Macrophage lipid accumulation in the presence of immunosuppressive drugs mycophenolate mofetil and cyclosporin A.

OBJECTIVE: Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). METHODS: Differentiated M0, M1 and M2 subsets of THP-1 human macrophages were subjected to various concentrations of either MPA or CsA. Expression of proteins involved in reverse cholesterol transport (ABCA1 and 27-hydroxylase) and scavenger receptors, responsible for uptake of modified lipids (CD36, ScR-A1, CXCL16 and LOX-1), were evaluated by real-time PCR and confirmed with Western blot. DiI-oxidized LDL internalization assay was used to assess foam cell formation. The influence of MPA was also evaluated in BMDM obtained from atherosclerosis-prone transgenic mice, ApoE-/- and ApoE-/-Fas-/-. RESULTS: In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. CONCLUSIONS: Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.

Awareness of Chronic Kidney Disease and Depressive Symptoms: National Health and Nutrition Examination Surveys 2005-2010.

BACKGROUND: Depressive symptoms are common in patients with chronic kidney disease (CKD) and may stem from distress associated with CKD awareness. So far, no studies have examined this association. The objective of this study was to evaluate the association between awareness of CKD and depressive symptoms. METHODS: We included adults with stages 1-4 CKD (estimated glomerular filtration rate 15-60 ml/min/1.73 m2 or urine albumin-to-creatinine ratio ≥30 mg/g) using the National Health and Nutrition Examination Surveys from 2005 to 2010. Depressive symptoms were categorized as minimal (9-item Patient Health Questionnaire (PHQ-9) score 0-4), subthreshold (PHQ-9 score 5-14) and severe (PHQ-9 score ≥15). Participants were classified as aware of CKD if they answered yes to the question: 'Have you ever been told you have weak or failing kidneys?' Multivariable logistic regression was used to identify variables independently associated with at least subthreshold depressive symptoms (PHQ-9 ≥5). RESULTS: In 2,500 participants with CKD, the weighted prevalence was 21.4% for subthreshold and 3.1% for severe depressive symptoms. The weighted prevalence of CKD awareness was 6.4%. Independent predictors of depressive symptoms included younger age, female gender, never been married, less than high-school education, annual family income <$20,000, obesity, smoking, cardiovascular comorbidity and mental health visit in the past year. CKD awareness was independently associated with a 1.66 greater odds of depressive symptoms (95% CI 1.01-2.74, p < 0.05). CONCLUSIONS: Awareness of CKD is significantly associated with depressive symptoms independent of known confounding factors. Future studies should examine mediators of this association, especially in light of national efforts to promote CKD awareness.

Cholesterol Metabolism in CKD.

Patients with chronic kidney disease (CKD) have a substantial risk of developing coronary artery disease. Traditional cardiovascular disease (CVD) risk factors such as hypertension and hyperlipidemia do not adequately explain the high prevalence of CVD in CKD. Both CVD and CKD are inflammatory states and inflammation adversely affects lipid balance. Dyslipidemia in CKD is characterized by elevated triglyceride levels and high-density lipoprotein levels that are both decreased and dysfunctional. This dysfunctional high-density lipoprotein becomes proinflammatory and loses its atheroprotective ability to promote cholesterol efflux from cells, including lipid-overloaded macrophages in the arterial wall. Elevated triglyceride levels result primarily from defective clearance. The weak association between low-density lipoprotein cholesterol level and coronary risk in CKD has led to controversy over the usefulness of statin therapy. This review examines disrupted cholesterol transport in CKD, presenting both clinical and preclinical evidence of the effect of the uremic environment on vascular lipid accumulation. Preventative and treatment strategies are explored.

Nephrology elective experience during medical residency: a national survey of US nephrology fellowship training program directors.

Interest in nephrology careers continues to decline in the United States. The reasons for this declining interest are not fully understood but it is plausible that inadequate exposure to the full spectrum of what a career in nephrology encompasses may be part of the explanation. Inpatient-based nephrology electives have been a common venue for residents to gain exposure to nephrology but little is known regarding the details of such electives and how often they include outpatient experiences. We carried out a national survey of nephrology fellowship training program directors to obtain data on the content of nephrology elective experiences as well as their ideas on how to promote interest in the field. The survey revealed the majority of elective experiences to be either exclusively or heavily inpatient based, with only a small percentage having a substantial outpatient component, particularly in outpatient dialysis or transplantation. Training program directors felt that providing greater outpatient experiences to residents during elective rotations would be an effective means to promote interest in nephrology, along with structured faculty mentoring. Our findings suggest that current approaches to the nephrology elective experience are heavily inpatient-based and might benefit from incorporating much more of the rich spectrum of activities a career in nephrology entails. Hopefully such efforts can create and enhance interest in careers in nephrology and potentially begin a sustained reversal of an unfortunate and serious decline in interest.

Spontaneous clearance of hepatitis B surface antigenemia after long-term hemodialysis.

Persistent infection with the hepatitis B virus (HBV) [as indicated by chronic HBV surface antigenemia (HBsAg)] continues to be an important problem in end-stage renal disease (ESRD) patients and specifically in those receiving maintenance hemodialysis (HD). Patients on HD who are HBsAg-positive for a year have little chance of ever eliminating the virus; hence, clearance of HBsAg is a rare event in long-term HD patients. We report the case of a 62-year-old diabetic woman who was HBsAg-positive at the time she started HD and remained so until 10 years later when she became HBsAg-negative followed by the development of hepatitis B surface antibody (anti-HBs). Prior to her seroconversion, she suffered a persistent infection of her HD arteriovenous graft (AVG) that required prolonged antibiotics and several surgical procedures. We speculate that this immune stimulation contributed to her seroconversion.

Reversible anuric acute kidney injury secondary to acute renal autoregulatory dysfunction.

Autoregulation of glomerular capillary pressure via regulation of the resistances at the afferent and efferent arterioles plays a critical role in maintaining the glomerular filtration rate over a wide range of mean arterial pressure. Angiotensin II and prostaglandins are among the agents which contribute to autoregulation and drugs which interfere with these agents may have a substantial impact on afferent and efferent arteriolar resistance. We describe a patient who suffered an episode of anuric acute kidney injury following exposure to a nonsteroidal anti-inflammatory agent while on two diuretics, an angiotensin-converting enzyme inhibitor, and an angiotensin receptor blocker. The episode completely resolved and we review some of the mechanisms by which these events may have taken place and suggest the term "acute renal autoregulatory dysfunction" to describe this syndrome.

Determining the Association Between the Origin of Sepsis and the Severity of Sepsis in Intensive Care Unit (ICU) Patients Using Acute Physiology and Chronic Health Evaluation (APACHE) IV.

Objective The objective of this study is to compare the outcomes of hospital mortality, the requirement of invasive ventilation, vasopressor requirement, duration of vasopressor requirement, and duration of intensive care unit (ICU) stay among the different causes of sepsis and to determine which cause of sepsis had the most severe outcomes. Methods A retrospective chart review was done in critically ill adult patients who were admitted with sepsis to the ICU from July 2017 until July 2019. Acute Physiology and Chronic Health Evaluation (APACHE) IV scores were calculated on patients admitted to ICU on day one of ICU admission. Each patient was then evaluated for outcomes of hospital mortality, need for invasive ventilation, requirement of vasopressors, duration of vasopressors, and duration of ICU stay. The outcomes were then compared between the different sources of sepsis to determine which source of sepsis had the highest severity. Results In total, 176 patients were included in the study. Ninety-three patients were admitted with respiratory sepsis, 26 patients were admitted with gastrointestinal sepsis, 31 patients were admitted with urosepsis, and 26 patients were admitted with other miscellaneous causes of sepsis. The hospital mortality was highest in the respiratory sepsis group at 32%, with a trend towards statistical significance with a P value of 0.057. ICU stay duration was highest in patients with respiratory sepsis at six days, with a statistically significant P value of < 0.001. The need for invasive ventilation was highest in patients with respiratory sepsis at 64%, with a statistically significant P value of < 0.001. The requirement of vasopressor support was highest in patients with respiratory sepsis at 47% and the duration of vasopressors was highest in both respiratory and gastrointestinal sepsis at three days, however, there was no statistical significance. Conclusion Among the different origins of sepsis, the patients with respiratory sepsis had the most severe outcomes, with the highest need for invasive ventilation and the highest ICU stay duration.

Obesity as a barrier to living kidney donation: a center-based analysis.

BACKGROUND: Obesity is a major epidemic and may present a significant barrier to living kidney donation. The purpose of our study was to determine the frequency of obesity as an exclusion factor and assess how often these donors lose weight and donate. METHODS: A single center, retrospective analysis of 104 potential living kidney donors between 2008 and 2012. RESULTS: Of the 104 donors, 19 (18%) had a normal body mass index (BMI) of <25. Eighty-five of the 104 (82%) donors spanned the overweight to morbidly obese classifications. Thirty-eight (37%) were overweight (BMI 25-29.9). Twenty-four (23%) were categorized as class I obesity (BMI 30-34.9), 17 (16%) as class II obesity (BMI 35-39.9), and six (6%) as class III obesity (BMI >40). There were a total of 23 donors (22%) who were considered moderately and morbidly obese (BMI >35). Of these, only three (13%) succeeded at losing weight and donating. CONCLUSIONS: Obesity may be a frequent barrier to living kidney donation, directly leading to exclusion as a potential kidney donor in about one in five instances. Successful weight loss leading to donation appears to be infrequent, suggesting need to address obesity in the donor population.

Forty-eight hour kidney transplant admissions.

Forty-eight hour kidney transplantation admissions are a feasible option in selected recipients of live-donor allografts through the use of standardized post-operative protocols, multidisciplinary team patient care, and intensive follow-up at outpatient centers. Age, gender, and pre-transplant dialysis status did not impact the ability to achieve 48-hour admissions. We did not identify any other pre-operative risk factors that contributed to increased length of stay. Although ABO and highly sensitized recipients had longer lengths of stay, the subgroup was too small to achieve statistical significance. We did not encounter any readmissions within the first seven post-operative days. Further improvements in clinical management will enhance the potential to shorten the length of hospital stay for all kidney transplant recipients.

Evidence-based nephrology-rheumatology debates: a novel educational experience during nephrology fellowship training.

Medical educators have called for novel learning methods that supplement the traditional lecture format. Fellowship education involves didactics and pedagogic strategies using a variety of learning tools in order to improve critical thinking skills. Debating is one such tool that can enhance critical thinking skill. However, to the best of our knowledge, evidence-based debating among two different internal medicine subspecialty fields during fellowship training has never been reported. In this article, we describe an innovative educational experience for trainees using the evidence-based debate format. Two teams consisting of equal number of first- and second-year nephrology and rheumatology fellows participated in our annual interdivisional debate session. Topics that have been debated over the last three annual debate sessions include management of small vessel vasculitis and lupus nephritis. To assess the educational experience of the debate session, all fellow participants were asked to complete an anonymous on-line survey following the debate. The survey consisted of several questions using a 5-point Likert scale. All fellow participants enjoyed the debate format and found this experience to be thought-provoking and to enhance their self-directed learning.