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Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications
Porphyrias are a group of rare disorders originating from an enzyme dysfunction in the
pathway of heme biosynthesis. Depending on the specific enzyme involved, porphyrias manifest
under drastically different clinical pictures. The most dramatic presentation of the four congenital
acute hepatic porphyrias (AHPs: acute intermittent porphyria—AIP, ALAD deficiency, hereditary
coproporphyria—HCP, and porphyria variegata—VP) consists of potentially life-threatening neurovisceral
attacks, for which givosiran, a novel and effective siRNA-based therapeutic, has recently
been licensed. Nonetheless, the clinical manifestations of acute porphyrias are multifaceted and do
not limit themselves to acute attacks. In particular, porphyria-associated kidney disease (PAKD) is a
distinct, long-term degenerating condition with specific pathological and clinical features, for which a
satisfactory treatment is not available yet. In PAKD, chronic tubule-interstitial damage has been most
commonly reported, though other pathologic features (e.g., chronic fibrous intimal hyperplasia) are
consistent findings. Given the relevant role of the kidney in porphyrin metabolism, the mechanisms
possibly intervening in causing renal damage in AHPs are different: among others, d-aminolevulinic
acid (ALA)-induced oxidative damage on mitochondria, intracellular toxic aggregation of porphyrins
in proximal tubular cells, and derangements in the delicate microcirculatory balances of the kidney
might be implicated. The presence of a variant of the human peptide transporter 2 (PEPT2), with
a greater affinity to its substrates (including ALA), might confer a greater susceptibility to kidney
damage in patients with AHPs. Furthermore, a possible effect of givosiran in worsening kidney
function has been observed. In sum, the diagnostic workup of AHPs should always include a baseline
evaluation of renal function, and periodic monitoring of the progression of kidney disease in patients
with AHPs is strongly recommended. This review outlines the role of the kidney in porphyrin
metabolism, the available evidence in support of the current etiologic and pathogenetic hypotheses,
and the known clinical features of renal involvement in acute hepatic porphyrias