PhD candidate, Monash University/Baker heart and diabetes institute
About 40-80% of patients with heart failure suffer from kidney damage, and the co-existence of both heart and kidney dysfunction is associated with poor clinical outcomes. To date, there are no treatments for this disease, and this is largely due to our poor understanding of the underlying causes that lead to kidney failure in the setting of heart failure. This is the aim of my research, and I hope that my research will provide insight to the underlying mechanisms of this disease state, and hopefully, provide the basis for a new treatment target.
Abstract: Heart and kidney failure continued to be of increasing prevalence in today's society, and their comorbidity has synergistic effect on the morbidity and mortality of patients. Cardiorenal syndrome (CRS) is a complex disease with multifactorial pathophysiology. Better understanding of this pathophysiological network is crucial for the successful intervention to prevent advancement of the disease process. One of the major factors in this process is neurohormonal activation, predominantly involving renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP). Heart failure causes reduced cardiac output/cardiac index (CO/CI) and fall in renal perfusion pressures resulting in activation of baroreceptors and RAAS, respectively. Activated baroreceptors and RAAS stimulate the release of AVP (non-osmotic pathway), which acts on V2 receptors located in the renal collecting ducts, causing fluid retention and deterioration of heart failure. Effective blockade of AVP action on V2 receptors has emerged as a potential treatment option in volume overload conditions especially in the setting of hyponatremia. Vasopressin receptor antagonists (VRAs), such as vaptans, are potent aquaretics causing electrolyte-free water diuresis without significant electrolyte abnormalities. Vaptans are useful in hypervolemic hyponatremic conditions like heart failure and liver cirrhosis, and euvolemic hyponatremic conditions like syndrome of inappropriate anti-diuretic hormone secretion. Tolvaptan and conivaptan are pharmaceutical agents that are available for the treatment of these conditions.
Pub.: 21 Jul '17, Pinned: 28 Aug '17
Abstract: Chronic kidney disease (CKD) is considered a global public health issue. The latest international clinical guideline emphasizes characterization of CKD with both glomerular filtration rate (GFR) and albuminuria. CKD is closely related to cardiac disease and increases the risk of adverse outcomes among patients with cardiovascular disease (CVD). Indeed, numerous studies have investigated the association of CKD measures with prognosis among patients with CVD, but most of them have focused on kidney function, with limited data on albuminuria. Consequently, although there are several risk prediction tools for patients with CVD incorporating kidney function, to our knowledge, none of them include albuminuria. Moreover, the selection of the kidney function measure (e.g., serum creatinine, creatinine-based estimated GFR, or blood urea nitrogen) in these tools is heterogeneous. In this review, we will summarize these aspects, as well as the burden of CKD in patients with CVD, in the current literature. We will also discuss potential mechanisms linking CKD to secondary events and consider future research directions. Given their clinical and public health importance, for CVD we will focus on 2 representative cardiac diseases: myocardial infarction and heart failure.
Pub.: 07 Jul '17, Pinned: 27 Aug '17
Abstract: Renal dysfunction (RD) is associated with increased morbidity and mortality in heart failure (HF). At present, no specific treatment for patients with RD, to prevent progression of HF, has been developed. How different hormone axes—and thereby potential treatment options—are affected by RD in HF warrants further investigations.Patients with left ventricular ejection fraction (LVEF) <0.45% were enrolled prospectively from an outpatient HF clinic. Glomerular filtration rate was estimated by the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR), and patients were grouped by eGFR: eGFR group I, ≥90 mL/min/1.73 m2; eGFR group II, 60–89 mL/min/1.73 m2; and eGFR group III, ≤59 mL/min/1.73 m2. Multivariate linear regression models were developed to evaluate the associations between eGFR groups and hormones. A total of 149 patients participated in the study. Median age was 69 [interquartile range (IQR): 64–73] and 26% were female; LVEF was 33% (IQR: 27–39), 78% were in functional class II–III, median eGFR was 74 (54–89) mL/min/1.73 m2, and median N-terminal pro-brain natriuretic peptide was 1303 pg/mL (IQR: 441–2740). RD was associated with increased aldosterone, parathyroid hormone (PTH), and copeptin concentrations (P < 0.05 for all) after adjustment for traditional confounders and medical treatment.RD is associated with increased concentrations of aldosterone, PTH, and copeptin in systolic HF outpatients. Our results underscore the importance of treatment with mineralocorticoid receptor antagonist in systolic HF in particular in patients with RD and suggest that vasopressin and parathyroid receptor antagonism are potential treatment options in HF patients with known RD.
Pub.: 11 Jul '17, Pinned: 27 Aug '17
Abstract: This study was focused on survival analysis of heart failure patients who were admitted to Institute of Cardiology and Allied hospital Faisalabad-Pakistan during April-December (2015). All the patients were aged 40 years or above, having left ventricular systolic dysfunction, belonging to NYHA class III and IV. Cox regression was used to model mortality considering age, ejection fraction, serum creatinine, serum sodium, anemia, platelets, creatinine phosphokinase, blood pressure, gender, diabetes and smoking status as potentially contributing for mortality. Kaplan Meier plot was used to study the general pattern of survival which showed high intensity of mortality in the initial days and then a gradual increase up to the end of study. Martingale residuals were used to assess functional form of variables. Results were validated computing calibration slope and discrimination ability of model via bootstrapping. For graphical prediction of survival probability, a nomogram was constructed. Age, renal dysfunction, blood pressure, ejection fraction and anemia were found as significant risk factors for mortality among heart failure patients.
Pub.: 21 Jul '17, Pinned: 27 Aug '17
Abstract: Endothelial dysfunction (ED) has emerged as a critical process in cardiorenal syndrome (CRS). The concept that ED is closely linked with cardiac and renal dysfunction has become an important target for CRS-related research and clinical practice.The sequence of events leading to ED is initiated by type I endothelial activation (almost immediately) and type II endothelial activation (over hours, days, and even months), followed by endothelial apoptosis and endothelial necrosis. The fact that ED is a continual cellular event divides this process into reversible ED (endothelial activation) and irreversible ED (endothelial apoptosis and necrosis). This basic research-defined concept may have clinical implications. Although most antihypertensive drugs (ACE inhibitors, statins, etc.) are effective in patients with hypertension and diabetes, some of them have proved to be ineffective, which may partly be attributed to irreversible ED. Even though the etiology of ED consists mainly of asymmetric dimethylarginine, nitric oxide, oxidative stress, and anti-endothelial cell antibodies, many other inducers of ED have been identified. In addition, a distinct role of ED has been reported for each type of CRS in humans.Further study is warranted to prove whether ED holds promise as a pharmacological target in CRS patients.
Pub.: 15 Jun '17, Pinned: 27 Aug '17
Abstract: The cardiorenal syndrome (CRS) is a major health problem in our aging population. The term was introduced to cover disorders of the kidneys and heart, whereby dysfunction of one organ may induce dysfunction of the other. As the natural history of the CRS is mostly slow, hence difficult to explore in clinical trials, adequate animal models combining cardiovascular and renal disease are required. Therefore, we developed and characterized a usable model for CRS type 4, i.e. chronic kidney disease (CKD) causing cardiac dysfunction.CKD was induced in rats by supplementing the diet with adenine. During 8 weeks, several aspects of CRS were studied: CKD, mineral-bone disorder (MBD), cardiovascular disease, and (iron-deficiency) anemia. Hereto, the following parameters were monitored: serum creatinine, calcium, phosphate, FGF23, dynamic bone parameters, aortic Ca deposits, heart weight, serum NT-proANP, Hct, Hb, reticulocytes, spleen iron, and serum hepcidin.Animals developed a severe CKD together with a disturbed mineral balance as reflected by the increased serum creatinine and phosphorus levels and decreased serum calcium levels; and in association herewith aberrations in hormonal levels of FGF-23. In turn, the well-known and highly undesirable complications of CKD, i.e. high turnover bone disease and pathological vessel calcification were induced. Furthermore (iron-deficiency) anemia developed quickly.The animal model described in this article in many aspects mimics the human situation of the CRS type 4 and will be useful to concomitantly evaluate the effects of new treatment strategies on the various aspects of CRS.
Pub.: 25 Jul '17, Pinned: 27 Aug '17