Burl R. Don

Serum albumin: relationship to inflammation and nutrition.

Hypoalbuminemia is the result of the combined effects of inflammation and inadequate protein and caloric intake in patients with chronic disease such as chronic renal failure. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis, while inflammation alone is associated with a greater fractional catabolic rate (FCR) and, when extreme, increased transfer of albumin out of the vascular compartment. A vicious cascade of events ensues in which inflammation induces anorexia and reduces the effective use of dietary protein and energy intake and augments catabolism of the key somatic protein, albumin. Hypoalbuminemia is a powerful predictor of mortality in patients with chronic renal failure, and the major cause of death in this population is due to cardiovascular events. Inflammation is associated with vascular disease and likely causes injury to the vascular endothelium, and hypoalbuminemia as two separate expressions of the inflammatory process. Albumin has a myriad of important physiologic effects that are essential for normal health. However, simply administering albumin to critically ill patients with hypoalbuminemia has not been shown to improve survival or reduce morbidity. Thus the inference from these clinical studies suggests that the cause of hypoalbuminemia, rather than low albumin levels specifically, is responsible for morbidity and mortality.

POOR NUTRITIONAL STATUS AND INFLAMMATION: Serum Albumin: Relationship to Inflammation and Nutrition

Hypoalbuminemia is the result of the combined effects of inflammation and inadequate protein and caloric intake in patients with chronic disease such as chronic renal failure. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis, while inflammation alone is associated with a greater fractional catabolic rate (FCR) and, when extreme, increased transfer of albumin out of the vascular compartment. A vicious cascade of events ensues in which inflammation induces anorexia and reduces the effective use of dietary protein and energy intake and augments catabolism of the key somatic protein, albumin. Hypoalbuminemia is a powerful predictor of mortality in patients with chronic renal failure, and the major cause of death in this population is due to cardiovascular events. Inflammation is associated with vascular disease and likely causes injury to the vascular endothelium, and hypoalbuminemia as two separate expressions of the inflammatory process. Albumin has a myriad of important physiologic effects that are essential for normal health. However, simply administering albumin to critically ill patients with hypoalbuminemia has not been shown to improve survival or reduce morbidity. Thus the inference from these clinical studies suggests that the cause of hypoalbuminemia, rather than low albumin levels specifically, is responsible for morbidity and mortality.

The tissue renin-angiotensin system in rats with fructose-induced hypertension: overexpression of type 1 angiotensin II receptor in adipose tissue.

Objective Fructose feeding induces hypertension, insulin-resistance and hypertriglyceridemia in Sprague-Dawley rats. The mechanisms of fructose-induced hypertension are as yet unknown. Here we investigate the effects of fructose feeding and of varying salt intake on blood pressure, glucose tolerance, plasma renin activity, and tissue angiotensinogen, renin, and AT1 receptor mRNA levels in this model of hypertension. Design and methods To investigate the role of the renin-angiotensin system in fructose-induced hypertension we measured angiotensinogen, renin and angiotensin II type 1 (AT1) receptor mRNA levels in tissues of Sprague-Dawley rats that were fed either standard rat chow or a diet containing 66% fructose. Results Blood pressure (P <0.05) and triglyceride (P <0.01) levels were significantly greater in the fructosefed animals. Plasma glucose and insulin responses to an oral glucose load were significantly greater (P <0.05) in fructose-fed than control rats. Angiotensinogen mRNA levels in liver and fat, and renin mRNA levels in kidney did not differ between fructose-fed and control animals. Levels of AT1 receptor mRNA were significantly greater in the fat obtained from fructose-fed rats than in that from control rats (P <0.05), but this was not so in the kidney. To determine whether fructose-induced hypertension is dependent on dietary salt content, rats were fed standard rat chow and a fructose-enriched diet with low and high sodium chloride concentrations. Blood pressure increased significantly (P <0.05) only in the fructose-fed rats receiving the high-salt diet. Similarly, increased AT1 receptor mRNA levels were observed only in the fructosefed rats that were maintained on the high-salt diet. Conclusions Fructose feeding induces hypertension in normal- or high-salt fed animals and it is associated with an increased expression of the AT1 receptor in adipose tissue. These findings suggest that AT1 receptors might play a role in the pathophysiology of metabolic and hemodynamic abnormalities induced by fructose feeding.

The pharmacokinetics of etanercept in patients with end-stage renal disease on haemodialysis

Inflammation is strongly associated with malnutrition and cardiovascular risk in patients with chronic renal failure on haemodialysis (HD). The acute‐phase inflammatory response, defined by the increased synthesis of positive acute‐phase proteins, is stimulated by the production of such cytokines as interleukin 6 (IL‐6), interleukin 1 (IL‐1) and tumour necrosis factor‐α TNF‐α The availability of cytokine antagonists allows testing of the hypothesis that suppression of inflammation reverses the malnutrition‐inflammation syndrome in HD patients. Etanercept is a soluble TNF‐α receptor fusion protein used to suppress inflammation in rheumatoid and psoriatic arthritis. Its metabolism in HD patients is unknown. In a study designed to test the safety and pharmacokinetics of etanercept in HD patients, etanercept was administered to six HD patients with albumin levels above 4.2 g dL−1 and C‐reactive protein levels <5 mg L−1 (five men, one woman, age range 34–59 years). Etanercept (25 mg) was administered subcutaneously twice weekly immediately after dialysis for 13–16 weeks. Etanercept concentrations were measured pre‐ and post‐dialysis by ELISA. Concentrations were compared graphically to assess whether, firstly, dialysis affects etanercept apparent clearance and, secondly, etanercept kinetics were similar between HD patients and the more extensively studied psoriasis population with normal renal function (PS). The second stage examined model‐based parameter predictions of the terminal elimination rate constant (k) for HD patients. Steady‐state etanercept levels were comparable between HD and PS patients. Treatment with HD had no effect on etanercept levels. When etanercept was discontinued, the terminal rate constant for HD patients was not significantly different from that observed in PS patients. No adverse effects were noted during the 3‐month treatment phase and subsequent 6‐month follow‐up. Albumin and C‐reactive protein levels did not change in these non‐inflamed patients during the study period. The pharmacokinetics of etanercept in patients with chronic renal failure on HD are similar to patients with normal renal function. It is, therefore, feasible to administer etanercept to HD patients without adjusting the dose

The Effect of Angiotensin-Converting Enzyme Inhibition and Dietary Protein Restriction in the Treatment of Proteinuria

Both angiotensin-converting enzyme inhibitors and dietary protein restriction have been reported to reduce urinary protein losses in patients with chronic glomerular diseases. We evaluated these two therapies in 12 such patients ingesting a constant metabolic diet containing 1.6 g protein/kg body weight per day. After a steady-state was achieved during a 3-week baseline period, patients were randomly assigned to either enalapril, titrated to reduce mean arterial pressure by 10 mm Hg, or an isocaloric 0.8 g/kg protein diet. Five patients in each group completed 3 additional weeks of observation during the treatment period. Enalapril resulted in an average reduction in urinary protein and albumin losses of 26% and 33%, respectively, without reducing creatinine clearance. Albumin synthesis was unchanged and nitrogen balance increased slightly (+142.8 +/- 85.7 mmol/d [+2.0 +/- 1.2 g/d], P = 0.075). Dietary protein restriction had no consistent effect on proteinuria or albuminuria, whereas albumin synthesis (25.9 +/- 3.4 v 21.5 +/- 2.9 g/d/1.73 m2, P less than 0.05) and nitrogen balance (-135.6 +/- 92.8 mmol/d [-1.9 +/- 1.3 g/d], P = 0.10) decreased. Both therapies resulted in a modest increase in plasma potassium concentration. Whether the maintenance of albumin synthesis in the presence of a reduction in urinary protein losses will convey a long-term advantage to treatment of proteinuric patients with angiotensin-converting enzyme inhibitors remains to be determined.

Comparison of bioimpedance and dual-energy x-ray absorptiometry for measurement of fat mass in hemodialysis patients.

Background: Fat mass (FM) is measured with dual-energy X-ray absorptiometry (DXA), but is expensive and not portable. Multifrequency bioimpedance spectroscopy (BIS) measures total body water (TBW), intracellular water (ICW) and extracellular water (ECW). FM is calculated by subtracting fat-free mass (FFM) from weight assuming a fractional hydration of FFM of 0.73. Hemodialysis (HD) patients, however, have nonphysiologic expansion of ECW. Our aim was to apply a model to estimate FM in HD patients and controls. Methods: We estimated the hydration of FFM in healthy subjects and HD patients with BIS (Impedimed multifrequency) assuming a hydration of 0.73 or using a model allowing ECW and ICW to vary, deriving a value for FM accounting for variances in ECW and ICW. FM was measured by DXA (Hologic Discovery W) in 25 controls and in 11 HD patients. We measured TBW, ECW and ICW with BIS and calculated FM using either weight - TBW/0.73 or with a model accounting for variations in ECW/ICW to estimate FM. Results: ECW/ICW was greater in HD patients than in controls (0.83 ± 0.08 vs. 0.76 ± 0.04; p = 0.001). FM (kg) measured by DXA or estimated from TBW using constant hydration or accounting for variations in ECW/ICW was not significantly different in controls or in HD patients. Values obtained by all methods correlated (p < 0.001) and none of the Bland-Altman plots regressed (r2 = 0.00). FM measured by DXA and by BIS in both controls and HD patients combined correlated (r2 = 0.871). Conclusion: Expansion of ECW in HD patients is statistically significant; however, the effect on hydration of FFM was insufficient to cause significant deviation from values derived using a hydration value of 0.73 within the range of expansion of ECW in the HD patient population studied here.

Abnormalities of Glomerular Eicosanoid Metabolism in States of Glomerular Hyperfiltration

The glomerulus is a complex structure that functions primarily to produce an ultrafiltrate of plasma. Micropuncture studies in the Munich-Wistar rat have identified the major physical determinants of the glomerular filtration rate (GFR): glomerular plasma flow; afferent protein concentration; transcapillary hydraulic-pressure difference; and the glomerular capillary ultrafiltration coefficient (Kf) (1). Studies in this model also indicate that a number of circulating hormones (e.g., parathyroid hormone, vasopressin), as well as other biological messengers that are produced in the kidney and that act locally through an autacrine or paracrine mechanism (prostaglandins, angiotensin II, histamine, and brady-kinin), can affect the GFR (2). In addition to vasoactive effects on the afferent and efferent renal arterioles with subsequent alteration of renal vascular resistance, many of these substances affect the filtration process by a reduction in Kf, an action that appears to be mediated by contraction of the glomerular mesangial cell and reduction of the glomerular capillary surface area. This may be due to a direct contractile effect of the agonist on the mesangial cell, as in the case of angiotensin II and vasopressin, or by secondary activation of the renin-angiotensin system (2–3).

Severe hypercalcemic hyperparathyroidism developing in a patient with hyperaldosteronism and renal resistance to parathyroid hormone

We evaluated an African American woman referred in 1986 at age 33 years because of renal potassium and calcium wasting and chronic hip pain. She presented normotensive, hypokalemic, hypocalcemic, normophosphatemic, and hypercalciuric. Marked hyperparathyroidism was evident. Urinary cyclic adenosine monophosphate (cAMP) excretion did not increase in response to parathyroid hormone (PTH) infusion, indicating renal resistance to PTH. X‐rays and bone biopsy revealed severe osteitis fibrosa cystica, confirming skeletal responsiveness to PTH. Renal potassium wasting, suppressed plasma renin activity, and elevated plasma and urinary aldosterone levels accompanied her hypokalemia, suggesting primary hyperaldosteronism. Hypokalemia resolved with spironolactone and, when combined with dietary sodium restriction, urinary calcium excretion fell and hypocalcemia improved, in accord with the known positive association between sodium intake and calcium excretion. Calcitriol and oral calcium supplements did not suppress the chronic hyperparathyroidism nor did they reduce aldosterone levels. Over time, hyperparathyroid bone disease progressed with pathologic fractures and persistent pain. In 2004, PTH levels increased further in association with worsening chronic kidney disease. Eventually hypercalcemia and hypertension developed. Localizing studies in 2005 suggested a left inferior parathyroid tumor. After having consistently declined, the patient finally agreed to neck exploration in January 2009. Four hyperplastic parathyroid glands were removed, followed immediately by severe hypocalcemia, attributed to “hungry bone syndrome” and hypoparathyroidism, which required prolonged hospitalization, calcium infusions, and oral calcitriol. Although her bone pain resolved, hyperaldosteronism persisted.

Contents Vol. 122, 2012

Chronic Kidney Disease and Hypertension Vlado Perkovic , Sydney Adeera Levin, Vancouver, B.C. Ron Gansevoort, Groningen Acute Kidney Injury Ravi Mehta, San Diego, Calif. Nitin Kolhe, Derby Dialysis John Daugirdas, Chicago, Ill. Colin Hutchison, Hawkes Bay Casper Fraansen, Groningen Patient Subjective Experience, Healthcare Delivery and Innovation in Practice Richard Fluck, Derby Edwina Brown, London Crossover States with Non-Renal Organ Systems Chris Chan, Toronto, Ont. Tobias Breidthardt, Basel Nick Selby, Derby Transplantation Anil Chandraker, Boston, Mass. Alan Salama, London Editor-in-Chief

POOR NUTRITIONAL STATUS AND INFLAMMATION: Serum Albumin: Relationship to Inflammation and Nutrition: SERUM ALBUMIN

Hypoalbuminemia is the result of the combined effects of inflammation and inadequate protein and caloric intake in patients with chronic disease such as chronic renal failure. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis, while inflammation alone is associated with a greater fractional catabolic rate (FCR) and, when extreme, increased transfer of albumin out of the vascular compartment. A vicious cascade of events ensues in which inflammation induces anorexia and reduces the effective use of dietary protein and energy intake and augments catabolism of the key somatic protein, albumin. Hypoalbuminemia is a powerful predictor of mortality in patients with chronic renal failure, and the major cause of death in this population is due to cardiovascular events. Inflammation is associated with vascular disease and likely causes injury to the vascular endothelium, and hypoalbuminemia as two separate expressions of the inflammatory process. Albumin has a myriad of important physiologic effects that are essential for normal health. However, simply administering albumin to critically ill patients with hypoalbuminemia has not been shown to improve survival or reduce morbidity. Thus the inference from these clinical studies suggests that the cause of hypoalbuminemia, rather than low albumin levels specifically, is responsible for morbidity and mortality.