Minimal change nephrotic syndrome and classical Hodgkin's ...

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original article

& 2006 International Society of Nephrology

Minimal change nephrotic syndrome and classical Hodgkin’s lymphoma: Report of 21 cases and review of the literature V Audard1, F Larousserie2, P Grimbert1, M Abtahi1, J-J Sotto3, A Delmer4, F Boue5, D Nochy6, N Brousse2, R Delarue7, P Remy1, P Ronco8, D Sahali1, P Lang1,9 and O Hermine7,9 1

Department of Nephrology, Henri Mondor Hospital, Paris 12 University, Creteil, Paris, France; 2Department of Pathology, Necker-Enfants Malades Hospital, Paris, France; 3Department of Haematology, CHU de Grenoble, Paris, France; 4Department of Haematology Hotel Dieu Hospital, Paris, France; 5Department of Internal Medicine; Antoine Beclere Hospital, Clamart, Paris, France; 6 Department of Pathology, Hospital Europeen Georges Pompidou, Paris, France; 7Department of Haematology, Necker Enfants Malades Hospital, Paris, France and 8Department of Nephrology, Tenon Hospital, Paris, France

Minimal change nephrotic syndrome (MCNS) is described as a paraneoplastic manifestation of classical Hodgkin’s lymphoma (cHL). We reassessed the pathophysiological and clinical significance of this association. A retrospective study was performed to evaluate a cohort of adult patients who developed MCNS and cHL. Twenty-one patients recruited in 15 French centers were analyzed. cHL was associated with inflammatory and general symptoms in most cases. The morphological subtype was predominantly nodular sclerosis (71.4%). MCNS appeared before the diagnosis of lymphoma in eight patients (38.1%) and in this case, it was characterized by a nephrotic syndrome (NS) frequently resistant (50%) or dependent (12.5%) to steroid treatment. Interestingly, diagnosis (3–120 months after MCNS) and effective treatment of the hemopathy were associated with the disappearance of the MCNS. cHL was diagnosed before MCNS in nine patients (42.9%), and in this case, glomerulopathy was associated with cHL relapse in 55.5% of cases. In four patients (19%), the two diseases occurred simultaneously. Extensive immunohistochemical study of lymph nodes was performed in eight patients and did not reveal particular features. In conclusion, MCNS associated with cHL is frequently dependent or resistant to steroid regimen, but remission of NS is obtained with the cure of lymphoma. Kidney International (2006) 69, 2251–2260. doi:10.1038/sj.ki.5000341; published online 3 May 2006 KEYWORDS: minimal change nephrotic syndrome; classical Hodgkin’s lymphoma; Th2 cytokines; steroid-resistant nephrotic syndrome

Correspondence: P Lang, Service de Ne´phrologie, Hoˆpital Henri Mondor, Cre´teil, France. O Hermine, Service d’He´matologie, Hoˆpital Necker Enfants Malades, Paris, France. E-mails: [email protected] or [email protected] 9

These authors contributed equally to this work

Received 9 September 2005; revised 29 November 2005; accepted 3 January 2006; published online 3 May 2006 Kidney International (2006) 69, 2251–2260

Although it is well recognized that many types of glomerulonephritis are associated with classical Hodgkin’s disease (cHL), the incidence of nephrotic syndrome (NS) is low and estimated at about 0.5 to 1%.1 In two largest studies of 1700 Hodgkin’s disease patients, two glomerulopathies were significantly associated with cHL, amyloidosis (0.1% of cases) and minimal change nephrotic syndrome (MCNS) (0.4% of cases).2,3 MCNS is a clinical and pathological entity defined by selective proteinuria and hypoalbuminemia that occurs in the absence of cellular glomerular infiltrates or immunoglobulin deposits.4 Although pathogenesis of MCNS is unclear, many observations point to an immune origin.5 Currently, it is hypothesized that MCNS is a consequence of immune cell dysfunction that may lead to release of a glomerular permeability factor.6 A close relationship between the courses of cHL and MCNS has been reported in patients who suffer from both diseases, particularly in that remission of MCNS occurs after successful treatment of cHL, suggesting that MCNS is a paraneoplastic syndrome in the context of cHL.7 The pathogenesis of this association remains poorly understood and the underlying molecular link is still unknown. Alteration in T-lymphocyte functions that occurs in some patients with cHL might be incriminated.5,7,8 Recent advances in pathophysiological understanding of both diseases led us to reassess the significance of this association, by revisiting clinical, histological, laboratory, and therapeutic data. We conducted a retrospective study of 21 adult patients who developed both diseases. Patients were separated into three groups, based on the interval between onset of the two diseases (MCNS occurring before, after, or simultaneously with cHL). The aim of this study was to identify some features specific to this association, which may provide new insights into the pathophysiology of these diseases. 2251

original article

V Audard et al.: Minimal change NS and cHL

RESULTS

Two patients (pt7 and pt12) initially steroid-sensitive became steroid-resistant, following a new episode of MCNS relapse. Overall, five patients (pt6, pt7, pt11, pt12, and pt15) were steroid-resistant and two (pt8 and pt20) steroid-dependent (7/18 ¼ 38.8%). In six of these seven patients, the effective treatment of cHL upon diagnosis, established after 3–120 months of steroid dependency or resistance, was associated with remission of MCNS. The patient 15 was still in complete response of cHL. Three patients (14.3%) did not receive steroid therapy to treat MCNS. Chemotherapy alone induced remission of MCNS in two cases (pt13 and pt21). Spontaneous remission of NS occurred in the last patient (pt17). Cyclosporin A was started in four patients (pt7, pt11, pt12, and pt15) because of steroid-resistant or -dependent NS, and was ineffective in all cases. Five patients (23.8%) (pt2, pt7, pt10, pt12, and pt18) had MCNS relapse between 12 months and 10 years after the first episode of NS. None of the patients had progressed toward end-stage renal failure at the end of the follow-up (mean follow-up 6.3 years). We did not observe any correlations between the stage or the subtypes of cHL and remission of NS (P ¼ 1 and 0.26, respectively). Moreover, the risk of relapse of MCNS was not associated with the stage and subtypes of cHL (P ¼ 0.47 and 0.53, respectively).

The natural history of cHL and MCNS, including clinical, histological, laboratory, and therapeutic characteristics, was analyzed in 21 patients, 14 male and seven female patients. MCNS characteristics

Clinical characteristics of MCNS at presentation are presented in Table 1. The average age at diagnosis was 28.5 years (range 16–54 years). Every patient manifested all features of NS. A renal biopsy was performed in 19 patients and histological examination was not performed in one patient because of anticoagulant therapy (pt5) and in another patient because of remission of a pure NS within 5 days after the institution of cHL treatment (pt2). Results of kidney biopsy are listed in Table 2. Five patients presented, on renal tissue biopsy, a minor interstitial infiltrate (pt7, pt11, pt15, pt18, and pt21), whereas kidney biopsy showed in two other patients (pt1 and pt19) an uncommon intense inflammatory interstitial infiltrate during the course of MCNS. In these two cases, immunophenotyping of this infiltrate did not show lymphomatous infiltration but revealed a T-cell reactive infiltrate mainly composed of CD4 þ and CD8 þ T cells. Response to treatment and outcome of MCNS are listed in Table 3. Initial treatment consisted in steroids in 18 patients. Eleven patients received exclusively steroid treatment, whereas steroids were included in chemotherapy in five patients (pt2, pt4, pt14, pt16, and pt19). In the last two patients (pt1 and pt3), steroid treatment was started in parallel to chemotherapy. Thirteen of 18 patients treated with steroids went into remission (72.2%), whereas three (pt6, pt11, and pt15) were steroid-resistant (16.7%) and two (pt8 and pt20) were steroid-dependent (11.1%) after initial therapy. Glomerular disease went into remission in all patients treated simultaneously for the two diseases.

cHL characteristics

Clinical presentation, response, and outcome of cHL are summarized in Table 4. Lymphoma was discovered during management of steroid-resistant NS in two patients (pt6 and pt11). In other cases, the diagnosis resulted from etiological investigation of systemic symptoms such as prolonged fever (pt9, pt13, and pt17) and peripheral lymphadenopathies (n ¼ 16), including four patients with simultaneous MCNS (pt1, pt2, pt3, and pt4).

Table 1 | Baseline clinical characteristics of patients with MCNS Patients Men/women Age at onset (years) Mean delay MCNS/cHL cHL/MCNS Urinary protein (g/day) Serum albumin (g/l) Lower than 20 g/l Microscopic hematuria Renal insufficiency (4120 mmol/l) Hypertension Thrombotic event

MCNS before cHL (N=8)

MCNS and cHL simultaneously (N=4)

MCNS after cHL (N=9)

Total (N=21)

Men: 6 Women: 2 26.6 28.8 months (range 3–120 months)

Men: 4 Women: 0 25

Men: 4 Women: 5 33.8 59 months (range 2–156 months)

Men: 14 Women: 7 28.5 (range 16–54)

10.5 14 7/8 2/8 0/8 1/8 1/8

11.7 15.5 4/4 1/4 0/4 2/4 1/4

10.4 17.2 7/9 1/9 2/9 0/9 0/9

10.9 (range 3–30) 15.6 (range 7–28) 18/21 4/21 (19%) 2/21 (9.5%) 3/21 (14.3%) 2/21 (9.5%)

cHL, classical Hodgkin’s lymphoma; Ig, immunoglobin; MCNS, minimal change nephrotic syndrome.

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Table 2 | Histological findings in 19 of 21 patients with MCNS at presentation Patients

Glomeruli

Tubules

Vessels

Interstitium

Immunofluorescence

MCNS before cHL (N=8) Seven kidney biopsies MCNS and cHL simultaneously (N=4) Three kidney biopsies MCNS after cHL (N=9) Nine kidney biopsies

Normal 7/7

Normal 7/7

Normal 7/7

Normal 3/3

Normal 3/3

Normal 3/3

Normal 5/7 Interstitial infiltrate 2/7 Normal 2/3

Negative 4/7 IgM 3/7 Negative 3/3

Normal 9/9

Normal 8/9 Necrotizing tubulopathy 1/9

Normal 7/9 Endarteritis, fibrosis: 2/9

Interstitial infiltrate 1/3 Normal 5/9 Interstitial infiltrate 4/9

Negative 9/9

cHL, classical Hodgkin’s lymphoma; MCNS, minimal change nephrotic syndrome.

Table 3 | Treatment (initial and during relapse) and outcome of patients with MCNS Patients Initial treatment with steroids

Initial steroid responsiveness

Initial treatment without steroids




Total (N=21)

8/8

4/4 2/4 (included in chemotherapy 2/4 (in parallel to chemotherapy)

6/9 3/6 (included in chemotherapy 3/6 (without chemotherapy)

18/21 5/18 (included in chemotherapy)

Remission: 4/4 (100%) Resistant: 0/4 (0%) Dependent: 0/4 (0%) 0/4

Remission: 4/6 (66.6%) Resistant: 1/6 (16.7%) Dependent: 1/6 (16.7%) 3/9 2/3 chemotherapy without steroids 1/3 spontaneously remission Remission 2/2

1/4 (25%) Remission: 1/1 (100%)

1/9 (11.1%) Remission 1/1 (100%)

Remission: 5/8 (62.5%) Resistant: 2/8 (25%) Dependent: 1/8 (12.5%) 0/8

Outcome during treatment without steroids Relapse 3/8 (37.5%) Responsiveness to steroids during Remission: 1/3 (33.3%) relapse Resistant 2/3 (66.7%) Outcome of resistant or dependent Remission (5/5) patients (initial or during a relapse) with chemotherapy

No cHL relapse 1/2 Remission: 1/2

11/18 alone 2/18 (in parallel to chemotherapy) Remission: 13/18 (72.2%) Resistant: 3/18 (16.7%) Dependent: 2/18 (11.1%) 3/21 (14.3%)

5/21(23.8%) Remission 3/5 (60%) Resistant 2/5 (40%) Remission: 6/7 corresponding to 100% of patients achieved chemotherapy


Histological examination showed nodular sclerosis Hodgkin’s lymphoma in 15 cases (71.4%) and mixed cellularity in five cases (23.8%). In one case, disease exclusively involved bone marrow (pt7). Extensive immunohistochemical study of lymph nodes was performed in eight patients and the results are listed in Table 5 (see below). Systemic symptoms (B) were noted in 15 cases (71. 4%). Inflammatory markers were present (b) in 19 patients (90.5%). Human immunodeficiency virus serology was negative in all tested patients (n ¼ 17). The outcome for each patient is shown in Table 6. After induction treatment, all patients were in remission. cHL relapse occurred in five patients (pt13, pt14, pt16, pt19, and pt20) within a period ranging from 15 months to 13 years. One patient died because of septic shock during his second lymphoma relapse (pt13). Description MCNS and cHL according to the interval between onset of the two diseases

Three groups of patients were defined according to the interval between the onset of the two diseases. Kidney International (2006) 69, 2251–2260

MCNS and cHL occurring simultaneously. Four patients (19%, pt1–pt4) presented cHL simultaneously with NS. Nodular sclerosing subtype was found in four patients and detailed immunohistochemical study was performed in two patients (Table 5). We were unable to demonstrate T or B immunophenotype of Hodgkin and Reed–Sternberg (HRS) cells in these patients. The cellular infiltrate in lymphomatous tissue contained no neoplastic inflammatory cells, as is observed in cHL without MCNS. Only one patient presented an inflammatory infiltrate in the renal interstitium and no immunoglobulin (Ig)M deposit was observed in the mesangium (Table 2). All these patients were in complete remission from both diseases after chemotherapy (containing steroids in two cases or combined with a steroid-free regimen in the two others) (Tables 3 and 4). In one patient, isolated NS recurred 10 years later without evidence of cHL relapse (pt2) (Table 6). None of the patients had cHL relapse in this subgroup. MCNS preceding cHL (at least 2 months between the occurrence of the two diseases). This population consisted

in eight patients (38.1%) (pt5–pt12). Median interval 2253

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Table 4 | Clinical characteristics of patients with cHL at presentation Patients Men/women Age at onset (years) Clinical presentation




Total (N=21)

Men: 6 Women: 2 28.7 Isolated lymph node involvement: 5/8 (62.5%)

Men: 4 Women: 0 25 Lymph node involvement associated with NS: 4/4 (100%)

Men: 4 Women: 5 28 Isolated lymph node involvement: 7/9 (17.7%)

Men: 14 Women: 7 27.2 (range 17–65) Isolated lymph node involvement: 12 (57.1%)

Others: 2/9 (22.3%)

Associated with NS: 4 (19%)

Isolated NS resistant to steroids: 2/8 (25%) Others: 1/8 (12.5%)

Isolated NS: 2 (9.5%) Others: 3 (14.3%)

Ann Arbor staging

I: 1 II: 4 III: 2 IV: 1

I: 1 II: 1 III: 2 IV: 0

I: 1 II: 6 III:1 IV: 1

I: 3 (14.3%) II: 11 (52.4%) III: 5 (23.8%) IV: 2 (9.5%)

WHO classification

Nodular sclerosis: 7/8 Exclusive bone marrow involvement: 1/8

Nodular sclerosis: 4/4

Nodular sclerosis: 4/9 Mixed cellularity: 5/9

Nodular sclerosis: 15 (71.4%) Mixed cellularity: 5 (23.8%) Exclusive bone marrow involvement: 1 (4.8%)

Systemic symptoms A/B

A: 2 B: 6

A: 1 B: 3

A: 3 B: 6

A: 6 (28.6%) B: 15 (71.4%)

Inflammatory syndrome a/b

A: 0 b: 8

a: 0 b: 4

a: 2 b: 7

A: 2 (9.5%) b: 19 (90.5%)

Complete remission: 8/8

Complete remission: 4/4

Complete remission : 9/9

Complete remission: 21

0/8

0/4

5/9

5/21

Initial induction treatment responsiveness Relapse

cHL, classical Hodgkin’s lymphoma; MCNS, minimal change nephrotic syndrome; NS, nephrotic syndrome.

between the two diseases was 28.8 months (range 3–120 months) (Table 1). Renal biopsy revealed inflammatory interstitial infiltrate in two cases (pt7 and pt11) and IgM deposits in three cases (pt5, pt9, and pt11). No correlation between these findings and the time to onset of cHL (Table 2) or steroid resistance was identified. Patients in this subgroup showed a poor response to the steroid regimen as compared to patients with MCNS alone (Tables 3 and 6). Thus, NS was steroid-resistant at the first onset in two patients (pt6 and pt11), and steroid-dependent in one patient (pt8). It was steroid-sensitive in five patients (pt5, pt7, pt9, pt10, and pt12), but two of them experienced NS relapse (pt7 and pt12) and became steroid-resistant (Table 6). Cyclosporin A was given to three patients (pt11, pt12, and pt7) to control the NS (Table 3), but failed to induce remission and NS persisted up to the diagnosis of cHL, which was made respectively 2.5 months, 15 months, and 6.5 years after introduction of cyclosporin A. At cHL diagnosis, cyclosporin A was discontinued. Interestingly, effective treatment of cHL with chemotherapy was associated in all cases with complete resolution of MCNS (Table 6). MCNS relapse alone, without concomitant active cHL, occurred in one patient (pt12). 2254

Immunophenotyping of HRS cells did not reveal evidence for a T-cell origin of the neoplastic cells (Table 5). MCNS appearing in the course of cHL (at least 2 months between the occurrence of the two diseases). Nine patients

fulfilled these criteria (42.5%) (pt13–pt21). The average interval between the two diseases was 59 months (range 2–156 months). Remission of cHL was seen in all patients following chemotherapy. After induction treatment, five patients (55.5%) experienced cHL relapse, which closely preceded or occurred simultaneously with MCNS (pt13, pt14, pt16, pt19, and pt20) (Tables 4 and 6). In three other patients (pt15, pt17, and pt18), MCNS occurred without cHL relapse (Table 6). In one patient (pt21), MCNS occurred between the first and second course of chemotherapy, which resulted in complete remission of NS. In contrast to other subgroups, histological analyses of lymph nodes showed a mixed cellularity but not a sclerosing subtype in four patients (pt14, pt16, pt17, and pt19). Extensive phenotyping was performed in two patients (pt20 and pt21) and did not reveal evidence for a T-cell origin of HRS cells (Table 5). Specific treatment of MCNS consisted in steroid therapy in six patients. Steroid therapy was included within the Kidney International (2006) 69, 2251–2260

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Table 5 | Immunohistochemical study of lymphomatous tissue from eight patients Patients

Type

CD30

CD15

CD20

CD3

CD8

TiA1

LMP

EBER

+ + + +

+ + + +

+

+ +

MCNS and cHL simultaneously Pt1 NS Pt3 NS

+ +

+ +

cHL before MCNS Pt20 Pt21

NS NS

+ +

+ +

+

+

Patients

CD20

CD3

CD8

TiA1

HRS cells: , negative; +, positive MCNS before cHL Pt6 Pt8 Pt9 Pt10

NS NS NS NS

Granzyme

CD15

Cellular background: , no cellular subset stained; +, cellular subset stained present MCNS before cHL Pt6 Pt8 Pt9 Pt10

+ + + +

+ + + +

+ + + +

+ + +

+

+ + +

MCNS and cHL simultaneously P1 + P3 +

+ +

+ +

+ +

+

cHL before MCNS P20 P21

+ +

+ +

+ +

+ +

+ +

+ +

cHL, classical Hodgkin’s lymphoma; HRS, Hodgkin and Reed–Sternberg; MCNS, minimal change nephrotic syndrome; NS, nodular sclerosis subtype.

chemotherapy regimen in three patients (pt14, pt16, and pt19), with a complete remission of both diseases in all cases (Table 6). In three others (pt15, pt18, and pt20), exclusive steroid therapy was initiated without chemotherapy, but only one patient (pt18) achieved a complete response (Table 6). One patient (pt20) was steroid-dependent, whereas another (pt15) was steroid- and cyclosporine-dependent (Table 6). Interestingly, in the first case (pt20), successful treatment of cHL relapse (13 months after the onset of MCNS) was associated with complete remission of NS. Among the last three patients, one presented spontaneous remission of MCNS (pt17) and the two others (pt13, pt21) were successfully treated by chemotherapy without steroids, with complete remission of both diseases. DISCUSSION

In this retrospective French survey, we have identified 21 adult patients who presented both MCNS and cHL. Although there are strong suggestions of a link between MCNS and cHL, only small-scale studies have been published and do not provide a clear picture with respect to diagnosis, outcome, and treatment. Furthermore, no extensive studies of the pathological features of this association have been performed. Kidney International (2006) 69, 2251–2260

We deliberately excluded patients suffering from nodular lymphocyte-predominant Hodgkin’s lymphoma (HL), which represents approximately 5% of all cases of Hodgkin’s disease, as these two entities do not have an identical molecular basis.9 Moreover, pediatric cases of this association have been described, but we exclusively studied patients older than 16 years.10 Temporal relationship between onset of NS and cHL

In the largest reported meta-analysis, Eagen and Lewis11 noted that 12 out of 26 patients had cHL and MCNS simultaneously, whereas NS preceded lymphoma in three cases and manifested after lymphoma in 11 cases. In only five cases, the interval between the occurrence of the two diseases was above 12 months. By contrast, our results indicate a median time of 15 months (range 0–156). Only four patients (19%) concurrently developed MCNS and cHL. Nevertheless, five additional patients simultaneously experienced cHL relapse and NS. The longest between-disease interval reported in the literature is 42 months.12 Here, we report two patients, in whom the interval was 120 and 156 months, suggesting that this association may appear with a long lag time. This discrepancy is likely owing to the fact that previous reports are based on small series, which in most cases report 2255

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Table 6 | Outcome of 21 patients with MCNS and cHL Start followup (years)

Interval between the two diseases (months)

MCNS remission

MCNS and cHL occurring simultaneously Pt1 1990 0 Yes

cHL remission Yes

Pt2

1990

0

Yes

Yes

Pt3

1999

0

Yes

Yes

Pt4

1999

0

Yes

Yes

MCNS before cHL Pt5 1997 Pt6 1995

10 3

Yes Steroid resistance (for 3 months) Steroid and cyclosporine resistance after the relapse (for 84 months) Steroid dependence (for 7 months) Yes Yes Steroid and cyclosporine resistance (for 5 months) Steroid and cyclosporine resistance after the relapse (for 18 months)

Yes Yes

Pt7

1991

120

Yes

Pt8

1999

7

Pt9 Pt10 Pt11

1995 1999 2001

30 25 5

Pt12

1998

29

cHL before MCNS Pt13 1986

15

Yes

Yes Yes

Yes Yes Yes Yes Yes

Pt14

1973

156

Yes

Pt15

1977

104

Pt16

1983

39

Steroid and cyclosporine Yes resistance Yes Yes

Pt17 Pt18 Pt19

1984 1989 1985

17 67 104

Yes Yes Yes

Yes Yes Yes

Pt20

1997

30

Yes

Pt21

2002

2

Steroid dependence after the relapse (for 13 months) Yes

Yes

MCNS relapse (delay in months after the first episode of MCNS)

cHL relapse (delay in months after the first episode of cHL)

No

No

2000

Yes (120)

No

2002

No

No

2002

No

No

2002

Not done Complete remission Complete remission

No No

No No

2002 2002

Yes (36)

No

2002

Complete remission Not done Not done Complete remission Complete remission

No

No

2002

No Yes (16) No

No No No

2002 2002 2002

Yes (11)

No

2002

No

Yes (15)

1990

No

Yes (156)

1987

no

No

1998

No

Yes (39)

1990

No Yes (78) No

No No Yes (104)

1988 2002 1998

No

Yes (43)

2002

No

No

2002

Outcome of MCNS with chemotherapy Complete remission Complete remission Complete remission Complete remission

Complete remission, Complete remission Not done Complete remission Not done Not done Complete remission Complete remission Complete remission after the second course of chemotherapy

End of follow-up (years)


only concomitant cases. One could also argue that in such cases, MCNS and cHL are not related. However, although not present at diagnosis of cHL 156 months earlier (pt14), the occurrence of MCNS concomitantly with cHL relapse strongly suggests a link between the two diseases. In this case, it is reasonable to hypothesize that either MCNS was not diagnosed at the first occurrence of cHL or that the biology of the tumor cells may have changed during relapse. In another case (pt7), MCNS occurred 120 months before the 2256

onset of cHL. Interestingly, in this patient, MCNS only resolved with chemotherapy of cHL, suggesting a link between the two diseases. Of note, MCNS that occurred a long time before cHL is usually resistant to and/or dependent on steroid or cyclosporine therapy. This observation raises two questions. First, should investigations to search for cHL be performed in therapy-resistant MCNS? Second, is cHL occurring after a long history of resistant MCNS related to immunosuppression? Kidney International (2006) 69, 2251–2260


Risk factors for development of MCNS during the course of cHL

It has been reported that MCNS is more frequently associated with cHL exhibiting a mixed cellularity histological subtype.13 In contrast, our study shows that the nodular sclerosing subtype is predominant (71.4%). In order to shed light on pathophysiology of this association, immunohistochemical examination of lymph node tissue biopsy specimens was extensively performed in eight patients. Although HRS cells seem to derive from germinal center B cells,14 studies of T-cell receptor-b and Ig gene rearrangements of micro-manipulated HRS cells in cHL suggest that, in rare cases, HRS cells may derive from T cells.15,16 Our immunohistochemical analysis suggests that cHL tumor cells do not exhibit a T-cell phenotype. Moreover, no excess of reactive T cells was observed when compared to cHL without MCNS (Table 5 and data not shown). It has been reported that Epstein–Barr virus is present in the lesions of about 40% of cHL cases,17,18 a frequency that is similar to ours (37.5%). As in other studies, we were not able to identify a particular subgroup of patients at high risk of MCNS, with respect to age, sex, or stage of the disease. In contrast, systemic symptoms were found in approximately 72% of cases, a frequency higher than that observed in cHL without MCNS (40% of cases).17 Furthermore, cHL with MCNS is also characterized by high prevalence of inflammatory syndrome, which was present in 90.5% of case. Both these findings were not previously reported and may result from an excessive production of inflammatory cytokines. Several reports have shown that patients with B symptoms had higher serum interleukin (IL)-6 levels than asymptomatic patients.19 A possible link between the presence of B symptoms and MCNS is hard to establish. First, in contrast to amyloidosis, MCNS is not a kidney disease associated with inflammation. Second, the serum level of IL-6 is normal in classical MCNS,6 and it has been demonstrated that prolonged overexpression of IL-6 in transgenic animal leads to glomerulonephritis histologically characterized by mesangial proliferation.20 Inflammatory status is a poor predictor of cHL in MCNS patients because, in most cases, MCNS, regardless of its etiology, is associated with disturbance of inflammatory proteins. Characteristics and treatment of MCNS associated with cHL

The characteristics of cHL-associated MCNS do not differ from those of classical glomerular disease. An interstitial infiltrate was observed in seven patients and was apparently neither associated with the risk of developing cHL nor with steroid resistance. In our study, NS recurred in five cases and was predictive of cHL relapse in three cases (pt7, pt10, and pt12) with potentially long intervals (9, 102, and 7 months, respectively). Therefore, patients with NS and a history of cHL should be investigated for lymphoma relapse. Kidney International (2006) 69, 2251–2260

original article

Effective treatment of cHL is generally associated with simultaneous remission of NS whatever the therapeutic strategy, which included chemotherapy, field irradiation, and lymph node surgery, thus confirming the paraneoplastic nature of this glomerulopathy.2,21–24 As in our study, 100% of patients efficiently treated for HL in Eagen’s study were also in remission from NS.11 Moreover, in our study, all patients treated by chemotherapy for MCNS (when the two diseases occurred simultaneously, during a cHL relapse or in patient with steroid-dependent or resistant NS) went into remission of NS after successful treatment of Hodgkin’s disease whatever the type of chemotherapy regimen used, and even if steroids were not used. In fact, as previously described by others, our findings suggest that MCNS remission is rather conditioned by the response of lymphoma to chemotherapy than by the type of treatment proposed for cHL. Therefore, the prognosis of MCNS seems to be directly related to the prognosis of cHL. Likewise, Stephan et al.10 described a case where ineffective chemotherapy for cHL was associated with persistence of proteinuria. We observed that patients who presented with MCNS preceding cHL displayed a high frequency of steroid resistance (50%). To our knowledge, our study reports the first cases of cyclosporine-resistant NS preceding cHL.25 We could hypothesize that HRS or environmental tumor cells may secrete a glomerular permeability factor before the onset of cHL. The resolution of MCNS after cHL treatment emphasizes this hypothesis. When MCNS occurs after cHL, steroids constitute the first line of treatment after excluding the HL relapse. Nevertheless, even in the absence of cHL relapse, chemotherapy (MOPP regimen) led to the remission from recurrent MCNS in patients with a history of cHL associated with steroidresistant MCNS.26 Pathogenic hypothesis T-cell function similarities between the two diseases.

Our extensive immunohistochemical study of lymphomatous tissues was performed in eight patients in order to investigate whether or not a T-cell origin of HRS cells was associated with MCNS. We failed to demonstrate HRS expression of markers that are typical for T cell. Therefore, although we did not perform an analysis for Ig and T-cell receptor rearrangements, it is likely that in our group of patients, no special origin of HRS is associated with MCNS. However, it remains to be determined whether tumor cells and/or infiltrating cells including T cells may produce a putative circulating factor that impairs the glomerular filtration barrier. In agreement with the hypothesis of T-cell impairment, many similarities concerning T-cell function during the two diseases have been documented. Clinical observations and experimental data suggest that both diseases are associated with an expansion of T cells polarized towards a Th2 phenotype.6,14 This might explain why patients with MCNS and 2257

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Hodgkin’s disease often exhibit a defect in delayedtype hypersensitivity response, suggesting an abnormal Th1-dependent cellular immunity.6,27 Moreover, it has recently been shown that T lymphocytes from MCNS display downregulation of the IL-12 receptor b2 subunit during relapse, suggesting that T cells of MCNS are driven early towards a Th2 phenotype.28 Role of cytokines. Some clinical and histopathological features, characteristics of cHL, have been linked to an abnormal production of cytokines.29 Th2 cytokines seem to be involved in both diseases, particularly IL-13. In situ hybridization has shown that IL-13 and its receptor (IL-13-Ra1) are constitutively expressed by HRS cells.30 Furthermore, neutralization of anti-IL-13 antibody inhibits proliferation of the Hodgkin’s disease-derived cell line HDLM-2.29 Yap et al.31 have demonstrated increased production of IL-13 mRNA in T lymphocytes of patients with MCNS during MCNS relapse. Interestingly, the IL-4 and IL-13 receptors are expressed by podocytes in various glomerular diseases, raising the possibility that IL-13 might contribute to the pathophysiology of proteinuria.32 Van Den Berg et al.32 have demonstrated that IL-4 and IL-13 increase transcellular ion transport, but they do not affect the permeability to macromolecules. Role of NF-kB overexpression. Most cytokines whose levels are thought to be increased during active MCNS and cHL and downregulated during remissions are partly or predominantly regulated by the nuclear factor-kB (NF-kB) proteins.33 During MCNS relapses, peripheral mononuclear cells, including T cells, exhibit high NF-kB binding activity, which returns to basal levels during remissions.34 Consistent NF-kB overexpression in HRS cells in cHL lymph nodes has also been reported.35,36 Several mechanisms have been implicated in this constitutive activation: clonal deleterious mutations in the IkBa gene, and constitutive stimulation of receptors such as CD40, RANK, and LMP1.14,17,37–39 As HL is associated with upregulation of NF-kB, independently of kidney disease, an additional as yet undetermined mechanism may explain the cooccurrence of MCNS.

cHL characterization All patients underwent a histological study of the lymph nodes or extranodal lesions to confirm the diagnosis of cHL. The diagnosis of cHL required the finding of HRS cells in an appropriate cellular background of reactive leukocytes, histiocytes, and in some cases fibrosis.40 The histological subtypes were defined according to the WHO classification of HL (nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted cHL).41 The modified (Cotswolds revision) Ann Arbor staging system was detailed for each patient.42 Systemic symptoms at presentation consisting in fever, weight loss, and night sweats were recorded (A: absence/B: presence). Laboratory parameters of inflammatory syndrome including C-reactive protein, sedimentation rate, and fibrinogen levels were assessed (a: absence/b: presence). Treatment of HL was, in most cases, based on combined treatment with radiotherapy and classical chemotherapy of cHL.43 The first-line chemotherapy regimen used in our patients included ABVD regimen (adriamycin, bleomycine, vinblastine, dacarbazine) in nine patients (pt2, pt3, pt4, pt5, pt6, pt12, pt13, pt17, and pt21), MOPP regimen (mechloretamin, oncovin, procarbazin, prednisone) in three patients (pt15, pt16, and pt19), MOPP/ABV regimen in four patients (pt1, pt9, pt11, and pt18), and BEACOPP regimen (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazin, prednisone, gencitabizine) in two patients (pt7 and pt8). OPPA regimen (oncovin, prednisone, procarbazin, doxorubucin) and EBVP regimen (epirubicin, bleomycin, vinblastine, prednisone) were started in two patients (pt10 and pt20, respectively). The last patient received Velbe alone for the treatment of cHL (pt14). Partial remission was defined by persistence of tumor mass and/ or clinical and/or laboratory symptoms after induction therapy. Relapse was confirmed by histological examination. Eight patients with biopsy-proven cHL were extensively reviewed histologically to characterize the immunophenotype of HRS and background cells. Lymph nodes were fixed in 4% formaldehyde or in Bouin solution. Immunohistochemistry was performed for all the antigens using the avidin–biotin technique after antigen retrieval with monoclonal antibodies against CD3 (1/250), CD20 (1/200), CD15 (1/50), CD8 (1/200), from Dakocytomation (Trappes, France), CD30 (1/50), TiA1 (1/100) from Immunotech (Marseille, France), and Granzyme (1/50) from Monosan (Perrayen yvelines, France). Epstein–Barr virus was detected in paraffin-embedded sections by immunohistochemistry using a monoclonal anti-latent membrane protein1 antibody and/or by in situ hybridization with fluorescein isothiocyanate-labeled EBV RNA -specific oligonucleotides.

Conclusion

Characterization of minimal change NS Diagnostic criteria for MCNS were based on clinical and laboratory symptoms and in most cases on results of histological examination of kidney specimens. NS was clinically defined by urinary protein above 3 g/24 h and serum albumin below 30 g/l. Histologically, MCNS was defined by the presence of minimal change glomerular lesions and absence of segmental sclerosis by optical microscopy, negative immunofluorescence, or presence of IgM deposits in the mesangium.44 Although MCNS therapy for children is well standardized,13 there is no consensus for treatment in adult patients. However, most were treated according to the protocol of Glassok.45

Our study confirms the link between MCNS and cHL, and strongly suggests that chemotherapy is the best treatment of MCNS associated with cHL. Although rare and still unexplained, this association may shed light on the pathophysiology and treatment of both diseases. MATERIALS AND METHODS Patient population Twenty-one patients older than 16 years of age suffering from cHL and MCNS were identified and followed between 1973 and 2004 in 15 nephrology and hematology centers at French hospitals. 2258


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Complete remission was defined by the return of urine protein to the normal range of less than 0.3 g/24 h, and relapse as reappearance of proteinuria for more than 1 week. Steroid dependence was defined as proteinuria relapse when the steroid dose was tapered. Steroid resistance was defined as the persistence of NS after an average of 10 weeks of prednisolone or prednisone treatment (range 8–12 weeks) at 1 mg/kg/day. Initial steroid treatment consisted in oral prednisolone or prednisone (1 mg/kg/day) or intravenous pulses of methylprednisolone (when included in the chemotherapy). Impaired renal function was defined as a serum creatinine level exceeding 120 mmol/l. Statistical analysis In order to compare clinical data and outcome of renal disease, statistical analysis was performed using the Fisher’s exact test for categorical data and the Mann–Whitney test for non-parametric variables. A P-value o0.05 was considered statistically significant.

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ACKNOWLEDGMENTS

We acknowledge Dr Beaufils (Department of Pathology, la Pitie´ Salpeˆtrie`re Hospital), Dr Mougenot (Department of Pathology, Tenon Hospital), Professor Piette (Department of Internal Medicine, La Pitie´ Salpeˆtrie`re Hospital), Dr Melin and Professor Chanard (Department of Nephrology, Centre Hospitalier Universitaire de Reims), Dr Amaria (Department of Nephrology, Centre Hospitalier du Havre), Professor Rossert (Department of Nephrology, HEGP Hospital), Dr Guigonis and Professor Bensman (Department of Nephrology, Trousseau Hospital), Professor Lemeur (Department of Nephrology, Centre Hospitalier Universitaire de Limoges), Professor Esnault (Department of Nephrology, Centre Hospitalier Universitaire de Nantes), Professor Oksenhendler (Department of haematology Saint Louis Hospital), Professor Desablens (department of Haematology, Centre Hospitalier Universitaire d’Amiens), Professor Baumelou (Department of Nephrology, La Pitie´ Salpeˆtrie`re Hospital), Dr Beaufils (Department of Internal Medicine, Centre Hospitalier Ge´ne´ral de Saint Germain en Laye), and Dr Meeus and Dr Kourilsky (Department of Nephrology, Centre Hospitalier d’Evry) for their help in the care and follow-up of the patients. REFERENCES 1. Moulin B, Chantrel F, Petitjean P, Ronco P. Glomerular lesions in chronic lymphoproliferative disorders. J Nephrol 1995; 8: 20–26. 2. Plager J, Stutzman L. Acute nephrotic syndrome as a manifestation of active Hodgkin’s Disease. Report of four cases and review of the literature. Am J Med 1971; 50: 56–66. 3. Kramer P, Sizoo W, Twiss EE. Nephrotic syndrome in Hodgkin’s disease. Report of five cases and review of the literature. Neth J Med 1981; 24: 114–119. 4. Habib R, Kleinknecht C. The primary nephrotic syndrome of childhood. Classification and clinicopathologic study of 406 cases. Pathol Annu 1971; 6: 417–474. 5. Shalhoub RJ. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 1974; 2: 556–560. 6. Grimbert P, Audard V, Remy P et al. Recent approaches to the pathogenesis of minimal-change nephrotic syndrome. Nephrol Dial Transplant 2003; 18: 245–248. 7. Ronco PM. Paraneoplastic glomerulopathies: new insights into an old entity. Kidney Int 1999; 56: 355–377. 8. Alpers CE, Cotran RS. Neoplasia and glomerular injury. Kidney Int 1986; 30: 465–473. 9. Diehl V, Sextro M, Franklin J et al. Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin’s disease and lymphocyte-rich classical Hodgkin’s disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin’s Disease. J Clin Oncol 1999; 17: 776–783. 10. Stephan JL, Deschenes G, Perel Y et al. Nephrotic syndrome and Hodgkin disease in children: a report of five cases. Eur J Pediatr 1997; 156: 239–242.


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