Polyclonal immunoglobulin G deposits with distinctive appearance in the tubular basement membrane: A report of two cases

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The histological presentation of the tubulointerstitium in renal biopsies can vary considerably. When tubulointerstitial alterations are identified through light microscopy, additional evaluation with immunofluorescence and electron microscopy may assist in diagnosis. This report describes two slowly progressive atypical cases of tubulointerstitial disease. Renal biopsy in both cases revealed tubular atrophy and interstitial fibrosis with limited inflammatory cell infiltration, along with polyclonal linear immunoglobulin G (IgG) staining pattern along the thickened tubular basement membrane (TBM) and distinctive electron-dense deposits. Case Presentation: Case 1: A 65-year-old Japanese man with a history of chronic obstructive pulmonary disease, benign prostatic hyperplasia, and hypertension presented with anorexia and malaise 1 week prior to admission. Blood tests demonstrated marked renal impairment. Renal biopsy findings included relatively preserved glomeruli, widespread tubular atrophy, and significant interstitial fibrosis. Immunofluorescence showed linear deposition of IgG as well as kappa and lambda light chains along the TBM. Complement components C3 was also positive, and C1q were weakly positive. No IgG subclass restriction was noted. Electron microscopy revealed electron-dense deposits within the TBM and on the epithelial side of the TBM, exhibiting a mottled and speckled appearance. Case 2: A 52-year-old Japanese man who had undergone allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia developed mild proteinuria and renal dysfunction 7 years post-transplant. Renal biopsy indicated thrombotic microangiopathy, with glomeruli showing diffuse mesangial expansion and focal mesangiolysis. There was also diffuse TBM thickening and interstitial fibrosis with scattered cellular infiltration. Immunofluorescence demonstrated linear staining of polyclonal IgG and both light chains along the TBM. C3 was also positive while C1q was negative. IgG subclass staining revealed positivity for IgG1 and IgG4. Electron microscopy again identified electron-dense deposits within the reticulated TBM. Conclusions: These two cases demonstrated linear IgG immunofluorescence and distinctive electron-dense deposits in the TBM characterized by a mottled and speckled pattern. Although the underlying pathophysiological mechanisms remain unclear, further research is necessary to elucidate the nature of this form of tubulointerstitial disease. Tubulointerstitial diseases Polyclonal IgG deposition Linear IgG immunofluorescence Electron-dense deposits Renal biopsy Tubular Basement Membrane Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Tubulointerstitial diseases can develop in a wide range of clinical settings, including infections, adverse drug reactions, autoimmune conditions, exposure to toxins, obstructive uropathies such as hydronephrosis and reflux nephropathy, metabolic disorders, hematologic malignancies, glomerular diseases, and vascular-related conditions such as hypertension. 1) These disorders are typically associated with mild proteinuria and minimal urinary sediment abnormalities, with either acute or chronic compromise of renal function. Clinically, tubulointerstitial injury may be indicated by elevated levels of urinary β2-microglobulin (β2MG) or Nacetylβ-D-glucosaminidase (NAG), along with unexplained increases in serum creatinine (Cr). Renal biopsy plays an essential role in diagnosis, allowing assessment of immunoglobulin (Ig) and complement component deposition patterns, either linear or granular, on immunofluorescence—as well as TBM deposits observed using electron microscopy. These assessments assist in reaching diagnostic conclusions. In this report, we describe two atypical cases showing polyclonal IgG deposits within thickened TBM and minimal interstitial inflammation, which do not fit established categories of tubulointerstitial diseases. Case Presentation Case 1 A 66-year-old Japanese man had been diagnosed with chronic obstructive pulmonary disease (COPD) 3 years prior to admission and was prescribed tiotropium bromide hydrate 2.5 µg, L-carbocisteine 1500 mg, long-acting beta-agonists, and inhaled corticosteroids (salmeterol xinafoate and fluticasone propionate). He also had a history of using oral steroids use during COPD exacerbations and had smoked 40 cigarettes per day for 35 years. He was receiving treatment for hypertension with olmesartan 20 mg and nifedipine 20 mg, with adequate blood pressure control. He denied having diabetes mellitus or a family history of kidney disease. Three years before admission, his serum Cr was 0.77 mg/dL, which increased to 1.29 mg/dL 2 months later; however, urinary protein and occult blood tests were negative. No routine laboratory monitoring had been performed since that time. Two years before admission, he began experiencing lower urinary tract symptoms, including nocturia, a sensation of incomplete bladder emptying, and urinary urgency. He was initially prescribed the alpha-adrenergic antagonist tamsulosin hydrochloride 0.2 mg, which was later changed to the 5α-reductase inhibitor dutasteride 0.5 mg, 1 year and 4 months before admission. Two weeks prior to admission, he developed general malaise, anorexia, nausea, and vomiting, prompting a visit to our hospital. At the time of his emergency room visit, physical examination showed a blood pressure of 118/61mmHg, pulse rate of 80 beats/min, and body temperature of 35.7°C. Oxygen saturation on air was 98%, with a slightly elevated respiratory rate of 17 breaths/min. The only notable physical finding was pallor of the palpebral conjunctiva. Arterial blood gas analysis on room air revealed a pH of 7.15, pCO 2 of 20.8mmHg, an anion gap (AG) of 14.9, and a corrected bicarbonate (HCO 3 ) level of 10.0 mmol/L, consistent with high AG metabolic acidosis complicated by respiratory compensation. Urinalysis showed a specific gravity of 1.020, urine pH of 5.0, proteinuria (2+) quantified as 0.9 g/g Cr, occult blood (2+), glucose (1+), and was negative for ketones. The fractional excretion of sodium (FENa) was 12.6%. Urinary β2MG was markedly elevated at 24,173 µg/L (reference range, 0–200 µg/L). Urinary sediment analysis revealed 5–9 erythrocytes, 5–9 leukocytes, and 10–99 granular casts per high-power field. No urine eosinophils were observed. Complete blood count (CBC) results showed a white blood cell (WBC) count of 10.8 × 10 4 /µL, with neutrophils accounting for 78% and eosinophils 0.5%. Red blood cell count was 272 × 10 4 /µL (reference, 430–570 × 10 4 /µL), hemoglobin 8.1 g/dL, and hematocrit 24.3%. Platelet count was 17.7 × 10 4 /µL. Serum biochemistry revealed total protein (TP) of 5.9 g/dL, albumin (Alb) 3.2 g/dL, urea nitrogen (UN) 177.3 mg/dL, Cr 16.32 mg/dL, and an estimated glomerular filtration rate (eGFR) of 2.7 mL/min/1.73m 2 . Uric acid was 8.0 mg/dL, sodium 135 mEq/L, potassium 5.9 mEq/L, chloride 113 mEq/L, corrected calcium 7.7 mg/dL, and phosphorus 9.0 mg/dL, indicating advanced renal failure. Immunological evaluation showed IgG 1687 mg/dL (reference, 870–1700 mg/dL), IgA 155 mg/dL (110–410 mg/dL), IgM 20 mg/dL (33–190 mg/dL), and a kappa/lambda light chain ratio of 1.131 (0.48–1.804). IgE was within normal limits at 80 IU/mL (< 170 IU/mL). C-reactive protein (CRP) was 0.65 mg/dL (< 0.30 mg/dl). Hypergammaglobulinemia was not evident, and no monoclonal protein (M-protein) was detected in either serum or urine. Complement levels were within normal range (C3 92 mg/dL, C4 33 mg/dL, CH50 42.8 U/mL). Screening markers for infection, including Treponema pallidum antibody (TP-Ab), hepatitis B surface antigen (HBs-Ag), hepatitis B Surface antibody (HBs-Ab), hepatitis C virus antibody (HCV-Ab), and human immunodeficiency virus antibody (HIV-Ab), yielded negative results. Autoimmune serologies, including antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-ds-DNA-Ab), anti-Smith antibody (anti-Sm-Ab), anti-SS-A antibody (SS-A-Ab), anti-SS-B antibody (SS-B-Ab), cryoglobulin, myeloperoxidase-anti neutrophil cytoplasmic antibody (MPO-ANCA), proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA), and anti-glomerular basement membrane antibody (anti-GBM Ab), were all negative. Plain computed tomography revealed emphysematous changes in the lungs and mild bilateral renal atrophy. No prostatic hypertrophy or abnormal organ masses were detected. The patient was admitted to our hospital on an emergency basis due to severe renal dysfunction. Following admission, due to the patient’s general condition characterized by severe renal dysfunction accompanied by anorexia and dehydration, he received 2–3 L of isotonic fluid intravenously each day. Despite this, there was no increase in urine output, and renal dysfunction did not improve. A renal biopsy was performed on the ninth day to investigate the underlying cause of severe renal failure. Light microscopy revealed that the specimen contained 2 cores with a total of 37 glomeruli and a cortex-to-medulla ratio of 5:5. Seven glomeruli exhibited global sclerosis, 13 were collapsed, and the remaining glomeruli, although somewhat collapsed, appeared relatively preserved without mesangial matrix expansion or hypercellularity (Fig. 1 A). A mild, nonspecific infiltrate of lymphocytes and plasma cells was observed around atrophic tubules and within the interstitium (Fig. 1 B). A few tubules remained non-atrophic but showed basement membrane thickening. There was no clear evidence of tubulitis. Interstitial fibrosis and tubular atrophy involved more than 90% of the cortical area, although inflammatory changes within the fibrotic interstitium were minimal (Fig. 1 C). No eosinophil infiltration was observed. In the medullary region, several foci of inflammatory cells, including localized neutrophils, were present. Vascular changes included mild to moderate intimal thickening in arteries ranging from arcuate to interlobular vessels. Arteriolar hyalinosis was not observed. On immunofluorescence, using a grading scale from (−) to (2+), linear staining of the TBM for IgG was observed at 2 + intensity (Figs. 1 D and 1 E), along with C3 at 2+ (Fig. 1 F) and C1q (1+) (Fig. 1 G). No restriction was seen in IgG subclass or in kappa and lambda light chain staining (Figs. 1 H and 1 I). Electron microscopy revealed electron-dense deposits in the thickened TBM and on the epithelial side of TBM, characterized by a mottled and speckled pattern (Figs. 2 B and 2 D). Corticosteroid therapy was not initiated due to the presence of uremic symptoms and the histological findings indicating an irreversible condition characterized by severe tubular atrophy and interstitial fibrosis. A dialysis catheter was placed in the right internal jugular vein, and hemodialysis was initiated on the twelfth day. The severe anemia noted at admission improved after several sessions of hemodialysis. His overall condition showed significant improvement, and an arteriovenous fistula was subsequently created. Hemodialysis was subsequently continued. Case 2 A 52-year-old Japanese man, diagnosed with acute myeloid leukemia 7 years before admission, underwent allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-C allotype-mismatched bank donor after receiving remission with idarubicin and cytarabine (IDA-AraC), followed by consolidation therapy with high-dose cytarabine (HDCA), cyclophosphamide, and total body irradiation (TBI). Graft-versus-host disease (GVHD) prophylaxis was administered using tacrolimus and methotrexate. Although specific details are unavailable, vancomycin and other antibiotics were used to treat infectious complications during chemotherapy prior to the transplantation. Four years before admission, he was referred to his primary care physician for the management of hypertension, glucose intolerance, hyperuricemia, and dyslipidemia. He was prescribed amlodipine 10 mg, valsartan 80 mg, febuxostat 20 mg, and simvastatin 5 mg, with good disease control. Proteinuria developed 3 years after allogeneic HSCT. Although his serum Cr level remained at approximately 1.0 mg/dL until 6 years post-transplant, he was referred to our hospital due to an increase in serum Cr to 1.65 mg/dL. At the initial visit, physical examination showed a blood pressure of 136/85 mmHg, a pulse rate of 61 beats/min, and a body temperature of 36.5°C. No edema or other apparent abnormalities were observed. Urinalysis revealed a urine specific gravity of 1.004, pH of 6.0, trace proteinuria (0.43 g/gCr), and negative results for occult blood, glucose, and ketones. The FENa was 1.44%, urinary β2MG was 2144 µg/L, and urinary NAG was 2.5 U/L (reference range, 0–11.5 U/L). Urinary sediment examination showed no erythrocytes or leukocytes, and urinary eosinophils were absent. The CBC was within normal limits, and the automated WBC differential showed no abnormalities. Blood biochemistry indicated normal liver function (TP 7.5 g/dL, Alb 4.5 g/dL, total bilirubin 1.2 mg/dL, aspartate aminotransferase (AST) 22 U/L, alanine aminotransferase (ALT) 21 U/L, lactate dehydrogenase (LDH) 218 U/L) but mild renal impairment (blood UN 19.8 mg/dL, Cr 1.54 mg/dL, eGFR 38.9 mL/min/1.73m 2 ). Postprandial glucose was 119 mg/dL, and HbA1c was 6.6%. CRP was negative. Immunological testing showed IgG 1212 mg/L (IgG4 71 mg/dL), IgA 298 mg/dL, IgM 74 mg/dL, and a kappa/lambda ratio of 0.958. Hypergammaglobulinemia was not observed, and no monoclonal protein was detected in either serum or urine. The IgE level was elevated at 1108.8 IU/mL (reference range, 15.0–390.0 IU/mL). Complement levels were within normal limits (C3 110 mg/dL, C4 19 mg/dL, CH50 46.0 U/mL). Tests for rheumatoid factor, ANA, anti-ds-DNA-Ab, anti-Sm-Ab, anti-SS-A-Ab, anti-SS-B-Ab, cryoglobulin, MPO-ANCA, PR3-ANCA, and anti-GBM Ab were all negative. All infectious markers were also negative. Abdominal ultrasonography showed no abnormal masses and both kidneys were of normal size. A renal biopsy was performed 2 months later due to an increase in serum Cr to 1.52 mg/dL, in order to investigate the unknown cause of renal dysfunction identified 3 months after the initial visit. On light microscopy, the specimen included 1 core containing 16 glomeruli, with a cortex-to-medulla ratio of 10:0. Five glomeruli exhibited global sclerosis, and one was collapsed. Mesangial expansion with focal mesangiolysis, consistent with renal thrombotic microangiopathy (TMA), was noted (Fig. 3 A). Approximately 20% of the cortical area demonstrated diffuse thickening of the proximal TBM (Fig. 3 B), along with interstitial fibrosis and scattered inflammatory cell infiltration. Mild intimal thickening of the interlobular artery was observed. Arteriolar hyalinosis was not prominent. Immunofluorescence revealed diffuse linear staining for IgG (1+), C3 (1+), kappa light chain (1+), and lambda light chain (1+) along the TBM. Staining for IgG subclasses in TBM deposits showed IgG1 (1+) and IgG4 (1+) (Figs. 3 E and 3 F). In the glomeruli, segmental positivity for fibrinogen, IgM, and C3, and to a lesser degree IgA, was observed and interpreted as nonspecific trapping. There was no evidence of kappa or lambda light chain restriction (Figs. 3 H and 3 I). Electron microscopy demonstrated mottled and speckled deposits (Figs. 4 A) within the thickened TBM. Electron microscopy of silver-impregnated sections showed layered and reticulated TBM in the deposits (Figs. 4 B, 4 C and 4 D). In the glomeruli, mesangial expansion and subendothelial widening were present, accompanied by focal effacement of podocyte foot processes. Following the renal biopsy, he was discharged with conservative management and monitoring for renal dysfunction; however, his serum Cr has gradually increased to 2.0 mg/dL over the following 5 years. Discussion and Conclusions Tubulointerstitial diseases can develop under various conditions 1) and are classified into immune-mediated and nonimmune mechanisms. 2) Although the clinical courses of our two cases were entirely different, the morphological findings suggested a similar pattern of deposition in the TBM. Tubulointerstitial involvement is more closely associated with renal prognosis than glomerular abnormalities, 3) and its presence should be considered when renal dysfunction progressively declines despite the absence of abnormalities on urinalysis. The renal biopsy findings in our two cases were marked by tubulointerstitial lesions featuring linear polyclonal IgG staining on immunofluorescence and distinctive electron-dense deposits within the TBM. In Case 1, there was no glomerular involvement, but severe tubular atrophy and interstitial fibrosis were present, along with linear polyclonal IgG deposits along the TBM observed on immunofluorescence, raising the possibility of primary anti-TBM nephritis. 4) Primary anti-TBM nephritis is a rare condition in which an immune response is triggered by antibodies (anti-TBM antibodies) against a specific antigen peptide (54–58 kD) found in the proximal TBM, leading to tubulointerstitial nephritis (TIN). 4) Anti-TBM antibodies are also known to play a significant role in the pathogenesis of TIN in several other renal disorders. 5)−9) The histological characteristics of anti-TBM nephritis include TBM damage with mononuclear cell infiltration, edema, and fibrosis in the interstitial tissue, along with strong, diffuse linear fluorescence for IgG and C3 along the TBM, without deposits. 4) The glomeruli and arteries typically showed nonspecific changes, unless other diseases are present. In Case 1, the presence and characteristics of the electron-dense deposits in the TBM were not consistent with anti-TBM nephritis. Although the ultrastructual appearance of the deposits and the mild tubulointerstitial inflammation were atypical for anti-TBM nephritis, the patient’s blood sample was tested for anti-TBM antibodies using the indirect immunofluorescence method, 10) after informed consent was obtained. This test showed no evidence of linear fluorescence for IgG in the TBM. In Case 2, which was accompanied by glomerular lesions due to TMA, anti-TBM antibody testing was not performed. However, the presence of distinctive polyclonal electron-dense deposits in the TBM were considered atypical for anti-TBM nephritis. The electron-dense deposits in both cases exhibited fine granular characteristics, resembling those seen in light chain deposition disease (LCDD) 11) , which is classified under monoclonal immunoglobulin deposition diseases (MIDD). MIDD is a condition in which immunoglobulin molecules or their fragments, known as paraproteins, are deposited monoclonally in the glomeruli and TBM. 12) LCDD is characterized by the absence of immunoglobulin and complement component deposits. Immunofluorescence typically reveals monoclonal linear deposit of kappa or lambda light chains along the glomerular basement membrane, mesangial areas, and TBM. In some LCDD cases, there is no glomerular proteinuria, 13) and deposits are found only in the TBM. 14) Electron microscopy reveals granular to amorphous deposits in the TBM. However, in our two cases, polyclonal IgG, along with kappa and lambda light chains, were detected, and monoclonal immunoglobulinemia was not observed in serum or urine, suggesting that these findings are not explained by LCDD. In Case 2, the glomerular TMA lesion featuring mesangial expansion with mesangiolysis was associated with post-allogeneic HSCT and may have been triggered by GVHD. However, the presence of diffuse tubular atrophy and interstitial fibrosis with linear polyclonal IgG deposits along the TBM, in the absence of significant interstitial inflammation, was also noted. The pathogenesis of renal dysfunction following allogeneic HSCT varies depending on the timing of onset. Acute TMA associated with GVHD, acute TIN, and tubular injury resulting from viral infections or cytotoxic agents (such as calcineurin inhibitors) have been observed. 15) In the chronic phase, renal damage may be linked to endothelial injury caused by chronic TMA, TBI, and hypertension. 16) Although there are reports on renal pathology after allogeneic HSCT, it remains underexplored. One report described polyclonal IgG deposits in the TBM with minimal glomerular involvement occurring 10 years after allogeneic HSCT, 17) which improved with prednisolone treatment, leading to a reduction in serum Cr levels. Another case described membranous nephropathy with extensive granular deposits of IgG (IgG1 and IgG4), C3, and kappa and lambda light chains in the TBM after allogeneic HSCT. 18) These findings suggest that polyclonal IgG immune deposits in the TBM may contribute to renal dysfunction following allogeneic HSCT. However, the histopathology, in Case 2, did not align with these two cases in that the tubular polyclonal deposit was linear, and the significance of linear polyclonal IgG—particularly IgG4, in the TBM has not been described in GVHD. IgG4-related kidney disease (IgG4-RKD) was considered in the differential diagnosis of tubulointerstitial diseases for immunofluorescence showing deposition of IgG, including IgG4 along the TBM in our two cases. IgG4-RKD is characterized by the infiltration of plasma cell–rich interstitial inflammation and fibrosis. 19) IgG4-RKD can be diagnosed through serological and histological findings, including increased numbers of IgG4-positive plasma cells. Immunofluorescence typically reveals granular immune complex deposits in the TBM, containing IgG4, C3, C1q, and both kappa and lambda light chains. 20) IgG subclass testing often shows positivity for any or all IgG subclasses, including IgG1–IgG4. 21) Although our two cases showed positivity for IgG subclasses, including IgG4 in the TBM, the linear immunofluorescence staining in the TBM did not support a diagnosis of IgG4-RKD. Although it is well-established that diabetic nephropathy can lead to nonspecific polyclonal linear IgG deposits in the TBM, 22) a previously reported case of diabetic glomerulosclerosis with powdery dense deposits in the TBM 23) highlighted the challenge of distinguishing such findings from diabetes-related alterations, such as atrophic and lamellated TBM. Notably, despite some structural differences, our two cases bear resemblance to the case of polyclonal IgG deposition disease (PIDD) reported by Markowitz et al., 24) which exhibited curvilinear and membranous structures located within the TBM. The deposition of polyclonal light chains on the proximal TBM has been reported to lead to the loss of the brush border and subsequent tubulointerstitial injury. 25),26) Anti-brush border antibody, in which polyclonal immunoglobulins are specifically deposited on the proximal TBM, 27) is recognized as one of the antibodies (megalin) targeting the low-density lipoprotein receptor-related protein 2 (LRP2), which helps explain the mechanism of proximal TBM injury and the subsequent development of tubulointerstitial fibrosis. However, renal biopsy findings in our two cases showed no evidence of granular polyclonal IgG deposits in the TBM that would suggest immune complex formation, and the deposits were present in both the proximal and distal TBM. In conclusion, we present two rare cases characterized by linear immunofluorescence with electron-dense deposits that have a mottled arrangement in thickened TBM. These findings were difficult to categorize into any specific tubulointerstitial disease despite subclinical evidence of renal dysfunction progression. Although the pathophysiology in our two cases remains unclear, detailed histopathological analysis including electron microscopy of silver-impregnated sections may assist in the identification of similar future cases. Further investigation is needed to better understand this form of tubulointerstitial disease. Abbreviations TBM, Tubular basement membrane MIDD, Monoclonal immunoglobulin deposition disease LCDD, Light chain deposition disease PIDD, Polyclonal immunoglobulin G deposition disease Declarations Ethics approval and consent to participate Not applicable Consent for publication Written informed consent was obtained from the patients for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the journal’s editor. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare no competing interests. Funding The authors received no specific funding for this work. Author’s contributions YS collected the patient’s clinical data, performed the renal biopsy, and contributed to writing the manuscript. AH, a pathologist at Keio University Hospital, conducted the histological examination of the kidney and made significant contributions to writing the manuscript. KK, TA, and HT supervised the manuscript. All authors have read and approved the final version of the manuscript. Acknowledgments Not applicable. References Rastegar A, Kashgarian M. The clinical spectrum of tubulointerstitial nephritis. Kidney Int. 1998;54:313–27. Andres GA, McCluskey RT. Tubular and interstitial renal disease due to immunologic mechanisms. Kidney Int. 1975;7:271–89. Mackensen-Haen S, Bader R, Grund KE, Bohle A. Correlations between renal cortical interstitial fibrosis, atrophy of the proximal tubules, and impairment of the glomerular filtration rate. Clin Nephrol. 1981;15:167–71. Lusco MA, Fogo AB, Najafian B, Alpers CE. AJKD atlas of renal pathology: anti-tubular basement membrane antibody disease. Am J Kidney Dis. 2017;70:e3–4. 10.1053/j.ajkd.2017.05.001 . Rotellar C, Noel LH, Droz D, Kreis H, Berger J. Role of antibodies directed against tubular basement membranes in human renal transplantation. Am J Kidney Dis. 1986;7:157–61. McPhaul JJ Jr, Dixon FJ. Characterization of human antiglomerular basement membrane antibodies eluted from glomerulonephritic kidneys. J Clin Invest. 1970;49:308–17. Makker SP. Tubular basement membrane antibody-induced interstitial nephritis in systemic lupus erythematosus. Am J Med. 1980;69:949–52. Morel-Maroger L, Kourilsky O, Mignon F, Richet G. Antitubular basement membrane antibodies in rapidly progressive poststreptococcal glomerulonephritis: report of a case. Clin Immunol Immunopathol. 1974;2:185–94. Border WA, Lehman DH, Egan JD, Sass HJ, Glode JE, Wilson CB. Antitubular basement-membrane antibodies in methicillin-associated interstitial nephritis. N Engl J Med. 1974;291:381–4. Bergstein J, Litman N. Interstitial nephritis with anti-tubular-basement-membrane antibody. N Engl J Med. 1975;292:875–8. Leung N, Bridoux F, Batuman V, Chaidos A, Cockwell P, D’Agati VD, et al. Evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2019;15:45–59. Lin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol. 2001;12:1482–92. Sicard A, Karras A, Goujon J-M, Sirac C, Bender S, Labatut D, et al. Light chain deposition disease without glomerular proteinuria: a diagnostic challenge for the nephrologist. Nephrol Dial Transpl. 2014;29:1894–902. 10.1093/ndt/gfu045 . Gokden N, Cetin N, Colakoglu N, Kumar J, Abul-Ezz S, Barlogie B, et al. Morphologic manifestations of combined light-chain deposition disease and light-chain cast nephropathy. Ultrastruct Pathol. 2007;31:141–9. Renaghan AD, Jaimes EA, Malyszko J, Perazella MA, Sprangers B, Rosner MH. Acute kidney injury and CKD associated with hematopoietic stem cell transplantation. Clin J Am Soc Nephrol. 2020;15:289–97. Noël C, Hazzan M, Noël-Walter MP, Jouet JP. Renal failure and bone marrow transplantation. Nephrol Dial Transpl. 1998;13:464–6. 10.1093/ndt/13.10.2464 . Zhou W, Qi C, Zhang M, Hou X, Ni Z. Tubular basement membrane deposits after allogeneic hematopoietic stem cell transplantation. BMC Nephrol. 2023;24:242. 10.1186/s12882-023-03296-x . Nasr SH, Leung N, Said SM, Alkhateeb HB, Madden BJ, Charlesworth MC, et al. Membranous nephropathy with extensive tubular basement membrane deposits following allogeneic hematopoietic cell transplant: a report of 5 cases. Am J Kidney Dis. 2022;79:904–8. Saeki T, Kawano M. IgG4-related kidney disease. Kidney Int. 2014;85:251–7. Raissian Y, Nasr SH, Larsen CP, Colvin RB, Smyrk TC, Takahashi N, et al. Diagnosis of IgG4-related tubulointerstitial nephritis. J Am Soc Nephrol. 2011;22:1343–52. Yamaguchi Y, Kanetsuna Y, Honda K, Yamanaka N, Kawano M, Nagata M. Characteristic tubulointerstitial nephritis in IgG4-related disease. Hum Pathol. 2012;43:536–49. Miller K, Michael AF. Immunopathology of the renal extracellular membranes in diabetes mellitus. Specificity of tubular basement-membrane immunofluorescence. Diabetes. 1976;25:701–8. Watanabe H, Takeuchi Y, Taniuchi S, Sato H, Nakamura Y, Sasano H, et al. Polyclonal immunoglobulin G deposition on the tubular basement membrane in diabetic nephropathy: a case report. Pathol Int. 2020;70:463–9. Markowitz GS, Fine PL, Kunis CL, Yu Z, D'Agati V. Polyclonal immunoglobulin G deposition disease: a unique entity. Am J Kidney Dis. 1998;32:328–33. Sirac C, Batuman V, Sanders PW. The proximal tubule toxicity of immunoglobulin light chains. Kidney Int Rep. 2021;6:1225–31. Parasuraman R, Wolforth SC, Wiesend WN, Dumler F, Rooney MT, Li W, et al. Contribution of polyclonal free light chain deposition to tubular injury. Am J Nephrol. 2013;38:465–74. Rosales IA, Collins AB, do Carmo PAS, Tolkoff-Rubin N, Smith RN, Colvin RB. Immune complex tubulointerstitial nephritis due to autoantibodies to the proximal tubule brush border. J Am Soc Nephrol. 2016;27:380–4. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 27 Oct, 2025 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 08 Jul, 2025 Reviews received at journal 05 Jul, 2025 Reviews received at journal 30 Jun, 2025 Reviews received at journal 26 Jun, 2025 Reviewers agreed at journal 26 Jun, 2025 Reviewers agreed at journal 26 Jun, 2025 Reviewers agreed at journal 26 Jun, 2025 Reviewers invited by journal 26 Jun, 2025 Editor assigned by journal 26 Jun, 2025 Editor invited by journal 26 Jun, 2025 Submission checks completed at journal 20 Jun, 2025 First submitted to journal 20 Jun, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6893222","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":478647733,"identity":"1e23e80f-2652-4e61-9c20-135c6acb1319","order_by":0,"name":"Yusuke Sakamaki","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYHACZhBhwMbewCABFUkgUgvPAVK1MEgkwLXgBwbnDz82+JljZ8wn+fbgrRs1DPL8DQzPHuDVciPNOLF3W7IZm3ResnXOMQbDGQcY0g3wa2EwPsC7jdmGTTrHTDq3gYFxAwNDGl4XGpw//vng3231NmySZ8Ba7AlrOZBjnMy77bAZmwQPWEsiQS2SN3KKjWW3HTdm48kxBvpFInnGYQJ+4Tt/fLPk223VhvPbzxjezqmxse1v70l7gE+LwgFUPtBJzDxp+HQwyDdgirEfw6tlFIyCUTAKRhwAAPh8REyOhB5WAAAAAElFTkSuQmCC","orcid":"","institution":"National Defense Medical College","correspondingAuthor":true,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Sakamaki","suffix":""},{"id":478647734,"identity":"75107b0e-8f50-45c3-ac4a-f86c800b5508","order_by":1,"name":"Akinori Hashiguchi","email":"","orcid":"","institution":"Keio University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Akinori","middleName":"","lastName":"Hashiguchi","suffix":""},{"id":478647735,"identity":"a3df6f4f-2fba-4e89-bef2-9e424096a8d4","order_by":2,"name":"Konosuke Konishi","email":"","orcid":"","institution":"Keio University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Konosuke","middleName":"","lastName":"Konishi","suffix":""},{"id":478647736,"identity":"7ca451d1-3b8e-4fef-8801-355824af8982","order_by":3,"name":"Takashi Araki","email":"","orcid":"","institution":"Hino Municipal Hospital","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Araki","suffix":""},{"id":478647737,"identity":"ba923e2f-8179-4207-a413-225166e2c1ff","order_by":4,"name":"Hirobumi Tokuyama","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hirobumi","middleName":"","lastName":"Tokuyama","suffix":""}],"badges":[],"createdAt":"2025-06-14 09:53:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6893222/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6893222/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-025-04522-4","type":"published","date":"2025-10-27T15:56:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":85822962,"identity":"1c0577d0-ecd0-47e4-9242-eefd79ad6ff4","added_by":"auto","created_at":"2025-07-02 06:51:59","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5237918,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRenal biopsy findings: Case 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRepresentative light microscopy and immunofluorescence images.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA) The glomeruli were relatively unaffected. Interstitial fibrosis and tubular atrophy were observed in the cortex. Thickened tubular basement membranes were observed (Periodic Acid–Schiff: PAS, × 100)\u003c/p\u003e\n\u003cp\u003eB) Lymphocyte and plasma cell infiltration were present nonspecifically in the scar (hematoxylin eosin; HE, × 100)\u003c/p\u003e\n\u003cp\u003eC) Severe interstitial fibrosis was evident (Masson trichrome; MT, × 40)\u003c/p\u003e\n\u003cp\u003eD) Diffuse and linear immunofluorescence staining for IgG along the TBM, with no staining in the glomerular capillary wall or mesangial area (× 200)\u003c/p\u003e\n\u003cp\u003eE) A high-power view of (D) (× 400)\u003c/p\u003e\n\u003cp\u003eF–I) Diffuse and linear staining for C3(F), C1q (G), kappa (H), and lambda light chains (I) along TBM (× 400)\u003c/p\u003e","description":"","filename":"Figure14.1.png","url":"https://assets-eu.researchsquare.com/files/rs-6893222/v1/69b035431cb004024a1b28cb.png"},{"id":85822972,"identity":"7f66d42a-bf45-4843-aeec-6c871d7166f6","added_by":"auto","created_at":"2025-07-02 06:52:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1626744,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRenal biopsy findings: Case 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eElectron microscopic images.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA) A low-power view of the specimen (Uranyl acetate and lead citrate)\u003c/p\u003e\n\u003cp\u003eB) A high-power view of the box area shown in (A), showing a mottled and speckled pattern of deposits in the TBM and the epithelial side of the TBM (Uranyl acetate and lead citrate)\u003c/p\u003e\n\u003cp\u003eC) A low-power view of another tubule shown in (A) (Uranyl acetate and lead citrate)\u003c/p\u003e\n\u003cp\u003eD) A high-power view of the box area shown in (C), showing mottled and speckled deposits in the TBM (Uranyl acetate and lead citrate)\u003c/p\u003e","description":"","filename":"Figure14.2.png","url":"https://assets-eu.researchsquare.com/files/rs-6893222/v1/6f7d61f202552087259d42ae.png"},{"id":85824235,"identity":"7e7f087e-3580-4adb-9095-d751092a1e34","added_by":"auto","created_at":"2025-07-02 06:59:59","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4848820,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRenal biopsy findings: Case 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRepresentative light microscopy and immunofluorescence images.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA) Mesangial expansion with features of mesangiolysis (HE, × 400)\u003c/p\u003e\n\u003cp\u003eB) Mild interstitial fibrosis and tubular atrophy with scattered inflammatory cells (PAS, × 100)\u003c/p\u003e\n\u003cp\u003eC) MT (× 100)\u003c/p\u003e\n\u003cp\u003eD) Diffuse and linear staining for IgG along TBM (× 200)\u003c/p\u003e\n\u003cp\u003eE) IgG1 subclass (× 400)\u003c/p\u003e\n\u003cp\u003eF) IgG4 subclass (× 400)\u003c/p\u003e\n\u003cp\u003eG–I) Diffuse and linear staining for C3(G), kappa (H), and lambda light chains (I) along TBM (× 400)\u003c/p\u003e","description":"","filename":"Figure14.3.png","url":"https://assets-eu.researchsquare.com/files/rs-6893222/v1/9aafed149f65b75d5129d983.png"},{"id":85822975,"identity":"28b7f12a-27a6-4f31-bdc2-e1052da5290c","added_by":"auto","created_at":"2025-07-02 06:52:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2445299,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRenal biopsy findings: Case 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eElectron microscopic images.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA) Mottled and speckled pattern of deposits in the TBM (Uranyl acetate and lead citrate)\u003c/p\u003e\n\u003cp\u003eB) Lamellated (indicated by left arrow) and reticulated TBM (indicated by right arrow) were observed in the silver-impregnated section. The TBM had a darker and more enhanced appearance compared to the deposits.\u003c/p\u003e\n\u003cp\u003eC) Mottled and speckled deposits in the reticulated TBM (Silver-impregnated section)\u003c/p\u003e\n\u003cp\u003eD) A high-power view of the box area shown in C) (Silver-impregnated section)\u003c/p\u003e","description":"","filename":"Figure14.4.png","url":"https://assets-eu.researchsquare.com/files/rs-6893222/v1/2809af1eaa6f54ea9444e02e.png"},{"id":95041345,"identity":"6e873cdd-db0e-464f-be46-5ce42be7f57e","added_by":"auto","created_at":"2025-11-03 16:11:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":16148346,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6893222/v1/e26f8977-282c-4273-9787-3e1f09f604f4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Polyclonal immunoglobulin G deposits with distinctive appearance in the tubular basement membrane: A report of two cases","fulltext":[{"header":"Background","content":"\u003cp\u003eTubulointerstitial diseases can develop in a wide range of clinical settings, including infections, adverse drug reactions, autoimmune conditions, exposure to toxins, obstructive uropathies such as hydronephrosis and reflux nephropathy, metabolic disorders, hematologic malignancies, glomerular diseases, and vascular-related conditions such as hypertension.\u003csup\u003e1)\u003c/sup\u003e These disorders are typically associated with mild proteinuria and minimal urinary sediment abnormalities, with either acute or chronic compromise of renal function. Clinically, tubulointerstitial injury may be indicated by elevated levels of urinary β2-microglobulin (β2MG) or Nacetylβ-D-glucosaminidase (NAG), along with unexplained increases in serum creatinine (Cr). Renal biopsy plays an essential role in diagnosis, allowing assessment of immunoglobulin (Ig) and complement component deposition patterns, either linear or granular, on immunofluorescence\u0026mdash;as well as TBM deposits observed using electron microscopy. These assessments assist in reaching diagnostic conclusions. In this report, we describe two atypical cases showing polyclonal IgG deposits within thickened TBM and minimal interstitial inflammation, which do not fit established categories of tubulointerstitial diseases.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCase 1\u003c/h2\u003e \u003cp\u003eA 66-year-old Japanese man had been diagnosed with chronic obstructive pulmonary disease (COPD) 3 years prior to admission and was prescribed tiotropium bromide hydrate 2.5 \u0026micro;g, L-carbocisteine 1500 mg, long-acting beta-agonists, and inhaled corticosteroids (salmeterol xinafoate and fluticasone propionate). He also had a history of using oral steroids use during COPD exacerbations and had smoked 40 cigarettes per day for 35 years. He was receiving treatment for hypertension with olmesartan 20 mg and nifedipine 20 mg, with adequate blood pressure control. He denied having diabetes mellitus or a family history of kidney disease. Three years before admission, his serum Cr was 0.77 mg/dL, which increased to 1.29 mg/dL 2 months later; however, urinary protein and occult blood tests were negative. No routine laboratory monitoring had been performed since that time. Two years before admission, he began experiencing lower urinary tract symptoms, including nocturia, a sensation of incomplete bladder emptying, and urinary urgency. He was initially prescribed the alpha-adrenergic antagonist tamsulosin hydrochloride 0.2 mg, which was later changed to the 5α-reductase inhibitor dutasteride 0.5 mg, 1 year and 4 months before admission. Two weeks prior to admission, he developed general malaise, anorexia, nausea, and vomiting, prompting a visit to our hospital.\u003c/p\u003e \u003cp\u003eAt the time of his emergency room visit, physical examination showed a blood pressure of 118/61mmHg, pulse rate of 80 beats/min, and body temperature of 35.7\u0026deg;C. Oxygen saturation on air was 98%, with a slightly elevated respiratory rate of 17 breaths/min. The only notable physical finding was pallor of the palpebral conjunctiva. Arterial blood gas analysis on room air revealed a pH of 7.15, pCO\u003csub\u003e2\u003c/sub\u003e of 20.8mmHg, an anion gap (AG) of 14.9, and a corrected bicarbonate (HCO\u003csub\u003e3\u003c/sub\u003e) level of 10.0 mmol/L, consistent with high AG metabolic acidosis complicated by respiratory compensation. Urinalysis showed a specific gravity of 1.020, urine pH of 5.0, proteinuria (2+) quantified as 0.9 g/g Cr, occult blood (2+), glucose (1+), and was negative for ketones. The fractional excretion of sodium (FENa) was 12.6%. Urinary β2MG was markedly elevated at 24,173 \u0026micro;g/L (reference range, 0\u0026ndash;200 \u0026micro;g/L). Urinary sediment analysis revealed 5\u0026ndash;9 erythrocytes, 5\u0026ndash;9 leukocytes, and 10\u0026ndash;99 granular casts per high-power field. No urine eosinophils were observed. Complete blood count (CBC) results showed a white blood cell (WBC) count of 10.8 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e/\u0026micro;L, with neutrophils accounting for 78% and eosinophils 0.5%. Red blood cell count was 272 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e/\u0026micro;L (reference, 430\u0026ndash;570 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e/\u0026micro;L), hemoglobin 8.1 g/dL, and hematocrit 24.3%. Platelet count was 17.7 \u0026times; 10\u003csup\u003e4\u003c/sup\u003e/\u0026micro;L. Serum biochemistry revealed total protein (TP) of 5.9 g/dL, albumin (Alb) 3.2 g/dL, urea nitrogen (UN) 177.3 mg/dL, Cr 16.32 mg/dL, and an estimated glomerular filtration rate (eGFR) of 2.7 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e. Uric acid was 8.0 mg/dL, sodium 135 mEq/L, potassium 5.9 mEq/L, chloride 113 mEq/L, corrected calcium 7.7 mg/dL, and phosphorus 9.0 mg/dL, indicating advanced renal failure. Immunological evaluation showed IgG 1687 mg/dL (reference, 870\u0026ndash;1700 mg/dL), IgA 155 mg/dL (110\u0026ndash;410 mg/dL), IgM 20 mg/dL (33\u0026ndash;190 mg/dL), and a kappa/lambda light chain ratio of 1.131 (0.48\u0026ndash;1.804). IgE was within normal limits at 80 IU/mL (\u0026lt;\u0026thinsp;170 IU/mL). C-reactive protein (CRP) was 0.65 mg/dL (\u0026lt;\u0026thinsp;0.30 mg/dl). Hypergammaglobulinemia was not evident, and no monoclonal protein (M-protein) was detected in either serum or urine. Complement levels were within normal range (C3 92 mg/dL, C4 33 mg/dL, CH50 42.8 U/mL). Screening markers for infection, including Treponema pallidum antibody (TP-Ab), hepatitis B surface antigen (HBs-Ag), hepatitis B Surface antibody (HBs-Ab), hepatitis C virus antibody (HCV-Ab), and human immunodeficiency virus antibody (HIV-Ab), yielded negative results. Autoimmune serologies, including antinuclear antibody (ANA), anti-double-stranded DNA antibody (anti-ds-DNA-Ab), anti-Smith antibody (anti-Sm-Ab), anti-SS-A antibody (SS-A-Ab), anti-SS-B antibody (SS-B-Ab), cryoglobulin, myeloperoxidase-anti neutrophil cytoplasmic antibody (MPO-ANCA), proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA), and anti-glomerular basement membrane antibody (anti-GBM Ab), were all negative. Plain computed tomography revealed emphysematous changes in the lungs and mild bilateral renal atrophy. No prostatic hypertrophy or abnormal organ masses were detected. The patient was admitted to our hospital on an emergency basis due to severe renal dysfunction.\u003c/p\u003e \u003cp\u003eFollowing admission, due to the patient\u0026rsquo;s general condition characterized by severe renal dysfunction accompanied by anorexia and dehydration, he received 2\u0026ndash;3 L of isotonic fluid intravenously each day. Despite this, there was no increase in urine output, and renal dysfunction did not improve. A renal biopsy was performed on the ninth day to investigate the underlying cause of severe renal failure. Light microscopy revealed that the specimen contained 2 cores with a total of 37 glomeruli and a cortex-to-medulla ratio of 5:5. Seven glomeruli exhibited global sclerosis, 13 were collapsed, and the remaining glomeruli, although somewhat collapsed, appeared relatively preserved without mesangial matrix expansion or hypercellularity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). A mild, nonspecific infiltrate of lymphocytes and plasma cells was observed around atrophic tubules and within the interstitium (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). A few tubules remained non-atrophic but showed basement membrane thickening. There was no clear evidence of tubulitis. Interstitial fibrosis and tubular atrophy involved more than 90% of the cortical area, although inflammatory changes within the fibrotic interstitium were minimal (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). No eosinophil infiltration was observed. In the medullary region, several foci of inflammatory cells, including localized neutrophils, were present. Vascular changes included mild to moderate intimal thickening in arteries ranging from arcuate to interlobular vessels. Arteriolar hyalinosis was not observed. On immunofluorescence, using a grading scale from (\u0026minus;) to (2+), linear staining of the TBM for IgG was observed at 2\u0026thinsp;+\u0026thinsp;intensity (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE), along with C3 at 2+ (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF) and C1q (1+) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG). No restriction was seen in IgG subclass or in kappa and lambda light chain staining (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eH and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eI). Electron microscopy revealed electron-dense deposits in the thickened TBM and on the epithelial side of TBM, characterized by a mottled and speckled pattern (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCorticosteroid therapy was not initiated due to the presence of uremic symptoms and the histological findings indicating an irreversible condition characterized by severe tubular atrophy and interstitial fibrosis. A dialysis catheter was placed in the right internal jugular vein, and hemodialysis was initiated on the twelfth day. The severe anemia noted at admission improved after several sessions of hemodialysis. His overall condition showed significant improvement, and an arteriovenous fistula was subsequently created. Hemodialysis was subsequently continued.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCase 2\u003c/h3\u003e\n\u003cp\u003eA 52-year-old Japanese man, diagnosed with acute myeloid leukemia 7 years before admission, underwent allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-C allotype-mismatched bank donor after receiving remission with idarubicin and cytarabine (IDA-AraC), followed by consolidation therapy with high-dose cytarabine (HDCA), cyclophosphamide, and total body irradiation (TBI). Graft-versus-host disease (GVHD) prophylaxis was administered using tacrolimus and methotrexate. Although specific details are unavailable, vancomycin and other antibiotics were used to treat infectious complications during chemotherapy prior to the transplantation. Four years before admission, he was referred to his primary care physician for the management of hypertension, glucose intolerance, hyperuricemia, and dyslipidemia. He was prescribed amlodipine 10 mg, valsartan 80 mg, febuxostat 20 mg, and simvastatin 5 mg, with good disease control. Proteinuria developed 3 years after allogeneic HSCT. Although his serum Cr level remained at approximately 1.0 mg/dL until 6 years post-transplant, he was referred to our hospital due to an increase in serum Cr to 1.65 mg/dL.\u003c/p\u003e \u003cp\u003eAt the initial visit, physical examination showed a blood pressure of 136/85 mmHg, a pulse rate of 61 beats/min, and a body temperature of 36.5\u0026deg;C. No edema or other apparent abnormalities were observed. Urinalysis revealed a urine specific gravity of 1.004, pH of 6.0, trace proteinuria (0.43 g/gCr), and negative results for occult blood, glucose, and ketones. The FENa was 1.44%, urinary β2MG was 2144 \u0026micro;g/L, and urinary NAG was 2.5 U/L (reference range, 0\u0026ndash;11.5 U/L). Urinary sediment examination showed no erythrocytes or leukocytes, and urinary eosinophils were absent. The CBC was within normal limits, and the automated WBC differential showed no abnormalities. Blood biochemistry indicated normal liver function (TP 7.5 g/dL, Alb 4.5 g/dL, total bilirubin 1.2 mg/dL, aspartate aminotransferase (AST) 22 U/L, alanine aminotransferase (ALT) 21 U/L, lactate dehydrogenase (LDH) 218 U/L) but mild renal impairment (blood UN 19.8 mg/dL, Cr 1.54 mg/dL, eGFR 38.9 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e). Postprandial glucose was 119 mg/dL, and HbA1c was 6.6%. CRP was negative. Immunological testing showed IgG 1212 mg/L (IgG4 71 mg/dL), IgA 298 mg/dL, IgM 74 mg/dL, and a kappa/lambda ratio of 0.958. Hypergammaglobulinemia was not observed, and no monoclonal protein was detected in either serum or urine. The IgE level was elevated at 1108.8 IU/mL (reference range, 15.0\u0026ndash;390.0 IU/mL). Complement levels were within normal limits (C3 110 mg/dL, C4 19 mg/dL, CH50 46.0 U/mL). Tests for rheumatoid factor, ANA, anti-ds-DNA-Ab, anti-Sm-Ab, anti-SS-A-Ab, anti-SS-B-Ab, cryoglobulin, MPO-ANCA, PR3-ANCA, and anti-GBM Ab were all negative. All infectious markers were also negative. Abdominal ultrasonography showed no abnormal masses and both kidneys were of normal size. A renal biopsy was performed 2 months later due to an increase in serum Cr to 1.52 mg/dL, in order to investigate the unknown cause of renal dysfunction identified 3 months after the initial visit.\u003c/p\u003e \u003cp\u003eOn light microscopy, the specimen included 1 core containing 16 glomeruli, with a cortex-to-medulla ratio of 10:0. Five glomeruli exhibited global sclerosis, and one was collapsed. Mesangial expansion with focal mesangiolysis, consistent with renal thrombotic microangiopathy (TMA), was noted (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Approximately 20% of the cortical area demonstrated diffuse thickening of the proximal TBM (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB), along with interstitial fibrosis and scattered inflammatory cell infiltration. Mild intimal thickening of the interlobular artery was observed. Arteriolar hyalinosis was not prominent. Immunofluorescence revealed diffuse linear staining for IgG (1+), C3 (1+), kappa light chain (1+), and lambda light chain (1+) along the TBM. Staining for IgG subclasses in TBM deposits showed IgG1 (1+) and IgG4 (1+) (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eE and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eF). In the glomeruli, segmental positivity for fibrinogen, IgM, and C3, and to a lesser degree IgA, was observed and interpreted as nonspecific trapping. There was no evidence of kappa or lambda light chain restriction (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eH and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eI). Electron microscopy demonstrated mottled and speckled deposits (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA) within the thickened TBM. Electron microscopy of silver-impregnated sections showed layered and reticulated TBM in the deposits (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB, \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC and \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD). In the glomeruli, mesangial expansion and subendothelial widening were present, accompanied by focal effacement of podocyte foot processes.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFollowing the renal biopsy, he was discharged with conservative management and monitoring for renal dysfunction; however, his serum Cr has gradually increased to 2.0 mg/dL over the following 5 years.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eTubulointerstitial diseases can develop under various conditions\u003csup\u003e1)\u003c/sup\u003e and are classified into immune-mediated and nonimmune mechanisms.\u003csup\u003e2)\u003c/sup\u003e Although the clinical courses of our two cases were entirely different, the morphological findings suggested a similar pattern of deposition in the TBM. Tubulointerstitial involvement is more closely associated with renal prognosis than glomerular abnormalities,\u003csup\u003e3)\u003c/sup\u003e and its presence should be considered when renal dysfunction progressively declines despite the absence of abnormalities on urinalysis.\u003c/p\u003e \u003cp\u003eThe renal biopsy findings in our two cases were marked by tubulointerstitial lesions featuring linear polyclonal IgG staining on immunofluorescence and distinctive electron-dense deposits within the TBM. In Case 1, there was no glomerular involvement, but severe tubular atrophy and interstitial fibrosis were present, along with linear polyclonal IgG deposits along the TBM observed on immunofluorescence, raising the possibility of primary anti-TBM nephritis.\u003csup\u003e4)\u003c/sup\u003e Primary anti-TBM nephritis is a rare condition in which an immune response is triggered by antibodies (anti-TBM antibodies) against a specific antigen peptide (54\u0026ndash;58 kD) found in the proximal TBM, leading to tubulointerstitial nephritis (TIN).\u003csup\u003e4)\u003c/sup\u003e Anti-TBM antibodies are also known to play a significant role in the pathogenesis of TIN in several other renal disorders.\u003csup\u003e5)\u0026minus;9)\u003c/sup\u003e The histological characteristics of anti-TBM nephritis include TBM damage with mononuclear cell infiltration, edema, and fibrosis in the interstitial tissue, along with strong, diffuse linear fluorescence for IgG and C3 along the TBM, without deposits.\u003csup\u003e4)\u003c/sup\u003e The glomeruli and arteries typically showed nonspecific changes, unless other diseases are present. In Case 1, the presence and characteristics of the electron-dense deposits in the TBM were not consistent with anti-TBM nephritis. Although the ultrastructual appearance of the deposits and the mild tubulointerstitial inflammation were atypical for anti-TBM nephritis, the patient\u0026rsquo;s blood sample was tested for anti-TBM antibodies using the indirect immunofluorescence method,\u003csup\u003e10)\u003c/sup\u003e after informed consent was obtained. This test showed no evidence of linear fluorescence for IgG in the TBM. In Case 2, which was accompanied by glomerular lesions due to TMA, anti-TBM antibody testing was not performed. However, the presence of distinctive polyclonal electron-dense deposits in the TBM were considered atypical for anti-TBM nephritis.\u003c/p\u003e \u003cp\u003eThe electron-dense deposits in both cases exhibited fine granular characteristics, resembling those seen in light chain deposition disease (LCDD)\u003csup\u003e11)\u003c/sup\u003e, which is classified under monoclonal immunoglobulin deposition diseases (MIDD). MIDD is a condition in which immunoglobulin molecules or their fragments, known as paraproteins, are deposited monoclonally in the glomeruli and TBM.\u003csup\u003e12)\u003c/sup\u003e LCDD is characterized by the absence of immunoglobulin and complement component deposits. Immunofluorescence typically reveals monoclonal linear deposit of kappa or lambda light chains along the glomerular basement membrane, mesangial areas, and TBM. In some LCDD cases, there is no glomerular proteinuria,\u003csup\u003e13)\u003c/sup\u003e and deposits are found only in the TBM.\u003csup\u003e14)\u003c/sup\u003e Electron microscopy reveals granular to amorphous deposits in the TBM. However, in our two cases, polyclonal IgG, along with kappa and lambda light chains, were detected, and monoclonal immunoglobulinemia was not observed in serum or urine, suggesting that these findings are not explained by LCDD.\u003c/p\u003e \u003cp\u003eIn Case 2, the glomerular TMA lesion featuring mesangial expansion with mesangiolysis was associated with post-allogeneic HSCT and may have been triggered by GVHD. However, the presence of diffuse tubular atrophy and interstitial fibrosis with linear polyclonal IgG deposits along the TBM, in the absence of significant interstitial inflammation, was also noted. The pathogenesis of renal dysfunction following allogeneic HSCT varies depending on the timing of onset. Acute TMA associated with GVHD, acute TIN, and tubular injury resulting from viral infections or cytotoxic agents (such as calcineurin inhibitors) have been observed.\u003csup\u003e15)\u003c/sup\u003e In the chronic phase, renal damage may be linked to endothelial injury caused by chronic TMA, TBI, and hypertension.\u003csup\u003e16)\u003c/sup\u003e Although there are reports on renal pathology after allogeneic HSCT, it remains underexplored. One report described polyclonal IgG deposits in the TBM with minimal glomerular involvement occurring 10 years after allogeneic HSCT,\u003csup\u003e17)\u003c/sup\u003e which improved with prednisolone treatment, leading to a reduction in serum Cr levels. Another case described membranous nephropathy with extensive granular deposits of IgG (IgG1 and IgG4), C3, and kappa and lambda light chains in the TBM after allogeneic HSCT.\u003csup\u003e18)\u003c/sup\u003e These findings suggest that polyclonal IgG immune deposits in the TBM may contribute to renal dysfunction following allogeneic HSCT. However, the histopathology, in Case 2, did not align with these two cases in that the tubular polyclonal deposit was linear, and the significance of linear polyclonal IgG\u0026mdash;particularly IgG4, in the TBM has not been described in GVHD.\u003c/p\u003e \u003cp\u003eIgG4-related kidney disease (IgG4-RKD) was considered in the differential diagnosis of tubulointerstitial diseases for immunofluorescence showing deposition of IgG, including IgG4 along the TBM in our two cases. IgG4-RKD is characterized by the infiltration of plasma cell\u0026ndash;rich interstitial inflammation and fibrosis.\u003csup\u003e19)\u003c/sup\u003e IgG4-RKD can be diagnosed through serological and histological findings, including increased numbers of IgG4-positive plasma cells. Immunofluorescence typically reveals granular immune complex deposits in the TBM, containing IgG4, C3, C1q, and both kappa and lambda light chains.\u003csup\u003e20)\u003c/sup\u003e IgG subclass testing often shows positivity for any or all IgG subclasses, including IgG1\u0026ndash;IgG4.\u003csup\u003e21)\u003c/sup\u003e Although our two cases showed positivity for IgG subclasses, including IgG4 in the TBM, the linear immunofluorescence staining in the TBM did not support a diagnosis of IgG4-RKD.\u003c/p\u003e \u003cp\u003eAlthough it is well-established that diabetic nephropathy can lead to nonspecific polyclonal linear IgG deposits in the TBM,\u003csup\u003e22)\u003c/sup\u003e a previously reported case of diabetic glomerulosclerosis with powdery dense deposits in the TBM\u003csup\u003e23)\u003c/sup\u003e highlighted the challenge of distinguishing such findings from diabetes-related alterations, such as atrophic and lamellated TBM. Notably, despite some structural differences, our two cases bear resemblance to the case of polyclonal IgG deposition disease (PIDD) reported by Markowitz et al.,\u003csup\u003e24)\u003c/sup\u003e which exhibited curvilinear and membranous structures located within the TBM.\u003c/p\u003e \u003cp\u003eThe deposition of polyclonal light chains on the proximal TBM has been reported to lead to the loss of the brush border and subsequent tubulointerstitial injury.\u003csup\u003e25),26)\u003c/sup\u003e Anti-brush border antibody, in which polyclonal immunoglobulins are specifically deposited on the proximal TBM,\u003csup\u003e27)\u003c/sup\u003e is recognized as one of the antibodies (megalin) targeting the low-density lipoprotein receptor-related protein 2 (LRP2), which helps explain the mechanism of proximal TBM injury and the subsequent development of tubulointerstitial fibrosis. However, renal biopsy findings in our two cases showed no evidence of granular polyclonal IgG deposits in the TBM that would suggest immune complex formation, and the deposits were present in both the proximal and distal TBM.\u003c/p\u003e \u003cp\u003eIn conclusion, we present two rare cases characterized by linear immunofluorescence with electron-dense deposits that have a mottled arrangement in thickened TBM. These findings were difficult to categorize into any specific tubulointerstitial disease despite subclinical evidence of renal dysfunction progression. Although the pathophysiology in our two cases remains unclear, detailed histopathological analysis including electron microscopy of silver-impregnated sections may assist in the identification of similar future cases. Further investigation is needed to better understand this form of tubulointerstitial disease.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eTBM, Tubular basement membrane\u003c/p\u003e\n\u003cp\u003eMIDD, Monoclonal immunoglobulin deposition disease\u003c/p\u003e\n\u003cp\u003eLCDD, Light chain deposition disease\u003c/p\u003e\n\u003cp\u003ePIDD, Polyclonal immunoglobulin G deposition disease\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003epublication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patients for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the journal’s editor.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003einterests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors received no specific funding for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor’s\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003econtributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYS collected the patient’s clinical data, performed the renal biopsy, and contributed to writing the manuscript. AH, a pathologist at Keio University Hospital, conducted the histological examination of the kidney and made significant contributions to writing the manuscript. KK, TA, and HT supervised the manuscript. All authors have read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRastegar A, Kashgarian M. The clinical spectrum of tubulointerstitial nephritis. Kidney Int. 1998;54:313\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAndres GA, McCluskey RT. Tubular and interstitial renal disease due to immunologic mechanisms. Kidney Int. 1975;7:271\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMackensen-Haen S, Bader R, Grund KE, Bohle A. Correlations between renal cortical interstitial fibrosis, atrophy of the proximal tubules, and impairment of the glomerular filtration rate. Clin Nephrol. 1981;15:167\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLusco MA, Fogo AB, Najafian B, Alpers CE. AJKD atlas of renal pathology: anti-tubular basement membrane antibody disease. Am J Kidney Dis. 2017;70:e3\u0026ndash;4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1053/j.ajkd.2017.05.001\u003c/span\u003e\u003cspan address=\"10.1053/j.ajkd.2017.05.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRotellar C, Noel LH, Droz D, Kreis H, Berger J. Role of antibodies directed against tubular basement membranes in human renal transplantation. Am J Kidney Dis. 1986;7:157\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcPhaul JJ Jr, Dixon FJ. Characterization of human antiglomerular basement membrane antibodies eluted from glomerulonephritic kidneys. J Clin Invest. 1970;49:308\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMakker SP. Tubular basement membrane antibody-induced interstitial nephritis in systemic lupus erythematosus. Am J Med. 1980;69:949\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorel-Maroger L, Kourilsky O, Mignon F, Richet G. Antitubular basement membrane antibodies in rapidly progressive poststreptococcal glomerulonephritis: report of a case. Clin Immunol Immunopathol. 1974;2:185\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorder WA, Lehman DH, Egan JD, Sass HJ, Glode JE, Wilson CB. Antitubular basement-membrane antibodies in methicillin-associated interstitial nephritis. N Engl J Med. 1974;291:381\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBergstein J, Litman N. Interstitial nephritis with anti-tubular-basement-membrane antibody. N Engl J Med. 1975;292:875\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeung N, Bridoux F, Batuman V, Chaidos A, Cockwell P, D\u0026rsquo;Agati VD, et al. Evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2019;15:45\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLin J, Markowitz GS, Valeri AM, et al. Renal monoclonal immunoglobulin deposition disease: the disease spectrum. J Am Soc Nephrol. 2001;12:1482\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSicard A, Karras A, Goujon J-M, Sirac C, Bender S, Labatut D, et al. Light chain deposition disease without glomerular proteinuria: a diagnostic challenge for the nephrologist. Nephrol Dial Transpl. 2014;29:1894\u0026ndash;902. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ndt/gfu045\u003c/span\u003e\u003cspan address=\"10.1093/ndt/gfu045\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGokden N, Cetin N, Colakoglu N, Kumar J, Abul-Ezz S, Barlogie B, et al. Morphologic manifestations of combined light-chain deposition disease and light-chain cast nephropathy. Ultrastruct Pathol. 2007;31:141\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRenaghan AD, Jaimes EA, Malyszko J, Perazella MA, Sprangers B, Rosner MH. Acute kidney injury and CKD associated with hematopoietic stem cell transplantation. Clin J Am Soc Nephrol. 2020;15:289\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNo\u0026euml;l C, Hazzan M, No\u0026euml;l-Walter MP, Jouet JP. Renal failure and bone marrow transplantation. Nephrol Dial Transpl. 1998;13:464\u0026ndash;6. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/ndt/13.10.2464\u003c/span\u003e\u003cspan address=\"10.1093/ndt/13.10.2464\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou W, Qi C, Zhang M, Hou X, Ni Z. Tubular basement membrane deposits after allogeneic hematopoietic stem cell transplantation. BMC Nephrol. 2023;24:242. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12882-023-03296-x\u003c/span\u003e\u003cspan address=\"10.1186/s12882-023-03296-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNasr SH, Leung N, Said SM, Alkhateeb HB, Madden BJ, Charlesworth MC, et al. Membranous nephropathy with extensive tubular basement membrane deposits following allogeneic hematopoietic cell transplant: a report of 5 cases. Am J Kidney Dis. 2022;79:904\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaeki T, Kawano M. IgG4-related kidney disease. Kidney Int. 2014;85:251\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRaissian Y, Nasr SH, Larsen CP, Colvin RB, Smyrk TC, Takahashi N, et al. Diagnosis of IgG4-related tubulointerstitial nephritis. J Am Soc Nephrol. 2011;22:1343\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamaguchi Y, Kanetsuna Y, Honda K, Yamanaka N, Kawano M, Nagata M. Characteristic tubulointerstitial nephritis in IgG4-related disease. Hum Pathol. 2012;43:536\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller K, Michael AF. Immunopathology of the renal extracellular membranes in diabetes mellitus. Specificity of tubular basement-membrane immunofluorescence. Diabetes. 1976;25:701\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatanabe H, Takeuchi Y, Taniuchi S, Sato H, Nakamura Y, Sasano H, et al. Polyclonal immunoglobulin G deposition on the tubular basement membrane in diabetic nephropathy: a case report. Pathol Int. 2020;70:463\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarkowitz GS, Fine PL, Kunis CL, Yu Z, D'Agati V. Polyclonal immunoglobulin G deposition disease: a unique entity. Am J Kidney Dis. 1998;32:328\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSirac C, Batuman V, Sanders PW. The proximal tubule toxicity of immunoglobulin light chains. Kidney Int Rep. 2021;6:1225\u0026ndash;31.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParasuraman R, Wolforth SC, Wiesend WN, Dumler F, Rooney MT, Li W, et al. Contribution of polyclonal free light chain deposition to tubular injury. Am J Nephrol. 2013;38:465\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosales IA, Collins AB, do Carmo PAS, Tolkoff-Rubin N, Smith RN, Colvin RB. Immune complex tubulointerstitial nephritis due to autoantibodies to the proximal tubule brush border. J Am Soc Nephrol. 2016;27:380\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Tubulointerstitial diseases, Polyclonal IgG deposition, Linear IgG immunofluorescence, Electron-dense deposits, Renal biopsy, Tubular Basement Membrane","lastPublishedDoi":"10.21203/rs.3.rs-6893222/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6893222/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Tubulointerstitial diseases arise from various etiologies, including infections, medications, autoimmune conditions, and systemic disorders. The histological presentation of the tubulointerstitium in renal biopsies can vary considerably. When tubulointerstitial alterations are identified through light microscopy, additional evaluation with immunofluorescence and electron microscopy may assist in diagnosis. This report describes two slowly progressive atypical cases of tubulointerstitial disease. Renal biopsy in both cases revealed tubular atrophy and interstitial fibrosis with limited inflammatory cell infiltration, along with polyclonal linear immunoglobulin G (IgG) staining pattern along the thickened tubular basement membrane (TBM) and distinctive electron-dense deposits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 1:\u003c/strong\u003e A 65-year-old Japanese man with a history of chronic obstructive pulmonary disease, benign prostatic hyperplasia, and hypertension presented with anorexia and malaise 1 week prior to admission. Blood tests demonstrated marked renal impairment. Renal biopsy findings included relatively preserved glomeruli, widespread tubular atrophy, and significant interstitial fibrosis. Immunofluorescence showed linear deposition of IgG as well as kappa and lambda light chains along the TBM. Complement components C3 was also positive, and C1q were weakly positive. No IgG subclass restriction was noted. Electron microscopy revealed electron-dense deposits within the TBM and on the epithelial side of the TBM, exhibiting a mottled and speckled appearance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2:\u003c/strong\u003e A 52-year-old Japanese man who had undergone allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia developed mild proteinuria and renal dysfunction 7 years post-transplant. Renal biopsy indicated thrombotic microangiopathy, with glomeruli showing diffuse mesangial expansion and focal mesangiolysis. There was also diffuse TBM thickening and interstitial fibrosis with scattered cellular infiltration. Immunofluorescence demonstrated linear staining of polyclonal IgG and both light chains along the TBM. C3 was also positive while C1q was negative. IgG subclass staining revealed positivity for IgG1 and IgG4. Electron microscopy again identified electron-dense deposits within the reticulated TBM.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e These two cases demonstrated linear IgG immunofluorescence and distinctive electron-dense deposits in the TBM characterized by a mottled and speckled pattern. Although the underlying pathophysiological mechanisms remain unclear, further research is necessary to elucidate the nature of this form of tubulointerstitial disease.\u003c/p\u003e","manuscriptTitle":"Polyclonal immunoglobulin G deposits with distinctive appearance in the tubular basement membrane: A report of two cases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-02 06:51:54","doi":"10.21203/rs.3.rs-6893222/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-07-08T08:48:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-05T22:15:02+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-30T19:31:32+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-27T00:09:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"160986598093919439633059205974492837599","date":"2025-06-26T18:55:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7537400972158058667911020577588648897","date":"2025-06-26T18:50:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"130424383166063737286288584094219715167","date":"2025-06-26T18:43:39+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-26T18:09:42+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-26T15:35:47+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-26T07:22:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-20T10:45:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-06-20T10:41:58+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bac7b131-3eea-4636-912b-37a47a7faf20","owner":[],"postedDate":"July 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T16:09:04+00:00","versionOfRecord":{"articleIdentity":"rs-6893222","link":"https://doi.org/10.1186/s12882-025-04522-4","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2025-10-27 15:56:50","publishedOnDateReadable":"October 27th, 2025"},"versionCreatedAt":"2025-07-02 06:51:54","video":"","vorDoi":"10.1186/s12882-025-04522-4","vorDoiUrl":"https://doi.org/10.1186/s12882-025-04522-4","workflowStages":[]},"version":"v1","identity":"rs-6893222","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6893222","identity":"rs-6893222","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}