Pathogenic Bordetella bacteria use protein adhesins to infect the ciliated respiratory epithelia of vertebrate hosts. In this work, we show that the filamentous hemagglutinin FhaB adhesin of Bordetella carries a C-terminal microtubule-binding domain (FhaB-CT), which is translocated into host cells to promote colonization. FhaB-CT delivery is required to occupy a niche at the base of cilia in airway epithelia, and mutant bacteria lacking this domain are defective for nasal colonization. These observations suggest that FhaB-CT is transferred into motile respiratory cilia to interact with core axonemal microtubules. We propose that Bordetella adheres initially to the tips of cilia and then deploys multiple FhaB adhesins to migrate to the base of the cilia forest, where the bacteria resist removal by the mucociliary "escalator" that normally clears the respiratory tract of microbes.

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic form of chronic kidney disease characterized by highly variable rates of progression. This variability suggests that nutritional, lifestyle, and environmental factors may significantly influence disease course. Despite its prevalence, pharmacological treatment options for ADPKD remain very limited, underscoring the urgent need for safe and effective therapeutic strategies. Recent research has identified ADPKD as a metabolic disorder at the cellular level, marked by impaired mitochondrial function and a pathological reliance on glucose metabolism in affected cells. Ketogenic metabolic therapy (KMT) targets this metabolic vulnerability and has shown promising outcomes in both preclinical models and early clinical studies. KMT encompasses a range of interventions including ketogenic diets, intermittent fasting, time-restricted feeding, and supplementation with the ketone body β-hydroxybutyrate (BHB). Accumulating evidence suggests that BHB is the principal renoprotective mediator underlying the therapeutic benefits of KMT. Beyond serving as an alternative energy substrate, BHB exerts pleiotropic signaling effects that may synergistically contribute to reduced cyst proliferation, inflammation, oxidative stress, and fibrosis, while enhancing mitochondrial function. These attributes position BHB as a renoprotective signaling hormone. Importantly, chronic suppression of endogenous ketogenesis is common in modern societies because of dietary and lifestyle patterns and may deprive tissues of BHB’s pleiotropic signaling functions. In this narrative review, we summarize the current understanding of KMT and BHB in the context of ADPKD and discuss their potential as safe, noninvasive, and disease-modifying interventions.

Background:Autosomal-dominant polycystic kidney disease (ADPKD) is a common hereditary form of chronic kidney disease with limited pharmacological treatment options. Emerging evidence suggests that metabolic interventions, including ketogenic dietary strategies and reducing lithogenic risk, may positively influence disease progression. Objectives:This study evaluated real-world outcomes from the Ren-Nu™ program, a remotely administered educational program for individuals with ADPKD that combines the use of a medical food with nutrition and lifestyle changes, including a very-low-carbohydrate ketogenic diet and reduction of renal lithogenic stressors. Ren-Nu™ was launched in 2021 as a collaboration between scientists and nutrition experts from the University of California Santa Barbara and Santa Barbara Nutrients, Inc, and dietitians from Kidney Nutrition Institute. Methods:Data from 103 ADPKD participants who completed the Ren-Nu™ program between 2021 and 2023 were analyzed in this longitudinal, baseline- controlled evaluation. The 3-month intervention included structured dietary education, regular dietitian and nutritionist support, and supplementation with KetoCitra®, a medical food providing beta-hydroxybutyrate (BHB), citrate, minerals, and alkali base. Primary outcomes included estimated glomerular filtration rate (eGFR), body mass index (BMI), anti-hypertensive medication usage, and self-reported symptom burden. Safety was assessed through routine metabolic biomarkers. Results:Participants demonstrated high adherence to nutritional ketosis, leading to a significant improvement in BMI. Renal function significantly improved, showing an eGFR increase of 6.3% (from 58.4 to 61.6 ml/min/1.73 m2; P < 0.001). There was a notable decrease in anti-hypertensive medication use and significant reductions in self-reported kidney pain and headaches. Safety markers, including lipid profiles, electrolytes, and acid-base balance, remained stable throughout the intervention. Conclusion:Use of KetoCitra® supported by nutrition and lifestyle changes in the Ren-Nu™ program demonstrates feasibility, safety, and clinically meaningful improvements in metabolic health, renal function,  and quality.

BACKGROUND:Lifestyle interventions targeting metabolic health may influence chronic kidney disease (CKD) risk, particularly among adults with type 2 diabetes and obesity. We evaluated real-world associations between a telehealth-delivered, individualized nutrition therapy program (VINT) and CKD incidence and progression compared with usual care. METHODS:We conducted a retrospective, propensity score-matched cohort study using the Komodo Healthcare Map, a longitudinal U.S. administrative claims database. Adults enrolled in a telehealth-delivered nutrition therapy emphasising carbohydrate reduction, VINT (n = 11 077) were matched 1:1 to usual-care controls on demographic, clinical, and medication covariates, over 5 years of follow-up. Primary outcomes were new-onset CKD, CKD stage ≥ 3, and CKD stage ≥ 4. Secondary outcomes included renal safety events. Cox proportional hazards and Poisson regression models were used to estimate hazard ratios (HRs) and incidence rate ratios (IRRs). RESULTS:VINT participation was associated with a lower incidence of new-onset CKD (10.1 vs. 15.6 per 1000 person-years; HR 0.64, 95% CI 0.53-0.77; p < 0.001), CKD stage ≥ 3 (HR 0.57, 95% CI 0.45-0.73; p < 0.001), and CKD stage ≥ 4 (HR 0.38, 95% CI 0.18-0.79; p = 0.009). No increased risk of kidney stones, metabolic acidosis, diabetic ketoacidosis, or gout was observed in VINT compared with the UC group. CONCLUSIONS:In this large, real-world matched cohort, participation in a telehealth-delivered nutrition therapy emphasising carbohydrate reduction was associated with lower CKD incidence and progression without increased renal adverse events. These findings suggest that individualized nutrition therapy may be a safe and scalable approach to CKD prevention and management in adults with metabolic disease, warranting further prospective investigation.

ADPKD is a progressive cystic disorder characterized by increasing total kidney volume (TKV), declining kidney function, and limited disease-modifying options. Emerging preclinical and clinical evidence suggests metabolic interventions may influence cyst growth, but longitudinal imaging data in humans remain limited. We conducted a retrospective case series of four self-referred individuals (ages 33–71) with genetically confirmed truncating PKD1 variants who independently implemented metabolic interventions of varying duration and intensity, including carbohydrate restriction, intermittent fasting, and supplementation with a ketone- and citrate-based medical food (KetoCitra®). Intervention periods ranged from 6 months to approximately 4 years and followed prior phases of documented kidney volume enlargement. Serial abdominal imaging obtained during routine clinical care was re-analyzed using standardized volumetric software to assess TKV, liver volume, and Mayo imaging classification trajectories. Across all four cases, stabilization or reduction in TKV relative to prior growth trends was observed during intervention periods, accompanied by preserved kidney function. One participant transitioned from Mayo Class 1C to 1B, while the remaining three demonstrated downward shifts in Mayo imaging trajectory within their existing classifications. Reductions or attenuated increases in liver volume were also observed in cases with polycystic liver disease. Interventions were reported to be feasible and well tolerated, with no serious adverse events. These observations align with emerging preclinical and clinical evidence suggesting metabolic interventions may attenuate TKV progression in ADPKD. While limited by sample size and intervention heterogeneity, this case series provides hypothesis-generating data to inform prospective controlled trials.

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. 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. 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. 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.

Pathogenic Bordetella bacteria infect the ciliated respiratory epithelia of mammalian and avian hosts. Several bacterial proteins mediate host cell adhesion, but filamentous hemagglutinin (FhaB) is a principal adhesin because mutants lacking this protein exhibit profound colonization defects. Here, we show that FhaB carries a C-terminal microtubule-binding domain (FhaB-CT), which is translocated into the host-cell cytoplasm to promote bacterial colonization. Cryogenic electron microscopy of microtubule-bound FhaB-CT shows that the domain binds primarily to α-tubulin through a network of polar interactions. Live-cell microscopy of infected tracheal explants reveals that FhaB-CT delivery is required for Bordetella to occupy a niche at the base of cilia on airway epithelia. Finally, we demonstrate that the microtubule-binding domain is required for long-term colonization of the mouse nasal cavity by B. pertussis . These observations suggest that the FhaB-CT domain is delivered into motile cilia, where it interacts with axonemal microtubules. We propose that Bordetella initially adhere to the tips of cilia, then deploy multiple FhaB adhesin molecules to migrate to the base of the cilial forest. This mechanism enables Bordetella to resist removal by the mucociliary 'escalator' that clears the respiratory tract of microbes and debris.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that is caused by mutations in PKD genes. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a class of medications that mimic the actions of the hormone GLP-1, conferring beneficial effects on weight management and other metabolic conditions. However, whether GLP-1RA plays a kidney-protective action in ADPKD remains unknown. In this study, we define the role and mechanisms of one of the most popular GLP-1RA agonists, Semaglutide, in ADPKD. We show that the expression of GLP-1R is decreased in Pkd1 mutant renal epithelial cells and kidneys. Treatment with Semaglutide delays cyst growth in aggressive and long-lasting Pkd1 mutant mouse models. Treatment with Semaglutide (1) decreases glucose uptake, ATP generation, and glycolysis, (2) deactivates PKD-associated signaling pathways, including Rb, S6, and Stat3, resulting in a decrease in cell proliferation, (3) deactivates NF-kB signaling pathways, resulting in a decrease in the expression of cytokines and the recruitment of macrophages, (4) normalizes mitochondrial morphology and function, (5) induces Pkd1 mutant renal epithelial cell death, (6) induces ketosis characterized by an increase in serum level of beta-hydroxybutyrate (BHB) and the activation of AMPK, and (7) alleviates renal fibrosis through deactivation of TGF-b signaling in Pkd1 mutant mouse kidneys. This study highlights the potential of GLP-1R agonists as a novel therapeutic strategy for ADPKD treatment.

Introduction:Diabetic nephropathy (DN), a common complication of type 2 diabetes (T2D), is characterized by declining kidney function and an increased risk of end-stage kidney disease (ESKD). Slowing the decline in estimated glomerular filtration rate (eGFR) significantly reduces ESKD risk. While pharmacological treatments, such as SGLT2i, have demonstrated renoprotective effects, emerging evidence suggests that low-grade ketosis may mediate these benefits, and therefore be accessible through lifestyle modification. Methods:This post-hoc analysis evaluates the impact of a very low-carbohydrate intervention including nutritional ketosis, delivered through a continuous care intervention (CCI), on eGFR slope and inflammation over two years. The analysis included 262 T2D participants in the CCI group and 87 in the usual care (UC) group. The primary aim was to assess the relationship between blood β-hydroxybutyrate (BHB) and eGFR slope. A secondary aim explored changes in inflammatory markers including high sensitivity C-reactive protein (hs-CRP) and neutrophil-lymphocyte ratio (NLR). Latent class trajectory modeling was used to categorize ketosis adherence classes in the CCI group based on longitudinal BHB levels. Results:CCI participants experienced a significant eGFR slope increase of 0.91 mL/min/1.73m2/year, compared to a decline in UC (-0.68 mL/min/1.73m2/year). Greater mean BHB at 365 days (β = 0.1, p = 0.002) was independently associated with greater eGFR improvement that persisted after adjusting for demographics, weight change and baseline medication use. A dose-response relationship emerged between ketosis classes and eGFR improvement, particularly among participants with baseline eGFR <90 mL/min/1.73m2. Higher ketosis adherence also correlated with significant reductions in inflammatory markers, such as NLR and hsCRP, suggesting anti-inflammatory benefits. Conclusion:This analysis highlights nutritional ketosis as a potential non-pharmacological approach to improve or stabilize eGFR and reduce inflammation in T2D. Randomized controlled trials are needed to validate these findings and assess the synergistic effects of ketogenic diets combined with pharmacotherapies to optimize kidney outcomes in chronic kidney disease.

Polycystic kidney disease (PKD) is characterized by the development of fluid-filled kidney cysts and relentless progression to renal failure. Current treatments have adverse effects and limited efficacy, enhancing the need for improved therapeutics. Here, we provide a proof of concept for the use of dimeric immunoglobulin A (IgA) (dIgA) monoclonal antibodies (mAbs) to target epithelial-enclosed cysts, by exploiting their ability to transcytose via the polymeric immunoglobulin receptor highly expressed on renal cyst-lining cells. We engineered an antagonistic dIgA mAb against the cell mesenchymal-epithelial transition (cMET) receptor, a driver of cyst progression, and demonstrated its specific binding and inhibition of cMET in vitro. In vivo studies in PKD rodent models showed efficient targeting of the mAb to renal cyst lumens and its ability to slow disease progression without apparent adverse effects. This study presents an intriguing avenue for developing antibody-based therapies for PKD and similar diseases by repurposing existing immunoglobulin G (IgG) mAbs into dIgA mAbs for superior targeting to epithelial-enclosed compartments.

Objective To evaluate the real-world effectiveness and safety of a telehealth-delivered, individualized nutrition therapy (VINT) for the prevention and progression of chronic kidney disease (CKD) among adults with type 2 diabetes and obesity. Design Retrospective, propensity score-matched cohort study using administrative claims data. Setting Komodo Healthcare Map, a longitudinal U.S. claims database containing medical and pharmacy data. Participants 8,391 adults enrolled in the VINT program were matched 1:1 with 8,391 usual-care controls on demographic, clinical, and medication covariates, with up to five years of follow-up. Main outcome measures Primary outcomes were new-onset CKD, CKD stage ≥ 3, and CKD stage ≥ 4. Secondary outcomes included regression or stability among those with baseline CKD and safety outcomes (kidney stones, gout, and acidosis). Cox proportional hazards and Poisson regression models were used to estimate hazard ratios (HRs) and incidence rate ratios (IRRs). Results VINT participation was associated with lower incidence of new-onset CKD (10.8 vs 15.7 per 1,000 person-years; HR 0.67, 95% CI 0.54-0.83; p<0.001), CKD stage ≥ 3 (HR 0.55, 95% CI 0.42-0.72; p<0.001), and CKD stage ≥ 4 (HR 0.34, 95% CI 0.16-0.71; p=0.004). Among participants with baseline CKD, regression or stability occurred in 96.8% of VINT vs 87.6% of controls (p=0.005). There was no increased risk of kidney stones, acidosis, or gout. Conclusions In this large, real-world matched cohort, participation in a telehealth-delivered individualized lifestyle intervention emphasizing carbohydrate restriction was associated with significantly lower CKD incidence and progression, without increased adverse renal outcomes. ### Competing Interest Statement Three authors (SJA, PVS, AW) are employees of Virta Health and offered stock options. One author (JSV) is a co-founder and shareholder of the company. Virta Health provides a remote care intervention including individualized nutrition therapy for people with type 2 diabetes and related metabolic conditions. These authors and other coauthors contributed to the study design, data analysis, interpretation, and manuscript preparation. All other authors declare no competing interests related to the data source, data analysis, interpretation, or reporting of this study. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets analyzed in this study are not publicly available because they were obtained through a commercial license from the data vendor. Access to these data is restricted, and they were used solely under the terms of the license granted for this study.