Urinary N-acetyl-ß-glucosaminidase excretion is a marker of tubular cell dysfunction and a predictor of outcome in primary glomerulonephritis

Claudio Bazzi1,, Concetta Petrini2, Virginia Rizza2, Girolamo Arrigo1, Pietro Napodano1, Maria Paparella1 and Giuseppe D'Amico1

1 Division of Nephrology and Dialysis and 2 Biochemical Laboratory, San Carlo Borromeo Hospital, Milan, Italy



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The urinary excretion of N-acetyl-ß-glucosamynidase (NAG) is increased in subjects exposed to substances toxic for renal tubular cells. In experimental and human glomerular diseases, its increased excretion is probably due to the dysfunction of tubular epithelial cells induced by increased traffic of proteins in the tubular lumen. The first aim of this study was to evaluate whether NAG excretion is correlated not only with the amount of proteinuria but also with some proteinuric components which reflect both glomerular capillary wall damage (IgG) and an impairment of tubular reabsorption of microproteins ({alpha}1 microglobulin). The second aim was to assess whether NAG excretion has a predictive value on functional outcome and response to therapy.

Methods. In 136 patients with primary glomerulonephritis [74 with idiopathic membranous nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and 18 with minimal change disease (MCD)] urinary NAG excretion was measured by a colorimetric method and expressed in units per gram of urinary creatinine.

Results. Using univariate linear regression analysis NAG excretion in all 136 patients was significantly dependent on IgG excretion, 24-h proteinuria, fractional excretion of {alpha}1 microglobulin (FE {alpha}1m) and diagnosis. Using multiple linear regression analysis, NAG excretion was significantly dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67 patients with nephrotic syndrome (NS) and baseline normal renal function, by multiple linear regression, NAG excretion was significantly dependent on IgG excretion (P=0.0004), 24-h proteinuria (P=0.0067) and FE {alpha}1-m (P=0.0032) (R2=0.63). In 66 patients with NS and normal baseline renal function (MCD 10 patients; FSGS 20 patients; IMN 36 patients), according to values below or above defined cut-offs (IMN, <= or >18 U/g urinary Cr; FSGS and MCD, <= or >24 U/g urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients (P=0.0002) and 77 vs 14% of FSGS patients (P=0.005). Progression to chronic renal failure (CRF) was 0 vs 47% in IMN patients (P=0.001) and 8 vs 57% in FSGS patients (P=0.03). Using Cox model, in IMN patients only NAG excretion (P=0.01, RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients had NAG excretion values below the chosen cut-off, and 90% of them developed remission. Response to immunosuppressive therapy was significantly different in patients with NAG excretion values below or above the cut-offs.

Conclusion. Urinary NAG excretion can be considered as a reliable marker of the tubulo-toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion values show a significant relationship with 24-h proteinuria, IgG excretion and FE {alpha}1m. Its determination may be a non-invasive, useful test for the early identification of patients who will subsequently develop CRF or clinical remission and responsiveness to therapy.

Keywords: glomerulonephritis; NAG excretion; nephrotic syndrome; outcome



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Over the past 10 years, many investigators [14] have suggested, mainly on the basis of some evidence in experimental models, that the abnormal and sustained tubular traffic of proteins occurring in most forms of glomerular diseases might be toxic for the tubular cells and responsible for the tubulo-interstitial lesions frequently associated with these diseases. In various human glomerular diseases, a correlation has been demonstrated between extent of proteinuria, tubulo-interstitial damage (TID) and progression to chronic renal failure (CRF) [14]; however, a direct demonstration of a toxic effect on the tubular cells by sustained and protracted proteinuria in chronic glomerular diseases in man is still lacking. This explains the interest in the search for reliable markers of tubular damage in the urine of patients with glomerular diseases. N-Acetyl-ß-glucosaminidase (NAG), a urinary enzyme, has been proposed as a valuable marker. It is a lysosomal enzyme of 130 kDa molecular mass, normally excreted in low amounts in urine as a consequence of the normal exocytosis process [5]. It has been found to be increased after exposure to various toxic substances, such as lead and cadmium [6,7], solvents [5], contrast media [5], aminoglycoside antibiotics [8], nephrotoxic drugs used to treat cancer [9], puromycin aminonucleoside-induced glomerulonephritis (GN) in rats [10] and various human glomerular diseases, including diabetic nephropathy [1113]. In glomerular diseases, analysis of isoenzymes of NAG demonstrated that the increased urinary excretion of this enzyme is due to an increased release by the renal tubular cells and not to increased filtration across the damaged glomerular capillary wall [11].

In the present study, in 136 patients with three different types of biopsy-proven chronic GN characterized by severe proteinuria [idiopathic membranous nephropathy (IMN), primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD)] we measured the urinary excretion of NAG, expressed in units per gram of urinary creatinine. The aims of the study were: (i) to evaluate whether NAG excretion is associated not only with the amount of proteinuria but also with some qualitative features of proteinuria, which reflect both glomerular capillary wall damage (IgG excretion) and impairment of tubular reabsorption of low molecular weight proteins [fractional excretion of {alpha}1 microglobulin (FE {alpha}1m)] due to functional or structural damage of tubular epithelial cells; (ii) to assess whether NAG excretion is associated with functional outcome (remission or progression to CRF) and responsiveness to immunosuppressive therapy.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
One hundred and thirty-six patients with biopsy-proven primary GN were included in the study (Table 1Go): 74 patients had IMN, 44 patients FSGS and 18 patients MCD. None of the patients was on tubulo-toxic therapy. Some clinical features of the patients studied are reported in Table 1Go.


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Table 1.  Clinical features of patients at the beginning of the study

 
Eighty-six of these patients represented all new patients with IMN, FSGS and MCD diagnosed in our unit from January 1992 to December 1998; in these patients the evaluation of proteinuria was performed at the same time as renal biopsy; 50 patients, diagnosed before 1992, had measurement of NAG and proteins excretion 80±61 months after renal biopsy.

A nephrotic syndrome (NS), defined as 24-h proteinuria >=3.5 g/day and serum albumin <3 g/dl, was present in 69% of patients with IMN, in 70% with FSGS and 56% with MCD; in the other patients, with the exception of a few who were in remission, a proteinuria in non-nephrotic range was present. Three-quarters of the patients with IMN and FSGS and all of those with MCD had normal renal function [serum creatinine (sCr) <=1.4 mg/dl] at the start of the study (Table 1Go). The functional outcome could be evaluated in 88 patients with baseline normal renal function: 22 of them had non-nephrotic proteinuria (follow up 44±15 months); 66 patients had NS (follow up IMN patients, 42±23 months; FSGS patients, 44±22 months).

In patients with NS and baseline normal renal function, the clinical outcome was defined as follows: complete remission, 24-h proteinuria <0.2 g/day with normal renal function and inactive urinary sediment; partial remission, 24-h proteinuria <2.0 g/day with normal renal function; persistent proteinuria, proteinuria >2.0 and <3.5 g/day with normal renal function; persistent NS, proteinuria persistently >=3.5 g/day with normal renal function; progression to CRF, end-stage renal disease (ESRD) or doubling of sCr. Response to therapy in patients with baseline NS and normal renal function was considered the development of complete or partial remission, assessed at the last observation.

Methods
For each patient 24-h urine collection and a second morning urine sample were obtained. Total urinary proteins were measured by Coomassie blue method and expressed in grams per 24 h. sCr and urinary creatinine were measured automatically on a HITACHI 717 Instrument (Boehringer, Mannheim, Germany) by the Jaffè method without deproteinization and expressed respectively in mg/dl and mg/l. Serum and urinary IgG, transferrin and {alpha}1m were measured in second morning urine samples by an immuno-nephelometric method on BNA Nephelometer (Behring, Milan, Italy) using rabbit sera anti-human IgG, transferrin and {alpha}1m (Behring). The FE {alpha}1m, expressed as per cent of creatinine clearance, was calculated according to the formula:


The excretion of IgG was expressed in milligrams per gram of urinary creatinine (mg/g urinary Cr) and logarithmically transformed. The selectivity index (SI) was calculated according to the Cameron and Blanford [14] formula: proteinuria was defined selective if SI was <=0.20 and non-selective if SI was >0.20. For the determination of NAG in the second morning urine samples, a colourimetric assay was performed using 3-cresolsulfonphthaleyn-N-acetyl-ß-D-glucosaminide which is hydrolysed by NAG with the release of 3-cresolsulfonphthaleyn sodium salt, which is measured photometrically at 580 nm on a HITACHI 717 Instrument; the results were expressed in units per gram of urinary creatinine (U/g urinary Cr) and logarithmically transformed.

Renal biopsies were performed and evaluated by previously published standard histologic and immunofluorescence methods [15]. A semi-quantitative evaluation of some histologic parameters was performed in patients in whom characterization of proteinuria and renal biopsy were performed at the same time. The extent of the tubulo-interstitial changes was evaluated according to the method of Risdon et al. [16]. Ten consecutive microscopic fields of the cortex of each biopsy sample were examined with a x40 objective. A field was graded 0 if there was not tubular atrophy and 1 or 2 if tubular atrophy was focal or diffuse. In a similar fashion, interstitial fibrosis and/or infiltration were graded 0, 1 or 2 if absent, focal or diffuse, respectively. The tubular and interstitial scores so obtained were summed to obtain a single score for the TID, which was then classified as follows: 0 or 1, lesions absent or very mildly focal; 2, focal tubular and interstitial lesions; and 3 or 4, diffuse lesions. The patients with a score 0–1 were compared with patients with scores >=2.

Statistical methods
Data were expressed as mean values±SD; the mean of quantitative variables was compared with the Student's t-test. The significance of differences between proportions was tested by the {chi}2 test. To evaluate the differences in the rates of outcomes, statistical methods appropriate for the analysis of censored data were used [17], as the duration of patients' follow-up was not uniform. Proteinuric variables were tested individually for prognostic significance using time of entry to CRF or remission as the measure of outcome. The cumulative survival curves were derived by the Kaplan–Meier method [18]. The equality of survival curves obtained for different groups of patients was assessed by the log-rank test. Differences were considered significant with P value <0.05. The relationship between baseline NAG excretion and 24-h proteinuria, IgG excretion, SI, FE {alpha}1m and diagnosis were assessed by univariate linear regression and by multiple linear regression. Multivariate analysis of the risk factors was performed using Cox's proportional hazard model [19].



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Correlation between NAG excretion, proteinuric variables and diagnosis
Using univariate linear regression analysis, in which baseline NAG excretion was modelled with 24-h proteinuria, IgG excretion, FE {alpha}1m, SI and diagnosis in all 136 patients studied, the excretion of NAG was significantly dependent on IgG excretion, 24-h proteinuria, FE {alpha}1m, diagnosis but not on SI (Table 2Go). Using multiple regression analysis, NAG excretion was dependent only on IgG excretion (P=0.0001) and 24-h proteinuria (P=0.026) (R2=0.69). Limiting the analysis to 67 patients with NS and baseline normal renal function, using univariate linear regression analysis, the NAG excretion was significantly dependent on IgG excretion, 24-h proteinuria, FE {alpha}1m and SI, but not on diagnosis (Table 2Go). Using multiple regression analysis, NAG excretion was dependent on IgG excretion (P=0.0004), FE {alpha}1m (P=0.0032) and 24-h proteinuria (P=0.0067) (R2=0.63).


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Table 2.  Regression between NAG excretion, proteinuric variables and diagnosis in all patients studied (n=136) and in patients with NS and baseline normal renal function (n=67)

 

NAG excretion in nephrotic patients with abnormal renal function
Average NAG excretion in 19 patients with NS and baseline impairment of renal function [sCr=2.62±1.59 mg/dl] did not differ significantly from that measured in the 67 patients with NS and baseline normal renal function (sCr 0.99±0.19 mg/dl): 25.4±23.9 vs 17.4±12.5 U/g urinary Cr (P=0.17). The mean value of protein excretion was comparable in the two groups (8.0±5.6 g/day in CRF patients and 7.9±2.6 g/day in those with normal function) (P=0.91).

NAG excretion and tubulo-interstitial damage in nephrotic patients with normal renal function
In 43 patients with NS and normal renal function (FSGS 15 patients; MGN 28 patients, sCr 0.97±0.17), who performed renal biopsy and NAG excretion measurement at the same time, the NAG excretion was compared in patients with absent or very focal TID (score 0–1) and patients with damage that was focal at tubular and interstitial level or diffuse in both areas (score >=2). In FSGS, 10 patients with a score 0–1 had NAG excretion of 15.8±9.1 U/g urinary Cr, while in five patients with a score >=2 the NAG excretion was 25.6±20.3 (P=0.35). In IMN, 22 patients with a score 0–1 had a mean NAG excretion of 14.9±12.1 U/g urinary Cr, while in six patients with a score >=2 the mean NAG excretion was 18.9±13.4 (P=0.49).

NAG excretion as predictor of outcome
The functional outcome could be evaluated in 88 patients with baseline normal renal function: 22 of them had non-nephrotic proteinuria and 66 had NS; the starting point of the follow up was the date of NAG measurement, which for 56 patients was at the same time of renal biopsy.

All patients with non-nephrotic proteinuria, who had NAG excretion significantly lower than patients with NS (5.9±6.0 vs 17.4±12.6 U/g urinary Cr: P=0.01), maintained normal renal function at the last observation (follow up 44±15 months). The overall functional outcome of the 66 patients with NS and baseline normal renal function is shown in Table 3Go. To assess the predictive value on functional outcome of NAG excretion and 24-h proteinuria, the IMN patients were divided into two subgroups with NAG excretion <=18 vs >18 U/g urinary Cr and proteinuria <=5.0 vs >5.0 g/day; similarly, the FSGS patients were divided into two subgroups with NAG excretion <=24 vs >24 U/g urinary Cr and proteinuria <=7.0 vs >7.0 g/day; different cut-offs were chosen for the two diseases, taking into account the different mean values of NAG excretion and 24-h proteinuria.


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Table 3.  Functional outcome in 66 patients with NS and baseline normal renal function

 
As shown in Table 4Go, in IMN patients (follow up 42±23 months) the remission and progression rates were different in patients with proteinuria below or above the cut-off; however, the differences did not achieve a statistical significance; on the contrary, remission (P=0.0002) and progression (P=0.001) rates were significantly different in patients with NAG excretion below or above the cut-off (Table 4Go; Figures 1Go and 2Go). With the Cox model using two variables (24-h proteinuria and NAG excretion), IMN patients’ progression to CRF was significantly associated with NAG excretion (P=0.01, RR 5.8), but not with 24-h proteinuria (P=0.34; RR 0.35); no association was found between remission, NAG excretion and 24-h proteinuria.


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Table 4.  Progression and remission rates in 36 IMN patients with NS and baseline normal renal function (sCr 0.98±0.20 mg/dl) according to NAG excretion and proteinuria (follow up 42±23 months)

 


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Fig. 1.  Probability of complete or partial remission of NS according to NAG excretion values in 36 patients with IMN (NAG <=18 vs >18 U/g urinary Cr) and in 20 patients with FSGS (NAG <=24 vs >24 U/g urinary Cr).

 


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Fig. 2.  Probability of maintaining normal renal function (no ESRD nor doubling of sCr) according to NAG excretion values in 36 IMN and 20 FSGS patients with NS and baseline normal renal function.

 
As shown in Table 5Go, in FSGS patients (follow up 44±22 months) remission rate was significantly different (P=0.03) and progression rate of borderline significance (P=0.054) according to proteinuria levels; the differences were significant according to NAG excretion both for remission (P=0.005) and progression rates (P=0.03) (Table 5Go; Figures 1Go and 2Go). In FSGS patients, multivariate analysis was not performed because of the small number of patients. In MCD, all patients had NAG excretion <=24 U/g urinary Cr: 90% developed complete or partial remission and only one patient had persistent non-nephrotic proteinuria. The NAG excretion values of patients who developed remission were very similar, irrespective of diagnosis [IMN 22 patients, 11.5±6.6 U/g urinary Cr; FSGS 11 patients, 15.7±12.7 U/g urinary Cr; MCD nine patients, 11.7±5.5 U/g urinary Cr].


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Table 5.  Progression and remission rates in 20 FSGS patients with NS and baseline normal renal function (sCr 1.02±0.17 mg/dl) according to NAG excretion and proteinuria (follow up 44±22 months)

 
At presentation, arterial hypertension was present in 15 of 36 IMN patients (42%) and in 10 of 20 FSGS patients (50%): all were treated with antihypertensive agents and diuretics, usually with a good control of blood pressure. In IMN, remission was 67 vs 57% (P n.s.) and progression 27 vs 14% (P n.s.) in patients with or without arterial hypertension. In FSGS, remission was 70 vs 40% (P n.s.) and progression 30 vs 20% (P n.s.) in patients with or without hypertension.

NAG excretion and response to therapy
The response to therapy according to NAG excretion was evaluated in 36 patients with IMN, NS and baseline normal renal function: 19 of them have been treated only with supportive therapy, 17 patients have been treated with immunosuppressive therapy, three with steroids alone (starting dose 1 mg/kg/day: duration of therapy 4–10 months) and 14 with steroids and cyclophosphamide on alternate months for 6 months according to the protocol of Ponticelli et al. [20]. In 21 patients with NAG excretion <=18 U/g urinary Cr, according to treatment (10 patients) or no treatment (11 patients), remission was 90 vs 82% (P=0.60) and progression to CRF was 0 vs 0% (P n.s.); in 15 patients with NAG excretion >18 U/g urinary Cr, according to treatment (seven patients) or no treatment (eight patients), remission was 43 vs 12% (P=0.11) and progression to CRF 14 vs 75% (P=0.02). In FSGS, a comparison between treatment or no treatment was not possible, as all patients have been treated (five with steroids alone and 15 with steroids and cyclophosphamide), but the response to therapy was significantly different in patients with NAG excretion below or above the cut-off, both for remission (77 vs 14%: P=0.005) and progression to CRF (8 vs 57%: P=0.03).

In conclusion the evaluation of NAG excretion seems useful for predicting therapy responsiveness and, at least in IMN patients, may be useful to identify the patients who deserve immunosuppressive therapy.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
NAG, a lysosomal enzyme normally excreted in low amounts in the urine as a consequence of the physiological exocytosis process in the proximal tubular cells, is excreted in abnormally high amounts in many situations characterized by exposure of these cells to various toxic substances [59], in PAN-induced GN in rats [10] and in some human glomerulonephritides [1113]. It has been demonstrated that in GN the increased urinary concentration is due to the increased excretion of an isoenzyme which is synthesized in the tubular cells and not to increased filtration of the serum isoenzyme in the tubular lumen as a consequence of the altered permeability of the glomerular capillary wall [11]. It has also been demonstrated that in proteinuric glomerular diseases the increased excretion of NAG can occur even in the absence of morphological evidence of tubular cells damage, probably reflecting increased lysosomal activity of these cells due to the increased uptake of filtered proteins, and it is therefore an indicator of the functional status of the renal tubules as well as tubular damage. The suggested dependence of the increased excretion of NAG from an activated process of exocytosis by the proximal tubular cells, induced in the proteinuric conditions by an abnormally high uptake and catabolism of filtered proteins, might explain the described relationship between urinary NAG values and severity of proteinuria [1013]. It might also explain why the progressive rise in NAG excretion in proteinuric glomerular diseases is slowed down when a severe degree of renal impairment develops, probably due to a reduction of the functioning nephrons and tubular cell numbers [11].

The TID due to the increased protein traffic across the tubular cells is presently considered the most important determinant for the progression to CRF of patients with proteinuric glomerular diseases. Several experimental models showed that the excessive reabsorption of abnormally filtered proteins by proximal tubular cells upregulates the cellular expression of several inflammatory and vasoactive genes, with the release into the interstititium of substances that trigger interstitial inflammatory infiltration, fibroblast proliferation and fibrosis. Recently, it has been demonstrated that not only the quantity but also the quality of proteinuria may play a role in determining the TID. We demonstrated that in some proteinuric glomerulonephritides [21] the severity of TID correlates with selectivity of proteinuria and fractional excretion of {alpha}1m; moreover, in patients with IMN we showed that [22] the urinary excretion of IgG, but not of albumin and transferrin, correlates with the extent of TID. These observations are in support of the hypothesis suggested by Abbate et al. [23] that IgG may be the toxic mojety of proteinuria. The central role of tubular damage in determining the progression to CRF in proteinuric glomerular diseases explains the interest in the search for a reliable urinary marker of the tubular damage secondary to protein loss and for the identification of the features of proteinuria that may be responsible for such a damage. Our data suggest that the lysosomal enzyme NAG may be this urinary marker.

In our study, we confirmed the correlation between the increase of NAG excretion and the extent of proteinuria in patients with normal renal function and proteinuria in the nephrotic or non-nephrotic range that were affected by MCD, FSGS and IMN. In a linear multiple regression analysis, particularly in patients with NS and normal renal function, the excretion of NAG was significantly dependent not only on 24-h proteinuria (P=0.0067), but mainly on IgG excretion (P=0.0004) and FE {alpha}1m (P=0.0032). These observations suggest that the degree of tubular damage, of which urinary NAG excretion is a marker, is significantly correlated with the two main lesions that characterize GN: the alteration of perm-selectivity and the TID, of which the urinary excretion of IgG and {alpha}1m are biochemical markers.

The correlation between the NAG excretion and the quantity and quality of proteinuria may assign to this urinary marker a predictive value on functional outcome: in fact, the differences in remission and progression rate according to 24-h proteinuria did not attain a statistical significance in IMN patients, while the differences according to NAG excretion were significant both for remission and progression; in FSGS patients the progression rates were significantly different and remission rates at the limit of statistical significance according to the amount of proteinuria, but the differences were higher and more significant according to NAG excretion. Moreover, our results show that NAG excretion has a predictive value on response to therapy: in IMN patients with NAG excretion below the cut-off there was no difference between treated or untreated patients (remission 90 vs 82%; progression 0 vs 0%), while in patients with values above the cut-off there was a significant difference for progression to CRF between treated or untreated patients (14 vs 75%: P=0.02). In FSGS, the remission and progression rates were significantly different in patients with NAG excretion below or above the cut-off.

In conclusion, the level of NAG excretion may be a useful non-invasive and easily repeatable test for assessing an initial malfunction or damage of the proximal tubular epithelial cells in the early stages of potentially progressive diseases; the extent of NAG excretion is dependent not only on the quantity but also on some qualitative aspects of proteinuria; finally, it has a predictive value on functional outcome and response to therapy.



   Acknowledgments
 
The secretarial assistance of Ms Angela Carosi and Ms Sonia Benuzzi are gratefully acknowledged.



   Notes
 
Correspondence and offprint requests to: Claudio Bazzi, MD, Division of Nephrology and Dialysis, San Carlo Borromeo Hospital, Via Pio II, 3, I-20153 Milan, Italy. Email: giuseppe.damico{at}oscb.sined.net Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 18.11.00
Accepted in revised form: 19. 7.02





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