Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis.

Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.

Myocardin-Related Transcription Factor Mediates Epithelial Fibrogenesis in Polycystic Kidney Disease.

Polycystic kidney disease (PKD) is characterized by extensive cyst formation and progressive fibrosis. However, the molecular mechanisms whereby the loss/loss-of-function of Polycystin 1 or 2 (PC1/2) provokes fibrosis are largely unknown. The small GTPase RhoA has been recently implicated in cystogenesis, and we identified the RhoA/cytoskeleton/myocardin-related transcription factor (MRTF) pathway as an emerging mediator of epithelium-induced fibrogenesis. Therefore, we hypothesized that MRTF is activated by PC1/2 loss and plays a critical role in the fibrogenic reprogramming of the epithelium. The loss of PC1 or PC2, induced by siRNA in vitro, activated RhoA and caused cytoskeletal remodeling and robust nuclear MRTF translocation and overexpression. These phenomena were also manifested in PKD1 (RC/RC) and PKD2 (WS25/-) mice, with MRTF translocation and overexpression occurring predominantly in dilated tubules and the cyst-lining epithelium, respectively. In epithelial cells, a large cohort of PC1/PC2 downregulation-induced genes was MRTF-dependent, including cytoskeletal, integrin-related, and matricellular/fibrogenic proteins. Epithelial MRTF was necessary for the paracrine priming of the fibroblast-myofibroblast transition. Thus, MRTF acts as a prime inducer of epithelial fibrogenesis in PKD. We propose that RhoA is a common upstream inducer of both histological hallmarks of PKD: cystogenesis and fibrosis.

Assessing the Risk of Progression to Kidney Failure in Patients With Autosomal Dominant Polycystic Kidney Disease.

While autosomal dominant polycystic kidney disease (ADPKD) is a dichotomous diagnosis, substantial variability in disease severity exists. Identification of inherited risk through family history, genetic testing, and environmental risk factors through clinical assessment are important components of risk assessment for optimal management of patients with ADPKD. Genetic testing is especially helpful in cases with diagnostic uncertainty, particularly in cases with no apparent family history, in young cases (age less than 25 years) where a definitive diagnosis is sought, or in atypical presentations with early, severe, or discordant findings. Currently, risk assessment in ADPKD may be performed with the use of age-adjusted estimated glomerular filtration rate thresholds, evidence of rapid estimated glomerular filtration rate decline on serial measurements, age- and height-adjusted total kidney volume by Mayo Clinic Imaging Classification, or evidence of early hypertension and urological complications combined with PKD1 or PKD2 mutation class; however, caveats exist with each of these approaches. Fine-tuning of risk stratification with advanced imaging features and biomarkers is the subject of research but is not yet ready for general clinical practice. While conservative treatment strategies will be advised for all patients, those with the greatest rate of disease progression will have the most benefit from aggressive disease-modifying therapy. In this narrative review, we will summarize the evidence behind the clinical assessment and risk stratification of patients with ADPKD.

Real-life use of tolvaptan in ADPKD: a retrospective analysis of a large Canadian cohort.

Tolvaptan is the first disease-modifying drug proven to slow eGFR decline in high-risk patients with ADPKD. However, barriers from the patient perspective to its use in real-life settings have not been systemically examined in a large cohort. This was a single-center, retrospective study of 523 existing or new patients with ADPKD followed at the Center for Innovative Management of PKD in Toronto, Ontario, between January 1, 2016 to December 31, 2018. All patients underwent clinical assessment including total kidney volume measurements and Mayo Clinic Imaging Class (MCIC). Those who were deemed to be at high risk were offered tolvaptan with their preference (yes or no) and reasons for their choices recorded. Overall, 315/523 (60%) patients had MCIC 1C-1E; however, only 96 (30%) of them were treated with tolvaptan at their last follow-up. Among these high-risk patients, those not treated versus treated with tolvaptan were more likely to have a higher eGFR (82 ± 26 vs. 61 ± 27 ml/min/1.73 m2), CKD stages 1-2 (79% vs. 41%), and MCIC 1C (63% vs. 31%). The most common reasons provided for not taking tolvaptan were lifestyle preference related to the aquaretic effect (51%), older age ≥ 60 (12%), and pregnancy/family planning (6%). In this real-world experience, at least 60% of patients with ADPKD considered to be at high risk for progression to ESKD by imaging were not treated with tolvaptan; most of them had early stages of CKD with well-preserved eGFR and as such, were prime targets for tolvaptan therapy to slow disease progression. Given that the most common reason for tolvaptan refusal was the concern for intolerability of the aquaretic side-effect, strategies to mitigate this may help to reduce this barrier to tolvaptan therapy.

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.

Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Preclinical evaluation of tolvaptan and salsalate combination therapy in a Pkd1-mouse model.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder and an important cause of end stage renal disease (ESRD). Tolvaptan (a V2R antagonist) is the first disease modifier drug for treatment of ADPKD, but also causes severe polyuria. AMPK activators have been shown to attenuate cystic kidney disease. Methods: In this study, we tested the efficacy of the combined administration of salsalate (a direct AMPK activator) and tolvaptan using clinically relevant doses in an adult-onset conditional Pkd1 knock-out (KO) mouse model. Results: Compared to untreated Pkd1 mutant mice, the therapeutic effects of salsalate were similar to that of tolvaptan. The combined treatment tended to be more effective than individual drugs used alone, and was associated with improved kidney survival (p < 0.0001) and reduced kidney weight to body weight ratio (p < 0.0001), cystic index (p < 0.001) and blood urea levels (p < 0.001) compared to untreated animals, although the difference between combination and single treatments was not statistically significant. Gene expression profiling and protein expression and phosphorylation analyses support the mild beneficial effects of co-treatment, and showed that tolvaptan and salsalate cooperatively attenuated kidney injury, cell proliferation, cell cycle progression, inflammation and fibrosis, and improving mitochondrial health, and cellular antioxidant response. Conclusion: These data suggest that salsalate-tolvaptan combination, if confirmed in clinical testing, might represent a promising therapeutic strategy in the treatment of ADPKD.

Atypical Polycystic Kidney Disease as defined by Imaging.

Using age- and height-adjusted total kidney volume, the Mayo Clinic Imaging Classification provides a validated approach to assess the risk of chronic kidney disease (CKD) progression in autosomal dominant polycystic kidney disease (ADPKD), but requires excluding patients with atypical imaging patterns, whose clinical characteristics have been poorly defined. We report an analysis of the prevalence, clinical and genetic characteristics of patients with atypical polycystic kidney disease by imaging. Patients from the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease recruited between 2016 and 2018 completed a standardized clinical questionnaire, kidney function assessment, genetic testing, and kidney imaging by magnetic resonance or computed tomography. We compared the prevalence, clinical features, genetics, and renal prognosis of atypical versus typical polycystic kidney disease by imaging. Forty-six of the 523 (8.8%) patients displayed atypical polycystic kidney disease by imaging; they were older (55 vs. 43 years; P < 0.001), and less likely to have a family history of ADPKD (26.1% vs. 74.6%; P < 0.001), a detectable PKD1 or PKD2 mutation (9.2% vs. 80.4%; P < 0.001), or progression to CKD stage 3 or stage 5 (P < 0.001). Patients with atypical polycystic kidney disease by imaging represent a distinct prognostic group with a low likelihood of progression to CKD.

Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD. STUDY DESIGN: STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m2. SETTING & PARTICIPANTS: Enrollment included 236 and 242 patients in stages 1 and 2, respectively. INTERVENTIONS: In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo. OUTCOMES: Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2). RESULTS: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early. LIMITATIONS: The short follow-up period after the end of treatment and limited generalizability of the findings. CONCLUSIONS: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels. FUNDING: This study was funded by Sanofi. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03523728.

Autosomal Dominant Polycystic Kidney Disease: Role of Imaging in Diagnosis and Management.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder with progressive renal function decline, and disease severity is determined based on the type of genetic mutation. The diagnosis is usually established at imaging, primarily at US, and is based on age-dependent criteria and the number of visible cysts. ADPKD is classified into class 1 (typical) and class 2 (atypical) according to the Mayo Clinic Imaging Classification (MCIC) system. Height-adjusted total kidney volume (TKV) has emerged as a predictor of future renal function decline and renal failure in ADPKD, and several methods can be used for estimation. MCIC class 1 ADPKD is further subdivided into five types based on height-adjusted TKV (A, B, C, D, and E). Patients with a larger height-adjusted TKV (ie, MCIC 1C-E) are at high risk for progression to end-stage renal disease and will potentially benefit from vasopressin receptor antagonists, which have been shown to reduce the rate of cyst growth and slow renal function decline. Other renal complications primarily relate to hemorrhage within cysts or cyst infections. Subtraction images are key for assessment of complex cysts when malignancy is suspected, as the presence of protein and blood can limit the assessment for an enhancing component. The radiologist has a central role in establishing a diagnosis, excluding mimics, identifying complications, assessing severity, and predicting future renal failure. Interventional radiologists play a therapeutic role in management of complications by cyst drainage, sclerotherapy, or embolization. © RSNA, 2022 Online supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.

Urinary epidermal growth factor/monocyte chemotactic peptide 1 ratio as non-invasive predictor of Mayo clinic imaging classes in autosomal dominant polycystic kidney disease.

BACKGROUND: Age- and height-adjusted total kidney volume is currently considered the best prognosticator in patients with autosomal dominant polycystic kidney disease. We tested the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for the prediction of the Mayo Clinic Imaging Classes. METHODS: Urinary epidermal growth factor and monocyte chemotactic peptide 1 levels were measured in two independent cohorts (discovery, n = 74 and validation set, n = 177) and healthy controls (n = 59) by immunological assay. Magnetic resonance imaging parameters were used for total kidney volume calculation and the Mayo Clinic Imaging Classification defined slow (1A-1B) and fast progressors (1C-1E). Microarray and quantitative gene expression analysis were used to test epidermal growth factor and monocyte chemotactic peptide 1 gene expression. RESULTS: Baseline ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 correlated with total kidney volume adjusted for height (r = - 0.6, p < 0.001), estimated glomerular filtration rate (r = 0.69 p < 0.001), discriminated between Mayo Clinic Imaging Classes (p < 0.001), and predicted the variation of estimated glomerular filtration rate at 10 years (r = - 0.51, p < 0.001). Conditional Inference Trees identified cut-off levels of the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for slow and fast progressors at > 132 (100% slow) and < 25.76 (89% and 86% fast, according to age), with 94% sensitivity and 66% specificity (p = 6.51E-16). Further, the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 at baseline showed a positive correlation (p = 0.006, r = 0.36) with renal outcome (delta-estimated glomerular filtration rate per year, over a mean follow-up of 4.2 ± 1.2 years). Changes in the urinary epidermal growth factor and monocyte chemotactic peptide 1 were mirrored by gene expression levels in both human kidney cysts (epidermal growth factor: - 5.6-fold, fdr = 0.001; monocyte chemotactic peptide 1: 3.1-fold, fdr = 0.03) and Pkd1 knock-out mouse kidney (Egf: - 14.8-fold, fdr = 2.37E-20, Mcp1: 2.8-fold, fdr = 6.82E-15). CONCLUSION: The ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 is a non-invasive pathophysiological biomarker that can be used for clinical risk stratification in autosomal dominant polycystic kidney disease.

The STAGED-PKD 2-Stage Adaptive Study With a Patient Enrichment Strategy and Treatment Effect Modeling for Improved Study Design Efficiency in Patients With ADPKD.

Rationale & Objective: Venglustat, a glucosylceramide synthase inhibitor, inhibits cyst growth and reduces kidney failure in mouse models of autosomal dominant polycystic kidney disease (ADPKD). STAGED-PKD aims to determine the safety and efficacy of venglustat and was designed using patient enrichment for progression to end-stage kidney disease and modeling from prior ADPKD trials. Study Design: STAGED-PKD is a 2-stage, international, double-blind, randomized, placebo-controlled trial in adults with ADPKD (Mayo Class 1C-1E) and estimated glomerular filtration rate (eGFR) 45-<90 mL/min/1.73 m2 at risk of rapidly progressive disease. Enrichment for rapidly progressing patients was identified based on retrospective analysis of total kidney volume (TKV) and eGFR slope from the combined Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease and HALT Progression of Polycystic Kidney Disease A studies. Setting & Participants: Target enrollment in stages 1 and 2 was 240 and 320 patients, respectively. Interventions: Stage 1 randomizes patients 1:1:1 to venglustat 8 mg or 15 mg once daily or placebo. Stage 2 randomizes patients 1:1 to placebo or venglustat, with the preferred dose based on stage 1 safety data. Outcomes: Primary endpoints are TKV growth rate over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary endpoints include: annualized rate of change in eGFR from baseline to 18 months (stage 1); annualized rate of change in TKV based on magnetic resonance imaging from baseline to 18 months (stage 2); and safety, tolerability, pain, and fatigue (stages 1 and 2). Limitations: If stage 1 is unsuccessful, patients enrolled in the trial may develop drug-related adverse events that can have long-lasting effects. Conclusions: Modeling allows the design and powering of a 2-stage combined study to assess venglustat's impact on TKV growth and eGFR slope. Stage 1 TKV assessment via a nested approach allows early evaluation of efficacy and increased efficiency of the trial design by reducing patient numbers and trial duration. Funding: This study was funded by Sanofi. Trial registration: STAGED-PKD has been registered at ClinicalTrials.gov with study number NCT03523728.

Shared pathobiology identifies AMPK as a therapeutic target for obesity and autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian kidney disease, affecting approximately one in 1,000 births and accounting for 5% of end-stage kidney disease in developed countries. The pathophysiology of ADPKD is strongly linked to metabolic dysregulation, which may be secondary to defective polycystin function. Overweight and obesity are highly prevalent in patients with ADPKD and constitute an independent risk factor for progression. Recent studies have highlighted reduced AMP-activated protein kinase (AMPK) activity, increased mammalian target of rapamycin (mTOR) signaling, and mitochondrial dysfunction as shared pathobiology between ADPKD and overweight/obesity. Notably, mTOR and AMPK are two diametrically opposed sensors of energy metabolism that regulate cell growth and proliferation. However, treatment with the current generation of mTOR inhibitors is poorly tolerated due to their toxicity, making clinical translation difficult. By contrast, multiple preclinical and clinical studies have shown that pharmacological activation of AMPK provides a promising approach to treat ADPKD. In this narrative review, we summarize the pleiotropic functions of AMPK as a regulator of cellular proliferation, macromolecule metabolism, and mitochondrial biogenesis, and discuss the potential for pharmacological activation of AMPK to treat ADPKD and obesity-related kidney disease.

Safety of High-Dose 3% Sodium Tetradecyl Sulfate for Sclerotherapy of Renal Cysts in Patients with Autosomal Dominant Polycystic Kidney Disease.

This study assessed the safety profile of high-volume (>10 mL) 3% sodium tetradecyl sulfate (STS) sclerotherapy for the treatment of renal cysts in patients with autosomal dominant polycystic kidney disease. A total of 211 sclerotherapy treatments were performed in 169 patients over a 5-year period, with a comparison of 2 patient cohorts based on the STS volumes used. The first cohort (n = 112) received a high volume (greater than 10 mL) of STS, and the second cohort (n = 57) received a low volume (less than 10 mL). The minor adverse event rate for the cohorts was 14.5% and 9.6%, respectively (P = .310), with postprocedure pain being the most common event. One major adverse event occurred, for which the patient required hospitalization for infection after low-volume STS treatment. Doses of STS higher than those currently recommended by the Food and Drug Administration for intravascular use allow large renal cysts to be treated safely in the setting of autosomal dominant polycystic kidney disease.

Dietary Interventions in Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of renal cysts, leading to the loss of functional nephrons. Recommendations for individuals with ADPKD to maintain a healthy diet and lifestyle are largely similar to those for the general population. However, recent evidence from preclinical models suggests that more tightly specified dietary regimens, including caloric restriction, intermittent fasting, and ketogenic diets, hold promise to slow disease progression, and the results of ongoing human clinical trials are eagerly awaited. These dietary interventions directly influence nutrient signaling and substrate availability in the cystic kidney, while also conferring systemic metabolic benefits. The present review focuses on the importance of local and systemic metabolism in ADPKD and summarizes current evidence for dietary interventions to slow disease progression and improve quality of life.

LAMA2 and LOXL4 are candidate FSGS genes.

BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is a histologic pattern of injury that characterizes a wide spectrum of diseases. Many genetic causes have been identified in FSGS but even in families with comprehensive testing, a significant proportion remain unexplained. METHODS: In a family with adult-onset autosomal dominant FSGS, linkage analysis was performed in 11 family members followed by whole exome sequencing (WES) in 3 affected relatives to identify candidate genes. RESULTS: Pathogenic variants in known nephropathy genes were excluded. Subsequently, linkage analysis was performed and narrowed the disease gene(s) to within 3% of the genome. WES identified 5 heterozygous rare variants, which were sequenced in 11 relatives where DNA was available. Two of these variants, in LAMA2 and LOXL4, remained as candidates after segregation analysis and encode extracellular matrix proteins of the glomerulus. Renal biopsies showed classic segmental sclerosis/hyalinosis lesion on a background of mild mesangial hypercellularity. Examination of basement membranes with electron microscopy showed regions of dense mesangial matrix in one individual and wider glomerular basement membrane (GBM) thickness in two individuals compared to historic control averages. CONCLUSIONS: Based on our findings, we postulate that the additive effect of digenic inheritance of heterozygous variants in LAMA2 and LOXL4 leads to adult-onset FSGS. Limitations to our study includes the absence of functional characterization to support pathogenicity. Alternatively, identification of additional FSGS cases with suspected deleterious variants in LAMA2 and LOXL4 will provide more evidence for disease causality. Thus, our report will be of benefit to the renal community as sequencing in renal disease becomes more widespread.

Follistatin-Like-1 (FSTL1) Is a Fibroblast-Derived Growth Factor That Contributes to Progression of Chronic Kidney Disease.

Our understanding of the mechanisms responsible for the progression of chronic kidney disease (CKD) is incomplete. Microarray analysis of kidneys at 4 and 7 weeks of age in Col4a3-/- mice, a model of progressive nephropathy characterized by proteinuria, interstitial fibrosis, and inflammation, revealed that Follistatin-like-1 (Fstl1) was one of only four genes significantly overexpressed at 4 weeks of age. mRNA levels for the Fstl1 receptors, Tlr4 and Dip2a, increased in both Col4a-/- mice and mice subjected to unilateral ureteral obstruction (UUO). RNAscope® (Advanced Cell Diagnostics, Newark CA, USA) localized Fstl1 to interstitial cells, and in silico analysis of single cell transcriptomic data from human kidneys showed Fstl1 confined to interstitial fibroblasts/myofibroblasts. In vitro, FSTL1 activated AP1 and NFκB, increased collagen I (COL1A1) and interleukin-6 (IL6) expression, and induced apoptosis in cultured kidney cells. FSTL1 expression in the NEPTUNE cohort of humans with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and IgA nephropathy (IgAN) was positively associated with age, eGFR, and proteinuria by multiple linear regression, as well as with interstitial fibrosis and tubular atrophy. Clinical disease progression, defined as dialysis or a 40 percent reduction in eGFR, was greater in patients with high baseline FSTL1 mRNA levels. FSTL1 is a fibroblast-derived cytokine linked to the progression of experimental and clinical CKD.

Tackling Dialysis Burden around the World: A Global Challenge.

CKD is a global problem that causes significant burden to the healthcare system and the economy in addition to its impact on morbidity and mortality of patients. Around the world, in both developing and developed economies, the nephrologists and governments face the challenges of the need to provide a quality and cost-effective kidney replacement therapy for CKD patients when their kidneys fail. In December 2019, the 3rd International Congress of Chinese Nephrologists was held in Nanjing, China, and in the meeting, a symposium and roundtable discussion on how to deal with this CKD burden was held with opinion leaders from countries and regions around the world, including Australia, Canada, China, Hong Kong, Singapore, Taiwan, the UK, and the USA. The participants concluded that an integrated approach with early detection of CKD, prompt treatment to slow down progression, promotion of home-based dialysis therapy like peritoneal dialysis and home HD, together with promotion of kidney transplantation, are possible effective ways to combat this ongoing worldwide challenge.

Risk of Hospital Encounters With Kidney Stones in Autosomal Dominant Polycystic Kidney Disease: A Cohort Study.

BACKGROUND: There is a perception that patients with autosomal dominant polycystic kidney disease (ADPKD) are more likely to develop kidney stones than the general population. OBJECTIVE: To compare the rate of hospital encounter with kidney stones and the rate of stone interventions between patients with and without ADPKD. DESIGN: Retrospective cohort study. SETTING: Ontario, Canada. PATIENTS: Patients with and without ADPKD who had a prior hospital encounter between 2002 and 2016. MEASUREMENTS: Rate of hospital encounter with kidney stones and rate of stone intervention. METHODS: We used inverse probability exposure weighting based on propensity scores to balance baseline indicators of health between patients with and without ADPKD. We followed each patient until death, emigration, outcomes, or March 31, 2017. We used a Cox proportional hazards model to compare event rates between the two groups. RESULTS: Patients with ADPKD were at higher risk of hospital encounter with stones compared with patients without ADPKD (81 patients of 2094 with ADPKD [3.8%] vs 60 patients of 1902 without ADPKD [3.2%]; 8.9 vs 5.1 events per 1000 person-years; hazard ratio 1.6 [95% CI, 1.3-2.1]). ADPKD was not associated with a higher risk of stone intervention (49 of 2094 [2.3%] vs 47 of 1902 [2.4%]; 5.3 vs 3.9 events per 1000 person-years; hazard ratio 1.2 [95% CI = 0.9-1.3]). LIMITATIONS: We did not have information on kidney stone events outside of the hospital. There is a possibility of residual confounding. CONCLUSION: ADPKD was a significant risk factor for hospital encounters with kidney stones.

CONTEXTE: Il existe une perception selon laquelle les patients atteints de polykystose rénale autosomique dominante (ADPKD) seraient plus susceptibles de développer des calculs rénaux que la population générale. OBJECTIF: Comparer les taux d'hospitalisations et d'interventions pour calculs rénaux entre des patients atteints ou non d'ADPKD. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Ontario, Canada. SUJETS: Des patients atteints ou non d'ADPKD qui avaient déjà été hospitalisés entre 2002 et 2016. MESURES: Les taux d'hospitalisations et d'interventions pour calculs rénaux. MÉTHODOLOGIE: Nous avons utilisé une pondération d'exposition à probabilité inverse fondée sur les scores de propension afin d'équilibrer les indicateurs de santé de base entre les patients atteints ou non d'ADPKD. Nous avons suivi chaque patient jusqu'à son décès, jusqu'à son émigration, jusqu'au résultat ou jusqu'au 31 mars 2017. Nous avons utilisé un modèle de risques proportionnels de Cox pour comparer les taux d'événements entre les deux groupes. RÉSULTATS: Les patients atteints d'ADPKD présentaient un risque plus élevé d'être hospitalisés pour calculs rénaux que les patients non atteints d'ADPKD (81 patients sur 2094 atteints d'ADPKD [3,8 %] contre 60 patients sur 1902 sans ADPKD [3,2 %]; 8,9 contre 5,1 événements pour 1 000 années-personnes; risque relatif: 1,6 [IC 95 %: 1,3 à 2,1]). L'ADPKD n'a pas été associée à un risque plus élevé d'interventions pour retirer des calculs rénaux (49 patients sur 2094 atteints d'ADPKD [2,3 %] contre 47 patients sur 1902 sans ADPKD [2,4 %]; 5,3 contre 3,9 événements pour 1 000 années-personnes; risque relatif: 1,2 [IC 95 %: 0,9 à 1,3]). LIMITES: Nous n'avions pas d'information sur les événements liés aux calculs rénaux à l'extérieur de l'hôpital. Il existe une possibilité de facteurs de confusion résiduels. CONCLUSION: L'ADPKD s'est avéré un facteur de risque important d'être hospitalisé pour des calculs rénaux.