Hematologic response and kidney outcomes of monoclonal gammopathy of renal significance excluding AL amyloidosis: a report of six cases

Abstract

Background

Monoclonal gammopathy of renal significance (MGRS) is defined as a B-cell or plasma cell clonal lymphoproliferation that produces a monoclonal immunoglobulin causing kidney lesions without leading to tumor-related complications. Although MGRS does not require hematological therapy based on tumor burden, most therapies are still carried out in accordance with hematological guidelines. AL amyloidosis is the most common form of MGRS, and substantial evidence has been accumulated regarding its treatment and response assessment. However, evidence for non-AL amyloidosis MGRS remains limited because of its rarity. This report describes six cases of non-AL amyloidosis MGRS, with the aim of contributing to the evidence base for this rare disease entity by outlining their clinical courses.

Case presentation

The six cases of non-AL amyloidosis MGRS included two with cryoglobulinemic glomerulonephritis and one each with C3 glomerulopathy, histiocytic glomerulopathy, light chain deposition disease (LCDD), and heavy chain deposition disease (HCDD). In an untreated case, one patient with C3 glomerulopathy progressed to end-stage kidney disease within 30 months of diagnosis. In contrast, patients with cryoglobulinemic glomerulonephritis, LCDD, and HCDD who received clone-directed therapy and achieved hematological complete response exhibited renal response. Of those who underwent clone-directed therapy but achieved only a hematological very good partial response, one case of cryoglobulinemic glomerulonephritis showed renal response, whereas another case of histiocytic glomerulopathy did not. In all six cases, fluctuations in the difference between involved and uninvolved free light chains (dFLC) paralleled changes in urinary protein levels, suggesting that dFLC may serve as a useful marker of disease activity. Although two of the three patients who did not achieve sufficiently reduced dFLC levels failed to obtain a renal response, all three patients who achieved greater reductions in dFLC demonstrated favorable kidney outcomes.

Conclusions

These cases underscore the importance of implementing clone-directed therapy in the management of non-AL amyloidosis MGRS and suggest that achieving lower dFLC levels may contribute to improved kidney outcomes.

Clinical trial number

Not applicable

Background

Monoclonal gammopathy of renal significance (MGRS) is defined as a B-cell or plasma cell clonal lymphoproliferation that produces a monoclonal immunoglobulin causing kidney lesions without leading to tumor complications [1, 2]. Although MGRS does not require hematological therapy based on tumor burden, most therapies are still carried out in accordance with hematological guidelines [3–5]. AL amyloidosis is the most common form of MGRS, and substantial evidence has been accumulated regarding its treatment and response assessment [6, 7]. However, evidence for non-AL amyloidosis MGRS remains limited because of its rarity. As a result, no standardized treatment for non-AL amyloidosis MGRS has been established, and clone-directed therapy, adapted from regimens used for multiple myeloma (MM) or AL amyloidosis, is currently administered at the discretion of individual clinicians [1–3, 8].

According to the current AL amyloidosis guidelines, complete response (CR) is defined by normalization of the serum free light chain (FLC) ratio and absence of M protein in immunofixation electrophoresis (IFE), whereas a difference between involved and uninvolved free light chains (dFLC) < 40 mg/L qualifies as a very good partial response (VGPR) [9]. More recently, the clinical relevance of dFLC is increasing, and a post-treatment dFLC < 10 mg/L has been proposed as a “low dFLC” response, which is associated with improved overall and kidney survival [10, 11]. This threshold is now used as a criterion for CR in clinical trials for AL amyloidosis [7].

From March 2017 to April 2023, six cases of non-AL amyloidosis MGRS were diagnosed by kidney biopsy in accordance with the International Kidney and Monoclonal Gammopathy Research Group (IKMG) recommendations [12]. We reported these cases, focusing on treatment regimens and changes in dFLC, proteinuria, and kidney function, to contribute to the evidence base for this rare disease entity by outlining their clinical courses.

Case presentation

A summary of the six cases is presented in Table 1; Fig. 1. As response criteria specific to non-AL amyloidosis are lacking, we adopted those employed in recent guidelines and clinical trials of AL amyloidosis [7, 13].

Table 1.

Summary of six cases of monoclonal gammopathy of renal significance

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Baseline data(at kidney biopsy)
Age	72	67	26	37	60	43
Sex	Man	Man	Woman	Woman	Man	Woman
eGFR, mL/min/1.73m2	21	29	62	70	30.7	32.7
Urinary protein, g/day	1.99	1.78	3.51	4.89	2.96	4.21
sFLC (κ/λ), mg/L	105/45.5	161/18.8	66/15.5	23.8/219	1010/86.4	48.1/203
sFLC ratio	2.31	8.57	4.30	0.11	11.7	0.24
dFLC, mg/L	59.5	142.2	51.2	196.2	923.6	154.9
IFE	IgM-κ	IgM-κ	IgG-κ	IgG-λ	monoclonal κ FLCs	monoclonal λ FLCs
Kidney pathology
Year of kidney biopsy	2018	2021	2019	2019	2021	2023
Pathological diagnosis	C3 nephropathy	Cryoglobulinemic Glomerulonephritis	Histiocytic Glomerulopathy	Cryoglobulinemic Glomerulonephritis	LCDD	HCDD
Glomerular global sclerosis, %	60	0	4	0	67	0
IF/TA, %	50	10	20	5	50	10
Follow-up data
Treatment	Conservative therapy	Bor + PSL	BD→BD+Dara	Bor + PSL (DEX) →LEN+Dara + DEX	BD+Dara→Dara	BD→Dara + DEX
Therapy cycles	N/A	37	8→15	46→8	1→23	3→8
Adverse events	N/A	no	no	no	fever, malaise	nausea
Follow-up, months	28	44	29	65	24	18
Data at last follow-up
eGFR, mL/min/1.73m2	5	68	83	81	28.3	38.6
Urinary protein, g/day	7.23	0.17	9.78	0.36	0.25	0.21
sFLC (κ/λ), mg/L	247.0/107.0	40.4/10.4	41.0/1.4	4.6/8.1	20.8/18.2	12.4/12.1
sFLC ratio	2.31	3.88	29.3	0.57	1.14	1.02
dFLC, mg/L	140.0	30.0	29.6	3.5	2.6	0.3
Hematological response	NR	VGPR	VGPR	CR	CR	CR
Renal response	ESKD	Yes	No	Yes	Yes	Yes

Abbreviations: BD, bortezomib/dexamethasone; BJP, Bence Jones protein; Bor, bortezomib; CR, complete response; Dara, daratumumab; DEX, dexamethasone; dFLC, difference between involved and uninvolved free light chains; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; FLC, free light chain; HCDD, heavy chain deposition disease; IFE, immunofixation electrophoresis; IF/TA, interstitial fibrosis/tubular atrophy; LCDD, light chain deposition disease; LEN, lenalidomide; N/A, not applicable; NR, no response; PSL, prednisolone; sFLC, serum free light chain; VGPR, very good partial response

Fig. 1.

Clinical courses of seven patients with monoclonal gammopathy of renal significance. Red, blue, and green lines indicate the differences between the involved and uninvolved free light chains (dFLC), estimated glomerular filtration rate, and urinary protein levels, respectively. Abbreviation: Bor, bortezomib; CR, complete response; CyA, cyclosporine; Dara, daratumumab; DEX, dexamethasone; dFLC, difference between involved and uninvolved free light chains; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; HCDD, heavy chain deposition disease; LCDD, light chain deposition disease; LEN, lenalidomide; NR, no response; PGNMID, proliferative glomerulonephritis with monoclonal IgG deposits; PSL, prednisolone; UP, urinary protein; VGPR, very good partial response

Case 1

A 72-year-old man underwent a kidney biopsy for kidney dysfunction and proteinuria. Serum IFE revealed IgM-κ type M-protein. Kidney histopathology showed endocapillary hypercellularity, basement membrane double contours, and dominant C3 deposition, consistent with C3 glomerulopathy (Fig. 2A–D). Bone marrow biopsy revealed < 10% plasma cells, supporting the diagnosis of MGRS. The patient was an older adult with hypertension and diabetes and already had advanced kidney dysfunction at diagnosis (estimated glomerular filtration rate, 21 mL/min/1.73 m²). Histology showed severe damage, with 60% glomerular global sclerosis and 50% interstitial fibrosis/tubular atrophy. Considering the limited expected benefit and the high risk of complications, conservative therapy was chosen. Despite this approach, dFLC and proteinuria remained elevated, leading to progressive kidney deterioration and initiation of hemodialysis 30 months after diagnosis.

Fig. 2.

Representative histopathological findings of MGRS cases. (A–D) Case 1 (C3 glomerulopathy): Light microscopy (LM) demonstrates endocapillary hypercellularity with mesangial expansion and focal duplication of the glomerular capillary walls. Immunostaining shows weak IgG staining with strong C3 positivity. Electron microscopy (EM) reveals band-like intramembranous electron-dense deposits within the glomerular basement membrane. (A) Periodic acid–Schiff stain, original magnification ×200; (B) IgG staining by immunoenzyme method, original magnification ×200; (C) C3 staining by immunoenzyme method, original magnification ×200; (D) electron microscopy, original magnification ×25,000. (E–H) Case 2 (cryoglobulinemic glomerulonephritis): LM demonstrates diffuse intracapillary hyaline thrombi with associated endocapillary hypercellularity. Immunostaining shows strong positivity for IgM and κ light chain. EM reveals subendothelial electron-dense deposits. (E) Periodic acid–Schiff stain, original magnification ×400; (F) IgM staining by immunofluorescence, original magnification ×400; (G) κ light chain staining by immunofluorescence, original magnification ×400; (H) electron microscopy, original magnification ×10,000. (I–L) Case 3 (histiocytic glomerulopathy): LM shows nodular glomerulosclerosis with lobular accentuation and infiltration of cells within the glomerular capillary lumina. Immunostaining demonstrates positivity for κ light chain, whereas λ light chain is negative. Immunoelectron microscopy reveals immunogold labeling for κ light chains yielded positive results in lysosomes. (I) Periodic acid–Schiff stain, original magnification ×200; (J) κ light chain staining by immunoenzyme method, original magnification ×200; (K) λ light chain staining by immunoenzyme method, original magnification ×200; (L) Immunoelectron microscopy using a primary antibody against κ light chains and a 10-nm gold-conjugated secondary antibody; original magnification ×45,000. (M–P) Case 4 (cryoglobulinemic glomerulonephritis): LM demonstrates endocapillary hypercellularity with mesangial expansion and lobular accentuation of the glomerular capillary tufts. Immunostaining shows strong positivity for IgG and λ light chain. EM reveals subendothelial electron-dense deposits. (M) Periodic acid–Schiff stain, original magnification ×400; (N) IgG staining by immunofluorescence, original magnification ×400; (O) λ light chain staining by immunofluorescence, original magnification ×400; (P) electron microscopy, original magnification ×8,500. (Q–T) Case 5 (light chain deposition disease): LM demonstrates nodular lesions within the mesangial regions. Immunostaining showed faint granular positivity for κ light chains in parts of the basement membrane and the mesangial areas, with absence of λ light chain staining. EM reveals finely granular electron-dense deposits with a linear distribution along the glomerular basement membranes. (Q) Periodic acid–Schiff stain, original magnification ×400; (R) κ light chain staining by immunoenzyme method, original magnification ×400; (S) λ light chain staining by immunoenzyme method, original magnification ×400; (T) electron microscopy, original magnification ×6,000. (U–X). Case 6 (heavy chain deposition disease): LM demonstrates endocapillary hypercellularity with lobular accentuation of the glomerular capillary tufts and duplication of the glomerular basement membranes. Immunostaining shows no significant staining for either κ or λ light chain. EM reveals finely granular electron-dense deposits with a linear distribution along the glomerular basement membranes. (U) Periodic acid-methenamine-silver stain, original magnification ×200; (V) κ light chain staining by immunofluorescence, original magnification ×400; (W) λ light chain staining by immunofluorescence, original magnification ×400; (X) electron microscopy, original magnification ×6,000

Case 2

A 67-year-old man underwent a kidney biopsy to evaluate kidney dysfunction and proteinuria. Reduced serum complement levels were observed (C3, 52 mg/dL; C4, 9 mg/dL; CH50, 25.6 U/mL), and serum IFE showed IgM-κ type M-protein with cryoglobulinemia. Kidney histopathology demonstrated cryoglobulinemic glomerulonephritis with κ light chain deposition, consistent with MGRS (Fig. 2E–H), as bone marrow findings showed < 10% plasma cells. Prednisolone (PSL) was initiated following confirmation of kidney histopathological findings. Flow cytometry of bone marrow cells showed that approximately half were CD138 positive, with few CD19- or CD20-positive cells detected. Based on these findings, bortezomib was added in combination with PSL to target plasma cells. The patient responded promptly, with a rapid reduction in proteinuria and discontinuation of PSL within 3 months. The dFLC level, 142.2 mg/L at biopsy, steadily declined with treatment, achieving VGPR at 20 months. Kidney function remained stable during follow-up.

Case 3

A 26-year-old woman underwent a kidney biopsy for the evaluation of nephrotic syndrome. Serum IFE revealed IgG-κ type M-protein, and no serum cryoglobulins were detected. In the absence of schistocytes, elevated lactate dehydrogenase levels, or decreased haptoglobin levels, thrombotic microangiopathy was considered unlikely. Kidney histopathology showed glomerular capillaries filled with histiocytes strongly positive for κ light chain but not λ light chain. Immunoelectron microscopy revealed enlarged lysosomes in histiocytes containing κ light chains, with no evidence of κ light chain deposition in the basement membrane, supporting a diagnosis of histiocytic glomerulopathy with noncrystalline inclusion. (Fig. 2I–L) [14]. Bone marrow biopsy revealed < 10% plasma cells. Bortezomib and dexamethasone (BD) therapy was initiated 3 months after biopsy. After eight cycles, dFLC and proteinuria decreased but rose again at 12 months, prompting the addition of daratumumab. Fifteen cycles of BD and daratumumab were administered. Hematologic VGPR was achieved, though proteinuria remained elevated and fluctuated. Follow-up ended 29 months after the patient was transferred.

Case 4

A 37-year-old woman underwent a kidney biopsy for the evaluation of proteinuria. Complement levels at the time of kidney biopsy showed reduced C3 (85 mg/dL) and C4 (13 mg/dL), with preserved CH50 (56.4 U/mL), and the renal histopathology was consistent with cryoglobulinemic glomerulonephritis (Fig. 2M–P). Treatment with PSL was subsequently initiated, resulting in an initial clinical response. However, 1 year after the initiation of therapy, proteinuria increased again. Further evaluation at that time demonstrated IgG-λ–type M-protein with cryoglobulinemia on serum IFE. A subsequent bone marrow biopsy revealed less than 10% plasma cells. Bortezomib was then initiated targeting the monoclonal gammopathy, resulting in CR within 2 months. PSL was gradually tapered over 2 years, with a subsequent switch to dexamethasone. CR was maintained for 14 months after BD. When dFLC rose again, therapy was switched to lenalidomide, daratumumab, and dexamethasone 45 months after initial treatment, leading to another CR within 2 months. Proteinuria paralleled dFLC and is currently < 0.5 g/day under hematologic CR.

Case 5

A 60-year-old man underwent a kidney biopsy for kidney dysfunction and proteinuria. Urinary IFE revealed monoclonal κ FLCs. Light microscopy showed nodular mesangial lesions positive for κ light chains, and electron microscopy revealed fine granular electron-dense deposits in glomerular and tubular basement membranes and the mesangium, consistent with light chain deposition disease (LCDD) (Fig. 2Q–T). Bone marrow biopsy revealed < 10% plasma cells, supporting the diagnosis of MGRS. Proteinuria improved initially with supportive care, but dFLC remained markedly elevated. BD and daratumumab therapy were initiated 6 months after biopsy. BD was discontinued after the first course because of fever and malaise; daratumumab was continued. CR was achieved and maintained for 15 months under clone-directed therapy.

Case 6

A 43-year-old woman underwent a kidney biopsy for kidney dysfunction and proteinuria. Urinary IFE revealed monoclonal λ FLCs. Light microscopy showed lobulated glomerular tufts, double-contour basement membranes, and nodular mesangial lesions. Neither κ nor λ light chain deposition was detected in the mesangium. Electron microscopy revealed fine granular electron-dense deposits in the glomerular basement membrane, subendothelial space, and tubular basement membrane, consistent with heavy chain deposition disease (HCDD) (Fig. 2U–X). Bone marrow biopsy revealed < 10% plasma cells. BD therapy was started 2 months after diagnosis. dFLC levels dropped rapidly, followed by reduced proteinuria. BD was discontinued after three cycles because of severe nausea, and was replaced with daratumumab and dexamethasone. Hematologic CR and proteinuria remission were achieved. Therapy was completed after eight cycles, with sustained kidney function and proteinuria remission.

Discussion and conclusions

In this report, we describe the clinical courses of six patients with MGRS, focusing on serial changes in dFLC, urinary protein levels, and kidney function. These cases provide valuable insights into treatment strategies and the monitoring of MGRS. Notably, a parallel trend between dFLC and proteinuria was observed in most cases, underscoring the utility of dFLC as a surrogate marker for disease activity. Although all patients who achieved hematologic CR (dFLC < 10 mg/L) demonstrated a kidney response, two of the three patients who achieved VGPR (10 ≤ dFLC < 40 mg/L) failed to obtain a kidney response. This could be explained by the definition of CR used in this study, which required normalization of the serum FLC ratio and a dFLC < 10 mg/L, as specified in the updated International Society of Amyloidosis criteria [9].

In our cases, all three patients who achieved a kidney response (Cases 4, 5, and 6) showed normalization of the serum FLC ratio, whereas the two patients without a kidney response (Cases 1 and 3) maintained elevated serum FLC ratios. These findings suggest that the serum FLC ratio may also serve as a useful biomarker in non-AL amyloidosis MGRS. In contrast, a previous report including a case series of 13 patients with LCDD and HCDD showed three cases of hematologic CR as defined by the conventional criteria; normalization of the serum FLC ratio and absence of M protein in IFE, with only one exhibiting a kidney response [15]. The disparity in kidney response despite hematologic CR between our patients and those in previous studies highlights the clinical importance of achieving a “low dFLC” threshold in patients with non-AL amyloidosis MGRS, similar to that emphasized for AL amyloidosis. Notably, in Case 4, dFLC elevation was observed prior to proteinuria recurrence. This finding suggests that continuous monitoring of dFLC may serve as an early indicator of disease relapse and support timely adjustments in treatment intensity or regimen.

Our findings reinforce the therapeutic significance of clone-directed therapy in MGRS. The patient who did not undergo clone-directed therapy (Case 1) progressed to end-stage kidney disease. In contrast, patients treated with bortezomib- or daratumumab-based regimens showed a rapid decline in dFLC and better preservation of kidney function. Accurate renal pathological diagnosis is essential for the appropriate implementation of clone-directed therapy, and clinicians should evaluate renal biopsy specimens with consideration of the various pathological subtypes of MGRS. In some cases, immunologic staining is useful for establishing the diagnosis. In particular, in Case 3, differentiation from LCDD was challenging; however, immunoelectron microscopy enabled definitive discrimination between the two entities. In LCDD and HCDD, kidney outcomes are generally poor because of irreversible histological alterations [16, 17]. However, in Case 5 and 6, a kidney response was achieved despite severe histopathological findings at the time of biopsy. This may be attributed to the short interval between diagnosis and the initiation of clone-directed therapy, reaffirming the concept that “time is kidney.”

In MGRS, achievement of ≥ VGPR has been reported to be associated with improved renal outcomes [18, 19]. Among the patients who received clone-directed therapy, a renal response was not achieved only in Case 3 (histiocytic glomerulopathy). In this case, although VGPR was achieved, it could not be sustained. The use of daratumumab in treatment regimens may be effective. In Cases 4, 5, and 6, hematological responses were maintained with daratumumab therapy. These findings are consistent with a previous report showing rapid FLC reduction with daratumumab in patients with MM and severe renal failure [20]. Even in the absence of a renal response, achieving a hematologic response remains important. This consideration is particularly relevant when kidney transplantation is selected as renal replacement therapy. Recurrence is common across MGRS-associated lesions after transplantation, and a complete hematologic response could reduce the risk of recurrence and graft loss [21, 22].

Our reports have several limitations. MGRS represents a highly heterogeneous and rare group of disorders, and the present case reports do not encompass the full spectrum of MGRS. Therefore, whether the clinical utility of dFLC observed in the present case reports is applicable to all forms of MGRS requires further investigation with a larger accumulation of cases. In addition, repeated IFE studies and bone marrow examinations were not systematically performed in these cases. As a result, treatment response could not be assessed in full accordance with the criteria for AL amyloidosis or those proposed by the International Myeloma Working Group.

In conclusion, these cases underscore the clinical importance of clone-directed therapy in non-AL amyloidosis MGRS and suggest that dFLC may serve as a useful clinical biomarker, with greater reductions in dFLC potentially contributing to improved kidney outcomes. The correlation between dFLC and proteinuria highlights the utility of early individualized and hematologically guided interventions.

Abbreviations

BD

Bortezomib and dexamethasone

BJP

Bence Jones protein

CR

Complete response

dFLC

Difference between involved and uninvolved free light chains

ESKD

End-stage kidney disease

FLC

Free light chain

HCDD

Heavy chain deposition disease

IFE

Immunofixation electrophoresis

LCDD

Light chain deposition disease

MM

Multiple myeloma

MGRS

Monoclonal gammopathy of renal significance

PGNMID

Proliferative glomerulonephritis with monoclonal IgG deposits

PSL

Prednisolone

VGPR

Very good partial response

Author contributions

Research idea: HN and KH; data acquisition: HN, YS, and KH; data analysis/interpretation: HN; writing: HN and KH; figure preparation: HN, TN, YS, AK, and KH; supervision or mentorship: MO, KS, NT, SY, and TY.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This case report was prepared as part of a study titled “Investigation of Treatment and Prognosis of Monoclonal Gammopathy of Renal Significance,” approved by the Ethics Committee of Jikei University School of Medicine (approval no: 36–148[12257]). The study was performed in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The requirement for informed consent from the patients was waived because of the retrospective nature of the study. Instead, all individual participants were provided the opportunity to opt out of this study.

Consent for publication

Written informed consent was obtained from the patient for the publication of this case report. In cases where written informed consent could not be obtained directly, the study details were explained, and the obtained consent was documented in the electronic medical record.

Competing interests

The authors declare no competing interests.