Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease.

Mitochondria abnormalities in skeletal muscle may contribute to frailty and sarcopenia, commonly present in patients with chronic kidney disease (CKD). Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD We tested the hypothesis that mitochondrial structure and function worsens with the severity of CKD Mitochondrial volume density, mitochondrial DNA (mtDNA) copy number, BNIP3, and PGC1α protein expression were evaluated in skeletal muscle biopsies obtained from 27 subjects (17 controls and 10 with CKD stage 5 on hemodialysis). We also measured mtDNA copy number in peripheral blood mononuclear cells (PBMCs), plasma isofurans, and plasma F2-isoprostanes in 208 subjects divided into three groups: non-CKD (eGFR>60 mL/min), CKD stage 3-4 (eGFR 60-15 mL/min), and CKD stage 5 (on hemodialysis). Muscle biopsies from patients with CKD stage 5 revealed lower mitochondrial volume density, lower mtDNA copy number, and higher BNIP3 content than controls. mtDNA copy number in PBMCs was decreased with increasing severity of CKD: non-CKD (6.48, 95% CI 4.49-8.46), CKD stage 3-4 (3.30, 95% CI 0.85-5.75, P = 0.048 vs. non-CKD), and CKD stage 5 (1.93, 95% CI 0.27-3.59, P = 0.001 vs. non-CKD). Isofurans were higher in patients with CKD stage 5 (median 59.21 pg/mL, IQR 41.76-95.36) compared to patients with non-CKD (median 49.95 pg/mL, IQR 27.88-83.46, P = 0.001), whereas F2-isoprostanes did not differ among groups. Severity of CKD is associated with mitochondrial dysfunction and markers of oxidative stress. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD Further studies are required to evaluate mitochondrial function in vivo in patients with different CKD stages

Use of Antihypertensive Agents and Association With Risk of Adverse Outcomes in Chronic Kidney Disease: Focus on Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers.

Background Our objective was to determine patterns of antihypertensive agent use by stage of chronic kidney disease (CKD) and to evaluate the association between different classes of antihypertensive agents with nonrenal outcomes, especially in advanced CKD . Methods and Results We studied 3939 participants of the CRIC (Chronic Renal Insufficiency Cohort) study. Predictors were time-dependent angiotensin-converting enzyme inhibitor or angiotensin receptor blocker , β-blocker, and calcium channel blocker use (versus nonuse of agents in each class). Outcomes were adjudicated heart failure events or death. Adjusted Cox models were used to determine the association between predictors and outcomes. We also examined whether the associations differed based on the severity of CKD (early [stage 2-3 CKD ] versus advanced disease [stage 4-5 CKD ]). During median follow-up of 7.5 years, renin-angiotensin-aldosterone system inhibitor use plateaued during CKD stage 3 (75%) and declined to 37% by stage 5, while β-blocker, calcium channel blocker, and diuretic use increased steadily with advancing CKD . Renin-angiotensin-aldosterone system inhibitor use was associated with lower risk of heart failure (hazard ratio, 0.79; 95% confidence interval, 0.67-0.97) and death (hazard ratio, 0.78; 95% confidence interval, 0.67-0.90), regardless of severity of CKD . Calcium channel blocker use was not associated with risk of heart failure or death, regardless of the severity of CKD . β-Blocker use was associated with higher risk of heart failure (hazard ratio, 1.62; 95% confidence interval, 1.29-2.04) and death (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43), especially during early CKD ( P<0.05 for interaction). Conclusions Angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use decreased, while use of other agents increased with advancing CKD . Use of agents besides angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be associated with suboptimal outcomes in patients with CKD

The epidemiology of chronic kidney disease (CKD) in rural East Africa: A population-based study.

BackgroundChronic kidney disease (CKD) may be common among individuals living in sub-Saharan Africa due to the confluence of CKD risk factors and genetic predisposition.MethodsWe ascertained the prevalence of CKD and its risk factors among a sample of 3,686 participants of a population-based HIV trial in rural Uganda and Kenya. Prevalent CKD was defined as a serum creatinine-based estimated glomerular filtration rate <60 mL/min/1.73m2 or proteinuria (urine dipstick ≥1+). We used inverse-weighting to estimate the population prevalence of CKD, and multivariable log-link Poisson models to assess the associations of potential risk factors with CKD.ResultsThe estimated CKD prevalence was 6.8% (95% CI 5.7-8.1%) overall and varied by region, being 12.5% (10.1-15.4%) in eastern Uganda, 3.9% (2.2-6.8%) in southwestern Uganda and 3.7% (2.7-5.1%) in western Kenya. Risk factors associated with greater CKD prevalence included age ≥60 years (adjusted prevalence ratio [aPR] 3.5 [95% CI 1.9-6.5] compared with age 18-29 years), HIV infection (aPR 1.6 [1.1-2.2]), and residence in eastern Uganda (aPR 3.9 [2.6-5.9]). However, two-thirds of individuals with CKD did not have HIV, diabetes, or hypertension as risk factors. Furthermore, we noted many individuals who did not have proteinuria had dipstick positive leukocyturia or hematuria.ConclusionThe prevalence of CKD is appreciable in rural East Africa and there are considerable regional differences. Conventional risk factors appear to only explain a minority of cases, and leukocyturia and hematuria were common, highlighting the need for further research into understanding the nature of CKD in sub-Saharan Africa

Knowledge and Awareness Among Patients with Chronic Kidney Disease Stage 3

Knowledge is a prerequisite for changing behavior, and is useful for improving outcomes and reducing mortality rates in patients diagnosed with chronic kidney disease (CKD). The purpose of this article is to describe baseline CKD knowledge and awareness obtained as part of a larger study testing the feasibility of a self-management intervention. Thirty patients were recruited who had CKD Stage 3 with coexisting diabetes and hypertension. Fifty-four percent of the sample were unaware of their CKD diagnosis. Participants had a moderate amount of CKD knowledge. This study suggests the need to increase knowledge in patients with CKD Stage 3 to aid in slowing disease progression

Primary care physicians' perceptions of barriers and facilitators to management of chronic kidney disease: A mixed methods study.

BackgroundGiven the high prevalence of chronic kidney disease (CKD), primary care physicians (PCPs) frequently manage early stage CKD. Nonetheless, there are challenges in providing optimal CKD care in the primary care setting. This study sought to understand PCPs' perceptions of barriers and facilitators to the optimal management of CKD.Study designMixed methods study.Settings and participantsCommunity-based PCPs in four US cities: Baltimore, MD; St. Louis, MO; Raleigh, NC and San Francisco, CA.MethodologyWe used a self-administered questionnaire and conducted 4 focus groups of PCPs (n = 8 PCPs/focus group) in each city to identify key barriers and facilitators to management of patients with CKD in primary care.Analytic approachWe conducted descriptive analyses of the survey data. Major themes were identified from audio-recorded interviews that were transcribed and coded by the research team.ResultsOf 32 participating PCPs, 31 (97%) had been in practice for >10 years, and 29 (91%) practiced in a non-academic setting. PCPs identified multiple barriers to managing CKD in primary care including at the level of the patient (e.g., low awareness of CKD, poor adherence to treatment recommendations), the provider (e.g., staying current with CKD guidelines), and the health care system (e.g., inflexible electronic medical record, limited time and resources). PCPs desired electronic prompts and lab decision support, concise guidelines, and healthcare financing reform to improve CKD care.ConclusionsPCPs face substantial but modifiable barriers in providing care to patients with CKD. Interventions that address these barriers and promote facilitative tools may improve PCPs' effectiveness and capacity to care for patients with CKD

Contrast-enhanced ultrasound examination for the assessment of renal perfusion in cats with chronic kidney disease

Background: Contrast-enhanced ultrasound examination (CEUS) is a functional imaging technique allowing noninvasive assessment of tissue perfusion. Studies in humans show that the technique holds great potential to be used in the diagnosis of chronic kidney disease (CKD). However, data in veterinary medicine are currently lacking. Objectives: To evaluate renal perfusion using CEUS in cats with CKD. Animals: Fourteen client-owned cats with CKD and 43 healthy control cats. Methods: Prospective case-controlled clinical trial using CEUS to evaluate renal perfusion in cats with CKD compared to healthy control cats. Time-intensity curves were created, and perfusion parameters were calculated using off-line software. A linear mixed model was used to examine differences between perfusion parameters of cats with CKD and healthy cats. Results: In cats with CKD, longer time to peak and shorter mean transit times were observed for the renal cortex. In contrast, a shorter time to peak and rise time were seen for the renal medulla. The findings for the renal cortex indicate decreased blood velocity and shorter total duration of enhancement, likely caused by increased vascular resistance in CKD. Increased blood velocity in the renal medulla has not been described before and may be because of a different response to regulatory factors in cortex and medulla. Conclusions and Clinical Importance: Contrast-enhanced ultrasound examination was capable of detecting perfusion changes in cats with CKD. Further research is warranted to assess the diagnostic capabilities of CEUS in early stage of the disease process

Mechanism of Action and Clinical Attributes of Auryxia® (Ferric Citrate).

Chronic kidney disease (CKD) is a major cause of morbidity and premature mortality and represents a significant global public health issue. Underlying this burden are the many complications of CKD, including mineral and bone disorders, anemia, and accelerated cardiovascular disease. Hyperphosphatemia and elevated levels of fibroblast growth factor 23 (FGF23) have been identified as key independent risk factors for the adverse cardiovascular outcomes that frequently occur in patients with CKD. Auryxia® (ferric citrate; Keryx Biopharmaceuticals, Inc., Boston, MA, USA) is an iron-based compound with distinctive chemical characteristics and a mechanism of action that render it dually effective as a therapy in patients with CKD; it has been approved as a phosphate binder for the control of serum phosphate levels in adult CKD patients treated with dialysis and as an iron replacement product for the treatment of iron deficiency anemia in adult CKD patients not treated with dialysis. This review focuses on Auryxia, its mechanism of action, and the clinical attributes that differentiate it from other, non-pharmaceutical-grade, commercially available forms of ferric citrate and from other commonly used phosphate binder and iron supplement therapies for patients with CKD. Consistent with the chemistry and mechanism of action of Auryxia, multiple clinical studies have demonstrated its efficacy in both lowering serum phosphate levels and improving iron parameters in patients with CKD. Levels of FGF23 decrease significantly with Auryxia treatment, but the effects associated with the cardiovascular system remain to be evaluated in longer-term studies

Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.

Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice