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This Month’s Highlights

	Basic Science Articles

Top Basic Science Articles Clinical Science Articles

MPO—A Good Guy or a Bad Guy in GN?

Neutrophils are the principal effector cells that cause tissue injury in antibody/complement-mediated glomerulonephritis (GN). They release reactive oxygen species and myeloperoxidases (MPO) that interact with a halide to form hypohalous acids, which damage the glomerular basement membrane. To examine the role of MPO in other types of glomerular injury, Odobasic et al. utilized MPO knockout mice and a model of crescentic GN that has an early antibody/neutrophil-mediated phase and a later T cell/macrophage phase. Not surprisingly, they found disease in the knockout mice was reduced in the early phase but not in the later phase, in which there was augmentation of T cell responses and cellular infiltrates. The results suggest a dual role for MPO as a mediator of tissue injury in some settings where antibodies and neutrophils predominate and as a suppressor of injury in other settings where T cells and macrophages are more important. See Odobasic et al., pages 760–770.

Measurements of Oxidized Albumin Can Distinguish Active from Inactive Disease in Children with Idiopathic FGS.

The mechanism(s) that produces the massive increase in glomerular albumin permeability in idiopathic focal glomerular sclerosis (FGS) continues to elude us. Many studies in models of podocyte injury that mimic FGS implicate podocyte-derived oxidants, although the circulating factor that induces podocytes to overproduce oxidants is unknown. This study by Musante et al. follows up on those experimental observations by using mass spectroscopy to look for evidence of oxidative processes in the plasma of 51 children with FGS in native kidneys or recurrent in transplants. They demonstrate increased oxidation of plasma albumin in all patients with active disease that is reduced or absent in remission and, of particular interest, also absent in nephrotic patients with other glomerular diseases. The relationship between oxidized albumin and the pathogenesis of idiopathic FGS remains speculative, and it seems likely an effect and not a cause. However, the remarkable specificity of the findings, if confirmed, suggest a new approach to looking for permeability factors and assessing disease activity that might allow better adjustment of therapy and prediction of outcomes. See Musante et al., pages 799–810.

A Way to Increase Clearance of Protein-Bound Uremic Solutes.

Since the HEMO Study, increased attention is being placed on the potential pathophysiologic importance of protein-bound uremic solutes that are not well-cleared by conventional hemodialysis. Recent evidence suggests that these may contribute substantially to uremic toxicity. Although solute uptake by sorbents has long been considered a potential treatment for uremia, whether sorbents can increase solute clearance above levels obtained by hemodialysis has not been well studied. Meyer and colleagues assessed the extent to which protein-bound solute clearances can be augmented by adding a sorbent to the dialysate in an ex vivo model of dialysis. As anticipated, conventional hemodialysis resulted in minimal clearances of the protein-bound solutes indican, p-cresol sulfate, and p-cresol. The addition of activated charcoal resulted in a substantial enhancement in clearance of all protein-bound solutes without changing the clearance of urea. These results suggest a possible therapeutic approach to augmenting the clearance of protein-bound solutes in uremia, which may have corresponding benefits on the uremic syndrome and uremic toxicity. See Meyer et al., pages 868–874.

	Clinical Science Articles

Top Basic Science Articles Clinical Science Articles

 
A Better Way to Monitor Glycemic Control in Dialysis Patients.

It is uncertain how to assess the gylcemic control of ESRD patients. Using hemoglobin (HbA1c) depends on a steady-state hemoglobin and normal red blood cell survival, and neither condition is met in patients receiving renal replacement therapy. Inaba and colleagues address this problem by examining the associations between HbA1c, glycated albumin, and casual blood sugar measurements in hemodialysis patients. They note that all three measures are substantially higher in diabetic compared with nondiabetic patients, and that glycated albumin provided a better measure of glycemic control when compared with albumin. Of particular interest was the inverse association between erythropoietin dose and HbA1c, which suggests that a shift to younger erythrocytes in these patients may contribute to lower levels of glycated HbA1c in patients with similar levels of casual blood glucose. Decisions about glycemic control in hemodialysis patients that rely solely on HbA1c may result in errors. See Inaba et al., pages 896–903.

Insulin Stimulates Renin and Renal Vasodilation.

Perlstein et al. explore the complex influences of insulin on renal vascular tone: Insulin stimulates the renin-angiotensin system and also induces renal vasodilation. Renal plasma flow and plasma renin activity were measured serially during euglycemic clamp studies in 15 subjects. The response to insulin was measured from time 0 to 180 min. An angiotensin receptor blocker (ARB) was then administered, and the response was measured for 90 min. Insulin infusion increased both plasma renin activity (P < 0.01) and renal plasma flow (P < 0.01). Greater vasodilation to ARB occurred during insulin infusion compared with control (P = 0.02). Blunting of the renal vasodilator response to insulin and increased vasodilator response to ARB was seen in those in whom insulin increased plasma rennin activity, which demonstrates a balance between angiotensin II–mediated vasoconstriction and other vasodilator pathways stimulated by insulin. See Perlstein et al., pages 944–951.

Do Patients with High Ferritin and Low TSAT Benefit from Iron? Results of the DRIVE Study.

The management of anemic hemodialysis patients with high serum ferritin and low transferrin saturation (TSAT) has long been a clinical dilemma. In this issue of JASN, results from the Dialysis Patients’ Response to Intravenous (IV) Iron with Elevated Ferritin (DRIVE) Study, which randomized 134 patients with hemoglobin 11 g/dl, ferritin 500 to 1200 ng/ml, TSAT <25%, and epoetin dose >22,500 IU/wk are presented. Patients received either no iron or 1000 mg IV of ferric gluconate divided over eight dialysis sessions. Patients who received ferric gluconate had a proportionately greater erythropoietic response to IV iron, and the hemoglobin response occurred faster than in patients not receiving IV iron. This important study demonstrates that short-term administration of IV iron is efficacious and safe in anemic hemodialysis patients with high serum ferritin levels, albeit at the cost of a further increase in serum ferritin. Further research will be required to assess the long-term implications of IV iron administration in this patient population. See Coyne et al., pages 975–984.

Effects of Immunosuppressants on Tregs in Kidney Transplant Recipients.

Carefully controlled studies by many groups using animal models have documented that CD4⁺CD25^hi Foxp3⁺ T cells with regulatory or suppressive properties (Tregs) are important in the development and maintenance of immune tolerance, particularly in the case of allogeneic transplants. Much less is known about Treg number and function in standard clinical settings where recipients of kidney allografts are being treated with immunosuppressant medications. In this issue of JASN, Noris and colleagues study Tregs in kidney transplant patients who underwent lymphodepletion therapy with Campath 1H, followed by maintenance immunosuppression with either sirolimus or cyclosporine A. Their data suggest that, compared with sirolimus, cyclosporine A has a relative inhibitory effect on the homeostatic expansion of Treg after lymphodepletion, as well as having an inhibitory effect on Treg function. Their results imply that in vivo expansion of Treg is dependent on both lymphopenia and calcineurin signaling. The findings may have important implications for designing approaches to induce robust clinical tolerance to allografts. See Noris et al., pages 1007–1018.

Related Articles

Endogenous Myeloperoxidase Promotes Neutrophil-Mediated Renal Injury, but Attenuates T Cell Immunity Inducing Crescentic Glomerulonephritis

Dragana Odobasic, A. Richard Kitching, Timothy J. Semple, and Stephen R. Holdsworth
J. Am. Soc. Nephrol. 2007 18: 760-770. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Related Collections Related Articles