An excess of PBG may alter this process and prevent the formation

An excess of PBG may alter this process and prevent the formation of active PBGD holoenzyme causing a further drop in PBGD activity [28]. The reduced hepatic quality control ALAD activity associated with renal impairment did not modify ALA accumulation as suggested by unchanged urinary ALA excretions in the AIP mice. In fact, the inhibition of ALAD is only significant for ALA accumulation when important ALAD deficiency is observed. This is the case of the homozygous patients with ALAD deficiency, lead poisoning and hereditary tyrosinemia deficiency where the hepatic ALAD activity is less than 1% of the reported normal activity [29], [30]. In conclusion, consecutive phenobarbital challenge in mice caused slight degrees of renal lesions unrelated to porphyria and indicated that massive porphyrin or porphyrin precursor excretion, or their passage through the kidney, did not modify renal function in AIP mice.

However, conclusions obtained in the AIP mouse model cannot be extrapolated to chronic AIP disease and we cannot disregard the potential deleterious effect of high porphyrin and porphyrin precursor accumulation maintained during years. Indeed, once end stage renal disease was established we cannot rule out the deleterious effect of porphyrin accumulation since dialysis membranes display a limit efficiency to filter these molecules [11]. Our results indicate that progressive renal insufficiency in AIP mice may aggravate the acute porphyria state. These data may illustrate the pathophysiology in AIP patients afflicted by recurrent acute attacks and renal failure.

This is an extremely vulnerable clinical condition in which the development of severe neuropathic complications is very likely. Even though dialysis membranes are able to clear porphyrin precursors [6], [11], [31], [32], ALA and PBG accumulate during the inter-dialysis period and may be responsible for the progression of nerve damage. Increased PBG is nonenzymatically polymerized to uroporphyrin I, a molecule that is not cleared by dialysis leading to accumulation of serum porphyrins and consequently to photosensitivity skin damage [11]. The increase in PBG/ALA ratio should be considered a warning sign for potentially life-threatening aggravation of the porphyric condition. These patients should be candidates for combined kidney and liver transplantation, in order to correct the primary enzyme deficiency as well as restore renal function.

These data and other recent cases have clarified previous concerns and could help to formulate the indications for and the timing of transplantation in AIP. Materials and Methods Animal studies. Experimental protocols were performed according to European Council Batimastat Guidelines. Acceptable standards of humane animal care and treatment employed in these mice (ref. no. CEEA022-06) and the experimental design of this study (ref. no.

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