CHU Rangueil, Département de néphrologie et transplantation d’organes & Centre de référence maladies rénales rares, INSERM 1048 et Université Toulouse-3, Toulouse
A number of recent findings have shed light on pathophysiology of autosomal dominant polycystic kidney and liver diseases (ADPKD/ADPLD). First, the genes responsible for prominent involvement of the kidney (PKD1, PKD2, and in few cases GANAB and DNAJB11), or the liver (PRKCSH, SEC63, SEC61B, ALG8 and LRP5) were identified. Second, the recognition of polycystin-1 (PC1) and polycystin-2 (PC2) encoded respectively by PKD1 and PKD2 as ciliary proteins. The primary cilia is a receptor expressed in all epithelial cells, including cholangiocytes and tubular renal cells the liver and kidney cysts derive from. PC1 is a mechanoreceptor and PC2 a calcium channel. These proteins are coupled in cell membrane of primary cilia and regulate intracellular calcium, hence cAMP. Except LRP5, ADPLD-associated genes are involved in the ER-dependant glycoprotein quality control mechanism. PC1 deficiency related to PKD1 mutation, PC1 incorrect glycosylation or folding, and PC1-PC2 interaction, all result in cAMP-activation and cell proliferation that contribute to cyst growth. Third, the availability of drugs that decrease intracellular cAMP allows targeted treatment in PKD/PLD. Tolvaptan, a specific V2 receptor for AVP acts on tubular cells, slows both renal cysts enlargement and total kidney volume growth (TKV) and finally decrease (–30%) the annual slope of the GFR in patients with progressive renal failure. Somatostatine analogs can also reduce the volume of massively enlarged polycystic liver. Finally, tools have been proposed to assess the risk of progression to end-stage renal failure. Relying on MRI of the kidneys, the Mayo Clinic classification predicts the risk of ESRD according to total kidney volume at given age. The PRO-PKD score provide estimate of age at ESRD according to simple clinical characteristics and identification of the family mutation in PKD1/PKD2 families.
This work is licensed under a
Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License