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Query: UMLS:C0035078 (renal failure)
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The effect of inhibiting the renin-angiotensin system was evaluated in male Sprague-Dawley rats with reduced renal mass produced by right nephrectomy and infarction of two-thirds of the left kidney. Separate groups of rats were then administered the angiotensin receptor antagonists, A-81988 or losartan (DuP 753), the angiotensin converting enzyme inhibitor, enalapril, or vehicle (tap water) in their drinking water for 4 weeks. Tail cuff blood pressures and blood samples were obtained weekly. Excretory function during week 4 was evaluated using metabolic cages. Rats with reduced renal mass were characterized by a significant elevation in systolic blood pressure and urinary protein excretion along with a reduced urine osmolality. At 1 mg/kg/day, A-81988 prevented the hypertension and the development of proteinuria. A-81988 administration also improved urinary concentrating ability because urine osmolality was significantly higher in this group compared to untreated controls. The same dose of losartan or enalapril was ineffective at controlling the development of the hypertension, indicating that A-81988 is more potent in vivo. Despite the maintenance of systemic hypertension, losartan significantly blunted the proteinuria compared to vehicle-treated controls. At a dose of 10 mg/kg/day, losartan and enalapril also prevented the increase in systolic blood pressure and proteinuria and produced an increase in urine osmolality. These data support the hypothesis that angiotensin receptor antagonists have beneficial effects in forms of renal failure associated with proteinuria and diminished concentrating ability.
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PMID:Angiotensin II receptor blockade improves renal function in rats with reduced renal mass. 824 38

Whether any class of antihypertensive drugs has specific renoprotective effects above and beyond lowering of blood pressure is still debatable. The renin-angiotensin system (RAS) is both localized and has many actions within the kidney, on intrarenal hemodynamics, on the mesangial cell, as well as stimulating growth factors and cytokines. Angiotensin converting enzyme (ACE) inhibitors have been shown to ameliorate the progression of renal failure. How much of this beneficial effect is due to their hemodynamic effects, how much to non-hemodynamic effects and how much to their effects on bradykinin and other putative ACE substrates is still unclear. Experimentally it can be shown that inhibiting ACE but preventing the fall in systemic blood pressure by salt loading abolishes renoprotection. Bradykinin has been implicated in both the beneficial and the adverse effects of ACE inhibitors. Because of this and because ACE inhibitors may not provide complete blockade of the RAS, angiotensin receptor (AT1R) antagonists have been developed. Experimentally AT1R antagonists have been shown to reproduce most of the beneficial effects of ACE inhibitors. The experience in humans is more limited but they have been demonstrated to be efficacious in hypertension, to reduce proteinuria, and produce a favorable hemodynamic effect in congestive cardiac failure with a low incidence of adverse effects and without cough. Calcium channel blockers (CCB) also have additional properties that may provide renoprotection beyond lowering blood pressure. However, as the different types of CCB block different calcium channels their effects may differ substantially. The inconsistency of the data in the renoprotective effect of CCB may reflect these differences. Quantitatively probably the most important factor in preventing the progress of renal failure by antihypertensive drugs is strict control of blood pressure. Lowering blood pressure by drugs is most likely effective by both reducing physical and sheer stress damage, as well as turning off the signal for the activation and production of vasoactive peptides and cytokines.
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PMID:Comparison of renin-angiotensin to calcium channel blockade in renal disease. 940 14

Two problems in the treatment of hypertension continue to be largely unsolved. The first, and more simple, is our inability to adequately control blood pressure in the majority of hypertensive patients. This not only reflects the difficulty of retaining patients in effective treatment programs, but also of convincing physicians to strive for optimal blood pressure levels. There is a continuing need for new antihypertensive drugs and combinations to help accomplish these goals. The second major problem is that the major clinical endpoints, including coronary events and renal failure, have not been adequately reduced by traditional therapies. Standard regimens, particularly those including diuretics, have protected against strokes and heart failure. Our improved understanding of vascular biology in hypertension has directed interest to the mechanisms in hypertensive patients that might accelerate atherosclerosis and vascular events in these individuals. This involves addressing the concomitant metabolic risk factors that comprise the "Hypertension Syndrome," and, perhaps of equal importance, finding therapies that directly inhibit unwanted types of growth and proliferative activities within the walls of critical arteries. Many substances within the endothelium and the vascular wall may participate as initiators or mediators of pathology, but most information thus far has focused on the renin-angiotensin system. Angiotensin converting enzyme inhibitors (and potentially angiotensin receptor blockers) have provided coronary and renal protection in various cardiovascular conditions, though not yet in formal hypertension trials. Calcium channel blockers have also shown promise, including recent stroke and cardiovascular benefits in patients with isolated systolic hypertension, but, again, definitive coronary data in hypertension are awaited. Unless concomitant conditions mandate the selection of a particular antihypertensive drug class, physicians currently have a dilemma: should they choose drugs from older classes that have not provided full protection? Or, should they prescribe newer agents with exciting potential but with, as yet, unproved endpoint benefits in hypertension? Until currently ongoing prospective trials of antihypertensive therapy are completed, physicians must be guided by their own interpretations of the available data.
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PMID:Translating data on antihypertensive drugs into clinical practice. 965 68

One hundred years ago, in 1898, Professor Robert Tigerstedt, Karolinska institutet, Sweden, discovered renin. The subsequent elaboration in 1960 of the renin-angiotensin-aldosterone system signalled the start of modern hypertension research. The kidney takes part in blood pressure regulation in a number of ways. Indications are that increased renovascular resistance due to increased renin-angiotensin activity is of importance for the barostatic function of the kidneys and for the pathogenesis of human hypertension. Several commonly used, efficacious and well tolerated antihypertensive agents act by blocking the renin-angiotensin system, thus normalising kidney function. A number of current large-scale trials--utilising ACE inhibitors and angiotensin receptor antagonists--will, it is hoped, elucidate the proper role of 'anti-renin therapy' in the treatment of hypertension. Thanks to effective modern management of hypertension, renal failure due to hypertensive kidney disease is rare in Sweden today.
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PMID:[A 100-year perspective on renal function and hypertension. Anti-renin therapy has made hypertensive renal failure a rarity]. 1060 12

Hypertension is often referred to as the "silent killer" because most hypertensive patients are asymptomatic until cardiovascular sequelae such as stroke, myocardial infarction, heart failure, or renal failure occur. LVH is a common finding in patients with hypertension, especially African-Americans. Data from the Framingham Heart Study indicate that LVH is an independent risk factor for major cardiovascular events. In the Amlodipine Cardiovascular Community Trial, 37% of 124 hypertensive patients screened by means of echocardiography had LVH at baseline. Although there was no difference in the prevalence of LVH by gender or age, African-American patients were nearly twice as likely to have LVH than white patients (64% vs. 34%, p<0.05). Hence, aggressive therapy to reach target goals outlined in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) is especially important in this group of patients. Even lifestyle modifications such as weight reduction and limitation of salt intake, if sufficiently aggressive, can lead to regression of LVH, as demonstrated by results of the Treatment of Mild Hypertension Study (TOMHS). Most classes of antihypertensive drugs are effective in causing regression of LVH. Vasodilators, such as minoxidil and hydralazine, do not have an effect on regression, possibly because reflex tachycardia and stimulation of catecholamines and the renin-angiotensin system associated with these agents may negate the benefit of reduced afterload. There is some controversy regarding the ability of the angiotensin receptor blockers to reduce LVH. In some studies, these agents were associated with regression, whereas in others they were not. Whether targeting LVH as the primary treatment goal in hypertensive patients will have long-term benefits on outcome above and beyond simply reducing blood pressure is not clear.
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PMID:Case 3: A patient with systemic hypertension and left ventricular hypertrophy. 1072 68

A 67-year-old man with a one-and-a half-year history of Raynaud's phenomenon was admitted to our hospital for progressive dyspnea occurring over the previous two weeks. Physical examination revealed a blood pressure of 200/124 mmHg, and slightly tight and smooth skin of the fingers, hands and forearms. Laboratory evaluation included serum creatinine of 5.42 mg/dl, plasma renin activity > 20 ng/ml/hr, and antinuclear antibody with a titer of 1 : 1,280. Renal biopsy was performed and the histopathological findings showed that some glomeruli exhibited ischemic retraction with wrinkling of the basement membranes, and that one arteriole exhibited significant intimal hyperplasia with luminal stenosis. These findings were compatible with scleroderma renal crisis (SRC). On the 5th day, serum creatinine had risen to 9.16 mg/dl, and he required temporary hemodialysis therapy. After the administration of captopril was started, his blood pressure fell to 160/86 mmHg and serum creatinine was reduced to 5.12 mg/dl. On the 9th day, he exhibited skin eruptions, and captopril was discontinued accordingly and temocapril started. Because of continued eruptions, temocapril was replaced by losartan. His blood pressure was controlled easily and his serum creatinine level reduced steadily. One year after the start of losartan, serum creatinine was 2.25 mg/dl and blood pressure was 130/82 mmHg. SRC is a life-threatening manifestation of systemic sclerosis. In the late 1970s, angiotensin converting enzyme (ACE) inhibitor was introduced and has dramatically improved the outcome in SRC patients. As ACE inhibitors act mainly on hyperreninemic renal vasoconstrictive hypertension in SRC, we would expect losartan, a selective antagonist of angiotensin receptor subtype 1, to be interchangeable with ACE inhibitors in SRC. In 1997, Caskey and colleagues reported the failure of losartan to control hypertension in a patient of SRC, and the reason has remained unclear. We report here, a case of SRC whose blood pressure was controlled successfully and his renal failure reversed by the administration of losartan.
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PMID:[Successful use of angiotensin II receptor antagonist (losartan) in a patient with scleroderma renal crisis]. 1077 77

Urothelium synthesizes a group of integral membrane proteins called uroplakins, which form two-dimensional crystals (urothelial plaques) covering >90% of the apical urothelial surface. We show that the ablation of the mouse uroplakin III (UPIII) gene leads to overexpression, defective glycosylation, and abnormal targeting of uroplakin Ib, the presumed partner of UPIII. The UPIII-depleted urothelium features small plaques, becomes leaky, and has enlarged ureteral orifices resulting in the back flow of urine, hydronephrosis, and altered renal function indicators. Thus, UPIII is an integral subunit of the urothelial plaque and contributes to the permeability barrier function of the urothelium, and UPIII deficiency can lead to global anomalies in the urinary tract. The ablation of a single urothelial-specific gene can therefore cause primary vesicoureteral reflux (VUR), a hereditary disease affecting approximately 1% of pregnancies and representing a leading cause of renal failure in infants. The fact that VUR caused by UPIII deletion seems distinct from that caused by the deletion of angiotensin receptor II gene suggests the existence of VUR subtypes. Mutations in multiple gene, including some that are urothelial specific, may therefore cause different subtypes of primary reflux. Studies of VUR in animal models caused by well-defined genetic defects should lead to improved molecular classification, prenatal diagnosis, and therapy of this important hereditary problem.
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PMID:Ablation of uroplakin III gene results in small urothelial plaques, urothelial leakage, and vesicoureteral reflux. 1108 99

Chronic azotemic renovascular disease is common in patients with atherosclerosis. Its prevalence appears to be increasing in the aging population. How often it is the primary cause of end-stage renal disease (ESRD) is not yet certain. Some studies suggest that 10%-40% of elderly hypertensive patients with newly documented ESRD and no demonstrable primary renal disease have significant renal artery stenosis (RAS). Atherosclerotic vascular occlusive disease of the renal arteries does progress, but current rates of progression and occlusion are lower than those reported a decade ago. Methods of identifying patients whose renal function is at true risk from vascular occlusive disease and determining who will benefit from intervention remain elusive. The presence of RAS in an azotemic patient can be assessed with noninvasive and risk-free radiologic techniques, including Duplex doppler velicometry and magnetic resonance angiography. Functional tests that predict the change in renal function after revascularization are not yet available. However, a renal length of greater than 7.5 cm in the absence of renal cysts and a short history of renal functional deterioration indicate a good prognosis. Patients with recent deterioration in renal function, those with bilateral renal artery stenosis or stenosis to a single functioning kidney, those with flash pulmonary edema, advanced chronic renal failure, or ESRD (who have much to gain), those with reversible azotemia during angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARB) therapy, and those whose conditions cannot be managed medically should be considered for revascularization. Results from recent controlled clinical trials of the response to percutaneous transluminal renal artery angioplasty (PTRA) and stenting indicate that improvement in blood pressure control or renal function is not a predictable outcome of renal revascularization. In azotemic groups, 25%-30% of patients achieve important recovery of renal function. Thus, significant progress has been made recently in determining whether RAS is a frequent, treatable cause of renal failure. The decision to recommend revascularization remains a difficult balance between the risks and expense of the procedure and the undoubted benefits that accrue if renal function is successfully stabilized.
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PMID:Renal artery stenosis: a common, treatable cause of renal failure? 1116 Jul 87

These 25 lessons 1) review the roles of plasma renin levels for causing malignant and most essential hypertension and their related vascular injuries (heart attack, heart failure, kidney failure and stroke); 2) review how antihypertensive anti-R drugs that block renin activity (beta blockers, the first converting enzyme inhibitor from venom, and the first angiotensin receptor blocker) were used to reveal plasma renin involvement in the hypertension of medium and high renin patients and to show; 3) that the 30% with low renin essential hypertension do not respond to R drugs, are not prone to heart attack or stroke, and BP is corrected instead by the natriuretic anti-V drugs (diuretics, spironolactone, CCB, alpha blockers); 4) thus, all hypertensives can be divided into R patients who have too much renin vasoconstriction or V patients who instead have predominant sodium-volume mediation. Furthermore, all antihypertensive drug classes can be divided into R drugs that block the renin factor, or V drugs that reduce body sodium volume; 5) these findings document our conception of two biochemically and physiologically different final factors that sustain all BP in which the sodium-volume factor continuously sustains cardiac output and flow while plasma renin-angiotensin sets total peripheral resistance (TPR), which, within the Poiseuille Equation (BP = cardiac output [CO] x TPR) describes our [Na+-volume x renin-angiotensin vasoconstriction] model that supports all normotension or hypertension; 6) in this light, we designed a visit-by-visit method for treating untreated hypertensives using the ambient plasma renin level and BP responses to guide primary drug therapy against either the V or R factor; and 7) for also correcting nonresponders receiving multiple drugs where renin testing correctly guides addition or subtraction of drugs depending on whether the test indicates unresponsiveness due to a reactive sodium-volume excess, or to lack of effectiveness of an R drug in a V patient or of a V drug in an R patient, or from large reactive increases in renin that override the R drug, calling for strengthening the R and/or removing V drugs. This objective, biochemically based method results in effective longterm BP control of nearly all patients using fewer, but the correct drug(s) for each individual.
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PMID:Abstract, closing summary, and table of contents for Laragh's 25 lessons in pathophysiology and 12 clinical pearls for treating hypertension. 1177 22

Progressive renal failure occurs in a large number of patients even in the absence of the original cause of injury. It is suggested that the initial reduction in nephron number progressively damages the remaining ones. Various mechanisms underlie the pathogenesis of progressive glomerular injury. Several studies have extensively shown that both dietary protein restriction and pharmacologic intervention with ACE-inhibitiors and angiotensin receptor antagonists effectively slow the progression of chronic renal diseases. This article will present treatment recommendations designed to delay the progression of chronic renal disease, to optimize its medical management and to reduce complications induced by renal insufficiency including hypertension, renal osteodystrophy and anemia. Ten steps in the management of patients with chronic renal failure recommended by an international panel of experts based on existing guidelines are presented.
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PMID:[Supportive medical management of patients with chronic renal failure]. 1197 99

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