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Glomerular diseases due to nonamyloid fibrillar deposits

Glomerular diseases due to nonamyloid fibrillar deposits
Authors:
Fernando C Fervenza, MD, PhD
Sanjeev Sethi, MD, PhD
Section Editors:
Richard J Glassock, MD, MACP
Brad H Rovin, MD
Deputy Editor:
Albert Q Lam, MD
Literature review current through: Oct 2022. | This topic last updated: Jul 16, 2021.

INTRODUCTION — Glomerular disease may be associated with the appearance of fibrillar deposits in the mesangium or glomerular basement membrane. The fibrils are Congo red positive in amyloidosis and are typically Congo red negative in other forms. The most common forms of nonamyloid fibrillary glomerular deposition diseases are fibrillary glomerulonephritis and immunotactoid glomerulopathy.

Fibrillary glomerulonephritis [1-7] and immunotactoid glomerulopathy [3,5,6,8-10] are uncommon, but distinctly different, causes of glomerular disease. Both disorders result from deposits derived from immunoglobulins [10]. Other forms of nonamyloid fibrillary deposition disease have been described in which the deposits are composed of fibronectin (fibronectin glomerulopathy) or atypical type III collagen fibrils (collagenofibrotic glomerulopathy). (See 'Pathology and pathogenesis' below and 'Other fibrillary disorders' below.)

Glomerular disease associated with amyloid deposits is discussed separately. (See "Renal amyloidosis".)

FIBRILLARY AND IMMUNOTACTOID DISEASE — Fibrillary glomerulonephritis and immunotactoid glomerulopathy are uncommon disorders, being present in 0.5 to 1.4 percent of native kidney biopsies [3,6]. They are separate disorders [2,3,9,11,12], with fibrillary glomerulonephritis accounting for approximately 85 to 90 percent of cases [3,5,9]. The identification of the protein DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9) in the glomeruli of patients with fibrillary glomerulonephritis but not in those with immunotactoid glomerulopathy [13-15] has made it clear that the two are distinct, pathogenically unrelated disease entities. (See 'Fibrillary glomerulonephritis' below.)

Pathology and pathogenesis

Fibrillary glomerulonephritis

Pathology – The diagnosis of fibrillary glomerulonephritis is established by kidney biopsy, with the pathognomonic changes seen on electron microscopy and with immunofluorescence or immunohistochemical staining for DNAJB9.

Light microscopy – The light microscopic findings are nondiagnostic and variable, showing patterns that may be seen with other glomerulonephritides [3,4]. These include focal mesangial (the most common) or diffuse proliferative or membranoproliferative glomerulonephritis (with or without crescent formation), a membranous pattern, and mesangial expansion with amorphous material that may be suggestive of amyloidosis or light chain deposition disease (picture 1). In a study of 66 patients, the most common histologic patterns were mesangioproliferative/sclerosing glomerulonephritis and membranoproliferative glomerulonephritis, which were observed in 71 percent and 15 percent, respectively [4]. A crescentic glomerulonephritis can be seen in 17 to 50 percent of cases [2-4,15,16], but cases with >50 percent of glomeruli involvement are rare.

Immunofluorescence – Immunofluorescence microscopy is positive for immunoglobulin G (IgG), C3, and both kappa and lambda (ie, polyclonal) light chains [1,4,11,17]. There is usually predominant deposition of some IgG subclasses, particularly IgG4 and to a lesser extent IgG1. In a single-center series of 61 patients with fibrillary glomerulonephritis, immunofluorescence microscopy in 19 cases found polytypic deposits (all with IgG1 and IgG4 subclasses) in 15, with the remaining four having monotypic deposits (two IgG1 and two IgG4) [3]. Immunoglobulin A (IgA), immunoglobulin M (IgM), and C1q deposition may also be seen [4]. The fibrillary deposits may be so extensive that the IgG deposition may be linear, similar to that seen in anti-glomerular basement membrane antibody disease (picture 2) [1,6,16,18]. Extraglomerular staining, most commonly involving the tubular basement membranes, has been reported in 30 to 50 percent of cases [15,19]. Rare cases of immunoglobulin-negative fibrillary glomerulonephritis have also been described [20].

The detection of monotypic deposits by standard frozen section immunofluorescence should be confirmed by paraffin immunofluorescence, which may reveal "masked" polytypic deposits in nearly one-half of cases and thereby prevent the misdiagnosis of these patients with monoclonal fibrillary glomerulonephritis [21].

Electron microscopy – Electron microscopy shows random fibrillar deposits in the mesangium and glomerular capillary walls that are clearly distinct from those seen in amyloidosis (picture 3). The fibrils are larger than those in amyloidosis (16 to 24 nm in fibrillary glomerulonephritis versus 10 nm in diameter in amyloidosis). The fibrils in fibrillary glomerulonephritis (picture 4) are randomly arranged, whereas microtubules observed in immunotactoid glomerulopathy form parallel bundles [3,10]. (See 'Immunotactoid glomerulopathy' below.)

Congo red staining – In contrast to amyloid fibrils, the fibrils in fibrillary glomerulonephritis usually do not stain with Congo red or thioflavine-T or with antibodies to a specific light chain (either lambda or kappa) or to serum amyloid A [1,2,4]. However, one study described a series of patients with fibrillary glomerulonephritis whose glomerular deposits were Congo red positive [22]. Given these findings, the presence or absence of Congo red staining should not solely be used to distinguish between fibrillary glomerulonephritis and renal amyloidosis. Other diagnostic methods, such as mass spectrometry and immunohistochemistry (for DNAJB9), are important in making this distinction.

Pathogenesis – Fibrillary glomerulonephritis was initially considered to be an idiopathic disorder [3]. However, approximately 30 to 50 percent of patients have a history of malignancy (4 to 23 percent), monoclonal gammopathy (4 to 16 percent), or autoimmune disease (13 to 30 percent of patients) [4,7]. A link between fibrillary glomerulonephritis and hepatitis C has also been described [4,19,22,23]. Other common comorbidities include diabetes mellitus and hypertension, reported in approximately 30 and 75 percent of cases, respectively. (See 'Associated diseases' below.)

Proteomic studies have identified DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9) as a potential novel, highly specific biomarker for the diagnosis of fibrillary glomerulonephritis [13,14]. DNAJB9, a protein involved in the endoplasmic reticulum stress response, was found to be highly enriched in the glomeruli of patients with fibrillary glomerulonephritis but not in those of patients with amyloidosis or other glomerular diseases or healthy subjects (picture 5). Immunofluorescence microscopy confirmed positive staining for DNAJB9 in glomerular capillary walls and the mesangium of all patients with fibrillary glomerulonephritis, while no staining was observed in patients with amyloidosis or other glomerular diseases or healthy controls [13-15]. In addition, immunoelectron microscopy demonstrated localization of DNAJB9 to fibrils in fibrillary glomerulonephritis but not to amyloid fibrils or immunotactoid glomerulopathy microtubules [15].

The role of DNAJB9 in the pathogenesis of fibrillary glomerulonephritis is unclear. Colocalization of staining for DNAJB9 and IgG within glomerular deposits suggests that DNAJB9 could represent a putative autoantigen in fibrillary glomerulonephritis. However, a circulating DNAJB9 autoantibody has not been identified in these patients to support this theory [13,15]. Another possibility is that DNAJB9 may be a protein that secondarily binds to misfolded IgG molecules by recognizing aggregation-prone motifs [7,24]. This hypothesis could explain the poor response to rituximab and other immunosuppressive agents in patients with fibrillary glomerulonephritis. Further studies are required to determine the role of DNAJB9 in the pathogenesis of this disease. (See 'Treatment' below.)

Case reports of a familial form of fibrillary glomerulonephritis have been described [25-28]. These cases predated the discovery of DNAJB9 as a disease marker, and DNAJB9 staining to confirm the diagnosis was not performed.

Immunotactoid glomerulopathy

Pathology – Immunotactoid glomerulopathy, in contrast to fibrillary glomerulonephritis, is characterized by the formation of microtubules on electron microscopy. In addition, these microtubules are typically much larger than the fibrils in fibrillary glomerulonephritis (17 to 52 versus 16 to 24 nm in diameter) (picture 4) [2,6,9,10,29]. However, due to the overlap, substructure diameter alone is insufficient to distinguish between fibrillary glomerulonephritis and immunotactoid glomerulopathy. Immunostaining for the marker DNAJB9, which is positive among patients with fibrillary glomerulonephritis (see 'Fibrillary glomerulonephritis' above), is uniformly negative.

Most patients have either a circulating paraprotein or monoclonal immunoglobulin deposition in the glomeruli on immunofluorescence microscopy with a restricted light chain, either kappa or lambda [3,6,9,11,29] (see 'Diagnosis' below). Deposits are almost always composed of IgG (predominantly IgG1 or IgG2) [29,30].

Pathogenesis – Most cases of immunotactoid glomerulopathy are associated with a lymphocytic or plasma cell disorder, either indolent according to hematologic criteria (and corresponding to monoclonal gammopathy of renal significance) or symptomatic. Some authors call this disorder glomerulonephritis with organized monoclonal microtubular immunoglobulin deposits (GOMMID) [11]. Tubulointerstitial infiltration with malignant B cells may be observed in patients with immunotactoid glomerulopathy associated with symptomatic chronic lymphocytic leukemia or B cell lymphoma. The absence of detectable circulating cryoglobulins is required to establish the diagnosis of immunotactoid glomerulopathy.

In a study of 14 patients with immunotactoid glomerulopathy, glomerular deposits were composed of monotypic IgG in 13 patients who also had a monoclonal immunoglobulin of the same isotype in the serum and/or the cytoplasm of lymphocytes [11]. In addition, a lymphoproliferative disease was observed in seven patients. By comparison, none of nine patients with fibrillary glomerulonephritis had a paraprotein or a lymphoproliferative disorder, while eight of the nine patients had polyclonal immunoglobulin glomerular deposits.

Similar findings were reported in another series of 16 patients with immunotactoid glomerulopathy, in whom a serum monoclonal protein was detected in 63 percent and hypocomplementemia was present in 46 percent [31]. A hematologic malignancy was identified in six (38 percent) patients, including three with chronic lymphocytic leukemia, two with lymphoplasmacytic lymphoma, and two with multiple myeloma.

Thus, a careful search for a B cell or plasma cell lymphoproliferative disease should be part of the routine evaluation of patients with immunotactoid glomerulopathy. (See 'Diagnosis' below.)

Clinical features

Typical presentation — The presenting clinical features of fibrillary glomerulonephritis and immunotactoid glomerulopathy are similar to those in other forms of glomerular disease [2,4,5,8,10,29,31,32]. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

The largest reported experience described the clinical features in 186 patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy [5]. Approximately 90 percent of patients had fibrillary glomerulonephritis but the clinical findings were similar in both disorders. Both affect middle-aged individuals, with the reported age at diagnosis ranging from 41 to 80 years [7,31].

The following findings were noted at presentation:

Hematuria in 70 percent

Proteinuria in 100 percent, with nephrotic syndrome (protein excretion ≥3.5 g/day) in 70 to 75 percent

Kidney function impairment (serum creatinine ≥1.5 mg/dL [133 micromol/L]) in 50 to 55 percent

Hypertension in 65 to 70 percent

Monoclonal gammopathy in 16 to 63 percent

A similar spectrum of findings was reported in two independent series of immunotactoid glomerulopathy [29,30]. In both of these studies, 33 percent of patients had hypocomplementemia. In one study, a serum or urine monoclonal protein was detected more frequently among patients with monoclonal immunotactoid glomerulopathy compared with those with polyclonal immunotactoid glomerulopathy (50 and 42 percent versus 16 and 0 percent, respectively) [29].

Associated diseases — Most cases of fibrillary glomerulonephritis were previously considered idiopathic. However, 30 to 50 percent of cases of fibrillary glomerulonephritis are associated with malignancy, monoclonal gammopathy, autoimmune disease, or infections [3-5,11,33].

The frequency with which these associated disorders occur was illustrated in a report of 66 patients with fibrillary glomerulonephritis [4]:

Fifteen patients (23 percent) had an associated malignancy, which was diagnosed 15 years before to 10 years after the onset of kidney disease [4]. Six of the 15 malignancies were due to multiple myeloma or leukemia.

Eleven patients (17 percent) had a monoclonal gammopathy, which is similar to the 15 percent incidence reported in another study [3]. However, subsequent studies have found that the vast majority of cases of DNAJB9-positive fibrillary glomerulonephritis are not associated with monoclonal gammopathy, whereas rare cases of DNAJB9-negative fibrillary glomerulonephritis (<2 percent) appear to be associated with a monoclonal gammopathy of renal significance [21]. Whether these rare DNAJB9-negative cases are truly fibrillary glomerulonephritis is questionable. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance".)

Ten patients (15 percent) had autoimmune disorders (most often Crohn disease, lupus, Graves' disease, and immune thrombocytopenia [ITP]).

Cases of fibrillary glomerulonephritis associated with Sjögren's syndrome [34,35], rheumatoid arthritis [36], and Behçet syndrome [37] have also been described.

By contrast, immunotactoid glomerulopathy is more frequently associated with chronic lymphocytic leukemia and related B cell lymphomas or multiple myeloma [3,5,11,29,31,33]. In the largest series of 73 patients, 48 (66 percent) had a hematologic disorder, including lymphoma in 41 percent (mainly chronic lymphocytic leukemia/small lymphocytic lymphoma), monoclonal gammopathy in 20 percent, and multiple myeloma in 6 percent [29]. Patients with immunotactoid glomerulopathy and monoclonal deposits in the kidney had a much higher incidence of hematologic disorders than those with polyclonal deposits.

Both fibrillary glomerulonephritis and immunotactoid glomerulopathy have been described in patients with hepatitis C virus (HCV) infection [4,23]. Fibrillary glomerulonephritis has been also described in association with anti-glomerular basement membrane disease [38].

Rare extrarenal involvement — The fibril or microtubule deposition in these conditions is almost always limited to the kidney [8]. There are, however, a small number of observations suggesting a systemic component in rare patients with fibrillary glomerulonephritis and immunotactoid glomerulopathy:

Both disorders can recur in the kidney transplant [4,5,9,39,40]. However, in one series of patients with fibrillary deposits (fibrillary glomerulonephritis or monoclonal gammopathy with fibrillary deposits), only those with a monoclonal gammopathy developed recurrent disease [40]. Thus, it is important to distinguish patients with monoclonal gammopathy with fibrillary deposits from those with true fibrillary glomerulonephritis. (See 'End-stage kidney disease' below.)

Two cases of patients with fibrillary glomerulonephritis and extrarenal involvement have been described. One case report described a patient with fibrillary glomerulonephritis who had fibril deposition in the alveolar capillaries, leading to fatal pulmonary hemorrhage [41]. However, it should be recognized that distinguishing alveolar matrix fibrils from true fibrillary fibers can be difficult [42]. A second case report detailed the autopsy of a patient with fibrillary glomerulonephritis who was found to have fibrils in the kidney and spleen but no other organs [43].

Similarly, a few cases of immunotactoid glomerulopathy with extrarenal involvement have been reported: two with immunotactoid deposition in the bone marrow [44,45], two with skin involvement manifesting as leukocytoclastic skin vasculitis [11,46], and one with peripheral neuropathy due to perineural monotypic IgG deposits with similar ultrastructural microtubular organization to the glomerular deposits [11].

Diagnosis — The diagnosis of fibrillary glomerulonephritis or immunotactoid glomerulopathy is made by kidney biopsy in a patient with suspected glomerular disease. Fibrillary glomerulonephritis can be distinguished from immunotactoid glomerulopathy on the basis of electron microscopy as well as positive immunofluorescence staining for DNAJB9. (See 'Pathology and pathogenesis' above and "Glomerular disease: Evaluation and differential diagnosis in adults".)

There are no established, noninvasive laboratory tests to diagnose fibrillary glomerulonephritis or immunotactoid glomerulopathy. However, one study found that serum levels of DNAJB9 were fourfold higher in patients with fibrillary glomerulonephritis compared with healthy controls and patients with multiple myeloma, immunoglobulin light chain (AL) amyloidosis, and other glomerular diseases (including immunotactoid glomerulopathy) [47]. Serum DNAJB9 levels predicted a diagnosis of fibrillary glomerulonephritis with a sensitivity and specificity of 67 and 98 percent, respectively. These findings suggest that DNAJB9 could be useful as a serum biomarker for the diagnosis of fibrillary glomerulonephritis, although validation in larger, prospective studies is needed. Testing for serum DNAJB9 is not yet commercially available.

Patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy should be evaluated for secondary causes as follows:

Patients with a diagnosis of fibrillary glomerulonephritis should be screened for malignancy, monoclonal gammopathy, autoimmune disease, and HCV infection (see 'Associated diseases' above). The temporal relationship with these diseases is variable. As an example, malignancy may precede, be concomitant with, or follow the diagnosis by many years [48]. Thus, ongoing monitoring is warranted in these patients. We perform the following tests at the time the kidney disease is diagnosed:

Complete blood count with differential (should be repeated at least annually)

Serum and urine protein electrophoresis with immunofixation and serum free light chains (should be repeated at least annually)

Tests for HCV and HIV

Antinuclear antibody (ANA) and, if positive, anti-double stranded DNA (anti-dsDNA), anti-Sm, anti-Ro/SSA, and anti-LA/SSB

C3 and C4 complement levels

Cryoglobulins

Chest radiograph

Patients without known cancer who are diagnosed with fibrillary glomerulonephritis should undergo age- and risk-appropriate cancer screening, if not already performed.

Patients with a diagnosis of immunotactoid glomerulopathy should be screened for monoclonal gammopathy with serum and urine electrophoresis with immunofixation and serum free light chain levels. In those with confirmed monotypic deposits and/or monoclonal gammopathy, additional investigations may be required to characterize the nature of the underlying clonal disorder, including bone marrow examination with flow cytometry, and, when a B cell lymphoproliferative disease is suspected, flow cytometry of blood lymphocytes; computed tomography (CT) scan of the chest, abdomen, and pelvis; and/or positron emission tomography (PET) scan. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Subsequent evaluation of patients with confirmed MGRS'.)

Treatment

Our approach to therapy — Fibrillary and immunotactoid glomerular disease are difficult to treat and there are no randomized controlled trials to guide optimal therapy. Although we consider these disorders to be two pathologically distinct processes, our approach to treatment in patients without a secondary cause is similar for both and is based primarily upon the limited available data from retrospective studies and case series and our own clinical experience. There are no therapies that have been clearly shown to be beneficial for either fibrillary glomerulonephritis or immunotactoid glomerulopathy. Patients who have a possible secondary cause for these disorders, such as malignancy, monoclonal gammopathy, infection, or autoimmune disease, may benefit from treatment of the underlying disorder. This is especially true for patients with a monoclonal gammopathy who may benefit from B cell or plasma cell targeted therapy. In patients with idiopathic disease, our approach to treatment is generally determined by the severity of kidney dysfunction. (See 'Patients with secondary causes' below.)

A case series of 27 patients synthesized the data from these and 197 patients reported in five previous case series; during an average of four to five years of follow-up, four patients (2 percent) had complete remission, 12 (5 percent) had partial remission, 32 (14 percent) had progressive kidney disease, and 96 (45 percent) developed end-stage kidney disease (ESKD) [19]. Nearly all were treated with angiotensin inhibition, and 85 patients received immunosuppressive therapy. Those with milder disease were more likely to attain a complete or partial remission. In two of these six series, for example, 7 of 15 patients had mild disease at the time of kidney biopsy as defined by a normal estimated glomerular filtration rate (eGFR) and non-nephrotic-range proteinuria [4,19].

Patients with secondary causes — As described above, malignancy, monoclonal gammopathy, and autoimmune diseases occur in more than one-third of patients with fibrillary glomerulonephritis, and chronic lymphocytic leukemia and related B cell lymphomas have been associated with immunotactoid glomerulopathy. Both fibrillary glomerulonephritis and immunotactoid glomerulopathy have been associated with HCV infection. Thus, a careful search for a secondary cause should be part of the routine evaluation of these disorders. Ongoing screening may be warranted since these disorders can first be detected after the diagnosis of the kidney disease. (See 'Associated diseases' above and 'Diagnosis' above.)

In patients with fibrillary glomerulonephritis who have an associated malignancy or autoimmune disorder, we advocate for treatment of these conditions as appropriate in consultation with a hematologist/oncologist or rheumatologist, respectively.

In patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy who have an associated monoclonal gammopathy (ie, patient has monotypic deposits on immunofluorescence staining of the kidney biopsy or a detectable serum or urine monoclonal protein) with or without a detectable plasma or B cell clone, we treat with therapy directed against the pathologic clone responsible for the monoclonal gammopathy [49,50]. This approach is similar to that used for patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) [51], as discussed separately. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'Patients with PGNMID'.)

In patients with immunotactoid glomerulopathy who have an associated monoclonal gammopathy but no detectable plasma or B cell clone, treatment with rituximab-based therapy to eradicate a "hypothesized B cell clone" is a potential initial option, given the high incidence of underlying B cell disorders in immunotactoid glomerulopathy [30,50].

In patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy who have chronic HCV infection and have not yet received therapy, we advocate for treatment of HCV as appropriate. However, evidence that treating HCV infection results in improvement of fibrillary glomerulonephritis is lacking. (See "Overview of the management of chronic hepatitis C virus infection".)

In addition to addressing the underlying disorder, we administer therapies aimed at reducing proteinuria, controlling blood pressure, and slowing the progression of kidney disease, as discussed below. (See 'Estimated GFR ≥60 mL/min/1.73 m2 and proteinuria <3.5 g/day' below.)

Patients should be routinely monitored during treatment for signs of kidney disease progression. We typically monitor serum creatinine concentration and urine protein excretion every three to six months. If patients do not show signs of improvement of their kidney disease following treatment of the underlying disorder, treatment with immunosuppressive therapy can be considered on a case-by-case basis. (See 'Estimated GFR <60 mL/min/1.73 m2 or proteinuria >3.5 g/day' below.)

Effective therapy directed at the underlying disorder appears to have a beneficial effect on the kidney disease [11,31,33,52,53]:

In a study of 12 patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy who had nephrotic syndrome and a lymphoproliferative disease and/or monoclonal gammopathy, complete or partial remission of the nephrotic syndrome occurred in 10 of the 12 patients after the initiation of chemotherapy, with a parallel improvement in the hematologic disease [11].

In a series of 27 patients with immunotactoid glomerulopathy, 18 had a bone marrow or peripheral blood clonal disorder (16 lymphocytic and two plasmacytic) [30]. Among the 21 patients who received treatment with alkylating agents or rituximab- or bortezomib-based chemotherapy, 18 achieved a renal response. After a median of 40 months, 16 patients had a sustained renal response, seven developed ESKD, and six died. A hematologic response after clone-directed chemotherapy was associated with favorable outcomes. Similar findings were reported in another retrospective study, in which patients with monoclonal immunotactoid glomerulopathy who were treated with clone-directed therapy had higher rates of remission (50 versus 24 percent) and lower rates of ESKD (11 versus 53 percent) compared with those with polyclonal immunotactoid glomerulopathy who received immunosuppressive therapy or supportive care only [29].

Patients with idiopathic disease — In patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy who do not have a secondary cause of their kidney disease, our approach to treatment depends upon the severity of their kidney disease.

Estimated GFR ≥60 mL/min/1.73 m2 and proteinuria <3.5 g/day — In patients with relatively preserved kidney function (estimated glomerular filtration rate [eGFR] of ≥60 mL/min/1.73 m2) and subnephrotic-range proteinuria (<3.5 g/day), we prefer a more conservative initial approach to treatment. We treat these patients with antiproteinuric therapy (angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]), blood pressure control, and dietary sodium restriction indefinitely. In addition, we administer lipid-lowering therapy as appropriate for patients with hyperlipidemia and advocate weight reduction in patients who are overweight or obese. These general issues are discussed in detail elsewhere:

(See "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Effect of renin-angiotensin system inhibitors on progression of CKD'.)

(See "Dietary recommendations for patients with nondialysis chronic kidney disease", section on 'Salt intake'.)

(See "Lipid management in patients with nondialysis chronic kidney disease".)

We monitor the patient by obtaining serum creatinine concentration and urine protein excretion every three to six months. In patients who respond to conservative therapy (ie, proteinuria decreases and serum creatinine and eGFR remain stable), we continue these measures and monitor the patient closely for signs of disease progression. Patients who develop progressive loss of kidney function or worsening proteinuria despite maximal conservative therapy should be considered for immunosuppressive therapy, as discussed below. (See 'Estimated GFR <60 mL/min/1.73 m2 or proteinuria >3.5 g/day' below.)

The benefits of conservative antiproteinuric therapy in patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy are unclear. In a study of 61 patients with fibrillary glomerulonephritis who were followed for a mean of 52 months, 16 patients were treated with angiotensin blockade alone [4]. Two of these patients had complete remission, two had partial remission, eight had progressive kidney disease, and four progressed to ESKD. By contrast, in another study of 27 patients with fibrillary glomerulonephritis followed for a mean of 46 months, none of the 14 patients treated with angiotensin blockade alone attained a complete or partial remission [19].

Estimated GFR <60 mL/min/1.73 m2 or proteinuria >3.5 g/day — There are no randomized trials to guide the optimal therapy in patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy who have abnormal kidney function (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) or nephrotic range proteinuria (>3.5 g/day), and no immunosuppressive therapies have been clearly shown to be beneficial. However, given the generally poor prognosis associated with these disorders (see 'Prognosis' below), it is reasonable to offer a trial of immunosuppressive therapy after discussing the potential risks and benefits of treatment with the patient. We prefer the use of rituximab, administered either as four weekly doses of 375 mg/m2 intravenously (IV) or as 1 g IV initially followed 14 days later by another 1 g dose, based upon observational data suggesting a benefit in some patients. In addition, we administer conservative measures used to control blood pressure and reduce protein excretion for the duration of the disease, as described above. (See 'Estimated GFR ≥60 mL/min/1.73 m2 and proteinuria <3.5 g/day' above.)

We monitor the patient by obtaining serum creatinine concentration and urine protein excretion every three to six months. In patients who respond to rituximab therapy (ie, proteinuria decreases and/or serum creatinine and eGFR remain stable), we continue monitoring the patient for signs of disease progression every three to six months. If proteinuria decreases but the patient does not go into complete remission (ie, proteinuria <300 mg/24 hours) after a minimum of six months follow-up, we measure the patient’s B cell counts (CD19-positive cells by flow cytometric analysis). If the CD19-positive B cell count is >5 per microL, we redose the patient with a single dose of rituximab 1 g IV. If, after the second course of rituximab, proteinuria stabilizes but the patient does not achieve complete remission, we assume that residual proteinuria is due to chronic damage and continue conservative therapy without redosing rituximab. In patients who do not respond to rituximab therapy, we typically do not offer additional immunosuppressive therapy, since the risks of treatment (eg, infection, malignancy) likely outweigh any potential benefits.

Some but not all reports suggest that rituximab may be associated with complete or partial remission of proteinuria in patients with fibrillary glomerulonephritis [4,19,28,52,54,55]:

One case series reported outcomes of 12 patients with fibrillary glomerulonephritis who were treated with rituximab (1 g IV for two doses or 375 mg/m2 for four weekly doses); all patients received an ACE inhibitor or ARB [55]. At baseline, median serum creatinine was 2.1 mg/dL (range 0.7 to 2.7 mg/dL), median eGFR was 39 mL/min/1.73 m2 (range 21 to 98 mL/min/1.73 m2), and median proteinuria was 4.5 g/day (range 0.2 to 7.5 g/day). Four patients did not develop progressive kidney disease, three had progressive kidney disease without reaching ESKD, and five patients progressed to ESKD. Patients who did not develop progressive disease had lower baseline serum creatinine values, higher eGFR, and a shorter median duration from diagnosis to treatment compared with those who progressed.

In a study of 27 adults with fibrillary glomerulonephritis, all patients were given renin-angiotensin system inhibitors and 13 received immunosuppressive therapy, including rituximab (seven patients) and cyclophosphamide (three patients). After a median 46-month follow-up, renal response occurred in 6 of 13 patients who received immunosuppressive therapy with rituximab (five patients) or cyclophosphamide (one patient). By contrast, chronic kidney disease progressed in 12 of 14 patients who were not given immunosuppressive therapy, 10 of whom reached ESKD [19].

A third series examined outcomes of 11 patients with idiopathic fibrillary glomerulonephritis who received rituximab (1 g intravenously [IV] on days 1 and 15, followed by an identical regimen six months later) [56]. At 12 months, there was no significant difference in median 24-hour creatinine clearance compared with baseline (47.7 versus 43.7 mL/min/body surface area, respectively). Proteinuria decreased from a median of 4428 mg/day to 1936 mg/day, although this change was not statistically significant. One patient achieved complete remission of proteinuria, and two patients had partial remission of proteinuria.

Rituximab also appeared to be effective in a case report of recurrent immunotactoid glomerulopathy in the transplant that had not responded to conventional immunosuppressive therapy [57]. (See 'End-stage kidney disease' below.)

Immunosuppressive therapy with glucocorticoids with or without other agents (eg, cyclophosphamide, mycophenolate mofetil, cyclosporine, melphalan, azathioprine, and rapamycin) has been reported in uncontrolled studies with limited and inconsistent results [3,4,10,19,58].

It has been suggested that patients with idiopathic fibrillary glomerulonephritis or immunotactoid glomerulopathy should be treated according to the findings on light microscopy [3]. The rationale for such an approach is based upon the observation that patients with a membranoproliferative pattern of injury progress faster to ESKD than patients with a mesangioproliferative pattern [4]. However, as discussed above, the mesangioproliferative pattern may represent an earlier stage of pathogenic process rather than milder disease. Consistent with this hypothesis is the observation that, when renal histology was stratified by immunosuppressive therapy, there was no effect of immunosuppression on the rate of progression to ESKD. (See 'Prognosis' below.)

Patients with crescentic glomerulonephritis — In patients presenting with a rapidly progressive glomerulonephritis and crescents on kidney biopsy, we suggest treatment with high-dose glucocorticoids and cyclophosphamide as used in other forms of crescentic glomerulonephritis [59,60]. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis", section on 'Treatment'.)

End-stage kidney disease — Dialysis or kidney transplantation can be performed in patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy who progress to ESKD. With kidney transplantation, recurrent disease can develop in the allograft in both disorders [4,5,39,40,61], but the rate of progression is usually slower than in the native kidney [5,39,40,61,62]. The rate of recurrence appears be higher in patients who have a monoclonal gammopathy [40], which occurs in both disorders. (See 'Associated diseases' above.)

Specific data on the rate of recurrence in fibrillary glomerulonephritis are limited to relatively small numbers of patients [4,39,40,57,63-65]. The following findings are illustrative:

One report evaluated 14 patients with DNAJB9-positive fibrillary glomerulonephritis who underwent kidney transplantation and had protocol allograft biopsies at 4, 12, 24, 60, and 120 months posttransplantation [63]. At a median of 5.7 years posttransplantation, three patients developed biopsy-proven recurrent disease; the median time to recurrence was 10.2 years. The remaining 11 patients had no evidence of histologic recurrence on the last posttransplant biopsy, although median follow-up time in these patients was less at 4.4 years. In three patients (21 percent), a monoclonal protein was detectable in serum obtained pretransplantation; none of these patients developed recurrent fibrillary glomerulonephritis.

A study from the Australia and New Zealand Dialysis and Transplant Registry reported the prognosis of 55 patients with ESKD due to fibrillary glomerulonephritis and 11 patients with immunotactoid glomerulopathy [64]. Patients with fibrillary glomerulonephritis had survival rates on dialysis that were comparable with those of patients with other causes of ESKD. However, patients with immunotactoid glomerulopathy had inferior survival on dialysis. Among patients who were transplanted, recurrent disease occurred in 1 of 13 patients with fibrillary glomerulonephritis and 1 of 4 patients with immunotactoid glomerulopathy.

In a report of two patients with immunotactoid glomerulopathy who underwent kidney transplantation plus two others in case reports, two developed recurrent disease at two- to six-year follow-up [39]. In other case reports of immunotactoid glomerulopathy, more aggressive immunosuppressive therapy (including plasma exchange, pulse methylprednisolone, and cyclophosphamide pulses rather than azathioprine) [57] or the use of rituximab [65] appeared to be beneficial.

A case of familial fibrillary glomerulonephritis recurring following a living-related kidney transplant has been reported [66].

In summary, kidney transplantation is a reasonable therapeutic option for patients with fibrillary glomerulonephritis who develop ESKD. In those with an associated monoclonal gammopathy, a thorough evaluation of the monoclonal gammopathy should be addressed prior to transplantation. Immunotactoid glomerulopathy may recur in the kidney allograft and may result in loss of the allograft [29,30]. In patients with monoclonal immunotactoid glomerulopathy, treatment of the monoclonal gammopathy should be addressed prior to transplantation.

Prognosis — Approximately 40 to 50 percent of reported patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy develop ESKD within two to six years [1-4,6,8,10,19,28]. In a single-center series that included 61 patients with fibrillary glomerulonephritis, the mean time to ESKD varied according to the histologic findings on light microscopy [3]:

7 months with diffuse sclerosing glomerulonephritis

20 months with diffuse proliferative glomerulonephritis

44 months with membranoproliferative glomerulonephritis

80 months with mesangioproliferative/sclerosing disease

87 months with membranous glomerulonephritis

Similar findings were noted in another single-center series of 66 patients with fibrillary glomerulonephritis, including a shorter time to ESKD in patients with membranoproliferative glomerulonephritis compared with mesangial proliferative/sclerosing disease [4]. However, the distinction between mesangioproliferative and membranoproliferative glomerulonephritis is likely related to the timing of the kidney biopsy rather than differences in pathogenesis, with mesangial proliferation representing a lesion seen at an early stage during the pathogenic process and a membranoproliferative pattern of injury seen at a late stage of the process [67].

It has been suggested that the prognosis may be better in immunotactoid glomerulopathy than in fibrillary glomerulonephritis [6,31]. However, a study that combined the clinical characteristics of 25 patients evaluated at one center with those of 161 patients described in various studies published between 1977 to 1994 found little, if any, difference in clinical outcomes in these two disorders (table 1) [5,61]. A case of spontaneous remission of immunotactoid glomerulopathy has been described [68]. (See 'Clinical features' above.)

OTHER FIBRILLARY DISORDERS — Unlike fibrillary glomerulonephritis and immunotactoid glomerulopathy, other nonamyloid fibrillary glomerular diseases have been described in which staining for immunoglobulins is negative.

Fibronectin glomerulopathy — Fibronectin glomerulopathy is an autosomal dominant disorder associated with massive deposition of fibronectin. It presents with proteinuria, often in the nephrotic range, in the third to fourth decade and slowly progresses to end-stage kidney disease (ESKD). Fibronectin glomerulopathy may recur after kidney transplantation [69]. (See "Glomerulopathy with fibronectin deposits".)

Collagenofibrotic glomerulopathy — Collagenofibrotic glomerulopathy, also called collagen type III glomerulopathy, is a rare disorder that is characterized by the massive accumulation of atypical type III collagen fibrils in the mesangium and subendothelial space (picture 6) [70,71]. Light microscopy reveals findings consistent with membranoproliferative glomerulonephritis, including a double-contour appearance of the peripheral capillary walls. A definitive diagnosis requires electron microscopy, which reveals fibers with a transverse band structure and a distinctive periodicity of approximately 60 nm [70]. This is the same as that observed with type III collagen.

Controversy exists as to whether collagenofibrotic glomerulopathy is a primary disease of the kidney or a systemic process. Marked elevations in serum type III procollagen peptide levels are observed [70]. Some cases have been described in families, suggesting an autosomal recessive disorder [70].

Affected patients typically present with proteinuria and edema, with frequent progression to ESKD [70]. There is no specific therapy.

Other — Patients with nail-patella syndrome and hereditary multiple exostoses syndrome (also called hereditary multiple osteochondromas syndrome) may develop nephrotic syndrome associated with glomerular fibrillar collagen deposition [72]. (See "Nail-patella syndrome", section on 'Renal manifestations' and "Chondrosarcoma", section on 'Secondary peripheral chondrosarcoma'.)

Fibrils can also be seen in patients with diabetic glomerulosclerosis, a rare condition known as diabetic fibrillosis [73]. Within the kidney, these fibrils are localized to the mesangium, are segmental in fashion, and are bundle-like and not randomly arranged. Immunofluorescence staining for DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9) is negative.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY AND RECOMMENDATIONS

General principles – Glomerular disease may be associated with the appearance of fibrillar deposits in the mesangium or glomerular basement membrane. The fibrils are Congo red positive in amyloidosis and are typically Congo red negative in other forms. The most common forms of nonamyloid fibrillary glomerular deposition diseases are fibrillary glomerulonephritis and immunotactoid glomerulopathy. Both disorders probably result from deposits derived from immunoglobulins. Cases of Congo red-positive fibrillary glomerulonephritis have been reported. Other forms of nonamyloid fibrillary deposition disease have been described in which the deposits are composed of fibronectin (fibronectin glomerulopathy) or atypical type III collagen fibrils (collagenofibrotic glomerulopathy). (See 'Introduction' above.)

Pathogenesis – Fibrillary glomerulonephritis and immunotactoid glomerulopathy are uncommon but distinct disorders. The identification of the protein DnaJ heat shock protein family (Hsp40) member B9 (DNAJB9) in the glomeruli of patients with fibrillary glomerulonephritis but not in those with immunotactoid glomerulopathy has made it clear that the two are distinct, pathogenically unrelated disease entities. (See 'Pathology and pathogenesis' above.)

Clinical features – Patients with both fibrillary and immunotactoid disease present with significant proteinuria that is often in the nephrotic range; other findings include microscopic hematuria, hypertension, and kidney function impairment that may progress rapidly. Approximately one-half of the patients with fibrillary glomerulonephritis develop end-stage kidney disease (ESKD) within two to six years. Most cases of fibrillary glomerulonephritis and immunotactoid glomerulopathy are idiopathic. However, fibrillary glomerulonephritis has been associated with malignancy, monoclonal gammopathy, autoimmune disease, or infection in 30 to 50 percent of cases. Up to 40 percent of cases of immunotactoid glomerulopathy are associated with a B cell or plasma cell lymphoproliferative disorder. (See 'Clinical features' above.)

Diagnosis – The diagnosis of fibrillary glomerulonephritis or immunotactoid glomerulopathy is made by kidney biopsy in a patient with suspected glomerular disease. Fibrillary glomerulonephritis can be distinguished from immunotactoid glomerulopathy on the basis of electron microscopy as well as positive immunofluorescence staining for DNAJB9. Patients with a diagnosis of either fibrillary glomerulonephritis or immunotactoid glomerulopathy should be screened for malignancy, monoclonal gammopathy, autoimmune disease, and viral infections such as hepatitis C virus (HCV) and HIV. (See 'Diagnosis' above.)

Treatment – Fibrillary and immunotactoid glomerular disease are difficult to treat and there are no randomized controlled trials to guide optimal therapy. Although we consider these disorders to be two pathologically distinct processes, our approach to treatment in patients with no secondary cause is similar for both and is based primarily upon the limited available data from retrospective studies and case series and our own clinical experience. There are no therapies that have been clearly shown to be beneficial for either idiopathic fibrillary glomerulonephritis or immunotactoid glomerulopathy. Patients with fibrillary glomerulonephritis who have a possible secondary cause for these disorders, such as malignancy, monoclonal gammopathy, infection, or autoimmune disease, may benefit from treatment of the underlying disorder. In patients with idiopathic fibrillary glomerulonephritis or immunotactoid glomerulopathy, our approach to treatment is generally determined by the severity of kidney dysfunction (see 'Our approach to therapy' above):

For patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 and proteinuria <3.5 g/day, we suggest a conservative initial approach to treatment. We treat these patients with antiproteinuric therapy (angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]), blood pressure control, and dietary sodium restriction indefinitely. (See 'Estimated GFR ≥60 mL/min/1.73 m2 and proteinuria <3.5 g/day' above.)

For patients with an eGFR <60 mL/min/1.73 m2 or proteinuria >3.5 g/day, we suggest treatment with rituximab in addition to conservative measures used to control blood pressure and reduce protein excretion (Grade 2C). We typically administer rituximab as four weekly doses of 375 mg/m2 intravenously (IV) or as 1 g IV initially followed 14 days later by another 1 g dose. (See 'Estimated GFR <60 mL/min/1.73 m2 or proteinuria >3.5 g/day' above.)

For patients presenting with a rapidly progressive glomerulonephritis and crescents on kidney biopsy, we suggest treatment with high-dose glucocorticoids and cyclophosphamide as used in other forms of crescentic glomerulonephritis. (See 'Patients with crescentic glomerulonephritis' above.)

End-stage kidney disease – Dialysis or kidney transplantation can be performed in patients with fibrillary glomerulonephritis or immunotactoid glomerulopathy who progress to ESKD. With kidney transplantation, recurrent disease can develop in the allograft in both disorders, but the rate of progression is usually slower than in the native kidney. The rate of recurrence appears to be higher in patients who have a monoclonal gammopathy. (See 'End-stage kidney disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Gerald B Appel, MD, who contributed to an earlier version of this topic review.

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References