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 complexcellular interactions that take place among circulating cells,between circulating cells and glomerular cells, and among glomerularcells themselves and how these relate to glomerular injury andrepair is occurring weekly as new mediators with multiple activitiesare discovered and examined in disease. Interferon-inducibleprotein 10 (IP-10), a CXC chemokine that attracts mononuclearcells, is one such multifunctional molecule that is expressedby glomerular cells. In this study, using the Thy 1 model ofmesangioproliferative glomerulonephritis, Kawachi et al. showthat mesangial immune injury in the intact animal is associatedwith upregulation of IP-10 and its receptors in podocytes—notthe cells originally targeted. Moreover, if IP-10 is blocked,several manifestations of the disease, including proteinuria,are substantially worsened. These observations not only establisha role for IP-10 in modulation of the glomerular response toimmune injury through non-chemokine functions, but they suggestthat it is part of the discussion that occurs between mesangialcells and podocytes in containing and/or repairing this much-studiedtype of glomerular injury. The study adds to a growing bodyof literature that documents these local cellular interactionsand their role in renal disease and should provide a stimulusfor 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 rolefor epidermal growth factor (EGF) signaling through the EGFreceptor (EGFR) in an experimental model of HgCl2-induced acuterenal failure. Using a unique strain of mice that is deficientin EGFR signaling, the authors demonstrate that such animalshave delayed recovery from the acute renal failure injury. Previousstudies have shown that increased renal expression of EGFR andits ligands occurs in response to acute toxic or ischemic renalinjury and have indicated that exogenous administration of EGFaccelerates recovery from such injury. What has not been shown,for the EGF ligand/receptor system specifically and growth factorsin general, is that complete deletion of the activity for anendogenous growth factor directly inhibits functional repair.The data in this study provide further support for the ideathat exogenous EGF may be a useful treatment for acute toxicand perhaps ischemic renal injury in humans. All of us remaincautiously aware that the leap from efficacy of treatment inrodent models to treatment of patients has not been successfullyaccomplished in the setting of growth factor therapy of acuterenal failure.
Role of 12-Lipoxygenasein the Stimulation of p38 Mitogen-Activated Protein Kinase and Collagen 5 (IV) in Experimental Diabetic Nephropathy and in Glucose-Stimulated Podocytes Why Does GBM Get Thickened in Diabetic Nephropathy?
Because the best structural correlateof the reduction in renal function in diabetic nephropathy ismesangial matrix expansion, studies to unravel the pathogenesisof diabetic nephropathy have focused heavily on mesangial cells.Recently, however, the discovery of a host of new podocyte-specificproteins, and their roles in proteinuric diseases, has shiftedthe attention of the renal research community to the less well-studiedpodocyte. Diabetic nephropathy, like most non-inflammatory,nephrotic glomerular diseases, is one of the diseases of podocytedysfunction. Adler et al. fulfill the editor’s dream byproviding BOTH in vitro and correlative in vivo data to demonstratethat 12-lipoxygenase, an enzyme in the arachidonic acid pathway,is upregulated in podocytes in response to high glucose andis associated with increased expression of type IV collagen,which is apparently mediated through the MAP kinase signalingpathway. This article provides new insights into the role ofthe podocyte, which presumably is responsible for creating thethickened basement membrane seen in diabetic nephropathy, indiabetes and how high glucose causes this to happen. It alsoidentifies new potential targets for therapy (12 lipoxygenaseand MAP kinase) to be pursued in our ongoing battle againstthis 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 chronickidney disease is associated with increased risk of cardiovasculardisease and that patients with end-stage renal disease are atmarkedly increased risk of death from CVD compared with thegeneral population. The report by Ix et al. extends these observationsin individuals with non-ESRD chronic kidney disease. The authorsexamined the association between CKD defined by 24-h creatinineclearance 60 ml/min and the presence ischemia induced duringa graded exercise ECG in a contemporary cohort recruited fromthe community. There are several important points in this report.First, 23% of the 431 participants had CKD. Participants withCKD were older and were more likely to have had a myocardialinfarction and coronary artery bypass graft and impaired leftventricular function. They were more likely to have lower hemoglobinand serum albumin values, and less than one third were treatedwith an angiotensin-converting enzyme inhibitor (ACEI). Second,the prevalence of inducible ischemia among cohort members was27%; 40% among those with CKD. Third, among those participantswith inducible ischemia, 33% had CKD (OR, 2.3; 95% CI, 1.4 to3.8). Finally, as noted by the authors, individuals with stablecardiovascular disease may well benefit from screening for CKDbecause the prevalence of impaired renal function among thesepatients was 1 in 3. These observations strengthen the argumentthat patients with CVD should be considered a high risk groupthat will benefit from screening for CKD and subsequent effortsto improve the use of ACEI therapy, anemia control and, theuse 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 investigatorsaddress the apparent benefit of high-flux dialysis on cardiacdeath and the composite outcome of first hospitalization forcardiac disease or cardiac death. The effect differed with pre-randomizationtime 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, andspecific causes of death. Alternative statistical analyses arealso applied to the data. The discussion is an in-depth explorationof causality and provides direction for future research in thisarea.
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 ofa representative sample of hemodialysis treatment facilitiesin the United States, Japan, and Europe. DOPPS provides a meansfor comparing patient characteristics, treatment patterns, andoutcomes of care across disparate populations and healthcaresystems for the purpose of identifying factors that are associatedwith the best outcomes for hemodialysis patients. The reportby Goodkin et al. in this issue of JASN examines the degreeto which mortality differences across the participating DOPPSregions can be explained by differences in the patients acceptedfor treatment. The authors report that there are substantialregional differences in the prevalence of comorbid conditionsamong new hemodialysis patients, with those in the US reportedto have higher rates of diabetes and cardiovascular diseaseat the inception of dialysis. However, these differences areinsufficient to explain the regional variations in mortality.These observations should generate further hypotheses regardingthe 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 acutetubular necrosis and transplantation, much of the injury thatoccurs takes place during reperfusion (ischemic-reperfusioninjury). Other studies in cell culture systems have suggesteda role for protective factors in blocking this injury, particularlyheme-oxygenase 1 (HO-1) and vascular endothelial growth factor(VEGF). In this study, Lemos et al. bring those observationsto the bedside by using molecular technology to study expressionof HO-1 and VEGF at three time points in cadaver kidneys beforeand after transplantation. They show a reduction in gene andprotein expression of these factors, which correlates with worserenal function, suggesting that they do serve a protective effectin humans in vivo. The challenge now is to determine how toupregulate them before ischemic injury and to demonstrate aprotective effect.
5 (IV) in Experimental Diabetic Nephropathy and in Glucose-Stimulated Podocytes
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. 
