ABSTRACT
BACKGROUND: Tubular biomarkers, which reflect tubular dysfunction or injury, are associated with incident chronic kidney disease and kidney function decline. Several tubular biomarkers have also been implicated in the progression of autosomal dominant polycystic kidney disease (ADPKD). We evaluated changes in multiple tubular biomarkers in four groups of patients with ADPKD who participated in one of two clinical trials (metformin therapy and diet-induced weight loss), based on evidence suggesting that such interventions could reduce tubule injury. METHODS: 66 participants (26 M/40 F) with ADPKD and an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73m2 who participated in either a metformin clinical trial (n = 22 metformin; n = 23 placebo) or dietary weight loss study (n = 10 daily caloric restriction [DCR]; n = 11 intermittent fasting [IMF]) were included in assessments of urinary tubular biomarkers (kidney injury molecule-1 [KIM-1], fatty-acid binding protein [FABP], interleukin-18 [IL-18], monocyte chemoattractant protein-1 [MCP-1], neutrophil gelatinase-associated lipocalin [NGAL], clusterin, and human cartilage glycoprotein-40 [YKL-40]; normalized to urine creatinine), at baseline and 12 months. The association of baseline tubular biomarkers with both baseline and change in height-adjusted total kidney volume (HtTKV; percent change from baseline to 12 months) and estimated glomerular filtration rate (eGFR; absolute change at 12 months vs. baseline), with covariate adjustment, was also assessed using multiple linear regression. RESULTS: Mean ± s.d. age was 48 ± 8 years, eGFR was 71 ± 16 ml/min/1.73m2, and baseline BMI was 30.5 ± 5.9 kg/m2. None of the tubular biomarkers changed with any intervention as compared to placebo. Additionally, baseline tubular biomarkers were not associated with either baseline or change in eGFR or HtTKV over 12 months, after adjustments for demographics, group assignment, and clinical characteristics. CONCLUSIONS: Tubular biomarkers did not change with dietary-induced weight loss or metformin, nor did they associate with kidney disease progression, in this cohort of patients with ADPKD.
Subject(s)
Biomarkers , Caloric Restriction , Glomerular Filtration Rate , Kidney Tubules , Metformin , Polycystic Kidney, Autosomal Dominant , Humans , Metformin/therapeutic use , Polycystic Kidney, Autosomal Dominant/urine , Polycystic Kidney, Autosomal Dominant/drug therapy , Polycystic Kidney, Autosomal Dominant/diet therapy , Male , Female , Biomarkers/urine , Middle Aged , Kidney Tubules/pathology , Kidney Tubules/drug effects , Adult , Lipocalin-2/urine , Chemokine CCL2/urine , Fatty Acid-Binding Proteins/urine , Hepatitis A Virus Cellular Receptor 1/metabolism , Hepatitis A Virus Cellular Receptor 1/analysis , Chitinase-3-Like Protein 1/urine , Hypoglycemic Agents/therapeutic useSubject(s)
Lanthanum , Oxidative Stress , Phosphates , Renal Insufficiency, Chronic , Lanthanum/therapeutic use , Lanthanum/pharmacology , Humans , Oxidative Stress/drug effects , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/drug therapy , Phosphates/blood , Male , Female , Middle AgedABSTRACT
Genetic testing can provide valuable information to mitigate personal disease risk, but the use of genetic results in life insurance underwriting is known to deter many consumers from pursuing genetic testing. In 2019, following Australian Federal Parliamentary Inquiry recommendations, the Financial Services Council (FSC) introduced an industry-led partial moratorium, prohibiting life insurance companies from using genetic test results for policies up to $AUD500,000. We used semi-structured interviews to explore genetic test consumers' experiences and views about the FSC moratorium and the use of genetic results by life insurers. Individuals who participated in an online survey and agreed to be re-contacted to discuss the issue further were invited. Interviews were 20-30-min long, conducted via video conference, transcribed verbatim and analysed using inductive content analysis. Twenty-seven participants were interviewed. Despite the moratorium, concerns about genetic discrimination in life insurance were prevalent. Participants reported instances where life insurers did not consider risk mitigation when assessing risk for policies based on genetic results, contrary to legal requirements. Most participants felt that the moratorium provided inadequate protection against discrimination, and that government legislation regulating life insurers' use of genetic results is necessary. Many participants perceived the financial limits to be inadequate, given the cost-of-living in Australia. Our findings indicate that from the perspective of participants, the moratorium has not been effective in allaying fears about genetic discrimination or ensuring adequate access to life insurance products. Concern about genetic discrimination in life insurance remains prevalent in Australia.
Subject(s)
Genetic Testing , Insurance, Life , Humans , Insurance, Life/legislation & jurisprudence , Genetic Testing/legislation & jurisprudence , Genetic Testing/economics , Australia , Female , Male , Adult , Middle Aged , Aged , Qualitative ResearchABSTRACT
RATIONALE & OBJECTIVE: Body mass index (BMI) is an independent predictor of kidney disease progression in individuals with autosomal dominant polycystic kidney disease (ADPKD). Adipocytes do not simply act as a fat reservoir but are active endocrine organs. We hypothesized that greater visceral abdominal adiposity would associate with more rapid kidney growth in ADPKD and influence the efficacy of tolvaptan. STUDY DESIGN: A retrospective cohort study. SETTING & PARTICIPANTS: 1,053 patients enrolled in the TEMPO 3:4 tolvaptan trial with ADPKD and at high risk of rapid disease progression. PREDICTOR: Estimates of visceral adiposity extracted from coronal plane magnetic resonance imaging (MRI) scans using deep learning. OUTCOME: Annual change in total kidney volume (TKV) and effect of tolvaptan on kidney growth. ANALYTICAL APPROACH: Multinomial logistic regression and linear mixed models. RESULTS: In fully adjusted models, the highest tertile of visceral adiposity was associated with greater odds of annual change in TKV of≥7% versus<5% (odds ratio [OR], 4.78 [95% CI, 3.03-7.47]). The association was stronger in women than men (interaction P<0.01). In linear mixed models with an outcome of percent change in TKV per year, tolvaptan efficacy (% change in TKV) was reduced with higher visceral adiposity (3-way interaction of treatment ∗ time ∗ visceral adiposity, P=0.002). Visceral adiposity significantly improved classification performance of predicting rapid annual percent change in TKV for individuals with a normal BMI (DeLong's test z score: -2.03; P=0.04). Greater visceral adiposity was not associated with estimated glomerular filtration rate (eGFR) slope in the overall cohort; however, visceral adiposity was associated with more rapid decline in eGFR slope (below the median) in women (fully adjusted OR, 1.06 [95% CI, 1.01-1.11] per 10 unit increase in visceral adiposity) but not men (OR, 0.98 [95% CI, 0.95-1.02]). LIMITATIONS: Retrospective; rapid progressors; computational demand of deep learning. CONCLUSIONS: Visceral adiposity that can be quantified by MRI in the coronal plane using a deep learning segmentation model independently associates with more rapid kidney growth and improves classification of rapid progression in individuals with a normal BMI. Tolvaptan efficacy decreases with increasing visceral adiposity. PLAIN-LANGUAGE SUMMARY: We analyzed images from a previous study with the drug tolvaptan conducted in patients with autosomal dominant polycystic kidney disease (ADPKD) to measure the amount of fat tissue surrounding the kidneys (visceral fat). We had previously shown body mass index can predict kidney growth in this population; now we determined whether visceral fat was an important factor associated with kidney growth. Using a machine learning tool to automate measurement of fat in images, we observed that visceral fat was independently associated with kidney growth, that it was a better predictor of faster kidney growth in lean patients than body mass index, and that having more visceral fat made treatment of ADPKD with tolvaptan less effective.
Subject(s)
Disease Progression , Intra-Abdominal Fat , Polycystic Kidney, Autosomal Dominant , Tolvaptan , Humans , Polycystic Kidney, Autosomal Dominant/drug therapy , Male , Female , Retrospective Studies , Tolvaptan/therapeutic use , Tolvaptan/pharmacology , Adult , Intra-Abdominal Fat/diagnostic imaging , Middle Aged , Cohort Studies , Antidiuretic Hormone Receptor Antagonists/therapeutic use , Obesity, Abdominal , Body Mass Index , Magnetic Resonance Imaging , AdiposityABSTRACT
RATIONALE & OBJECTIVE: In this pilot study, we hypothesized that autosomal dominant polycystic kidney disease (ADPKD) is characterized by impaired kidney oxidative metabolism that associates with kidney size and cyst burden. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: Twenty adults with ADPKD (age, 31±6 years; 65% women; body mass index [BMI], 26.8 [22.7-30.4] kg/m2; estimated glomerular filtration rate [eGFR, 2021 CKD-EPI creatinine], 103±18mL/min/1.73m2; height-adjusted total kidney volume [HTKV], 731±370mL/m; Mayo classifications 1B [5%], 1C [42%], 1D [21%], and 1E [32%]) and 11 controls in normal weight category (NWC) (age, 25±3 years; 45% women; BMI, 22.5 [21.7-24.2] kg/m2; eGFR, 113±15mL/min/1.73m2; HTKV, 159±31mL/m) at the University of Colorado Anschutz Medical Campus. PREDICTORS: ADPKD status (yes/no) and severity (Mayo classifications). OUTCOME: HTKV and cyst burden by magnetic resonance imaging, kidney oxidative metabolism, and perfusion by 11C-acetate positron emission tomography/computed tomography, insulin sensitivity by hyperinsulinemic-euglycemic clamps (presented as ratio of M-value of steady state insulin concentration [M/I]). ANALYTICAL APPROACH: For categorical variables, χ2/Fisher's exact tests, and for continuous variables t tests/Mann-Whitney U tests. Pearson correlation was used to estimate the relationships between variables. RESULTS: Compared with NWC individuals, the participants with ADPKD exhibited lower mean±SD M/I ratio (0.586±0.205 vs 0.424±0.171 [mg/kg lean/min]/(µIU/mL), P=0.04), lower median cortical perfusion (1.93 [IQR, 1.80-2.09] vs 0.68 [IQR, 0.47-1.04] mL/min/g, P<0.001) and lower median total kidney oxidative metabolism (0.17 [IQR, 0.16-0.19] vs. 0.14 [IQR, 0.12-0.15] min-1, P=0.001) in voxel-wise models excluding cysts. HTKV correlated inversely with cortical perfusion (r: -0.83, P < 0.001), total kidney oxidative metabolism (r: -0.61, P<0.001) and M/I (r: -0.41, P = 0.03). LIMITATIONS: Small sample size and cross-sectional design. CONCLUSIONS: Adults with ADPKD and preserved kidney function exhibited impaired renal perfusion and kidney oxidative metabolism across a wide range of cysts and kidney enlargements. FUNDING: Grants from government (National Institutes of Health, Centers for Disease Control and Prevention) and not-for-profit (JDRF) entities. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study numbers NCT04407481 and NCT04074668. PLAIN-LANGUAGE SUMMARY: In our study, we explored how a common genetic kidney condition, autosomal dominant polycystic kidney disease (ADPKD), relates to kidney metabolism. ADPKD leads to the growth of numerous cysts in the kidneys, which can impact their ability to work properly. We wanted to understand the kidneys' ability to process oxygen and blood flow in ADPKD. Our approach involved using advanced imaging techniques to observe kidney metabolism and blood flow in people with ADPKD compared with healthy individuals. We discovered that those with ADPKD had significant changes in kidney oxygen metabolism even when their kidney function was still normal. These findings are crucial as they provide deeper insights into ADPKD, potentially guiding future treatments to target these changes.
Subject(s)
Glomerular Filtration Rate , Kidney , Polycystic Kidney, Autosomal Dominant , Humans , Polycystic Kidney, Autosomal Dominant/metabolism , Polycystic Kidney, Autosomal Dominant/pathology , Polycystic Kidney, Autosomal Dominant/complications , Polycystic Kidney, Autosomal Dominant/diagnostic imaging , Female , Pilot Projects , Male , Adult , Cross-Sectional Studies , Kidney/pathology , Kidney/diagnostic imaging , Kidney/metabolism , Young Adult , Energy Metabolism/physiology , Cysts/metabolism , Cysts/pathology , Cysts/diagnostic imagingABSTRACT
Genetic risk information for medically actionable conditions has relevance for patients' blood relatives. However, cascade testing uptake in at-risk families is <50%, and the burden of contacting relatives is a significant barrier to dissemination of risk information. Health professionals (HPs) could notify at-risk relatives directly, with patients' consent. This practice is supported by international literature, including strong public support. However, there is little exploration of the Australian public's views about this issue. We surveyed Australian adults using a consumer research company. Respondents were provided a hypothetical scenario and asked about views and preferences regarding direct contact by HPs. 1030 members of the public responded, with median age 45 y and 51% female. The majority would want to be told about genetic risk for conditions that can be prevented/treated early (85%) and contacted directly by a HP (68%). Most preferred a letter that included specific information about the genetic condition in the family (67%) and had no privacy concerns about HPs sending a letter using contact details provided by a relative (85%). A minority (< 5%) had significant privacy concerns, mostly about use of personal contact information. Concerns included ensuring information was not shared with third parties. Almost 50% would prefer that a family member contacted them before the letter was sent, while about half did not prefer this or were unsure. The Australian public supports (and prefers) direct notification of relatives at risk of medically actionable genetic conditions. Guidelines would assist with clarifying clinicians' discretion in this area.
Subject(s)
Informed Consent , Patients , Adult , Humans , Female , Middle Aged , Male , Australia , Risk Factors , Surveys and QuestionnairesABSTRACT
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development and continued growth of multiple cysts in the kidneys leading to ultimate loss of kidney function in most patients. Currently, tolvaptan is the only agency approved therapy to slow kidney disease advancement in patients with faster progressing disease underscoring the need for additional ADPKD therapies suitable for all patients. We previously showed that pravastatin slowed kidney disease progression in children and young adults with ADPKD. However, the intervention has not been tested in an adult cohort. AIMS: The aim of the study is to conduct a single center, randomized, placebo-controlled double-blinded clinical trial to determine the efficacy of pravastatin on slowing kidney disease progression in adult patients with early stage ADPKD. METHODS: One hundred and fifty adult patients with ADPKD and eGFR ≥60 ml/min/1.73m2 will be enrolled in the study and randomized to receive 40 mg/day pravastatin or placebo for a period of 2-years. OUTCOMES: The primary outcome of the trial is change in total kidney volume assessed by magnetic resonance imaging (MRI). Secondary outcomes include change in kidney function by iothalamate GFR and renal blood flow and markers of inflammation and oxidative stress. CONCLUSION: This study will assess the kidney therapeutic benefits of pravastatin in adult patients with ADPKD. The recruitment goal of 150 subjects was attained and the study is ongoing. REGISTRATION: This study is registered on Clinicaltrials.gov # NCT03273413.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Polycystic Kidney, Autosomal Dominant , Young Adult , Child , Humans , Adult , Polycystic Kidney, Autosomal Dominant/diagnostic imaging , Polycystic Kidney, Autosomal Dominant/drug therapy , Polycystic Kidney, Autosomal Dominant/complications , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Pravastatin/therapeutic use , Double-Blind Method , Disease Progression , Glomerular Filtration RateABSTRACT
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation and progressive kidney function loss. Dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet have recently emerged as potential strategies to induce metabolic reprogramming and slow ADPKD progression. We review the available evidence supporting the efficacy and safety of these interventions in ADPKD. Dietary interventions show promise in managing ADPKD by improving metabolic health and reducing oxidative stress. However, while preclinical studies have shown favorable outcomes, limited clinical evidence supports their effectiveness. In addition, the long-term consequences of these dietary interventions, including their effect on adverse events in patients with ADPKD, remain uncertain. To optimize ADPKD management, patients are advised to follow a dietary regimen that aims to achieve or maintain an ideal body weight and includes high fluid intake, low sodium, and limited concentrated sweets. Caloric restriction seems particularly beneficial for patients with overweight or obesity because it promotes weight loss and improves metabolic parameters. Supplementation with curcumin, ginkgolide B, saponins, vitamin E, niacinamide, or triptolide has demonstrated uncertain clinical benefit in patients with ADPKD. Notably, ß -hydroxybutyrate supplements have shown promise in animal models; however, their safety and efficacy in ADPKD require further evaluation through well-designed clinical trials. Therefore, the use of these supplements is not currently recommended for patients with ADPKD. In summary, dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet hold promise in ADPKD management by enhancing metabolic health. However, extensive clinical research is necessary to establish their effectiveness and long-term effects. Adhering to personalized dietary guidelines, including weight management and specific nutritional restrictions, can contribute to optimal ADPKD management. Future research should prioritize well-designed clinical trials to determine the benefits and safety of dietary interventions and supplementation in ADPKD.
ABSTRACT
Genetic risk information has relevance for patients' blood relatives. However, cascade testing uptake in at-risk families is <50%. International research supports direct notification of at-risk relatives by health professionals (HPs), with patient consent. However, HPs express concerns about the privacy implications of this practice. Our privacy analysis, grounded in a clinically relevant hypothetical scenario, considers the types of personal information involved in direct notification of at-risk relatives and the application of Australian privacy regulations. It finds that collecting relatives' contact details, and using those details (with patient consent) to notify relatives of possible genetic risk, does not breach Australian privacy law, providing that HPs adhere to regulatory requirements. It finds the purported "right to know" does not prevent disclosure of genetic information to at-risk relatives. Finally, the analysis confirms that the discretion available to HPs does not equate to a positive duty to warn at-risk relatives. Thus, direct notification of a patient's at-risk relatives regarding medically actionable genetic information, with patient consent, is not a breach of Australian privacy regulations, providing it is conducted in accordance with the applicable principles set out. Clinical services should consider offering this service to patients where appropriate. National guidelines would assist with the clarification of the discretion for HPs.
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SIGNIFICANCE STATEMENT: Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. In this randomized, controlled trial, treatment with sodium bicarbonate (NaHCO 3 ) did not improve vascular endothelial function or reduce arterial stiffness in participants with CKD stage 3b-4 with normal serum bicarbonate levels. In addition, NaHCO 3 treatment did not reduce left ventricular mass index. NaHCO 3 did increase plasma bicarbonate levels and urinary citrate excretion and reduce urinary ammonium excretion, indicating that the intervention was indeed effective. NaHCO 3 therapy was safe with no significant changes in BP, weight, or edema. These results do not support the use of NaHCO 3 for vascular dysfunction in participants with CKD. BACKGROUND: Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. Prospective interventional trials with sodium bicarbonate (NaHCO 3 ) are lacking. METHODS: We conducted a randomized, double-blind, placebo-controlled trial examining the effect of NaHCO 3 on vascular function in 109 patients with CKD stage 3b-4 (eGFR 15-44 ml/min per 1.73 m 2 ) with normal serum bicarbonate levels (22-27 mEq/L). Participants were randomized 1:1 to NaHCO 3 or placebo at a dose of 0.5 mEq/lean body weight-kg per day for 12 months. The coprimary end points were change in brachial artery flow-mediated dilation (FMD) and change in aortic pulse wave velocity over 12 months. RESULTS: Ninety patients completed this study. After 12 months, plasma bicarbonate levels increased significantly in the NaHCO 3 group compared with placebo (mean [SD] difference between groups 1.35±2.1, P = 0.003). NaHCO 3 treatment did not result in a significant improvement in aortic pulse wave velocity from baseline. NaHCO 3 did result in a significant increase in flow-mediated dilation after 1 month; however, this effect disappeared at 6 and 12 months. NaHCO 3 resulted in a significant increase in 24-hour urine citrate and pH and a significant decrease in 24-hour urine ammonia. There was no significant change in left ventricular mass index, ejection fraction, or eGFR with NaHCO 3 . NaHCO 3 treatment was safe and well-tolerated with no significant changes in BP, antihypertensive medication, weight, plasma calcium, or potassium levels. CONCLUSION: Our results do not support the use of NaHCO 3 for vascular dysfunction in participants with CKD and normal serum bicarbonate levels.
Subject(s)
Cardiovascular Diseases , Renal Insufficiency, Chronic , Humans , Sodium Bicarbonate/therapeutic use , Bicarbonates , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Pulse Wave Analysis , Prospective Studies , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Double-Blind MethodABSTRACT
INTRODUCTION: Cerebrovascular dysfunction, characterized by increased brain pulsatile flow, reduced cerebrovascular reactivity, and cerebral hypoperfusion precedes the onset of dementia and is linked to cognitive dysfunction. Autosomal dominant polycystic kidney disease (ADPKD) may increase the risk of dementia, and intracranial aneurysms are more prevalent in ADPKD patients. However, cerebrovascular function has not been previously characterized in patients with ADPKD. METHODS: Using transcranial Doppler, we compared middle cerebral artery (MCA) pulsatility index (PI, cerebrovascular stiffness) and MCA blood velocity response to hypercapnia (normalized for blood pressure and end-tidal CO2, cerebrovascular reactivity) in patients with early-stage ADPKD versus age-matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function) and measured carotid-femoral pulse-wave velocity (PWV, aortic stiffness). RESULTS: Fifteen participants with ADPKD (9F, 27 ± 4 yrs, eGFR: 106 ± 22 mL/min/1.73 m2) were compared to 15 healthy controls (8F, 29 ± 4 yrs, eGFR: 109 ± 14 mL/min/1.73 m2). MCA PI was unexpectedly lower in ADPKD (0.71 ± 0.07) versus controls (0.82 ± 0.09 AU; p < 0.001); however, normalized MCA blood velocity in response to hypercapnia did not differ between groups (2.0 ± 1.2 vs. 2.1 ± 0.8 %Δ/mm Hg; p = 0.85). Lower MCA PI was associated with a lower crystalized composite score (cognition), which persisted after adjustment for age, sex, eGFR, and education (ß = 0.58, p = 0.007). There was no association of MCA PI with carotid-femoral PWV (r = 0.01, p = 0.96), despite greater carotid-femoral PWV in ADPKD, suggesting MCA PI reflects vascular properties other than arterial stiffness (such as low wall shear stress) in ADPKD. DISCUSSION/CONCLUSION: MCA PI is lower in patients with ADPKD. Follow-up research on this observation is merited as low PI has been associated with intracranial aneurysm in other populations.
Subject(s)
Dementia , Polycystic Kidney, Autosomal Dominant , Vascular Stiffness , Humans , Polycystic Kidney, Autosomal Dominant/complications , Hypercapnia , Blood Pressure/physiology , Cognition/physiology , Blood Flow Velocity/physiologyABSTRACT
Autosomal dominant polycystic kidney disease is a slowly progressive, lifelong disease characterized by continuous development and enlargement of kidney cysts. Thus, nonpharmacological interventions are crucial in disease management and have the potential for a large clinical impact as standalone interventions or in conjunction with pharmacological therapies. Current potential strategies regarding nonpharmacological management of autosomal dominant polycystic kidney disease include nonpharmacological management of blood pressure, calorie restriction, weight loss or weight management, enhanced hydration, limiting caffeine, dietary sodium restriction, protein restriction or altering the type of protein intake, phosphorus restriction, and reducing net acid load. This brief review discusses the available evidence, including cell culture, animal, epidemiological, and clinical studies, regarding the utility of such strategies in the nonpharmacological management of autosomal dominant polycystic kidney disease. We assert that lifestyle modification strategies should be a critical aspect of the treatment of autosomal dominant polycystic kidney disease, while further trial and mechanistic evidence continue to become available.
Subject(s)
Kidney Neoplasms , Polycystic Kidney, Autosomal Dominant , Sodium, Dietary , Animals , Polycystic Kidney, Autosomal Dominant/diagnosis , Sodium Chloride, Dietary , Blood PressureABSTRACT
Patients with chronic kidney disease (CKD) are more likely to die of cardiovascular diseases, including cerebrovascular disease, than to progress to end-stage kidney disease. Cerebrovascular dysfunction, characterized by reduced cerebrovascular reactivity, cerebral hypoperfusion, and increased pulsatile flow within the brain, precedes the onset of dementia and is linked to cognitive dysfunction. However, whether impaired cerebrovascular function is present in non-dialysis dependent CKD is largely unknown. Using transcranial Doppler, we compared middle cerebral artery (MCA) blood velocity response to hypercapnia (normalized for blood pressure and end-tidal CO2 ; a measure of cerebrovascular reactivity) and MCA pulsatility index (PI; a measure of cerebrovascular stiffness) in patients with stage 3-4 CKD vs. age-matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function), measured carotid-femoral pulse-wave velocity (PWV; aortic stiffness), and assessed ex vivo nitric oxide (NO) and reactive oxygen species (ROS) production from human brain endothelial cells incubated with serum obtained from study participants. MCA PI was higher in patients with CKD vs. controls; however, normalized MCA blood velocity response to hypercapnia did not differ between groups. Similar results were observed in a validation cohort of midlife and older adults divided by the median estimated glomerular filtration rate (eGFR). MCA PI was associated with greater large-elastic artery stiffness (carotid-femoral PWV), worse executive function (trails B time), lower eGFR, and higher ex vivo ROS production. These data suggest that impaired kidney function is associated with greater cerebrovascular stiffness, which may contribute to the known increased risk for cognitive impairment in patients with CKD.
Subject(s)
Renal Insufficiency, Chronic , Vascular Stiffness , Humans , Aged , Endothelial Cells , Hypercapnia , Reactive Oxygen Species , Blood Pressure/physiology , Vascular Stiffness/physiology , Cerebrovascular Circulation/physiology , Pulse Wave Analysis/methodsABSTRACT
Background: No previous health-economic evaluation has assessed the impact and cost-effectiveness of offering combined adult population genomic screening for mutliple high-risk conditions in a national public healthcare system. Methods: This modeling study assessed the impact of offering combined genomic screening for hereditary breast and ovarian cancer, Lynch syndrome and familial hypercholesterolaemia to all young adults in Australia, compared with the current practice of clinical criteria-based testing for each condition separately. The intervention of genomic screening, assumed as an up-front single cost in the first annual model cycle, would detect pathogenic variants in seven high-risk genes. The simulated population was 18-40 year-olds (8,324,242 individuals), modelling per-sample test costs ranging AU$100-$1200 (base-case AU$200) from the year 2023 onwards with testing uptake of 50%. Interventions for identified high-risk variant carriers follow current Australian guidelines, modelling imperfect uptake and adherence. Outcome measures were morbidity and mortality due to cancer (breast, ovarian, colorectal and endometrial) and coronary heart disease (CHD) over a lifetime horizon, from healthcare-system and societal perspectives. Outcomes included quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER), discounted 5% annually (with 3% discounting in scenario analysis). Findings: Over the population lifetime (to age 80 years), the model estimated that genomic screening per-100,000 individuals would lead to 747 QALYs gained by preventing 63 cancers, 31 CHD cases and 97 deaths. In the total model population, this would translate to 31,094 QALYs gained by preventing 2612 cancers, 542 non-fatal CHD events and 4047 total deaths. At AU$200 per-test, genomic screening would require an investment of AU$832 million for screening of 50% of the population. Our findings suggest that this intervention would be cost-effective from a healthcare-system perspective, yielding an ICER of AU$23,926 (â¼£12,050/14,110/US$15,345) per QALY gained over the status quo. In scenario analysis with 3% discounting, an ICER of AU$4758/QALY was obtained. Sensitivity analysis for the base case indicated that combined genomic screening would be cost-effective under 70% of simulations, cost-saving under 25% and not cost-effective under 5%. Threshold analysis showed that genomic screening would be cost-effective under the AU$50,000/QALY willingness-to-pay threshold at per-test costs up to AU$325 (â¼£164/192/US$208). Interpretation: Our findings suggest that offering combined genomic screening for high-risk conditions to young adults would be cost-effective in the Australian public healthcare system, at currently realistic testing costs. Other matters, including psychosocial impacts, ethical and societal issues, and implementation challenges, also need consideration. Funding: Australian Government, Department of Health, Medical Research Future Fund, Genomics Health Futures Mission (APP2009024). National Heart Foundation Future Leader Fellowship (102604).
ABSTRACT
Patients with chronic kidney disease (CKD) commonly experience sex hormone disturbances, which may be associated with the risk of cardiovascular disease (CVD) and mortality. This review aimed to systematically evaluate current findings on the association of sex hormone levels with the risk of CVD events and mortality (CVD and all-cause) in the CKD population. Articles were systematically searched in CINAHL, Cochrane, and PubMed. A total of 1739 articles were independently screened by two reviewers and 17 prospective cohort studies were included. The clinical conditions of the patients were those with non-dialysis CKD [mean/median estimated glomerular filtration rate (eGFR) between 15-51 ml/min/1.73 m2 ] and those on chronic dialysis (mean/median vintage between 6-125 months). The sample size ranged from 111 to 2419 and the mean/median age of subjects ranged from 52 to 72 years. The sex hormones studied were testosterone, estradiol, prolactin, dehydroepiandrosterone sulfate, and relaxin. A random-effects model was used to generate a pooled hazard ratio (HR) to evaluate the association of total testosterone levels with the risk of CVD and all-cause mortality. Most studies examined total testosterone levels (11 out of 17 studies) and studied only male patients (12 out of 17 studies). A lower total testosterone level was associated with a higher risk of CVD mortality [HR 4.37 (95% CI 1.40-13.65)] and all-cause mortality [1.96 (1.35-2.83)] in males with CKD. To conclude, there is a strong need for additional studies examining the association of sex hormones with cardiovascular and mortality risk in female patients with CKD.
Subject(s)
Cardiovascular Diseases , Renal Insufficiency, Chronic , Humans , Male , Female , Middle Aged , Aged , Cardiovascular Diseases/etiology , Prospective Studies , Risk Factors , Renal Insufficiency, Chronic/complications , Gonadal Steroid Hormones , TestosteroneABSTRACT
Variants in the ACTA1 gene are a common cause of nemaline myopathy (NM); a muscle disease that typically presents at birth or early childhood with hypotonia and muscle weakness. Here, we generated an induced pluripotent stem cell line (iPSC) from lymphoblastoid cells of a 3-month-old female patient with intermediate NM caused by a dominant ACTA1 variant (c.515C > A (p.Ala172Glu)). iPSCs showed typical morphology, expressed pluripotency markers, demonstrated trilineage differentiation potential, and had a normal karyotype. This line complements our previously published ACTA1 iPSC lines derived from patients with typical and severe NM.
Subject(s)
Induced Pluripotent Stem Cells , Myopathies, Nemaline , Actins/genetics , Actins/metabolism , Child, Preschool , Female , Humans , Induced Pluripotent Stem Cells/metabolism , Infant , Infant, Newborn , Muscle, Skeletal/metabolism , Mutation , Myopathies, Nemaline/geneticsABSTRACT
Nemaline myopathy (NM) is a congenital skeletal muscle disorder that typically results in muscle weakness and the presence of rod-like structures (nemaline bodies) in the sarcoplasma and/or in the nuclei of myofibres. Two induced pluripotent stem cell (iPSC) lines were generated from the lymphoblastoid cells of a 1-month-old male with severe NM caused by a homozygous recessive mutation in the ACTA1 gene (c.121C > T, p.Arg39Ter). The iPSC lines demonstrated typical morphology, expressed pluripotency markers, exhibited trilineage differentiation potential and displayed a normal karyotype. These isogenic lines represent a potential resource to investigate and model recessive ACTA1 disease in a human context.