperate in a corrective manner when the natural 'uraemia'. The term 'uraemia', which was introduced state of the body was disturbed. In 1878 Claude in medical nomenclature in 1840 by Piorry and Bernard made the distinction between the 'milieu l'Heritier, means literally 'urine in the blood'. ext6rieur', in which the whole organism exists, and Piorry and l'Heritier regarded the manifestations of the 'milieu interieur', in which the cells live. After renal failure as a form of poisoning of the blood considering some of the mechanisms involved he due to the resorption of urine. The term is now used copyright. wrote in his now classical sentence that: ' .. tous clinically to describe that state associated with the les mecanismes vitaux, quelque varies qu'ils soient, retention of nitrogenous metabolic products and n'ont toujours qu'un but, celui de maintenir l'unite characterized by a raised blood urea concentration des conditions de la vie dans le milieu interieur.' though the level does not necessarily correlate well The concept of an internal environment that was with other aspects of renal insufficiency. The in- maintained in a steady state was further developed crease in the blood urea concentration is perhaps during the next 50 years and the term homeostasis the most striking abnormality of the body fluids in was introduced by Walter B. Cannon to describe renal failure, although it is not the most important http://jcp.bmj.com/ the physiologically constant state of the body. In functionally. Urea is formed only in the liver and 1929 he wrote: 'The coordinated physiological may be regarded as the end product of protein reactions which maintain most of the steady states catabolism, whether the protein is derived from in the body are so complex, and so peculiar to the diet or tissues. In acute renal failure the corre- living organism, that it has been suggested (Cannon, lation between the severity of the illness and the 1925) that a specific designation for these states be level of the blood urea concentration applies more employed-homeostasis'. The role of the kidney in closely than it does in chronic renal failure. In on September 27, 2021 by guest. Protected homeostasis is perhaps best expressed in the sentence chronic renal failure the plasma creatinine concen- of J. P. Peters (1935) who wrote: 'The kidneys tration seems to offer a better index of the severity appear to serve as the ultimate guardians of the of the degree of failure than does the blood urea constitution of the internal environment.' The level, particularly when the patient is on a low- kidney carries out its homeostatic functions by the protein diet. processes of glomerular filtration and of tubular Bostock (1827a, b), who carried out the chemical reabsorption and secretion, and thus regulates the examinations of serum from Richard Bright's concentration of metabolic end products, the osmo- patients, was the first to draw attention to the raised tic pressure, the volume and the ionic composition blood urea level found in chronic renal failure. He re- of the internal environment. In chronic renal ported that the serum 'was found to consist in part failure, the end results of the disturbances of renal of an animal matter possessing peculiar properties function are alterations in the constitution of the which seemed to approach those of urea'. Two internal environment which are of fundamental years later Christison (1829) isolated urea from the biochemical significance. blood of patients with chronic renal failure and 541 J Clin Pathol: first published as 10.1136/jcp.21.5.541 on 1 September 1968. Downloaded from 542 M. R. Wills reported that in these patients 'urea exists in con- dialysate, were maintained in apparently normal siderable quantity in the blood when it is materially condition for several months. The only variable in defective in the urine'. The controversial role of their experiment was the high urea content of the urea in the causation of the clinical symptoms seen extracellular fluid and they attributed the observed in chronic renal failure was first raised by Bright in clinical abnormalities to this variable. 1831. He reported that in many cases the serum Although the elevation of blood urea concentra- 'was slightly impregnated with urea' but in other tion may or may not of itself cause symptoms, it is cases this 'impregnation' was much less apparent generally accepted that products of protein cata- and he concluded that the raised blood urea level bolism are a major feature of the uraemic state and 'may be but in part a cause of general derange- that some of the intermediate breakdown products ment of the system'. Since then there have been accumulate and play a role in the development of conflicting reports and the position remains con- the toxicity of uraemia. The earlier workers searched troversial. Pitts (1968) stated that when 'urea is for a single toxic substance to account for the clinical administered to a normal person in amounts suffi- symptoms seen in uraemia. Foster (1915) reported cient to achieve blood levels comparable to those the isolation of an organic base from the blood of found in chronic renal failure, it causes thirst and uraemic patients which when injected into guinea polyuria but none of the other manifestations of pigs caused toxic symptoms within five minutes after uraemia'. The position is, however, by no means as injection. The initial symptoms were rapid brea- clear cut as this statement would suggest. In 1822 thing and muscular twitching followed by convul- Segalas d'Etchepare gave urea intravenously to dogs sions which terminated in death. The substance and reported that the only effect was to cause isolated was probably guanidine or a guanidine- polyuria. Bollman and Mann (1927), also using dogs, like derivative (Harrison and Mason, 1937). During reported that after ureteral transplantation into the this period many other substances were implicated jejunum or ileum, despite a marked elevation in the and included creatinine, potassium, 'nephrolysins', blood urea concentration, there were no symptoms and phenols (Harrison and Mason, 1937). Mason, of uraemia. In support of the view that a high blood Resnik, Minot, Rainey, Pilcher, and Harrison urea level of itself has little or no effect is the work (1937) discounted the so-called 'unitary' theories ofcopyright. of Merrill, Legrain, and Hoigne (1953). These uraemia because they had received neither clinical workers haemodialyzed chronic uraemic patients nor experimental support, in that no one substance against high urea bath levels and noted that there was of itself toxic at the blood levels found in urae- was an excellent clinical response despite the lack mia. They suggested that the symptoms seen were of a change in the blood urea level. Other reports, the result of the 'summated expression of a number however, ascribe a toxic role to urea itself at high of interplaying factors each of which in the last and Wickett is the result of the underlying disorder of blood levels. Hewlett, Gilbert, (1916) analysis http://jcp.bmj.com/ gave urea by mouth to normal human subjects and function - failure to excrete the end products of raised their blood urea concentration to levels in metabolism'. In support of this view is the work of the range from 160 to 245 mg/100 ml. The subjects Olsen and Bassett (1951) who studied the blood noted that definite symptoms occurred at the time levels of phenol, urea nitrogen, guanidine, and when the blood urea levels were at their highest. The creatinine in uraemic patients and attempted to symptoms they experienced consisted of 'headache, correlate them with the severity of the uraemia. dizziness, apathy, drowsiness, bodily weakness, and They reported that the blood levels of phenol, fatigue'. Severe symptoms were reported by Groll- although increased, 'could not be correlated with on September 27, 2021 by guest. Protected man and Grollman (1959) at higher blood urea central nervous system depression nor could those of levels using dogs as their experimental animal. guanidine be correlated either with gastrointes- These workers studied bilaterally nephrectomized tinal stimulation or degree of elevation of blood dogs who were maintained by intermittent peri- pressure'. They concluded that 'uraemia remains a toneal lavage. In one group the blood urea levels clinical entity without a direct known chemical were maintained at high levels by using a dialysate basis'. with a high urea concentration. At blood urea The organic substances known or reported to levels of 370 to 480 mg/100 ml clinical symptoms accumulate in uraemic blood include urea, crea- of intoxication became apparent. The first symp- tinine, creatine, uric acid, certain amino acids, toms noted were of weakness and anorexia, followed polypeptides, indican, hippuric acid, conjugates of by vomiting and diarrhoea, the latter terminating in phenol, phenolic and indolic acids and their conju- bowel haemorrhage; the symptoms finally culmi- gates, organic acids of the tri-carboxylic acid cycle, nated in coma.