BASIC SCIENCE
Immunology and Pathology
Interferon-Inducible Protein-10 Has a Different Role in Podocyte During Thy 1.1 Glomerulonephritis
Mesangial Cells Talk to the Podocytes through IL10.
⇓ Progress in unraveling the complex cellular interactions that take place among circulating cells, between circulating cells and glomerular cells, and among glomerular cells themselves and how these relate to glomerular injury and repair is occurring weekly as new mediators with multiple activities are discovered and examined in disease. Interferon-inducible protein 10 (IP-10), a CXC chemokine that attracts mononuclear cells, is one such multifunctional molecule that is expressed by glomerular cells. In this study, using the Thy 1 model of mesangioproliferative glomerulonephritis, Kawachi et al. show that mesangial immune injury in the intact animal is associated with upregulation of IP-10 and its receptors in podocytes—not the cells originally targeted. Moreover, if IP-10 is blocked, several manifestations of the disease, including proteinuria, are substantially worsened. These observations not only establish a role for IP-10 in modulation of the glomerular response to immune injury through non-chemokine functions, but they suggest that it is part of the discussion that occurs between mesangial cells and podocytes in containing and/or repairing this much-studied type of glomerular injury. The study adds to a growing body of literature that documents these local cellular interactions and their role in renal disease and should provide a stimulus for further exploration of this important area.
Pathophysiology of Renal Disease and Progression
Importance of Functional EGF Receptors in Recovery from Acute Nephrotoxic Injury
Growth Factors and Renal Failure: Another Chapter in a Continuing Story.
⇓ These experiments demonstrate a role for epidermal growth factor (EGF) signaling through the EGF receptor (EGFR) in an experimental model of HgCl2-induced acute renal failure. Using a unique strain of mice that is deficient in EGFR signaling, the authors demonstrate that such animals have delayed recovery from the acute renal failure injury. Previous studies have shown that increased renal expression of EGFR and its ligands occurs in response to acute toxic or ischemic renal injury and have indicated that exogenous administration of EGF accelerates recovery from such injury. What has not been shown, for the EGF ligand/receptor system specifically and growth factors in general, is that complete deletion of the activity for an endogenous growth factor directly inhibits functional repair. The data in this study provide further support for the idea that exogenous EGF may be a useful treatment for acute toxic and perhaps ischemic renal injury in humans. All of us remain cautiously aware that the leap from efficacy of treatment in rodent models to treatment of patients has not been successfully accomplished in the setting of growth factor therapy of acute renal failure.
Role of 12-Lipoxygenasein the Stimulation of p38 Mitogen-Activated Protein Kinase and Collagen α5 (IV) in Experimental Diabetic Nephropathy and in Glucose-Stimulated Podocytes
Why Does GBM Get Thickened in Diabetic Nephropathy?
⇓ Because the best structural correlate of the reduction in renal function in diabetic nephropathy is mesangial matrix expansion, studies to unravel the pathogenesis of diabetic nephropathy have focused heavily on mesangial cells. Recently, however, the discovery of a host of new podocyte-specific proteins, and their roles in proteinuric diseases, has shifted the attention of the renal research community to the less well-studied podocyte. Diabetic nephropathy, like most non-inflammatory, nephrotic glomerular diseases, is one of the diseases of podocyte dysfunction. Adler et al. fulfill the editor’s dream by providing BOTH in vitro and correlative in vivo data to demonstrate that 12-lipoxygenase, an enzyme in the arachidonic acid pathway, is upregulated in podocytes in response to high glucose and is associated with increased expression of type IV collagen, which is apparently mediated through the MAP kinase signaling pathway. This article provides new insights into the role of the podocyte, which presumably is responsible for creating the thickened basement membrane seen in diabetic nephropathy, in diabetes and how high glucose causes this to happen. It also identifies new potential targets for therapy (12 lipoxygenase and MAP kinase) to be pursued in our ongoing battle against this most destructive of renal diseases.
CLINICAL SCIENCE
Clinical Nephrology
Association between Renal Insufficiency and Inducible Ischemia in Patients with Coronary Artery Disease: The Heart and Soul Study
The Heart and Soul Study: Is CKD as Bad for Your Heart as ESRD?
⇓ It is increasingly clear that chronic kidney disease is associated with increased risk of cardiovascular disease and that patients with end-stage renal disease are at markedly increased risk of death from CVD compared with the general population. The report by Ix et al. extends these observations in individuals with non-ESRD chronic kidney disease. The authors examined the association between CKD defined by 24-h creatinine clearance ≤ 60 ml/min and the presence ischemia induced during a graded exercise ECG in a contemporary cohort recruited from the community. There are several important points in this report. First, 23% of the 431 participants had CKD. Participants with CKD were older and were more likely to have had a myocardial infarction and coronary artery bypass graft and impaired left ventricular function. They were more likely to have lower hemoglobin and serum albumin values, and less than one third were treated with an angiotensin-converting enzyme inhibitor (ACEI). Second, the prevalence of inducible ischemia among cohort members was 27%; 40% among those with CKD. Third, among those participants with inducible ischemia, 33% had CKD (OR, 2.3; 95% CI, 1.4 to 3.8). Finally, as noted by the authors, individuals with stable cardiovascular disease may well benefit from screening for CKD because the prevalence of impaired renal function among these patients was 1 in 3. These observations strengthen the argument that patients with CVD should be considered a high risk group that will benefit from screening for CKD and subsequent efforts to improve the use of ACEI therapy, anemia control and, the use of other renoprotective therapies.
Dialysis
Effect of High-Flux Hemodialysis on Clinical Outcomes: Results of the HEMO Study
The HEMO Study: Was It Really Negative?
⇓ In this issue, the HEMO study investigators address the apparent benefit of high-flux dialysis on cardiac death and the composite outcome of first hospitalization for cardiac disease or cardiac death. The effect differed with pre-randomization time on dialysis, and this interaction is explored in detail. Among the variables addressed are patient characteristics, dialyzers, reprocessing techniques, B2M clearances and concentrations, interactions of baseline factors with flux intervention, and specific causes of death. Alternative statistical analyses are also applied to the data. The discussion is an in-depth exploration of causality and provides direction for future research in this area.
The Effects of Comorbid Conditions and Demographic Factors on Mortality among Hemodialysis Patients in Europe, Japan, and the United States in the Dialysis Outcomes and Practice Patterns Study (DOPPS)
What Explains the Differences in Mortality in Dialysis Patients between Countries? It’s Not What You Think.
⇓ DOPPS is a longitudinal study of a representative sample of hemodialysis treatment facilities in the United States, Japan, and Europe. DOPPS provides a means for comparing patient characteristics, treatment patterns, and outcomes of care across disparate populations and healthcare systems for the purpose of identifying factors that are associated with the best outcomes for hemodialysis patients. The report by Goodkin et al. in this issue of JASN examines the degree to which mortality differences across the participating DOPPS regions can be explained by differences in the patients accepted for treatment. The authors report that there are substantial regional differences in the prevalence of comorbid conditions among new hemodialysis patients, with those in the US reported to have higher rates of diabetes and cardiovascular disease at the inception of dialysis. However, these differences are insufficient to explain the regional variations in mortality. These observations should generate further hypotheses regarding the root causes for these persistent mortality differences.
Transplantation
Differential Expression of HO-1 and VEGF in Cadaveric and Living Donor Kidneys after Ischemia-Reperfusion
Do We Now Have a Way to Protect from Ischemia Reperfusion Injury in Transplants? Maybe!
⇓ Under ischemic conditions like acute tubular necrosis and transplantation, much of the injury that occurs takes place during reperfusion (ischemic-reperfusion injury). Other studies in cell culture systems have suggested a role for protective factors in blocking this injury, particularly heme-oxygenase 1 (HO-1) and vascular endothelial growth factor (VEGF). In this study, Lemos et al. bring those observations to the bedside by using molecular technology to study expression of HO-1 and VEGF at three time points in cadaver kidneys before and after transplantation. They show a reduction in gene and protein expression of these factors, which correlates with worse renal function, suggesting that they do serve a protective effect in humans in vivo. The challenge now is to determine how to upregulate them before ischemic injury and to demonstrate a protective effect.
- © 2003 American Society of Nephrology
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