Dr Leonard Ebah, one of our Specialist Trainees in Renal Medicine has just completed his PhD research, carried out under the supervision of Dr Mitra, Professor Brenchley and Dr Hutchison.
Purpose of the research:
The research began in 2008 and focussed on toxin accumulation within the body fluids of patients with kidney disease. Renal failure results in the accumulation of waste products of metabolism or toxins within body fluids, causing harmful effects on the cells, and responsible for several of the complications seen in kidney disease. Urea, creatinine, potassium and phosphate are well known toxins, but hundreds of others have been identified, with probably thousands more to be discovered.
Current knowledge on the accumulation of such toxins and their removal by dialysis is based on measurements in blood only. However, blood only contains a tiny fraction of body fluids (about 6%), the rest being lodged within the cells (intracellular) and around the cells (tissue fluid). This research investigated whether tissue fluid (which is closer to the cells) contained the same levels of toxins as blood, and whether blood toxin removal by dialysis results in effective toxin removal, i.e. removal from tissue fluid.
How it was carried out:
The investigators devised various methods of painlessly sampling tissue fluid through the skin. These included microneedles (very tiny needles less than half a millimetre in length), reverse iontophoresis (the use of a small current to noninvasively sample toxins like urea and potassium through the skin) and microdialysis (using the principles of dialysis to extract skin tissue fluid toxins via a tiny catheter).
The tissue fluid levels of small toxins like urea and creatinine were similar to blood levels, however, larger toxins like some proteins (e.g. beta-2 microglobulin, which is seen in the blood of long term dialysis patients) were found to be retained in tissue fluid, and in some cases were detected earlier in tissue fluid before plasma levels became measurable. Tissue fluid may therefore be a toxin “reservoir”, causing harmful effects on the cells of patients with kidney failure. During dialysis, the removal of toxins (even small toxins like phosphate) from blood was not immediately followed by reduction in tissue fluid levels. As such, some larger toxins may not be efficiently removed from tissue fluid by dialysis; hence tissue fluid levels may need to be monitored to check for effective toxin removal. It is likely that some of the beneficial effects seen with long hours and daily dialysis are due to improved removal of toxins from other fluid compartments such as tissue fluid. The non-invasive measurement of toxins through the skin by reverse iontophoresis and microneedles also provides an exciting opportunity to explore the simplification of diagnosis and monitoring (e.g. remote sampling at home) of kidney disease in the future.
This research has been received with much enthusiasm, winning awards from Bionow and the North West Development Agency. The full reports of the findings could be accessed through the University of Manchester website (www.manchester.ac.uk/escholar) and some scientific journals (Blood Purification 2011, European Journal of Clinical Investigation 2012). The investigators will like to sincerely thank all the patients and volunteers who participated in the study and the CAPD, Renal Unit and Wellcome Trust CRF Staff without whom this project could not be realised. CMFT, University of Manchester and Wellcome Trust CRF provided financial support.