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BackgroundThe global prevalence and recurrence rate of kidney stones is very high. Recent studies of Randall plaques and urinary components in vivo , and in vitro including gene manipulation, have attempted to reveal the pathogenesis of kidney stones. However, the evidence remains insufficient to facilitate the development of novel curative therapies. The involvement of renal and peripheral macrophages in inflammatory processes offers promise that might lead to the development of therapeutic targets. The present systematic literature review aimed to determine current consensus about the functions of macrophages in renal crystal development and suppression, and to synthesize evidence to provide a basis for future immunotherapy.MethodsWe systematically reviewed the literature during February 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles investigating the relationship between macrophages and urolithiasis, particularly calcium oxalate (CaOx) stones, were extracted from PubMed, MEDLINE, Embase, and Scopus. Study subjects, languages, and publication dates were unrestricted. Two authors searched and screened the publications.ResultsAlthough several studies have applied mixed modalities, we selected 10, 12, and seven (total, n = 29) of 380 articles that respectively described cultured cells, animal models, and human samples.The investigative trend has shifted to macrophage phenotypes and signaling pathways, including micro (m)-RNAs since the discovery of macrophage involvement in kidney stones in 1999. Earlier studies of mice-associated macrophages with the acceleration and suppression of renal crystal formation. Later studies found that pro-inflammatory M1- and anti-inflammatory M2-macrophages are involved. Studies of human-derived and other macrophages in vitro and ex vivo showed that M2-macrophages (stimulated by CSF-1, IL-4, and IL-13) can phagocytose CaOx crystals, which suppresses stone development. The signaling mechanisms that promote M2-like macrophage polarization toward CaOx nephrocalcinosis, include the NLRP3, PPARγ-miR-23-Irf1/Pknox1, miR-93-TLR4/IRF1, and miR-185-5p/CSF1 pathways.Proteomic findings have indicated that patients who form kidney stones mainly express M1-like macrophage-related proteins, which might be due to CaOx stimulation of the macrophage exosomal pathway.ConclusionsThis systematic review provides an update regarding the current status of macrophage involvement in CaOx nephrolithiasis. Targeting M2-like macrophage function might offer a therapeutic strategy with which to prevent stones via crystal phagocytosis.

In our previous report, M2-macrophage (Mφs) deficient mice showed increased renal calcium oxalate (CaOx) crystal formation; however, the role of Mφs-related-cytokines and chemokines that affect kidney stone formation remains unknown. Here, we investigated the role of M1/M2s in crystal development by using in vitro and in vivo approaches. The crystal phagocytic rate of bone marrow-derived M2Mφs was higher than that of bone marrow-derived Mφs and M1Mφs and increased on co-culture with renal tubular cells (RTCs). However, the amount of crystal attachment on RTCs reduced on co-culture with M2Mφs. In six hyperoxaluric C57BL/6J mice, M1Mφ transfusion and induction by LPS and IFN-γ facilitated renal crystal formation, whereas M2Mφ transfusion and induction by IL-4 and IL-13 suppressed renal crystal formation compared with the control. These M2Mφ treatments reduced the expression of crystal-related genes, such as osteopontin and CD44, whereas M1Mφ treatment increased the expression of pro-inflammatory and adhesion-related genes such as IL-6, inducible NOS, TNF-α, C3, and VCAM-1. The expression of M2Mφ-related genes was lower whereas that of M1Mφ-related genes was higher in papillary tissue of CaOx stone formers. Overall, our results suggest that renal crystal development is facilitated by M1Mφs, but suppressed by M2Mφs.

The pathogenesis of kidney stone formation includes multi-step processes involving complex interactions between mineral components and protein matrix. Calcium-binding proteins in kidney stones have great influences on the stone formation. The spatial distributions of these proteins in kidney stones are essential for evaluating the in vivo effects of proteins on the stone formation, although the actual distribution of these proteins is still unclear. We reveal micro-scale distributions of three different proteins, namely osteopontin (OPN), renal prothrombin fragment 1 (RPTF-1), and calgranulin A (Cal-A), in human kidney stones retaining original mineral phases and textures: calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD). OPN and RPTF-1 were distributed inside of both COM and COD crystals, whereas Cal-A was distributed outside of crystals. OPN and RPTF-1 showed homogeneous distributions in COM crystals with mosaic texture, and periodically distributions parallel to specific crystal faces in COD crystals. The unique distributions of these proteins enable us to interpret the different in vivo effects of each protein on CaOx crystal growth based on their physico-chemical properties and the complex physical environment changes of each protein. This method will further allow us to elucidate in vivo effects of different proteins on kidney stone formation.

Difficulty in performing ureteroscopic lithotripsy (URSL) depends on endoscopic findings surrounding calculi. In this multicentre prospective cohort study of 185 patients with a single ureteral stone who underwent ureteroscopic lithotripsy registered in the SMART study between January 2014 and February 2017, we established a classification of endoscopic findings and analysed risk factors for ureteral changes. We evaluated endoscopic findings (oedema, polyps, ureteral mucosa-stone adherence, and distal ureteric tightness) based on the SMART classification. Operative time and ureteral injuries were significantly correlated with endoscopic finding grades. Multivariate analyses revealed that mucosa-stone adherence (MSA) was strongly affected by hydronephrosis grade (odds ratio, 12.4; p  = 0.022) and the interval before surgery (odds ratio, 1.10; p  = 0.012). The cutoff value for MSA was 98 days, with a predictive accuracy of 0.78. Risk factors for distal ureteric tightness were age (odds ratio, 0.96; p  = 0.004) and early intervention (odds ratio, 0.90; p  = 0.023). The cutoff value was 34 days, with a predictive accuracy of 0.72. In conclusion, appropriate intervention around 34 days (limited to 98 days) after symptom onset is necessary for treating ureteral calculi. Even if intervention passed 98 days post-symptom onset, staged URSL, alternative procedures, and detailed informed consent should be planned in advance, assuming strong MSA.

We sought to identify and quantitatively analyze calcium oxalate (CaOx) kidney stones on the order of micrometers, with a focus on the quantitative identification of calcium oxalate monohydrate (COM) and dihydrate (COD). We performed Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction (PXRD), and microfocus X-ray computed tomography measurements (microfocus X-ray CT) and compared their results. An extended analysis of the FTIR spectrum focusing on the 780 cm −1 peak made it possible to achieve a reliable analysis of the COM/COD ratio. We succeeded in the quantitative analysis of COM/COD in 50-μm 2 areas by applying microscopic FTIR for thin sections of kidney stones, and by applying microfocus X-ray CT system for bulk samples. The analysis results based on the PXRD measurements with micro-sampling, the microscopic FTIR analysis of thin sections, and the microfocus X-ray CT system observation of a bulk kidney stone sample showed roughly consistent results, indicating that all three methods can be used complementarily. This quantitative analysis method evaluates the detailed CaOx composition on the preserved stone surface and provides information on the stone formation processes. This information clarifies where and which crystal phase nucleates, how the crystals grow, and how the transition from the metastable phase to the stable phase proceeds. The phase transition affects the growth rate and hardness of kidney stones and thus provides crucial clues to the kidney stone formation process.

This prospective ex vivo study investigated microdamage to single-use flexible ureteroscopes (fURS) after ureteroscopy and endoscopic combined intrarenal surgery (ECIRS). The performance of 30 WiScope devices (OTU Medical, San Jose, CA, USA) was examined immediately after use, dividing them into three equal groups: ureteroscopy and ECIRS in the prone and supine positions. The overall scope of microdamage assessment included the scope deflection, bending radius, resolution, and water flow rate. Additionally, we analyzed the association between scope status and surgical parameters. The deflection, bending radius, and resolution remained similarly above the thresholds in all groups. However, the water flow rate was below the threshold in seven scopes (70%) in the ureteroscopy group and none in the ECIRS groups ( P  = 0.001). Univariate and multivariable logistic regression analyses demonstrated that basket wire catheter use was associated with an increased risk for overall scope microdamage (odds ratio [OR], 22.70; P  = 0.006 and OR, 22.40; P  = 0.019, respectively). Stone size, total laser energy, and surgical position were not associated with a risk for scope microdamage. In conclusion, ureteroscopy was more closely associated with scope damage than ECIRS, and basket wire catheter use seemed to inflict more damage to the fURS.

In inflammation, osteopontin (OPN) acts as both a stone matrix component for calcium oxalate (CaOx) crystal formation and an inflammatory mediator. While previous studies have demonstrated the individual roles of OPN and macrophages (Mφ) in renal CaOx stone formation during inflammation, their interaction remains poorly understood. This study aimed to elucidate the role of OPN in modulating Mφ function during crystal formation, using an ex vivo model. Bone marrow-derived macrophages (BMDM) were isolated from eight-week-old male C57BL/6J wild-type and OPN knockout mice. BMDMs from OPN-positive (BMDM OPN+ ) and OPN-negative (BMDM OPN− ) mice were co-cultured with fluorescently labeled CaOx monohydrate (COM) crystals for phagocytosis assays and analyzed using the IN Cell Analyzer 6000. We further performed real-time quantitative reverse transcription PCR and RNA sequencing to identify gene expression profiles and clarify the role of OPN in Mφ function. The assay analysis demonstrated that phagocytosis rates were significantly higher in BMDM OPN− than in BMDM OPN+ . Inflammatory markers, such as IL-6, TNF, CD44, were upregulated following COM exposure, and IL-6 expression was significantly lower in BMDM OPN− than in BMDM OPN+ . RNA sequencing revealed that BMDM OPN− exhibited a less pro-inflammatory and more anti-inflammatory phenotype ( Csf2 l ow , Irf5 low , Itgax low , Csf1 high , Cd163 high ), resembling M2-like Mφs. Further functional analysis indicated that OPN knockdown in Mφs increased the S100 family and CREB signaling, which enhanced the M2-like phenotype shift and phagosome formation. In conclusion, OPN plays a critical role in enhancing pro-inflammatory Mφ function, potentially limiting COM phagocytosis. Modulating OPN expression in circulating Mφs may represent a therapeutic approach for kidney stone disease.

FAN score is reportedly associated with prognostic outcomes in patients with urothelial carcinoma being treated with immune check point inhibitors. However, the prognostic impact of pre-treatment FAN score in patients with metastatic renal cell carcinoma (RCC) treated with nivolumab plus ipilimumab remains unclear. We retrospectively evaluated the association between pre-treatment FAN score and prognostic outcomes in 154 patients with metastatic RCC treated with nivolumab plus ipilimumab. The pre-treatment FAN score was ‘0’ in 56 patients (36%), ‘1’ in 60 patients (40%), ‘2’ in 37 patients (24%) and ‘3’ in one patient (1%). Progression-free survival was not significantly different between patients with different FAN scores, but second progression-free survival (PFS2), cancer-specific survival (CSS) and overall survival (OS) were significantly different. In multivariable Cox proportional hazard analyses, FAN score ≥ 2 was a significant predictor of poor PFS2 (vs. FAN score 0, HR: 2.43, 95% CI 1.21–4.87, P  =  0.01 ), poor CSS (vs. FAN score 0, HR: 2.71, 95% CI 1.13–6.47, P  =  0.02 ) and poor OS (vs. FAN score 0, HR: 2.42, 95% CI 1.11–5.25, P  =  0.02 ). High pre-treatment FAN score could be a significant independent predictor of poor prognosis in patients receiving nivolumab plus ipilimumab for metastatic RCC.

This study evaluated the adherence of bacteria, calcium, and magnesium to three different ureteral stents after endoscopic surgery for urinary calculi. We randomly assigned 61 patients requiring the insertion of ureteral stents after urinary calculi treatment into three groups: Percuflex with a coating composition of Hydroplus ( n  = 21); Tria with a coating composition of Percushied ( n  = 22); and InLay Optima, which had a proprietary pHreeCoat coating ( n  = 18). All stents were removed and evaluated 1 month after treatment. The primary outcome was biomineral attachment to the ureteral stent. Calcium and magnesium contents were measured using atomic absorption spectrometry after the stent had been vortexed in a solution of saline and hydrochloric acid at pH 2. Bacteria were measured through flow cytometry of the washing solution collected by decantation after stent fragments had been immersed and vortexed in a saline solution. Median amounts of calcium and magnesium adhered to Percuflex were significantly higher than those adhered to Tria and InLay Optima. The median number of bacteria adhered was also highest in Percuflex compared to that in the other two groups, although without a statistically significant difference. These findings suggest that selecting stents with superior coating materials enhances patient outcomes and reduces stent-related complications.