Organized deposits
Non-organized deposits
Type-1 cryoglobulinemic GN
Light and heavy chain deposition disease (LHCDD)
Immunotactoid GN
Proliferative GN with monoclonal Ig deposits(PGNMID)
Light and heavy chain amyloidosis (Fibrillary GN)
Nonproliferative GN with monoclonal Ig deposits
In type 1 cryoglobulinemia, a membranoproliferative glomerulonephritis (MPGN) with macrophage infiltration is the most characteristic histologic pattern and the deposits are typically, but not invariably, organized into fibrillary or microtubular structures at the ultrastructural level. The hallmark of immunotactoid glomerulonephritis is the presence of highly organized non-amyloidotic microtubular deposits, usually of >30 nm in diameter, with hollow cores and parallel stacking, although thinner tubules can be observed [6]. Light and heavy chain amyloidosis is extremely rare and, similar to AL amyloidosis, is characterized by the presence of Congo red-positive deposits composed of haphazardly oriented fibrils that measure 8–14 nm in diameter. Among diseases with non-organized deposits, LHCDD is characterized by the presence of nodular sclerosing glomerulopathy by light microscopy, linear staining of glomerular and tubular basement membranes for a single heavy and light chain by immunofluorescence, and non-fibrillar, granular electron-dense deposits involving glomerular and tubular basement membranes by electron microscopy. Recently, a second entity has emerged, which is characterized by non-Randall-type and non-organized glomerular Ig deposition that does not conform to any of the previous categories [11–14]. In most cases reviewed by Nasr in 2004 [15] and 2009 [16], lesions were those of MPGN. The authors coined the term proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) to call this new entity. In other rarer cases, lesions were those of atypical membranous nephropathy (MN) [13, 15, 17–19]. Although the clinicopathological presentation of these patients is shared with common cases of MPGN and MN, specificity is provided by the monoclonal Ig deposits which should lead to adapted diagnostic procedure and therapeutic strategy.
In this chapter, we revisit the spectrum of non-organized monoclonal Ig deposits. We will discuss important diagnostic issues including demonstration of monoclonality of the deposits and search for underlying lymphocyte and/or plasma cell proliferation, as well as the treatment options in the light of recent pathophysiologic and therapeutic advances.
Proliferative GN with Non-Organized Monoclonal Ig Deposits
Alpers et al. [11] first described six patients with an MPGN pattern of GN, including mesangial hypercellularity, increased mesangial matrix and mesangial interposition, and monoclonal IgGκ and C3 staining. Granular subendothelial and mesangial deposits were seen by electron microscopy. None of these six patients had detectable serum or urine monoclonal Ig, and bone marrow examination in four patients was normal. The authors pointed out the female predominance (five of the six patients), the young age of onset (31 years old or less in three patients), and the absence of overt plasma cell dyscrasia.
Bridoux et al. [13] reported the cases of five patients manifesting glomerulopathy with non-organized, non-Randall-type monoclonal Ig deposits; two of these patients being described in detail by Touchard [12]. The mean age was 54 ± 17 years. All patients presented with microhematuria and renal failure; four of five had a nephrotic syndrome. Kidney biopsy revealed atypical membranous, endocapillary proliferative, and membranoproliferative patterns. By immunofluorescence, the glomerular capillary wall deposits consisted of IgG3κ in two patients, IgG3λ in one, IgG2κ in one, and isolated λLC in one. Corresponding monoclonal proteins were detected in serum or urine in three patients.
In 2004, Nasr et al. [15] reported the first extensive description of PGNMID in a series of 10 patients, and recently enlarged this series to 37 cases [16], thus allowing a thorough description of the disease
Epidemiology
Nasr et al. [15] reported a biopsy incidence of 0.21 % of a total of 4650 native biopsies referred to the Renal Pathology Laboratory of Columbia University College of Physicians and Surgeons from January 2000 to February 2003. By comparison, the biopsy incidences of AL amyloidosis and Randall-type MIDD were 1.66 and 0.52 % over the same time period, respectively. In Japan, Masai et al. [20] identified four patients with PGNMID after reviewing 5443 kidney biopsies (biopsy incidence of 0.07 %).
Clinical Features
In Nasr et al.’s largest series, the majority of patients were white (81 %) and female (62 %). All patients were adults and had a mean age of 55 years (range 20–81). At presentation, all patients had proteinuria. Proteinuria was in the nephrotic range in 69 % of patients, and 49 % developed full nephrotic syndrome. Microhematuria was documented in 77 % of patients. Two-thirds of patients had renal insufficiency, including three who were on hemodialysis. None of the patients had significant extra-renal symptoms. A case where crescentic glomerulonephritis was superimposed to PGNMID was recently reported with autoimmune hemolytic anemia, thus widening the spectrum of PGNMID [21]. Two cases with a rapidly favorable outcome were associated with Parvovirus B19 infection, suggesting that virus infection-associated immune disorders could be implicated in the pathogenesis of PGNMID [22].
Pathologic Findings
Four histologic patterns were observed. The most common seen in 57 % of cases was MPGN, often associated with endocapillary hypercellularity including focal macrophage infiltration. The second most common pattern, seen in 35 %, was predominantly endocapillary proliferative GN. The third histologic pattern, seen in 5 % of cases, was predominantly membranous GN but with focal endocapillary hypercellularity and segmental membranoproliferative features. The fourth and rarest pattern was pure mesangial proliferative GN. Crescents were present in 32 % of cases. Interstitial inflammation was predominantly focal and associated with a variable degree of tubular atrophy and arteriosclerosis.
Results of immunofluorescence staining with anti-LC isotype and anti-Ig subclass antibodies obtained in three different series [13, 16, 20] are shown in Table 11.2. Deposits were identified exclusively in the glomeruli. They were mostly granular and localized to the glomerular capillary wall and mesangium. IgG was the only Ig deposited, with the exception of a case where only λLC was detected [13] and another case with exclusive IgM κ deposits [23]. All cases showed LC isotype restriction, including 30 cases (76.9 %) with sole positivity for κ. Ig subclass analysis showed a huge predominance of IgG3 (69.2 % of cases), whereas IgG3 represents a minor subclass in healthy subjects (8 %) and myeloma patients (4 %) [24]. No case showed positivity for IgG4. On statistical analysis, IgG3 subtype correlated with the absence of M-spike, with only 2 of 21 patients with IgG3 deposits having a positive M-spike in Nasr et al.’s series [16]. Immunofluorescence studies using antibodies specific for γ-heavy chain, CH1, Ch2, and CH3 domains, and γ3 hinge did not show apparent deletion [16, 20].
Table 11.2
Glomerular immunofluorescence staining in patients with PGNMID
Parameter | No. of patients | Percentage of patients |
|---|---|---|
IgG | 45/46 | 97.8 |
IgG1κ | 7/39 | 17.9 |
IgG1λ | 2/39 | 5.1 |
IgG2κ | 1/39 | 2.6 |
IgG2λ | 2/39 | 5.1 |
IgG3κ | 22/39 | 56.4 |
IgG3λ | 5/39 | 12.8 |
C3 | 40/41 | 97.6 |
C1q | 27/40 | 67.5 |
In all cases, granular electron-dense deposits were confined to the glomerular compartment, while they were both glomerular and tubular in LHCDD. They were primarily subendothelial and mesangial, but subepithelial deposits were also seen. In Nasr et al.’s series [16], some patients showed rare ill-defined fibrils with focal lattice-like arrays although the deposits never formed well-organized structures as seen in fibrillary or immunotactoid GN.
Immunologic Data.
Only 14 of 52 (27 %) patients had evidence of dysproteinemia by serum and/ or urine electrophoresis and immunofixation [11, 13, 16, 20]. Of the 26 of 37 patients reported by Nasr et al. [16] who had no detectable monoclonal component in serum or urine, four were tested with the serum free LC assay; of these, three were found to have normal κ:λ ratio, and one (who had glomerular monoclonal IgG3κ deposits) had an elevated κ:λ ratio.
Bone marrow examination, performed in 30 patients [11, 16, 20], showed marrow plasmacytosis in two patients and clear signs of myeloma in one patient. None of the patients had lymphadenopathy, hepatomegaly, or lymphoma.
Search for cryoglobulinemia was negative in all patients (performed repeatedly in many patients), and none of the patients had any systemic manifestations of cryoglobulinemia. Serum complement was decreased in 11 of 41 (27 %) patients [16, 20]. Of the 11 patients with hypocomplementemia, 8 had IgG3 glomerular deposits and 3 had IgG1 glomerular deposits.
Treatment Outcome
In the largest series reported so far [16], 18 of 37 patients received immunosuppressive agents either with or without concurrent renin–angiotensin system (RAS) blockade. It is remarkable that 12 patients (37.5 %) developed complete (n = 4) or partial (n = 8) remission, whereas only two reached ESRD (Table 11.3).
Table 11.3
Clinical follow-up of patients with PGNMID
Parameter | Value |
|---|---|
Duration of follow-up (mo; mean [range]) | 30.3 (1.0–114.0) |
Treatment | |
None | 5 (15.6) |
RAS blockade alone | 9 (28.1) |
Immunosuppressor agents | 18 (56.3) |
Steroids | 11 |
Cyclophosphamide | 3 |
Cyclosporine | 2 |
Mycophenolate mofetil | 5 |
Rituximab | 4 |
Chlorambucil | 1 |
Thalidomide | 2 |
Bortezomib (velcade) | 1 |
Outcomea | |
CR | 4 (12.5) |
PR | 8 (25.0) |
PRD | 12 (37.5) |
Persistent hematuria (with normal creatinine and no proteinuria) | 1 (3.1) |
ESRD | 7 (21.9) |
Death | 5 (15.6) |
Transplantation
Because 20–25 % of PGNMID progress to ESRD [16], potential recurrence of the disease in the allograft is an important issue. Nasr et al. [25] reported recurrence of PGNMID in four Caucasians (three women and one man), although no patient had a detectable circulating monoclonal component or hematologic malignancy. Recurrence was first documented by biopsy performed at a mean of 3.8 months posttransplant because of renal insufficiency (four patients), proteinuria (three patients), and microhematuria (three patients). Histologic patterns in the allograft were endocapillary or mesangial GN.
Monoclonal IgG deposits (three IgG3κ and one IgG3λ) in the transplants had identical heavy and light chain isotypes as in the native kidneys. Recurrence was treated with combined high-dose prednisone plus rituximab (n = 3) or plus cyclosporine (n = 1). After a mean posttransplant follow-up of 43 months, all four patients achieved reduction in proteinuria and three had reduction in creatinine. Repeat biopsies showed reduced histologic activity after treatment.
Posttransplant PGNMID has also been reported by other authors [26–28], either as a recurrence of a pre-transplant PGNMID or as a de novo glomerulopathy, in patients having reached ESRD for other reasons, such as polycystic disease or type-1 diabetes mellitus. These observations confirm the severity of the disease and the poor renal outcome despite non-rituximab immunosuppressive regimens.
Nonproliferative GN with Non-Organized Monoclonal Ig Deposits
Next to PGNMID, isolated case reports and small series suggested that some patients developed GNMID with no or minimal glomerular cell proliferation. One of the patients reported by Bridoux et al. [13] and described in detail by Touchard [12] had nephrotic syndrome related to thickened glomerular capillary walls with IgG3λ and complement deposits. Immunoblotting revealed the presence of monoclonal IgG3λ. Evans et al. [18] described a patient with follicular B-cell lymphoma who developed nephrotic syndrome related to subepithelial granular IgG1κ deposits. One patient in Nasr et al.’s series [15] of PGNMID had a pattern of MN, however, with segmental membranoproliferative features and IgG1κ deposits.
Komatsuda et al. [19] reviewed 5,443 kidney biopsies from their own department in Akita (Japan) and identified three patients with monoclonal immunoglobulin deposition disease associated with membranous features. All patients had proteinuria, and one patient developed nephrotic syndrome. Renal insufficiency was not observed. Cryoglobulin or monoclonal protein in serum and urine was not detected. A renal biopsy showed thickening of the glomerular capillary walls and spike formation. Tubulointerstitial and vascular alterations were mild or absent. Immunofluorescence studies revealed granular IgG3κ deposits in two patients and IgG1κ deposits in one patient, along the glomerular capillary walls. Significant deposition along the tubular basement membranes was not observed in any patient. Immunofluorescence studies using antibodies specific for γ-heavy chain Fab containing CH1 domain, CH2 domain, and CH3 domain did not show any apparent deletion. On confocal microscopy, glomerular colocalization of light and heavy chains was observed. Electron microscopy showed predominant subepithelial granular deposits without distinct ultrastructural organization. All patients were treated with steroids, and good effects were observed. A follow-up renal biopsy performed in one patient showed histological improvement. No patient developed myeloma or other hematological malignancy during the course of follow-up (mean 44 months).
Revisiting the Disease Spectrum of GN with Monoclonal Ig Deposits
To get further insight into the glomerulopathies with monoclonal Ig deposits, we recently reviewed the cases of 26 patients with non-cryoglobulinemic GN and monoclonal Ig deposits referred to three nephrology departments in Paris between 1980 and 2008 [17]. We found that there were more patients with MN (n = 14) than with MPGN (n = 12) (Fig. 11.1). In five of the MN patients, the glomerular lesions were, however, atypical with mesangial hypertrophy and increased mesangial cellularity (Fig. 11.1a). Overall, extracapillary proliferation with crescents was observed in 13 cases (4 of 14 MN, 9 of 12 MPGN), whereas glomerular necrotic lesions were present in only six biopsies. Interstitial inflammation with infiltration by neutrophils and nonmalignant lymphocytes was noted in 17 patients (65 %). Interstitial fibrosis with tubular atrophy ranged from absent or mild (57 %) to moderate (27 %) and severe (16 %). Vascular lesions were frequent, mainly arteriolar hyalinosis (15/26) and arteriosclerosis (19/26).
Fig. 11.1
Pathological findings in glomerulonephritis with monoclonal Ig deposits. Light microscopy findings in MN membranous nephropathy, showing immune deposits on the external side of the glomerular basement membrane, with frequent mesangial hypertrophy (a, Masson’s trichrome stain); the deposits have irregular size (inset a) and are embedded in basement membrane expansions (b, JMS stain). In patients with membranoproliferative pattern, light microscopy shows proliferation of mesangial cells (c, Masson’s trichrome stain) and double contours (d, JMS stain). By immunofluorescence, parietal granular IgG deposits in MN (e) are different from the more diffuse pattern seen in the MPGN (f). Ultrastuctural studies found that most patients have granular, non-organized deposits in the subepithelial (g) or subendothelial spaces, whereas in some cases, the deposits show microtubular substructure (h), as previously described in immunotactoid glomerulonephritis. From Guiard et al. [17], with permission
Demographic, clinical, and biological characteristics of these patients are shown in Table 11.4. At presentation, all patients had glomerular proteinuria >1 g/24 h and most (85 %) of the patients presented with nephrotic syndrome. Mean serum creatinine level at presentation was 211 μmol/l (eGFR: 49.3 ± 34.6 ml/min/1.73 m2), and 14 of 26 (54 %) patients initially had significant renal dysfunction, including three patients who needed temporary hemodialysis. In eight cases (31 %), a circulating monoclonal IgG was detected by standard methods (serum and urine protein electrophoresis with immunofixation). In all of these cases, the serum monoclonal IgG had the same light and heavy chain isotype as the monoclonal compound identified in the glomerular deposits, on the renal biopsy. Hypocomplementemia was observed in 8 of 22 patients (36 %) with available data, showing either isolated C4 or combined C3 and C4 consumption. Low serum complement concentration was equally observed among patients with either MPGN or MN and independently of the monoclonal IgG isotype. Serum cryoglobulin, hepatitis C, hepatitis B, and HIV serology were negative in all patients.
Table 11.4
Demographic, clinical, and biological characteristics at presentation of patients with non-cryoglobulinemic GN with monoclonal Ig deposits
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