Andrew A. House

State-of-the-Art PaperCardiorenal Syndrome

The term cardiorenal syndrome (CRS) increasingly has been used without a consistent or well-accepted definition. To include the vast array of interrelated derangements, and to stress the bidirectional nature of heart-kidney interactions, we present a new classification of the CRS with 5 subtypes that reflect the pathophysiology, the time-frame, and the nature of concomitant cardiac and renal dysfunction. CRS can be generally defined as a pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction of 1 organ may induce acute or chronic dysfunction of the other. Type 1 CRS reflects an abrupt worsening of cardiac function (e.g., acute cardiogenic shock or decompensated congestive heart failure) leading to acute kidney injury. Type 2 CRS comprises chronic abnormalities in cardiac function (e.g., chronic congestive heart failure) causing progressive chronic kidney disease. Type 3 CRS consists of an abrupt worsening of renal function (e.g., acute kidney ischemia or glomerulonephritis) causing acute cardiac dysfunction (e.g., heart failure, arrhythmia, ischemia). Type 4 CRS describes a state of chronic kidney disease (e.g., chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy, and/or increased risk of adverse cardiovascular events. Type 5 CRS reflects a systemic condition (e.g., sepsis) causing both cardiac and renal dysfunction. Biomarkers can contribute to an early diagnosis of CRS and to a timely therapeutic intervention. The use of this classification can help physicians characterize groups of patients, provides the rationale for specific management strategies, and allows the design of future clinical trials with more accurate selection and stratification of the population under investigation.

Effect of B-Vitamin Therapy on Progression of Diabetic Nephropathy: A Randomized Controlled Trial

CONTEXT Hyperhomocysteinemia is frequently observed in patients with diabetic nephropathy. B-vitamin therapy (folic acid, vitamin B(6), and vitamin B(12)) has been shown to lower the plasma concentration of homocysteine. OBJECTIVE To determine whether B-vitamin therapy can slow progression of diabetic nephropathy and prevent vascular complications. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized, double-blind, placebo-controlled trial (Diabetic Intervention with Vitamins to Improve Nephropathy [DIVINe]) at 5 university medical centers in Canada conducted between May 2001 and July 2007 of 238 participants who had type 1 or 2 diabetes and a clinical diagnosis of diabetic nephropathy. INTERVENTION Single tablet of B vitamins containing folic acid (2.5 mg/d), vitamin B(6) (25 mg/d), and vitamin B(12) (1 mg/d), or matching placebo. MAIN OUTCOME MEASURES Change in radionuclide glomerular filtration rate (GFR) between baseline and 36 months. Secondary outcomes were dialysis and a composite of myocardial infarction, stroke, revascularization, and all-cause mortality. Plasma total homocysteine was also measured. RESULTS The mean (SD) follow-up during the trial was 31.9 (14.4) months. At 36 months, radionuclide GFR decreased by a mean (SE) of 16.5 (1.7) mL/min/1.73 m(2) in the B-vitamin group compared with 10.7 (1.7) mL/min/1.73 m(2) in the placebo group (mean difference, -5.8; 95% confidence interval [CI], -10.6 to -1.1; P = .02). There was no difference in requirement of dialysis (hazard ratio [HR], 1.1; 95% CI, 0.4-2.6; P = .88). The composite outcome occurred more often in the B-vitamin group (HR, 2.0; 95% CI, 1.0-4.0; P = .04). Plasma total homocysteine decreased by a mean (SE) of 2.2 (0.4) micromol/L at 36 months in the B-vitamin group compared with a mean (SE) increase of 2.6 (0.4) micromol/L in the placebo group (mean difference, -4.8; 95% CI, -6.1 to -3.7; P < .001, in favor of B vitamins). CONCLUSION Among patients with diabetic nephropathy, high doses of B vitamins compared with placebo resulted in a greater decrease in GFR and an increase in vascular events. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN41332305.

An immune reconstitution syndrome-like illness associated with Cryptococcus neoformans infection in organ transplant recipients.

BACKGROUND We describe an immune reconstitution syndrome (IRS)-like entity in the course of evolution of Cryptococcus neoformans infection in organ transplant recipients. METHODS The study population comprised a cohort of 83 consecutive organ transplant recipients with cryptococcosis who were observed for a median of 2 years in an international, multicenter study. RESULTS In 4 (4.8%) of the 83 patients, an IRS-like entity was observed a median of 5.5 weeks after the initiation of appropriate antifungal therapy. Worsening of clinical manifestations was documented, despite cultures being negative for C. neoformans. These patients were significantly more likely to have received tacrolimus, mycophenolate mofetil, and prednisone as the regimen of immunosuppressive therapy than were all other patients (P = .007). The proposed basis of this phenomenon is reversal of a predominantly Th2 response at the onset of infection to a Th1 proinflammatory response as a result of receipt of effective antifungal therapy and a reduction in or cessation of immunosuppressive therapy. CONCLUSIONS This study demonstrated that an IRS-like entity occurs in organ transplant recipients with C. neoformans infection. Furthermore, this entity may be misconstrued as a failure of therapy. Immunomodulatory agents may have a role as adjunctive therapy in such cases.

Cryptococcus neoformans in Organ Transplant Recipients: Impact of Calcineurin-Inhibitor Agents on Mortality

Variables influencing the risk of dissemination and outcome of Cryptococcus neoformans infection were assessed in 111 organ transplant recipients with cryptococcosis in a prospective, multicenter, international study. Sixty-one percent (68/111) of the patients had disseminated infection. The risk of disseminated cryptococcosis was significantly higher for liver transplant recipients (adjusted hazard ratio [HR], 6.65; P=.048). The overall mortality rate at 90 days was 14% (16/111). The mortality rate was higher in patients with abnormal mental status (P=.023), renal failure at baseline (P=.028), fungemia (P=.006), and disseminated infection (P=.035) and was lower in those receiving a calcineurin-inhibitor agent (P=.003). In a multivariable analysis, the receipt of a calcineurin-inhibitor agent was independently associated with a lower mortality (adjusted HR, 0.21; P=.008), and renal failure at baseline with a higher mortality rate (adjusted HR, 3.14; P=.037). Thus, outcome in transplant recipients with cryptococcosis appears to be influenced by the type of immunosuppressive agent employed. Additionally, discerning the basis for transplant type-specific differences in disease severity has implications relevant for yielding further insights into the pathogenesis of C. neoformans infection in transplant recipients.

Homocysteine-Lowering and Cardiovascular Disease Outcomes in Kidney Transplant Recipients Primary Results From the Folic Acid for Vascular Outcome Reduction in Transplantation Trial

Background— Kidney transplant recipients, like other patients with chronic kidney disease, experience excess risk of cardiovascular disease and elevated total homocysteine concentrations. Observational studies of patients with chronic kidney disease suggest increased homocysteine is a risk factor for cardiovascular disease. The impact of lowering total homocysteine levels in kidney transplant recipients is unknown. Methods and Results— In a double-blind controlled trial, we randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of the primary composite arteriosclerotic cardiovascular disease outcome (myocardial infarction, stroke, cardiovascular disease death, resuscitated sudden death, coronary artery or renal artery revascularization, lower-extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair). Mean follow-up was 4.0 years. Treatment with the high-dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome (n=547 total events; hazards ratio [95 confidence interval]=0.99 [0.84 to 1.17]), secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86 to 1.26]), or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93 to 1.43]) compared to the low-dose multivitamin. Conclusions— Treatment with a high-dose folic acid, B6, and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00064753.

Epidemiology of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference

Sean M. Bagshaw, Dinna N. Cruz, Nadia Aspromonte, Luciano Daliento, Federico Ronco, Geoff Sheinfeld, Stefan D. Anker, Inder Anand, Rinaldo Bellomo, Tomas Berl, Ilona Bobek, Andrew Davenport, Mikko Haapio, Hans Hillege, Andrew House, Nevin Katz, Alan Maisel, Sunil Mankad, Peter McCullough, Alexandre Mebazaa, Alberto Palazzuoli, Piotr Ponikowski, Andrew Shaw, Sachin Soni, Giorgio Vescovo, Nereo Zamperetti, Pierluigi Zanco, Claudio Ronco and for the Acute Dialysis Quality Initiative (ADQI) Consensus Group

Homocysteine-Lowering and Cardiovascular Disease Outcomes in Kidney Transplant Recipients

Background— Kidney transplant recipients, like other patients with chronic kidney disease, experience excess risk of cardiovascular disease and elevated total homocysteine concentrations. Observational studies of patients with chronic kidney disease suggest increased homocysteine is a risk factor for cardiovascular disease. The impact of lowering total homocysteine levels in kidney transplant recipients is unknown. Methods and Results— In a double-blind controlled trial, we randomized 4110 stable kidney transplant recipients to a multivitamin that included either a high dose (n=2056) or low dose (n=2054) of folic acid, vitamin B6, and vitamin B12 to determine whether decreasing total homocysteine concentrations reduced the rate of the primary composite arteriosclerotic cardiovascular disease outcome (myocardial infarction, stroke, cardiovascular disease death, resuscitated sudden death, coronary artery or renal artery revascularization, lower-extremity arterial disease, carotid endarterectomy or angioplasty, or abdominal aortic aneurysm repair). Mean follow-up was 4.0 years. Treatment with the high-dose multivitamin reduced homocysteine but did not reduce the rates of the primary outcome (n=547 total events; hazards ratio [95 confidence interval]=0.99 [0.84 to 1.17]), secondary outcomes of all-cause mortality (n=431 deaths; 1.04 [0.86 to 1.26]), or dialysis-dependent kidney failure (n=343 events; 1.15 [0.93 to 1.43]) compared to the low-dose multivitamin. Conclusions— Treatment with a high-dose folic acid, B6, and B12 multivitamin in kidney transplant recipients did not reduce a composite cardiovascular disease outcome, all-cause mortality, or dialysis-dependent kidney failure despite significant reduction in homocysteine level. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00064753.

Genetic Variation in PPARG Encoding Peroxisome Proliferator-Activated Receptor γ Associated With Carotid Atherosclerosis

Background and Purpose— Peroxisome proliferator-activated receptor γ is a crucial molecule in atherogenesis because it is associated with metabolic risk factors such as obesity and diabetes and also plays a key role in subcellular metabolism of arterial wall macrophage foam cells. Genetic variation in PPARG has been associated with metabolic and cardiovascular end points. Methods— We investigated the relationship between 2 common PPARG polymorphisms, namely P12A and c.1431C>T, and carotid atherosclerosis in a sample of 161 Canadian aboriginal people. Dependent variables were carotid intima media thickness (IMT), assessed using B-mode ultrasonography, and total carotid plaque volume (TPV), assessed using 3D ultrasound. Results— Using multivariate analysis, we found that subjects with ≥1 PPARG A12 allele had less carotid IMT than others (0.72±0.03 versus 0.80±0.02 mm; P =0.0045), with no between-genotype difference in TPV. In contrast, subjects with the PPARG c.1431T allele had greater TPV than others (124±18.4 versus 65.1±23.7 mm3; P =0.0079), with no between-genotype difference in IMT. Conclusions— The findings show an association between PPARG genotypes and carotid arterial phenotypes, and further reflect the prevailing view that the PPARG A12 allele protects against deleterious phenotypes. Also, whereas IMT and TPV are somewhat correlated with each other, they might also represent distinct traits with discrete determinants representing different stages of atherogenesis.

Pulmonary Cryptococcosis in Solid Organ Transplant Recipients: Clinical Relevance of Serum Cryptococcal Antigen

BACKGROUND The role of serum cryptococcal antigen in the diagnosis and determinants of antigen positivity in solid organ transplant (SOT) recipients with pulmonary cryptococcosis has not been fully defined. METHODS We conducted a prospective, multicenter study of SOT recipients with pulmonary cryptococcosis during 1999-2006. RESULTS Forty (83%) of 48 patients with pulmonary cryptococcosis tested positive for cryptococcal antigen. Patients with concomitant extrapulmonary disease were more likely to have a positive antigen test result (P=.018), and antigen titers were higher in patients with extrapulmonary disease (P=.003) or fungemia (P=.045). Patients with single nodules were less likely to have a positive antigen test result than were those with all other radiographic presentations (P=.053). Among patients with isolated pulmonary cryptococcosis, lung transplant recipients were less likely to have positive cryptococcal antigen test results than were recipients of other types of SOT (P=.003). In all, 38% of the patients were asymptomatic or had pulmonary cryptococcosis detected as an incidental finding. Nodular densities or mass lesions were more likely to present as asymptomatic or incidentally detected pulmonary cryptococcosis than as pleural effusions and infiltrates (P=.008). CONCLUSIONS A positive serum cryptococcal antigen test result in SOT recipients with pulmonary cryptococcosis appears to reflect extrapulmonary or more advanced radiographic disease.

Progression of Carotid Plaque Volume Predicts Cardiovascular Events

Background and Purpose— Carotid ultrasound evaluation of intima-media thickness (IMT) and plaque burden has been used for risk stratification and for evaluation of antiatherosclerotic therapies. Increasing evidence indicates that measuring plaque burden is superior to measuring IMT for both purposes. We compared progression/regression of IMT, total plaque area (TPA), and total plaque volume (TPV) as predictors of cardiovascular outcomes. Methods— IMT, TPA, and TPV were measured at baseline in 349 patients attending vascular prevention clinics; they had TPA of 40 to 600 mm2 at baseline to qualify for enrollment. Participants were followed up for ⩽5 years (median, 3.17 years) to ascertain vascular death, myocardial infarction, stroke, and transient ischemic attacks. Follow-up measurements 1 year later were available in 323 cases for IMT and TPA, and in 306 for TPV. Results— Progression of TPV predicted stroke, death or TIA (Kaplan-Meier logrank P=0.001), stroke/death/MI (P=0.008) and Stroke/Death/TIA/Myocardial infarction (any Cardiovascular event) (P=0.001). Progression of TPA weakly predicted Stroke/Death/TIA (P=0.097) but not stroke/death/MI (P=0.59) or any CV event (P=0.143); likewise change in IMT did not predict Stroke/Death/MI (P=0.13) or any CV event (P=0.455 ). In Cox regression, TPV progression remained a significant predictor of events after adjustment for coronary risk factors (P=0.001) but change in TPA did not. IMT change predicted events in an inverse manner; regression of IMT predicted events (P=0.004). Conclusions— For assessment of response to antiatherosclerotic therapy, measurement of TPV is superior to both IMT and TPA.