Citations

Abstract Background and Aims Seven new advanced therapies, belonging to three new classes, have been approved for the treatment of inflammatory bowel diseases (IBD) since 2021. We examined trends in utilization of advanced therapies in the USA since 2021. Methods Using de-identified electronic health record data from 71 US health systems, we examined quarterly trends in utilization of different advanced therapies in patients with ulcerative colitis and Crohn’s disease between 2021 and 2025, using interrupted time-series analysis utilizing Prais–Winsten regression. Results In 11 093 patients with ulcerative colitis treated with advanced therapies, we observed an increase in use of upadacitinib (12.1% in Q2/2025; P < .001, compared with first quarter of prescription), interleukin-23p19 (IL23p19) antagonists (5.5%; P = .03), and ustekinumab (9.5%; P = .04), decline in use of tumor necrosis factor (TNF) antagonists (34.5%; P = .003), and stable use of vedolizumab (33.6%; P = .17) and sphingosine-1 phosphate receptor modulators (1.6%; P = .28). In 15 951 patients with Crohn’s disease treated with advanced therapies, we observed an increase in use of IL23p19 antagonists (15.0% in Q1/2025; P = .003) and upadacitinib (5.9%; P < .001) and decline in use of TNF antagonists (50.2%; P = .001) and ustekinumab (13.5%; P < .001). Conclusions Contemporary trends in advanced therapy utilization in patients with IBD suggest an increased utilization of upadacitinib and anti-interleukins, accompanied by a decline in use of TNF antagonists in the USA.

Abstract Background and Aims Patients with ADPKD exhibit an increased prevalence of kidney stones with a significant overrepresentation of uric acid (UA) stones which has led to the previous suggestion that UA may be associated with disease progression in ADPKD. However, available results are controversial and the exact mechanism remains unknown. Since we have previously reported that calcium-based microcrystals worsen ADPKD disease progression we hypothesized that renal UA crystallization could affect PKD disease progression and aimed to investigate this in animal models of PKD and the AD(H)PKD registry at the University Hospital Cologne. Method WT and Pkd1+/− rats were supplemented with UA and the uricase inhibitor oxonic acid from 8 to 10 weeks of age to induce moderate hyperuricemia causing renal UA crystal deposition. This was followed by washout from 10 to 18 weeks to analyze crystal clearance. For additional treatment with the ketone beta-hydroxybutyrate (BHB) and alkaline Citrate, adult rats received a solution containing 2.1% BHB and 13.75 mM tripotassium citrate/16.75 mM citric acid in the drinking water from 14 to 18 weeks of age. Human data including eGFR, UA levels in serum, spot urine and 24-hour urine and urine pH were used from the AD(H)PKD study (Clinical Trials ID: NCT02497521) and analyzed using multivariable linear models. Results UA crystal deposition in Pkd1+/− rats led to significantly increased kidney growth, tubule dilation and UA crystal burden compared to UA-treated WT controls. Dilated tubules exhibited strong TLR-4 expression, NLRP3 activation, recruitment of peritubular macrophages and intraluminal neutrophils undergoing NETosis. Strikingly—although untreated heterozygous Pkd1+/− rats fail to develop a polycystic phenotype—UA-treated Pkd1+/− rats developed polycystic kidney disease after 8 weeks washout period with persistent activation of TLR4, NLRP3, pericystic macrophages and intracystic neutrophils. UA-treated WT rats displayed a normalization of renal tubules. Previously, we demonstrated that treatment with BHB and Citrate can ameliorate PKD disease progression. BHB has been reported to inhibit TLR4-NLRP3 signaling and citrate can prevent UA deposition due to urine alkalinization. Therefore, we induced UA crystal deposition in Pkd1+/− followed by 4 weeks of normal diet to allow crystal clearance, followed by treatment with BHB/Citrate in the drinking water. Remarkably, BHB/Citrate potently inhibited the progression to PKD in Pkd1+/− rats by ameliorating cyst growth, TLR4-NLRP3 activation, and macrophage and neutrophil recruitment. Translational analysis of UA stone forming parameters in the AD(H)PKD patient registry showed a correlation of serum and urine UA concentration with eGFR slope. However, significance of this association was lost after adjusting for eGFR, age and sex. In contrast, analysis of the Marshal lithogenic risk score which combines urine UA with urine pH to predict the risk for UA crystal/stone formation showed a significant and independent impact on eGFR slope. Conclusion Our results suggest that UA exposure is a sufficient environmental hit to induce cystogenesis in a heterozygous Pkd1 rat model. A heterozygous Pkd1 gene mutation as observed in ADPKD patients creates a hyperresponsive renal phenotype upon UA crystal formation leading to exaggerated tubule dilation, persistent inflammation, fibrosis and progression to PKD. Treatment with BHB/Citrate significantly reduces TLR4-NLRP3 activation and macrophage/ neutrophil recruitment leading to a significant amelioration of UA-induced cystogenesis. We conclude that UA crystal deposition could accelerate PKD disease progression by NLRP3-mediated and macrophage/neutrophil-based hyperinflammation. BHB/Citrate could not only prevent UA crystallization but ameliorate UA-associated kidney injury and ADPKD disease progression. Finally, the translational analysis in the AD(H)PKD patient registry suggest that, although not showing serum uric acid as independent risk factor, the lithogenic risk- largely driven by the combination of urine uric acid and urine pH- could be a driver of PKD disease progression.

Abstract Background and Aims Although the choice of dialysis technique is based on several factors, patient survival is undoubtedly one of the most relevant. In a context where randomization to either peritoneal dialysis (PD) or hemodialysis (HD) proved to be extremely challenging, previous meta-analyses were greatly limited due to the inclusion of historical studies. Method We performed a systematic review by searching multiple databases up to April 22nd, 2022. We included studies meeting the following criteria: adult patients (>18 years) with end-stage kidney disease on dialysis; comparison of PD versus HD; reporting mortality data via intention-to-treat analysis; initiation of dialysis after 2000; patient classification by dialysis modality at 90 days post-initiation; and ≥50 patients per group (Figs 1 and 2). The primary outcome was the association between dialysis modality (PD vs HD) and mortality assessed via hazard ratios (HR) [Fig. 3]. Subgroup analyses were conducted to explore potential sources of heterogeneity, including sex, age, diabetes, dialysis vintage, geographical location, HD access, and study cohort inclusion period [Figs 4 and 5]. Results Database search yielded 5317 citations, from which, 27 observational studies met the eligibility criteria, including 1 033 362 incident dialysis patients [Figs 1 and 2]. The pooled mortality HR for PD versus HD was 1.01 (95% CI 0.93–1.10 [Fig. 3]). Heterogeneity was substantial (I2 = 94%) and was largely explained by different baseline features of the included populations. A statistically significant subgroup effect was demonstrated for age (>65 vs.<65 years; P = 0.01), geographical location of the studies (Oceania vs. Europe vs. Asia vs. North America; P < 0.01), and HD vascular access (central venous catheter vs. arteriovenous fistula; P < 0.01, only one study included) [Figs 4 and 5]. Conclusion This meta-analysis suggests that overall PD and incentre HD likely carry equivalent survival benefits. However, differences were detected among subgroups based on age, geographic location, HD access type, but not on sex, diabetes status, dialysis vintage and study cohort inclusion period.

Abstract Background and Aims Almost 36 million US adults (1 in 7, 14%) suffer from chronic kidney disease (CKD), and precision strategies to offset the progression to end-stage kidney disease are in dire need. We took advantage of a novel preclinical translational model of CKD in swine and single nucleus RNA sequencing (snRNA-seq) to identify potential therapeutic targets via characterization of the renal cell-specific transcriptomic landscape. Method Normal and CKD pigs were euthanized after 14 weeks (n = 3/group), kidneys were harvested, nuclei isolated, libraries prepared, and snRNA-seq performed. UMAP plots were generated with Seurat (v4.4.0) using default parameters. The expression profile of marker genes across single nuclei clusters was visualized to define renal cell types and ranked based on the number of differentially expressed genes (DEGs). The top cell type was subjected to subsequent analysis and DEG sorted based on their involvement in angiogenesis, inflammation, and fibrosis, which are prominent injury pathways in the pathophysiology of CKD. To mechanistically study the role of top overlapping candidate DEGs and support their potential as therapeutic targets, in vitro studies in primary renal vascular endothelial cells (RECs) were performed. Results A total of 39,935 nuclei were analyzed. Thirty clusters were identified and filtered by canonical gene markers, revealing 18 unique renal cell types (Fig. 1A). Endothelial cells exhibited the highest number of DEGs (Fig. 1B). Volcano plots (Fig. 1C) and Venn diagram (Fig. 1D) analysis of endothelial cells identified unique DEGs among three main renal injury pathways in CKD (angiogenesis, inflammation, fibrosis), with 2 overlapping DEGs (VWF, LAMA3) upregulated and participating in inflammation and fibrosis. Targeted silencing of VWF and LAMA3 (randomly selected) in RECs using siRNA ameliorated C5b9 and TGF-ẞ immunoreactivity, suggesting attenuated inflammatory and fibrogenic activity, respectively (Fig. 1E). Conclusion Our work characterized the single-nuclear renal cell transcriptomic landscape of a translational model of CKD and identified endothelial cells as the cluster with the largest number of DEGs. Our observations support the candidacy of VWF and LAMA3 as potential targets to decrease renal endothelial cell inflammation and fibrosis, which could pave the way for new therapeutic strategies in patients with CKD.

Abstract Background and Aims Almost 36 million US adults (1 in 7, 14%) suffer from chronic kidney disease (CKD), which is more prevalent in the elderly, affecting up to 34% of adults ≥ over 65. CKD has limited therapeutic options, partly due to the lack of large animal models that allow the translational study of the impact of age on CKD. This work reports the first preclinical model of CKD in naturally aged swine. Method CKD was induced in naturally aged (6-9 years old) and young (3 months old) domestic pigs (bilateral renal artery stenosis + high-cholesterol/high-carbohydrate diet), followed for 14 weeks, and compared to normal controls (n = 4–5/group). Renal hemodynamics were quantified in vivo by multidetector CT. Metabolic parameters, renal microvascular (MV) architecture (3D-micro-CT), and morphometric analysis (staining) were investigated ex vivo. Results Both young and old pigs developed CKD, but the renal and metabolic phenotype was accentuated in aging animals. We found that superimposition of aging on CKD resulted in higher triglycerides, glucose levels, insulin resistance, and adipose tissue accumulation (subcutaneous, visceral, perirenal) (Fig. 1A and B), accompanied by a more severe renal dysfunction (C), cortical MV rarefaction, and reduced peritubular capillary density (D and E), and more severe structural damage disclosed by increased glomerulosclerosis, tubule-interstitial fibrosis, and tubular injury (F). Notably, the severity of renal MV rarefaction in aging CKD correlated with functional and structural abnormalities (simple linear regression analysis, G). Conclusion Our study establishes the first large animal model of aging CKD, allowing the investigation of age as a biological variable in kidney-metabolic diseases. Age exacerbates metabolic and renal abnormalities, and our data support the critical role of renal MV disease in aging CKD and suggest that its exacerbation is a potential key player in its progression. This novel translational platform could foster new studies toward the elucidation of novel mechanisms of age-related deterioration of renal function in CKD and for developing therapeutic interventions.

Abstract Background and Aims Patients with chronic kidney disease (CKD) have a higher risk of developing heart failure with preserved ejection fraction (HFpEF). Growing evidence supports that changes in cardiac microcirculation are a major pathophysiological driver of HFpEF. We created a model of CKD stage 3 that subsequently developed a cardiac phenotype with numerous traits of HFpEF (CKD-HFpEF), including microvascular (MV) rarefaction and decreased availability of the pro-angiogenic growth factor vascular endothelial growth factor (VEGF) in the heart. We hypothesize that cardiac VEGF therapy will attenuate MV injury and improve cardiac function in CKD-HFpEF. Method CKD and normal pigs (n = 6 each, 3 males/3 females) were studied for 14 weeks. In addition, CKD-HFpEF pigs (n = 6, 3 males/3 females) were treated after 6 weeks of disease with a single intracoronary (IC) administration of VEGF attached to a drug-delivery vector (ELP-VEGF) that increases cardiac targeting, and effects quantified 8 weeks later. Renal (multi-detector CT) and cardiac (echocardiography, PV loops) morphology and function were quantified in vivo, microvascular (MV) density (3D micro-CT) ex vivo, and cardiac expression of VEGF was quantified by qPCR and western blot, as VEGF-related genes by bulk mRNA-sequencing (n = 3/group). Results A single IC administration of ELP-VEGF improved MV density and rescued cardiac function compared to placebo similarly in male and female pigs and independent of hypertension (Fig. 1A–C). These improvements were accompanied by improved mRNA and protein expression of VEGF and restored expression of VEGF-related pro- and anti-angiogenic genes (Fig. 1D and E). Conclusion Our study supports the prominent role of cardiac MV disease in the development of HFpEF in CKD, supports the critical need for healthy VEGF signaling to preserve the heart in CKD, and shows the feasibility of a potential new therapeutic strategy via a targeted mechanistic intervention.

Abstract Background and Aims Malignancy is commonly seen in patients with membranous Nephropathy (MN) with a prevalence up to 22%. M-type phospholipase A2 receptor (PLA2R) antigen and its associated antibody account for up to 80% of the cases but its association with malignancy is less clear. To date, no study has specifically evaluated cancer incidence and risk factors in patients with PLA2R associated MN as most studies were conducted in an era before many MN antigens were identified. Here, we report cancer incidence, types of cancer, and effect of immunosuppressive therapy and clinical parameters in a cohort of patients with PLA2R-associated MN. Method A single center retrospective cohort study in adults with diagnosis of PLA2R associated MN from 1/1/1996 to 12/31/2021. Follow-up was defined as the time from MN diagnosis to the last follow-up or if the patient initiated dialysis or underwent transplantation. The primary outcome in this study was the incidence of cancer events reported as cancer incidence/1000 patients/year. The cancer events were compared to the age-adjusted United States (U.S.) general population using Centers for Disease Control (C.D.C) data. The standardized incidence ratio (SIR) was calculated by dividing the cancer rates in our cohort to the cancer rates in general population. Time-to-event analysis was conducted using the Kaplan-Meier method. The log-rank test compared age, sex, smoking habits, hypertension, diabetes, body mass index (BMI), previous immunosuppression (IS), remission of the MN, PLA2R titers at the time of diagnosis. Cox proportional hazards regression was used to evaluate the associations between baseline characteristics and cancer incidence. For the multivariate model of cancer incidence, we evaluated variables clinically relevant for the outcome. Results We identified 239 patients with PLA2R-associated MN, with mean (±SD) age of 52 (±13) years, with 72.8% male (n = 174), median [IQR] BMI of 29.8 [26.3, 33.6] kg/m2, median eGFR of 68 [45, 94] ml/min, median proteinuria of 8.2 [5.1, 11.2] g/24h, and median PLA2R titers of 38 [9, 122] RU/ml. Common comorbidities included hypertension (60.2%), and diabetes (17.1%). Majority of patients drank alcohol (90.7%) and 32.6% were smokers (active or former). Of 239 patients, 15 had a history of cancer before the MN diagnosis. But in all these patients, cancer had been treated and was considered to be in full remission. A diagnosis of cancer was made in 37 patients (15.4%) during a median follow-up of 60 [27.5, 145.5] months. Incidence of cancer in our cohort was 22.6 [95% CI, 15.9 to 31.1] per 1000 persons/year. In comparison, age adjusted U.S. general population has a lower cancer incidence of 15.9 [95% CI, 15.9 to 16.1] cases per 1000 person/year. The resulting SIR of cancer in our cohort was 1.42. This SIR is lower than the one reported by Bjørneklett and al. (2007) in a Norwegian cohort that included all patients with MN and was not limited to PLA2R-positive MN. The cumulative incidence of cancer diagnosis is shown in Fig. 1. Mean age at cancer diagnosis was 66 (±10.2) years old. Prostate cancer was the most common (n = 11) type of cancer, followed by skin cancer (n = 9), followed by cancer of the urinary tract (n = 5). In univariate and multivariate analysis (Table 1), only older age (>65 years) and tobacco use were associated with statistically significant increased risk of cancer. Other clinical parameters such as sex, eGFR, baseline proteinuria, BMI, hypertension, diabetes, alcohol use, anti-PLA2R antibody titer, type of immunosuppression, remission status (partial, complete, no response) were not associated with a significant increased risk of cancer. Conclusion Patients with PLA2R associated MN are at increased risk of developing cancer following diagnosis compared to general population and routine age-appropriate cancer screening in this population is essential. The increased incidence of cancer is independent of IS therapy, response to therapy or other comorbidities. These data suggests that there are likely mechanisms beyond the traditional risk factors at play that may be unique to the presence of PLA2R antibodies.

Abstract Background and Aims Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are emerging as an essential part of the new standard of care for proteinuria, alongside renin-angiotensin system (RAS) inhibitors in patients with proteinuric chronic kidney disease (CKD). Subgroup analysis of EMPA-KIDNEY and DAPA-CKD trials done in patients with glomerular diseases [IgA Nephropathy (IgAN) and focal and segmental glomerulosclerosis (FSGS)] showed these agents are less effective in reducing proteinuria compared to other agents like Sparsentan, or Double RAS Blockade. Also, the antiproteinuric effects of SGLT2i in patients with glomerular diseases is not well understood. To date, no study has specifically evaluated the effects of body mass index (BMI) on the antiproteinuric efficacy of SGLT2. Here we report the impact of BMI on the antiproteinuric efficacy of SGLT2i in non-diabetic patients with glomerular diseases. Method Single-center retrospective cohort study. Inclusion criteria (1) adult patients with a biopsy-proven glomerular disease or genetic diagnosis [i.e., Collagen IV mutations] from January 1st, 2019, to December 31st, 2023, (2) no Diabetes Mellitus, (3) proteinuria more than 0.75 g/24 h at the time of initiation of treatment despite optimized blood pressure control with renin-angiotensin system (RAS) inhibition at maximum tolerated dose (5) no concomitant use of induction immunosuppression therapy—stable maintenance immunosuppression was allowed. Patients with active neoplasia, no follow-up available after initiation of therapy or kidney transplant were excluded. Baseline was defined as the time of the initiation of SGLT2i. Laboratory values, including proteinuria, serum creatinine, and estimated glomerular filtration rate (eGFR), were obtained at baseline and 6 months. Changes in laboratory values over time were analyzed using the paired t-test and the signed-rank test, depending on the distribution. Weight status was classified based on BMI in three categories: regular (BMI < 25 kg/m2), overweight (25–29.9 kg/m2), and obese (>30 kg/m2). Results We identified 115 non-diabetic patients with glomerular diseases. Median age [IQR] at the time of SGLT2i initiation was 49.1 [35.4, 61.5] years; 74 (64.3%) patients were male, and 96 (83.5%) patients were white, with the second most common ethnicity being Asian with 10 (8.7%) patients. Median BMI for the entire cohort was 28.2 [26.0, 33.1] Kg/m2. Fifty-three (46.1%) patients had IgAN, 22 (19.1%) had secondary FSGS (sFSGS), 3 (2.6%) primary FSGS (pFSGS), and 12 (10.4%) genetic FSGS (gFSGS), with collagen IV mutations as the most common cause of gFSGS. Kidney function and proteinuria over time are presented in Table 1. Significant declines in eGFR [−1.77 ml/min/1.73m2 95% CI: (−4.2, −1.19)] and proteinuria [−0.58 g/24h 95% CI (−0.91, −0.44)] were observed at 6 months in the entire cohort compared to baseline. However, in the subgroup analysis by BMI strata, i.e., <25, 25-29.9, ≥30, the reduction in proteinuria was statistically significant only in overweight and obese patients. The expected early drop in eGFR was not observed in patients with a normal BMI. However, the decline in eGFR progressively increased and was statistically significant in the obese group (Fig. 1). Conclusion The principal finding of the present study is the lack of significant proteinuria reduction in patients with BMI<25 kg/m², which contrasts with the significant reductions observed in overweight and obese patients. SGLT2i's main antiproteinuric mechanism of action involves reducing glomerular hyperfiltration, which is commonly seen in patients with diabetes and obesity. In non-diabetic patients with glomerulopathies, proteinuria may be sustained by mechanisms not dependent on glomerular hyperfiltration, especially in those patients with normal BMI. These findings are crucial to advocate a personalized approach to treatment, challenging the “one-size-fits-all” strategy.

Abstract Background and Aims PKD1 and PKD2 are the two major genes in autosomal dominant polycystic kidney disease (ADPKD). Up to 15% of patients with ADPKD-like phenotype are genetically unresolved (GUR) or carry variants in minor cystogenes including IFT140. Here, we describe features of an ADPKD-like phenotype linked to monoallelic predicted loss-of-function (pLoF) variants in a new candidate cystogene, IFT172. The IFT172 protein is part of the IFT-B subcomplex and plays a role in protein trafficking within primary cilia. Biallelic variants in IFT172 cause a severe ciliopathy. Method A total of ∼3200 unrelated individuals with cystic kidney disease (CyKD) underwent genetic testing employing whole-exome sequencing (WES) or massive-parallel-sequencing (MPS) gene panels in Brest, Lyon and in Rochester, MN. In addition, 185 individuals ICD coded as CyKD from Mayo Clinic Biobank (MCBB) underwent WES. Clinical and genetic data of individuals with predicted loss-of-function variants of IFT172 were collected and analyzed. Also, the Genomics England 100kG Project cohort was screened for pLoF variants in IFT172. Results In the CyKD population, 18 patients with a monoallelic pLoF variant in IFT172 were identified. In the MCBB CyKD cohort, 3 individuals had IFT172 pLoF variants. We describe the clinical presentation of these 21 affected individuals (15 males). Median age at CyKD diagnosis was 67 (range 34–88) years. Family history for CyKD was positive in 10 (48%), negative in 9 (42%) and not known in 2 (10%) individuals. Arterial hypertension was present in 9 (45%) patients, in three of them diagnosed before age of 50 years and in 6 at a later age. Hypertension status was not known in 10 of them. A majority of the patients presented with multiple bilateral cortical kidney cysts with moderate kidney enlargement or normal-sized kidneys with large, exophytic kidney cysts and were classified as Mayo Imaging Class 2A. In one patient, unilateral CyKD was present with >10 cysts. Liver cysts were present in 4 (19%) and gout in three (15%) patients. None of the three patients who underwent screening were found to have intracranial aneurysm. Median eGFR at diagnosis (N = 19) was 53 (range 29–119) ml/min/1.73 m2. Of 15 patients older than 60 y, one had CKD stage G1, 5 stage G2, 3 stage G3a, 5 stage G3b and one G4. Only one patient of African descent (APOL1 G1/G0) reached kidney failure at age of 43 y, likely due to additional contribution of uncontrolled hypertension and poorly controlled diabetes. In addition, in two patients, the IFT172 pLoF variant was identified alongside a pathogenic variant in PKD1 (p.Gln2519*) or PKD2 (c.844-1G>T). Both progressed to kidney failure at an earlier age than typically observed with PKD1 or PKD2 alone, at 29 and 52 years, respectively. Familial segregation is ongoing. Of the total of 94,799 patients recruited in “rare disease program” within 100kG Project, 51 carried monoallelic pLoF variants in IFT172 (genetic prevalence: 5.38 [0.95 CI 3.9–6.86] per 10,000). Four of them (7.8%) had CyKD. Conclusion Carriers of monoallelic pLoF variants in IFT172 are likely to develop cystic kidney disease (CyKD) that is atypical of classical ADPKD, generally associated with a favorable kidney prognosis. Nonetheless, individuals over the age of 60 may have an increased risk of progressing to CKD stage G3 or worse. Disease penetrance in IFT172 pLoF variant carriers appears to be incomplete, similar to what is observed in IFT140.