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Item Albuminuria and masked uncontrolled hypertension in chronic kidney disease(Oxford, 2017-12) Agarwal, Rajiv; Medicine, School of MedicineBackground Masked uncontrolled hypertension (MUCH) is associated with greater target organ damage such as left ventricular hypertrophy, increased arterial stiffness and albuminuria. Whether MUCH independently associates with greater cardiovascular end-organ damage or kidney damage is unclear. The objective of this study was to assess the strength of the relationship of MUCH (awake ambulatory blood pressure ≥135/85 mmHg and clinic blood pressure <140/90 mmHg) with target organ damage. Methods In a cross-sectional study at a veterans' administration medical center, clinically normotensive veterans without chronic kidney disease (CKD) (n = 29) and 287 patients with CKD and controlled hypertension (CH, n = 193), MUCH (n = 67) and uncontrolled hypertension (UCH, n = 27) had evaluation of target organ damage. Target organ damage was measured by echocardiography [left ventricular mass index (LVMI)], arterial ultrasonography [aortic pulse wave velocity (PWV)] and 24-h urine collection [albuminuria (urine albumin to creatinine ratio)] in all participants. Results Compared to that of controls, LVMI was higher by 21.8 g/m2 (CI, 4.0–39.7 g/m2) in CH, 27.9 (CI, 8–47.8) in MUCH and 39.5 (CI, 15.7–63.2) in UCH (P < 0.01 for group differences, P < 0.01 for linear trend). Although differences persisted after adjustment for age, sex and race, they lost significance after adjustments for cardiovascular risk factors and their treatment. Compared to that of controls, PWV was different among CH, MUCH and UCH (P = 0.04 for group differences, P = 0.02 for linear trend). However, differences lost significance after adjustments for age, sex and race. Compared to that of controls, log2 UACR was higher by 2.40 mg/mg (CI, 1.28–3.52) in CH, 4.94 (CI, 3.70–6.18) in MUCH and 6.01 (CI, 4.49–7.53) in UCH (P < 0.0001 for group difference, P < 0.0001 for linear trend). Differences persisted after adjustment for age, sex and race, cardiovascular risk factors and their treatment and cardiovascular disease (P < 0.0001 for group difference, P < 0.0001 for linear trend). Conclusions MUCH is more strongly related to albuminuria compared with cardiovascular damage as assessed by left ventricular mass and PWV. A graded and an independent relationship of blood pressure classification status with albuminuria is consistent with the hypothesis that renal mechanisms may be more important than cardiovascular disease in mediating the pathogenesis of MUCH.Item Association of Finerenone Use With Reduction in Treatment-Emergent Pneumonia and COVID-19 Adverse Events Among Patients With Type 2 Diabetes and Chronic Kidney Disease: A FIDELITY Pooled Secondary Analysis(American Medical Association, 2022-10) Pitt, Bertram; Agarwal, Rajiv; Anker, Stefan D.; Ruilope, Luis M.; Rossing, Peter; Ahlers, Christiane; Brinker, Meike; Joseph, Amer; Lambelet, Marc; Lawatscheck, Robert; Filippatos, Gerasimos S.; Medicine, School of MedicineImportance Patients with chronic kidney disease and type 2 diabetes have a higher risk of developing pneumonia as well as an increased risk of severe COVID-19–associated adverse events and mortality. Therefore, the anti-inflammatory effects of mineralocorticoid receptor antagonists via blockade of the mineralocorticoid receptor may alter the risk of pneumonia and COVID-19–associated adverse events in patients with chronic kidney disease and type 2 diabetes. Objective To evaluate whether the selective, nonsteroidal mineralocorticoid receptor antagonist finerenone is associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Design, Setting, and Participants This secondary analysis used patient-level data from FIDELITY, a prespecified pooled analysis of 2 multicenter, double-blind, placebo-controlled, event-driven, phase 3 randomized clinical trials: FIDELIO-DKD and FIGARO-DKD, conducted between September 2015 and February 2021. Patients in FIDELIO-DKD or FIGARO-DKD with type 2 diabetes and chronic kidney disease (urine albumin to creatine ratio, 30-5000 mg/g, estimated glomerular filtration rate ≥25 mL/min/1.73 m2) were assessed. Data were analyzed from May 15, 2021, to July 28, 2022. Exposure Patients were randomized to finerenone (10 or 20 mg once daily) or matching placebo. Main Outcomes and Measures The main outcomes were investigator-reported incidences of treatment-emergent infective pneumonia adverse events and serious adverse events (during and up to 3 days after treatment) and any COVID-19 adverse events. Results Of 13 026 randomized patients (mean [SD] age, 64.8 [9.5] years; 9088 [69.8%] men), 12 999 were included in the FIDELITY safety population (6510 patients receiving finerenone; 6489 patients receiving placebo). Over a median (range) treatment duration of 2.6 (0-5.1) years, finerenone was consistently associated with reduced risk of pneumonia and serious pneumonia vs placebo. Overall, 307 patients (4.7%) treated with finerenone and 434 patients (6.7%) treated with placebo experienced pneumonia (hazard ratio [HR], 0.71; 95% CI, 0.64-0.79; P < .001). Serious pneumonia occurred in 171 patients (2.6%) treated with finerenone and 250 patients (3.9%) treated with placebo (HR, 0.69; 95% CI, 0.60-0.79; P < .001). Incidence proportions of COVID-19 adverse events were 86 patients (1.3%) in the finerenone group and 118 patients (1.8%) in the placebo group (HR, 0.73; 95% CI, 0.60-0.89; P = .002). Conclusions and Relevance These findings suggest that mineralocorticoid receptor blockade with finerenone was associated with protection against pneumonia and COVID-19 adverse events in patients with type 2 diabetes and chronic kidney disease. Further clinical studies may be warranted. Trial Registration ClinicalTrials.gov identifiers: FIDELIO-DKD: NCT02540993; FIGARO-DKD: NCT02545049Item Cardiovascular Functional Changes in Chronic Kidney Disease: Integrative Physiology, Pathophysiology and Applications of Cardiopulmonary Exercise Testing(Frontiers, 2020-09-15) Lim, Kenneth; McGregor, Gordon; Coggan, Andrew R.; Lewis, Gregory D.; Moe, Sharon M.; Medicine, School of MedicineThe development of cardiovascular disease during renal impairment involves striking multi-tiered, multi-dimensional complex alterations encompassing the entire oxygen transport system. Complex interactions between target organ systems involving alterations of the heart, vascular, musculoskeletal and respiratory systems occur in Chronic Kidney Disease (CKD) and collectively contribute to impairment of cardiovascular function. These systemic changes have challenged our diagnostic and therapeutic efforts, particularly given that imaging cardiac structure at rest, rather than ascertainment under the stress of exercise, may not accurately reflect the risk of premature death in CKD. The multi-systemic nature of cardiovascular disease in CKD patients provides strong rationale for an integrated approach to the assessment of cardiovascular alterations in this population. State-of-the-art cardiopulmonary exercise testing (CPET) is a powerful, dynamic technology that enables the global assessment of cardiovascular functional alterations and reflects the integrative exercise response and complex machinery that form the oxygen transport system. CPET provides a wealth of data from a single assessment with mechanistic, physiological and prognostic utility. It is an underutilized technology in the care of patients with kidney disease with the potential to help advance the field of cardio-nephrology. This article reviews the integrative physiology and pathophysiology of cardio-renal impairment, critical new insights derived from CPET technology, and contemporary evidence for potential applications of CPET technology in patients with kidney disease.Item Cinacalcet Administration by Gastrostomy Tube in a Child Receiving Peritoneal Dialysis(Pediatric Pharmacy Advocacy Group and Allen Press Publishing Services, 2014-07) Nichols, Kristen R.; Knoderer, Chad A.; Johnston, Bethanne; Wilson, Amy C.; Department of Pediatrics, Indiana University School of MedicineA 2-year-old male with chronic kidney disease with secondary hyperparathyroidism developed hypercal - cemia while receiving calcitriol, without achieving a serum parathyroid hormone concentration within the goal range. Cinacalcet 15 mg (1.2 mg/kg), crushed and administered via gastrostomy tube, was added to the patient’s therapy. This therapy was effective in achieving targeted laboratory parameters in our patient despite instructions in the prescribing information that cinacalcet should always be taken whole.Item A comparison of calcium to zoledronic acid for improvement of cortical bone in an animal model of CKD(Published article can be found at: http://onlinelibrary.wiley.com/doi/10.1002/jbmr.2089/abstract doi: 10.1002/jbmr.2089, 2013-09-03) Moe, Sharon M.; Chen, Neal X.; Newman, Christopher L.; Gattone II, Vincent H.; Organ, Jason M.; Chen, Xianming; Allen, Matthew R.Patients with chronic kidney disease (CKD) have increased risk of fractures, yet the optimal treatment is unknown. In secondary analyses of large randomized trials, bisphosphonates have been shown to improve bone mineral density and reduce fractures. However, bisphosphonates are currently not recommended in patients with advanced kidney disease due to concern about over-suppressing bone remodeling, which may increase the risk of developing arterial calcification. In the present study we used a naturally occurring rat model of CKD with secondary hyperparathyroidism, the Cy/+ rat, and compared the efficacy of treatment with zoledronic acid, calcium given in water to simulate a phosphate binder, and the combination of calcium and zoledronic acid. Animals were treated beginning at 25 weeks of age (approximately 30% of normal renal function) and followed for ten weeks. The results demonstrate that both zoledronic acid and calcium improved bone volume by microCT and both equally suppressed mineral apposition rate, bone formation rate, and mineralizing surface of trabecular bone. In contrast, only calcium treatment with or without zoledronic acid improved cortical porosity and cortical biomechanical properties (ultimate load and stiffness) and lowered parathyroid hormone (PTH). However, only calcium treatment led to the adverse effects of increased arterial calcification and fibroblast growth factor 23 (FGF23). These results suggest zoledronic acid may improve trabecular bone volume in CKD in the presence of secondary hyperparathyroidism, but does not benefit extraskeletal calcification or cortical biomechanical properties. Calcium effectively reduces PTH and benefits both cortical and trabecular bone yet increases the degree of extra skeletal calcification.Item A Comparison of the Safety and Efficacy of HX575 (Epoetin Alfa Proposed Biosimilar) with Epoetin Alfa in Patients with End-Stage Renal Disease(Karger, 2017-11) Weir, M. R.; Pergola, P. E.; Agarwal, Rajiv; Fink, J.; Kopyt, N.; Singh, A.; Kumar, J.; Schmitt, S.; Schaffar, G.; Rudy, A.; McKay, J.; Kanceva, R.; Medicine, School of MedicineBackground: HX575 (biosimilar epoetin alfa) was approved in Europe in 2007 for the treatment of chronic kidney disease (CKD)-related anemia. This study assessed the clinical equivalence of HX575 with the US-licensed reference epoetin alfa (Epogen®/Procrit®, Amgen/Janssen) following subcutaneous (SC) administration in dialysis patients with CKD-related anemia. Methods: This randomized, double-blind, parallel-group, multicenter study (NCT01693029) was conducted at 49 US clinical sites. Eligible patients were aged ≥18 years, had end-stage renal disease, were on hemodialysis or peritoneal dialysis for ≥6 months (or ≥12 months in the case of a failed kidney transplant), and were receiving treatment with stable SC doses of epoetin alfa. Eligible patients also had mean hemoglobin (Hb) concentration between 9.0 and 11.5 g/dL during the screening period. The primary endpoint was the mean absolute change in Hb concentration between the screening/baseline period (week-4 to week-1) and the evaluation period (weeks 21 to 28). Results: Hb values at the end of the evaluation period and the Hb change from baseline to evaluation period were similar between treatment groups. The estimated difference between groups in mean absolute change in Hb concentration was –0.093 g/dL, with 90% CI (–0.23 to 0.04) entirely within the pre-specified equivalence limits (–0.5 to 0.5 g/dL). The safety profile of each medicine was similar and as expected in dialysis patients, and neither method of treatment led to the development of neutralizing, clinically relevant antibodies. Conclusions: SC HX575 in dialysis patients with renal anemia was therapeutically equivalent to the reference medicine in terms of maintaining stable Hb levels and safety.Item Cortical Bone Mechanical Properties Are Altered in an Animal Model of Progressive Chronic Kidney Disease(2014-06) Newman, Christopher L.; Moe, Sharon M.; Chen, Neal X.; Hammond, Max A.; Wallace, Joseph M.; Nyman, Jeffry S.; Allen, Matthew R.Chronic kidney disease (CKD), which leads tocortical bone loss and increasedporosity,increases therisk of fracture. Animal models have confirmed that these changes compromise whole bone mechanical properties. Estimates from whole bone testing suggest that material properties are negatively affected, though tissue-level assessmentshavenot been conducted. Therefore, the goal of the present study was to examine changes in cortical bone at different length scales using a rat model with theprogressive development of CKD. At 30 weeks of age (~75% reduction in kidney function), skeletally mature male Cy/+ rats were compared to their normal littermates. Cortical bone material propertieswere assessed with reference point indentation (RPI), atomic force microscopy (AFM), Raman spectroscopy,and high performance liquid chromatography (HPLC). Bones from animals with CKD had higher (+18%) indentation distance increase and first cycle energy dissipation (+8%) as measured by RPI.AFM indentation revealed a broader distribution of elastic modulus values in CKD animals witha greater proportion of both higher and lower modulus values compared to normal controls. Yet, tissue composition, collagen morphology, and collagen cross-linking fail to account for these differences. Though the specific skeletal tissue alterations responsible for these mechanical differences remain unclear, these results indicate that cortical bone material properties are altered in these animals and may contribute to the increased fracture risk associated with CKD.Item Deconstructing Disease-Related Malnutrition: A New Assessment Framework for Clinical Practice(Elsevier, 2023-04-27) St-Jules, David E.; Lloyd, Lyn; Meade, Anthony; Biruete, Annabel; Kistler, Brandon; Carrero, Juan-Jesus; Medicine, School of MedicineProtein-energy wasting (PEW) is a key cause of functional impairment and poor health outcomes in people with chronic kidney disease. While PEW can be mitigated with nutrition therapy, it is a complex myriad of disorders with numerous interacting etiologies and corresponding presentations, which make it difficult to diagnose and manage in practice. A variety of scoring rubrics have been developed to facilitate malnutrition assessment. Although these tools have greatly benefited the recognition and treatment of PEW, the typical format of grading specified PEW indicators has the potential to overlook or overstate highly relevant individual-specific factors. This review presents a simple framework for malnutrition assessment that can be used to complement and evaluate conventional assessment tools. Unlike standard tools, which are designed to identify and rate malnutrition risk and severity, the malnutrition framework is conceptual model that organizes PEW assessment into three distinct, but interacting facets of PEW risk: nutrient balance, nutrition status, and malnutrition risk. The new framework encourages critical thinking about PEW risk that may help clinicians plan and interpret assessments to efficiently and effectively manage this condition.Item Delayed systolic blood pressure recovery following exercise as a mechanism of masked uncontrolled hypertension in chronic kidney disease(Oxford, 2017-10) Agarwal, Rajiv; Pappas, Maria K.; Medicine, School of MedicineBackground Among people treated for hypertension, the presence of elevated blood pressure (BP) out of the clinic but normal BP in the clinic is called masked uncontrolled hypertension (MUCH). What causes MUCH remains unknown. The purpose of this study was to answer the question of whether patients with MUCH have an increased hemodynamic reactivity to exercise and delayed hemodynamic recovery following exercise. Methods Four groups were compared: controlled hypertension (CH, n = 58), MUCH (n = 34) and uncontrolled hypertension (UCH, n = 12), all of which had chronic kidney disease (CKD), and a group of healthy normal volunteers who did not have hypertension or CKD (n = 16). All participants underwent assessment of 24-h ambulatory BP monitoring, BP measurement during a graded symptom-limited exercise using a cycle ergometer and BP recovery over 7 min following exercise. Results Exercise-induced increase in systolic BP was similar among the four groups. When compared with healthy controls, recovery of systolic BP following termination of exercise was blunted among the CKD groups in unadjusted (P < 0.0001) and adjusted (P < 0.001) models. During recovery, the healthy control group had 5.9% decline in systolic BP per minute. In contrast, MUCH had only 3.3% per minute reduction and the UCH group had 0.3% reduction per minute. A test of linear trend was significant (P = 0.002, adjusted model). Conclusion Because there was no impairment in the heart rate recovery among groups, we speculate that the parasympathetic pathway appears intact among treated hypertensives with CKD. However, the failure to withdraw sympathetic tone upon termination of exercise causes ongoing vasoconstriction and delayed systolic BP recovery providing a biological basis for MUCH. Delayed recovery from exercise-induced hypertension in those with poorly controlled BP provides potentially a new target to assure round-the-clock BP control.Item Effect of Etelcalcetide vs Placebo on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism(AMA, 2017-01) Block, Geoffrey A.; Bushinsky, David A.; Cunningham, John; Drueke, Tilman B.; Ketteler, Markus; Kewalramani, Reshma; Martin, Kevin J.; Mix, Christian; Moe, Sharon M.; Patel, Uptal D.; Silver, Justin; Spiegel, David M.; Sterling, Lulu; Walsh, Liron; Chertow, Glenn M.; Department of Medicine, School of MedicineImportance Secondary hyperparathyroidism contributes to extraskeletal complications in chronic kidney disease. Objective To evaluate the effect of the intravenous calcimimetic etelcalcetide on serum parathyroid hormone (PTH) concentrations in patients receiving hemodialysis. Design, Setting, and Participants Two parallel, phase 3, randomized, placebo-controlled treatment trials were conducted in 1023 patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism. Trial A was conducted in 508 patients at 111 sites in the United States, Canada, Europe, Israel, Russia, and Australia from March 12, 2013, to June 12, 2014; trial B was conducted in 515 patients at 97 sites in the same countries from March 12, 2013, to May 12, 2014. Interventions Intravenous administration of etelcalcetide (n = 503) or placebo (n = 513) after each hemodialysis session for 26 weeks. Main Outcomes and Measures The primary efficacy end point was the proportion of patients achieving greater than 30% reduction from baseline in mean PTH during weeks 20-27. A secondary efficacy end point was the proportion of patients achieving mean PTH of 300 pg/mL or lower. Results The mean age of the 1023 patients was 58.2 (SD, 14.4) years and 60.4% were men. Mean PTH concentrations at baseline and during weeks 20-27 were 849 and 384 pg/mL vs 820 and 897 pg/mL in the etelcalcetide and placebo groups, respectively, in trial A; corresponding values were 845 and 363 pg/mL vs 852 and 960 pg/mL in trial B. Patients randomized to etelcalcetide were significantly more likely to achieve the primary efficacy end point: in trial A, 188 of 254 (74.0%) vs 21 of 254 (8.3%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.4%-72.1%) and in trial B, 192 of 255 (75.3%) vs 25 of 260 (9.6%; P < .001), for a difference in proportions of 65.7% (95% CI, 59.3%-72.1%). Patients randomized to etelcalcetide were significantly more likely to achieve a PTH level of 300 pg/mL or lower: in trial A, 126 of 254 (49.6%) vs 13 of 254 (5.1%; P < .001), for a difference in proportions of 44.5% (95% CI, 37.8%-51.2%) and in trial B, 136 of 255 (53.3%) vs 12 of 260 (4.6%; P < .001), for a difference in proportions of 48.7% (95% CI, 42.1%-55.4%). In trials A and B, respectively, patients receiving etelcalcetide had more muscle spasms (12.0% and 11.1% vs 7.1% and 6.2% with placebo), nausea (12.4% and 9.1% vs 5.1% and 7.3%), and vomiting (10.4% and 7.5% vs 7.1% and 3.1%). Conclusions and Relevance Among patients receiving hemodialysis with moderate to severe secondary hyperparathyroidism, use of etelcalcetide compared with placebo resulted in greater reduction in serum PTH over 26 weeks. Further studies are needed to assess clinical outcomes as well as longer-term efficacy and safety.