Kunal Chaudhary

Insulin enhances the gain of arterial baroreflex control of muscle sympathetic nerve activity in humans

Recent animal studies indicate that insulin increases arterial baroreflex control of lumbar sympathetic nerve activity; however, the extent to which these findings can be extrapolated to humans is unknown. To begin to address this, muscle sympathetic nerve activity (MSNA) and arterial blood pressure were measured in 19 healthy subjects (27 ± 1 years) before, and for 120 min following, two common methodologies used to evoke sustained increases in plasma insulin: a mixed meal and a hyperinsulinaemic euglycaemic clamp. Weighted linear regression analysis between MSNA and diastolic blood pressure was used to determine the gain (i.e. sensitivity) of arterial baroreflex control of MSNA. Plasma insulin was significantly elevated within 30 min following meal intake (Δ34 ± 6 uIU ml−1; P < 0.05) and remained above baseline for up to 120 min. Similarly, after meal intake, arterial baroreflex‐MSNA gain for burst incidence and total MSNA was increased and remained elevated for the duration of the protocol (e.g. burst incidence gain: −3.29 ± 0.54 baseline vs.−5.64 ± 0.67 bursts (100 heart beats)−1 mmHg−1 at 120 min; P < 0.05). During the hyperinsulinaemic euglycaemic clamp, in which insulin was elevated to postprandial concentrations (Δ42 ± 6 μIU ml−1; P < 0.05), while glucose was maintained constant, arterial baroreflex‐MSNA gain was similarly enhanced (e.g. burst incidence gain: −2.44 ± 0.29 baseline vs.−4.74 ± 0.71 bursts (100 heart beats)−1 mmHg−1 at 120 min; P < 0.05). Importantly, during time control experiments, with sustained fasting insulin concentrations, the arterial baroreflex‐MSNA gain remained unchanged. These findings demonstrate, for the first time in healthy humans, that increases in plasma insulin enhance the gain of arterial baroreflex control of MSNA.

Uric Acid – Key Ingredient in the Recipe for Cardiorenal Metabolic Syndrome

Elevated serum uric acid levels are a frequent finding in persons with obesity, hypertension, cardiovascular and kidney disease as well as in those with the cardiorenal metabolic syndrome (CRS). The increased consumption of a fructose-rich Western diet has contributed to the increasing incidence of the CRS, obesity and diabetes especially in industrialized populations. There is also increasing evidence that supports a causal role of high dietary fructose driving elevations in uric acid in association with the CRS. Animal and epidemiological studies support the notion that elevated serum uric acid levels play an important role in promoting insulin resistance and hypertension and suggest potential pathophysiological mechanisms that contribute to the development of the CRS and associated cardiovascular disease and chronic kidney disease. To this point, elevated serum levels of uric acid appear to contribute to impaired nitric oxide production/endothelial dysfunction, increased vascular stiffness, inappropriate activation of the renin-angiotensin-aldosterone system, enhanced oxidative stress, and maladaptive immune and inflammatory responses. These abnormalities, in turn, promote vascular, cardiac and renal fibrosis as well as associated functional abnormalities. Small clinical trials have suggested that uric acid-lowering therapies may be beneficial in such patients; however, a consensus on the treatment of asymptomatic hyperuricemia is lacking. Larger randomized controlled trials need to be performed in order to critically evaluate the beneficial effect of lowering serum uric acid in patients with the CRS and those with diabetes and/or hypertension.

Inhibition of nitric oxide synthase evokes central sympatho-excitation in healthy humans

Animal studies have indicated that nitric oxide is a key signalling molecule involved in the tonic restraint of central sympathetic outflow from the brainstem. Extension of these findings to humans has been difficult because systemic infusion of nitric oxide synthase (NOS) inhibitors increases blood pressure due to inhibition of endothelial NOS, resulting in activation of the arterial baroreflex and subsequent inhibition of central sympathetic outflow. To overcome this confounding inhibitory influence of the baroreflex, in the current study we directly measured skin sympathetic nerve activity (SNA), which is not under baroreceptor control. Healthy, normotensive humans were studied before, during a 60 min intravenous infusion of the NOS inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME; 4 mg kg−1), and for 120 min following the infusion (i.e. 180 min total). Skin SNA and arterial blood pressure (BP) were continuously measured. BP was increased from baseline at the end of the l‐NAME infusion (Δ14 ± 2 mmHg; P < 0.05) and remained significantly elevated for the remainder of the experiment (Δ18 ± 3 mmHg; P < 0.05). Similarly, systemic NOS inhibition produced time‐dependent increases in skin SNA, such that skin SNA was elevated at the end of the l‐NAME infusion (total activity, 200 ± 22% baseline; P= 0.08) and was further increased at the end of the study protocol (total activity, 350 ± 41% baseline; P < 0.05). Importantly, skin SNA remained unchanged during time and hypertensive (phenylephrine) control experiments. These findings indicate that pharmacological inhibition of NOS causes sympathetic activation and support a role of nitric oxide in central sympathetic control in humans.

The Emerging Role of Biomarkers in Diabetic and Hypertensive Chronic Kidney Disease

Currently used measures to assess kidney function and injury are largely inadequate. Markers such as serum creatinine, formulas to estimate glomerular filtration rate, cystatin C, and proteinuria largely identify an underlying disease process that is well established. Thus, there has been a recent effort to identify new biomarkers that reflect kidney function, early injury, and/or repair that ultimately can relate to progression or regression of damage. Several biomarkers emerged recently that are able to detect kidney damage earlier than is currently possible with traditional biomarkers such as serum creatinine and proteinuria. Identification of urine biomarkers has proven to be beneficial in recent years because of ease of handling, stability, and the ability to standardize the various markers to creatinine or other peptides generally already present in the urine. Recent markers such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and podocin have garnered a lot of attention. The emergence of these and other biomarkers is largely because of the evolution of novel genomic and proteomic applications in investigations of acute kidney injury and chronic kidney disease. In this article, we focus on the applications of these biomarkers in disease.

Treatment of 25-OH vitamin D deficiency in older men with chronic kidney disease stages 3 and 4 is associated with reduction in cardiovascular events.

Observational studies in healthy people suggest an inverse relationship between serum 25-hydroxyvitamin D (25OHD) levels and cardiovascular (CV) mortality. Treating vitamin D deficiency in patients with moderate chronic kidney disease (CKD) may reduce CV events in this high-risk population. Study data were abstracted from Harry S. Truman Memorial Veterans Hospital electronic medical record system. The medical records of all veterans who had CKD stages 3 and 4 and had 25OHD levels determined from April 2006 to September 2007 were reviewed. Patients with 25OHD deficiency, serum level <30 ng/mL, were included (N = 126, all men, mean age = 70 years). Successful 25OHD replacement was defined as prescription of ergocalciferol sufficient to increase serum 25OHD level by 25% from baseline within 6 months (treatment group, n = 90). Otherwise patients were considered as untreated controls (n = 36). The date when the 25OHD level was drawn was considered as the date of inclusion. All the patients were followed up from the date of inclusion until July 2009 to capture CV events prospectively. During mean follow-up of 27.2 months, 44% of the controls had CV events, whereas only 21% of the patients in the treatment group had CV events (P = 0.001). In multivariate logistic regression analysis, adjusting for CV disease predictors age, initial parathyroid hormone level, statin use, history of CV disease, and glomerular filtration rate, the estimated odds ratio for 25OHD replacement status was 0.37 (95% confidence interval: 0.14–1.0). Treatment of 25OHD deficiency with ergocalciferol in patients with moderate CKD is associated with significant reduction in CV events.

Peritoneal Dialysis Drop-out: Causes and Prevention Strategies

Peritoneal dialysis (PD) as a renal replacement therapy (RRT) has become wide spread since its inception more than twenty-five years back. Since then, several advances have been made and PD has been accepted as an alternative therapy to hemodialysis (HD), with excellent survival, lower cost, and improved quality of life. In spite of comparable survival of HD and PD, improved PD techniques over the last few years, and lower health care costs with PD, PD prevalence remains low in many countries. An important reason for the low PD prevalence is patient dropouts, that is, transfer to HD. The reasons for dropouts are multifactorial, that is, modality related, system related, and patient related. These include episodes of peritonitis, catheter-related problems, ultrafiltration failure, patient fatigue, and provider comfort. This review discusses the various factors that contribute to PD dropout and the strategies to prevent it.

Hypertension in Cardiovascular and Kidney Disease

The relationship between hypertension and chronic kidney disease (CKD) is bidirectional in nature and, generally, management strategies for cardiovascular risk reduction also attenuate progression of CKD. Prevalent hypertension increases with diminishing kidney function, and the management strategy changes with level of kidney function. In this review, we will examine the evidence for management of hypertension, as a modifiable risk factor for cardiovascular disease in CKD, and the impact of this management on progression of CKD.

Intraperitoneal Drug Therapy: An Advantage

The peritoneum is a cavity which has been successfully utilized by nephrologists to perform peritoneal dialysis (PD) in patients with renal failure. The physiologic characteristic of the peritoneal cavity not only helps remove toxic metabolites from the body, but also provides a useful portal of entry in the body for several pharmacological agents. Several medications such as antibiotics are given via the intraperitoneal (IP) route in PD patients to treat episodes of peritonitis. More recently the IP route has been used for chemotherapy in patients with intra-abdominal malignancies, i.e. gynecological and gastrointestinal cancers and has shown very promising results. In patients with peritoneal surface malignancies, perioperative IP chemotherapy has been used with good results. The rate and amount of drug transfer in the peritoneum are dependent on several factors. Factors such as peritoneal inflammation, surface area, peritoneal blood flow, time of contact, etc, influence the drug transfer. This review discusses the usefulness of IP drug therapy and the factors influencing it, as well as strategies to increase the efficacy, and conclude that IP route is an alternate route to the more conventional drug delivery routes, and can be successfully used when the target is within the peritoneal cavity or adjacent tissue.

Review: Renin-angiotensin-aldosterone system intervention in the cardiometabolic syndrome and cardio-renal protection

The metabolic syndrome, also known as the cardiometabolic syndrome (CMS), is a state of metabolic and vascular dysregulation that is associated with activation of the renin-angiotensin-aldosterone system (RAAS). Clinical components of the CMS include central or visceral obesity, hypertension (HTN), dyslipidemia, insulin resistance/hyperinsulinemia, and microalbuminuria that collectively convey increases in oxidative stress, inflammation, and subsequent endothelial dysfunction. The cardio-renal inflammation and oxidative stress enhanced in the CMS increases the risk for cardiovascular disease (CVD) and renal disease end-points such as stroke, congestive heart failure, and chronic kidney disease (CKD). The development of proteinuria is known to herald progressive kidney disease (e.g. CKD) and both are now well accepted as CVD risk factors. Evidence suggests a role for visceral obesity, insulin resistance/hyperinsulinemia, HTN, and other components of the CMS lead to an increased risk for proteinuria and progressive loss of renal function. Intervention with agents that block the RAAS (e.g. ACE inhibitors and Angiotensin type 1 receptor blockers) have been shown to reduce proteinuria, CKD progression, and CVD events. Herein, we will examine the relationship between RAAS intervention and reductions in CKD and CVD events.

In Peritoneal Dialysis, Is There Sufficient Evidence to Make “PD First” Therapy?

Since its introduction more than 3 decades ago, the use of peritoneal dialysis (PD) has increased greatly due to its simplicity, convenience, and low cost. Advances in technique, antibiotic prophylaxis, and the introduction of newer solutions have improved survival, quality of life, and reduced rate of complications with PD. In Hong Kong, approximately 80% end-stage renal disease (ESRD) patients perform PD; in others, that is, Canada, Australia, and New Zealand, 20%–30% patients use PD. However, in the United States, the annual rate of prevalent patients receiving PD has reduced to 8% from its peak of 15% in mid-1980s. PD as the initial modality is being offered to far less patients than hemodialysis (HD), resulting in the current annual incidence rate of less than 10% in USA. There are many reasons preventing the PD first initiative including the increased numbers of in-center hemodialysis units, physician comfort with the modality, perceived superiority of HD, risk of peritonitis, achieving adequate clearances, and reimbursement incentives to providers. Patient fatigue, membrane failure, and catheter problems are other reasons which discourage PD utilization. In this paper, we discuss the available evidence and provide rationale to support PD as the initial renal replacement modality for ESRD patients.