Postdialysis outcomes associated with consistent anemia treatment in predialysis patients with chronic kidney disease.

AIMS: Anemia and cardiovascular (CV) events are major complications of chronic kidney disease (CKD) during dialysis. We conducted a retrospective observational study in CKD patients with anemia to evaluate the association between predialysis use of erythropoiesis-stimulating agents (ESAs) and postdialysis CV outcomes. METHODS: The study analyzed claims data on incident hemodialysis patients aged > or = 18 years (identified between January 2000 and November 2005). Patients were identified as anemic and ESA-treated prior to dialysis. ESA treatment was categorized into 4 consistency groups (from least to most consistent ESA use). RESULTS: Of 5,848 hemodialysis patients, 52% were identified as anemic prior to onset of dialysis. Predialysis ESA treatment was received by 62% of anemic patients, with only 23% receiving the most consistent treatment. The risk of a CV event was significantly lower for the ESA-treated compared with ESA-untreated patients (relative risk (RR) 0.70, 95% (95% confidence intervals (CI) 0.61 - 0.82)). Compared with ESA-untreated, those who received ESAs had significantly lower risk of acute myocardial infarction (RR 0.65 (95% CI 0.44 - 0.95)) or inpatient mortality (RR 0.52 (95% CI 0.40 - 0.68)). ESA-treated patients in each of the 4 consistency groups had significantly lower risk of CV events compared with ESA-untreated patients, with the greatest benefit seen in patients who received most consistent ESA (RR 0.61 (95% CI 0.48 - 0.76)). CONCLUSIONS: This analysis suggests consistent ESA use to treat anemia of CKD in the predialysis period is associated with improved cardiovascular outcomes in postdialysis patients.

Infectious complications of the hemodialysis access.

Infectious complications of the vascular access are a major source of morbidity and mortality among hemodialysis (HD) patients. Numerous reports implicate the vascular access in up to 48 to 73% of all bacteremias in HD patients. The incidence of vascular access-related infection is highest when central venous dialysis catheters are employed. Native arteriovenous fistulas carry the lowest risk of infection. Unfortunately, prosthetic arteriovenous grafts, which represent the most common type of HD access in the United States, have been repeatedly shown to be a risk factor for bacteremic and nonbacteremic infections. Silent infection in old nonfunctional clotted prosthetic arteriovenous grafts has recently been recognized as a frequent cause of bacteremia and morbidity among HD patients. High proportions of infections related to the vascular access are caused by staphylococcal organisms, which carry high rates of mortality, recurrence, and metastatic complications. Management of vascular access-related infection has two aspects: The first relates to the choice, duration, and mode of administration of antibiotic therapy. Empiric antibiotic therapy, guided by demographic data and severity of illness, should be employed when the causative organisms are unknown. Prolonged administration of specific parenteral antibiotics is crucial in decreasing complications of infection, especially in cases of staphylococcal bacteremia. The second aspect relates to management of the vascular access. Efforts directed toward bacteriological cure should be concurrent with efforts to preserve native venous access sites whenever possible. Efforts to prevent vascular access-related infection should focus on increasing placement of arteriovenous fistulas and minimizing insertion of central venous dialysis catheters. Careful inspection and monitoring of the vascular access is of paramount importance in early detection of vascular access site-related infections. Several new approaches aimed at preventing catheter and prosthetic graft-related infection are being explored.

Reciprocal regulation of LTA(4) hydrolase expression in human monocytes by gamma-interferon and interleukins 4 and 13: potential relevance to leukotriene regulation in glomerular disease.

BACKGROUND/AIMS: Leukotriene A(4) (LTA(4)) hydrolase catalyzes the final step in the synthesis of leukotriene B(4) (LTB(4)). TH-1- and TH-2-derived cytokines may regulate LTB(4) synthesis by monocytes through their actions on the expression of LTA(4) hydrolase. METHODS: Freshly isolated monocytes were incubated with pro- and anti-inflammatory cytokines for 36 h. mRNA expression was determined by Northern blot, protein expression was determined by Western blot and LTB(4) synthesis was determined by ELISA. RESULTS: Interferon-gamma (a TH-2-derived cytokine) increased significantly LTA(4) hydrolase mRNA expression, whereas interleukin (IL)-4 and IL-13 (both TH-2-derived cytokines) decreased LTA(4) hydrolase mRNA expression in these cells. The same effects were seen on the expression of immunoreactive LTA(4) hydrolase after incubating the monocytes with either TH-1- or TH-2-derived cytokines. The monocyte-derived cytokine IL-1 beta did not show any significant effect on LTA(4) hydrolase mRNA expression. When LTB(4) release was measured, both IL-1 beta and interferon-gamma significantly increased LTB(4) production by monocytes, while TH-2 cytokines (IL-4 and IL-13) decreased it. CONCLUSION: The opposing effects of TH-1- and TH-2-derived cytokines on the expression of LTA(4) hydrolase mRNA may regulate LTB(4) synthesis by monocytes during inflammation.

Novel approaches to treatment of glomerulonephritis.

Our improved understanding of the mechanisms of glomerular injury has allowed the design of novel therapeutic strategies to treat glomerulonephritis. While elimination of the etiologic factors continues to be a difficult task, modulation of the inflammatory response seems more promising at present. Several proinflammatory mediators have been identified as therapeutic targets and their inhibition has ameliorated glomerular injury in experimental animals. The role of anti-inflammatory molecules and the phenomenon of immunotolerance have gained particular attention and may prove to be useful therapeutically. Mediators of tissue repair have been found to contribute to glomerular destruction, and their inhibition was protective in a variety of experiments. In this review we discuss some of these novel approaches which may be targeted against human glomerulonephritis in the near future.

Reversible renal failure in a patient with the hypereosinophilia syndrome during therapy with alpha interferon.

Human recombinant interferon (IFN)-alpha (alpha)-2b was given to a 57-year-old man with hypereosinophilia syndrome refractory to prednisone and hydroxyurea. One year later, he developed progressive renal failure and nephrotic-range proteinuria. Percutaneous kidney biopsy showed focal and segmental glomerular and mesangial sclerosis, chronic interstitial nephritis, and focal tubular necrosis. Discontinuation of cytokine therapy led to marked improvement in renal function and significant reduction in proteinuria. The potential role of IFN-alpha as the cause of renal failure and nephrotic-range proteinuria is discussed. The spectrum of renal disease attributed to IFN-alpha and the proposed pathogenic mechanisms are reviewed.

Expression of recombinant rat interleukin-13 (IL-13) and generation of a neutralizing rat IL-13 antiserum.

Using baculoviral and bacterial systems, we expressed biologically active recombinant rat IL-13 and generated neutralizing rat IL-13 antiserum. Recombinant rat IL-13 produced by baculovirus-infected insect cells stimulated proliferation of TF-1 premyeloid cell line and induced expression of 15-lipoxygenase mRNA in human peripheral blood monocytes. Antiserum generated by immunizing a rabbit with recombinant bacterial rat IL-13 specifically inhibited TF-1 proliferation induced by baculoviral rat IL-13 but did not neutralize human IL-13 mitogenic activity. Western blotting with anti-rat IL-13 serum revealed a approximately 12 kD protein band in supernatants of insect cells infected with recombinant baculovirus carrying the rat IL-13 cDNA. The availability of recombinant rat IL-13 and rat IL-13 antibodies should facilitate studying the role of IL-13 in rat models of human inflammatory disorders.

Contrasting effects of proinflammatory and T-helper lymphocyte subset-2 cytokines on the 5-lipoxygenase pathway in monocytes.

Human peripheral blood monocytes (HPBMs) express 5-lipoxygenase (5-LO) and 5-LO activating protein (FLAP), and hence have an ability to synthesize proinflammatory leukotrienes (LTs). Regulation of 5-LO and FLAP expression is a major determinant of cellular LT synthesis. We examined the effects of proinflammatory [interleukin (IL)-1 and interferon (IFN)-gamma] and T helper lymphocyte subset 2 (TH-2; IL-4 and IL-13) cytokines on (1) LTB4 production, and (2) 5-LO and FLAP expression in HPBMs. We show that IL-1 and IFN-gamma stimulate, whereas IL-4 and IL-13 inhibit ionophore-activated LTB4 release. The stimulatory effects of IL-1 and IFN-gamma were apparent at 16 to 36 hours of incubation. IL-1 modestly increased FLAP mRNA and significantly increased 5-LO mRNA steady state levels at 24 and 36 hours of incubation, respectively. IFN-gamma did not change the mRNA or protein expression of either 5-LO or FLAP. The inhibitory effects of IL-4 and IL-13 were associated with decreased FLAP mRNA and protein steady state levels. These results demonstrate that regulation of monocyte LTB4 biosynthesis by different cytokines proceeds via different pathways that partly involve modulation of the expression of the key proteins, 5-LO and FLAP. In addition, the contrasting effects of proinflammatory and TH-2-derived cytokines on monocyte LTB4 production demonstrate mechanisms by which cytokine subpopulations may modulate monocyte function in inflammation.

Role of leukotrienes and lipoxygenases in glomerular injury.

The 5-lipoxygenated metabolites of arachidonic acid, the leukotrienes, are increasingly recognized as major mediators of early glomerular hemodynamic and structural deterioration during experimental glomerulonephritis. Generation of these metabolites is largely by infiltrating leukocytes, but can also occur by intrinsic glomerular cells via transcellular metabolism of intermediates. In several animal models of glomerulonephritis and other renal pathologic states, leukotrienes have been shown to exert adverse effects in the glomerulus. Leukotriene B4 augments neutrophil infiltration, and leukotrienes C4 and D4 mediate potent vasoconstrictor effects on the glomerular microcirculation. Selective blockade of the 5-lipoxygenase pathway in the course of glomerular injury is associated with a significant amelioration of the deterioration of renal hemodynamic and structural parameters. 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), the immediate product of arachidonate 15-lipoxygenase, and the lipoxins, which are produced by sequential 15- and 5- or 5- and 12-lipoxygenation of arachidonic acid are also generated in the course of glomerular injury. These eicosanoids have actions that contrast with those of leukotrienes. 15-S-HETE antagonizes leukotriene-induced neutrophil chemotaxis and lipoxin A4 antagonizes the effects of leukotrienes C4 and D4 on the glomerular microcirculation. The contrasting effects of 5- and 15-lipoxygenase products may represent endogenous pro- and anti-inflammatory influences that could ultimately regulate the extent and severity of glomerular inflammation. The recent availability of safe and effective 5-lipoxygenase inhibitors will be helpful to test the effect of blocking leukotriene production on the course of human glomerulonephritis and other disease states.

Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes.

15-Lipoxygenase (15-LO) catalyzes hydroperoxidation of fatty acids, a reaction of potential relevance to inflammation, membrane remodeling, and atherosclerosis. In human leukocytes, 15-lipoxygenation of arachidonic acid produces 15-(S)-hydroxyeicosatetraenoic acid and lipoxin A4, which suppress white cell chemotaxis, adherence, and activation, and antagonize proinflammatory leukotrienes. Interleukin (IL)-13, produced by T-helper subset 2 (TH-2) lymphocytes, specifically and potently induced 15-LO gene expression and enzyme activity in human monocytes. Among other TH-2 lymphokines, this induction of 15-LO is shared by IL-4 but not by IL-10. Interferon-gamma, a product of TH-1 lymphocytes, blocked IL-13-mediated induction of 15-LO. The induction of the anti-inflammatory 15-LO pathway by IL-13 reveals a new facet of IL-13 biology that supports its role as a cytokine with potential to down-regulate inflammatory pathways. The contrasting effects of interferon-gamma and IL-13 on 15-LO induction demonstrate mechanisms by which T-lymphocyte subsets may modulate macrophage/monocyte function in inflammation or atherosclerosis.

Endothelin in kidney disease.

The role of endothelin in renal physiology and pathophysiology continues to be the subject of intense current research. Further insight into the mechanisms of interaction of endothelin in the kidney has provided a better understanding of its effects on renal hemodynamics and tubular function. Of interest is the emerging role of endothelin as a potential physiologic osmotic regulator of sodium and water reabsorption in the renal medulla. Increasing evidence implicates endothelin in the pathophysiology of progressive glomerulosclerosis, postischemic renal failure, cyclosporine-induced nephrotoxicity, and radiocontrast-induced nephropathy. The recent finding of elevated plasma endothelin levels in patients with the hepatorenal syndrome is particularly exciting and implicates a potential role for endothelin in the pathophysiology of the renal failure that occurs in patients with this syndrome.

Taurine transport across the small intestine of adult and suckling rats.

1. Taurine accumulation in intestinal cells of adult and suckling rats reached steady-state after 60 min with an In/Out ratio of 1.46 and 4.66 in the adult and suckling rats respectively. 2. The accumulative capacity of the intestinal strips isolated from suckling rats is almost four times higher than that of adult rats. 3. The steady-state uptake of taurine by the adult and suckling rats intestinal cells is saturable, sodium-dependent and inhibited by ouabain. 4. The calculated Vmax of the mediated component of the steady-state uptake in the suckling rats is three times greater than that of the adult rats, and the affinity is seven fold greater in the suckling as compared to the adult. 5. Taurine influx across the mucosal membrane in the suckling rat is significantly greater than that of the control adult.