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Seymour Rosen

Publications and source records attributed to Seymour Rosen.

At least 19 recordsLinked to original sources
PubMed2006

Immunohistochemical detection of hypoxia-inducible factor-1alpha in human renal allograft biopsies.

Although it generally is accepted that renal hypoxia may occur in various situations after renal transplantation, direct evidence for such hypoxia is lacking, and possible implications on graft pathophysiology remain obscure. Hypoxia-inducible factors (HIF) are regulated at the protein level by oxygen-dependent enzymes and, hence, allow for tissue hypoxia detection. With the use of high-amplification HIF-1alpha immunohistochemistry in renal biopsies, hypoxia is shown at specific time points after transplantation with clinicohistologic correlations. Immediately after engraftment, in primarily functioning grafts, abundant HIF-1alpha is present and correlates with cold ischemic time >15 h and/or graft age >50 yr (P < 0.04). In contrast, a low HIF-1alpha score correlates with primary nonfunction, likely reflecting loss of oxygen consumption for tubular transport. Protocol biopsies at 2 wk show widespread HIF-1alpha induction, irrespective of histology. Beyond 3 mo, both protocol biopsies and indicated biopsies are virtually void of HIF-1alpha, with the only exception being clinical/subclinical rejection. HIF-derived transcriptional adaptation to hypoxia may counterbalance, at least partly, the negative impact of cold preservation and warm reflow injury. Transient hypoxia at 2 wk may be induced by hyperfiltration, hypertrophy, calcineurin inhibitor-induced toxicity, or a combination of these. Lack of detectable HIF-1alpha at 3 mo and beyond suggests that at this time point, graft oxygen homeostasis occurs. The strong correlation between hypoxia and clinical/subclinical rejection in long-term grafts suggests that hypoxia is involved in such graft dysfunction, and HIF-1alpha immunohistochemistry could enhance the specific diagnosis of acute rejection.

Adult↗
PubMed2006

Urothelial mucosal malformation: a rare cause for ureteropelvic junction obstruction.

Ureteropelvic junction obstruction (UPJO) constitutes a significant cause of morbidity in children and exists in a wide range of severity and clinical manifestations. The cause of UPJO remains largely unknown except for a small group, in which crossing vessels have been considered etiological. Herein we describe a unique case in which intraluminal occlusion was the result of mucosal malformation, characterized by invaginated and branching urothelial epithelium present in the lamina propria. We believe that the present case is the first such description of this type of alteration.

Adult↗
PubMed2006

Current understanding of HIF in renal disease.

Hypoxia-inducible factors (HIF) are ubiquitous transcription factors regulated by oxygen-dependent proteolysis, and hence rapidly mount an adaptational response to hypoxia. The HIF system is apparently more complex than initially considered in the perspective of the increasing number of HIF target genes, and the inter-relationship with various additional regulatory pathways. Regional hypoxia is believed to play a major role in renal disease. Experimental data confirm a role for HIF in renal pathophysiology. The discovery of HIF prolyl-hydroxylases as key enzymes of oxygen sensing and HIF proteolysis offer new possibilities to therapeutically target HIF. Herein, we review basic concepts of HIF regulation, and existing data on HIF activation in renal disease.

Animals↗
PubMed2006

Acute-on-chronic renal failure in the rat: functional compensation and hypoxia tolerance.

BACKGROUND: We hypothesized that chronic renal parenchymal disease may predispose to acute renal failure (ARF), facilitating the induction of hypoxic medullary tubular injury. METHODS: To induce chronic renal parenchymal injury, rats underwent sham operation (control) or bilateral 50-min clamping of the renal artery [ischemia-reperfusion (IR)]. One or 3 months later, both groups were subjected to an ARF protocol, consisting of radiocontrast and the inhibition of prostaglandin and nitric oxide synthesis. Renal function and morphology were determined 24 h later. RESULTS: Chronic tubulointerstitial changes (fibrosis, atrophy and hypertrophy) in the IR group correlated with baseline tubular function, but glomerular function was preserved. Functional deterioration after the ARF protocol was only marginally more pronounced in the IR group, and the degree of medullary acute tubular necrosis (ATN) was unaffected by prior IR. The extent of both tubular necrosis and chronic tubulointerstitial changes independently predicted the acute decline in renal function. Immunostaining of IR kidneys disclosed critically low medullary pO2 (determined by pimonidazole adducts), regional hypoxic cell response (hypoxia-inducible factors) and upregulation of endothelin-B receptors. CONCLUSIONS: Compensatory changes result in normal plasma creatinine 1 and 3 months after IR, despite diminished tubular function. Preexisting renal disease only marginally predisposes to ARF, and the extent of ATN is not significantly enhanced. These findings illustrate the complex interaction between chronic and acute renal injury and dysfunction and parallel the difficulty of their assessment in the clinical practice. Adaptive cellular responses to chronic hypoxia in conjunction with parenchymal loss and decreased oxygen demand might alleviate acute hypoxic injury.

Acute Kidney Injury↗
PubMed2006

A role for erythropoietin in the attenuation of radiocontrast-induced acute renal failure in rats.

BACKGROUND: Radiocontrast-induced nephropathy (CIN) remains an important iatrogenic cause of acute renal failure in high-risk patients, despite the development of safer contrast media, the improvement of hydration protocols, and the introduction of additional preventive strategies. Erythropoietin (EPO) pretreatment may confer protection against acute renal failure through the induction of stress response genes. METHODS: The effect of EPO has been evaluated in a rat model of CIN, induced by iothalamate, following the inhibition of nitric oxide- and prostaglandin-synthesis with indomethacin and N(omega) nitro-L-arginine methyl ester (L-NAME). Twenty-two male Sprague-Dawley rats were subjected to saline (CTR) or EPO injections (3000 U/kg and 600 U/kg, 24 and 2 h before the induction of CIN, respectively). RESULTS: The decline in creatinine clearance in CTR animals from 0.38 +/- 0.03 to 0.28 +/- 0.03 mL/min/100 g (p < 0.005), was prevented by EPO pretreatment (from 0.34 +/- 0.02 to 0.32 +/- 0.03 mL/min/100 g, NS). The extent of medullary thick ascending limb- and S3-tubular damage in the outer medulla, however, was comparable in the two experimental groups. CONCLUSIONS: EPO pretreatment prevents renal dysfunction in a rat model of CIN. Further experimental and clinical studies are required to confirm these preliminary conclusions regarding a potential protective potency of EPO against CIN.

Acute Kidney Injury↗
PubMed2006

Renal parenchymal oxygenation and hypoxia adaptation in acute kidney injury.

The pathogenesis of acute kidney injury (AKI), formally termed acute tubular necrosis, is complex and, phenotypically, may range from functional dysregulation without overt morphological features to literal tubular destruction. Hypoxia results from imbalanced oxygen supply and consumption. Increasing evidence supports the view that regional renal hypoxia occurs in AKI irrespective of the underlying condition, even under circumstances basically believed to reflect 'direct' tubulotoxicity. However, at present, it is remains unclear whether hypoxia per se or, rather, re-oxygenation (possibly through reactive oxygen species) causes AKI. Data regarding renal hypoxia in the clinical situation of AKI are lacking and our current concepts regarding renal oxygenation during acute renal failure are presumptive and largely derived from experimental studies. There is robust experimental evidence that AKI is often associated with altered intrarenal microcirculation and oxygenation. Furthermore, renal parenchymal oxygen deprivation seems to participate in the pathogenesis of experimental AKI, induced by exogenous nephrotoxins (such as contrast media, non-steroidal anti-inflammatory drugs or amphotericin), sepsis, pigment and obstructive nephropathies. Sub-lethal cellular hypoxia engenders adaptational responses through hypoxia-inducible factors (HIF). Forthcoming technologies to modulate the HIF system form a novel potential therapeutic approach for AKI.

Adaptation, Physiological↗
PubMed2005

ApoSense: a novel technology for functional molecular imaging of cell death in models of acute renal tubular necrosis.

PURPOSE: Acute renal tubular necrosis (ATN), a common cause of acute renal failure, is a dynamic, rapidly evolving clinical condition associated with apoptotic and necrotic tubular cell death. Its early identification is critical, but current detection methods relying upon clinical assessment, such as kidney biopsy and functional assays, are insufficient. We have developed a family of small molecule compounds, ApoSense, that is capable, upon systemic administration, of selectively targeting and accumulating within apoptotic/necrotic cells and is suitable for attachment of different markers for clinical imaging. The purpose of this study was to test the applicability of these molecules as a diagnostic imaging agent for the detection of renal tubular cell injury following renal ischemia. METHODS: Using both fluorescent and radiolabeled derivatives of one of the ApoSense compounds, didansyl cystine, we evaluated cell death in three experimental, clinically relevant animal models of ATN: renal ischemia/reperfusion, radiocontrast-induced distal tubular necrosis, and cecal ligature and perforation-induced sepsis. RESULTS: ApoSense showed high sensitivity and specificity in targeting injured renal tubular epithelial cells in vivo in all three models used. Uptake of ApoSense in the ischemic kidney was higher than in the non-ischemic one, and the specificity of ApoSense targeting was demonstrated by its localization to regions of apoptotic/necrotic cell death, detected morphologically and by TUNEL staining. CONCLUSION: ApoSense technology should have significant clinical utility for real-time, noninvasive detection of renal parenchymal damage of various types and evaluation of its distribution and magnitude; it may facilitate the assessment of efficacy of therapeutic interventions in a broad spectrum of disease states.

Acute Disease↗
PubMed2005

Effect of nicotine on the renal microcirculation in anesthetized rats: a potential for medullary hypoxic injury?

BACKGROUND: Cigarette smoking has been associated with accelerated renal dysfunction among patients with chronic renal disease. Conceivably, repeated parenchymal hypoxic injury, induced by nicotine-related vasomotor changes, might contribute to the progression of renal failure in smokers. METHODS: Renal blood flow and selective cortical and outer medullary blood flows were determined in anesthetized rats. Changes in total renal, cortical and medullary vascular resistance were calculated. Nicotine was repeatedly infused at rising doses (50-200 microg/kg) to intact (CTR) animals and to rats chronically administered with nicotine in their drinking water (NIC). In a complementary study, nicotine-treated and control rats were subjected to medullary hypoxic stress, induced by radiocontrast and indomethacin. RESULTS: Chronic nicotine exposure led to lower baseline renal blood flow and creatinine clearance. Nicotine infusion induced a transient dose-dependent rise in blood pressure, renal blood flow and cortical flow, with a corresponding decline in renal vascular resistance and cortical resistance in both experimental groups. However, while medullary flow increased in CTR by up to 16 +/- 6%, it remained unchanged or even somewhat declined in the NIC group. Calculated medullary resistance reciprocally declined in CTR while it rose in the NIC group (p < 0.001). In animals subjected to radiocontrast and indomethacin, nicotine intensified renal dysfunction, associated with focal medullary hypoxic damage. CONCLUSIONS: Chronic exposure to nicotine selectively compromises the outer medullary microcirculation, blunting a local vasodilatory response to acute nicotine administration. Repeated acute-on-chronic exposure to nicotine may predispose to hypoxic medullary injury.

Acute Kidney Injury↗
PubMed2005

Regional alterations in renal haemodynamics and oxygenation: a role in contrast medium-induced nephropathy.

Although the nature of renal dysfunction following the use of iodinated radiological contrast agents has long been a matter of dispute, tubular hypoxic injury does play a central role as indicated by both clinical observations and experimental animal models. Indeed, radiocontrast agents induce renal parenchymal hypoxic stress resulting from a critically low ambient pO2 that develops particularly in the renal medulla. This medullary oxygen insufficiency is a reflection of both increased oxygen consumption for solute reabsorption and a reduction of regional inner medullary blood flow. Cellular adaptation to hypoxia is mediated by hypoxia-induced transcription factors (HIFs), which are regulated by oxygen-dependent proteolysis. HIF action confers cell protection through a wide array of target genes, thus restricting tubular epithelial damage. Most clinical risk factors for contrast nephropathy are characterized by predisposition to medullary oxygen insufficiency (such as altered nitric oxide or prostaglandin synthesis, both vital in maintaining medullary oxygenation), by co-existing vasoconstrictive stimuli, by enhanced transport workload or by structurally altered microcirculation. Under such predisposing conditions, regional hypoxic stress may intensify and surpass the capacity for the generation of adaptive responses, evolving into apoptotic or necrotic tubular cell death, associated with renal dysfunction. Amelioration of medullary hypoxic stress should be taken into account when designing strategies to prevent or attenuate contrast media-induced nephropathy.

Animals↗
PubMed2005

Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia.

BACKGROUND: Medullary hypoxia is believed to play an important role in the pathogenesis of acute renal failure (ARF). Hypoxia-inducible transcription factors (HIF) are recognized as master regulators of hypoxic adaptation, but little is known about their role in renal disease. METHODS: A multi-insult rat model of ARF combining the application of contrast medium with nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition was used to study chronology and distribution of the oxygen regulated HIF isoforms HIF-1alpha and HIF-2alpha in comparison with the hypoxia-marker pimonidazole between 10 minutes and 48 hours after injury induction. Treatment with furosemide was used to study HIF expression under conditions of ameliorated tissue injury. RESULTS: Contrast medium in combination with NOS and COX inhibition resulted in widespread induction of HIF in the outer and inner medulla that was initiated within 10 minutes, reached the highest levels at 2 hours and diminished 8 hours to 24 hours thereafter. HIF isoforms were expressed in a cell type-specific fashion: HIF-1alpha in tubular and HIF-2alpha in interstitial and endothelial cells. The degree of HIF-1alpha accumulation varied between nephron segments, being much stronger in collecting ducts than in medullary thick ascending limb of the loop of Henle (mTAL). Comparison with pimonidazole staining and the effect of furosemide indicated that HIF induction in mTAL is maximal with moderate hypoxia and declines with increasing severity of hypoxia. CONCLUSION: A complex pattern of HIF activation appears to play an important role in tissue preservation as a response to regional renal hypoxia. The limited capacity of mTAL cells for HIF activation may explain their susceptibility to injury.

Acute Kidney Injury↗
PubMed2004

The fibrinolytic system attenuates vascular tone: effects of tissue plasminogen activator (tPA) and aminocaproic acid on renal microcirculation.

1. The renal medulla is a major source of plasminogen activators (PA), recently shown to induce vasodilation in vitro. Treatment with PA inhibitors has been associated with renal dysfunction, suggesting compromised renal microvasculature. We investigated the impact of the PA inhibitor epsilon amino-caproic acid (EACA) upon vascular tone in vitro, and studied the effect of both tPA and EACA upon intrarenal hemodynamics in vivo. 2. In vitro experiments were carried out in isolated aortic rings and with cultured vascular smooth muscle cells. Studies of renal microcirculation and morphology were conducted in anesthetized Sprague-Dawley rats. 3. In isolated aortic rings, EACA (but not the other inhibitors of the fibrinolytic system PAI-1 or alpha-2 antiplasmin) reduced the half-maximal effective concentration of phenylephrine (PE) required to induce contraction (from 32 nm in control solution to 2 and 0.1 nm at EACA concentrations of 1 and 10 microm, respectively). Using reteplase (retavase) in the same model, we also provide evidence that the vasoactivity of tPA is in part kringle-dependent. In cultured vascular smooth muscle cells, Ca(2+) internalization following PE was enhanced by EACA, and retarded by tPA. 4. In anesthetized rats, EACA (150 mg x kg(-1)) did not affect systemic blood pressure, total renal or cortical blood flow. However, the outer medullary blood flow declined 12+/-2% below the baseline (P<0.03). By contrast, tPA (2 mg x kg(-1)), transiently increased outer medullary blood flow by 8+/-5% (P<0.02). Fibrin microthrombi were not found within the renal microvasculature in EACA-treated animals. 5. In conclusion, both fibrinolytic and antifibrinolytic agents modulate medullary renal blood flow with reciprocal effects of vasodilation (PA) and vasoconstriction (EACA). In vitro studies suggest that these hemodynamic responses are related to direct modulation of the vascular tone.

Aminocaproic Acid↗
PubMed2003

Extended prostate needle biopsy improves concordance of Gleason grading between prostate needle biopsy and radical prostatectomy.

PURPOSE: We examined the concordance of Gleason scores in prostate needle biopsy specimens and the corresponding radical retropubic prostatectomy specimens in a cohort of patients grouped according to the number of cores obtained during diagnostic needle biopsy. MATERIALS AND METHODS: We reviewed clinical and pathological data on a cohort of 466 men diagnosed with localized prostate cancer by needle biopsies who underwent radical retropubic prostatectomy between January 1, 1990 and July 31, 2001. Two study groups were identified, including 126 patients diagnosed with prostate cancer by extended needle biopsies (10 or more cores) and 340 diagnosed with cancer by nonextended needle biopsies (9 or fewer cores). Mean age was 60 years and median prostate specific antigen was 5.8 ng./ml. The median number of cores in the extended and nonextended biopsy groups was 12 and 6, respectively. The concordance of Gleason score in the needle biopsy and prostatectomy specimens was compared and correlated with the number of cores on needle biopsy. RESULTS: In the whole cohort 311 patients (67%) had identical Gleason scores on the needle biopsy and prostatectomy specimens, while 53 (11%) were over graded and 102 (22%) were under graded on needle biopsy. In patients who underwent extended needle biopsies the accuracy rate for Gleason scoring was 76% with 10% over and 14% under graded. The highest accuracy rates were in patients with 13, 14 and 16 cores (89%, 87% and 100%, respectively). No patients in the extended needle biopsy group had a discrepancy of more than 2 Gleason units in grade in the biopsy and surgical specimens. In those who underwent nonextended needle biopsies the accuracy rate for Gleason scoring was 63% with 12% over and 25% under graded. There were significantly different rates of accuracy (p = 0.008) and under grading (p = 0.01) in the 2 needle biopsy groups. Patients with a needle biopsy Gleason score of less than 7 had significantly higher concordance with the prostatectomy Gleason score when extended biopsies were done compared with nonextended biopsies (p = 0.001). CONCLUSIONS: Prostate cancer grading by extended needle biopsy is a better predictor of the final Gleason score than nonextended needle biopsy, as determined by radical prostatectomy histological evaluation. Therefore, extended prostate needle biopsy provides better guidance to determine the appropriate treatment in patients with prostate cancer.

Biopsy, Needle↗
PubMed2003

Dye-induced nephropathy.

The expanding use of imaging and interventional studies with iodinated radiologic contrast agents underscores the potential risk for dye nephropathy. Currently, dye-induced nephropathy is one of the leading causes of iatrogenic acute kidney failure, accounting for about 10% of renal failure in intensive care units. In this review, the pathophysiology of radiocontrast nephropathy is discussed, with a special emphasis on the importance of medullary hypoxic damage. The risk factors and clinical course of dye nephropathy, as well as its prevention or potential therapeutic interventions, are discussed in this perspective.

Cell Hypoxia↗
PubMed2003

Effect of poly(ADP-ribose) polymerase inhibition on outer medullary hypoxic damage.

Poly(ADP-ribose) polymerase (PARP) activation after free-radical-induced DNA damage depletes cellular energy stores and participates in ischemia-reflow injury. We studied the potential protective effect of the water-soluble PARP inhibitor 3-aminobenzamide (3-AB) in a rat model of acute renal failure (ARF) from combined administration of radiocontrast, indomethacin and N(omega)-nitro-L-arginine methyl ester. Kidney function at 24 h was better preserved in rats treated with 3-AB as compared to control animals. However, the extent of tubular hypoxic damage was not significantly mitigated. It is concluded that PARP inhibition may attenuate renal dysfunction in this model of ARF with medullary hypoxic tubular injury even while the extent of tubular necrosis is not significantly altered. Further studies of this dyssynchrony of structure and function may provide important insights into the sequence of events that promotes renal failure after medullary injury.

Acute Kidney Injury↗
PubMed2002

Association between prostate cancer and serum testosterone levels.

BACKGROUND: The purpose of the current study was to determine whether the presence of prostate cancer altered serum testosterone levels. METHODS: Initially, we evaluated both serum total and free testosterone levels in patients with either high-grade (n = 18) or moderate-grade (n = 146) prostate cancer, detected by prostate needle biopsies. Then both serum total and free testosterone levels, before and after prostatectomy, were compared in 79 of the 164 men with prostate cancer. RESULTS: In the first setting, serum total and free testosterone levels (307 +/- 24 ng/dl and 1.14 +/- 0.09 ng/dl) in patients with high-grade prostate cancer were significantly lower than those in patients with moderate-grade prostate cancer (452 +/- 12 ng/dl and 1.51 +/- 0.04 ng/dl) and those without prostate cancer (451 +/- 17 ng/dl and 1.55 +/- 0.06 ng/dl). After prostatectomy in 79 patients with prostate cancer, serum levels of both total and free testosterone (511 +/- 15 ng/dl and 1.78 +/- 0.05 ng/dl) were found significantly elevated when compared with their respective presurgical total and free testosterone levels (450 +/- 17 ng/dl and 1.60 +/- 0.06 ng/dl). CONCLUSION: Our findings show that serum total and free testosterone levels in patients with prostate cancer are altered, supporting the possibility that prostate cancer may inhibit serum testosterone levels.

Adult↗
PubMed2002

Proximal tubular injury attenuates outer medullary hypoxic damage: studies in perfused rat kidneys.

The straight segment (S3) of the proximal tubule is predominantly damaged during renal ischemia-reflow, whereas medullary thick ascending limbs (mTALs) are principally affected in other models of hypoxic acute tubular necrosis (ATN). Since the latter injury pattern largely depends on the extent of reabsorptive activity during hypoxic stress, we hypothesized that proximal tubular damage might attenuate downstream mTAL injury by means of diminished distal solute delivery for reabsorption. In isolated rat kidneys perfused for 90 min with oxygenated Krebs-Henseleit solution, mTAL necrosis developed in 75 +/- 3% of tubules in the mid-inner stripe of the outer medulla. By contrast, S3 segments in the outer stripe were minimally affected, with tubular fragmentation involving some 5 +/- 2% of tubules. In kidneys subjected in vivo to proximal tubular injury and subsequently used for isolated perfusion studies, the injury pattern was inverted: following 20 and 30 min ischemia and reflow for 24 h, S3 fragmentation rose to 18 +/- 16% and 72 +/- 13%, while mTAL damage was reduced to 33 +/- 10 and 24 +/- 8%, respectively. In kidneys subjected in vivo to D-serine S3 necrosis rose to 100%, while mTAL damage fell to 1 +/- 1% (p < 0.001). Substantial S3 tubular collapse (involving approximately 30% of tubules) and inner stripe interstitial hemorrhage were also noted, exclusively in kidneys subjected to ischemia-reflow. Proximal tubular necrosis alone or in combination with collapse inversely correlated with mTAL necrosis (R = -0.51 and -0.72, respectively, p < 0.003). This cogent inverse association might imply that disruption of the proximal nephron attenuates downstream mTAL necrosis by a reduction of distal tubular reabsorptive workload.

Animals↗