Light chain-mediated acute tubulointerstitial nephritis as the sole manifestation of monoclonal gammopathy of renal significance in a young adult

Summary

Light-chain-mediated acute tubulointerstitial nephritis (LC-ATIN) is an uncommon, under-recognised lesion within the spectrum of monoclonal gammopathy of renal significance (MGRS). It typically presents with acute kidney injury (AKI), minimal proteinuria and nonspecific symptoms, complicating diagnosis and risking progression to end-stage kidney disease. We report a man in his early 40s with unexplained AKI whose diagnosis was established after kidney biopsy demonstrating kappa-restricted tubular basement membrane deposits on immunofluorescence and electron microscopy. Bone marrow evaluation identified a small kappa-restricted plasma cell clone, confirming MGRS. He received clone-directed therapy followed by autologous stem cell transplantation (ASCT) to deepen haematological response and preserve renal function. Although ASCT may improve response depth in related MGRS entities, its benefit in LC-ATIN remains unproven. This case highlights the importance of serum free light chain testing, early biopsy and timely clone-directed therapy in unexplained AKI, including in younger patients.

Background

Monoclonal gammopathy of renal significance (MGRS) comprises kidney lesions caused by nephrotoxic monoclonal immunoglobulins produced by small B-cell or plasma-cell clones that do not meet criteria for overt haematological malignancy but result in clinically meaningful renal injury.^{1 2} Among MGRS lesions, light chain deposition disease (LCDD) is well recognised, whereas light-chain-mediated acute tubulointerstitial nephritis (LC-ATIN) is rare and frequently under-recognised because patients present with non-specific symptoms, bland urinalysis, minimal or absent proteinuria and routine protein electrophoresis may be unrevealing.^{3 4}

Case presentation

A man in his early 40s with gastric sleeve surgery (10 years ago) presented with 6 months of fatigue, myalgias and chronic headaches to his primary care in March. He reported regular use of over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) without relief. He denied rash, sicca symptoms, constitutional complaints, recreational drugs, urinary or gastrointestinal symptoms, nephrolithiasis, recent illness or supplement or creatine use. Blood work showed creatinine of 1.08 mg/dL, haemoglobin 14.5 g/dL and a positive ANA (1:640) which prompted rheumatologic referral. He rescheduled his rheumatology visit from September to December.

Ultimately rheumatology evaluation in December revealed a negative extractable nuclear antigen panel and no clinical evidence of autoimmune disease, vasculitis or infection

However, compared with 9 months prior in March, his December blood work showed relative anaemia (11.9 g/dL), new-onset hypertension (140/100 mm Hg, for which amlodipine 5 mg daily was initiated) and renal failure (creatinine 2.44 mg/dL). Serum electrophoresis (SPEP) showed normal total protein and albumin with all globulin fractions within reference ranges (albumin 4.8 g/dL; α1 0.3 g/dL; α2 0.8 g/dL; β 0.8 g/dL), and immunotyping revealed no monoclonal protein. Urine electrophoresis (UPEP) demonstrated normal urine protein <6 mg/dL, albumin 19.7% and globulin 80.3%. Immunoglobulin levels: IgG 1166 mg/dL (range 613–1295 mg/dL), IgA 232 mg/dL (range 69–309 mg/dL) and IgM 73 mg/dL (range 53–334 mg/dL).

2 weeks later, nephrology evaluation showed creatinine rise to 3.05 mg/dL (eGFR 25 mL/min/1.73 m²) with uncontrolled hypertension despite amlodipine 10 mg daily, requiring addition of metoprolol XL 50 mg daily and hydralazine 50 mg three times a day. Comprehensive metabolic panel and urinalysis were unremarkable, except for a urine protein-to-creatinine ratio of 0.08 g/g.

Investigations

Evaluation for secondary hypertension was negative, including levels of adrenal hormones; cortisol (16.1 (range 4.0–22.0 ug/dL)), aldosterone (12 (range; ≤21 ng/dL)), plasma normetanephrine, free plasma (0.75 (range <0.90 nmol/L)) and plasma metanephrine free plasma 0.24 (range <0.50 nmol/L)) were all normal except mild elevated renin activity reflecting renal disease (renin activity (6.7 ng/mL/hour, sodium replete range <0.6–3.0)). Renal ultrasound and renal artery duplex were normal. Non-contrast CT of abdomen and pelvis was unremarkable. Given the absence of clear aetiology, a renal biopsy was performed but yielded an inadequate sample, necessitating a repeat biopsy.

Light microscopy demonstrated a total of 18 glomeruli, of which one was globally sclerosed. There was no significant mesangial expansion, hypercellularity, crescents, endocapillary proliferation, microthrombi or necrosis. Focal mild interstitial fibrosis involving <25% of cortical tissue, along with tubular atrophy and lymphocyte-predominant multifocal inflammatory infiltrates with scattered eosinophils and focal interstitial oedema, was noted. Immunofluorescence (IF) containing five glomeruli showed strong kappa light chain staining (2–3+) of interstitial and tubular basement membranes with minimal lambda (0–1+). The glomeruli showed no significant reaction for IgG, IgA, IgM, C3, C1q, kappa, lambda or fibrin. No evidence of proliferative glomerulonephritis, immune complex-mediated disease or oxalate crystal deposition was identified. Congo red and Thioflavin T stains were negative. Electron microscopy (EM) contained two glomeruli, and ultrastructural preservation was excellent. No thin fibrils were identified. EM demonstrated granular electron-dense material within tubular basement membranes, consistent with monotypic light chain deposition (figures15).

Figure 1. H&E: displaying interstitial fibrosis and inflammatory reaction.

Figure 5. IF with no significant kappa staining of glomeruli. IF, immunofluorescence.

Figure 2. Immunofluorescence for kappa light chain reveals strong staining along the tubular basement membranes.

Figure 3. Immunofluorescence with negative lambda light chain along the tubular basement membranes.

Figure 4. Electron microscopy highlights (*) accumulation of fine granular electron-dense materials in the tubular basement membranes.

Postbiopsy, serum free light chains (sFLCs) showed elevated kappa (309 mg/L (range 3.3–19.4 mg/L)), normal lambda (25.5 mg/L (range 5.7–26.3 mg/L)) and a markedly elevated kappa/lambda ratio of 12.12 (range 0.26–1.64 mg/L). Urine FLC testing revealed elevated kappa (87.7 mg/L (range 0–32.9 mg/L)) relative to lambda (14.3 mg/L (0–3.8 mg/L)) with a ratio of 6.13 (0.43–8.66). Under normal physiology, sFLCs are filtered at the glomerulus and catabolised by the proximal tubule cells.⁵ Kappa FLC, a monomer (~25 kDa), is filtered and cleared more efficiently than lambda FLC, which circulates predominantly as a dimer (~50 kDa).⁶ In this patient with impaired glomerular filtration and light chain-mediated proximal tubular injury, both glomerular filtration and tubular catabolism of FLC are reduced. This likely accounts for the narrowing of the urinary kappa/lambda ratio towards the normal range despite significant clonal kappa overproduction, as reduced filtration disproportionately affects the smaller, more efficiently filtered kappa monomer, while impaired proximal tubular metabolism diminishes catabolism of both sFLC. His urinary immunofixation displayed a faint kappa band, further supporting a monoclonal kappa process.

Bone marrow revealed an 8%–10% kappa-restricted plasma cell clone (Congo red-negative), consistent with MGRS given the associated renal injury. Flow cytometry confirmed clonality, and fluorescence in situ hybridisation detected t(11;14). PET imaging showed no radiographic evidence for sarcoidosis, IgG₄-related disease, malignancy or lytic bone lesions.

Differential diagnosis

Medication-induced interstitial nephritis was considered, given NSAIDs exposure. While both drug-induced AIN and LC-ATIN can show interstitial oedema, mixed inflammatory infiltrates and tubulitis, the presence of monotypic kappa deposition along tubular basement membranes on IF argued against drug-induced nephritis.⁷

IgG4-related TIN (tubulointerstitial nephritis) was unlikely given the negative systemic evaluation, and lack of storiform fibrosis or IgG₄-rich plasma cells on biopsy.⁸ Although IgG₄ levels were not tested, his total IgG levels were normal. Congo red was negative on both marrow and renal biopsy, together with negative thioflavin T staining on the renal biopsy and the absence of fibrils on EM, ruled out AL amyloidosis.¹

His sleeve gastrectomy carries a risk for enteric hyperoxaluria, which can cause crystal-induced tubulointerstitial nephritis. Oxalate crystal deposition provokes a renal inflammatory response, causing interstitial nephritis and tubular injury that can present as acute or chronically progressive kidney disease.⁹ However, there were no oxalate crystals in the biopsy.

LCDD was excluded because light chain deposition was confined to the tubulointerstitium without glomerular or vascular involvement and nephrotic-range proteinuria or nodular glomerulosclerosis was absent.¹,⁴⁹

Monotypic lymphocyte/plasma cell–rich interstitial nephritis involves direct neoplastic infiltration of the renal interstitium by clonal B lymphocytes or plasma cells, whereas in LC-ATIN the interstitial inflammation is a reactive process driven by light chain-mediated tubular injury. Therefore, the mixed, polyclonal nature of this patient’s interstitial infiltrate argued against monotypic interstitial nephritis.^{3 4 10}

Treatment/outcome and follow-up

After a second haematology consultation at a transplant centre, the diagnosis of kappa LC-ATIN as MGRS was favoured. Steroids were deferred in favour of immediate clone-directed therapy with planned autologous stem cell transplantation (ASCT) consolidation. Plasma cells with t(11;14) translocation express high levels of the anti-apoptotic protein B-cell lymphoma 2 (BCL2), conferring BCL2 dependency with important prognostic and therapeutic implications, particularly in AL amyloidosis, plasma cell leukaemia and myeloma.¹¹ Despite the patient’s t(11;14) status making the clone biologically susceptible to BCL-2 inhibition, venetoclax, a BCL-2 inhibitor, was not used as frontline therapy in this patient because it is not currently approved or recommended as first-line treatment for myeloma or MGRS.¹² The patient began Dara-KRd regimen (daratumumab, carfilzomib, lenalidomide and dexamethasone), achieving significant reduction of sFLC within 11 days (serum kappa level 27.2 mg/dL, serum lambda 19.2 mg/L and ratio of 1.42), confirming chemosensitivity. This was followed by high dose melphalan conditioning and ASCT. Ten months post-transplant, blood pressure averages~120/80 mm Hg on amlodipine 10 mg daily and carvedilol 12.5 mg two times per day. However, at ten months post-transplant, kidney function remains impaired with creatinine 3.01 mg/dL (eGFR 25 mL/min/1.73 m²), (figure 6) with a normal serum kappa 18.4 mg/L with slight elevation of urine kappa 36.3 mg/L (0–32.9 mg/L) with negative immunofixation in both serum and urine for monoclonal protein. A repeat renal biopsy is pending to determine whether there is an active inflammatory component, given normal light chains, or whether irreversible interstitial fibrosis, already present at diagnosis, is the predominant driver of renal dysfunction.

Figure 6. Renal function (creatinine) over clinical course.

Discussion

MGRS lesions arise from nephrotoxic monoclonal immunoglobulins produced by small clonal populations, typically serum M-protein <30 g/L and <10% monoclonal bone marrow plasma cells.^{1 2} Although both MGRS and LC-ATIN predominantly affect adults >50 years old, younger individuals are not exempt.¹,⁴¹³ Unlike LCDD, LC-ATIN is characterised by monotypic light chain deposition confined to the tubulointerstitium, often with bland urine and minimal proteinuria, features that can obscure recognition and delay care.¹,⁴ This case illustrates that reliance on SPEP and UPEP alone risks false reassurance. sFLC assays and immunofixation are more sensitive for detecting low-level monoclonal proteins and should be obtained when clinical suspicion persists.^{1 14} Kidney biopsy with kappa and lambda IF and EM is decisive to distinguish LC-ATIN from other MGRS lesions: LCDD, cast nephropathy, AL amyloidosis, immunotactoid glomerulonephritis, C3 glomerulopathy with monoclonal gammopathy, immune complex-mediated disease, IgG4-related disease, drug or crystal-induced interstitial nephritis.¹,⁴⁷

Filtered monoclonal light chains are endocytosed by proximal tubular epithelial cells, where physicochemical properties determine nephrotoxicity. Nephrotoxic light chains can bind tubular basement membranes and activate inflammatory pathways, recruiting interstitial immune cells, and causing tubulitis and fibrosis.¹⁵ The extent of organ injury relates more to the intrinsic properties of the light chain than to absolute burden, consistent with significant renal dysfunction in this patient despite modestly elevated isolated kappa sFLC. The prominent interstitial inflammatory response with dendritic cell activation, tubulitis and inflammatory cell infiltration distinguishes LC-ATIN from other MGRS lesions and has therapeutic implications. Accordingly, the treatment goal extends beyond light chain reduction to include resolution of interstitial inflammation.¹,49 13 15 16

LC-ATIN is among the rarest MGRS manifestations, consistently accounting for 0.2%–0.75% of kidney biopsies across published cohorts. Gu and Herrera identified 8 cases among 4296 kidney biopsies (~0.19%), while Cheng et al reported 38 cases among 5043 biopsies (~0.75%).^{3 4} Herrera¹⁰ identified 28 cases of tubulopathy-associated ATIN among 5410 kidney biopsies (0.5%), with acute kidney injury in nearly all cases, kappa light-chain restriction in 16/28 (57%), and Bence-Jones proteinuria in 18/27 (66%).^{8 9} In a separate cohort, Allinovi et al found an underlying monoclonal gammopathy in 8 of 32 patients (25%) with biopsy-proven tubulointerstitial nephritis; however, definitive LC-ATIN, defined by κ-restricted tubular basement membrane deposits and monotypic B-cell or plasma cell-rich interstitial infiltrates was confirmed in only four cases. LC-ATIN, therefore, accounted for 0.5% of all kidney biopsies (4/827) and 4% of monoclonal gammopathy-related nephropathies (4/95). Notably, none of the confirmed cases were initially suspected clinically, underscoring that LC-ATIN remains an under-recognised entity requiring a high index of suspicion and careful IF evaluation.¹² LC-ATIN is not listed as a distinct entity in the 2025 Renal Pathology Society/International Kidney and Monoclonal Gammopathy Research Group consensus classification, though light chain proximal tubulopathy (LCPT) is recognised, and Cheng et al classify LC-ATIN as a variant of LCPT.^{4 17}

Management of MGRS prioritises early clone-directed therapy to halt ongoing kidney injury, regardless of whether criteria for overt multiple myeloma (MM) are met as in this case. Early reduction of circulating FLCs correlates with renal recovery in monoclonal light chain-mediated kidney disease.^{12 18} The decision to pursue ASCT consolidation rather than clone-directed therapy alone was driven by several converging factors. National Comprehensive Cancer Network (NCCN) guidelines for monoclonal immunoglobulin deposition disease (MIDD) state that ASCT consolidation is preferable in eligible patients with organ damage, and the NCCN MGRS algorithm directs plasma cell-related MGRS to be treated per the myeloma management pathway.¹⁹ Kourelis et al²⁰ from Mayo Clinic confirmed that patients receiving ASCT or proteasome inhibitor-based therapies were significantly more likely to achieve at least a haematologic complete or very good response compared with other therapies (66% vs 2%).²⁰ Leung et al² stated that a more complete haematologic response may be achieved with high-dose melphalan followed by ASCT in MIDD.² Gozzetti et al found that ASCT led to better haematologic responses than other treatment modalities in a multicentre MGRS cohort, and the European Society for Blood and Marrow Transplantation (EBMT) retrospective study of 51 LCDD patients demonstrated that ASCT deepened haematologic response (very good partial response (>90% reduction in monoclonal protein) or better improved from 41% to 66% post-ASCT), with 88% 6-year overall survival.^{21 22}

The strongest argument for ASCT, however, is durability of response. Tubulointerstitial MGRS lesions carry a high risk of progression to chronic kidney disease once interstitial fibrosis is established. In a young patient with decades of remaining life, relapse even at low levels could cause irreversible fibrotic progression. The EBMT LCDD series reported a 6-year progression-free survival of ~44%, indicating that even with ASCT, relapse remains a concern requiring ongoing surveillance.²² ASCT may offer a deeper and more durable haematologic response in this setting; however, no published data exist for ASCT specifically in LC-ATIN, and the balance of risk and benefit cannot be established from a single case. ASCT’s true benefit in LC-ATIN remains unproven and warrants further study. The decision for ASCT was extrapolated from LCDD, MIDD and broader MGRS evidence.^{2 22} Although this patient had 8%–10% bone marrow plasma cells with biopsy-proven renal injury, the 2014 International Myeloma Working Group update specifies that only cast nephropathy qualifies as a myeloma-defining renal event.¹⁸ The clinical decision was driven by the direct causal link between the clone and progressive, potentially irreversible renal injury, rather than by strict adherence to the MM diagnostic threshold. Of note, his serum kappa levels increased mildly to levels at 27.1 mg/L pre-transplant, after near-normalisation to 19.7 mg/L with chemotherapy. Ultimately, his renal function prechemotherapy prognosticated his current renal function(figure 6), suggesting timing of diagnosis and treatment is essential to renal prognosis.^{2 3 10 12 21}

For patients with MGRS who progress to end-stage kidney disease, kidney transplantation is preferred, but recurrence is common if the clone is not eradicated, with rates up to ~90% in some subtypes such as proliferative glomerulonephritis with monoclonal IgG deposits.^{1 2 23} Ongoing haematologic surveillance is essential to detect early relapse and intervene before further irreversible renal injury occurs.

Learning points.

• Kidney biopsy should be done in patients with unexplained acute kidney injury, bland urinalysis and minimal proteinuria, when initial evaluation is unrevealing.

• Light-chain-mediated acute tubulointerstitial nephritis is an uncommon cause of kidney failure that may present with a bland urinalysis and minimal proteinuria.

• Serum free light chain testing and immunofixation provide greater sensitivity than electrophoresis and are essential when suspicion for monoclonal gammopathy of renal significance (MGRS) persists.

• Renal injury in MGRS reflects the pathogenicity of the light chain rather than the size of the plasma cell clone, and even small clones can cause severe kidney dysfunction.

• Early initiation of clone-directed therapy may rapidly reduce pathogenic light chains and promote renal recovery, even when criteria for overt multiple myeloma are not met.