Introduction

Plasma cell dyscrasias such as multiple myeloma (MM) result from the clonal proliferation of plasma cells and subsequent overproduction of immunoglobulins, including free light chains. Renal dysfunction is a core manifestation of plasma cell dyscrasias. A broad range of kidney pathogenesis can occur, including light chain cast nephropathy, monoclonal immunoglobulin (Ig) deposition disease, light chain amyloidosis, light chain proximal tubulopathy (LCPT), and tubulointerstitial nephritis [1,2,3].

Free light chains (FLCs) are low molecular weight proteins that are normally produced in abundance by the lymphoid tissue (around 500 mg/day). They are relatively freely filtered at the glomerulus and reabsorbed and hydrolyzed very efficiently by the proximal tubules via clathrin-dependent endocytosis by the megalin/cubilin receptor system, such that only 1–10 mg of FLCs appear in the urine daily [4]. The overproduction of monoclonal FLCs, particularly in the setting of MM, often overcomes the capacity of the proximal tubular epithelium to process all filtered FLCs, leading to overflow proteinuria. A large amount of free LC is produced that cannot be completely reabsorbed in the proximal renal tubule, causing proximal tubular damage. LCPT, a rare manifestation of monoclonal gammopathy, is characterized by cytoplasmic inclusions of monoclonal LC within proximal tubular epithelial cells [5].

Case

A 73-year-old Japanese woman who had no history of urinary abnormalities until 1 year prior to admission was noted to have urinary protein and hypertension on a health examination and visited the regional clinic for further investigations. She had immunoglobulin G (IgG) λ M protein and was suspected of having MM. She was referred to our hospital for further evaluation and treatment.

On admission, the patient was 139 cm tall, weighed 41.4 kg, and had a blood pressure of 147/96 mmHg, pulse of 93/min, and temperature of 36.3 °C. Cardiac, pulmonary, and abdominal examination findings were unremarkable.

Laboratory data were as follows (Table 1). Urinalysis revealed massive proteinuria (2+, 3.6 g/day) without hematuria and positive for Bence Jones protein. The urinary β-2microglobulin (β-2MG) level was 678 ng/mL. Laboratory testing revealed normal values of serum total protein (8.2 g/dL), albumin (4.6 g/dL), creatinine (0.5 mg/dL), uric acid (3.3 mg/dL), and HCO3 (27 nmol/mL). Serum immunoglobulin G was 1910 mg/dL with suppression of immunoglobulin A (IgA 16.4 mg/dL) and immunoglobulin M (IgM 7.0 mg/dL). Level of third complement component (C3) was 82 mg/dL (normal 50–130 mg/dL); the fourth component (C4) level was 19 mg/dL (normal 10–50 mg/dL); hemolytic complement activity via the classical pathway (CH50) was 16 U/mL (normal 25.0–48.0 U/mL). Serum protein electrophoresis showed an M-spike with monoclonal IgG λ. Urinary protein electrophoresis with immunofixation also showed a monoclonal λ Bence Jones protein. FLC κ was 1.4 mg/L and λ was 2350 mg/L for a λ/κ ratio of 1679.

Table 1 Laboratory findings
Full size table

A bone marrow examination revealed hypocellular marrow with 35% atypical plasma cells. Ninety percent of the plasma cells were positive for CD138 and λ chain despite being negative for κ chain, IgG, IgA, and IgM.

A renal biopsy revealed that all seven glomeruli were present without significant pathologic alternations, but a tubular cast was observed partially in tubules without tubular atrophy or a crystalline structure. The proximal tubular cells are variably distended with reactive nuclei, droplets/globules and vacuoles (Fig. 1). Direct Fast Scarlet staining was absent both in glomerulus and vascular wall. Immune deposits of IgG, IgA, IgM, C1q, C3c, C3d, C4c, fibrinogen, κ light chains, and λ light chains were absent in the glomerulus (Fig. 2). Only λ light chains were positive in the tubules and the urinary cast. We also performed immunohistochemical staining for κ, λ, CD10 (proximal tubules), and epithelial membrane antigen (distal tubules) to identify the tubule level. The materials for immunofluorostains (κ, λ) and immunohistochemistry (CD10, EMA) were using formalin-fixed paraffin-embedded serial sections. IF were performed using re-embedding material from fixed paraffin-embedded section. The immunohistochemical staining revealed that the λ light chain-positive tubules were at the proximal level (Fig. 3). Electron microscopy revealed nonspecific findings include increased lysosomes with irregular contours and mottled appearance (arrows) without either crystal formation or bundles (Fig. 4). This change is also nonspecific, but commonly present in this LCPT subtype (without organized inclusion).

Fig. 1
figure 1

Renal biopsy findings light microscopy. a Masson Trichrome stain; ×40. b Periodic acid–Schiff (PAS) stain; ×400. c Masson Trichrome stain; magnification × 400. d Periodic acid–Schiff (PAS) stain; ×400. Light microscopy images show no remarkable glomerular changes. Tubular casts were observed partially in tubules without tubular atrophy or a crystalline structure. The proximal tubular cells are variably distended with reactive nuclei, droplets/globules and vacuoles

Full size image
Fig. 2
figure 2

Immunofluorescent findings of immunoglobulin and complement. Immune deposits of IgG, IgA, IgM, C1q, C3c, C3d, C4c, fibrinogen, κ and λ light chains were absent in glomerulus

Full size image
Fig. 3
figure 3

Immunofluorescent findings of κ and λ light chains and immunohistochemical staining of CD10 and epithelial membrane antigen (EMA) in tubulus, original magnification ×100. κ light chain was absent, but λ light chain was positive in tubules. Distribution of λ light chain-positive tubulus was same as CD10 positive tubulus

Full size image
Fig. 4
figure 4

Electron microscopic findings. a Low power field, b high power field. Electron microscopy findings include lysosomes with irregular contours and mottled appearance (arrow) without either crystal formation or bundles in proximal tubules

Full size image

Her renal manifestation was diagnosed as LCPT due to MM findings on renal biopsy.

Clinical follow-up (Fig. 5)

Fig. 5
figure 5

Clinical course

Full size image

At the time of LCPT diagnosis, considering her advanced age (73 years) and lack of nephrology and hematology symptoms, the patient chose follow-up observations rather than chemotherapy. However, the FLC λ increased to 6620 mg/dL (λ/κ ratio of 2758) with elevation of urinary β-2MG to 14,150 ng/mL 8 months after the renal biopsy. Her estimated glomerular filtration rate (eGFR) decreased from 87 to 47 mL/min/1.73 m2 and she developed progressive anemia (Hb 10 g/dL). Ld therapy (lenalidomide 15 mg/day, on days 1 through 21 in combination with dexamethasone 40 mg/day once a week (day 1, 8, 15, 22) of each 28-day cycle) was initiated. The Ld therapy reduced the light chain, λ/κ ratio, urinary protein level, and urinary β-2MG level and increased the eGFR. After 6 cycles of the Ld therapy, she achieved hematologic remission, the proteinuria resolved, urinary β-2MG decreased to 1100 ng/dL, and eGFR increased to 56 mL/min/1.73 m2 without major complication. Ixazomib [4 mg/day once a week for 2 weeks (day 1, 8, 15)] was added on Ld therapy as iLd treatment for maintenance therapy. 1 year after treatment, she is fine and maintained remission as FLC κ was 2.0 mg/L and λ was 65.2 mg/dL for a λ/κ ratio of 32.6, urinary β-2MG decreased to 660 ng/dL, eGFR 55 mL/min/1.73 m2.

Discussion

LCPT associated with plasma cell dyscrasias is a rare abnormality. The prevalence of LCPT is reportedly low (2.5–5%) among dysproteinemia-related renal disease [6,7,8]. However, the true incidence of LCPT is unknown because a renal biopsy has a bias in patients with unexplained renal insufficiency and/or significant proteinuria. The IF staining features of FLC and electron microscopic appearance of inclusion were specific and varied. Cases of κ-light chain storage are more common than those of λ, and crystal formation may be associated with light chain subtype. Stoke reported that 40 of 46 light chains were κ [8]. Crystalline LCPT is almost exclusively seen in κ-restricted disease with rare examples of λ-restricted intracytoplasmic crystals [6, 9]. Although the reason for the κ predominance is not yet clearly understood, resistance to enzymes in the lysosome is considered one reason. Stokes reported that most patients had proteinuria (98%) and renal insufficiency (83%). Urinary protein excretion was often heavy (> 1 g/day in 87% and > 3 g/day in 37%), but hypoalbuminemia was not seen [8]. This means the proteinuria consisted predominantly of FLC rather than albumin. These characteristics were consistent in this case.

One-third of LCPT patients, all with crystalline LCPT, had one or more features of Fanconi syndrome (FS), including normoglycemic glycosuria, metabolic acidosis, hypophosphatemia, bone pain, and aminoaciduria. FS often triggers the suspicion of LCPT [10, 11]. This case was λ-type FLC without crystalline LCPT and did not show any signs of FS as in Stokes’ review [8].

FS is uncommon in adults and more often signifies the presence of a plasma cell dyscrasia. The propensity for the light chains in LCFS (light chain Fanconi syndrome) to form crystals that precipitate in cytoplasm of proximal tubules appears to be determined by their amino acid sequences and the resultant physical and chemical properties. Aucounturier reported characterization of a monoclonal κ-cDNA from a LCFS patient closely fit into the VK1 subgroup [12]. Protease treatment of the light chain produced an elongated NH2-terminal fragment of the variable (V) domain that was resistant to further degradation and was able to form crystals when bound to itself or intact κ-light chains.

Most crystalline LCPT cases require pronase digestion of formalin-fixed sections for the detection of monoclonal light chains, whereas non-crystalline LCPT can be detected by immunofluorescence microscopy (IF) of frozen tissue in all patients [13]. This also matches our diagnosis using only IF and not by using pronase digestion of formalin-fixed sections in this case of non-crystalline LCPT.

Stokes reported follow-up outcomes of 30 crystalline LCPT and 6 non-crystalline LCPT cases as median kidney survival of 135 months and 64 months, respectively. Stokes reported that the morphologic findings of light chain crystalline inclusions in the proximal tubular cytoplasm are often not a harbinger of progressive renal failure. Non-crystalline LCPT was particularly uncommon in the study by Stokes and colleagues (only 6 cases). The significance of light chain proximal tubulopathy without crystal formation is debatable. Specifically, whether the findings shown here represent a true lesion or simply a physiologic process in the setting of excess free light chains. This is an important distinction considering the fact that end organ damage is frequently used in treatment algorithms for plasma cell dyscrasia. If this is merely a physiologic process in the setting of excess FLC then this is best considered a coincidental finding and not an indication for treatment of the plasma cell dyscrasia. Alternatively, if this is determined to be a lesion resulting from the presence of excessive and aberrant free light chains, treatment of the underlying plasma cell dyscrasia is warranted in many cases based on this finding. This case supported that non-crystalline LCPT cases preserved kidney function despite persistent massive light chain proteinuria, but it was exacerbated within few months both hematologically and nephrologically when follow-up without treatment, and remission was achieved by chemotherapy. So more patients need to be studied in future to determine if there are significant clinical and prognostic differences between crystalline and non-crystalline LCPT.

The International Kidney and Monoclonal Gammopathy Research Group recommends chemotherapy or stem cell transplantation for LCPT even before worsening hematologic disease occurs [14]. Kidney function showed a general improvement trend in patients who were treated with chemotherapy alone or chemotherapy and stem cell transplantation [8]. Furthermore, renal involvement is an independent predictor of poor outcomes in MM [15], and early identification of LCPT may help stratify risk factors and drive patient management.

This case did not show major renal manifestations such as acute kidney injury by cast nephropathy, AL amyloidosis, monoclonal immunoglobulin deposition disease, or FS. In this case, careful observation of tubules enabled the diagnosis of LCPT despite absence of any signs of acute tubular injury or tubular dysfunction as in cases of FS.

Initially, this case was follow-up without chemotherapy considering her elderly and asymptomatic, but treatment after 8 months was successful. Lenalidomide, an immunomodulatory drug, has been shown to improve the outcomes of patients with newly diagnosed, previously treated or refractory MM [16, 17]. Lenalidomide has been shown to induce apoptosis of MM cells and inhibit angiogenesis and blocks the binding of MM cells to the bone marrow stromal cells [18]. Recently Kimura reported three cases of light chain deposition disease (LCDD) treated with lenalidomide therapy, resulting in hematologic responses accompanied by a significant reduction in proteinuria and improvement in the renal function [19]. With recent advances in the treatment of myeloma by proteasome inhibitor and lenalidomide, early intervention should be considered if monoclonal gammopathy of undetermined significance (MGUS) also presents as MGRS.

Further pathological and clinical investigations of future cases are required and important to further our understanding of this disease entity.

Conclusion

Here, we reported a case of LCPT without Fanconi syndrome in IgG λ-type multiple myeloma as a rare manifestation of paraproteinemia that was successfully treated with Ld therapy.