Zeid Khitan

Fructose: a key factor in the development of metabolic syndrome and hypertension.

Diabetes mellitus and the metabolic syndrome are becoming leading causes of death in the world. Identifying the etiology of diabetes is key to prevention. Despite the similarity in their structures, fructose and glucose are metabolized in different ways. Uric acid, a byproduct of uncontrolled fructose metabolism is known risk factor for hypertension. In the liver, fructose bypasses the two highly regulated steps in glycolysis, glucokinase and phosphofructokinase, both of which are inhibited by increasing concentrations of their byproducts. Fructose is metabolized by fructokinase (KHK). KHK has no negative feedback system, and ATP is used for phosphorylation. This results in intracellular phosphate depletion and the rapid generation of uric acid due to activation of AMP deaminase. Uric acid, a byproduct of this reaction, has been linked to endothelial dysfunction, insulin resistance, and hypertension. We present possible mechanisms by which fructose causes insulin resistance and suggest actions based on this association that have therapeutic implications.

Role of Dietary Components in Modulating Hypertension

Hypertension is a major health issue, particularly in medically underserved populations that may suffer from poor health literacy, poverty, and limited access to healthcare resources. Management of the disease reduces the risk of adverse outcomes, such as cardiovascular or cerebrovascular events, vision impairment due to retinal damage, and renal failure. In addition to pharmacological therapy, lifestyle modifications such as diet and exercise are effective in managing hypertension. Current diet guidelines include the DASH diet, a low-fat and low-sodium diet that encourages high consumption of fruits and vegetables. While the diet is effective in controlling hypertension, adherence to the diet is poor and there are few applicable dietary alternatives, which is an issue that can arise from poor health literacy in at-risk populations. The purpose of this review is to outline the effect of specific dietary components, both positive and negative, when formulating a dietary approach to hypertension management that ultimately aims to improve patient adherence to the treatment, and achieve better control of hypertension.

Hypertonicity: Clinical entities, manifestations and treatment

Hypertonicity causes severe clinical manifestations and is associated with mortality and severe short-term and long-term neurological sequelae. The main clinical syndromes of hypertonicity are hypernatremia and hyperglycemia. Hypernatremia results from relative excess of body sodium over body water. Loss of water in excess of intake, gain of sodium salts in excess of losses or a combination of the two are the main mechanisms of hypernatremia. Hypernatremia can be hypervolemic, euvolemic or hypovolemic. The management of hypernatremia addresses both a quantitative replacement of water and, if present, sodium deficit, and correction of the underlying pathophysiologic process that led to hypernatremia. Hypertonicity in hyperglycemia has two components, solute gain secondary to glucose accumulation in the extracellular compartment and water loss through hyperglycemic osmotic diuresis in excess of the losses of sodium and potassium. Differentiating between these two components of hypertonicity has major therapeutic implications because the first component will be reversed simply by normalization of serum glucose concentration while the second component will require hypotonic fluid replacement. An estimate of the magnitude of the relative water deficit secondary to osmotic diuresis is obtained by the corrected sodium concentration, which represents a calculated value of the serum sodium concentration that would result from reduction of the serum glucose concentration to a normal level.

Uric Acid-Induced Adipocyte Dysfunction Is Attenuated by HO-1 Upregulation: Potential Role of Antioxidant Therapy to Target Obesity

Increased uric acid levels have been implicated in the pathogenesis of metabolic syndrome. To examine the mechanisms by which this occurs, we hypothesized that an increase in heme oxygenase 1, a potent antioxidant gene, will decrease uric acid levels and adipocyte dysfunction via suppression of ROS and xanthine oxidase (XO) levels. We examined the effect of uric acid on adipogenesis in human mesenchymal stem cells (MSCs) in the presence and absence of cobalt protoporphyrin (CoPP), an HO-1 inducer, and tin mesoporphyrin (SnMP), an HO activity inhibitor. Uric acid increased adipogenesis by increasing NADPH oxidase expression and elevation in the adipogenesis markers C/EBPα, PPARγ, and Mest, while decreasing small lipid droplets and Wnt10b levels. We treated MSCs with fructose, a fuel source that increases uric acid levels. Our results showed that fructose increased XO expression as compared to the control and concomitant treatment with CoPP significantly decreased XO expression and uric acid levels. These beneficial effects of CoPP were reversed by SnMP, supporting a role for HO activity in mediating these effects. These findings demonstrate that increased levels of HO-1 appear crucial in modulating the phenotype of adipocytes exposed to uric acid and in downregulating XO and NADPH oxidase levels.

Hypertonicity: Pathophysiologic Concept and Experimental Studies

Disturbances in tonicity (effective osmolarity) are the major clinical disorders affecting cell volume. Cell shrinking secondary to hypertonicity causes severe clinical manifestations and even death. Quantitative management of hypertonic disorders is based on formulas computing the volume of hypotonic fluids required to correct a given level of hypertonicity. These formulas have limitations. The major limitation of the predictive formulas is that they represent closed system calculations and have been tested in anuric animals. Consequently, the formulas do not account for ongoing fluid losses during development or treatment of the hypertonic disorders. In addition, early comparisons of serum osmolality changes predicted by these formulas and observed in animals infused with hypertonic solutions clearly demonstrated that hypertonicity creates new intracellular solutes causing rises in serum osmolality higher than those predicted by the formulas. The mechanisms and types of intracellular solutes generated by hypertonicity and the effects of the solutes have been studied extensively in recent times. The solutes accumulated intracellularly in hypertonic states have potentially major adverse effects on the outcomes of treatment of these states. When hypertonicity was produced by the infusion of hypertonic sodium chloride solutions, the predicted and observed changes in serum sodium concentration were equal. This finding justifies the use of the predictive formulas in the management of hypernatremic states.

Fluid balance concepts in medicine: Principles and practice

The regulation of body fluid balance is a key concern in health and disease and comprises three concepts. The first concept pertains to the relationship between total body water (TBW) and total effective solute and is expressed in terms of the tonicity of the body fluids. Disturbances in tonicity are the main factor responsible for changes in cell volume, which can critically affect brain cell function and survival. Solutes distributed almost exclusively in the extracellular compartment (mainly sodium salts) and in the intracellular compartment (mainly potassium salts) contribute to tonicity, while solutes distributed in TBW have no effect on tonicity. The second body fluid balance concept relates to the regulation and measurement of abnormalities of sodium salt balance and extracellular volume. Estimation of extracellular volume is more complex and error prone than measurement of TBW. A key function of extracellular volume, which is defined as the effective arterial blood volume (EABV), is to ensure adequate perfusion of cells and organs. Other factors, including cardiac output, total and regional capacity of both arteries and veins, Starling forces in the capillaries, and gravity also affect the EABV. Collectively, these factors interact closely with extracellular volume and some of them undergo substantial changes in certain acute and chronic severe illnesses. Their changes result not only in extracellular volume expansion, but in the need for a larger extracellular volume compared with that of healthy individuals. Assessing extracellular volume in severe illness is challenging because the estimates of this volume by commonly used methods are prone to large errors in many illnesses. In addition, the optimal extracellular volume may vary from illness to illness, is only partially based on volume measurements by traditional methods, and has not been determined for each illness. Further research is needed to determine optimal extracellular volume levels in several illnesses. For these reasons, extracellular volume in severe illness merits a separate third concept of body fluid balance.

Dietary potassium and cardiovascular profile. Results from the modification of diet in renal disease dataset

Editor: We have recently reported that dietary potassium correlates negatively with body mass index (BMI) and proteinuria.1 Moreover, high potassium diets have a protective effect against the development of vascular damage induced by salt loading.2 In an effort to dissect the possible mechanisms of the benefits of dietary potassium, we studied the relationship between daily potassium intake and several markers of interest to cardiovascular disease and hypertension. We performed analysis on the baseline data of the National Institute of Healthfunded Modification of Diet in Renal Disease (MDRD) study. We performed bivariate correlation (Pearson) between dietary potassium (food only) intake and BUNtocreatinine ratio (BUN:Cr), serum calcium (mg/dL), hematocrit (%), hemoglobin A1C (%), serum uric acid (mg/dL), and stroke volume (SV) estimated according to a validated equation using noninvasive parameters.3 Our results revealed a significant positive correlation between daily potassium intake and BUN:Cr, hematocrit, and serum calcium and significant negative correlation with SV, serum uric acid, and hemoglobin A1C. The descriptive statistics of the variables studied, and bivariate correlations with dietary potassium are shown in Table. The statistical associations of dietary potassium intake with SV, BUN:Cr, serum calcium, and HCT are similar to those of thiazide diuretics. These similarities can be explained by the effect of orally ingested potassium on an illdefined gastrointestinal sensor that leads through a feedforward mechanism to dephosphorylation of the sodiumchloride cotransporter in the distal convoluted tubules. This effect is equivalent to the effect of thiazide diuretics and explains the antihypertensive property of dietary potassium.4 On the other hand, effects of dietary potassium on uric acid and hemoglobin A1C are opposite to what is expected from thiazide diuretics. Production of uric acid, the end product of xanthine metabolism in humans, yields an equimolar amount of superoxide. Experimentally, a highpotassium diet was shown to have a potent protective effect on left ventricular active relaxation independent of blood pressure, partly through the inhibition of cardiac NADPH oxidase activity.5 In another study, the antihypertensive effect of dietary potassium was accompanied by sympathetic nerve inhibition in saltsensitive hypertension, a marker of insulin resistance.6 Renalase, a monoamine oxidase in the blood that is primarily secreted by the kidneys can metabolize catecholamines and regulate sympathetic activity. Renalase mRNA and protein levels increased along with decreased catecholamine levels in plasma and led to a decrease in blood pressure in saltsensitive rats treated with high salt/potassium intake, compared with that of the high salt intake saltsensitive control rats.7 Moreover, reactive oxygen species are a critical mediator of the NaKATPase pump signaling, and their generation can be attenuated by potassium transit into the cells.8 Taking into consideration the type of the dataset analyzed and the crosssectional nature of the analysis, our results cannot be expanded beyond a correlation, but when taken together with other existing evidence from animal and human experiments, it is reasonable to conclude that the protective effects of a high potassium diet can be explained by its antihypertensive and antioxidant properties.

Establishing the presence or absence of chronic kidney disease: Uses and limitations of formulas estimating the glomerular filtration rate.

The development of formulas estimating glomerular filtration rate (eGFR) from serum creatinine and cystatin C and accounting for certain variables affecting the production rate of these biomarkers, including ethnicity, gender and age, has led to the current scheme of diagnosing and staging chronic kidney disease (CKD), which is based on eGFR values and albuminuria. This scheme has been applied extensively in various populations and has led to the current estimates of prevalence of CKD. In addition, this scheme is applied in clinical studies evaluating the risks of CKD and the efficacy of various interventions directed towards improving its course. Disagreements between creatinine-based and cystatin-based eGFR values and between eGFR values and measured GFR have been reported in various cohorts. These disagreements are the consequence of variations in the rate of production and in factors, other than GFR, affecting the rate of removal of creatinine and cystatin C. The disagreements create limitations for all eGFR formulas developed so far. The main limitations are low sensitivity in detecting early CKD in several subjects, e.g., those with hyperfiltration, and poor prediction of the course of CKD. Research efforts in CKD are currently directed towards identification of biomarkers that are better indices of GFR than the current biomarkers and, particularly, biomarkers of early renal tissue injury.

Bilateral renal cortical necrosis associated with smoking synthetic cannabinoids

Synthetic cannabinoids have become a common drug of abuse in recent years and their toxicities have come to light as well. They are known to be notorious for the kidneys, with acute tubular necrosis, acute interstitial nephritis and rhabdomyolysis induced renal injury being the frequent nephrotoxic outcomes in users. We report a case of bilateral renal cortical necrosis, leading to irreversible renal damage and lifelong dialysis dependency.

Association between dietary potassium, body mass index, and proteinuria in normotensive and hypertensive individuals: Results from the Modification of Diet in Renal Disease study baseline data

In a metaanalysis, it was shown that potassium supplementation is associated with lower blood pressure in hypertensive individuals especially when they consume high sodium and low potassium and are not taking antihypertensive medication.1 Pregnant women with preeclampsia have greater morbidity and poorer outcomes if their dietary intake is relatively low on potassium and high on sodium.2 We studied the relationship between dietary potassium, body mass index (BMI) (kg/m2), and urinary protein excretion (g/d) in normotensive as well as hypertensive individuals. We performed analysis on the baseline data of the National Institutes of Health–funded Modification of Diet in Renal Disease (MDRD) study. We categorized the study population’s BMI levels into low (<18.5), normal (18.5–24.9), overweight (25–29.9), obesity grade I (30.0–34.9), and obesity grade II or more (≥35.0). We also classified the MDRD cohort into normotensive (systolic blood pressure <140 mm Hg) and hypertensive (systolic blood pressure ≥140 mm Hg) categories. We reviewed and tabulated data on the total daily sodium intake (mmol/d), total daily potassium intake (mg/d), and urinary protein excretion (g/d). The potassium intake was further divided into low potassium intake (<3500 g/d) and high potassium intake (≥3500 g/d) groups. We performed Spearman correlation (nonparametric) between dietary potassium and sodium intake and dietary potassium and urinary protein excretion. We used analysis of variance to compare potassium intake across different levels of BMI. Statistical analysis was performed using SPSS version 21 (IBM Corp, Armonk, NY). Hypertensives and normotensives were tabulated and analyzed separately. A total of 3678 persons comprised the entire cohort. The mean intake of sodium (mean±standard deviation) was not different between the low potassium and high potassium intake groups (40.2±17.2 vs 45.0±19.5, P=.18). However, among hypertensives, the mean intake of sodium was slightly higher among persons with high potassium intake (P=.01). In normotensives, mean potassium intake was significantly different among different levels of BMI (as shown in the Figure) and was found to have a negative correlation with urine protein excretion (P<.01 and P=.04, respectively) but not in hypertensives (P=.14 and P=.27, respectively). Daily potassium intake positively correlated with daily sodium intake in both normotensives and hypertensives (Spearman’s rho 0.35 and 0.30, respectively; P<.01). After evaluating for sodium intake, an increase in BMI was associated with progressively decreasing dietary potassium intake in normotensives but not in hypertensives. In this study, we highlight the association between low dietary potassium and increase in BMI as well as the negative correlation between dietary potassium and urinary protein in normotensive individuals. Oral potassium loading has been shown to suppress renin activity in normal and hypertensive individuals.3 Moreover, dietary potassium through its action on poorly identified GI receptors can elicit a feedforward control on the kidneys resulting in rapid dephosphorylation of the renal sodiumchloride cotransporter.4 Theoretically, this mimics the anti-proteinuric effect of blocking the reninangiotensinaldosterone axis in combination with a thiazide diuretic, respectively. Our study has limitations. First, it is a crosssectional study that might not represent a consistent pattern of daily intake. Moreover, a diet high in potassium is generally considered “healthy” and persons with higher BMIs are less likely to consume potassiumrich foods. Our results need to be further examined and validated in a dietary interventional study.