A Variant of Peptide Transporter 2 Predicts the Severity of Porphyria-Associated Kidney Disease

Abstract

CKD occurs in most patients with acute intermittent porphyria (AIP). During AIP, <i>δ</i>-aminolevulinic acid (ALA) accumulates and promotes tubular cell death and tubulointerstitial damage. 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. We tested the hypothesis that <i>PEPT2</i> genotypes affect the severity and prognosis of porphyria-associated kidney disease. We analyzed data from 122 individuals with AIP who were followed from 2003 to 2013 and genotyped for <i>PEPT2</i> At last follow-up, carriers of the <i>PEPT2*1*1</i> genotype (higher affinity variant) exhibited worse renal function than carriers of the lower affinity variants <i>PEPT2*1/*2</i> and <i>PEPT2*2/*2</i> (mean±SD eGFR: 54.4±19.1, 66.6±23.8, and 78.1±19.9 ml/min per 1.73 m², respectively). Change in eGFR (mean±SD) over the 10-year period was -11.0±3.3, -2.4±1.9, and 3.4±2.6 ml/min per 1.73 m² for <i>PEPT2*1/*1</i>, <i>PEPT2*1*2</i>, and <i>PEPT*2*2*2</i> carriers, respectively. At the end of follow-up, 68% of <i>PEPT2*1*1</i> carriers had an eGFR<60 ml/min per 1.73 m², compared with 37% of <i>PEPT2*1*2</i> carriers and 15% of <i>PEPT2*2*2</i> carriers. Multiple regression models including all confounders indicated that the <i>PEPT2*1*1</i> genotype independently associated with an eGFR<60 ml/min per 1.73 m² (odds ratio, 6.85; 95% confidence interval, 1.34 to 46.20) and an annual decrease in eGFR of >1 ml/min per 1.73 m² (odds ratio, 3.64; 95% confidence interval, 1.37 to 9.91). Thus, a gene variant is predictive of the severity of a chronic complication of AIP. The therapeutic value of PEPT2 inhibitors in preventing porphyria-associated kidney disease warrants investigation.