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This Month’s Highlights

Cell and Transport Physiology
Investigations of Pharmacologic Properties of the Renal CLC-K1 Chloride Channel Co-expressed with Barttin by the Use of 2-(p-Chlorophenoxy)Propionic Acid Derivatives and Other Structurally Unrelated Chloride Channel Blockers
Are New Diuretics on the Horizon?
Diuretics are important in the multidrug approach needed to reach blood pressure targets in patients with chronic kidney disease. Loop agents and thiazides interact with apical membrane Na⁺ transporters. New approaches can be focused on the mechanisms by which NaCl is transported across the basolateral membrane. Chloride channels (CLC-K1 and CKC-K2) have gained prominence in this regard, underscored by genetic defects that can affect these channels (Bartter syndrome and perhaps some cases of Gitelman syndrome). Liantonio et al. describe the interactions among CLC-K1, its accessory beta subunit (barttin), and chlorophenoxy-propionic acid derivatives. Structure-activity relations are explored, and it is noted that this class of agents is effective from the basolateral (blood) side of the cells. The potency of the current generation of agents is not yet adequate to consider their clinical utility, but this approach may be worthwhile in developing new therapeutic agents with diuretic potential.Page 13

Cell Biology
Angiotensin II Type 1-Receptor Mediated Changes in Heparan Sulfate Proteoglycans in Human SV40 Transformed Podocytes
The Effect of ACE Inhibition on Proteinuria May Not Be Entirely Hemodynamic.
Although the role of AngII in regulating post-glomerular resistance and intraglomerular pressure is well known, there has been an expanding literature on AngII effects that are independent of hemodynamics and that may contribute to renal disease. These include induction of interstitial disease and fibrosis, effects on TGF-, and several others. In this article, Brinkkoeter et al. examine AngII effects on podocyte production of negatively charged heparan sulfate proteoglycans (HSPG), molecules that constitute a major portion of the negative charge barrier to protein filtration. They find a marked decrease in both cell and matrix HSPG associated with AngII expression. These changes could explain the loss of the charge barrier in proteinuric diseases like diabetic nephropathy, and they also contribute to the reduction of proteinuria seen with AngII inhibitors, which could presumably restore the charge barrier as well as reduce intraglomerular pressure.Page 33

Hemodynamics and Vascular Regulation
Oxidant Stress Leads to Impaired Regulation of Renal Cortical Oxygen Consumption by Nitric Oxide in the Aging Kidney
Oxidant Stress and Aging - YES or NO?
This study examines regulation of renal oxygen consumption in the aging rat kidney. Specifically, this study shows decreased ability of the aged rat to regulate oxygen consumption via NO production. The finding is reversed by the super oxide dismutase mimetic tempol and the NAD(P)H oxidase inhibitor Apocynin, indirectly suggesting that super oxide production from NAD(P)H oxidase was the reason for decreased NO bioavailability. While this report provides evidence in support of the first of two possibilities, it remains unresolved from this and other reports of decreased renal NO in aging animals whether it is indeed increased oxidative stress that quenches NO or decreased NO production that is most responsible for the exaggeration of the harmful effects of oxidative stress that cause renal injury in aging. Definition of the relative importance of these two pathophysiologic scenarios continues to be a challenge for future studies.Page 52

Immunology and Pathology
Podocytes Populate Cellular Crescents in a Murine Model of Inflammatory Glomerulonephritis
Are Podocytes Previously Unrecognized Contributors to Glomerular Crescent Formation?
Crescents represent the clinician’s nightmare: the sign of severe capillary wall injury and usually a rapid and often irreversible loss of renal function. Previously regarded as reflecting only a proliferation of parietal epithelial cells lining Bowman’s capsule, we now recognize that crescents mark disruption not only in glomerular basement membrane but also in Bowman’s capsule and have a multicellular composition that includes monocytes and fibroblasts derived from the interstitium and parietal epithelial cells. Further insight into the composition of crescents is provided by this study, which uses podocyte-specific markers and transgenic mice to establish that up to 25% of cells populating glomerular crescents in the mouse are actually derived from podocytes, although they lack podocyte-specific markers. However, mice are not humans, and the remarkable podocyte proliferation that occurs in nephritic mouse glomeruli after deposition of this antibody is unique, raising the question of whether these structures are truly crescents in the traditional sense. More work will be required to show that a similar process occurs in human disease.Page 61

Pathophysiology of Renal Disease and Progression
Prevention of Acute Ischemic Renal Failure by Targeted Delivery of Growth Factors to the Proximal Tubule in Transgenic Mice: The Efficacy of Parathyroid Hormone-Related Protein and Hepatocyte Growth Factor
Why Do Diabetic Glomeruli Have So Much Extracellular Matrix?
One of the principal pathologic features of diabetic nephropathy is the excess of extracellular matrix in the form of both expanded mesangial matrix and thickening of glomerular basement membrane (GBM). While considerable attention has been given to the role of mesangial cells in diabetic nephropathy, the GBM thickening is presumably a consequence of podocyte dysfunction, a considerably less-studied area. Adler et al. from Harbor-UCLA provide convincing data from both cell-culture and whole-animal studies to show that exposure to high glucose stimulates the 12-lipoxygenase pathway in podocytes, which signals the p38-Map kinase pathway to activate synthesis of the -5 chain of type IV collagen. The fact that changes similar to those observed in cell culture were also documented in the intact diabetic animal provides strong evidence that the in vitro observations are relevant to what occurs in vivo. While the complex processes that regulate matrix synthesis and degradation in the GBM are certainly more complicated than this, the study does provide novel information on the role of glucose in the pathogenesis of diabetic nephropathy. The next step will be to see if this process can be ameliorated with 12-lipoxygenase inhibitors such as nonsteroidal antiinflammatory agents.Page 112

Basic Dialysis
Glycosaminoglycans Enhance the Trifluoroethanol-Induced Extension of ₂-Microglobulin-Related Amyloid Fibrils at a Neutral pH
From ₂ Microglobulin to Amyloid - A Role for GAGs?
It is now well known that ₂-microglobulins can form amyloid and that this has been an important source of morbidity complicating dialysis therapy. This study uses a reagent, trifluoroethanol, that induces the extension of ₂-microglobulin-related amyloid fibrils under experimental conditions. Despite not normally being found in the body, the effect of trifluoroethanol in this experimental setting demonstrates the possibility that potentially other more biologically relevant agents may denature specific proteins enough to permit amyloid fibril formation at physiologic pH. The fact that glycosaminoglycans accelerate this process is of interest, implying that cell surface heparan sulfate proteoglycans could contribute to the process of ₂-microglobulin amyloid formation.Page 126

CLINICAL SCIENCE

Clinical Nephrology
Timing of Complications in Percutaneous Renal Biopsy
What Is the Optimal Time to Observe Patients for Complications after Renal Biopsy?
For all of us who do percutaneous renal biopsies on native kidneys, as well as for those who refer such patients to radiologists, the issue of how long a patient must be observed after biopsy to ensure that complications have not occurred is an important one. Clinical lore suggests that 8 to 12 h is reasonable, which used to result in overnight stays in the hospital. However, emphasis on cost control has reduced that period to a few hours in most centers. This article from a busy and experienced group at Rush-Presbyterian-St. Luke’s Hospital in Chicago provides data on complication rates in 750 patients biopsied with modern real-time ultrasound technology and spring-loaded needles. It documents a higher complication rate in patients with renal insufficiency and provides good data to justify an observation period of up to 24 h after biopsy.Page 142

Effects of Early and Late Intervention with Epoetin on Left Ventricular Mass among Patients with Chronic Kidney Disease (Stage 3 or 4): Results of a Randomized Clinical Trial
EPO-Does It Also Improve the Heart?
A report by Roger et al. in this issue of JASN describes a carefully designed and conducted clinical trial that examined the effect of anemia correction on the development and progression of left ventricular hypertrophy (LVH) among patients with moderate to severe chronic kidney disease (CKD). The result of the trial was unexpected, and no differences were noted in left ventricular mass index (LVMi) or progression of LVH between the erythropoietin-treated and comparison groups. The authors note that the expected separation in hemoglobin levels was not achieved during the study, with mean hemoglobin of 122 ± 7 g/L in the intervention group and 110 ± 10 g/L in the control group. Further, few patients in the intervention (50%) or the comparison (19%) arms actually achieved the planned hemoglobin levels. Among those subjects who did achieve protocol targets, changes in LVMi were consistent with previous studies. Overall, the 2-yr LVMi increase in the treated subjects was 44% less than that observed in the control subjects, 2.5 ± 20 g/m² versus 4.5 ± 20 g/m² (difference, 2.0 g/m²; 95% CI, -8.4 to 4.0; P = 0.44). On the basis of these observations, the authors estimate that a study would need a total of 1571 patients to demonstrate a significant difference between groups achieving this degree of separation in hemoglobin levels. Clearly, this small multicenter study illustrates the need for larger trials of the anemia/LVH hypothesis and raises important issues about the design of future interventions. Until evidence from more and larger studies is available, the role of anemia correction in the management of cardiovascular disease risk in the pre-ESRD phase of CKD will remain uncertain.Page 148

Dialysis
Factors that Affect Postdialysis Rebound in Serum Urea Concentration, Including the Rate of Dialysis: Results from the HEMO Study
What Are the Determinats of How Much Rebound in BUN Occurs after Dialysis?
Daugirdas et al. present a detailed analysis of the variables that affect the postdialysis rebound in serum urea concentration. The equilibrated Kt/V has been estimated as a linear function of single pool Kt/V and the rate of dialysis (K/V). Data from 1331 HEMO study subjects identified greater urea rebound in African-American patients, male patients, those without congestive heart failure, those with greater age, those with higher ultrafiltration rate, and those with low predialysis or intradialysis systolic blood pressure. Optimum values for the slope term (B) were determined for arteriovenous access and for venous catheters at two sampling times: immediate and 20 s after dialysis. The authors suggest that variability associated with other factors is consistent with a regional blood flow model of urea kinetics.Page 194

Transplantation
Proteomic-Based Detection of Urine Proteins Associated with Acute Renal Allograft Rejection
A Dipstick Test for Acute Rejection? The Promise of Proteomics—Almost!
The quest for development of biological markers of renal allograft dysfunction and novel non-invasive diagnostic tools for renal allograft rejection led Schaub et al. to perform an interesting study exploring protein clusters by mass spectrometry of urine samples. The results identified a unique cluster in the majority of rejecting recipients but not in normals or other groups who are either stable or have dysfunction due to ischemia or glomerulopathy. This is a cross-sectional study, and the data require prospective validation to define predictive value and utility in surveillance and interventions. More importantly, the data will stimulate further research aimed at identifying the proteins and leading to development of novel therapeutic targets. These types of studies, coupled with published and ongoing studies to look at message level of specific genes or microarray analysis, are invaluable tools in the quest to define biological markers of renal allograft dysfunction in transplantation.Page 219

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Prevention of Acute Ischemic Renal Failure by Targeted Delivery of Growth Factors to the Proximal Tubule in Transgenic Mice: The Efficacy of Parathyroid Hormone-Related Protein and Hepatocyte Growth Factor

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