Kidney injury during VEGF inhibitor therapy

Antiangiogenic therapy targeting vascular endothelial growth factor (VEGF) or its receptor (VEGFR) has proven its effect in the treatment of several types of cancer, including renal cell carcinoma (RCC). However, treatment can be accompanied by notable adverse effects. Mild proteinuria and hypertension are often seen, but sometimes nephrotic range proteinuria and÷or renal insufficiency develop. In recent years insight into the toxic effects of anti-VEGF therapy in the kidney has increased. A few biopsies have been done and thrombotic microangiopathy is reported in the majority of cases. However, other patterns of kidney injury have been described as illustrated by the case of a 62-year-old patient who presented two years after initiation of the VEGFR inhibitor cediranib with a nephrotic syndrome and acute renal failure. Kidney biopsy disclosed focal segmental glomerulosclerosis (FS GS) and interstitial nephritis. Partial remission was achieved after stopping the cediranib and a short course of prednisone. We review the different forms of kidney injury that could be caused by anti-VEGF therapy.     

Intravitreous anti-VEGF for diabetic retinopathy: hopes and fears for a new therapeutic strategy

Vascular endothelial growth factor (VEGF) plays a key role in the development of both proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DMO). In recent years, anti-VEGF agents have emerged as new approaches to the treatment of these devastating diabetic complications. Although Phase III studies in the diabetic population are needed, intravitreal anti-VEGF therapy is currently being used in clinical practice. Intravitreal injection is an effective means of delivering anti-VEGF drugs to the retina. However, this is an invasive procedure associated with potentially serious complications, such as endophthalmitis or retinal detachment, which may be significant for patients requiring serial treatment over many years. In addition, although delivered within the vitreous, anti-VEGF drugs could pass into the systemic circulation, which could potentially result in hypertension, proteinuria, increased cardiovascular events and impaired wound healing. Pegaptanib, ranibizumab and bevacizumab are the currently available anti-VEGF agents. Ranibizumab and bevacizumab block all VEGF isoforms, thus impairing both physiological and pathological neovascularisation. Pegaptanib only blocks the VEGF₁₆₅ isoform, and would therefore seem the best option for avoiding systemic adverse effects in diabetic patients, although this remains to be demonstrated in clinical trials. In this regard, head-to-head studies designed to evaluate not only the efficacy, but also the systemic adverse effects of these drugs in a high-risk population such as diabetic patients are warranted.     

Pregnancy-induced hypertension--a particular pathogenic model. Similarities with other forms of arterial hypertension

Hypertension is in 85 to 90% of cases of unknown etiology, in spite of efforts undertaken by modern medicine to elucidate it. Numerous experimental studies were conducted in order to explain the pathogeny of this disease. Recent observations revealed that during therapy with anti-VEGF medication,used in treating different forms of cancer, hypertension and proteinuria occur, and at kidney level endothelial injuries appear similar to pregnancy-related hypertension. Antiangiogenic factors, such as sFlt-1, are produced during pregnancy-induced hypertension, especially in preeclampsia. They block the circulating VEGF. Consequently, proteinuria, and sometimes oedema occur together with hypertension. Renal injuries are of glomerular endotheliosis type. It is appreciated that one can draw a parallel between these pathologic situations, as is ablative treatment of antiangiogenic medication (anti-VEGF) and pregnancy-induced hypertension, preeclampsia, respectively. Since in pregnancy-induced hypertension angiogenic factors have an important role, we analyse their implication in other types of hypertension, in myocardial infarction, and in endothelial dysfunction in the course of CKD. The main pathogenic mechanism of pregnancy-induced hypertension that causes the disease is placental ischaemia. This is followed by the placental release of pressor substances that are involved both in generalised endotheliosis that characterizes the disease, and in hypertension. The prototype hypertension caused by renal ischaemia is renal artery stenosis. Both pregnancy-induced hypertension and hypertension in renal artery stenosis have a similar factor in their pathogeny, that is organ ischaemia with production of consecutive pressor substances. Since this ischaemic factor can intervene in other forms of hypertension, its characterisation becomes of importance at present. Thus, pregnancy-induced hypertension in pregnancy can represent a real pathogenic model of hypertension that is reflected in non-pregnancy hypertension. The paper presents the particularities of pregnancy-induced hypertension, as well as its parallelism with other types of hypertension that are determined by organ ischaemia or that produce ablation of angiogenic factors.     

玻璃体内注射抗血管内皮生长因子药物对糖尿病肾脏损害的影响

目的:观察玻璃体内抗血管内皮生长因子(VEGF)治疗对糖尿病患者肾脏损害的影响。方法:收集2016年6月至2019年9月收治的接受璃体内抗VEGF治疗糖尿病视网膜病变(DR)后肾脏损害明显加重的患者,回顾性分析其临床、病理特征及预后。结果:共9例DR分期Ⅲ~Ⅴ期患者纳入本研究。玻璃体内抗VEGF治疗后,1例基线仅有高血压无蛋白尿的患者临床病理表现符合血栓性微血管病(TMA);1例基线有蛋白尿、无高血压的患者出现血压明显升高,肾脏病理表现糖尿病肾病(DN)。另7例基线有蛋白尿和高血压的患者均表现为肾脏损害加速进展,尿蛋白定量、血清肌酐(SCr)和血压较基线明显升高(2例行肾脏病理符合DN),1例合并急性心肌梗死。9例均需增加降压药物种类或剂量以维持血压平稳,1例TMA患者同时给予小剂量糖皮质激素治疗。9例患者中位随访14.9(4.5,21.5)月,1例TMA患者蛋白尿转阴,肾功能部分恢复;1例新发高血压患者SCr保持稳定;余7例肾功能持续进展,多次用药的4例患者中3例进展为终末期肾病。结论:DR患者玻璃体内抗VEGF治疗可加重肾脏损害和高血压,故在治疗前后应密切监测尿蛋白、肾功能和血压,关注可能的不良事件。     

Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice

BACKGROUND & AIMS: Portal hypertension is a frequent syndrome that develops in patients with chronic liver diseases, which are one of the most common causes of death in adults worldwide. The most serious clinical consequences of portal hypertension are related to the development of portal-systemic collateral vessels. Those include hepatic encephalopathy and massive bleeding from ruptured gastroesophageal varices. The high relevance of these collateral vessels prompted us to investigate the mechanism underlying its formation in a murine model of portal hypertension. METHODS: To determine whether the development of portal-systemic collateral vessels in portal hypertension is a vascular endothelial growth factor (VEGF)-dependent angiogenic process, we assessed the effects of a monoclonal antibody against VEGF receptor-2 on the formation of these collateral vessels in mice with portal hypertension induced by partial portal vein ligation. We also studied the effects of a selective and specific inhibitor of VEGF receptor-2 autophosphorylation in partial portal vein-ligated rats. RESULTS: A significant and marked inhibition in the formation of portal-systemic collateral vessels was observed in both partial portal vein-ligated mice and rats treated with anti-VEGF receptor-2 monoclonal antibodies or with the inhibitor of VEGF receptor-2 autophosphorylation, respectively, compared with animals receiving control solutions. CONCLUSIONS: Our present study shows that formation of collateral vessels is an angiogenesis-dependent process that can be markedly inhibited by blockade of the VEGF signaling pathway. These findings will make angiogenesis a focal point of research in portal hypertension and may lead to novel approaches for therapy of patients with chronic liver diseases.     

Endostatin lowers blood pressure via nitric oxide and prevents hypertension associated with VEGF inhibition

Antiangiogenesis therapy has become a vital part of the armamentarium against cancer. Hypertension is a dose-limiting toxicity for VEGF inhibitors. Thus, there is a pressing need to address the associated adverse events so these agents can be better used. The hypertension may be mediated by reduced NO bioavailability resulting from VEGF inhibition. We proposed that the hypertension may be prevented by coadministration with endostatin (ES), an endogenous angiogenesis inhibitor with antitumor effects shown to increase endothelial NO production in vitro. We determined that Fc-conjugated ES promoted NO production in endothelial and smooth muscle cells. ES also lowered blood pressure in normotensive mice and prevented hypertension induced by anti-VEGF antibodies. This effect was associated with higher circulating nitrate levels and was absent in eNOS-knockout mice, implicating a NO-mediated mechanism. Retrospective study of patients treated with ES in a clinical trial revealed a small but significant reduction in blood pressure, suggesting that the findings may translate to the clinic. Coadministration of ES with VEGF inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression.     

Anti-VEGF– and anti-VEGF receptor–induced vascular alteration in mouse healthy tissues

Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti–VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1–specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF–specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti-VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF–specific drugs.     

Hypertonie und renale thrombotische Mikroangiopathie unter anti-angiogener Tumortherapie

Anti-angiogenic therapies (AAT) targeting the VEGF signaling pathway (VSP) are increasingly used by oncologists for palliative treatment of patients with various solid tumors. While these non-curative drugs may improve certain treatment endpoints in selected cancer entities, clinical data suggest that they also cause a number of serious cardiovascular and renal side effects at rather high rates. For instance, the incidence of clinical hypertension has been estimated to be 19-24% and may be even higher with more potent second-generation VSP inhibitors. Onset of proteinuria has been observed in up to 20% of treated cases. Another frequently occurring renal complication under AAT is the development of renal thrombotic microangiopathy (TMA). This pattern of injury is the same as found in patients with pre-eclampsia, also a disease of disordered VEGF signaling and endothelial dysfunction. Because use of these medications continues to grow and many new formulations in development, there is an increasing need for the nephrologist to learn how to diagnose and manage VSP inhibitor toxicities. But at the same time there is a great opportunity to try connect these adverse events and clinical phenotypes back to the molecular mechanisms precipitating them. Consistent with the concept of personalized medicine, we may at some point use this new knowledge to individualize and hence optimize therapies for patients undergoing anti-angiogenic treatment.     

Kidney Diseases Associated With Anti-Vascular Endothelial Growth Factor (VEGF): An 8-year Observational Study at a Single Center

Expanded clinical experience with patients taking antiangiogenic compounds has come with increasing recognition of the renal adverse effects. Because renal histology is rarely sought in those patients, the renal consequences are underestimated. Antiangiogenic-treated-cancer patients, who had a renal biopsy for renal adverse effects from 2006 to 2013, were included in the current study. Clinical features and renal histologic findings were reviewed. Our cohort was 100 patients (58 women) with biopsy-proven kidney disease using anti-vascular endothelial growth factor (VEGF) therapy with a mean age of 59.8 years (range, 20–85 yr). Patients were referred for proteinuria, hypertension, and/or renal insufficiency. Kidney biopsy was performed 6.87 ± 7.18 months after the beginning of treatment. Seventy-three patients experienced renal thrombotic microangiopathy (TMA) and 27 patients had variable glomerulopathies, mainly minimal change disease and/or collapsing-like focal segmental glomerulosclerosis (MCN/cFSGS). MCN/cFSGS-like lesions developed mainly with tyrosine-kinase inhibitors, whereas TMA complicated anti-VEGF ligand. Thirty-one percent of TMA patients had proteinuria up to 1 g/24 h. Half of TMA cases are exclusively renal localized. Pathologic TMA features are intraglomerular exclusively. MCN/cFSGS glomeruli displayed a high abundance of KI-67, but synaptopodin was not detected. Conversely, TMA glomeruli exhibited a normal abundance of synaptopodin-like control, whereas KI-67 was absent. Median follow-up was 12 months (range, 1–80 mo). Fifty-four patients died due to cancer progression. Hypertension and proteinuria resolved following drug discontinuation and antihypertensive agents. No patient developed severe renal failure requiring dialysis. Drug continuation or reintroduction resulted in a more severe recurrence of TMA in 3 out of 4 patients requiring maintenance of anti-VEGF agents despite renal TMA. In conclusion, TMA and MCN/cFSGS are the most frequent forms of renal involvement under anti-VEGF therapy. Careful risk-benefit assessment for individual patients should take into account risk factors related to the host and the tumor.     

Is fixed combination therapy appropriate for initial hypertension treatment?

Recent clinical trials in hypertension prove how seldom single drug therapy achieves target blood pressure (BP) and reduces cardiovascular morbidity and mortality. A natural response is the testing and marketing of fixed-dose combination products for hypertension, of which 14 have been approved in the United States since 1993. Currently, only five products are indicated by the Food and Drug Administration for initial therapy of hypertension; all include a diuretic. To achieve such an indication, studies must show not only safety and efficacy of the combination, but also BP lowering that is at least additive compared with the two agents given separately, as well as a "synergy" not present when each agent is given alone. Some advantages to initial combination therapy include greater BP reduction, improved adherence to pill taking, fewer side effects, and lower cost. The most likely candidates for initial combination therapy are patients with initial BP higher than 160/100 mm Hg, or those with a BP goal lower than the customary 140/90 mm Hg. These include patients with target organ damage, clinical cardiovascular disease, proteinuria, renal impairment, or diabetes mellitus. In many of these circumstances, an angiotensin converting enzyme inhibitor or angiotensin II receptor antagonist is frequently recommended; adding a diuretic or calcium antagonist to it is much more likely to result in achievement of the BP goal. More research is being done to explore the combination of not only two representatives from classes of conventional agents, but also other drugs that may help address the multiple manifestations of the "metabolic syndrome" that often accompanies hypertension.     

Is fixed combination therapy appropriate for initial hypertension treatment?

Recent clinical trials in hypertension prove how seldom single drug therapy achieves target blood pressure (BP) and reduces cardiovascular morbidity and mortality. A natural response is the testing and marketing of fixed-dose combination products for hypertension, of which 14 have been approved in the United States since 1993. Currently, only five products are indicated by the Food and Drug Administration for initial therapy of hypertension; all include a diuretic. To achieve such an indication, studies must show not only safety and efficacy of the combination, but also BP lowering that is at least additive compared with the two agents given separately, as well as a "synergy" not present when each agent is given alone. Some advantages to initial combination therapy include greater BP reduction, improved adherence to pill taking, fewer side effects, and lower cost. The most likely candidates for initial combination therapy are patients with initial BP higher than 160/100 mm Hg, or those with a BP goal lower than the customary 140/90 mm Hg. These include patients with target organ damage, clinical cardiovascular disease, proteinuria, renal impairment, or diabetes mellitus. In many of these circumstances, an angiotensin converting enzyme inhibitor or angiotensin II receptor antagonist is frequently recommended; adding a diuretic or calcium antagonist to it is much more likely to result in achievement of the BP goal. More research is being done to explore the combination of not only two representatives from classes of conventional agents, but also other drugs that may help address the multiple manifestations of the "metabolic syndrome" that often accompanies hypertension.     

Drug insight: antiangiogenic therapies for gastrointestinal cancers--focus on monoclonal antibodies

Tumor angiogenesis is strongly induced by vascular endothelial growth factor (VEGF), which is overexpressed in most human gastrointestinal cancers. VEGF overexpression is known to be associated with poor prognosis and survival in patients with various solid tumors. The humanized monoclonal anti-VEGF antibody bevacizumab (Avastin, Genentech Inc., South San Francisco, CA) is a prototypic antiangiogenic compound, and has proven therapeutic benefit combined with conventional chemotherapy-namely, significantly improved progression-free survival in patients with metastatic colorectal cancer. Bevacizumab is the only anti-VEGF antibody that has been approved by the FDA and the European Medicines Agency for the treatment of metastatic colorectal cancer. Several ongoing clinical studies are evaluating the potential of bevacizumab therapy for other gastrointestinal cancers, in combination with chemotherapy, other targeted therapies and/or radiation. Soluble chimeric receptors, tyrosine kinase inhibitors, and monoclonal antibodies against VEGF and molecular targets in the integrin and Delta-like protein 4-Notch pathways are being developed. As tumors acquire resistance to anti-VEGF therapy, further development of antiangiogenic and vascular targets and therapy is warranted.     

Therapeutic potential of nitric oxide donors in the prevention and treatment of angiogenesis-inhibitor-induced hypertension

Angiogenesis is critical to tumor growth as well as to metastases. This process is tightly regulated by pro- and anti-angiogenic growth factors and their receptors. Some of these factors are highly specific for the endothelium—e.g., vascular endothelial growth factor (VEGF). A variety of drugs that target VEGF or its receptors have been developed for the treatment of different tumor types and a number of new agents is expected to be introduced within the coming years. However, clinical experience has revealed that inhibition of VEGF induces several side effects including hypertension and renal and cardiac toxicity. Angiogenesis-inhibitor-induced hypertension represents “crux medicorum” as it is often pharmacoresistant to antihypertensive therapy. We consider two most important pathomechanisms in the development of hypertension induced by angiogenesis inhibitors. The first represents direct inhibition of NO production leading to reduced vasodilatation and the second consists in increased proliferation of vascular medial cells mediated by NO deficiency and is resulting in fixation of hypertension. Based on the results of experimental and clinical studies as well as on our clinical experience, we assume that NO donors could be successfully used not only for the treatment of developed angiogenesis-inhibitor-induced hypertension but also for preventive effects. We thoroughly documented three clinical cases of cancer patients with resistant hypertension who on receiving NO donor treatment achieved target blood pressure level and a good clinical status.     

Rapid decrease in tumor perfusion following VEGF blockade predicts long-term tumor growth inhibition in preclinical tumor models

Vascular endothelial growth factor (VEGF) is a key upstream mediator of tumor angiogenesis, and blockade of VEGF can inhibit tumor angiogenesis and decrease tumor growth. However, not all tumors respond well to anti-VEGF therapy. Despite much effort, identification of early response biomarkers that correlate with long-term efficacy of anti-VEGF therapy has been difficult. These difficulties arise in part because the functional effects of VEGF inhibition on tumor vessels are still unclear. We therefore assessed rapid molecular, morphologic and functional vascular responses following treatment with aflibercept (also known as VEGF Trap or ziv-aflibercept in the United States) in preclinical tumor models with a range of responses to anti-VEGF therapy, including Colo205 human colorectal carcinoma (highly sensitive), C6 rat glioblastoma (moderately sensitive), and HT1080 human fibrosarcoma (resistant), and correlated these changes to long-term tumor growth inhibition. We found that an overall decrease in tumor vessel perfusion, assessed by dynamic contrast-enhanced ultrasound (DCE-US), and increases in tumor hypoxia correlated well with long-term tumor growth inhibition, whereas changes in vascular gene expression and microvessel density did not. Our findings support previous clinical studies showing that decreased tumor perfusion after anti-VEGF therapy (measured by DCE-US) correlated with response. Thus, measuring tumor perfusion changes shortly after treatment with VEGF inhibitors, or possibly other anti-angiogenic therapies, may be useful to predict treatment efficacy.     

Hypertension in pregnancy

From the clinical point of view proteinuric hypertension or preeclampsia is the most important form of hypertension in pregnancy and carries the greatest risks for mother and foetus. The syndrome 'preeclampsia' differs from other types of hypertension and its effects on mother and foetus are not clearly benefited by lowering the blood pressure with drugs. The characteristic morphological changes and altered vascular reactivity which develop in preeclampsia commence at about 14 weeks gestation, long before hypertension or proteinuria appear. Many abnormalities in coagulation mechanisms appear in preeclampsia and some may play an important part in pathogenesis. Increased plasminogen activator inhibitor may play a key role. Antihypertensive drugs used during pregnancy may reduce foetal mortality and the incidence of preeclampsia. Calcium supplementation and aspirin may reduce the incidence of preeclampsia in high risk subjects. Heparin and dipyridamole may reduce the risk of preeclampsia in high risk patients with renal disease.     

Direct regulation of prostate blood flow by vascular endothelial growth factor and its participation in the androgenic regulation of prostate blood flow in vivo

Previous studies on prostate blood flow regulation have indicated that androgen regulates prostate blood flow. However, the mechanism responsible for this regulation is unknown. In the present study, we focused on the effects of vascular endothelial growth factor (VEGF), a key factor responsible for angiogenesis and androgenic blood flow regulation. We examined in vivo the effect of VEGF on prostate blood flow and its participation in the androgenic regulation of this blood flow using a castrated rat model following subcapsular intraprostatic injection method. We found that VEGF is involved in blood flow regulation with an activity equal to that of dihydrotestosterone (DHT). The effect of VEGF on prostate blood flow was already seen at 30 min after the administration. The elevating effect of DHT on castrated rat prostate blood flow was abolished by coadministration of DHT with neutralizing anti-VEGF antibody. The change in VEGF-A mRNA expression in response to androgen stimulation was examined by double-fluorescent probe quantitative PCR (Taqman PCR). The results showed that androgenic regulation of VEGF gene expression occurred shortly after androgen stimulation. VEGF gene up-regulation was abolished or down-regulated by coadministration of neutralizing anti-VEGF antibody. This is the first report on the importance of VEGF in the androgenic regulation signaling pathway that affects prostate blood flow. Alternative treatment targeted toward anti-VEGF activity as a substitute for ordinary antiandrogenic therapy may be effective against prostate diseases, especially those with androgen-independent and hyperhemorrhagic status.     

Efficacy of vascular endothelial growth factor in the treatment of experimental gastric injury

BACKGROUND/AIMS: Studies indicate that angiogenesis is important in tissue healing. However, the role of vascular endothelial growth factor (VEGF) in tissue healing has not been established. The aim of the study is to determine whether VEGF has a gastroprotective role in experimental gastric injury. METHODS: Acute gastric injury was induced in Sprague-Dawley rats by intragastric administration of 100% ethanol. Expression of gastric VEGF was determined in tissue homogenates by enzyme-linked immunosorbent assay and in paraffin-embedded sections by immunohistochemistry. The effect of systemic administration of anti-VEGF antibodies and recombinant VEGF on injury severity was assessed macroscopically and microscopically. RESULTS: Gastric VEGF concentrations peaked at 6 h and again 3 days after acute injury. The presence of VEGF was demonstrated in epithelial cells and in mononuclear cells. Blocking endogenous VEGF effects with anti-VEGF antibodies exacerbated mucosal injury. Administration of recombinant VEGF after the onset of injury reduced the severity of mucosal injury, irrespective of the timing of initial treatment with VEGF. Immunohistochemical detection of vascular endothelial cells revealed that the VEGF-induced mucosal repair is closely related to the degree of angiogenesis. CONCLUSION: The results provide strong evidence for the role of VEGF in the repair of tissue damage induced by ethanol. The results also show how VEGF may be used in a clinical setting to treat some acute gastric lesions.     

Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression

The semaphorins and plexins comprise a family of cysteine-rich proteins implicated in control of nerve growth and development and regulation of the immune response. Our group and others have found that Semaphorin 4D (SEMA4D) and its receptor, Plexin-B1, play an important role in tumor-induced angiogenesis, with some neoplasms producing SEMA4D in a manner analogous to vascular endothelial growth factor (VEGF) in order to attract Plexin-B1-expressing endothelial cells into the tumor for the purpose of promoting growth and vascularity. While anti-VEGF strategies have been the focus of most angiogenesis inhibition research, such treatment can lead to upregulation of pro-angiogenic factors that can compensate for the loss of VEGF, eventually leading to failure of therapy. Here, we demonstrate that SEMA4D cooperates with VEGF to promote angiogenesis in malignancies and can perform the same function in a setting of VEGF blockade. We also show the potential value of inhibiting SEMA4D/Plexin-B1 signaling as a complementary mechanism to anti-VEGF treatment, particularly in VEGF inhibitor-resistant tumors, suggesting that this may represent a novel treatment for some cancers.     

Sind alle Antihypertensiva nephroprotektiv?

Blood pressure, together with proteinuria, represents one of the most important factors in the progression of chronic renal failure (CRF). Antihypertensive therapy is beneficial to slow down the progression of a variety of chronic renal diseases, no matter what the cause. Intraglomerular hypertension, increased glomerular permeability and proteinuria should be identified, since they can be treated to prevent or minimize further glomerular injury.But not all antihypertensive drugs are equally effective to prevent the progression of CRF. Recent large trials indicate that blood pressure lowering obtained by intervention in the renin-angiotensin-aldosterone system (RAAS) has an additive renoprotective effect in diabetic and nondiabetic renal diseases. In nondiabetic patients, the AIPRI and REIN studies support that angiotensin-converting enzyme (ACE) inhibitors have a long-term renoprotective effect. The benefits of ACE inhibitors can be demonstrated even in patients who are not hypertensive. Angiotensin II receptor antagonists are shown to be renoprotective in type 2 diabetics (RENAAL and IDNT). However, whether these renoprotective effects are due to blood pressure reduction or due to the specific pharmacologic RAAS blockade is still a matter of debate. This discussion is still open, because the reduction in blood pressure levels was lower in patients treated with a drug that interferes with the RAAS compared with other antihypertensive regimens. It is concluded that both ACE inhibitors and AT II receptor antagonists are lowering the intraglomerular pressure independent of any change in systemic blood pressure by dilatation of the efferent arteriole of the glomerulus. These additional nonpressure-related effects may protect renal function by their antiproteinuric effect. In addition, beneficial effect of ACE inhibitors are related to reduction of AT II, which has potent proinflammatory effects independent of its hemodynamic influences.Other drugs, such as diuretics, beta blockers, and hydralazine, do not induce efferent dilatation and, therefore, may be less likely to reverse intraglomerular hypertension. For example, hydralazine and nifedipine appear to produce prominent afferent or preglomerular arteriolar dilatation. This will allow more of the systemic pressure to be transmitted to the glomerulus. Therefore, short-acting dihydropyridine calcium channel blockers (CCB) are not recommended. By comparison, long-acting dihydropyridines such as diltiazem and verapamil are less potent vasodilators and may primarily decrease the resistance of the efferent arteriole, similar to the ACE inhibitors. They may have an antiproteinuric activity. Yet, there is lack of large prospective randomized trials.A beta blocker as antihypertensive agent is indicated as second- or third-line drug especially in patients with additional cardiovascular disease. Other antihypertensive drugs can be added as necessary to achieve the treatment goals for arterial hypertension. The use of a diuretic will often be helpful in patients who already have renal insufficiency, since fluid overload is an important cause of hypertension and may also enhance the effectiveness of drugs that interfere with the RAAS. alpha(1)-receptor or sympathetic blockers are further possible drugs for combination antihypertensive therapy.     

Hypertension management in patients with diabetic nephropathy

Treatment of hypertension, to reverse and delay proteinuria progression and kidney failure, is the primary focus of medical management in patients with diabetic nephropathy. The initial choice for hypertension treatment in those with early nephropathy involves agents that block the renin-angiotensin system. However, it is not clear what the best choices for further drug therapy management are, because there are few data concerning the impact that antihypertensive drug combinations have on hard clinical outcomes, such as preventing the need for dialysis, and death. Patients usually require several drugs for controlling hypertension, which becomes harder to control as nephropathy progresses. In this review, it is suggested that quantitatively tracking proteinuria to guide therapy and a broad focus on the cardiovascular and renal end points are important for best outcomes in patients. Strategies may vary based on stage of disease, comorbidities, and age. Therapies not directed specifically at hypertension may also significantly aid hypertension management in prevention of progressive nephropathy, comorbidities, and mortality.