The effect of etanercept on suppression of the systemic inflammatory response in chronic hemodialysis patients.

BACKGROUND: Inflammation strongly predicts all-cause and cardiovascular mortality among dialysis patients. The negative acute-phase proteins, albumin and prealbumin are both inversely associated with mortality. Both albumin and prealbumin levels are decreased by inflammation. We carried out a pilot study to establish whether treatment with the tumor necrosis factor-alpha; receptor antagonist etanercept would be safe and result in improved levels of albumin and prealbumin in inflamed hypoalbuminemic (albumin < 3.8 g/dl, CRP > 8.0 mg/l) prevalent hemodialysis patients. METHODS: We excluded patients who had infectious risk (hepatitis C or B positive, HIV positive, purified protein derivative (PPD) positive or having a history of tuberculosis, having a tunneled dialysis catheter) to find patients having both hypoalbuminemia and inflammation. Of 433 less than 6% met the inclusion criteria. 10 patients were randomized to receive etanercept or placebo twice weekly for 44 weeks. RESULTS: There were no adverse infectious events. There was no significant difference for any of the measurements between the two groups. However there was a significant difference in the time-dependent effects of etanercept on prealbumin: increasing 20% in the etanercept group while decreasing in the placebo group. CONCLUSIONS: Administration of a TNF-alpha; receptor antagonist appears safe in this selected population, despite the large increase in infectious risk observed in the dialysis patient population. The effect on surrogate markers of inflammation is small.

Extended daily dialysis vs. continuous hemodialysis for ICU patients with acute renal failure: a two-year single center report.

Extended daily dialysis (EDD) is an easily implemented alternative to continuous renal replacement therapy (CRRT) in the intensive care unit (ICU). Since EDD offers most of the advantages of CRRT, we sought to compare the effectiveness of these two modalities. In this 2-year study, 54 ICU patients with ARF were treated with either continuous hemodialysis (CHD) or EDD. Oliguria was present in 64% of patients who received CHD vs. 73% of EDD patients (p=NS) while 93% of CHD and 81% of EDD patients required mechanical ventilation (p=NS). Patients treated with EDD were younger than those who received CHD (47.0 +/- 12.6 vs. 56.7 +/- 13.7, p=0.009), but there were no significant differences in gender or mean APACHE II scores at the time of randomization. Mean arterial blood pressures measured during treatment were maintained between 70 and 80 mmHg for both EDD and CHD and average daily serum electrolyte levels fell within normal ranges for EDD and CHD. Average daily fluid input and output were 5.8 +/- 3.3 L and 6.0 +/- 3.2 L for CHD vs. 3.3 +/- 2.6 and 3.0 +/- 1.7 L for EDD after exclusion of data from 2 burn patients. Hourly heparin anticoagulation rates were 1080 U/hour for CHD and 643 U/hour for EDD, p=0.02. Anticoagulation-free treatments were performed during 43% of all EDD treatments vs. 21% of all CHD treatments, p<0.001. Clotting of the dialyzer or circuit occurred at least once during 51% of all CHD treatment days vs. 22% of EDD treatments (p<0.001). We conclude that EDD is a safe, effective alternative to CRRT that offers comparable hemodynamic stability and excellent small solute control.

A strategy for the treatment of calcific uremic arteriolopathy (calciphylaxis) employing a combination of therapies.

Calcific uremic arteriolopathy (calciphylaxis) is one of the more devastating complications that can develop in patients with chronic renal failure. This disorder is associated with calcium-phosphorus deposition in the subcutaneous arterial vessels and presents as a progressive ischemic necrosis of the skin resulting in large subcutaneous ulcerations with eschar formation. Mortality rates are substantially greater in chronic renal failure patients with calciphylaxis, and the major cause of death is infection and sepsis. We have developed a treatment strategy that employs a combination of therapies, which is based on reducing the known risk factors for the development of calciphylaxis as well as utilization of a number of treatment modalities that have been proven successful in the treatment of this disorder.

Pharmacokinetics of thalidomide in patients with impaired renal function and while on and off dialysis.

There is a renewed interest in thalidomide for use in malignancies and systemic inflammatory diseases. Reduced renal function is not uncommon among patients with these disease states but the pharmacokinetics has not been fully investigated. The aim of this study was to investigate the pharmacokinetics of thalidomide in haemodialysis patients while on and off dialysis and in myeloma patients with varying degrees of renal function. Two studies were performed. To establish the pharmacokinetics of thalidomide in patients with mild to moderate renal failure, blood samples were taken over 12 weeks from 40 patients with multiple myeloma. A second study was performed in six patients with end-stage renal disease both on a non-dialysis day and before and during a haemodialysis session. Thalidomide concentration was determined by HPLC. A one-compartment open model with first-order absorption and elimination was used to fit total thalidomide concentration to population pharmacokinetics and statistical models using the NONMEM program. Clearance and volumes were slightly below 10 L h-1 and 1 L kg-1, respectively, in both patient groups. The inter- and intra-patient variability was low. Clearance was doubled during dialysis. There was no correlation between thalidomide clearance and renal function. In conclusion, the pharmacokinetics of thalidomide in patients with renal failure are very similar to values reported by others for patients with normal renal function. Although clearance during dialysis is doubled, thalidomide dose need not be changed for patients with decreased kidney function. There is also no need for a supplementary dose due to haemodialysis.

Serum ferritin is a marker of morbidity and mortality in hemodialysis patients.

We tested the hypothesis that a high concentration of serum ferritin, a frequently used marker of iron stores in dialysis patients and an acute-phase reactant, may be a marker of morbidity and mortality in these patients. To evaluate the impact of ferritin on morbidity and mortality, we reviewed the 6-month hospitalization rates in our dialysis patients retrospectively and subsequently reviewed the mortality among these patients over a 12-month period of time prospectively. One hundred one adult hemodialysis patients (59 men and 42 women; age, 54 +/- 15 years) who had been on hemodialysis for 38 +/- 27 months were studied. All but 5 patients were on intravenous iron with similar iron administration pattern. In the retrospective cohort, ferritin's correlation coefficients for hospitalization days and frequency (both r = +0.39, P: < 0.001) were higher compared with the albumin correlations for hospitalization days (r = -0.31, P: = 0.001) and frequency (r = -0.28, P: = 0.005) and correlation coefficients remained similarly significant after case-mix adjustment. In the prospective study, the "predeath" value of serum ferritin for 17 deceased patients (891 +/- 476 ng/mL) was higher than both their "initial" value (619 +/- 345 ng/mL, P: = 0.007) and the mean ferritin value of 84 surviving and withdrawing patients (639 +/- 358 ng/mL, P: = 0.001). Although Cox proportional hazard analysis showed a significant odds ratio of death only for serum albumin and not for ferritin, logistic regression analysis using the predeath values confirmed the significant impact of both decreased serum albumin and increased serum ferritin as markers of dialysis mortality. After case-mix adjustment, the relative risks of death for a 500 ng/dL increase in serum ferritin was 2.71 (95% confidence interval, 1.06 to 7.02) and for a 0.5 g/dL decrease in serum albumin was 4.48 (95% confidence interval, 1.77 to 11.33). Hence, serum ferritin is a strong predictor of hospitalization in dialysis patients. Although serum albumin is found to be a strong long-term marker of mortality in hemodialysis patients, an increase in serum ferritin appears to be a more reliable short-term marker of death over a 12-month period. Therefore, in the setting of uniform iron administration, a high serum ferritin may be a morbidity risk factor and a recent increase in serum ferritin may carry an increase in the risk of death in these patients.

Leptin is a negative acute phase protein in chronic hemodialysis patients.

BACKGROUND: Hypoalbuminemia strongly predicts death in hemodialysis patients and results from both inflammation and malnutrition. One potential link between malnutrition and inflammation is appetite suppression triggered by inflammation. Leptin is secreted by adipose tissue and suppresses appetite, and it is also a positive acute phase protein in the rat. Factored for body weight, leptin is known to be increased in hemodialysis patients, but its relationship to inflammation is unknown. METHODS: We examined the relationship between spontaneously occurring activation of the acute phase response and leptin levels in 29 chronic hemodialysis patients. Serum samples were obtained three times weekly for six weeks and then monthly from 29 chronic hemodialysis patients, and the levels of the positive acute phase proteins [C-reactive protein (CRP), alpha1-acid glycoprotein (alpha1 AG), serum amyloid A, ceruloplasmin] and the negative acute phase proteins (albumin and transferrin) as well as leptin and interleukin-6 (IL-6) were measured. RESULTS: Positive and negative acute phase proteins were evaluated at the maximum CRP (mean, 9.42 +/- 1.14 mg/dL) and minimum values (mean, 0.41 +/- 0.09 mg/dL). When CRP was elevated, leptin levels were significantly reduced, as were the negative acute phase proteins albumin and transferrin. Serum amyloid A, ceruloplasmin, alpha1 acid glycoprotein, and IL-6 were all significantly increased at the maximum CRP level, compatible with general activation of the acute phase response. The change in leptin correlated negatively with the change in CRP (R = 0.437, P = 0.018), as did changes in albumin (R = 0.620, P < 0.001). CONCLUSIONS: Leptin is not increased as a consequence of inflammation in hemodialysis patients, but behaves as a negative rather than as a positive acute phase protein. Inflammation is unlikely to reduce appetite in dialysis patients through a leptin-mediated mechanism.

The effect of trimethoprim on potassium and uric acid metabolism in normal human subjects.

BACKGROUND: Trimethoprim used in combination with other antibiotics, has been implicated in causing hyperkalemia and hypouricemia in patients with acquired immune deficiency syndrome (AIDS). In experimental animal models, trimethoprim has been demonstrated to block sodium channels and Na+-K+-ATPase in the distal nephron and thus impair potassium excretion. Although the data from the experimental models suggest that trimethoprim reduces urinary potassium excretion, the retrospective clinical studies have confounding factors that prevent a rigorous demonstration that the hyperkalemia and hypouricemia are due solely to the effects of trimethoprim on solute excretion. AIM: The purpose of this study was to evaluate the effect of trimethoprim on potassium and uric acid balance in normal human subjects. METHODS: Five normal human subjects were admitted to the general clinical research center and placed on a fixed metabolic diet. After a 4-day control period, the subjects were given trimethoprim (15 mg/kg/day) orally for 5-7 days followed by a 4-day recovery period. Free-flow blood samples and 24-hour urine collections were obtained daily. RESULTS: Treatment with trimethoprim resulted in a significant increase in plasma potassium concentration (4.5 +/- 0.1 versus 3.7 +/- 0.1 mmol/l, p < 0.005) and significant decrease in serum uric acid concentration (3.8 +/- 0.4 versus 5.6 +/- 0.5 mg/dl, p < 0.001). Treatment with trimethoprim significantly increased the urinary excretion of uric acid, but did not significantly decrease potassium excretion during the 7-day treatment period. There was, however, a significant decrease in potassium excretion observed during the first 48 hours of trimethoprim treatment. In one subject where repeat studies were performed using different dosages, the effect on potassium and uric acid levels appeared to be dose-dependent. CONCLUSIONS: Trimethoprim increases plasma potassium concentration probably by reducing urinary potassium excretion. Trimethoprim decreases serum uric acid levels by augmenting urinary uric acid excretion. This uricosuric effect may be due to the ability of trimethoprim to impair urate reabsorption by the urate-anion exchanger in the proximal tubule.

Assessment of inflammation and nutrition in patients with end-stage renal disease.

Malnutrition commonly occurs in patients with end-stage renal disease (ESRD), and hypoalbuminemia is considered the best clinical marker of malnutrition and mortality in this population. Recently, it has been recognized that a substantial number of patients with ESRD have serologic evidence of an augmented inflammatory response and moreover, inflammation may be as or more important than protein intake in causing hypoalbuminemia. In addition, the presence of inflammation may be a more powerful predictor of mortality than dietary protein intake. The presence of inflammation is often subtle and is detected by increased levels of the positive acute phase proteins, most notably C-reactive protein. The causes of the stimulation of the systemic inflammatory response may include reaction to dialyzer membranes, increased production of advanced glycosylated end-products, oxidative stress of uremia and overt and occult infections, especially unrecognized arteriovenous graft infections. There is a complex relationship between inflammation and nutritional status. Inflammation can cause both anorexia with protein-calorie malnutrition as well as wasting through mechanisms mediated by cytokines. Novel therapies will need to be developed to counter this systemic inflammation since it appears to be a major cause of mortality in patients with end-stage renal disease.

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 fructose-fed 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 fructose-fed 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.

Tesio catheter: radiologically guided placement, mechanical performance, and adequacy of delivered dialysis.

PURPOSE: Tunneled catheters are an alternative means of vascular access for patients in need of hemodialysis who cannot undergo dialysis through a surgical shunt. This study was undertaken to evaluate the performance of the Tesio dialysis catheter. MATERIALS AND METHODS: A prospective study of the Tesio catheter was performed. Follow-up data regarding catheter function and adequacy of dialysis were obtained from nine hemodialysis facilities. RESULTS: Seventy-nine Tesio catheters were placed in 71 patients. Immediate technical success was 99% (78 of 79 catheters). The procedure complication rate was 9% (seven catheters). Only two complications required intervention: one fatal air embolism and one chest wall hematoma. Sixty-seven catheters in 60 patients were followed up for a total of 4,367 catheter days. Overall, catheter-related infection occurred in 9% (six of 67 catheters). Primary catheter patency was 87% at 1 week, 82% at 1 month, 72% at 3 months, and 66% at 6 months. Mean blood flow was 286 mL/min immediately after insertion, 301 mL/min at 3 months, and 306 mL/min at 6 months. Adequate dialysis dose as reflected by a urea reduction ratio of 60 or more or a urea kinetic modeling, or Kt/V, value of 1.2 or more was observed on at least one occasion for 74% and 76% of catheters, respectively. CONCLUSION: The Tesio catheter is a reasonable means of vascular access for patients who undergo dialysis but are not candidates for surgical shunt placement.

The renin-angiotensin system in streptozotocin-induced diabetes mellitus in the rat.

It has been hypothesized that the renin-angiotensin system plays a pathophysiologic role in the renal hemodynamic abnormalities that occur in diabetes mellitus and thereby contributes to the development of diabetic nephropathy. In this study, the tissue-specific regulation of renin and angiotensinogen mRNA levels and the abundance of glomerular angiotensin II receptors were examined in male Sprague-Dawley rats (160 to 240 g) made diabetic with streptozotocin. One subgroup of diabetic rats remained untreated, whereas a second diabetic subgroup received twice-daily doses of insulin to ameliorate hyperglycemia. Animals were euthanized 2 wk after the induction of diabetes. Mean plasma glucose levels at the time of euthanasia were significantly elevated in the untreated diabetic animals when compared with controls or insulin-treated diabetic rats. Weight gain was similar in control and insulin-treated diabetic rats, whereas the untreated diabetic rats gained significantly less. Plasma renin concentration did not differ between control, diabetic, and insulin-treated diabetic groups. In the kidney, no significant differences were found in either angiotensinogen or renin mRNA levels in diabetic animals, whereas glomerular angiotensin II receptors were significantly less abundant in untreated rats as compared with control or insulin-treated diabetic subgroups. Angiotensinogen mRNA levels were significantly lower in the livers and adrenals of diabetic rats in comparison to those in controls and insulin-treated diabetic rats, whereas angiotensinogen mRNA levels in the brain remained unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal mediators of amino acid-induced glomerular hyperfiltration in humans.

It has been speculated that glucoregulatory hormones and/or renal autacoids mediate the increase in glomerular filtration rate (GFR) induced by the administration of protein or amino acids. Because infusion of a mixture of amino acids (AA mix), but not of branched-chain amino acids (BCAA) alone, increases GFR, we performed a crossover study in seven normal subjects in which the glomerular hemodynamic effects of separate 3-h infusions of these two amino acid solutions were compared with changes in potential mediators of this response, i.e., glucoregulatory hormones, renin, vasodilatory prostaglandins (PGs), and guanosine 3',5'-cyclic monophosphate (cGMP). As expected, infusion of the AA mix but not BCAA resulted in a prompt and sustained increase in GFR. Both infusions caused a significant increase in plasma insulin, whereas glucagon increased only with the AA mix. Plasma growth hormone was initially unchanged with both infusions but increased after 2 h of BCAA. Neither infusion significantly increased the urinary excretion of PGE2, 6-keto-PGF1 alpha, or cGMP. Both infusions resulted in a small but significant decrease in plasma renin activity. Infusion of BCAA but not the AA mix resulted in a progressive decrease in plasma glucose and potassium concentrations and an increase in renal sodium reabsorption that may have resulted from stimulation of insulin secretion that was not counterbalanced by a simultaneous increase in glucagon. Thus only changes in glucagon exhibited a significant temporal relationship with changes in GFR, lending further support to a role for glucagon as a mediator of amino acid-induced glomerular hyperfiltration.

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.

Hyperkalemia in acute glomerulonephritis due to transient hyporeninemic hypoaldosteronism.

Transient hyperkalemia has been reported to occur in patients with acute glomerulonephritis, but the pathogenetic mechanism has not been investigated systematically. We studied the mechanism of hyperkalemia (5.7 to 6.7 mmol/liter) in four men with post-infectious glomerulonephritis. All four patients had clinical findings consistent with acute glomerulonephritis (edema, hypertension, proteinuria, hematuria, and an elevated ASO titer) and a renal biopsy performed in three of the patients confirmed the diagnosis. In comparison to normal subjects (N = 18), plasma aldosterone (5.4 +/- 1.6 vs. 22.8 +/- 2.6 ng/dl, P less than 0.005) and plasma renin activity (0.3 +/- 0.2 vs. 4.3 +/- 0.6 ng/ml/hr, P less than 0.005) were reduced. Hyperkalemia resolved within one to two weeks in two patients as the nephritis resolved and diuresis ensued, and aldosterone and renin levels obtained at follow-up visits were normal. Hyperkalemia persisted despite furosemide-induced diuresis in the other two patients, but resolved with fludrocortisone treatment. Thus, hyperkalemia in patients with acute glomerulonephritis is a manifestation, in part, of hyporeninemic hypoaldosteronism. It is ameliorated by mineralocorticoid therapy and improves spontaneously with resolution of the glomerulonephritis.

Dietary protein intake modulates glomerular eicosanoid production in the rat.

The quantity of protein in the diet modulates glomerular function. To study the effect of dietary protein intake on glomerular eicosanoid production, rats were randomized to either a high- (40%) or low- (8.5%) protein isocaloric diet. Ten to fourteen days later glomeruli were isolated and incubated in the absence (basal) and presence (stimulated conditions) of arachidonic acid, and production rates of prostaglandin (PG) E2, PGF2 alpha, and thromboxane B2 (TxB2) were determined by direct radioimmunoassay. Under basal conditions, glomerular production of all three eicosanoids was significantly greater in rats ingesting the high-protein diet. Glomerular production of PGE2 and TxB2 was also greater in animals fed the high-protein diet in the presence of arachidonic acid, suggesting that glomerular cyclooxygenase activity was augmented. In contrast, ingestion of a high-protein diet was not associated with a significant increase in eicosanoid production by renal papillae or in TxB2 release by clotting blood. To investigate the potential role of the renin-angiotensin system in the dietary protein-induced modulation of glomerular eicosanoid production, rats ingesting a high- or low-protein diet were randomized to treatment with an angiotensin-converting enzyme inhibitor or no therapy. Enalapril attenuated the dietary protein-induced augmentation in glomerular eicosanoid production. This effect occurred only when administered in vivo, since the active metabolite enalapril did not alter PGE2 production by isolated glomeruli when added in vitro. Dietary protein intake also modulated glomerular eicosanoid production in three models of experimental renal disease in the rat (streptozotocin-induced diabetes mellitus, Heymann nephritis, and partial renal ablation).(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes, dietary protein and glomerular hyperfiltration.

These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs Homer A. Boushey, Professor of Medicine, and David G. Warnock, Associate Professor of Medicine, under the direction of Dr Lloyd H. Smith, Jr, Professor of Medicine and Associate Dean in the School of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA 94143.