Abstract
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, δ-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.
Highlights
Introduction distributed under the terms andPorphyrias are a group of rare disorders originating from an enzyme dysfunction in the metabolic pathway of heme biosynthesis [1]
peptide transporter 2 (PEPT2) is inhibited by losartan [35], and the use of this angiotensin II receptor blocker has been proposed as a treatment to slow down the progression of porphyria associated kidney disease [31]
When proximal tubular cells are incubated with PBG, the latter is completely metabolized into uroporphyrinogen I and III [16]: it has been conjectured that the observed intracellular inclusions could be aggregates of uroporphyrin obtained by the uncatalyzed polymerization and cyclisation of four
Summary
It is generally assumed that the kidney contributes to heme production as the third major synthesizing organ, after the bone marrow and the liver—which account, respectively, for 80% and 15% of total heme biosynthesis [19]. ALAS in the kidney is somewhat more refractory to induction by porphyrinogenic stimuli. A greater ratio of ferrochelatase-to-ALAS activity has been detected in renal compared to liver cells. Together with other pieces of evidence, these observations have led to the hypothesis that the kidney could benefit from a higher content of intracellular, regulatory “free” heme, which could function as a protective buffer to acute heme-depleting stimuli [20]. This being considered, it might be of interest to estimate the amount of the “free”. Studies on the kidney’s porphyrin clearance, as well as observations on lead intoxication [24] and on patients with variegate porphyria [24,25], point to a renal endogenous production of coproporphyrin
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