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.