Emily P. McQuarrie

Determinants of Left Ventricular Mass and Hypertrophy in Hemodialysis Patients Assessed by Cardiac Magnetic Resonance Imaging

BACKGROUND AND OBJECTIVES Left ventricular hypertrophy (LVH) is an independent risk factor for premature cardiovascular death in hemodialysis (HD) patients and one of the three forms of uremic cardiomyopathy. Cardiovascular magnetic resonance (CMR) is a volume-independent technique to assess cardiac structure. We used CMR to assess the determinants of left ventricular mass (LVM) and LVH in HD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 246 HD patients (63.8% male; mean age 51.5 +/- 12.1 yr) underwent CMR on a postdialysis day. LVM was measured from a stack of cine loops and indexed for body surface area (LVM index [LVMI]). Demographic, past biochemical, hematologic, and dialysis data were collected by patient record review. Results up to 180 d before CMR were collected. LVH was defined as LVMI >84.1 g/m(2) (male) or >76.4 g/m(2) (female). RESULTS A total of 157 (63.8%) patients had LVH. LVH was more common in patients with higher predialysis systolic BP, predialysis pulse pressure, and calcium-phosphate product (Ca X PO4). Furthermore, LVH was significantly associated with higher end-diastolic and systolic volumes and lower ejection fraction. There were positive correlations with LVMI and end-diastolic and systolic volumes. There were weak positive correlations among LVMI, mean volume of ultrafiltration, and Ca X PO4. Using multivariate linear and logistic regression (entering one BP and cardiac variable), the independent predictors of LVMI and LVH were end-diastolic volume, predialysis systolic BP, and Ca X PO4. CONCLUSIONS The principal determinants of LVM and LVH in HD patients are end-diastolic LV volume, predialysis BP, and Ca X PO4.

Association of Left Atrial Volume With Mortality Among ESRD Patients With Left Ventricular Hypertrophy Referred for Kidney Transplantation

Background Left ventricular hypertrophy (LVH) is common in patients with end-stage renal disease (ESRD) and an independent risk factor for premature cardiovascular death. Left atrial volume (LAV), measured using echocardiography, predicts death in patients with ESRD. Cardiovascular magnetic resonance (CMR) imaging is a volume-independent method of accurately assessing cardiac structure and function in patients with ESRD. Study Design Single-center prospective observational study to assess the determinants of all-cause mortality, particularly LAV, in a cohort of ESRD patients with LVH, defined using CMR imaging. Setting & Participants 201 consecutive ESRD patients with LVH (72.1% men; mean age, 51.6 ± 11.7 years) who had undergone pretransplant cardiovascular assessment were identified using CMR imaging between 2002-2008. LVH was defined as left ventricular mass index >84.1 g/m2 (men) or >74.6 g/m2 (women) based on published normal left ventricle dimensions for CMR imaging. Maximal LAV was calculated using the biplane area-length method at the end of left ventricle systole and corrected for body surface area. Predictors CMR abnormalities, including LAV. Outcome All-cause mortality. Results 54 patients died (11 after transplant) during a median follow-up of 3.62 years. Median LAV was 30.4 mL/m2 (interquartile range, 26.2-58.1). Patients were grouped into high (median or higher) or low (less than median) LAV. There were no significant differences in heart rate and mitral valve Doppler early to late atrial peak velocity ratio. Increased LAV was associated with higher mortality. Kaplan-Meier survival analysis showed poorer survival in patients with higher LAV (log rank P = 0.01). High LAV and left ventricular systolic dysfunction conferred similar risk and were independent predictors of death using multivariate analysis. Limitations Only patients undergoing pretransplant cardiac assessment are included. Limited assessment of left ventricular diastolic function. Conclusions Higher LAV and left ventricular systolic dysfunction are independent predictors of death in ESRD patients with LVH.

Demonstration of blood pressure-independent noninfarct myocardial fibrosis in primary aldosteronism: a cardiac magnetic resonance imaging study.

Background—Primary aldosteronism (PA) is common and associates with excess cardiovascular morbidity independent of blood pressure. Exposure to aldosterone and sodium leads to cardiac fibrosis and hypertrophy in humans and animals possibly mediated by inflammation and oxidative stress. We aimed to clarify the effects of aldosterone excess on myocardial structure and composition in human subjects with PA and essential hypertension using contrast-enhanced cardiac magnetic resonance imaging as well as explore the mechanistic basis for any observed differences. Methods and Results—Twenty-seven subjects with recently diagnosed PA and 54 essential hypertension controls were recruited. Subjects underwent gadolinium-enhanced cardiac magnetic resonance; noninfarct related myocardial fibrosis was identified by a diffuse pattern of late gadolinium enhancement. Patients also underwent assessment of pulse wave velocity, measurement of circulating superoxide anion and C-reactive protein, as well as blood pressure and biochemical assessment. Subjects were well matched with no difference in severity or duration of hypertension. There was a significant increase in the frequency of noninfarct late gadolinium enhancement in PA (70%) when compared with essential hypertension subjects (13%; P<0.0001) with no difference in left ventricular mass. Pulse wave velocity, superoxide, and C-reactive protein were significantly higher in subjects with PA. Conclusions—These data illustrate that patients with PA exhibit frequent myocardial fibrosis as demonstrated by late gadolinium enhancement using cardiac magnetic resonance imaging; this finding is independent of blood pressure. This may be mediated partly through inflammation and oxidative stress. This study highlights the importance of specific targeting of aldosterone excess as well as blood pressure reduction to minimize cardiac morbidity in PA.

Association between proteinuria and left ventricular mass index: a cardiac MRI study in patients with chronic kidney disease

BACKGROUND Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. We hypothesized that the level of proteinuria would correlate with left ventricular mass, providing a potential link between elevated protein excretion, left ventricular hypertrophy (LVH) and the increased mortality seen in patients with CKD. In order to do this, we assessed the determinants of left ventricular mass, measured using cardiac magnetic resonance (CMR) imaging, in patients with CKD. METHODS Patients attending the renal clinic with CKD stages 2-4 and diabetic nephropathy (n = 26) and IgA nephropathy (n = 23) were recruited. They underwent detailed demographic, biochemical and vascular phenotyping and CMR imaging. Proteinuria was measured using spot protein:creatinine ratio (PCR). Left ventricular mass index (LVMI) was calculated from short-axis cine imaging using Argus software and adjusted for body surface area. RESULTS Log-PCR correlated significantly with LVMI, as did waist circumference, pulse pressure and systolic blood pressure. LVMI was higher in men. When these variables were entered into a linear regression model, log-PCR (P = 0.006) and systolic blood pressure (P < 0.001) independently predicted LVMI. Renal function was not associated with LVMI. CONCLUSIONS Using volume-independent CMR imaging, we have demonstrated that the level of urinary protein excretion is independently and significantly associated with left ventricular mass in patients with CKD. This relationship was independent of blood pressure. This finding provides a novel link between CKD and increased cardiovascular risk.

Fibroblast Growth Factor 23 Predicts Left Ventricular Mass and Induces Cell Adhesion Molecule Formation

Elevated FGF-23 is a predictor of mortality and is associated with LVH in CKD. It may be a biomarker or a direct toxin. We assessed the relationship between FGF-23 and LVH in CKD using CMRI. In vitro we studied the effect of phosphate, FGF-23, and Klotho on E-selectin and VCAM production in HUVECs. FGF-23 concentration correlates negatively with eGFR and positively with LVMI. FGF-23 was an independent predictor of LVH in CKD. E-selectin and VCAM production was elevated in HUVECs cultured in high phosphate with FGF-23 or Klotho. This effect was attenuated in cells exposed to both FGF-23 and Klotho. FGF-23 is an independent predictor of LVH as measured by CMRI. We show preliminary data which supports that FGF-23 is toxic resulting in activation of the vascular endothelium. We do not prove causality with elevated FGF-23 and LVH. Further research should ascertain if lowering levels of FGF-23 translates to improved clinical outcomes.

Fractional excretions of albumin and IgG are the best predictors of progression in primary glomerulonephritis

BACKGROUND Proteinuria is the most sensitive predictor of development of progressive renal insufficiency, with increasing focus on the composition of proteinuria, particularly high molecular weight proteins such as immunoglobulin G (IgG) (molecular weight 150 kDa). Differing methods of assessing excretion of proteinuria molecules have limited interpretation of results. We aimed to assess the utility of available indices of IgG, total proteinuria and albumin excretions as predictors of chronic kidney disease (CKD) progression in patients with primary glomerulonephritis. METHODS We recruited 97 patients with primary glomerulonephritis and measured 24-h urinary protein excretion, 24-h urinary albumin excretion, selectivity index, albumin:creatinine ratio, urinary IgG:creatinine ratio, fractional excretion of albumin (FE Alb) and fractional excretion of IgG (FE IgG) at baseline. The composite endpoint was developing stage 5 CKD, requiring RRT or death. Receiver operating characteristics curve analysis was used to assess the value of each measure in predicting outcome. From this analysis, high- and low-risk patient groups according to each measure were established. These were then tested using Kaplan-Meier and Cox survival analysis. RESULTS During a median follow-up of 7.07 years, 23 patients developed the primary endpoint. FE IgG and FE Alb were the most sensitive predictive tests. The hazard ratios (HR) of developing the primary endpoint using FE IgG [HR 37.1 (95% CI 8.6-158.8)] and FE Alb [HR 35.2 (95% CI 8.2-150.8)] cut-offs were double those using the other measures. CONCLUSIONS FE IgG and FE Alb are superior to conventional measures of proteinuria in predicting outcome in patients with primary glomerulonephritis, possibly because they are more accurate indicators of impairment of glomerular permselectivity. FE Alb should be used, in conjunction with other measures of proteinuria, in future studies of prediction of CKD progression.

Association Between Urinary Sodium, Creatinine, Albumin, and Long-Term Survival in Chronic Kidney Disease

Dietary sodium intake is associated with hypertension and cardiovascular risk in the general population. In patients with chronic kidney disease, sodium intake has been associated with progressive renal disease, but not independently of proteinuria. We studied the relationship between urinary sodium (UNa) excretion and UNa to creatinine ratio and mortality or requirement for renal replacement therapy in chronic kidney disease. Adult patients attending a renal clinic who had ≥1 24-hour UNa measurement were identified. Twenty-four-hour UNa measures were collected and UNa to creatinine ratio calculated. Time to renal replacement therapy or death was recorded. Four hundred twenty-three patients were identified with mean estimated glomerular filtration rate of 48 mL/min per 1.73 m2. Ninety patients required renal replacement therapy and 102 patients died. Mean slope decline in estimated glomerular filtration rate was −2.8 mL/min per 1.73 m2 per year. Median follow-up was 8.5 years. Patients who died or required renal replacement therapy had significantly higher UNa excretion and UNa to creatinine ratio, but the association with these parameters and poor outcome was not independent of renal function, age, and albuminuria. When stratified by albuminuria, UNa to creatinine ratio was a significant cumulative additional risk for mortality, even in patients with low-level albuminuria. There was no association between low UNa and risk, as observed in some studies. This study demonstrates an association between UNa excretion and mortality in chronic kidney disease, with a cumulative relationship between sodium excretion, albuminuria, and reduced survival. These data support reducing dietary sodium intake in chronic kidney disease, but additional study is required to determine the target sodium intake.

The incidence of biopsy-proven IgA nephropathy is associated with multiple socioeconomic deprivation.

Chronic kidney disease is more common in areas of socioeconomic deprivation, but the relationship with the incidence and diagnosis of biopsy-proven renal disease is unknown. In order to study this, all consecutive adult patients undergoing renal biopsy in West and Central Scotland over an 11-year period were prospectively analyzed for demographics, indication, and histologic diagnosis. Using the Scottish Index of Multiple Deprivation, 1555 eligible patients were separated into quintiles of socioeconomic deprivation according to postcode. Patients in the most deprived quintile were significantly more likely to undergo biopsy compared with patients from less deprived areas (109.5 compared to 95.9 per million population/year). Biopsy indications were significantly more likely to be nephrotic syndrome, or significant proteinuria without renal impairment. Patients in the most deprived quintile were significantly more likely to have glomerulonephritis. There was a significant twofold increase in the diagnosis of IgA nephropathy in the patients residing in the most compared with the least deprived postcodes not explained by the demographics of the underlying population. Thus, patients from areas of socioeconomic deprivation in West and Central Scotland are significantly more likely to undergo native renal biopsy and have a higher prevalence of IgA nephropathy.

CARDIOVASCULAR DISEASE IN RENAL TRANSPLANT RECIPIENTS

Renal transplant recipients have a markedly increased risk of premature cardiovascular disease (CVD) compared with the general population, although considerably lower than that of patients receiving maintenance haemodialysis. CVD in transplant recipients is poorly characterised and differs from the nonrenal population, with a much higher proportion of fatal to nonfatal cardiac events. In addition to traditional ischaemic heart disease risk factors such as age, gender, diabetes and smoking, there are additional factors to consider in this population such as the importance of hypertension, left ventricular hypertrophy and uraemic cardiomyopathy. There are factors specific to transplantation such immunosuppressive therapies and graft dysfunction which contribute to this altered risk profile. However, understanding and treatment is limited by the absence of large randomised intervention trials addressing risk factor modification, with the exception of the ALERT study. The approach to managing these patients should begin early and be multifactorial in nature.

Acute tubulointerstitial nephritis in Scotland

BACKGROUND AND AIMS Acute tubulointerstitial nephritis (ATIN) is a potentially reversible cause of acute kidney injury with the majority of cases drug related. Our aims were to examine the incidence profile of patients with ATIN in Scotland and to assess the impact of corticosteroid treatment. DESIGN AND METHODS All adult patients with biopsy-proven ATIN, diagnosed between 2000 and 2012, presenting to renal units serving 1.9 of Scotlands 5 million population were included. Patient demographics, presenting, aetiologic and pathologic features, treatment given and outcome were extracted from patient records. RESULTS In total, 171 cases representing 4.7% of native renal biopsies were identified. Median serum creatinine (sCr) was 327 μmol/l at biopsy (106 μmol/l at baseline). Eosinophilia, fever or rash was present in 57% with all 3 in only 1.1%. Active urinary sediment was found in 68%. Aetiology appeared drug induced in 73%. Proton pump inhibitors (PPIs) were likely causative in almost as many cases as antibiotics (35% each) and were more frequently implicated than non-steroidal anti-inflammatory drugs (20%). Number of PPI-related cases paralleled the rising prescription of these drugs. Corticosteroids were prescribed in 59% of drug-induced ATIN (median sCr at biopsy: 356 μmol/l vs. 280 μmol/l in those managed conservatively). There was no difference in sCr at 1, 6 and 12 months, with similar proportions of both groups experiencing complete renal recovery (48% vs. 41%) and becoming dialysis dependent (10% in both). CONCLUSIONS Incidence of biopsy-proven ATIN in Scotland has been rising over the past decade with the majority of cases drug induced. Evidence supporting corticosteroid treatment is lacking.