Maintenanceof an electrochemical gradient from the extracellular to theintracellular milieu is essential for normal cellular functionand is ultimately dependent upon the ubiquitous Na,K-ATPase.In addition to its pump function, recent studies have indicatedthat Na,K-ATPase also transduces signals and specifically activatesNF-B via IP3 receptors, which interact with the Na,K-ATPasecytoplasmic tail. In this issue of JASN, Li et al. demonstratethat low concentrations of ouabain, which do not inhibit thepump function, will activate the signaling activity of Na,K-ATPaseand that the resultant NF-B activation prevents apoptosis inresponse to serum deprivation. Therefore, these studies serveto highlight a potentially important function for Na,K-ATPaseseparate from its transport functions and raise the possibilitythat endogenous ouabain-like compounds might play a role incell growth and development. See Li et al., pages 1848–1857.
Yet Another Nonhemodynamic Effect of RAS Blockade That May Relate to Progression.
The workby Liang et al. in this issue of JASN addresses three very topicalissues in one study: the role of podocytes in progression, theability of different glomerular cell types to talk to each other,and the mechanisms by which blockade of the renin-angiotensinsystem (RAS) slows progression. Working with cells in culture,Liang et al. show that normal podocytes support endothelialcell growth and sprouting (and hence capillary remodeling andrepair) through vascular EGF (VEGF) and angiopoeitin I–dependentmechanisms, that injured podocytes lose this ability as theydownregulate VEGF and angiopoeitin I (thus inhibiting remodelingand accelerating progression), and that this loss of VEGF andangiopoeitin I effect can be reversed by angiotensin receptorblockade. It is, of course, a long way from the culture plateto people, but if the same phenomena can be shown to occur invivo, these observations would provide important new insightsof potential therapeutic significance in chronic kidney disease.See Liang et al., pages 1886–1895.
RPGN: Is It the ANCA Antibody, or Is It the T Cells—or Could It Be Both?
The roleof humoral (antineutrophil cytoplasmic antibodies [ANCA]) versuscell-mediated immune mechanisms in ANCA-positive crescenticglomerular nephritis (GN) has been controversial for years.These authors from Melbourne have been the leading proponentsof cellular mechanisms independent of antibody in producingcrescentic GN. However, this study suggests a need for compromise!Ruth et al. provide evidence in mice for a two-step processin which ANCA leads first to glomerular neutrophil recruitment,and release and localization of MPO antigen in capillaries,followed by injury resulting from the interaction of T cellsrather than antibody with the planted myeloperoxidase antigen,resulting in crescentic GN without immune deposits. These observations,of course, were made in manipulated mouse models. However, theydo provide proof of concept, and if similar events occur inhumans they could unify these currently conflicting hypothesesof the mechanisms underlying ANCA-positive GN into one conceptof the pathogenesis of the disease. See Ruth et al., pages 1940–1949.
Acuterenal failure (ARF) due to ischemic injury is a major causeof morbidity and mortality. Interestingly, previous ischemiaconditions the kidney to make it more resistant to repeatedischemic injury. However, for obvious reasons, this insightdoes not lend itself to therapeutic application. In elegantstudies by Bernhardt et al., the authors exploit this previousobservation and induce the specific protective factor upregulatedby previous ischemia, hypoxia-inducible factor (HIF), by preventingits degradation with a novel inhibitor of HIF prolyl hydroxylase,FG 4487. Preconditioning with FG4487 augmented HIF expressionand protected kidneys from subsequent hypoxic injury with decreasedrenal dysfunction and morphologic injury. These exciting resultsindicate that such approaches could have clinical relevancein protecting from ischemia-induced ARF. See Bernhardt et al.,pages 1970–1978.
More on Complement Regulatory Proteins and Atypical Hemolytic Uremic Syndrome.
A majoradvance in the past several years in understanding the pathogenesisof non–shigatoxin-induced, or "atypical," hemolytic uremicsyndrome (HUS) is the discovery that many of these patientsexhibit inherited or acquired deficiencies or mutations in proteinsthat regulate complement activation and thereby complement-mediatedattack on endothelial cells. Particularly common are circulatingfactor H and cell-bound membrane co-factor protein (MCP) abnormalities.This study extends those observations by documenting MCP mutationsin 10% of patients with atypical HUS and showing that most ofthese patients do not develop ESRD clinically. Moreover, incontrast to patients with circulating factor H deficiencies,they do not have a high risk for recurrence in transplants.Understanding of the different types of complement regulatorydisorders involved in the pathogenesis of HUS and how they differclinically now offers opportunities for screening and potentialnew therapies for these patients that may lead to considerableimprovement in their management and prognosis. See Fremeaux-Bacchiet al., pages 2017–2025.
It isgenerally understood that chronic kidney disease increases anindividual’s risk of death, and that most persons withimpaired kidney function will die before reaching ESRD. Thesystematic review of this problem by Tonelli and his colleaguesin this issue of JASN draws attention to just how importantthis association is. They abstracted data from 39 studies involvingmore than 1.3 million individuals to assess the impact of impairedkidney function on subsequent survival. They found, as expected,an increased risk of death among individuals with kidney disease.However, the risk increased exponentially, not in a linear fashion,and was greater among younger individuals and in studies withlower baseline prevalence of cardiovascular disease, and theseassociations persisted after controlling for other risk factors.These unique findings and the unexpected nature of the populationsat greatest risk are worth noting and should amplify the messageto clinicians that a properly interpreted serum creatinine isan extremely powerful risk stratification tool. See Tonelliet al., pages 2034–2047.
The roleof renal artery disease in outcomes of kidney disease remainsuncertain. There is clear evidence that renal artery stenosisis associated with hypertension, increased risk of impairedkidney function, progression of kidney disease, and death. Muiand associates provide further evidence that renal artery stenosiscomplicating peripheral vascular disease is associated withincreased prevalence of kidney disease and is an independentpredictor of mortality in these patients. Beyond the prognosticinformation, however, the clinical implications of incidentallydiscovered renal artery stenosis are uncertain, and evidenceregarding the utility of revascularization for control of hypertensionand renoprotection is incomplete. The high prevalence of renalartery disease in patients with peripheral vascular diseasewith a mean systolic blood pressure of 153 mmHg reported byMui et al. clearly suggests that this population might yieldvolunteers for well-designed clinical studies comparing optimalmedical therapy alone to stenting with optimal medical therapy,such as the ongoing Cardiovascular Outcomes in Renal AtheroscleroticLesions (CORAL) study (http://www.coralclinicaltrial.org/).See Mui et al., pages 2069–2074.
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B via IP3 receptors, which interact with the Na,K-ATPase cytoplasmic tail. In this issue of JASN, Li et al. demonstrate that low concentrations of ouabain, which do not inhibit the pump function, will activate the signaling activity of Na,K-ATPase and that the resultant NF-
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Na,K-ATPase--A New Role for...
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