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Urinary NGAL Marks Cystic Disease in HIV-Associated Nephropathy

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Urinary NGAL Marks Cystic Disease in HIV-Associated Nephropathy JASN Express. Published on July 23, 2009 as doi: 10.1681/ASN.2009010065 BRIEF COMMUNICATION www.jasn.org Urinary NGAL Marks Cystic Disease in HIV-Associated Nephropathy Neal Paragas,* Thomas L. Nickolas,* Christina Wyatt,† Catherine S. Forster,* Meghan Sise,* Susan Morgello,† Bernd Jagla,* Charles Buchen,* Peter Stella,* Simone Sanna-Cherchi,* Maria Luisa Carnevali,‡ Silvia Mattei,‡ Achiropita Bovino,‡ Lucia Argentiero,‡ ʈ Andrea Magnano,‡ Prasad Devarajan,§ Kai M. Schmidt-Ott, Landino Allegri,‡ Paul Klotman,† Vivette D’Agati,* Ali G. Gharavi,* and Jonathan Barasch* BRIEF COMMUNICATION *College of Physicians and Surgeons, Columbia University, New York, New York; †The Mount Sinai School of Medicine, New York, New York; ‡University of Parma, Parma, Italy; §Cincinnati Children’s Hospital Medical Center, Cincinnati, ʈ Ohio; and Max Delbruck Center for Molecular Medicine, Berlin, Germany ABSTRACT Nephrosis and a rapid decline in kidney function characterize HIV-associated eases, definitive diagnosis of HIVAN re- nephropathy (HIVAN). Histologically, HIVAN is a collapsing focal segmental glo- quires a kidney biopsy. In fact, half of all merulosclerosis with prominent tubular damage. We explored the expression of patients with presumed HIVAN dem- neutrophil gelatinase-associated lipocalin (NGAL), a marker of tubular injury, to onstrated different types of lesions once determine whether this protein has the potential to aid in the noninvasive biopsied.11,12 diagnosis of HIVAN. We found that expression of urinary NGAL was much higher Neutrophil gelatinase-associated li- in patients with biopsy-proven HIVAN than in HIV-positive and HIV-negative pocalin (NGAL) is a 22-kD protein that patients with other forms of chronic kidney disease. In the HIV-transgenic mouse is markedly upregulated in renal tubules model of HIVAN, NGAL mRNA was abundant in dilated, microcystic segments of and urine (uNGAL) in response to epi- the nephron. In contrast, urinary NGAL did not correlate with proteinuria in thelial damage.13–15 Expression of human or in mouse models. These data show that marked upregulation of NGAL NGAL peaks 12 h after acute injury14,15 accompanies HIVAN and support further study of uNGAL levels in large cohorts but remains elevated if injury is severe.16 to aid in the noninvasive diagnosis of HIVAN and screen for HIVAN-related In our study of 650 patients presenting tubular damage. to an inner-city emergency department, we found that a single, spot uNGAL test J Am Soc Nephrol 20: 1687–1692, 2009. doi: 10.1681/ASN.2009010065 could distinguish ongoing injury from physiologic changes in renal function found in prerenal azotemia and from In 2007 alone, there were 2.7 million uria. Kidney biopsies demonstrate his- periods of slow or limited progression new infections with HIV and 2 million tologic abnormalities in both glomeruli found during the course of many types HIV-related deaths worldwide.1 An im- and tubules, including collapsing FSGS, of CKD (“stable CKD”).13 However, in portant complication of HIV is a form podocyte proliferation and dedifferen- of kidney disease called HIV-associated tiation, tubular dilation, microcyst for- Received January 16, 2009. Accepted April 22, nephropathy (HIVAN), which occurs mation, and tubulointerstitial inflam- 2009. predominantly in patients of African mation.6,7 The pathogenesis is believed Published online ahead of print. Publication date descent.2–4 The prevalence of HIVAN to be due to dysregulation of podocytes available at www.jasn.org. 8,9 may be as high as 15% of HIV patients and tubular epithelia by HIV-1 itself. N.P., T.L.N., and C.W. contributed equally to this work. (based upon autopsy data), and 4232 Early identification of HIVAN is impor- C.S.F. and M.S. contributed equally to this work. new cases of HIVAN reached ESRD be- tant because highly active antiretroviral tween 2002 and 2006 in the United therapy (HAART), corticosteroids, and Correspondence: Dr. Jonathan Barasch, Columbia 5 University, PS 10-501, 630 West 168th Street, New States. inhibition of renin–angiotensin may York, New York 10032. Phone: 212-305-1890; Fax: HIVAN is a rapidly progressive form delay disease progression6,10,11. None- 212-305-3475; E-mail: [email protected] of chronic kidney disease (CKD) char- theless, because HIV infection may be Copyright ᮊ 2009 by the American Society of acterized by nephrotic range protein- associated with other glomerular dis- Nephrology J Am Soc Nephrol 20: 1687–1692, 2009 ISSN : 1046-6673/2008-1687 1687 BRIEF COMMUNICATION www.jasn.org that study, we noted that one CKD pa- teinuria. uNGAL showed no correlation summary, rather than renal failure itself, tient later diagnosed with HIVAN (T. L. with eGFR in HIVAN (r ϭ 0.082, P ϭ characteristics of HIVAN appeared to ac- Nickolas, unpublished observations) 0.8), whereas it was inversely related to celerate uNGAL expression. The lack of had markedly elevated levels of uNGAL, eGFR in two other forms of CKD (Figure association between uNGAL and glo- suggesting that HIV-associated tubular 1), membranous nephropathy (r ϭϪ merular functional markers (eGFR and disease regulated its expression. 0.665, P ϭ 0.004), and FSGS (r ϭ proteinuria) implied that HIVAN stimu- To test the association of uNGAL and Ϫ0.753, P ϭ 0.03). In fact, five HIVAN lated uNGAL at a tubular site. HIV, we examined a cohort of 13 pa- patients with relatively preserved kidney Because HIV-transgenic mice (Tg- tients with biopsy-proven HIVAN. Biop- function (serum creatinine Ͻ2, mean FVB)17 display a syndrome identical to sied or autopsied kidneys showed global eGFR 79.4, range 117.35 to 56.22) and HIVAN18 and lack the confounds typi- (41% of nephrons per section), collaps- limited proteinuria (0.68 g/L, range 0.0 cally present in human cohorts, we mea- ing (19%), and segmental (12%) glomer- to 3.0 mg/ml) demonstrated markedly sured NGAL expression in kidneys of Tg- ulosclerosis and tubular atrophy (48%) elevated levels of uNGAL (mean 401 ng/ FVB and wild-type (WT) littermates and microcysts (18%), consistent with ml, range 42 to 1285 ng/ml), suggesting (Affymetrix, Mouse Genome 430 2.0 mi- HIVAN. This group was compared with that uNGAL can be expressed early in the croarrays; Geo Accession Number Series 24 race-matched HIV-positive controls course of progressive renal failure due to GSE14221). NGAL was one of the most with normal kidney function, defined as HIVAN. Consistently, there was no cor- highly upregulated genes among 39,000 an estimated GFR (eGFR) Ն60 ml/min relation between uNGAL and protein- transcripts, demonstrating 62- and 109- and no evidence of proteinuria. Com- uria (r ϭϪ0.28, P ϭ 0.4). In contrast, fold increases at 6 and 8 wk, respectively parisons were also made to HIV-positive uNGAL levels were significantly corre- (Figure 2A). After GC content-robust and HIV-negative cohorts with other lated with viral load (R ϭ 0.469, P ϭ microarray averaging (GC-RMA) nor- forms of CKD. 0.005), and there was a suggestion that malization of TgFVB and WT samples, Patients with HIVAN had signifi- uNGAL was suppressed by HAART NGAL was the most upregulated gene cantly lower CD4 counts and higher viral (three of the patients with low levels of (TgFVB versus WT, P ϭ 1.4 ϫ 10Ϫ70). In loads, serum creatinine levels, and pro- uNGAL were receiving HAART). In fact, out of 23 proven AKI and 35 proven teinuria compared with HIV-positive, race-matched controls (Table 1). In HIVAN, uNGAL was upregulated 11- fold in comparison with that of HIV- positive race-matched controls without kidney disease (mean values, 748 Ϯ 1160 ␮g/g creatinine in HIVAN versus 68 Ϯ 98 ␮g/g creatinine without HIVAN; P value 0.006). Furthermore, in comparison with HIV-positive patients with CKD of non-HIVAN etiology (CKD, HIV-posi- tive), uNGAL was upregulated approxi- mately fivefold regardless of race-match- ing (Table 2). Moreover, uNGAL was 34- fold higher in patients with HIVAN compared with HIV-negative patients with CKD secondary to membranous nephropathy (n ϭ 16), non-HIVAN FSGS (n ϭ 7), or diabetic and hyperten- sive kidney diseases (n ϭ 12).13 In fact, uNGAL levels in patients with HIVAN were more typical of patients presenting to an inner-city emergency department with acute kidney injury (AKI) (n ϭ 30, Figure 1. uNGAL levels displayed as a function of eGFR in patients with CKD due to Table 2) than those in the same emer- HIVAN, non-HIVAN FSGS, and diabetic and membranous Nephropathies. There was no gency department with stable CKD ϭ ϭ ϭ correlation between the GFR and uNGAL in the HIVAN population (r 0.082, P 0.8) (CKD, HIV-negative, n 106). or the patients with diabetic nephropathy (r ϭϪ0.348, P ϭ 0.4), but a significant The enhanced expression of uNGAL correlation existed between GFR and uNGAL for both non-HIVAN FSGS (r ϭϪ0.753, P ϭ in HIVAN was not due to higher levels of 0.03) and membranous nephropathy (r ϭϪ0.665, P ϭ 0.00). All data were log-trans- serum creatinine, lower eGFR, or pro- formed. 1688 Journal of the American Society of Nephrology J Am Soc Nephrol 20: 1687–1692, 2009 www.jasn.org BRIEF COMMUNICATION Table 1. Mean values and cohort characteristics for HIV-positive patients with NGAL mRNA was detected in 39% of HIVAN or race-matched controlsa microcysts (n ϭ 2698 microcysts), in HIV-Positive both medulla and cortex. In contrast, All Patients HIVAN Race-Matched NGAL mRNA was not detected in non- Controls cystic tubules. This unexpected finding (13 ؍ n) (37 ؍ n) suggested that NGAL was likely induced (24 ؍ n) Age (yrs) 46 (10) 42 (9.6) 48 (10) by a local stimulus associated with cysto- Male (%) 68 62 71 genesis rather than a global stimulus Hepatitis B (%) 13 10 14 such as proteinuria, luminal debris, uri- Hepatitis C (%) 33 10 45 nary iron, or ischemic injury.
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