Proliferative Glomerulonephritis With Monoclonal Immunoglobulin Deposits in a Kidney Allograft

Kidney Biopsy Teaching Case Proliferative Glomerulonephritis With Monoclonal Immunoglobulin Deposits in a Kidney Allograft Ibrahim Batal, MD,1 Vanesa Bijol, MD,1 Robert L. Schlossman, MD,2 and Helmut G. Rennke, MD1 Paraprotein may accumulate in glomeruli and cause kidney damage associated with variable histopathologic patterns and a characteristic immunofluorescence staining restricted to a single light chain and/or a single heavy chain isotype. Hence, such glomerular injury includes diseases caused by deposition of a monoclonal light chain, heavy chain, or entire immunoglobulin (light and heavy chains), which may manifest as proliferative glomerulonephritis. In this report, we focus on the latter as the least characterized of the 3, particularly in the transplantation setting. We describe a case of late transplant dysfunction associated with glomerular immunoglobulin G1/k deposits. We also present our experience with proliferative glomerulonephritis and monoclonal immunoglobulin deposits in transplant and native kidney biopsies, with reference to the literature. Am J Kidney Dis. 63(2):318-323. ª 2014 by the National Kidney Foundation, Inc. INDEX WORDS: Paraprotein; proliferative glomerulonephritis; transplant glomerulitis.

INTRODUCTION The spectrum of kidney diseases associated with hematologic malignancies and paraproteinemia is ever expanding.1,2 Reduced kidney function may result from direct infiltration of the kidney parenchyma by neoplastic cells or from the toxic and structural effects of accumulated light chain, heavy chain, or entire immunoglobulin, which can manifest as proliferative glomerulonephritis (GN). Proliferative GN with monoclonal immunoglobulin deposits is the focus of this report. The pathophysiology, prognosis, and association of this specific form of glomerular injury with lymphoproliferative disorders have not been well characterized. Our knowledge of this particular entity in the kidney transplant is limited further to a few case reports and very small case series.3-7 We report a case of immunoglobulin G1 (IgG1)/k GN that was detected in a transplant biopsy specimen 17 years posttransplantation. From 1Pathology, Brigham and Women’s Hospital and Harvard Medical School; and 2Hematology Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA. Received April 5, 2013. Accepted in revised form July 31, 2013. Originally published online September 18, 2013. Because an author of this manuscript is an editor for AJKD, the peer-review and decision-making processes were handled entirely by an Associate Editor (Greg Knoll, MD, MSc, FRCPC) who served as Acting Editor-in-Chief. Details of the journal’s procedures for potential editor conflicts are given in the Editorial Policies section of the AJKD website. Address correspondence to Ibrahim Batal, MD, Kidney Pathology Service, Department of Pathology, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail: ibatal@ partners.org  2014 by the National Kidney Foundation, Inc. 0272-6386/$36.00 http://dx.doi.org/10.1053/j.ajkd.2013.07.015 318

CASE REPORT Clinical History and Laboratory Data The patient, a 61-year-old man who presented with end-stage kidney disease presumably due to hypertension, received a living unrelated kidney transplant and was maintained on treatment with cyclosporine, mycophenolate mofetil, and prednisone. The posttransplantation course was fairly uneventful. Sixteen years posttransplantation, the patient was found to have adenocarcinoma of the prostate, multiple basal cell carcinomas, and a single focus of invasive squamous cell carcinoma of the skin. One year later, he presented with an elevated serum creatinine level (1.8 mg/dL [corresponding to estimated glomerular filtration rate (eGFR) by the isotope-dilution mass spectrometry–traceable 4-variable MDRD (Modification of Diet in Renal Disease) Study equation of 39 mL/min/1.73 m2]8 from a baseline of 1.5 mg/dL [eGFR of 48 mL/min/1.73 m2]), proteinuria (21), and hematuria (21). A kidney transplant biopsy was performed.

Kidney Biopsy The sample contained 23 glomeruli, 12 (52%) of which were globally sclerosed. By light microscopy, nonsclerosed glomeruli showed mild expansion of the mesangial matrix, mild mesangial proliferation, minimal glomerulitis, and infrequent double contours (Fig 1A). The biopsy revealed a mild form of acute tubular injury manifested by focal tubular distention and low epithelial lining. There also was moderate tubular atrophy and interstitial fibrosis without significant interstitial inflammation or tubulitis. Arteries and arterioles did not show endotheliitis, but showed severe and moderate sclerosis, respectively. Congo Red staining was negative. By immunofluorescence microscopy, segmental granular deposition of IgG, C3, C1q, and k light chain (but not l light chain) was detected in mesangial areas and along some glomerular capillary walls (Fig 2). Staining for IgG subclasses showed restriction to IgG1 only (Fig 2). Staining for C4d was negative in peritubular capillaries. By electron microscopy, glomerular capillary walls appeared segmentally distorted by the presence of subendothelial and rare subepithelial electron-dense deposits, which focally assembled in fibrillary structures (Fig 1B and 1C). Focal effacement of visceral epithelial cell foot processes was present. The mesangium contained electron-dense and fibrillary material. Am J Kidney Dis. 2014;63(2):318-323

Monoclonal Immunoglobulin and Glomerular Disease

Figure 1. Kidney biopsy findings and serum studies. (A) Glomerulus with mild expansion of the mesangial matrix and mild segmental mesangial proliferation (periodic acid–Schiff stain; original magnification, 3400). (B) Electron-dense deposits are present in the subendothelial, mesangial, and subepithelial locations (electron microscopy; original magnification, 38,000). (C) Segmentally, the deposits consisted of randomly oriented nonbranching fibrils (mean thickness, 16.7 nm; electron microscopy; original magnification, 313,000). (D) Serum protein electrophoresis revealed hypogammaglobulinemia and an M spike located within the beta region (arrow). (E) Serum protein immunofixation confirmed the presence of a monoclonal band with immunoglobulin M/l light chain specificity.

Diagnosis In summary, the biopsy showed proliferative GN with monoclonal IgG1/k deposits and fibrillary substructural organization superimposed on mild acute tubular injury and moderate to severe chronic changes of the parenchyma. There was no significant evidence for T-cell–mediated rejection or C4d staining along the peritubular capillaries. The differential diagnosis included fibrillary GN and cryoglobulinemic GN. The former is unlikely because conventional fibrillary GN is a polyclonal process and is characterized by intense IgG4 reactivity.9 Our patient has not been studied serologically for cryoglobulinemia, which cannot be excluded with certainty. Notably, hyaline thrombi, IgM deposits, and microtubular substructures, which are the hallmark of cryoglobulinemic GN,10 were not present. Regardless, from a pathophysiologic point of view, we believe this process would best be classified as paraprotein-induced GN rather than conventional polyclonal immune-complex–mediated GN; analyzing biopsy specimens with monoclonal immunoglobulin deposits and fibrillary substructures or type 1 cryoglobulinemic GN using molecular techniques and Am J Kidney Dis. 2014;63(2):318-323

mass spectrometry has proved that such cryoglobulins and fibrils are in fact assembled paraprotein.11-13

Clinical Follow-up Serum protein electrophoresis (SPEP) revealed an M-spike (Fig 1D) with IgM/l specificity on serum protein immunofixation (SPIF; Fig 1E). Physical examination was negative for lymphadenopathy. Bone marrow biopsy showed normocellular marrow with no significant abnormalities, and flow cytometry of the bone marrow aspirate showed too few plasma cells to assess for clonality. Cytogenetic studies of bone marrow cells were equivocal and showed a 20q deletion in 1 of 20 metaphases analyzed. Thus, the patient had IgG1/k deposits in glomeruli, circulating IgM/l, but no unequivocal evidence of a demonstrable hematologic malignancy. The discrepancy between tissue and serologic results is interesting. The presence of monoclonal IgM in serum, but not glomeruli, could be attributed to the large size of IgM, which does not filter and probably would have low affinity to deposit in the kidney. The detection of IgG/k in glomeruli, but not serum, could result from producing a small amount of monoclonal 319

Batal et al

Figure 2. Immunofluorescence microscopy. There was intense staining for g heavy chain (g: 31/41) and k light chain (k: 21/41) with negative l light chain (original magnifications, 3 200). Analysis of g heavy chain subclasses (bottom row) revealed intense staining for g1 (31/41) subclass with negative staining for g2, g3, and g4 subclasses (original magnification, 3400).

IgG, which might be beyond the level of detection by SPIF. Such IgG, on account of its size, can filter and would have high glomerular affinity. In older case series, biclonal gammopathies were found in up to 3.2% of all gammopathies.14 More recently, Sethi et al15 detected biclonal gammopathies in 4 of 24 (17%) patients with M spike and membranoproliferative GN. Given the equivocal results of bone marrow biopsy, the extent of long-term changes in the kidney parenchyma, and the lack of rapid deterioration of kidney function, the patient was not treated. Serum creatinine levels deteriorated gradually. Fifteen months later, the patient had a serum creatinine level of 2.4 mg/dL (eGFR of 28 mL/min/1.73 m2).

Additional Investigations This case turned our attention to investigate the association of proliferative GN plus monoclonal immunoglobulin deposits with hematologic abnormalities and suboptimal kidney function. We retrospectively reviewed all transplant and native kidney biopsies accessioned in our institution from January 2010 to January 2013. This study was approved by the Institutional Review Board (#2011P002692). Of 659 transplant biopsy specimens, 10 (1.5%) samples from 8 patients revealed proliferative GN with monoclonal immunoglobulin deposits (Table 1). Most patients showed glomerular IgG/k and a diffuse proliferative or membranoproliferative appearance reminiscent of transplant glomerulitis with or 320

without chronic transplant glomerulopathy, respectively. Of 5 patients with available clinical information, 2 showed monoclonal bands by SPIF and the other 3 showed hypogammaglobulinemia. Most of these patients developed transplant failure (n 5 3) or low eGFR within 13 months of follow-up (n 5 1; Table 1). We also retrieved 38 native kidney biopsy specimens with proliferative GN and monoclonal immunoglobulin deposits (0.8% of total biopsies; Box 1). Similar to transplant biopsy specimens, the predominant immunofluorescence staining was IgG/k and the predominant light microscopic patterns were diffuse proliferative and/or membranoproliferative. Most of these biopsy specimens were from outside institutions, where only limited clinical and follow-up information were available to us. However, histopathologic evaluation of these kidney biopsy specimens uncovered evidence of hematologic malignancies or other form of paraprotein deposition in 7 of 38 (18%) patients (myeloma cast nephropathy [n 5 1], infiltration of the kidney parenchyma by B-cell lymphoma [n 5 5], or multiple myeloma [n 5 1]; Box 1).

DISCUSSION Renal paraprotein accumulation is a wellestablished cause of kidney damage. Depending on the characteristics of such paraprotein (eg, type [light chain, heavy chain, or entire immunoglobulin], Am J Kidney Dis. 2014;63(2):318-323

Monoclonal Immunoglobulin and Glomerular Disease Table 1. Transplant Recipients With Biopsies Showing Proliferative Glomerulonephritis With Monoclonal Immunoglobulin Deposits Pt No.

Age (y)

Sex

ESKD Cause

Time Post-Tx

1

67

M

Presumed PIGN

22 y

MPGN

IgA/k

Severe

ND

2

52

M

Unknown

5 mo

DPGN & MPGN

IgG/kb

Mild

SPEP: HGG NA

Failed (6 mo post-bx)

3

63

M

MPGNc

4y

DPGN & MPGN

IgG3/k

Mild

SPEP: HGG NA

NA

4

61

M

Presumed HTN

17 y

MPGN

IgG1/k

Moderate SPIF: IgM/l

5

43

F

MPGNc

5y

DPGN & MPGN (80% crescents)

IgG3/k

Mild

6

39

F

NA

NA

FPGN & MPGN

IgG/kb

Moderate NA

7

44

F

Presumed HTN

1.5 mo

Mesangioproliferative IgA/k

8

71

F

NA

3y

DPGN & MPGN

LM Pattern

IF Findings

IgG3/k

IFTA

Hematologic Workup

Follow-up Bx

NAa

NA

SPEP: HGG 1 mo later: similar findingsd

Transplant Survival

Failed (1 y post-bx)

Functioning (15 mo post-bx eGFR: 28) Failed (5 mo post-bx)

NA

NA

Mild

SPIF: IgG/k

2 mo later: IgA/k

Functioning (12 mo post-bx eGFR: 46)

Mild

NA

NA

NA

Note: Based on retrospective review of biopsies accessioned in our institution from January 2010 to January 2013. Abbreviations: Bx, biopsy; DPGN, diffuse proliferative GN; eGFR, estimated glomerular filtration rate (in mL/min/1.73 m2); ESKD, end-stage kidney disease; FPGN, focal proliferative GN; GN, glomerulonephritis; HGG, hypogammaglobulinemia; HTN, hypertension; IF, immunofluorescence microscopy; IFTA, interstitial fibrosis and tubular atrophy; IgA, immunoglobulin A; LM, light microscopy; MPGN, membranoproliferative GN; NA, information not available; ND, not done; PIGN, postinfection GN; pt, patient; SPEP, serum protein electrophoresis; SPIF, serum protein immunofixation; Tx, transplantation. a One previous biopsy (18 years post-Tx) also showed IgA/k. b Staining for IgG subclasses not performed. c No description of IF staining for k and l light chains in the native kidney biopsy, which also showed a membranoproliferative pattern of injury. d Additionally, a previous transplant biopsy performed 5 years earlier (8 weeks post-Tx) described dull irregular and sparse IgG/k in glomeruli and the possibility of paraprotein was suggested.

size [truncated vs large], charge, solubility, and filtration capability), variable patterns and ultrastructural appearances of the deposits are appreciated.16-19 GN with monoclonal immunoglobulin deposits is not a rare form of glomerular injury.15,20,21 In our experience and that of others,15 any class of monoclonal immunoglobulin can accumulate in glomeruli, causing an inflammatory (nephritic) picture when deposited in the subendothelial and/or mesangial space or, occasionally, a membranous (nephrotic) pattern when deposited in the subepithelial space.20 The largest series of GN with monoclonal IgG deposits included 37 patients with predominant IgG3/k staining and endocapillary and/or membranoproliferative appearance.21 Because only one patient had multiple myeloma and none developed overt hematologic malignancy on follow-up, the authors of this study concluded that GN with monoclonal IgG deposits does not appear to be a precursor of multiple myeloma.21 This study enhanced our understanding of this process, but we believe that several other observations it contained need to be stressed. Of the patients in that series, 60% progressed to end-stage kidney disease or had persistently decreased kidney function. In addition to the patient Am J Kidney Dis. 2014;63(2):318-323

with multiple myeloma, the study included a patient with kidney AL amyloidosis, another patient with 5% light-chain–restricted plasma cells on bone marrow biopsy, and 30% of patients had detectable circulating paraprotein. Furthermore, the follow-up period was not extensive enough to confirm the lack of association between this form of GN and hematologic malignancies; it is well known that kidney manifestations of some hematologic disorders can antedate the clinical presentations by several years.22,23 Finally, although no cases of overt lymphomas could be detected in this study, the existence of in situ, smoldering, or other indolent B-cell lymphomas24-27 cannot be completely ruled out. In recent decades, evidence of an association between GN with monoclonal immunoglobulin deposits and hematologic abnormalities has started to emerge.28-30 Guiard et al20 detected circulating paraprotein and overt hematologic malignancies, mostly in the form of lymphomas, in 8 of 26 (30%) and 9 of 26 (35%) such patients, respectively. Sethi et al15 studied patients with membranoproliferative GN and serologic evidence of M spikes; in their cohort, 11 of 18 (61%) patients who had GN with monoclonal immunoglobulin deposits showed evidence of 321

Batal et al Box 1. Patients With Native Kidney Biopsies Showing Proliferative Glomerulonephritis With Monoclonal Immunoglobulin Deposits No. of biopsies 38 (from 38 patients) Age (years) 58 6 19; range, 21-94 Sex 18 (47%) women, 20 (53%) men Light microscopya DPGN & MPGN: 24 (63%) FPGN: 4 (11%) Mesangioproliferative: 7 (18%) Sclerosing: 3 (8%) Immunofluorescence microscopy IgG/k: 22 (57%)b IgM/k: 6 (16%) IgA/k: 4 (11%) IgG/l: 3 (8%) IgA/l: 2 (5%) IgM/l: 1 (3%) Evidence of hematologic malignancies (in total, 7 biopsies, or 18%) 1 cast nephropathy (IgA/k) 1 infiltration by MM (IgG/k) 1 CLL (IgG/k) 3 LGBCL (1 IgG/l & 2 IgM/k) 1 ALHSL (IgM/l) Note: Based on retrospective review of biopsies accessioned in our institution from January 2010 to January 2013. Abbreviations: ALHSL, atypical lymphocytes highly suspicious for lymphoma; CLL, chronic lymphocytic leukemia, DPGN, diffuse proliferative GN; FPGN, focal proliferative GN; GN, glomerulonephritis; LGBCL, low grade B-cell lymphoma; MM, multiple myeloma; MPGN, membranoproliferative GN. a Notably, 9 (24%) biopsy specimens showed some degree of cellular crescents. b Subtyping for IgG was only performed in 9 biopsies and showed IgG3 (n 5 6) and IgG1 (n 5 3).

Lorenz et al31 had detectable M spikes or overt hematologic malignancies. When SPEP/UPEP were performed in our study (n 5 5), we found that 2 patients had detectable M spike, whereas the other 3 were found to have hypogammaglobulinemia. In conclusion, proliferative GN with monoclonal immunoglobulin deposits is not encountered infrequently. This understudied entity is associated with circulating paraprotein (30% of patients), overt hematologic malignancies (up to 35% of patients), and can recur in the transplant. Therefore, we strongly believe that this process should be regarded as a paraprotein-induced disease rather than a conventional immune complex–mediated GN, for which the possibility of hematologic abnormalities easily can be overlooked. Alternatively, many cases are not supported by clinical or laboratory evidence of overt lymphoproliferative diseases and frequently are classified as monoclonal gammopathy of undetermined significance (MGUS). Because these diseases have poor prognosis and are likely to cause deterioration in kidney function, the term MGUS can be misleading.15 We believe that such processes would be characterized better as “monoclonal gammopathy of renal significance,” as recently suggested.32 Although more studies are needed to increase our understanding of this disease, early detection, prudent hematology workup, and prompt management and follow-up could be important to potentially slow down the deterioration of kidney function.

ACKNOWLEDGEMENTS Support: Dr Batal was supported by an American Society of Transplantation Clinical Fellowship Grant. Financial Disclosure: The authors declare that they have no relevant financial interests.

REFERENCES hematologic malignancies (lymphomas [46%], plasma cell dyscrasias [36%], or both [18%]). Notably, the predominant immunofluorescence pattern was IgM/k (n 5 6), followed by IgG/k (n 5 3) and IgG/l (n 5 2). Despite the lack of clinical and follow-up information, including cryoglobulin studies, our data showed that 18% of patients with GN and monoclonal immunoglobulin deposits had evidence of hematologic malignancies, mostly in the form of low-grade lymphomas (Table 1). The literature on GN with monoclonal immunoglobulin deposits in the kidney transplant is very scant. Most available reports describe a recurrent3-5,7 rather than de novo6 form of this disease. The predominant light microscopic manifestations are in the form of glomerular inflammation and/or remodeling.4-6,31 None of the 6 patients presented by Nasr et al5 or 322

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