1456 Nephrol Dial Transplant (2011): Editorial Comments

17. Aliotta JM, Sanchez-Guijo FM, Dooner GJ et al. Alteration of marrow 19. Atay S, Gercel-Taylor C, Kesimer M et al. Morphologic and prote-
cell gene expression, protein production, and engraftment into lung by omic characterization of exosomes released by cultured extravillous
lung-derived microvesicles: a novel mechanism for phenotype modu- trophoblast cells. Exp Cell Res 2011 (In press)
lation. Stem Cells 2007; 25: 22452256 20. Collino F, Deregibus MC, Bruno S et al. Microvesicles derived from
18. Ratajczak MZ, Lee H, Wysoczynski M et al. Novel insight into stem adult human bone marrow and tissue specific mesenchymal stem cells
cell mobilization-plasma sphingosine-1-phosphate is a major chemo- shuttle selected pattern of miRNAs. PLoS One 2010; 5: e11803
attractant that directs the egress of hematopoietic stem progenitor
cells from the bone marrow and its level in peripheral blood increases
during mobilization due to activation of complement cascade/
membrane attack complex. Leukemia 2010; 24: 976985 Received for publication: 2.3.11; Accepted in revised form: 4.3.11

Nephrol Dial Transplant (2011) 26: 14561458

doi: 10.1093/ndt/gfr146
Advance Access publication 12 April 2011

Urinary neutrophil gelatinase-associated lipocalin (NGAL) for the

detection of acute kidney injury after orthotopic liver transplantation

Thorsten Feldkamp, Anja Bienholz and Andreas Kribben

Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Essen, Germany

Correspondence and offprint requests to: Andreas Kribben; E-mail: [email protected]

Acute kidney injury (AKI) is a frequent complication after In this issue of Nephrology Dialysis Transplantation,
orthotopic liver transplantation (OLT). The incidence of Wagener et al. [7] propose increased urinary neutrophil
post-operative AKI according to acute kidney injury net- gelatinase-associated lipocalin (NGAL)/creatinine ratio as
work criteria can be estimated to be as high as 60% of all an early predictor of AKI following OLT. The data source
patients after liver transplantation [13]. Besides increasing is a prospective cohort study of 92 patients undergoing
morbidity and length of hospitalization, graft survival is OLT at a single centre between 2008 and 2010 (18 living
significantly reduced, even with only modest increase of related, 74 deceased). Patients underwent OLT for different
serum creatinine (> 0.5 mg/dL, AKIN Stage 1) [3,4]. Post- reasons (hepatitis C, hepatitis B, nutritive toxic liver cir-
operative AKI is also an independent risk factor for mortal- rhosis, primary sclerosing cholangitis) and showed a modi-
ity during the first year after transplantation [1]. fied end stage liver disease score of 21.9 7.4 prior to
The development of AKI following liver transplantation surgery. Patients did not require renal replacement therapy
is multifactorial and influenced by numerous pre-, intra- preoperatively and apparently had intact kidney function
and post-operative factors. During the preoperative period, according to the serum creatinine (0.99 0.64 mg/dL).
conditions predisposing for post-operative AKI can be Urine samples were collected after induction of anaesthesia
present. The most commonly observed preoperative renal prior to incision, immediately after portal reperfusion of the
dysfunction is due to the hepato-renal syndrome character- liver graft and then 3, 18 and 24 h later. To compensate for
ized by arterial vasodilatation mainly in the splanchnic possible urinary dilution or concentration, the results of the
vessel area and severe renal vasoconstriction. Intraopera- NGAL measurements are given as urinary NGAL/creatin-
tive factors include long periods of vascular crossclamping, ine ratio. AKI was defined according to the RIFLE criteria
hypotension, high doses of vasopressors and large volume by an increased serum creatinine of >150% after OLT
load. Post-operative hypotension and calcineurin inhibitors compared to preoperative values.
such as cyclosporine and tacrolimus also support condi- Thirty-seven patients (40.2%) developed AKI during the
tions potentially culminating in AKI [4]. post-operative period. In those patients, serum creatinine
Currently, there are no effective measures or treatment concentration significantly increased at Day 2 after trans-
strategies available for the prevention or treatment of AKI. plantation, whereas urinary NGAL/creatinine ratio already
The development of effective interventions is hampered by showed a significant increase after 3 h. According to the
the limited ability of early detection of AKI [5, 6]. In order study, there is a diagnostic benefit of 2 days using urinary
to develop and evaluate strategies for the prevention and NGAL compared to serum creatinine for the diagnosis of
treatment of AKI, there is a great need for early biomarkers. AKI after OLT. Interestingly, in patients with AKI, NGAL

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For Permissions, please e-mail: [email protected]
Nephrol Dial Transplant (2011): Editorial Comments 1457
already declined between 3 and 18 h after OLT and there To our knowledge, the study by Wagener et al. included
was no significant difference between the AKI and non- the largest cohort for diagnosing AKI using urinary NGAL
AKI group after 24 h. This time course suggests that the in patients undergoing liver transplantation so far. In an
increase in urinary NGAL/creatinine is specific for the kid- observational study on novel biomarkers in patients under-
ney injury during OLT. Just before transplantation, and going liver transplantation, Portal et al. collected data on
immediately after reperfusion, there were no differences 95 patients for AKI. But mainly due to many patients with
in urinary NGAL/creatinine concentration between patients anuria, they were able to collect urine in 46 of 95 patients
with AKI and those without AKI. The investigators con- only [10]. This might be a reason why urinary NGAL
clude that urinary NGAL/creatinine ratio is an early marker although being a powerful predictor for AKI and present-
of AKI after liver transplantation, which, because of its high ing better results than serum creatininewas outperformed
sensitivity and specificity, might be a useful surrogate end by plasma NGAL in this study.
point of AKI in clinical trials. Opinions are diverse concerning normalization of urinary
Urinary NGAL might be a more sensitive marker for NGAL to urine creatinine concentration as presented by
AKI, especially in patients after liver transplantation, than Wagener et al. This illustrates the attempt to compensate
serum creatinine because unlike serum creatinine, it is not for possible urinary dilution or concentration [7]. On the
dependent on drugs, muscle mass or liver metabolism [8]. other hand, adjustment for urine creatinine implicates a
Urinary NGAL is mainly produced by the distal nephron steady state for urine creatinine during the development of
after injury and is immediately secreted into the urine. In AKI, which is clearly not the case. However, studies normal-
contrast, plasma NGAL is a product of multiple sources. izing for urine creatinine show slightly higher AUCROC
Nevertheless, AKI also triggers increasing amounts of mes- values and increased statistical significance [9].
senger RNA in other tissues than the distal nephron includ- A very important feature of the study of Wagener et al.
ing liver and lung [9]. This might explain why both urinary is that the measurement of urinary NGAL was performed
and plasma NGAL proved to be reliable markers for AKI in very early (3 h after the insult). This might enhance the
children after cardiac surgery with an AUCROC of >0.9 specifity of urinary NGAL compared to plasma NGAL;
[14]. But also in patients with AKI after liver transplant- unfortunately plasma NGAL was not measured in this
ation, it was shown to be of benefit. In a prospective study study. Nevertheless, although not applicable in the state of
of 59 patients undergoing liver transplantation between anuria, one would assume that measurement of urinary
2007 and 2008, plasma NGAL was measured [11]. Forty- NGAL could be a more pure predictor of AKI with less
five of these patients had a preserved preoperative renal confounding variables and being more restricted to tubular
function (serum creatinine <1.5 mg/dL without renal damage.
replacement therapy). More than 50% (24 patients) fulfilled For future development of effective tools against AKI,
this studys definition of AKI (50% increase in serum cre- early predictors are necessary. Urinary NGAL seems to be
atinine compared to baseline). A single measurement of a promising novel biomarker. But clearly, more studies are
plasma NGAL 2 h after reperfusion was a fairly good mar- needed to understand the origin of urinary NGAL and the
ker for the development of AKI with an AUCROC of 0.79 mechanisms of renal NGAL secretion in response to the
at a cut-off value of 139 ng/mL. However, in other studies renal insult. Therefore, larger multicentre studies with
with different cohorts, NGAL performed less well and the well-defined patient cohorts and uniform mechanisms of
range of the reported specifity and sensitivity is quite large renal injury are needed. This would not only give us valu-
(AUCROC between 0.610.96) [9]. This was ascribed to able information of the usefulness of NGAL as a biomarker
more confounding variables in adults such as age and pre- for AKI but would also allow us to study the impact of
existing (latent) chronic kidney disease. This is probably the different renal injury mechanisms on the diagnostic per-
reason why NGAL measurement performs better in patients formance of NGAL.
with baseline eGFR >60 mL/min [12]. A way to minimize
the confounding factor of pre-existing tubular damage
might be to report the data as a difference to baseline mea- Conflict of interest statement. TF and AK have received lecture fees from
B Braun, Amgen, Cellpharm, Novartis, Otsuka, and are supported by re-
surements [11]. Additionally, plasma NGAL might not be search grants from B Braun, Fresenius Kabi and Roche.
specific for renal damage since NGAL is produced at a
low level in many different tissues. Besides by renal cells,
it is secreted especially by injured epithelial cells of the (See related article by Wagener et al. Urinary neutrophil gelatinase-asso-
ciated lipocalin as a marker of acute kidney injury after orthotopic liver
colon, liver and lung and as a product of many cancers [9] transplantation. Nephrol Dial Transplant 2011; 26: 17171723)
and as an acute-phase protein by activated neutrophils and
other cells [11]. A prospective observational study analysed
NGAL levels in patients in an intensive-care setting. A signifi- References
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AKI [13]. This suggests that plasma NGAL might be a good vival after liver transplantation. Transplant Proc 2010; 42: 36343638
2. Kundakci A, Pirat A, Komurcu O et al. Rifle criteria for acute kidney
biomarker for inflammation, but in the context of a systemic
dysfunction following liver transplantation: incidence and risk fac-
inflammatory reaction, it loses power to predict the develop- tors. Transplant Proc 2010; 42: 41714174
ment or prognosis of AKI. The use of urinary NGAL might 3. Sauer K, Saner F, Geis A et al. The impact of acute kidney injury on
be a possibility to increase the specificity of the detection of mortality and morbidity in patients after liver transplantation. Trans-
renal damage in the context of inflammation. plant Int 2010; 23: 20
1458 Nephrol Dial Transplant (2011): Editorial Comments
4. Barri YM, Sanchez EQ, Jennings LW et al. Acute kidney injury 10. Portal AJ, McPhail MJW, Bruce M et al. Neutrophil gelatinase-asso-
following liver transplantation: definition and outcome. Liver Transpl ciated lipocalin predicts acute kidney injury in patients undergoing
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gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis liver transplantation as determined by neutrophil gelatinase-associated
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26: 17171723 jury in critical illness. Intensive Care Med 2010; 36: 452461
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9. Devarajan P. Review: neutrophil gelatinase-associated lipocalin: A
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2010; 15: 419428 Received for publication: 22.2.11; Accepted in revised form: 22.2.11

Nephrol Dial Transplant (2011) 26: 14581460

doi: 10.1093/ndt/gfr145
Advance Access publication 5 April 2011

Congenital solitary functioning kidneys: which ones warrant follow-up

into adult life?

Valentina Corbani1, Gian Marco Ghiggeri2 and Simone Sanna-Cherchi3

1
S.C. Nephrology and Dialysis, SantAndrea Hospital, La Spezia, Italy, 2Division of Pediatric Nephrology, G. Gaslini Institute, Genoa,
Italy and 3Division of Nephrology, Columbia University, NY, USA
Correspondence and offprint requests to: Simone Sanna-Cherchi; E-mail: [email protected]

Keywords: congenital anomalies of the kidney and urinary tract 116 had a primary congenital solitary functioning kidney
(CAKUT); paediatric nephrology; solitary kidney (pSFK) and 90 had a secondary solitary functioning kidney
(sSFK) after unilateral nephrectomy due to congenital
anomalies of the kidney or urinary tract. Ipsilateral
Congenital anomalies of the kidney and urinary tract CAKUT was present in 30% of children from both
(CAKUT) are the leading cause of paediatric end-stage groups. Among the patients with pSFK (which encom-
renal failure (ESRF) [1,3]. The clinical spectrum of passes unilateral renal agenesis and multicystic dysplastic
CAKUT includes a variety of malformations of the urinary kidney), ipsilateral anomalies were significantly more
tract. Understanding the rate of progression for the different frequent in cases with renal agenesis. Similarly, high blood
CAKUT categories and predicting long-term outcome is pressure was present in comparable proportions between
critical for a correct clinical management of these patients pSFK and sSFK, and it was significantly higher in the
and for the transition of care from paediatric to adult subgroup with renal agenesis. About 20% of children were
nephrology. using renoprotective agents and 12% had albuminuria.
Among CAKUT categories, congenital solitary func- Overall, >30% of patients with SFK showed evidence of
tioning kidney (SFK) has been the object of debate whether renal injury. These data indicate that a significant fraction
it constitutes a benign condition or presents a significant of children with congenital solitary kidney show evidence
risk of progression to ESRF [214]. of renal parenchyma damage early in life and can poten-
In the present issue of Nephrology Dialysis and Trans- tially progress to ESRF in adulthood. These numbers are
plantation, Westland et al. report on the results of the consistent with our previous report on long-term outcome
KIMONO-study (REF ID pending). The authors analysed in CAKUT patients, in which 50% of children with solitary
a large cohort of 206 children with SFK of congenital kidney reached ESRF by the age of 30 [11]. Westland et al.
origin to identify indicators of renal injury. Among them, explored the rate of progression by generalized estimated

The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
For Permissions, please e-mail: [email protected]