Therapeutic Potential of Extracellular Vesicles in Hypertension-Associated Kidney Disease.

Hypertension-mediated organ damage frequently includes renal function decline in which several mechanisms are involved. The present review outlines the state of the art on extracellular vesicles in hypertension and hypertension-related renal damage. Emerging evidence indicates that extracellular vesicles, small vesicles secreted by most cell types and body fluids, are involved in cell-to-cell communication and are key players mediating biological processes such as inflammation, endothelial dysfunction or fibrosis, mechanisms present the onset and progression of hypertension-associated kidney disease. We address the potential use of extracellular vesicles as markers of hypertension-mediated kidney damage severity and their application as therapeutic agents in hypertension-associated renal damage. The capacity of exosomes to deliver a wide variety of cargos to the target cell efficiently makes them a potential drug delivery system for treatment of renal diseases.

Daily Low-intensity Pulsed Ultrasound Ameliorates Renal Fibrosis and Inflammation in Experimental Hypertensive and Diabetic Nephropathy.

The estimated morbidity rate of chronic kidney disease is 8% to 16% worldwide, and many patients with chronic kidney disease eventually develop renal failure. Thus, the development of new therapeutic strategies for preventing renal failure is crucial. In this study, we assessed the effects of daily low-intensity pulsed ultrasound (LIPUS) therapy on experimental hypertensive nephropathy and diabetic nephropathy. Unilateral nephrectomy and subcutaneous infusion of angiotensin II via osmotic mini-pumps were used to induce hypertensive nephropathy in mice. Immunohistochemistry revealed that daily LIPUS treatment ameliorated renal fibrosis and infiltration of inflammatory cells induced by angiotensin II. A similar therapeutic effect was also observed in mice with angiotensin II-induced hypertensive nephropathy in which splenectomy was performed. In addition, LIPUS treatment significantly decreased systolic blood pressure after 21 days. Subsequently, db/db mice with unilateral nephrectomy developed proteinuria; daily LIPUS treatment significantly reduced proteinuria after 42 days. In addition, immunohistochemistry revealed that renal fibrosis was significantly ameliorated by LIPUS treatment. Finally, LIPUS stimulation suppressed TGF-ß1 (transforming growth factor-ß1)-induced phosphorylation of Smad2 and Smad3 in HK-2 (human proximal tubular cell line) cells. LIPUS treatment may be a useful therapy for preventing the progression of renal fibrosis in patients with chronic kidney disease.

Renovascular Hypertension.

Renovascular disease (RVD) is a major cause of secondary hypertension. Atherosclerotic renal artery stenosis is the most common type of RVD followed by fibromuscular dysplasia. It has long been recognized as the prototype of angiotensin-dependent hypertension. However, the mechanisms underlying the physiopathology of hypertensive occlusive vascular renal disease are complex and distinction between the different causes of RVD should be made. Recognition of these distinct types of RVD with different degrees of renal occlusive disease is important for management. The greatest challenge is to individualize and implement the best approach for each patient in the setting of widely different comorbidities.

Outcome of posterior urethral valve in 64 children: a single center's 22-year experience.

BACKGROUND: Posterior urethral valve (PUV) is the most serious form of congenital anomalies of kidney and urinary tract (CAKUT) in boys with significant risk of progression to chronic kidney disease (CKD). We present our long-term results in children with PUV. METHODS: Retrospective chart review of 113 children with PUV followed within the years of 1996-2018 was performed. Clinical, laboratory and epidemiologic parameters were analyzed for their impact on renal outcome. RESULTS: The median age of diagnosis was 1.00 month (1.00-132.00) and the median follow-up period was 70 months (60.00-216.00). Antenatal diagnosis was present in 33 patients (51.5%) mainly with bilateral hydronephrosis and oligohydramnios. The most common postnatal presentation was recurrent urinary tract infection (UTI) in 14 cases (21.9%) and incontinence in three cases (4.7%). Vesicoureteral-reflux (VUR) was present in 31 cases (48.4%). All patients had surgery and urinary diversion was needed in 18 (28.2%). Varying stages of chronic kidney disease (CKD) developed in 23 cases (35.9%) and rise in serum creatinine was especially prominent after the 4th year of follow-up. Of 23 CKD patients, seven (10.9%) were in ESRD and on dialysis. Mortality occurred in one (1.5%) patient. Hypertension, proteinuria and high initial serum creatinine (>1.28 mg/dL) were statistically significant risk factors for CKD, as expected. Surprisingly VUR and UTI did not show such a significant impact on CKD development. Antenatal detection was with significantly less risk for CKD. CONCLUSIONS: Our results confirm that PUV has a considerable risk for CKD development. Antenatal diagnosis, management of proteinuria and hypertension may modify this progression. But already injured kidneys still have a potential risk. The need for further research to evaluate the impact of any intervention on long term renal outcome is obvious.

Identification of potential biomarkers and therapeutic targets for human IgA nephropathy and hypertensive nephropathy by bioinformatics analysis.

In order to further elucidate the potential correlations and treatments of IgA nephropathy (IgAN) and hypertensive nephropathy (HT), bioinformatics analysis of IgAN and HT was performed. The mRNA expression profiles of human renal biopsy samples from patients with IgAN, patients with HT and pre­transplant healthy living controls (LD) were downloaded from the Gene Expression Omnibus database. Then, the differentially expressed genes (DEGs) were identified and functions of DEGs were analyzed. Finally, the regulatory networks containing DEGs and related­transcription factors (TFs) were constructed using Cytoscape software. When compared with the LD group, 134 and 188 DEGs were obtained in the IgAN and HT groups, respectively. A total of 39 genes were altered in the HT group when compared with the IgAN group. In addition, 66 genes were shared in the IgAN and HT groups when compared with the LD group, 6 of which [early growth response 1, activating transcription factor 3, nuclear receptor subfamily 4 group A member 2 (NR4A2), NR4A1, v­maf avian musculoaponeurotic fibrosarcoma oncogene homolog F and Kruppel like factor 6] were identified as TFs. In addition, DEGs including interleukin (IL) 1 receptor antagonist, collagen type 4 α2 chain, IL8, FBJ murine osteosarcoma viral oncogene homolog and somatostatin were enriched in a number of inflammation­associated biological processes, and DEGs including structural maintenance of chromosomes protein 3, v­crk avian sarcoma virus CT10 oncogene homolog and myosin 6 were enriched in non­inflammation­associated biological processes. Therefore, the differentially expressed TF genes and the genes associated with inflammation may be effective as potential therapeutic targets for IgAN and HT.

Therapeutic potentials of mesenchymal stem cells on the renal cortex of experimentally induced hypertensive albino rats: Relevant role of Nrf2.

Bone marrow derived-mesenchymal stem cells (BM-MSCs) have brought great attention in regenerative medicine field, various experimental & clinical trials were held to investigate their therapeutic effects in different disorders. We designed a histological & immunohistochemical study to evaluate effectiveness of MSCs therapy in withhold of end-stage renal disease (ESRD) secondary to hypertension which has become a growing & striking public health problem. 30 adult male albino rats were utilized, 20 of them were exposed to experimental induction of hypertension, then divided equally to MSCs treated group (injected with 1×106 fluorescent labeled cell i.v./rat), while the second one was left without treatment. Renal specimens were subjected to histopathological, ultrastructural and immunohistochemical examination for Nrf2 in addition to biochemical estimation of serum urea & creatinine. Our results documented that BM-derived MSCs exerts considerable reversing effect of histopathologic and ultrastructural hypertensive nephropathy. Moreover, immunohistochemical results clearly pointed to relevant role of Nrf2 pathway in MSCs related renal therapeutic effects.

[A retrospective clinical analysis of 16 patients with scleroderma renal crisis].

OBJECTIVE: To analyze the clinical features, laboratory tests, treatments and outcome of patients with scleroderma renal crisis (SRC). METHODS: We retrospectively reviewed the clinical and laboratory data of 16 patients with scleroderma renal crisis in Peking Union Medical College Hospital from May 2004 to May 2013. The treatment and outcome of SRC patients were also retrospectively analyzed. RESULTS: There were a total of 16 SRC patients including 5 male patients and 11 females. The median age at SRC onset was (49.9 ± 12.3) years. It usually took 3.2 years from the diagnosis of systemic sclerosis (SSc) to SRC attack. Ten SRC patients belonged to diffuse cutaneous systemic sclerosis (dcSSc), and 6 patients were limited cutaneous systemic sclerosis (lcSSc). Among SRC patients, 16/16 were negative of anti-centromere antibodies (ACAs). All these 16 patients had hypertension and renal insufficiency, including 8 dialysis dependent after the onset of SRC and 7 with thrombotic microangiopathy. There were 3 patients receiving renal biopsy. The pathological findings were mainly summarized as intimal thickening and stenosis of renal arterioles. Among 13 patients with long-term followed-up, 11 patients received angiotensin converting enzyme inhibitors (ACEI), 5 patients died, 2 patients were dialysis dependent. Only 1 patient stopped dialysis after the combination treatment of ACEI and endothelin receptor antagonist. Another 5 patients didn't need dialysis. CONCLUSION: SRC usually occurred at the early course of SSc. dcSSc was more frequent than lcSSc. ACAs were rarely found in SRC patients. The immediate and sufficient use of ACEIs was still the cornerstone of SRC treatment. Future studies are needed to evaluate the efficacy of endothelin receptor antagonist in the treatment of SRC.

Broken guidewire - A tale of three cases.

Guidewire fracture is a rare complication of percutaneous coronary intervention. Retained guide wire fragments in the coronary tree can cause thrombosis, embolic phenomena, dissection, perforation, and vessel occlusion. The management of this complication is still debated and it involves conservative management of leaving wire alone, percutaneous retrieval of fractured fragment, use of second stent to crush the wire, or open heart surgery. Here, I am reporting three cases of broken guidewire and they have been managed in three different ways.

Renal dysfunction and intragraft proMMP9 activity in renal transplant recipients with interstitial fibrosis and tubular atrophy.

Chronic renal allograft injury is reflected by interstitial fibrosis and tubular atrophy (IF/TA) and by the accumulation of extracellular matrix (ECM). Metalloproteinases (MMPs) are renal physiologic regulators of ECM degradation. Changes in MMPs expression or activity may disturb ECM turnover leading to glomerular scarring and worsening renal function. Our goal was to investigate intragraft MMP2 and MMP9 activities and their correlation with renal dysfunction. Plasma MMP2 and MMP9 activities were analyzed as noninvasive markers of renal allograft deterioration. Transplanted patients were biopsied and histopathologically characterized as IF/TA+ or IF/TA-. Renal function was evaluated by serum creatinine, glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease equation and urinary protein/creatinine ratio. Kidney and plasma MMP2 and MMP9 activities were analyzed by zymography. A significant renal dysfunction was observed in IF/TA+ patients. Intragraft proMMP9 showed a significant higher activity in IF/TA+ than in IF/TA- samples and was inversely correlated with the GFR. Intragraft proMMP2 activity tended to increase in IF/TA+ samples, although no statistic significance was reached. Circulating proMMP2 and proMMP9 activities did not show significant differences between groups. Our data provide evidence that correlates intragraft proMMP9 activity with the fibrotic changes and renal dysfunction observed in IF/TA.

Treatment of hypertension in patients with atherosclerotic renal artery stenosis, updated.

Atherosclerotic renal artery stenosis (ARAS) is a fairly common disease of elderly patients and is discovered incidentally in 6.3% to 38% in those undergoing diagnostic cardiac or abdominal angiography. Of those patients diagnosed with renal artery stenosis, in 90% it is due to ARAS and in 10% to fibromuscular dysplasia (FMD), which is a disease of younger persons, mostly females. Renal artery stenosis is frequently associated with hypertension and impaired renal function, and it is perceived by many physicians as the primary cause of hypertension and renal failure. For this reason, they believe that hypertension and renal failure can be significantly improved by performing percutaneous transluminal renal angioplasty (PTRA) with a stent placement as the preferred treatment instead of medical therapy. This practice has led to an increase in angioplasties, especially by interventional cardiologists who are familiar with the procedure. However, the results of several randomized studies comparing interventional therapy with medical therapy have shown no significant difference between the 2 treatment modalities in blood pressure reduction and prevention and in worsening of renal function. Similar results have been found by nonrandomized trials in patients treated selectively with PTRA. For this review, a Medline search was conducted of the English-language literature from January 1, 2006 to December 31, 2013, using the terms atherosclerotic renal artery stenosis and renal artery stenosis; 6 pertinent randomized studies were selected. These studies, with collateral literature, are discussed in this review. The data show that PTRA with stent plus medical therapy in patients with ARAS is not superior to medical therapy alone in lowering the blood pressure, in preventing renal function deterioration, and in reducing all-cause mortality, cardiovascular morbidity or mortality, and strokes.

Smad7 inhibits AngII-mediated hypertensive nephropathy in a mouse model of hypertension.

The TGFß (transforming growth factor ß)/SMAD and NF-κB (nuclear factor κB) signalling pathways play a key role in hypertensive nephropathy. The present study examined whether targeting these pathways by SMAD7, a downstream inhibitor of both pathways, blocks AngII (angiotensin II)-induced hypertensive kidney disease in mice. A doxycycline-inducible SMAD7-expressing plasmid was delivered into the kidney by a non-invasive ultrasound-microbubble technique before and after AngII infusion. Results showed that pre-treatment with SMAD7 prevented AngII-induced progressive renal injury by inhibiting an increase in proteinuria and serum creatinine while improving the glomerular filtration rate. Similarly, treatment with SMAD7 in the established hypertensive nephropathy at day 14 after AngII infusion halted the progressive renal injury. These preventive and therapeutic effects of SMAD7 on hypertensive kidney injury were associated with inhibition of AngII-induced up-regulation of SMURF2 (SMAD-specific E3 ubiquitin protein ligase 2) and Sp1 (specificity protein 1), blockade of TGFß/Smad3-mediated renal fibrosis and suppression of NF-κB-driven renal inflammation. Moreover, overexpression of SMAD7 also prevented AngII-induced loss of renal miR-29b, an miRNA with an inhibitory role in both TGFß/Smad3 and NF-κB pathways. In conclusion, SMAD7 may be a therapeutic agent for AngII-mediated hypertensive nephropathy. Inhibition of the Sp1/SMAD3/NF-κB/miR-29b regulatory network may be a mechanism by which SMAD7 inhibits hypertensive nephropathy.

Almanac 2013: novel non-coronary cardiac interventions.

Recent innovations in interventional cardiology have dramatically expanded the therapeutic options for patients with cardiac conditions. Interventional cardiology is no longer limited to the treatment of coronary artery disease but allows also treatment of valvular disease, stroke prevention, hypertension, etc. One of the most important new treatment options is the percutaneous treatment for aortic valve stenosis (transcatheter aortic valve implantation), since aortic valve disease is a rather common problem in elderly patients, with many of them at high risk for surgery. Similarly, mitral regurgitation is often associated with comorbidities which make surgery high risk. The MitraClip is a promising percutaneous alternative to surgical valve repair or replacement. Other procedures discussed in this review are the percutaneous left atrial appendage closure as a non-pharmacologic therapy to prevent strokes, and renal denervation for resistant hypertension. This review explains the basic principles of these procedures, the most important clinical evidence, and also provides additional recent clinical data on each of these them.

Technical discussion of diagnostic angiography and intervention of atherosclerotic renal artery stenosis.

Renal artery stenting remains an important adjuvant treatment for true-resistant hypertension, although recent disappointing randomized trials highlight the importance of careful patient selection. Safe and successful renal interventions begin with critical core knowledge regarding renal artery anatomy and understanding the often hostile nature of the parent vessel (pararenal aorta). Armed with fundamental knowledge about anatomy and renal ostial disease pathology, it becomes easier to understand the advantages of less traumatic access techniques and how low-profile contemporary flexible stents have enhanced outcomes. In addition to suggested techniques based on detailed understanding of the vessel architecture and pathology, we will review the current available US Food and Drug Administration-approved balloon-expandable on-label renal stents and discuss the role of intravascular ultrasound for definition of lesion severity, stent sizing, and stent apposition. The durability of renal stenting will also be discussed, as will the velocity criteria for duplex surveillance. Lastly, the current empirical data related to renal embolic protection is provided, along with insight into technical issues in this domain.

Results of the major randomized clinical trials of renal stenting and implications for future treatment strategies.

The management of atherosclerotic renovascular disease remains an area of controversy. This review details the results of major clinical trials and their implications for contemporary treatment recommendations for affected patients.

[Glomerulonephritis and vasculitis as causes of arterial hypertension]. / Glomerulonephritis und Vaskulitis als Ursacheneiner arteriellen Hypertonie.

The various types of glomerulonephritis, including many forms of vasculitis, are responsible for about 15% of cases of end-stage renal disease (ESRD). Arterial hypertension represents a frequent finding in patients suffering from glomerulonephritis or vasculitis and hypertension also serves as an indicator for these severe types of diseases. In addition, there are symptoms and signs like hematuria, proteinuria and renal failure. Especially, rapidly progressive glomerulonephritis (RPGN) constitutes a medical emergency and must not be missed by treating physicians. This disease can either occur limited to the kidneys or in the context of a systemic inflammatory disorder, like a vasculitis. If left untreated, RPGN can lead to a necrotizing destruction of glomeruli causing irreversible kidney damage within several months or even weeks. With respect to the immunologically caused vasculitis, there are - depending upon the severity and type of organ involved - many clinical warning signs to be recognized, such as arterial hypertension, hemoptysis, arthalgias, muscle pain, palpable purpura, hematuria, proteinuria and renal failure. In addition, constitutional signs, such as fever and loss of body weight may occur concurrently. Investigations of glomerulonephritis or vasculitis must contain a careful and complete examination of family history and medications used by the respective patient. Thereafter, a thorough clinical examination must follow, including skin, joints and measurement of arterial blood pressure. In addition, a spectrum of laboratory analyses is required in blood, such as full blood screen, erythrocyte sedimentation rate, CRP, creatinine, urea and glucose, and in urine, including urinalysis looking for hematuria, red cell casts and proteinuria. Importantly, proteinuria needs to be quantified by the utilization of a random urine sample. Proteinuria > 3g/d is diagnostic for a glomerular damage. These basic tests are usually followed by more specialized analyses, such as a screening for infections, including search for HIV, hepatitis B or C and various bacteria, and for systemic inflammatory diseases, including tests for antibodies, such as ANA, anti-dsDNA, ANCA, anti-GBM and anti-CCP. In cases of membranous nephropathy, antibodies against phospholipase-A2-receptor need to be looked for. Depending upon the given clinical circumstances and the type of disease, a reasonable tumor screening must be performed, especially in cases of membranous and minimal-change nephropathy. Finally, radiological examinations will complete the initial work-up. In most cases, at least an ultrasound of the kidney is mandatory. Thereafter, in most cases a renal biopsy is required to establish a firm diagnosis to define all treatment options and their chance of success. The elimination of a specific cause for a given glomerulonephritis or vasculitis, such as an infection, a malignancy or a drug-related side-effect, remains the key principle in the management of these diseases. ACE-inhibitors, angiotensin receptor-blockers, aldosteron antagonists and renin-inhibitors remain the mainstay in the therapy of arterial hypertension with proteinuria. Only in cases of persistently high proteinuria, ACE-inhibitors and angiotensin receptor blockers can be prescribed in combination. Certain types of glomerulonephritis and essentially all forms of vasculitis require some form of more specific anti-inflammatory therapy. Respective immunosuppressive drug regimens contain traditionally medications, such as glucocorticoids (e. g. prednisone), cyclosporine A, mycophenolate mofetil, cyclophosphamide, and azathioprine. With respect to more severe forms of glomerulonephritis and vasculitis, the antibody rituximab represents a new and less toxic alternative to cyclophosphamide. Finally, in certain special cases, like Goodpasture's syndrome or severe ANCA-positive vasculitis, a plasma exchange will be useful and even required.

Mid-aortic syndrome in two preterm infants.

We report mid-aortic syndrome (MAC) in two preterm infants. Both infants developed malignant hypertension refractory to medical therapy and died early in infancy. Thus far, this account is of the two youngest patients with MAC.

Scleroderma renal crisis: a rare but severe complication of systemic sclerosis.

Scleroderma renal crisis (SRC) is a major complication in patients with systemic sclerosis (SSc). It is characterized by malignant hypertension and oligo/anuric acute renal failure. SRC occurs in 5% of patients with SSc, particularly in the first years of disease evolution and in the diffuse form. The occurrence of SRC is more common in patients treated with glucocorticoids, the risk increasing with increasing dose. Left ventricular insufficiency and hypertensive encephalopathy are typical clinical features. Thrombotic microangiopathy is detected in 43% of the cases. Anti-RNA-polymerase III antibodies are present in one third of patients who develop SRC. Renal biopsy is not necessary if SRC presents with classical features. However, it can help to define prognosis and guide treatment in atypical forms. The prognosis of SRC has dramatically improved with the introduction of angiotensin-converting enzyme inhibitors (ACEi). However, 5 years survival in SSc patients who develop the full picture of SRC remains low (65%). SRC is often triggered by nephrotoxic drugs and/or intravascular volume depletion. The treatment of SRC relies on aggressive control of blood pressure with ACEi, if needed in combination with other types of antihypertensive drugs. Dialysis is frequently indicated, but can be stopped in approximately half of patients, mainly in those for whom a perfect control of blood pressure is obtained. Patients who need dialysis for more than 2 years qualify for renal transplantation.

Renovascular hypertension and ischemic nephropathy.

Renovascular disease remains among the most prevalent and important causes of secondary hypertension and renal dysfunction. Many lesions reduce perfusion pressure including fibromuscular diseases and renal infarction, but most are caused by atherosclerotic disease. Epidemiologic studies establish a strong association between atherosclerotic renal-artery stenosis (ARAS) and cardiovascular risk. Hypertension develops in patients with renovascular disease from a complex set of pressor signals, including activation of the renin-angiotensin system (RAS), recruitment of oxidative stress pathways, and sympathoadrenergic activation. Although the kidney maintains function over a broad range of autoregulation, sustained reduction in renal perfusion leads to disturbed microvascular function, vascular rarefaction, and ultimately development of interstitial fibrosis. Advances in antihypertensive drug therapy and intensive risk factor management including smoking cessation and statin therapy can provide excellent blood pressure control for many individuals. Despite extensive observational experience with renal revascularization in patients with renovascular hypertension, recent prospective randomized trials fail to establish compelling benefits either with endovascular stents or with surgery when added to effective medical therapy. These trials are limited and exclude many patients most likely to benefit from revascularization. Meaningful recovery of kidney function after revascularization is limited once fibrosis is established. Recent experimental studies indicate that mechanisms allowing repair and regeneration of parenchymal kidney tissue may lead to improved outcomes in the future. Until additional staging tools become available, clinicians will be forced to individualize therapy carefully to optimize the potential benefits regarding both blood pressure and renal function for such patients.

Severe renal failure and microangiopathic hemolysis induced by malignant hypertension--case series and review of literature.

Malignant nephrosclerosis is acute renal failure in the setting of malignant hypertension and may be associated with thrombotic microangiopathy. Although the prognosis has improved considerably over the past decades, renal dysfunction remains an important cause of morbidity and mortality. Adequate control of blood pressure is crucial, allows gradual healing of the necrotizing vascular lesions and may induce stabilization and improvement of renal function in about 50 - 80% of involved patients. In addition, recent investigations have provided a better understanding of the pathophysiology of malignant hypertension and offer possibilities for identifying patients at risk. We report 3 patients who developed severe acute renal failure requiring dialysis initiation in the setting of malignant hypertension. All patients had kidney biopsy proven malignant nephrosclerosis and presented with symptoms of thrombotic microangiopathy. Despite adequate blood pressure control the prognosis of our patients varied.