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Key Points Genetic testing of individuals suspected of monogenic urinary stone disease resolved 34% of families with 22 different genes detected. Resolved individuals had a lower baseline and last visit eGFR and earlier age of stone presentation than the unresolved group. Specific phenotypes and younger diagnostic age were associated with a monogenic cause, allowing refinement of future screenings. Background Urinary stone disease with a clear genetic cause, monogenic stone disease (MSD), is increasingly recognized as a significant proportion of the total population. When MSD is suspected, genetic testing provides a firm diagnosis that can alter management and treatment. Here, we present testing results from a large cohort with suspected MSD. Methods Patients with features suggestive of MSD (early onset, family history, frequent stones, nephrocalcinosis [NC], and/or CKD) were recruited by the Rare Kidney Stone Consortium and genotyped for up to 160 known or candidate MSD genes via a targeted massively parallel sequencing panel. We compared clinical and biochemical features between genetically resolved MSD and unresolved individuals. Results Of 426 families (657 patients) enrolled, 145 (34%) were resolved with identified disease associated variants in 22 known MSD genes. Ninety-nine families were biallelic, 37 monoallelic, and two digenic. An additional 21 of the 231 screened family members were resolved. Genes identified in ten or more families include the following: AGXT , HOGA1 , SLC34A3 , CYP24A1 , SLC3A1 , and CLCN5 . Compared with the unresolved group, MSD probands had a lower baseline and last visit eGFR, earlier age of stone presentation, and more stone events and procedures/year of life. The resolve rate was higher in those <16 years, and NC was seen earlier in the MSD group. Overall, NC was a risk factor for lower eGFR. Among the specific disorders, patients with primary hyperoxaluria had the earliest age of stone and NC diagnosis, and as expected, the highest urinary oxalate level. Conclusions Our study emphasizes the value of selecting patients enriched for factors associated with MSD, and comprehensive genetic testing to achieve a high yield of genetic diagnoses. Significant clinical and biochemical characteristics of patients with MSD were defined. A definitive MSD diagnosis facilitates individualized management and strategies to delay disease progression in probands and affected family members.

Key Points Circulating proteins independently associated with kidney stone diagnosis are related to kidney stone matrix. Lower circulating uromodulin and higher scavenger receptor cysteine-rich domain-containing group B protein levels were associated with higher kidney stone risk, whereas kidney stone presence elevates plasma matrix metalloproteinase 7 level. The protective effect of uromodulin against kidney stones was independent of kidney function. Background Kidney stones are increasingly recognized as a systemic disorder with a high global prevalence. However, large proteomics studies are lacking. Methods An individual-level proteomics study with rigorous adjustments was performed on 35,331 UK Biobank participants to uncover the independent associations between 2922 circulating proteins and prevalent kidney stone disease. Mendelian randomization analysis was used to assess causal relationships. Findings were validated using genomic data from the Mayo Clinic Biobank ( N =43,744), concentration-response analysis, transcriptomics analyses, and additional genome-wide association studies. Results Nine plasma proteins were independently associated with a kidney stone diagnosis, including reduced uromodulin (UMOD; β , −0.10; 95% confidence interval [CI], −0.15 to −0.05) and elevated scavenger receptor cysteine-rich domain-containing group B protein (SSC4D; β , 0.28; 95% CI, 0.17 to 0.38) and were enriched in extracellular matrix pathways. Mendelian randomization analysis revealed that the presence of kidney stone contributed to elevated levels of matrix metalloproteinase 7. Conversely, lower plasma UMOD (odds ratio [OR], 0.93; 95% CI, 0.90 to 0.97) and higher plasma SSC4D (OR, 1.10; 95% CI, 1.02 to 1.18) were associated with kidney stone risk. These associations were consistently replicated in the Mayo Clinic Biobank dataset (UMOD; OR, 0.92; 95% CI, 0.86 to 0.98; SSC4D; OR, 1.13; 95% CI, 1.01 to 1.27) and further validated by a concentration-response analysis. Single-nucleus RNA sequencing and quantitative trait loci analyses confirmed consistent associations between thick ascending limb UMOD expression and stone former status and with blood and urine UMOD concentrations. Genome-wide association study analysis, adjusted for eGFR, suggested that the protective role of UMOD against kidney stones was independent of kidney function. Conclusions This study highlights significant associations between concentrations of specific blood proteins and a history of kidney stones. Several implicated proteins are related to kidney stone matrix, with UMOD independently associated with lower risk and SSC4D with higher risk of kidney stones.

BackgroundVariable flip angle (VFA) and modified Look–Locker inversion recovery (MOLLI) are frequently used for noninvasive evaluation of renal interstitial fibrosis (IF) in chronic kidney disease (CKD). However, controversy remains over which method is preferred.PurposeTo compare the diagnostic efficacy of VFA and MOLLI for T1 mapping in evaluating renal IF.Study TypeProspective.SubjectsFifty‐one participants with CKD (CKD stage 1–5, 35 males) and 18 healthy volunteers (eight males).Field Strength/Sequence3.0 T, three‐dimensional gradient echo sequence for B1+ VFA, and two‐dimensional gradient echo sequence for MOLLI.AssessmentImage quality was assessed on a five‐point scale. Cortex and medulla T1 values (cT1 and mT1), corticomedullary T1 value difference (ΔT1, medulla − cortex), and corticomedullary T1 value ratio (ratio T1, cortex:medulla) were compared between VFA and MOLLI as well as between IF grade (0–4) based on biopsy.Statistical TestsIntraclass correlation coefficient, Bland–Altman analysis, analysis of variance, Kruskal–Wallis test, correlation analysis, and receiver operating characteristics analysis with the area under the curve (AUC). P‐value <0.05 was considered significant.ResultsMOLLI provided significantly better image quality compared to VFA. cT1 and mT1 values significantly differed between VFA and MOLLI (cT1‐VFA: 1771.4 ± 139.4 msec vs. cT1‐MOLLI: 1729.9 ± 132.1 msec; mT1‐VFA: 2076.0 [interquartile range (IQR): 2045.9–2129.9] msec vs. mT1‐MOLLI: 2039.2 [IQR: 1997.8–2071.6] msec). ΔT1 and ratio T1 values were not different between VFA and MOLLI (ΔT1: 300.8 ± 71.4 vs. 306.0 ± 78.4, respectively, P = 0.33 and ratio T1: 0.85 ± 0.038 vs. 0.85 ± 0.041, respectively, P = 0.064). No difference was observed between T1 variables and T1 mapping methods in diagnosing IF.Data ConclusionΔT1 and ratio T1 were not different between VFA and MOLLI. Both VFA and MOLLI are effective for noninvasive assessment of renal IF.Level of Evidence2Technical EfficacyStage 2

Key Points Common kidney stones are unlikely to be an independent and direct cause of CKD in the general population. CKD may protect against kidney stones because of changes in key urinary factors critical for stone formation. Background Kidney stones and CKD are common disorders with a substantial interaction. Although observational studies have suggested a potential for enhanced CKD risk after prior kidney stones, the exact relationship remains ambiguous. Methods Shared comorbidities between two diseases were identified using unbiased screening. Genome-wide association study summary statistics were obtained from the UK Biobank (UKBB), FinnGen, and CKDGen, followed by genetic association analyses across various traits. Bidirectional Mendelian randomization (MR) analyses were performed to define causal links, complemented by multivariable MR that included the shared comorbidities including hypertension, diabetes, and obesity. Observational analyses were undertaken using cohorts from the Mayo Clinic and a UKBB subset. Results Despite identifying a total of 123 conditions as shared comorbidities, there was no significant genetic correlation between kidney stones and CKD. Unadjusted MR analysis revealed no significant association between kidney stones and CKD risk (UKBB [exposure]/FinnGen [outcome]: odds ratio [OR]=0.97, 95% confidence interval [CI], 0.88 to 1.06; FinnGen/UKBB: OR=1.17, 95% CI, 0.98 to 1.39). Kidney stones did significantly associate with a higher urinary albumin-creatinine ratio ( β =0.014, 95% CI, 0.002 to –0.025), but this association disappeared in the multivariable MR model ( β =0.009, 95% CI, −0.003 to 0.020). Furthermore, in a cross-sectional analysis limited to the UKBB cohort, a robust regression model did not detect an independent association between kidney stones and urinary albumin-creatinine ratio ( β =0.16, 95% CI, −0.04 to 0.35) or eGFR ( β =0.10, 95% CI, −0.07 to 0.28). Conversely, CKD associated with a diminished risk of kidney stones in multivariable MR models (UKBB/FinnGen: OR=0.77, 95% CI, 0.69 to 0.87; FinnGen/UKBB: OR=0.73, 95% CI, 0.66 to 0.81). Furthermore, in the Mayo Clinic cohort with available urinary biochemistries, lower eGFR was associated with lower urinary calcium excretion and urinary calcium oxalate/phosphate supersaturation. Conclusions In this study, kidney stones were not independently associated with CKD. Conversely, CKD was associated with a lower risk of calcium kidney stones likely via changes in key urinary traits, including lower calcium excretion.

Abstract The dismal outcome of acute leukemia undergoing immunophenotype-switch, compounded by the increased incidence in the era of immunotherapy, highlights the need for in-depth systemic studies. We investigated the clinicopathological, cytogenetic, and molecular features of 33 patients experiencing switch between acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The median duration from the primary diagnosis to lineage switch was 7.8 months, with the subsequent median survival being < 3 months. The majority experienced a transition from B-ALL to AML. The AML cases demonstrated a spectrum of differentiation, ranging from minimal to erythroid, with monocytic being the most common. Cytogenetic analysis revealed 11q23/KMT2A fusions as the most recurrent abnormalities (n = 18); also observed were complex karyotype, 7/7q-, 9p-/CDKN2A deletion, t(5;14)/TCLX3::BCL11b, t(8;9)/PCM1::JAK2, t(9;22)/BCR::ABL1, and t(12;19)/TCF3::ZNF384. Remarkably, in 60% of patients lacking KMT2A fusions, a chronic myeloid neoplasm was observed preceding the first leukemia. In contrast, no prior hematological malignancies were observed in KMT2A cases. Deep mutational profiling reinforced the inherent clonal relationship between the initial and subsequent leukemias, evident from the overlapping mutational signatures. The presence of distinct additional mutations across the two phases supports the long-standing theory of lineage switch emerging via divergent evolution of a multipotential progenitor.