Hyperuricemia: An Intriguing Connection to Metabolic Syndrome, Diabetes, Kidney Disease, and Hypertension.

PURPOSE OF THE REVIEW: Our review explores the epidemiology, physiology, and clinical data surrounding the connection between hyperuricemia and metabolic syndrome, chronic kidney disease, and hypertension. RECENT FINDINGS: Compelling physiologic mechanisms have been proposed to explain a causal relationship between hyperuricemia and metabolic syndrome, chronic kidney disease, and hypertension but clinical studies have given mixed results in terms of whether intervening with hyperuricemia using urate-lowering therapy has any beneficial effects for patients with these conditions. Despite the large amount of research already put into this topic, more randomized placebo-controlled trials are needed to more firmly establish whether a cause-effect relationship exists and whether lowering uric acid levels in patients with these conditions is beneficial.

Obstructive Sleep Apnea and Hypertension: Updates to a Critical Relationship.

PURPOSE OF REVIEW: Obstructive sleep apnea (OSA) is an underdiagnosed illness linked to essential hypertension (HTN), resistant hypertension (r-HTN), and cardiovascular disease (CVD). This review provides updates on the epidemiology, pathophysiology, and treatments of OSA-associated HTN. RECENT FINDINGS: Mild sleep apnea increases the risk for HTN. Eighty-nine percent of young patients aged 18-35 with HTN not attributed to secondary causes have underlying OSA. Home sleep studies are noninferior to formal polysomnography for OSA diagnosis. Nocturnal oxygen desaturation rate is positively correlated with HTN severity. Gut microbiome neo-colonization in response to high-fat diet cravings in patients with OSA alters immune function and worsens HTN. Carbonic anhydrase inhibitors and probiotics show newfound potential for OSA-associated HTN treatment. OSA recognition improves hospital outcomes after a STEMI. Hypoxia-inducible factor (HIF) transcription increases in a dose-dependent manner to hypoxia, and HIFs are strongly linked to cancer growth. OSA and HTN are comorbid conditions with adversely connected pathophysiology including sympathetic hyperactivity, gut dysbiosis, proinflammation, endothelial damage, rostral fluid shifts, pharyngeal collapse, intravascular fluid retention, nocturnal energy expenditure, and metabolic derangements. The dose-response effect of OSA on HTN severity challenges blood pressure (BP) control, so those with refractory HTN should be screened for OSA.

Hypertension, Obesity, and COVID-19: a Collision of Pandemics.

PURPOSE OF REVIEW: To highlight the epidemiology and pathophysiology of hypertension and obesity in COVID-19 infection RECENT FINDINGS: Hypertension and obesity have emerged as significant risk factors for contracting the COVID-19 virus and the subsequent severity of illness. ACE2 receptor expression and dysregulation of the RAAS pathway play important roles in the pathophysiology of these associations, as do the pro-inflammatory state and cytokine dysregulation seen in obesity. Some of these patterns have also been seen historically in other viral illnesses. Understanding the mechanisms behind the associations between COVID-19, hypertension, and obesity is important in developing effective targeted therapies and monitoring vaccine response and efficacy. More research is needed to apply our growing knowledge of the pathophysiology of COVID-19, hypertension, and obesity to prevention and treatment. Interventions focusing on lifestyle modification in managing hypertension and obesity can potentially have a positive impact on containing this pandemic and future viral illness outbreaks.

First Course DASH, Second Course Mediterranean: Comparing Renal Outcomes for Two "Heart-Healthy" Diets.

PURPOSE OF REVIEW: To review studies evaluating renal outcomes based on patient adherence to the Mediterranean diet or to the Dietary Approaches to Stop Hypertension (DASH) diet and to determine which diet is most effective in preventing and managing renal disease. RECENT FINDINGS: Both the DASH and Mediterranean diets have shown many health benefits, including reduced risk for chronic kidney disease (CKD), nephrolithiasis, mortality due to all renal causes and composite outcomes. Both diets have shown a decrease in estimated glomerular filtration rates (eGFR) decline with a concomitant improvement in mortality and dialysis initiation. In summary, both diets resulted in similar magnitudes of risk reduction when comparing equivocal levels of adherence to each diet. Review of evidence for renal outcomes shows strikingly similar effects for both DASH and Mediterranean diets. We hypothesize that these results are due to the overlap in nutritional composition. Both encourage whole foods such as fruits, vegetables, beans/legumes, whole grains, and nuts. Additionally, they restrict animal protein consumption and limit processed and fast foods. Determining a nutritional management intervention for renal impairment is clinically important as approximately 1% of the USA annual budget is spent on end stage renal disease (ESRD) treatment. We believe either diet could be incorporated into a patient's management when considering their renal health. In conclusion, we urge physicians to help patients choose either the DASH diet or Mediterranean diet based on the patient preference.

The Incidence and Pathophysiology of the Obesity Paradox: Should Peritoneal Dialysis and Kidney Transplant Be Offered to Patients with Obesity and End-Stage Renal Disease?

PURPOSE OF REVIEW: To educate nephrologists and primary-care physicians about the incidence, pathophysiology, and survival benefits of the obesity paradox in end-stage renal disease (ESRD). This review also discusses the future of kidney transplant and peritoneal dialysis in obese dialysis patients. RECENT FINDINGS: Obesity paradox in ESRD was first reported three decades ago, and since then, there have been several epidemiological studies that confirmed the phenomenon. Regardless of the anthropometric indices used to define obesity in ESRD patients, these markers serve to predict the dialysis patient's survival. The pathophysiology of obesity paradox tends to be multifactorial. Recent cohort studies demonstrated a survival benefit in all race and ethnic groups, but Hispanics and blacks experienced increased survival rates when compared to non-Hispanic whites. Obese dialysis patients should be offered peritoneal dialysis, especially if they are new to dialysis and have an adequate renal residual function. Several studies have shown that the benefit of receiving kidney transplant in obese patients exceeds the risks. The robotic-assisted kidney transplant (RAKT) procedure is the latest innovation that could offer hope for obese dialysis patients who have been denied or are waiting for kidney transplant. The obesity paradox phenomenon in ESRD is a unique illustration of survival benefit in a population that has a high overall annual mortality. Peritoneal dialysis should be encouraged for obese patients who have preserved residual renal function. Kidney transplant centers should encourage RAKT utilization in obese dialysis patients instead of denying them a kidney transplant.

Successful return to peritoneal dialysis after a case of relapsing Sphingomonas paucimobilis peritonitis
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Sphingomonas paucimobilis is an uncommon source of peritonitis in patients undergoing peritoneal dialysis (PD). Although only a small number of cases have been reported, treatment failure rate is extremely high, with removal of the peritoneal dialysis catheter noted in ~ 50% of reported cases. The potential damage to the peritoneal membrane from peritonitis with this organism and the ability to return to PD after infection is unknown. We report a unique case in which a patient was able to successfully return to PD after relapsing Sphingomonas paucimobilis peritonitis, without apparent effects to dialysis clearance or ultrafiltration.
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Ferric Citrate Reduces Intravenous Iron and Erythropoiesis-Stimulating Agent Use in ESRD.

Ferric citrate (FC) is a phosphate binder with shown efficacy and additional effects on iron stores and use of intravenous (iv) iron and erythropoiesis-stimulating agents (ESAs). We provide detailed analyses of changes in iron/hematologic parameters and iv iron/ESA use at time points throughout the active control period of a phase 3 international randomized clinical trial. In all, 441 subjects were randomized (292 to FC and 149 to sevelamer carbonate and/or calcium acetate [active control (AC)]) and followed for 52 weeks. Subjects on FC had increased ferritin and transferrin saturation (TSAT) levels compared with subjects on AC by week 12 (change in ferritin, 114.1±29.35 ng/ml; P<0.001; change in TSAT, 8.62%±1.57%; P<0.001). Change in TSAT plateaued at this point, whereas change in ferritin increased through week 24, remaining relatively stable thereafter. Subjects on FC needed less iv iron compared with subjects on AC over 52 weeks (median [interquartile range] dose=12.9 [1.0-28.9] versus 26.8 [13.4-47.6] mg/wk; P<0.001), and the percentage of subjects not requiring iv iron was higher with FC (P<0.001). Cumulative ESA over 52 weeks was lower with FC than AC (median [interquartile range] dose=5303 [2023-9695] versus 6954 [2664-12,375] units/wk; P=0.04). Overall, 90.3% of subjects on FC and 89.3% of subjects on AC experienced adverse events. In conclusion, treatment with FC as a phosphate binder results in increased iron parameters apparent after 12 weeks and reduces iv iron and ESA use while maintaining hemoglobin over 52 weeks, with a safety profile similar to that of available binders.

Anti-hypertensive drug treatment of patients with and the metabolic syndrome and obesity: a review of evidence, meta-analysis, post hoc and guidelines publications.

Epidemiological studies have shown an increasing prevalence of obesity and the metabolic syndrome worldwide. Lifestyle modifications that include dietary changes, weight reduction, and exercise are the cornerstones in the treatment of this pathology. However, adherence to this approach often meets with failure in clinical practice; therefore, drug therapy should not be delayed. The ideal pharmacological antihypertensive regimen should target the underlying mechanisms involved in this syndrome, including sympathetic activation, increased renal tubular sodium reabsorption, and overexpression of the renin-angiotensin-aldosterone system by the adipocyte. Few prospective trials have been conducted in the search of the ideal antihypertensive regimen in patients with obesity and the metabolic syndrome. We summarize previously published ad hoc studies, prospective studies, and guideline publications regarding the treatment of hypertension in patients with obesity and the metabolic syndrome. We conclude that the optimal antihypertensive drug therapy in these patients has not been defined. Though caution exists regarding the use of thiazide diuretics due to potential metabolic derangements, there is insufficient data to show worsened cardiovascular or renal outcomes in patients treated with these drugs. In regard to beta blockers, the risk of accelerating conversion to diabetes and worsening of inflammatory mediators described in patients treated with traditional beta blockers appears much less pronounced or absent when using the vasodilating beta blockers. Renin-angiotensin-aldosterone system (RAAS) inhibition with an ACE or an ARB and treatment with calcium channel blockers appears safe and well tolerated in obesity-related hypertension and in patients with metabolic syndrome. Future prospective pharmacological studies in this population are needed.

The impacts of obesity on the cardiovascular and renal systems: cascade of events and therapeutic approaches.

There is a neglected epidemic of both obesity and metabolic syndrome in industrialized and unindustrialized countries all over the globe. Both conditions are associated with a high incidence of other serious pathologies, such as cardiovascular and renal diseases. In this article, we review the potential underlying mechanisms by which obesity and metabolic syndrome promote hypertension, including changes in cardiovascular-renal physiology induced by leptin, the sympathetic nervous system, the renin-angiotensin-aldosterone system, insulin resistance, free fatty acids, natriuretic peptides, and proinflammatory cytokines. We also discuss the potential underlying mechanisms by which obesity promotes other cardiovascular and renal conditions, as well as available nonpharmacologic and pharmacologic approaches for treating obesity-induced hypertension. The findings presented herein suggest that adipocytes may be a key regulator of cardiovascular and renal function.

Commentary on the 2014 BP guidelines from the panel appointed to the Eighth Joint National Committee (JNC 8).

The recently published article "2014 Evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8)" (James et al., JAMA 311: 507-520, 2014) has generated considerable controversy. In this commentary, we evaluate the document and compare the recommendations contained within it with those of the JNC 7 and other national and international guidelines. The evidence quality rating approach followed by the article "2014 Evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8)" (James et al., JAMA 311: 507-520, 2014) disqualified nearly 98% of previous studies from review; as a result, some of the key recommendations were on the basis of expert opinion alone. We are especially concerned that the recommendation to raise the systolic/diastolic BP levels at which treatment is initiated to ≥150/≥90 mmHg in adults≥60 years old may affect cardiovascular and renal health in these patients. Additionally, we recommend that hypertension guidelines should be updated every 3-4 years with a fresh approach to the definition of target BP levels, the use of modern technology in the diagnosis of hypertension, and the treatment of hypertension in special populations not addressed in earlier guidelines.

Assessment and management of hypertension in patients on dialysis.

Hypertension is common, difficult to diagnose, and poorly controlled among patients with ESRD. However, controversy surrounds the diagnosis and treatment of hypertension. Here, we describe the diagnosis, epidemiology, and management of hypertension in dialysis patients, and examine the data sparking debate over appropriate methods for diagnosing and treating hypertension. Furthermore, we consider the issues uniquely related to hypertension in pediatric dialysis patients. Future clinical trials designed to clarify the controversial results discussed here should lead to the implementation of diagnostic and therapeutic techniques that improve long-term cardiovascular outcomes in patients with ESRD.

Polypharmacy in chronic kidney disease: Health outcomes & pharmacy-based strategies to mitigate inappropriate polypharmacy.

The rising prevalence of comorbidities in an increasingly aging population has sparked a reciprocal rise in polypharmacy. Patients with chronic kidney disease (CKD) have a greater burden of polypharmacy due to the comorbidities and complications associated with their disease. Polypharmacy in CKD patients has been linked to myriad direct and indirect costs for patients and the society at large. Pharmacists are uniquely positioned within the healthcare team to streamline polypharmacy management in the setting of CKD. In this article, we review the landscape of polypharmacy and examine its impacts through the lens of the ECHO model of Economic, Clinical, and Humanistic Outcomes. We also present strategies for healthcare teams to improve polypharmacy care through comprehensive medication management process that includes medication reconciliation during transitions of care, medication therapy management, and deprescribing. These pharmacist-led interventions have the potential to mitigate adverse outcomes associated with polypharmacy in CKD.

Potential role of uric acid in metabolic syndrome, hypertension, kidney injury, and cardiovascular diseases: is it time for reappraisal?

Elevated serum uric acid concentration is a common laboratory finding in subjects with metabolic syndrome/obesity, hypertension, kidney disease and cardiovascular events. Hyperuricemia has been attributed to hyperinsulinemia in metabolic syndrome and to decreased uric acid excretion in kidney dysfunction, and is not acknowledged as a main mediator of metabolic syndrome, renal disease, and cardiovascular disorder development. However, more recent investigations have altered this traditional view and shown, by providing compelling evidence, to support an independent link between hyperuricemia and increased risk of metabolic syndrome, diabetes, hypertension, kidney disease and cardiovascular disorders. However, despite these new findings, controversy regarding the exact role of uric acid in inducing these diseases remains to be unfolded. Furthermore, recent data suggest that the high-fructose diet in the United State, as a major cause of hyperuricemia, may be contributing to the metabolic syndrome/obesity epidemic, diabetes, hypertension, kidney disease and cardiovascular disorder. Our focus in this review is to discuss the available evidence supporting a role for uric acid in the development of metabolic syndrome, hypertension, renal disease, and cardiovascular disorder; and the potential pathophysiology mechanisms involved.

Non-communicable disease: a welcome and long needed addition to the WHO's 2012 World Heath Statistics.

The World Health Organization's annual report World Health Statistics 2012 was recently published. In addition to annually published indicators of health, this year's report contains a highlighted new section on non-communicable diseases and their impact on world health. The section gives particular attention to hypertension and obesity. Interestingly, despite worldwide increases in obesity and metabolic syndrome, hypertension rates have actually improved in wealthy nations since 1980, while rates have greatly increased in developing regions and particularly in Africa. Potential contributors to these disparities likely include access to screening and treatment, and the rise of high sodium and low potassium processed foods in poorer nations. It will be imperative in years to come to identify and employ the success seen in wealthy nations worldwide to improve outcomes and productivity in the developing world.

Lipid nephrotoxicity: new concept for an old disease.

The prevalence of obesity in the United States remains high, exceeding 30% in most states. As this trend continues unhindered, we will continue see a persistent rise in obesity-related metabolic effects­hypertension, dyslipidemia, diabetes mellitus, and atherosclerosis. These diseases are also the leading causes of chronic kidney diseases and end-stage renal disease. The lipid nephrotoxicity hypothesis, proposed over three decades ago, suggested that proteinuria, decreased albumin levels, and the resultant hyperlipidemia may cause a glomerulosclerosis similar to atherosclerosis. More recent studies have demonstrated the role of oxidized high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles in the progression of kidney disease. Elucidation of the role of lipid-lowering therapies and the concomitant improvement in tubulointerstitial and glomerular diseases is a further evidence of the role of lipids in renal injury. Synergistic effects of lipid-lowering drugs and blockers of the renin-angiotensin-aldosterone system (RAAS) in renal protection have also been documented. Dyslipidemia in renal disease is usually characterized by elevated LDL cholesterol, low HDL cholesterol, and high triglycerides. After an initial glomerular injury, likely to be inflammatory, a series of self-perpetuating events occur. Increased glomerular basement permeability leads to loss of lipoprotein lipase activators, which results in hyperlipidemia. Circulating LDL has a charge affinity for glycoaminoglycans in the glomerular basement membrane and further increases its permeability. Substantial amounts of filtered lipoprotein cause proliferation of mesangial cells. Proximal tubules reabsorb some of the filtered lipoprotein, and the remainder is altered during passage through the nephron. If intraluminal pH is close to the isoelectric point of the apoprotein, luminal apoprotein will precipitate, causing tubulointerstitial disease. This review shows the evidence for the role of lipids in development of chronic renal disease, the pathophysiology of lipid nephrotoxicity, and strategies available to clinicians to slow the progression of disease.

Evaluating Factors Contributing to Dropout in a Large Peritoneal Dialysis Program.

BACKGROUND: The low prevalence of peritoneal dialysis (PD) (9%) vs. hemodialysis (HD) (88.2%) is partly due to patient dropout from therapy. METHODS: This retrospective study identified patients who withdrew from PD between 2016 and 2018 in our program. We evaluated all other factors as controllable losses. Analysis included time on therapy at dropout (very early, early or late) and method of initiation (HD to PD conversion, unplanned PD, or planned start). RESULTS: Eighty-three patients enrolled into our PD program. 27 dropped out; 24 were due to controllable factors, 3 due to death, with a median age at dropout of 52 years old. We determined psychosocial factors (PF) to be the largest controllable factor influencing dropout; contributing a 63% rate among all controllable factors. When considering time until dropout, 100% of very early dropout patients and 50% of late dropout patients did so due to PF. Among early dropout patients 67% dropped out due to other medical reasons. The mean time to dropout for PF, other, and infection (INF) were 13, 26, and 33 months, respectively. When considering type of initiation, we found PF to be the largest attributable factor with 50% of unplanned, 100% of planned, and 50% of conversions stopping therapy. CONCLUSIONS: Our study indicates that the primary reason for controllable loss from therapy was secondary to PF regardless of the time on therapy or the method of initiation to therapy.

The obesity paradox and cardiovascular disease.

Obesity is increasingly recognized as a global pandemic that threatens the health of millions of people. Obesity is considered to be an important cardiovascular risk factor, but there is increasing evidence that patients with elevated body mass index may be better off than others if they develop cardiovascular or renal disease. This phenomenon has been described as the "obesity paradox" or "reverse epidemiology." This article reviews some recent publications that have studied this phenomenon as it relates to heart failure, coronary artery disease, peripheral arterial disease, kidney disease, and a cohort of patients undergoing nonbariatric surgery.

Tesaglitazar, a dual peroxisome proliferator-activated receptor agonist (PPAR alpha/gamma), improves metabolic abnormalities and reduces renal injury in obese Zucker rats.

Metabolic syndrome increases the risk of developing diabetes as well as cardiovascular and kidney diseases. This research studied the effects of tesaglitazar, a dual-acting peroxisome proliferator-activated receptor (PPAR)alpha/gamma agonist, on metabolic abnormalities and kidney injury in obese Zucker rats (OZR). Lean Zucker rats (LZR) and OZR were used as control groups. Tesaglitazar (1 micromol/kg/day) was given for 8 weeks in the treatment group (OZR-T). Metabolic parameters, 24-hour urine albumin excretion, and tail blood pressure were measured. Glomerular filtration rate by inulin clearance, abdominal fat and renal histology were determined at the end of the study. In comparison with the OZR and OZR-T groups, the LZR control animals' parameters were significantly more favorable in all measures. Tesaglitazar treatment in OZR significantly reduced nonfasting glucose, C-reactive protein levels and improved dyslipidemia. Body weight, blood pressure and urine albumin excretion were lower, but the adjusted glomerular filtration rate higher, in the OZR-T group than in the OZR controls. Glomerular area, mesangial expansion and tubulointerstitial changes were ameliorated, and the glomerular expression of desmin was markedly more decreased in the OZR-T group than in the OZR controls. Therefore, the PPAR alpha/gamma agonist tesaglitazar significantly improved metabolic abnormalities and renal function, decreased blood pressure, and protected against glomerular and interstitial damage in OZR.