1] INSERM U1147, Centre Universitaire des Saints Pères, Paris, France [2] Service de Biochimie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France [3] Service de Néphrologie, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France [4] Université Paris Descartes, Paris, France.
1] INSERM U1147, Centre Universitaire des Saints Pères, Paris, France [2] Université Paris Descartes, Paris, France.
Kidney Int. 2015 Aug;88(2):386-95. doi: 10.1038/ki.2015.97. Epub 2015 Apr 1.
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 m(2) 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.
急性间歇性卟啉症（AIP）是一种由于羟甲基胆素合酶（HMBS）缺乏导致血红素合成障碍的遗传性疾病，导致卟啉前体δ-氨基乙酰丙酸和卟胆原的过度产生。本研究旨在描述与 AIP 相关的慢性肾脏病的临床和生物学特征、肾脏病理学和细胞机制。2003 年，在法国卟啉症中心，共纳入了 415 名 HMBS 缺乏症患者进行基于人群的研究。2013 年进行了随访研究，评估了患者的临床、生物学和组织学参数。体外模型用于确定卟啉前体是否促进肾小管和内皮细胞的细胞毒性。多达 59%的有症状的 AIP 患者发生慢性肾脏病，肾小球滤过率每年下降约 1ml/min/1.73m²。绝大多数情况下无蛋白尿。肾脏病理学为慢性肾小管间质性肾病，伴有纤维性内膜增生和局灶性皮质萎缩。我们的实验数据提供了证据，表明卟啉前体可促进内质网应激、凋亡和近端肾小管细胞的上皮表型改变。总之，在伴有严重增生性动脉硬化的慢性肾小管间质性肾病和/或局灶性皮质萎缩的情况下，应考虑 AIP 相关慢性肾脏病的诊断。
