Uraemia; Its Causes and Consequences

Created on Sun, 04/10/2016 - 21:25
Last updated on Wed, 04/27/2016 - 04:15

"Uraemia" is a term which tends to be appied to describe the syndrome associated with an accumulation of all sorts of renally cleared waste products, and is not necessarily referring to the accumulation of urea alone. However, urea is the most abundant waster product among those whcih accumulate, and it seems to have some important toxic effects.

Urea has been asked about in Question 6.3 from the second paper of 2012 and Question 6.2  from the first paper of 2008. Specifically, the college had asked about the meaning of an isolated raised urea in a patient with trivially elevated creatinine. This will be addressed first, so that the time-poor exam candidate is able to rapidly refer to a table of differentials and clinical features. The excellent LITFL page on this topic was a major source of inspiration for this chapter.

Causes of a Raised Urea

Increased exogenous urea

  • Urea administration (eg. for management of SIADH)

Decreased urea clearance

Increased renal reabsorption of urea

  • States of apparent hypovolemia (eg. CCF, renal artery stenosis)
  • Actual hypovolemia (i.e. dehydration)

Decreased renal clearance of urea

  • Decreased glomerular filtration rate (eg. renal failure)
  • Decreased active tubular secretion (corticosteroids)

Increased urea synthesis

Increased protein intake

  • High protein diet
  • Gastrointestinal haemorrhage
  • Parenteral oversupplementation of amino acids (TPN)

Increased protein catabolism

  • Corticosteroids
  • Trauma
  • Burns
  • Major surgery
  • Starvation (acute)
Clinical Manifestations of Uraemia

Cardiovascular

  • Pericardial rub
  • Pericardial effusion

Miscellaneous

  • Mixed metabolic acidosis
  • Uraemic foetor
  • Pruritis
  • "Uraemic frost"
  • Nail atrophy
  • Sallow skin colouration and melanosis

Neurological

  • Uraemic encephalopathy
  • Peripheral neuropathy

Endocrine

  • Improved glycaemic control in diabetics

Gastrointestinal

  • Nausea
  • Vomiting

Haematological

  • Platelet dysfunction

The clinical manifeststaions of uraemia are of course the consequence of the accumulation of numerous different uraemic toxins. Urea itself has surprisingly few ill effects. The following physiological effects have been identified from experiment and observation:

  • Inhibition of Na-K-2Cl co-transporter in the red blood cells: this is a co-transporter involved in the regulation of cell volume and extracellular potassium concentration. Urea starts to interfere with this process at a serum level of around 45mmol/L and reaches half-maximal inhibition at around 63 mmol/L (Lim et al, 1995). The co-transporter is ubiquitous (one might recall it from the Loop of Henle, where it is inhibited by frusemide) and plays numerous body-wide roles. The main upshot of this inhibitory effect is a failure to maintain normal transmembrane ion concentration gradients, which seems like a fairly major thing.
  • Inhibition of enzyme function which occurs by two main effects. One is by direct inhibition, as in the case of xanthine oxidase (Rajagopalan et al, 1961), and the other is by reducing intracellular macromolecular crowding (Yancey et al, 1982) as in the case of lactate dehydrogenase. It is unknown which enzymes are most affected, but the effect is a fairly general one (i.e. fundamental protein properties are affected), and so one might infer that all enzymes are affected to some extent.
  • Nitric oxide synthase inhibition at the post-transcription level in the macrophage - this effect is seen at 10mmol/L, and reaches its maximum around 100mmol/L (Prabhakar et al, 1997). The implication is that this somehow contributes to the chronic cardiovascular disease of the renal failure patient (by opposing vasodilation and promoting vasoconstriction). It is also suggested as the cause of urea-induced
  • Carbamoylation of proteins, which irreversibly changes their function: urea transforms spontaneously into isocyanic acid, which goes on to carbamoylate all sorts of things. Carbamoylated molecules can "block, enhance, or be excluded from metabolic pathways" (Kraus and Kraus, 2001). Again, nonspecific and widespread effects are to be expected.
  • UpToDate also mentions several other possible effcets, which include the disruption of intestinal barrier function (in vitro), the production of radical oxygen species, an increase in insulin resistance, and the generation of guanidine derivatioves (which are themselves toxic).

However, urea is probably one of the minor players in the pathogenesis of uraemic syndrome. It just happens to be a convenient marker solute. Specifically, an increased clearance of urea does not seem to correlate with improved survival (Eknoyan et al, 2002) - which it would, if urea was really the culprit. Moreover, the addition of urea to dialysate did not make any difference in uraemic symptoms (Johnson et al, 1972). Urea has no effect on neurology or platelet function.

 

References

Walser, Mackenzie, and Leonard J. Bodenlos. "Urea metabolism in man." Journal of Clinical Investigation 38.9 (1959): 1617.

Vanholder, Raymond, and R. I. T. A. DE SMET. "Pathophysiologic effects of uremic retention solutes." Journal of the American Society of Nephrology 10.8 (1999): 1815-1823.

Pumphrey, C. W., and E. R. Beck. "Raised blood urea concentration indicates considerable blood loss in acute upper gastrointestinal haemorrhage." Br Med J 280.6213 (1980): 527-528.

Wray, S. H., R. S. Kocen, and K. J. Wright. "The Effect of Tetracycline on Blood Urea." Postgraduate medical journal 41.471 (1965): 18.

Feinfeld, Donald A., et al. "Massive and disproportionate elevation of blood urea nitrogen in acute azotemia." International urology and nephrology 34.1 (2002): 143-145.

Lim, Jayton, Chris Gasson, and Deepak M. Kaji. "Urea inhibits NaK2Cl cotransport in human erythrocytes." Journal of Clinical Investigation 96.5 (1995): 2126.

Rajagopalan, K. V., Irwin Fridovich, and Philip Handler. "Competitive inhibition of enzyme activity by urea." J Biol Chem 236 (1961): 1059-1065.

Yancey, Paul H., et al. "Living with water stress: evolution of osmolyte systems." Science 217.4566 (1982): 1214-1222.

Prabhakar, Sharma S., et al. "Urea inhibits inducible nitric oxide synthase in macrophage cell line." American Journal of Physiology-Cell Physiology 273.6 (1997): C1882-C1888.

Kraus, Lorraine M., and Alfred P. Kraus. "Carbamoylation of amino acids and proteins in uremia." Kidney International 59 (2001): S102-S107.

Eknoyan, Garabed, et al. "Effect of dialysis dose and membrane flux in maintenance hemodialysis." New England Journal of Medicine 347.25 (2002): 2010-2019.

Johnson, W. J., et al. "Effects of urea loading in patients with far-advanced renal failure." Mayo Clinic Proceedings. Vol. 47. No. 1. 1972.