Oncogenic mechanisms in renal insufficiency.

The prevalence of both cancer and end-stage renal disease is increasing. In addition, medical advances have meant increased survival rates for both diseases. Many chemotherapeutics are renally excreted, and conversely, renal insufficiency promotes a pro-neoplastic state, including genitourinary and other cancers. Dialysis prolongs life while increasing cancer risk. Proposed oncogenic mechanisms include immune dysfunction, chronic inflammation, changes in gut microbiota and stimulation of the renin-angiotensin system. This review summarizes current concepts in the relationship between cancer and renal insufficiency.

Therapeutic implications of shared mechanisms in non-alcoholic fatty liver disease and chronic kidney disease.

The most common cause of liver disease worldwide is now non-alcoholic fatty liver disease (NAFLD). NAFLD refers to a spectrum of disease ranging from steatosis to non-alcoholic steatohepatitis, causing cirrhosis, and ultimately hepatocellular carcinoma. However, the impact of NAFLD is not limited to the liver. NAFLD has extra-hepatic consequences, most notably, cardiovascular and renal disease. NAFLD and chronic kidney disease share pathogenic mechanisms including insulin resistance, lipotoxicity, inflammation and oxidative stress. Not surprisingly, there has been a recent surge in efforts to manage NAFLD in an integrated way that not only protects the liver but also delays comorbidities such as chronic kidney disease. This concept of simultaneously addressing the main disease target and comorbidities is key to improve outcomes, as recently demonstrated by clinical trials of SGLT2 inhibitors and GLP1 receptor agonists in diabetes. HIF activators, already marketed in China, also have the potential to protect both liver and kidney, as suggested by preclinical data. This review concisely discusses efforts at identifying common pathogenic pathways between NAFLD and chronic kidney disease with an emphasis on potential paradigm shifts in diagnostic workup and therapeutic management.

Atrial fibrillation and chronic kidney disease conundrum: an update.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and it is frequently encountered in chronic kidney disease (CKD) subjects. CKD patients are already at high risk for cardiovascular (CV) complications and the addition of AF further aggravates the prognosis. Data is missing regarding on how to best approach CKD patients with AF, due to lack of randomized controlled trials (RCTs). AF and CKD have a double edged-sword relationship. On one hand, there are kidney-specific mechanisms which can alter cardiac structure and predispose to AF, and on the other hand the development of AF itself can accelerate the progression of CKD. Furthermore, the synergistic effect of these two entities raises serious issues concerning the balance between bleeding and thrombotic risk. Anticoagulant treatment can be challenging, especially in end stage renal disease (ESRD), where the net clinical benefit is still unclear. The decision of rate vs. rhythm control lies mostly on general consensus, rather than on RCTs. The purpose of this review is to reinforce the symbiotic relationship between AF and CKD, to briefly summarize the current state of the therapeutic approach in this particular population and to highlight novel potential therapeutic strategies.

A comprehensive review on apolipoproteins as nontraditional cardiovascular risk factors in end-stage renal disease: current evidence and perspectives.

PURPOSE: Nontraditional cardiovascular risk factors such as lipoprotein(a) (Lp(a)), the genetic polymorphisms of apolipoprotein(a), apolipoprotein E (ApoE), and apolipoprotein B (ApoB) increase the prevalence of atherosclerosis in end-stage renal disease (ESRD) through quantitative and qualitative alterations. Given the high burden of cardiovascular fatal events in ESRD, this review aims to gather studies depicting apolipoproteins' changes in ESRD, to describe current evidence and to explore potential lipid-lowering therapies. METHODS: We searched the electronic database of PubMed, SCOPUS, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins in ESRD. Randomized controlled trials, observational studies (including case-control, prospective, or retrospective cohort), and reviews/meta-analysis were included if reference was made to apolipoproteins and cardiovascular consequences in ESRD. RESULTS: 21 studies met the inclusion criteria. We found a significant correlation between Lp(a) plasma concentrations and atherosclerosis. Lp(a) levels were independent risk factors for atherothrombosis and cardiovascular mortality. LMW apo(a) phenotype proved to be the best predictor for coronary events in ESRD. Single nucleotide polymorphisms in ApoE gene affected the expression and function of the protein, increasing the risk of cardiovascular events. ApoB had a significant correlation with the value of carotid intima-media thickness and vascular stiffness. CONCLUSIONS: The picture of "lipid milieu" in ESRD has not been clearly described. Novel studies show that specific apolipoproteins suffer modifications in uremic patients, being correlated with cardiovascular events. Probably in the next years, the treatment of dyslipidemia in ESRD will not merely target LDL or total cholesterol, but specific isoforms of apolipoproteins which seem to become the central part of the problem.

Addition of silymarin to renin-angiotensin system blockers in normotensive patients with type 2 diabetes mellitus and proteinuria: a prospective randomized trial.

BACKGROUND: In the last decade, despite constant investigation, no current single treatment has been able to decrease the incidence of diabetic nephropathy and to significantly reduce progression of diabetic CKD. METHODS: Patients with type 2 diabetes mellitus and proteinuria (>0.5 g/day) after a screening and treatment optimization phase were randomly assigned to receive silymarin or placebo. The primary outcome was a composite outcome: mortality, decline of eGFR > 50% and renal replacement therapy. Secondary outcomes were a composite renal outcome (defined as a decline of eGFR ≥ 50% or ESRD) and also to test the effect of silymarin on the change in eGFR and proteinuria. We also assessed the adverse effects (hospitalizations, headache or gastrointestinal symptoms) during the study. RESULTS: One hundred and two patients were included in the study. There were no significant differences between the two study groups regarding the primary and renal outcomes (HR 0.62, 95% CI 0.3-1.2, p = 0.15; HR 0.56, 95% CI 0.26-1.24, p = 0.16, respectively). At study end, eGFR declined significantly in both arms (p < 0.001), irrespective of the treatment group allocation, and there were no significant changes in proteinuria. There was a significant difference in hospitalizations rates between the two study groups (0.61, 95% CI 0.44-0.85). CONCLUSIONS: Silymarin did not show a significant reduction in the primary and secondary outcomes. Importantly, silymarin treatment was associated with a significant reduction in the hospitalization rate.

Posterior reversible encephalopathy syndrome in children with kidney disease.

Posterior reversible encephalopathy syndrome (PRES) has been described as a neurological condition observed in a variety of clinical settings and is characterized by focal neurological deficits, seizures, headaches, altered mental status, and visual impairment, associated with transient typical lesions on neuroimaging, predominantly in the posterior part of the brain. The most common risk factors for PRES are hypertension, renal diseases, and the use of calcineurin inhibitors. The incidence of PRES in children with renal disorders varies between 4 and 9%, according to different reports. Vasogenic cerebral edema is considered the major pathophysiological mechanism of PRES. There are two main theories regarding the genesis of this edema: (1) hyperperfusion, due to autoregulatory failure of the cerebral vasculature, and (2) hypoperfusion, due to vasoconstriction of the cerebral arteries. In addition, PRES might also be the result of a systemic inflammatory state causing endothelial dysfunction. The management of PRES includes BP control, treatment of seizures, and removal of or reduction in calcineurin inhibitors. Intravenous administration of antihypertensive therapy is preferred, and various drugs have been used in this regard, including nicardipine, labetalol, sodium nitroprusside, and hydralazine. The prognosis of PRES is usually benign, except for rare cases with intracranial hemorrhage.

Electrocardiogram abnormalities and heart rate variability in predicting mortality and cardiovascular events among hemodialyzed patients.

PURPOSE: The aim of the study was to evaluate the correlation between electrocardiographic parameters and heart rate variability with cardiovascular events and mortality among chronic hemodialysis patients. METHODS: In this prospective study, we enrolled 116 asymptomatic patients in whom we performed ambulatory 24-h electrocardiographic Holter monitoring and before and after hemodialysis electrocardiographs. We measured the interval (PR, QRS, QTc, QTc dispersion) differences on the surface electrocardiographs and obtained frequency-domain measures from Holter monitoring (VLF, LF, HF and the LF/HF ratio). RESULTS: During the follow-up period, 13 participants died (11.2 %) and 16 (13.8 %) patients experienced a cardiovascular event. The pre-post-dialysis difference in QTc interval was the best predictor for cardiovascular events (95 % CI 0.453-0.786), while pre-dialysis QRS interval was the predictor for all-cause mortality (95 % CI 1.134-3.136). Also, both outcomes were predicted by pre-post-dialysis difference in PR interval and VLF. CONCLUSIONS: Interval changes during hemodialysis are predictive for cardiovascular events and mortality. Autonomic dysfunction and changes in PR should be monitored routinely, particularly in patients with suspected coronary artery disease.

The prognostic value of electrocardiographic estimation of left ventricular hypertrophy in dialysis patients.

BACKGROUND: Left ventricular hypertrophy (LVH) is associated with poor cardiovascular outcome in CKD. Electrocardiogram (ECG) is low-cost but infrequently used to assess presence of LVH in dialysis patients. The aim of this study was to establish which ECG-determined LVH method is most sensitive in dialysis patients, and also most predictive of death. METHODS: This was a longitudinal observational study in dialysis patients from a single center, undergoing interval ECGs. Fourteen methods of ECG LVH assessment were compared. Survival was also compared between four LVH evolutionary categories: persistent LVH; new LVH; LVH regression; and no LVH. RESULTS: The study included 418 dialysis patients (46.3% women, mean age 51 years, mean follow up 67 months, 76 deaths, 37 cardiovascular deaths). LVH prevalence varied according to method (range 13.4-41.9%). No measurement predicted all-cause mortality. After Cox regression, there was an independent association between LVH and cardiovascular mortality using Novacode (HR = 3.04; 95% [CI] = 1.11-8.28, P < 0.05), but not with other methods. Patients with persistent ECG changes of LVH had increased risk of cardiovascular mortality compared to other LVH evolutionary categories (P < 0.044). CONCLUSIONS: ECG scoring of LVH can be predictive of cardiovascular mortality. The Novacode method, based on repolarization abnormalities, is a better predictor than standard ECG techniques that are based on voltage criteria. Novacode LVH estimation at dialysis initiation may prove to be a noninvasive and cost-effective bedside tool for cardiovascular risk stratification in patients receiving dialysis.