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This Month’s Highlights

Cell Biology
Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy
Is PDGF-B the Wrong PDGF to Be Targeting in Mesangial Proliferative GN?

Mesangial cell proliferation is a central feature of several glomerular diseases, including IgA nephropathy, lupus nephritis, and others. Proliferation precedes and leads to other components of the mesangial response to injury, including matrix expansion. Studies performed primarily in immune models of mesangioproliferative GN in rats have clearly established a role for PDGF-B, acting in an autocrine fashion, in mediating the proliferation that follows immune injury. More recently, mesangial expression of the newer PDGF isoforms C and D has been described. In this study, Hudkins et al. investigate the roles of these newer isoforms in vivo by manipulating mice to overproduce PDGF-B, -C, and -D and noting that PDGF-D was not only the most effective of the three in inducing mesangial proliferation, but it actually produced it in the absence of prior mesangial injury. Whether this demonstration that PDGF-D is a much more potent mitogen than the more frequently studied PDGF-B is true in other species than the mouse and whether it participates in the glomerular response to injury requires additional study. Nevertheless, the question is an important one because the development of reagents to block growth factors like PDGF in human renal disease is already well underway. Page 286

Hemodynamics and Vascular Regulation

The SOD Mimetic Tempol Ameliorates Glomerular Injury and Reduces Mitogen-Activated Protein Kinase Activity in Dahl Salt-Sensitive Rats
Is CKD Another Target for Antioxidant Therapy?

Few therapies have been shown to reduce progressive renal disease. Reactive oxygen species (ROS) are increased in a variety of renal diseases and are detrimental through their actions on DNA, protein, and lipids. Nishiyama et al. asked if inhibition of ROS is a potential future therapy for renal disease? To answer this, they administered an inhibitor of ROS formation, Tempol (a superoxide dismutase mimetic), to Dahl salt-sensitive rats. When placed on a high-salt diet, these animals develop hypertension and histological features of progressive renal disease. Although Tempol lowered blood pressure to levels similar to the anti-hypertensive hydrallazine, blocking ROS significantly improved renal function and reduced extracellular matrix accumulation. Tempol mediated these effects in part by inhibiting specific mitogen-activated protein kinase (MAPK) signaling pathways. These results suggest the possibility of targeting ROS as a therapeutic option for the future. Clinical studies are now needed. Page 306

Immunology and Pathology

Chemokine Receptor CCR1 but not CCR5 Mediates Leukocyte Recruitment and Subsequent Renal Fibrosis after Unilateral Ureteral Obstruction
The CC Chemokine Receptor Story Takes an Interesting Twist.

Progressive kidney disease is typically associated with an interstitial infiltrate of multifunctional mononuclear cells that actively participate in the fibrogenic process. Localized secretion of chemokines has been shown to both recruit and activate leukocytes, acting via specific chemokine receptors. Chemokine/chemokine receptor pathophysiology is complex, with more than 50 ligands and 17 receptors identified. The present study investigates the role of two CC chemokine receptors, CCR1 and CCR5, in progressive obstructive nephropathy by comparing outcomes in genetically deficient mice. Both receptors bind to the chemokines MIP-1 and RANTES; CCR5 also binds MIP-1. Renal expression of both CCR1 and CCR5 increased in response to obstruction. Surprisingly, CCR1 deficiency or CCR1 inhibition decreased the number of F4/80+ interstitial macrophages, CD3+ T cells, FSP-1+ fibroblasts, TGF- expression, and fibrosis severity, and CCR5 deficiency had no effect. It appears that the role of these receptors is organ-specific and disease-specific, as CCR1 deficiency worsened crescentic nephrotoxic serum nephritis in another study. As we learn more, new questions arise; for now, it seems that CCR1 expression is not good for scarring kidneys. Page 337

Pathophysiology of Renal Disease and Progression

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model
Bone Morphogenetic Protein-7: A Therapeutic Option for Adynamic Bone Disease?

Bone morphogenetic proteins (BMP) were originally found as biological principles promoting bone formation. They turned out to be extremely pleiotropic principles upregulating the expression of BMP-dependent proteins in different tissues. Knockout experiments showed that apart from its effects on bone development, BMP-7 is also involved in kidney development. It is also expressed in the adult kidney. BMP-7 induces osteoblast differentiation. In a model of adynamic bone disease, the authors used BMP-7 to evaluate its therapeutic potential for this condition. It is admittedly difficult to experimentally reproduce adynamic bone disease. To the extent that the data in this model can be extrapolated to human adynamic bone disease, however, the demonstration that bone histomorphometric parameters could be normalized is definitely of interest. Page 359

The Role of p38 Mitogen-Activated Protein Kinase Activation in Renal Fibrosis

Can Direct Attacks on Intracellular Signaling Pathways Prevent Progressive Kidney Disease?

Mitogen-activated protein kinases (MAPK) are intracellular signaling molecules that elicit diverse proinflammatory and profibrotic effects in vitro. Several MAPK inhibitors have been developed and are in various stages of clinical trials. In this study of rats with obstructive nephropathy, the MAPK kinase pathway was shown to be activated in kidney tubules and interstitial myofibroblasts, as indicated by increased levels of total phosphorylated p38 MAPK and p38. Treatment with an orally active specific inhibitor of p38 MAPK (NPC 31169) significantly reduced the severity of renal fibrosis. Why did this happen? Remarkably, the degree of interstitial inflammation and TGF- levels were not altered. This beneficial effect was associated with a reduction in the number of interstitial myofibroblasts, heat shock protein 47, and connective tissue growth factor mRNA levels. How p38 MAPK regulates interstitial myofibroblast recruitment is an important future question. Page 370

CLINICAL SCIENCE

Clinical Nephrology
The Value of N-Acetylcysteine in the Prevention of Radiocontrast Agent-Induced Nephropathy Seems Questionable
Serum Creatinine – Does It Adequately Reflect Renal Function When the Patient Is Treated with Acetylcysteine?

There has been considerable recent interest in whether N-acetylcysteine’s antioxidative properties cause it to protect against radiocontrast-induced acute renal failure. The literature is quite controversial, not the least because different end points have been investigated. In some papers, changes in serum creatinine was the end point. The study by Hoffmann et al. adds another twist to the discussion by showing that serum creatinine concentrations may change artifactually and independently of changes in GFR when N-acetylcysteine is administered to healthy subjects. The authors did not study uremic individuals or individuals receiving radiocontrast. Therefore a definite answer to the issue is not provided, but the findings raise the possibility of artifactual changes in serum creatinine by N-acetylcysteine and caution against accepting serum creatinine as a measure of GFR under these conditions. Page 407

Epidemiology and Outcomes

The Number, Quality, and Coverage of Randomized Controlled Trials in Nephrology
Evidence-Based Medicine: Is Nephrology Keeping Up?

The randomized clinical trial is the standard for the evidence clinicians use to guide their diagnostic, prognostic, and therapeutic decision-making. Strippoli et al. compare the number and quality of randomized clinical trials in nephrology to those of twelve other medical subspecialties. They report that the number of published trials varied substantially among subspecialties, and nephrology lagged behind that of all other subspecialties. They also note that the overall quality of the reported trials in nephrology could be improved and that trials in critical areas like glomerulonephritis that are used to guide evidence-based decision-making are conspicuously low in number. JASN recognizes the need to improve the quality of reporting of clinical trials submitted for publication, and it recently adopted the CONSORT guidelines for reporting randomized clinical trials (Ann Intern Med 134: 657–662, 2001). Page 411

Randomized Trial of Folic Acid for Prevention of Cardiovascular Events in End-Stage Renal Disease
Should We Be Treating Elevated Homocysteine Levels to Prevent CVD among ESRD Patients?

Patients with chronic kidney disease experience a higher prevalence and risk of death from CVD than do comparably aged individuals in the general population. Observational studies have found an increased prevalence and an independent association between elevated levels of serum homocysteine in ESRD patients and risk of cardiovascular disease. Serum homocysteine levels are responsive to dietary supplementation with folic acid and vitamin B12, and it is attractive to propose cardioprotective interventions on the basis of these observations. The report by Wrone et al. that composite rates of mortality and cardiovascular events did not decline with increasing levels of folic acid therapy and that high baseline levels of homocysteine were associated with lower event rates suggests that additional evidence is needed. As noted by the authors, the trial findings fail to support any reduction in CVD events of folic acid doses above 1 mg/d. Furthermore, the inverse association between homocysteine levels and subsequent increased CVD morbidity and mortality reported by Worne et al. and others is provocative and unexplained. Page 420

A Low, Rather than a High, Total Plasma Homocysteine Is an Indicator of Poor Outcome in Hemodialysis Patients
Is Homocysteine a Marker for Adverse Outcomes for ESRD Patients?

Nutrition trumps atherosclerotic risk among prevalent dialysis patients. Patients with chronic kidney disease (CKD) experience increased risk of cardiovascular disease. Elevated levels of homocysteine are associated with increased risk of atherosclerotic cardiovascular disease in the general population, and most patients with CKD have hyperhomocysteinemia due to impaired clearance of homocysteine. On the basis of these observations, it has been widely speculated that elevated levels of homocysteine may contribute to the increased mortality due to cardiovascular disease (CVD) among patients with CKD. The report in by Kalantar-Zadeh et al. sheds additional light on this hypothesis. They observed that hospitalization and mortality rates were higher among patients with low homocysteine levels. Further, homocysteine appeared to be a marker for nutritional status and was unrelated to multiple markers for inflammation. These findings suggest that risk of malnutrition substantially outweighs that of the increased risk of CVD associated with high homocysteine levels. While it remains possible that homocysteine is a risk factor for CVD among well-nourished CKD patients, this possibility is not supported by the randomized controlled trial of folate supplementation reported by Wrone et al. in this issue of JASN. These issues should be explored among patients with a spectrum of CKD including ESRD. Page 442

Dialysis

Increased Plasma S-nitrosothiol Concentration Predicts Cardiovascular Outcome in Patients with End-Stage Renal Disease: A Prospective Study
S-nitrosothiol Bioavailability Might Be an Important Risk Factor for CVD.

The high prevalence and increased risk of death from cardiovascular disease is of central concern for nephrologists. There is substantial evidence that the burden of CVD among CKD patients is due, in part, to inflammation and increased oxidative stress. Massy et al. present additional information supporting this concept. They used S-nitrosothiol concentrations in hemodialysis patients as a measure of oxidative stress. They observed a substantial increased risk of CVD among those individuals with the highest levels of S-nitrosothiol. As discussed by the authors, interpretation of these findings depends, in part, on whether S-nitrosothiol is functioning predominately as a potential NO donor or to detoxify peroxynitrate, a product of oxidative stress. In view of the increased risk CVD experienced by individuals with the highest levels of S-nitrosothiol, the latter possibility is at least reasonable. How might this increased risk be medicated? The authors report an association between pulse pressure and S-nitrosothiol and suggest that this may reflect endothelial dysfunction due to decreased bioavailability of NO. The clinical relevance of these findings remains to be established by replication in other observational studies. If sustained, then S-nitrosothiol may be a reasonable therapeutic target for interventions that modify the effects of S-nitrosothiol on the bioavailability of NO. Page 470

Human Renal Pathology

Chymase-like Angiotensin II–generating Activity in End-stage Human Autosomal Dominant Polycystic Kidney Disease
ACE-Independent Angiotensin II Production in Polycystic Kidneys.

Autosomal dominant polycystic kidney disease (ADPKD) is associated with activation of the renin-angiotensin system and systemic hypertension. However, chronic administration of angiotensin-converting enzyme (ACE) inhibitors has not been proven to preserve renal function in ADPKD. In this issue, McPherson et al. examine the involvement of chymase in the intrarenal production of angiotensin II (AngII) in ADPKD patients. Chymase is a serine protease that is released by mast cells and cleaves AngI to produce AngII. Chymase therefore represents an ACE-independent pathway of AngII production. Recent studies have shown that chymase is normally expressed in mesangial cells and vascular smooth muscle cells in the kidney. Expression increases in diabetic nephropathy and interstitial fibrosis. McPherson et al. found that chymase-dependent production of AngII was increased in kidneys with end-stage ADPKD. The production of AngII could be blocked with an inhibitor of chymase, but it was not affected by ACE inhibition. Chymase activity was present in kidney homogenates, but it was absent from the cyst fluid. Antibody staining showed that chymase was produced by mast cells in the regions of interstitial fibrosis. These results suggest that chymase may represent an ACE-independent mechanism for increased AngII production in ADPKD. AngII receptor blockade or chymase inhibition may be useful for reducing the effects of AngII and preserving renal function in ADPKD. Page 493

Related Articles

Exogenous PDGF-D Is a Potent Mesangial Cell Mitogen and Causes a Severe Mesangial Proliferative Glomerulopathy

Kelly L. Hudkins, Debra G. Gilbertson, Matthew Carling, Sekiko Taneda, Steven D. Hughes, Matthew S. Holdren, Thomas E. Palmer, Stavros Topouzis, Aaron C. Haran, Andrew L. Feldhaus, and Charles E. Alpers
J. Am. Soc. Nephrol. 2004 15: 286-298. [Abstract] [Full Text] [PDF]

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