The reninsystem is much more complex than thought even five years ago.One of the recent surprises is the demonstration of specificprorenin binding sites in the kidney. Binding by the receptornot only generates angiotensin, but also triggers angiotensin-independentsignaling. Together with the long-known fact that elevated plasmaprorenin is not only correlated with but is even a predictorof microvascular complications in type 1 and type 2 diabetes,prorenin and its receptor binding have become hot candidatesin the genesis of diabetic nephropathy—and with the availabilityof renin inhibitors have even become potential targets for treatment.To provide evidence for such a role of prorenin, Stankovic etal. examined whether there was a relation between prorenin concentrationsand the increase of renal plasma flow as an index of angiotensindependency of renal perfusion in diabetic patients as comparedwith controls. The positive news is that there was a tight correlationin diabetics, but not in controls. The downside is that becauseof the tight correlation between prorenin and renin, this observationdoes not yet unambiguously nail down prorenin as the culprit.See Stankovic et al., pages 3293–3299.
Becauseno specific markers of kidney stem cells have been identified,researchers have investigated whether markers of stem cellsin other tissues are expressed in the kidney. Sca-1 is a markerof adult bone marrow stem cells and is known to be expressedin blood vessels and tubular epithelial cells in the kidney.Dekel and colleagues at the Weizmann Institute found that Sca-1is also expressed on interstitial cells in the adult kidney.The Sca-1+ cells could be purified from the renal interstitiumand exhibited several stem cell properties including self-renewaland multipotency. Moreover, when the Sca-1+ cells were directlyinjected into the kidney after ischemic injury, they adopteda tubular phenotype. These findings suggest that Sca-1+ cellsin the renal interstitium may represent adult stem cells thatcan contribute to kidney repair. See Dekel et al., pages 3300–3314.
More on the Pathogenesis of ANCA-Positive Crescentic Glomerulonephritis.
WhetherANCA-associated crescentic glomerulonephritis (GN) is mediatedby ANCA and neutrophils or by T cell–immune mechanismshas been debated for more than two decades. Although there isstrong experimental evidence to support both processes, onlythe antibody-induced mechanism would seem to require the participationof neutrophils. In this paper, Schreiber and colleagues fromNorth Carolina demonstrate that, in the presence of ANCA, myeloperoxidase(MPO)-producing neutrophils are required for necrotic crescenticGN to develop. The paper provides further support for a roleof both ANCA and neutrophils in ANCA-positive disease, and themodel described here is probably the most robust of the rodentmodels of ANCA-positive GN described to date. However, the debatedoes not end here. JASN recently published a report of anothermouse model of crescentic GN in which neutrophil-derived MPO,ANCA, and CD4+ T cells sensitized to MPO were all required forfull expression of the lesion (Holdsworth et al., JASN 17: 1940,2006). Like many debates in medicine, it may turn out that bothsides are right! See Schreiber et al., pages 3355–3364.
Paying the "Toll" in Murine Lupus.
The clinicalexpression of lupus nephritis is influenced by both geneticand environmental factors. Because Toll-like receptors (TLR)are increasingly implicated as regulators of innate and adaptiveimmunity, it is possible that TLR stimulation could affect theclinical manifestations of this complex disease. To addressthis possibility, Pawar and colleagues tested the effects ofinjecting various TLR ligands into mice predisposed to developa model of murine lupus nephritis. Stimulation through TLR9,but not TLR3 or TLR7, significantly augmented lupus nephritisin MRLlpr/lpr mice but not in control mice. The effect of TLR9stimulation was motif specific (CpG DNA), was blocked by coinjectionof inhibitory DNA, and was associated with augmented IL-12 andIFN production as well as enhanced B cell proliferation andautoantibody production. The findings support the concept thatbacterial pathogens could trigger disease through the releaseof TLR9 ligands, including CpG DNA. See Pawar et al., pages3365–3373.
ACE Inhibitor Therapy and New Onset Microalbuminuria.
The BergamoNephrologic Diabetic Complications Trial (BENEDICT) demonstratedprevention of microalbuminuria by angiotensin-converting enzyme(ACE) inhibitor therapy, but the independent effect of bloodpressure (BP) control was not evaluated. In a post hoc analysisof these data, Ruggenenti et al. examined whether BP controlcan reduce the risk for microalbuminuria in type 2 diabeticpatients, and whether there is an enhanced effect when BP wasachieved by ACE inhibitor therapy (trandolopril) compared withverapamil, with target BP of 130/80. The relationships of baselineBP, BP reduction, and follow-up BP with the incidence of microalbuminuriain 1204 hypertensive type 2 diabetic patients and treated for3.6 yr. Follow-up BP after month 3 and the reduced versus baselineBP independently predicted the risk of new-onset microalbuminuriawith ACE inhibitor but not verapamil. The ACE inhibitor effectwas present even when BP was poorly controlled, consistent withprevention of new-onset albuminuria independent of the BP effect.See Ruggenenti et al., pages 3472–3481.
Do Regional Differences in Mortality Alter Mortality Rates in Dialysis Patients?
Internationalcomparisons of cardiovascular disease were found to be a powerfulmeans of generating and testing hypotheses to explain country-to-countryvariations in risk. The report by Yoshino and his colleaguesin this issue of JASN uses this approach to examine the associationbetween atherosclerotic cardiovascular disease and risk of deathamong stage V-D chronic kidney disease patients. They note thatthe mortality rate from atherosclerotic cardiovascular diseasein the general population was strongly associated with mortalityfrom all causes and atherosclerotic cardiovascular disease asreported for dialysis patients in the same population, and thatthere were substantial regional differences in death rates forboth the general and dialysis populations. This suggests thatthe increased risk for atherosclerotic cardiovascular diseaseconferred by population-to-population differences in behavioral,dietary, environmental, and genetic risk factors follows chronickidney disease patients throughout the progression of theirdisease and raises the question of the need to adjust mortalitycomparisons among dialysis populations for differences in backgroundmortality rates. See Yoshino et al., pages 3510–3519.
Why Do Mucosal Infections Exacerbate IgA Nephropathy?
It hasnow been established that defects in O-glycosylation of IgA1molecules are involved in the pathogenesis of IgA nephropathyand that this defect is not generic to the B cell but occurssomewhere in the course of development of a subset of B cellsafter antigen exposure. To test the hypothesis that the siteof antigen exposure might be a determinant, Smith and colleaguesimmunized IgA patients and controls with both a systemic anda mucosal antigen and examined the IgA immune response. Theyconfirmed the elevated levels of abnormally glycosylated IgA1in the IgA patients but found that both patients and controlsproduce the range of IgA glycoforms. However, mucosal antigenexposure seemed to elicit more of the abnormal IgA1 antibodies,indicating that the site of antigen exposure may be importantin the development of IgA aggregates likely to deposit in themesangium, which perhaps explains the clinical association betweendisease exacerbation and mucosal infections. See Smith et al.,pages 3520–3528.
More on IgA in IgA Nephropathy.
Considerableprogress has been made recently in understanding the role ofIgA in the pathogenesis of IgA nephropathy, first by sortingout the secretory versus mucosal origins of the IgA, then understandingthe role of the two major IgA subclasses (IgA1 and IgA2), andfinally recognizing the importance of defects in O-glycosylationin mesangial deposition of the IgA aggregates and the mesangialresponse to them. This study from The Netherlands by Oortwijnand colleagues fills in some of the gaps in this rapidly evolvingstory by looking at the characteristics of patient-derived IgAsubclasses in light of these observations. The authors foundthat polymeric IgA1, known to be the most common form of IgAin mesangial deposits, has several unique properties includingdifferent glycosylation, more secretory component, better complementactivating ability, and more effects on mesangial cells thanmonomeric IgA. These properties likely account for why enhanceddeposition of this particular type of IgA is so pathogenic inIgA nephropathy. These findings bring together several previouslydiscordant observations and further advance our understandingof the most common form of glomerulonephritis around the world.See Oortwijn et al., pages 3529–3539.
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production as well as enhanced B cell proliferation and autoantibody production. The findings support the concept that bacterial pathogens could trigger disease through the release of TLR9 ligands, including CpG DNA. See Pawar et al., pages 3365–3373. 
