Treatment Patterns Among Adults and Children With Membranous Nephropathy in the Cure Glomerulonephropathy Network (CureGN)

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Abstract

Introduction

The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Glomerulonephritis recommend that patients with membranous nephropathy (MN) at risk for progression receive immunosuppressive therapy (IST), usually after 6 months of observation. A cyclophosphamide (CYC) or calcineurin inhibitor (CNI)–based regimen is recommended as first-line IST. However, the extent to which KDIGO recommendations are adopted in practice remains largely unknown.

Methods

We evaluated prescribing practice among patients with primary MN (diagnosed 2010–2018) enrolled in the Cure Glomerulonephropathy Network (CureGN) cohort study. We also evaluated the availability of testing for phospholipase A2 receptor (PLA2R) in the contemporary era.

Results

Among 361 patients (324 adults and 37 children) with MN who were IST-naïve at biopsy and had at least 6 months of follow-up, 55% of adults and 58% of children initiated IST <6 months after biopsy. Of these, 1 in 5 had no indication for (i.e., urine protein-to-creatinine ratio [uPCR] <4 g/g) or an apparent contraindication to (i.e., an estimated glomerular filtration rate [eGFR] <30 ml/min per 1.73 m ²) IST. As first-line IST, half of treated patients received either CYC (16% of adults; 0% of children) or a CNI (40% and 46%, respectively), whereas 1 in 5 received corticosteroid monotherapy (20% and 27%, respectively) and 1 in 6 rituximab (15% and 15%, respectively). More than 80% of surveyed centers had access to PLA2R testing.

Conclusion

These findings suggest that providers are not aware of, or lack confidence in, current KDIGO guidelines for MN. Treatment patterns observed in this cohort might critically inform the drafting of planned updates to KDIGO guidelines.

Graphical abstract

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Most cited references 16

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Primary Membranous Nephropathy.

William G. Couser (2017)

Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and 20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN. Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels (15%), or serum anti-THSD7A (3%-5%). The remaining 10% without demonstrable anti-PLA2R/THSd7A antibody or antigen likely have PMN probably secondary to a different, still unidentified, anti-podocyte antibody. Considerable clinical and experimental data now suggests these antibodies are pathogenic. Clinically, 80% of patients with PMN present with nephrotic syndrome and 20% with non-nephrotic proteinuria. Untreated, about one third undergo spontaneous remission, especially those with absent or low anti-PLA2R levels, one-third progress to ESRD over 10 years, and the remainder develop nonprogressive CKD. Proteinuria can persist for months after circulating anti-PLA2R/THSD7A antibody is no longer detectable (immunologic remission). All patients with PMN should be treated with supportive care from the time of diagnosis to minimize protein excretion. Patients with elevated anti-PLA2R/THSD7A levels and proteinuria >3.5 g/d at diagnosis, and those who fail to reduce proteinuria to <3.5 g after 6 months of supportive care or have complications of nephrotic syndrome, should be considered for immunosuppressive therapy. Accepted regimens include steroids/cyclophosphamide, calcineurin inhibitors, and B cell depletion. With proper management, only 10% or less will develop ESRD over the subsequent 10 years.

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Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up.

Karine Dahan, Hanna Debiec, Emmanuelle Plaisier … (2017)

Randomized trials of rituximab in primary membranous nephropathy (PMN) have not been conducted. We undertook a multicenter, randomized, controlled trial at 31 French hospitals (NCT01508468). Patients with biopsy-proven PMN and nephrotic syndrome after 6 months of nonimmunosuppressive antiproteinuric treatment (NIAT) were randomly assigned to 6-month therapy with NIAT and 375 mg/m(2) intravenous rituximab on days 1 and 8 (n=37) or NIAT alone (n=38). Median times to last follow-up were 17.0 (interquartile range, 12.5-24.0) months and 17.0 (interquartile range, 13.0-23.0) months in NIAT-rituximab and NIAT groups, respectively. Primary outcome was a combined end point of complete or partial remission of proteinuria at 6 months. At month 6, 13 (35.1%; 95% confidence interval [95% CI], 19.7 to 50.5) patients in the NIAT-rituximab group and eight (21.1%; 95% CI, 8.1 to 34.0) patients in the NIAT group achieved remission (P=0.21). Rates of antiphospholipase A2 receptor antibody (anti-PLA2R-Ab) depletion in NIAT-rituximab and NIAT groups were 14 of 25 (56%) and one of 23 (4.3%) patients at month 3 (P<0.001) and 13 of 26 (50%) and three of 25 (12%) patients at month 6 (P=0.004), respectively. Eight serious adverse events occurred in each group. During the observational phase, remission rates before change of assigned treatment were 24 of 37 (64.9%) and 13 of 38 (34.2%) patients in NIAT-rituximab and NIAT groups, respectively (P<0.01). Positive effect of rituximab on proteinuria remission occurred after 6 months. These data suggest that PLA2R-Ab levels are early markers of rituximab effect and that addition of rituximab to NIAT does not affect safety.

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A Proposal for a Serology-Based Approach to Membranous Nephropathy.

An S De Vriese, Richard Glassock, Karl A. Nath … (2017)

Primary membranous nephropathy (MN) is an autoimmune disease mainly caused by autoantibodies against the recently discovered podocyte antigens: the M-type phospholipase A2 receptor 1 (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A). Assays for quantitative assessment of anti-PLA2R antibodies are commercially available, but a semiquantitative test to detect anti-THSD7A antibodies has been only recently developed. The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN. Levels of anti-PLA2R antibodies and possibly, anti-THSD7A antibodies tightly correlate with disease activity. Low baseline and decreasing anti-PLA2R antibody levels strongly predict spontaneous remission, thus favoring conservative therapy. Conversely, high baseline or increasing anti-PLA2R antibody levels associate with nephrotic syndrome and progressive loss of kidney function, thereby encouraging prompt initiation of immunosuppressive therapy. Serum anti-PLA2R antibody profiles reliably predict response to therapy, and levels at completion of therapy may forecast long-term outcome. Re-emergence of or increase in antibody titers precedes a clinical relapse. Persistence or reappearance of anti-PLA2R antibodies after kidney transplant predicts development of recurrent disease. We propose that an individualized serology-based approach to MN, used to complement and refine the traditional proteinuria-driven approach, will improve the outcome in this disease.

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Author and article information

Contributors

Louis-Philippe Laurin

Journal

Journal ID (nlm-ta): Kidney Int Rep

Journal ID (iso-abbrev): Kidney Int Rep

Title: Kidney International Reports

Publisher: Elsevier

ISSN (Electronic): 2468-0249

Publication date PMC-release: 16 September 2019

Publication date Collection: December 2019

Publication date (Electronic): 16 September 2019

Volume: 4

Issue: 12

Pages: 1725-1734

Affiliations

[1 ]Division of Nephrology, Stanford University School of Medicine, Palo Alto, California, USA

[2 ]Division of Nephrology, Department of Pediatrics, University of Michigan, Ann Arbor, Michigan, USA

[3 ]Division of Nephrology, Columbia University, New York, New York, USA

[4 ]Division of Nephrology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

[5 ]Division of Nephrology, Department of Pediatrics, LSU Health and Children’s Hospital, New Orleans, Louisiana, USA

[6 ]UNC Kidney Center, Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, North Carolina, USA

[7 ]Center for Pediatric Nephrology, Cleveland Clinic Children’s, Cleveland, Ohio, USA

[8 ]Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA

[9 ]Children’s Mercy Hospital, Kansas City, Missouri, USA

[10 ]Division of Pediatric Nephrology, Department of Pediatrics, University of Minnesota Masonic Children’s Hospital, Minneapolis, Minnesota, USA

[11 ]Division of Pediatric Kidney Services and Hypertension, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon, USA

[12 ]Division of Nephrology, Department of Pediatrics, Children’s Hospital of Philadelphia, Wynnewood, Pennsylvania, USA

[13 ]JW Riley Hospital for Children, Indiana University School of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA

[14 ]Division of Nephrology, Department of Pediatrics, New York University School of Medicine, New York, New York, USA

[15 ]Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA

[16 ]Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA

[17 ]Division of Pediatric Nephrology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA

[18 ]Division of Kidney, Urologic, and Hematologic Diseases, The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA

[19 ]Center for Translational Research, Children’s National Health System, Washington, DC, USA

[20 ]Division of Nephrology, Maisonneuve-Rosemont Hospital, Department of Medicine, University of Montreal, Montreal, Quebec, Canada

Author notes

[∗ ] Correspondence: Louis-Philippe Laurin, Division of Nephrology, Maisonneuve-Rosemont Hospital, 5415, Boulevard de l’Assomption, Montreal (Quebec), Canada H1T 2M4. louis-philippe.laurin@ 123456umontreal.ca

Article

Publisher ID: S2468-0249(19)31483-4

DOI: 10.1016/j.ekir.2019.09.005

PMC ID: 6895579

PubMed ID: 31844809

SO-VID: 49f5108b-40be-4e5b-95f6-c4e051c8f0e4

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 23 May 2019

Date revision received : 21 August 2019

Date accepted : 2 September 2019

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