Relationship between adiposity and cardiovascular risk factors in prevalent hemodialysis patients.

OBJECTIVE: Increased body mass index (BMI) is associated with reduced all-cause and cardiovascular (CV) mortality in hemodialysis (HD) patients, whereas CV risk increases with BMI in the general population. In the general population, obesity is associated with inflammation, decreased high-density lipoprotein (HDL) cholesterol, increased low-density lipoprotein (LDL) cholesterol, and triglycerides (TGs), all risk factors for CV disease. Low-density lipoprotein cholesterol does not predict CV risk in HD, whereas increased C-reactive protein and interleukin-6 (IL-6), low HDL and apolipoprotein (apo) AI, and increased fasting TGs do predict risk. Renal failure is associated with dyslipidemia and inflammation in normal-weight patients. We hypothesized that the effects of obesity may be obscured by renal failure in HD. METHODS: We explored the relationship between adipose tissue pools and distribution, i.e., subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) (measured by magnetic resonance imaging) and measures of inflammation (C-reactive protein, IL-6, ceruloplasmin, and alpha1 acid glycoprotein), HDL and LDL cholesterol, total TGs, apo AI, apo B, apo CII (an activator of lipoprotein lipase), apo CIII (an inhibitor of lipoprotein lipase), and the adipokines, leptin and adiponectin, in 48 patients with prevalent HD. RESULTS AND CONCLUSIONS: Total TG concentrations were positively correlated with VAT controlled for age, sex, and weight. Both apo CII and apo CIII were correlated only with VAT. Adiponectin was inversely correlated with VAT, and leptin was positively associated with SAT. C-reactive protein and alpha1 acid glycoprotein were weakly associated with SAT, whereas ceruloplasmin was strongly associated with VAT according to multiple regression analysis. In contrast, apo B, LDL, apo AI, HDL, and IL-6 were not correlated with any measure of body composition, potentially mitigating the effects of obesity in HD.

Estimation of adipose pools in hemodialysis patients from anthropometric measures.

OBJECTIVE: Adiposity, measured as increased body mass index (BMI), is associated with reduced all-cause and cardiovascular (CV) mortality in hemodialysis (HD) patients, whereas CV risk increases with BMI in the general population. A major limitation of BMI as a measure of adiposity is its failure to distinguish muscle and fat compartments. In addition, the biology of different adipose compartments is not the same. The visceral adipose tissue (VAT) mass is especially biologically active, secreting a variety of cytokines and adipokines. Alternate methods of estimating body composition were found to have a greater association with CV risk factors than BMI in several populations. We measured total adipose tissue, subcutaneous adipose tissue, and VAT in 48 prevalent HD patients, using magnetic resonance imaging. METHODS AND RESULTS: Based on these measurements, we developed parsimonious multiple-regression models to estimate these adipose compartments using age, sex, BMI, weight, maximum abdominal circumference (MAC), and race. The parsimonious models for VAT included only age, race, and MAC (adjusted r(2) = 0.776, P < .0001), whereas the subcutaneous adipose tissue model included sex, weight, age, and BMI (adjusted r(2) = 0.91, P < .0001) rather than MAC. The total adipose tissue model included BMI, sex, weight, and age (adjusted r(2) = 0.905, P < .0001). CONCLUSION: We propose that measurements of MAC, in addition to height and weight, be included in studies relating body composition to outcomes, because this measure provides a better estimate of the metabolically active VAT pool.

Quest for V: body composition could determine dialysis dose.

Since the demonstration that dialysis patients with lower body weight have a higher mortality than larger patients, there has been much interest in determining possible mechanisms and any possible relationships to the dialysis dose. Arguments have been made against using Kt/V(urea) as the basis for dialysis prescription. Efforts have been made to determine a parameter of dialysis delivery independent of body size. An emerging area of intense research interest has explored the body composition determinants of resting metabolic rate. Based on the knowledge of in vitro organ tissue energy production, newer high-resolution imaging methods have been applied as a means of establishing the sources of resting energy production in chronic kidney disease (CKD) patients. However, the linkages between resting energy expenditure (REE), body composition, and survival have not received much attention despite various studies exploring the effect of renal dysfunction and of the hemodialysis process on REE. We explore possible mechanisms leading to a higher mortality in smaller (lower body mass index) patients. The hypothesis of Morton and Singer is discussed. We have hypothesized that delivery of dialysis based on visceral organ volume (V(organ)), which could be the appropriate representation of uremic toxin generation, would be more logical than the current practice. This retains the concept of Kt/V but suggests that instead of the total V, a component related to major metabolic activity might represent the volume of interest. As per our hypothesis, smaller dialysis patients would need relatively a higher dialysis dose delivery, as expressed by current Kt/V, in order to achieve the same level of clearance of uremic toxins as in larger patients.

Fluid dynamics during hemodialysis in relationship to sodium gradient between dialysate and plasma.

Fluid shifts during hemodialysis involve changes in both extracellular and intracellular volumes. This study aimed to determine the effect of intradialytic sodium gradients (GNa), that is, the difference between dialysate and serum sodium concentration, on dynamics of extracellular and intracellular volumes in a group of maintenance hemodialysis patients. Extracellular volume change (deltaECV) between predialysis and postdialysis periods was determined by whole-body bioimpedance spectroscopy; intracellular volume change (deltaICV) was indirectly derived as the difference between deltaECV and the change in body weight, corrected for intradialytically given fluids. A total of 200 bioimpedance measurements were performed in 32 dialysis patients. Extracellular and intracellular volume changes were -2.6 +/- 0.9 L (range: -4.7 to -0.5 L) and -0.2 +/- 0.7 L (range: -2.5 to +1.5 L), respectively. There was a significant correlation between deltaICV and GNa; deltaICV = -0.12 * GNa + 0.26 (p < 0.001). In contrast, GNa was not correlated with deltaECV. We conclude that the sodium gradient between dialysate and plasma has a significant effect on the ICV during dialysis. Hemodialysis with GNa = 0 mmol/L should be sought to prevent ICV shrinking or swelling and to prevent excessive thirst, consequently high interdialytic weight gains, and ultrafiltration rates.

Acute oxalate nephropathy associated with orlistat, a gastrointestinal lipase inhibitor.

Orlistat is an oral inhibitor of gastrointestinal lipase used for weight reduction in obese patients. Although most adverse drug effects manifest in the gastrointestinal tract, this is the first reported case of orlistat-induced acute kidney injury secondary to acute oxalate nephropathy in a white woman with underlying chronic kidney disease. Acute kidney injury was associated temporally with an increased dose of orlistat and the development of increased fat malabsorption (more frequent loose oily stools). Urine sediment showed abundant calcium oxalate crystals and increased 24-hour urine oxalate concentration. Kidney biopsy showed deposition of calcium oxalate crystals within tubular lumens, consistent with acute oxalate nephropathy. Orlistat therapy was discontinued, and oral fluid intake was increased. A second kidney biopsy performed 1 month later to evaluate the slow resolution of kidney failure did not show calcium oxalate crystals within tubules. A steady improvement in renal function subsequently was observed. Results of a repeated 24-hour urine oxalate collection performed 3 weeks later when kidney function had improved were within normal limits.

Size matters: body composition and outcomes in maintenance hemodialysis patients.

In hemodialysis patients a low body mass index (BMI) is correlated with an unfavorable clinical outcome, a phenomenon known as "reverse epidemiology". Mechanisms underlying this observation are unclear. We propose the following: uremic toxin generation occurs predominantly in visceral organs and the mass of key uremiogenic viscera (gut, liver) relative to body weight is higher in small people. Consequently, the rate of uremic toxin generation per unit of BMI is higher in patients with a low BMI. Body water, mainly determined by muscle mass, serves as a dilution compartment for uremic toxins. Therefore, the concentration of uremic toxins is higher in small subjects. Uremic toxins are taken up by adipose and muscle tissues, subsequently metabolized and stored. Thus, the larger the ratio of fat and muscle mass to visceral mass, the lower the concentration of uremic toxins and the better the survival. To test this hypothesis, studies on uremic toxin kinetics in relation to body composition are needed.

Interdialytic weight gain: implications in hemodialysis patients.

Interdialytic weight gain (IDWG) is an easily measurable parameter in the dialysis unit, routinely assessed at the beginning of the dialysis session. It is used along with clinical symptoms and signs and predialysis blood pressure readings to make decisions regarding the amount of fluid removal during a dialysis session. IDWG is also used as a basis for fluid and salt intake recommendations. However, advising fluid and salt restriction based solely on IDWG may not be appropriate because of its status as a nutritional indicator, as well. Very few studies have been designed to determine the direct effect of IDWG on morbidity and mortality. Any such effect is confounded by residual renal function and various comorbidities, the effects of which might be difficult to separate from those of IDWG. Most attempts to control IDWG have concentrated on requiring patients to reduce fluid and dietary salt intake. Although there does not seem to be a consensus at this point, it is likely that within the lower values of IDWG (less than 5.7% of dry weight), tighter control of fluid and salt intake might not be warranted since these values may reflect higher protein and calorie intake, indicating better nutritional status.

Assessment of body composition in long-term hemodialysis patients: rationale and methodology.

Protein-energy malnutrition is seen in patients with advanced stages of chronic kidney disease (CKD) and is even more pronounced in patients receiving long-term hemodialysis treatment. Both entities have great impact on patient morbidity and mortality. Analysis of body composition is an integral part of nutritional assessment and includes the estimation of muscle, fat, and fat-free mass, as well as the extracellular water compartment. Clinical assessment of these compartments is difficult, and gold-standard methods such as tracer dilution, magnetic resonance imaging, and dual-energy x-ray absorptiometry are expensive, cumbersome, and rarely available. We report an ongoing study of body composition in hemodialysis patients involving deuterium and sodium bromide dilution, total body potassium counting, magnetic resonance imaging, whole-body and segmental bioimpedance spectroscopy, and anthropometry. The goals of the study are (1) to validate bioimpedance technology against gold-standard methods for assessment of the various body compartments, (2) to directly quantify visceral adipose tissue mass, a potential source of cytokine production (adipokines) promoting chronic inflammation, and to study its relation to inflammatory markers, and (3) to directly quantify visceral organ mass and to study its relation to uremia toxin generation as assessed by protein catabolic rate and resting energy expenditure. Preliminary results based on up to 40 hemodialysis patients are reported.

Nitric oxide and hemodialysis.

Nitric oxide (NO), previously thought of as a noxious gas, is now recognized as an important mediator of vascular responsiveness. Soon after its discovery, it was realized that the actions of NO are similar to the previously described endothelium-derived relaxing factor (EDRF). It is synthesized in the vascular endothelium utilizing the enzyme nitric oxide synthase (NOS) and diffuses in the adjacent vascular media, where it has a vasodilatory action. Opposing actions of NO and vasoconstrictor agents (such as endothelin-1, angiotensin IotaIota, and others) maintain the vascular tone of the renal arteries. The same balance at the level of the macula densa maintains glomerular filtration rate (GFR) during varying levels of salt excretion. Lack of NO can result in disruption of this fine balance, with resultant vasoconstriction and disease progression, hypertension, and accelerated atherosclerosis. In addition, hypertension may result from positive salt balance that occurs when macula densa NOS is inhibited. While most investigators report low levels of NO in uremic subjects, the levels in hemodialysis (HD) patients have not been characterized adequately. This is primarily because HD patients are exposed to both stimulatory and inhibitory factors for NO synthesis. Retention of inhibitors of NOS tends to decrease NO levels, whereas production of NO will be increased by cytokines generated during blood-dialyzer interaction. There is less disagreement, however, over the finding of elevated levels in those with dialyzer reactions and dialysis-induced hypotension. Recent developments in the isolation of inducible and constitutive forms of NOS makes understanding of its pathophysiologic effects more complete. Newer treatment directed at inhibiting only the inducible forms of NOS (sparing the constitutive forms) may soon be found useful for the treatment and prevention of hypotension and dialyzer reactions in HD patients.