Renal toxicity mediated by glucose degradation products in a rat model of advanced renal failure.
BACKGROUND
In peritoneal dialysis (PD) residual renal function contributes to improved patient survival and quality of life. Glucose degradation products (GDP) generated by heat sterilization of PD fluids do not only impair the peritoneal membrane, but also appear in the systemic circulation with the potential for organ toxicity. Here we show that in a rat model of advanced renal failure, GDP affect the structure and function of the remnant kidney.


METHODS
Sprague-Dawley rats were randomly assigned to a two stage subtotal nephrectomy (SNX) or sham operation and were left untreated for 3 weeks. The SNX + GDP group continuously received chemically defined GDP intravenously for 4 weeks; the SNX and the sham-operated rats remained without GDP. The complete follow-up for all groups was 7 weeks postoperatively. We analysed renal damage using urinary albumin excretion as well as a semiquantitative score for glomerulosclerosis and tubulointerstitial damage, as well as for immunohistochemical analyses.


RESULTS
The SNX + GDP rats developed significantly more albuminuria and showed a significantly higher score of glomerulosclerosis index (GSI) and tubulointerstitial damage index (TII) as compared to SNX or control rats. In the SNX + GDP group the expression of carboxymethyllysine and methylglyoxal was significantly higher in the tubulointerstitium and the glomeruli compared to the SNX rats. Caspase 3 staining and TUNEL assay were more pronounced in the tubulointerstitium and the glomeruli of the SNX + GDP group. In SNX + GDP animals, the expression of the slit diaphragm protein nephrin, was significantly lower compared to SNX or control animals.


CONCLUSIONS
In summary, our data suggests that GDP can significantly advance chronic kidney disease and argues that PD solutions containing high GDP might deteriorate residual renal function in PD.
Müller-Krebs
S
S
Medical University of Heidelberg, Heidelberg, Germany.
Kihm
L P
LP
Zeier
B
B
Gross
M L
ML
Deppisch
R
R
Wieslander
A
A
Henle
T
T
Penndorf
I
I
Oh
J
J
Reiser
J
J
Nawroth
P P
PP
Zeier
M
M
Schwenger
V
V
D000818:Animals; D015314:Dialysis Solutions; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000032:analysis*; D008297:Male; D010530:Peritoneal Dialysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D051437:Renal Insufficiency / Q000378:metabolism*
D015314:Dialysis Solutions; D017127:Glycation End Products, Advanced; D005947:Glucose