Poorna R. Karuparthi

Nephrogenic Systemic Fibrosis: A Mysterious Disease in Patients with Renal Failure—Role of Gadolinium-Based Contrast Media in Causation and the Beneficial Effect of Intravenous Sodium Thiosulfate

Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NSF) is an emerging scleromyxedema-like cutaneous disorder of unknown cause that is seen in patients with renal failure, and the number of reported cases has grown significantly since its first recognition. Recent case reports associated the use of gadolinium (Gd3+)-based contrast agents with the development of NSF. Herein is reported an additional patient who had NSF and had multiple previous exposures to Gd3+-based magnetic resonance imaging studies and had marked improvement in pain and skin changes after a trial of intravenous sodium thiosulfate. Discussed are the possible association of Gd3+-based contrast media with the development of NSF and potential for the use of sodium thiosulfate in the treatment of NSF.

Attenuation of NADPH Oxidase Activation and Glomerular Filtration Barrier Remodeling With Statin Treatment

Activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase by angiotensin II is integral to the formation of oxidative stress in the vasculature and the kidney. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibition is associated with reductions of oxidative stress in the vasculature and kidney and associated decreases in albuminuria. Effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition on oxidative stress in the kidney and filtration barrier integrity are poorly understood. To investigate, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and renin-angiotensin system activation, and an immortalized murine podocyte cell line. We treated young, male Ren2 and Sprague-Dawley rats with rosuvastatin (20 mg/kg IP) or placebo for 21 days. Compared with controls, we observed increases in systolic blood pressure, albuminuria, renal NADPH oxidase activity, and 3-nitrotryosine staining, with reductions in the rosuvastatin-treated Ren2. Structural changes on light and transmission electron microscopy, consistent with periarteriolar fibrosis and podocyte foot-process effacement, were attenuated with statin treatment. Nephrin expression was diminished in the Ren2 kidney and trended to normalize with statin treatment. Angiotensin II-dependent increases in podocyte NADPH oxidase activity and subunit expression (NOX2, NOX4, Rac, and p22phox) and reactive oxygen species generation were decreased after in vitro statin treatment. These data support a role for increased NADPH oxidase activity and subunit expression with resultant reactive oxygen species formation in the kidney and podocyte. Furthermore, statin attenuation of NADPH oxidase activation and reactive oxygen species formation in the kidney/podocyte seems to play roles in the abrogation of oxidative stress-induced filtration barrier injury and consequent albuminuria.

Renin Inhibition Attenuates Insulin Resistance, Oxidative Stress, and Pancreatic Remodeling in the Transgenic Ren2 Rat

Emerging evidence indicates that pancreatic tissue expresses all components of the renin-angiotensin system. However, the functional role is not well understood. This investigation examined renin inhibition on pancreas structure/function in the transgenic Ren2 rat harboring the mouse renin gene, a model of tissue renin overexpression. Renin is the rate-limiting step in the generation of angiotensin II (Ang II), which stimulates the generation of reactive oxygen species in a variety of tissues. Overexpression of renin in Ren2 rats results in hypertension, insulin resistance, and cardiovascular and renal damage. Young (6-7 wk old) insulin-resistant male Ren2 and age-matched insulin sensitive Sprague Dawley rats were treated with the renin inhibitor, aliskiren (50 mg/kg.d by ip injection), or placebo for 21 d. At 21 d, the Ren2 demonstrated insulin resistance with increased islet insulin, Ang II, and reduced total insulin receptor substrate (IRS)-1, IRS-2, and Akt immunostaining. There was increased islet nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and subunits (p47(phox) and Rac1) as well as increased nitrotyrosine immunostaining (each P < 0.05). These functional abnormalities were associated with a disordered islet architecture; increased islet-exocrine interface, pericapillary fibrosis, and structurally abnormal mitochondria and content in endocrine and exocrine pancreas. In vivo treatment with aliskiren normalized systemic insulin resistance and islet insulin, Ang II, NADPH oxidase activity/subunits, and nitrotyrosine and improved total IRS-1 and Akt phosphorylation (each P < 0.05) as well as islet/exocrine structural abnormalities. Collectively, these data suggest that pancreatic functional/structural changes are driven, in part, by tissue renin-angiotensin system-mediated increases in NADPH oxidase and reactive oxygen species generation, abnormalities attenuated with direct renin inhibition.

Ultrastructure of Islet Microcirculation, Pericytes and the Islet Exocrine Interface in the HIP Rat Model of Diabetes

Context: The transgenic human islet amyloid polypeptide (HIP) rat model of type 2 diabetes mellitus (T2DM) parallels the functional and structural changes in human islets with T2DM. Objective: The transmission electron microscope (TEM) was utilized to observe the ultrastructural changes in islet microcirculation. Methods: Pancreatic tissue from male Sprague Dawley rats (2, 4, 8, 14 months) were used as controls (SDC) and compared to the 2-, 4-, 8- and 14-month-old HIP rat models. Results: The 2-month-old HIP model demonstrated no islet or microcirculation remodeling changes when compared to the SDC models. The 4-month-old HIP model demonstrated significant pericapillary amyloid deposition and diminution of pericyte foot processes as compared to the SDC models. The 8-month-old model demonstrated extensive islet amyloid deposition associated with pericyte and β-cell apoptosis when compared with SDC. The 14-month-old HIP model demonstrated a marked reduction of β-cells and intra-islet capillaries with near complete replacement of islets by amyloidoses. Increased cellularity in the region of the islet exocrine interface was noted in the 4- to 14-month-old HIP models as compared to SDC. In contrast to intra-islet capillary rarefaction there was noticeable angiogenesis in the islet exocrine interface. Pericytes seemed to be closely associated with collagenosis, intra-islet adipogenesis and angiogenesis in the islet exocrine interface. Conclusion: The above novel findings regarding the microcirculation and pericytes could assist researchers and clinicians in a better morphological understanding of T2DM and lead to new strategies for prevention and treatment of T2DM.

Fluid overload and acute kidney injury

Acute kidney injury is commonly encountered in critically ill patients, and is associated with worse outcomes. Fluid therapy is a key component in the management of these patients, often leading to fluid overload, especially in the setting of septic acute kidney injury. Emerging data overwhelmingly suggest that fluid overload in these patients may be associated with adverse outcomes. Management of such patients should include a strategy of early guided resuscitation, followed by careful assessment of fluid status, and early initiation of renal replacement therapy as soon as it is deemed safe, aiming for a neutral or negative fluid balance. This review will focus on the pathophysiological link between fluid overload and acute kidney injury, mechanisms of organ dysfunction in fluid overload, and strategies for management.

Chronic kidney disease and cardiovascular risk

Chronic kidney disease (CKD) is a global public health concern, and there is emerging a strong relationship between CKD and increased cardiovascular disease (CVD) risk. CKD in the presence of other co-morbidities such as type 2 diabetes mellitus (T2DM) and hypertension (HTN) can lead to early progression to end-stage renal disease (ESRD/stage V CKD) and confer a greater risk for CVD morbidity and mortality. CVD events are the leading cause of premature death in patients with CKD, even before their progression to ESRD, with the rate of CVD progression being twice as common compared with the general population. The higher mortality from CVD persists even after adjusting for most of the traditional risk factors, suggesting the possible contributions of uremia-related, nontraditional risk factors. This has led to the current understanding that the pathophysiology of CVD in CKD involves a complex interplay of both the traditional as well as nontraditional, uremia-related risk factors. This review will elaborate on the pathophysiology of CVD in CKD and will discuss the role of microalbuminuria (MAU)-proteinuria as a potential diagnostic and prognostic tool for CVD in CKD risk assessment.

Ultrastructure Study of Transgenic Ren2 Rat Aorta – Part 1: Endothelium and Intima

Background: The renin-angiotensin-aldosterone system plays an important role in the development and progression of hypertension and accelerated atherosclerosis (atheroscleropathy) associated with the cardiorenal metabolic syndrome and type 2 diabetes mellitus. Additionally, the renin-angiotensin-aldosterone system plays an important role in vascular-endothelial-intimal cellular and extracellular remodeling. Methods: Thoracic aortas of young male transgenic heterozygous (mRen2)27 (Ren2) rats were utilized for this ultrastructural study. This lean model of hypertension, insulin resistance and oxidative stress harbors the mouse renin gene with increased local tissue (aortic) levels of angiotensin II and angiotensin type 1 receptors and elevated plasma aldosterone levels. Results: The ultrastructural observations included marked endothelial cell retraction, separation, terminal nuclear lifting, adjacent duplication, apoptosis and a suggestion of endothelial progenitor cell attachment. The endothelium demonstrated increased caveolae, microparticles, depletion of Weibel-Palade bodies, loss of cell-cell and basal adhesion hemidesmosome-like structures, platelet adhesion and genesis of subendothelial neointima. Conclusion: These observational ultrastructural studies of the transgenic Ren2 vasculature provide an in-depth evaluation of early abnormal remodeling changes within conduit-elastic arteries under conditions of increased local levels of angiotensin II, oxidative stress, insulin resistance and hypertension.

Understanding essential hypertension from the perspective of the cardiometabolic syndrome

Hypertension (HTN) is an important modifiable risk factor for major health problems such as coronary heart disease, stroke, congestive heart failure, end-stage renal disease, and peripheral vascular disease. Because of the associated morbidity and mortality, and the cost to society, HTN is an important public health challenge. HTN is frequently associated with other cardiovascular disease risk factors constituting the cardiometabolic syndrome, which individually and synergistically influence the pathophysiology of HTN, and the resultant increased redox stress contributes to the remodeling changes in key organs such as the heart and kidney. Remodeling at the subcellular level, and extracellular matrix in the heart and kidney of the hypertensive Ren2 transgenic rat model of tissue angiotensin II overexpression (TG(mREN-2)27), compared with the Sprague Dawley control rat model, has been observed by light and electron microscopy and are discussed. A better understanding of the pathophysiology of HTN may provide clinician and researcher, tools to effectively investigate and manage this complicated disease process.

Effects of endothelial growth media on proepicardial cell gene expression and morphogenesis in 3D collagen matrices

Proepicardial cells (PE) contribute to embryonic coronary vessel and epicardial development. Cells from the PE region can differentiate into coronary vascular smooth muscle cells and fibroblasts in vitro, but the endothelial specification capability of these cells is controversial. We sought to examine the effects of endothelial cell growth media on gene expression and the morphogenic properties of proepicardial cells in three-dimensional (3D) matrices. A primary culture of avian PE cells was subjected to molecular characterization with selected endothelial specific markers. Morphogenic properties of PE cells were assessed by in vitro assays of coronary vasculogenesis and invasion, which utilized highly defined, serum free, three-dimensional matrix conditions. PE cells maintained mixed cell population properties in the culture based on morphogenic features, immunohistochemistry, and the gene expression data. When suspended in a 3D vasculogenesis in vitro assay, PE cells formed intracellular vacuoles and assembled into multicellular tubes. Further, ultrastructural analysis revealed the presence of pinocytic vacuoles, intercellular junctions, and endothelial specific Weibel Palade bodies. In the invasion assay, PE cells spontaneously invaded control matrices. This invasion was markedly enhanced by lysophosphatidic acid (94 ± 9.6 vs. 285.6 ± 54.9, p < 0.05) and was completely blocked with synthetic broad-spectrum metalloproteinase inhibitor GM6001. Isolated PE cells grown in endothelial cell media represent mixed-cell population, characterized by both smooth muscle and endothelial gene expression. When placed in 3D in vitro assays, PE cells manifest morphogenic properties, including multicellular tube assembly and invasion.

Obesity and chronic kidney disease: therapeutic implications

Obesity has now reached epidemic proportions, with far-reaching healthcare and economic implications. Obesity has been associated with end-organ damage in several tissues including the kidney and is one of the most important modifiable and preventable causes of death. Insulin resistance and the compensatory hyperinsulinemia, oxidative stress and adipocytokines, among others, have been implicated in the causation of obesity-related kidney damage. Obesity-related focal glomerulosclerosis is now a well recognized distinct histopathological entity and its pathophysiology has been related to the ‘hyperfiltration’ mechanism associated with increased renal plasma flow and glomerular filtration rate. This review will discuss the epidemiology and pathophysiology of obesity-related kidney damage with special focus on the central role of insulin resistance/hyperinsulinemia, adipocytokines and oxidative stress, as well as summarize the current evidence and recommendations in the management of this condition.