Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial.

Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans (AAs). Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2571 AAs from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary, or carotid artery revascularization) and CKD (eGFR under 60 ml/min per 1.73 m(2) and/or UACR over 30 mg/g). AA SPRINT participants were 45.3% female with a mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mm Hg, eGFR 76.3 (77.1) ml/min per 1.73 m(2), and UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08-1.73) and log UACR estimated slope (β) 0.33) and negatively associated with eGFR (β -3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82-1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not with prevalent CVD in AAs with a UACR under 1000 mg/g

Development and Standardization of a Furosemide Stress Test to Predict the Severity of Acute Kidney Injury

Introduction: In the setting of early acute kidney injury (AKI), no test has been shown to definitively predict the progression to more severe stages. Methods: We investigated the ability of a furosemide stress test (FST) (one-time dose of 1.0 or 1.5 mg/kg depending on prior furosemide-exposure) to predict the development of AKIN Stage-III in 2 cohorts of critically ill subjects with early AKI. Cohort 1 was a retrospective cohort who received a FST in the setting of AKI in critically ill patients as part of Southern AKI Network. Cohort 2 was a prospective multicenter group of critically ill patients who received their FST in the setting of early AKI. Results: We studied 77 subjects; 23 from cohort 1 and 54 from cohort 2; 25 (32.4%) met the primary endpoint of progression to AKIN-III. Subjects with progressive AKI had significantly lower urine output following FST in each of the first 6 hours (p\u3c0.001). The area under the receiver operator characteristic curves for the total urine output over the first 2 hours following FST to predict progression to AKIN-III was 0.87 (p = 0.001). The ideal-cutoff for predicting AKI progression during the first 2 hours following FST was a urine volume of less than 200mls(100ml/hr) with a sensitivity of 87.1% and specificity 84.1%.Conclusions: The FST in subjects with early AKI serves as a novel assessment of tubular function with robust predictive capacity to identify those patients with severe and progressive AKI. Future studies to validate these findings are warranted. © 2013 Chawla et al. licensee BioMed Central Ltd

The severity of acute kidney injury predicts progression to chronic kidney disease

Acute kidney injury (AKI) is associated with progression to advanced chronic kidney disease (CKD). We tested whether patients who survive AKI and are at higher risk for CKD progression can be identified during their hospital admission, thus providing opportunities to intervene. This was assessed in patients in the Department of Veterans Affairs Healthcare System hospitalized with a primary diagnosis indicating AKI (ICD9 codes 584.xx). In the exploratory phase, three multivariate prediction models for progression to stage 4 CKD were developed. In the confirmatory phase, the models were validated in 11,589 patients admitted for myocardial infarction or pneumonia during the same time frame that had RIFLE codes R, I, or F and complete data for all predictor variables. Of the 5351 patients in the AKI group, 728 entered stage 4 CKD after hospitalization. Models 1, 2, and 3 were all significant with ‘c' statistics of 0.82, 0.81, and 0.77, respectively. In model validation, all three were highly significant when tested in the confirmatory patients, with moderate to large effect sizes and good predictive accuracy (‘c' 0.81–0.82). Patients with AKI who required dialysis and then recovered were at especially high risk for progression to CKD. Hence, the severity of AKI is a robust predictor of progression to CKD

Statistical methods for building better biomarkers of chronic kidney disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149268/1/sim8091.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149268/2/sim8091_am.pd

A Loss of Function Screen of Identified Genome-Wide Association Study Loci Reveals New Genes Controlling Hematopoiesis

The formation of mature cells by blood stem cells is very well understood at the cellular level and we know many of the key transcription factors that control fate decisions. However, many upstream signalling and downstream effector processes are only partially understood. Genome wide association studies (GWAS) have been particularly useful in providing new directions to dissect these pathways. A GWAS meta-analysis identified 68 genetic loci controlling platelet size and number. Only a quarter of those genes, however, are known regulators of hematopoiesis. To determine function of the remaining genes we performed a medium-throughput genetic screen in zebrafish using antisense morpholino oligonucleotides (MOs) to knock down protein expression, followed by histological analysis of selected genes using a wide panel of different hematopoietic markers. The information generated by the initial knockdown was used to profile phenotypes and to position candidate genes hierarchically in hematopoiesis. Further analysis of brd3a revealed its essential role in differentiation but not maintenance and survival of thrombocytes. Using the from-GWAS-to-function strategy we have not only identified a series of genes that represent novel regulators of thrombopoiesis and hematopoiesis, but this work also represents, to our knowledge, the first example of a functional genetic screening strategy that is a critical step toward obtaining biologically relevant functional data from GWA study for blood cell traits

Effect of Bariatric Surgery on CKD Risk

Obesity is linked to the development and progression of CKD, but whether bariatric surgery protects against CKD is poorly understood. We, therefore, examined whether bariatric surgery influences CKD risk. The study included 2144 adults who underwent bariatric surgery from March of 2006 to April of 2009 and participated in the Longitudinal Assessment of Bariatric Surgery-2 Study cohort. The primary outcome was CKD risk categories as assessed by the Kidney Disease Improving Global Outcomes (KDIGO) consortium criteria using a combination of eGFR and albuminuria. Patients were 79% women and 87% white, with a median age of 46 years old. Improvements were observed in CKD risk at 1 and 7 years after surgery in patients with moderate baseline CKD risk (63% and 53%, respectively), high baseline risk (78% and 56%, respectively), and very high baseline risk (59% and 23%, respectively). The proportion of patients whose CKD risk worsened was ≤10%; five patients developed ESRD. Sensitivity analyses using year 1 as baseline to minimize the effect of weight loss on serum creatinine and differing eGFR equations offered qualitatively similar results. Treatment with bariatric surgery associated with an improvement in CKD risk categories in a large proportion of patients for up to 7 years, especially in those with moderate and high baseline risk. These findings support consideration of CKD risk in evaluation for bariatric surgery and further study of bariatric surgery as a treatment for high-risk obese patients with CKD

A quasi-experimental test of an intervention to increase the use of thiazide-based treatment regimens for people with hypertension

BACKGROUND: Despite recent high-quality evidence for their cost-effectiveness, thiazides are underused for controlling hypertension. The goal of this study was to design and test a practice-based intervention aimed at increasing the use of thiazide-based antihypertensive regimens. METHODS: This quasi-experimental study was carried out in general medicine ambulatory practices of a large, academically-affiliated Veterans Affairs hospital. The intervention group consisted of the practitioners (13 staff and 215 trainees), nurses, and patients (3,502) of the teaching practice; non-randomized concurrent controls were the practitioners (31 providers) and patients (18,292) of the non-teaching practices. Design of the implementation intervention was based on Rogers' Diffusion of Innovations model. Over 10.5 months, intervention teams met weekly or biweekly and developed and disseminated informational materials among themselves and to trainees, patients, and administrators. These teams also reviewed summary electronic-medical-record data on thiazide use and blood pressure (BP) goal attainment. Outcome measures were the proportion of hypertensive patients prescribed a thiazide-based regimen, and the proportion of hypertensive patients attaining BP goals regardless of regimen. Thirty-three months of time-series data were available; statistical process control charts, change point analyses, and before-after analyses were used to estimate the intervention's effects. RESULTS: Baseline use of thiazides and rates of BP control were higher in the intervention group than controls. During the intervention, thiazide use and BP control increased in both groups, but changes occurred earlier in the intervention group, and primary change points were observed only in the intervention group. Overall, the pre-post intervention difference in proportion of patients prescribed thiazides was greater in intervention patients (0.091 vs. 0.058; p = 0.0092), as was the proportion achieving BP goals (0.092 vs. 0.044; p = 0.0005). At the end of the implementation period, 41.4% of intervention patients were prescribed thiazides vs. 30.6% of controls (p < 0.001); 51.6% of intervention patients had achieved BP goals vs. 44.3% of controls (p < 0.001). CONCLUSION: This multi-faceted intervention appears to have resulted in modest improvements in thiazide prescribing and BP control. The study also demonstrates the value of electronic medical records for implementation research, how Rogers' model can be used to design and launch an implementation strategy, and how all members of a clinical microsystem can be involved in an implementation effort