Monoclonal Immunoglobulin Crystalline Membranous Nephropathy.

Monoclonal immunoglobulin (MIg) crystalline nephropathies are rare lesions resulting from precipitation of MIgs in the kidney as intracellular or extracellular crystals. We describe a patient with multiple myeloma (IgGλ) and diabetes who presented with nephrotic range proteinuria. Kidney biopsy revealed membranous nephropathy superimposed on diabetic glomerulosclerosis. Glomeruli were negative for PLA2R, THSD7A, and NELL-1. Ultrastructurally, the subepithelial deposits were composed of crystals (ranging from rhomboid to rod to needle shaped), which failed to stain for immunoglobulins by routine immunofluorescence but stained for IgG+λ by paraffin immunofluorescence after pronase digestion. RNA-based immunoglobulin repertoire sequencing performed on bone marrow aspirate identified an IgGλ (γ1) clone, which was highly atypical, combining an extensively mutated (23.6%) Ig heavy chain derived from the IGHV1-24 with low pI and unusual mutations and a light chain derived from an extremely rare germline gene (IGLV10-54). This report expands the pathologic spectrum of MIg crystalline nephropathies by describing a unique case of crystalline nephropathy with IgGλ deposits manifesting as membranous nephropathy.

Clinicopathologic Characteristics of Crystalglobulin-Induced Nephropathy: A Case Series.

RATIONALE & OBJECTIVE: Crystalglobulinemia is a rare syndrome characterized by intravascular crystallization of monoclonal immunoglobulins (MIgs). Data on kidney involvement are limited to case reports. This series characterizes the clinicopathologic spectrum of crystalglobulin-induced nephropathy (CIN). STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Nineteen CIN cases were identified from the nephropathology archives of Mayo Clinic and Columbia University. CIN was defined by intravascular (extracellular) MIg crystals visible by light (LM) and electron microscopy (EM). FINDINGS: Among the cases, 68% were male and 65% were Caucasian (median age 56 years). Most patients presented with severe AKI (median creatinine 3.5 mg/dL), hematuria, and mild proteinuria (median 1.1 g). Common extrarenal manifestations were constitutional (67%), cutaneous (56%), and rheumatologic (50%). Fifty percent of cases had hypocomplementemia. The hematologic disorders were monoclonal gammopathy of renal significance (MGRS) (72%), lymphoma (17%), or myeloma (11%), with 65% of these disorders discovered concomitantly with CIN. All patients had MIg identified on SPEP/SIF (IgGκ in 65%). The sFLC ratio was outside the renal range in 40%, and bone marrow biopsy detected the responsible clone in 67%. On LM, crystals involved glomeruli (100%) and vessels (47%), often with an inflammatory reaction (89%) and fibrin (58%). All cases exhibited crystal substructures (mostly paracrystalline) by EM. Immunofluorescence (IF) on paraffin embedded tissue was more sensitive than frozen tissue (92% versus 47%) for demonstrating the crystal composition (IgGκ in 63%). Follow up (median 20 months) was available in 16 patients. Eighty-one percent received steroids, 44% plasmapheresis, 38% hemodialysis, and 69% chemotherapy. Ninety-percent of patients who received clone-directed therapy achieved kidney recovery vs. 20% of those who did not (p=0.017). LIMITATIONS: Retrospective design, small sample size. CONCLUSIONS: CIN is a rare cause of nephropathy associated with lymphoplasmacytic disorders (mostly MGRS) and typically presents with severe AKI and extrarenal manifestations. Diagnosis often requires IF performed on paraffin embedded kidney tissue. Prompt initiation of clone-directed therapy, coupled with corticosteroids and plasmapheresis, may lead to recovery of kidney function.

Pathological characteristics of light chain crystalline podocytopathy.

Monoclonal immunoglobulin light chain (LC) crystalline inclusions within podocytes are rare, poorly characterized entities. To provide more insight, we now present the first clinicopathologic series of LC crystalline podocytopathy (LCCP) encompassing 25 patients (68% male, median age 56 years). Most (80%) patients presented with proteinuria and chronic kidney disease, with nephrotic syndrome in 28%. Crystalline keratopathy and Fanconi syndrome were present in 22% and 10%, respectively. The hematologic condition was monoclonal gammopathy of renal significance (MGRS) in 55% and multiple myeloma in 45%. The serum monoclonal immunoglobulin was IgG κappa in 86%. Histologically, 60% exhibited focal segmental glomerulosclerosis (FSGS), often collapsing. Ultrastructurally, podocyte LC crystals were numerous with variable effacement of foot processes. Crystals were also present in proximal tubular cells as light chain proximal tubulopathy (LCPT) in 80% and in interstitial histiocytes in 36%. Significantly, frozen-section immunofluorescence failed to reveal the LC composition of crystals in 88%, requiring paraffin-immunofluorescence or immunohistochemistry, with identification of kappa LC in 87%. The LC variable region gene segment, determined by mass spectrometry of glomeruli or bone marrow plasma cell sequencing, was IGKV1-33 in four and IGKV3-20 in one. Among 21 patients who received anti-plasma cell-directed chemotherapy, 50% achieved a kidney response, which depended on a deep hematologic response. After a median follow-up of 36 months, 26% progressed to kidney failure and 17% died. The mean kidney failure-free survival was 57.6 months and was worse in those with FSGS. In sum, LCCP is rare, mostly associates with IgG κappa MGRS, and frequently has concurrent LCPT, although Fanconi syndrome is uncommon. Paraffin-immunofluorescence and electron microscopy are essential to prevent misdiagnosis as primary FSGS since kidney survival depends on early diagnosis and subsequent clone-directed therapy.

The characteristics of seronegative and seropositive non-hepatitis-associated cryoglobulinemic glomerulonephritis.

The clinicopathologic characteristics and long-term outcome of non-hepatitis-associated cryoglobulinemic glomerulonephritis (CryoGN) are not well-defined and cases with undetectable serum cryoglobulin (seronegative CryoGN) have not been investigated. To resolve this, we retrospectively identified 81 patients with biopsy-proven non-hepatitis CryoGN, including 22 with seronegative CryoGN. The median age was 61 years and 76% presented with nephritic syndrome. A hematologic condition was found in 89% of patients, including monoclonal gammopathy of renal significance (65%) and symptomatic lymphoproliferative disorder (35%). In the seropositive group, 56% had type II, 29% type I, and 8% type III cryoglobulin. Extrarenal manifestations, mostly of skin, were present in 64% and were significantly less common in seronegative CryoGN. Glomerular deposits by immunofluorescence were IgM dominant (84%) and polytypic (70%) in the seropositive group, whereas 52% of seronegative cases had monotypic deposits (i.e., type I cryoglobulin). Ultrastructurally, the deposits were organized in 77% of cases. Substructure appearance significantly differed according to the type of CryoGN, forming most commonly short cylindrical structures in type II and other organized substructures in type I CryoGN. Most patients were treated with clone-directed therapy. On follow up (median 33 months), 77% had partial or complete remission, 10% reached kidney failure and 14% died. Predictors of kidney failure on univariate analysis were AKIN stage 3, positive rheumatoid factor and biclonal gammopathy at diagnosis. We conclude that most CryoGN cases (types I and II) are due to a hematologic condition and are associated with favorable outcome after clone-directed therapy. Seronegative CryoGN accounts for about a quarter of cases and is mostly a kidney-limited disease. Thus, further investigations are needed to unravel the pathophysiology of seronegative CryoGN.

The characteristics of patients with kidney light chain deposition disease concurrent with light chain amyloidosis.

The type of monoclonal light chain nephropathy is thought to be largely a function of the structural and physiochemical properties of light chains; hence most affected patients have only one light chain kidney disease type. Here, we report the first series of kidney light chain deposition disease (LCDD) concomitant with light chain amyloidosis (LCDD+AL), with or without light chain cast nephropathy (LCCN). Our LCDD+AL cohort consisted of 37 patients (54% females, median age 70 years (range 40-86)). All cases showed Congo red-positive amyloid deposits staining for one light chain isotype on immunofluorescence (62% lambda), and LCDD with diffuse linear staining of glomerular and tubular basement membranes for one light chain isotype (97% same isotype as the amyloidogenic light chain) and ultrastructural non-fibrillar punctate deposits. Twelve of 37 cases (about 1/3 of patients) had concomitant LCCN of same light chain isotype. Proteomic analysis of amyloid and/or LCDD deposits in eight revealed a single light chain variable domain mutable subgroup in all cases (including three with separate microdissections of LCDD and amyloid light chain deposits). Clinical data on 21 patients showed proteinuria (100%), hematuria (75%), kidney insufficiency and nephrotic syndrome (55%). Extra-kidney involvement was present in 43% of the patients. Multiple myeloma occurred in 68% (about 2/3) of these patients; none had lymphoma. On follow up (median 16 months), 63% developed kidney failure and 56% died. The median kidney and patient survivals were 12 and 32 months, respectively. LCDD+AL mainly affected patients 60 years of age or older. Thus, LCDD+AL could be caused by two pathological light chains produced by subclones stemming from one immunoglobulin light chain lambda or kappa rearrangement, with a distinct mutated complementary determining region.

Membranous Nephropathy With Extensive Tubular Basement Membrane Deposits Following Allogeneic Hematopoietic Cell Transplant: A Report of 5 Cases.

Tubular basement membrane (TBM) deposits are very uncommon in non-lupus membranous nephropathy. We report 5 patients with membranous nephropathy and extensive TBM deposits following allogeneic hematopoietic cell transplant. Patients presented with nephrotic syndrome (3 also had acute kidney injury) late post-transplant in association with chronic graft-versus-host disease (cGVHD). Kidney biopsies revealed global subepithelial and extensive TBM immune complex deposits, accompanied by acute tubular injury (n = 4) and tubulointerstitial inflammation (n = 4). Proteomic analysis of glomeruli in 4 cases identified PLA2R in 1, with no significant protein spectra for PLA2R, THSD7A, EX1/2, NELL-1, PCDH7, NCAM1, or SEMA3B detected in the remaining 3. On follow-up (for a mean 42 months), 4 patients had complete and 1 partial remission following prednisone and/or rituximab therapy. We propose that membranous nephropathy with extensive TBM deposits is a distinctive clinicopathologic lesion associated with allogeneic hematopoietic cell transplant. Pathogenesis likely involves cGVHD-driven antibodies against glomerular and TBM components, the identity of which remains to be elucidated.

Immunofluorescence staining for immunoglobulin heavy chain/light chain on kidney biopsies is a valuable ancillary technique for the diagnosis of monoclonal gammopathy-associated kidney diseases.

Heavy chain/light chain (HLC) antibodies target conformational epitopes at the junctions of the heavy chain and light chain constant regions (CH1 and CL) of serum IgGκ, IgGλ, IgAκ, IgAλ, IgMκ, and IgMλ to provide quantitation of intact HLC pairs. Here, we developed an HLC tissue immunofluorescence protocol to test if it can complement conventional immunofluorescence in the diagnosis of monoclonal gammopathy-associated kidney diseases. HLC immunofluorescence was performed on archived frozen tissue of 104 kidney biopsies. The sensitivity and specificity of HLC immunofluorescence was confirmed by testing cases of lupus nephritis, other polyclonal immunoglobulin nephropathies, and light chain nephropathies (light chain amyloidosis and deposition disease). Testing of ten cases of the IgG variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits excluded monoclonal deposits in two by revealing positivity for IgGκ and IgGλ. Testing of 12 cases of monotypic IgA nephropathy excluded monoclonal deposits in six by revealing staining for IgAκ and IgAλ. Testing of six cases of monotypic fibrillary glomerulonephritis excluded monoclonal deposits in three by revealing positivity for IgGκ and IgGλ. None of 14 cases of glomerulonephritis in which HLC immunofluorescence unmasked polytypic deposits were associated with a serum or urine monoclonal immunoglobulins matching the conventional immunofluorescence results. HLC immunofluorescence outperformed paraffin immunofluorescence and IgG subclass staining in 10/13 (77%) of cases. Testing of 18 cases of cryoglobulinemic glomerulonephritis showed better correlation with serum cryoprecipitate immunofixation than conventional immunofluorescence with regards to the type of cryoglobulin in 47% of cases. Thus, HLC immunofluorescence is a valuable ancillary technique in kidney pathology for the diagnosis of monoclonal gammopathy-associated nephropathies, and could be utilized to confirm or exclude the monoclonal nature of deposits.

Immunotactoid glomerulopathy is a rare entity with monoclonal and polyclonal variants.

Immunotactoid glomerulopathy (ITG) is a rare form of glomerulonephritis for which our understanding is limited to case reports and small case series. Herein we describe the clinical, pathologic, and outcome characteristics of 73 patients with ITG who typically presented with proteinuria, hematuria, and renal insufficiency. Hematologic disorders were present in 66% of patients, including lymphoma in 41% (mainly chronic lymphocytic leukemia/small lymphocytic lymphoma), monoclonal gammopathy in 20%, and multiple myeloma in 6%. Light microscopy revealed endocapillary proliferative (35%), membranoproliferative (29%) and membranous (29%) patterns of glomerular involvement. Electron microscopy revealed characteristic microtubular deposits with a diameter of 14-60 nm, hollow cores, frequent parallel alignment, and a predominant distribution outside of the lamina densa of the glomerular basement membrane. Importantly, immunofluorescence revealed IgG-dominant staining which was light chain and IgG subclass restricted in 67% of cases, indicating monoclonal composition. This finding was used to distinguish monoclonal and polyclonal variants of ITG. As compared to polyclonal, monoclonal ITG had a higher incidence of lymphoma (53% vs. 11%), multiple myeloma (8% vs. 0), and monoclonal gammopathy (22% vs. 16%). Monoclonal ITG was more commonly treated with clone-directed therapy, which was associated with more frequent remission and less frequent end stage kidney disease. Thus, a third of ITG cases are polyclonal but a quarter of these cases are associated with hematologic conditions, underscoring the need for hematologic evaluation in all patients with ITG. Hence, based on these distinctions, ITG should be subclassified into monoclonal and polyclonal variants. Prognosis of ITG is good if the underlying hematologic condition is treated.

Immunoglobulin-Negative DNAJB9-Associated Fibrillary Glomerulonephritis: A Report of 9 Cases.

Fibrillary glomerulonephritis (FGN) was previously defined by glomerular deposition of haphazardly oriented fibrils that stain with antisera to immunoglobulins but do not stain with Congo red. We report what is to our knowledge the first series of immunoglobulin-negative FGN, consisting of 9 adults (7 women and 2 men) with a mean age at diagnosis of 66 years. Patients presented with proteinuria (100%; mean protein excretion, 3g/d), hematuria (100%), and elevated serum creatinine level (100%). Comorbid conditions included carcinoma in 3 and hepatitis C virus infection in 2; no patient had hypocomplementemia or monoclonal gammopathy. Histologically, glomeruli were positive for DNAJB9, showed mostly mild mesangial hypercellularity and/or sclerosis, and were negative for immunoglobulins by immunofluorescence on frozen and paraffin tissue. Ultrastructurally, randomly oriented fibrils measuring 13 to 20nm in diameter were seen intermingling with mesangial matrix in all and infiltrating glomerular basement membranes in 5. On follow-up (mean duration, 21 months), 2 had disease remission, 4 had persistently elevated serum creatinine levels and proteinuria, and 3 required kidney replacement therapy. Thus, rare cases of FGN are not associated with glomerular immunoglobulin deposition, and the diagnosis of FGN in these cases can be confirmed by DNAJB9 immunostaining. Pathogenesis remains to be elucidated.

DNAJB9-positive monotypic fibrillary glomerulonephritis is not associated with monoclonal gammopathy in the vast majority of patients.

The association of fibrillary glomerulonephritis (FGN) with monoclonal gammopathy has been controversial, although monotypic FGN is currently classified as a monoclonal gammopathy of renal significance (MGRS) lesion. To define this lesion, we correlated findings by immunofluorescence on frozen and paraffin tissue, IgG subtype staining and serum protein electrophoresis with immunofixation in patients with monotypic FGN. Immunofluorescence was performed on paraffin sections from 35 cases of DNAJB9-associated FGN that showed apparent light chain restriction of glomerular IgG deposits by standard immunofluorescence on frozen tissue. On paraffin immunofluorescence, 15 cases (14 lambda and one kappa restricted cases on frozen tissue immunofluorescence) showed no light chain restriction, 19 showed similar light chain restriction, and one was negative for both light chains. Seven of the 15 cases with masked polyclonal deposits also had IgG subclass restriction and these cases would have been diagnosed as a form of monoclonal protein-associated glomerulonephritis if paraffin immunofluorescence was not performed. Monotypic FGN (confirmed by paraffin immunofluorescence and IgG subclass restriction) accounted for only one of 151 (0.7%) patients with FGN encountered during the last two years. Only one of 11 of cases had a detectable circulating monoclonal protein on serum protein electrophoresis with immunofixation. We propose that paraffin immunofluorescence is required to make the diagnosis of lambda-restricted monotypic FGN as it unmasked polytypic deposits in over half of patients. When confirmed by paraffin immunofluorescence and IgG subclass staining, DNAJB9-positive monotypic FGN is very rare and is not associated with monoclonal gammopathy in the vast majority of patients. Thus, there is a question whether this lesion should be included in MGRS-related diseases.

Light chain only variant of proliferative glomerulonephritis with monoclonal immunoglobulin deposits is associated with a high detection rate of the pathogenic plasma cell clone.

IgG (mainly IgG3) is the most commonly involved isotype in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID). Here we describe the first series of PGNMID with deposition of monoclonal immunoglobulin light chain only (PGNMID-light chain). This multicenter cohort of 17 patients presented with nephritic or nephrotic syndrome with underlying hematologic conditions of monoclonal gammopathy of renal significance (71%) or multiple myeloma (29%). Monoclonal immunoglobulin was identified by serum and urine immunofixation in 65% and 73%, respectively, with abnormal serum free light chain in 83%, and a detectable bone marrow plasma cell clone in 88% of patients. Renal biopsy showed a membranoproliferative pattern in most patients. By immunofluorescence, deposits were restricted to glomeruli and composed of restricted light chain (kappa in 71%) and C3, with granular appearance and subendothelial, mesangial and subepithelial distribution by electron microscopy. Proteomic analysis in four cases of kappa PGNMID-light chain revealed spectra for kappa constant and variable domains, without evidence of Ig heavy chains; spectra for proteins of the alternative pathway of complement and terminal complex were detected in three. The classical pathway was not detected in three cases. After median follow up of 70 months, the renal response was dependent on a hematologic response and occurred in six of ten patients treated with plasma cell-directed chemotherapy but none of five patients receiving other therapies. Thus, PGNMID-light chain differs from PGNMID-IgG by higher frequency of a detectable pathogenic plasma cell clone. Hence, proper recognition is crucial as anti-myeloma agents may improve renal prognosis. Activation of an alternative pathway of complement by monoclonal immunoglobulin light chain likely plays a role in its pathogenesis.

The sensitivity and specificity of the routine kidney biopsy immunofluorescence panel are inferior to diagnosing renal immunoglobulin-derived amyloidosis by mass spectrometry.

Immunoglobulin light chain amyloidosis is the most frequent type of renal amyloidosis in the United States, accounting for 81% of cases. Accurate typing is crucial for early diagnosis and treatment of immunoglobulin-derived amyloidosis and to avoid treating other amyloidoses with potentially toxic chemotherapy. Immunofluorescence is the first step to type renal immunoglobulin-derived amyloidosis but the performance characteristics of this method are largely unknown. Here, we establish the sensitivity and specificity of immunofluorescence for diagnosing immunoglobulin-derived amyloidosis in patients whose amyloid typing was performed by the current gold standard of laser microdissection/mass spectrometry. Renal biopsy pathology reports originating from several institutions with a diagnosis of amyloidosis and which had amyloid typing by laser microdissection/mass spectrometry performed at our center were reviewed. Reported immunofluorescence staining for kappa or lambda of 2+ or more, with weak or no staining for the other light chain was considered positive for light chain amyloidosis by immunofluorescence. Based on microdissection/mass spectrometry results, of the 170 cases reviewed, 104 cases were typed as immunoglobulin-derived amyloidosis and 66 were typed as non-immunoglobulin-derived amyloidosis. Immunofluorescence sensitivity for diagnosing immunoglobulin-derived amyloidosis was 84.6%. The remaining 16 cases could not be diagnosed by immunofluorescence due to reported weak staining for all antigens or reported lack of preferential staining for one antigen. Immunofluorescence specificity was 92.4%. Five cases, all amyloid A amyloidosis, were misdiagnosed as immunoglobulin-derived amyloidosis by immunofluorescence. Immunofluorescence failed to accurately differentiate immunoglobulin-derived from non-immunoglobulin-derived amyloidosis in 12.3% of cases of renal amyloidosis. Relying on immunofluorescence alone for determining immunoglobulin-derived vs. non-immunoglobulin-derived amyloidosis may lead to misdiagnosis. Thus, immunofluorescence has inferior sensitivity and specificity compared with laser microdissection/mass spectrometry in the typing of immunoglobulin-derived amyloidosis.

Paraneoplastic Cast Nephropathy Associated With Pancreatic Mixed Acinar-Neuroendocrine Carcinoma: A Case Report.

Acute kidney injury is common in patients with cancer and may result from sepsis, obstruction, radiotherapy, chemotherapeutic agents, and nonsteroidal anti-inflammatory drugs. Rare reports of acute kidney injury due to cast nephropathy in patients with pancreatic acinar cell carcinoma have been described, but a pathogenetic link between cast nephropathy and carcinoma was not established. We report a patient with pancreatic mixed acinar-neuroendocrine carcinoma who developed severe acute kidney injury. Kidney biopsy showed cast nephropathy characterized by fractured periodic acid-Schiff-negative casts, associated with mononuclear and giant cell reaction. The patient did not have multiple myeloma and casts did not show immunoglobulin light chain restriction on immunofluorescence. Analysis using liquid chromatography-tandem mass spectrometry and immunohistochemistry identified 2 acinar cell-specific proteins, regenerating islet-derived 1α and carboxypeptidase A1, in both tubular casts and tumor cells. Thus, this case demonstrates that solid tumor-specific proteins can be nephropathic by obstructing renal tubules, resulting in acute kidney injury, a previously proposed but not characterized pathophysiologic mechanism for paraneoplastic nephropathy associated with carcinoma.

Heavy Chain Fibrillary Glomerulonephritis: A Case Report.

Heavy chain amyloidosis and heavy chain deposition disease are the only known kidney diseases caused by the deposition of truncated immunoglobulin heavy chains. Fibrillary glomerulonephritis typically results from deposition of DNAJB9 (DnaJ heat shock protein family [Hsp40] member B9) and polytypic immunoglobulin G (IgG). We describe a patient with monoclonal gammopathy (IgG with λ light chain) who developed DNAJB9-negative fibrillary glomerulonephritis leading to end-stage kidney disease, with recurrence in 2 kidney allografts. Pre- and postmortem examination showed glomerular deposition of Congo red-negative fibrillar material that was determined to be immunoglobulin heavy chain. We propose the term "heavy chain fibrillary glomerulonephritis" to describe this lesion, which appears to be a rare kidney complication of monoclonal gammopathy. The diagnosis should be suspected when the kidney biopsy shows fibrillary glomerulonephritis with negative staining for immunoglobulin light chains and DNAJB9; the diagnosis can be confirmed using immunochemical and molecular studies.

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is associated with high rate of early recurrence in the allograft.

The characteristics of allograft proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) are not well defined. To better characterize this disease we retrospectively identified 26 patients with allograft PGNMID, including 16 followed with early protocol biopsies. PGNMID was found to be a recurrent disease in most (89%) patients. A diagnostic biopsy was done for proteinuria and/or increased creatinine in most patients. Median time from transplant to diagnostic biopsy was 5.5 months, with detection within three to four months post-transplant in 86% of patients. Mesangial proliferative glomerulonephritis was the most common pattern on the diagnostic biopsy with 89% of cases showing immunoglobulin G3 subtype restriction. A detectable serum paraprotein was present in 20% of patients. During a mean follow up of 87 months from implantation, 11 of 25 patients lost their allograft largely due to PGNMID within a mean of 36 months from diagnosis. Median graft survival was 92 months. Independent predictors of graft loss were a higher degree of peak proteinuria and longer time from implantation to diagnosis. Sixteen patients were treated with immunosuppressive therapy which resulted in over 50% reduction in proteinuria in 60%, and improvement of glomerular pathology in nine of 13 patients. However, 44% of responders subsequently relapsed. Thus, PGNMID has a high recurrence rate in renal allografts occurring early with detection enhanced by protocol biopsies. Graft outcome is guarded as nearly half of patients lose their graft within three years from diagnosis. Hence, there is a need for better treatment strategies for this disease.

Congophilic Fibrillary Glomerulonephritis: A Case Series.

RATIONALE & OBJECTIVE: Congo Red positivity with birefringence under polarized light has traditionally permitted classification of organized glomerular deposits as from amyloid or nonamyloid diseases. The absence of congophilia has been used to differentiate fibrillary glomerulonephritis (GN) from amyloidosis. We describe a series of fibrillary GN cases in which the deposits are Congo Red-positive (congophilic fibrillary GN) and discuss the role of DNAJB9 in distinguishing congophilic fibrillary GN from amyloidosis. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Analysis of the clinicopathologic characteristics of 18 cases of congophilic fibrillary GN. Mass spectrometry was performed and compared with 24 cases of Congo Red-negative fibrillary GN, 145 cases of amyloidosis, and 12 apparently healthy individuals. DNAJB9 immunohistochemistry was obtained for a subset of cases. RESULTS: The proteomic signature of amyloid was not detected using mass spectrometry among cases of congophilic fibrillary GN. DNAJB9, a recently discovered proteomic marker for fibrillary GN, was detected using mass spectrometry in all cases of fibrillary GN regardless of congophilia and was absent in cases of amyloidosis and in healthy individuals. DNAJB9 immunohistochemistry confirmed the mass spectrometry findings. The congophilic fibrillary GN cases included 11 men and 7 women with a mean age at diagnosis of 65 years. Concomitant monoclonal gammopathy, hepatitis C virus infection, malignancy, or autoimmune disease was present in 35%, 22%, 17%, and 11% of patients, respectively. No patient had evidence of extrarenal amyloidosis. Patients presented with proteinuria (100%), nephrotic syndrome (47%), hematuria (78%), and chronic kidney disease (83%). After a mean follow-up of 23 months, 31% of patients progressed to end-stage kidney disease and the remaining 69% had persistently reduced kidney function. LIMITATIONS: Retrospective nature. Blinded pathology evaluations were not performed. CONCLUSIONS: The congophilic properties of organized fibrillary deposits should not be solely relied on in differentiating fibrillary GN from renal amyloidosis. Mass spectrometry and DNAJB9 immunohistochemistry can be useful in making this distinction.

Silent diabetic nephropathy.

Moderately increased albuminuria is widely accepted as the first clinical sign of diabetic nephropathy. However, previous morphometric studies and the autopsy study by Klessens et al. have clearly demonstrated that by the time moderately increased albuminuria is evident, the kidneys in some diabetic patients have already undergone glomerular and tubulointerstitial damage, which indicates that it is not a sensitive marker for diabetic nephropathy. Hence, there is a need for new biomarkers of early diabetic nephropathy.