Low-molecular-weight proteins as prognostic markers in idiopathic membranous nephropathy

Abstract

Background: Accurate prediction of prognosis in idiopathic membranous nephropathy (iMN) allows restriction of immunosuppressive therapy to patients at high risk for ESRD. Here we re-evaluate urinary low-molecular-weight proteins as prognostic markers and explore causes of misclassification.

Design, setting, participants, & measurements: In a cohort of 129 patients with serum creatinine concentration <135 μmol/L and proteinuria ≥3.0 g/10 mmol, urinary α1- (uα1m) and β2-microglobulin (uβ2m) excretion rate was determined. Urinary α1m and uβ2m-creatinine ratio was also obtained. We defined progression as a rise in serum creatinine ≥50% or ≥25% and an absolute level ≥135 μmol/L.

Results: Median survival time was 25 months, and 47% of patients showed progression. The area under the receiver operating characteristic curve for uβ2m was 0.81 (95% CI: 0.73 to 0.89). Using a threshold value of 1.0 μg/min, sensitivity and specificity were 73% and 75%, respectively. Similar accuracy was observed for the uβ2m-creatinine ratio with sensitivity and specificity of 75% and 73%, respectively, at a threshold of 1.0 μg/10 mmol creatinine. Similar accuracy was found for uα1m and uα1m-creatinine ratio. Blood Pressure and cholesterol contributed to misclassification. Repeated measurements improved accuracy in patients with persistent proteinuria: the positive predictive value of uβ2m increased from 72% to 89% and the negative predictive value from 76% to 100%.

Conclusions: Urinary excretion of uα2m and uβ2m predict prognosis in iMN. A spot urine sample can be used instead of a timed sample. A repeated measurement after 6 to 12 months increases prognostic accuracy.

Figure 1.

Flowchart of the inclusion of patients.

Figure 2.

Patient outcomes. The solid line represents renal survival without progression. The dot and dashed line represents partial remission defined as proteinuria <3.5 g/d and <50% since baseline, the long dashed line partial remission (proteinuria <2.0 g/d), and the short dashed line complete remission (proteinuria <0.2 g/d).

Figure 3.

Left: ROC curves for prognostic accuracy of urinary excretion rate of α1- (dashed line) and β2-microglobulin (solid line) and IgG (dot and dashed line). Both α1- and β2-microglobulin excretions rates are expressed in μg/min and IgG in mg/24 h. Areas under the curve were as follows: uα1m: 0.81 (95% confidence interval: 0.73 to 0.88), uβ2m: 0.81 (0.73 to 0.89), and IgG: 0.75 (0.66 to 0.84). Right: ROC curves for the prognostic accuracy of α1- (dashed line) and β2-microglobulin (solid line) and IgG (dot and dashed line). When expressed as mg/10 mmol creatinine. Areas under the ROC curve were as follows: uα1m/creat: 0.80 (0.72 to 0.87), uβ2m/creat: 0.80 (0.72 to 0.88), and uIgG/creat: 0.74 (0.66 to 0.83).