Daratumumab-Based Regimen Significantly Induced Remission of Crystalline Light Chain Proximal Tubulopathy: A Case Report

Introduction

The International Kidney and Monoclonal Gammopathy Research Group first proposed the concept of monoclonal gammopathy of renal significance (MGRS) in 2014 [1]. MGRS was defined as a condition in which B-cell or plasma-cell clonal proliferation does not meet the diagnostic criteria for malignant hematological diseases but results in renal damage directly or indirectly due to the production of monoclonal immunoglobulins [2]. Light chain proximal tubulopathy (LCPT), as a rare renal disease secondary to MGRS, is characterized by the accumulation of monoclonal light chains in proximal tubules causing tubular injury, accounting for 4% to 5% of light chain-related renal diseases [3]. However, there are currently no established, precise treatment guidelines for LCPT. Here, we report a case of LCPT that responded effectively to a daratumumab-based regimen.

Case Report

A 57-year-old Chinese male patient experienced fatigue, increased nocturia, and foamy urine for 3 months. His feeling of fatigue had been worsening gradually, and he presented to the local hospital. An elevated serum creatinine level was observed, and conventional symptomatic treatment yielded unsatisfactory results. Subsequent screening for secondary renal disease revealed abnormal serum immunofixation electrophoresis and serum-free light chain assay results, as shown in Table 1. Bone marrow aspiration revealed an elevated proportion of erythroblasts and decreased proportion of myelocytes. Bone marrow biopsy showed essentially the normal proliferation of hematopoietic tissue, presence of granulocytes, scattered lymphocytes, and detection of a small number of immature plasma cells, suspicious for monoclonal plasma cells (cells accounted for <5%). Decalcified sections showed essentially normal hematopoietic tissue. In situ hybridization for Epstein-Barr virus showed Epstein-Barr virus-encoded RNA was negative. Special staining showed reticulin fibers consistent with myelofibrosis grade 0 (MF-0), and no abnormalities were observed in amyloid staining. Chromosomal karyotype analysis revealed no abnormal chromosomal abnormalities. Flow cytometry showed 0.22% of nucleated cells with abnormal phenotype monoclonal plasma cells. A comprehensive myeloma workup revealed an M-protein band on serum protein electrophoresis, which formed specific reaction bands with anti-IgA and anti-Kappa antibodies, consistent with IgA-Kappa-type M proteinemia, as shown in Figure 1. The patient came to our hospital for further diagnosis and treatment. He had a history of asthma, but was not on specific medication.

After admission, his blood pressure was 95/65 mm Hg. Laboratory tests results are shown in Table 1. Cardiac magnetic resonance imaging revealed mild edema at the basal interventricular septum of the left ventricle, with no significant abnormalities in cardiac function and no characteristic features of myocardial amyloidosis.

Renal biopsy was performed, and the optical microscopy showed 2 renal biopsy tissues, consisting of approximately 95% cortical tissue. There was a total of 19 glomeruli, with 8 showing segmental sclerosis/damage. Mild segmental proliferation of open glomerular mesangial cells and matrix was observed, with no obvious endothelial cell proliferation, as shown in Figure 2A. One glomerulus showed capsular adhesion, as shown in Figure 2B. The basement membrane showed no diffuse thickening or splitting, with some segments showing ribbon-like vacuolar degeneration. Granular degeneration of tubular epithelial cells was observed, with protein casts seen in some tubular lumens. Eosinophilic needle-like crystal structures were observed in some tubular lumens, without birefringence under polarized light and negative immunofluorescence, as shown in Figure 2C. Mild tubular atrophy and interstitial fibrosis (approximately 15%–20%) were observed. Mononuclear lymphocyte infiltration was observed in multiple small foci of the renal interstitium, with 1 small focus showing neutrophil aggregation and occasional eosinophils. Multiple renal small arteries showed intimal thickening greater than the medial layer. The negative Congo red staining effectively excluded amyloidosis in this case. Immunofluorescence detection of immunoglobulin (Ig) G, IgA, IgM, complement component (C)3, C1q, C4, fibrin-related antigen, albumin, Kappa light chain, and Lambda light chain was negative. Immunofluorescence detection of IgG1–4 was negative. After proteinase digestion, paraffin direct immunofluorescence showed Kappa light chain+++ and Lambda light chain+, both absorbed by tubular epithelial cells, as shown in Figure 3. Electron microscopy revealed 1 glomerulus in the submitted renal tissue. Endothelial cells showed no obvious proliferation. Most segments of the glomerular basement membrane showed no significant changes, with a few segments showing thinning (thickness approximately 207 nm) or curling, and no obvious electron-dense deposits were observed. Foot process swelling and partial vacuolar changes were observed, with partial fusion of foot processes. Mesangial cell and mesangial matrix proliferation were mild, with no obvious electron-dense deposits in the mesangial area. However, some tubular epithelial cells showed increased lysosomes, some of which displayed a crystalline, lattice-like structure, as shown in Figure 4. Based on the comprehensive immunofluorescence findings, monoclonal light chain deposition was observed in renal tubular cells. Additionally, electron microscopy revealed lysosomal inclusions and crystalline deposits in the tubular epithelial cells. The pathological diagnosis was proximal tubular disease associated with light chains.

To elucidate the marrow genetics, bone marrow aspiration was repeated. Next-generation sequencing of the IGH gene showed no apparent abnormalities. Fluorescence in situ hybridization (FISH) indicated a possible IgH gene deletion. Flow cytometry revealed plasma cells comprising 0.1% of all nucleated cells, with approximately 0.05% plasma cells (of all nucleated cells) considered likely to represent monoclonal abnormal plasma cells with abnormal phenotypes. Initially, during screening for secondary kidney injury factors, serum immunofixation revealed the presence of an M-protein. Subsequently, renal biopsy demonstrated light chain deposition within the renal tubular epithelial cells, along with intracellular crystalline inclusions. Based on these findings, we established the diagnosis of LCPT.

Initially, oral lenalidomide was administered at the outpatient clinic for 1 month, but creatinine levels were not reduced or controlled. As a further treatment, daratumumab (16 mg/kg) and dexamethasone (40 mg) was administered every 3 weeks for a total of 5 cycles, during which the serum creatinine level peaked at 310 μmol/L. Then the patient began the daratumumab (16 mg/kg), bortezomib (1.3 mg/m2), cyclophosphamide (300 mg/m2), and dexamethasone (40 mg) (Dara-CyborD) regimen every 4 weeks for 2 cycles. After this treatment, regular monitoring showed a progressive decrease in creatinine levels, as depicted in Figure 5, and the patient experienced a reduction in nocturia episodes. Six months after Dara-CyborD treatment, serum creatinine levels decreased to 149 μmol/L; serum and urine immunofixation plus light chain quantitative analyses showed disappearance of M protein. Serum free Kappa light chain was less than 20 mg/L, and the difference in serum free light chains was not detected, suggesting the hematologic complete remission. Bone marrow examination revealed that immature plasma cells were not detected. FISH revealed no more abnormal signals, and flow cytometry showed no more monoclonal abnormal plasma cells. Minimal residual disease testing detected no IGH or IGK clonal rearrangements.

Discussion

Maldonado et al first described and defined LCPT in 1975, attributing it to the deposit of monoclonal light chains in proximal tubules, leading to impaired proximal tubular reabsorption [4]. LCPT predominantly affects men, with a median age of 60 years (range: 39–87 years). Typical clinical manifestations include Fanconi syndrome, presenting with renal glycosuria, aminoaciduria, phosphaturia, and proximal renal tubular acidosis [5].

The clinical presentation of this disease is diverse, primarily characterized by mild to moderate proteinuria and renal dysfunction, although our patient presented with renal dysfunction without proteinuria. Literature reports indicate various clinical manifestations of the disease, including arthritis, hypokalemia, osteomalacia, massive proteinuria, and acute kidney injury [6,7]. In the present case, the initial clinical manifestations were fatigue and increased nocturia. Subsequent comprehensive serum immunofixation suggested IgA-Kappa–type M proteinemia, leading to a confirmed diagnosis of LCPT through further renal biopsy and bone marrow aspiration.

The diagnosis of LCPT relies on the pathological findings of renal biopsy. Microscopic examination in the present case revealed granular degeneration of renal tubular epithelial cells, with some tubules showing protein cast formation. Eosinophilic needle-like crystals were observed within diluted tubules. Although conventional direct immunofluorescence for Kappa and Lambda light chains was negative, paraffin immunofluorescence demonstrated intense staining for Kappa light chains, suggesting that when M-protein deposits are not detected in frozen sections, paraffin immunofluorescence after protease digestion should be performed to reveal these “masked” monoclonal immunoglobulins. Electron microscopy showed increased lysosomes in a few renal tubular epithelial cells, some of which contained a crystalline, lattice-like structure. Approximately 70% to 80% of crystalline LCPT cases are Kappa light chain, while non-crystalline types are predominantly Lambda light chain type [8,9], consistent with the findings in this case and the reported literature. Compared with non-crystalline LCPT, crystalline LCPT is associated with more severe pathological tubular injury and a propensity for acute clinical manifestations.

The International Kidney Disease and Monoclonal Immunoglobulin Disease Research Group proposed the preliminary therapeutic principles for LCPT with the aim of suppressing the production of monoclonal light chains. For patients with LCPT without multiple myeloma, it is recommended to adopt the treatment regimen used for multiple myeloma [10]. Currently, the preferred approaches include proteasome inhibitors, such as bortezomib, ixazomib, and carfilzomib; immunomodulatory agents, such as thalidomide, pomalidomide, and lenalidomide; and combination chemotherapy based on glucocorticoids. A few clinical case reports have shown that lenalidomide is an effective treatment for LCPT [11–13].

With the clinical promotion of daratumumab, its application is increasing in MGRS [14], especially for patients with a poor response to conventional chemotherapy or rapidly progressing renal dysfunction [15]. Daratumumab, a CD38 monoclonal antibody, is administered either as monotherapy or in combination with proteasome inhibitors or immunomodulatory agents. The recommended dosage is 16 mg/kg per week for 8 weeks, followed by biweekly injections for a total of 8 doses, then continued injections every 4 weeks. In a case in which lenalidomide was initially used, serum creatinine levels increased from 252 μmol/L to 285 μmol/L, indicating inadequate efficacy. After switching to thalidomide, the creatinine level decreased to 226 μmol/L. In the sixth course of treatment, bortezomib was added, resulting in a further reduction of creatinine to 173 μmol/L. However, neurological symptoms (numbness in the left lower limb) appeared after 2 cycles of bortezomib, leading to its discontinuation. Subsequent electromyography showed no more abnormalities. Thalidomide was replaced with lenalidomide, but the patient continued to experience recurrent numbness in the left lower limb. Consequently, lenalidomide was discontinued, requiring careful clinical attention.

Regarding the prognosis of patients with LCPT, a study in the United States found that the average survival time for patients with LCPT is 135.0±5.5 months [5]. Few patients maintain stable kidney function. Most of them progress to end-stage kidney disease, with the majority experiencing chronic kidney disease. Despite the limited use of the standard D-CyBorD regimen in this case (only 2 cycles given, due to adverse effects, such as to bortezomib), the patient achieved hematological complete response, evidenced by negative urine M protein, significantly reduced free light chain difference (less than 10 mg/L), disappearance of plasma cell clones, and a strict definition of hematological complete remission. This refers to the complete normalization of all measurable parameters related to the underlying clonal plasma cell disorder that produces the pathogenic light chains. Moreover, creatinine levels decreased, suggesting that the D-CyBorD regimen can induce hematological and renal function remission in crystalline LCPT and can be considered as the effective and promising strategy treatment for this subtype.

Conclusions

LCPT is a rare form of monoclonal immunoglobulin disease. Its clinical manifestations, laboratory test results, diagnosis, treatment regimen selection, and associated adverse effects are presented in this case to enhance understanding of the disease. In recent years, case reports on LCPT have increased gradually. With the continuous elucidation of clinical features, enriched histopathological and hematological testing methods, and an expanding array of treatment options, the renal function improvement in patients is increasing. However, the prognosis remains poor for patients with late-stage disease and severe organ damage. Thus, early diagnosis and prompt treatment targeting plasma cell clearance, such as with the Dara-CyborD regimen, are highly desirable to delay the progression of LCPT.