BASIC SCIENCE
Cell and Transport Physiology
Antidiuretic Effect of Hydrochlorothiazide in Lithium-Induced Nephrogenic Diabetes Insipidus is Associated With Upregulation of Aquaporin-2, Na-Cl Cotransporter and Epithelial Sodium Channel
Regulating H2O Transport: Effects of Thiazide Diuretics.
Clinical conditions (lithium, hypercalcemia, etc.) with impaired water reabsorption in nephrogenic diabetes insipidus (NDI) and decreased Aquaporin-2 abundance. Thiazide diuretics blunt the polyuria in NDI, an effect attributed to volume contraction, reduced glomerular filtration and enhanced proximal reabsorption. The studies by Kim et al. in this issue, provide a better understanding of the effects of thiazide diuretics in lithium-induced NDI, which include a well-coordinated increase in the sodium transport capacity (NaCl cotransporters and epithelial sodium channels), as well as Aquaporin-2 in the aldosterone-responsive distal nephron. Enhance water reabsorption via Aquaporin-2 requires an increase in medullary tonicity, yet NaCl cotransporter expression is usually ascribed to the cortical diluting segments. The response to hydrochlorothiazide is concentration of the urine and reduced urine volume, implying that increased salt transport in the concentrating segments (thick ascending limb), perhaps mediated by vasopressin, also plays an important role in this response to thiazide diuretics. Page 2836
Genetics and Development
WT1 Activates a Glomerular-Specific Enhancer Identified from the Human Nephrin Gene
Toward a Better Podocyte. Using the Nephrin Promoter to Overexpress Proteins in a Podocyte Specific Fashion.
Quests to better understand the glomerular barrier to protein filtration have taken on many forms over the past several decades from the purely structural using transmission electron microscopy, to the functional with emphasis on size and charge-selective properties of the filter to now molecular with the recognition that a mutation in the slit diaphragm protein nephrin underlies congenital nephrotic syndrome. The nephrin story has sparked an avalanche of research to identify, establish function for and eventually to manipulate such missing or abnormal proteins that underlie what are now termed “podocytopathies”. Quaggin et al. colleagues lead us further toward that goal by identifying a 183 base pair segment that is homologous between the human and mouse nephrin promoters and showing that it can be utilized to express a test protein in a podocyte specific distribution in transgenic mice, and that the tumor suppressor gene WT1 enhances that expression. The paper is an important technical advance, and the intensity of the podocyte protein expression achieved is nicely illustrated in this month’s cover photo. Page 2851
Basic Mineral Metabolism
Human Vascular Smooth Muscle Cells Undergo Vesicle-Mediated Calcification in Response to Changes in Extracellular Calcium and Phosphate Concentrations
Higher Extracellular Calcium Concentrations Induce Calcification in Vascular Smooth Muscle Cells. Or Does Calcium Induce Vascular Calcification.
Cardiovascular disease is the leading cause of death among hemodialysis patients and disorders of mineral metabolism have been linked to vascular calcification in epidemiological studies. Vascular calcification has been ascribed to supersaturation of calcium and phosphorus and subsequent precipitation. More recently, investigators have demonstrated calcification to be an active process, potentially exacerbated or inhibited by serum factors. Reynolds et al. demonstrate that modest elevations in extracellular calcium and phosphorus concentrations independently and synergistically induce human vascular smooth muscle cell calcification by release of membrane-bound matrix vesicles in viable cells and apoptotic bodies in dying cells. Exposure to serum diminish, and pre-treatment of vascular smooth muscle cells with warfarin enhance, vesicle calcification. These data bring us several steps closer to understanding the process of vascular calcification, and toward understand the mechanism(s) by which chronic kidney disease contributes to the process. Page 2857
Pathophysiology of Renal Disease and Progression
Hepatocyte Growth Factor Ameliorates Renal Interstitial Inflammation in Rat Remnant Kidney by Modulating Tubular Expression of MCP-1 and RANTES
Attacking Renal Inflammation in CKD.
Hepatocyte growth factor (HGF) is emerging as an impressive anti-fibrotic agent based on reports that it attenuates chronic renal injury in several experimental models. How does it work? The initial studies demonstrated HGF effects on the production of pro-fibrotic growth factors such as TGF-(. However, more recent studies have identified direct effects of HGF that might prevent chronic kidney damage such as enhanced degradation of extracellular matrix and blockade of tubular epithelial-to-mesenchymal transition to interstitial myofibroblasts. The study by Gong et al. in this issue of JASN, uncovers a new aspect of HGF biology that is highly relevant to progressive kidney disease. Using a rat remnant kidney model, administration of exogenous HGF significantly reduced tubular chemokine production (MCP-1 and RANTES) and the number of interstitial macrophages and was associated with reduced kidney fibrosis, proteinuria and serum creatinine levels. Neutralization of endogenously produced HGF had the reverse outcome. In vitro studies confirmed that HGF inhibited MCP-1 and RANTES production by cultured tubular cells. There is a significant body of literature supporting a direct relationship between activated interstitial macrophages and progressive kidney disease. HGF therapy can be added to the growing list of therapeutic strategies that might prevent CKD by suppressing that interstitial inflammatory response to chronic injury. Page 2868
Basic Transplantation
Selectin Inhibitor Bimosiamose Prolongs Survival of Kidney Allografts by Reduction in Intragraft Production of Cytokines and Chemokines
Inhibiting Selectins in Experimental Renal Transplantation.
In this manuscript, Langer et al. studied the effects of selectin ligand inhibition on kidney allograft survival in an experimental model of renal transplantation in rats. They show that administration of the selectin inhibitor Bimosiamose prevents acute rejection and increases allograft survival in this model. Importantly, the agent was also synergistic with existing immunosuppressive agents in promoting graft survival. The effect was associated with decreased expression of chemokines and cytokines in the graft. Although the exact mechanism of action of this novel agent is not defined this is a potentially clinically relevant manuscript. Future work should focus on defining exact mechanism of action, studying its effect on chronic rejection and translating its effect to a large animal model and ultimately humans. Page 2893
CLINICAL SCIENCE
Epidemiology and Outcomes
Association of Chronic Kidney Disease and Anemia with Physical Capacity: The Heart and Soul Study
It’s Not Just Anemia that Makes CKD Patients Tired.
Both severe anemia and advanced chronic kidney disease (CKD) have been associated with decreased exercise capacity. In this issue, Odden et al. have addressed these associations in patients with coronary artery disease from the Heart and Soul Study. Among 954 eligible patients, 24% had a creatinine clearance <60 ml/min and 9% had Hb <12 g/L. Compared to patients with higher values, patients with either anemia or CKD had lower self-reported physical function and lower objective exercise capacity. Subjects with both anemia and CKD had lower physical function and exercise capacity than patients with either condition alone. Among patients with coronary artery disease, moderately severe CKD and anemia appear to be independently associated with decreased physical capacity. Page 2908
Effect of an Increase in CRP Level During a Hemodialysis Session on Mortality
Can Measuring CRP Predict Death in Dialysis Patients?
Inflammation, estimated by serum C-reactive protein (CRP), is associated with worse clinical outcomes in patients treated with dialysis. In this issue, Korevaar et al. report that, among hemodialysis patients with an elevated serum CRP concentration, an increase in serum CRP (>0.5mg/L) during a single hemodialysis treatment was associated with an increased risk of death. For each 1 mg/L CRP increase, there was a 9% increased mortality risk. The independent patient related variables associated with an increase in serum CRP were increased age and low serum cholesterol while the dialysis related variables were higher dialysate flow rate and use of two dialysis needles. The 2 yr survival rate was 66% for the group without an increase in CRP compared to 44% for those with an increase (P = 0.09). These data should stimulate a search for dialysis related variables, which might be causally associated and amenable to change. Page 2916
Clinical Dialysis
Racial and Center Differences in Hemodialysis Adequacy in Children Treated at Pediatric Centers: A NAPRTCS Report
Is There Racial Bias in Dialysis Delivery to Kids?
The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) group has made a major contribution to understanding the prevalence of adequacy of hemodialysis in children treated with hemodialysis in North America. Adequate dialysis, defined as >75% of calculated Kt/V values greater >1.2, was achieved in 70% of the patients evaluated. The statistically significant predictors of inadequate dialysis dose were male gender, black race, larger body surface area and absence of Kt/V reporting at a center. The study limitations included participation of 50% of eligible centers, the potential for selection bias and a relatively small final sample size. Nevertheless, this study identified inadequate dialysis in about 30% of these patients and demonstrated gender and racial disparities in achieving target Kt/V values. Page 2923
- © 2004 American Society of Nephrology
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