Fibrosis and evidence for epithelial‐mesenchymal transition in the kidneys of patients with staghorn calculi
Authors: Boonla Chanchai , Krieglstein Kerstin , Bovornpadungkitti Sombat , Strutz Frank , Spittau Björn , Predanon Chagkrapan , Tosukhowong Piyaratana 
Published: March 2011

Study Type – Therapy (case control)

Level of Evidence 2b

What’s known on the subject? and What does the study add?

It has been shown that patients with nephrolithiasis did not have normal kidney function (retrospective study). Renal inflammation and fibrosis have been shown in kidney biopsies of nephrolithiasis patients, particularly those with brushite and cystine stones. No pathological change in kidney biopsies of patients with idiopathical calcium oxalate stone is noted.

Our cross‐sectional study of patients with large kidney stone formation (mostly staghorn stones) shows that the patients have reduced overall kidney function regardless of stone type, and robust signs of inflammation and fibrosis are observed in stone‐containing renal tissues. Reduced kidney function is closely associated with the degree of renal fibrosis. This is the first study demonstrating that renal tubular cells in stone‐baring kidneys are undergoing epithelial‐mesenchymal transition, and TGF‐β1 is overproduced in these mesenchymalized cells.

OBJECTIVES

• To quantify fibrotic lesions in renal tissues obtained from patients with large calculi and to evaluate association with renal function.

• Presence of epithelial‐mesenchymal transition (EMT) in stone‐containing renal tissues was investigated.

PATIENTS, SUBJECTS AND METHODS

• In all, 50 patients with nephrolithiasis with large calculi and matched healthy controls (37) were recruited.

• Plasma creatinine (Cr) and corrected Cr clearance (CCr) were determined in all subjects.

• Of the 50 patients, 38 had renal tissue available for histological analysis. Fibrosis was assessed by Masson’s trichrome staining. Co‐expression of epithelial cytokeratins and mesenchymal markers [α‐smooth muscle actin (αSMA) and vimentin] in renal tubular cells was detected by dual immunofluorescence staining.

• Expression of fibronectin, transforming growth factor β1 (TGF‐β1) and CD68 were investigated.

RESULTS

• Overall, the kidney function of the patients was significantly reduced, indicated by increased plasma Cr and decreased corrected CCr compared with healthy controls.

• Inflammation grading in renal tissues of the patients was correlated with the percentage of the fibrotic area. Renal fibrosis was inversely correlated with renal function.

• Cytokeratins co‐expressed with αSMA and vimentin were found in nephrolithiatic renal tubular cells, and these cells strongly expressed fibronectin and TGF‐β1.

• Infiltration of CD68‐positive cells was a common finding in the inflamed renal sections.

CONCLUSIONS

• Kidneys of large stone‐forming patients had robust signs of inflammation and fibrosis, and there was a close correlation of renal fibrosis with renal dysfunction.

• This is the first study to show evidence for renal tubular cells showing signs of EMT in large stone‐containing kidneys. Plausibly, TGF‐β1 triggers EMT, which at least in part contributes to large stone‐induced renal fibrosis.