Elevated serum bicarbonate concentration in chronic kidney disease: a call to find the cause

In this issue, Dobre et al1 reported an observational study looking at results of annually measured serum bicarbonate concentration in participants with chronic kidney disease (CKD) enrolled in the Chronic Renal Insufficiency Cohort (CRIC) using the marginal structural model, a validated statistical method,2 to estimate the cumulative effect over the period of the study and their effects on adjudicated heart failure events, atherosclerotic events, renal disease progression, and mortality. In their analysis, they included patients aged 21 to 74 years with estimated glomerular filtration rate of 20 to 70 mL/min per 1.73 m2 and excluded patients with NYHA Class III/IV heart failure. The final study population of this analysis included 3586 participants. They adjusted all models for age, gender, race/ethnicity, clinical center, estimated glomerular filtration rate, proteinuria, diabetes, systolic blood pressure, cardiovascular disease at baseline, chronic obstructive pulmonary disease, tobacco use, diuretic and alkali medication used, low-density lipoprotein, Fibroblast growth factor-23 (FGF-23), and high-sensitivity C-reactive protein. In their analysis, over an average of 6 years of followup, they found a statistically significant higher rate of heart failure events and mortality in participants who maintained serum bicarbonate \u3e26 mmol/L, while participants who maintained serum bicarbonate \u3c22 mmol/L had increased risk of renal disease progression defined as halving of estimated glomerular filtration rate or end-stage renal disease. On the other hand, there was no association between serum bicarbonate levels and atherosclerotic cardiovascular events. In subgroup analysis, the relationship between serum bicarbonate concentration and heart failure and renal events was consistent across categories of race/ ethnicity, diabetes, or baseline kidney function. The strength of association between serum bicarbonate \u3e26 and \u3c22 and heart failure and renal events, respectively, persisted after excluding participants taking alkali therapy, or who had chronic obstructive pulmonary disease (COPD) or cardiovascular disease at baseline. On the other hand, the study was not powered to exclude participants on diuretic therapy (60% of the study cohort were taking diuretics), which is a major cause of metabolic alkalosis

MRSA induced pulmonary-renal syndrome

We present a rare case of pulmonary-renal syndrome secondary to recurrent MRSA spondylodiscitis. The mechanism of involvement of each organ system is unique. The organs, lung and kidneys, have been affected by different pathologic processes that were induced, we think, by the chronic MRSA infection

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

Pregnancy Induced Microangiopathy, HELLP OR TTP!

Introduction: Thrombotic thrombocytopenic purpura (TTP) in pregnancy is rare and can be fatal if misdiagnosed.Typically patients present with microangiopathic hemolytic anemia, thrombocytopenia, Altered mental status, fever, and renal abnormalities Case Description: We are presenting a case of 26 year old pregnant female presented with elevated BP. She had scattered Bruises in her legs, thighs and arms along with +2 bilateral pitting leg edema. Initial and subsequent laboratory studies showed features of microangiopathic hemolytic anemia (MAHA), which brought up the suspicion of HELLP (hemolysis, elevated liver enzymes, low platelets )syndrome initially. Labor was induced after transfusion of 2 units of PRBCs and 2 units of Platelets. The patient platelets and hemoglobin showed no improvement after delivery and she continued to have hemolysis despite delivery and steroids administration. So daily therapeutic plasma exchange was initiated as the index of suspicion for TTP increased. After two sessions, there was a significant improvement in the platelet count and hemolysis profile which were normalized by the 4th session. Conclusion: Congenital TTP is a rare syndrome that clinicians should be aware of. Early initiation of plasma exchange dramatically improves survival from less than 10% to approximately 80%. This can only be achieved by having high level of suspicion and awareness to this possibility

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

HO-1 Upregulation Attenuates Adipocyte Dysfunction, Obesity, and Isoprostane Levels in Mice Fed High Fructose Diets

Background. Fructose metabolism is an unregulated metabolic pathway and excessive fructose consumption is known to activate ROS.HO-1 is a potent antioxidant gene that plays a key role in decreasing ROS and isoprostanes.We examinedwhether the fructosemediated increase in adipocyte dysfunction involves an increase in isoprostanes and that pharmacological induction ofHO-1would decrease both isoprostane levels and adipogenesis. Methods and Results. We examined the effect of fructose, on adipogenesis in human MSCs in the presence and absence of CoPP, an inducer of HO-1. Fructose increased adipogenesis and the number of large lipid droplets while decreasing the number of small lipid droplets ( \u3c 0.05). Levels of heme and isoprostane in fructose treated MSC-derived adipocytes were increased. CoPP reversed these effects andmarkedly increasedHO-1 and theWnt signaling pathway. Thehigh fructose diet increased heme levels in adipose tissue and increased circulating isoprostane levels ( \u3c 0.05 versus control). Fructose diets decreasedHO-1 and adiponectin levels in adipose tissue. Induction ofHO-1 by CoPP decreased isoprostane synthesis ( \u3c 0.05 versus fructose). Conclusion. Fructose treatment resulted in increased isoprostane production and adipocyte dysfunction, which was reversed by the increased expression of HO-1

Why Does Obesity Lead to Hypertension? Further Lessons from the Intersalt Study.

Objectives To analyze correlations between major determinants of blood pressure (BP), in efforts to generate and compare predictive models that explain for variance in systolic, diastolic, and mean BP amongst participants of the Intersalt study. Methods Data from the Intersalt study, consisting of nearly 10,000 subjects from 32 different countries, were reviewed and analyzed. Published mean values of 24 hour urinary electrolyte excretion (Na+, K+), 24 hour urine creatinine excretion, body mass index (BMI, kg/m^2), and blood pressure data were extracted and imported into Matlab™ for stepwise linear regression analysis. Results As shown earlier, strong correlations between urinary sodium excretion (UNaV) and systolic, diastolic and mean blood pressure were noted as well as between UNaV and the age dependent increase in systolic blood pressure. Of interest, BMI and urinary creatinine excretion rate (UCrV) also both correlated with systolic blood pressure, but the ratio of BMI/UCrV, constructed to be a measure of obesity, correlated negatively with systolic blood pressure. Conclusions Our results offer population-based evidence suggesting that increased size due to muscle mass rather than adiposity may correspond more to blood pressure. Additional data bases will need to be sampled and analyzed to further validate these observations

Predicting Adverse Outcomes in End Stage Renal Disease: Machine Learning Applied to the United States Renal Data System

We examined machine learning methods to predict death within six months using data derived from the United States Renal Data System (USRDS). We specifically evaluated a generalized linear model, a support vector machine, a decision tree and a random forest evaluated within the context of K-10 fold validation using the CARET package available within the open source architecture R program. We compared these models with the feed forward neural network strategy that we previously reported on with this data set

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

Alkali Therapy in Lactic Acidosis

This report attempts to frame the debate about clinical administration of sodium bicarbonate in the setting of lactic acidosis in terms of simple questions. Specifically, we address why we develop lactic acidosis in some circumstances, how acute lactic acidosis impairs cardiovascular function and why sodium bicarbonate may have deleterious effects which limit its utility. We also attempt to explore treatment alternatives to sodium bicarbonate