Development of an electronic health record-based chronic kidney disease registry to promote population health management.

BACKGROUND: Electronic health record (EHR) based chronic kidney disease (CKD) registries are central to population health strategies to improve CKD care. In 2015, Partners Healthcare System (PHS), encompassing multiple academic and community hospitals and outpatient care facilities in Massachusetts, developed an EHR-based CKD registry to identify opportunities for quality improvement, defined as improvement on both process measures and outcomes measures associated with clinical care. METHODS: Patients are included in the registry based on the following criteria: 1) two estimated glomerular filtration rate (eGFR) results < 60 ml/min/1.73m2 separated by 90 days, including the most recent eGFR being < 60 ml/min/1.73m2; or 2) the most recent two urine protein values > 300 mg protein/g creatinine on either urine total protein/creatinine ratio or urine albumin/creatinine ratio; or 3) an EHR problem list diagnosis of end stage renal disease (ESRD). The registry categorizes patients by CKD stage and includes rates of annual testing for eGFR and proteinuria, blood pressure control, use of angiotensin converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), nephrotoxic medication use, hepatitis B virus (HBV) immunization, vascular access placement, transplant status, CKD progression risk; number of outpatient nephrology visits, and hospitalizations. RESULTS: The CKD registry includes 60,503 patients and has revealed several opportunities for care improvement including 1) annual proteinuria testing performed for 17% (stage 3) and 31% (stage 4) of patients; 2) ACE-I/ARB used in 41% (stage 3) and 46% (stage 4) of patients; 3) nephrotoxic medications used among 23% of stage 4 patients; and 4) 89% of stage 4 patients lack HBV immunity. For advanced CKD patients there are opportunities to improve vascular access placement, transplant referrals and outpatient nephrology contact. CONCLUSIONS: A CKD registry can identify modifiable care gaps across the spectrum of CKD care and enable population health strategy implementation. No linkage to Social Security Death Master File or US Renal Data System (USRDS) databases limits our ability to track mortality and progression to ESRD.

Soluble erythropoietin receptor contributes to erythropoietin resistance in end-stage renal disease.

BACKGROUND: Erythropoietin is a growth factor commonly used to manage anemia in patients with chronic kidney disease. A significant clinical challenge is relative resistance to erythropoietin, which leads to use of successively higher erythropoietin doses, failure to achieve target hemoglobin levels, and increased risk of adverse outcomes. Erythropoietin acts through the erythropoietin receptor (EpoR) present in erythroblasts. Alternative mRNA splicing produces a soluble form of EpoR (sEpoR) found in human blood, however its role in anemia is not known. METHODS AND FINDINGS: Using archived serum samples obtained from subjects with end stage kidney disease we show that sEpoR is detectable as a 27kDa protein in the serum of dialysis patients, and that higher serum sEpoR levels correlate with increased erythropoietin requirements. Soluble EpoR inhibits erythropoietin mediated signal transducer and activator of transcription 5 (Stat5) phosphorylation in cell lines expressing EpoR. Importantly, we demonstrate that serum from patients with elevated sEpoR levels blocks this phosphorylation in ex vivo studies. Finally, we show that sEpoR is increased in the supernatant of a human erythroleukaemia cell line when stimulated by inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha implying a link between inflammation and erythropoietin resistance. CONCLUSIONS: These observations suggest that sEpoR levels may contribute to erythropoietin resistance in end stage renal disease, and that sEpoR production may be mediated by pro-inflammatory cytokines.

Molecular mechanisms of preeclampsia.

Preeclampsia is a major cause of maternal, fetal and neonatal mortality worldwide. The mechanisms that initiate preeclampsia in humans have been elusive, but some parts of the puzzle have begun to come together. A key discovery in the field was the realization that its major phenotypes, such as hypertension and proteinuria, are due to excess circulating soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1). sFlt-1 is an endogenous anti-angiogenic protein that is made by the placenta and acts by neutralizing the pro-angiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). More recently, soluble endoglin, another circulating anti-angiogenic protein was found to synergize with sFlt-1 and contribute to the pathogenesis of preeclampsia. Abnormalities in these circulating angiogenic proteins are not only present during clinical preeclampsia, but also antedate clinical symptoms by several weeks. This review will summarize our current understanding of the molecular mechanism of preeclampsia, with an emphasis on the recently characterized circulating anti-angiogenic proteins.

Insulin resistance and alterations in angiogenesis: additive insults that may lead to preeclampsia.

Altered angiogenesis and insulin resistance, which are intimately related at a molecular level, characterize preeclampsia. To test if an epidemiological interaction exists between these two alterations, we performed a nested case-control study of 28 women who developed preeclampsia and 57 contemporaneous controls. Serum samples at 12 weeks of gestation were measured for sex hormone binding globulin (SHBG; low levels correlate with insulin resistance) and placental growth factor (PlGF; a proangiogenic molecule). Compared with controls, women who developed preeclampsia had lower serum levels of SHBG (208+/-116 versus 256+/-101 nmol/L, P=0.05) and PlGF (16+/-14 versus 67+/-150 pg/mL, P<0.001), and in multivariable analysis, women with serum levels of PlGF < or =20 pg/mL had an increased risk of developing preeclampsia (odds ratio [OR] 7.6, 95% CI 1.4 to 38.4). Stratified by levels of serum SHBG (< or =175 versus >175 mg/dL), women with low levels of SHBG and PlGF had a 25.5-fold increased risk of developing preeclampsia (P=0.10), compared with 1.8 (P=0.38) among women with high levels of SHBG and low levels of PlGF. Formal testing for interaction (PlGFxSHBG) was significant (P=0.02). In a model with 3 (n-1) interaction terms (high PlGF and high SHBG, reference), the risk for developing preeclampsia was as follows: low PlGF and low SHBG, OR 15.1, 95% CI 1.7 to 134.9; high PlGF and low SHBG, OR 4.1, 95% CI 0.45 to 38.2; low PlGF and high SHBG, OR 8.7, 95% CI 1.2 to 60.3. Altered angiogenesis and insulin resistance are additive insults that lead to preeclampsia.

First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia.

An imbalance of pro- and antiangiogenic factors may lead to preeclampsia (PE). In this prospective nested case-control study, we investigated whether first trimester serum levels of placental growth factor (PlGF), a potent angiogenic factor, and its soluble inhibitor, soluble fms-like tyrosine kinase 1 (sFlt1), distinguished women who developed PE (n = 40) from those who developed gestational hypertension (n = 40), delivered a small for gestational age (SGA) newborn (n = 40), or completed a full term normal pregnancy (n = 80). Compared with controls, serum PlGF levels were lower among women who developed PE (23 +/- 24 pg/ml vs. 63 +/- 145 pg/ml; P < 0.01) or gestational hypertension (27 +/- 19 pg/ml; P = 0.03), or who delivered a SGA newborn (21 +/- 16 pg/ml; P < 0.01). In contrast, serum sFlt1 levels did not markedly differ between the groups: PE, 1048 +/- 657 pg/ml; gestational hypertension, 942 +/- 437 pg/ml; SGA newborns, 1011 +/- 479 pg/ml; and normal controls, 973 +/- 490 pg/ml. Multivariable analysis adjusting for potential confounders and serum sFlt1 levels demonstrated a 3.7-fold (95% confidence interval, 1.2-12.5) increase in risk for PE for every log unit decrease in serum levels of PlGF compared with controls. Analyses for gestational hypertension and SGA were not significant. Examined in tertiles, the risk for PE was increased 28.7-fold (95% confidence interval, 2.3-351.0) in the third (<12 pg/ml) compared with the first (>39 pg/ml) PlGF tertile. First trimester serum levels of PlGF and sFlt1 may identify women at high risk for PE.