Search

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.

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.

Introduction Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings. Case report Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes. Conclusion Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.

BACKGROUND In patients with secondary (autoimmune) membranous nephropathy, two novel proteins, Exostosin 1 and Exostosin 2 (EXT1/EXT2), are potential disease antigens, biomarkers, or both. In this study, we validate the EXT1/EXT2 findings in a large cohort of membranous lupus nephritis. METHODS We conducted a retrospective cohort study of patients with membranous lupus nephritis, and performed immunohistochemistry studies on the kidney biopsy specimens against EXT1 and EXT2. Clinicopathologic features and outcomes of EXT1/EXT2-positive versus EXT1/EXT2-negative patients were compared. RESULTS Our study cohort included 374 biopsy-proven membranous lupus nephritis cases, of which 122 (32.6%) were EXT1/EXT2-positive and 252 (67.4%) were EXT1/EXT2-negative. EXT1/EXT2-positive patients were significantly younger (P=0.01), had significantly lower serum creatinine levels (P=0.02), were significantly more likely to present with proteinuria ≥3.5 g/24 h (P=0.009), and had significantly less chronicity features (glomerulosclerosis, P=0.001 or interstitial fibrosis and tubular atrophy, P

Background Coexistence of fibrillary glomerulonephritis (FGN) and immunoglobulin A (IgA) nephropathy (IgAN) in the same kidney biopsy (FGN–IgAN) is rare, and the clinicopathologic characteristics and outcome of this dual glomerulopathy are unknown. Methods In this study, 20 patients with FGN–IgAN were studied and their characteristics were compared with 40 FGN and 40 IgAN control patients. Results Concurrent IgAN was present in 1.8% of 847 consecutive FGN cases and was the second most common concurrent glomerulopathy after diabetic nephropathy. FGN–IgAN patients were overwhelmingly White (94%) and contrary to FGN patients were predominantly (60%) males. Compared with IgAN patients, FGN–IgAN patients were older, had higher proteinuria, a higher incidence of renal insufficiency, and a lower incidence of microhematuria and gross hematuria at diagnosis. Six (30%) patients had malignancy, autoimmune disease or hepatitis C infection, but none had a secondary cause of IgAN or clinical features of Henoch–Schonlein purpura. Histologically, all cases exhibited smudgy glomerular staining for immunoglobulin G and DnaJ homolog subfamily B member 9 (DNAJB9) with corresponding fibrillary deposits and granular mesangial staining for IgA with corresponding mesangial granular electron-dense deposits. On follow-up (median 27 months), 10 of 18 (56%) FGN–IgAN patients progressed to end-stage kidney disease (ESKD), including 5 who subsequently died. Serum creatinine at diagnosis was a poor predictor of renal survival. The proportion of patients reaching ESKD or died was higher in FGN–IgAN than in IgAN. The median Kaplan–Meier ESKD-free survival time was 44 months for FGN–IgAN, which was shorter than IgAN (unable to compute, P = 0.013) and FGN (107 months, P = 0.048). Conclusions FGN–IgAN is very rare, with clinical presentation and demographics closer to FGN than IgAN. Prognosis is guarded with a median renal survival of 3.6 years. The diagnosis of this dual glomerulopathy requires careful evaluation of immunofluorescence findings, and electron microscopy or DNAJB9 immunohistochemistry.

Rationale & Objective Fibrillary glomerulonephritis (FGN) is a rare glomerular disease that often progresses to kidney failure requiring kidney replacement therapy. We have recently identified a novel biomarker of FGN, DnaJ homolog subfamily B member 9 (DNAJB9). In this study, we used sequential protocol allograft biopsies and DNAJB9 staining to help characterize a series of patients with native kidney FGN who underwent kidney transplantation. Study Design Case series. Setting & Participants Between 1996 and 2016, kidney transplantation was performed on 19 patients with a reported diagnosis of FGN in their native/transplant kidneys. Using standard diagnostic criteria and DNAJB9 staining, we excluded 5 patients (4 atypical cases diagnosed as possible FGN and 1 donor-derived FGN). Protocol allograft biopsies had been performed at 4, 12, 24, 60, and 120 months posttransplantation. DNAJB9 immunohistochemistry was performed using an anti-DNAJB9 rabbit polyclonal antibody. Pre- and posttransplantation demographic and clinical characteristics were collected. Summary statistical analysis was performed, including nonparametric statistical tests. Observations The 14 patients with FGN had a median posttransplantation follow-up of 5.7 (IQR, 2.9-13.8) years. 3 (21%) patients had recurrence of FGN, detected on the 5- (n = 1) and 10-year (n = 2) allograft biopsies. Median time to recurrence was 10.2 (IQR, 5-10.5) years. Median levels of proteinuria and iothalamate clearance at the time of recurrence were 243 mg/d and 56 mL/min. The remaining 11 patients had no evidence of histologic recurrence on the last posttransplantation biopsy, although the median time of follow-up was significantly less at 4.4 (IQR, 2.9-14.4) years. 3 (21%) patients had a monoclonal protein detectable in serum obtained pretransplantation; none of these patients had recurrent FGN. Limitations Small study sample and shorter follow-up time in the nonrecurrent versus recurrent group. Conclusions In this series, FGN had an indolent course in the kidney allograft in that detectable histologic recurrence did not appear for at least 5 years posttransplantation.

The aim of this report is to review two patients who developed proteinuria in pregnancy after kidney transplant in order to highlight the importance of maintaining a broad differential and the diagnostic utility of kidney biopsy in this clinical scenario.Two cases of women with kidney transplants who presented with proteinuria in pregnancy are described and the literature is reviewed.In both cases, a kidney biopsy allowed for prompt diagnosis and treatment.Kidney biopsy should be considered an important diagnostic tool in this clinical scenario.ACE: angiotensin-converting enzyme; ESKD: end-stage kidney disease; FSGS: focal segmental glomerulosclerosis; RAAS: renin aldosterone angiotensin system.

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.

Pauci-immune glomerulonephritis in the native kidney presents with renal insufficiency, proteinuria, and hematuria, and is usually due to anti-neutrophil cytoplasmic antibodies. Rarely, kidney transplants can show this pattern as de novo disease. We performed a retrospective analysis in 10 cases of de novo pauci-immune glomerulonephritis. The mean time from transplant to diagnostic biopsy was 32 months (range, 4-96). All biopsies showed focal necrotizing or crescentic glomerulonephritis (mean 16% glomeruli, range 2-36%). Immunofluorescence and electron microscopy showed a pauci-immune pattern. No patients had evidence of systemic vasculitis. Anti-neutrophil cytoplasmic antibody results were available for 7 patients and were negative in all but one. Most patients had functioning grafts at one year after diagnosis. Two patients had repeat biopsies that showed continued active glomerulonephritis. We report the first clinicopathologic series of de novo pauci-immune glomerulonephritis which appears to be a unique pathologic entity that may occur early or late post-transplant and in our cohort is not associated with systemic vasculitis and usually not associated with anti-neutrophil cytoplasmic antibodies. The degree of crescent formation and renal impairment are milder than those of pauci-immune crescentic glomerulonephritis in the native kidney.

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.

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.

Immunofluorescence on frozen tissue is the gold standard immunohistochemical technique for evaluation of immune deposits in the kidney. When frozen tissue is not available or lacks glomeruli, immunofluorescence can be performed on paraffin tissue after antigen retrieval (paraffin immunofluorescence). Excellent results can be obtained by paraffin immunofluorescence in most immune complex–mediated glomerulonephritides and dysproteinemia-associated kidney lesions, and thus this technique has become a valuable salvage technique in renal pathology. Furthermore, new data have emerged suggesting that paraffin immunofluorescence can be used as an unmasking technique, as it is more sensitive than frozen tissue immunofluorescence in some kidney lesions, such as crystalline light chain proximal tubulopathy and is needed to establish the diagnosis of certain unique lesions, such as membranous-like glomerulopathy with masked IgG kappa deposits and membranoproliferative glomerulonephritis with masked monotypic Ig deposits. However, it is important to recognize and be aware of the limitations and pitfalls associated with paraffin immunofluorescence. These include poor sensitivity for detection of C3 deposits and for the diagnosis of primary membranous nephropathy. Here, we summarize the available techniques of paraffin immunofluorescence, review its role and performance as a salvage and unmasking technique in renal pathology, address its limitations and pitfalls, and highlight unusual forms of glomerulopathy that require paraffin immunofluorescence for diagnosis.

Introduction Fibrillary glomerulonephritis (FGN) is a rare disease with unknown pathogenesis and a poor prognosis. Until now, the diagnosis of this disease has required demonstration of glomerular deposition of randomly oriented fibrils by electron microscopy that are Congo red negative and stain with antisera to Igs. We recently discovered a novel proteomic tissue biomarker for FGN, namely, DNAJB9. Methods In this work, we developed DNAJB9 immunohistochemistry and tested its sensitivity and specificity for the diagnosis of FGN. This testing was performed on renal biopsy samples from patients with FGN (n = 84), amyloidosis (n = 21), a wide variety of non-FGN glomerular diseases (n = 98), and healthy subjects (n = 11). We also performed immunoelectron microscopy to determine whether DNAJB9 is localized to FGN fibrils. Results Strong, homogeneous, smudgy DNAJB9 staining of glomerular deposits was seen in all but 2 cases of FGN. The 2 cases that did not stain for DNAJB9 were unique, as they had glomerular staining for IgG only (without κ or λ) on immunofluorescence. DNAJB9 staining was not observed in cases of amyloidosis, in healthy subjects, or in non-FGN glomerular diseases (with the exception of very focal staining in 1 case of smoking-related glomerulopathy), indicating 98% sensitivity and > 99% specificity. Immunoelectron microscopy showed localization of DNAJB9 to FGN fibrils but not to amyloid fibrils or immunotactoid glomerulopathy microtubules. Conclusion DNAJB9 immunohistochemistry is sensitive and specific for FGN. Incorporation of this novel immunohistochemical biomarker into clinical practice will now allow more rapid and accurate diagnosis of this disease.

Introduction Alport syndrome (AS) is a genetic disorder characterized by progressive hematuric nephropathy with or without sensorineural hearing loss and ocular lesions. Previous studies on AS included mostly children. Methods To determine the prognostic value of loss of staining for collagen type IV alpha 5 (COL4A5) and its relationship with the ultrastructural glomerular basement membrane alterations, we performed direct immunofluorescence using a mixture of fluorescein isothiocyanate-conjugated and Texas-red conjugated antibodies against COL4A5 and COL4A2, respectively, on renal biopsies of 25 males with AS (including 16 who were diagnosed in adulthood). Results All patients showed normal positive staining of glomerular basement membranes and tubular basement membranes for COL4A2. Of the 25 patients, 10 (40%) patients showed loss of staining for COL4A5 (including 89% of children and 13% of adults) and the remaining 15 (60%) had intact staining for COL4A5. Compared with patients with intact staining for COL4A5, those with loss of staining had more prominent ultrastructural glomerular basement membrane alterations and were younger at the time of biopsy. By Kaplan-Meier survival analysis and Cox regression analysis, loss of staining for COL4A5 predicted earlier progression to overt proteinuria and stage 2 chronic kidney disease or worse. By multivariate Cox regression analysis, loss of staining for COL4A5 was an independent predictor of the development of overt proteinuria and stage 2 chronic kidney disease or worse. Discussion Thus, the COL4A5 expression pattern has an important prognostic value and it correlates with the severity of ultrastructural glomerular basement membrane alterations in males with AS. Loss of COL4A5 staining is uncommon in patients with AS diagnosed in their adulthood.

Pauci-immune glomerulonephritis in the native kidney presents with renal insufficiency, proteinuria, and hematuria, and is usually due to anti-neutrophil cytoplasmic antibodies. Rarely, kidney transplants can show this pattern as de novo disease. We performed a retrospective analysis in 10 cases of de novo pauci-immune glomerulonephritis. The mean time from transplant to diagnostic biopsy was 32 months (range, 4-96). All biopsies showed focal necrotizing or crescentic glomerulonephritis (mean 16% glomeruli, range 2-36%). Immunofluorescence and electron microscopy showed a pauci-immune pattern. No patients had evidence of systemic vasculitis. Anti-neutrophil cytoplasmic antibody results were available for 7 patients and were negative in all but one. Most patients had functioning grafts at one year after diagnosis. Two patients had repeat biopsies that showed continued active glomerulonephritis. We report the first clinicopathologic series of de novo pauci-immune glomerulonephritis which appears to be a unique pathologic entity that may occur early or late post-transplant and in our cohort is not associated with systemic vasculitis and usually not associated with anti-neutrophil cytoplasmic antibodies. The degree of crescent formation and renal impairment are milder than those of pauci-immune crescentic glomerulonephritis in the native kidney.

Renal extramedullary hematopoiesis is rarely recognized in the antemortem setting. We identified 14 patients with renal extramedullary hematopoiesis on antemortem specimens from 1994 to 2015. The mean age was 68 years (range 47-87 years); males predominated (M:F=9:5). All presented with renal insufficiency, including five (36%) with acute kidney injury. The mean serum creatinine at biopsy was 2.9 mg/dl (range 1.2-7.3 mg/dl). All had proteinuria (mean 7.9 g/24 h; range 0.5-28; n=13), including 9 with ≥3 g/24 h. Renal extramedullary hematopoiesis appeared histologically as an interstitial infiltrate (n=12) and/or a perirenal infiltrate (n=3) or mass-like lesion (n=1). Five were misdiagnosed as interstitial nephritis. Concurrent glomerular disease was prevalent and included fibrillary-like glomerulonephritis (n=3), chronic thrombotic microangiopathy (n=5), focal segmental glomerulosclerosis (n=6), and diabetic glomerulosclerosis (n=2). All patients had an underlying hematologic malignancy: primary myelofibrosis in 9, myeloproliferative neoplasm not otherwise specified in 1, essential thrombocythemia in 1, polycythemia vera in 1, and plasma cell myeloma in 2. Clinical follow-up was available in 12 patients, mean of 29 months (range 4-120 months). In 10 patients for whom treatment history could be obtained, 9 were treated with chemotherapy, and 1 was treated with steroids. The mean creatinine at last follow-up was 2 mg/dl (range 1.2-3.9 mg/dl) (n=9). Ten patients died in the follow-up period from their underlying hematological disease and had persistent renal disease. The two remaining patients had persistent chronic kidney disease. Renal extramedullary hematopoiesis should be considered in the differential diagnosis of interstitial infiltrates, particularly in the presence of a glomerulopathy and a hematologic malignancy.

The diagnosis of membranoproliferative glomerulonephritis (MPGN) has recently undergone change from an electron microscopy-based classification scheme to one based largely on immunofluorescence findings. This change is due to the recognition that many of these cases are driven by abnormalities of the alternative complement cascade, resulting in the concept of C3 glomerulopathy. Here we reviewed our case files to identify those with an MPGN pattern that show false negative staining for monoclonal immunoglobulins by routine immunofluorescence. Monoclonal immunoglobulin deposits were unmasked by performing immunofluorescence on formalin-fixed paraffin embedded tissue after protease digestion. Clinico-pathological details of 16 such cases with a mean serum creatinine of 2.7 mg/dl and mean 24 h proteinuria of 7.1 g were then determined. Hypocomplementemia was present in two-thirds of patients. Fourteen patients had a paraprotein on serum immunofixation, all of which matched the biopsy immunofluorescence staining pattern. Bone marrow biopsy showed plasma cell dyscrasia or B-cell lymphoproliferative disorder in 13 patients. Ten of these patients had findings on biopsy most consistent with C3 glomerulonephritis prior to performing paraffin immunofluorescence. Thus a high index of suspicion is necessary to avoid misdiagnosis in these cases, as many would have been mistakenly diagnosed as C3 glomerulopathy or unclassified MPGN if paraffin immunofluorescence was not performed.

Acute interstitial nephritis (AIN) is an important cause of acute kidney injury (AKI), and its prevalence in the elderly may be increasing. It is largely unknown whether AIN in the elderly is similar to that in younger adults; therefore, we investigated the causes and characteristics of AIN in 45 elderly patients (65 years and older) and in 88 younger adults (18-64 years old). Compared with younger patients, the elderly had significantly more drug-induced AIN (87 vs. 64%), proton pump inhibitor-induced AIN (18 vs. 6%), but significantly less AIN due to autoimmune or systemic causes (7 vs. 27%). The two most common culprit drugs in the elderly were penicillin and omeprazole. Compared with younger patients, the elderly had higher prevalence of baseline CKD, higher peak creatinine, and more need for dialysis, all of which were significant. Among the elderly, 86% showed partial or complete recovery within 6 months. Significantly shorter delays in initiation of steroids correlated with recovery at 6 months. Lack of early recovery tended to correlate with progressive CKD. Compared with antibiotic-induced AIN, proton pump inhibitor-induced AIN had less severe AKI, but a longer duration of drug exposure, and was less likely to recover by 6 months, all significant. Thus, the vast majority of AIN cases in the elderly are due to drugs, primarily owing to proton pump inhibitors and antibiotics, while AIN of autoimmune or systemic origin is uncommon.

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.

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.

Amyloidosis derived from leukocyte chemotactic factor 2 (ALECT2) is a recently described disease. Here, we report the characteristics and outcome of 72 patients with renal ALECT2, which included 19 who had another kidney disease on biopsy. Ninety-two percent of patients were Hispanics and over half were elderly. Three had other organ, but not cardiac, amyloidosis involvement. All patients without concurrent disease, except three, presented with chronic renal insufficiency. Proteinuria was variable and absent in a third, whereas nephrotic syndrome and hematuria were rare. After a median follow-up of 26 months, one-third developed end-stage renal disease (ESRD). The median renal survival was 62 months. Independent predictors of renal survival were serum creatinine at diagnosis, with a value of 2.0mg/dl being the best cutoff for predicting ESRD, percentage global glomerulosclerosis, and presence of diabetes. Only four patients died and four had received chemotherapy for an erroneous diagnosis of immunoglobulin light chain-derived amyloidosis. Five patients underwent kidney transplantation; none had graft loss but one had disease recurrence. Patient survival is superior to renal immunoglobulin light chain-derived amyloidosis and reactive amyloidosis largely due to the absence of cardiac involvement. Thus, renal ALECT2 mainly affects elderly Hispanics who typically present with chronic renal insufficiency and bland urine sediment, with or without proteinuria.

Mitochondrial NADH dehydrogenase 5 (MT-ND5) Asp393Asn missense mutation is established to cause mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS).1,2 We describe a case and family with this mutation and a divergent phenotype that eluded diagnosis. We suggest an expanded nomenclature, m itochondrial c erebellar a taxia, r enal failure, n europathy, and e ncephalopathy (MCARNE).

Summary Background and objectives The kidney is the organ most commonly involved in systemic amyloidosis. This study reports the largest clinicopathologic series of renal amyloidosis. Design, setting, participants, & measurements This study provides characteristics of 474 renal amyloidosis cases evaluated at the Mayo Clinic Renal Pathology Laboratory from 2007 to 2011, including age, sex, serum creatinine, proteinuria, type of amyloid, and tissue distribution according to type. Results The type of amyloid was Ig amyloidosis in 407 patients (85.9%), AA amyloidosis in 33 (7.0%), leukocyte chemotactic factor 2 amyloidosis in 13 (2.7%), fibrinogen A α chain amyloidosis in 6 (1.3%), Apo AI, Apo AII, or Apo AIV amyloidosis in 3 (0.6%), combined AA amyloidosis/Ig heavy and light chain amyloidosis in 1 (0.2%), and unclassified in 11 (2.3%). Laser microdissection/mass spectrometry, performed in 147 cases, was needed to determine the origin of amyloid in 74 of the 474 cases (16%), whereas immunofluorescence failed to diagnose 28 of 384 light chain amyloidosis cases (7.3%). Leukocyte chemotactic factor 2 amyloidosis and Apo AI, Apo AII, or Apo AIV amyloidosis were characterized by diffuse interstitial deposition, whereas fibrinogen A α chain amyloidosis showed obliterative glomerular involvement. Compared with other types, Ig amyloidosis was associated with lower serum creatinine, higher degree of proteinuria, and amyloid spicules. Conclusions In the authors’ experience, the vast majority of renal amyloidosis cases are Ig derived. The newly identified leukocyte chemotactic factor 2 amyloidosis form was the most common of the rarer causes of renal amyloidosis. With the advent of laser microdissection/mass spectrometry for amyloid typing, the origin of renal amyloidosis can be determined in >97% of cases.

We present a case of JC polyomavirus (JCV)-associated nephropathy (PyVAN) in an asymptomatic deceased-donor kidney transplant recipient. Despite the presence of viral cytopathic effect in the kidney biopsy and positive BK polyomavirus (BKV) in situ hybridization (ISH), BKV real-time polymerase chain reaction (PCR) results of plasma and urine were negative. JCV ISH was performed and was found to be positive. JCV real-time PCR on urine, plasma, and the kidney biopsy tissue was positive. Reduction in immunosuppression resulted in resolution of JCV viremia. This case highlights that JC-PyVAN is a distinct clinical entity and is likely to have a better clinical outcome than BK-PyVAN. Concurrent infection with BKV and JCV may occur, but may be difficult to confirm owing to the potential for cross reactivity between BKV and JCV IHS stains. This article is protected by copyright. All rights reserved.

Background Immunotactoid glomerulopathy (ITG) is a rare glomerular disease. Here, we report the largest clinicopathologic series of ITG and define its proteomic profile. Methods The characteristics of 16 ITG patients who were identified from our pathology archives are provided between 1993 and 2011. We also performed laser microdissection and mass spectrometry (LMD/MS) in three cases. Results Presentation included proteinuria (100%), nephrotic syndrome (69%), renal insufficiency (50%) and microhematuria (80%). Hypocomplementemia was present in 46% and a serum M-spike in 63%. Hematologic malignancy was present in 38%, including chronic lymphocytic leukemia in 19%, lymphoplasmacytic lymphoma in 13% and myeloma in 13%. The pattern of glomerular injury was membranoproliferative (56%), membranous (31%) or proliferative (13%) glomerulonephritis. The microtubular deposits were immunoglobulin light chain restricted in 69% and had a mean diameter of 31 nm (range 17-52). During an average of 48 months of follow-up for 12 patients, 50% had remission, 33% had persistent renal dysfunction and 17% progressed to end-stage renal disease. Proteomic analysis by LMD/MS revealed the presence of immunoglobulins, monotypic light chains, complement factors of the classical and terminal pathway and small amount of serum amyloid P-component. Conclusions Hematologic malignancy, particularly lymphoma, is not uncommon in ITG. ITG appears to have a better prognosis than other paraprotein-related renal lesions, with a half of patients expected to recover kidney function with immunosuppressive therapy or chemotherapy. The proteomic profile of ITG is consistent with deposition of monotypic immunoglobulins and activation of the classical and terminal pathway of complement.

Background: Renal involvement is common in multiple myeloma. In this study, we examined kidney biopsy findings in patients with multiple myeloma and correlated them with their clinical renal and hematologic characteristics. Study Design: Case series. Setting & Participants: 190 Mayo Clinic patients with multiple myeloma who underwent kidney biopsy between 1997-2011 were identified from our kidney biopsy database. Patients had an established diagnosis of multiple myeloma or multiple myeloma was diagnosed shortly after the results of kidney biopsy, which prompted bone marrow biopsy. Predictors:Myeloma cast nephropathy (MCN), AL amyloidosis, and monoclonal immunoglobulin deposition disease (MIDD). Outcomes & Measurements: Renal morphologic changes, clinical renal and hematologic characteristics at kidney biopsy, renal and patient outcomes. Results: Paraprotein-associated lesions were seen in 73% of patients; non‐paraprotein-associated lesions, in 25%; and no pathology, in 2%. The most common paraprotein-associated lesions were MCN (33%), MIDD (22%), and amyloidosis (21%). The most common non‐paraprotein-associated lesions were acute tubular necrosis (9%), hypertensive arteriosclerosis (6%), and diabetic nephropathy (5%). Patients with MIDD were younger than those with MCN or amyloidosis. Urine paraprotein size and bone marrow plasma cell percentage were higher in MCN than amyloidosis or MIDD. Nephrotic syndrome was more common in amyloidosis than MIDD. Percentage of albuminuria was highest in amyloidosis and lowest in MCN. Median kidney survival from kidney biopsy was 20, 30, and 51 months for MCN, amyloidosis, and MIDD, respectively (P 0.2). Median patient survival from multiple myeloma diagnosis was 44, 58, and 62 months for MCN, amyloidosis, and MIDD, respectively (P 0.4). Limitations: Retrospective nature. Conclusions: The spectrum of renal lesions in multiple myeloma is more heterogeneous than previously reported. Clinical features favoring amyloidosis over MIDD include older age, absence of kidney failure, presence of nephrotic syndrome, absence of hematuria, and 50% albuminuria. Am J Kidney Dis. 59(6):786-794. © 2012 by the National Kidney Foundation, Inc.

In the kidney, immunoglobulin light chain amyloidosis (AL) can be deposited in vascular-limited AL (V-AL) or diffuse (D-AL) pattern. These patterns are associated with different clinical presentations. A nested case study was performed to describe these differences. V-AL was defined by the vascular-limited deposits. Cases were matched for age, sex and date of renal biopsy. There were 12 cases of V-AL (mean age 61 ± 11 years) and 24 cases of D-AL. Median follow-up was 26 months for V-AL and 38 months for D-AL, P = 0.14. Lambda was more common in D-AL (83.3%) than V-AL (50%, P = 0.04). Cardiac function was similar between the two groups. V-AL patients presented with lower renal function (serum creatinine = 2.1 versus 1.3 mg/dL, P = 0.02; estimated glomerular filtration rate 31 versus 59 mL/min/1.73m(2), P = 0.01 and creatinine clearance 38.5 versus 64 mL/min/1.73m(2), P = 0.02, respectively). Proteinuria was low grade in V-AL [0.4 (0.09-0.98) g/day] compared to nephrotic range in D-AL patients [8.0 (0.2-22) g/day, P < 0.001]. Stem cell transplantation was performed on 62.5% of the D-AL but on only 25% of the V-AL, P = 0.08. Median survival was longer in patients with D-AL (77.2 months) versus V-AL (40.6 months, log-rank P = 0.02). Our study found that V-AL patients presented with more severe renal insufficiency and less proteinuria than D-AL. There was a preference for λ light chain in the D-AL that was not noted in the V-AL. Patients with D-AL in this study had a longer median survival but most of them were stem cell transplantation candidates.

IgG4-related systemic disease is an autoimmune disease that was first recognized in the pancreas but also affects other organs. This disease may manifest as tubulointerstitial nephritis (IgG4-TIN), but its clinicopathologic features in the kidney are not well described. Of the 35 patients with IgG4-TIN whose renal tissue specimens we examined, 27 (77%) had acute or progressive chronic renal failure, 29 (83%) had involvement of other organ systems, and 18 of 23 (78%) had radiographic abnormalities. Elevated total IgG or IgG4 serum levels were present in 79%. All pathologic specimens featured plasma cell–rich TIN, with most showing diffuse, expansile interstitial fibrosis. Immune complexes along the tubular basement membranes were present in 25 of 30 (83%). All specimens had a moderate to marked increase in IgG4+ plasma cells by immunohistochemistry. We used a control group of 175 pathologic specimens with plasma cell–rich interstitial infiltrates that can mimic IgG4-TIN to examine the diagnostic utility of IgG4 immunostaining. Excluding pauci-immune necrotizing and crescentic glomerulonephritis, IgG4 immunohistochemistry had a sensitivity of 100% (95% CI 90–100%) and a specificity of 92% (95% CI 86–95%) for IgG4-TIN. Of the 19 patients with renal failure for whom treatment and follow-up data were available, 17 (89%) responded to prednisone. In summary, because no single test definitively diagnoses IgG4-related systemic disease, we rely on a combination of histologic, immunophenotypic, clinical, radiographic, and laboratory features. When the disease manifests in the kidney, our data support diagnostic criteria that can distinguish IgG4-TIN from other types of TIN.

Summary Background and objectives Fibrillary glomerulonephritis (FGN) is a rare primary glomerular disease. Most previously reported cases were idiopathic. To better define the clinical-pathologic spectrum and prognosis, we report the largest single-center series with the longest follow-up. Design, setting, participants, & measurements The characteristics of 66 FGN patients who were seen at Mayo Clinic, Rochester, between 1993 and 2010 are provided. Results The mean age at diagnosis was 53 years. Ninety-five percent of patients were white, and the female:male ratio was 1.2:1. Underlying malignancy (most commonly carcinoma), dysproteinemia, or autoimmune disease (most commonly Crohn9s disease, SLE, Graves9 disease, and idiopathic thrombocytopenic purpura), were present in 23, 17, and 15% of patients, respectively. Presentation included proteinuria (100%), nephrotic syndrome (38%), renal insufficiency (66%), hematuria (52%), and hypertension (71%). The most common histologic pattern was mesangial proliferative/sclerosing GN followed by membranoproliferative GN. During an average of 52.3 months of follow-up for 61 patients with available data, 13% had complete or partial remission, 43% had persistent renal dysfunction, and 44% progressed to ESRD. The disease recurred in 36% of 14 patients who received a kidney transplant. Independent predictors of ESRD by multivariate analysis were older age, higher creatinine and proteinuria at biopsy, and higher percentage of global glomerulosclerosis. Conclusions Underlying malignancy, dysproteinemia, or autoimmune diseases are not uncommon in patients with FGN. Prognosis is poor, although remission may occur in a minority of patients without immunosuppressive therapy. Age, degree of renal impairment at diagnosis, and degree of glomerular scarring are predictors of renal survival.

Summary Background and objectives Proliferative GN with monoclonal IgG deposits (PGNMID) is a newly described entity resembling immune complex GN. Its potential to recur in the allograft is undefined. Design, setting, participants, & measurements The first cases of recurrent PGNMID in the allograft are reported. Results The cohort includes four Caucasians (3 women, 1 man) with a mean age 58.5 years. No patient had M spike or hematologic malignancy. Recurrence was first documented by biopsy at a mean of 3.8 months posttransplant for indications of renal insufficiency in four patients, proteinuria in three patients, and microhematuria in three patients. Monoclonal IgG deposits (3 IgG3κ and 1 IgG3λ) in the transplants had identical heavy- and light-chain isotypes as in the native kidneys. In two patients, a pattern of endocapillary GN was identified in the native and transplant biopsies, whereas two patients with membranoproliferative GN in the native kidney developed endocapillary or mesangial GN in the transplant. Recurrence was treated with combined high-dose prednisone plus rituximab (n = 3) or plus cyclophosphamide (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. Conclusions PGNMID can recur in the transplant despite the absence of a serum M spike. Recurrence is heralded by proteinuria, hematuria, and allograft dysfunction and manifests diverse histologic patterns. Although the pathogenesis remains unknown, early immunosuppressive therapy appears to stabilize the course.

Background and objectives: Amyloidosis is a group of disorders characterized by accumulation of extracellular deposition of proteins as insoluble aggregates. The clinical management of amyloidosis is based on identifying the underlying etiology and accurate typing of the amyloid. Ig heavy chain amyloid involving the kidney is poorly recognized and often poses a diagnostic dilemma. Design, setting, participants, & measures: In this study, we describe the use of laser microdissection (LMD) and mass spectrometry (MS)–based proteomic analysis for the accurate typing of 14 cases of amyloidosis. We also describe the clinicopathologic findings of four problematic cases of renal Ig heavy chain amyloidosis that required LMD/MS proteomic analysis for accurate typing of the amyloid. Results: LMD/MS proteomic data of four cases of Ig heavy chain renal amyloidosis showed Ig heavy chains with or without light chains. The break up of the Ig heavy chains was as follows: one case showed Igγ1 chain constant region and λ light chains, one case showed Igα chain constant region and κ light chains variable and constant regions, whereas two cases showed Igγ3 chain constant region and heavy chains variable region I and/or III without light chains. We compare the LMD/MS proteomic data of Ig heavy chain renal amyloid with that of other types of amyloid, including Ig light chains, serum amyloid A, fibrinogen A-α chain renal amyloid, and transthyretin amyloid. Conclusions: We conclude that LMD/MS is a sensitive and specific tool for diagnosis and accurate typing of renal amyloidosis, including Ig heavy chain amyloid.

C1q nephropathy is an uncommon glomerular disease characterized by dominant or codominant mesangial staining for C1q in the absence of systemic lupus erythematosus. There are no series in the literature addressing the significance of C1q deposition in the renal allograft. We retrospectively analyzed 24 patients, most of whom were white (83%) and male (63%), with a mean age at transplant of 31 years. None of the patients were diagnosed with C1q nephropathy in the native kidney or had any features of systemic lupus erythematosus. The mean time from transplant to detection of mesangial C1q deposits was 37 months (12 months in 71% of cases). Half of the patients had a preceding infection. The indication for biopsy was surveillance (63%) or graft dysfunction (37%). At biopsy, 52% had proteinuria (1g/day in only 17%). The mean creatinine was 1.8 mg per 100 ml. Only 9% developed hematuria and none had hypoalbuminemia. The glomerular pattern on light microscopy was mesangial hypercellularity (46%), focal segmental glomerulosclerosis (21%), or no lesions (33%). All cases showed intense (or=2+) dominant (67%) or codominant (33%) mesangial staining for C1q on immunofluorescence. Mesangial electron-dense deposits were seen in 82% of cases. On follow-up (mean 1 year) of the 10 patients without rejection, most had stable creatinine with no or stable proteinuria, and none lost their graft. We conclude that C1q-dominant mesangial deposition in the renal allograft is a morphological pattern with no apparent clinical significance in the majority of patients. It is usually detected after the first year. The rate of preceding infection and the prevalence of proteinuria seem to be similar to the renal transplant recipients in general. Most cases show mesangial hypercellularity or no glomerular changes on light microscopy.

Waldenström's macroglobulinemia is rare lymphoproliferative disorder characterized by the presence of a monoclonal IgM paraproteinemia. Cryoglobulinemia is a common sequela of Waldenström's macroglobulinemia present in 8-18% of the patients. Cryoglobulinemia has also been described as occurring after treatment with rituximab. In the previous report, the cryoglobulinemia was a transient phenomenon and did not carry any adverse effect. We present a case of an 80-year-old male with Waldenström's macroglobulinemia in whom the rituximab-induced cryoglobulinemia resulted in acute renal failure and a vasculitic rash. Cryoglobulins level reached a peak of 63%. The patient was successfully treated with plasmapheresis, chlorambucil and prednisone, with near-complete recovery of renal function. As this case illustrates, the rituximab-induced cryoglobulin is not always benign. Pre- and post-treatment monitoring of the cryoglobulin level is advised in these patients.

Proteinuria is associated with reduced kidney allograft survival. Herein we assessed the association between proteinuria, graft histology and survival. The cohort included 613 kidney allograft recipients who had proteinuria (measured) and surveillance biopsies at 1-year posttransplant. Proteinuria150 mg/day was detected in 276 patients (45%) and in 182 of these, proteinuria was below 500. In84% of patients even low levels of proteinuria were associated with albuminuria. Proteinuria was associated with the presence of graft glomerular pathology and the use of sirolimus. Eighty percent of patients with proteinuria1500 mg/day had glomerular pathology on biopsy. However, lower levels of proteinuria were not associated with specific pathologies at 1 year. Compared to no sirolimus, sirolimus use was associated with higher prevalence of proteinuria (40% vs. 76%, p0.0001) and higher protein excretion (378 + 997 vs. 955 + 1986 mg/day, p0.0001). Proteinuria was associated with reduced graft survival (HR = 1.40, p = 0.001) independent of other risk factors including, glomerular pathology, graft function, recipient age and acute rejection. The predominant pathology in lost allografts (n = 57) was glomerular, particularly in patients with 1-year proteinuria500. Thus, proteinuria, usually at low levels (500 mg/day), is present in 45% of recipients at 1 year. However, and even low levels of proteinuria relate to poor graft survival. Proteinuria and glomerular pathology relate independently to survival.

Context.—Management of laboratories and pathology practices is increasingly complex. Residents and fellows in laboratory medicine and pathology need more structured curricula in leadership and management (L&M) training to function as medical and laboratory directors. Objective.—To define a curriculum that provides basic competency in L&M for residents and fellows in pathology. Design.—A year-long formal L&M course included didactic lectures, interactive sessions, case scenarios, team-building exercises, formal team presentations (capstone project), and precourse and postcourse assessment of L&M knowledge. The curriculum meets requirements of American College of Graduate Medical Education and supports goals for leadership training of the College of American Pathologists. Participants evaluated (5-point scale) the content and speakers of all sessions. Trainees were evaluated after considering postcourse examination results, quality of the capstone presentation, and a global assessment. Results.—The 5 non-capstone sessions received evaluation scores ranging from 4.4 (informatics) to 5 (L&M basics). Postcourse test scores showed significant improvement when compared with the pretest scores for the 2003– 2004 and 2004–2005 trainee cohorts. Conclusions.—Short-term results indicate that the course described improves trainee knowledge of L&M issues.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) has been described as a new entity resembling immune-complex glomerulonephritis (GN). The recurrence of proliferative GN with monoclonal IgG in the renal allograft has been reported. However, recurrence of proliferative GN with monoclonal IgA after renal allograft is undefined. We previously reported a case of a 35-year-old woman with proliferative glomerulonephritis with monoclonal lambda (λ) with mesangial and subendothelial paracrystalline deposits in the native kidney and initially undetectable circulating monoclonal protein or clone by bone marrow biopsy or flow cytometry. Despite immunosuppressive therapy, her renal disease progressed to end-stage of renal disease (ESRD) and the patient ultimately received a renal allograft. Transplantation was followed by recurrence of IgA-λ PGNMID 4 months after renal transplantation and was associated the diagnosis of multiple myeloma. To the best of our knowledge recurrence of IgA PGNMID with paracrystalline deposits has not been previously reported.

Anti-glomerular basement membrane disease has been reported to coexist with anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis. Seronegative anti-GBM disease has been previously described and mostly blamed for the relative insensitivity of earlier serologic assays. A 58-year-old male was transferred to our facility for acute kidney injury. Prior to his hospital admission, the patient had a 2 week history of progressive fatigue, fevers, anorexia, vomiting, decreased urine output, sinus congestion, and non-productive cough. His creatinine reached 13 mg/dL. P-ANCA was positive, anti GBM antibody was negative twice, and urinalysis showed hematuria. Chest x-ray demonstrated diffuse opacities, concerning for pulmonary hemorrhage. Renal biopsy showed a severe necrotizing and crescentic glomerulonephritis with circumferential crescents. There was bright linear glomerular basement membrane staining with IgG consistent with anti-GBM disease. Given these findings, the patient was started on oral cyclophosphamide (160 mg daily), in addition to pulse dose methylprednisolone. He was also initiated on therapeutic plasma exchange. Due to worsening renal function, hemodialysis was started. The patient was discharged from the hospital and completed a course of treatment with cyclophosphamide and prednisone but remains oligo-anuric and hemodialysis dependent at 150 days since presentation. This case highlights the importance of tissue diagnosis in situations similar to this.

Granulomatous interstitial nephritis (GIN) is an uncommon pathologic lesion encountered in 0.5% to 5.9% of renal biopsies. Drugs, sarcoidosis, and infections are responsible for most cases of GIN. Malignancy is not an established cause of GIN. Here, we report a series of 5 patients with GIN secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients were mostly elderly white males with an established history of CLL/SLL who presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), leukocyturia, and mild proteinuria. One had nephromegaly. In 2 patients, the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis. Kidney biopsy in all patients showed GIN concomitant with CLL/SLL leukemic interstitial infiltration. Granulomas were nonnecrotizing and epithelioid and were associated with giant cells. One biopsy showed granulomatous arteritis. One patient had a granulomatous reaction in lymph nodes and skin. Steroids with/without CLL/SLL-directed chemotherapy led to partial improvement of kidney function in all patients except 1 who had advanced cortical scarring on biopsy. In conclusion, we report an association between CLL/SLL and GIN. Patients typically present with severe renal failure due to both GIN and leukemic interstitial infiltration, which tends to respond to steroids with/without CLL/SLL-directed chemotherapy. The pathogenesis of GIN in this clinical setting is unknown but may represent a local hypersensitivity reaction to the CLL/SLL tumor cells.

The purpose of this study was to characterize the histology of antibody-mediated rejection (AMR) in ABO blood-group-incompatible (ABOI) kidney transplants as well as on protocol biopsies performed at the time of stable allograft function. Between 5/99 and 1/02, we performed 32 ABOI kidney transplants (13 A2, 19 non-A2 blood-group living donors). Nineteen biopsies were performed for allograft dysfunction, and 127 protocol biopsies were performed 0, 3, 7, 14, 28 days and 3 and 12 months post transplant. Twenty-five of 32 patients have functioning allografts (mean 585 days post transplant). Nine of 32 (28%) developed clinical AMR. Biopsy revealed glomerular thrombi (78%), mesangiolysis (78%), peritubular capillary C4d staining (56%) and neutrophil infiltration (67%), interstitial hemorrhage and necrosis (56%) and arteriolar thrombi (33%). Subclinical AMR was diagnosed by protocol biopsies in four patients. Findings consisted of glomerular thrombi (100%), mesangiolysis (25%), and C4d staining (100%). In late protocol biopsies performed 214-420 days post transplant, mild mesangiolysis was seen in 2/17 (11.7%), and C4d immunostaining was detected in 3/12 (25%). AMR is characterized by glomerular thrombi, mesangiolysis, peritubular capillary neutrophil infiltration interstitial hemorrhage, necrosis, and C4d deposition. Glomerular thrombi appear early in AMR and may appear prior to graft dysfunction.