Claudio Rigatto

Electrocardiographic Left Ventricular Hypertrophy in Renal Transplant Recipients: Prognostic Value and Impact of Blood Pressure and Anemia

Left ventricular hypertrophy (LVH) is an independent risk factor for death and cardiovascular disease in the general population and dialysis patients. However, the causes and consequences of LVH have not been well described in renal transplant recipients (RTR). A retrolective cohort study was conducted in 473 RTR who were alive and free of cardiac disease at 1 yr. LVH was defined using the Cornell electrocardiographic (EKG) criteria. A total of 416 patients had an interpretable first-year EKG (88%), and 284 had an interpretable fifth-year EKG (78% of 5-yr survivors). Baseline characteristics were similar in patients with and without EKG. Of 416 patients, 57 had LVH in the first year, whereas 38 of 284 patients had LVH in the fifth year, of which 18 cases were de novo. Baseline LVH was a risk factor for death (RR 1.9 [1.22, 3.22]) and congestive heart failure (CHF) (RR 2.27 [1.08, 4.81]) and was independent of other major prognostic variables. Persistent or de novo LVH in the fifth year predicted subsequent death (RR 2.15 [1.14,4.01]) and CHF (2.71 [1.17, 6.30]). Anemia and diastolic BP were independent risk factors for increasing Cornell voltage (a marker of LV mass) between first and fifth years. Systolic BP was the only predictor of de novo LVH at 5 yr. It seems that EKG LVH is a significant risk factor for death and CHF in RTR and that anemia and hypertension are risk factors for LV growth. Whether aggressive treatment of hypertension and anemia can improve outcomes merits further study.

Mass spectrometry-based proteomic analysis of urine in acute kidney injury following cardiopulmonary bypass: a nested case-control study.

BACKGROUND The early evolution of acute kidney injury (AKI) in humans is difficult to study noninvasively. We hypothesized that urine proteomics could provide insight into the early pathophysiology of human AKI. STUDY DESIGN A prospective nested case-control study (n = 250) compared serial urinary proteomes of 22 patients with AKI and 22 patients without AKI before, during, and after cardiopulmonary bypass surgery. OUTCOMES AKI was defined as a greater than 50% increase in serum creatinine level, and non-AKI, as less than 10% increase from baseline. MEASUREMENTS Serum creatinine, urine protein-creatinine ratio, neutrophil gelatinase-associated lipocalin (NGAL), alpha1-microglobulin, interferon-inducible protein-10 (IP-10), monokine induced by interferon gamma (Mig), interferon-inducible T cell alpha chemoatractant (I-TAC), interleukin 6 (IL-6), IL-1beta, and IL-10. Urine protein profiling by means of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). RESULTS SELDI-TOF-MS showed intraoperative tubular stress in both groups on arrival to the intensive care unit, evidenced by beta2-microglobulinuria. Non-AKI proteomes returned toward baseline postoperatively. In contrast, AKI proteomes showed a second phase of tubular injury/stress with the reappearance of beta2-microglobulin and multiple unidentified peaks (3 to 5 and 6 to 8 kDa) and the appearance of established tubular injury markers: urinary protein, alpha1-microglobulin, and NGAL. Furthermore, 2 novel peaks (2.43 and 2.78 kDa) were found to be dominant in postoperative non-AKI urine samples. The 2.78-kDa protein was identified as the active 25-amino acid form of hepcidin (hepcidin-25), a key regulator of iron homeostasis. Finally, an inflammatory component of reperfusion injury was evaluated by means of enzyme-linked immunosorbent assay analysis of candidate chemokines (IP-10, I-TAC, and Mig) and cytokines (IL-6, IL-1beta, and IL-10). Of these, IP-10 was upregulated in patients with versus without AKI postoperatively. LIMITATIONS This is an observational study. SELDI-TOF-MS is a semiquantitative technique. CONCLUSIONS Evaluation of human AKI revealed early intraoperative tubular stress in all patients. A second phase of injury observed in patients with AKI may involve IP-10 recruitment of inflammatory cells. The enhancement of hepcidin-25 in patients without AKI may suggest a novel role for iron sequestration in modulating AKI.

Systematic review and meta-analysis of incidence, prevalence and outcomes of atrial fibrillation in patients on dialysis

BACKGROUND The reported incidence, prevalence and outcomes of atrial fibrillation (AF) in patients with end-stage renal disease (ESRD) are variable. The risks and benefits of warfarin anticoagulation need to be defined as the risk of bleeding in ESRD patients may overwhelm the benefits of embolic stroke prevention. We undertook a systematic literature review to clarify these issues. METHODS A literature search was undertaken using Medline and EMBASE from 1990 to September 2011. Studies that reported incidence, prevalence or selected outcomes in ESRD patients with AF were included. Cross-sectional, cohort and randomized controlled trials with >25 participants were included. The lists of authors and abstracts from the search were reviewed by two investigators to determine the manuscripts for full text review. Data were abstracted to a form designed specifically for this study. The quality of the studies was assessed using the Newcastle-Ottawa scale. Event rates were calculated using a random-effects model. RESULTS Twenty-five studies met our inclusion criteria. The prevalence of AF was 11.6% and the overall incidence was 2.7/100 patient-years. The risk of mortality and stroke was increased in ESRD patients with AF at 26.9 and 5.2/100 patient-years versus 13.4 and 1.9/100 patient-years compared with ESRD patients without AF. The majority of studies do not support a protective effect for warfarin in ESRD patients with AF. CONCLUSIONS The incidence and prevalence of AF in ESRD patients are higher than in the general population and are associated with an increased risk of stroke and mortality. An appropriately designed randomized controlled trial is required to determine whether anticoagulation is an appropriate therapeutic strategy in patients with end-stage renal disease and atrial fibrillation.

Risk prediction models for patients with chronic kidney disease: a systematic review.

BACKGROUND Patients with chronic kidney disease (CKD) are at increased risk for kidney failure, cardiovascular events, and all-cause mortality. Accurate models are needed to predict the individual risk for these outcomes. PURPOSE To systematically review risk prediction models for kidney failure, cardiovascular events, and death in patients with CKD. DATA SOURCES MEDLINE search of English-language articles published from 1966 to November 2012. STUDY SELECTION Cohort studies that examined adults with any stage of CKD who were not receiving dialysis and had not had a transplant; had at least 1 year of follow-up; and reported on a model that predicted the risk for kidney failure, cardiovascular events, or all-cause mortality. DATA EXTRACTION Reviewers extracted data on study design, population characteristics, modeling methods, metrics of model performance, risk of bias, and clinical usefulness. DATA SYNTHESIS Thirteen studies describing 23 models were found. Eight studies (11 models) involved kidney failure, 5 studies (6 models) involved all-cause mortality, and 3 studies (6 models) involved cardiovascular events. Measures of estimated glomerular filtration rate or serum creatinine level were included in 10 studies (17 models), and measures of proteinuria were included in 9 studies (15 models). Only 2 studies (4 models) met the criteria for clinical usefulness, of which 1 study (3 models) presented reclassification indices with clinically useful risk categories. LIMITATION A validated risk-of-bias tool and comparisons of the performance of different models in the same validation population were lacking. CONCLUSION Accurate, externally validated models for predicting risk for kidney failure in patients with CKD are available and ready for clinical testing. Further development of models for cardiovascular events and all-cause mortality is needed. PRIMARY FUNDING SOURCE None.

Earlier onset of complications in youth with type 2 diabetes

OBJECTIVE To evaluate the risk of complications in youth with type 2 diabetes. RESEARCH DESIGN AND METHODS Population-based cohorts of 342 youth (1–18 years of age) with prevalent type 2 diabetes, 1,011 youth with type 1 diabetes, and 1,710 nondiabetic control youth were identified between 1986 and 2007 from a clinical registry and linked to health care records to assess long-term outcomes using ICD-9CM and ICD-10CA codes. RESULTS Youth with type 2 diabetes had an increased risk of any complication (hazard ratio 1.47 [95% CI 1.02–2.12]). Significant adverse clinical factors included age at diagnosis (1.08 [1.02–2.12]), HbA1c (1.06 [1.01–1.12]), and, surprisingly, renin-angiotensin-aldosterone system (RAAS) inhibitor use (1.75 [1.27–2.41]). HNF-1α G319S polymorphism was protective in the type 2 diabetes cohort (0.58 [0.34–0.99]). Kaplan-Meier statistics revealed an earlier diagnosis of renal and neurologic complications in the type 2 diabetes cohort, manifesting within 5 years of diagnosis. No difference in retinopathy was seen. Cardiovascular and cerebrovascular diseases were rare; however, major complications (dialysis, blindness, or amputation) started to manifest 10 years after diagnosis in the type 2 diabetes cohort. Youth with type 2 diabetes had higher rates of all outcomes than nondiabetic control youth and an overall 6.15-fold increased risk of any vascular disease. CONCLUSIONS Youth with type 2 diabetes exhibit complications sooner than youth with type 1 diabetes. Younger age at diagnosis is potentially protective, and glycemic control is an important modifiable risk factor. The unexpected adverse association between RAAS inhibitor use and outcome is likely a confounder by indication; however, further evaluation in young people is warranted.

The impact of frailty on outcomes after cardiac surgery: A systematic review

OBJECTIVE Current preoperative assessments for cardiac surgery, such as the European System for Cardiac Operative Risk Evaluation II and the Society of Thoracic Surgeons risk score, are limited in their ability to predict postoperative outcomes. This is thought to be due to the reliance on chronological age as a predictor of health. In geriatrics, frailty assessments have been developed as a tool in determining physiologic functioning capacity. Whether or not frailty predicts postoperative outcomes independent of existing cardiac preoperative risk scores remains unknown. METHODS We performed a systematic review to determine the association of frailty with negative postoperative outcomes such as major adverse cardiac and cerebrovascular events (MACCE) in patients undergoing cardiac surgery. We searched PubMed, EMBASE, the Cochrane library, and Ageline from inception until July 2013 and screened 5913 abstracts for potential inclusion. Of these, 6 studies examined the relationship between objective frailty assessments and postoperative outcomes. Our included studies evaluated 4756 patients undergoing cardiac surgery. RESULTS Frailty, defined using multiple criteria, had a strong positive relationship with the risk of MACCE (odds ratio, 4.89; 95% confidence interval, 1.64-14.60). Relationships were stronger in older patients undergoing transcatheter aortic valve replacement (TAVR) than younger patients undergoing coronary artery bypass grafting and valvular surgery (hazard ratio for frailty in TAVR, 3.31-4.89 vs hazard ratio for non-TAVR, 1.10-3.16). CONCLUSIONS Patients deemed frail, determined using an objective assessment tool, have a higher likelihood of experiencing mortality, morbidity, functional decline, and MACCE following cardiac surgery, regardless of definition. Further study is needed to determine which components of frailty are most predictive of negative postoperative outcomes before integration in risk prediction scores.

High Burden of Kidney Disease in Youth-Onset Type 2 Diabetes

OBJECTIVE To evaluate renal outcomes and survival in youth with type 2 diabetes (T2DM) versus type 1 diabetes (T1DM) versus nondiabetic control subjects. RESEARCH DESIGN AND METHODS In total, 342 prevalent youth (aged 1–18 years) with T2DM, 1,011 youth with T1DM, and 1,710 control subjects identified from 1986 to 2007 were anonymously linked to health care records housed at the Manitoba Centre for Health Policy to assess long-term outcomes using ICD codes. RESULTS Youth with T2DM were found to have a fourfold increased risk of renal failure versus youth with T1DM. Risk factors associated with renal failure were renin angiotensin aldosterone system inhibitor use and albuminuria in adolescence. Compared with control subjects (age, sex, and postal code matched), youth with T2DM had a 23-fold increased risk of renal failure and a 39-fold increased risk of dialysis. Kaplan-Meier survival at 10 years was 91.4% in the type 2 diabetic group versus 99.5% in the type 1 diabetic group (P < 0.0001). Renal survival was 100% at 10 years in both groups. It decreased to 92.0% at 15 years and 55.0% at 20 years in the type 2 diabetic group but remained stable in the type 1 diabetic group (P < 0.0001). CONCLUSIONS Youth with T2DM are at high risk of adverse renal outcomes and death. Albuminuria and angiotensin aldosterone system inhibitor use, which may be a marker of severity of disease, are associated with poor outcomes in early adulthood.

A Nurse-coordinated Model of Care versus Usual Care for Stage 3/4 Chronic Kidney Disease in the Community: A Randomized Controlled Trial

BACKGROUND AND OBJECTIVES It is unclear how to optimally care for chronic kidney disease (CKD). This study compares a new coordinated model to usual care for CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A randomized trial in nephrology clinics and the community included 474 patients with median estimated GFR (eGFR) 42 ml/min per 1.73 m(2) identified by laboratory-based case finding compared care coordinated by a general practitioner (controls) with care by a nurse-coordinated team including a nephrologist (intervention) for a median (interquartile range [IQR]) of 742 days. 32% were diabetic, 60% had cardiovascular disease, and proteinuria was minimal. Guided by protocols, the intervention team targeted risk factors for adverse kidney and cardiovascular outcomes. Serial eGFR and clinical events were tracked. RESULTS The average decline in eGFR over 20 months was -1.9 ml/min per 1.73 m(2). eGFR declined by ≥4 ml/min per 1.73 m(2) within 20 months in 28 (17%) intervention patients versus 23 (13.9%) control patients. Control of BP, LDL, and diabetes were comparable across groups. In the intervention group there was a trend to greater use of renin-angiotensin blockers and more use of statins in those with initial LDL >2.5 mmol/L. Treatment was rarely required for anemia, acidosis, or disordered mineral metabolism. Clinical events occurred in 5.2% per year. CONCLUSIONS Patients with stage 3/4 CKD identified through community laboratories largely had nonprogressive kidney disease but had cardiovascular risk. Over a median of 24 months, the nurse-coordinated team did not affect rate of GFR decline or control of most risk factors compared with usual care.

Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis

OBJECTIVES We performed a systematic review and meta-analysis to understand the role of flow-mediated dilatation (FMD) of the brachial artery (BA) and peripheral arterial tonometry (PAT) in predicting adverse events, including cardiovascular (CV) events and all-cause mortality. BACKGROUND FMD of the BA and PAT are non-invasive measures of endothelial function. Impairment of endothelial function is associated with increased CV events. While FMD is the more widely used and studied technique, PAT offers several advantages. The purpose of this systematic review and meta-analysis is to determine whether brachial FMD and PAT are independent risk factors for future CV events and mortality. METHODS Multiple electronic databases were searched for articles relating FMD or PAT to CV events. Data were extracted on study characteristics, study quality, and study outcomes. Relative risks (RRs) from individual studies were combined and a pooled multivariate RR was calculated. RESULTS Thirty-six studies for FMD were included in the systematic review, of which 32 studies consisting of 15, 191 individuals were meta-analysed. The pooled RR of CV events and all-cause mortality per 1% increase in brachial FMD, adjusting for potential confounders, was 0.90 (0.88-0.92). In contrast, only three studies evaluated the prognostic value of PAT for CV events, and the pooled RR per 0.1 increase in reactive hyperaemia index was 0.85 (0.78-0.93). CONCLUSION Brachial FMD and PAT are independent predictors of CV events and all-cause mortality. Further research to evaluate the prognostic utility of PAT is necessary to compare it with FMD as a non-invasive endothelial function test in clinical practice.

Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury.

Acute kidney injury (AKI) is associated with pro-longed hospitalization, substantial health care re-source consumption, high mortality, and can lead toprogressive chronic kidney disease (CKD), includingchronic kidney failure, in survivors. The CanadianSociety of Nephrology (CSN) believes there is a needto develop clinical practice guidelines for patientswith AKI; however, efforts to synthesize knowledgefrom clinical studies evaluating the prevention andtreatmentofAKIandtogenerateguidelineshavebeenlimited. One barrier has been the absence of consen-sus on the definition of AKI, with more than 35definitionsofAKIpublishedtodate.Further,thereisaperceivedlackofeffectiveprophylacticandtreatmentstrategies for AKI, and it is challenging to developguidelines that involve multiple stakeholders fromdiversedisciplinesincludingnephrology,criticalcare,and radiology, all of which are important end users ofguidelines forAKI. In this context, the KDIGO (Kid-neyDisease:ImprovingGlobalOutcomes)AKIwork-ing group has recently published new criteria for thedefinition and classification of AKI, as well as aclinicalpracticeguidelineaddressingbothAKIpreven-tion and treatment.