RESUMEN

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease with various etiologies, including idiopathic cases and associations with autoimmune diseases, neoplasms, and viral infections, such as Hepatitis C. We present a case of a patient who developed acute kidney injury (AKI) with atypical clinical features. A subsequent renal biopsy confirmed the diagnosis of FGN, with distinct immunofluorescence staining for DNAJB9. The patient tested positive for Hepatitis C antibodies with an undetectable viral load, indicating a past infection that had self-cleared. This finding prompted further investigation of the association between Hepatitis C and the development of FGN.

RESUMEN

BACKGROUND: Glomerulopathy with fibrillary deposits is not uncommon in routine nephropathology practice, with amyloidosis and fibrillary glomerulonephritis being the two most frequently encountered entities. Renal amyloid heavy and light chain (AHL) is relatively uncommon and its biopsy diagnosis is usually limited to cases that show strong equivalent staining for a single immunoglobulin (Ig) heavy chain and a single light chain, further supported by mass spectrometry (MS) and serum studies for monoclonal protein. But polyclonal light chain staining can pose a challenge. CASE SUMMARY: Herein we present a challenging case of renal AHL with polyclonal and polytypic Ig gamma (IgG) staining pattern by immunofluorescence. The patient is a 62-year-old Caucasian male who presented to an outside institution with a serum creatinine of up to 8.1 mg/dL and nephrotic range proteinuria. Despite the finding of a polyclonal and polytypic staining pattern on immunofluorescence, ultrastructural study of the renal biopsy demonstrated the presence of fibrils with a mean diameter of 10 nm. Congo red was positive while DNAJB9 was negative. MS suggested a diagnosis of amyloid AHL type with IgG and lambda, but kappa light chains were also present supporting the immunofluorescence staining results. Serum immunofixation studies demonstrated IgG lambda monoclonal spike. The patient was started on chemotherapy. The chronic renal injury however was quite advanced and he ended up needing dialysis shortly after. CONCLUSION: Tissue diagnosis of AHL amyloid can be tricky. Thorough confirmation using other available diagnostic techniques is recommended in such cases.

RESUMEN

Fibrillary glomerulonephritis (FGN) is a glomerular disease described since 1977, with a prevalence in renal biopsies of less than 1%. It presents as renal failure, proteinuria, haematuria and hypertension in middle-aged adults. It is defined histologically, using light microscopy, which reveals organised deposits of fibrils measuring around 20nm, which are negative for Congo red staining. Electron microscopy, the first gold standard for diagnosis, has now been superseded by immunohistochemistry using the anti-DNAJB9 antibody. The discovery of this molecule has revolutionised the diagnosis of GNF, thanks to its excellent sensitivity and specificity (98% and 99% respectively). The association of GNF with hepatitis C virus, autoimmune diseases, neoplasia or haemopathy is debated. Renal prognosis is guarded, with 50% of patients progressing to end-stage renal failure within 2 to 4years of diagnosis. In the absence of randomised controlled trials, the recommended treatment is based on nephroprotective measures, corticosteroid therapy and possibly a second-line immunosuppressant such as rituximab. After renal transplantation, recovery or recurrence is possible. The pathophysiology of the disease is still poorly understood, and further studies are needed.

RESUMEN

Monoclonal gammopathy of renal significance (MGRS) has gained importance because identifying the monoclonal deposit and addressing it, rather than treating renal dysfunction as the primary pathology, has salvaged the patients from progressing into end-stage renal disease. Since it affects elderly population, there could be a propensity to misdiagnose them with cardiorenal syndrome. We present four patients of MGRS diagnosed from our center. They presented with proteinuria or unexplained renal dysfunction. Three of the patients were diagnosed to have amyloidosis, of which two had lambda-type and one had kappa amyloidosis. The fourth patient had fibrillary glomerulonephritis with kappa restriction, further evaluation of which led to diagnosis of chronic lymphocytic leukemia. Absence of "M" band in protein electrophoresis and a normal bone marrow study should not stop physicians from further evaluation. Quantitative serum immunofixation electrophoresis and electron microscopic examination of renal biopsy have become a comprehensive diagnostic tool in such patients.

RESUMEN

Fibrillary glomerulonephritis (FGN) is a rare immune-mediated glomerular disease traditionally characterized by the presence of amyloid-like, randomly aligned, fibrillary deposits in the capillary wall, measuring approximately 20 nm in diameter and composed of polyclonal IgG. FGN is usually a primary disease with no pathognomonic clinical or laboratory findings. More than that, on light microscopic evaluation, it can receive various histological patterns, rendering its diagnosis indistinguishable. However, the identification by immunohistochemistry of a novel biomarker, DNA-J heat-shock protein family member B9 (DNAJB9), has created a new era in FGN diagnosis even in the absence of electron microscopy. Typically, most patients manifest various degrees of renal insufficiency, hypertension, microscopic hematuria, proteinuria, and occasionally frank nephrotic syndrome. The prognosis is usually severe and progression to end-stage kidney disease (ESKD) is the rule, given that no specific treatment is available until now, despite the fact that in small studies rituximab-based therapy seems to alleviate the severity and improve the disease progression. Herein, we report the case of a 63-year-old Caucasian man presenting with uncontrolled hypertension, headache, shortness of breath, and lower limb edema. Diagnostic evaluation revealed mild deterioration of kidney function, nephrotic range proteinuria, and faint IgGκ monoclonal bands in serum and urine immunofixation. After negative meticulous investigation for secondary nephrotic syndrome causes, the patient underwent a kidney biopsy. Biopsy sample showed two glomeruli with mesangial expansion and thickened glomerular basement membrane (GBM) on light microscopy, a pattern masquerading as membranous nephropathy stage III-IV, while IgG and C3 were 1-2+ on GBM and mesangium in immunofluorescence. Thickened GBM with fibrils on electron microscopy were found, while DNAJB9 in immunohistochemistry was positive, confirming FGN. Once diagnosis of FGN was made, a combination of steroids with rituximab was initiated while the patient was receiving the standard anti-hypertensive therapy, simultaneously with a sodium-glucose cotransporter-2 (SGLT2) inhibitor. The 12-month follow-up showed approximately 85% decrease in proteinuria alongside stabilization of kidney function and blood pressure normalization. Hence, in this article, we aim to highlight that DNAJB9-associated FGN may mimic membranous glomerulopathy stage III-IV on light microscopy, especially when a small kidney sample with extensive involvement by fibrils of GBM is examined. Moreover, we underscore the fact that ultramicroscopic examination is of crucial importance in the differential diagnosis of glomerular deposition diseases and that DNAJB9 identification on immunohistochemistry consists of a revolutionary and robust biomarker in FGN diagnosis.

RESUMEN

Introduction: Immune checkpoint inhibitor (ICPI) therapy is used to treat various malignancies; however, it can be associated with off-target effects including kidney injury. Acute tubulointerstitial nephritis is the most commonly described renal pathology associated with ICPIs, although less frequently, glomerulopathies may be identified when a kidney biopsy is performed in the work-up of acute kidney injury (AKI). Case Presentation: Two patients with small cell carcinoma of the lung were treated with etoposide, carboplatin, and the ICPI atezolizumab. During 2 and 1.5 months of atezolizumab therapy, respectively, patients developed AKI, hematuria, and proteinuria, and kidney biopsies were performed. Both biopsies showed fibrillary glomerulonephritis with focal crescentic features. One patient died 5 days after the kidney biopsy, while the second showed improvement of renal function after discontinuation of atezolizumab and initiation of corticosteroid therapy. Discussion: We describe two cases of fibrillary glomerulonephritis with crescents after administration of atezolizumab. Development of impaired kidney function following initiation of ICPI therapy in both cases raises the possibility that ICPI therapy may potentiate the development of endocapillary proliferation and crescents (i.e., an "active" glomerulitis) via immune modulation. Thus, exacerbation of underlying glomerulonephritis should be kept in the differential diagnosis of patients who develop AKI, proteinuria, and hematuria following ICPI therapy.

RESUMEN

Fibrillary glomerulonephritis is a rare condition characterized by glomerular accumulation of non-branching fibrils, leading to hematuria, proteinuria, and hypertension. It is often associated with malignancy but has no known cause. A 66-year-old Caucasian female with a history of vulvar squamous cell carcinoma presented with one month of painless hematuria in the setting of new-onset progressive renal dysfunction and nephrotic range proteinuria. Comprehensive evaluation, including renal biopsy with staining for DnaJ heat shock protein family member B9 (DNAJB9), provided a definitive diagnosis of fibrillary glomerulonephritis. The patient initially received rituximab and prednisone therapy. Unfortunately, her renal function continued to decline over the next month, requiring re-hospitalization with initiation of hemodialysis. To our knowledge, this is the first case describing an association between vulvar squamous cell carcinoma and fibrillary glomerulonephritis.

RESUMEN

Various hematologic malignancies can lead to renal complications. The most common of these hemopathies to affect the kidney is multiple myeloma, however an increasing number of kidney diseases are associated with other monoclonal gammopathies. It is recognized that clones in small abundance can be responsible for severe organ damage, thus the concept of monoclonal gammopathy of renal significance (MGRS) has emerged. Although the hemopathy in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with multiple myeloma, the diagnosis of a renal complication changes the therapeutic management. Preservation and restoration of renal function is possible with treatment targeting the responsible clone. In this article, we take as an example immunotactoid and fibrillary glomerulopathies, two distinct entities with different etiologies and consequently different management. Immunotactoid glomerulopathy is most often associated with monoclonal gammopathy or chronic lymphocytic leukemia, the deposits on renal biopsy are monotypic, and treatment is therefore based on clone targeting. Fibrillary glomerulonephritis, on the other hand, is caused by autoimmune diseases or solid cancers. Deposits on renal biopsy are in the vast majority polyclonal. There is a specific immunohistochemical marker, DNAJB9, and treatment is less well established.

RESUMEN

BACKGROUND: Fibrillary (FGN) and immunotactoid (IT) glomerulonephritis are uncommon. AIMS: To evaluate the prevalence, clinicopathological correlations and outcomes of FGN and IT in our regional centre in Australia. METHODS: We interrogated a renal biopsy database for cases of FGN and IT from 2000 to 2020. Data included demographics, serum creatinine, haematuria status, proteinuria, comorbidities and histopathological findings. RESULTS: We had 14 cases of FGN and t of IT. The mean presenting age was 59.8 years, and 42.9% were males. No patients with FGN had dysproteinaemia, whereas both patients with IT had chronic lymphocytic leukaemia. At presentation, 75% of patients with FGN and both patients with IT had haematuria; all had proteinuria. Mean albumin-creatinine ratio at presentation was 254 mg/mmol for FGN and 604 mg/mmol for IT. Mean presenting serum creatinine was 149 µmol/L for FGN and 95 µmol/L for IT. Four patients with FGN (28.6%) received immunomodulatory therapy. The prognosis of FGN was poor, with six patients (46.2%) reaching end-stage kidney disease after a median of 42 months (range 1-96 months). All patients presenting with proteinuria <30 mg/mmol entered complete remission; patients with higher-grade proteinuria exhibited progressive chronic kidney disease. Patients with IT had complete remission with treatment of underlying haematological disease. CONCLUSION: FGN is rare, with poor response to immunomodulatory therapy. It carries poor renal prognosis. Less proteinuria at diagnosis may predict a more benign disease course. IT is associated with haematological malignancy and carries better prognosis and response to treatment.

Asunto(s)

RESUMEN

Fibrillary glomerulonephritis (FGN) is a very rare manifestation of glomerulonephritis characterized by the presence of deposits of randomly oriented microfibrils (10-30 nm size) in the glomeruli and visible on electron microscopy. Our patient is a 63-year-old African American male who presented with a past medical history of cirrhosis; he was initially suspected to have hepatorenal syndrome, but on kidney biopsy, and was diagnosed with FGN. Possible multiple myeloma was suspected due to its strong association with FGN and an elevated serum kappa-lambda ratio in the patient. This was confirmed by bone biopsy to be smoldering myeloma.

RESUMEN

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease characterized by a challenging diagnostic workup requiring ultrastructural identification of 20 nm-thick randomly oriented fibrillar deposits. However, the recent introduction of DNAJB9 as a putative diagnostic marker of FGN could thoroughly improve this diagnostic scenario. This study aims to assess the DNAJB9 immunohistochemical expression in a large series of FGN cases and to eventually confirm its role as a diagnostic marker of FGN. We evaluated the immunohistochemical expression of DNAJB9 (Rabbit Polyclonal, ThermoFisher) in a series of 77 FGN and 128 non-FGN cases diagnosed between January 1992 and June 2022 at the Pathology Unit of the AOU Città della Salute e della Scienza Hospital. DNAJB9 was expressed in 73 of the 74 evaluable FGN cases, mostly showing a strong glomerular positivity (68 cases). Additionally, DNAJB9 resulted positive in all challenging scenarios [early-stage (6), congophilic (4), combined (4), and uncertain (4) cases of FGN)]. DNAJB9 was negative in all non-FGN cases, eventually resulting in a specificity of 100% and sensitivity of 99%. In conclusion, we confirmed the role of DNAJB9 as a diagnostic marker of FGN. Its adoption in the clinical routine will allow a faster, more feasible, and more accurate FGN diagnosis.

RESUMEN

Fibrillary glomerulonephritis (FGN) is a rare but severe kidney disease found to have non-amyloid fibrillary deposits in the mesangium and/or glomerular capillary wall. It was initially thought to be idiopathic, but recent studies show an association with autoimmune disease, malignancy, and hepatitis C infection. We report a case of a non-diabetic patient presenting with long-standing microscopic hematuria, progressive proteinuria, hypertension, and worsening kidney function. The kidney biopsy demonstrated subepithelial fibrillar deposits of size 17 mm randomly oriented with one partial cellular crescent on electron microscopy. Direct immunofluorescence showed no staining for IgG or light chains. It was weakly positive for Congo red staining with a slightly higher serum free kappa/lambda light chain ratio, but serum immunofixation showed no monoclonal protein detection. We empirically treated with rituximab but with no clear benefit or no renal recovery and eventually started on hemodialysis. FGN has an extremely poor prognosis with very few treatment options available. We report this case to emphasize the need for larger, multi-center studies for treatment approaches with collaborating and consolidating data from case reports and case series due to the rarity of the disease.

RESUMEN

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease featured by the randomly arranged 12- to 24-nm fibrils under electron microscopy (EM). Up to 10% of FGN patients have monoclonal gammopathy. However, distinguishing between FGN as monoclonal gammopathy of renal significance (MGRS) and FGN from other causes with incidental monoclonal gammopathy of undetermined significance (MGUS) can be challenging, as the current way of demonstrating monoclonality is flawed due to (1) the suboptimal sensitivity of kappa staining by immunofluorescence in frozen tissue (IF-F) as compared to pronase-digested paraffin sections (IF-P), causing incorrect labeling of light chain restriction; (2) the unavailability of immunoglobulin G (IgG) subtyping in some centers; and (3) the unavailability of tests demonstrating the monoclonality of highly variable VH or VL domains in immunoglobulin structures in clinical use. The discovery of DnaJ homolog subfamily B member 9 (DNAJB9) allows diagnosis for FGN with less reliance on EM, and the summary of recent studies revealed that genuine MGRS is extremely rare among FGN. Further research integrating IF-P, IgG subtyping, VH or VL domain monoclonality confirmation, and DNAJB9 as diagnostic modalities, with corresponding clinical data including treatment response and prognosis, is required for a better understanding of this subject.

Asunto(s)

RESUMEN

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease. FGN is characterized by the deposition of randomly arranged, nonbranching microfibrils in the mesangium and glomerular basement membrane. The discovery of DNAJ homolog subfamily B member 9 (DNAJB9) in 2017 was a breakthrough, and DNAJB9 has been proven to be extremely useful for the definitive diagnosis of FGN. While FGN often occurs in middle-aged individuals, this case was diagnosed at a relatively young age of 17. We performed renal biopsy, and light microscopic study revealed mesangial proliferation with expansion and subepithelial deposits. Electron microscopic study showed glomerular deposition of randomly oriented nonbranching fibrils with a mean of 20 nm. However, direct first scarlet stain for amyloidosis was weakly positive. Therefore, we confirmed the diagnosis of FGN and eliminated the presence of amyloidosis with mass spectrometry. This is the first case in Japan in which the complication of amyloidosis was ruled out with mass spectrometry and FGN was diagnosed using immunostaining and mass spectrometry of DNAJB9. We began treatment with cyclosporine A. One and a half years after the start of the treatment, kidney function continues to be normal.

Asunto(s)

RESUMEN

Introduction: Fibrillary glomerulonephritis (FGN) is a rare glomerular disease with poor prognosis, characterized by deposition of randomly arranged fibrillar material measuring 10-30 nm in diameter. This diagnosis is confirmed with DNAJB9 immunohistochemistry as well as ultrastructural examination. Ultrastructurally, the fibrillary material seen in this entity may be confused with diabetic fibrillosis occurring in diabetic nephropathy. Case Presentation: We present a case of a 63-year-old African American male with remote hepatitis C virus (HCV) infection and type II diabetes mellitus who presented with chronic kidney disease and nephrotic range proteinuria. A kidney biopsy revealed PAS-positive mesangial matrix expansion consistent with diabetic nephropathy and focal randomly oriented fibril deposition on ultrastructural examination. Immunofluorescence for immunoglobulin G and light chains was negative by both routine and paraffin immunofluorescence. Immunohistochemistry for DNAJB9 was diffusely positive, confirming co-existing FGN. Discussion/Conclusion: Patients with diabetic nephropathy and FGN have similar clinicopathologic presentations with a slowly progressive onset of kidney failure and proteinuria. In diabetic patients with fibrillary deposits under ultrastructural examination, concurrence of these disease entities must be considered. In this patient with remote HCV infection that was successfully treated years before, it is possible that in the absence of an FGN trigger, there was a loss of antigenicity with a loss of immunoglobulin staining. Therefore, we recommend DNAJB9 immunostaining for patients with remote HCV infection to avoid this diagnostic pitfall. Further studies are needed to determine the potential role of HCV infection in the initiation and etiopathogenesis of FGN.

RESUMEN

Background: Fibrillary glomerulonephritis (FGN) is found in approximately 1% of native kidney biopsies and was traditionally defined by glomerular deposition of fibrils larger than amyloid (12-24 nm diameter) composed of polyclonal IgG. Recent identification of DNAJB9 as a sensitive and specific marker of FGN has revolutionized FGN diagnosis and opened new avenues to studying FGN pathogenesis. In this review, we synthesize recent literature to provide an updated appraisal of the clinical and pathologic features of FGN, discuss diagnostic challenges and pitfalls, and propose molecular models of disease in light of DNAJB9. Summary: DNAJB9 tissue assays, paraffin immunofluorescence studies, and IgG subclass testing demonstrate that FGN is distinct from other glomerular diseases with organized deposits and highlight FGN morphologic variants. Additionally, these newer techniques show that FGN is only rarely monoclonal, and patients with monoclonal FGN usually do not have a monoclonal gammopathy. DNAJB9 mutation does not appear to affect the genetic architecture of FGN; however, the accumulation of DNAJB9 in FGN deposits suggests that disease is driven, at least in part, by proteins involved in the unfolded protein response. Treatments for FGN remain empiric, with some encouraging data suggesting that rituximab-based therapy is effective and that transplantation is a good option for patients progressing to ESKD. Key Messages: DNAJB9 aids in distinguishing FGN from other glomerular diseases with organized deposits. Further investigations into the role of DNAJB9 in FGN pathogenesis are necessary to better understand disease initiation and progression and to ultimately develop targeted therapies.

RESUMEN

Introduction: The term monoclonal gammopathy of renal significance (MGRS) has been described to include patients with renal manifestations associated with circulating monoclonal proteins with or without a clonal lymphoproliferation (B-cell or plasma cell) and not meeting diagnostic criteria for an overt hematological malignancy. A host of MGRS-associated lesions have been described that involve various renal compartments. Our study describes the histomorphological spectrum of MGRS cases at our center in the last 5 years and description as per the classification system of the International Kidney and Monoclonal Gammopathy Research Group (IKMG). Material and Methods: Retrospective analysis was carried out of all the renal biopsies with characteristic monoclonal immunoglobulin lesions for histopathological diagnosis between years 2015 and 2020 and reviewed by two independent pathologists. Results: Most patients in the study belonged to the fifth decade, with a median age of 50 years (mean 50.14 ± 10.43) range (24-68 years) with a male preponderance. Most patients presented with proteinuria as the sole manifestation (66.6%). Many of the patients (48%) had an M spike by serum protein electrophoresis or urinary protein electrophoresis with an abnormal serum free light chain assay (60.8%). AL amyloidosis was the most common diagnosis observed on histopathological evaluation (68.7%), followed by light chain deposition disease (10.4%). Conclusion: MGRS lesions are infrequently encountered in the practice of nephropathology and pose a diagnostic challenge due to the limitation of a congruent clinical or hematological picture. A thorough histological examination with immunofluorescence and electron microscopy often precipitates in the right diagnosis and prompts timely management.

RESUMEN

Objective:To summarize and analyze the clinicopathological characteristics of patients with DNAJ heat shock protein family member B9 (DNAJB9)-positive fibrillary glomerulonephritis (FGN).Methods:The clinical and pathological data of 5 patients with DNAJB9-positive FGN diagnosed in Peking University First Hospital from January 2011 to January 2021 were retrospectively collected and analyzed.Results:Among the 5 patients, the female to male ratio was 4∶1, and the median age was 29 years old (24-71 years old). The clinical manifestations included 2 cases with nephrotic syndrome and 3 cases with proteinuria. One patient had gross hematuria, and 4 cases had mild microscopic hematuria. None of the 5 patients had evidence of monoclonal gammopathy. The renal pathological pattern of FGN showed mesangial-proliferative glomerulonephritis, mesangial nodular sclerosis, membranoproliferative glomerulonephritis, and atypical membranous nephropathy. Crescents formation could be accompanied. Immunofluorescence staining showed smudgy and granular IgG and C3 deposition in the mesangial region and capillary wall, and the subtypes of IgG were mainly IgG1 and IgG4. Under electron microscopy, fibrillary deposits with a diameter of 8-30 nm were observed in the mesangial and subendothelial area, accompanied by deposition in basement membrane and occasionally subepithelial area. The renal prognosis of FGN patients was poor. One patient entered end-stage renal disease within one week, and another patient entered end-stage renal disease within one year despite immunosuppressant therapy in 2 cases with nephrotic syndrome at onset. One patient had worsening proteinuria despite renin-angiotensin system (RAS) blocker treatment. Two patients achieved complete renal remission and stable renal function after RAS blocker treatment.Conclusions:Most FGN patients in China are young people. The main clinical manifestations are proteinuria or mild microscopic hematuria. The diagnosis depends on the discovery of fibrillary deposits in the mesangial area and subendothelial area with a diameter of about 10-30 nm under the electron microscope. DNAJB9 protein immunohistochemical staining can be used as an important marker for the diagnosis of FGN. The prognosis of FGN kidney is poor, and there is no effective targeted treatment option now.

RESUMEN

The occurrence of renal amyloidosis and fibrillary glomerulonephritis in the same biopsy specimen is exceptional and poses a diagnostic challenge. We describe the case of a non-Hispanic White patient with end-stage kidney disease due to fibrillary glomerulonephritis who received a second living donor kidney from a Hispanic individual. A 40-month-posttransplantation biopsy performed for an elevated serum creatinine level revealed interstitial congophilic deposits and glomerular noncongophilic fibrillary deposits, in addition to rejection. Separate laser microdissections of the glomerular and interstitial deposits followed by liquid chromatography-tandem mass spectrometry (LC MS/MS) revealed DNAJB9 peptide spectra in glomeruli and a peptide profile consistent with leukocyte chemotactic factor 2 (ALECT2) amyloidosis in the interstitium. Based on these findings, a 2-week-posttransplantation biopsy was re-reviewed and analyzed using LC MS/MS, which revealed a peptide profile consistent with ALECT2 amyloidosis in the interstitium, without peptide spectra for ALECT2 or DNAJB9 in glomeruli. The findings were consistent with donor-derived ALECT2 amyloidosis and recurrent fibrillary glomerulonephritis. At 49 months posttransplantation, allograft function was stable with minimal proteinuria. Thus, LC MS/MS was crucial to establish the accurate diagnosis of these 2 nephropathies characterized by fibrillary deposits. The indolent posttransplantation course suggests that donated kidneys with focal interstitial ALECT2 deposits may be suitable for transplantation but the deposits persist for many years.