Immunotactoid Glomerulopathy: A Rare Glomerular Disease Case Study

Introduction

Immunotactoid glomerulopathy (ITG) is a rare form of immunoglobulin-derived fibrillary glomerular disease found in only 0.04% of native kidney biopsies.[1] It is characterized by deposition of parallelly arranged microtubules with hollow cores with diameter of 15 to 50 nm, located in the subepithelial space, mesangium, and/or subendothelial space of the glomerulus.[1–3] Based on these unique electron microscopic properties, ITG should be distinguished from other Congo red negative glomerulopathies: cryoglobulinemia, systemic lupus erythematosus (SLE) and fibrillary glomerulonephritis.[3] ITG is primary glomerulopathy subdivided into monoclonal and polyclonal variants with clinical and therapeutic implications.[1] A significant number of patients with monoclonal variant of ITG had lymphoproliferative disorders that produced monoclonal immunoglobulins that caused kidney damage.[1,4] Diabetes mellitus could be associated with an ITG.[1] Hypertension, nephrotic proteinuria, chronic kidney disease, extensive glomerular involvement, and tubulointerstitial scarring were factors associated with the poorer prognosis of the ITG.[4]

Two cases with diabetes mellitus presented with nephrotic syndrome and chronic kidney disease were diagnosed with ITG by kidney biopsy. There was a reduction in the proteinuria in both cases with the immunosuppressive treatment, with no improvement in kidney function.

Case 1

A 39-year-old woman with a history of insulin-dependent type 2 diabetes mellitus, hypothyroidism, thrombophilia, infertility, hypertension, nephrotic syndrome, and chronic kidney disease was admitted to our hospital for kidney biopsy. The physical examination of the patient revealed pitting edema in lower extremities bilaterally, and fine crackles in the bases of the lung lobes. One year ago, the patient was diagnosed with chronic kidney disease (CKD) with serum creatinine level of 1.5 mg/dL (normal for women: 0.5–1.1 mg/dL), serum blood urea nitrogen (BUN) level of 23.8 mg/dL (normal: 6–24 mg/dL), and 24-hour proteinuria of 2.7 g (<0.2 g). The progression of the CKD (serum creatinine level of 2.8 mg/dL, BUN level of 66.9 mg/dL, and proteinuria of 5.4 g/d) was noted in the patient after a period of one year. There was an absence of diabetic retinopathy. The serum immunoglobulins, serum complement compounds (C3 and C4), anti–double stranded DNA (anti-dsDNA), and serum-free light chains were negative. Antibodies against hepatitis B, hepatitis C, and HIV were not detected. A percutaneous ultrasound-guided kidney biopsy was performed. Five glomeruli were obtained: two glomeruli showed global sclerosis; three glomeruli had thickened glomerular basement membrane, diffuse and irregular mesangial nodules composed by “fibrillar-like” material negative for PAS and silver stain. Tubular atrophy and interstitial fibrosis were present. Electron microscopy indicated microtubular structures with hollow cores and thickened walls arranged in parallel arrays with average diameter of 35 nm, located predominantly in subendothelial space and mesangium of the glomeruli [Figure 1]. The final diagnosis of diabetic glomerulopathy with superimposed immunotactoid glomerulopathy was established. The patient was treated with mycophenolate mofetil (daily dose of 2000 mg) combined with dexamethasone (daily dose of 5 mg with slow tapering), and angiotensin II receptor blocker. Two months after initiation of the treatment, the 24-hour proteinuria decreased to 1.8 g, and remained stable over the next six months, with complete remission of the edema, but with the persistence of CKD.

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Figure 1

Electron microscopy showing massive accumulation of organized moderate dense deposits in capillary loops and mesangial regions (1a - magnification × 10000). On higher magnification, the mesangial deposits exhibited characteristic microtubular substructure, with hollow cores and thickened walls focally arranged in parallel arrays typical of immunotactoid glomerulopathy (1b - magnification × 50000 and 1c – magnification × 150000)

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Discussion

Immunotactoid glomerulopathy belongs to a heterogeneous group of glomerular diseases characterized by deposition of fibrils or microtubules in different zones of the glomeruli.[5] The exact pathogenesis of ITG remains unclear. Circulating immune complexes or in situ reaction of antibodies directed against native or “planted” antigens within glomeruli were not identified in this disease, suggesting that ITG represents a unique pathogenic mechanism of glomerular injury.[6] The physiochemical environment of glomerulus and/or some circulating factor may trigger the deposition of a “yet-to-be” identified protein with the intrinsic ability of polymerization.[1]

Clinically and/or serologically, patients with ITG have no evidence of cryoglobulinemia, amyloidosis, systemic lupus erythematosus, or a paraproteinemia, diseases associated with glomerular deposits with tactoidal or fibrillar characteristics.[6] Immunotactoid glomerulopathy is a primary glomerulopathy, with the clinical presentation like other primary glomerular diseases. Patients present with proteinuria (nephrotic range in more than 60%), and over a half of the patients have hypertension, hematuria, CKD, and hematologic disorders.[1,6–8] The recurrence to allograft was seen in half of the transplanted patients, but usually with a more benign course.[5] In the largest available series of 73 patients with ITG, Nasr et al.[1] reported that all patients had proteinuria (nephrotic range in 76% of the patients), and nephrotic syndrome was present in more than half of the patients (57%). The other reported comorbidities were hypertension (88%), diabetes mellitus (15%), and autoimmune diseases (14%).[1] In the study of Korbet et al.,[6] progression to kidney failure had occurred in more than 40% of patients, and recurrence of ITG in the renal allograft was detected in two out of four transplanted patients. The present case patients with ITG had diabetes mellitus with a sudden increase of 24-hour proteinuria in nephrotic range, with an absence of diabetic retinopathy. Hypertension and CKD were also present in both cases, at the time of diagnosis, and the second patient developed kidney failure with the need for hemodialysis treatment.

The most frequently encountered patterns of glomerular injury seen by light microscopy in ITG patients were endocapillary proliferative glomerulonephritis (GN), membranoproliferative GN (MPGN), and membranous GN.[1,9] The IgG (mean intensity 2.3+; on a scale of 0–3+) and C3 (mean intensity 2+; on a scale of 0–3+) were the most frequently deposited in the glomeruli of patients with ITG on immunofluorescence.[1,10] Ultrastructural evaluation usually revealed glomerular electron-dense microtubules with a mean diameter of 30 nm and hollow cores arranged in parallel arrays.[1,3,6,9] In MPGN and endocapillary proliferative GN, deposits were located in subepithelial space, whereas membranous GN showed global deposits distribution.[1] Diffuse and irregular nodular expansion of glomerular mesangial matrix found in our first case patient was highly suggestive of diabetic glomerulosclerosis, but the electron microscopic analysis demonstrated fibrillary background of these nodules and established the final diagnosis of ITG. In our second case patient, glomerular sclerosis and tubular atrophy were more prominent, associated with severe loss of kidney function.

To date, there is no proven effective therapy for ITG. In a study by Nasr et al.[1] out of 48 patients with available data on treatment, 9 (19%) received only supportive therapy, 5 (10%) received steroid monotherapy, and 34 (71%) received immunosuppressive/chemotherapy (rituximab, cyclophosphamide, bendamustine, fludarabine, pentostatin, mycophenolate mofetil, lenalidomide) with or without steroids. Out of five patients treated with steroid monotherapy, one patient achieved complete remission, one patient had stable proteinuria with CKD, and three progressed to kidney failure. Out of 34 patients who were treated with immunosuppressive agents with or without steroids, 14 (42%) achieved complete remission, 11 (33%) were with CKD, 6 (18%) partial remission, and 2 (6%) progressed to kidney failure. The serum creatinine level, diabetes mellitus, and moderate-to-severe tubulointerstitial scarring were factors associated with worse outcome (kidney failure or death).[1,4] Two smaller studies reported worse response of ITG to immunosuppressive therapy (12.5% and 14.2%, respectively) with development of kidney failure over 2-4 years in 50% of treated patients.[11,12] Contrary to this, clone-directed therapy (chemotherapy) in monoclonal ITG was associated with a more favorable prognosis.[1]

Conclusion

The presence of proteinuria and CKD in a patient with diabetes almost always suggests diabetic nephropathy. The development of diabetic nephropathy is usually a progressive process that takes years. Other causes of proteinuria should be considered in patients with diabetes with new onset of nephrotic proteinuria when there is no evidence of microvascular disease. Diabetes mellitus could be associated with an immunotactoid glomerulopathy. Immunotactoid glomerulopathy is a rare glomerular disease with poor prognosis, often progressing to kidney failure within a few years.