Anti-Tubular Basement Membrane Antibody Nephritis Manifesting in a Patient With Chronic Lymphocytic Leukemia: A Very Rare Case Report

Abstract

Anti-tubular basement membrane (anti-TBM) antibody nephritis is a rare type of tubulointerstitial nephritis associated with progressive decline in kidney function. It is characterized histopathologically by tubular atrophy and dilation, interstitial fibrosis, lymphocyte and macrophage-predominant cellular infiltration, and linear deposition of IgG and complement along the tubular basement membrane. We herein present a case of a 69-year-old male who was recently diagnosed with chronic lymphocytic leukemia (CLL) and was referred for evaluation of kidney failure, ultimately diagnosed as anti-TBM antibody nephritis progressing into end-stage kidney disease (ESKD). This case report highlights the management challenges of anti-TBM antibody nephritis as a rare kidney disorder.

Introduction

Anti-tubular basement membrane (anti-TBM) antibody nephritis is a very uncommon disease associated with autoantibodies to a non-collagenous 54 to 58 kD protein in proximal tubular basement membranes (TBMs), called tubulointerstitial nephritis antigen (TIN-ag).^1,2

The disease might be idiopathic or due to secondary causes and could present in an acute or chronic setting.^1,2 Secondary etiologies of anti-TBM could be due to lupus nephritis, drug-induced interstitial nephritis, pyelonephritis, acute rejection of kidney allograft, or post-bone marrow transplant. It is also associated with membranous nephropathy or other renal disorders, such as anti-glomerular basement membrane (anti-GBM) antibody disease. ¹ The primary diagnostic characteristics of anti-TBM antibody nephritis include marked interstitial nephritis featuring lymphoplasmacytic infiltration with occasional neutrophils, acute and chronic tubular injury, linear deposition of IgG and complement C3 along TBMs present by immunofluorescence microscopy, and detection of anti-TBM antibodies in the serum.^2,3 This report describes a case of a patient with a history of cutaneous basal cell carcinoma, adenocarcinoma of the prostate, and chronic lymphocytic leukemia (CLL) who was subsequently diagnosed with chronic kidney disease due to anti-TBM antibody nephritis.

Case Presentation

A 69-year-old male with a past medical history of hypertension, cutaneous basal cell carcinoma, and prostatic adenocarcinoma treated with proton therapy and leuprolide visited his oncologist as a follow-up for his recently diagnosed CLL. A nephrology consultation was sought due to the progressive worsening of kidney function. At the time of consultation, serum creatinine (Cr) was 2.5 mg/dL, compared with his baseline Cr of 1.1 mg/dL 3 months prior with mild non-anion gap metabolic acidosis. The patient was not on any medications at that time. There was no history of urinary retention or obstructive uropathy. A computed tomography (CT) scan revealed a homogenously enhanced soft tissue mass in the mediastinum and retroperitoneum, measuring 9.7 × 8.3 cm. This mass was suspected of lymphoma, encasing vital structures such as aorta, celiac axis, superior mesenteric artery, and renal arteries and partially involving the inferior vena cava. Initial differential diagnosis included monoclonal gammopathies, tumor lysis syndrome, and renal ischemia resulting from the encasement of renal arteries by the tumor. Laboratory results were normal for serum uric acid, lactate dehydrogenase, phosphorus, and calcium levels, making tumor lysis syndrome less likely. Serologies for anti-nuclear antibody (ANA), anti-dsDNA and anti-GBM antibodies, cryoglobulins, and anti-neutrophil cytoplasmic antibody (ANCA) panel were also negative. Serum protein electrophoresis (SPEP) with immunofixation revealed an IgG lambda light chain band. Urine protein electrophoresis (UPEP) disclosed a small gamma spike measuring 5 mg/dL, raising suspicion for monoclonal gammopathy or multiple myeloma. Serum levels of IgA, IgG, IgM, and C3 were normal, and C4 was low (8.9 mg/dL).

A urine dipstick test showed proteinuria and glycosuria despite no prior history of diabetes mellitus. A spot urine protein to Cr ratio (UPCR) was 773 mg/g. Renal ultrasound demonstrated normal kidney size and echogenicity without any signs of hydronephrosis. The patient’s serum Cr level continued to rise, reaching 3.6 mg/dL 2 months post-initial consultation, prompting the decision to proceed with a kidney biopsy.

The initial pathology examination indicated the presence of 27 glomeruli, with 7 (22%) being obsolescent. The non-sclerosed glomeruli showed focal modest mesangial expansion and focal segmental glomerulosclerosis. There was extensive interstitial fibrosis and tubular atrophy (IFTA), involving approximately 90% of cortical parenchyma, accompanied by mild interstitial edema, focal tubulitis, and patchy interstitial lymphoplasmacytic inflammation (Figure 1A). Renal parenchymal involvement by lymphoma was ruled out by immunohistochemical stains for CD3, CD20, PAX5, CD5, and CD23. Immunofluorescent microscopy displayed linear staining of most TBMs for polytypic IgG with no kappa/light chain bias, C3, and focally for C1q. No staining of glomerular or Bowman’s basement membranes was evident (Figure 1B). Electron microscopy did not reveal any immune deposits in the glomeruli or TBMs (Figure 1C and D). There was no evidence of a paraprotein-related nephropathy by light, immunofluorescent, or electron microscopy. Altogether, the findings were interpreted as anti-TBM antibody nephritis with prominent chronicity with an element of ischemic nephropathy, likely related to the mass encasing renal arteries.

Figure 1.

(A) Periodic acid-Schiff (PAS) staining shows inflammation within and among tubules (on the left) and a well-preserved glomerulus (on the right). (B) Immunofluorescence (IF) microscopy shows linear staining of the tubular basement membranes for IgG without staining of the glomerulus (far right). (C) Electron microscopy (EM) of the glomerulus shows mild effacement of podocyte foot processes, normal thickness, without abnormal lamination or associated electron dense deposits. (D) EM of tubules shows moderate to marked atrophy with variable acute injury and thickened tubular basement membranes.

The R-CVP (rituximab-cyclophosphamide, vincristine, prednisone) cycle of chemotherapy, along with filgrastim injection, was initiated to reduce the mass and salvage renal function. The patient’s kidney function continued to deteriorate, progressing to end-stage kidney disease (ESKD) within 3 months of initial consult; therefore, hemodialysis was initiated.

The patient underwent multiple cycles of chemotherapy. However, due to recent hospitalizations for shortness of breath, pleural effusion, the need for symptom management, and several comorbidities, palliative care or hospice was recommended.

Discussion

Anti-TBM antibody nephritis is a rare immune-mediated disease associated with antibodies against a component of the TBM and characterized by progressive chronic tubulointerstitial injury with sparing glomeruli. The disease has been reported either as a primary phenomenon or in the context of other conditions.

Primary anti-TBM antibody disease is caused by an autoantibody against a protein called TIN-ag. ² This antigen has been identified as a 58-kDa extracellular matrix non-collagenous protein restrictively expressed in the proximal TBM by Kanwar et al ⁴ and as 54-kDa protein with its gene mapped to chromosome 6p11.2-12 by Ikeda et al. ⁵ Although the function of this antigen is not yet completely understood, during embryonic life, TIN-ag is involved in tubulogenesis by promoting cell adhesion through interactions with type IV collagen and laminin.^5-7 In addition, TIN-ag serves as a ligand for integrins α3β1 and αVβ3, and thus, it is involved in maintaining the integrity of the kidney TBM. ⁸ The pathogenesis of anti-TBM antibody nephritis has not been clearly defined. It is unclear whether kidney damage is mediated directly by these antibodies or if kidney tubular damage is the initial insult that stimulates the development of the antibodies. ⁹ Several studies have used animal models to demonstrate the association of these antibodies with tubulointerstitial nephritis. Injection of anti-TBM antibodies from the sera of patients with anti-TBM disease has been demonstrated to cause typical findings of anti-TBM antibody nephritis in animal models. ⁹

Anti-TBM antibody nephritis has also been reported in association with other diseases or medications. The present case is the first report of anti-TBM antibody nephritis in a background of a lymphoplasmacytic neoplasm, whereas a literature review revealed no clear association between lymphoproliferative disorders and anti-TBM disease. However, given the phenomenon of paraneoplastic antibody production by some lymphoid malignancies and the temporal association of the 2 conditions in this patient, we suspect CLL may have contributed to the development of anti-TBM nephritis. Rifai et al ¹ reported a case of anti-TBM nephritis in a patient receiving nivolumab infusions for the treatment of urothelial carcinoma with concurrent pyelonephritis. Border et al ¹⁰ described a patient developing anti-TBM antibody nephritis following receiving methicillin.

Similar to our case, the immunoglobulin detected in anti-TBM antibody nephritis is usually of the IgG class, although an example of pathogenic IgA anti-TBM antibodies is reported in the context of Goodpasture’s syndrome. ¹¹

Clinical presentation often includes acute and chronic kidney dysfunction, polyuria, polydipsia, subnephrotic proteinuria, and microscopic hematuria. ⁹ Our case presented with elevated serum Cr, non-anion gap metabolic acidosis, glucosuria, and subnephrotic range proteinuria.

Table 1 provides a summary of reported anti-TBM cases, including the case presented in this report.

Table 1.

Summary of reported anti-TBM cases

Case	Age/sex	Medical history	Diagnosis	Initial/final creatinine	Serologic/immunological findings	Kidney biopsy	Immunofluorescence microscopy	Treatment	Outcome
Rifai AO, et al 1	71/male	High-grade urothelial carcinoma with lymphovascular invasion treated with gemcitabine and cisplatin followed by radical cystectomy and ileal conduit Ongoing nivolumab infusions for 16 months Atrial fibrillation treated with apixaban and benazepril	Acute kidney injury secondary to nivolumab therapy	Initial: 4.4 mg/dL Final: 9.6 mg/dL	Negative for ANA, ANCA, anti-GBM antibodies, anti-TBM antibodies	17 glomeruli with 3 globally sclerotic; no mesangial or endocapillary hypercellularity, fibrinoid necrosis, or crescents; Moderate IFTA; dense interstitial inflammation with eosinophils, neutrophils, lymphocytes, plasma cells, histiocytes; neutrophil-rich inflammation with tubulitis	Strong linear IgG and C3 staining (3+ each) along the proximal TBM; no glomerular or distal tubular staining; IgG subclasses (IgG1, IgG2, IgG3, IgG4) positive along TBM (3+) No TBM deposits on electron microscopy	IV methylprednisolone, IV ceftriaxone, nivolumab discontinued, oral prednisone after discharge, hemodialysis	Gradual improvement in kidney function with cessation of hemodialysis Serologic remission with negative anti-TBM antibodies after steroid therapy and discontinuation of nivolumab Patient remained off dialysis post-treatment
Border WA, et al 10	29/male	Gunshot wound to the left thigh	Methicillin-induced acute interstitial nephritis	Initial: 1.6 mg/dL Final: 3.9 mg/dL	Negative skin tests for penicillin G, methicillin; negative for anti-methicillin/penicillin antibodies in hemagglutination test	Severe interstitial disease with essentially normal glomeruli and vessels; marked degeneration of tubules; inflammatory infiltrate with eosinophils and plasma cells	IgG and C3 in a linear pattern along TBM of cortical tubules; fibrin deposits in interstitium; no IgA/IgM deposits; methicillin antigen present along TBM; glomeruli negative for IgG, IgA, IgM, C3, and fibrin	Wound care, oral penicillin V, oxacillin, prednisone, methicillin discontinued, intermittent hemodialysis	Discharged to outpatient hemodialysis Persistent kidney impairment with diminished tubular function
Our case	69/male	Hypertension Cutaneous BCC Prostatic adenocarcinoma treated with proton therapy and leuprolide CLL	Anti-tubular basement membrane antibody nephritis	Initial: 2.5 mg/dL Final: 3.6 mg/dL	Normal serum IgA, IgG, IgM; low C4; negative for ANA, anti-dsDNA, anti-GBM, cryoglobulins, and ANCA panel; IgG lambda light chain band on SPEP	27 glomeruli, 7 obsolescent; focal mesangial expansion and segmental glomerulosclerosis; extensive IFTA (90% of cortex); mild interstitial edema, focal tubulitis, patchy lymphoplasmacytic inflammation	Linear staining of TBM for IgG, C3, and focal staining for C1q; no glomerular or Bowman’s basement membrane staining No immune deposits on electron microscopy	R-CVP chemotherapy regimen, filgrastim, hemodialysis	Progressed to ESKD and palliative care/hospice recommended due to multiple comorbidities

Abbreviations: BCC, basal cell carcinoma; CLL, chronic lymphocytic leukemia; ESKD, end-stage kidney disease; GBM, glomerular basement membrane; IFTA, interstitial fibrosis and tubular atrophy; IV, intravenous; R-CVP, rituximab-cyclophosphamide, vincristine, prednisone; SPEP, serum protein electrophoresis; TBM, tubular basement membrane.

In summary, anti-TBM antibody nephritis is an immune-mediated disease associated with antibodies against a component of the TBM and characterized by progressive chronic tubulointerstitial injury with sparing glomeruli. ² There is currently no clearly defined specific treatment for this disorder, and management remains largely supportive. Anti-TBM antibody nephritis has been reported in kidney allograft in patients who did not have the antigen. ²

This case highlights the management challenges of anti-TBM antibody nephritis as a rare kidney disorder. Although the diagnosis was confirmed through a kidney biopsy, the primary challenge was preventing the disease from advancing to a severe stage, as the patient already had significant IFTA at the time of diagnosis. This emphasizes the importance of early diagnosis, even when treatment, such as chemotherapy for the presumed underlying condition, has been initiated.

This case also highlights the limited existing literature supporting a direct relationship between lymphoproliferative disorders and anti-TBM disease.

A more specific recommendation for future research would be to investigate whether underlying malignancies contribute to anti-TBM antibody nephritis or if patients with lower IFTA might benefit from immunosuppressive therapy to improve clinical outcomes. This targeted approach could provide clearer insights into immune-mediated kidney injury mechanisms and inform potential therapeutic interventions.