Kidney Involvement in Acute Hepatic Porphyrias: Pathophysiology and Diagnostic Implications

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.

Keywords: aminolevulinic acid; chronic kidney disease; givosiran; kidney; kidney transplantation; nephropathy; nitric oxide; porphobilinogen; porphyria; porphyrins.

Figure 1

Mechanisms of kidney damage in acute hepatic porphyrias. The capacity for heme biosynthesis in the kidney parallels the activity of detoxifying cytochromes and other heme-dependent functions. Compared to the liver, the kidney could benefit from a higher content of intracellular regulatory “free” heme, serving as a protective buffer to acute heme-depleting stimuli. Histopathological findings in patients with porphyria-associated kidney disease have shown chronic tubulointerstitial damage and chronic fibrous intimal hyperplasia associated with focal cortical atrophy. PEPT2 is a proton-coupled symporter expressed on the brush border of tubular proximal cells: the PEPT2*1 variant has a greater affinity to its substrates (including δ-aminolevulinic acid—ALA) compared to PEPT2*2, and its presence has been independently associated with a worse decline in renal function in patients with HMBS mutation. At the intracellular level, ALA undergoes a multistep reaction in the presence of iron and O₂ to produce dioxovaleric acid, a highly reactive oxidant: among others, this is a mechanism by which ALA could exert its mitochondrial toxicity. When proximal tubular cells are incubated with porphobilinogen (PBG), the latter is completely metabolized into uroporphyrinogen I and III: thus, the uncatalyzed polymerization and cyclisation of four PBG molecules may lead to the intracellular accumulation of (uro)porphyrin aggregates. Porphyrins have been shown to produce reactive oxygen species (ROS) and cause intracellular protein aggregation without prior photosensitization; this process could both trigger and be accelerated by an oxidizing milieu. Relative heme depletion, as well as hemodynamic rearrangements due to sudden alterations in the levels of circulating ALA, could impact the delicate microcirculatory balances of the kidney regulated by nitric oxide synthases (NOSs), soluble guanylyl cyclases (sGC) or other hemeproteins with vasoactive effects. Other possible mechanisms of kidney damage are discussed in the text. Created with BioRender.com (last accessed date: 5 December 2021).