10 The current pathophysiologic model proposes that during AIP attacks, ALA and PBG are excreted in large amounts in the urine, which promotes tubular toxicity and AKI, followed by regeneration and scarring. 10 Experimental evidence indicates that ALA and PBG promote renal epithelial cell apoptosis and phenotypic changes suggestive of the epithelial-to-mesenchymal transition. 6– 9 The prevalence of porphyria associated kidney disease (PAKD) is >50% in individuals with AIP and is characterized by a chronic tubulo-interstitial nephropathy, associated with approximately half of cases with severe arteriosclerosis and fibroproliferative intimal hyperplasia. 5 CKD and hepatocellular carcinoma are major long-term complications of AIP. During AIP attacks, the porphyrin precursors δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) accumulate and are massively excreted in urine as a consequence of enzymatic blockade, where their presence confirms the diagnosis. 3, 4 The acute clinical expression of AIP is a neurovisceral attack, characterized by severe abdominal pain, often complicated by agitation, peripheral neuropathy, and even coma. Mutations in the gene encoding hydroxymethylbilane synthase ( HMBS), which occur in one in 1675 people in Europe 1 and have a very low penetrance 2, are responsible for acute intermittent porphyria (AIP), an inherited autosomal dominant disorder affecting the synthesis of heme. The therapeutic value of PEPT2 inhibitors in preventing porphyria-associated kidney disease warrants investigation. Thus, a gene variant is predictive of the severity of a chronic complication of AIP. At the end of follow-up, 68% of PEPT2*1*1 carriers had an eGFR1 ml/min per 1.73 m 2 (odds ratio, 3.64 95% confidence interval, 1.37 to 9.91). At last follow-up, carriers of the PEPT2*1*1 genotype (higher affinity variant) exhibited worse renal function than carriers of the lower affinity variants PEPT2*1/*2 and PEPT2*2/*2 (mean±SD eGFR: 54.4☑9.1, 66.6☒3.8, and 78.1☑9.9 ml/min per 1.73 m 2, respectively). We analyzed data from 122 individuals with AIP who were followed from 2003 to 2013 and genotyped for PEPT2. We tested the hypothesis that PEPT2 genotypes affect the severity and prognosis of porphyria-associated kidney disease. The human peptide transporter 2 (PEPT2) expressed by proximal tubular cells mediates the reabsorption of ALA, and variants of PEPT2 have different affinities for ALA.

During AIP, δ-aminolevulinic acid (ALA) accumulates and promotes tubular cell death and tubulointerstitial damage. CKD occurs in most patients with acute intermittent porphyria (AIP).

The transporter 2