The regulation of proximaltubule transport by parathyroid hormone (PTH) is a classic physiologicinterest; inhibition of phosphate absorption and Na+/H+ exchange(NHE) are very familiar. The mechanisms were illuminated bythe cloning of the relevant Na+-dependent phosphate co-transporterand the NHE III isoform, and by subsequent demonstration byEd Weinman’s group of two "adapter" proteins, termed NHEregulatory factors (NHERF), that are centrally involved in theregulatory processes. Their functional domains have been defined,and more importantly there are sites of protein–proteininteractions that couple the NHERF to signal transduction pathwaysand cytoskeletal proteins, especially in the brush border microvilli.As described by Khundmiri et al., the importance of NHERF, andespecially their PDZ domains, in the regulation of basolateralhormone receptors and the 1 subunit of the Na-K-ATPase (by phosphorylation),as well as the apical transporters, now paints a broad pictureof the coordination of transport mechanisms across the entireproximal tubule cell. See Khundmiri et al., pages 2598–2607.
Why Do Steroids Work in Podocyte Diseases—Could It Be a Local Rather Than Systemic Effect?
Glucocorticoids remain oneof the mainstays of therapy for a variety of glomerular diseases.In addition to direct immunomodulatory effects, glucocorticoidsare also potent anti-inflammatory agents. However, previousstudies have indicated that glucocorticoids are effective therapeuticagents in puromycin aminonucleoside nephrosis, an animal modelof minimal change disease and focal glomerulosclerosis thatdoes not appear to have a predominant immunologic and/or inflammatoryetiology. In this issue of JASN, Wada et al.utilized an in vitromodel of puromycin-induced podoctye injury and determined thatthe glucocorticoid dexamethasone can directly decrease apoptosisby modifying expression of p53 and Bcl-2 related proteins. Theconclusion of this study that, in glomerular injury, an additionaltherapeutic effect of glucocorticoids is by direct protectiveeffects on podocytes will undoubtedly generate further investigationto test this novel hypothesis in vivo. See Wada et al., pages2615–2625.
Who Are the Baddest Cells—The Residents or the Invaders?
Conventional views of inflammationhave long focused on circulating leukocytes as the major effectorarm of the inflammatory response. Students of glomerular diseasewere among the first to postulate, and then prove, that residentglomerular cells could also serve as nephritogenic effectorcells. However, in most forms of glomerulonephritis, there isevidence for participation of both cell types, and the respectiverole of each has been impossible to quantify. In this study,Timoshanko and colleagues created two types of chimeric mice:one in which only circulating leukocytes lack the nephritogenicfactor GM-CSF, and one in which only renal cells lack it. Theyreport that the absence of GM-CSF at both sites confers substantialprotection from glomerular inflammation, and that renal cellscontribute significantly more to the inflammatory changes thanthe circulating ones do. The findings can be confidently relatedonly to one factor, GM-CSF, and one model, but provide strongevidence for the role of resident glomerular cells in mediatingglomerulonephritis. See Timoshanko et al., pages 2646–2656.
cAMP Is Good for You in Chronic Noncystic Kidney Disease.
Administration of a vasopressin2 receptor antagonist to animals has identified an importantassociation between reduced cAMP generation and attenuated polycystickidney disease. On the other hand, several recent studies havereported significant antifibrotic effects of pentoxifylline(PTX), a nonselective phosphodiesterase inhibitor that increasescAMP levels. In this issue of JASN, Lin et al. report that PTXsignificantly reduces interstitial macrophages, myofibroblasts,and fibrosis severity after ureteral obstruction. A series ofin vitro studies identified two molecular pathways targetedby PTX in renal tubular cells and fibroblasts. First, PTX blocksthe ability of TGF- to initiate connective tissue growth factor(CTGF) gene transcription via a pathway that involves proteinkinase A, cAMP generation, and activation of the cAMP responseelement binding protein. Second, PTX blocks the profibroticeffects of CTGF, such as fibroblast collagen synthesis and tubularepithelial cell transition to smooth muscle actin–expressingcells. Stay tuned as the cAMP story continues to unfold. SeeLin et al., pages 2702–2713.
Mechanisms of Xenograft Loss beyond Hyperacute Rejection.
Humans and nonhuman primateshave natural antibodies specific for the gal (1,3) Gal (Gal)epitope expressed on pig endothelium. These antibodies causecomplement-dependent, hyperacute xenograft rejection. The productionand use of pigs transgenic for human decay accelerating factor(hDAF), a cell-surface molecule that inhibits C3 convertaseactivity, has been employed in an effort to circumvent thisprocess. The study by Shimizu et al. confirms that hyperacuterejection of hDAF-transgenic pig thymokidney grafts is preventablein baboons, if anti-Gal antibodies are removed extracorporeallyprior to transplant. Nonetheless, the subsequent return of detectableanti-Gal antibodies in the recipients was associated with lategraft loss. Pathologic examination of the rejected kidneys revealedthrombotic microangiopathy and C4d deposition, characteristicof acute humoral injury. The findings underscore the strengthof the humoral barrier to xenografts and suggest that additionalapproaches, including the use of genetically engineered, Gal-deficientpig organs, will be required to improve xenograft survival.See Shimizu et al., pages 2732–2745.
Clinical Science Articles
Renal Dysplasia Due to Mutation of Pax-2.
Pax-2 is a transcriptionfactor required for normal kidney development. Knockout micelacking Pax-2 fail to develop kidneys and ureters, and heterozygousmutant mice have renal hypoplasia. Humans with mutations ofPax-2 develop renal-coloboma syndrome, an autosomal dominanttrait characterized by bilateral renal hypoplasia and opticdisc colobomas. Fletcher et al. describe the first family withrenal-coloboma syndrome in which one affected family memberhad multicystic renal dysplasia and another individual had ureteralobstruction at the ureteropelvic junction. Genetic analysisrevealed that the affected individuals had a frameshift mutationin the Pax-2 gene. Sporadic multicystic renal dysplasia is frequentlyassociated with ipsilateral ureteral atresia and is thoughtto arise from intrauterine urinary tract obstruction. Althoughtheir findings need to be reproduced in other families, thestudy by Fletcher et al. suggests that mutations of Pax-2 mayproduce ureteral abnormalities that result in inherited multicysticrenal dysplasia. See Fletcher et al., pages 2754–2761.
Low Birth Weight: An Early Start on Chronic Kidney Disease.
During the last decade evidencehas accumulated that low birth weight is associated with thedevelopment of hypertension, diabetes, and atherosclerotic heartdisease later in adult life. The mechanisms that link fetaldevelopment and adult disease are poorly understood and mayrange from persistent adaptations to malnutrition during fetaldevelopment to impaired organogenesis. Keijzer-Veen et al. reportin this issue of JASN that very premature, low birth-weightinfants display by early adulthood lower glomerular filtrationrates and increased albumin excretion rates compared to normalbirth weight infants. These observations complement those ofassociations between birth weight and risk of ESRD, and showthat increased risk of kidney disease is independent of developmenthypertension, diabetes, and cardiovascular disease later inlife. Though the differences in renal function are relativelysmall, it may be that low birth weight acts as a factor thatpredisposes individuals to progressive kidney injury in thepresence of factors such as hypertension or hyperglycemia, whichinitiate glomerular injury. Low birth weight and prematurityare associated with lower socioeconomic status and are morelikely to occur among minority populations, two groups at increasedrisk for ESRD. It may be that part of this risk is mediatedby the effects of early intrauterine growth and raise the possibilitythat one step in the primary prevention of chronic kidney diseasemay be found in better prenatal care. See Keijzer-Veen et al.,pages 2762–2768.
Antimicrobial Locking Solutions Can Reduce Dialysis Catheter–Related Sepsis.
For patients receiving maintenancehemodialysis, an autogenous arteriovenous fistula is the accessof choice. However, in current clinical practice, the use oftunneled hemodialysis catheters for access is substantial andgrowing at an alarming rate. Widespread application of tunneleddialysis catheters exposes patients to a number of potentialrisks, of which catheter-related bacteremia is the most frequentand devastating. In this issue of JASN, Weijmer et al., reportthe results of a multicenter, double-blind, randomized, controlledtrial comparing the use of unfractionated heparin with high-concentrationtrisodium citrate as an interdialytic locking solution for hemodialysiscatheters. The study was stopped prematurely because of a dramaticdifference in the rates of catheter-related bacteremia. Furthermore,no serious adverse events were encountered. Will the use ofinterdialytic antimicrobial locking solutions become a standardcomponent of clinical practice in the future? See Weijmer etal., pages 2769–2777.
1 subunit of the Na-K-ATPase (by phosphorylation), as well as the apical transporters, now paints a broad picture of the coordination of transport mechanisms across the entire proximal tubule cell. See Khundmiri et al., pages 2598–2607. 
to initiate connective tissue growth factor (CTGF) gene transcription via a pathway that involves protein kinase A, cAMP generation, and activation of the cAMP response element binding protein. Second, PTX blocks the profibrotic effects of CTGF, such as fibroblast collagen synthesis and tubular epithelial cell transition to 
