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Diabetes & Renal Failure

Dr W.D. Comper

Diabetic kidney disease is a serious diabetic complication which in a large number of cases requires dialysis or organ transplantation, or may even lead to death. It is a particularly serious problem for indigenous races. The Pima Indians in South-West United States have one of the worst incidences of diabetes-renal failure in the world. The incidence of end-stage renal disease has also risen dramatically in all Aboriginal communities in the last 10 years. It is now recognised that the progression of the disease can be monitored by the presence of albumin in the urine or microalbuminuria. Albumin is normally a relatively minor component in the urine but it becomes the major component as kidney disease becomes worse.

Recent studies by our group using radioactive albumin in rats and in humans have demonstrated that albumin is normally broken down as it passes through the kidney. The breakdown occurs in tubular cells where albumin is taken up by lysosomes, degraded to peptides, which are then regurgitated back into the urinary space and ultimately excreted. The broken down albumin (fragments) represents a greater proportion (90-95%) of urinary albumin than intact albumin (5-10%). This has not been previously known since conventional assays only detect intact albumin. We have also found that the proportion of intact and broken down albumin is reversed in early experimental diabetes. The importance of this observation is that (intact) microalbuminuria in humans may be directly associated with the decreased breakdown of albumin as it passes through the kidney. This may be an early biochemical marker which can account for the increase in (intact)albumin in the urine in diabetes. If the changes in albumin fragmentation precede the onset of microalbuminuria, as suggested by preliminary data in animals and in humans, the development of an assay which detects the proportion of intact and broken down albumin in urine may provide sensitive procedure to detect albuminuria (intact and fragments) in diabetes earlier than the conventional methods available. Early detection of diabetic kidney disease, possibly by several years, will allow intervention which could prevent or delay the progression of the disease or prolong the lifespan of the patient.

Drug interventions such as angiotensin converting enzyme (ACE) inhibitors and aminoguanidine are currently being used on patients to retard the progression of microalbuminuria. The exact mechanism of action of these drugs is not known. They will be examined to determine whether changes in the intact and fragment proportions of albumin accompanying diabetic kidney disease can be reversed. Lysosomal endopeptidase activity responsible for the breakdown of albumin will be examined in diabetic rats. We suggest that changes in the lysosomal processing of albumin are directly related to the cause of diabetic kidney disease

Project areas (Dr W. D. Comper and Dr G. Jerums (Austin Hospital)

  1. Lysosomal enzyme activity in diabetes
  2. Drug intervention studies to minimise the onset of microalbuminuria in diabetes
  3. Examination of the molecular fragments of albumin formed during renal passage