A reader comments on acute cardiorenal syndrome (March 2018).

Although acute kidney injury (AKI) is common in heart failure, yet the impact of the onset, timing, and duration of AKI on short-term outcomes is not well studied. AKI was defined as an increase in serum creatinine SCr of ≥0.3 mg/dl or 1.5 times relative to the admission and further categorized as transient AKI (T-AKI: SCr returning to within 10% of baseline); sustained AKI (S-AKI: those with at least 72 hours of hospital stay and did not meet T-AKI); and unknown duration AKI (U-AKI: those with less than 72 hours stay and did not meet T-AKI). Reference category was no AKI (stable or <0.3 mg/dl change in SCr). The main outcome was 30-day all-cause hospital readmission. Unadjusted and adjusted association between AKI category of interest and main outcome was represented as percent and relative risks with 95% CIs. Statistical significance was set at an alpha of 0.05. From the Cerner Health Facts sample, 14,017 of 22,059 available subjects met the eligibility criteria. Approximately, 19.2% of our sample met the primary outcome. Compared with no AKI (readmission rate of 17.7%; 95% CI 16.4% to 18.9%), the adjusted rate of readmission was highest in patients with S-AKI (22.8%, 95% CI 20.8% to 24.8%; p <0.001), followed by 20.2% (95% CI 17.5% to 22.8%; p = 0.05) in T-AKI patients. Compared with no AKI, the adjusted relative risk of 30-day readmission was 1.29 (95% CI 1.17 to 1.42), 1.14 (95% CI 1.00 to 1.31), and 1.12 (95% CI, 1.01 to 1.26) in S-AKI, T-AKI, and U-AKI, respectively. In conclusion, both sustained AKI and patients with transient elevation still remain at a higher risk of readmission within 30 days. Future studies should focus on examining process-of-care after discharge in patients with different patterns of AKI.

Chronic kidney disease (CKD) is often the result of incomplete recovery of renal function from a variety of causes of acute tubulointerstitial injury. Exposure to ethylene glycol, chlorinated hydrocarbons, paraquat, or toxic mushrooms often causes severe acute kidney injury (AKI), leading to chronic tubulointerstitial nephritis (TIN) and CKD, including end-stage renal disease. Ethylene glycol intoxication often leads to chronic TIN and CKD from direct renal tubular toxicity and from interstitial calcium oxalate deposition. Chlorinated hydrocarbon exposure can cause dialysis-dependent AKI, but only rarely causes CKD from interstitial calcium deposition. Paraquat intoxication causes dose-dependent AKI and often Fanconi syndrome in up to 50% of patients, but only 15% of these patients survive, so CKD is rarely seen as a complication. The toxic mushrooms Cortinarius and Amanita phalloides often cause delayed AKI leading to CKD, chronic dialysis, or renal transplantation.

Commentary on Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014;370(1):13-22.Atherosclerotic renal artery stenosis is common, especially among patients older than 50 years and with atherosclerosis in other vascular beds.1Zoccali C. Mallamaci F. Finocchiaro P. Atherosclerotic renal artery stenosis: epidemiology, cardiovascular outcomes, and clinical prediction rules.J Am Soc Nephrol. 2002; 13: S179-S183Crossref PubMed Google Scholar The introduction of endovascular techniques as an alternative to surgical revascularization led to widespread application, with more than 20,000 renal artery stent placements annually by 2000.2Murphy T.P. Soares G. Kim M. Increase in utilization of percutaneous renal artery interventions by Medicare beneficiaries, 1996-2000.AJR Am J Roentgenol. 2004; 183: 561-568Crossref PubMed Scopus (108) Google Scholar These procedures usually are undertaken with the intention to improve blood pressure control or stabilize kidney function. In clinical practice, it is unclear how frequently these goals are achieved and how outcomes compare with optimal medical treatment alone. In addition, atherosclerotic renal artery stenosis is associated strongly with cardiovascular morbidity and mortality,3Conlon P.J. Athirakul K. Kovalik E. et al.Survival in renal vascular disease.J Am Soc Nephrol. 1998; 9: 252-256PubMed Google Scholar but most studies evaluating the effects of endovascular treatment of atherosclerotic renal artery stenosis have been underpowered to assess these hard end points. In order to address these important issues, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) Study recently was completed and published in the New England Journal of Medicine.4Cooper C.J. Murphy T.P. Cutlip D.E. et al.Stenting and medical therapy for atherosclerotic renal-artery stenosis.N Engl J Med. 2014; 370: 13-22Crossref PubMed Scopus (634) Google ScholarWhat Does This Important Study Show?CORAL was a large, multicenter, open-label, randomized, controlled trial (RCT) comparing medical therapy alone to medical therapy plus stenting in patients with atherosclerotic renal artery stenosis and hypertension, chronic kidney disease, or both. The primary end point was a composite of cardiovascular events (hospitalization for congestive heart failure, myocardial infarction, or cerebrovascular accident), kidney outcomes (a 30% reduction in estimated glomerular filtration rate computed from the 4-variable Modification of Diet in Renal Disease [MDRD] Study equation or need for dialysis therapy), and mortality over a median of 43 months. Medical therapy consisted of a protocol based on national guidelines for the management of cardiovascular risk factors, including hypertension, smoking, dyslipidemia, diabetes, and chronic kidney disease. Hypertension therapy consisted of a prespecified algorithm starting with candesartan (Table 1).Table 1Optimal Medical Therapy for Atherosclerotic Renal Artery Stenosis in CORALCardiovascular Risk FactorGoal of TherapyGuidelineTherapiesHypertension without comorbid conditions With diabetes With CKDBP, <140/90 mm HgBP, <130/80 mm HgBP, <130/80 mm HgJNC 71. Candesartan (lisinopril)2. DiureticaDiuretic was hydrochlorothiazide (provided in combination with candesartan by a voucher system without cost to patient) or furosemide for creatinine level>2mg/dL.3. OtherbStep 3 antihypertensive therapy was left to the discretion of the site investigator and guided by comorbid conditions and could include calcium channel blocker, β-blocker, vasodilator, or α-blocker; Caduet (amlodipine besylate/atorvastatin calcuim; Pfizer Inc) was available through a voucher system without cost to patients.HyperlipidemiaLDL-C, < 70 mg/dLATP IIILifestyle modificationMedical therapy/statinDiabetesHemoglobin A1c, < 7%ADAUsual therapiesSmokingCessationAHAHouston-Miller and TaylorEducation/local resourcesCKDManage potassium, phosphorus, anemiaKDOQIUsual therapiesAtherosclerosisAntiplatelet effectAHAAspirin, clopidogrel, ticlopidineNote: Conversion factor for units: LDL-C in mg/dL to mmol/L, ×0.02586.Abbreviations: ADA, American Diabetes Association; AHA/ACC, American Heart Association/American College of Cardiology; ATP, National Heart Lung and Blood Institute Adult Treatment Panel; BP, blood pressure; CKD, chronic kidney disease; CORAL, Cardiovascular Outcomes in Renal Atherosclerotic Lesions; JNC, Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure; KDOQI, National Kidney Foundation Kidney Disease Outcomes Quality Initiative; LDL-C, low-density lipoprotein cholesterol.a Diuretic was hydrochlorothiazide (provided in combination with candesartan by a voucher system without cost to patient) or furosemide for creatinine level > 2 mg/dL.b Step 3 antihypertensive therapy was left to the discretion of the site investigator and guided by comorbid conditions and could include calcium channel blocker, β-blocker, vasodilator, or α-blocker; Caduet (amlodipine besylate/atorvastatin calcuim; Pfizer Inc) was available through a voucher system without cost to patients. Open table in a new tab CORAL trial design was based on 3 important premises. First was the concept that available data supported clinical equipoise regarding the role of stenting in atherosclerotic renal artery stenosis regardless of patient characteristics. Sites were encouraged to enroll all eligible patients, and it was assumed that investigators could not predict which patients would benefit from stenting. Second was the assumption that blood pressure could be controlled with or without stenting. The effect of therapy on blood pressure was not a primary end point, and investigators were charged with achieving equal blood pressure control in both study arms. To this end, each site had an interventional angiographer and a separate hypertension expert (nephrologist, cardiologist, or hypertension specialist) managing risk factors. A risk factor oversight committee tracked progress and assisted sites in achieving target blood pressures using a prespecified protocol. Third, CORAL was the first trial to mandate angiotensin receptor blockers or angiotensin-converting enzyme inhibitors as first-line therapy in the hypertension management protocol.5Dworkin L. Murphy T. In the literature: is there any reason to stent atherosclerotic renal artery stenosis?.Am J Kidney Dis. 2010; 56: 259-263Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar The rationale was that stenting should be compared to medical therapy that could optimally mitigate the adverse effects of an activated renin-angiotensin-aldosterone system (RAAS) due to atherosclerotic renal artery stenosis.Blood pressure control in CORAL was achieved using a similar number of antihypertensive medications, regardless of randomization to stenting or medical therapy alone (3.3 vs 3.5). Importantly, there was a 15– to 16–mm Hg improvement in systolic blood pressure in both study arms that was maintained throughout the study. In contrast to other RCTs, difficult-to-control blood pressure was not an indication to cross over to the stent arm.CORAL reported no significant difference in the frequency of the composite primary end point between groups randomly assigned to stenting plus medical therapy or medical therapy alone (35.1% and 35.8% respectively; hazard ratio with stenting, 0.94 [95% confidence interval (CI), 0.76-1.17]; P = 0.58). In addition, there was no significant difference in all-cause mortality or any of the individual components of the primary composite outcome. During follow-up, there was a small but significant difference in blood pressure favoring the stent group (−2.3 [95% CI, −4.4 to −0.2] mm Hg; P = 0.03), which did not influence the primary outcome. Subgroup analysis failed to show a benefit of stenting in patients with the highest degree of stenosis (>80%) or bilateral atherosclerotic renal artery stenosis.Though a well-conducted trial, CORAL has some important limitations. Enrollment did not require true resistant hypertension or corroborative data to support the presence of renovascular hypertension, such as lateralizing renal vein renin levels. Similar to other RCTs discussed next, many enrolled participants may have had essential hypertension and hypertensive nephrosclerosis, conditions unlikely to benefit from stenting. Exclusion criteria precluded enrolling patients with episodes of congestive heart failure within the past 30 days, a group of patients that may benefit from stenting.6Cooper C. Murphy T. Matsumoto A. et al.Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial.Am Heart J. 2006; 152: 59-66Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar During recruitment, more than 2,000 screened individuals were not randomly assigned based on patient or physician preference or reasons not specified. Accordingly, it is likely that some high-risk patients were not enrolled. Finally, although the study initially required angiographically defined atherosclerotic renal artery stenosis, a later protocol change opened a pathway for randomization based on noninvasive imaging, leading to ∼25% enrollment based on duplex ultrasound criteria without angiographic confirmation in those randomly assigned to medical therapy alone.How Does This Study Compare With Prior Studies?Prior to CORAL, there were 6 published RCTs of medical therapy versus medical therapy plus renal artery endovascular intervention.7Khumbani D.J. Bavry A.A. Harvey J.E. et al.Clinical outcomes after percutaneous revascularization versus medical management in patients with significant renal artery stenosis: a meta-analysis of randomized controlled trials.Am Heart J. 2011; 161: 622-630Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar In all 6 studies, no significant difference in outcomes was found between groups treated with the intervention versus medical therapy alone. Studies published prior to 2001 were limited by small numbers of participants, use of angioplasty without stenting, and evaluation of outcomes limited to blood pressure control and/or changes in kidney function. In addition, 2 studies had high crossover rates (26% and 44%) from medical therapy to endovascular intervention.8van Jaarsveld B.C. Krijnen P. Pieterman H. et al.The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group.N Engl J Med. 2000; 342: 1007-1101Crossref PubMed Scopus (810) Google Scholar, 9Plouin P.F. Chatellier G. Darne B. et al.Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group.Hypertension. 1998; 31: 823-829Crossref PubMed Scopus (565) Google ScholarCORAL set out to avoid the pitfalls of the other RCTs by including a large number of participants with hemodynamically significant atherosclerotic renal artery stenosis. CORAL enrolled the largest number of participants of all these trials (947 participants), and all participants had renal artery imaging reviewed by an angiographic core laboratory. Approximately 70% of participants were randomly assigned based on angiographically defined atherosclerotic renal artery stenosis > 60%. In contrast, 2 prior small trials randomly assigned participants based on noninvasive imaging.10Scarpionni R. Michieletti E. Cristinelli L. et al.Atherosclerotic renovascular disease: medical therapy versus medical therapy plus renal artery stenting in preventing renal failure progression. The rationale and study design of a prospective, multicenter and randomized trial (NITER).J Nephrol. 2005; 18: 423-428PubMed Google Scholar, 11Bax L. Wolttlez A.J. Kouwenberg H.J. et al.Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function.Ann Intern Med. 2009; 150: 840-848Crossref PubMed Scopus (533) Google Scholar Both the Stent Placement in Patients With Atherosclerotic Renal Artery Stenosis and Impaired Renal Function (STAR) and Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trials enrolled patients using a lower (>50%) stenosis threshold and subsequently were criticized for including participants with non–hemodynamically significant atherosclerotic renal artery stenosis.5Dworkin L. Murphy T. In the literature: is there any reason to stent atherosclerotic renal artery stenosis?.Am J Kidney Dis. 2010; 56: 259-263Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 11Bax L. Wolttlez A.J. Kouwenberg H.J. et al.Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function.Ann Intern Med. 2009; 150: 840-848Crossref PubMed Scopus (533) Google Scholar, 12The ASTRAL InvestigatorsRevascularization versus medical therapy for renal-artery stenosis.N Engl J Med. 2009; 361: 1953-1962PubMed Google Scholar CORAL also sought to avoid the selection bias inherent in prior trials. For example, in ASTRAL, participants were enrolled only if there was uncertainty that the patient would have a worthwhile clinical benefit from revascularization,11Bax L. Wolttlez A.J. Kouwenberg H.J. et al.Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function.Ann Intern Med. 2009; 150: 840-848Crossref PubMed Scopus (533) Google Scholar suggesting that there were some patients, likely those with more significant atherosclerotic renal artery stenosis, for whom investigators were certain there would be a benefit associated with revascularization. Enrollment in STAR required blood pressure to be controlled prior to entry.Another important difference between CORAL and prior RCTs was the lower frequency of reported kidney and cardiovascular events. Despite a longer median follow-up (43 vs 33 months), mortality, cardiovascular events, and progression to end-stage renal disease were lower in CORAL than ASTRAL. In CORAL, death from any cause occurred in 13.7% and 16.1% of the stent and medical groups, respectively, whereas ASTRAL reported 25.5% mortality for both arms. In CORAL, cardiovascular events occurred in 15% compared to 35% in ASTRAL, and dialysis-dependent kidney failure occurred in 0.9% of CORAL participants versus 8% in ASTRAL.CORAL made great efforts to select sites with experienced interventionalists and required a rigorous roll-in period to ensure adequate technical skill. Despite these precautions, there was a 5.2% complication rate in the stent arm. Complication rates were even higher in other previously published RCTs (7%-31%), including reports of serious adverse events including deaths and atheroembolism.8van Jaarsveld B.C. Krijnen P. Pieterman H. et al.The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group.N Engl J Med. 2000; 342: 1007-1101Crossref PubMed Scopus (810) Google Scholar, 11Bax L. Wolttlez A.J. Kouwenberg H.J. et al.Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function.Ann Intern Med. 2009; 150: 840-848Crossref PubMed Scopus (533) Google Scholar, 12The ASTRAL InvestigatorsRevascularization versus medical therapy for renal-artery stenosis.N Engl J Med. 2009; 361: 1953-1962PubMed Google ScholarWhat Should Clinicians and Researchers Do?Clinicians now have evidence supporting the relative effectiveness and safety of medical therapy compared to stenting for the treatment of atherosclerotic renal artery stenosis. The medical management strategies used in CORAL should serve as a model for best management of these patients. In the past, “uncontrolled” blood pressure was thought to be an indication to consider stenting in patients with atherosclerotic renal artery stenosis.10Scarpionni R. Michieletti E. Cristinelli L. et al.Atherosclerotic renovascular disease: medical therapy versus medical therapy plus renal artery stenting in preventing renal failure progression. The rationale and study design of a prospective, multicenter and randomized trial (NITER).J Nephrol. 2005; 18: 423-428PubMed Google Scholar, 13Hirsch A.T. Haskal Z.J. Hertzer N.R. et al.ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary—a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.J Am Coll Cardiol. 2006; 47: 1239-1312Abstract Full Text Full Text PDF PubMed Scopus (1059) Google Scholar CORAL shows that stenting is not associated with clinically significant improvement in blood pressure control in most patients or with reduced antihypertensive medication requirements. Clinicians caring for patients with atherosclerotic renal artery stenosis need to closely evaluate their individual threshold for recommending stenting based solely on “uncontrolled” hypertension. CORAL highlights the important role of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors as the foundation for blood pressure control in atherosclerotic renal artery stenosis. In CORAL, these agents appeared both effective and safe (when delivered/monitored by expert hypertension specialists) even in patients with bilateral stenoses or atherosclerotic renal artery stenosis to a single functioning kidney. This challenges traditional teaching that RAAS blockade is contraindicated in these patients due to the risk of acute kidney injury.Though stenting is not superior to medical therapy that is focused on blood pressure control with RAAS antagonists and aggressive cardiovascular risk management, in some patients, medical therapy will fail. Recognition of these high-risk clinical phenotypes, likely under-represented in RCTs, should prompt consideration of renal revascularization (Box 1). Further investigations are needed to develop accurate methods (eg, radiographic studies and biomarkers) to identify patients most likely to benefit from endovascular interventions. The establishment of multicenter registries could help this endeavor.Box 1High-Risk Patients With Atherosclerotic Renal Artery Stenosis in Whom Medical Therapy FailedIschemic nephropathy•Recent rapid decline in kidney function due to reduced glomerular capillary pressure associated with high-grade atherosclerotic renal artery stenosis and not consistent with the course of hypertensive nephrosclerosis or other kidney disease•Acute or subacute kidney injury due to angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy due to the presence of atherosclerotic renal artery stenosis without other cause and with compelling indication for these medications (cardiomyopathy, renovascular hypertension, and proteinuric kidney disease)•Progressive kidney function decline and/or kidney atrophy with imaging or biomarkers supporting atherosclerotic renal artery stenosis as the causeResistant renovascular hypertension•Resistant renovascular hypertension with end-organ risk or injury despite optimal medical therapy under the care of a hypertension specialist with collaborative efforts among specialistsRecurrent flash pulmonary edema•Frequent hospitalizations for otherwise unexplained episodes of pulmonary edema in the presence of hemodynamically significant atherosclerotic renal artery stenosis following failed attempts to treat medicallyIntolerance of or nonadherence to optimal medical therapyClinicians and patients considering the option of stenting should be aware of potential complications. These risks should be weighed against the uncertain benefits of renal artery stenting on a case-by-case basis. In addition, a strategy for monitoring and treatment of in-stent stenosis needs to be defined prior to intervention.14Boateng F. Greco B. Renal artery stenosis: prevalence of, risk factors for, and management of in-stent stenosis.Am J Kidney Dis. 2012; 61: 147-160Abstract Full Text Full Text PDF PubMed Scopus (28) Google ScholarAs we attempt to optimize care of patients with atherosclerotic renal artery stenosis, attention should shift toward aggressive cardiovascular risk factor management and identification of patients for whom best therapy is failing. In these high-risk patients, close collaboration between specialists mirroring the paradigm in CORAL should guide decisions regarding optimal treatment. Commentary on Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014;370(1):13-22. Commentary on Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014;370(1):13-22. Commentary on Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med. 2014;370(1):13-22. Atherosclerotic renal artery stenosis is common, especially among patients older than 50 years and with atherosclerosis in other vascular beds.1Zoccali C. Mallamaci F. Finocchiaro P. Atherosclerotic renal artery stenosis: epidemiology, cardiovascular outcomes, and clinical prediction rules.J Am Soc Nephrol. 2002; 13: S179-S183Crossref PubMed Google Scholar The introduction of endovascular techniques as an alternative to surgical revascularization led to widespread application, with more than 20,000 renal artery stent placements annually by 2000.2Murphy T.P. Soares G. Kim M. Increase in utilization of percutaneous renal artery interventions by Medicare beneficiaries, 1996-2000.AJR Am J Roentgenol. 2004; 183: 561-568Crossref PubMed Scopus (108) Google Scholar These procedures usually are undertaken with the intention to improve blood pressure control or stabilize kidney function. In clinical practice, it is unclear how frequently these goals are achieved and how outcomes compare with optimal medical treatment alone. In addition, atherosclerotic renal artery stenosis is associated strongly with cardiovascular morbidity and mortality,3Conlon P.J. Athirakul K. Kovalik E. et al.Survival in renal vascular disease.J Am Soc Nephrol. 1998; 9: 252-256PubMed Google Scholar but most studies evaluating the effects of endovascular treatment of atherosclerotic renal artery stenosis have been underpowered to assess these hard end points. In order to address these important issues, the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) Study recently was completed and published in the New England Journal of Medicine.4Cooper C.J. Murphy T.P. Cutlip D.E. et al.Stenting and medical therapy for atherosclerotic renal-artery stenosis.N Engl J Med. 2014; 370: 13-22Crossref PubMed Scopus (634) Google Scholar What Does This Important Study Show?CORAL was a large, multicenter, open-label, randomized, controlled trial (RCT) comparing medical therapy alone to medical therapy plus stenting in patients with atherosclerotic renal artery stenosis and hypertension, chronic kidney disease, or both. The primary end point was a composite of cardiovascular events (hospitalization for congestive heart failure, myocardial infarction, or cerebrovascular accident), kidney outcomes (a 30% reduction in estimated glomerular filtration rate computed from the 4-variable Modification of Diet in Renal Disease [MDRD] Study equation or need for dialysis therapy), and mortality over a median of 43 months. Medical therapy consisted of a protocol based on national guidelines for the management of cardiovascular risk factors, including hypertension, smoking, dyslipidemia, diabetes, and chronic kidney disease. Hypertension therapy consisted of a prespecified algorithm starting with candesartan (Table 1).Table 1Optimal Medical Therapy for Atherosclerotic Renal Artery Stenosis in CORALCardiovascular Risk FactorGoal of TherapyGuidelineTherapiesHypertension without comorbid conditions With diabetes With CKDBP, <140/90 mm HgBP, <130/80 mm HgBP, <130/80 mm HgJNC 71. Candesartan (lisinopril)2. DiureticaDiuretic was hydrochlorothiazide (provided in combination with candesartan by a voucher system without cost to patient) or furosemide for creatinine level>2mg/dL.3. OtherbStep 3 antihypertensive therapy was left to the discretion of the site investigator and guided by comorbid conditions and could include calcium channel blocker, β-blocker, vasodilator, or α-blocker; Caduet (amlodipine besylate/atorvastatin calcuim; Pfizer Inc) was available through a voucher system without cost to patients.HyperlipidemiaLDL-C, < 70 mg/dLATP IIILifestyle modificationMedical therapy/statinDiabetesHemoglobin A1c, < 7%ADAUsual therapiesSmokingCessationAHAHouston-Miller and TaylorEducation/local resourcesCKDManage potassium, phosphorus, anemiaKDOQIUsual therapiesAtherosclerosisAntiplatelet effectAHAAspirin, clopidogrel, ticlopidineNote: Conversion factor for units: LDL-C in mg/dL to mmol/L, ×0.02586.Abbreviations: ADA, American Diabetes Association; AHA/ACC, American Heart Association/American College of Cardiology; ATP, National Heart Lung and Blood Institute Adult Treatment Panel; BP, blood pressure; CKD, chronic kidney disease; CORAL, Cardiovascular Outcomes in Renal Atherosclerotic Lesions; JNC, Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure; KDOQI, National Kidney Foundation Kidney Disease Outcomes Quality Initiative; LDL-C, low-density lipoprotein cholesterol.a Diuretic was hydrochlorothiazide (provided in combination with candesartan by a voucher system without cost to patient) or furosemide for creatinine level > 2 mg/dL.b Step 3 antihypertensive therapy was left to the discretion of the site investigator and guided by comorbid conditions and could include calcium channel blocker, β-blocker, vasodilator, or α-blocker; Caduet (amlodipine besylate/atorvastatin calcuim; Pfizer Inc) was available through a voucher system without cost to patients. Open table in a new tab CORAL trial design was based on 3 important premises. First was the concept that available data supported clinical equipoise regarding the role of stenting in atherosclerotic renal artery stenosis regardless of patient characteristics. Sites were encouraged to enroll all eligible patients, and it was assumed that investigators could not predict which patients would benefit from stenting. Second was the assumption that blood pressure could be controlled with or without stenting. The effect of therapy on blood pressure was not a primary end point, and investigators were charged with achieving equal blood pressure control in both study arms. To this end, each site had an interventional angiographer and a separate hypertension expert (nephrologist, cardiologist, or hypertension specialist) managing risk factors. A risk factor oversight committee tracked progress and assisted sites in achieving target blood pressures using a prespecified protocol. Third, CORAL was the first trial to mandate angiotensin receptor blockers or angiotensin-converting enzyme inhibitors as first-line therapy in the hypertension management protocol.5Dworkin L. Murphy T. In the literature: is there any reason to stent atherosclerotic renal artery stenosis?.Am J Kidney Dis. 2010; 56: 259-263Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar The rationale was that stenting should be compared to medical therapy that could optimally mitigate the adverse effects of an activated renin-angiotensin-aldosterone system (RAAS) due to atherosclerotic renal artery stenosis.Blood pressure control in CORAL was achieved using a similar number of antihypertensive medications, regardless of randomization to stenting or medical therapy alone (3.3 vs 3.5). Importantly, there was a 15– to 16–mm Hg improvement in systolic blood pressure in both study arms that was maintained throughout the study. In contrast to other RCTs, difficult-to-control blood pressure was not an indication to cross over to the stent arm.CORAL reported no significant difference in the frequency of the composite primary end point between groups randomly assigned to stenting plus medical therapy or medical therapy alone (35.1% and 35.8% respectively; hazard ratio with stenting, 0.94 [95% confidence interval (CI), 0.76-1.17]; P = 0.58). In addition, there was no significant difference in all-cause mortality or any of the individual components of the primary composite outcome. During follow-up, there was a small but significant difference in blood pressure favoring the stent group (−2.3 [95% CI, −4.4 to −0.2] mm Hg; P = 0.03), which did not influence the primary outcome. Subgroup analysis failed to show a benefit of stenting in patients with the highest degree of stenosis (>80%) or bilateral atherosclerotic renal artery stenosis.Though a well-conducted trial, CORAL has some important limitations. Enrollment did not require true resistant hypertension or corroborative data to support the presence of renovascular hypertension, such as lateralizing renal vein renin levels. Similar to other RCTs discussed next, many enrolled participants may have had essential hypertension and hypertensive nephrosclerosis, conditions unlikely to be

Department of Medicine, Tufts University School of Medicine; and Renal Division, Baystate Medical Center, Springfield, MA * See also p. 2584. Dr. Freda lectured for the Roche Diagnostics Speaker’s Bureau and his institution received support for travel from Gambro.

Commentary on Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012;367(24):2296-2304. Commentary on Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med. 2012;367(24):2296-2304. In the United States, more than 1 million patients are admitted annually for acute decompensated heart failure (ADHF). Moreover, many patients with ADHF are discharged without clinical evidence of adequate decongestion.1Freda B.J. Slawsky M. Mallidi J. Braden G.L. Decongestive treatment of acute decompensated heart failure: cardiorenal implications of ultrafiltration and diuretics.Am J Kidney Dis. 2011; 58: 1005-1017Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Approximately 25% of patients with ADHF are readmitted during the next 30 days,2Ross J.S. Chen J. Lin Z. et al.Recent national trends in readmission rates after heart failure hospitalization.Circ Heart Fail. 2010; 3: 97-103Crossref PubMed Scopus (351) Google Scholar and up to 20% die within 6 months.3O'Connor C.M. Hasselblad V. Mehta R.H. et al.Triage after hospitalization with advanced heart failure: the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness) risk model and discharge score.J Am Coll Cardiol. 2010; 55: 872-878Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar During the last 10-20 years, several therapies have been shown to have a beneficial impact on the clinical course of patients with chronic congestive heart failure4McMurray J.J. Clinical practice Systolic heart failure.N Engl J Med. 2010; 362: 228-238Crossref PubMed Scopus (322) Google Scholar; however, similar advances have not occurred for the treatment of ADHF.5Kociol R.D. Konstam M.A. Nesiritide ASCENDs the ranks of unproven treatments for acute heart failure.Am J Kidney Dis. 2012; 60: 8-11Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Although there are multiple facets to achieving the compensated state in ADHF, the main focus ultimately is on therapies directly responsible for removing excess sodium and water. Declining kidney function during treatment of the congested state (ie, cardiorenal syndrome type I) is one of the strongest predictors of short- and long-term adverse events, including readmission and mortality.1Freda B.J. Slawsky M. Mallidi J. Braden G.L. Decongestive treatment of acute decompensated heart failure: cardiorenal implications of ultrafiltration and diuretics.Am J Kidney Dis. 2011; 58: 1005-1017Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar The mechanisms behind this relationship are complex and likely are patient specific. Diuretics and blood-based extracorporeal ultrafiltration are the main decongestive therapies. Peritoneal-based ultrafiltration has been used as well. Recent studies have shown that ultrafiltration is a very effective method for removing excessive fluid from selected patient populations with ADHF.1Freda B.J. Slawsky M. Mallidi J. Braden G.L. Decongestive treatment of acute decompensated heart failure: cardiorenal implications of ultrafiltration and diuretics.Am J Kidney Dis. 2011; 58: 1005-1017Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar The UNLOAD (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure) Study reported that ultrafiltration removed a greater volume of fluid than did a diuretic-based regimen.6Costanzo M.R. Guglin M.E. Saltzberg M.T. et al.Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure.J Am Coll Cardiol. 2007; 49: 675-683Abstract Full Text Full Text PDF PubMed Scopus (889) Google Scholar Patients in the ultrafiltration arm of the UNLOAD Study also had a statistically significant decrease in readmissions without an increase in adverse events. Thus, it appeared that ultrafiltration might affect ADHF favorably. However, there were concerns about whether diuretics were used optimally in the control group in this study. Additionally, although the change in serum creatinine (SCr) levels was not increased significantly in the ultrafiltration arm at any point in follow-up, twice as many patients in the ultrafiltration arm experienced an increase in SCr level >0.3 mg/dL during the first 24 hours of therapy. Finally, questions remained after this trial about which patients with ADHF should receive ultrafiltration (eg, early vs later in the course of cardiorenal syndrome type I), how ultrafiltration should be performed (eg, duration of treatment and titration to clinical targets), and how ultrafiltration and diuretic treatments differ in terms of safety, especially regarding the development of kidney failure. Against this background, the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure), which compared ultrafiltration versus stepped pharmacologic (loop diuretic–based) decongestion, was published.7Bart B.A. Goldsmith S.R. Lee K.L. et al.Ultrafiltration in decompensated heart failure with cardiorenal syndrome.N Engl J Med. 2012; 367: 2296-2304Crossref PubMed Scopus (713) Google Scholar CARRESS-HF was a prospective randomized controlled trial sponsored by the National Heart, Lung, and Blood Institute and conducted at 22 centers. Patients with ADHF were eligible if there was evidence of persistent congestion with an increase in SCr level ≥0.3 mg/dL. Participants were randomly assigned to either ultrafiltration (Aquadex System 100; CHF Solutions) or stepped pharmacologic therapy involving increasing doses of loop diuretics (with or without metolazone), vasodilators, and/or inotropes based on a treatment algorithm. The primary end point was a bivariate response, including changes in SCr level and body weight 96 hours after randomization. Power calculations suggested the inclusion of 100 patients in each arm; however, enrollment was terminated early (94 patients in each arm) by the Data Safety Monitoring Board because of a lack of benefit on primary and secondary end points and an increase in adverse events in the ultrafiltration group. Ultrafiltration was inferior to stepped pharmacologic therapy with respect to the bivariate primary end point (P = 0.003) primarily because of a significant increase in SCr level in the ultrafiltration group compared to stepped pharmacologic therapy (an increase of 0.23 ± 0.70 mg/dL for the ultrafiltration group vs a decrease of 0.04 ± 0.53 mg/dL for the pharmacology group; P = 0.002). There was no significant difference in weight loss at 96 hours between the 2 groups (5.7 ± 3.9 vs 5.5 ± 5.1 kg in the ultrafiltration and stepped pharmacologic therapy groups, respectively; P = 0.58). At the 60-day follow-up, there were no significant differences in weight loss, mortality, or rate of hospitalization for heart failure between the 2 groups. Also, during the 60-day follow-up period, patients in the ultrafiltration group had significantly higher rates of investigator-reported serious adverse events (72% vs 57%; P = 0.03), including kidney failure, bleeding complications, and intravenous catheter–related complications. There are 5 randomized controlled trials comparing ultrafiltration to diuretics in patients with ADHF (Table 1). Three of the studies used the Aquadex System 100 machine, whereas the study by Hanna et al8Hanna M.A. Tang W.H. Teo B.W. et al.Extracorporeal ultrafiltration vs. conventional diuretic therapy in advanced decompensated heart failure.Congest Heart Fail. 2012; 18: 54-63Crossref PubMed Scopus (53) Google Scholar used System One (NxStage), and the ULTRADISCO (Diuretics on Clinical, Biohumoral and Haemodynamic Variables in Patients With Decompensated Heart Failure) Study9Giglioli C. Landi D. Cecchi E. et al.Effects of ULTRAfiltration vs. DIureticS on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart failure: the ULTRADISCO study.Eur J Heart Fail. 2011; 13: 337-346Crossref PubMed Scopus (111) Google Scholar used the Prisma System (Hospal-Gambro Dasco). In the RAPID-CHF (Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure),10Bart B.A. Boyle A. Bank A.J. et al.Ultrafiltration versus usual care for hospitalized patients with heart failure: the Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial.J Am Coll Cardiol. 2005; 46: 2043-2046Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar UNLOAD, ULTRADISCO, and CARRESS-HF studies, patients were included if they met the clinical criteria for congestion and excluded if they required vasoactive medicines. In the study by Hanna et al,8Hanna M.A. Tang W.H. Teo B.W. et al.Extracorporeal ultrafiltration vs. conventional diuretic therapy in advanced decompensated heart failure.Congest Heart Fail. 2012; 18: 54-63Crossref PubMed Scopus (53) Google Scholar patients were included if they had congestion, defined as elevated pulmonary artery capillary wedge pressure ≥20 mm Hg, and vasoactive medicines were permitted.8Hanna M.A. Tang W.H. Teo B.W. et al.Extracorporeal ultrafiltration vs. conventional diuretic therapy in advanced decompensated heart failure.Congest Heart Fail. 2012; 18: 54-63Crossref PubMed Scopus (53) Google ScholarTable 1Randomized Controlled Trials of UF Versus DiureticsStudyDiuretic DosingUFR and DurationFluid LossChange in Kidney FunctionHospital ReadmissionCARRESS-HF7Bart B.A. Goldsmith S.R. Lee K.L. et al.Ultrafiltration in decompensated heart failure with cardiorenal syndrome.N Engl J Med. 2012; 367: 2296-2304Crossref PubMed Scopus (713) Google Scholar (n = 188)Stepped algorithm of furosemide and metolazone titrated to daily urine output of 3-5 L; many received continuous infusion of loop diuretic and 46% received metolazonePrescribed UFR, 200 mL/h; median duration of UF, 40 (IQR, 28-67) hWeight loss at 96 h of 5.7 (UF) vs 5.5 kg (diuretic), P = 0.87Change in SCr at 96 h of +0.23 (UF) vs −0.04 mg/dL (diuretic), P = 0.003HF hospitalization at 60 d in 26% (UF) vs 26% (diuretic), P = 0.97; any-cause hospitalization at 60 d in 51% (UF) vs 40% (diuretic), P = 0.12UNLOAD6Costanzo M.R. Guglin M.E. Saltzberg M.T. et al.Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure.J Am Coll Cardiol. 2007; 49: 675-683Abstract Full Text Full Text PDF PubMed Scopus (889) Google Scholar (n = 200)Dosing at discretion of physician; average daily dose of furosemide, 181 mg; 32% received continuous infusion of diureticPrescribed UF duration and UFR (max, 500 mL/h) at discretion of physician; average UFR, 241 mL/h; average UF duration, 12.3 hWeight loss at 48 h of 5.0 (UF) vs 3.1 kg (diuretic), P = 0.001>0.3 mg/dL increase in SCr at 24 h in 14.4% (UF) vs 7.7% (diuretic), P = 0.53; at 48 h: 26.5% (UF) vs 20.3% (diuretic), P = 0.43HF rehospitalization at 90 d in 18% (UF) vs 32% (diuretic), P = 0.037; unscheduled office and ER visits in 21% (UF) vs 44% (diuretic), P = 0.009RAPID-CHF10Bart B.A. Boyle A. Bank A.J. et al.Ultrafiltration versus usual care for hospitalized patients with heart failure: the Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial.J Am Coll Cardiol. 2005; 46: 2043-2046Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar (N = 40)Dosing at discretion of physician; median daily dose of furosemide, 160 mgSingle 8-h session, with most sessions removing 3-4 LWeight loss at 24 h of 2.5 (UF) vs 1.86 kg (diuretic), P = 0.240; fluid removal at 24 h of 4.65 (UF) vs 2.84 L (diuretic), P = 0.001No significant difference in change in SCrNRHanna et al8Hanna M.A. Tang W.H. Teo B.W. et al.Extracorporeal ultrafiltration vs. conventional diuretic therapy in advanced decompensated heart failure.Congest Heart Fail. 2012; 18: 54-63Crossref PubMed Scopus (53) Google Scholar (N = 36)Dosing at discretion of physician (dose NR)UF started at 400 mL/h × 6 h, then decreased to 200 mL/h guided by hemodynamic and clinical assessment and blood volume monitor; mean UFR, 272 mL/hTime to achieve PCWP ≤18 is 22 (UF) vs 34.8 h (diuretic), P = 0.081; total volume removed of 5.2 (UF) vs 2.2 L (diuretic), P = 0.041No significant difference in change in SCr or serum CysCReadmission at 90 d in 42% (UF) vs 35% (diuretic), P = 0.087ULTRADISCO9Giglioli C. Landi D. Cecchi E. et al.Effects of ULTRAfiltration vs. DIureticS on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart failure: the ULTRADISCO study.Eur J Heart Fail. 2011; 13: 337-346Crossref PubMed Scopus (111) Google Scholar (N = 30)Continuous infusion of furosemide, 250-500 mg/d, titrated to urine output >2 L/d, signs and symptoms of congestion, hemodynamic targets and change in SCr; dose NRUFR, 100-300 mL/h, titrated according to SBP (87% had UFR of 100 mL/h); duration according to signs and symptoms of congestion and hemodynamic targets; median duration, 46 (IQR, 39-71) hCumulative fluid loss at 36 h of 9.7 (UF) vs 7.8 kg (diuretic), P = 0.047No significant difference in change in SCr at end of treatmentNRAbbreviations: CysC, cystatin C; ER, emergency room; HF, heart failure; IQR, interquartile range; NR, not reported; PCWP, pulmonary capillary wedge pressure (in mm Hg); SBP, systolic blood pressure; SCr, serum creatinine (mg/dL); UF, ultrafiltration; UFR, ultrafiltration rate (mL/h). Open table in a new tab Abbreviations: CysC, cystatin C; ER, emergency room; HF, heart failure; IQR, interquartile range; NR, not reported; PCWP, pulmonary capillary wedge pressure (in mm Hg); SBP, systolic blood pressure; SCr, serum creatinine (mg/dL); UF, ultrafiltration; UFR, ultrafiltration rate (mL/h). Although baseline kidney function was similar among the studies (SCr of 1.5-1.9 mg/dL), CARRESS-HF was the only study to specifically target worsening kidney function (increase in SCr ≥0.3 mg/dL) as an inclusion criterion. All studies aimed to achieve clinically defined targets of decongestion except for the study by Hanna et al,8Hanna M.A. Tang W.H. Teo B.W. et al.Extracorporeal ultrafiltration vs. conventional diuretic therapy in advanced decompensated heart failure.Congest Heart Fail. 2012; 18: 54-63Crossref PubMed Scopus (53) Google Scholar which also targeted an improvement in pulmonary artery capillary wedge pressure to ≤18 mm Hg, and the ULTRADISCO Study,9Giglioli C. Landi D. Cecchi E. et al.Effects of ULTRAfiltration vs. DIureticS on clinical, biohumoral and haemodynamic variables in patients with deCOmpensated heart failure: the ULTRADISCO study.Eur J Heart Fail. 2011; 13: 337-346Crossref PubMed Scopus (111) Google Scholar which used a minimally invasive device to monitor hemodynamic parameters, including blood pressure, cardiac index, and stroke volume index. All studies applied ultrafiltration relatively early in the course of hospitalization. The treating physician managed diuretic dosing according to clinical judgment and baseline diuretic doses, except in CARRESS-HF, in which a stepped-care algorithm aimed at achieving daily urine output of 3-5 L was used. In patients who failed to meet this goal with escalating diuretic doses, clinicians also could consider dopamine, dobutamine, nesiritide, nitroglycerin, or escalation to hemodynamic-guided therapy, left ventricular assist device, dialysis, or crossover to ultrafiltration. Compared with other recent trials, the stepped-care algorithm in CARRESS-HF used more distal-acting diuretics (ie, metolazone was used in ∼50%) and continuous infusion of loop diuretics. In all the previous studies, either fluid removal or weight loss was significantly greater in the ultrafiltration group. However, in CARRESS-HF, there was no significant difference in mean weight loss at 96 hours between groups. CARRESS-HF is the only randomized controlled trial to report a significantly increased incidence of worsening kidney function in the ultrafiltration group compared to the diuretic group, although there was a trend of increased kidney injury in the UNLOAD Study. Although SCr levels returned to baseline values in the ultrafiltration group during follow-up in CARRESS-HF, there was a significantly greater reduction in SCr levels in the diuretic group at 60 days despite a similar decrease in weight in both groups. In contrast to UNLOAD, there was not a significant reduction in heart failure readmission in the ultrafiltration group in CARRESS-HF. In addition, in CARRESS-HF, there was a nonsignificant trend toward a higher all-cause readmission rate in the ultrafiltration group (51% vs 40%; P = 0.14). A similar trend was noted in the ultrafiltration group in the study by Hanna et al.8Hanna M.A. Tang W.H. Teo B.W. et al.Extracorporeal ultrafiltration vs. conventional diuretic therapy in advanced decompensated heart failure.Congest Heart Fail. 2012; 18: 54-63Crossref PubMed Scopus (53) Google Scholar CARRESS-HF highlights the poor prognosis of patients with ADHF. Even in the setting of a closely monitored clinical trial, rates of clinical decongestion were low at 4 days (9%-10%) and more than one-third of patients died or were readmitted to the hospital within 60 days. Ultrafiltration is a very effective method to remove fluid from congested patients with ADHF. However, it appears that ultrafiltration joins the ranks of other strategies, such as nesiritide11O'Connor C.M. Starling R.C. Hernandez A.F. et al.Effect of nesiritide in patients with acute decompensated heart failure.N Engl J Med. 2011; 365: 32-43Crossref PubMed Scopus (1051) Google Scholarand Swan-Ganz catheter–guided treatment,12Binanay C. Califf R.M. Hasselblad V. et al.Evaluation study of congestive heart failure and pulmonary artery catheterization effectiveness: the ESCAPE trial.JAMA. 2005; 294: 1625-1633Crossref PubMed Scopus (1088) Google Scholar that cannot be applied broadly across most patients with ADHF or cardiorenal syndrome. As shown in CARRESS-HF, when diuretic dosages are titrated effectively and in a timely manner that uses a continuous infusion of loop diuretics and adds distal-acting diuretics, it is possible in many patients to remove an amount of fluid similar to ultrafiltration. The use of continuous diuretic infusion and distal diuretics may be particularly important in patients with kidney disease and cardiorenal syndrome, in which diuretic resistance is more likely. Although the meaning of transient increases in SCr levels in individual patients is difficult to interpret, it is clear from CARRESS-HF and other studies that ultrafiltration has no “kidney-sparing” benefit. Ultrafiltration clearly is more expensive than diuretics, a difference that is particularly striking if it is unable to reduce readmissions.1Freda B.J. Slawsky M. Mallidi J. Braden G.L. Decongestive treatment of acute decompensated heart failure: cardiorenal implications of ultrafiltration and diuretics.Am J Kidney Dis. 2011; 58: 1005-1017Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar At the present time, we can recommend ultrafiltration only in patients with ADHF who are unable to achieve decongestion with a rational stepped-up diuretic regimen and usual hemodynamic care. Although ultrafiltration has been effective at removing fluid in these patients with otherwise refractory disease, some may progress to requiring dialysis and have poor outcomes despite this treatment.1Freda B.J. Slawsky M. Mallidi J. Braden G.L. Decongestive treatment of acute decompensated heart failure: cardiorenal implications of ultrafiltration and diuretics.Am J Kidney Dis. 2011; 58: 1005-1017Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 13Patarroyo M. Wehbe E. Hanna M. et al.Cardiorenal outcomes after slow continuous ultrafiltration therapy in refractory patients with advanced decompensated heart failure.J Am Coll Cardiol. 2012; 60: 1906-1912Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar Because readmission and mortality rates remain high for patients with ADHF and cardiorenal syndrome, further studies are needed to guide clinicians in the use of diuretics and ultrafiltration. In order to improve care, we need methods that optimize active monitoring of congestion and the hemodynamic and kidney responses to treatment that go beyond measurement of body weight and SCr.14Ronco C. Kaushik M. Valle R. Aspromonte N. Peacock W.F. Diagnosis and management of fluid overload in heart failure and cardio-renal syndrome: the “5B” approach.Semin Nephrol. 2012; 32: 129-141Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.

Among the various renal manifestations of sarcoidosis, granulomatous inflammation confined to the tubulointerstitial compartment is the most commonly reported finding. We present the case of a 66-year-old man with acute kidney injury, hypercalcemia, mild restrictive pulmonary disease, and neurologic signs of parietal lobe dysfunction. Kidney biopsy showed diffuse interstitial inflammation with noncaseating granulomas that exhibited the unusual feature of infiltrating the walls of small arteries with destruction of the elastic lamina, consistent with granulomatous vasculitis. The findings of granulomatous interstitial nephritis on kidney biopsy, hypercalcemia, and possible cerebral and pulmonary involvement in the absence of other infectious, drug-induced, or autoimmune causes of granulomatous disease established the diagnosis of sarcoidosis. Pulse methylprednisolone followed by maintenance prednisone therapy led to improvement in kidney function, hypercalcemia, and neurologic symptoms. Vasculocentric granulomatous interstitial nephritis with granulomatous vasculitis is a rare and under-recognized manifestation of renal sarcoidosis.

Its routine use is not supported at this time, but there is evidence to suggest giving it to patients with baseline renal dysfunction.

Veldhuisen DJ, Gans RO, Janssen WM, Grobbee DE, de Jong PE; Prevention of Renal and Vascular End StageDisease (PREVEND) Study Group: Urinary albumin excretion predicts cardiovascular and noncardiovascularmortality in general population.Circulation 106: 1777– 1782, 2002 5. Cao JJ, BiggsML, Barzilay J, Konen J, Psaty BM, Kuller L, Bleyer AJ,Olson J, Wexler J, Summerson J, Cushman M: Cardiovascular and mortality risk prediction and stratification using urinary albumin excretion in older adults ages 68-102: The Cardiovascular Health Study. Atherosclerosis 197: 806–813, 2008 6. Drury PL, Ting R, Zannino D, Ehnholm C, Flack J, Whiting M, Fassett R, Ansquer JC, Dixon P, Davis TM, Pardy C, Colman P, Keech A: Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetologia 54: 32–43, 2011 7. Dinneen SF, Gerstein HC: The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med 157: 1413–1418, 1997 8. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT; Chronic Kidney Disease Prognosis Consortium: Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: A collaborative meta-analysis. Lancet 375: 2073– 2081, 2010 9. van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey A, de Jong P, Gansevoort RT, van der Velde M, Matsushita K, Coresh J, Astor BC, Woodward M, Levey AS, de Jong PE, Gansevoort RT, LeveyA, El-NahasM, Eckardt KU, Kasiske BL, Ninomiya T, Chalmers J, Macmahon S, Tonelli M, Hemmelgarn B, Sacks F, Curhan G, Collins AJ, Li S, Chen SC, Hawaii Cohort KP, Lee BJ, Ishani A, Neaton J, Svendsen K, Mann JF, Yusuf S, Teo KK, Gao P, Nelson RG, Knowler WC, Bilo HJ, Joosten H, Kleefstra N, Groenier KH, Auguste P, Veldhuis K, Wang Y, Camarata L, Thomas B, Manley T; Chronic Kidney Disease Prognosis Consortium: Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts. Kidney Int 79: 1341–1352, 2011 10. Ruggenenti P, Porrini E, Motterlini N, Perna A, Ilieva AP, Iliev IP, Dodesini AR, Trevisan R, Bossi A, Sampietro G, Capitoni E, Gaspari F, Rubis N, Ene-Iordache B, Remuzzi G, for the BENEDICT Study Investigators: Measurable urinary albumin predicts cardiovascular risk among normoalbuminuric patients with type 2 diabetes. J Am Soc Nephrol 23: 1717–1724, 2012 11. Maione A, Navaneethan SD, Graziano G, Mitchell R, Johnson D, Mann JF, Gao P, Craig JC, Tognoni G, Perkovic V, Nicolucci A, De Cosmo S, Sasso A, Lamacchia O, Cignarelli M, Manfreda VM, Gentile G, Strippoli GF: Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and combined therapy in patients with microand macroalbuminuria and other cardiovascular risk factors: A systematic review of randomized controlled trials. Nephrol Dial Transplant 26: 2827– 2847, 2011 12. Fink HA, Ishani A, Taylor BC, Greer NL, MacDonald R, Rossini D, Sadiq S, Lankireddy S, Kane RL, Wilt TJ: Screening for, monitoring, and treatment of chronic kidney disease stages 1 to 3: A systematic review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline. Ann Intern Med 156: 570–581, 2012

nosis and treatment. 2,3 The natural history of IgAN can range from clinically silent urinary abnormalities and preserved renal function over many decades to ESRD. Progression to ESRD occurs in 10%–50% of patients, usually developing slowly over 20 years. 4,5 Ten-year renal survival rates (62%–98%) are also highly variable. 6,7 In regions where renal biopsies are routinely performed for isolated urinary abnormalities (microscopic hematuria, minimal proteinuria ,0.5 g/d), the incidence of IgAN is higher, and the estimates of renal survival are affected by lead-time bias. A more fully informed understanding of the natural history of IgAN across its entire clinical and histologic spectrum could assist clinicians in assessing prognosis and implementing treatment. Muchhasbeenlearnedoverthelast20–30yearsregarding risk stratification of IgAN. 3 Clinical parameters that correlate with increased risk of progression of disease include proteinuria .1 g/d, hypertension, and reduced GFR. The impact of these variables on prognosis is strengthened when they are followed over time. In contrast to other glomerular diseases, proteinuria in IgAN at an excretion rate of even 0.5–1.0 g/d is associated with risk of ESRD. 3

In patients with acute decompensated heart failure (ADHF), treatment aimed at adequate decongestion of the volume overloaded state is essential. Despite diuretic therapy, many patients remain volume overloaded and symptomatic. In addition, adverse effects related to diuretic treatment are common, including worsening kidney function and electrolyte disturbances. The development of decreased kidney function during treatment affects the response to diuretic therapy and is associated with important clinical outcomes, including mortality. The occurrence of diuretic resistance and the morbidity and mortality associated with diuretic therapy has stimulated interest to develop effective and safe treatment strategies that maximize decongestion and minimize decreased kidney function. During the last few decades, extracorporeal ultrafiltration has been used to remove fluid from diuretic-refractory hypervolemic patients. Recent clinical studies using user-friendly machines have suggested that ultrafiltration may be highly effective for decongesting patients with ADHF. Many questions remain regarding the comparative impact of diuretics and ultrafiltration on important clinical outcomes and adverse effects, including decreased kidney function. This article serves as a summary of key clinical studies addressing these points. The overall goal is to assist practicing clinicians who are contemplating the use of ultrafiltration for a patient with ADHF. Am J Kidney Dis. 58(6): 1005-1017. (C) 2011 by the National Kidney Foundation, Inc.

Hyponatremia, in its most severe form, requires urgent infusion of hypertonic saline to correct cerebral edema. However, overly rapid correction of chronic hyponatremia can cause osmotic demyelination syndrome. The authors review the treatment of hyponatremia in order to provide clinicians with a sound approach in a variety of settings in which severity, symptoms, and underlying disease states influence therapy. Also discussed is the current role of vasopressin antagonists in treatment.

Hyponatremia is common in hospitalized patients. By taking a careful and logical approach, one can promptly recognize the causative factor or factors in nearly all cases. Most cases of hyponatremia are due to impaired renal water excretion, and recognizing the cause and pathophysiologic process makes it possible to provide focused individualized care and avoid mistreatment.