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NDT Advance Access published online on February 28, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn007
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Beta-2-microglobulin is superior to N-acetyl-beta-glucosaminidase in predicting prognosis in idiopathic membranous nephropathy

Julia M. Hofstra1, Jeroen K. J. Deegens1, Hans L. Willems2 and Jack F. M. Wetzels1

1 Department of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands 2 Department of Clinical Chemistry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

Correspondence and offprint requests to: Julia M. Hofstra, Department of Nephrology 464, Radboud University Nijmegen Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: +31-24-3614761; Fax: +31-24-3540022; E-mail: J.Hofstra{at}nier.umcn.nl



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background: An accurate prediction of prognosis in patients with idiopathic membranous nephropathy (iMN) would allow restriction of immunosuppressive treatment to patients who are at highest risk for end-stage renal disease (ESRD). Several markers of proximal tubular cell injury have been used as predictors of prognosis. In this study we compared the accuracy of urinary beta-2-microglobulin (Uβ2m) and N-acetyl-beta-glucosaminidase (Uβ-NAG) in predicting renal insufficiency and remission rates.

Methods: Fifty-seven patients with iMN (38 M, 19 F; age 48 ± 16 years), a nephrotic syndrome and a serum creatinine level <135 µmol/l were studied prospectively. At baseline, a standardised measurement was carried out to determine renal function and protein excretion. The end-point renal failure was defined as a serum creatinine exceeding 135 µmol/l or an increase in serum creatinine by >50%. Remission was defined as a proteinuria <2.0 g/day with stable renal function.

Results: The mean follow-up was 80 ± 36 months. The mean serum creatinine concentration was 89 ± 20 µmol/l, serum albumin 24 ± 5.3 g/l and proteinuria 8.9 ± 4.8 g/24 h. Thus far, 28 (49%) patients have reached the predefined end point of renal failure. Multivariate analysis identified Uβ2m as the strongest independent predictor for the development of renal insufficiency. Sensitivity and specificity were 81 and 90% respectively for Uβ2m (threshold value 54 µg/mmol cr), and 74 and 81% respectively for Uβ-NAG (threshold value 2.64 U/mmol cr). The overall remission rate was 44%. A remission occurred in 78% of patients with low Uβ2m and in 14% of patients with high Uβ2m, and respectively in 71% of patients with low Uβ-NAG and 21% of patients with high Uβ-NAG.

Conclusions: Although both Uβ2m and Uβ-NAG predicted progression and remission in iMN, Uβ2m was more accurate. High specificity in predicting prognosis should be pursued to avoid unnecessary immunosuppressive therapy. We therefore conclude that Uβ2m is superior to Uβ-NAG in predicting prognosis in patients with iMN.

Keywords: beta-2-microglobulin; membranous nephropathy; N-acetyl-beta-glucosaminidase; prognostic markers; renal outcome



   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Idiopathic membranous nephropathy (iMN) is the most common cause of the nephrotic syndrome in adults. Its natural course when untreated is variable: 14–56% of patients develop a spontaneous remission whereas 34–62% of patients develop renal insufficiency [1]. Whether patients with iMN should be treated with immunosuppressive therapy has been heavily debated in recent decades [1–4]. Randomized controlled trials showed a treatment benefit in patients with iMN and a nephrotic syndrome. Still many authors argue against such a strategy, which exposes many patients unnecessarily to toxic agents [4]. We are also in favour of a restrictive treatment strategy, limiting immunosuppressive treatment to patients at highest risk for end-stage renal disease (ESRD) [1,5]. Our group demonstrated that such a strategy is feasible with high renal survival rates [6].

Evidence of renal function deterioration is probably the most specific marker of ESRD [1,7,8]. However, postponing the start of treatment until renal insufficiency is apparent has unwanted effects: side effects of treatment are more frequent and more severe, and renal function may not normalise [1,5]. Therefore, specific markers that allow prediction of prognosis in the early phase of the disease are desirable.

We and others showed that patients at highest risk for progressive renal failure can be identified by measuring markers of renal tubular injury in the urine [9–13]. In a previous study we validated the use of the low molecular weight (LMW) protein beta-2-microglobulin (β2m) as a highly accurate marker in predicting the development of renal insufficiency [10]. However, the use of β2m poses some problems in daily clinical practice. At first, urinary β2m (Uβ2m) can only be measured when urinary pH exceeds 6.0. In more acidic urine β2m is unstable and rapidly degrades. In our centre, patients are instructed to take oral sodium bicarbonate before urine samples are collected. In spite of this, in ~7% of patients the urinary pH remains below 6.0. Secondly, the methods used for the β2m measurement are not available in every clinic and require some experience [14]. Thus, although Uβ2m is a predictive marker with high sensitivity and specificity, an alternative marker could be of use.

Several other markers can be considered to serve as this alternative. The excretion of the LMW protein alfa-1-microglobulin ({alpha}1m) has been studied in patients with iMN [10,12]. Although its predictive value was similar to β2m, no validation study has been done. Bazzi et al. used SDS–PAGE gel electrophoresis and observed that multiple bands in the low molecular weight region, evidence of tubular proteinuria, predicted prognosis [13]. Urinary excretion of IgG also has a predictive value in iMN [10,12]. When combining some of the above-mentioned markers, specificity can be somewhat increased [10]. Bazzi et al. evaluated the predictive value of the tubular lysosomal enzyme N-acetyl-beta-glucosaminidase (β-NAG) on functional outcome and response to therapy in patients with primary glomerulonephritis [11]. In 36 patients with iMN and a nephrotic syndrome, urinary β-NAG (Uβ-NAG) predicted both progression and remission with high sensitivity. The measurement of Uβ-NAG does not require special precautions for collecting urine samples. Thus, Uβ-NAG may be preferable to Uβ2m in daily clinical practice.

In this study we compared the accuracy of Uβ2m and Uβ-NAG in predicting functional outcome (renal insufficiency and remission rates) in patients with iMN.



   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
For this study we have used urine samples collected from patients who participated in a prospective study to validate the predictive value of Uβ2m. Details of this study have been described [10]. In brief, we included patients with biopsy-proven iMN, a baseline serum creatinine ≤135 µmol/l, proteinuria ≥3.5 g/day and/or serum albumin ≤30 g/l and a follow-up of at least 12 months. Patients were excluded when they had been treated with immunosuppressive agents other than corticosteroids before the baseline measurements.

All patients were evaluated at baseline using a standardised protocol of urine and blood measurements as described [10]. In brief, patients come to our ward after an overnight fast. They are instructed to take 4000 mg of oral sodium bicarbonate in the evening before their visit to ensure that urinary pH exceeds 6.0, which is mandatory for the measurement of Uβ2m. In the morning of the measurement, patients are not allowed to take diuretics. Upon arrival, 375 to 500 ml tap water is given to enforce diuresis. The patients remain supine during 2 h except for voiding. Timed urine samples are collected, and in the middle of this collection period, a blood sample is taken. At baseline two 24-h urine samples are collected for assessment of daily excretion of total protein and creatinine. Techniques for the measurements of creatinine, β2m and standard laboratory parameters were described before [10].

In addition, aliquots of urine were centrifuged and the supernatant was stored at –70°C. In the clinical chemistry laboratory, measurement of urinary β-NAG was performed at intervals of 2–3 months. The maximal storage time of these samples thus was <3 months. For the determination of β-NAG a colourimetric assay was performed, using 3-cresolsulfonphthalein-N-acetyl-β-D-glucosaminide, which is hydrolyzed by NAG with the release of 3-cresolsulfonphthalein, which is measured photometrically at 580 nm (Roche Diagnostics, nr 10875406001). Results of the β-NAG measurements were entered in the clinical laboratory files and were not known to the treating physicians. After the first evaluation and baseline measurement, patients were prospectively followed throughout the years and data on treatment, remission and survival were obtained.

For the current study, the data of the Uβ-NAG were entered in the study database. In addition, the follow-up of all participating patients was extended and completed. The primary aim of the present study was to compare the accuracy of Uβ-NAG and Uβ2m for predicting renal survival. The secondary aim was to evaluate the value of the different markers for predicting the occurrence of a remission, either partial or complete.

Definitions and calculations
Renal failure was defined as an increase in serum creatinine by >50% from baseline or a serum creatinine >135 µmol/l. In our institution this level of renal insufficiency is used to advise start of immunosuppressive therapy. Survival was calculated using the date of the baseline measurements as t = 0. Partial remission (PR) was defined as proteinuria <2.0 g/day with stable renal function. Complete remission (CR) was defined as proteinuria <0.2 g/day with a stable serum creatinine concentration. Endogenous creatinine clearance (ECC) was calculated from parameters measured in 24-h urine samples, collected at t = 0. Besides this, we estimated GFR (eGFR) by applying the extended MDRD formula [15].

Uβ2m is expressed as microgram per millimol of urinary creatinine (µg/mmol cr), and the reference value in healthy volunteers is <22 µg/mmol cr. Uβ-NAG is expressed as units per millimol of urinary creatinine (U/mmol cr), and the reference value in healthy volunteers is <0.2 U/mmol cr.

Statistical analyses
The correlation between Uβ2m and Uβ-NAG (non-parametric distributions) was analysed by Spearman's rank coefficient of correlation. Renal survival and remission rates were calculated using Kaplan–Meier curves. The equality of survival for different groups was assessed by the log-rank test. Predictive accuracy was assessed by making receiver operating characteristics (ROC) curves. We determined the area under the curve (AUC) and calculated the sensitivity and specificity by using the most discriminative threshold values for both markers.

We evaluated the effect of the different parameters in predicting renal survival. Univariate analysis and multivariate analysis using the Cox proportional hazard model with a forward stepwise procedure was performed to identify the best independent predictive marker. For this purpose, non-parametric values were transformed using log 10 transformation.

All data are presented as means (±SD) or medians (range) when appropriate. All statistics were performed using SPSS software, version 12.0.1 (Chicago, IL). Differences were considered significant with P-value <0.05.



   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
We studied 57 patients (38 M, 19 F; age 48 ± 16 years) with iMN, who fulfilled our inclusion criteria. Baseline characteristics of these patients are given in Table 1. Two patients had been treated with prednisone.


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  		Table 1 Baseline characteristics of patients with iMN (n = 57)

 
Uβ2m and Uβ-NAG correlated very well (r = 0.841). However, there were 22 patients with a normal Uβ2m level at the baseline measurement, whereas Uβ-NAG was elevated in all patients.

Patients have been followed for 80 ± 36 months (range 12–143 months). Thus far, 28 (49%) patients have reached the predefined end point of renal failure. Overall renal survival rates were 79% at 6 months, 67% after 1 year and 51% after 3 years. The reason for renal failure was an increase in serum creatinine by >50% in four patients and a serum creatinine >135 µmol/l in 24 patients.

The use of a fixed serum creatinine as end point can be debated [10]. Theoretically, a small increase of serum creatinine concentration may be sufficient to cause a patient to fulfil the renal failure criteria. Therefore we also assessed the rate of deterioration of renal function. In the 28 patients who reached the predefined end point of renal failure, serum creatinine had increased by an average of 49% from 101 ± 18 to 149 ± 23 µmol/l. The estimated GFR was 57 ± 19 ml/min/1.73 m2 at baseline and 35 ± 9 ml/min/1.73 m2 at the end point. The absolute decrease of eGFR averaged 48 ml/min/1.73 m2/year. For comparison, in the non-failure group the serum creatinine was 0.86 ± 0.16 mg/dl at baseline and 0.88 ± 0.21 at the end of the follow-up; the average change of eGFR was –0.9 ml/min/1.73 m2/year.

A remission occurred in 25 patients (44%); in 12 patients this was a complete remission. Remission rates were 9% at 6 months, 14% after 1 year, 36% after 3 years and 44% after 5 years. During the follow-up four patients relapsed (one from CR, three from PR).

ROC curves were made to assess the predictive accuracy of Uβ-NAG and Uβ2m. From the coordinate points of the ROC curves sensitivity and specificity for both parameters were calculated, using the best discriminative thresholds (Table 2).


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  		Table 2 Sensitivity, specificity, PPV and NPV of the most discriminative thresholds of urinary proteins for the prediction of renal failure in patients with iMN

 
Renal survival curves using the risk stratification for Uβ-NAG and Uβ2m are depicted in Figures 1 and 2. Renal survival was 32% at 1 year in patients with high Uβ2m (>54 µg/mmol cr) and 93% in patients with low Uβ2m (≤54 µg/mmol cr). At the end of the follow-up the survival rates were 12% and 83% respectively. The survival rates at 1 year in high (threshold >2.64 U/mmol cr) and low Uβ-NAG (≤2.64 U/mmol cr) groups were 36% and 89% respectively. At the end of the follow-up the renal survival was 20% in patients with high Uβ-NAG and 74% in patients with low Uβ-NAG. All differences in survival were highly significant. The calculated sensitivity and specificity were respectively 82% and 90% for Uβ2m and 74% and 81% for Uβ-NAG.


Figure 1
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  		Fig. 1 Renal survival in patients with iMN with urinary beta-2-microglobulin excretion ≤54 µg/mmol cr (low Uβ2m) and >54 µg/mmol cr (high Uβ2m). See the Methods section for definitions of renal failure.

 

Figure 2
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  		Fig. 2 Renal survival in patients with iMN with urinary N-acetyl-beta glucosaminidase excretion ≤2.64 U/mmol cr (low Uβ-NAG) and >2.64 U/ mmol cr (high Uβ-NAG). See the Methods section for definitions of renal failure.

 
In univariate analysis, the following parameters were significantly related to renal survival: serum creatinine, serum albumin, proteinuria and urinary excretion of Uβ2m and Uβ-NAG (all P < 0.001). Multivariate analysis revealed that Uβ2m was the strongest independent risk factor (relative risk 2.69; 95% confidence interval 1.82–3.98). After Uβ2m, serum creatinine was identified as the second independent predictive factor (relative risk 1.04; 95% confidence interval 1.00–1.07).

The probability of reaching a remission using risk stratification with the best discriminative thresholds for remission is depicted in Figures 3 and 4. A spontaneous remission occurred in 78% of patients with low Uβ2m (≤40 µg/ mmol cr) and in 14% of patients with high Uβ2m (>40 µg/ mmol cr), and respectively in 71% of patients with low Uβ-NAG (≤2.50 U/mmol cr) and in 21% of patients with high Uβ-NAG (>2.50 U/mmol cr). The calculated sensitivity and specificity for predicting a remission were respectively 87 and 83% for Uβ2m and 70 and 78% for Uβ-NAG (Table 3).


Figure 3
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  		Fig. 3 Probability of remission (proteinuria <2.0 g/day) in patients with iMN with urinary beta-2-microglobulin ≤40 µg/mmol cr (low Uβ2m) and >40 µg/mmol cr (high Uβ2m).

 

Figure 4
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  		Fig. 4 Probability of remission (proteinuria <2.0 g/day) in patients with iMN with urinary N-acetyl-beta-glucosaminidase ≤2.50 U/mmol cr (low Uβ-NAG) and >2.50 U/mmol cr (high Uβ-NAG).

 

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  		Table 3 Sensitivity, specificity, PPV and NPV of the most discriminative thresholds of urinary proteins for the prediction of remission in patients with iMN

 


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our data indicate that Uβ2m is more accurate than Uβ-NAG in predicting prognosis of patients with iMN. This conclusion holds for both renal outcome parameters, i.e. renal function and remission of proteinuria.

Our study may be criticized because we used a fixed value of serum creatinine of 135 µmol/l as the end point for defining renal failure. We feel that it is not justified to withhold immunosuppressive treatment in patients with more severe renal insufficiency. However, it has been shown in many studies that moderate renal insufficiency with serum creatinine levels of 125–135 µmol/l is an accurate predictor of ESRD [7,16–18]. Furthermore, it is evident from a percentual change in serum creatinine and decrease in eGFR that renal function was severely disturbed at the end point. When compared to the non-failure group there was a highly significant difference in the decrease of eGFR over time, indicating that with this end point we are able to identify progressors and non-progressors.

The validity of Uβ2m in predicting renal failure was established in our previous study [10]. The current data show that specificity and sensitivity remain similar also after a more prolonged period of follow-up. This is not unexpected since most patients with iMN will reach their ‘destiny’ within 5 years after the onset of the disease [17]. Follow-up beyond this period therefore has no major influence on the outcome statistics of renal failure. The value of Uβ2m in predicting a remission was not evaluated in our previous study. As expected, a low urinary excretion of β2m is a favourable prognostic sign, with a high sensitivity in predicting the development of a spontaneous remission. Late spontaneous remissions can occur up to 75 months after the start of the disease.

In our study Uβ-NAG was less accurate than Uβ2m for predicting progressive disease and remission. Bazzi et al. reported a sensitivity and specificity of respectively 100 and 72% for Uβ-NAG for predicting progression in a subgroup of 36 patients with iMN and a nephrotic syndrome [11]. The higher sensitivity in Bazzi's study can on the one hand be the consequence of differences between the study populations. More important, on the other hand, are the differences in end points in the two studies; in Bazzi's study, progression was defined as progression to chronic renal failure (not otherwise specified), ESRD or doubling of serum creatinine. The progression rate after a follow-up of 42 ± 23 months was only 19%. We have used a less conservative renal end-point definition and noted a progression rate of 49% after 3 years. These differences likely explain the difference in reported sensitivities of Uβ-NAG between our and Bazzi's study.

Both β2m and β-NAG are considered reliable markers of proximal tubular cell injury. How can the differences in accuracy be explained? β2m is a LMW protein that is readily filtered through the glomerulus and almost completely reabsorbed by the proximal tubulus. When brush border cells in the proximal tubulus are damaged, the reabsorption of β2m is impaired, leading to an increased urinary β2m excretion. Although in theory destruction of a very small number of cells may occur without any noteworthy effect on the reabsorptive capacity of the proximal tubulus cells, β2m is a reliable early marker of tubulo-interstitial injury.

β-NAG is an enzyme that is localized in the lysosomes of the proximal tubular cells. Severe tubular cell injury, characterized by damage of the cell membranes, will lead to losses of cytosolic and lysosomal enzymes in the urine. However, the exocytosis–endocytosis pathway is responsible for some spilling of β-NAG in the urine, independent of cell injury [19,20]. Increased activity of the lysosomal pathway may cause increased loss of β-NAG. Since proteinuria stimulates lysosomal activity, exocytosis of lysosomal content may be responsible for the increased Uβ-NAG excretion in patients with proteinuria. Our data are in agreement with these observations. In many patients with a normal Uβ2m, Uβ-NAG was already elevated. Thus, Uβ-NAG is a less specific marker of tubular injury than Uβ2m.

Are these differences between β2m and β-NAG relevant for daily clinical practice? Let us assume an imaginary patient cohort of 100 patients with iMN. Based on the natural history of iMN, one would predict that 45 of these patients eventually will progress to renal failure [1]. Using Uβ2m, with a calculated sensitivity and specificity of respectively 82 and 90%, five patients will be wrongly classified as high risk and receive unnecessary immunosuppressive therapy, whereas in eight patients treatment will unjustly be withheld or postponed. The overall accuracy of Uβ2m in predicting renal failure is 87%. Based on Uβ-NAG, with a calculated sensitivity and specificity of respectively 74 and 81%, 10 patients will receive unnecessary immunosuppressive treatment and 12 patients will not receive early treatment. The overall accuracy of Uβ-NAG in predicting renal failure is 78%. In this imaginary cohort using Uβ-NAG instead of Uβ2m to identify patients at risk for renal failure (and thus identify patients for receiving immunosuppressive therapy) would have led to overtreatment of five additional patients (100%). Similar calculations can be made regarding the predictive performance of a spontaneous remission.

We feel that an ideal prognostic marker should especially reach a high specificity in predicting ESRD, to avoid unnecessary treatment in patients who will never progress to renal failure. Based on both specificity and overall accuracy, Uβ2m is superior to Uβ-NAG in predicting progression in patients with iMN, although the differences in the AUC's are rather small. Despite its disadvantage of instability in acid urine, Uβ2m seems to be more useful in daily clinical practice. The costs of both assays are comparable.

In conclusion, both Uβ2m and Uβ-NAG predicted progression and remission in iMN. Use of prognostic markers allows identification of high-risk patients at an early stage and will lead to better patient selection for treatment. High specificity in predicting prognosis should be pursued to avoid unnecessary immunosuppressive therapy. As Uβ2m is more accurate than Uβ-NAG, we prefer Uβ2m to Uβ-NAG.

Conflict of interest statement. There is no conflict of interest. The results presented in this paper have not been published previously in whole or part, except in abstract format.



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 19.10.07
Accepted in revised form: 3. 1.08


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