Resveratrol improved kidney function and structure in malignantly hypertensive rats by restoration of antioxidant capacity and nitric oxide bioavailability.

BACKGROUND: The main cause of death among patients with malignant hypertension is a kidney failure. The promising field in essential and malignant hypertension therapy could be centered on the amelioration of oxidative stress using antioxidant molecules like resveratrol. Resveratrol is a potent antioxidative agent naturally occurred in many plants that possess health-promoting properties. METHODS: In the present study, we investigated the therapeutic potential of resveratrol, a polyphenol with anti-oxidative activity, in NG-L-Arginine Methyl Ester (L-NAME) treated spontaneously hypertensive rats (SHR) - malignantly hypertensive rats (MHR). RESULTS: Resveratrol significantly improves oxidative damages by modulation of antioxidant enzymes and suppression of prooxidant factors in the kidney tissue of MHR. Enhanced antioxidant defense in the kidney improves renal function and ameliorates the morphological changes in this target organ. Besides, protective properties of resveratrol are followed by the restoration of the nitrogen oxide (NO) pathway. 4) Conclusion: Antioxidant therapy with resveratrol could represent promising therapeutical approach in hypertension, especially malignant, against kidney damage.

Resveratrol Protects Cardiac Tissue in Experimental Malignant Hypertension Due to Antioxidant, Anti-Inflammatory, and Anti-Apoptotic Properties.

Hypertension is one of the most prevalent and powerful contributors of cardiovascular diseases. Malignant hypertension is a relatively rare but extremely severe form of hypertension accompanied with heart, brain, and renal impairment. Resveratrol, a recently described grape-derived, polyphenolic antioxidant molecule, has been proposed as an effective agent in the prevention of cardiovascular diseases. This study was designed to examine chronic resveratrol administration on blood pressure, oxidative stress, and inflammation, with special emphasis on cardiac structure and function in two models of experimental hypertension. The experiments were performed in spontaneously (SHRs) and malignantly hypertensive rats (MHRs). The chronic administration of resveratrol significantly decreased blood pressure in both spontaneously and malignant hypertensive animals. The resveratrol treatment ameliorated morphological changes in the heart tissue. The immunohistochemistry of the heart tissue after resveratrol treatment showed that both TGF-ß and Bax were not present in the myocytes of SHRs and were present mainly in the myocytes of MHRs. Resveratrol suppressed lipid peroxidation and significantly improved oxidative status and release of NO. These results suggest that resveratrol prevents hypertrophic and apoptotic consequences induced by high blood pressure with more pronounced effects in malignant hypertension.

Scleroderma renal crisis.

Scleroderma renal crisis (SRC) is a rare but life-threatening complication of systemic sclerosis (SSc) characterized by malignant hypertension and acute kidney injury. Historically, SRC was the leading cause of death in SSc. However, with the advent of angiotensin converting enzyme (ACE) inhibitors, mortality rates have decreased significantly. Nevertheless, one-year outcomes remain poor, with over 30% mortality and 25% of patients remaining dialysis-dependent. There is an urgent need to improve early recognition and treatment, and to identify novel treatments to improve outcomes of SRC. In this chapter, the clinical features, classification, pathophysiology, differential diagnosis, management and outcomes of SRC are presented. Specific issues relating to pregnancy, prophylactic ACE inhibition and management of essential hypertension are also discussed.

Correlations Between Interleukin-11 Expression and Hypertensive Kidney Injury in a Rat Model of Renovascular Hypertension.

BACKGROUND: Interleukin-11 (IL-11) is a pleiotropic cytokine of the interleukin-6 family. Recent studies revealed its crucial role in the development of cardiovascular fibrosis. In this study we examined IL-11 expression levels in the heart and the kidney exposed to high blood pressure in renovascular hypertensive rats and their correlations to fibrotic markers and kidney injury. METHODS: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats. IL-11 expression was measured by real-time polymerase chain reaction in the left ventricle and the right kidney. The correlation of cardiac IL-11 expression with biomarkers of renal fibrosis was assessed. We further investigated IL-11 expression in 2K1C rats grouped into rats with malignant vs. nonmalignant hypertension (distinguishing criteria: weight loss, number of fibrinoid necrosis, and onion skin lesions). RESULTS: Thirty-five days after clipping, mean arterial pressure was significantly increased in 2K1C. Renal IL-11 expression was elevated in 2K1C. In the heart there was only a trend toward higher IL-11 expression in 2K1C. IL-11 in the kidney in 2K1C correlated with the expression of transforming growth factor (TGF)-ß1/2, collagens, fibronectin, osteopontin, as well as tissue inhibitors of metalloprotease 1/2. There were also correlations of IL-11 with tissue collagen expansion, number of activated fibroblasts and serum creatinine, but no correlation with mean arterial pressure. Renal expression of IL-11 was highest in rats with malignant hypertension. CONCLUSIONS: Renal IL-11 expression of renovascular hypertensive rats is markedly increased and correlates with profibrotic markers and loss of function and might therefore serve as a biomarker for the severity of hypertensive nephrosclerosis.

Optical coherence tomography angiography findings in malignant hypertensive retinopathy / Achados da angiografia por tomografia de coerência óptica na retinopatia hipertensiva maligna

ABSTRACT A 33-year-old male presented to our clinic with low vision in both eyes that started during the previous week. Visual acuity was 20/63 in the right eye and 20/50 in the left eye. Fundus examination revealed signs of hypertensive retinopathy; thus, a multidisciplinary approach was adopted for the diagnosis and treatment of this patient. We consulted the nephrology and cardiology departments on this case. Upon diagnosing malignant hypertension and renal failure, the patient was put on hemodialysis. His visual acuity was 20/20 at 6 months, whereas foveal assessment on optical coherence tomography angiography revealed neither marked superficial and deep capillary density loss and foveal avascular zone enlargement nor a decrease in disc flow and radial peripapillary capillary density. Early diagnosis and treatment of malignant hypertension are critical in preventing progression of end-organ damage including the eyes. Optical coherence tomography angiography may be useful in cases when fundus fluorescein angiography is relatively contraindicated (e.g., renal failure).

RESUMO Um homem de 33 anos apresentou-se à nossa clínica com baixa visão em ambos os olhos que começou uma semana antes. A acuidade visual foi de 20/63 no olho direito e 20/50 no olho esquerdo. O exame de fundo de olho revelou sinais de retinopatia hipertensiva; então, adotou-se uma abordagem multidisciplinar para o diagnóstico e tratamento desse paciente. Consultamos os departamentos de nefrologia e cardiologia neste caso. Ao diagnosticar hipertensão maligna e insuficiência renal, o paciente foi colocado em hemodiálise. Sua acuidade visual era 20/20 aos 6 meses, enquanto a avaliação foveal com angiotomografia de coerência óptica não revelou perda de densidade capilar superficial e profunda acentuada e aumento da zona avascular foveal nem uma diminuição no fluxo de disco e na densidade capilar peripapilar radial. O diagnóstico precoce e o tratamento da hipertensão maligna são fundamentais na preveção da progressão de danos nos órgãos-alvo, incluindo os olhos. A Angiografia por tomografia de coerência óptica pode ser útil nos casos em que a angiografia com fluoresceína do fundo de olho é relativamente contraindicada (por exemplo, insuficiência renal).

Optical coherence tomography angiography findings in malignant hypertensive retinopathy.

A 33-year-old male presented to our clinic with low vision in both eyes that started during the previous week. Visual acuity was 20/63 in the right eye and 20/50 in the left eye. Fundus examination revealed signs of hypertensive retinopathy; thus, a multidisciplinary approach was adopted for the diagnosis and treatment of this patient. We consulted the nephrology and cardiology departments on this case. Upon diagnosing malignant hypertension and renal failure, the patient was put on hemodialysis. His visual acuity was 20/20 at 6 months, whereas foveal assessment on optical coherence tomography angiography revealed neither marked superficial and deep capillary density loss and foveal avascular zone enlargement nor a decrease in disc flow and radial peripapillary capillary density. Early diagnosis and treatment of malignant hypertension are critical in preventing progression of end-organ damage including the eyes. Optical coherence tomography angiography may be useful in cases when fundus fluorescein angiography is relatively contraindicated (e.g., renal failure).

Thrombomodulin and Endothelial Dysfunction: A Disease-Modifier Shared between Malignant Hypertension and Atypical Hemolytic Uremic Syndrome.

Thrombomodulin (TM) is an endothelial glycoprotein that is present in all blood vessels. Five percent of all patients with atypical hemolytic uremic syndrome (aHUS) have mutations in the gene coding for TM, with a peak presentation in young children. Mutations often translate into quantitative and qualitative abnormalities of this endothelial glycoprotein. Outcome of the TM-associated aHUS is relatively poor with frequent relapses after transplantation despite its membrane-bound character. We observed a woman presenting with malignant hypertension (MHT) and associated kidney, brain, cardiac, and hematological involvement with thrombotic microangiopathy on kidney biopsy. She had a documented mutation of the gene coding for TM, which was associated with both aHUS and an increased risk for venous and arterial thrombosis. As TM has anti-coagulant, anti-inflammatory, and cytoprotective properties and also attenuates alternative complement activation, this glycoprotein could play an active role in other diseases with endothelial involvement apart from aHUS. We discuss the potential role of TM in the pathophysiology of various endotheliopathies including MHT. We also provide a framework for future therapeutic options.

The endothelium as the common denominator in malignant hypertension and thrombotic microangiopathy.

The endothelium plays a pivotal role in vascular biology. The endothelium is the primary site of injury in thrombotic microangiopathies including malignant hypertension. Endothelial injury in thrombotic microangiopathies is the result of increased shear stress, toxins, and/or dysregulated complement activation. Endothelial injury can lead to microvascular thrombosis resulting in ischemia and organ dysfunction, the clinical hallmarks of thrombotic microangiopathies. Currently, available therapies target the underlying mechanisms that lead to endothelial injury in these conditions. Ongoing investigations aim at identifying drugs that protect the endothelium.

[Malignant hypertension and cardiac decompensation after overuse of nasal decongestant: A case report and literature review]. / Hypertension artérielle maligne et décompensation cardiaque globale après consommation abusive de vasoconstricteur par voie nasale : à propos d'un cas et revue de la littérature.

INTRODUCTION: Vasoconstrictors, widely prescribed in the congestive states during acute rhinitis, are responsible for many cases of drug-related iatrogenic disease. CASE REPORT: We report the case of a 40-year-old man, who presented with an episode of malignant hypertensive crisis associated with life-threatening congestive heart decompensation. The patient interview revealed consumption to supra-therapeutic dosage of an association of naphazoline and prednisolone nasal sprays. The diagnostic work-up allowed to rule out disease-related causes of secondary hypertension. The drug-related disease was thus retained. CONCLUSION: The results of the literature review showed many cases of vasoconstrictor poisoning responsible for central nervous system and cardiovascular involvement, especially in young children. This first case of heart failure related to nasal decongestant administration increases the scope of potentially serious risks of these drugs and demonstrates the outreach needs for health professionals and patients about their proper use.

Malignant hypertension: new aspects of an old clinical entity.

Malignant hypertension (MHT), also known as accelerated-malignant hypertension or malignant-phase hypertension, is the most severe form of arterial hypertension. It is defined clinically as high blood pressure (BP) levels associated with lesions of the retinal fundus (flame-shaped hemorrhages, exudates, or cotton wool spots, with or without papilledema). Despite the availability of a vast range of antihypertensive agents, MHT continues to be a significant clinical challenge. Although its prevalence is very low, the absolute number of new cases has not changed over the past decades. While the role of the activation of the renin-angiotensin-aldosterone system and endothelial dysfunction in the pathogenesis of MHT has been well described, recent studies have indicated that the immune system may also play an important role in the development of this condition. Patients with MHT are characterized by pronounced target organ damage, including structural and functional cardiac abnormalities. MHT is frequently complicated by renal insufficiency and end-stage renal disease. The survival rates for patients with MHT have improved considerably with increased availability of antihypertensive treatment. However, renal insufficiency and end-stage renal disease still remain a significant cause of morbidity and mortality in this patient group. In conclusion, MHT is not a "vanishing disease" because there is a relatively stable number of new cases per year. Nonetheless, prognosis and survival rates in these patients have improved significantly owing to earlier detection, stricter BP control, lower BP targets, better choice of antihypertensive drugs, and availability of hemodialysis and renal transplantation.

Successful Treatment with an Antihypertensive Drug Regimen Including Eplerenone in a Patient with Malignant Phase Hypertension with Renal Failure.

A 28-year-old man was referred to our hospital for the treatment of congestive heart failure and severe hypertension. The patient was diagnosed with malignant phase hypertension based on the presence of marked hypertension with left ventricular hypertrophy, exudate retinopathy, and renal failure. Intensive therapy for hypertension and heart failure with a combination of antihypertensive drugs including nitroglycerin, nifedipine, eplerenone and candesartan successfully lowered his blood pressure and further improved the renal function. Eplerenone could be one of the choices of antihypertensive drugs in combination therapy in patients with malignant phase hypertension with progressive heart and renal failure.

Blood-retina-barrier disruption accompanying blood-brain-barrier dysfunction in posterior reversible encephalopathy syndrome.

Blood-brain-barrier dysfunction is well known to accompany hypertensive posterior reversible encephalopathy syndrome (PRES) and is considered as the culprit of vasogenic edema and cerebral hemorrhage observed as part of this syndrome. An 84-year-old female was admitted with a diagnosis of PRES in the setting of malignant hypertension. The clinical course was further complicated by ischemic stroke and seizures. Contrast enhanced fluid attenuated inversion recovery (FLAIR) studies revealed diffuse enhancement within the subarachnoid space extending to regions without evidence of cytotoxic or vasogenic edema. These findings suggestive of increased permeability were not only confined to the blood-brain-barrier, but also involved the blood-retina-barrier interface. Our observations suggest that pathologic conditions that disrupt the integrity of blood-brain-barrier might concomitantly affect retinal microcirculation, which highly resembles cerebral microcirculation both anatomically and functionally. Imaging modalities sensitive for detection of blood-brain-barrier dysfunction, such as contrast enhanced FLAIR, might be helpful in identifying these abnormalities.

Malignant hypertension and retinopathy in a western lowland gorilla (Gorilla gorilla gorilla).

BACKGROUND: A 34-year-old western lowland gorilla presented with peracute blindness. METHODS: Clinical evaluation, diagnostic imaging, laboratory analyses, blood pressure measurements, and necropsy were performed. RESULTS: The clinical and postmortem findings supported malignant hypertension. CONCLUSIONS: We describe a case of naturally occurring hypertensive encephalopathy and retinopathy in a gorilla.

Mesangial cells are responsible for orchestrating the renal podocytes injury in the context of malignant hypertension.

AIM: Two populations of renal cells fully possess functional contractile cell apparatus: mesangial cells and podocytes. Previous studies demonstrated that in the context of malignant hypertension overproduction of Angiotensin-II by the contracting mesangial cells aggravated hypercellularity and apoptosis of adjacent cell populations. The role of podocytes in pathogenesis of malignant hypertension is unclear. We investigated responsiveness of normal vs. hyperglycaemic podocytes to pressure in a model of malignant hypertension. METHODS: Rat renal podocytes and mesangial cells were subjected to high hydrostatic pressure, using an in vitro model of malignant hypertension. Part of them was pre-exposed to hyperglycaemic medium. Alternatively, the cells were cultured in conditioned medium collected from mesangial cells pre-exposed to pressure. RESULTS: Angiotensin-II was significantly increased in normoglycaemic mesangial cells subjected to pressure, triggering enhanced proliferation and apoptosis. No augmented Angiotensin-II, proliferation or apoptosis were evident in pressure-exposed normoglycaemic podocytes. In hyperglycaemic mesangial cells, but not podocytes, basal Angiotensin-II and apoptosis were augmented, along with abrogated proliferation. Challenge with exogenous Angiotensin-II or Angiotensin-II-containing conditioned medium, induced apoptosis both in podocytes and mesangial cells. CONCLUSIONS: 1. Unlike mesangial cells, podocytes do not respond to high pressure or hyperglycaemia per se. Resultantly, neither high pressure nor hyperglycaemia, trigger apoptosis of podocytes in vitro. However, surplus of Angiotensin-II, amply produced in vivo by the adjacent mesangial cells, would seem to be sufficient for initiating apoptosis of both mesangial cells and podocytes. 2. Hyperglycaemia abrogates cell replication. Resultantly, in diabetic patients regeneration of renal tissue damaged by the incidence of malignant hypertension may become compromised or completely lost.

Does obesity influence target organ damage and outcomes in patients with malignant phase hypertension? The West Birmingham Malignant Hypertension Project.

Several studies have suggested that hypertension has a stronger detrimental impact on cardiovascular outcome in lean than in obese persons, but neutral or opposite results have also been reported. We investigated the impact of baseline body mass index (BMI) at presentation with the most severe form of hypertension, that is, malignant phase hypertension (MPH) on the primary outcome of 'death or dialysis' in these patients. A total of 184 patients (overall mean (s.d.) age 48 (13) years; 61% male; 62% White-European; 20% African-Caribbean, 18% South-Asian) from the West Birmingham MPH Register were included. The patients were grouped according to their BMI (underweight, normal weight, overweight and obese groups). Ninety-three primary outcomes occurred during a median (interquartile range) follow-up of 10.7 (5.8-18.6) years. No significant baseline differences in age or ethnicity were seen between the study groups. Overweight and obese patients included a larger proportion of females, but less smokers than those underweight or of normal weight. There was no inter-group difference in retinopathy (P=0.25), proteinuria (P=0.08), haematuria (P=0.56) and left ventricular hypertrophy (P=0.14). In univariate analyses, BMI was predictive of death or dialysis (0.95 (0.90-1.00), P=0.046) but multivariate analyses showed that only baseline age (odds ratio (95% confidence intervals) 1.06 (1.03-1.09), P<0.001), smoking (2.89 (1.40-5.92), P=0.004), creatinine level (1.01 (1.01-1.02), P=0.001) and estimated glomerular filtration rates (0.99 (0.93-1.00), P=0.047) were independently associated with death or dialysis. BMI was not an independent predictor of adverse outcomes in MPH patients. Age, smoking status, creatinine levels and estimated glomerular filtration rates at diagnosis of MPH were independent predictors for death or dialysis in this high-risk population of hypertensive patients.

Hemolytic-uremic syndrome, malignant hypertension and IgA nephropathy: successful treatment with plasma exchange therapy.

A young patient with hemolytic-uremic syndrome and malignant hypertension with serious deterioration of renal function is described whose biopsy specimen showed additional IgA mesangial deposits. The patient responded to steroid treatment and to plasma exchange therapy without the need of hemodialysis sessions. In the following years, he achieved clinical remission and his blood pressure was in normal ranges without any further complications. IgA glomerulonephritis is rarely associated to hemolytic-uremic syndrome and malignant hypertension, with only a few previously described cases. We present an overview of potential pathophysiological connections between these diseases.

Imatinib ameliorates renal morphological changes in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension.

The present study was performed to assess the effects of the platelet-derived growth factor (PDGF) receptor kinase inhibitor imatinib mesylate on the renal morphological changes occurring during the development of malignant hypertension in transgenic rats with inducible expression of the Ren2 gene [TGR(Cyp1a1Ren2)]. Arterial blood pressure was measured by radiotelemetry in male Cyp1a1-Ren2 rats during control conditions and during dietary administration of indole-3-carbinol (I3C; 0.3%) for 14 days to induce malignant hypertension. Rats induced with I3C (n = 5) had higher mean arterial pressures (178 ± 4 vs. 109 ± 2 mmHg, P < 0.001) and increased urinary albumin excretion (Ualb; 13 ± 5 vs. 0.6 ± 0.2 mg/day) compared with noninduced rats (n = 5). Chronic administration of imatinib (60 mg·kg(-1)·day(-1) in drinking water, n = 5) did not alter the magnitude of the hypertension (176 ± 8 mmHg) but prevented the increase in Ualb (1.6 ± 0.3 mg/day). Quantitative analysis of proliferating cell nuclear antigen using immunohistochemistry demonstrated increased proliferating cell number in cortical tubules (38 ± 5 vs. 18 ± 1 cells/mm(2)) and cortical interstitium (40 ± 7 vs. 13 ± 6 cells/mm(2)) of hypertensive rat kidneys. Renal cortical fibrosis evaluated by picrosirius red staining showed increased collagen deposition in kidneys of the hypertensive rats (1.6 ± 0.1 vs. 0.4 ± 0.1% of cortical area). Imatinib attenuated the increase in proliferating cell number in cortical tubules and interstitium (22 ± 5 vs. 38 ± 5 and 22 ± 6 vs. 40 ± 7 cells/mm(2), respectively) and reduced the degree of collagen deposition (0.8 ± 0.2 vs. 1.6 ± 0.1%) in the kidneys of hypertensive rats. These findings demonstrate that the renal pathological changes that occur during the development of malignant hypertension in Cyp1a1-Ren2 rats involve activation of PDGF receptor kinase.

A rare case of malignant-phase hypertension with pulmonary alveolar hemorrhage.

Malignant-phase hypertension is characterized clinically by severe accelerating hypertension with neuroretinopathy or papilledema and by evidence of renal damage. A Japanese male in his early thirties presented with hemoptysis and general fatigue. He had a 5-year history of hypertension, but had not received any treatment. His blood pressure was 290/150 mmHg and his serum creatinine level was 8.24 mg/dL. Chest X-rays and computed tomography scans of the chest revealed a pulmonary alveolar hemorrhage. He was suspected of having vasculitis syndrome or Goodpasture's syndrome, but his renal biopsy specimen showed malignant nephrosclerosis. Myeloperoxidase antineutrophil cytoplasmic antibody (ANCA), proteinase-3 ANCA and antiglomerular basement membrane antibody were negative. He was treated with a calcium antagonist and a ß-blocker, followed by an angiotensin-converting enzyme inhibitor. After the administration of the ß-blocker, his blood pressure decreased and his renal function gradually improved. This is a rare case of malignant-phase hypertension with pulmonary alveolar hemorrhage; this condition should be considered in the differential diagnosis in order to avoid unnecessary treatment such as immunosuppressive therapy.