Chronic hypertension in AIP has an estimated incidence DAPT secretase supplier of 36�C55% [3]. However, long-term treatment with modern antihypertensive drugs has minor the repercussion on renal function. There are few studies in which biopsies have been performed in patients with AIP. In one large population study [4], 16 patients were found with renal impairment with no other cause than AIP. Nine of the 10 patients that underwent renal biopsy had hypertension. The biopsies showed varying degrees of nephrosclerosis, moderate tubular atrophy and interstitial fibrosis and vessel wall thickening. Other few authors reported nephrosclerosis and shrunken kidney more in accordance to hypertension damage [6], [7], [8].

Finally, renal biopsy data from patients without hypertension or glomerular lesions but with features of tubulointerstitial disease suggest an enhanced susceptibility to the nephrotoxic effects of porphyrin precursors and porphyrins [9], [10]. Both types of damages directly or indirectly may point to active AIP, with or without frequent hemin administration [11], as an important factor causing renal disease. Of interest, a selective accumulation and excretion of PBG has been found in most porphyric patients with renal failure [9], [11] and an increased PBG/ALA ratio was proposed as a warning sign associated to changes in the renal filtration. In the present work, using an AIP mouse model [12], we studied the effects on renal function of repetitive acute attacks, as well as the effects of partial or total nephrectomy causing renal insufficiency.

This report is the first in vivo study to address the liver-kidney interaction during acute porphyric attacks. Although the mouse is a predictive model for AIP, extrapolation to human disease is considered and discussed in the paper. Results Successive induced biochemical attacks increased porphyrin precursor accumulation with no impact on renal function The AIP mouse model exhibits a 70% loss of PBGD activity in the liver and replicates the drug-precipitated biochemical abnormalities of acute porphyria in humans [12]. The administration of four consecutive intraperitoneal daily doses of phenobarbital massively increased urinary excretion of heme precursors and decreased motor function. Histopathological findings include axonal neuropathy and decrease nerve conduction with aging [12],[13].

In order to study the nephrotoxic effects of porphyrin precursors Carfilzomib and porphyrins, seven successive attacks over 14 weeks were induced in one year old male AIP mice. Matched wild type mice were used as controls. As expected, phenobarbital challenge increased urine levels of ALA, PBG (Figure 1A) and porphyrins (Figure 1B) in AIP mice. The mean excretion of PBG (��g per mg creatinine) was twice as high as the excretion of ALA (Figure 1A), i.e. PBG/ALA ratio 2. The daily amount of PBG and ALA excreted in the urine after the 7th phenobarbital challenge was significantly higher than that after the 3rd challenge.