David Sola-Del Valle

Diagnostic and Prognostic Stratification in the Emergency Department Using Urinary Biomarkers of Nephron Damage: A Multicenter Prospective Cohort Study

OBJECTIVES This study aimed to determine the diagnostic and prognostic value of urinary biomarkers of intrinsic acute kidney injury (AKI) when patients were triaged in the emergency department. BACKGROUND Intrinsic AKI is associated with nephron injury and results in poor clinical outcomes. Several urinary biomarkers have been proposed to detect and measure intrinsic AKI. METHODS In a multicenter prospective cohort study, 5 urinary biomarkers (urinary neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid binding protein, urinary interleukin-18, and cystatin C) were measured in 1,635 unselected emergency department patients at the time of hospital admission. We determined whether the biomarkers diagnosed intrinsic AKI and predicted adverse outcomes during hospitalization. RESULTS All biomarkers were elevated in intrinsic AKI, but urinary neutrophil gelatinase-associated lipocalin was most useful (81% specificity, 68% sensitivity at a 104-ng/ml cutoff) and predictive of the severity and duration of AKI. Intrinsic AKI was strongly associated with adverse in-hospital outcomes. Urinary neutrophil gelatinase-associated lipocalin and urinary kidney injury molecule 1 predicted a composite outcome of dialysis initiation or death during hospitalization, and both improved the net risk classification compared with conventional assessments. These biomarkers also identified a substantial subpopulation with low serum creatinine at hospital admission, but who were at risk of adverse events. CONCLUSIONS Urinary biomarkers of nephron damage enable prospective diagnostic and prognostic stratification in the emergency department.

NGAL (Lcn2) monomer is associated with tubulointerstitial damage in chronic kidney disease

The rate of progression of chronic kidney disease (CKD) is difficult to predict using single measurements of serum creatinine or proteinuria. On the other hand, documented tubulointerstitial disease presages worsening CKD, but kidney biopsy is not practical for routine use and generally does not sample the tubulointerstitial compartment of the medulla. Perhaps a urine test that correlates with specific histological findings may serve as a surrogate for the kidney biopsy. Here we compared both immunoblot analysis (under non-reducing conditions) and a commercially available monomer immunoassays of Neutrophil Gelatinase Associated Lipocalin (NGAL) with pathological changes found in kidney biopsies, to determine whether specific histological characteristics associated with a specific NGAL species. We found that the urine of patients with advanced CKD contained NGAL monomers as well as higher molecular weight complexes containing NGAL, identified by MALDI-TOF/TOF mass spectroscopy. The NGAL monomer significantly correlated with glomerular filtration rate, interstitial fibrosis and tubular atrophy. Hence, specific assays of the NGAL monomer implicate histology associated with progressive, severe CKD.The type and the extent of tissue damage inform the prognosis of chronic kidney disease (CKD), but kidney biopsy is not a routine test. Urinary tests that correlate with specific histological findings might serve as surrogates for the kidney biopsy. We used immunoblots and ARCHITECT-NGAL assays to define the immunoreactivity of urinary neutrophil gelatinase-associated lipocalin (NGAL) in CKD, and we used mass spectroscopy to identify associated proteins. We analyzed kidney biopsies to determine whether specific pathological characteristics associated with the monomeric NGAL species. Advanced CKD urine contained the NGAL monomer as well as novel complexes of NGAL. When these species were separated, we found a significant correlation between the NGAL monomer and glomerular filtration rate (r=-0.53, P<0.001), interstitial fibrosis (mild vs. severe disease; mean 54 vs. 167 μg uNGAL/g Cr, P<0.01), and tubular atrophy (mild vs. severe disease; mean 54 vs. 164 μg uNGAL/g Cr, P<0.01). Monospecific assays of the NGAL monomer demonstrated a correlation with histology that typifies progressive, severe CKD.

Urinary NGAL is a useful clinical biomarker of HIV-associated nephropathy

BACKGROUND Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is expressed by kidney tubules that are acutely damaged, but few studies have investigated the association of neutrophil gelatinase-associated lipocalin (NGAL) with different forms of chronic kidney disease (CKD). HIV-associated nephropathy (HIVAN) is a progressive form of CKD characterized by collapsing focal segmental glomerulosclerosis and microcytic tubular dilatation that typically leads to end-stage renal disease (ESRD). METHODS Previously, we reported that microcystic tubular dilatations specifically expressed NGAL RNA, implying that the detection of uNGAL protein could mark advanced HIVAN. To test this idea, we performed a comparative study of diverse proteinuric glomerulopathies in 25 patients who were HIV positive. RESULTS Eighteen patients had HIVAN and seven had other glomerulopathies (four membranoproliferative glomerulonephritis, one membranous glomerulonephritis, one amyloid and one malarial GN). HIVAN and non-HIVAN patients did not differ with respect to age, ethnicity, serum creatinine, estimated GFR, proteinuria or the prevalence of hypocomplementemia (6 versus 29%, P = 0.18), but HIVAN patients were less likely to have HCV infections. HIVAN patients expressed 4-fold higher levels of uNGAL than the patients with other glomerulopathies [387 ± 338 versus 94 ± 101 μg/g urine creatinine (uCr), P = 0.02]. A cutpoint of 121.5 μg uNGAL/g uCr demonstrated 94% sensitivity and 71% specificity for the diagnosis of HIVAN, with an area under the receiver operator characteristic curve of 0.88. CONCLUSION In summary, while HIVAN disease is currently diagnosed only by kidney biopsy, uNGAL can distinguish HIVAN from other proteinuric glomerulopathies in the HIV-infected patient, likely because of its specific expression from characteristic microcysts.

Urine neutrophil gelatinase-associated lipocalin identifies unilateral and bilateral urinary tract obstruction

BACKGROUND Urinary tract obstruction (UTO) is a common problem that can lead to permanent loss of kidney function. Unilateral UTO may be difficult to diagnose. Urinary neutrophil gelatinase-associated Lipocalin (uNGAL) may identify unilateral and bilateral UTO. METHODS Retrospective case-control study of patients undergoing hospital admission at three sites. UTO was determined by review of medical records and cases were matched to control patients. uNGAL was measured by immunoblot. RESULTS Twenty-four unilateral UTO and 15 bilateral UTO cases were identified. Admission serum creatinine (sCr) (milligram per decilitre) was significantly higher in bilateral UTO, 2.0 (1.1-5.3), but not unilateral UTO, 1.1 (0.8-1.5), compared to controls, 0.9 (0.8-1.2). uNGAL (nanogram per millilitre) was significantly higher both in patients with bilateral UTO, 140 (40-450), and unilateral UTO, 50 (20-100), compared to controls, 20 (10-45). DISCUSSION uNGAL identifies kidney injury in unilateral and bilateral UTO even in the absence of an elevated sCr.

American Society of Anesthesiologists classification in cataract surgery: Results from the Ophthalmic Surgery Outcomes Data Project.

Purpose To explore the association of American Society of Anesthesiologists (ASA) classification with cataract surgery outcomes. Setting Five Veterans Affairs Medical Centers, United States. Design Retrospective observational cohort study. Methods The study analyzed the outcomes of cataract surgery cases. Corrected distance visual acuity (CDVA), unanticipated events, and vision‐related quality of life (VRQL) were assessed using the National Eye Institute Visual Function Questionnaire (NEI‐VFQ), comparing ASA classes I through IV. For some analyses, ASA classes I and II were designated as Group A and ASA classes III and IV were designated Group B. Results Of the 4923 cases, 875 (17.8%) were in Group A, 4032 (81.9%) were in Group B, and 16 (0.3%) had missing data. The mean CDVA and mean composite NEI‐VFQ score improved after cataract surgery in both groups (P < .0001); however, Group A had a better mean postoperative CDVA and postoperative VFQ composite scores than Group B (P < .0001, both outcomes). A higher ASA class was associated with an increased risk for 2 unanticipated events; that is, clinically significant macular edema (CSME) (Group A: 4 [0.47%] versus Group B: 50 [1.28%]; adjusted odds ratio [OR], 3.02; 95% confidence interval [CI], 1.02‐13.05; P = 0.04) and readmission to the hospital within 30 days (2 [0.23%] versus 56 [1.41%]; OR, 8.26; 95% CI, 1.71‐148.62; P = .004) Conclusions Among United States veterans, the ASA classification could be an important predictor of VRQL and visual outcomes. In this cohort, it was associated with an increased risk for 2 serious unanticipated events—CSME and readmission to the hospital—both costly, unwanted outcomes. Financial Disclosure Dr. Vollman is a consultant to Forsight Vision5. None of the authors has a financial or proprietary interest in any material or method mentioned.

The ISNT Rule: How Often Does It Apply to Disc Photographs and Retinal Nerve Fiber Layer Measurements in the Normal Population?

PURPOSE To determine what percentage of normal eyes follow the ISNT rule, and whether ISNT rule variants may be more generalizable to the normal population. DESIGN Cross-sectional study. METHODS Setting: Institutional setting. STUDY POPULATION Total of 110 normal subjects. OBSERVATION PROCEDURES Neuroretinal rim assessments from disc photographs and retinal nerve fiber layer (RNFL) thickness measurements from spectral-domain optical coherence tomography. MAIN OUTCOME MEASURES The percentages of subjects that obeyed the ISNT rule and its variants. RESULTS The ISNT rule is only valid for 37.0% of disc photograph rim assessments and 43.8% of RNFL measurements. Deviation of the nasal sector from the expected ISNT pattern was a major cause for the ISNT rule not being obeyed for both rim and RNFL assessments. Specifically, 10.9% of subjects had wider nasal rims than the inferior rims, 29.4% had wider nasal rims than the superior rims, 14.7% had narrower nasal rims than the temporal rims, and 42.9% had thinner nasal RNFLs compared to the temporal quadrant. Exclusion of the nasal quadrant from the ISNT rule significantly increased the validity of ISNT variant rules, with 70.9% and 76.4% of disc photographs following the IST rule and the IS rule, respectively. Similarly, for RNFL thickness, 70.9% and 71.8% of patients followed the IST and IS rule, respectively. CONCLUSIONS The ISNT rule is only valid for about a third of disc photographs and less than half of RNFL measurements in normal patients. ISNT rule variants, such as the IST and IS rule, may be considered, as they are valid in more than 70% of patients.

A rapidly enlarging swelling of the left orbit.

A previously well 16 year old girl presented to acute medical admissions (walk-in assessment clinic) with a one week history of swelling of her left eyelid. She was prescribed amoxicillin for a presumed folliculitis. She re-presented one week later to the emergency department because the swelling had steadily worsened over the past two weeks. It was tender to palpation but there was no pain with movement. Visual acuity was reduced in the left eye to 6/9 (previously 6/6), and although the swelling appeared to push her left eye “down and to the side” she denied diplopia. Pupils were equal and reactive, and the conjunctiva on the left was mildly injected superonasally. Her eye movements were normal. She had no history of trauma, insect bites, fever, or fatigue. Blood test results were unremarkable. Her medical history consisted of two right eyebrow cysts removed six years earlier. Family history included a mother with three basal cell carcinomas and a maternal grandmother with chronic lymphocytic leukaemia. She had no history of alcohol, smoking, or illicit drug use. In the emergency department she was given a second course of systemic antibiotics and scheduled for a follow-up appointment in the ophthalmology clinic nine days later. In clinic, her visual acuity had drastically decreased to 6/60, the mass had increased in size and felt fluctuant, and her upgaze was now restricted (fig 1⇓). ### 1. What differential diagnoses should have been considered at first presentation? #### Short answer An orbital mass carries a wide differential diagnosis, with three main categories: infectious causes, orbital tumours, and inflammatory lesions. #### Long answer Eye “lumps” are poorly understood by non-specialists so important diagnoses can …