Kidney Energetics and Cyst Burden in Autosomal Dominant Polycystic Kidney Disease: A Pilot Study.

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.

Changes in tubular biomarkers with dietary intervention and metformin in patients with autosomal dominant polycystic kidney disease: a post-hoc analysis of two clinical trials.

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.

Cerebrovascular Pulsatility Index Is Reduced in Autosomal Dominant Polycystic Kidney Disease.

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.

Metabolic reprogramming in a slowly developing orthologous model of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease and affects 1 in 1,000 individuals. There is accumulating evidence suggesting that there are shared cellular mechanisms responsible for cystogenesis in human and murine PKD and that reprogramming of metabolism is a key disease feature. In this study, we used a targeted metabolomics approach in an orthologous mouse model of PKD (Pkd1RC/RC) to investigate the metabolic modifications a cystic kidney undergoes during disease progression. Using the Kyoto Encyclopedia of Genes and Genomes pathway database, we identified several biologically relevant metabolic pathways that were altered early in this disease (in 3-mo-old Pkd1RC/RC mice), the most highly represented being arginine biosynthesis and metabolism and tryptophan and phenylalanine metabolism. During the next 6 mo of disease progression, multiple uremic solutes accumulated in the kidney of cystic mice, including several established markers of oxidative stress and endothelial dysfunction (allantoin, asymmetric dimethylarginine, homocysteine, malondialdehyde, methionine sulfoxide, and S-adenosylhomocysteine). Levels of kynurenines and polyamines were also augmented in kidneys of Pkd1RC/RC versus wild-type mice, as were the levels of bacteria-produced indoles, whose increase within PKD kidneys suggests microbial dysbiosis. In summary, we confirmed previously published and identified novel metabolic markers and pathways of PKD progression that may prove helpful for diagnosis and monitoring of cystic kidney disease in patients. Furthermore, they provide targets for novel therapeutic approaches that deserve further study and hint toward currently understudied pathomechanisms.NEW & NOTEWORTHY This report delineates the evolution of metabolic changes occurring during autosomal dominant polycystic kidney disease (ADPKD) progression. Using an orthologous model, we performed kidney metabolomics and confirmed dysregulation of metabolic pathways previously found altered in nonorthologous or rapidly-progressive PKD models. Importantly, we identified novel alterations, including augmentation of kynurenines, polyamines, and indoles, suggesting increased inflammation and microbial dysbiosis that provide insights into PKD pathomechanisms and may prove helpful for diagnosing, monitoring, and treating ADPKD.

Metformin Therapy in Autosomal Dominant Polycystic Kidney Disease: A Feasibility Study.

RATIONALE & OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that leads to kidney failure and has few treatment options. Metformin is well tolerated and safe in other patient populations. The primary objective of this clinical trial was to determine the safety and tolerability of metformin in patients with ADPKD and without diabetes mellitus. STUDY DESIGN: Prospective randomized controlled double-blind clinical trial. SETTING & PARTICIPANTS: 51 adults aged 30-60 years with ADPKD, without diabetes, and an estimated glomerular filtration rate (eGFR) 50-80 mL/min/1.73 m2. EXPOSURE: Metformin (maximum dose 2,000 mg/d) or placebo for 12 months. OUTCOME: Coprimary end points were the percentage of participants in each group prescribed at the end of the 12-month period: (1) the full randomized dose or (2) at least 50% of the randomized dose. Secondary and exploratory outcomes were the effect of metformin compared with placebo on (1) the percentage change in total kidney volume (TKV) referenced to height (htTKV in mL/m) and (2) the change in eGFR over a 12-month period. RESULTS: The participants' mean age was 48 ± 8 (SD) years, and eGFR was 70 ± 14 mL/min/1.73 m2. The metformin group had no cases of lactic acidosis, and there was 1 episode of mild hypoglycemia in each group. Participants in the metformin group reported more adverse symptoms, mostly related to the gastrointestinal tract. Eleven of 22 metformin-treated participants (50%) completed the treatment phase on the full dose compared with 23 of 23 in the placebo group (100%). In the metformin group, 82% of participants tolerated at least 50% of the dose, compared with 100% in the placebo group. In exploratory analyses, changes in htTKV or eGFR were not significantly different between the groups. LIMITATIONS: Short study duration. CONCLUSIONS: We found that 50% or more of the maximal metformin dose was safe and well tolerated over 12 months in patients with ADPKD. Safety of other preparations of metformin as well as its efficacy should be tested in future clinical trials. FUNDING: Government and philanthropic grants (NIDDK and the Zell Foundation). TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02903511.

Endocannabinoid System in Polycystic Kidney Disease.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder characterized by renal cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. The endocannabinoid (EC) system is present in the kidney and has recently emerged as an important player in inflammation and the pathogenesis of progressive kidney disease. METHODS: Data on ECs were collected using a validated mass spectrometry assay from a well-characterized cohort of 102 ADPKD patients (at baseline and after 2- and 4 years on standard vs. rigorous blood-pressure control) and compared to 100 healthy subjects. RESULTS: Compared to healthy individuals, we found higher interleukins-6 and -1b as well as reduced plasma levels of anandamide (AEA), 2-arachidonoyl-glycerol (2-AG), and their congeners in ADPKD patients. Baseline AEA concentration negatively associated with the progression of ADPKD as expressed by the yearly percent change in height-corrected total kidney volume and positively with the yearly change in renal function (measured as estimated glomerular filtration rate, ΔeGFR). AEA analog palmitoylethanolamide (PEA) is also associated positively with the yearly change in eGFR. DISCUSSION AND CONCLUSION: The results of the present study suggest that ADPKD patients present with lower levels of ECs and that reestablishing the normality of the renal EC system via augmentation of AEA, PEA, and 2-AG levels, either through the increase of their synthesis or through a reduction of their degradation, could be beneficial and may present a promising therapeutic target in said patients.

Mineral bone disease in autosomal dominant polycystic kidney disease.

Mice with disruption of Pkd1 in osteoblasts demonstrate reduced bone mineral density, trabecular bone volume and cortical thickness. To date, the bone phenotype in adult patients with autosomal dominant polycystic kidney disease (ADPKD) with stage I and II chronic kidney disease has not been investigated. To examine this, we characterized biochemical markers of mineral metabolism, examined bone turnover and biology, and estimated risk of fracture in patients with ADPKD. Markers of mineral metabolism were measured in 944 patients with ADPKD and other causes of kidney disease. Histomorphometry and immunohistochemistry were compared on bone biopsies from 20 patients with ADPKD with a mean eGFR of 97 ml/min/1.73m2 and 17 healthy individuals. Furthermore, adults with end stage kidney disease (ESKD) initiating hemodialysis between 2002-2013 and estimated the risk of bone fracture associated with ADPKD as compared to other etiologies of kidney disease were examined. Intact fibroblast growth factor 23 was higher and total alkaline phosphatase lower in patients with compared to patients without ADPKD with chronic kidney disease. Compared to healthy individuals, patients with ADPKD demonstrated significantly lower osteoid volume/bone volume (0.61 vs. 1.21%) and bone formation rate/bone surface (0.012 vs. 0.026 µm3/µm2/day). ESKD due to ADPKD was not associated with a higher risk of fracture as compared to ESKD due to diabetes (age adjusted incidence rate ratio: 0.53 (95% confidence interval 0.31, 0.74) or compared to other etiologies of kidney disease. Thus, individuals with ADPKD have lower alkaline phosphatase, higher circulating intact fibroblast growth factor 23 and decreased bone formation rate. However, ADPKD is not associated with higher rates of bone fracture in ESKD.

Detection and characterization of mosaicism in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1 and PKD2 are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novo mutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1 and PKD2 employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1 mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1 population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information.

KIM-1 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease: HALT-PKD Results.

BACKGROUND: Cyst compression of renal tubules plays a role in the progression of autosomal dominant polycystic kidney disease (ADPKD) and may induce expression of kidney injury molecule-1 (KIM-1). Whether urinary KIM-1 indexed for creatinine (uKIM-1/Cr) is a prognostic marker of disease progression in ADPKD is unknown.In this secondary analysis of a prospective cohort study, we sought to determine whether patients with high as opposed to low uKIM-1/CR at baseline had greater rates of eGFR loss and height-adjusted total kidney volume (HtTKV) increase. METHODS: Baseline uKIM-1/Cr values were obtained from 754 participants in Halt Progression of Polycystic Kidney Disease (HALT-PKD) studies A (early ADPKD) and B (late ADPKD). The predictor was uKIM-1/Cr, which was dichotomized by a median value of 0.2417 pg/g, and the primary outcomes were measured longitudinally over time. Mixed-effects linear models were used in the analysis to calculate the annual slope of change in eGFR and HtTKV. RESULTS: Patients with high uKIM-1/Cr (above the median) had an annual decline in eGFR that was 0.47 mL/min greater than that in those with low uKIM-1/Cr (p = 0.0015) after adjustment for all considered covariates. This association was seen in study B patients alone (0.45 mL/min; p = 0.009), but not in study A patients alone (0.42 mL/min; p = 0.06). High baseline uKIM-1/Cr was associated with higher HtTKV in the baseline cross-sectional analysis compared to low uKIM-1/Cr (p = 0.02), but there was no difference between the groups in the mixed-effects model annual slopes. CONCLUSION: Elevated baseline uKIM-1/Cr is associated with a greater decline in eGFR over time. Further research is needed to determine whether uKIM-1/Cr improves risk stratification in patients with ADPKD.

Mineralocorticoid Antagonism and Vascular Function in Early Autosomal Dominant Polycystic Kidney Disease: A Randomized Controlled Trial.

RATIONALE & OBJECTIVE: Vascular dysfunction, characterized by impaired vascular endothelial function and increased large-elastic artery stiffness, is evident early in autosomal dominant polycystic kidney disease (ADPKD) and is an important predictor of cardiovascular events and mortality. Aldosterone excess has been implicated in the development of endothelial dysfunction and arterial stiffness, in part by causing increased oxidative stress and inflammation. We hypothesized that aldosterone antagonism would reduce vascular dysfunction in patients with early-stage ADPKD. STUDY DESIGN: Prospective, randomized, controlled, double-blind, clinical trial. SETTING & PARTICIPANTS: 61 adults aged 20 to 55 years with ADPKD, estimated glomerular filtration rate ≥ 60mL/min/1.73m2, and receiving a renin-angiotensin-aldosterone system inhibitor. INTERVENTION: Spironolactone (maximum dose, 50mg/d) or placebo for 24 weeks. OUTCOMES: Change in brachial artery flow-mediated dilation (FMDBA) was the primary end point and change in carotid-femoral pulse-wave velocity (CFPWV) was the secondary end point. RESULTS: 60 participants completed the trial. Participants had a mean age of 34±10 (SD) years, 54% were women, and 84% were non-Hispanic white. Spironolactone did not change FMDBA (8.0% ± 5.5% and 7.8% ± 4.3% at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 8.4% ± 6.2% and 8.0% ± 4.6%; P=0.9for comparison of change between groups) or CFPWV (640±127 and 603±101cm/s at baseline and 24 weeks, respectively, vs corresponding values in the placebo group of 659±138 and 658±131cm/s; P=0.1). Brachial systolic blood pressure was reduced with spironolactone (median change, -6 [IQR, -15, 1] vs -2 [IQR, -7, 10] mm Hg in the placebo group; P=0.04). Spironolactone did not change the majority of circulating and/or endothelial cell markers of oxidative stress/inflammation and did not change vascular oxidative stress. LIMITATIONS: Low level of baseline vascular dysfunction; lack of aldosterone measurements. CONCLUSIONS: 24 weeks of aldosterone antagonism reduced systolic blood pressure without changing vascular function in patients with early-stage ADPKD. FUNDING: NIDDK, NIH National Center for Advancing Translational Sciences, and the Zell Family Foundation. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01853553.

Overweight and Obesity Are Predictors of Progression in Early Autosomal Dominant Polycystic Kidney Disease.

The association of overweight/obesity with disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD) remains untested. We hypothesized that overweight/obesity associates with faster progression in early-stage ADPKD. Overall, 441 nondiabetic participants with ADPKD and an eGFR>60 ml/min per 1.73 m2 who participated in the Halt Progression of Polycystic Kidney Disease Study A were categorized on the basis of body mass index (BMI; calculated using nonkidney and nonliver weight) as normal weight (18.5-24.9 kg/m2; reference; n=192), overweight (25.0-29.9 kg/m2; n=168), or obese (≥30 kg/m2; n=81). We evaluated the longitudinal (5-year) association of overweight/obesity with change in total kidney volume (TKV) by magnetic resonance imaging using linear regression and multinomial logistic regression models. Among participants, mean±SD age was 37±8 years, annual percent change in TKV was 7.4%±5.1%, and BMI was 26.3±4.9 kg/m2 The annual percent change in TKV increased with increasing BMI category (normal weight: 6.1%±4.7%, overweight: 7.9%±4.8%, obese: 9.4%±6.2%; P<0.001). In the fully adjusted model, higher BMI associated with greater annual percent change in TKV (ß=0.79; 95% confidence interval [95% CI], 0.18 to 1.39, per 5-unit increase in BMI). Overweight and obesity associated with increased odds of annual percent change in TKV ≥7% compared with <5% (overweight: odds ratio, 2.02; 95% CI, 1.15 to 3.56; obese: odds ratio, 3.76; 95% CI, 1.81 to 7.80). Obesity also independently associated with greater eGFR decline (slope) versus normal weight (fully adjusted ß =-0.08; 95% CI, -0.15 to -0.02). In conclusion, overweight and, particularly, obesity are strongly and independently associated with rate of progression in early-stage ADPKD.

CD8+ T cells modulate autosomal dominant polycystic kidney disease progression.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited nephropathy. To date, therapies alleviating the disease have largely focused on targeting abnormalities in renal epithelial cell signaling. ADPKD has many hallmarks of cancer, where targeting T cells has brought novel therapeutic interventions. However, little is known about the role and therapeutic potential of T cells in ADPKD. Here, we used an orthologous ADPKD model, Pkd1 p.R3277C (RC), to begin to define the role of T cells in disease progression. Using flow cytometry, we found progressive increases in renal CD8+ and CD4+ T cells, correlative with disease severity, but with selective activation of CD8+ T cells. By immunofluorescence, T cells specifically localized to cystic lesions and increased levels of T-cell recruiting chemokines (CXCL9/CXCL10) were detected by qPCR/in situ hybridization in the kidneys of mice, patients, and ADPKD epithelial cell lines. Importantly, immunodepletion of CD8+ T cells from one to three months in C57Bl/6 Pkd1RC/RC mice resulted in worsening of ADPKD pathology, decreased apoptosis, and increased proliferation compared to IgG-control, consistent with a reno-protective role of CD8+ T cells. Thus, our studies suggest a functional role for T cells, specifically CD8+ T cells, in ADPKD progression. Hence, targeting this pathway using immune-oncology agents may represent a novel therapeutic approach for ADPKD.

Affected parent sex and severity of autosomal dominant polycystic kidney disease: a retrospective cohort study
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OBJECTIVE: Parental inheritance may differentially affect autosomal dominant polycystic kidney disease (-ADPKD) severity via genetic imprinting or in utero epigenetic modifications; however, evidence is inconsistent. We conducted a longitudinal retrospective cohort study to assess the association between sex of the affected parent and time to hypertension diagnosis, end-stage renal disease (ESRD), and death in patients with the PKD1 genotype. MATERIALS AND METHODS: 814 individuals who participated in research at the University of Colorado were studied. Kaplan-Meier survival analysis was performed. The predictor was parental sex, and outcomes were diagnosis of hypertension, progression to ESRD, and death. We also examined associations in four strata according to affected parent and participant sex, as previous studies have reported earlier onset of ESRD in males compared to females. RESULTS: The median follow-up for each outcome was as follows: hypertension, 30 (interquartile range (IQR): 18, 37); ESRD, 43 (IQR: 31, 52), death 39 (IQR: 25, 52) years of age. Among affected offspring in the entire cohort, there was no difference in hypertension diagnosis (p = 0.97) or progression to ESRD (p = 0.79) according to affected parent sex; however, participants with an affected mother were more likely to die than participants with an affected father (p < 0.05). In stratified analyses, males were more likely than females to develop hypertension and reach ESRD when the affected parent was the father (p < 0.01) but not when the affected parent was the mother (p ≥ 0.11). CONCLUSIONS: Our results are largely in contrast to the hypothesis that severity of ADPKD is worse with maternal inheritance of disease.
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Vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease.

Background: Adults with autosomal dominant polycystic kidney disease (ADPKD) exhibit vascular dysfunction, as evidenced by impaired endothelium-dependent dilation (EDD) and stiffening of the large elastic arteries. However, it is unknown whether vascular dysfunction begins earlier in the course of ADPKD. The aim of the study was to assess EDD and arterial stiffness in children and young adults with ADPKD. Methods: Fifteen children and young adults 6­22 years of age with ADPKD and normal renal function were prospectively recruited for participation in a cross-sectional study. Fifteen healthy controls were enrolled to match cases for age and sex. The primary outcomes were EDD, measured as brachial artery flow-mediated dilation (FMDBA), and arterial stiffness, measured as carotid-femoral pulse wave velocity (CFPWV). Results: ADPKD cases were more likely to be taking an angiotensin-converting enzyme inhibitor, but otherwise did not differ from controls in clinical characteristics, including blood pressure. FMDBA was 25% lower in children and young adults with ADPKD (7.7 ± 0.9%, mean ± SE) when compared with matched controls (10.2 ± 0.8%) (P < 0.05). CFPWV was 14% higher in children and young adults with ADPKD (544 ± 23 cm/s) when compared with matched controls (478 ± 17 cm/s) (P < 0.05). Secondary measures of arterial stiffness, carotid augmentation index and carotid systolic blood pressure were also increased in cases when compared with controls (P < 0.05). Conclusions: Impaired EDD and increased arterial stiffness, important independent predictors of future cardiovascular events and mortality, are evident very early in the course of ADPKD in the presence of normal kidney function. Novel interventions to reduce vascular dysfunction in children and young adults with ADPKD should be evaluated, as childhood and young adulthood may represent a critical therapeutic window to reduce future cardiovascular risk in patients with ADPKD.

Long-Term Outcomes in Patients with Very-Early Onset Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Long-term clinical outcomes in children with very-early onset (VEO; diagnosis in utero or within the first 18 months of life) autosomal dominant polycystic kidney disease (ADPKD) are currently not well understood. We conducted a longitudinal retrospective cohort study to assess the association between VEO status and adverse clinical outcomes. METHODS: Seventy patients with VEO-ADPKD matched (by year of birth, sex and race/ethnicity) to 70 patients with non-VEO-ADPKD who participated in research at the University of Colorado were studied. Kaplan-Meier survival analysis was performed. The predictor was VEO status, and outcomes were progression to end-stage renal disease (ESRD), development of hypertension, progression to estimated glomerular filtration rate (eGFR <90 ml/min/1.73 m2), glomerular hyperfiltration (eGFR ≥140 ml/min/1.73 m2) and height-adjusted total kidney volume (htTKV) measured by MRI ≥600 ml/m. RESULTS: Median follow-up was until 16.0 years of age. There were only 4 ESRD events during the follow-up period, all in the VEO group (p < 0.05). VEO patients were more likely to develop hypertension (hazard ratio, HR 3.15, 95% CI 1.86-5.34; p < 0.0001) and to progress to eGFR <90 ml/min/1.73 m2 (HR 1.97, 95% CI 1.01-3.84; p < 0.05) than non-VEO patients. There was no difference between groups in the development of glomerular hyperfiltration (HR 0.89, 95% CI 0.56-1.42; p = 0.62). There were only 7 patients who progressed to htTKV ≥600 ml/m, 4 in the VEO group and 3 in the non-VEO group (p < 0.01). CONCLUSIONS: Several clinical outcomes are worse in patients with VEO-ADPKD compared to non-VEO ADPKD. Children with VEO-ADPKD represent a particularly high-risk group of ADPKD patients.

Therapeutic Area Data Standards for Autosomal Dominant Polycystic Kidney Disease: A Report From the Polycystic Kidney Disease Outcomes Consortium (PKDOC).

Data standards provide a structure for consistent understanding and exchange of data and enable the integration of data across studies for integrated analysis. There is no data standard applicable to kidney disease. We describe the process for development of the first-ever Clinical Data Interchange Standards Consortium (CDISC) data standard for autosomal dominant polycystic kidney disease (ADPKD) by the Polycystic Kidney Disease Outcomes Consortium (PKDOC). Definition of common data elements and creation of ADPKD-specific data standards from case report forms used in long-term ADPKD registries, an observational cohort (Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease [CRISP] 1 and 2), and a randomized clinical trial (Halt Progression of Polycystic Kidney Disease [HALT-PKD]) are described in detail. This data standard underwent extensive review, including a global public comment period, and is now available online as the first PKD-specific data standard (www.cdisc.org/therapeutic). Submission of clinical trial data that use standard data structures and terminology will be required for new electronic submissions to the US Food and Drug Administration for all disease areas by the end of 2016. This data standard will allow for the mapping and pooling of available data into a common data set in addition to providing a foundation for future studies, data sharing, and long-term registries in ADPKD. This data set will also be used to support the regulatory qualification of total kidney volume as a prognostic biomarker for use in clinical trials. The availability of consensus data standards for ADPKD has the potential to facilitate clinical trial initiation and increase sharing and aggregation of data across observational studies and among completed clinical trials, thereby improving our understanding of disease progression and treatment.

Predictors of autosomal dominant polycystic kidney disease progression.

Autosomal dominant polycystic kidney disease is a genetic disorder associated with substantial variability in its natural course within and between affected families. Understanding predictors for rapid progression of this disease has become increasingly important with the emergence of potential new treatments. This systematic review of the literature since 1988 evaluates factors that may predict and/or effect autosomal dominant polycystic kidney disease progression. Predicting factors associated with early adverse structural and/or functional outcomes are considered. These factors include PKD1 mutation (particularly truncating mutation), men, early onset of hypertension, early and frequent gross hematuria, and among women, three or more pregnancies. Increases in total kidney volume and decreases in GFR and renal blood flow greater than expected for a given age also signify rapid disease progression. Concerning laboratory markers include overt proteinuria, macroalbuminuria, and perhaps, elevated serum copeptin levels in affected adults. These factors and others may help to identify patients with autosomal dominant polycystic kidney disease who are most likely to benefit from early intervention with novel treatments.

Bioactive lipid mediators in polycystic kidney disease.

Inflammatory activity is evident in patients with chronic kidney disease with limited data available in autosomal dominant polycystic kidney disease (ADPKD). We hypothesized that inflammation is an upstream event in the pathogenesis of ADPKD and may be a contributing factor in the disease severity and progression. Serum samples from 61 HALT study A group patients were compared with samples from 49 patients from HALT study B group with moderately advanced disease. Targeted MS analysis of bioactive lipid mediators as markers of inflammation was performed and correlated with eGFR and total kidney volume (TKV) normalized to the body surface area (BSAR) to assess if these markers are predictive of ADPKD severity. ADPKD patients with eGFR >60 ml/min/1.73 m(2) showed higher levels of 5- and 12/15-lipoxygenase (LOX) and cyclooxygenase, and generated higher levels of hydroxy-octadecadienoic acids 9-HODE and 13-HODE and HETEs 8-HETE, 11-HETE, 12-HETE, and 15-HETE as compared with healthy subjects. Linear regression of 9-HODE and 13-HODE revealed a significant relationship with eGFR and TKV, while 15-HETE significantly correlated with TKV/BSAR. Production of 20-HETE, a P450-produced metabolite of arachidonic acid, was higher in ADPKD patients as compared with healthy subjects and significantly correlated with eGFR and TKV/BSAR. Perturbation in fatty acid metabolism is evident early in ADPKD patients, even in those with preserved kidney function. The identified LOX pathways may be potential therapeutic targets for slowing down ADPKD progression.

Endothelial dysfunction and oxidative stress in polycystic kidney disease.

Cardiovascular disease (CVD) is the leading cause of premature mortality in ADPKD patients. The aim was to identify potential serum biomarkers associated with the severity of ADPKD. Serum samples from a homogenous group of 61 HALT study A ADPKD patients [early disease group with estimated glomerular filtration rate (eGFR) >60 ml·min(-1)·1.73 m(-2)] were compared with samples from 49 patients from the HALT study B group with moderately advanced disease (eGFR 25-60 ml·min(-1)·1.73 m(-2)). Targeted tandem-mass spectrometry analysis of markers of endothelial dysfunction and oxidative stress was performed and correlated with eGFR and total kidney volume normalized to the body surface area (TKV/BSA). ADPKD patients with eGFR >60 ml·min(-1)·1.73 m(-2) showed higher levels of CVD risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA), homocysteine, and S-adenosylhomocysteine (SAH) compared with the healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, SDMA, homocysteine, and SAH remained negatively correlated with eGFR. Resulting cellular methylation power [S-adenosylmethionine (SAM)/SAH ratio] correlated with the reduction of renal function and increase in TKV. Concentrations of prostaglandins (PGs), including oxidative stress marker 8-isoprostane, as well as PGF2α, PGD2, and PGE2, were markedly elevated in patients with ADPKD compared with healthy controls. Upon adjustments for age, sex, systolic blood pressure, and creatinine, increased PGD2 and PGF2α were associated with reduced eGFR, whereas 8-isoprostane and again PGF2α were associated with an increase in TKV/BSA. Endothelial dysfunction and oxidative stress are evident early in ADPKD patients, even in those with preserved kidney function. The identified pathways may provide potential therapeutic targets for slowing down the disease progression.

Statin therapy in patients with early-stage autosomal dominant polycystic kidney disease: Design and baseline characteristics.

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.