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A 19-year-old woman with a history of asthma presented with acute confusion following a near-drowning event 2 weeks prior to admission. She was found to have severe thrombocytopenia and microangiopathic hemolytic anemia (MAHA). The treatment for thrombotic thrombocytopenic purpura (TTP) was started on the day of admission due to high clinical suspicion. Subsequent workup confirmed a diagnosis of TTP with no clear etiology except the near-drowning incident. TTP following a near-drowning event has never been reported in the literature. Furthermore, she developed refractory TTP that required reinitiation of therapeutic plasma exchange and rituximab. After discharge, the patient had been doing well over a year of follow-up without remission.

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Nephropathy is a major microvascular complication of diabetes mellitus and often leads to terminal renal failure in addition to contributing significantly to cardiovascular morbidity and mortality. Despites continuous advances, the pathogenesis of diabetic nephropathy remains poorly understood. Recent studies have underscored the significance of structural and functional changes in podocytes in the development and progression of diabetic nephropathy. The role of podocytes in health and diabetic nephropathy and abnormalities including podocyte hypertrophy, effacement, and apoptosis, and a detailed discussion on the role played by the Wnt-ß-catenin signaling pathway in podocyte injury and dysfunction are the focus of this review. In addition, the role played by Wnt signaling in mediating the effects of known therapeutic strategies for diabetic nephropathy is also discussed.

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Diabetic nephropathy (DN) is currently well established as the most common cause of end-stage renal disease in most parts of the world. Notwithstanding the expanding basic and clinical research in this field, the pathogenesis remains far from clear and hence the treatment of DN remains suboptimal. There is a critical need for the development of newer therapeutic strategies including alternative and complementary therapies. One of the natural products that was extensively studied in cancer and other chronic disease states such as diabetes is curcumin, an active ingredient in turmeric, a spice extensively used in India. In this manuscript, we present a critical review of the experimental and clinical evidence that supports the use of curcumin and its analogs in DN as well as the various proposed mechanisms for its biological actions in health and disease states.

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Synthetic cannabinoids (SCB) are a family of chemicals that bind to cannabinoid receptors and cause psychoactive effects. Over the past few years, they have been increasingly used for recreational purposes, especially by young adults, and have been reported to have many adverse effects. Acute kidney injury (AKI) has been recently reported; the pathophysiology of SCB-induced AKI is unknown. We report three cases of AKI in the setting of SCB use. The peak serum creatinine levels ranged from 3.0 to 5.7 mg/dL; one patient required hemodialysis. SCB can induce AKI.

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BACKGROUND: One third of patients hospitalized for acute decompensated heart failure (ADHF) develop a worsening renal function (WRF) that is associated with increased in-hospital morbidity and mortality. However, previous investigations have not evaluated the various etiologies of WRF and its impact on prognosis. METHODS: A retrospective chart review was performed of patients admitted with ADHF who had a rise of serum creatinine ≥ 0.3 mg/dl on admission or during their hospital stay. The chart notes were reviewed for the suggested etiology of WRF. Cases were defined as ADHF associated WRF (ADHF-WRF) when there was no other explanation for WRF, plus an objective evidence of hypervolemia. Cases with WRF after 48 hours of a negative fluid balance were classified as diuresis-associated WRF (DA-WRF). RESULTS: ICD-9 codes identified 319 admissions with ADHF complicated with WRF. Fifty admissions were excluded. The most common causes of WRF were ADHF-WRF (43.1%) and DA-WRF (42.8%). Other causes included nephrotoxins (5.9%) and surgery (3.7%). The mortality rate was significantly lower with DA-WRF compared to ADHF-WRF; odds ratio 0.059 (95% CI 0.007 to 0.45, P = 0.006). Readmission at 30 days was higher in cases with ADHF-WRF (42%). CONCLUSIONS: WRF with ADHF is a heterogeneous group, and cases with ADHF-WRF had a higher in-hospital mortality and readmission rates.

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics. Although rare, clinicians need to keep in mind that their use may precipitate hyponatremia and syndrome of inappropriate antidiuretic hormone (SIADH), especially in high-risk patients with multiple comorbidities. In the kidneys, prostaglandins attenuate the water retention effect of antidiuretic hormone. NSAIDs cause a decrease in prostaglandins in the kidney and therefore the effect of ADH is potentiated. We report a case of SIADH that was associated with keterolac in a 65-year-old male. SIADH has not previously been reported with keterolac, a strong NSAID with comparable analgesic effect as morphine and meperidine. Keterolac may have unique properties different from other NSAIDS which may predispose to the development of hyponatremia. In our case, prolonged use of keterolac may have contributed to the development of SIADH and caution is needed when keterolac is used for prolonged duration. A review of the literature regarding development of SIADH and hyponatremia in the setting of NSAIDs is also presented.

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Several large-scale clinical studies have consistently demonstrated that use of inhibitors of renin-angiotensin system such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers was associated with significant reduction of new-onset diabetes in patients with insulin resistance such as primary hypertension. Such observations stimulated major investigations into the interaction of angiotensin and insulin signaling systems, which in turn led to the discovery of a cross talk at several steps between the 2 pathways. Evidence from these clinical trials and from the experimental models of insulin resistance including our findings in ZSF rat and other animal models will be discussed in this review.

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Translation of scientific discoveries into meaningful human applications, particularly novel therapies of human diseases, requires development of suitable animal models. Experimental approaches to test new drugs in preclinical phases often necessitated animal models that not only replicate human disease in etiopathogenesis and pathobiology but also biomarkers development and toxicity prediction. Whereas the transgenic and knockout techniques have revolutionized manipulation of rodents and other species to get greater insights into human disease pathogenesis, we are far from generating ideal animal models of most human disease states. The challenges in using the currently available animal models for translational research, particularly for developing potentially new drugs for human disease, coupled with the difficulties in toxicity prediction have led some researchers to develop a scoring system for translatability. These aspects and the challenges in selecting an animal model among those that are available to study human disease pathobiology and drug development are the topics covered in this detailed review.

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Renal glycosuria is defined as the excretion of glucose in urine in a normoglycemic state. It results from renal tubular dysfunction or immaturity of tubular function in the newborn. Etiologically, renal glycosuria is of 3 types-benign renal glycosuria, glycosuria with diabetes mellitus (including gestational diabetes) and tubular defects (Fanconi syndrome). Prognosis of benign renal glycosuria is excellent and reversible. Acute interstitial nephritis (AIN) is one of the main causes of acute renal failure and may often result in tubular dysfunction. In this study, the authors report the occurrence of AIN with acute renal failure that contributed to reversible renal glycosuria. The glycosuria observed in the patient of this study was an isolated tubular defect, with no phosphaturia, aminoaciduria or bicarbonaturia. Such a presentation is very rare in adults and has not been previously reported. These findings confirm that AIN with acute renal failure can cause an isolated tubular defect with benign reversible glycosuria in an adult.

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This report is based on the Federation of American Societies for Experimental Biology's symposium, "Engaging basic Scientists in Translational Research: Identifying Opportunities, Overcoming Obstacles," held in Chevy Chase, MD, March 24-25, 2011. Meeting participants examined the benefits of engaging basic scientists in translational research, the challenges to their participation in translational research, and the roles that research institutions, funding organizations, professional societies, and scientific publishers can play to address these challenges.

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The pathogenesis of diabetic nephropathy remains far from clear, partly due to the lack of a suitable animal model that mimics human renal disease in type 2 diabetes. In this study, the natural history of renal manifestations in ZSF1 rats, a recently developed rodent model of type 2 diabetes, is described. Male ZSF1 rats developed obesity and hyperglycemia by 20 weeks of age on a high-carbohydrate diet. They also developed systolic and diastolic hypertension, hypercholesterolemia, profound hypertriglyceridemia, proteinuria, and renal failure. Renal histology demonstrated changes consistent with early diabetic nephropathy, including arteriolar thickening, tubular dilation and atrophy, glomerular basement membrane thickening, and mesangial expansion. Furthermore, renal nitric oxide production was decreased, and homogenates from renal cortices demonstrated reduced expression of renal endothelial and inducible nitric oxide synthases. These changes were associated with increased urinary levels and renal expression of 8-hydroxydeoxyguanosine, an indicator of mitochondrial oxidative stress, as well as with increased renal peroxynitrite formation. Administration of either insulin or the antioxidant alpha-lipoic acid decreased proteinuria and oxidative stress, but only the former slowed progression of renal failure. We conclude that ZSF1 rats represent the best available rat model to study nephropathy from type 2 diabetes and that the renal lesions are associated with increased oxidative stress and decreased renal nitric oxide availability.

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Although several factors may mediate the development and progression of diabetic nephropathy, hyperlipidemia is now considered an independent and major determinant of progression of renal disease in diabetes. The following discussion focuses on the experimental evidence that incriminates hyperlipidemia as a pathogenic factor for diabetic nephropathy and the potential mechanisms that may mediate renal injury from hyperlipidemia, as well as the clinical studies involving therapeutic interventions for hyperlipidemia and their impact on progression of diabetic renal disease.

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Exhaled nitric oxide has been used as a means of indirectly measuring the underlying inflammation in asthma. The objectives of the study were to measure exhaled nitric oxide levels in asthma patients and healthy volunteers, to study peripheral blood lymphocyte cytokine expression, and to study the relationship between exhaled nitric oxide and intracellular cytokine expression. Exhaled nitric oxide was elevated in patients with moderate to severe asthma and with treatment decreased in the first week reaching to a near normal level by 4 weeks. Elevated exhaled nitric oxide was associated with decreased IL-4 and IL-13 cytokine expression by CD8 lymphocytes.

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Tested was the hypothesis that enhanced nitric oxide (NO) production that is stimulated by increased renal endothelin activity mediates decreased distal nephron HCO(3) secretion that is induced by dietary protein. Munich-Wistar rats that ate minimum electrolyte diets with 50% casein-provided protein (HiPro) compared with controls that ate 20% protein for 3 wk had higher urine excretion of endothelin-1 (80 +/- 15.7 versus 29 +/- 3.9 fmol/kg body wt per d; P < 0.02) and of the NO metabolites NO(2)/NO(3) (21.2 +/- 1.9 versus 14.9 +/- 0.8 mumol/kg body wt per d; P < 0.03). Bosentan, an endothelin A/B receptor antagonist, reduced HiPro rats' urine excretion of net acid (5859 +/- 654 versus 8017 +/- 1103 micromol/d; P < 0.03, paired t test) and NO(2)/NO(3) (18.1 +/- 1.1 versus 22.9 +/- 2.0 micromol/kg body wt per d; P < 0.05, paired t test). N-nitro-l-arginine methyl ester (L-NAME), an NO synthase inhibitor, also decreased urine net acid excretion (6621 +/- 717 versus 8449 +/- 1086 micromol/d; P < 0.05, paired t test) but was not additive to bosentan. L-NAME increased in situ late distal nephron HCO(3) delivery in HiPro rats (18.8 +/- 1.7 versus 9.6 +/- 1.4 pmol/mm per min; P < 0.001) that was mediated by increased distal nephron HCO(3) secretion (-7.2 +/- 0.7 versus -3.5 +/- 0.4 pmol/mm per min; P < 0.001) without changes in distal nephron transtubule HCO(3) permeability or H(+) secretion. Bosentan decreased H(+) secretion and increased HCO(3) secretion in the distal nephron of HiPro rats, but L-NAME had no additive effect on either component. The data support that dietary protein augments distal nephron acidification through decreased HCO(3) secretion that is mediated through endothelin-stimulated NO.

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Diabetic nephropathy is the most frequent cause of terminal renal failure, requiring renal replacement therapy. Although a number of factors may contribute to the development of renal disease in diabetes, the recent past has witnessed an explosive growth in literature pertaining to the role of nitric oxide in diabetic nephropathy. However, there are significant controversies in the findings of these studies partly because of the complex metabolic pathways involved in the generation and fate of nitric oxide in the diabetic kidney. The following discussion presents a critical and balanced review of the current understanding of this subject.

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BACKGROUND: Aging has considerable structural and functional effects on the vascular system of the kidney. One such effect is an alteration in vascular tone which potentially will initiate renal damage. Vascular tone is determined by the balance between vasoconstrictors and vasodilators. Therefore, we hypothesized that aging attenuates vasodilatory responses in the kidney. These changes may be mediated by a loss of nitric oxide and endothelial-derived hyperpolarizing factor (EDHF). METHODS: The systemic and renal responses of nitric oxide and EDHF were investigated in aging (18 months old) and young (3 months old) Sprague-Dawley rats. RESULTS: We demonstrated a general loss of vasodilatory responses in the aging kidney. In addition, nitric oxide levels were reduced in the serum and kidney cortex of aging versus young animals, although this was not accompanied with a loss of endothelial nitric oxide synthase (eNOS) protein in the kidney cortex. Aging animals also exhibited a loss in EDHF-mediated vasodilation following stimulation with either acetylcholine or bradykinin in the isolated perfused kidney. CONCLUSION: These findings indicate that not only a defect in the nitric oxide pathway, but also a loss of EDHF-mediated responses may be responsible for impaired vasodilation in the aging kidney. This may result in enhanced vasoconstrictive responses in aging which potentially will cause renal damage and ultimately a loss in glomerular filtration rate (GFR).

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BACKGROUND: Hyperuricemia has been linked to cardiovascular and renal diseases, possibly through the generation of reactive oxygen species (ROS) and subsequent endothelial dysfunction. The enzymatic effect of xanthine oxidase is the production of ROS and uric acid. Studies have shown that inhibiting xanthine oxidase with allopurinol can reverse endothelial dysfunction. Furthermore, rat studies have shown that hyperuricemia-induced hypertension and vascular disease is at least partially reversed by the supplementation of the nitric oxide synthase (NOS) substrate, L-arginine. Therefore, we hypothesized that uric acid induces endothelial dysfunction by inhibiting nitric oxide production. METHODS: Hyperuricemia was induced in male Sprague-Dawley rats with an uricase inhibitor, oxonic acid, by gavage; control rats received vehicle. Allopurinol was placed in drinking water to block hyperuricemia. Rats were randomly divided into four groups: (1) control, (2) allopurinol only, (3) oxonic acid only, and (4) oxonic acid + allopurinol. Rats were sacrificed at 1 and 7 days, and their serum analyzed for serum uric acid and nitrites/nitrates concentrations. The effect of uric acid on nitric oxide production was also determined in bovine aortic endothelial cells. RESULTS: Oxonic acid induced mild hyperuricemia at both 1 and 7 days (P < 0.05). Allopurinol reversed the hyperuricemia at 7 days (P < .001). Serum nitrites and nitrates (NO(X)) were reduced in hyperuricemic rats at both 1 and 7 days (P < .001). Allopurinol slightly reversed the decrease in NO(X) at 1 day and completely at 7 days (P < .001). There was a direct linear correlation between serum uric acid and NO(X) (R(2)= 0.56) and a trend toward higher systolic blood pressure in hyperuricemic rats (P= NS). Uric acid was also found to inhibit both basal and vascular endothelial growth factor (VEGF)-induced nitric oxide production in bovine aortic endothelial cells. CONCLUSION: Hyperuricemic rats have a decrease in serum nitric oxide which is reversed by lowering uric acid levels. Soluble uric acid also impairs nitric oxide generation in cultured endothelial cells. Thus, hyperuricemia induces endothelial dysfunction; this may provide insight into a pathogenic mechanism by which uric acid may induce hypertension and vascular disease.

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A growing body of evidence suggests that vasoactive factors produced in the kidney such as nitric oxide, endothelins, angiotensin, and prostaglandins participate actively in the regulation of acid-base homeostasis under physiologic conditions. In addition, recent reports indicate that alterations in the systemic acid-base status may also influence the generation of vasoactive cytokines in the kidney, which in turn may mediate the renal effector processes that tend to restore normality under such conditions. Metabolic acidosis, which so frequently accompanies many forms of chronic renal failure (CRF), may contribute to down-regulation of intrarenal nitric oxide production that characterizes CRF. Reduced extracellular pH inhibits inducible nitric oxide production in mesangial cells by altering the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidation, an important posttranslational mechanism in the inducible nitric oxide synthase (iNOS) activation. The underlying defects resulting in the uncoupling of NADPH oxidation in acidemic microenvironment are discussed. Acidosis stimulates renal production of endothelins, which mediate proximal tubular acidification by enhancing sodium-hydrogen exchanger-3 (NHE-3) activity. Renal endothelins mediate enhanced urinary acid excretion following dietary acid ingestion, an effect that is effectively blocked by endothelin receptor blockers. Reduced extracellular pH stimulates endothelin secretion from renal microvascular endothelial cells, which may promote enhanced acid excretion from the distal tubule under conditions of acidosis. These phenomena as well as the role of angiotensin and renal prostaglandins in mediating renal acidification in normal and acidotic conditions are discussed in this review, which describe the regulatory interaction between extracellular pH and renal vasoactive factors.

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Diabetic nephropathy is the leading cause of end-stage renal disease in the Western hemisphere. Endothelial dysfunction is the central pathophysiologic denominator for all cardiovascular complications of diabetes including nephropathy. Abnormalities of nitric oxide (NO) production modulate renal structure and function in diabetes but, despite the vast literature, major gaps exist in our understanding in this field because the published studies mostly are confusing and contradictory. In this review, we attempt to review the existing literature, discuss the controversies, and reach some general conclusions as to the role of NO production in the diabetic kidney. The complex metabolic milieu in diabetes triggers several pathophysiologic mechanisms that simultaneously stimulate and suppress NO production. The net effect on renal NO production depends on the mechanisms that prevail in a given stage of the disease. Based on the current evidence, it is reasonable to conclude that early nephropathy in diabetes is associated with increased intrarenal NO production mediated primarily by constitutively released NO (endothelial nitric oxide synthase [eNOS] and neuronal nitric oxide synthase [nNOS]). The enhanced NO production may contribute to hyperfiltration and microalbuminuria that characterizes early diabetic nephropathy. On the other hand, a majority of the studies indicate that advanced nephropathy leading to severe proteinuria, declining renal function, and hypertension is associated with a state of progressive NO deficiency. Several factors including hyperglycemia, advanced glycosylation end products, increased oxidant stress, as well as activation of protein kinase C and transforming growth factor (TGF)-beta contribute to decreased NO production and/or availability. These effects are mediated through multiple mechanisms such as glucose quenching, and inhibition and/or posttranslational modification of NOS activity of both endothelial and inducible isoforms. Finally, genetic polymorphisms of the NOS enzyme also may play a role in the NO abnormalities that contribute to the development and progression of diabetic nephropathy.

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BACKGROUND: Since chronic renal failure is associated with metabolic acidosis and down-regulation of intrarenal nitric oxide (NO) synthesis, I tested the hypothesis that acidosis may impair the intrarenal NO synthesis. The effects of alterations in extracellular pH were examined on inducible NO synthesis in murine mesangial cells (MMC) in culture. METHODS: NO synthesis was induced in MMC by bacterial lipopolysaccharide and tumor necrosis factor-alpha and assayed by an NO analyzer that measured nitrites and nitrates (NOx). The activity of inducible NO synthase (iNOS) enzyme was assayed by conversion of [3H]-arginine to [3H]-citrulline. Experimental groups included cells cultured with a pH of 7.3 (normal), or 7.0 (low) or 7.6 (high), and the assigned pH values were maintained by HEPES and Tris. RESULTS: NOx was decreased in MMC exposed to the reduced pH compared to other groups. [3H]-citrulline assay showed an 80% reduction in iNOS activity in stimulated MMC exposed to a reduced pH versus control pH (P < 0.01). iNOS mRNA and protein expression were similar in control and low pH cells. The iNOS inhibition was not reversed by supplementation of MMC with either l-arginine or tetrahydrobiopterin, a major co-factor for NOS enzyme. MMC re-incubated in control pH after being exposed to the low pH demonstrated re-inducibility of NOS activity. Furthermore, MMC exposed to low pH were associated with a higher NADP+/+[H]-citrulline ratio (3.2) compared to standard pH (1.7), indicating an increase in NADP+/+[H]-citrulline stoichiometries and uncoupling of nicotinamide adenine dinucleotide phosphate (NADPH) oxidation. In contrast, macrophages exposed to the reduced pH did not demonstrate uncoupling of NADPH oxidation. CONCLUSION: Acidosis impairs iNOS activity in MMC by a post-translational mechanism that involves uncoupling of NADPH oxidation.

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