Abstract
Chronic kidney disease is a long-term complication in acute intermittent porphyria (AIP). The pathophysiological significance of hepatic overproduction of the porphyrin precursors aminolevulinate acid (ALA) and porphobilinogen (PBG) in chronic kidney disease is unclear. We have investigated the effect of repetitive acute attacks on renal function and the effect of total or five-sixth nephrectomy causing renal insufficiency on hepatic heme synthesis in the porphobilinogen deaminase (PBGD)-deficient (AIP) mouse. Phenobarbital challenge in the AIP-mice increased urinary porphyrin precursor excretion. Successive attacks throughout 14 weeks led to minor renal lesions with no impact on renal function. In the liver of wild type and AIP mice, 5/6 nephrectomy enhanced transcription of the first and rate-limiting ALA synthase. As a consequence, urinary PBG excretion increased in AIP mice. The PBG/ALA ratio increased from 1 in sham operated AIP animals to over 5 (males) and over 13 (females) in the 5/6 nephrectomized mice. Total nephrectomy caused a rapid decrease in PBGD activity without changes in enzyme protein level in the AIP mice but not in the wild type animals. In conclusion, high concentration of porphyrin precursors had little impact on renal function. However, progressive renal insufficiency aggravates porphyria attacks and increases the PBG/ALA ratio, which should be considered a warning sign for potentially life-threatening impairment in AIP patients with signs of renal failure.
Highlights
Acute intermittent porphyria (AIP, OMIM 176000) is an inherited metabolic disease characterized by partial deficiency of hepatic porphobilinogen deaminase (PBGD)
In the present work, using an acute intermittent porphyria (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
In order to study the nephrotoxic effects of porphyrin precursors and porphyrins, seven successive attacks over 14 weeks were induced in one year old male AIP mice
Summary
Acute intermittent porphyria (AIP, OMIM 176000) is an inherited metabolic disease characterized by partial deficiency of hepatic porphobilinogen deaminase (PBGD). Chronic arterial hypertension and renal impairment become more common after middle age in AIP, especially in patients with frequent porphyric attacks [4,5]. 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. The mouse is a predictive model for AIP, extrapolation to human disease is considered and discussed in the paper
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