Low-and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy: A prospective study

Maria V. Irazabal; Alfonso Eirin; John Lieske; Laurence H. Beck; Sanjeev Sethi; Timothy M. Borland; John J. Dillon; Patrick H. Nachman; Samih H. Nasr; Lynn D. Cornell; Nelson Leung; Daniel C. Cattran; Fernando C. Fervenza

doi:10.1093/ndt/gfs379

Low-and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy: A prospective study

Maria V. Irazabal, Alfonso Eirin, John Lieske, Laurence H. Beck, Sanjeev Sethi, Timothy M. Borland, John J. Dillon, Patrick H. Nachman, Samih H. Nasr, Lynn D. Cornell, Nelson Leung, Daniel C. Cattran, Fernando C. Fervenza

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19 Scopus citations

Abstract

Background. Selective urinary biomarkers have been considered superior to total proteinuria in predicting response to treatment and outcome in patients with membranous nephropathy (MN). Methods. We prospectively tested whether urinary (U) excretion of retinol-binding protein (RBP), α1-microglobulin (α1M), albumin, immunoglobulinIgG and IgM and/or anti-phospholipase 2 receptor (PLA₂R) levels could predict response to rituximab (RTX) therapy better than standard measures in MN. We also correlated changes in antibodies to PLA₂R with these urinary biomarkers. Results . Twenty patients with MN and proteinuria (P) >5 g/24 h received RTX (375 mg/m ² × 4) and at 12 months, 1 patient was in complete remission (CR), 9 were in partial remission (PR), 5 had a limited response (LR) and 4 were non-responders (NR). At 24 months, CR occurred in 4, PR in 12, LR in 1, NR in 2 and 1 patient relapsed. By simple linear regression analysis, UIgG at baseline (mg/24 h) was a significant predictor of change in proteinuria at 12 months (Δ urinary protein) (P = 0.04). In addition, fractional excretion (FE) of IgG, urinary alpha 1 microglobulin (Uα1M) (mg/24 h) and URBP (μg/24 h) were also predictors of response (P = 0.05, 0.04, and 0.03, respectively). On the other hand, UIgM, FEIgM, albumin and FE albumin did not predict response (P = 0.10, 0.27, 0.22 and 0.20, respectively). However, when Results were analyzed in relation to proteinuria at 24 months, none of the U markers that predicted response at 12 m could predict response at 24 m (P = 0.55, 0.42, 0.29 and 0.20). Decline in anti-PLA₂R levels was associated with and often preceded urinary biomarker response but positivity at baseline was not a predictor of proteinuria response. Conclusions. The Results suggest that in patients with MN, quantification of low-, medium-and high-molecular-weight urinary proteins may be associated with rate of response to RTX, but do not correlate with longer term outcomes.

Original language	English (US)
Pages (from-to)	137-146
Number of pages	10
Journal	Nephrology Dialysis Transplantation
Volume	28
Issue number	1
DOIs	https://doi.org/10.1093/ndt/gfs379
State	Published - Jan 2013
Externally published	Yes

Bibliographical note

Funding Information:
Acknowledgments. The authors thank Mrs Lori Riess, for her outstanding role as research coordinator for the study. The study was supported by an unrestricted research grant from Genentech Inc., South San Francisco, CA, Biogen Idec, San Diego CA, the Department of Laboratory Medicine and Pathology, Mayo Clinic, the Fulk Family Foundation (FCF) and by a UL1-RR24150 grant to the Center for Translational Science Activities, Mayo Clinic. The results presented in this paper have not been published previously in whole or part, except in abstract format at the American Society of Nephrology meeting in Philadelphia, PA, November 2011.

Keywords

membranous nephropathy
rituximab
urinary proteins

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10.1093/ndt/gfs379

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Irazabal, M. V., Eirin, A., Lieske, J., Beck, L. H., Sethi, S., Borland, T. M., Dillon, J. J., Nachman, P. H., Nasr, S. H., Cornell, L. D., Leung, N., Cattran, D. C., & Fervenza, F. C. (2013). Low-and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy: A prospective study. Nephrology Dialysis Transplantation, 28(1), 137-146. https://doi.org/10.1093/ndt/gfs379

Irazabal, MV, Eirin, A, Lieske, J, Beck, LH, Sethi, S, Borland, TM, Dillon, JJ, Nachman, PH, Nasr, SH, Cornell, LD, Leung, N, Cattran, DC & Fervenza, FC 2013, 'Low-and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy: A prospective study', Nephrology Dialysis Transplantation, vol. 28, no. 1, pp. 137-146. https://doi.org/10.1093/ndt/gfs379

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title = "Low-and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy: A prospective study",

abstract = "Background. Selective urinary biomarkers have been considered superior to total proteinuria in predicting response to treatment and outcome in patients with membranous nephropathy (MN). Methods. We prospectively tested whether urinary (U) excretion of retinol-binding protein (RBP), α1-microglobulin (α1M), albumin, immunoglobulinIgG and IgM and/or anti-phospholipase 2 receptor (PLA2R) levels could predict response to rituximab (RTX) therapy better than standard measures in MN. We also correlated changes in antibodies to PLA2R with these urinary biomarkers. Results . Twenty patients with MN and proteinuria (P) >5 g/24 h received RTX (375 mg/m 2 × 4) and at 12 months, 1 patient was in complete remission (CR), 9 were in partial remission (PR), 5 had a limited response (LR) and 4 were non-responders (NR). At 24 months, CR occurred in 4, PR in 12, LR in 1, NR in 2 and 1 patient relapsed. By simple linear regression analysis, UIgG at baseline (mg/24 h) was a significant predictor of change in proteinuria at 12 months (Δ urinary protein) (P = 0.04). In addition, fractional excretion (FE) of IgG, urinary alpha 1 microglobulin (Uα1M) (mg/24 h) and URBP (μg/24 h) were also predictors of response (P = 0.05, 0.04, and 0.03, respectively). On the other hand, UIgM, FEIgM, albumin and FE albumin did not predict response (P = 0.10, 0.27, 0.22 and 0.20, respectively). However, when Results were analyzed in relation to proteinuria at 24 months, none of the U markers that predicted response at 12 m could predict response at 24 m (P = 0.55, 0.42, 0.29 and 0.20). Decline in anti-PLA2R levels was associated with and often preceded urinary biomarker response but positivity at baseline was not a predictor of proteinuria response. Conclusions. The Results suggest that in patients with MN, quantification of low-, medium-and high-molecular-weight urinary proteins may be associated with rate of response to RTX, but do not correlate with longer term outcomes.",

keywords = "membranous nephropathy, rituximab, urinary proteins",

author = "Irazabal, {Maria V.} and Alfonso Eirin and John Lieske and Beck, {Laurence H.} and Sanjeev Sethi and Borland, {Timothy M.} and Dillon, {John J.} and Nachman, {Patrick H.} and Nasr, {Samih H.} and Cornell, {Lynn D.} and Nelson Leung and Cattran, {Daniel C.} and Fervenza, {Fernando C.}",

note = "Funding Information: Acknowledgments. The authors thank Mrs Lori Riess, for her outstanding role as research coordinator for the study. The study was supported by an unrestricted research grant from Genentech Inc., South San Francisco, CA, Biogen Idec, San Diego CA, the Department of Laboratory Medicine and Pathology, Mayo Clinic, the Fulk Family Foundation (FCF) and by a UL1-RR24150 grant to the Center for Translational Science Activities, Mayo Clinic. The results presented in this paper have not been published previously in whole or part, except in abstract format at the American Society of Nephrology meeting in Philadelphia, PA, November 2011.",

year = "2013",

month = jan,

doi = "10.1093/ndt/gfs379",

language = "English (US)",

volume = "28",

pages = "137--146",

journal = "Nephrology Dialysis Transplantation",

issn = "0931-0509",

publisher = "Oxford University Press",

number = "1",

}

TY - JOUR

T1 - Low-and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy

T2 - A prospective study

AU - Irazabal, Maria V.

AU - Eirin, Alfonso

AU - Lieske, John

AU - Beck, Laurence H.

AU - Sethi, Sanjeev

AU - Borland, Timothy M.

AU - Dillon, John J.

AU - Nachman, Patrick H.

AU - Nasr, Samih H.

AU - Cornell, Lynn D.

AU - Leung, Nelson

AU - Cattran, Daniel C.

AU - Fervenza, Fernando C.

N1 - Funding Information: Acknowledgments. The authors thank Mrs Lori Riess, for her outstanding role as research coordinator for the study. The study was supported by an unrestricted research grant from Genentech Inc., South San Francisco, CA, Biogen Idec, San Diego CA, the Department of Laboratory Medicine and Pathology, Mayo Clinic, the Fulk Family Foundation (FCF) and by a UL1-RR24150 grant to the Center for Translational Science Activities, Mayo Clinic. The results presented in this paper have not been published previously in whole or part, except in abstract format at the American Society of Nephrology meeting in Philadelphia, PA, November 2011.

PY - 2013/1

Y1 - 2013/1

N2 - Background. Selective urinary biomarkers have been considered superior to total proteinuria in predicting response to treatment and outcome in patients with membranous nephropathy (MN). Methods. We prospectively tested whether urinary (U) excretion of retinol-binding protein (RBP), α1-microglobulin (α1M), albumin, immunoglobulinIgG and IgM and/or anti-phospholipase 2 receptor (PLA2R) levels could predict response to rituximab (RTX) therapy better than standard measures in MN. We also correlated changes in antibodies to PLA2R with these urinary biomarkers. Results . Twenty patients with MN and proteinuria (P) >5 g/24 h received RTX (375 mg/m 2 × 4) and at 12 months, 1 patient was in complete remission (CR), 9 were in partial remission (PR), 5 had a limited response (LR) and 4 were non-responders (NR). At 24 months, CR occurred in 4, PR in 12, LR in 1, NR in 2 and 1 patient relapsed. By simple linear regression analysis, UIgG at baseline (mg/24 h) was a significant predictor of change in proteinuria at 12 months (Δ urinary protein) (P = 0.04). In addition, fractional excretion (FE) of IgG, urinary alpha 1 microglobulin (Uα1M) (mg/24 h) and URBP (μg/24 h) were also predictors of response (P = 0.05, 0.04, and 0.03, respectively). On the other hand, UIgM, FEIgM, albumin and FE albumin did not predict response (P = 0.10, 0.27, 0.22 and 0.20, respectively). However, when Results were analyzed in relation to proteinuria at 24 months, none of the U markers that predicted response at 12 m could predict response at 24 m (P = 0.55, 0.42, 0.29 and 0.20). Decline in anti-PLA2R levels was associated with and often preceded urinary biomarker response but positivity at baseline was not a predictor of proteinuria response. Conclusions. The Results suggest that in patients with MN, quantification of low-, medium-and high-molecular-weight urinary proteins may be associated with rate of response to RTX, but do not correlate with longer term outcomes.

AB - Background. Selective urinary biomarkers have been considered superior to total proteinuria in predicting response to treatment and outcome in patients with membranous nephropathy (MN). Methods. We prospectively tested whether urinary (U) excretion of retinol-binding protein (RBP), α1-microglobulin (α1M), albumin, immunoglobulinIgG and IgM and/or anti-phospholipase 2 receptor (PLA2R) levels could predict response to rituximab (RTX) therapy better than standard measures in MN. We also correlated changes in antibodies to PLA2R with these urinary biomarkers. Results . Twenty patients with MN and proteinuria (P) >5 g/24 h received RTX (375 mg/m 2 × 4) and at 12 months, 1 patient was in complete remission (CR), 9 were in partial remission (PR), 5 had a limited response (LR) and 4 were non-responders (NR). At 24 months, CR occurred in 4, PR in 12, LR in 1, NR in 2 and 1 patient relapsed. By simple linear regression analysis, UIgG at baseline (mg/24 h) was a significant predictor of change in proteinuria at 12 months (Δ urinary protein) (P = 0.04). In addition, fractional excretion (FE) of IgG, urinary alpha 1 microglobulin (Uα1M) (mg/24 h) and URBP (μg/24 h) were also predictors of response (P = 0.05, 0.04, and 0.03, respectively). On the other hand, UIgM, FEIgM, albumin and FE albumin did not predict response (P = 0.10, 0.27, 0.22 and 0.20, respectively). However, when Results were analyzed in relation to proteinuria at 24 months, none of the U markers that predicted response at 12 m could predict response at 24 m (P = 0.55, 0.42, 0.29 and 0.20). Decline in anti-PLA2R levels was associated with and often preceded urinary biomarker response but positivity at baseline was not a predictor of proteinuria response. Conclusions. The Results suggest that in patients with MN, quantification of low-, medium-and high-molecular-weight urinary proteins may be associated with rate of response to RTX, but do not correlate with longer term outcomes.

KW - membranous nephropathy

KW - rituximab

KW - urinary proteins

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SN - 0931-0509

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ER -

Low-and high-molecular-weight urinary proteins as predictors of response to rituximab in patients with membranous nephropathy: A prospective study

Abstract

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