Fast Track
Diabetic Nephropathy—Is Prorenin a Culprit?
The renin system is much more complex than thought even five years ago. One of the recent surprises is the demonstration of specific prorenin binding sites in the kidney. Binding by the receptor not only generates angiotensin, but also triggers angiotensin-independent signaling. Together with the long-known fact that elevated plasma prorenin is not only correlated with but is even a predictor of microvascular complications in type 1 and type 2 diabetes, prorenin and its receptor binding have become hot candidates in the genesis of diabetic nephropathy—and with the availability of renin inhibitors have even become potential targets for treatment. To provide evidence for such a role of prorenin, Stankovic et al. examined whether there was a relation between prorenin concentrations and the increase of renal plasma flow as an index of angiotensin dependency of renal perfusion in diabetic patients as compared with controls. The positive news is that there was a tight correlation in diabetics, but not in controls. The downside is that because of the tight correlation between prorenin and renin, this observation does not yet unambiguously nail down prorenin as the culprit. See Stankovic et al., pages 3293–3299.
Basic Science Articles
Sca-1 Identifies Potential Kidney Stem Cells.
Because no specific markers of kidney stem cells have been identified, researchers have investigated whether markers of stem cells in other tissues are expressed in the kidney. Sca-1 is a marker of adult bone marrow stem cells and is known to be expressed in blood vessels and tubular epithelial cells in the kidney. Dekel and colleagues at the Weizmann Institute found that Sca-1 is also expressed on interstitial cells in the adult kidney. The Sca-1+ cells could be purified from the renal interstitium and exhibited several stem cell properties including self-renewal and multipotency. Moreover, when the Sca-1+ cells were directly injected into the kidney after ischemic injury, they adopted a tubular phenotype. These findings suggest that Sca-1+ cells in the renal interstitium may represent adult stem cells that can contribute to kidney repair. See Dekel et al., pages 3300–3314.
More on the Pathogenesis of ANCA-Positive Crescentic Glomerulonephritis.
Whether ANCA-associated crescentic glomerulonephritis (GN) is mediated by ANCA and neutrophils or by T cell–immune mechanisms has been debated for more than two decades. Although there is strong experimental evidence to support both processes, only the antibody-induced mechanism would seem to require the participation of neutrophils. In this paper, Schreiber and colleagues from North Carolina demonstrate that, in the presence of ANCA, myeloperoxidase (MPO)-producing neutrophils are required for necrotic crescentic GN to develop. The paper provides further support for a role of both ANCA and neutrophils in ANCA-positive disease, and the model described here is probably the most robust of the rodent models of ANCA-positive GN described to date. However, the debate does not end here. JASN recently published a report of another mouse model of crescentic GN in which neutrophil-derived MPO, ANCA, and CD4+ T cells sensitized to MPO were all required for full expression of the lesion (Holdsworth et al., JASN 17: 1940, 2006). Like many debates in medicine, it may turn out that both sides are right! See Schreiber et al., pages 3355–3364.
Paying the “Toll” in Murine Lupus.
The clinical expression of lupus nephritis is influenced by both genetic and environmental factors. Because Toll-like receptors (TLR) are increasingly implicated as regulators of innate and adaptive immunity, it is possible that TLR stimulation could affect the clinical manifestations of this complex disease. To address this possibility, Pawar and colleagues tested the effects of injecting various TLR ligands into mice predisposed to develop a model of murine lupus nephritis. Stimulation through TLR9, but not TLR3 or TLR7, significantly augmented lupus nephritis in MRLlpr/lpr mice but not in control mice. The effect of TLR9 stimulation was motif specific (CpG DNA), was blocked by coinjection of inhibitory DNA, and was associated with augmented IL-12 and IFNα 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.
Clinical Science Articles
ACE Inhibitor Therapy and New Onset Microalbuminuria.
The Bergamo Nephrologic Diabetic Complications Trial (BENEDICT) demonstrated prevention of microalbuminuria by angiotensin-converting enzyme (ACE) inhibitor therapy, but the independent effect of blood pressure (BP) control was not evaluated. In a post hoc analysis of these data, Ruggenenti et al. examined whether BP control can reduce the risk for microalbuminuria in type 2 diabetic patients, and whether there is an enhanced effect when BP was achieved by ACE inhibitor therapy (trandolopril) compared with verapamil, with target BP of 130/80. The relationships of baseline BP, BP reduction, and follow-up BP with the incidence of microalbuminuria in 1204 hypertensive type 2 diabetic patients and treated for 3.6 yr. Follow-up BP after month 3 and the reduced versus baseline BP independently predicted the risk of new-onset microalbuminuria with ACE inhibitor but not verapamil. The ACE inhibitor effect was present even when BP was poorly controlled, consistent with prevention 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?
International comparisons of cardiovascular disease were found to be a powerful means of generating and testing hypotheses to explain country-to-country variations in risk. The report by Yoshino and his colleagues in this issue of JASN uses this approach to examine the association between atherosclerotic cardiovascular disease and risk of death among stage V-D chronic kidney disease patients. They note that the mortality rate from atherosclerotic cardiovascular disease in the general population was strongly associated with mortality from all causes and atherosclerotic cardiovascular disease as reported for dialysis patients in the same population, and that there were substantial regional differences in death rates for both the general and dialysis populations. This suggests that the increased risk for atherosclerotic cardiovascular disease conferred by population-to-population differences in behavioral, dietary, environmental, and genetic risk factors follows chronic kidney disease patients throughout the progression of their disease and raises the question of the need to adjust mortality comparisons among dialysis populations for differences in background mortality rates. See Yoshino et al., pages 3510–3519.
Why Do Mucosal Infections Exacerbate IgA Nephropathy?
It has now been established that defects in O-glycosylation of IgA1 molecules are involved in the pathogenesis of IgA nephropathy and that this defect is not generic to the B cell but occurs somewhere in the course of development of a subset of B cells after antigen exposure. To test the hypothesis that the site of antigen exposure might be a determinant, Smith and colleagues immunized IgA patients and controls with both a systemic and a mucosal antigen and examined the IgA immune response. They confirmed the elevated levels of abnormally glycosylated IgA1 in the IgA patients but found that both patients and controls produce the range of IgA glycoforms. However, mucosal antigen exposure seemed to elicit more of the abnormal IgA1 antibodies, indicating that the site of antigen exposure may be important in the development of IgA aggregates likely to deposit in the mesangium, which perhaps explains the clinical association between disease exacerbation and mucosal infections. See Smith et al., pages 3520–3528.
More on IgA in IgA Nephropathy.
Considerable progress has been made recently in understanding the role of IgA in the pathogenesis of IgA nephropathy, first by sorting out the secretory versus mucosal origins of the IgA, then understanding the role of the two major IgA subclasses (IgA1 and IgA2), and finally recognizing the importance of defects in O-glycosylation in mesangial deposition of the IgA aggregates and the mesangial response to them. This study from The Netherlands by Oortwijn and colleagues fills in some of the gaps in this rapidly evolving story by looking at the characteristics of patient-derived IgA subclasses in light of these observations. The authors found that polymeric IgA1, known to be the most common form of IgA in mesangial deposits, has several unique properties including different glycosylation, more secretory component, better complement activating ability, and more effects on mesangial cells than monomeric IgA. These properties likely account for why enhanced deposition of this particular type of IgA is so pathogenic in IgA nephropathy. These findings bring together several previously discordant observations and further advance our understanding of the most common form of glomerulonephritis around the world. See Oortwijn et al., pages 3529–3539.
- © 2006 American Society of Nephrology
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