COMMENTARY

Membranoproliferative glomerulonephritis:the times they are a-changin’

Jan Willem Cohen Tervaert

Received: 1 July 2013 / Accepted: 30 July 2013 / Published online: 28 August 2013

� Japanese Society of Nephrology 2013

Keywords Membranoprolifertive

glomerulonephritis � Cryoglobulins � Hepatitis C �C3 glomerulonephritis � Dense deposit disease �Monoclonal gammopathy of renal significance

In 1964, the singer-songwriter Bob Dylan sang ‘The times

they are a-changin’ announcing that ‘the order is rapidly

fadin’. Anno 2013, pathologists and nephrologists may

have the same experience when reading the current issue of

‘Clinical and Experimental Nephrology’.

In a seminal paper, Hiramatsu et al. [1] describe their

long-term experience in diagnosing membranoproliferative

glomerulonephritis (MPGN) and conclude that it is time to

abandon the ‘old’ classification (MPGN type I, II, III) and

to start with a new classification based on new patho-

physiological insights that were made during recent years.

MPGN accounts for *2–3 % of renal biopsies; patients

most frequently present with a nephrotic syndrome [2].

MPGN was in the past classified according to histological

and ultrastructural findings showing mesangial interposi-

tion, duplication of glomerular basement membranes and

subendothelial, mesangial, intramembranous, and/or sub-

epithelial deposits. Immunofluorescence studies revealed

C3 deposits with or without immunoglobulin deposits.

During the last decade, it was appreciated that patho-

physiological mechanisms clearly differ between those

patients with MPGN and C3 alone compared to those with

MPGN and the combination of immunoglobulin and C3

deposits in the renal biopsy. Hence, a new classification of

MPGN has been proposed and patients are either classified

as having immunoglobulin-mediated disease, driven by

classical complement pathway activation, or as having non-

immunoglobulin-mediated disease, driven by alternative

complement pathway activation (reviewed in 3). Whereas

most attention went to the new category of non-immu-

noglobulin-mediated C3 glomerulonephritis (C3GN)

(either dense deposit disease, CFHR5 nephropathy, C3GN

related to other genetic complement abnormalities, auto-

immune C3GN, monoclonal gammopathy-associated

C3GN, or idiopathic C3GN) [3–5], the time has now come

to also reconsider the other form—immunoglobulin-medi-

ated MPGN.

Immunoglobulin-mediated or immune complex-associ-

ated MPGN can occur during chronic viral infections such

as hepatitis B or C, chronic bacterial infections such as

shunt nephritis and endocarditis, and during protozoal

infections such as schistosomiasis and malaria [4]. Immu-

noglobulin-mediated MPGN can also be associated with

liver diseases, lymphoproliferative and/or autoimmune

diseases such as Sjogren’s syndrome and systemic lupus

erythematosus. Finally, a true ‘ıdiopathic’ form of MPGN

exists which is nowadays considered to be extremely rare.

Hiramatsu et al. [1] studied 53 patients with MPGN

diagnosed in one single center over a period of 18 years. Of

these, 18 patients had MPGN secondary to lymphoprolif-

erative disorders, autoimmune diseases, (post) infectious

GN, or liver disease due to alcohol abuse or hepatitis B.

Four of the remaining 35 patients had C3GN, whereas 31

patients had immunoglobulin-mediated MPGN. Of these

This comment refers to the article available at

doi:10.1007/s10157-013-0810-z.

J. W. Cohen Tervaert (&)

Maastricht University, P.O. Box 5800, 6202 AZ Maastricht,

The Netherlands

e-mail: jw.cohentervaert@maastrichtuniversity.nl

J. W. Cohen Tervaert

Sint Franciscus Gasthuis, Rotterdam, The Netherlands

123

Clin Exp Nephrol (2014) 18:1–3

DOI 10.1007/s10157-013-0852-2

latter patients, 12 had hepatitis C (HCV) infection or cir-

culating cryoglobulins or both. Immunofluorescence stud-

ies of renal biopsies from these patients revealed IgM

staining in 75 % of cases and only rarely dominant IgG

staining. In contrast, in the nineteen cryoglobulin- and

HCV-negative patients, 89 % of the biopsies showed IgG

staining, whereas dominant IgM staining was only infre-

quently observed. Based on these findings, it is hypothe-

sized that immunoglobulin-mediated MPGN should be

classified into a cryoglobulin-positive form with IgM-

dominant depostions and a cryoglobulin-negative form

with IgG-dominant depostions. Frequently, this latter form

is associated with ‘monoclonal gammopathy of renal sig-

nificance’ and labelled proliferative GN with monoclonal

IgG deposits (PGNMID) [6–8].

This newly proposed classification, where patients are

classified as either C3GN (DDD or C3GN) or immuno-

globulin-mediated MPGN (either cryoglobulin-induced or

monoclonal gammopathy-induced) is simple and appeal-

ing. However, there are some caveats when patients are

classified based on the renal biopsy only. Firstly, immu-

noglobulin deposits may be present in C3GN biopsies.

Whether these deposits are considered to be ‘pauci-

immune’ or significant is subjective. Secondly, patients

with cryoglobulinemia sometimes have IgA and IgG

deposits instead of IgM (and IgG) deposits. Thirdly,

patients with a monoclonal gammopathy may present with

IgM-dominant depostions in the renal biopsy [9].

Importantly, this new classification requires an optimal

collaboration between clinician, pathologist and laboratory

specialist. Immunological tests that should be evaluated in

these patients are complement levels (CH50, C3, and C4),

IgM rheumatoid factor, hepatitis C serology, protein elec-

tropheresis of serum and urine, measurement of free light

chains in serum and urine, and cryoglobulins.

In particular, testing for cryoglobulins is a challenge for

the laboratory since the pre-analytical conditions must be

well controlled [10]. This implicates that the blood should

be collected in pre-warmed tubes (37�) and transported at

37� to the laboratory. Furthermore, the blood coagulation

and the centrifugation should occur at 37�. Interestingly, it

appears that in the UK only 35 % of laboratories perform

cryoglobulin detection procedures as proposed [11].

Therefore, false negative results for cryoglobulins may be

frequently observed.

Finally, a short discussion on the usefulness of the

classification for therapy is needed.

Although at present no definite therapies have been

proven to be universally beneficial, appealing treatment

policies based on pathophysiological mechanisms are now

being evaluated [3]. For instance, in patients with C3GN,

replacement of factor H (by plasma exchange) or therapy

directed at C5 (e.g., eculizumab) are potential options.

Otherwise, in patients with PGNMID, therapy should be

directed against the plasma cells that produce the mono-

clonal antibodies. Unfortunately, standard treatment pro-

tocols do not yet exist. Corticosteroids often in

combination with cyclophosphamide or other alkylating

agents, thalidomide, lenalidomide, rituximab and bortezo-

mib have all been used with variable rates of success. In

selected patients, autologous stem cell transplantation may

be considered [8].

When MPGN is induced by cryoglobulinemic vasculitis,

therapy must be instituted according to the underlying

cause. The therapy of (really) essential (hepatitis C nega-

tive) mixed cryoglobulinaemia is a combination of high-

dose corticosteroids, cyclophosphamide, and plasmaphe-

resis. After a remission is induced (generally after

3–6 months) cyclophosphamide can be stopped and aza-

thioprine or mycophenolate mofetil maintenance therapy

started and subsequently continued for 18–24 months.

Mycophenolate mofetil may also be used as an alternative

to cyclophosphamide for induction therapy. However,

complete clinical and immunological responses are only

obtained in 60–70 % of patients. Recently, cyclophospha-

mide has been succesfully replaced by rituximab. Impor-

tantly, since rituximab infusion is sometimes associated

with an exacerbation of cryoglobulin-related symptoms, it

is adviced to use the lymphoma dose: 4 weekly infusions of

375 mg/m2 and not the rheumatoid arthritis dose (2 weekly

infusions of 1,000 mg). Results obtained in patients with

(really) essential mixed cryoglobulinemic vasculitis treated

with Rituximab are comparable to the results obtained with

cyclophosphamide. Patients with relapses of their cryo-

globulinemic vasculitis, however, do better during treat-

ment with rituximab as compared to treatment with

cyclophosphamide [12].

Patients with hepatitis C-associated cryoglobulinaemic

vasculitis should be treated with an optimal antiviral reg-

imen with at least pegylated IFN-alpha and ribavirin. With

this regimen a virological response is obtained in 50–70 %

of patients. For patients with a hepatitis C genotype 1 a

protease inhibitor should probably be added (e.g., telapre-

vir or boceprevir). Other drugs with pangenotypic proper-

ties such as sofosbuvir are currently tested and will

probably in the near future be combined with interferon

and ribavirin to treat hepatitis C genotypes other than

genotype 1. Finally, other interesting new drugs are cur-

rently being tested as therapy for hepatitis C. One of them

is miraversen, a locked nucleic acid modified DNA

phosphorothioate antisense oligonucleotide that sequesters

mature miR-122 in a stable heteroduplex thereby inhibiting

the stability and propagation of hepatitis C [13].

In patients with HCV-positive cryoglobulin-induced

MPGN, rituximab should be used during the first month of

therapy before anti-virals are started. To control severe

2 Clin Exp Nephrol (2014) 18:1–3

123

and/or life-threatening manifestations in these patients, a

short course of corticosteroids in combination with plas-

mapheresis may be used.

References

1. Hiramatsu R, Hoshino J, Suwabe T, Sumida K, Hasegawa E,

Yamanouchi M, Hayami N, Sawa N, Takaichi K, Ohashi K, Fujii

T, Ubara Y Membranoproliferative glomerulonephritis and cir-

culating cryoglobulins. Clin Exp Nephrol. 2013. doi:10.1007/

s10157-013-0810-z.

2. van Paassen P, van Breda Vriesman PJ, van Rie H, Tervaert JW.

Signs and symptoms of thin basement membrane nephropathy: a

prospective regional study on primary glomerular disease-the

limburg renal registry. Kid Int. 2004;66(3):909–13.

3. Bomback AS, Appel GB. Pathogenesis of the C3 glomerulopa-

thies and reclassification of MPGN. Nat Rev Nephrol.

2012;8(11):634–42. doi:10.1038/nrneph.2012.213.

4. Sethi S, Fervenza FC, Zhang Y, Nasr SH, Leung N, Vrana J,

Cramer C, Nester CM, Smith RJ. Membranoproliferative glo-

merulonephritis and C3 glomerulopathy: resolving the confusion.

Clin J Am Soc Nephrol. 2011;6(5):1009–17. doi:10.2215/CJN.

07110810.

5. Zand L, Kattah A, Fervenza FC, Smith RJ, Nasr SH, Zhang Y,

Vrana JA, Leung N, Cornell LD, Sethi S. C3 glomerulonephritis

associated with monoclonal gammopathy: a case series. Am J

Kidney Dis. 2013;. doi:10.1053/j.ajkd.2013.02.370.

6. Nasr SH, Satoskar A, Markowitz GS, Valeri AM, Appel GB,

Stokes MB, Nadasdy T, D’Agati VD. Proliferative glomerulo-

nephritis with monoclonal IgG deposits. J Am Soc Nephrol.

2009;20(9):2055–64. doi:10.1681/ASN.2009010110.

7. Guiard E, Karras A, Plaisier E, Duong Van Huyen JP, Fakhouri F,

Rougier JP, Noel LH, Callard P, Delahousse M, Ronco P. Pat-

terns of noncryoglobulinemic glomerulonephritis with monoclo-

nal Ig deposits: correlation with IgG subclass and response to

rituximab. Clin J Am Soc Nephrol. 2011;6(7):1609–16. doi:10.

2215/CJN.10611110.

8. Leung N, Bridoux F, Hutchison CA, Nasr SH, Cockwell P,

Fermand JP, Dispenzieri A, Song KW, Kyle RA, International

Kidney and Monoclonal Gammopathy Research Group. Mono-

clonal gammopathy of renal significance: when MGUS is no

longer undetermined or insignificant. Blood. 2012;120(22):

4292–5. doi:10.1182/blood-2012-07-445304.

9. Audard V, Georges B, Vanhille P, Toly C, Deroure B, Fakhouri

F, Cuvelier R, Belenfant X, Surin B, Aucouturier P, Mougenot B,

Ronco P. Renal lesions associated with IgM-secreting monoclo-

nal proliferations: revisiting the disease spectrum. Clin J Am Soc

Nephrol. 2008;3(5):1339–49. doi:10.2215/CJN.01600408.

10. Tervaert JW, Van Paassen P, Damoiseaux J. Type II cryoglob-

ulinemia is not associated with hepatitis C infection: the dutch

experience. Ann NY Acad Sci. 2007;1107:251–8.

11. Vermeersch P, Gijbels K, Marien G, Lunn R, Egner W, White P,

Bossuyt X. A critical appraisal of current practice in the detec-

tion, analysis, and reporting of cryoglobulins. Clin Chem.

2008;54(1):39–43.

12. Terrier B, Krastinova E, Marie I, Launay D, Lacraz A, Belenotti

P, de Saint-Martin L, Quemeneur T, Huart A, Bonnet F, Le

Guenno G, Kahn JE, Hinschberger O, Rullier P, Diot E, Lazaro E,

Bridoux F, Zenone T, Carrat F, Hermine O, Leger JM, Mariette

X, Senet P, Plaisier E, Cacoub P. Management of noninfectious

mixed cryoglobulinemia vasculitis: data from 242 cases included

in the cryovas survey. Blood. 2012;119(25):5996–6004.

13. Liang TJ, Ghany MG. Drug therapy: current and future therapies

for hepatitis C virus infection. N Engl J Med. 2013;368:1907–17.

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