Acute intermittent porphyria (AIP) is a genetic disorder of the synthesis of heme caused by a deficiency in hydroxymethylbilane synthase (HMBS), leading to the overproduction of the porphyrin precursors δ-aminolevulinic acid and porphobilinogen. The aim of this study is to describe the clinical and biological characteristics, the renal pathology, and the cellular mechanisms of chronic kidney disease associated with AIP. A total of 415 patients with HMBS deficiency followed up in the French Porphyria Center were enrolled in 2003 in a population-based study. A follow-up study was conducted in 2013, assessing patients for clinical, biological, and histological parameters. In vitro models were used to determine whether porphyrin precursors promote tubular and endothelial cytotoxicity. Chronic kidney disease occurred in up to 59% of the symptomatic AIP patients, with a decline in the glomerular filtration rate of ~1 ml/min per 1.73 m² annually. Proteinuria was absent in the vast majority of the cases. The renal pathology was a chronic tubulointerstitial nephropathy, associated with a fibrous intimal hyperplasia and focal cortical atrophy. Our experimental data provide evidence that porphyrin precursors promote endoplasmic reticulum stress, apoptosis, and epithelial phenotypic changes in proximal tubular cells. In conclusion, the diagnosis of chronic kidney disease associated with AIP should be considered in cases of chronic tubulointerstitial nephropathy and/or focal cortical atrophy with severe proliferative arteriosclerosis.

Background: Acute intermittent porphyria (AIP) is an inherited disorder of haem metabolism characterized by life‐threatening acute neurovisceral attacks due to the induction of hepatic δ‐aminolevulinic acid synthase 1 (ALAS1) associated with hydroxymethylbilane synthase (HMBS) deficiency. So far, the treatment of choice is hemin which represses ALAS1. The main issue in the medical care of AIP patients is the occurrence of debilitating recurrent attacks.Objective: The aim of this study was to determine whether chronic hemin administration contributes to the recurrence of acute attacks.Methods: A follow‐up study was conducted between 1974 and 2015 and included 602 French AIP patients, of whom 46 had recurrent AIP. Moreover, we studied the hepatic transcriptome, serum proteome, liver macrophage polarization and oxidative and inflammatory profiles of Hmbs^−/− mice chronically treated by hemin and extended the investigations to five explanted livers from recurrent AIP patients.Results: The introduction of hemin into the pharmacopeia has coincided with a 4.4‐fold increase in the prevalence of chronic patients. Moreover, we showed that both in animal model and in human liver, frequent hemin infusions generate a chronic inflammatory hepatic disease which induces HO1 remotely to hemin treatment and maintains a high ALAS1 level responsible for recurrence.Conclusion: Altogether, this study has important impacts on AIP care underlying that hemin needs to be restricted to severe neurovisceral crisis and suggests that alternative treatment targeting the liver such as ALAS1 and HO1 inhibitors, and anti‐inflammatory therapies should be considered in patients with recurrent AIP.

Diamond-Blackfan anemia is a congenital erythroblastopenia characterized by blockade in erythroid differentiation related to impaired ribosome biogenesis. DBA phenotype and genotype are highly heterogeneous. We have previously identified two in vitro erythroid cell growth phenotypes for primary CD34+ cells from DBA patients and following shRNA knockdown of RPS19, RPL5 and RPL11 expression in normal human CD34+ cells. The haploinsufficient RPS19 in vitro phenotype is less severe than that of other two RP mutant genes. We further documented that proteasomal degradation of HSP70, the chaperon of GATA1 is a major contributor for the defect in erythroid proliferation, delayed erythroid differentiation, increased apoptosis and the decreased globin expression, all features of the severe DBA phenotype. In present study, we explored the hypothesis that an imbalance between globin and heme synthesis may be involved in pure red cell aplasia of DBA. We identified disequilibrium between the globin chain and the heme synthesis in erythroid cells of DBA patients. This imbalance led to accumulation of excess free heme and increased ROS production that was more pronounced in cells of the severe phenotype. Strikingly, rescue experiments with wild-type HSP70 restored GATA1 expression levels, increased globin synthesis there by reducing free heme excess resulting in decreased apoptosis of DBA erythroid cells. These results demonstrate the involvement of heme in DBA pathophysiology and a major role of HSP70 in the control of balanced heme/globin synthesis. Key points Mutations in genes other than RPS19 result in significant imbalance between globin and heme synthesis leading to excess free heme. Decreased levels of HSP70 and GATA1 account for excess free heme in DBA erythroblasts; HSP70 re-expression restore the globin/heme synthesis.

Vemurafenib is a new‐targeted therapy approved for the treatment of patients with V600E BRAF‐mutant metastatic melanoma. Among the cutaneous adverse events reported, the photosensitivity is frequently experienced. We aimed to characterize more deeply the mechanism leading to this photosensitivity as well as the corresponding UV spectrum. Phototests showed that the phototoxicity was UVA‐dependent since from normal value prior to vemurafenib treatment, the UVA‐minimal erythema dose decreased in 17 of 18 patients (94.4%) while the minimal erythema dose remained unchanged. Furthermore, a vemurafenib‐induced erythema appeared quickly during the UVA exposure contrarily to what is observed with a conventional drug‐induced phototoxicity showing an erythema 12–24 h after the phototesting. Vitamin PP concentration decreased, and porphyrin level significantly increased after 2 months of vemurafenib. Our study confirms the high risk of vemurafenib‐induced photosensitivity and indicates that it is possibly vitamin PP‐ and porphyrin dependent.

CKD occurs in most patients with acute intermittent porphyria (AIP). During AIP,δ-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 thatPEPT2genotypes 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 forPEPT2. At last follow-up, carriers of thePEPT2*1*1genotype (higher affinity variant) exhibited worse renal function than carriers of the lower affinity variantsPEPT2*1/*2andPEPT2*2/*2(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 m²forPEPT2*1/*1,PEPT2*1*2, andPEPT*2*2*2carriers, respectively. At the end of follow-up, 68% ofPEPT2*1*1carriers had an eGFR<60 ml/min per 1.73 m², compared with 37% ofPEPT2*1*2carriers and 15% ofPEPT2*2*2carriers. Multiple regression models including all confounders indicated that thePEPT2*1*1genotype independently associated with an eGFR1 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.