Breaking the ice: urine proteomics of medullary sponge kidney disease: Beyond the Abstract

Medullary sponge kidney (MSK) disease is a benign congenital disorder but sometimes leads to significant complications, particularly hematuria, urinary tract infection, and calcium nephrolithiasis. Three pathogenic factors including urinary stasis in the outpouchings (or cysts) of inner medullary collecting duct (IMCD), increased promoters (e.g., hypercalciuria, hyperuricosuria and hyperoxaluria) and decreased inhibitors (e.g., hypocitraturia) contribute to calcium nidus formation and eventually lithogenesis in MSK patients. Evidence of molecular stone pathogenesis in MSK is scant. 

Lessons learned from the roles of urinary stone inhibitors in calcium oxalate (CaOx) nephrolithiasis may help to define the molecular stone pathogenesis in MSK. Well-known stone inhibitors are mostly polyanionic molecules including glycosaminoglycans, pentosane polysulphate, citrate and urinary glycoproteins (3, 4). These molecules bind to positively charged sites on calcium stone nidus and thus inhibit crystal growth. While increasing in the negative zeta potential on the crystal surface leads to crystal-crystal repulsion which inhibits crystal aggregation and also blocks crystal adhesion against anionic surface molecules on renal tubular cells (4, 5). Therefore, the remaining tiny calcium crystals could be excreted into urine.

Alterations in quality or quantity of urinary stone inhibitors may lead to calcium lithogenesis. For example, two well-known CaOx stone inhibitors including osteopontin and Tamm-Horsfall glycoprotein have been found inside the kidney stone. Both proteins can act as promoter and inhibitor in different conditions. Osteopontin is a promoter in adherence of CaOx crystals on renal epithelial cells in vitro, whereas it is an inhibitor of CaOx crystal nucleation and aggregation (6). Similarly, Tamm-Horsfall glycoprotein becomes an active inhibitor of crystal aggregation at low pH and raising ionic strength due to an increase of its viscosity, but it is a powerful promoter in additional calcium ion condition (7). The decline in urinary concentrations of CaOx stone inhibitors, i.e., inter-alpha-trypsin inhibitor light chain (bikunin) and trefoil factor 1 which significantly reduced in CaOx stone formers compared to healthy individuals, may also participate in calcium lithogenesis (8, 9). 

Regarding hematuria and urinary tract infection in MSK patients, those complications may also aggravate calcium lithogenesis. Studies showed that red blood cell (RBC) membrane fragments and intact viable E. coli could promote CaOx crystal growth and aggregation in vitro (10, 11). These findings were in line with electron microscopic evidence and bacteriologic studies of the internal part of CaOx stone (12-14). Membrane-associated anionic molecules such as phosphatidylserine and surface glycoproteins in RBC membrane fragments and lipopolysaccharide in gram-negative bacterial cell wall may serve as lithogenic factors by attracting the nearby calcium ions and crystals onto these membranes, forming stone nidi, and eventually calcium nephrolithiasis. 

Taken together, molecular stone pathogenesis in MSK may be explored on the background of CaOx nephrolithiasis research. 

Written by: Wararat Chiangjong,1 and Somchai Chutipongtanate,1,*
1Pediatric Translational Research Unit, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Thailand.

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