Correspondence

secured. This patient commuted to and from the hospital on foot asan outpatient, and no bleeding complications occurred.8

The AVF was used for dialysis until living related kidneytransplantation was performed in October 2012. There is value inconsidering this option for dialysis access, avoiding the use ofmanmade objects.

Taiga Hara, MD, PhDTadashi Sofue, MD, PhD

Masakazu Kohno, MD, PhDKagawa University Hospital

Kagawa, JapanCorresponding author Taiga Hara: taiga@kms.ac.jp

AcknowledgementsFinancial Disclosure: The authors declare that they have no

relevant financial interests.

References1. National Kidney Foundation. KDOQI clinical practice guide-

lines for vascular access. Am J Kidney Dis. 1997;30(4 suppl 3):S150-S191.

2. Kumbar L, Karim J, Besarab A. Surveillance and monitoringof dialysis access. Int J Nephrol. 2012;2012:649735.

3. Pisoni RL, Arrington CJ, Albert JM, et al. Facility hemo-dialysis vascular access use and mortality in countries participatingin DOPPS: an instrumental variable analysis. Am J Kidney Dis.2009;53:475-491.

4. National Kidney Foundation. Clinical practice guidelines forvascular access. Am J Kidney Dis. 2006;48(4 suppl 13):S248-S273.

5. Gibson KD, Gillen DL, Caps MT, Kohler TR, Sherrard DJ,Stehman-Breen CO. Vascular access survival and incidence ofrevisions: a comparison of prosthetic grafts, simple autogenousfistulas, and venous transposition fistulas from the United StatesRenal Data System Dialysis Morbidity and Mortality Study.J Vasc Surg. 2001;34:694-700.

6. Flora HS, Chaloner EJ, Day C, Barker SG. The anklearterio-venous fistula: an approach to gaining vascular access forrenal haemodialysis. Eur J Vasc Endovasc Surg. 2001;22:376-378.

7. Kian K, Asif A. Status of research in vascular access fordialysis. Nephrol Dial Transplant. 2010;25:3682-3686.

8. Rim H, Shin HS, Jung YS. Arteriovenous fistula between theposterior tibial artery and great saphenous vein. Kidney Int.2012;81:925.

Originally published online October 21, 2013.� 2013 by the National Kidney Foundation, Inc.http://dx.doi.org/10.1053/j.ajkd.2013.08.020

RESEARCH LETTER

Anti–Phospholipase A2 Receptor Antibodies andMalignancy in Membranous Nephropathy

To the Editor:In developed countries, the vast majority (70%-80%) of mem-

branous nephropathy cases are idiopathic (iMN), whereas theremainder are due to various secondary causes, such as autoimmuneor infectious diseases, drugs, or malignancies.1 An association be-tween MN and malignancy has been described for decades and ac-counts forw10% of patients with MN.2,3 Previous studies reportedthat MN could appear as a paraneoplastic syndrome months andsometimes years before a (most often solid) tumor can be detected.3

Am J Kidney Dis. 2013;62(6):1221-1225

Differentiation between iMN and malignancy-associated MN(M-MN) is of clinical importance4 because treatment strategies differ.Recently, Beck et al5 identified a circulating antibody reactive

with the transmembrane glycoprotein M-type phospholipase A2

receptor (PLA2R) on the human podocyte. It has been demon-strated that antibodies to PLA2R (anti-PLA2R) are very specific foriMN, with anti-PLA2R detected in up to 82% of patients.6 Wehypothesized that testing for circulating anti-PLA2R could be auseful biomarker to differentiate iMN from M-MN.Between August 1980 and May 2011, we recruited 91 patients

with biopsy-proven MN without clinical suspicion of a secondarycause (Table 1). Serum samples were obtained at the time ofkidney biopsy. The presence of circulating anti-PLA2R wasdetermined by Western blot.5 Sixty-four (70%) patients haddetectable anti-PLA2R. Clinical data for these patients were ob-tained from medical records within the Limburg Renal Registry(see Item S1). Mean follow-up was 10.7 (0.1-30.9) years.Malignancies were observed in 16 (18%) patients, of which

15 were carcinomas. Four malignancies occurred during early(ie, ,2 years’ follow-up) and 12 during late follow-up (Item S1table a). All malignancies were detected during the past decade.The mean malignancy-free survival as calculated by Kaplan-Meierestimation was 23.36 1.6 (95% CI, 20.1-26.5) years. Malignancy-free survival was significantly shorter among patients with unde-tectable anti-PLA2R (P , 0.001; Fig 1).Two of 3 patients with early malignant disease and successful

tumor treatment entered remission in terms of proteinuria, whiledisease persisted in the other (Item S1 table a). Ten of 12 patientswith late malignant disease entered remission prior to the diagnosisof cancer. Two patients reached ESRD. The clinical significance ofanti-PLA2R status was analyzed by performing a multiple Coxregression. HRs for malignancy were 9.705 (95%CI, 2.324-40.537;P5 0.002) and 0.103 (95% CI, 0.025-0.430) for negative andpositive anti-PLA2R test results, respectively. In line with earlierstudies,7,8 age (HR, 1.080; 95% CI, 1.029-1.132; P 5 0.002) alsowas associated with malignant disease (Item S1 table b).Our study is the first indicating a prognostic role for anti-PLA2R

because a negative test result emerged as the most pronouncedprognostic factor for malignancy occurrence. However, late ma-lignancies also were observed in patients with anti-PLA2R. Qinet al6 described anti-PLA2R in 3 patients with M-MN. Remark-ably, all had persistent or recurrent proteinuria despite successfultumor treatment. In our study, most patients with late malignancyentered remission prior to the diagnosis of cancer, which suggeststhat the 2 diseases might have occurred coincidentally. Hence, wepostulate that these patients may have had 2 diseases, ie, iMN andan unrelated malignancy.Complementary to anti-PLA2R, circulating anti-podocyte anti-

bodies directed against cytoplasmic antigens have been found iniMN.9 At present, it is unknown whether patients with M-MNexpress such autoantibodies.Bjørneklett et al8 found an increased risk of developing cancer in

relation to the diagnosis of MN, which persists for many years. Twoexplanations were stated: (1) a long preclinical phase of the tumor inwhich kidney disease may be caused through immunologic mech-anisms, and (2) many patients with iMN are treated with immuno-suppressive therapy. In our study, we could not find an associationwith immunosuppressive therapy in our patients with M-MN.Of note, the anti-PLA2R–negative cohort likely represents a

mixture of distinct causes, only some of which may be associatedwith occult malignancy. Although serum samples were tested atthe time of biopsy, it is possible that a few of these patients couldhave had anti-PLA2R–associated disease and already enteredimmunologic remission. Staining the kidney biopsy specimens forthe PLA2R antigen or the predominance of the IgG4 subclasscould have given further evidence of the presence or absence ofanti-PLA2R-associated disease.10

1223

Table 1. Baseline Characteristics and Clinical Outcomes

Total (n 5 91)

PLA2R Antibody Test

PPositive (n 5 64) Negative (n 5 27)

Baseline characteristics

Male sex 63% 66% 56% 0.5

Age (y) 53.46 16.2 51.8 6 15.7 57.3 6 17.2 0.2

Anti-PLA2R 70%

Proteinuria (g/d) 7.16 4.7 7.36 5.1 6.6 6 3.4 0.9

Nephrotic-range proteinuria 77% 76% 81% 0.8

Serum creatinine (mg/dL) 1.26 0.9 1.36 1.0 1.1 6 0.7 0.06

eGFR (mL/min/1.73 m2) 1146 102 1186 119 1046 43 0.9

Follow-up

Duration (y) 10.7 6 7.5 11.3 6 8.1 9.2 6 5.8 0.4

Malignancy occurrence 18% 9% 37% 0.005

Malignancy-free survival (y) 23.3 6 1.6 26.1 6 1.7 14.96 2.3 ,0.001

Note: Continuous variables given as mean6SD. There were data missing for positive (proteinuria, n5 2; creatinine, n5 1; eGFR,

n5 3) and negative (eGFR, n5 1) subgroups.

Correspondence

In conclusion, our results suggest that patients with newlydiagnosed MN are unlikely to have an associated malignancy ifthey have detectable anti-PLA2R. This does not mean that theymay not develop a malignant tumor during extended follow-up,but it is likely that such tumors would be coincidental in an ag-ing population. However, the absence of anti-PLA2R at the time ofbiopsy increases the (small) risk of M-MN and merits more carefulsurveillance for an occult malignancy.

Sjoerd A.M.E.G. Timmermans, BSc,1 Rivka Ayalon, MD2

Pieter van Paassen, MD, PhD,1 Laurence H. Beck Jr, MD, PhD2

Henk van Rie,1 Joris J.J.M. Wirtz, MD, PhD3

Gaico H. Verseput, MD, PhD,4 Leon A. Frenken, MD, PhD5

David J. Salant, MD,2 and Jan Willem Cohen Tervaert, MD, PhD1

on behalf of the Limburg Renal Registry

Figure 1. Malignancy-free survival in patients with positive(n5 64) versus negative (n5 27) anti-PLA2R test results (log-rank P , 0.001). Mean values were 26.1 (95% CI, 22.7-29.4)and 14.9 (95% CI, 10.5-19.3) years, respectively. Dots arecensored patients.

1224

1Maastricht University Medical Center, Maastricht, the Netherlands2Boston University Medical Center, Boston, Massachusetts

3St Laurentius Hospital, Roermond, the Netherlands4Orbis Medical Center, Sittard-Geleen, the Netherlands

5Atrium Medical Center, Heerlen, the NetherlandsCorresponding author: jw.cohentervaert@maastrichtuniversity.nl

AcknowledgementsWe thank all participating nephrologists of the Limburg Renal

Registry: F. de Heer, M.M.E. Krekels, F. Stifft (Orbis MedicalCenter); S. Boorsma, W. Grave, J.J. Huitema (St LaurentiusHospital); N. ter Braak, S. Gaertner, J. Wolters (Atrium MedicalCenter); and J.P. Kooman, K.M.L. Leunissen, F.M. van der Sande(Maastricht University Medical Center). This work was supportedin part by NIH research grants DK090029 (D.J.S.) and DK097053to (L.H.B.) and a research grant from the NephCure Foundation(R.A.).

Supplementary MaterialItem S1: Detailed methods, malignancy during follow up, and

Cox regression analysis.Note: The supplementary material accompanying this article

(http://dx.doi.org/10.1053/j.ajkd.2013.07.019) is available atwww.ajkd.org

References1. Glassock RJ. The pathogenesis of idiopathic membranous

nephropathy: a 50-year odyssey. Am J Kidney Dis. 2010;56(1):157-167.

2. Brueggemeyer CD, Ramirez G. Membranous nephropathy: aconcern for malignancy. Am J Kidney Dis. 1987;9(1):23-26.

3. Burstein DM, Korbet SM, Schwartz MM. Membranousglomerulonephritis and malignancy. Am J Kidney Dis. 1993;22(1):5-10.

4. Kidney Disease: Improving Global Outcomes (KDIGO)Glomerulonephritis Work Group. Chapter 7: idiopathic membra-nous nephropathy. Kidney Int Suppl. 2012;2(2):186-197.

5. Beck LH, Bonegio RGB, Lambeau GR, et al. M-Typephospholipase A2 receptor as target antigen in idiopathic mem-branous nephropathy. N Engl J Med. 2009;361(1):11-21.

6. Qin W, Beck LH Jr, Zeng C, et al. Anti-phospholipase A2

receptor antibody in membranous nephropathy. J Am Soc Nephrol.2011;22(6):1137-1143.

Am J Kidney Dis. 2013;62(6):1221-1225

Correspondence

7. Lefaucheur C, Stengel B, Nochy D, et al. Membranous ne-phropathy and cancer: epidemiologic evidence and determinantsof high-risk cancer association. Kidney Int. 2006;70(8):1510-1517.

8. Bjorneklett R, Vikse BE, Svarstad E, et al. Long-term risk ofcancer in membranous nephropathy patients. Am J Kidney Dis.2007;50(3):396-403.

9. Murtas C, Bruschi M, Candiano G, et al. Coexistenceof different circulating anti-podocyte antibodies in membranousnephropathy. Clin J Am Soc Nephrol. 2012;7(9):1394-1400.

Am J Kidney Dis. 2013;62(6):1221-1225

10. Hoxha E, Kneissler U, Stege G, et al. Enhanced expressionof the M-type phospholipase A2 receptor in glomeruli correlateswith serum receptor antibodies in primary membranous nephrop-athy. Kidney Int. 2012;82(7):797-804.

Received February 26, 2013. Accepted in revised form July 23,2013. Originally published online September 9, 2013.

� 2013 by the National Kidney Foundation, Inc.http://dx.doi.org/10.1053/j.ajkd.2013.07.019

1225