Unique Transcriptional Programs Identify Subtypes of AKI.

Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to the injury of the kidney tubule and the epithelial cells thereof (AKI). Yet neither criterion emphasizes the etiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using laser microdissection to isolate specific domains of the kidney, followed by RNA sequencing, we found that thousands of genes responded specifically to iAKI or to vAKI, but very few responded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potential biomarkers of either iAKI or vAKI, but not both. Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function.

Antenatal Testing for Women With Preexisting Medical Conditions Using Only the Ultrasonographic Portion of the Biophysical Profile.

OBJECTIVE: To report the utility of the ultrasonographic biophysical profile, which includes all the components of a biophysical profile minus the nonstress test, in women with maternal indications for antepartum surveillance. METHODS: We conducted a case series reviewing the records of all women at 32 weeks of gestation or greater with at least one indication for antenatal testing (per the American College of Obstetricians and Gynecologists) delivered by a single maternal-fetal medicine practice between 2006 and 2018. Indications included diabetes, hypertension, lupus, antiphospholipid syndrome, sickle cell disease, renal disease, heart disease, hyperthyroidism, isoimmunization, inherited thrombophilia, and prior intrauterine fetal demise. Weekly ultrasonographic biophysical profiles were initiated at 32 weeks of gestation. We calculated the test-positive rate, the percentage of women delivered for an abnormal ultrasonography biophysical profile, and the intrauterine fetal demise rate (false-negative rate). RESULTS: Nine hundred eighty-five women underwent 3,981 ultrasonographic biophysical profiles (four per woman; range 1-11). Sixteen women had an abnormal ultrasonographic biophysical profile, for a test positive rate of 1.6% (95% CI 1.0-2.6%) per woman, or 0.4% (95% CI 0.3-0.7%) per ultrasonographic biophysical profile. Of the 16 women with abnormal ultrasonographic biophysical profiles, 13 were delivered with good outcomes and three women had normal follow-up testing and uncomplicated deliveries at a later date. There were three women with intrauterine fetal demise (false-negative rate of 0.3%, 95% CI 0.1-0.9%). One woman with intrauterine fetal demise had a factor V Leiden mutation, fetal ventriculomegaly, and fetal growth restriction. The second woman with intrauterine fetal demise had advanced maternal age, a factor V Leiden mutation, and fetal growth restriction. The third woman with intrauterine fetal demise had class B diabetes. All three intrauterine fetal demises were diagnosed antepartum with an interval from normal ultrasonographic biophysical profile to intrauterine fetal demise of 7, 7, and 6 days, respectively. CONCLUSION: The use of ultrasonographic biophysical profile in a high-risk cohort is associated with a very low test-positive rate and a very low incidence of intrauterine fetal demise. In women with preexisting medical conditions that place them at higher risk for intrauterine fetal demise, ultrasonographic biophysical profile can be used for antenatal testing.

Disposal of iron by a mutant form of lipocalin 2.

Iron overload damages many organs. Unfortunately, therapeutic iron chelators also have undesired toxicity and may deliver iron to microbes. Here we show that a mutant form (K3Cys) of endogenous lipocalin 2 (LCN2) is filtered by the kidney but can bypass sites of megalin-dependent recapture, resulting in urinary excretion. Because K3Cys maintains recognition of its cognate ligand, the iron siderophore enterochelin, this protein can capture and transport iron even in the acidic conditions of urine. Mutant LCN2 strips iron from transferrin and citrate, and delivers it into the urine. In addition, it removes iron from iron overloaded mice, including models of acquired (iron-dextran or stored red blood cells) and primary (Hfe-/-) iron overload. In each case, the mutants reduce redox activity typical of non-transferrin-bound iron. In summary, we present a non-toxic strategy for iron chelation and urinary elimination, based on manipulating an endogenous protein:siderophore:iron clearance pathway.