1,25(OH)2 vitamin D3 playsa central role in regulating kidney and intestinal calcium absorptionvia channels that have recently been identified as members ofthe Vth subfamily of the transient receptor potential cationchannel family (TRPV5). Renkema et al. used knockout mouse modelsto deftly explore the physiologic role of these channels. Ifthe kidney form expressed in the distal tubule was knocked out,circulating 1,25(OH)2 vitamin D3 increased and maintained calciumbalance by enhancing intestinal calcium uptake. If these animalswere crossed with mice that were 1-hydroxylase–deficient,the compensatory increase in active vitamin D3 did not occur,and these mice developed hypocalcemia, hyperparathyroidism,and rickets. These studies describe interactions between intestinal,kidney, and parathyroid functions, and provide solid evidencefor the localization and physiologic role of the TRPV5 channels,and the underlying importance of 1,25(OH)2 vitamin D3 in coordinatingtheir activity. See Renkema et al., pages 3188–3195.
Gene Expression in Developing Glomeruli.
Pod-1 is a basic helix-loop-helixtranscription factor expressed in developing and mature podocytes.Knockout mice lacking Pod-1 show arrested glomerular developmentas well as abnormalities in ureteric branching and the renalmesenchyme. To elucidate the role of Pod-1 in glomerular development,Cui et al. devised a new technique for analyzing gene expressionin developing glomeruli. Using magnetic beads, they isolatedlate S-shaped bodies, capillary-loop stage glomeruli, and maturingglomeruli from mouse embryos. They then performed microarrayanalyses to identify differences in gene expression betweenglomeruli isolated from Pod-1 knockout embryos and wild-typeembryos. These studies identified genes such as 8 integrin,3 chain of type IV collagen, and podocin that were downregulatedin the mutant glomeruli and represent potential downstream targetsof Pod-1. The technique described by Cui et al. should be generallyapplicable to the characterization of knockout mice with glomerularphenotypes. See Cui et al., pages 3247–3255.
How Do You Get Immunized to Your Own Kidney?
Remarkable progress hasbeen made recently in anti–glomerular basement membrane(GBM) nephritis, including the molecular identification of the"Goodpasture antigen," identifying conformational antigenicchanges that may confer autoimmunity and clarification of therole of GBM-reactive T cells in mediating nephritis. Still unknown,however, is exactly how one becomes immunized to antigens inthe GBM. This study by Robertson et al. provides a provocativeinsight into that process. Using a rat model of T cell–mediatedglomerulonephritis, they show that the first activation of Bcells producing anti-GBM antibody occurs in a single "renal-draininglymph node" in the hilus of a nephritic kidney some time afterthe initial glomerular injury takes place. The finding suggestsrelease of peptide antigen(s) related to the initial immunogen(epitope spreading) from the damaged kidney leading to systemicautoimmunity and a secondary anti-GBM antibody response. Thoughthe findings are unique to this particular model, they offera new approach to better understanding the origins of renalautoimmunity. See Robertson et al., pages 3256–3263.
Can We Treat the Mesangium and Spare the Patient?
The mesangium is a commonsite of injury in a variety of glomerular diseases such as IgAnephropathy, lupus nephritis, diabetes, and others. The systemictoxicity of most currently available immunosuppressive and anti-inflammatorydrugs limits their efficacy. But what if one could selectivelyadminister drugs directly to the site of injury in the mesangiumwithout exposing the rest of the body? In this study, Tuffinet al. convincingly show that this can be done by coupling liposomesto a small fragment of a mesangial cell-specific antibody andshowing that these immunoliposomes attach very selectively tomesangial cells, to be taken up by the cells without apparentconsequences. When a toxin is attached to the liposome, it deliversa selective blow to the mesangium in vivo without systemic toxicity.The study stops short of showing that a therapeutic agent similarlydelivered will have a beneficial effect on a mesangial diseaseprocess, but the stage is clearly set. See Tuffin et al., pages3295–3305.
That acute kidney failureincreases the risk of morbidity and mortality is one of theorganizing concepts of acute care nephrology and considerableattention has been devoted to identifying the optimal renalreplacement for the management of these patients. The reportby Chertow et al. in this issue of JASN brings attention tothe opposite end of the continuum of kidney injury in hospitalizedpatients. The authors report that even modest degrees of kidneyinjury are associated with increased risk of adverse outcomesduring hospitalization, extending previous reports in this journal(J Am Soc Nephrol 15:1697–1705, 2004; J Am Soc Nephrol16:195–200, 2005) and elsewhere. Although additional confirmationof these observations is clearly warranted, the possibilitythat much smaller perturbations in kidney function than werepreviously recognized may signal increased risk of adverse outcomesraises issues of immediate clinical relevance. First, shouldwe recommend closer monitoring of kidney function for all, orfor some subpopulations of hospitalized patients? Second, whatclinical recommendations should be made when patients with persistent,small elevations in serum creatinine are brought to our attention?Clearly one can recommend a review of renal drug dosing andfluid balance, but are there other aspects of patient care,like nutritional support, that should be modified? Third, whatrecommendations should we make with respect to subsequent in-hospitalmonitoring and readiness for discharge? The answers to theseas well as other management issues identified by cohort studiesthat were conducted to better define the demographic characteristicsand risk profile of this patient population require evidencefrom well-designed clinical trials. See Chertow et al., pages3365–3371.
Toward a Better Understanding of HEMO.
Two decades’ worthof observational data suggested that higher doses of delivereddialysis were associated with lower mortality rates. However,the HEMO study, a randomized, clinical trial, suggested thatlarge differences in the equilibrated, volume-indexed urea clearance(eKt/Vurea) did not result in significant improvements in survival,cause-specific survival, nutritional status, or health-relatedquality of life. In this issue of JASN, Greene et al. demonstratean eye-opening phenomenon: Within each randomized dose groupin HEMO (eKt/Vurea, 1.45 and 1.05), subjects in the lowest quintileof delivered dose experienced roughly twice the 1-yr mortalityrate of others who met prescribed dose targets. Indeed, therisk of death for subjects in the lowest quintile of the higherprescribed dose group was 60% higher than the risk of deathfor the aggregate of all subjects in the lower prescribed dosegroup, despite a higher mean eKt/Vurea. This study highlightsthe importance of intent-to-treat (rather than as-treated) analyses,and provides important insights into the strengths and weaknessesof observational studies and randomized clinical trials. SeeGreene et al., pages 3372–3381.
Xerostomia, Pilocarpine, and Interdialytic Weight Gain.
Achieving estimated dryweight goals in patients with large interdialytic weight gainsremains one of the more vexing problems in the management ofhemodialysis patients. Further, the etiology of hyperdipsiain many patients remains obscure. In this issue of JASN, Sunget al. examine the hypothesis that decreased salivary flow andxerostomia (dry mouth) are important contributors. In a randomizedtrial, administration of pilocarpine decreased thirst and interdialyticweight gain in hyperdipsic dialysis patients. Will pilocarpinebecome a frontline therapy for large weight-gainers? See Sunget al., pages 3419–3430.
Extending Comorbidity Analyses to Transplantion.
Although comorbid conditionsare known to influence survival in dialysis patients, a rolefor pretransplant comorbidity on posttransplant outcome is lesswell established. In the study by Wu et al., the investigatorsused the Charlson Comorbidity Index to assess the impact ofpretransplant comorbid conditions on graft and patient survivalin 715 renal allograft recipients. The authors found that increasedcomorbidity, including diabetes and heart failure, was associatedwith a higher incidence of patient death, both perioperativelyand >3 mo posttransplantation. The findings could have broadimplications for individualizing patient treatment protocols,for the design and interpretation of transplant studies, andfor developing policies regarding organ distribution. See Wuet al., pages 3438–3445.
Top
Basic Science Articles
Clinical Science Articles
-hydroxylase–deficient, the compensatory increase in active vitamin D3 did not occur, and these mice developed hypocalcemia, hyperparathyroidism, and rickets. These studies describe interactions between intestinal, kidney, and parathyroid functions, and provide solid evidence for the localization and physiologic role of the TRPV5 channels, and the underlying importance of 1,25(OH)2 vitamin D3 in coordinating their activity. See Renkema et al., pages 3188–3195. 
