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Item 4438 Twenty-four-hour Urinary Sodium Excretion Estimated from a Spot Urine Sample May Be Used as an Indicator of Intake in CKD Patients(Cambridge University Press, 2020-07-29) Lobene, Andrea; Stremke, Elizabeth; Moorthi, Ranjani; Moe, Sharon; Hill Gallant, Kathleen M.; Medicine, School of MedicineOBJECTIVES/GOALS: Sodium (Na) intake can elevate blood pressure and is a factor in developing chronic kidney disease (CKD). Twenty-four-hour urinary Na (24hUNa) is the gold standard for assessing Na intake but is burdensome. Validated equations estimate 24hUNa (e24hUNa) from a spot urine sample, but these estimations are not validated against a known Na intake in CKD. METHODS/STUDY POPULATION: The current study is a secondary analysis of a 9-day controlled feeding study in moderate CKD patients matched to healthy adults. Only CKD patients were used for the current analyses (n = 8). Participants consumed a controlled diet for 9 days, providing ~2400 mg Na/d as determined by inductively coupled plasma optical emission spectroscopy (ICP). On days 7 and 8, participants collected all urine in an inpatient setting, beginning with a fasting sample on day 7. Urine sample mineral analyses were performed by ICP and urinary creatinine by the Jaffe reaction. The day 7 fasting urine sample was used to calculate e24hUNa using 6 published equations. Log-transformed Na intake, measured 24hUNa, and e24hUNa were compared by repeated-measures ANOVA with planned contrasts using SAS. RESULTS/ANTICIPATED RESULTS: Fifty percent of the CKD patients (n = 4) were female; 63% (n = 5) were white, and 37% (n = 3) were black. On average, participants were aged 56.6 ± 13.8 y with a BMI of 31.7 ± 9.4 kg/m2 and eGFR of 40.7 ± 7.9 mL/min. Based on actual food intake, average Na intake on day 7 was 2024 ± 388 mg. Average measured 24hUNa was 2529 ± 1334 mg. The main ANOVA was significant (p = 0.02). Results from the planned contrasts found that e24hUNa from the SALTED cohort, an equation developed specifically for CKD patients, was significantly higher than both Na intake (p<0.001) and measured 24hUNa (p = 0.007). For the remaining 5 equations, e24hUNa was not significantly different from measured 24hUNa nor dietary Na intake. DISCUSSION/SIGNIFICANCE OF IMPACT : Our results suggest that e24hUNa calculated using most published equations may provide a reliable and low-burden method of assessing dietary Na intake in moderate CKD patients. These findings should be confirmed in larger samples. Additional studies are needed to validate or dispute the use of the SALTED equation for estimating Na intake.Item 547 The viscous and fermentability properties of dietary fiber impact on chronic kidney disease-mineral and bone disorder(Cambridge University Press, 2024-04-03) Biruete, Annabel; Chen, Neal X.; Srinivasan, Shruthi; O’Neill, Kalisha; Siles, Samantha; Hill Gallant, Kathleen; Moe, Sharon M.; Medicine, School of MedicineOBJECTIVES/GOALS: Dietary fiber has been used in other clinical populations to improve mineral disorders, but there is limited data in chronic kidney disease, despite the high prevalence of mineral and bone disorder (known as CKD-MBD). Our objective was to evaluate the effect of dietary fiber based on viscosity and fermentability on CKD-MBD outcomes. METHODS/STUDY POPULATION: 22-week-old male CKD rats (mild-to-moderate CKD) were randomly assigned to receive one of four fiber treatments (10% w/w each) based on fermentability and viscosity: 1) Cellulose (-fermentability, -viscosity), 2) Inulin (+fermentability, -viscosity), 3) Psyllium husk (-fermentability, +viscosity), or 4) Pectin (+ fermentability, +viscosity). Treatments lasted 10 weeks, and rats were euthanized at 32 weeks of age (kidney failure). Rats were placed in metabolic cages for 3 consecutive days the last week before euthanasia for mineral balance. At euthanasia, blood, tibia, heart, and aorta were collected for CKD-MBD assessment. Additional tissues collected included kidneys and all intestinal segments. RESULTS/ANTICIPATED RESULTS: Our preliminary data indicates that weight trajectories and survival were similar between treatment groups. At 33 weeks of age, kidney weight index (an indirect measurement of kidney function as this animal model develops polycystic kidneys) was lower in the psyllium-treated rats compared to all of the other treatments. Plasma phosphorus was lower with Psyllium and Pectin compared to Cellulose-treated rats. Left ventricular mass index was lower in the Inulin, Psyllium, and Pectin-treated rats compared to the Cellulose-treated rats. Ongoing tissue analyses include biochemical markers of mineral and bone metabolism (parathyroid hormone, fibroblast growth factor-23, and phosphorus balance), bone parameters (dynamic histomorphometry and microCT), and cardiovascular calcification. DISCUSSION/SIGNIFICANCE: Our preliminary data indicate that dietary fiber based on fermentability and viscosity impacts CKD-MBD outcomes and may be an innovative, low-cost intervention that can be trialed in people with CKD for the prevention and treatment of CKD-MBD.Item A novel murine model of combined insulin-dependent diabetes and chronic kidney disease has greater skeletal detriments than either disease individually(Elsevier, 2022-12) Damrath, John G.; Metzger, Corinne E.; Allen, Matthew R.; Wallace , Joseph M.; Anatomy, Cell Biology and Physiology, School of MedicineDiabetes and chronic kidney disease (CKD) consistently rank among the top ten conditions in prevalence and mortality in the United States. Insulin-dependent diabetes (IDD) and CKD each increase the risk of skeletal fractures and fracture-related mortality. However, it remains unknown whether these conditions have interactive end-organ effects on the skeleton. We hypothesized that combining IDD and CKD in mice would cause structural and mechanical bone alterations that are more deleterious compared to the single disease states. Female C57BL6/J mice were divided into four groups: 1) N=12 Control (CTRL), 2) N=10 Streptozotocin-induced IDD (STZ), 3) N=10 Adenine diet-induced CKD (AD), and 4) N=9 Combination (STZ+AD). STZ administration resulted in significantly higher blood glucose, HbA1c (p<0.0001), and glucose intolerance (p<0.0001). AD resulted in higher blood urea nitrogen (p=0.0002) while AD, but not STZ+AD mice, had high serum parathyroid hormone (p<0.0001) and phosphorus (p=0.0005). STZ lowered bone turnover (p=0.001). Trabecular bone volume was lowered by STZ (p<0.0001) and increased by AD (p=0.003). Tissue mineral density was lowered by STZ (p<0.0001) and AD (p=0.02) in trabecular bone but only lowered by STZ in cortical bone (p=0.002). Cortical porosity of the proximal tibia was increased by AD, moment of inertia was lower in both disease groups, and most cortical properties were lower in all groups vs CTRL. Ultimate force, stiffness, toughness, and total displacement/strain were lowered by STZ and AD. Fracture toughness was lower by AD (p=0.003). Importantly, Cohen’s D indicated that STZ+AD most strongly lowered bone turnover and mechanical properties. Taken together, structural and material-level bone properties are altered by STZ and AD while their combination resulted in greater detriments, indicating that improving bone health in the combined disease state may require novel interventions.Item A prespecified exploratory analysis from FIDELITY examined finerenone use and kidney outcomes in patients with chronic kidney disease and type 2 diabetes(Elsevier, 2023) Bakris, George L.; Ruilope, Luis M.; Anker, Stefan D.; Filippatos, Gerasimos; Pitt, Bertram; Rossing, Peter; Fried, Linda; Roy-Chaudhury, Prabir; Sarafidis, Pantelis; Ahlers, Christiane; Brinker, Meike; Joseph, Amer; Lawatscheck, Robert; Agarwal, Rajiv; FIDELIO-DKD and FIGARO-DKD Investigators; Medicine, School of MedicineIn FIDELITY, a prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies, finerenone was found to improve cardiorenal outcomes in patients with type 2 diabetes, a urine albumin-to-creatinine ratio of 30-5000 mg/g, an estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2 or more and also receiving optimized renin-angiotensin system blockade treatment. This present analysis focused on the efficacy and safety of finerenone on kidney outcomes. Among 13,026 patients with a median follow-up of three years, finerenone significantly reduced the hazard of a kidney composite outcome (time to kidney failure, sustained 57% or more decrease in eGFR from baseline, or kidney death) by 23% versus placebo (hazard ratio, 0.77; 95% confidence interval, 0.67-0.88), with a three-year absolute between-group difference of 1.7% (95% confidence interval, 0.7-2.6). Hazard ratios were directionally consistent for a prespecified baseline eGFR and urine albumin-to-creatinine ratio categories (Pinteraction = 0.62 and Pinteraction = 0.67, respectively), although there was a high degree of uncertainty in the 30-300 mg/g subgroup. Finerenone significantly reduced the hazard of end-stage kidney disease (ESKD) by 20% versus placebo (0.80; 0.64-0.99). Adverse events were similar between treatment arms, although hyperkalemia leading to treatment discontinuation occurred significantly more frequently with finerenone versus placebo (2.4% vs 0.8% and 0.6% vs 0.3% in patients with eGFR less than 60 vs. greater than or equal to 60 ml/min per 1.73 m2, respectively). Thus, finerenone improved kidney outcomes, reduced the hazard of ESKD, and is well tolerated in patients with chronic kidney disease and type 2 diabetes.Item Acute kidney injury is associated with impaired cognition and chronic kidney disease in a prospective cohort of children with severe malaria(Springer Nature, 2019-05-21) Conroy, Andrea L.; Opoka, Robert O.; Bangirana, Paul; Idro, Richard; Ssenkusu, John M.; Datta, Dibyadyuti; Hodges, James S.; Morgan, Catherine; John, Chandy C.; Pediatrics, School of MedicineBACKGROUND: Acute kidney injury (AKI) is a recognized complication of pediatric severe malaria, but its long-term consequences are unknown. METHODS: Ugandan children with cerebral malaria (CM, n = 260) and severe malaria anemia (SMA, n = 219) or community children (CC, n = 173) between 1.5 and 12 years of age were enrolled in a prospective cohort study. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to retrospectively define AKI and chronic kidney disease (CKD). Cognitive testing was conducted using the Mullen Scales of Early Learning in children < 5 and Kaufman Assessment Battery for Children (K-ABC) second edition in children ≥ 5 years of age. RESULTS: The prevalence of AKI was 35.1%, ranging from 25.1% in SMA to 43.5% in CM. In-hospital mortality was 11.9% in AKI compared to 4.2% in children without AKI (p = 0.001), and post-discharge mortality was 4.7% in AKI compared to 1.3% in children without AKI (p = 0.030) corresponding to an all-cause adjusted hazard ratio of 2.30 (95% CI 1.21, 4.35). AKI was a risk factor for short- and long-term neurocognitive impairment. At 1 week post-discharge, the frequency of neurocognitive impairment was 37.3% in AKI compared to 13.5% in children without AKI (adjusted odds ratio (aOR) 2.31 [95% CI 1.32, 4.04]); at 1-year follow-up, it was 13.3% in AKI compared to 3.4% in children without AKI (aOR 2.48 [95% CI 1.01, 6.10]), and at 2-year follow-up, it was 13.0% in AKI compared to 3.4% in children without AKI (aOR 3.03 [95% CI 1.22, 7.58]). AKI was a risk factor for CKD at 1-year follow-up: 7.6% of children with severe malaria-associated AKI had CKD at follow-up compared to 2.8% of children without AKI (p = 0.038) corresponding to an OR of 2.81 (95% CI 1.02, 7.73). The presenting etiology of AKI was consistent with prerenal azotemia, and lactate dehydrogenase as a marker of intravascular hemolysis was an independent risk factor for AKI in CM and SMA (p < 0.0001). In CM, AKI was associated with the presence and severity of retinopathy (p < 0.05) and increased cerebrospinal fluid albumin suggestive of blood-brain barrier disruption. CONCLUSIONS: AKI is a risk factor for long-term neurocognitive impairment and CKD in pediatric severe malaria.Item Altered O-glycomes of Renal Brush-Border Membrane in Model Rats with Chronic Kidney Diseases(MDPI, 2021-10-21) Yu, Aiying; Zhao, Jingfu; Zhong, Jieqiang; Wang, Junyao; Yadav, Shiv Pratap S.; Molitoris, Bruce A.; Wagner, Mark C.; Mechref, Yehia; Medicine, School of MedicineChronic kidney disease (CKD) is defined as a decrease in renal function or glomerular filtration rate (GFR), and proteinuria is often present. Proteinuria increases with age and can be caused by glomerular and/or proximal tubule (PT) alterations. PT cells have an apical brush border membrane (BBM), which is a highly dynamic, organized, and specialized membrane region containing multiple glycoproteins required for its functions including regulating uptake, secretion, and signaling dependent upon the physiologic state. PT disorders contribute to the dysfunction observed in CKD. Many glycoprotein functions have been attributed to their N- and O-glycans, which are highly regulated and complex. In this study, the O-glycans present in rat BBMs from animals with different levels of kidney disease and proteinuria were characterized and analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). A principal component analysis (PCA) documented that each group has distinct O-glycan distributions. Higher fucosylation levels were observed in the CKD and diabetic groups, which may contribute to PT dysfunction by altering physiologic glycoprotein interactions. Fucosylated O-glycans such as 1-1-1-0 exhibited higher abundance in the severe proteinuric groups. These glycomic results revealed that differential O-glycan expressions in CKD progressions has the potential to define the mechanism of proteinuria in kidney disease and to identify potential therapeutic interventions.Item Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy(Wolters Kluwer, 2019-01) Collins, Kimberly; Pratt, Victoria; Stansberry, Wesley; Medeiros, Elizabeth; Kannegolla, Karthik; Swart, Marelize; Skaar, Todd C.; Chapman, Arlene; Decker, Brian; Moorthi, Ranjani; Eadon, Michael; Medicine, School of MedicineHypertension and chronic kidney disease are inextricably linked. Hypertension is a well-recognized contributor to chronic kidney disease progression and, in turn, renal disease potentiates hypertension. A generalized approach to drug selection and dosage has not proven effective in managing these conditions, in part, because patients with heterogeneous kidney disease and hypertension etiologies are frequently grouped according to functional or severity classifications. Genetic testing may serve as an important tool in the armamentarium of clinicians who embrace precision medicine. Increasing scientific evidence has supported the utilization of genomic information to select efficacious antihypertensive therapy and understand hereditary contributors to chronic kidney disease progression. Given the wide array of antihypertensive agents available and diversity of genetic renal disease predictors, a panel-based approach to genotyping may be an efficient and economic means of establishing an individualized blood pressure response profile for patients with various forms of chronic kidney disease and hypertension. In this manuscript, we discuss the validation process of a Clinical Laboratory Improvement Amendments (CLIA)-approved genetic test to relay information on 72 genetic variants associated with kidney disease progression and hypertension therapy. These genomic-based interventions, in addition to routine clinical data, may help inform physicians to provide personalized therapy.Item Assessing cortical bone porosity with MRI in an animal model of chronic kidney disease(Elsevier, 2023) Newman, Christopher L.; Surowiec, Rachel K.; Swallow, Elizabeth A.; Metzger, Corinne E.; Kim, Jieun; Tomaschke, Andrew A.; Chen, Neal X.; Allen, Matthew R.; Wallace, Joseph M.; Moe, Sharon M.; Wu, Yu-Chien; Niziolek, Paul J.; Radiology and Imaging Sciences, School of MedicineChronic kidney disease (CKD) is characterized by secondary hyperparathyroidism and an increased risk of hip fractures predominantly related to cortical porosity. Unfortunately, bone mineral density measurements and high-resolution peripheral computed tomography (HR-pQCT) imaging have shortcomings that limit their utility in these patients. Ultrashort echo time magnetic resonance imaging (UTE-MRI) has the potential to overcome these limitations by providing an alternative assessment of cortical porosity. The goal of the current study was to determine if UTE-MRI could detect changes in porosity in an established rat model of CKD. Cy/+ rats (n = 11), an established animal model of CKD-MBD, and their normal littermates (n = 12) were imaged using microcomputed tomography (microCT) and UTE-MRI at 30 and 35 weeks of age (which approximates late-stage kidney disease in humans). Images were obtained at the distal tibia and the proximal femur. Cortical porosity was assessed using the percent porosity (Pore%) calculated from microCT imaging and the porosity index (PI) calculated from UTE-MRI. Correlations between Pore% and PI were also calculated. Cy/+ rats had higher Pore% than normal rats at both skeletal sites at 35 weeks (tibia = 7.13 % +/- 5.59 % vs. 0.51 % +/- 0.09 %, femur = 19.99 % +/- 7.72 % vs. 2.72 % +/- 0.32 %). They also had greater PI at the distal tibia at 30 weeks of age (0.47 +/- 0.06 vs. 0.40 +/- 0.08). However, Pore% and PI were only correlated in the proximal femur at 35 weeks of age (ρ = 0.929, Spearman). These microCT results are consistent with prior studies in this animal model utilizing microCT imaging. The UTE-MRI results were inconsistent, resulting in variable correlations with microCT imaging, which may be related to suboptimal bound and pore water discrimination at higher magnetic field strengths. Nevertheless, UTE-MRI may still provide an additional clinical tool to assess fracture risk without using ionizing radiation in CKD patients.Item Association of delayed cord clamping with acute kidney injury and two-year kidney outcomes in extremely premature neonates: a secondary analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT)(Research Square, 2024-07-19) Harer, Matthew; Zapata, Henry; Todurkar, Namrata; Favel, Kristen; Griffin, Russell; Starr, Michelle; Charlton, Jennifer; McAdams, Ryan; Askenazi, David; Kulkarni, Tapas; Menon, Shina; Mammen, Cherry; Pediatrics, School of MedicineBackground: Delayed cord clamping (DCC) occurs in most preterm births. Objective: Evaluate the association of DCC with acute kidney injury (AKI) and two-year kidney outcomes. Methods: Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates born 240/7 to 276/7 weeks' gestation. AKI and two year kidney outcomes were compared in neonates with DCC (≥30 seconds after delivery) to those with early cord clamping (ECC) (<30 seconds after delivery). Results: The incidence and severity of AKI did not differ between the DCC and ECC groups (aOR 1.17 [95%CI 0.76-1.80]). At two years corrected age, DCC was associated with a 4.5-fold times increased adjusted odds of eGFR <90 mL/min/1.73m2. No significant associations were noted between DCC and albuminuria or elevated BP. Conclusions: DCC was not associated with decreased neonatal AKI, but was associated with higher adjusted odds of eGFR <90 mL/min/1.73m2 at two years.Item Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial(American Heart Association, 2021) Ye, Nan; Jardine, Meg J.; Oshima, Megumi; Hockham, Carinna; Heerspink, Hiddo J. L.; Agarwal, Rajiv; Bakris, George; Schutte, Aletta E.; Arnott, Clare; Chang, Tara I.; Górriz, Jose L.; Cannon, Christopher P.; Charytan, David M.; de Zeeuw, Dick; Levin, Adeera; Mahaffey, Kenneth W.; Neal, Bruce; Pollock, Carol; Wheeler, David C.; Di Tanna, Gian Luca; Cheng, Hong; Perkovic, Vlado; Neuen, Brendon L.; Medicine, School of MedicineBackground: People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. Methods: The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4401 participants, of whom 3361 (76.4%) had baseline systolic BP ≥130 mm Hg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50 mm Hg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP-lowering therapy subgroups (all P interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP-lowering agents during the trial (hazard ratio, 0.68 [95% CI, 0.61-0.75]). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death caused by kidney or cardiovascular disease (hazard ratio, 0.70 [95% CI, 0.59-0.82]) was consistent across BP and BP-lowering therapy subgroups (all P interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. Conclusions: In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: