Progression Of Polycystic Kidney Disease Research Articles

Multi-omics profiling of mouse polycystic kidney disease progression at a single cell resolution.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and causes significant morbidity, ultimately leading to end-stage kidney disease. PKD pathogenesis is characterized by complex and dynamic alterations in multiple cell types during disease progression, hampering a deeper understanding of disease mechanism and the development of therapeutic approaches. Here, we generate a single nucleus multimodal atlas of an orthologous mouse PKD model at early, mid and late timepoints, consisting of 125,434 single-nucleus transcriptomic and epigenetic multiomes. We catalogue differentially expressed genes and activated epigenetic regions in each cell type during PKD progression, characterizing cell-type-specific responses to Pkd1 deletion. We describe heterogeneous, atypical collecting duct cells as well as proximal tubular cells that constitute cyst epithelia in PKD. The transcriptional regulation of the cyst lining cell marker GPRC5A is conserved between mouse and human PKD cystic epithelia, suggesting shared gene regulatory pathways. Our single nucleus multiomic analysis of mouse PKD provides a foundation to understand the earliest changes molecular deregulation in a mouse model of PKD at a single-cell resolution.

#1460 Targeting cyst progression: evaluation of anthelmintic and proton pump inhibitor in a rodent PKD model

Abstract Background and Aims In polycystic kidney disease (PKD) cyst formation and growth leads to progressive kidney damage. Recognizing the need for effective cyst-inhibitory drugs, we previously performed high-content screening of approved, repurposable drugs in a zebrafish model and identified several compounds with cyst-inhibitory activity and low toxicity. Here, we further tested two of the identified compounds, an anthelmintic agent and proton pump inhibitor, in a rodent model of PKD (PCK rat) for their cyst inhibitory and GFR-preserving capacity in mammals. Method The identified compounds were administered to 3-week-old male and female PCK rats for a total of 10 weeks to evaluate early drug effects on kidney function. Untreated PCK rats fed a normal ROD16 diet served as controls. After 5 weeks of treatment, total kidney and cystic volume and number of cysts were assessed in vivo by ultrasound. Following 10 weeks of treatment, kidney function was assessed by transcutaneous measurement of FITC-Sinistrin. After perfusion fixation in the same week, the kidneys, liver, heart, and pancreas were harvested for subsequent histological and molecular biological analyses. Results In male rats, 5-week proton pump inhibitor treatment was associated with a 50% reduction in the number of cysts (p < 0.05) and a nominal 22% reduction of fractional cystic kidney volume (CKV). Females showed a 16% reduction in cyst count and a modest reduction in fractional CKV. Treatment with the anthelmintic tended to reduce fractional CKV and cyst count in female animals whereas fractional cyst volume in males increased. After 10 weeks of treatment, a trend towards better preservation of GFR was observed for both therapies. Conclusion In conclusion, our study demonstrates a potential therapeutic benefit of a proton pump inhibitor and an anthelmintic agent in attenuating the progression of polycystic kidney disease (PKD) in a PCK rat model. The observed reductions in fractional cystic kidney volume and cyst count, coupled with marginal improvements in renal function, document a potential therapeutic effect of these compounds. Our preliminary findings justify further exploration of novel treatment modalities targeting cyst progression and renal dysfunction in this challenging clinical condition.

#1790 Metformin versus standard of care in slowing progression of autosomal dominant polycystic kidney disease and correlation with total kidney volume

Abstract Background and Aims Autosomal dominant kidney disease (ADPKD) is the most common monogenic disorder leading to renal failure with very limited therapeutic options. Apart from lifestyle modifications and control of hypertension, tolvaptan is the only Food and Drug Administration (FDA) approved disease modifying drug. Although, it has proven therapeutic benefit in slowing disease progression in high risk Mayo Class (Mayo Class 1C-E), the aquaretic potential, potential hepatotoxicity and the cost limits its widespread use especially in resource constrained country. Metformin has been shown to be effective in ADPKD in preclinical studies and is also well tolerated by the general population. We planned this study to assess the efficacy and safety of metformin in non diabetic ADPKD patients. Method Our study is a prospective, randomized controlled, open labelled clinical trial of 52 non diabetic adults 18 to 60 years of age with typical ADPKD, estimated glomerular filtration rate (eGFR) > 45 ml/min/m2 and no risk factors of rapid progression. Participants were randomized in a 1:1 ratio by a computer-generated random number table into Metformin + standard of care group (Metformin arm) and standard of care group (Placebo arm). Primary outcome of the study was to evaluate the effects of metformin versus placebo arm on the percentage and absolute change in eGFR over 6-month period. Secondary outcomes were to study the effect of metformin versus placebo arm on the percentage and absolute change in height adjusted total kidney volume (htTKV ml/m) at 6 months, to evaluate the effect of baseline plasma copeptin levels with percentage change in htTKV and eGFR over 6 months, to evaluate metformin tolerability, to evaluate the effects of metformin versus placebo on the changes in body weight, BMI, blood pressure and urine protein excretion at 6 months period. Results Mean (SD) age of the cohort was 37.15 (10.16) years with half of them being females. The mean (SD) baseline htTKV and eGFR was 335.67 (153.3) ml/m and 100.23 (25.95) ml/min/m2. Clinical exome sequencing was available in 9 (17.3%) patients of which two third had PKD1 mutation. Baseline characteristics were distributed equally across randomized groups. Baseline proteinuria was significantly higher in the Metformin arm (p = 0.014). The eGFR difference and percentage change in eGFR was not different between the groups at 6 months (p = 0.535, 0.483). There was no statistically significant difference in htTKV difference and percentage change in htTKV at 6 months between the groups although increase in htTKV was numerically smaller in the metformin group (p = 0.769, 0.805). Blood pressure, weight, body mass index (BMI) and proteinuria also did not differ between two groups. Half of the cohort tolerated the maximum dose of metformin. Around 2/3rd patients reported adverse effects most commonly asthenia. There was no lactic acidosis or significant gastrointestinal side effects as assessed by gastrointestinal rating scale (GSRS) scale. Baseline copeptin levels did not correlate with eGFR or htTKV difference at 6 months. Conclusion Metformin appears to be safe and tolerable in non diabetic ADPKD patients over 6 months. However larger clinical trials are needed to conclude regarding the efficacy in terms of eGFR decline or htTKV progression.

#2810 Exploring non-renal vasculature: therapeutic implications of proton pump inhibitor and anthelmintic treatment in PCK rat model

Abstract Background and Aims Cystic kidney diseases represent ciliopathies that can cause vascular damage through renal hypertension. Additionally, there is growing experimental evidence of endothelial cell abnormalities associated with ciliary protein deficiencies. PCK rats, a strain derived from Sprague-Dawley (SD) rats that develops both polycystic kidney disease (PKD) and liver disease, serve as a model for recessive PKD. The PCK rat model also presents abnormalities in non-renal vascular function. Another study from our group suggests a potential therapeutic benefit of repurposed therapy with a proton pump inhibitor (PPi) and an anthelmintic agent in attenuating the progression of PKD in a PCK rat model. Here, we investigated whether these drugs can also improve endothelial function. Method The compounds were administered to 3-week-old male and female PCK rats (n = 5-6) for a total of 10 weeks. Untreated PCK rats and age-matched SD rats (n = 5-6) served as controls. After perfusion fixation, the aorta was harvested and its thoracic rings were used to evaluate the contraction/relaxation responses ex vivo by organ bath experiments. Additional rings were preserved for histological and molecular biological analyses. Results Male PCK rats exhibited impaired endothelial function compared to healthy controls. Endothelium-dependent relaxation to acetylcholine was improved by 10% after treatment with PPi, while the anthelmintic administration had no protective effect. PKD also impaired endothelial function in female PCK rats compared to healthy SD controls. There was an improvement in endothelium-dependent relaxation to acetylcholine after treatment with PPi by 5.5%, while administration of the anthelmintic agent further impaired endothelial function. Conclusion 13-week-old PCK rats show endothelial dysfunction in non-renal vasculature. Treatment with a proton pump inhibitor improved endothelial function in male PCK rats to the level of healthy SD controls. By contrast, in a parallel study, the anthelmintic had a positive effect on renal function but a detrimental impact on endothelial function. These intricate relationships underscore the need for further exploration to understand the underlying mechanisms and broader implications of our findings, illustrating the challenges and potential avenues for the development of effective treatments for PKD.

The utility of serum neutrophil gelatinase-associated lipocalin level on predicting autosomal dominant polycystic kidney disease progression.

We focused on neutrophil gelatinase-associated lipocalin (NGAL) and autosomal dominant polycystic kidney disease (ADPKD) progression. ADPKD patients with an estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 were included. Serum NGAL level and NGAL to eGFR ratio (NGR), height-adjusted total kidney volume (hTKV) were assessed initially. Patients were followed-up for 5 years. Sixty one patients were enrolled and initial eGFR was 73.6 (48.9-101.5) ml/min/1.73m2. EGFR declined by 3.7 mL/min/1.73m2 per year. Thirty four patients (55.7%) exhibited rapid progression. Rapid progression group had lower serum NGAL levels (p < 0.001) and higher hTKV (p < 0.001). Lower serum NGAL level was a risk factor for rapid progression (p < 0.001). NGR was not associated with rapid progression. Serum NGAL level was predictive in for rapid progression ROC analysis (cut-off <10.62 ng/mL). Relatively lower serum NGAL levels can predict worse outcomes in ADPKD and can provide risk stratification in patients with ADPKD.

An Electronic Health Record-Integrated Application for Standardizing Care and Monitoring Patients With Autosomal Dominant Polycystic Kidney Disease Enrolled in a Tolvaptan Clinic: Design and Implementation Study.

Tolvaptan is the only US Food and Drug Administration-approved drug to slow the progression of autosomal dominant polycystic kidney disease (ADPKD), but it requires strict clinical monitoring due to potential serious adverse events. We aimed to share our experience in developing and implementing an electronic health record (EHR)-based application to monitor patients with ADPKD who were initiated on tolvaptan. The application was developed in collaboration with clinical informatics professionals based on our clinical protocol with frequent laboratory test monitoring to detect early drug-related toxicity. The application streamlined the clinical workflow and enabled our nursing team to take appropriate actions in real time to prevent drug-related serious adverse events. We retrospectively analyzed the characteristics of the enrolled patients. As of September 2022, a total of 214 patients were enrolled in the tolvaptan program across all Mayo Clinic sites. Of these, 126 were enrolled in the Tolvaptan Monitoring Registry application and 88 in the Past Tolvaptan Patients application. The mean age at enrollment was 43.1 (SD 9.9) years. A total of 20 (9.3%) patients developed liver toxicity, but only 5 (2.3%) had to discontinue the drug. The 2 EHR-based applications allowed consolidation of all necessary patient information and real-time data management at the individual or population level. This approach facilitated efficient staff workflow, monitoring of drug-related adverse events, and timely prescription renewal. Our study highlights the feasibility of integrating digital applications into the EHR workflow to facilitate efficient and safe care delivery for patients enrolled in a tolvaptan program. This workflow needs further validation but could be extended to other health care systems managing chronic diseases requiring drug monitoring.

β-Hydroxybutyrate Recapitulates the Beneficial Effects of Time-Restricted Feeding and Periodic Fasting in Multiple Rodent Models of Polycystic Kidney Disease

Polycystic kidney disease is a monogenic disease caused predominantly by mutations in the PKD1 or PKD2 genes. These mutations result in the formation of large fluid-filled cysts derived from kidney epithelial cells that slowly replace functional healthy tissue. Affected kidneys rely heavily on glycolysis to meet energy demands, and is accompanied by a reduction in fatty acid oxidation and mitochondrial function. We previously reported that interventions inducing a state of ketosis, including caloric restriction, time-restricted feeding (TRF), ketogenic diet, extended fasting, and ketone supplementation, ameliorate or reverse polycystic kidney disease progression in multiple animal models. To elaborate on the capability of ketosis to alter disease progression, we compared, head-to-head, the effects of a daily 16:8 TRF regimen to periodic 48-hour fasting (PF) in both juvenile and adult Cy/+ rats. We found that alternative fasting interventions prevent juvenile disease progression and partially reverse established kidney disease in adults. Further, to test our hypothesis that an increase in β-hydroxybutyrate (BHB) may mediate these beneficial effects, we administered BHB to adult Cy/+ rats and stereospecific isomers to two orthologous mouse models of PKD ( P kd1RC/RC, Pkd1-Ksp:Cre). BHB recapitulates the effects of fasting in these models independent of stereoisomer, reducing mTORC1 signaling, increasing GSK-3β phosphorylation, expression and translocation of Nuclear factor erythroid 2-related factor 2 (Nrf2) in cystic epithelia, and subsequent downstream targets of Nrf2. These findings extend and expand our previous report on the beneficial effects of ketosis on cystic disease progression and suggest that ketogenic metabolic interventions and BHB supplementation are capable of metabolic reprogramming in polycystic kidney disease. This work was supported by grants from the NIH (Grants R01DK109563, R01DK124895) and the US Department of Defense (Grant W81XWH2010827) to T.W., and gifts from the Amy P. Goldman Foundation and the Jarrett Family Fund to University of California, Santa Barbara, to support the work of T.W. The MRL Shared Experimental Facilities are supported by the MRSEC Program of the NSF under Award No. DMR 1720256; a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression

Polycystic kidney disease (PKD) is a genetic disorder characterized by bilateral cyst formation. We showed that PKD cells and kidneys display metabolic alterations, including the Warburg effect and glutaminolysis, sustained in vitro by the enzyme asparagine synthetase (ASNS). Here, we used antisense oligonucleotides (ASO) against Asns in orthologous and slowly progressive PKD murine models and show that treatment leads to a drastic reduction of total kidney volume (measured by MRI) and a prominent rescue of renal function in the mouse. Mechanistically, the upregulation of an ATF4–ASNS axis in PKD is driven by the amino acid response (AAR) branch of the integrated stress response (ISR). Metabolic profiling of PKD or control kidneys treated with Asns-ASO or Scr-ASO revealed major changes in the mutants, several of which are rescued by Asns silencing in vivo. Indeed, ASNS drives glutamine-dependent de novo pyrimidine synthesis and proliferation in cystic epithelia. Notably, while several metabolic pathways were completely corrected by Asns-ASO, glycolysis was only partially restored. Accordingly, combining the glycolytic inhibitor 2DG with Asns-ASO further improved efficacy. Our studies identify a new therapeutic target and novel metabolic vulnerabilities in PKD.

Long-Residence Time Peptide Antagonist for the Vasopressin V2 Receptor to Treat Autosomal Dominant Polycystic Kidney Disease.

The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence supports that vasopressin V2 receptor (V2R) antagonism effectively reduces cAMP levels, validating this receptor as a therapeutic target. Tolvaptan, an FDA-approved V2R antagonist, shows limitations in its clinical efficacy for ADPKD treatment. Therefore, the pursuit of better-in-class V2R antagonists with an improved efficacy remains pressing. Herein, we synthesized a set of peptide V2R antagonists. Peptide 33 exhibited a high binding affinity for the V2R (Ki = 6.1 ± 1.5 nM) and an extended residence time of 20 ± 1 min, 2-fold that of tolvaptan. This prolonged interaction translated into sustained suppression of cAMP production in washout experiments. Furthermore, peptide 33 exhibited improved efficacies over tolvaptan in both ex vivo and in vivo models of ADPKD, underscoring its potential as a promising lead compound for the treatment of ADPKD.

CD74 Promotes Cyst Growth and Renal Fibrosis in Autosomal Dominant Polycystic Kidney Disease.

The progression of autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease, is associated with renal interstitial inflammation and fibrosis. CD74 has been known not only as a receptor of macrophage migration inhibitory factor (MIF) it can also have MIF independent functions. In this study, we report unknown roles and function of CD74 in ADPKD. We show that knockout of CD74 delays cyst growth in Pkd1 mutant kidneys. Knockout and knockdown of CD74 (1) normalize PKD associated signaling pathways, including ERK, mTOR and Rb to decrease Pkd1 mutant renal epithelial cell proliferation, (2) decrease the activation of NF-κB and the expression of MCP-1 and TNF-alpha (TNF-α) which decreases the recruitment of macrophages in Pkd1 mutant kidneys, and (3) decrease renal fibrosis in Pkd1 mutant kidneys. We show for the first time that CD74 functions as a transcriptional factor to regulate the expression of fibrotic markers, including collagen I (Col I), fibronectin, and α-smooth muscle actin (α-SMA), through binding on their promoters. Interestingly, CD74 also regulates the transcription of MIF to form a positive feedback loop in that MIF binds with its receptor CD74 to regulate the activity of intracellular signaling pathways and CD74 increases the expression of MIF in ADPKD kidneys during cyst progression. We further show that knockout of MIF and targeting MIF with its inhibitor ISO-1 not only delay cyst growth but also ameliorate renal fibrosis through blocking the activation of renal fibroblasts and CD74 mediated the activation of TGF-β-Smad3 signaling, supporting the idea that CD74 is a key and novel upstream regulator of cyst growth and interstitial fibrosis. Thus, targeting MIF-CD74 axis is a novel therapeutic strategy for ADPKD treatment.

NRF2 in kidney physiology and disease.

The role of NRF2 in kidney biology has received considerable interest over the past decade. NRF2 transcriptionally controls genes responsible for cellular protection against oxidative and electrophilic stress and has anti-inflammatory functions. NRF2 is expressed throughout the kidney and plays a role in salt and water handling. In disease, animal studies show that NRF2 protects against tubulointerstitial damage and reduces interstitial fibrosis and tubular atrophy, and may slow progression of polycystic kidney disease. However, the role of NRF2 in proteinuric glomerular diseases is controversial. Although the NRF2 inducer, bardoxolone methyl (CDDO-Me), increases glomerular filtration rate in humans, it has not been shown to slow disease progression in diabetic kidney disease and Alport syndrome. Furthermore, bardoxolone methyl was associated with negative effects on fluid retention, proteinuria, and blood pressure. Several animal studies replicate findings of worsened proteinuria and a more rapid progression of kidney disease, although considerable controversy exists. It is clear that further study is needed to better understand the effects of NRF2 in the kidney. This review summarizes the available data to clarify the promise and risks associated with targeting NRF2 activity in the kidney.

Role of Female Sex Hormones in ADPKD Progression and a Personalized Approach to Contraception and Hormonal Therapy.

This review navigates the intricate relationship between gender, hormonal influences, and the progression of autosomal dominant polycystic kidney disease (ADPKD), highlighting the limited literature on this crucial topic. The study explores the impact of female sex hormones on liver and renal manifestations, uncovering gender-specific differences in disease progression. Actually, hormonal therapy in women with ADPKD remains a challenging issue and is a source of concern regarding its potential impact on disease outcomes, particularly at the hepatic level. Notably, women with ADPKD exhibit a slower renal disease progression compared to men, attributed to hormonal dynamics. This review sheds light on the role of estrogen in regulating pathways of the renin-angiotensin-aldosterone system, revealing its complex interplay and implications for cardiovascular and renal health. Therapeutic considerations for fertile women with ADPKD, including contraception options, are discussed, emphasizing the necessity for personalized approaches. In the postmenopausal phase, the review evaluates the role of hormonal replacement therapy, considering its potential benefits and risks in the context of ADPKD. The review concludes by underscoring the imperative need for tailored treatment approaches for ADPKD patients, considering individual risks and benefits. The scarcity of literature underlines the call for further research to enhance our understanding of optimal hormonal therapies in the context of ADPKD, ultimately paving the way for innovative and personalized therapeutic interventions.

CGAS Activation Accelerates the Progression of Autosomal Dominant Polycystic Kidney Disease.

The renal immune infiltrate observed in autosomal polycystic kidney disease contributes to the evolution of the disease. Elucidating the cellular mechanisms underlying the inflammatory response could help devise new therapeutic strategies. Here, we provide evidence for a mechanistic link between the deficiency polycystin-1 and mitochondrial homeostasis and the activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of the interferon genes (STING) pathway. Our data identify cGAS as an important mediator of renal cystogenesis and suggest that its inhibition may be useful to slow down the disease progression. Immune cells significantly contribute to the progression of autosomal dominant polycystic kidney disease (ADPKD), the most common genetic disorder of the kidney caused by the dysregulation of the Pkd1 or Pkd2 genes. However, the mechanisms triggering the immune cells recruitment and activation are undefined. Immortalized murine collecting duct cell lines were used to dissect the molecular mechanism of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) activation in the context of genotoxic stress induced by Pkd1 ablation. We used conditional Pkd1 and knockout cGas-/- genetic mouse models to confirm the role of cGAS/stimulator of the interferon genes (STING) pathway activation on the course of renal cystogenesis. We show that Pkd1 -deficient renal tubular cells express high levels of cGAS, the main cellular sensor of cytosolic nucleic acid and a potent stimulator of proinflammatory cytokines. Loss of Pkd1 directly affects cGAS expression and nuclear translocation, as well as activation of the cGAS/STING pathway, which is reversed by cGAS knockdown or functional pharmacological inhibition. These events are tightly linked to the loss of mitochondrial structure integrity and genotoxic stress caused by Pkd1 depletion because they can be reverted by the potent antioxidant mitoquinone or by the re-expression of the polycystin-1 carboxyl terminal tail. The genetic inactivation of cGAS in a rapidly progressing ADPKD mouse model significantly reduces cystogenesis and preserves normal organ function. Our findings indicate that the activation of the cGAS/STING pathway contributes to ADPKD cystogenesis through the control of the immune response associated with the loss of Pkd1 and suggest that targeting this pathway may slow disease progression.

Prospective Study on Individualized Dose Adjustment of Tolvaptan Based on Urinary Osmolality in Patients With ADPKD

IntroductionTolvaptan has been shown to reduce renal volume and delay disease progression in autosomal-dominant polycystic kidney disease (ADPKD). However, no biomarkers are currently available to guide dose adjustment. We aimed to explore the possibility of individualized tolvaptan dose adjustments based on cut-off values for urinary osmolality (OsmU). MethodsThis prospective cohort study included patients with ADPKD, with rapid disease progression. Tolvaptan treatment was initiated at a dose of 45/15 mg and increased based on OsmU, with a limit set at 200 mOsm/kg. Primary renal events (25% decrease in estimated glomerular filtration rate (eGFR) during treatment), within-patient eGRF slope and side effects were monitored during the 3-year follow-up. ResultsForty patients participated. OsmU remained below 200 mOsm/kg throughout the study period, and most patients required the minimum tolvaptan dose [mean dose, 64 (± 10) mg], with a low discontinuation rate (5%). The mean annual decline in eGFR was -3.05 (± 2.41) mL/min/1.73 m2 during tolvaptan treatment, compared with the period preceding treatment, corresponding to a reduction in eGFR decline of more than 50%. Primary renal events occurred in 20% of patients [mean time to onset, 31 months; 95% confidence interval (CI) = 28; 34]. ConclusionIndividualized tolvaptan dose adjustment based on OsmU in patients with ADPKD and rapid disease progression provided benefits in terms of reducing eGFR decline, compared with reference studies, and displayed lower dropout rates and fewer side effects. Further studies are required to confirm optimal strategies for the use of OsmU for tolvaptan dose adjustment in patients with ADPKD.

A combination of β-hydroxybutyrate and citrate ameliorates disease progression in a rat model of polycystic kidney disease.

Our research has shown that interventions producing a state of ketosis are highly effective in rat, mouse, and cat models of polycystic kidney disease (PKD), preventing and partially reversing cyst growth and disease progression. The ketone β-hydroxybutyrate (BHB) appears to underlie this effect. In addition, we have demonstrated that naturally formed microcrystals within kidney tubules trigger a renoprotective response that facilitates tubular obstruction clearance in healthy animals but, alternatively, leads to cyst formation in PKD. The administration of citrate prevents microcrystal formation and slows PKD progression. Juvenile Cy/+ rats, a nonorthologous PKD model, were supplemented from 3 to 8 wk of age with water containing titrated BHB, citrate, or in combination to find minimal effective and optimal dosages, respectively. Adult rats were given a reduced BHB/citrate combination or equimolar control K/NaCl salts from 8 to 12 wk of age. In addition, adult rats were placed in metabolic cages following BHB, citrate, and BHB/citrate administration to determine the impact on mineral, creatinine, and citrate excretion. BHB or citrate alone effectively ameliorates disease progression in juvenile rats, decreasing markers of cystic disease and, in combination, producing a synergistic effect. BHB/citrate leads to partial disease regression in adult rats with established cystic disease, inhibiting cyst formation and kidney injury. BHB/citrate confers benefits via multiple mechanisms, increases creatinine and citrate excretion, and normalizes mineral excretion. BHB and citrate are widely available and generally recognized as safe compounds and, in combination, exhibit high promise for supporting kidney health in polycystic kidney disease.NEW & NOTEWORTHY Combining β-hydroxybutyrate (BHB) and citrate effectively slows and prevents cyst formation and expansion in young Cy/+ rats using less BHB and citrate than when used alone, demonstrating synergy. In adult rats, the combination causes a partial reversal of existing disease, reducing cyst number and cystic area, preserving glomerular health, and decreasing markers of kidney injury. Our results suggest a safe and feasible strategy for supporting kidney health in polycystic kidney disease (PKD) using a combination of BHB and citrate.

Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Identifies Rapid Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

There is an unmet need for biomarkers of disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study investigated urinary extracellular vesicles (uEVs) as a source of such biomarkers. Proteomic analysis of uEVs identified matrix metalloproteinase 7 (MMP-7) as a biomarker predictive of rapid disease progression. In validation studies, MMP-7 was predictive in uEVs but not in whole urine, possibly because uEVs are primarily secreted by tubular epithelial cells. Indeed, single-nucleus RNA sequencing showed that MMP-7 was especially increased in proximal tubule and thick ascending limb cells, which were further characterized by a profibrotic phenotype. Together, these data suggest that MMP-7 is a biologically plausible and promising uEV biomarker for rapid disease progression in ADPKD. In ADPKD, there is an unmet need for early markers of rapid disease progression to facilitate counseling and selection for kidney-protective therapy. Our aim was to identify markers for rapid disease progression in uEVs. Six paired case-control groups ( n =10-59/group) of cases with rapid disease progression and controls with stable disease were formed from two independent ADPKD cohorts, with matching by age, sex, total kidney volume, and genetic variant. Candidate uEV biomarkers were identified by mass spectrometry and further analyzed using immunoblotting and an ELISA. Single-nucleus RNA sequencing of healthy and ADPKD tissue was used to identify the cellular origin of the uEV biomarker. In the discovery proteomics experiments, the protein abundance of MMP-7 was significantly higher in uEVs of patients with rapid disease progression compared with stable disease. In the validation groups, a significant >2-fold increase in uEV-MMP-7 in patients with rapid disease progression was confirmed using immunoblotting. By contrast, no significant difference in MMP-7 was found in whole urine using ELISA. Compared with healthy kidney tissue, ADPKD tissue had significantly higher MMP-7 expression in proximal tubule and thick ascending limb cells with a profibrotic phenotype. Among patients with ADPKD, rapid disease progressors have higher uEV-associated MMP-7. Our findings also suggest that MMP-7 is a biologically plausible biomarker for more rapid disease progression.

Metformin reduces decline in the estimated glomerular filtration rate during progression of autosomal dominant polycystic kidney disease: a systematic review and meta-analysis.

A meta-analysis (MA) was carried out to examine the influence of metformin on autosomal dominant polycystic kidney disease (ADPKD) patient prognosis. We reviewed and examined scientific articles from PubMed, Clinicalkey, Google Scholar, Medline, Embase, and Cochrane from the initiation date till June 2023 to identify investigations that examined metformin performance in managing ADPKD. Among the employed search terminology, we searched for terms such as "metformin" and "ADPKD". MA was conducted using the Cochrane Collaboration's RevMan version 5.3.0 (The Cochrane Collaboration, Oxford, UK). We identified 4 investigations, with 164 total subjects who fulfilled our inclusion criteria. The experimental cohort displayed a marked reduction in the decline of estimated glomerular filtration rate (eGFR) relative to controls [mean difference (MD) = 2.31, 95% confidence interval (CI) = 0.82-3.79, p = 0.002]. We observed no obvious difference in the height-adjusted total kidney volume alteration, gastrointestinal side effects, and hypoglycemia between the two cohorts. Metformin was easily tolerable and safe and substantially reduced the eGFR decline among ADPKD patients. Moreover, although metformin-treated patients were more likely to suffer gastrointestinal adverse events, we observed no discernible difference between the two cohorts.

Basigin Deficiency Induces Spontaneous Polycystic Kidney in Mice.

Polycystic kidney disease is the most common hereditary kidney disorder with early and frequent hypertension symptoms. The mechanisms of cyst progression in polycystic kidney disease remain incompletely understood. Bsg (basigin) heterozygous and homozygous knockout mice were generated using cas9 system, and Bsg overexpression was achieved by adeno-associated virus serotype 9 injection. Renal morphology was investigated through histological and imaging analysis. Molecular analysis was performed through transcriptomic profiling and biochemical approaches. Bsg-deficient mice exhibited significantly elevated arterial blood pressure. Further investigation demonstrated that Bsg deficiency triggers spontaneous cystic formation in mouse kidneys, which shares similar cyst pathological features and common transcriptional regulatory pathways with human polycystic kidney disease. Moreover, Bsg disruption promoted polycystin-1 ubiquitination and degradation, leading to activation of polycystic kidney disease associated cAMP and AMPK signaling pathways in Bsg knockout mouse kidneys. Finally, adeno-associated virus serotype 9 mediated Bsg reexpression reversed cystic progression in Bsg knockout mice in vivo, and Bsg overexpression inhibited the expansion of Madin-Darby canine kidney cysts in vitro. Our findings show that Bsg deficiency leads to an early-onset spontaneous polycystic kidney phenotype, suggesting that dysregulated Bsg signaling may be a contributing factor in cystogenesis.

Predicting autosomal dominant polycystic kidney disease progression: review of promising Serum and urine biomarkers.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the leading causes of end-stage renal disease. In spite of the recent tremendous progress in the understanding of ADPKD pathogenesis, the molecular mechanisms of the disease remain incompletely understood. Considering emerging new targeted therapies for ADPKD, it has become crucial to disclose easily measurable and widely available biomarkers for identifying patients with future rapid disease progression. This review encompasses all the research with a shared goal of identifying promising serum or urine biomarkers for predicting ADPKD progression or response to therapy. The rate of the ADPKD progress varies significantly between patients. The phenotypic variability is only partly explained by the underlying genetic lesion diversity. Considering significant decline in kidney function in ADPKD is not usually evident until at least 50% of the parenchyma has been destroyed, conventional kidney function measures, such as glomerular filtration rate (GFR), are not suitable for monitoring disease progression in ADPKD, particularly in its early stages. Since polycystic kidney enlargement usually precedes the decline in GFR, height-adjusted total kidney volume (ht-TKV) has been accepted as an early biomarker for assessing disease severity in ADPKD patients. However, since measuring ht-TKV is time-consuming and observer-dependent, the identification of a sensitive and quickly measurable biomarker is of a great interest for everyday clinical practice. Throughout the last decade, due to development of proteomic and metabolomic techniques and the enlightenment of multiple molecular pathways involved in the ADPKD pathogenesis, a number of urine and serum protein biomarkers have been investigated in ADPKD patients, some of which seem worth of further exploring. These include copeptin, angiotensinogen, monocyte chemoattractant protein 1, kidney injury molecule-1 and urine-to-plasma urea ratio among many others. The aim of the current review is to provide an overview of all of the published evidence on potentially clinically valuable serum and urine biomarkers that could be used for predicting disease progression or response to therapy in patients with ADPKD. Hopefully, this review will encourage future longitudinal prospective clinical studies evaluating proposed biomarkers as prognostic tools to improve management and outcome of ADPKD patients in everyday clinical practice.

Short salsalate administration affects cell proliferation, metabolism, and inflammation in polycystic kidney disease

Metabolic reprogramming is a driver of autosomal dominant polycystic kidney disease (ADPKD) progression and a potential therapeutic intervention route. We showed before that the AMP-associated protein kinase (AMPK) activator salsalate attenuates cystic disease progression. Here, we aim to study the early, direct effects of short salsalate treatment in adult-onset conditional Pkd1 deletion mice. Cystic mice were treated with salsalate for two weeks, after which NMR metabolomics and RNA sequencing analyses were performed. Pkd1 deletion resulted in clear metabolomic dysregulation. Short salsalate treatment has small, but significant, effects, reverting acetylcarnitine and phosphocholine concentrations back to wildtype levels, and showing associations with altered purine metabolism. RNA sequencing revealed that short salsalate treatment, next to restoring energy metabolism toward wildtype levels, also affects cell proliferation and inflammation, in PKD. We show that salsalate positively affects major dysregulated processes in ADPKD: energy metabolism, cell proliferation, and inflammation, providing more insights into its working mechanisms.