Non-shivering thermogenesis as a mechanism to facilitate sustainable weight loss.

Currently, there is a significant percentage of the population who are or will be classified as obese, necessitating novel strategies to facilitate sustainable weight loss. Reductions in basal metabolic rate occur in the face of weight loss and pose formidable barriers to individuals attempting to sustain meaningful weight reductions. Here, we discuss the mechanisms by which non-shivering thermogenesis may provide insight into metabolic pathways that can become druggable targets to facilitate sustainable weight loss. Specifically, we highlight the fact that non-shivering thermogenesis results in activation and expansion of brown and beige adipose tissues as well as activates pathways in skeletal muscle which increase metabolic flux and activity of muscle fibres through futile calcium cycling across the endoplasmic reticulum all facilitating an increase in metabolism. Finally, we highlight the fact there are sexual dimorphisms with respect to these metabolic processes in keeping with the National Institutes of Health mandate of treating sex as a biologic variable.

A sexually dimorphic hypothalamic response to chronic high-fat diet consumption.

In this review, we discuss the observations that, following chronic high-fat diet (HFD) exposure, male mice have higher levels of saturated fatty acids (FAs) and total sphingolipids, whereas lower amounts of polyunsaturated FAs in the central nervous system (CNS) than females. Furthermore, males, when compared with female mice, have higher levels of inflammatory markers in the hypothalamus following exposure to HFD. The increase in markers of inflammation in male mice is possibly due to the reductions in proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and estrogen receptor alpha (ERα), which is not recapitulated in female mice. Consistently, hypothalamic inflammation is induced both in male and female ERα total-body knockout mice when exposed to a HFD, thus confirming the key role of ERα in the regulation of HFD-induced hypothalamic inflammation. Finally, the HFD-induced depletion of hypothalamic ERα is associated with dysregulation in metabolic homeostasis, as evidenced by reductions in glucose tolerance and decrements in myocardial function.

Effectiveness of initiating treatment with valsartan/hydrochlorothiazide in patients with stage-1 or stage-2 hypertension.

This prospective, 6-week, multicenter, double-blind study examined the benefits of initiating treatment with combination valsartan/hydrochlorothiazide (HCTZ) compared with initial valsartan monotherapy for 648 patients with stage-1 or stage-2 hypertension (age=52.6+/-10 years; 54% male; baseline blood pressure (BP)=161/98 mm Hg, 32% stage 1). Patients were randomized to valsartan 80 mg (V-low), valsartan 160 mg (V-high) or valsartan/HCTZ 160/12.5 mg (V/HCTZ), and electively titrated after weeks 2 and 4 to the next dosage level (maximum dose valsartan/HCTZ 160/25 mg) if BP remained >140/90 mm Hg. At end of the study, patients initiated with V/HCTZ required less titration steps compared with the initial valsartan monotherapy groups (63 vs 86% required titration by study end, respectively) and reached the target BP goal of <140/90 mm Hg in a shorter period of time (2.8 weeks) (P<0.0001) vs V-low (4.3 weeks) and V-high (3.9 weeks). Initial combination therapy was also associated with higher BP control rates and greater reductions in both systolic and diastolic BP from baseline (63%, -27.7+/-13/-15.1+/-8 mm Hg) compared with V-low (46%, -21.2+/-13/-11.4+/-8 mm Hg, P<0.0001) or V-high (51%, -24.0+/-13/-12.0+/-10 mm Hg, P<0.01). Overall and drug-related AEs were mild to moderate and were similar between V/HCTZ (53.1 and 14.1%, respectively) and the two monotherapy groups, V-low (50.5 and 13.8%) and V-high (50.7 and 11.8%). In conclusion, initiating therapy with a combination of valsartan and low-dose HCTZ results in early, improved BP efficacy with similar tolerability as compared with starting treatment with a low or higher dose of valsartan for patients with stage-1 and stage-2 hypertension.

Impaired renal autoregulation: implications for the genesis of hypertension and hypertension-induced renal injury.

In summary, autoregulation of the renal vasculature provides a mechanism by which renal function is maintained relatively constant despite variations in systemic blood pressure. This system also provides a means for changes in blood pressure to occur without causing inappropriate alterations in urinary NaCl excretion. Alterations in the autoregulatory response can have clinical consequences. Increased activity of the TGF mechanism may be causally related to the development of some forms of hypertension. Decreased activity of TGF or an impaired myogenic response may help explain the increased susceptibility that certain patient groups exhibit toward hypertension-induced renal injury. The aggressive treatment of hypertension in patients with impaired renal autoregulation may be associated with an increase in the serum creatinine concentration. As long as this increase is neither excessive nor progressive, physicians should not be dissuaded from trying to achieve newly established blood pressure goals.

Individualizing the dialysate in the hemodialysis patient.

In most outpatient centers the dialysate is prepared centrally such that the composition of the dialysate is the same for all patients. When delivered in this manner most patients tolerate the procedure well. However, there are patients who tolerate the procedure poorly, which has prompted a great deal of research focused on individualizing the composition of the dialysate in order to improve patient tolerability. Prescribing a patient-specific dialysate will become increasingly important as the age of and number of comorbid conditions increase in the dialysis population. Patients with end-stage renal disease (ESRD) depend on dialysis to maintain fluid and electrolyte balance. Hemodialysis allows for solutes to diffuse between blood and dialysate such that, over the course of the procedure, plasma composition is restored toward normal values. The makeup of the dialysate is of paramount importance in accomplishing this goal. In most out-patient settings patients receive hemodialysis using dialysate prepared in bulk and delivered via a central delivery system so that the composition of the dialysate is the same for all patients. While most patients tolerate the procedure when administered in this fashion, many patients suffer from hemodynamic instability or symptoms of dialysis disequilibrium. One strategy to improve the clinical tolerance to dialysis is to adjust the dialysate composition according to the individual characteristics of the patient. This article reviews recent developments on how the dialysate can be manipulated in order to improve patient tolerance. Individualizing the dialysate composition is likely to gain increasing importance given the advancing age and increasing number of comorbid conditions found in ESRD patients.

Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose.

Most patients with phenobarbital overdose can be adequately treated with general supportive care, cathartics, activated charcoal, and a forced alkaline diuresis. In severely compromised patients, both hemodialysis and hemoperfusion have been used to enhance elimination of the drug. Of these two therapies, hemoperfusion is generally considered to be more effective because phenobarbital shows significant protein binding. Prior reports describing the use of hemodialysis in the treatment of phenobarbital overdose used small low-efficiency dialyzers at much lower blood flow rates compared with what is available today. In this report, a patient with life-threatening phenobarbital overdose is described who was treated with hemodialysis. This is the first reported case describing the effects of a high-efficiency dialyzer using high blood flow rates on phenobarbital pharmakokinetics. Using this technique, the clearance of phenobarbital was found to be greater than what has been previously reported with hemodialysis and greater than most reported cases describing the use of hemoperfusion. The procedure was associated with a rapid fall in phenobarbital levels and a dramatic improvement in the patient's clinical condition. The findings in this case show that use of a high-efficiency dialyzer with high blood flow rates is an effective therapy for patients with life-threatening phenobarbital poisoning. The excellent clearance of phenobarbital shown in this case, combined with the lack of thrombocytopenia, more widespread availability, and greater familiarity by the staff who administer it, support the idea that hemodialysis should be considered the preferred mode of extracorporeal therapy for phenobarbital intoxication.

Pathogenesis of ascites and renal salt retention in cirrhosis.

The sequence in which the various therapies discussed above are instituted can be viewed as a continuum that parallels the severity of the underlying cirrhotic state (Figure 6). In the earliest stages of the disease urinary sodium excretion is plentiful and negative salt balance can be achieved by simply lowering dietary sodium intake. As the disease advances neurohumoral effectors become more activated initially resulting in more intense renal salt retention and later in a progressive decline in renal function. Eventually, the filtered load of sodium becomes completely reabsorbed by the tubule and the final urine becomes virtually devoid of salt. If some component of the filtered load reaches the collecting duct or beyond, spironolactone will be effective in increasing urinary sodium excretion. Once sodium reabsorption is complete, proximal to the collecting duct, then thiazides and later loop diuretics will have to be added to spironolactone to increase urinary sodium excretion. Eventually, the filtered load is completely reabsorbed proximal to the thick ascending limb of Henle. At this point the patient is resistant to the effects of diuretics and requires more invasive procedures such as repetitive large volume paracentesis to remain in salt balance. In the terminal stages of the disease the glomerular filtration rate falls to such a degree that oliguria, azotemia, and eventually uremia are present and the patient is clinically diagnosed with hepatorenal syndrome. Vasoconstrictive input focused on the kidney is severe and irreversible. Renal failure is functional in nature; however, restoration of near normal renal function can be obtained following a liver transplant.

Sexual dysfunction in uremia.

In summary, sexual dysfunction is a common finding in both men and women with chronic renal failure. Common disturbances include erectile dysfunction in men, menstrual abnormalities in women, and decreased libido and fertility in both sexes. These abnormalities are primarily organic in nature and are related to uremia as well as the other comorbid conditions that frequently accompany the chronic renal failure patient. Fatigue and psychosocial factors related to the presence of a chronic disease are also contributory factors. Disturbances in the hypothalamic-pituitary-gonadal axis can be detected before the need for dialysis but continue to worsen once dialytic therapy is initiated. Impaired gonadal function is prominent in uremic men, whereas the disturbances in the hypothalamicpituitary axis are more subtle. By contrast, central disturbances are more prominent in uremic women. Therapy is initially directed toward optimizing the delivery of dialysis, correcting anemia with recombinant erythropoietin, and controlling the degree of secondary hyperparathyroidism with vitamin D. For many practicing nephrologists, sildenafil has become the first-line therapy in the treatment of impotence. In the hypogonadal man whose only complaint is decreased libido, testosterone may be of benefit. Regular gynecologic follow-up is required in uremic women to guard against potential complications of unopposed estrogen effect. Uremic women should be advised against pregnancy while on dialysis. Successful transplantation is the most effective means of restoring normal sexual function in both men and women with chronic renal failure.

Metabolic alkalosis.

In summary, the kidney possesses numerous mechanisms that help to prevent metabolic alkalosis. Maintenance of metabolic alkalosis for any length of time means that renal homeostatic mechanisms for HCO3- excretion have been disrupted. Understanding the mechanisms that may perturb the kidney's ability to correct alkalosis will lead to improved clinical approaches to differential diagnosis and treatment of the patient. Although metabolic alkalosis is frequently not dangerous, in certain settings metabolic alkalosis may contribute to mortality and should be treated aggressively.

Pathogenesis of edema formation in the nephrotic syndrome.

The development of edema in the nephrotic syndrome has traditionally been viewed as an underfill mechanism. According to this view, urinary loss of protein results in hypoalbuminemia and decreased plasma oncotic pressure. As a result, plasma water translocates out of the intravascular space and results in a decrease in intravascular volume. In response to the underfilled circulation, effector mechanisms are then activated that signal the kidney to secondarily retain salt and water. While an underfill mechanism may be responsible for edema formation in a minority of patients, recent clinical and experimental findings would suggest that edema formation in most nephrotic patients is the result of primary salt retention. Direct measurements of blood and plasma volume or measurement of neurohumoral markers that indirectly reflect effective circulatory volume are mostly consistent with either euvolemia or a volume expanded state. The ability to maintain plasma volume in the setting of a decreased plasma oncotic pressure is achieved by alterations in transcapillary exchange mechanisms known to occur in the setting of hypoalbuminemia that limit excessive capillary fluid filtration. The intrarenal mechanism responsible for primary sodium retention is not yet known, but may involve tubular resistance to the natriuretic effect of atrial natriuretic peptide.

Clinical acute renal failure with nonsteroidal anti-inflammatory drugs.

Under baseline euvolemic conditions, prostaglandins play little to no role in the minute-to-minute regulation of renal function. Where these compounds come to serve a major role is in the setting of a systemic or intrarenal circulatory disturbance. In the setting of a decreased absolute or effective circulatory volume, a number of vasoconstrictor effectors are stimulated whose function is to preserve the systemic circulation. At the same time, these compounds stimulate the synthesis of renal vasodilatory prostaglandins. In turn, prostaglandins oppose the vasoconstrictive effect of these effectors such that the renal circulation remains well-preserved while the rest of the circulation is clamped down. Predictably, inhibition of prostaglandin synthesis would lead to unopposed renal vasoconstriction, resulting in a precipitous decline in renal function. Clinical conditions in which the renal circulation is critically dependent on the effect of vasodilatory prostaglandins include volume depletion, congestive heart failure, and cirrhosis. There are other conditions in which the circulatory volume is normal, but due to the intrarenal generation of vasoconstrictors, the kidney is similarly dependent on vasodilatory prostaglandins. Such conditions include glomerulonephritis and urinary tract obstruction.

Lymphoproliferative disease presenting as obstructive uropathy after renal transplantation.

Lymphoproliferative disorders occur with a greater frequency in recipients of solid organ transplants. Unlike in the general population, these tumors tend to arise in extranodal sites and are often confined to a single organ. We report on a patient with lymphoproliferative disease confined to the hilum of the renal allograft. The only clinical clue to the presence of the tumor was an increase in the serum creatinine secondary to ureteral obstruction by the mass.

Leprosy-associated renal disease: case report and review of the literature.

Leprosy is an infectious disease the principal clinical manifestations of which are anesthetic skin lesions and the development of peripheral neuropathy. The most common renal manifestation in leprosy patients is glomerulonephritis. Both immunofluorescent and electron microscopic studies suggest that the varied glomerular lesions found in these patients are immune complex mediated. Other renal lesions that have been described include amyloidosis, tubulointerstitial disease, acute renal failure, and functional defects in the absence of identifiable histologic abnormalities. In this report, a patient is described who developed the clinical syndrome of rapidly progressive glomerulonephritis. The renal biopsy showed a diffuse endocapillary proliferative process with electron-dense deposits in the glomerular subendothelial and subepithelial spaces. Organisms consistent with Mycobacterium leprae were identified within several of the glomeruli.

Intravenous immunoglobulin-induced osmotic nephrosis.

Intravenous immunoglobulin preparations are being used for an increasing number of indications in clinical medicine. To minimize adverse reactions, sugar additives such as sucrose are added to some preparations to serve as stabilizing agents. We describe a patient treated with an immunoglobulin preparation containing sucrose who developed a fully reversible form of acute renal failure with histologic changes characterized by vacuolization and swelling of renal proximal tubular cells. We believe the high concentration of sucrose in the immunoglobulin preparation resulted in osmotic injury to the renal tubules. Such changes, which are identical to those described in humans and experimental animals given intravenous infusions of hypertonic sucrose, have come to be known as osmotic nephrosis. Risk factors for the development of this lesion are renal insufficiency and volume depletion. The risk for such injury can be minimized by further diluting the immunoglobulin preparation and slowing the infusion rate.