Fractional excretion of IgG in idiopathic membranous nephropathy with nephrotic syndrome: a predictive marker of risk and drug responsiveness
© Bazzi et al.; licensee BioMed Central Ltd. 2014
Received: 24 March 2014
Accepted: 1 May 2014
Published: 8 May 2014
Treatment of idiopathic membranous nephropathy with nephrotic syndrome is still controversial. There is currently little known about the clinical use of renal biomarkers which may explain contradictory results obtained from clinical trials. In order to assess whether IgG-uria can predict the outcome in membranous nephropathy, we examined the value of baseline EF-IgG in predicting remission and progression of nephrotic syndrome.
In a prospective cohort of 84 (34 female) idiopathic membranous nephropathy patients with nephrotic syndrome we validated the ability of the clinically available urine biomarker, IgG, to predict the risk of kidney disease progression and the beneficial effect of immunosuppression with steroids and cyclophosphamide. The fractional excretion of IgG (FE-IgG) and α1-microglobulin (FE-α1m), urine albumin/creatinine ratio, and eGFR were measured at the time of kidney biopsy. Primary outcome was progression to end stage kidney failure or kidney function (eGFR) decline ≥ 50% of baseline. Patients were followed up for 7.2 ± 4.1 years (range 1–16.8).
High FE-IgG (≥0.02) predicted an increased risk of kidney failure (Hazard Ratio, (HR) 8.2, 95%CI 1.0–66.3, p = 0.048) and lower chance of remission (HR 0.18, 95%CI 0.09–0.38, p < 0.001). The ten-year cumulative risk of kidney failure was 51.7% for patients with high FE-IgG compared to only 6.2% for patients with low FE-IgG. During the study, only 24% of patients with high FE-IgG entered remission compared to 90% of patients with low FE-IgG. Combined treatment with steroids and cyclophosphamide decreased the progression rate (–40%) and increased the remission rate (+36%) only in patients with high FE-IgG.
In idiopathic membranous nephropathy patients with nephrotic syndrome, FE-IgG could be useful for predicting kidney disease progression, remission, and response to treatment.
KeywordsAlbuminuria Idiopathic membranous glomerulonephritis Immunoglobulin G Steroids Cyclophosphamide ESRD Nephrotic syndrome Proteinuria Treatment outcome
Idiopathic membranous nephropathy (IMN) is a major cause of nephrotic syndrome (NS) in adult patients . NS is associated with an increased risk of kidney failure and death from cardiovascular causes . IMN is characterised by subepithelial localisation of IgG immune-complexes and lack of significant proliferation in the glomerular tuft. The recent discovery of the podocyte antigen PLA2R and its corresponding IgG autoantibodies confirmed the autoimmune nature of the disease .
There is no specific treatment for IMN. Early initiation of immunosuppressive treatment with steroids and cyclophosphamide has been recommended by some investigators [4, 5]. Because of the high rate of spontaneous remission (about 30%), others suggested an initial conservative approach [6, 7]. Immunosuppressive treatment could be harmful, but waiting until the condition starts to progress carries the risk of missing the “window of opportunity” for treatment [8–10]. Once this assessment is made, an individualised treatment based on risk versus benefit of the immunosuppressive treatment can be advocated .
Nowadays, the severity of kidney disease is commonly staged according to the kidney function estimated from serum creatinine (eGFR) . However, eGFR is not an early predictive marker for treatment decisions . Therefore, the search continues for early predictive markers that can estimate the risk of kidney disease progression. The ideal prognostic biomarker should be accurate and easy to implement in clinical practice. Such a biomarker could guide clinical decisions to avoid unnecessary treatment of patients who are not at risk of progression and to avoid unnecessary delay in initiation of treatment for those at high risk of progression to kidney failure.
As in other types of glomerular diseases, the primary main lesion in IMN is alteration of the glomerular filtration barrier (GFB) function with increased excretion of albumin (molecular radius, r =36 Å) and high molecular weight proteins such as IgG (r = 55 Å) and IgM (r = 120 Å) [13, 14]. Thus, increased urine IgG concentrations in nephrotic patients could reflect activity and severity of the glomerulonephritis [13, 15, 16]. Recent studies have shown that IgG-uria could provide early prognostic information for patients with glomerular disease [13, 15, 17, 18]. However, its value in predicting the remission and treatment outcome is still unclear. Using the data from the Milano and Lund glomerulonephritis longitudinal cohorts, we assessed whether IgG-uria can predict the functional outcome (remission versus progression) in patients with IMN and NS. We also evaluated the ability of IgG-uria to identify patients who might benefit from immunosuppressive treatment.
Baseline characteristics of patients with idiopathic membranous nephropathy and nephrotic syndrome, classified according to fractional excretion of IgG
No. of patients
55 ± 16
52 ± 15
58 ± 17
eGFR (ml/min/1.73 m2)
72 ± 26
88 ± 20
58 ± 23
eGFR < 60 ml/min/1.73 m2
BP ≥140/90 mmHg
Serum albumin g/L
23 ± 6
25 ± 5
22 ± 6
373 ± 256
243 ± 278
486 ± 177
0.052 ± 0.063
0.009 ± 0.005
0.090 ± 0.066
0.371 ± 0.409
0.124 ± 0.106
0.601 ± 0.447
10 ± 14
6 ± 10
13 ± 17
1.3 ± 1.3
0.7 ± 0.7
1.2 ± 0.7
86 ± 50
98 ± 51
77 ± 48
ACE inhibitors treatment
Treatment and follow-up
Thirty-five patients were treated only with supportive therapy, such as diuretics, antihypertensives, angiotensin enzyme inhibitors (ACEi/ARBs), statins, anti-platelet agents, and vitamin D3. Thirty-seven patients, besides supportive therapy, were treated soon after diagnosis with steroids and cyclophosphamide (St + Cyc) for six months according to the Ponticelli protocol: methylprednisolone 0.5–1.0 g iv for 3 days at the beginning of months 1, 3 and 5, followed by oral prednisolone 0.5 mg/kg/day during months 1, 3 and 5, and cyclophosphamide 1–2 mg/kg/day during months 2, 4 and 6 (lower dose of both drugs for elderly patients and patients with low GFR) . Twelve patients were treated with steroids alone: five with prednisone 1 mg/kg/day for 4–12 months, and seven with ACTH 1–2 mg weekly for 4–11 months. Patients were followed up until the last planned clinic visit in 2009. The primary outcome was progression to kidney failure defined as start of renal replacement therapy (ESRD) or reduction of eGFR by ≥ 50% of baseline. The secondary outcome was complete or partial remission of NS (proteinuria < 0.2 or < 2.0 g/day, respectively).
A blood sample and a second morning fresh urine sample were analysed for concentration of creatinine, albumin, IgG and alpha 1 microglobulin in the chemistry laboratory of Azienda Ospedaliera Ospedale San Carlo Borromeo, Milan, and in the chemistry laboratory of hospital of Lund. Serum creatinine (sCr) and urinary creatinine (uCr) were measured enzymatically and expressed in μmol/L. Serum and urinary IgG, albumin and α1-microglobulin (α1m) were measured by immunonephelometry method on a BNA nephelometer (Behring, Milan, Italy) using rabbit serum antihuman antibodies (Behring) , and by immunoturbidimetry using a Cobas Mira S system (Roche Inc.) .
Urinary albumin-to-creatinine ratio (mg/g) (ACR) is the ratio of urinary albumin (mg/L) to urinary creatinine (g/L); fractional excretion of IgG (FE-IgG) and α1m (FE-α1m), expressed per 100 ml of creatinine clearance, was calculated according to the formula FE-IgG = (urinary protein/serum protein) × (serum creatinine/urinary creatinine) × 100.
Glomerular filtration rate (eGFR) was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) formula .
Characteristics of receiver operating curves (ROC) for the investigated biomarkers: area under the curves (AUC), cut-off levels, sensitivity, specificity and likelihood ratio for predicting kidney failure (n 84) and No remission (n 70) in idiopathic membranous nephropathy patients with nephrotic syndrome
Prediction of kidney failure
High FE IgG and FE α1m
0.02 + 0.24
Prediction of no remission
High FE IgG and FE α1m
0.02 + 0.24
The fractional excretion of IgG (FE-IgG) was measured in 84 (34 female) patients Table 1. The overall average follow-up time was 86 ± 50 months (range 12–202). During follow-up, 20 patients progressed to kidney failure, 14 patients to ESRD, and 6 patients to eGFR ≤50% of baseline.
FE-IgG was strongly related to the baseline eGFR (r: –0.654, p = 0.01) and last eGFR (r: –0.570, p = 0.01), and weakly with global glomerulosclerosis (r = 0.380, p = 0.001) and tubulo-interstitial fibrosis (r = 0.297, p = 0.01). The optimal cut-off level for high FE-IgG was ≥ 0.02, for high FE-α1m ≥ 0.24, and for high ACR ≥ 4000 mg/g uCr (Table 2). FE-IgG had a better likelihood ratio for prediction of kidney failure thanFE-α1m, ACR or eGFR (Table 2).
Univariate Cox regression analysis for outcome of renal failure in 84 patients with idiopathic membranous nephropathy and nephrotic syndrome
ACR (2 groups)
FE IgG (2groups)
FE α1m (2 groups)
eGFR (2 groups)
Remission of nephrotic syndrome (NS)
The remission was more frequent and earlier in patients with low FE-α1m (82.8% of patients at 47.1 months, 95%CI: 27–67 months) than patients with high FE-α1m (29.3%, at 119.9 months, 95% CI: 96–144, p <0.001).
The remission was more frequent and earlier in patients with low ACR (75.8% of pats, at 55.1 months, 95% CI: 33–77), than patients with high ACR (29.7%, at 109.5 months, 95% CI: 86–133, p < 0.001).
Most of the patients with baseline eGFR ≥ 60 ml/min/1.73 m2 went into remission (69.6%, at 60.3 months, 95% CI: 41–79) compared to patients with baseline eGFR < 60 ml/min/1.73 m2 (16.7%, at 142.7 months, 95% CI: 118–167, p <0.001).
The multivariate Cox regression analysis identified only FE-IgG as an independent predictor for remission (HR 0.18, 95% CI, 0.09-0.38, p <0.001) (Figure 2).
IgG fractional excretion and response to treatment
Clinical, proteinuric and histologic parameters of 35 idiopathic membranous nephropathy patients with nephrotic syndrome not treated with immunosuppressive drugs and 37 others treated with combined steroids and cyclophosphamide
No. of patients
53 ± 17
56 ± 16
Baseline eGFR ml/min/1.73 m2
77 ± 27
69 ± 25
eGFR < 60 ml/min/1.73 m2
BP ≥140/90 mmHg
350 ± 242
379 ± 185
0.040 ± 0.055
0.067 ± 0.069
0.325 ± 0.382
0.435 ± 0.411
7.7 ± 10.7
11.3 ± 17.7
1.0 ± 0.9
1.4 ± 1.3
Time to reach ESRD (months)
55 ± 29
90 ± 46
Untreated and treated patient did not differ in overall remission rate (51.7% vs. 51.2%, p = 0.7). However, for patients with high FE-IgG, the remission rate was 0% for untreated and 36% for treated patients (p = 0.025). There was no difference in the frequency of remission between untreated and treated patients with low FE-IgG (93.7% vs. 84.6%, p = 0.23).
This longitudinal cohort study validated the predictive value of the fractional excretion of IgG in IMN patients with nephrotic syndrome. The heterogeneity of the progression to kidney failure in IMN patients and the lack of a reliable marker of disease severity has been a major confounding factor that contributed significantly to the contradictory results of the previous clinical treatment trials . A recent meta-analysis of 1025 patients enrolled in 18 random controlled trials showed an increase in the likelihood of remission for patients treated with steroids and alkylating agents, but there were no beneficial effects on kidney function . In our cohort, immunosuppressive treatment with steroids and cyclophosphamide significantly improved the clinical outcome only in patients with increased urinary excretion of IgG (FE-IgG ≥ 0.02). For these patients, immunosuppressive treatment reduced the 10-year incidence of kidney failure by 40% and increased the remission rate by 36%. Patients with lower concentrations of urine IgG (FE-IgG <0.020) went into spontaneous remission more frequently and maintained kidney function even without immunosuppressive treatment.
As in previous studies, our cohort showed that impairment of kidney function and increased proteinuria are associated with faster progression to kidney failure. However, the fractional excretion of IgG predicts both remission of NS (HR 0.18) and progression to kidney failure (HR 8.2) independently from albuminuria and GFR.
The role of albuminuria in the progression of kidney disease has been questioned in many experimental and clinical studies. The GFR estimated from serum creatinine is considered a late sign of the severity of kidney disease [22, 23]. Thus, inclusion of FE-IgG in clinical practice guidelines may provide a substantial improvement in risk prediction during the early stages of IMN. It might help clinicians to individualise treatment and thereby improve outcome. Patients with high FE-IgG may benefit from more intensive monitoring of kidney function and from early initiation of immunosuppressive therapy.
The last few years have seen the development of various new immunosuppressive treatments, such as mycophenolate mophetil, tacrolimus, rituximab, and synthetic ACTH for patients not responding to steroids and alkylating agents [24–28]. It will be of clinical interest to include FE-IgG in future treatment trials.
The main strength of our study, the possibility of using a simple, practical renal biomarker that can be included in routine clinical care for kidney disease patients, is particularly relevant. Urine IgG measured in a spot urine sample and calculation of FE-IgG can be integrated into the routine laboratory investigation in most clinical laboratories. Nephrotic patients are usually managed by kidney specialist, and the results of this study can be generalised among different health care systems.
Calculating the risk of kidney failure in nephrotic patients is important for management decisions, and maintaining kidney function is usually associated with better survival. Whether immunosuppressive treatment improves patient survival should be addressed in multicentre longitudinal studies on large numbers of patients.
In conclusion, in idiopathic membranous nephropathy patients with nephrotic syndrome, urinary excretion of IgG could be helpful, in addition to albuminuria, for assessment of the risk of disease progression and response to treatment. Validation of our results on a large external cohort and in new clinical trials is warranted.
We wish to thank Dr. Jawad Hashim, Department of Family Medicine, UAE University, for critical review of the statistical analysis, and Dr. Amin Bredan, for writing assistance.
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