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.

Endothelial Dysfunction in Acute Hepatic Porphyrias

“…Even though acute neurovisceral attacks are the most dramatic, and potentially life-threatening, clinical manifestations of acute porphyrias, patients affected by this group of diseases do suffer from chronic complications, which may be debilitating and have a considerable impact on their quality of life. In particular, patients with symptomatic AHPs are prone to develop long-term complications of vascular nature, such as arterial hypertension, chronic kidney disease (often termed porphyria-associated kidney disease-PAKD) [ 11 , 13 , 17 , 38 , 39 ], and thrombotic events [ 40 , 41 ]. Therefore, it could be reasonably conjectured a direct involvement of the endothelium, which could be a primary site of organ damage, in the pathogenesis of AHPs.…”

“…Patients with AHPs also suffer from long-term complications of the disease, such as arterial hypertension, chronic kidney disease, chronic neuropathy, and non-cirrhotic hepatocellular carcinoma [ 11 , 12 , 13 , 14 ]. In AHPs, the accumulation of toxic non-porphyrin heme precursors ( -aminolevulinic acid—ALA and porphobilinogen—PBG) is deemed to cause most clinical manifestations, including those with possible vascular involvement (arterial hypertension, headache, neurological symptoms, kidney impairment) [ 9 , 10 , 15 , 16 , 17 , 18 ]. Symptomatic patients with AHPs often undergo an off-label maintenance therapy with heme arginate, which aims to reduce the frequency of APAs [ 19 ].…”

“…Several pieces of evidence have shown that the availability and metabolism of heme are variably involved in the healthy functioning of the endothelium, as well as in endothelial dysfunction [ 21 , 22 , 23 , 24 , 25 , 26 ]. Furthermore, it has been postulated that non-porphyrin heme precursors may possibly cause endothelial damage, e.g., through the known oxidant properties of ALA [ 17 , 18 , 27 , 28 ].…”

An Overview of Acute Hepatic Porphyrias: Clinical Implications, Diagnostic Approaches, and Management Strategies

“…Recently, a modifier gene PEPT2 was found relevant to severe kidney disease in AIP patients. 18 , 19 …”

Challenges in diagnosis and management of acute hepatic porphyrias: from an uncommon pediatric onset to innovative treatments and perspectives

“…Additionally, patients with AHP can be at risk of experiencing numerous, multi-system, long-term complications and comorbidities as a result of the disease [22]. Long-term complications related to AHP and its treatment can include liver disease (e.g., hepatocellular carcinoma, fibrosis and cirrhosis), chronic kidney disease, peripheral neuropathy, chronic pain and systemic arterial hypertension [23,[27][28][29][30][31][32]. Comorbidities related to AHP can include anxiety, depression, elevated lipase/ amylase levels, pancreatitis, hypertension, tachycardia and cardiac arrhythmias [3,22,31,33].…”