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By G. Nemrok. University of Minnesota-Morris.

RENOVASCULAR DISEASE Clinical clues to the high-risk patient are sim ilar to the clinical presentations of ischemic renal disease shown in Figure 3-25 cheap pioglitazone 15 mg without a prescription diabetes symptoms groin itch. Nearly 75% of adults with a unilateral sm all kidney have sustained this renal atrophy due to large vessel occlusive disease from atherosclerosis cheap pioglitazone 45mg overnight delivery blood sugar conversion. Generalized atherosclerosis obliterans O ne third of these patients with a unilateral sm all kidney have Presumed renovascular hypertension high-grade stenosis of the artery involving the contralateral normal- Unilateral small kidney sized kidney buy pioglitazone 30 mg free shipping blood glucose vs serum glucose. Flash pulm onary edem a is another clue to bilateral Unexplained azotemia renovascular disease or high-grade stenosis involving a solitary Deterioration in renal function with BP reduction and/or ACE inhibitor therapy functioning kidney. These patients, usually hypertensive and with Flash pulmonary edema docum ented coronary artery disease and underlying hypertensive heart disease, present with the abrupt onset of pulm onary edem a. Left ventricular ejection fractions in these patients are not seriously im paired. Flash pulm onary edem a is associated with atherosclerotic FIGURE 3-28 renal artery disease and may occur with or without severe hypertension. Clinical clues to bilateral atherosclerotic renovascular disease. Renal revascularization to preserve kidney function or to prevent The patient at highest risk for developing renal insufficiency from life-threatening flash pulmonary edema may be considered in patients renal artery stenosis (ischem ic nephropathy) has sufficient arterial with high-grade arterial stenosis to a solitary kidney or high-grade stenosis to threaten the entire renal functioning m ass. Pecutaneous translum inal renal risk patients have high-grade (m ore than 75% ) arterial stenosis angioplasty (PTRA), renal artery stenting, or surgical renal revascu- to a solitary functioning kidney or high-grade (m ore than 75% ) larization m ay be em ployed. Patients with chronic total renal artery bilateral renal artery stenosis. Patients with two functioning occlusion bilaterally or in a solitary functioning kidney are candidates kidneys with only unilateral renal artery stenosis are not at for surgical renal revascularization, but are not candidates (from a significant risk for developing renal insufficiency because the technical standpoint) for PTRA or renal artery stents. Clinical clues suggesting PREDICTORS OF KIDNEY SALVAGEABILITY renal viability include 1) kidney size greater than 9 cm (pole-to- pole length) by lam inography (tom ography); 2) som e function of the kidney on either urogram or renal flow scan; 3) filling of distal renal arteries (by collaterals) angiographically, when the Kidney size >9 cm (laminography) m ain renal artery is totally occluded proxim ally (see Fig. Patients with m oderately severe Glomerular histology on renal biopsy azotem ia, eg, serum creatinine m ore than 3-4 m g/dL, are likely to have severe renal parenchym al scarring (see Fig. Exceptions to this observation are cases of FIGURE 3-29 total m ain renal artery occlusion wherein kidney viability is Predictors of kidney salvageability. In evaluating patients as m aintained via collateral circulation (see Figure 3-30). A kidney candidates for renal revascularization to preserve or im prove biopsy m ay guide subsequent decision m aking regarding renal renal function, som e determ ination should be m ade of the revascularization for the goal of im proving kidney function. FIGURE 3-30 This abdom inal aortogram reveals com - plete occlusion of the left m ain renal artery (panel A) with filling of the distal renal artery branches from collateral supply on delayed film s (panel B). The observation of collateral circulation when the m ain renal artery is totally occluded proxim ally suggests viable renal parenchym a. The biopsy in a patient with severe bilateral renal artery stenosis and a serum shows hypoperfused retracted glomeruli consistent with ischemia. The biopsy dem onstrates glom erular scle- There is no evidence of active glomerular proliferation or glomerular rosis, tubular atrophy, and interstitial fibrosis. Note intact tubular basement membranes and negligible glom erular and interstitial scarring predict irreversible loss of kidney interstitial scarring. Left renal revascularization resulted in recovery viability. This abdominal aortogram demonstrates a ragged aorta, total occlusion of the right main renal artery, and subtotal occlusion of the proximal left main renal artery. Such patients are at high-risk for atheroembolic renal disease following aortography, selective renal arteriography, pecutaneous transluminal renal angioplasty, renal artery stenting, or surgical renal revascularization. FIGURE 3-34 (see Color Plate) “Purple toe” syndrom e reflecting peripheral atheroem bolic disease in the patient in Figure 3-33 (ragged aorta), following an abdom inal aortogram. M icroem boli of atherom atous m aterial are readily identified by the characteristic appearance of cholesterol crystal inclusions that appear in a biconvex needle-shaped form. In routine paraffin-em bedded histologic sections, the cholesterol is not seen because the m ethods used in preparing sections dissolve the crystals; the characteristic biconvex clefts in the glom eruli (or blood vessels) persist, allowing easy identification. Several patterns of renal failure in patients with AERD are recognized: 1) insult (eg, abdom inal aortogram ) leads to end-stage renal disease (ESRD) over weeks to m onths; 2) insult leads to chronic stable renal insufficiency; 3) m ultiple insults (repeated angiographic procedures) lead to a step-wise rise in serum creatinine eventuating in end-stage renal failure; and 4) insult leading to ESRD over several weeks to m onths with recovery of som e renal function allowing for discontinuance of dialysis. FIGURE 3-36 Renal biopsy dem onstrating severe arteriolar nephrosclerosis. Arteriolar nephrosclerosis is intimately associated with hypertension. The histology of the kidney in arteriolar nephrosclerosis shows considerable variation in intensity and extent of the arteriolar lesions. Thickening of the vessel wall, edem a of the sm ooth m uscle cells, hypertrophy of the sm ooth m uscle cells, and hyaline degenera- tion of the vessel wall m ay be apparent depending on the severity of the nephrosclerosis. In addition to the vascular lesions of arteriolar nephrosclerosis there are abnorm alities of glom eruli, tubules, and interstitial areas that are believed to be secondary to the ischem ia that results from arteriolar insufficiency. Arteriolar nephrosclerosis is observed in patients with longstanding hypertension; the m ore severe the hypertension, the more severe the arteriolar nephrosclerosis. Arteriolar nephrosclerosis m ay also be seen in elderly norm otensive individuals and is frequently observed in elderly patients with gener- alized atherosclerosis or essential hypertension. FIGURE 3-37 Schematic representation of ischemic nephropathy. Patients with atherosclerotic renal artery Atherosclerosis Nephrosclerosis disease (ASO-RAD) often have coexisting renal parenchymal disease with varying degrees of nephrosclerosis (small vessel disease) or atheroembolic renal disease. W hether or not the renal insufficiency is solely attributable to renal artery stenosis, nephrosclerosis, or atheroembolic renal disease is difficult to determine. The term “ischemic nephropathy” is more complex than being simply due to atherosclerotic renal artery stenosis. In addition, in the azotemic patient with ASO- Atheroembolism RAD, one should exclude other potential or contributing causes of renal insufficiency such as obstructive uropathy, primary glomerular disease (suggested by heavy proteinuria), drug-related renal insufficiency (eg, nonsteroidal anti-inflammatory drugs), and uncontrolled blood pressure. Renovascular Hypertension and Ischemic Nephropathy 3. Atherosclerotic renal artery disease (ASO- 11% Other RAD) has been claimed to contribute to the ESRD population. This diagram from the US Renal Data System Coordinating Center 1994 report indicates that 29% of calendar year 12% 1991 incident patients entered ESRD programs because of “hypertension (HBP). Crude estimates of the percentage of patients entering DM ESRD programs because of ASO-RAD range from 1. Precise bases for making 5% these estimates are both unclear and confounded by the high likelihood of coexisting arterio- Urology 29% lar nephrosclerosis, type II diabetic nephropathy, and atheroembolic renal disease. ASO-RAD High blood as a major contributor to the ESRD population is probably small on a percentage basis, occu- 3% pressure Cyst pying some portion of the ESRD diagnosis “hypertension (HBP). Treatment of Renovascular Hypertension and Ischemic Nephropathy FIGURE 3-39 TREATM ENT OPTIONS FOR RENOVASCULAR Treatment options for renovascular hypertension and ischemic HYPERTENSION AND ISCHEM IC NEPHROPATHY nephropathy. The main goals in the treatment of renovascular hyper- tension or ischemic nephropathy are to control the blood pressure, to prevent target organ complications, and to avoid the loss of renal Pharmacologic antihypertensive therapy function. Although the issue of renal function may be viewed as PTRA mutually exclusive from the issue of blood pressure control, uncon- trolled hypertension may hasten a decline in renal function, and Renal artery stents renal insufficiency may produce worsening hypertension. Even in the Surgical renal revascularization presence of excellent blood pressure control, progressive arterial stenosis might worsen renal ischemia and promote renal atrophy and fibrosis.

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This RCT was pioglitazone 15 mg cheap diabetes symptoms numb lips, however purchase 45mg pioglitazone otc blood glucose definition, of good quality and found no significant difference in outcomes among patients treated with strict or lenient rate control except for stroke risk buy pioglitazone 15 mg lowest price can you reverse diabetes in dogs, which favored lenient rate control. However, further studies are needed that are adequately powered to evaluate clinically meaningful outcomes, including stroke risk, and these studies should also be carried out among general patients with AF but also among subgroups of patients, such as those with heart failure. In order to better compare future studies, achieving consensus on standardized definitions of strict and lenient rate control is needed. There also remains a need to define how best to assess the adequacy of rate control. Some investigators have relied on periodic Holter monitoring, but it remains unclear whether this is the best way to assess this important outcome. Research Gaps: Rate-Control Procedures Versus Drugs in Patients for Whom Initial Pharmacotherapy Was Ineffective Evidence gaps in the comparative effectiveness of rate-control procedures versus drugs in patients for whom initial pharmacotherapy was ineffective include: 127 • What are the comparative safety and effectiveness of newer procedural and other nonpharmacological rate-control therapies compared with pharmacological agents in patients with AF for whom initial pharmacotherapy was ineffective? Six RCTs examined this question but compared fairly different treatments for rate control, thus limiting our ability to combine studies to strengthen the power of these results. In terms of assessing subgroups of interest, only one study compared the comparative effectiveness of treatments among patients with a left ventricular ejection fraction (LVEF) ≤45 percent. Given the renewed interest in treatment of AF with rate-control therapies, it is somewhat surprising how few studies compared the effectiveness of different rate-control strategies. Further study is needed to evaluate AVN (or His bundle) ablation with pacemaker as well as specific rate-control agents for rate control and symptom management for patients who cannot tolerate pharmacological therapies. AVN ablation with pacemaker placement needs to be studied further regarding its effects on patients with different AF duration, type of AF, or underlying conditions such as heart failure. Further study is also needed to evaluate additional pacing strategies and the use of concomitant biventricular pacing. The timing of AVN ablation and pacemaker implantation needs to be better defined given that this procedure is one of last resort in patients with AF. All of the above treatment strategies should be evaluated in subgroups of interest such as sex, age, left ventricular function, and other comorbidities. In addition, further studies are needed to determine if treatment outcomes vary in patients with different types of AF. Research Gaps: Antiarrhythmic Drugs and Electrical Cardioversion for Conversion to Sinus Rhythm Evidence gaps in the comparative effectiveness of antiarrhythmic drugs and electrical cardioversion for conversion to sinus rhythm include: • What are the comparative safety and effectiveness of available antiarrhythmic agents and electrical cardioversion procedures for conversion of AF to sinus rhythm? Although 42 studies evaluated different approaches to cardioversion, the treatment arms were highly divergent and outcomes of interest were not reported for specific subgroups. Therefore, future research in this area needs to focus on subgroups of interest, in particular patients with underlying heart disease or heart failure. Differences in the comparative effectiveness of such treatments may also exist by sex, race, or age of patients. In addition, further research is needed to determine the most appropriate subsequent treatment step following a failed electrical 128 cardioversion. A specific area for future research would be to explore the risk for proarrhythmias especially in women (and particularly with certain medications like dofetilide). Research Gaps: Rhythm-Control Procedures and Drugs for Maintenance of Sinus Rhythm Evidence gaps in the comparative effectiveness of rhythm-control drugs and procedures for the maintenance of sinus rhythm include: • What are the comparative safety and effectiveness of newer procedural rhythm-control therapies, other nonpharmacological rhythm-control therapies, and pharmacological agents (either separately or in combination with each other) for maintenance of sinus rhythm in patients with AF? Sixty-two studies evaluated the comparative effectiveness of the relatively newer procedural rhythm-control therapies. However, these studies were not conducted in subgroups of interest and in general did not evaluate longer term outcomes. Despite the large number of trials, there is a need for further study to determine the comparative effectiveness of these procedures on longer term outcomes, including mortality, the occurrence of stroke, and heart failure. It is not clear if certain procedures achieve better outcomes in subgroups of patients, based either on underlying cardiac characteristics or duration or type of AF. It is also not clear if anticoagulation can be stopped safely after rhythm control has been achieved or the timing of this. Further study is needed on issues related to quality of life and cost. Although there are numerous drug therapies available for rhythm control of AF, the included RCTs all compare different combinations of drugs, limiting our ability to synthesize these results to increase their power. In addition, most studies of drug therapies reported outcomes related to rhythm control, while fewer reported long-term outcomes or complications related to therapy. Six studies did evaluate outcomes by subgroups of interest; however, these studies generally evaluated outcomes of rhythm control. Five studies reported longer-term outcomes, but these outcomes were not reported for subgroups of interest. Only one study evaluated quality of life, and the agents compared—digoxin and verapamil—are generally not used for rhythm control. Future studies are needed to compare the effectiveness of the most commonly used agents for rhythm control, and future studies are needed to evaluate longer-term outcomes, including mortality and cardiac outcomes such as heart failure, as well as outcomes related to adverse effects and quality of life, particularly for agents such as amiodarone which are known to have the potential for significant adverse effects. Unfortunately, long-term studies involving procedures are often difficult to design and execute. In addition to the need for significant resources, there are issues of cross over between arms, lack of compliance with the therapy, and loss of patients back to their referring physician making long-term followup difficult. Research Gaps: Rate- Versus Rhythm-Control Therapies Evidence gaps in the comparative effectiveness of rate- and rhythm-control strategies include: • What are the comparative safety and effectiveness of rate-control therapies versus rhythm-control therapies in patients with AF? Fourteen RCTs evaluated the comparative effectiveness of rate-control therapies versus rhythm-control therapies in patients with AF; however, few of these studies examined this issue in subgroups of interest. While studies have shown that a rate-control strategy is at least as good as a rhythm-control strategy, this may be only true in patients similar to the patients enrolled in the clinical trials; i. Studies that focus on younger patients or patients with more symptomatic AF would be of interest to the clinical and policymaking community. Also, trials evaluating longer term outcomes tended to be trials that included pharmacological agents, particularly for rhythm control. Few studies compared rate-control therapies to procedural-based rhythm-control therapies, which could be associated with fewer adverse effects than antiarrhythmic drug therapy. These newer procedural-based rhythm-control therapies should be compared with rate-control therapies for longer term outcomes including mortality, cardiac events, and stroke, as well as for adverse effects. Conclusions In assessing clinical outcomes associated with rate- versus rhythm-control strategies, our review of recent evidence agrees with prior reviews demonstrating little overall difference in outcomes between these two strategic approaches. However, it is important to acknowledge that these studies have focused primarily on a subset of patients with AF (typically older patients with fewer symptoms), and differences between the strategic approaches in other patients are largely unknown. In addition, there is a wide range of options within each strategic approach. Very few studies evaluated the comparative safety and effectiveness of specific rate-control drugs or procedures especially within specific subgroups of patients who are likely to be encountered in clinical practice (such as those with heart failure). In addition, very few studies were done to assess outcomes associated with strict versus more lenient rate-control targets. The wide variety of rhythm-control drugs and procedures also posed a challenge to quantitative assessments of the comparative safety and effectiveness of these different drugs and procedures. Importantly, the review highlights the need for more data on the effect of these procedures on final outcomes such as mortality, stroke, and cardiovascular hospitalizations. ACC/AHA/ESC 2006 Guidelines for the Temporal relations of atrial fibrillation and Management of Patients with Atrial congestive heart failure and their joint Fibrillation: a report of the American influence on mortality: the Framingham College of Cardiology/American Heart Heart Study. Association Task Force on Practice 2003;107(23):2920-5.

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Thirty-one of 32 Total 63 32 69 23 187 arteries with 60% to 79% stenosis using arteriography were identified as having 60% to 99% stenosis on duplex ultrasound and 67 of 69 arteries with 80% to 99% stenosis on arteriography were detected Sensitivity buy 30mg pioglitazone overnight delivery diabetes medications covered by medicare, 0 pioglitazone 45mg line metabolic disease questions. N evertheless purchase pioglitazone 45mg without prescription diabetes medications and bladder cancer, duplex ultrasound is currently highly sensitive and specific in patients with a high likelihood of renovascular disease in detecting patients with more or less than 60% renal artery stenosis. Accessory renal arteries are difficult to identify by ultra- sound and rem ain a lim itation of this test. Reductions of lum en diam eter of less SIGNIFICANCE OF THE STENOTIC LESION than 70% to 80% generally do not initiate renal ischem ia or acti- vation of the renin angiotensin system ; thus, before recom m end- ing a renal revascularization procedure, severe renal artery steno- Duration of hypertension <3–5 y sis (>75% reduction in lum en diam eter) should be observed on Appearance of lesion on angiogram (>75% stenosis) the renal angiogram. A lateralizing renal vein renin ratio (a com - Systolic-diastolic bruit in abdomen parison of renin harvested from the renal vein ipsilateral to the Renal vein renin ratio >1. Conversely, cure or m arked im provem ent in blood pressure following renal revascu- larization has been reported in nearly 50% of cases in the FIGURE 3-17 absence of lateralizing renal vein renins. H ypokalem ia, in the Determ ination of pathophysiologic significance of the stenotic absence of diuretic therapy, strongly suggests that the hyperten- lesion. The second step in m aking the diagnosis of renovascular sion is renovascular in origin, consequent to secondary aldostero- hypertension (RVH T) is to determ ine the pathophysiologic signif- nism. The sensitivity of an IVP in detecting unilateral RVH T is icance of the stenotic lesion dem onstrated by angiography. The relatively poor (about 75% ) and the overall sensitivity in detect- likelihood of cure of the hypertension by an interventive m aneu- ing patients with bilateral renal artery disease is only about 60%. A positive captopril provocation test, abnorm al rapid negative IVP provides strong evidence (98% to 99% certainty) sequence intravenous pyelogram (IVP), or positive captopril against RVH T. Renovascular Hypertension and Ischemic Nephropathy 3. The notion that patients with high PRA, even in the DISTINGUISH PATIENTS W ITH RVHT FROM face of high urinary sodium excretion, m ight turn out to have THOSE W ITH ESSENTIAL HYPERTENSION RVH T has not been supported by num erous clinical observations. H owever, the short-term (60- to 90-m inute) response of blood pressure and PRA to an oral dose (25 to 50 m g) of captopril has gained recent popularity as a screening test for presum ed RVH T. Stimulated PRA of 12 ng/mL/h or more Preparation of patients for this test is vital; ideally patients Absolute increase in PRA of 10 ng/mL/h or more should discontinue their antihypertensive m edications, m aintain Percent increase in PRA a diet adequate in salt, and have good renal function. A baseline Increase in PRA of 150% if baseline PRA >3 ng/mL/h blood pressure and PRA are obtained after which captopril is Increase in PRA of 400% if baseline PRA <3 ng/mL/h adm inistered; 60 m inutes after captopril adm inistration, a “post- captopril” PRA is obtained along with repeat m easurem ents of blood pressure. Early reports with this test indicated a high sensi- tivity and specificity (95% to 100% ) in identifying RVH T if all FIGURE 3-18 three of the renin criteria listed here were m et. Subsequent The captopril test: renin criteria that distinguish patients with reports have not been as encouraging such that the overall sensi- renovascular hypertension from those with essential hypertension. A, TcDPTA tim e-activity curves during asym m etry of renal size and function and on specific, captopril- baseline. B, TcDPTA tim e-activity curves after captopril adm inis- induced changes in the renogram, including delayed time to maximal tration. These curves represent a captopril renogram in a patient activity (≥11 m inutes), significant asym m etry of the peak of each with unilateral left renal artery stenosis. This diagnostic test has been kidney, m arked cortical retention of the radionuclide, and m arked used to screen for renal artery stenosis and to predict renovascular reduction in the calculated glom erular filtration rate of the kidney hypertension. Captopril renography appears to be highly sensitive ipsilateral to the stenosis. O ne m ust interpret the clinical and reno- and specific for detecting physiologically significant renal artery graphic data with caution, as protocols are com plex and diagnostic stenosis. Scintigrams and time-activity curves should both be analyzed criteria are not well standardized. N evertheless, captopril renogra- to assess renal perfusion, function, and size. If the renogram following phy appears to be an im provem ent over the captopril provocation captopril administration is abnormal (panel B, demonstrating delayed test, with m any reports indicating sensitivity and specificity from time to maximal activity and retention of the radionuclide in the right 80% to 95% in predicting an im provem ent in blood pressure kidney), another renogram may be obtained without captopril for following intervention. The diagnosis of renal artery stenosis is based on with perm ission. A brief duration of moderately severe hypertension is the m ost im portant clue Low (<1%) PRA M oderate (≈5%–15%) High (>25%) directing subsequent work-up for RVHT. Alternatively, in patients highly suspected to have RVHT, a captopril Captopril test, or captopril renogram, or stimulated renal vein renins, renogram followed by a renal arteriogram or (? Strong argum ents against RVHT include 1) long duration (more than 5 years) of hypertension, 2) old age, No further work-up Negative Positive Arteriogram + renal 3) generalized atherosclerosis, 4) increased vein renins serum creatinine, and 5) a normal serum potassium concentration. For these patients, particularly if the blood pressure is only mini- FIGURE 3-20 mally elevated or easily controlled with one or Suggested work-up for renovascular hypertension. Because the prevalence of renovascular hyper- two antihypertensive medications, further tension (RVHT) among hypertensive persons in general is approximately 2% or less, widespread work-up for RVHT is not indicated. Despite the proliferation of diagnostic tests from M ann and Pickering; with permission. This patient presented in 1977 with a recent appearance of hypertension and a blood pressure of 170/115 m m H g. Three years previously, when diagnosed with polycythem ia vera, an IVP was norm al. She was fol- lowed closely between 1974 and 1977 by her physician and was always norm otensive until the hypertension suddenly appeared. A repeat rapid sequence IVP dem onstrated a reduction in the size of the left kidney from 14 cm in height (1974) to 11. The renal arteriogram shown here indi- cates high-grade bilateral renal artery stenosis with the left kidney m easuring 11. Renal vein renins were obtained and lateralized strongly to the sm aller left kidney. The blood pressure was well controlled with inderal and chlorthalidone. Right aortorenal reim plantation was undertaken solely to preserve renal function. Blood pressure continued to require antihypertensive m edication, but was controlled to norm al levels with inderal and chlorthalidone. Renovascular Hypertension and Ischemic Nephropathy 3. This figure describes eight patients hospitalized because of severe hypertension and renal insufficiency. W ith m ed- ical m anagem ent of the hypertension (antihypertensive drug thera- py), four of the eight patients developed substantial worsening of B their renal function as m easured by serum creatinine; three of these four patients dem onstrated im provem ent following surgery or FIGURE 3-23 angioplasty. The other four patients (patients one to four) did not Im proved renal function dem onstrated by intravenous pyelography dem onstrate a worsening serum creatinine level with m edical thera- following left renal revascularization. A, preoperative IVP (5-m inute py; but three of these four patients showed im proved renal func- film ) in a 65-year-old white m an with a 15-year history of hyperten- tion following surgery or angioplasty. Note poorly functioning left kidney, coworkers; with perm ission. B, post operative IVP (5-m inute film) obtained following left aortorenal saphenous vein bypass grafting to the left kidney.