Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cystic kidney disease, with patients often having a positive family history that is characterized by a similar phenotype. However, in atypical cases, particularly those in which family history is unclear, a differential diagnosis between ADPKD and other cystic kidney diseases is important. When diagnosing ADPKD, cystic kidney diseases that can easily be excluded using clinical information include: multiple simple renal cysts, acquired cystic kidney disease (ACKD), multilocular renal cyst/multilocular cystic nephroma/polycystic nephroma, multicystic kidney/multicystic dysplastic kidney (MCDK), and unilateral renal cystic disease (URCD). However, there are other cystic kidney diseases that usually require genetic testing, or another means of supplementing clinical information to enable a differential diagnosis of ADPKD. These include autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant tubulointerstitial kidney disease (ADTKD), nephronophthisis (NPH), oral-facial-digital (OFD) syndrome type 1, and neoplastic cystic kidney disease, such as tuberous sclerosis (TSC) and Von Hippel-Lindau (VHL) syndrome. To help physicians evaluate cystic kidney diseases, this article provides a review of cystic kidney diseases for which a differential diagnosis is required for ADPKD.

Mutations in LAMB2 , encoding laminin β ₂ , cause Pierson syndrome and occasionally milder nephropathy without extrarenal abnormalities. The most deleterious missense mutations that have been identified affect primarily the N-terminus of laminin β ₂ . On the other hand, those associated with isolated nephropathy are distributed across the entire molecule, and variants in the β ₂ LEa-LF-LEb domains are exclusively found in cases with isolated nephropathy. Here we report the clinical features of mild isolated nephropathy associated with 3 LAMB2 variants in the LEa-LF-LEb domains (p.R469Q, p.G699R, and p.R1078C) and their biochemical characterization. Although Pierson syndrome missense mutations often inhibit laminin β ₂ secretion, the 3 recombinant variants were secreted as efficiently as WT. However, the β ₂ variants lost pH dependency for heparin binding, resulting in aberrant binding under physiologic conditions. This suggests that the binding of laminin β ₂ to negatively charged molecules is involved in glomerular basement membrane (GBM) permselectivity. Moreover, the excessive binding of the β ₂ variants to other laminins appears to lead to their increased deposition in the GBM. Laminin β ₂ also serves as a potentially novel cell-adhesive ligand for integrin α ₄ β ₁ . Our findings define biochemical functions of laminin β ₂ variants influencing glomerular filtration that may underlie the pathogenesis of isolated nephropathy caused by LAMB2 abnormalities.