Ramila A. Mehta

Defining High-Sensitivity Cardiac Troponin Concentrations in the Community

BACKGROUND High-sensitivity cardiac troponin (hs-cTn) assays are now available that can detect measurable troponin in significantly more individuals in the general population than conventional assays. The clinical use of these hs-cTn assays depends on the development of proper reference values. Therefore, our objective was to define hs-cTnI reference values and determinants in the general community, in a healthy reference cohort, and in subsets with diseases. MATERIALS AND METHODS A well-characterized community-based cohort of 2042 study participants underwent clinical assessment and echocardiographic evaluation. Baseline hs-cTnI measurements were obtained in 1843 individuals. A healthy reference cohort (n = 565) without cardiac, renal, or echocardiographic abnormalities was identified. RESULTS Measurable hs-cTnI was identified in 1716 (93%) of the community-based study cohort and 499 (88%) of the healthy reference cohort. Parameters that significantly contributed to higher hs-cTnI concentrations in the healthy reference cohort included age, male sex, systolic blood pressure, and left ventricular mass. Glomerular filtration rate and body mass index were not independently associated with hs-cTnI in the healthy reference cohort. Individuals with diastolic and systolic dysfunction, hypertension, and coronary artery disease (but not impaired renal function) had significantly higher hs-cTnI values than the healthy reference cohort. CONCLUSIONS We assessed an hs-cTnI assay with the aid of echocardiographic imaging in a large, well-characterized community-based cohort. hs-cTnI is remarkably sensitive in the general population, and there are important sex and age differences among healthy reference individuals. These results have important implications for defining hs-cTnI reference values and identifying disease.

Kidney stones are common after bariatric surgery

Obesity, a risk factor for kidney stones and chronic kidney disease (CKD), is effectively treated with bariatric surgery. However, it is unclear if surgery alters stone or CKD risk. To determine this we studied 762 Olmsted County, Minnesota residents who underwent bariatric surgery and matched them with equally obese control individuals who did not undergo surgery. The majority of bariatric patients underwent standard Roux-en-Y gastric bypass (RYGB) (78%), with the remainder having more malabsorptive procedures (very long limb RYGB or biliopancreatic diversion/duodenal switch; 14%), or restrictive procedures (laparoscopic banding or sleeve gastrectomy; 7%). Mean age was 45 years with 80% female. The mean preoperative BMI was 46.7 kg/m2 for both cohorts. Rates of kidney stones were similar between surgery patients and controls at baseline, but new stone formation significantly increased in surgery patients (11.0%) compared to controls (4.3%) during 6.0 years of follow up. After malabsorptive and standard surgery, the comorbidity-adjusted hazard ratio of incident stones was significantly increased to 4.15 and 2.13, respectively but not significantly changed for restrictive surgery. The risk of CKD significantly increased after the malabsorptive procedures (adjusted hazard ratio of 1.96). Thus, while RYGB and malabsorptive procedures are more effective for weight loss, both are associated with increased risk of stones, while malabsorptive procedures also increase CKD risk.

Stone Composition as a Function of Age and Sex

BACKGROUND AND OBJECTIVES Kidney stones are heterogeneous but often grouped together. The potential effects of patient demographics and calendar month (season) on stone composition are not widely appreciated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The first stone submitted by patients for analysis to the Mayo Clinic Metals Laboratory during 2010 was studied (n=43,545). Stones were classified in the following order: any struvite, any cystine, any uric acid, any brushite, majority (≥50%) calcium oxalate, or majority (≥50%) hydroxyapatite. RESULTS Calcium oxalate (67%) was the most common followed by hydroxyapatite (16%), uric acid (8%), struvite (3%), brushite (0.9%), and cystine (0.35%). Men accounted for more stone submissions (58%) than women. However, women submitted more stones than men between the ages of 10-19 (63%) and 20-29 (62%) years. Women submitted the majority of hydroxyapatite (65%) and struvite (65%) stones, whereas men submitted the majority of calcium oxalate (64%) and uric acid (72%) stones (P<0.001). Although calcium oxalate stones were the most common type of stone overall, hydroxyapatite stones were the second most common before age 55 years, whereas uric acid stones were the second most common after age 55 years. More calcium oxalate and uric acid stones were submitted in the summer months (July and August; P<0.001), whereas the season did not influence other stone types. CONCLUSIONS It is well known that calcium oxalate stones are the most common stone type. However, age and sex have a marked influence on the type of stone formed. The higher number of stones submitted by women compared with men between the ages of 10 and 29 years old and the change in composition among the elderly favoring uric acid have not been widely appreciated. These data also suggest increases in stone risk during the summer, although this is restricted to calcium oxalate and uric acid stones.

High-Sensitivity Troponin I and Amino-Terminal Pro-B–Type Natriuretic Peptide Predict Heart Failure and Mortality in the General Population

INTRODUCTION High-sensitivity cardiac troponin assays have potent prognostic value in stable cardiovascular disease cohorts. Our objective was to assess the prognostic utility of a novel cardiac troponin I (cTnI) high-sensitivity assay, independently and in combination with amino-terminal pro-B-type natriuretic peptide (NT-proBNP), for the future development of heart failure and mortality in the general community. METHODS A well-characterized community-based cohort of 2042 participants underwent clinical assessment and echocardiographic evaluation. Baseline measurements of cTnI with a high-sensitivity assay and NT-proBNP were obtained in 1843 individuals. Participants were followed for new-onset heart failure and mortality with median (25th, 75th percentile) follow-up of 10.7 (7.9, 11.6) and 12.1 (10.4, 13.0) years, respectively. RESULTS When measured with a high-sensitivity assay, cTnI greater than the sex-specific 80th percentile was independently predictive of heart failure [hazard ratio 2.56 (95% confidence interval 1.88-3.50), P < 0.001] and mortality [1.91(1.49-2.46), P < 0.001] beyond conventional risk factors in this community-based cohort, with significant increases in the net reclassification improvement for heart failure. The prognostic utility of cTnI measured with a high-sensitivity assay goes beyond NT-proBNP, yet our data suggest that these 2 assays are complementary and most beneficial when evaluated together in identifying at-risk individuals in the community. CONCLUSIONS Our findings lay the foundation for prospective studies aimed at identification of individuals at high risk by use of a multimarker approach, followed by aggressive prevention strategies to prevent subsequent heart failure.

Predictors of Incident ESRD among Patients with Primary Hyperoxaluria Presenting Prior to Kidney Failure

BACKGROUND AND OBJECTIVES Overproduction of oxalate in patients with primary hyperoxaluria (PH) leads to calcium oxalate deposition in the kidney and ESRD in a substantial number of cases. However, the key determinants for renal outcome remain unclear. Thus, we performed a retrospective analysis to identify predictors for renal outcome among patients with PH participating in the Rare Kidney Stone Consortium (RKSC) PH Registry. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We characterized clinical and laboratory features of patients enrolled in the RKSC PH Registry. We assessed correlation between urinary measures and eGFR at diagnosis by Spearman rank correlation and estimated renal survival using the Kaplan-Meier method. We determined factors associated with renal survival by Cox proportional hazard models. RESULTS Of 409 patients enrolled in the RKSC Registry as of March 2014, we excluded 112 patients who had ESRD at PH diagnosis from analysis. Among the remaining 297 patients, 65% had PH type 1, 12% had type 2, 13% had type 3, and 11% had unclassified PH. Median (25th, 75th percentile) age at PH diagnosis was 8.1 (4.0, 18.2) years with an eGFR of 73.0 (56.4, 97.5) ml/min per 1.73 m(2) and urinary oxalate excretion rate of 1.64 (1.11, 2.44) mmol/1.73 m(2) per 24 hours. During a median follow-up of 3.9 (1.0, 12.8) years, 59 (20%) patients developed ESRD. Urinary oxalate excretion at diagnosis stratified by quartile was strongly associated with incident ESRD (hazard ratio [HR], 3.4; 95% confidence interval [95% CI], 1.4 to 7.9). During follow-up there was a significant association between urinary oxalate quartile (Q) and incident ESRD (Q4 versus Q1: HR, 3.3; 95% CI, 1.2 to 9.3). This association remained even when adjusted for sex, age, and baseline eGFR (HR, 4.2; 95% CI, 1.6 to 10.8). CONCLUSIONS Among patients with PH, higher urinary oxalate excretion is predictive of poor renal outcome.

Nephrocalcinosis is a risk factor for kidney failure in primary hyperoxaluria

Stone formation and nephrocalcinosis are both very common features of primary hyperoxaluria, yet the extent of each disease varies markedly between patients. Here we studied whether kidney damage from nephrocalcinosis and/or stone related events contributed to end stage kidney disease (ESKD). Clinical information was analyzed from 348 patients enrolled in the Rare Kidney Stone Consortium Primary Hyperoxaluria registry and included demographic, laboratory and imaging features. Among all patients there were 277 with type 1, 37 with type 2, and 34 with type 3 primary hyperoxaluria. Overall, 58% passed a stone (mean 0.3/year) and one or more urologic procedures were required by 70% of patients (mean 0.15/year). Nephrocalcinosis was found in 34% of patients, including 41% with type 1 primary hyperoxaluria. High urine oxalate was associated with increased risk for both nephrocalcinosis and stone number, while low urine citrate was a risk factor for stone events and stone number. After adjustment for the type of primary hyperoxaluria, diagnosis by family screening and age at first image, the overall adjusted hazard ratio for ESKD among those with a history of nephrocalcinosis was 1.7 [95% CI 1.0–3.0], while the risk was 4.0 [1.9–8.5] for new onset nephrocalcinosis during follow-up. In contrast, the number of stones and stone events were not significantly associated with ESKD risk. Thus, nephrolithiasis and nephrocalcinosis appear to be pathophysiologically distinct entities. The presence of nephrocalcinosis implies increased risk for ESKD.

Outcomes After Implantable Cardioverter-Defibrillator Generator Replacement for Primary Prevention of Sudden Cardiac Death.

Background—The effectiveness of implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden death in patients with an ejection fraction (EF) ⩽35% and clinical heart failure is well established. However, outcomes after replacement of the ICD generator in patients with recovery of EF to >35% and no previous therapies are not well characterized. Methods and Results—Between 2001 and 2011, generator replacement was performed at 2 tertiary medical centers in 253 patients (mean age, 68.3±12.7 years; 82% men) who had previously undergone ICD placement for primary prevention but subsequently never received appropriate ICD therapy. EF had recovered to >35% in 72 of 253 (28%) patients at generator replacement. During median (quartiles) follow-up of 3.3 (1.8–5.3) years after generator replacement, 68 of 253 (27%) experienced appropriate ICD therapy. Patients with EF ⩽35% were more likely to experience ICD therapy compared with those with EF >35% (12% versus 5% per year; hazard ratio, 3.57; P=0.001). On multivariable analysis, low EF predicted appropriate ICD therapy after generator replacement (hazard ratio, 1.96 [1.35–2.87] per 10% decrement; P=0.001). Death occurred in 25% of patients 5 years after generator replacement. Mortality was similar in patients with EF ⩽35% and >35% (7% versus 5% per year; hazard ratio, 1.10; P=0.68). Atrial fibrillation (3.24 [1.63–6.43]; P<0.001) and higher blood urea nitrogen (1.28 [1.14–1.45] per increase of 10 mg/dL; P<0.001) were associated with mortality. Conclusions—Although approximately one fourth of patients with a primary prevention ICD and no previous therapy have EF >35% at the time of generator replacement, these patients continue to be at significant risk for appropriate ICD therapy (5% per year). These data may inform decisions on ICD replacement.

Outcomes in patients with sustained ventricular tachyarrhythmias occurring within 48 h of acute myocardial infarction: when is ICD appropriate?

AIMS Recent guidelines for implantable cardioverter-defibrillator (ICD) use in patients with early ventricular arrhythmia (VA) after acute myocardial infarction (MI) are based on systolic function and revascularization status, yet decision to implant an ICD remains highly subjective. We aimed to determine characteristics, utilization of ICDs, and long-term outcomes of survivors of early VA (<48 h) after acute MI. METHODS AND RESULTS We retrospectively analyzed clinical characteristics, ICD therapies, and survival in 128 patients with early VA after acute MI from 2002-12. Patients were classified for appropriateness of ICD implantation, per 2013 Appropriate Use Criteria (AUC). In 128 early VA survivors after MI, older age, female gender, history of coronary artery bypass graft surgery (CABG) or MI, non-ST-elevation MI or ventricular tachycardia (VT) at presentation predicted worse overall survival (all P < 0.05). While left ventricular ejection fraction (LVEF) did not predict mortality (HR = 1; P = 0.86), post-MI ventricular fibrillation (VF) portended a better long-term prognosis than VT (HR = 0.37; P = 0.001). Twenty-six (20%) early VA survivors received ICD, corresponding well with AUC. Implantable cardioverter-defibrillator recipients had lower post-MI LVEF (P = 0.02) and more frequently presented with non-ST-elevation MI (P = 0.007). Over 2.4 years of median follow-up, ICD recipients had a greater mortality rate than non-ICD recipients (42 vs. 17%; P = 0.02). Appropriate and inappropriate ICD discharges were high in ICD recipients. CONCLUSION Early VA survivors after MI receiving ICD due to suspected non-reversible arrhythmogenic substrate have high rates of appropriate ICD therapy and mortality. Our ICD implantation practice corresponds well with the AUC. Sustained monomorphic VT and non-ST-elevation MI at presentation predict increased risk for death. Larger prospective studies are necessary to confirm our findings, such as to provide evidence for future ICD guidelines.

The Changing Incidence and Presentation of Urinary Stones Over 3 Decades

Objective: To evaluate trends in the incidence of kidney stones and characteristics associated with changes in the incidence rate over 3 decades. Patients and Methods: Adult stone formers in Olmsted County, Minnesota, from January 1, 1984, to December 31, 2012, were validated and characterized by age, sex, stone composition, and imaging modality. The incidence of kidney stones per 100,000 person‐years was estimated. Characteristics associated with changes in the incidence rate over time were assessed using Poisson regression models. Results: There were 3224 confirmed symptomatic (stone seen), 606 suspected symptomatic (no stone seen), and 617 incidental asymptomatic kidney stone formers. The incidence of confirmed symptomatic kidney stones increased from the year 1984 to 2012 in both men (145 to 299/100,000 person‐years; incidence rate ratio per 5 years, 1.14, P<.001) and women (51 to 217/100,000 person‐years; incidence rate ratio per 5 years, 1.29, P<.001). Overall, the incidence of suspected symptomatic kidney stones did not change, but that of asymptomatic kidney stones increased. Utilization of computed tomography for confirmed symptomatic stones increased from 1.8% in 1984 to 77% in 2012; there was a corresponding higher increased incidence of symptomatic small stones (≤3 mm) than of larger stones (>3 mm). Confirmed symptomatic kidney stones with documented spontaneous passage also increased. The incidence of kidney stones with unknown composition increased more than that of stones with known composition. Conclusion: The incidence of both symptomatic and asymptomatic kidney stones has increased dramatically. The increased utilization of computed tomography during this period may have improved stone detection and contributed to the increased kidney stone incidence.

Pre- and Postoperative Predictors of Infection-Related Complications in Patients Undergoing Percutaneous Nephrolithotomy

INTRODUCTION We aim to describe pre- and postoperative predictors of infection-related complications in individuals undergoing percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS Patients treated with PCNL from 2009 to 2013 were reviewed. Patients with positive urine or stone cultures received extended antimicrobial treatment. All others received 7 days of empirical therapy preoperatively and postoperatively. Pre- and postoperative predictors of infectious complication were identified. RESULTS We identified 227 patients who underwent primary PCNL with infectious complications occurring in 37 (16%): 11 (5%) urinary tract infection/pyelonephritis, 21 (9%) systemic inflammatory response syndrome (SIRS), and 2 (0.9%) sepsis. There were no significant differences between those with and without infectious complication with regard to age, gender, stone size, presence of diabetes, or procedure duration. Those with infectious complication were more likely to have a positive intraoperative stone culture (p = 0.01), struvite stone composition (p < 0.01), staghorn calculi (p < 0.001), and multiple stones (p = 0.02). Preoperatively, on multivariable analysis, only the presence of a staghorn calculus remained independently associated with increased risks of fever/SIRS/sepsis (odds ratio [OR] 3.14; p = 0.02) and total infectious complications (OR 2.53; p = 0.02) following PCNL. After controlling for pre- and post-PCNL risk factors, again, only staghorn calculi remained significantly associated with fever/SIRS/sepsis (OR 3.41; p = 0.01) and total infectious complications (OR 2.91; p = 0.01), with presence of multiple stones approaching significance (OR 4.2, confidence interval [CI]: 0.96, 18.6; p = 0.06). CONCLUSIONS In individuals undergoing PCNL on preoperative antibiotics, risk of SIRS/sepsis was low. The presence of a staghorn calculus confers a greater than threefold increased risk of postoperative infection with multiple stones approaching a significant risk. Patients with large stone burdens should be counseled appropriately regarding these risks.