The Role of Oxidative Stress and Systemic Inflammation in Kidney Disease and Its Associated Cardiovascular Risk

Chronic kidney disease (CKD) is a major global health burden, with a prevalence of 10–15% and high mortality rates. In particular, CKD portends a disproportionately high risk of cardiovascular disease beyond the traditional cardiovascular risk factors, with pathophysiological factors such as oxidative stress, inflammation and hyperuricaemia considered to exert an additional role in accelerated atherosclerosis. The presence of heightened oxidative stress and systemic inflammation in CKD is associated with increased mortality. The possible underlying mechanisms include gut dysbiosis, dialysis factors, infections, metabolic acidosis and hyperuricaemia. The state of oxidative stress and systemic inflammation are closely linked and perpetuate each other resulting in progression of CKD and cardiovascular disease. Potential interventions to alleviate the oxidative stress and inflammation in CKD include lifestyle modifications including dietary changes and exercise, optimization of dialysis procedure and pharmacotherapeutic agents including antioxidants. They present a potentially highly effective approach to add to the currently available traditional risk-modification strategies. To date, the majority of the published trials have had a small number of participants with a short duration of follow up. Therefore, no robust evidence has been established. Larger trials with meaningful clinical outcomes and longer follow up are required to evaluate such potential therapies

Fluorophotometry as a diagnostic tool for the evaluation of dry eye disease

BACKGROUND: Dry eye disease is a common debilitating ocular disease. Current diagnostic tests used in dry eye disease are often neither sensitive nor reproducible, making it difficult to accurately diagnose and determine end points for clinical trials, or evaluate the usefulness of different medications in the treatment of dry eye disease. The recently developed fluorophotometer can objectively detect changes in the corneal epithelium by quantitatively measuring its barrier function or permeability. The purpose of the study is to investigate the use of corneal fluorescein penetration measured by the fluorophotometer as a diagnostic tool in the evaluation of dry eye patients. METHODS: Dry eye patients (16 eyes), who presented with a chief complaint of ocular irritation corresponding with dry eye, low Schirmer's one test (<10 mm after 5 minutes) and corneal fluorescein staining score of more than two, were included in the study. Normal subjects (16 eyes), who came for refraction error evaluation, served as controls. Institutional Review Board (IRB) approved consent was obtained before enrolling the subjects in the study and all questions were answered while explaining the risks, benefits and alternatives. All Fluorophotometry of the central corneal epithelium was done utilizing the Fluorotron Master (TradeMark). Each eye had a baseline fluorescein scan performed, after which 50 l of 1% sodium fluorescein dye was instilled. Three minutes later, the fluorescein was washed with 50 ml of normal saline. Fluorescein scans were then started immediately after washing and were recorded at 10, 20, 40, and 60 minutes thereafter. The corneal peak values of fluorescein concentration were recorded within the central cornea in both dry eyes and in controls. RESULTS: Ten minutes after fluorescein installition, patients with dry eye disease averaged a five-fold increase in corneal tissue fluorescein concentration (mean = 375.26 ± 202.67 ng/ml) compared with that of normal subjects (mean = 128.19 ± 85.84 ng/ml). Sixty minutes after dye installation, patients with dry eye disease still revealed higher corneal tissue fluorescein concentration (mean = 112.87 ± 52.83 ng/ml) compared with that of controls (mean = 40.64 ± 7.96 ng/ml), averaging a three-fold increase. CONCLUSION: Patients with dry eye disease demonstrated an increased corneal permeability and a slower rate of elimination to topically administered fluorescein when measured by the fluorophotometer. This suggests that fluorophotometry may serve as a valuable quantitative and objective tool for the diagnosis of dry eye disease, and in following patients' response to new treatment modalities. Fluorophotometry may serve as an objective non-invasive tool for end-point analysis in clinical trials of new treatments for dry eye disease

Postoperative outcomes of kidney transplant recipients undergoing non-transplant-related elective surgery: a systematic review and meta-analysis

BACKGROUND: Reliable estimates of the absolute and relative risks of postoperative complications in kidney transplant recipients undergoing elective surgery are needed to inform clinical practice. This systematic review and meta-analysis aimed to estimate the odds of both fatal and non-fatal postoperative outcomes in kidney transplant recipients following elective surgery compared to non-transplanted patients. METHODS: Systematic searches were performed through Embase and MEDLINE databases to identify relevant studies from inception to January 2020. Risk of bias was assessed by the Newcastle Ottawa Scale and quality of evidence was summarised in accordance with GRADE methodology (grading of recommendations, assessment, development and evaluation). Random effects meta-analysis was performed to derive summary risk estimates of outcomes. Meta-regression and sensitivity analyses were performed to explore heterogeneity. RESULTS: Fourteen studies involving 14,427 kidney transplant patients were eligible for inclusion. Kidney transplant recipients had increased odds of postoperative mortality; cardiac surgery (OR 2.2, 95%CI 1.9-2.5), general surgery (OR 2.2, 95% CI 1.3-4.0) compared to non-transplanted patients. The magnitude of the mortality odds was increased in the presence of diabetes mellitus. Acute kidney injury was the most frequently reported non-fatal complication whereby kidney transplant recipients had increased odds compared to their non-transplanted counterparts. The odds for acute kidney injury was highest following orthopaedic surgery (OR 15.3, 95% CI 3.9-59.4). However, there was no difference in the odds of stroke and pneumonia. CONCLUSION: Kidney transplant recipients are at increased odds for postoperative mortality and acute kidney injury following elective surgery. This review also highlights the urgent need for further studies to better inform perioperative risk assessment to assist in planning perioperative care

Perioperative outcomes and risk assessment in dialysis patients: current knowledge and future directions

Perioperative medicine is rapidly emerging as a key discipline to address the specific needs of high-risk surgical groups, such as those on chronic dialysis. Crude hospital separation rates for chronic dialysis patients are considerably higher than patients with normal renal function, with up to 15% of admission being related to surgical intervention. Dialysis dependency carries substantial mortality and morbidity risk compared to patients with normal renal function. This group of patients has a high comorbid burden and complex medical need, making accurate perioperative planning essential. Existing perioperative risk assessment tools are unvalidated in chronic dialysis patients. Furthermore, they fail to incorporate important dialysis treatment-related characteristics that could potentially influence perioperative outcomes. There is a dearth of information on perioperative outcomes of Australasian dialysis patients. Current perioperative outcome estimates stem predominantly from North American literature; however, the generalisability of these findings is limited, as the survival of North American dialysis patients is significantly inferior to their Australasian counterparts and potentially confounds reported perioperative outcomes; let alone regional variation in surgical indication and technique. We propose that data linkage between high-quality national registries will provide more complete data with more detailed patient and procedural information to allow for more informative analyses to develop and validate dialysis-specific risk assessment tools

NT-proBNP concentration and early cardiac dysfunction in patients receiving dialysis: a prospective cohort study

Introduction: The significance of N-terminal pro-B type natriuretic peptide (NT-proBNP) to detect heart failure in patients with end-stage kidney diseases on dialysis is controversial. To assess whether serial measurements of NT-proBNP can predict worsening cardiac function in dialysis patients. Methods: In this prospective, longitudinal, observational cohort study, the relationship between changes in monthly plasma NT-proBNP concentrations and changes in echocardiographic indices (left ventricular global longitudinal strain [GLS] and ejection fraction [LVEF]) were analyzed in dialysis patients without symptoms of heart failure over 24 months using multilevel mixed effects models. Results: The study included 40 dialysis patients who were followed for a median period of 24 months. Logarithmically transformed baseline plasma NT-proBNP levels were correlated positively with GLS (r = 0.48, p = 0.002) and negatively with LVEF (r = -0.44, p = 0.005). Time-averaged and maximum NT-proBNP values during the echocardiogram intervals were significantly correlated with GLS and LVEF over time. Every 1-unit increase in average NT-proBNP level during the echocardiogram interval was associated with a 0.99 (95% confidence interval, 0.41-1.56) higher GLS (%) and 2.90 (1.22-4.57) lower LVEF (%). Every 1-unit increase in maximum NT-proBNP level was associated with a 0.90 (0.35-1.45) higher GLS (%) and 2.67 (1.03-4.30) lower LVEF (%). This increase in GLS indicates a reduction in systolic performance. Conclusions: Our cohort study demonstrated that serial plasma NT-proBNP concentrations may be useful for early identification of individuals with worsening cardiac function over time

Postoperative mortality in patients on chronic dialysis following elective surgery: a systematic review and meta-analysis

Rationale & objective: The prognostic significance of dialysis-dependent end-stage kidney disease on postoperative mortality is unclear. This study aims to estimate the odds of postoperative mortality in patients receiving chronic dialysis undergoing elective surgery compared to patients with normal kidney function, and to examine the influence of comorbidities on the excess mortality risk. Methods: A systematic search of studies published up to January 2020 was conducted using MEDLINE, EMBASE and CENTRAL databases. Eligible studies reported postoperative 30-day or in-hospital mortality in chronic dialysis patients compared to patients with normal kidney function undergoing elective surgery. Two investigators independently reviewed all abstracts and performed risk of bias assessments using the Newcastle-Ottawa Scale. Quality of evidence was summarised in accordance with GRADE methodology (grading of recommendations, assessment, development and evaluation). Relative mortality risk estimates were obtained using random effects meta-analysis. Heterogeneity was explored using meta-regression. (PROSPERO CRD42017076565) Results: Forty-nine studies involving 41, 822 chronic dialysis and 10, 476, 321 non-dialysis patients undergoing elective surgery were included. Patients on chronic dialysis had a greatly increased postoperative mortality odds compared to patients with normal kidney function. The excess risk ranged from OR 10.8 (95%CI 7.3–15.9) following orthopaedic surgery to OR 4.0 (95%CI 3.2–4.9) after vascular surgery. Adjustment for age and comorbidity attenuated the excess odds but remained higher for patients on chronic dialysis, irrespective of surgical discipline. Meta-regression analysis demonstrated an inverse linear relationship between excess mortality risk and study-level mean age (slope -0.06; P = 0.001) and diabetes prevalence (slope -0.02; p = 0.001). Conclusions: Patients on chronic dialysis have an increased odds for postoperative mortality following elective surgery across all surgical disciplines. This relationship is consistent among all studies, with the excess postoperative mortality attributable to end-stage kidney disease and chronic dialysis treatment may be lower among older patients with diabetes

Assessment of cardiac structure and function in kidney failure: understanding echocardiography and magnetic resonance imaging for the nephrologist

Cardiovascular disease is the leading cause of death in patients with kidney failure or on chronic dialysis. Patients on chronic dialysis have a 10- to 50-fold increased risk of sudden cardiac death compared to patients with normal kidney function. Adverse changes in cardiac structure and function may not manifest with clinical symptoms in patients with kidney failure and, therefore, pose a challenge in identifying cardiac dysfunction early. Fortunately, there are multi-modality cardiac imaging techniques available, including echocardiography and cardiac magnetic resonance imaging, that can help our understanding of the pathophysiology of cardiac dysfunction in kidney failure. This review describes the benefits and limitations of these two commonly available cardiac imaging modalities to assess cardiac structure and function, thereby aiding nephrologists in choosing the most appropriate investigative tool based on individual clinical circumstances. For the purposes of this review, cardiac imaging for detection of coronary artery disease has been omitted

Long-term outcomes of patients with end-stage kidney disease due to membranous nephropathy: A cohort study using the Australia and New Zealand Dialysis and Transplant Registry

Clinical outcomes of patients with end-stage kidney disease (ESKD) secondary to membranous nephropathy (MN) have not been well described. This study aimed to evaluate patient and/or allograft outcomes of dialysis or kidney transplantation in patients with ESKD secondary to MN.All adult patients with ESKD commencing renal replacement therapy in Australia and New Zealand from January 1998 to December 2010 were extracted retrospectively from ANZDATA registry on 31st December 2013. Outcomes of MN were compared to other causes of ESKD. In a secondary analysis, outcomes of MN were compared to all patients with ESKD due to other forms of glomerulonephritis.Of 32,788 included patients, 417 (1.3%) had MN. Compared to other causes of ESKD, MN experienced lower mortality on dialysis (adjusted hazard ratio [aHR] 0.79, 95% CI 0.68-0.92, p = 0.002) and following kidney transplantation (aHR 0.57, 95% CI 0.33-0.97, p = 0.04), had a higher risk of death-censored kidney allograft failure (aHR 1.55, 95% CI: 1.00-2.41, p = 0.05) but comparable risk of overall kidney allograft failure (aHR 1.35, 95% CI 0.91-2.01, p = 0.13). Similar results were obtained using competing-risk regression analyses. MN patients were significantly more likely to receive a kidney transplant (aHR 1.38, 95% CI 1.16-1.63,

High dose methotrexate and extended hours high-flux hemodialysis for the treatment of primary central nervous system lymphoma in a patient with end stage renal disease

This report discusses the case of a 52 year old female with post-transplant lymphoproliferative disorder, confined to the central nervous system, which was managed with high dose methotrexate (HDMTX) in the context of end stage renal disease. The patient received two doses of HDMTX followed by extended hours high-flux hemodialysis, plasma methotrexate concentration monitoring and leucovorin rescue. The hemodialysis technique used was effective in clearing plasma methotrexate and allowed delivery of HDMTX to achieve complete remission with limited and reversible direct methotrexate-related toxicity. Dialysis-dependent renal failure does not preclude the use of HDMTX when required for curative therapy of malignancy