Browsing by Subject "CKD"
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Item Anemia and FGF23 elevation in CKD: Homeostatic Interactions and Emerging Therapeutics(Wolters Kluwer, 2022) Agoro, Rafiou; White, Kenneth E.; Medical and Molecular Genetics, School of MedicinePurpose of review: Chronic kidney disease (CKD) is a progressive disorder that is associated with development of elevated fibroblast growth factor 23 (FGF23) levels and anemia. Here, we review recent literature that extends our current knowledge on the interactions between FGF23 and anemia in CKD and the impact of anemia-targeting therapeutics on FGF23 elevation in CKD. Recent findings: The anemia of CKD is primarily driven by a lack of erythropoietin (EPO) and iron deficiency. In addition to EPO and iron replacement, novel drug classes to treat anemia have been approved or are in clinical development. A recent observational study provides supportive evidence for the hypothesis that FGF23 elevation in CKD mediates adverse effects of iron deficiency on the cardiovascular system in patients with CKD. Preclinical and clinical studies revealed that ferric citrate (FC), and hypoxia-induced factor-prolyl hydroxylase inhibitor (HIF-PHI) treatment may reduce elevated FGF23 levels in CKD, suggesting that correcting anemia in CKD could potentially lower FGF23 levels. However, as we describe, HIF-PHI have context-dependent effects. Moreover, whether a reduction in FGF23 will improve patient outcomes in patients with CKD remains to be determined. Summary: With the emergence of novel therapeutics to treat oxygen and iron utilization deficits in CKD, studies have investigated the impact of these new drugs on FGF23. Several of these drugs, including FC and HIF-PHIs, alleviate iron homeostasis alterations in CKD and are associated with FGF23 reduction. Herein, we review the relationships between oxygen/iron sensing and FGF23 in CKD, recent findings which link FGF23 with cardiac dysfunction, as well as future translational and clinical avenues.Item The Association Between Kidney Disease and Diabetes Remission in Bariatric Surgery Patients With Type 2 Diabetes(Elsevier, 2019-12) Friedman, Allon N.; Wang, Junyao; Wahed, Abdus S.; Docherty, Neil G.; Fennern, Erin; Pomp, Alfons; Purnell, Jonathan Q.; le Roux, Carel W.; Wolfe, Bruce; Medicine, School of MedicineRationale & objective: The association between bariatric surgery, type 2 diabetes, and chronic kidney disease (CKD) is poorly understood. We studied whether remission of type 2 diabetes induced by bariatric surgery influences markers of kidney disease, if CKD is associated with remission of diabetes after bariatric surgery, and if baseline levels of gut hormones and peptides modify these associations. Study design: Prospective observational study. Study participants: 737 bariatric surgery patients with type 2 diabetes who participated in a multicenter cohort study for up to 5 years. Predictors: Demographics, blood pressure, medications, type of bariatric surgery, anthropometrics, markers of kidney disease, and circulating levels of gut hormones and peptides. Outcomes: Estimated glomerular filtration rate (eGFR), urinary albumin excretion, prognostic risk for CKD, and remission of diabetes. Analytical approach: Linear mixed models for eGFR; generalized linear mixed models with logit link for albuminuria, prognostic risk for CKD, and diabetes remission. Results: Remission of diabetes at 5 years post-bariatric surgery was not independently associated with eGFR but was associated with lower risk for moderate/severe increase in albuminuria (risk ratio, 0.66; 95% CI, 0.48-0.90) and stabilization in prognostic risk for CKD. These findings were modified by baseline ghrelin level. Lower preoperative eGFR and greater prognostic risk for CKD were independently associated with reduced likelihood of diabetes remission. The association with preoperative GFR was modified by C-peptide level. Higher baseline circulating ghrelin level was independently associated with a lower prognostic risk for CKD. Limitations: A minority of participants had baseline CKD; lack of comparison group; no information on duration of diabetes, other clinical end points, or kidney biopsy results. Conclusions: Remission of type 2 diabetes 5 years after bariatric surgery was associated with improvements in albuminuria and stabilized prognostic risk for CKD, but not with eGFR. Lower kidney function and greater prognostic risk at the time of bariatric surgery was linked to a lower likelihood of diabetes remission. These results highlight the need to identify the mechanisms through which bariatric surgery may delay the long-term progression of CKD in type 2 diabetes. Keywords: C-peptide; CKD risk; Obesity; Roux-en-Y gastric bypass (RYGB); albuminuria; bariatric surgery; chronic kidney disease (CKD); diabetes remission; estimated glomerular filtration rate (eGFR); ghrelin; gut peptides; insulin; laparoscopic adjustable gastric banding (LAGB); modifiable risk factor; type 2 diabetes mellitus (T2DM); urinary albumin-creatinine ratio (UACR); weight loss.Item Calcitriol suppression of parathyroid hormone fails to improve skeletal properties in an animal model of chronic kidney disease(Karger, 2016) Newman, Christopher L.; Tian, Nannan; Hammond, Max A.; Wallace, Joseph M.; Brown, Drew M.; Chen, Neal X.; Moe, Sharon M.; Allen, Matthew R.; Department of Anatomy & Cell Biology, IU School of MedicineBACKGROUND: Chronic kidney disease (CKD) leads to complex metabolic changes and an increased risk of fracture. Currently, calcitriol is the standard of care as it effectively suppresses parathyroid hormone (PTH) levels in CKD patients. While calcitriol and its analogs improve BMD and reduce fractures in the general population, the extension of these benefits to patients with advanced kidney disease is unclear. Here, the impact of calcitriol on the skeleton was examined in the setting of reduction in PTH. METHODS: Male Cy/+ rats, a PKD-like CKD model, were treated with either vehicle or calcitriol for 5 weeks. Their normal littermates served as controls. Animals were assessed for changes in mineral metabolism and skeletal parameters (microCT, histology, whole bone mechanics and bone quality). RESULTS: PTH levels were significantly higher (12-fold) in animals with CKD compared to normal controls. CKD animals also exhibited negative changes in bone structural and mechanical properties. Calcitriol treatment resulted in a 60% suppression of PTH levels in animals with CKD. Despite these changes, it had no impact on bone volume (cortical or cancellous), bone turnover, osteoclast number or whole bone mechanical properties. CONCLUSIONS: These data indicate that while calcitriol effectively lowered PTH in rats with CKD, it did little to prevent the negative effects of secondary hyperparathyroidism on the skeleton.Item A comparison of calcium to zoledronic acid for improvement of cortical bone in an animal model of CKD(Wiley, 2014-04) Moe, Sharon M.; Chen, Neal X.; Newman, Christopher L.; Gattone II, Vincent H.; Organ, Jason M.; Chen, Xianming; Allen, Matthew R.; Department of Medicine, IU School of MedicinePatients 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 oversuppressing 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 10 weeks. The results demonstrate that both zoledronic acid and calcium improved bone volume by micro-computed tomography (µCT) and both equally suppressed the 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 Con: Nutritional vitaminDreplacement in chronic kidney disease and end-stage renal disease(Oxford, 2016) Agarwal, Rajiv; Georgianos, Panagiotis I.; Department of Medicine, IU School of MedicineInsufficiency of 25-hydroxyvitamin D [25(OH)D] is highly prevalent among patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD) and is a critical component in the pathogenesis of secondary hyperparathyroidism. Accordingly, current National Kidney Foundation—Kidney Disease Outcomes Quality Initiative and Kidney Disease: Improving Global Outcomes guidelines recommend the correction of hypovitaminosis D through nutritional vitamin D replacement as a first-step therapeutic approach targeting secondary hyperparathyroidism. In this Polar Views debate, we summarize the existing evidence, aiming to defend the position that nutritional vitamin D replacement is not evidence-based and should not be applied to patients with CKD. This position is supported by the following: (i) our meta-analysis of randomized controlled trials shows that whereas nutritional vitamin D significantly increases serum 25(OH)D levels relative to placebo, there is no evidence either in predialysis CKD or in ESRD that parathyroid hormone (PTH) is lowered; (ii) on the other hand, in randomized head-to-head comparisons, nutritional vitamin D is shown to be inferior to activated vitamin D analogs in reducing PTH levels; (iii) nutritional vitamin D is reported to exert minimal to no beneficial actions in a series of surrogate risk factors, including aortic stiffness, left ventricular mass index (LVMI), epoetin utilization and immune function among others; and (iv) there is no evidence to support a benefit of nutritional vitamin D on survival and other ‘hard’ clinical outcomes. Whereas nutritional vitamin D replacement may restore 25(OH)D concentration to near normal, the real target of treating vitamin D insufficiency is to treat secondary hyperparathyroidism, which is untouched by nutritional vitamin D. Furthermore, the pleotropic benefits of nutritional vitamin D remain to be proven. Thus, there is little, if any, benefit of nutritional vitamin D replacement in CKD.Item Effect of Bariatric Surgery on CKD Risk(American Society of Nephrology, 2018-04) Friedman, Allon N.; Wahed, Abdus S.; Wang, Junyao; Courcoulas, Anita P.; Dakin, Gregory; Hinojosa, Marcelo W.; Kimmel, Paul L.; Mitchell, James E.; Pomp, Alfons; Pories, Walter J.; Purnell, Jonathan Q.; le Roux, Carel; Spaniolas, Konstantinos; Steffen, Kristine J.; Thirlby, Richard; Wolfe, Bruce; Medicine, School of MedicineObesity is linked to the development and progression of CKD, but whether bariatric surgery protects against CKD is poorly understood. We, therefore, examined whether bariatric surgery influences CKD risk. The study included 2144 adults who underwent bariatric surgery from March of 2006 to April of 2009 and participated in the Longitudinal Assessment of Bariatric Surgery-2 Study cohort. The primary outcome was CKD risk categories as assessed by the Kidney Disease Improving Global Outcomes (KDIGO) consortium criteria using a combination of eGFR and albuminuria. Patients were 79% women and 87% white, with a median age of 46 years old. Improvements were observed in CKD risk at 1 and 7 years after surgery in patients with moderate baseline CKD risk (63% and 53%, respectively), high baseline risk (78% and 56%, respectively), and very high baseline risk (59% and 23%, respectively). The proportion of patients whose CKD risk worsened was ≤10%; five patients developed ESRD. Sensitivity analyses using year 1 as baseline to minimize the effect of weight loss on serum creatinine and differing eGFR equations offered qualitatively similar results. Treatment with bariatric surgery associated with an improvement in CKD risk categories in a large proportion of patients for up to 7 years, especially in those with moderate and high baseline risk. These findings support consideration of CKD risk in evaluation for bariatric surgery and further study of bariatric surgery as a treatment for high-risk obese patients with CKD.Item Effects of Bardoxolone Methyl in Alport Syndrome(Wolters Kluwer, 2022-12) Warady, Bradley A.; Pergola, Pablo E.; Agarwal, Rajiv; Andreoli, Sharon; Appel, Gerald B.; Bangalore, Sripal; Block, Geoffrey A.; Chapman, Arlene B.; Chin, Melanie P.; Gibson , Keisha L.; Goldsberry, Angie; Iijima, Kazumoto; Inker, Lesley A.; Kashtan, Clifford E.; Knebelmann, Bertrand; Mariani, Laura H.; Meyer, Colin J.; Nozu, Kandai; O’Grady, Megan; Rheault, Michelle N.; Silva, Arnold L.; Stenvinkel, Peter; Torra, Roser; Chertow, Glenn M.; Medicine, School of MedicineBackground and objectives Alport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome. Design, setting, participants, & measurements We randomly assigned patients with Alport syndrome, ages 12–70 years and eGFR 30–90 ml/min per 1.73 m2, to bardoxolone methyl (n=77) or placebo (n=80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight. Results Patients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4; P<0.001] and 7.4 [95% confidence interval, 3.1 to 11.7; P=0.0008] ml/min per 1.73 m2, respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1; P<0.001) and 4.4 (95% confidence interval, 0.7 to 8.1; P=0.02) ml/min per 1.73 m2 at 52 and 104 weeks, respectively. In a post hoc analysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 [95% confidence interval, −1.9 to 4.9] ml/min per 1.73 m2). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure. Conclusions In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different. Clinical Trial registry name and registration number: A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL), NCT03019185Item Erythropoietin and a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHDi) lowers FGF23 in a model of chronic kidney disease (CKD)(Wiley, 2020-03-31) Noonan, Megan L.; Clinkenbeard, Erica L.; Ni, Pu; Swallow, Elizabeth A.; Tippen, Samantha P.; Agoro, Rafiou; Allen, Matthew R.; White, Kenneth E.; Medical and Molecular Genetics, School of MedicineIron‐deficiency anemia is a potent stimulator of the phosphaturic hormone Fibroblast growth factor‐23 (FGF23). Anemia, elevated FGF23, and elevated serum phosphate are significant mortality risk factors for patients with chronic kidney disease (CKD). However, the contribution of anemia to overall circulating FGF23 levels in CKD is not understood. Our goal was to investigate the normalization of iron handling in a CKD model using the erythropoiesis stimulating agents (ESAs) Erythropoietin (EPO) and the hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) FG‐4592, on the production of, and outcomes associated with, changes in bioactive, intact FGF23 (“iFGF23”). Our hypothesis was that rescuing the prevailing anemia in a model of CKD would reduce circulating FGF23. Wild‐type mice were fed an adenine‐containing diet to induce CKD, then injected with EPO or FG‐4592. The mice with CKD were anemic, and EPO improved red blood cell indices, whereas FG‐4592 increased serum EPO and bone marrow erythroferrone (Erfe), and decreased liver ferritin, bone morphogenic protein‐6 (Bmp‐6), and hepcidin mRNAs. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by >70% after delivery of either ESA, with no changes in serum phosphate. ESA treatment also reduced renal fibrosis markers, as well as increased Cyp27b1 and reduced Cyp24a1 mRNA expression. Thus, improvement of iron utilization in a CKD model using EPO and a HIF‐PHDi significantly reduced iFGF23, demonstrating that anemia is a primary driver of FGF23, and that management of iron utilization in patients with CKD may translate to modifiable outcomes in mineral metabolism.Item Fractures in Patients with CKD: Time for Action(American Society of Nephrology, 2016-11-07) Moe, Sharon M.; Nickolas, Thomas L.; Medicine, School of MedicineItem A longitudinal study of the effects of age, sex and race on body composition in chronic kidney disease(Oxford University Press, 2019-03-07) Agarwal, Rajiv; Medicine, School of MedicineBackground Chronic kidney disease (CKD) is characterized by accelerated aging, but the age-related changes in body composition and its modification by sex and race are unclear. Methods We assembled a cohort of 516 patients with CKD and 45 healthy controls and serially measured body composition using air-displacement plethysmography for up to 6 years. Mixed models were used to evaluate simultaneously the baseline and longitudinal changes in body composition as influenced by age, sex and race. Results Compared with healthy controls, patients with CKD had a greater weight, body mass index (BMI), fat mass (FM) and percent body fat (BF%), but the changes over time in body composition were similar. Older age (>60 years) was a strong determinant of loss of weight, BMI, FM and fat-free mass (FFM), but not BF%. Compared with non-blacks, blacks had a higher FFM at baseline, but they lost FFM more rapidly. Compared with women, men had an accelerated loss of FFM and accumulation of FM. Taking interactions into account, we found that young black men had no significant change in weight due to the loss of FFM and the accumulation of FM, thereby masking obesity by conventional measurements. Conclusion Among patients with CKD, the changes in body composition are influenced by age, sex and race. Young black men have changes in body composition that may remain undetectable by conventional methods thus masking the occurrence of obesity.