Medullary sponge kidney (MSK) is a rare genetic disease (ORPHA1309) but it reaches a prevalence of 12-20% in kidney stones population (Gambaro G – 2006  (full text)).
MSK pathogenesis is not well understood: most likely it is a congenital anomaly with delayed expression, due to a disruption at the “ureteric bud/metanephric blastema” interface.Developmental genes, RET and its ligand, the glial cell-derived neurotrophic factor (GDNF), are pivotal in renal development and GDNF gene sequence variations have already been described in patients with MSK (Torregrossa R – 2010  (full text)).
Familial pedigrees of MSK patients suggest an autosomal dominant inheritance, with reduced penetrance and variable expressivity (Fabris A – 2013 ).
MSK is characterized by developmental abnormalities of the medullary pyramids with cystic dilatations of the collecting ducts and tubules and small stones, sometimes associated with micro-calcifications, a hallmark of MSK (Fig.1). It is also associated with tubular dysfunction leading to renal acidification defects and hypercalciuria. This picture is often incorrectly diagnosed as nephrolithiasis.
Association with extra renal malformations is also very frequent. Particularly, our group has already described that metabolic bone disease is often associated with MSK (Fig.2, Fabris – 2009  (full text)).
Idiopathic calcium nephrolithiasis (NL) has also been reported to be associated with bone demineralization (Fabris A – 2015 ).
We hypothesized that pathways involved in bone remodeling are more active in MSK than NL.
Patients and methods
Eleven MSK patients and 12 NL were studied: 24-h urine biochemistry and bone mineral content (BMC) are shown in the table (Fig.3). Urine proteomic profile was obtained. Proteins of interest were selected if ≥ 2-fold difference in spectral counts, and ≤0,05 p-value for Kurskal-Wallis test. Functional enrichments were analyzed with STRING v. 10.0. All patients had normal PTH values and eGFR>60 ml/min/1.73m2.
All variables were significantly different between MSK and NL patients (Fig.3).
MSK differed from NL in 328 proteins. 100 proteins were over expressed in MSK, 228 down expressed. According to the KEGG database, some of them are involved together in annotated pathways: CDH15, PTPRM in Cell adhesion molecules (CAMs) (Fig. 4a), PPP2CB , LAMB2, HSP90AA1 in PI3K-Akt signaling pathway (Fig. 4b).
Down regulated proteins are involved in cytoskeleton remodeling pathways: CDH1, CDH3, CDH6, CDH11, CDH13 play a role in connection of adjacent cells through calcium-dependent trans-dimerization of cadherin, in cadherin trans-homodimer, in cadherin/catenin complex (Fig.4c); IQGAP1, CD14, RAC3, F2, GNG12 take part into the regulation of actin cytoskeleton (Fig. 5a); RAP1B, RAC3, CSF1, EFNA1, GNG12 take part in Ras signaling pathway (Fig. 5b).
Our group has already found that many urine proteins detected in MSK are associated with extracellular matrix organization, a key biological processes in bone regulation (Fig. 6).PI3K-Akt pathway promotes RANKL-induced osteoclastogenesis by activating the GSK3β/NFATc1 signaling cascade and enhances osteoblast differentiation (Moon JB – 2012  (full text)). PI3Kγ has been proved to be responsible for a BMC reduction in a mouse model (Kang H – 2010  (full text)).The cadherin-catenin-actin complex is essential for osteoblast differentiation, osteogenesis process and it controls both Wnt (Marie PJ – 2013  (full text)) and PI3K/Akt (Guntur AR, 2012 ) pathways. These pathways have already been shown to be key regulators of bone mass.
Also Ras/MAPK pathway has been demonstrated to play a role in bone homeostasis and Ras proteins are expressed in osteoprogenitor cells; according to these findings, disorders of Ras/MAPK pathway, like Noonan and Costello syndrome, are associated with abnormal skeletal phenotype (eg. scoliosis, osteopenia)(Stevenson DA – 2011 ).
Bone remodeling pathways are more impaired in MSK in comparison with NL. These pathways exert a fundamental role in nephrocalcinosis pathogenesis and might be responsible for a worse BMC in patients with MSK.