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

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 marks cystic disease in HIV-associated nephropathy.

Nephrosis and a rapid decline in kidney function characterize HIV-associated nephropathy (HIVAN). Histologically, HIVAN is a collapsing focal segmental glomerulosclerosis with prominent tubular damage. We explored the expression of neutrophil gelatinase-associated lipocalin (NGAL), a marker of tubular injury, to determine whether this protein has the potential to aid in the noninvasive diagnosis of HIVAN. We found that expression of urinary NGAL was much higher in patients with biopsy-proven HIVAN than in HIV-positive and HIV-negative patients with other forms of chronic kidney disease. In the HIV-transgenic mouse model of HIVAN, NGAL mRNA was abundant in dilated, microcystic segments of the nephron. In contrast, urinary NGAL did not correlate with proteinuria in human or in mouse models. These data show that marked upregulation of NGAL accompanies HIVAN and support further study of uNGAL levels in large cohorts to aid in the noninvasive diagnosis of HIVAN and screen for HIVAN-related tubular damage.

Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury.

BACKGROUND: A single serum creatinine measurement cannot distinguish acute kidney injury from chronic kidney disease or prerenal azotemia. OBJECTIVE: To test the sensitivity and specificity of a single measurement of urinary neutrophil gelatinase-associated lipocalin (NGAL) and other urinary proteins to detect acute kidney injury in a spectrum of patients. DESIGN: Prospective cohort study. SETTING: Emergency department of Columbia University Medical Center, New York, New York. PARTICIPANTS: 635 patients admitted to the hospital with acute kidney injury, prerenal azotemia, chronic kidney disease, or normal kidney function. MEASUREMENTS: Diagnosis of acute kidney injury was based on the RIFLE (risk, injury, failure, loss, and end-stage) criteria and assigned by researchers who were blinded to experimental measurements. Urinary NGAL was measured by immunoblot, N-acetyl-beta-d-glucosaminidase (NAG) by enzyme measurement, alpha1-microglobulin and alpha(1)-acid glycoprotein by immunonephelometry, and serum creatinine by Jaffe kinetic reaction. Experimental measurements were not available to treating physicians. RESULTS: Patients with acute kidney injury had a significantly elevated mean urinary NGAL level compared with the other kidney function groups (416 microg/g creatinine [SD, 387]; P = 0.001). At a cutoff value of 130 microg/g creatinine, sensitivity and specificity of NGAL for detecting acute injury were 0.900 (95% CI, 0.73 to 0.98) and 0.995 (CI, 0.990 to 1.00), respectively, and positive and negative likelihood ratios were 181.5 (CI, 58.33 to 564.71) and 0.10 (CI, 0.03 to 0.29); these values were superior to those for NAG, alpha1-microglobulin, alpha1-acid glycoprotein, fractional excretion of sodium, and serum creatinine. In multiple logistic regression, urinary NGAL level was highly predictive of clinical outcomes, including nephrology consultation, dialysis, and admission to the intensive care unit (odds ratio, 24.71 [CI, 7.69 to 79.42]). LIMITATIONS: All patients came from a single center. Few kidney biopsies were performed. CONCLUSION: A single measurement of urinary NGAL helps to distinguish acute injury from normal function, prerenal azotemia, and chronic kidney disease and predicts poor inpatient outcomes.

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.

Raymond V. Damadian, M.D.: magnetic resonance imaging and the controversy of the 2003 Nobel Prize in Physiology or Medicine.

PURPOSE: On October 6, 2003 the Nobel Committee announced that Paul C. Lauterbur, PhD and Sir Peter Mansfield, PhD were awarded the Nobel Prize in Physiology or Medicine for their work on the development of magnetic resonance imaging. Dr. Raymond Damadian was excluded and a controversy ensued. MATERIALS AND METHODS: Unbiased secondary sources were examined and revealed the chronology of magnetic resonance imaging development. An examination of the patents and publications of Doctor Damadian was included in this documentation. RESULTS: In 1969 Doctor Damadian proposed the concept of a magnetic resonance scanner to the Human Research Council of New York City. His publication in the journal Science in 1971 also established his priority. He applied for a patent for his scanning method in 1972 and it was granted in 1974. Doctor Damadian published the first magnetic resonance imaging study of a human body in 1977. Doctor Lauterbur produced the first image of a live subject, a clam, and published the results in Nature in March 1973. He neglected to mention Damadian's work but he did include references which cited Damadian. This would start a controversy that continues to the present day. CONCLUSIONS: The Nobel Prize in Physiology or Medicine can be awarded to a maximum of 3 scientists for any single discovery but in this instance was only given to 2. Excluding Doctor Damadian seems to be a serious and purposeful omission. The deliberations of the Nobel Committee remain closed for 50 years and only after this time passes will the world know what contributed to the decision to exclude Damadian.