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A previous genome-wide association study (GWAS) reported three novel nephrolithiasis-susceptibility loci at 5q35.3, 7p14.3 and 13q14.1. Here, we investigated the association of these loci with nephrolithiasis by using an independent Japanese sample set. We performed case-control association analysis using 601 patients with nephrolithiasis and 201 control subjects. We selected seven single-nucleotide polymorphisms (SNPs): rs12654812 and rs11746443 from 5q35.3 (RGS14-SLC34A1-PFN3-F12); rs12669187 and rs1000597 from 7p14.3 (INMT-FAM188B-AQP1); and rs7981733, rs1170155, and rs4142110 from 13q14.1 (DGKH (diacylglycerol kinase)), which were previously reported to be significantly associated with nephrolithiasis. rs12654812, rs12669187 and rs7981733 were significantly associated with nephrolithiasis after Bonferroni's correction (P=3.12 × 10(-3), odds ratio (OR)=1.43; P=6.40 × 10(-3), OR=1.57; and P=5.00 × 10(-3), OR=1.41, respectively). Meta-analysis of current and previous GWAS results indicated a significant association with nephrolithiasis (P=7.65 × 10(-15), 7.86 × 10(-14) and 1.06 × 10(-9), respectively). We observed a cumulative effect with these three SNPs; individuals with three or more risk alleles had a 5.9-fold higher risk for nephrolithiasis development than those with only one risk allele. Our findings elucidated the significance of genetic variation at these three loci in nephrolithiasis in the Japanese population.

This study investigated the impact of relative dose intensity (RDI) on the effectiveness and safety of immuno-oncology plus tyrosine kinase inhibitor (IO-TKI) therapy in Japanese patients with renal cell carcinoma (RCC). A total of 145 patients receiving first-line treatment were analyzed: 55 received IO-TKI therapy and 90 received immuno-oncology combination (IO-IO) therapy. Patients in the IO-TKI group were divided based on an RDI threshold of 80% into high- and low-RDI groups. Median progression-free survival (mPFS) was significantly longer in the IO-TKI group compared to the IO-IO group (P < 0.05), while no significant difference in median overall survival (mOS) was observed (P = 0.53). Interestingly, the mOS tended to be shorter in the IO-TKI high-RDI group than in the IO-TKI low-RDI (P = 0.05) and IO-IO groups (P = 0.13). Moreover, treatment discontinuation due to adverse effects occurred earlier in the IO-TKI high-RDI group (P < 0.05). An association was found between RDI ≥ 80% in IO-TKI therapy, discontinuation due to adverse events, and poor prognosis. Careful dose adjustment of TKIs may be necessary to optimize outcomes in Japanese patients with RCC receiving IO-TKI combination therapy.

Immune checkpoint inhibitor (ICI)-based combination therapy has revolutionized first-line treatment outcomes for metastatic renal cell carcinoma (mRCC). In this study, we aimed to retrospectively analyze real-world clinical outcomes and toxicities of first-line ICI-based combination therapies, specifically nivolumab plus ipilimumab (IO+IO) and ICIs plus tyrosine kinase inhibitors (IO+TKI), in Japanese patients with mRCC aged ≥ 75 years compared with non-older adult patients. We retrospectively enrolled 156 patients with mRCC who received first-line IO+IO or IO+TKI between September 2018 and June 2024 at eight Japanese institutions. Patients were categorized into an older adult group (≥ 75 years, n=49) and a non-older adult group (< 75 years, n=107). We evaluated objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The overall ORR (47% vs. 59%, p=0.43) and DCR (86% vs. 83%, p=0.65) were comparable between groups. No significant differences were observed in PFS (median: 15.5 vs. 17.0 months, p=0.78) or OS (NA vs. 52.2 months, p=0.61). In the IO+IO regimen, the ORR, DCR, PFS, OS, and AE rates were comparable across age groups. However, in the IO+TKI regimen 　×cohort, the ORR was significantly lower in older adults (55% vs. 81%, p=0.04), and treatment discontinuation due to AEs was significantly higher in older adults (60% vs. 32%, p=0.02), with a shorter time to discontinuation despite no difference in the initial TKI dose and RDI. The non-older adult group showed significantly better PFS with IO+TKI compared with IO+IO (hazard ratio: 2.37, p=0.02). In contrast, in the older adult group, PFS and OS were approximately equivalent between the two regimens. Our real-world data indicated that ICI-based combination therapies are effective in patients with mRCC aged ≥75 years, with outcomes largely non-inferior to non-older adult patients. However, the comparable efficacy of IO+TKI and IO+IO in the older adult group, which may differs from that in the non-older adult group, highlights the importance of understanding the distinct characteristics of each regimen for individualized treatment selection and careful management, particularly regarding AE monitoring and dose adjustment in older adult patients receiving IO+TKI.

Background/Objectives: Nivolumab plus ipilimumab (IO–IO) provides durable clinical benefit in metastatic renal cell carcinoma (mRCC), yet long-term real-world data focusing on progression-free and treatment-free (PF–TF) survival remain limited. This study aimed to evaluate the long-term outcomes of IO–IO with a particular focus on the frequency and clinical characteristics of PF–TF. Methods: We retrospectively analyzed 63 patients with mRCC treated with first-line IO–IO across eight institutions with a minimum potential follow-up of five years. Progression-free survival (PFS), PFS2, and overall survival (OS) were assessed. PF–TF was defined as absence of disease progression and any cancer-directed therapy at the five-year landmark. Clinical and treatment-related factors were compared between patients with and without PF–TF. Results: The median PFS, PFS2, and OS were 7.5 (95% confidence interval [CI], 5.1–13.3), 26.2 (95% CI, 13.6–46.6), and 47.4 months (95% CI, 29.3–not reached), respectively. At 5 years, 11 patients (17%) achieved PF–TF. Baseline characteristics, IMDC risk classification, and peripheral blood biomarkers were not predictive of PF–TF. PF–TF was associated with the absence of bone metastases, presence of lymph node metastases, and occurrence of immune-related adverse events (irAEs), as well as the delayed onset of irAEs. No PF–TF patients required corticosteroid pulse therapy, and durable PF–TF was observed even after early treatment discontinuation due to adverse events. Conclusions: IO–IO demonstrated sustained long-term efficacy in real-world practice, with a subset achieving durable PF–TF. These findings highlight IO–IO as a strategy capable of providing long-term disease control with reduced treatment burden in selected patients with mRCC.

We previously established an experimental model of calcium oxalate crystal deposition in the mouse kidney using C57BL/6 mice. C57BL/6J (B6J) and C57BL/6N (B6N) are two core substrains of C57BL/6 mice. B6J and B6N substrains have approximately the same genomic sequence. However, in whole-genome analyses, substrains have slight genetic differences in some genes. In this study, we used these substrains as kidney crystal formation models and compared their genetic backgrounds to elucidate the pathogenic mechanisms of kidney stone formation. Eight-week-old male B6J and B6N mice (n = 15 in each group) were administered 80 mg/kg glyoxylate for 12 days, and the amount of kidney crystal depositions was compared. The expression levels of six genes (Snap29, Fgf14, Aplp2, Lims1, Naaladl2, and Nnt) were investigated by quantitative polymerase chain reaction, and the protein levels were evaluated by western blotting and immunohistochemistry. The amount of kidney crystal depositions was significantly higher in B6J mice than in B6N mice on days 6 and 12. The expression of nicotinamide nucleotide transhydrogenase (Nnt) gene was significantly lower in B6J mice than in B6N mice. The expression of Nnt protein was observed only in B6N mice, and preferential high expression was seen in renal tubular epithelial cells. The results of this study provide compelling evidence that differences in mouse substrains affect kidney crystal deposition and that the absence of Nnt protein could be involved in crystal formation in B6J mice.

Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases with complex genetic components. To identify a gene(s) susceptible to SLE, we performed a case-control association study using genome-wide gene-based single nucleotide polymorphisms (SNPs) in Japanese population. Here we report that an SNP (rs3748079) located in a promoter region of the inositol 1,4,5-triphosphate receptor type 3 ( ITPR3 ) gene on chromosome 6p21 was significantly associated with SLE in two independent Japanese case-control samples [ P  = 0.0000000178 with odds ratio of 1.88, 95% confidence interval (CI) of 1.51–2.35]. This particular SNP also revealed associations with rheumatoid arthritis (RA) ( P  = 0.0084 with odds ratio of 1.23, 95% CI of 1.05–1.43) and with Graves’ disease (GD) ( P  = 0.00036 with odds ratio of 1.57, 95% CI of 1.22–2.02). We found the binding of NKX2.5 specific to the non-susceptible T allele in the region including this SNP. Furthermore, an SNP in NKX2.5 also revealed an association with SLE ( P  = 0.0037 with odds ratio of 1.74, 95% CI of 1.19–2.55). Individuals with risk genotype of both ITPR3 and NKX2.5 loci have higher risk for SLE (odds ratio = 5.77). Our data demonstrate that genetic and functional interactions of ITPR3 and NKX2.5 play a crucial role in the pathogenesis of SLE.

Background Transverse testicular ectopia (TTE) is a rare anomaly in which both testes descend through a single inguinal canal into the same hemiscrotum. Although almost 20–50% of patients with TTE exhibit persistent Müllerian duct syndrome (PMDS) and many genetic analyses have been performed, no reports have described the genes contributing to TTE without PMDS. Here, we report two cases of TTE without PMDS using immunohistochemical staining and genetic analysis. Case presentation Two Asian patients with TTE without PMDS were subjected to orchiopexy. We performed testicular biopsies during operation and obtained blood samples before the operation. Testicular tissues were stained for c-kit, placental alkaline phosphatase (PLAP), and undifferentiated embryonic cell transcription factor 1 (UTF1) to evaluate the presence of intratubular malignant germ cells. Additionally, we performed polymerase chain reaction-based direct sequencing to identify single nucleotide polymorphisms in genes associated with regression of the Müllerian duct and testicular descent (that is, anti-Müllerian hormone [ AMH ], AMH receptor 2 [ AMHR2 ], insulin-like 3 [ INSL3 ], and relaxin family peptide receptor 2 [ RXFP2 ]). The three-dimensional structures of proteins were predicted using SWISS-MODEL. In immunohistochemical analysis, c-kit and UTF1 were positive, whereas PLAP was negative in three testicular tissue samples from the two patients. These features were also detected on the unaffected side. In variant analysis, common missense variants in the AMH gene (g.365G>T; c.165G>T; p.Ser49Ile [rs10407022]) were observed. All variants in INSL3 and RXFP2 genes were intronic or silent. Conclusions Because UTF1, a specific marker of spermatogonial stem cell activity, was expressed in both the affected and unaffected sides in the testicular tissues of two patients, the risk of malignancy may be high in these patients. Although the etiology of TTE without PMDS remains unclear, our variant analysis results were consistent with previous reports, and variants in the AMH gene (rs10407022) may contribute to the specific phenotype of TTE without PMDS.

Nephrolithiasis is a common urological trait disorder with acute pain. Although previous studies have identified various genetic variations associated with nephrolithiasis, the host genetic factors remain largely unidentified. To identify novel nephrolithiasis loci in the Japanese population, we performed large-scale GWAS (Genome wide association study) using 11,130 cases and 187,639 controls, followed by a replication analysis using 2,289 cases and 3,817 controls. The analysis identified 14 significant loci, including 9 novel loci on 2p23.2-3, 6p21.2, 6p12.3, 6q23.2, 16p12.3, 16q12.2, 17q23.2, 19p13.12, and 20q13.2. Interestingly, 10 of the 14 regions showed a significant association with any of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic background among nephrolithiasis patients and these quantitative traits. Four novel loci are related to the metabolic pathway, while the remaining 10 loci are associated with the crystallization pathway. Our findings demonstrate the crucial roles of genetic variations in the development of nephrolithiasis. Nephrolithiasis is a common urothelial disorders with frequent recurrence rate, but its genetic background is largely remained unidentified. Previous GWAS identified 6 genetic factors in total. Here we performed a GWAS using more than 200,000 samples in the Japanese populations, and identified 14 significant loci and nine of them are novel. We also found that 10 of the 14 loci showed a significant association with any of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (BMI, eGFR, UA, Ca etc). All 14 significant loci are associate with either metabolic or crystallization pathways. Thus, our findings elucidated the underlying molecular pathogenesis of nephrolithiasis.

Nephrolithiasis is a common urological trait disorder with acute pain. Although previous studies have identified various genetic variations associated with nephrolithiasis, the host genetic factors remain largely unidentified. To identify novel nephrolithiasis loci in the Japanese population, we performed large-scale GWAS (Genome wide association study) using 11,130 cases and 187,639 controls, followed by a replication analysis using 2,289 cases and 3,817 controls. The analysis identified 14 significant loci, including 9 novel loci on 2p23.2-3, 6p21.2, 6p12.3, 6q23.2, 16p12.3, 16q12.2, 17q23.2, 19p13.12, and 20q13.2. Interestingly, 10 of the 14 regions showed a significant association with any of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic background among nephrolithiasis patients and these quantitative traits. Four novel loci are related to the metabolic pathway, while the remaining 10 loci are associated with the crystallization pathway. Our findings demonstrate the crucial roles of genetic variations in the development of nephrolithiasis.