Histology also showed lack of tubulointerstitial damage and inflammatory cell infiltrate. These data suggested that the presumably noxious effect of porphyrin selleck precursors and porphyrins on renal parenchyma were not intensified after reduction of renal function in the AIP mice model during the observation time. Total nephrectomy induced a rapid decrease in PBGD activity in AIP mice In order to measure the impact of terminal renal disease on the hepatic heme synthesis pathway, a total nephrectomy was performed in another cohort of mice during a phenobarbital challenge. Lack of renal function produced a rapid accumulation of heme precursors in serum of the AIP mice (Table 1). Ten hours after nephrectomy, hepatic transcription levels of ALAS1 were found to be unchanged in both female (Figure 3A) and male AIP mice (Figure 4A) when compared with sex-matched wild type animals.

Of interest, a rapid decrease in hepatic PBGD activity was observed exclusively in AIP mice (Figure 3C and and4C),4C), with no changes in transcriptional activity (Figure S1) or enzyme protein level (Figure S3). It may be assumed that the observed aggravation of PBGD deficiency may be a consequence of further PBGD-inhibition caused by the large substrate accumulation caused by impaired glomerular filtration. Discussion Limited information is available on the association between acute intermittent porphyria and kidney failure. The development of end stage renal disease is a devastating complication in AIP patients with chronic active disease, leading to unavoidable vascular complications, dialysis treatment, progression of peripheral motor neuropathy and, occasionally, respiratory failure [15].

Such patients may also suffer from cutaneous bullous lesions resembling PCT [11], [16]. Current treatment of acute attacks involving intravenous administration of hemin and a high-carbohydrate diet only has a transitory effect and cannot prevent accumulation of porphyrin precursors and Anacetrapib porphyrins in-between cures [11]. There are no reports of longstanding follow-up of renal function in patients afflicted by recurrent acute attacks and only few studies have reported results of kidney biopsies in AIP patients with chronic disease [4], [9], [10]. The leading hypothesis is that the porphyric state may progressively damage the kidneys sufficiently to cause renal failure. It has been suggested that the presence of excessive amounts of porphyrin precursors and porphyrins causes cytotoxic or vasospastic renal vascular lesions leading to glomerulonephritis and tubulointerstitial nephritis [9], [10], [11]. Repeated hemin therapy may also contribute to renal damage [17], [18].