Prognosis after a complete remission in adult patients with idiopathic membranous nephropathy

doi:10.1016/S0272-6386(99)70138-1

American Journal of Kidney Diseases

Volume 33, Issue 6, June 1999, Pages 1026-1032

https://doi.org/10.1016/S0272-6386(99)70138-1 Get rights and content

Abstract

This review of the long-term outcome after a complete remission of proteinuria includes 82 adult patients with biopsy-proven idiopathic membranous glomerulonephritis (IMGN), who represented 25% of the total cases (82 of 323 cases) of IMGN in our registry. Complete remission was defined as at least two consecutive follow-up evaluations showing proteinuria of 0.3 g/d or less of protein. Before remission, 70% of the patients had nephrotic-range proteinuria (61% at presentation, 9% during follow-up), and 30% were always subnephrotic (protein level < 3.5 g/d). Mean total observation time was 101 ± 56 months, with a postremission period of 69 ± 60 months. Seventy-one percent of the patients remained in remission and 29% relapsed. In the relapse group, 46% relapsed to nephrotic-range proteinuria and 54% relapsed to subnephrotic levels. The plasma creatinine level remained stable in 86% of the patients (71 of 82 patients) but became or remained elevated despite a period of complete remission in the remaining 14% (8 of 82 patients). No patient went on to end-stage renal disease. Seventy-seven percent of the patients had no specific treatment within 6 months of remission, whereas 23% had steroid therapy alone or in combination with an immunosuppressive agent. In a multivariate analysis, the factors that favored both remission and its durability were persistent lower levels of proteinuria and female sex. Complete remission indicates an excellent long-term prognosis in patients with IMGN, but relapses are common and, in a small percentage, chronic renal insufficiency occurs. Thus, our data suggest that even this group of patients should be monitored on a regular basis.

Section snippets

Patients and methods

The patients included on this study were culled from the records of our glomerulonephritis registry. This is a database, started in 1974, composed of all biopsy-proven cases of glomerulonephritis from the Toronto area. The initial clinical and biochemical data are compiled from doctors' records by one of the registrars on a standard form. Periodic prospective reviews of the patient's records are performed, with all pertinent renal clinical and laboratory data entered onto an on-site computer.

Results

The registry contained 448 cases of membranous glomerulonephritis. The exclusion of secondary cases reduced this number to 323 patients designated as having idiopathic membranous glomerulonephritis (IMGN). In this group, the mean age was 46.7 years (range, 18 to 83 years), with a man to woman distribution of 214 to 109, or a ratio of almost 2:1. We examined the patients in this cohort and sorted all patients with documented proteinuria of 0.3 g/d or greater of protein on one occasion (n = 114).

Discussion

In our registry, of 323 patients with IMGN, 82 patients (25%) had a complete remission. This is in the same range as most other large studies.5, 6, 10, 11, 13 Our results also agree with those of others5, 6, 9, 11 that a remission most frequently occurs within 3 years of presentation (median, 2.6 years), although the range is very wide, with more than one fourth in our series remitting beyond that time.

Most natural history studies group their complete remission patients into one category and

Acknowledgements

Acknowledgment: The authors thank the following nephrologists who contributed patients to the glomerulonephritis registry: Drs J. Bargman, R. Bear, M. Berall, W. Berry, C.J. Cardella, P. Chan, S. Chow, W.T.W. Clarke, E.H. Cole, S. Donnelly, I.O. Elkan, S.S.A. Fenton, M.B. Goldstein, G. Hercz, M.R. Hockley, M.D. Johnson, K. Kamel, S.Y. Karanicolis, A.G. Logan, M.E. Manuel, D. Mendelssohn, J. Miller, B.C. Nathoo, P.S.Y. Ng, O. Ojo, D.G. Oreopoulos, Y.A. Pierattos, V. Poulopoulos, Y. Pei, J.

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This is critical because the impact of treatment on these very delayed outcomes makes proving efficacy, especially with the high relapse rate post-treatment, very difficult.66 Complete remission of proteinuria in MN is known to be associated with excellent long-term kidney survival67,68 but was not accepted by health regulatory agencies until a recent review concluded that complete remission could be used as an surrogate outcome measure in treatment trials.69 Also on their review, they indicated partial remission was also associated with an improved outcome, but the data were weaker and less secure than with complete remission.
Idiopathic membranous nephropathy (INM) remains a common cause of the nephrotic syndrome in adults. The autoimmune nature of IMN was clearly delineated in 2009 with the identification of the glomerular-deposited IgG to be a podocyte receptor, phospholipase A2 receptor (PLA2R) in 70% to 75% of cases. This anti-PLA2R autoantibody, predominantly the IgG4 subclass, has been quantitated in serum using an enzyme-linked immunosorbent assay and has been used to aid diagnosis and monitor response to immunosuppressive therapy. In 2014, a second autoantigen, thrombospondin type 1 domain–containing 7A (THSD7A), was identified. Immunostaining of biopsy specimens has further detected either PLA2R or THSD7A antigen in the deposited immune complexes in 5% to 10% of cases autoantibody seronegative at the time of biopsy. Therefore, the term IMN should now be superseded by the term primary or autoimmune MN (AMN) (anti-PLA2R or anti-THSD7A positive) classifying ∼80% to 90% of cases previously designated IMN. Cases of secondary MN associated with other diseases show much lower association with these autoantibodies, but their true incidence in secondary cases still needs to be defined. How knowledge of the autoimmune mechanism and the sequential measurement of these autoantibodies is likely to change the clinical management and trajectory of AMN by more precisely defining its diagnosis, prognosis, and treatment is discussed. Their application early in the disease course to new and old therapies will provide additional precision to AMN management. We also review innovative therapeutic approaches on the horizon that are expected to lead to our ultimate goal of improved patient care in A(I)MN.
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Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in white adults. It is defined by the presence of subepithelial immune deposits localized between the podocyte and the glomerular basement membrane (GBM) on electron microscopy (EM) examination. Clinical course is variable: Although up to 30% of patients are said to undergo spontaneous remission, greater than 40% of patients will eventually develop end-stage renal disease (ESRD). The discovery of two major podocytes antigens, the M-type phospholipase A2 receptor 1 (PLA2R1) and the thrombospondin type-1 domain-containing 7A (THSD7A) protein, have revolutionized our understanding of the pathogenesis of human MN. Approximately 75% of patients with active disease have circulating anti-PLA2R autoantibodies, and up to 10% of the patients with MN that are anti-PLA2R negative have antibodies against THSD7A. Mounting evidence suggests that quantification and follow-up of anti-PLA2R levels can help in accessing prognosis and evaluating response to treatment. Genetic studies are elucidating predisposing factors for development of the disease. Further research into the antigen-autoantibody systems and the role of antibody spreading and identification of additional antigenic targets is likely to contribute to improving understanding of the pathophysiology and treatment of patients with MN.
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Immunosuppressive therapy plays an important role in patients with high-risk idiopathic membranous nephropathy (IMN), but the therapeutic modality is still controversial.
Corticosteroid combined with oral tacrolimus (TAC, target trough blood concentration of 4–8 ng/mL), intravenous cyclophosphamide (CYC, 750 mg/m²/mo, or oral mycophenolate mofetil (MMF, 1.5–2.0 g/d) were randomly administered for 9 months to 90 patients with IMN proved with renal biopsy with severe proteinuria (>8 g/d).
Eighty-six of the 90 patients completed the study. The total remission (TR) rates in the TAC group were significantly higher than those in the CYC group at 1 and 2 months (p < 0.01) and the MMF group at 1–4 months (p < 0.01). The TR rates were 83.3%, 73.3%, and 70.0% in the TAC, CYC, and MMF groups at 9 months (p = 0.457), and there were no significant differences between the three groups from 5 to 9 months. Furthermore, TAC reduced proteinuria and ameliorated hypoalbuminemia more quickly and effectively than CYC and MMF. We observed no severe adverse events in the three groups.
Tacrolimus combined with corticosteroid had tolerable adverse effects and induced the remission of IMN more effectively and more rapidly. This is the first prospective randomized cohort study to compare three different therapies in patients at high risk for IMN. It provides strong evidence for choosing optimal treatment for patients with IMN. The long-term efficacy of this treatment strategy should be investigated further in future studies.
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: For the Glomerulonephritis Registry Group, Toronto, Canada.

: Address reprint requests to Daniel C. Cattran, MD, The Toronto Hospital, 101 College St, CCRW3-884, Toronto, Ontario, M5G 1L7 Canada. E-mail: [email protected]

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Original InvestigationPrognosis after a complete remission in adult patients with idiopathic membranous nephropathy

Abstract

Section snippets

Patients and methods

Results

Discussion

Acknowledgements

Kidney Int

Kidney Int

Am J Kidney Dis

Kidney Int

Am J Kidney Dis

Natural history, clinical course and morphological evolution of membranous nephropathy

Nephrol Dial Transplant

Membranous glomerulonephritis: Evolution of clinical and pathologic features

Ann Intern Med

Long-term outcome of idiopathic membranous nephropathy with nephrotic syndrome

Nephrol Dial Transplant

Long-term survival in idiopathic membranous glomerulonephritis: Can the course be clinically predicted?

Clin Nephrol

Survival in idiopathic membranous glomerulonephritis

Clin Nephrol

Prognosis of untreated patients with idiopathic membranous nephropathy

N Engl J Med

Clinical and morphologic evolution of idiopathic membranous nephropathy

Clin Nephrol

The natural history of renal function in untreated idiopathic membranous glomerulonephritis in adults

Clin Nephrol

The evolution of membranous glomerulonephritis reconsidered: New insights from a study of relapsing disease

Clin Nephrol

Long-term prognosis of idiopathic membranous glomerulonephritis

Am J Med

Original Investigation
Prognosis after a complete remission in adult patients with idiopathic membranous nephropathy