Liu CM. et al., 2025: Post-ESWL urinary osteopontin level and ion-activity product of calcium oxalate are associated with stone recurrence after 5-year follow-up.
Chia-Min Liu 1, Chan-Jung Liu 1 2, Ze-Hong Lu 1, Ho-Shiang Huang 3 4
1Department of Urology, National Cheng Kung University Hospital, No.138, Sheng-Li Road, Tainan City, Taiwan.
2Department of Urology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
3Department of Urology, National Cheng Kung University Hospital, No.138, Sheng-Li Road, Tainan City, Taiwan.
4Department of Urology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Abstract
Background: Calcium oxalate (CaOx) is the predominant component in over 80% of kidney stones. The formation and retention of kidney stones involve multiple mechanisms, including overgrowth on Randall's plaques-subepithelial calcium phosphate deposits in the renal papillae-and interactions between urinary crystals and renal tubular epithelial cells. Previous studies have shown that specific urinary proteins can either promote or inhibit CaOx crystal nucleation, growth, and retention. This study investigates changes in the urinary excretion of CaOx-related proteins before and after extracorporeal shock wave lithotripsy (ESWL), aiming to identify protein markers associated with stone formation and recurrence over a 5-year follow-up.
Methods: This study enrolled 54 patients with renal or ureteral stones treated with ESWL and 13 healthy controls. 24-hour urine samples were collected preoperatively and at 2 and 4 weeks post-ESWL for biochemical analysis. CaOx-related proteins were measured semi-quantitatively in urine samples before and after ESWL, including nucleolin-related protein (NRP), nuclear pore complex p62 (NPC), hyaluronic acid (HA), SLC26A6, CXCR4, osteopontin (OPN), Tamm-Horsfall protein (THP) and Matrix Metalloproteinase (MMPs). Statistical analyses, including Pearson correlation and logistic regression, were performed to identify factors related to 5-year stone recurrence. Statistical significance was set at p < 0.05.
Results: Before ESWL, stone patients exhibited significantly higher levels of NPC, HA, and CXCR4. All examined markers, except for Tamm-Horsfall protein, increased significantly at two weeks after ESWL. At four weeks post-EWSL, OPN and SLC26A6 remained higher. Correlations were observed between CXCR4, MMPs, stone size and ion-activity product of calcium oxalate (APCaOX), a measure of urinary calcium oxalate supersaturation. Logistic regression identified urinary OPN and APCaOX at 4 weeks post-ESWL as significant factors influencing 5-year stone recurrence, with a recurrence rate of 48.4%.
Conclusions: The persistence of certain urinary proteins after ESWL implied the risk of stone recurrence despite stone removal. The stone recurrence at 5 years was significantly associated with higher urinary OPN and higher APCaOX levels at four weeks post-ESWL, suggesting the potential predictive value of these markers.
BMC Urol. 2025 Apr 24;25(1):102. doi: 10.1186/s12894-025-01791-x. PMID: 40275250;
PMCID: PMC12023647 FREE ARTICLE
Comments 1
In this report the authors carried out an extensive analysis of crystallization- and stone-forming modifiers before and after SWL. The risk of recurrent stone formation was followed in a 5-year perspective. The analysis was extensive and comprised at least twelve urinary proteins.
The conclusion on recurrent stone formation might have been influenced by including in the analysis SWL-treated ureteral stones and by considering kidneys with residuals up to 3 mm as stone-free. Although such fragments might be clinically unproblematic, they certainly possess a risk of new stone formation, at least in a 5-year perspective.
The analysis of this large number of urinary macromolecules certainly was not without problems. One way the authors used to address the results statistically was to look at various correlations. The interpretation of such findings, however, was difficult and certainly might have been so for most readers.
The bottom-line of this study and the advanced analysis was that increased excretion of osteopontin associated with high levels of APCaOx might explain recurrent stone formation. Although these results might explain formation of recurrent stones, formation of CaOx also can be explained by the inherent risk directly caused by supersaturation with CaOx. This was initially mentioned by the authors.
It is not mentioned, and probably not analyzed which composition the recurrent stones had. In this regard it would have been highly interesting to find out if SWL caused increased risk of brushite stones as previously suggested [1]. In this report it might have been possible to get a hint of such an event provided phosphate (not reported) was included in the 24h analysis of urine after SWL. If the pH is representative, calculation of APCaP might enable an indirect conclusion on the approximate levels of APBrushite [2]. If the authors have saved urine from this experiment, my recommendation is that they analyze urine phosphate and also analyze late follow-up urine with this question in mind.
So far the authors should be congratulated on this extensive analysis of crystallization modulators.
References
1. Krambeck AE, Handa SE, Evan AP, Lingeman JE. Brushite stone disease as a consequence of lithotripsy? Urol Res. 2010 Aug;38(4):293-9. doi:
2. Tiselius HG.A simplified ion-activity product of calcium phosphate in urine. Eur Urol 10 (1984) 191-195
Hans-Göran Tiselius