Intrarenal inflammation has been implicated in the pathogenesis of nephrolithiasis, with prior work showing increased urine levels of IL-6, IL-8, and CCL-2 in stone patients. However, no studies have assessed for inflammation in the renal papillae. We sought to characterize novel papillary tip and urinary biomarkers in stone patients.
92 patients with nephrolithiasis undergoing percutaneous nephrolithotomy were enrolled. Papillary tip biopsies, kidney urine, and bladder urine were collected, as well as voided urine from 8 healthy volunteers. QT-PCR was performed to measure inflammatory gene expression.
84-gene PCR array revealed significant elevation of several cytokines in stone patients vs controls (fold change 2.3 - 694). 24 genes were selected for final analysis. In 41 pairs of urine samples, levels of CCL5, CD40, FasL, RIPK2, SELE, TLR3, and IL-15 were significantly elevated in kidney vs bladder urine (p0.0001 - 0.04). In 23 triplets of samples, expression of these cytokines plus CCL2, CCL7, CCR2, CSF1, CXCL9, and CXCL10 were significantly greater in papillary tips versus urine samples (p0.001 - 0.05). Cytokine elevation was independent of maximum post-operative heart rate, respiratory rate, temperature, leukocyte count, history of UTI in the past year, presence or absence of antibiotics at the time of surgery, and stone composition (all p>0.05) Conclusion: Expression of CCL-2, CCL-5, CCL-7, CCR-2, CD40, CSF1, CXCL-9, CXCL-10, Fas-L, RIPK2, SELE, and TLR-3, is markedly elevated in the papillary tips, kidney urine, and bladder urine of nephrolithiasis patients. Cytokine elevation was independent of signs of systemic inflammation. These findings further support the role of inflammation in nephrolithiasis, and imply that the inflammatory process likely begins at the renal papillae. These may represent novel biomarkers of stone disease which may be useful in basic nephrolithiasis research, disease diagnosis, and prognosis.
Journal of endourology. 2018 Jan 16 [Epub ahead of print]
Andrew Yang Sun, Bryan Hinck, Benjamin R Cohen, Karen Keslar, Robert L Fairchild, Manoj Monga
Cleveland Clinic, 2569, Glickman Urological and Kidney Institute , 9500 Euclid Avenue , Q10-1 , Cleveland, Ohio, United States , 44195-5243 ; ., Cleveland Clinic, 2569, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States ; ., Cleveland Clinic, 2569, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States ; ., Cleveland Clinic, 2569, Department of Immunology, Cleveland, Ohio, United States ; ., Cleveland Clinic, Department of Immunology, Cleveland, Ohio, United States ; ., Cleveland Clinic, 2569, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States ; .