Basic Science
Cell Biology
Protein Overload Induces Fractalkine Upregulation in Proximal Tubular Cells through NF-kB and p38 MAPK-Dependent Pathways
The Proteinuria-Interstitial Inflammation Connection: The List of Intermediaries Continues to Grow.
⇓ High-grade proteinuria actively contributes to renal structural damage and functional loss. Several mechanisms have been proposed, many dependent on the response of proximal tubular cells to elevated concentrations of normal and/or novel proteins in the glomerular ultrafiltrate. One consequence is the upregulated synthesis of leukocyte chemoattractant molecules such as chemokines and complement components. The results of the present study provide evidence that the chemokine fractalkine (CX3CL1) can be added to the list. Tubules were shown to synthesize fractalkine after exposure to high levels of albumin in vitro and in vivo via a mechanism partially accounted for by p38 mitogen-activated protein kinase and NF-κB activation. In vivo blockade of the fractalkine receptor (CX3CR1) modestly reduced interstitial inflammation in proteinuric mice, suggesting that, like the other tubular-derived chemoattractants, fractalkine acting in isolation cannot account for the full-spectrum interstitial inflammatory response that is juxtaposed between proteinuria and progressive renal disease.
Hemodynamics and Vascular Regulation
Chronic Renal Failure Accelerates Atherogenesis in Apolipoprotein E–Deficient Mice
A Step Toward Understanding Atherosclerosis, the Silent Killer of Dialysis Patients.
⇓ In the Seattle group’s 1974 seminal report on the extreme frequency of cardiac death in dialysis patients it had been postulated that atherogenesis was accelerated in uremia. The excess frequency of cardiac death in dialysis patients has been well documented since, but it had remained unclear whether the high prevalence of coronary atherosclerosis and the high incidence of coronary death were simply explained by the high burden of classical or nonclassical risk factors or whether uremia per se (or even renal disease in the absence of uremia) accelerates the growth of atherosclerotic plaques. Bro et al. now provide additional information that subtotal nephrectomy and even unilateral nephrectomy increase plaque area and aortic cholesterol content in a genetic model of atherosclerosis (apo E −/− mouse). Positive nitrotyrosine staining indicates a role for oxidative stress. If one wishes to reduce the shocking rate of cardiovascular death in renal patients, one must understand the pathomechanisms involved. This model will hopefully provide the necessary tools to get a handle on the pathophysiology that underlies accelerated atherogenesis.
Immunology and Pathology
Transgenic Overexpression of GATA-3 in T Lymphocytes Improved Autoimmune Glomerulonephritis in BXSB/MpJ-Yaa Genetic Background Mice
Reexamining the TH1/TH2 Paradigm in Autoimmune Glomerulonephritis.
⇓ Yoh et al. have explored the role of the transcription factor GATA-3, which plays an important role in Th2 differentiation, in then pathogenesis of autoimmune glomerulonephritis in a genetically susceptible mouse model. They used a transgenic approach in which GATA-3 was overexpressed in T cells. The transgenic mice had attenuated clinical and pathological manifestations of glomerulonephritis. Immunologically, the animals had T cell and B cell responses that are characteristics of a switch from Th1 to Th2, except that IL-4 production was unchanged; however, they did have inhibited IFN-γ production and increased IL-5 production. This study uses an interesting and novel approach for regulation of T helper cell differentiation by targeting the transcription factors that control such differentiation, confirming that a state of immune deviation from Th1 to Th2 is protective from autoimmune glomerulonephritis in genetically susceptible strains. The clinical applicability of such an approach requires development of novel strategies to target these transcription factors in humans.
Clinical Science
Clinical Nephrology
A Comparison of Prediction Equations for Estimating Glomerular Filtration Rate in Adults Without Kidney Disease
Measuring Renal Function: Will We Ever Get It Right?
There is continuing concern over the accuracy of estimating equations for GFR and creatinine clearance. The report by Lin et al. in this issue of JASN contributes additional evidence to this debate. They used iothalamate and DTPA to measure the GFR of healthy kidney transplant donor candidates and compared the results with those predicted by several estimating equations. They confirm previous reports that the MDRD has the best agreement with observed results and that all the equations systematically fail to estimate the observed GFR of patients with normal renal function. These observations extend previous reports to another population with normal renal function, providing additional evidence that the limitations of the current generation of estimating equations are likely to be experienced in other settings. Part of the problem with estimating equations is due to variable calibration of serum creatinine assays. National laboratories, encouraged in part by the National Kidney Disease Education Program (NKDEP), are in the process of standardizing serum creatinine essays. Clinicians must be aware, however, that, even after a uniformly calibrated serum creatinine assay is available, there is more work to be done before an entirely satisfactory estimating equation is available. Lin et al. also used their measured GFR results to derive the MDRD equation. The resulting parameter estimates were quite different from those derived for the original equation and, if applied to the original data, would likely systematically fail to estimate the observed GFR by the original MDRD study. A totally satisfactory equation awaits recalibration of the MDRD equation using a large sample of patients with a representative range of renal function. Clearly, this will need to take into account the new calibration of serum creatinine. We also need to insist on validation studies in populations other than the derivation population before we can rely on a newly calibrated equation with confidence.
The Urinary Excretion of Monocyte Chemoattractant Protein-1 in ADPKD
Chemokines in PKD: Can We Measure Progression?
⇓ Recent major developments in our understanding of the pathobiology of renal cystic disease have focused on identification and functional characterization of the molecules directly implicated in cystogenesis, the polycystins, and nephrocystin. The studies of Zheng et al. follow a different approach and implicate elevated production of the chemokine monocyte chemoattractant protein-1 (MCP-1) by cyst epithelium and its detection in urine as a new potential surrogate marker of disease progression in ADPKD. While the production of MCP-1 by tubular epithelial cells is not a novel finding, its potential importance in mediating the severity of disease in ADPKD, presumably by enhancement of tubulointerstitial inflammation, is novel. Skeptics will point out that MCP-1 has long been a favorite urinary marker for disease activity, having been proposed as a marker of active injury in such diseases as lupus nephritis, obstructive nephropathy, and other disorders. Unfortunately, it has yet to be established that MCP-1 is a better clinical marker than such common measures as proteinuria for any disease process for which it has been proposed. Nonetheless, hope springs eternal, and it would certainly be of great clinical usefulness if the findings of Zheng et al. can be further developed and validated as a measure of disease progression in ADPKD.
Epidemiology and Outcomes
Prospective Study of Neuropeptide Y as an Adverse Cardiovascular Risk Factor in End-Stage Renal Disease
Another Risk Factor for CVD in Dialysis Patients.
⇓ Cardiovascular disease is the most common comorbidity and cause of death among patients with end-stage renal disease (ESRD). The traditional Framingham risk factors are weakly and inconsistently predictive of risk of CVD in this population. Failure of conventional risk factors to explain the increased CVD risk has led to increased attention to novel factors, including ADMA, homocysteine, C-reactive protein, vascular calcification, and anemia, as mediating mechanisms for CVD in this population. Zoccali et al. report in this issue of JASN that neuropeptide Y is another candidate risk factor for CVD among ESRD patients. Plasma neuropeptide Y is a circulating polypeptide that increases in concentration during stress and is a measure of sympathetic nervous system activity. Plasma levels are increased among patients with ESRD, and the authors have described a previous association between neuropeptide Y and left ventricular hypertrophy and systolic dysfunction. The current study involves prevalent hemodialysis patients who were observed for an average of 34 mo and the association between baseline levels of neuropeptide Y and subsequent CVD. Neuropeptide Y plasma levels were high at baseline and were associated with higher plasma norepinephrine and epinephrine levels. In multivariate models an association OR (95% CI) was found between CVD and neuropeptide Y, 1.85 (1.27 to 2.69), after controlling for other risk factors, including norepinephrine, 1.05 (0.99 to 1.12). These findings add additional support for a role of sympathetic nervous system activation as a risk factor for CVD among ESRD patients. The results serve as additional evidence to support trials to determine the role blockade of the sympathetic nervous system in reducing the risk of CVD morbidity and mortality.
Dialysis
Regular Monitoring of Access Blood Flow Rate Fails to Improve Graft Survival: Results of a Randomized Controlled Trial
Access Flow Monitoring: What Is It Good For?
⇓ Current clinical practice guidelines recommend that graft blood flow be prospectively monitored and an access salvage procedure be considered when blood flow is low or declining. Moist et al. tested this recommendation in a randomized clinical trial by assigning patients to either routine graft surveillance (physical examination and dynamic venous pressure monitoring) or routine surveillance plus monitoring of graft blood flow. Patients were referred for angiography for abnormal physical findings and abnormal venous pressures. Further, intervention patients were referred for angiography if graft blood flow declined below 650 ml/min or by 20% from the previous measurement. Patients with a 50% or greater stenosis were referred for percutaneous transluminal angioplasty and, if significant stenosis persisted after the procedure, surgical revision. Intervention patients received more angiograms, and their vascular procedure rate was 50% higher than control patients, indicative of identification of stenotic lesions undetected by routine surveillance. Despite the more intensive use of diagnostic and AV graft salvage procedures in the intervention patients, time to first thrombosis (the main study outcome) and time to graft loss were the same for both groups. These unexpected results suggest that blood flow monitoring, when used with this particular stenotic graft salvage protocol, is ineffective in prolonging AV graft survival. As noted by the authors, the study does not refute the expectation that monitoring AV graft blood flow rates will identify stenotic lesions earlier, but rather calls into question the utility of both the intervention protocol and that of early, rather than late, use of salvage procedures. These issues must be resolved by further clinical trials.
Protocolized Anemia Management with Erythropoietin in Hemodialysis Patients: A Randomized Controlled Trial
Teamwork Works! It Is Now Evidence-Based.
⇓ The quality of medical care in the United States is highly variable due, in part, to the inconsistent application of standard therapy for common conditions. This was documented by a report from the Rand Corporation on the quality of adult health care (N Engl J Med 348: 2635–2646, 2003). An accompanying editorial identified the KDOQI evidence-based clinical practice guidelines, a succinct summary of standard therapy, and the CPM project, which provides information about adherence to recommended care, as examples of tools for remedying this variability (N Engl J Med 348: 2681, 2003). In this issue of JASN, Brimble et al. describe a third component for the effective translation of evidence-based medicine into clinical practice, an effective systematic approach to standard care. They describe the development and pilot testing of a team-based protocol for standard anemia management in their dialysis clinic. After the pilot test, the authors conducted a single-center randomized evaluation of their protocol. They report that the team-based protocol was as effective as care by individual clinicians and that it was associated with reduced erythropoietin requirements. This report nicely demonstrates how health services research can help establish an evidence-base for system changes that are designed to improve the quality of health care. Where might research like this lead? Consider an ESRD Network Medical Review Board whose CPM data identifies a treatment center that has less than optimal anemia control. On the basis of the work by Brimble et al., one can envision evidence-based recommendations that the center consider adoption of a multidisciplinary team protocol for anemia management that includes a nephrologist and nurse from the treatment center. If this comes to pass, it will reflect carefully designed and conducted studies like that reported by Brimble and his colleagues.
- © 2003 American Society of Nephrology
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