Light chain deposition disease (LCDD)

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Chapter

17

SECTION 3 - AL amyloidosis and light chain deposition disease

Light chain deposition disease (LCDD)

Contents

sFLC measurements are important in light chain deposition disease because:
  1. They are abnormal in 90% of patients at the time of diagnosis.
  2. They are useful for monitoring disease progress.
  3. They may identify patients who were previously unrecognised.

17.1. Introduction

The rare monoclonal immunoglobulin deposition diseases (MIDD) comprise light chain deposition disease (LCDD), light- and heavy-chain deposition disease (LHCDD) and heavy-chain deposition disease (HCDD) [1]. In LCDD, which comprises 80% of the cases of MIDD [2], monoclonal serum free light chains (sFLCs) are precipitated on the basement membranes of cells in the kidneys and other organs. As with AL amyloidosis, the disease is progressive and leads to organ failure of the kidneys, heart or liver and has a poor prognosis [3][4][1]. LCDD differs from AL amyloidosis by being more frequent in younger women (aged 30-50 years), and renal failure is a common presenting feature. The deposits usually contain κ FLCs (Vκ1 and Vκ4) without amyloid P component. Some of the patients have serum and urine monoclonal proteins detectable by electrophoretic tests. The clinical course of HCDD is similar to LCDD [5].

17.2. Diagnosis of LCDD using sFLC assays

Whilst a definitive diagnosis of LCDD is based on renal biopsy with thorough histological examination and electron microscopy [6], sFLC analysis should be included in the initial laboratory testing algorithm as the majority of patients will have monoclonal sFLCs. This was shown most recently in 18 LCDD patients who were included as part of a larger screening study aimed at evaluating several serum- and urine-based screening algorithms [7]. The analysis showed that sFLC testing alone, or a panel of serum protein electrophoresis (SPE) and sFLC were both as sensitive (77.8%) for LCDD detection as a panel of SPE, serum immunofixation electrophoresis (sIFE) and urine IFE (uIFE). The most recent IMWG guidelines [8] recommend the use of sFLC in combination with serum electrophoresis to screen for monoclonal gammopathies, with the exception of AL amyloidosis which additionally requires a 24-hour uIFE. Proposed screening algorithms are discussed further in Chapter 23 and guidelines are detailed in Chapter 25.

The above study by Katzmann et al. [7] supports previous studies by the same authors in which the diagnostic sensitivity of the sFLC tests in LCDD were evaluated. In one of these, 17 of 19 patients with LCDD had an abnormal sFLC κ/λ ratio, including 7 patients who were negative by sIFE (Table 17.1 and Figure 17.1). One sample was falsely negative by sFLC analysis but positive by sIFE. In a subsequent publication, 7 further patients were studied and all had abnormal sFLC κ/λ ratios [9].

A series of 17 patients with biopsy-proven LCDD was studied by Wechalekar et al [10]. sFLCs were abnormal with a clonal bias in 15 (88%) of the patients. Of these, 11 (64%) patients had κ excess, 4 (23%) had λ excess while 2 (11%) had polyclonal increased FLCs. The median κ and λ levels were 317 mg/L (range 8.5-2,260) and 64 mg/L (range 17-10,700), respectively. The authors concluded that measurement of sFLCs identified 33% more patients with LCDD than standard electrophoretic methods, and sFLC analysis is a useful addition to electrophoretic tests when screening for LCDD.

The largest single-centre series of renal MIDD consisted of 51 cases of LCDD, 7 cases of HCDD and 6 cases of LHCDD. Clinical features at presentation included proteinuria (97%), renal insufficiency (97%), hypertension (83%) and haematuria (62%). The κ/λ sFLC ratio was abnormal in all 51 patients (100%) tested, and was markedly abnormal (<0.125 or >8) in 78% [2].

Clinical case history No 8 illustrates the clinical sensitivity of the FLC tests compared with conventional serum and urine electrophoretic assays (Figure 17.2).

Monoclonal serum free light chains in light chain deposition disease
Figure 17.1.sFLCs and serum and urine electrophoretic tests in 19 patients with LCDD. BM = bone marrow. (Courtesy of RA Kyle and JA Katzmann).
Classification
Elevated
FLC
Abnormal
FLC κ/λ ratio
sIFE κ +ve 8/9 8/9
sIFE λ +ve 3/3 3/3
sIFE -ve; uIFE κ +ve 4/4 4/4
sIFE and uIFE -ve. BMPCs κ +ve 1/3 2/3
Total abnormal for sFLCs 16 17

Table 17.1. Detection rates by sFLCs in 19 LCDD patients. BMPC: bone marrow plasma cells.

Clinical case history No 8

Clinical case history No 8. Light chain deposition disease undetectable by conventional electrophoretic assays.

A 66-year-old man suffering from asthenia and anaemia was investigated for serum protein abnormalities. SPE, sIFE and uIFE tests showed no evidence of monoclonal immunoglobulins (Figure 17.2). Serum immunoglobulins were normal/low: IgG 8.5 g/L; IgA 0.4 g/L and IgM 0.2 g/L. However, sFLC concentrations were highly abnormal: κ 294 mg/L; λ 71.6 mg/L and κ/λ ratio 4.1. These results indicated a monoclonal gammopathy and renal impairment. FLC quantification allowed the depositing FLC to be easily identified and supported the clinical diagnosis of LCDD obtained by renal biopsy.

Normal serum protein electrophoresis and immunofixation electrophoresis in light chain deposition disease
Figure 17.2. LCDD showing normal SPE (scanning densitometry) and IFE, but sFLCs were highly abnormal (κ 294 mg/L: λ 71.6 mg/L and κ/λ ratio: 4.1). T: Protein stain. (Courtesy of L Guis) [11]
.

17.3. Monitoring LCDD using sFLC assays

It is logical to monitor LCDD patients using sFLC assays. Although there are no data validating the use of the sFLC assays in assessment of haematological response in patients with LCDD, the personal experience of many authors confirms their utility [12][13][14] and international guidelines now recommend sFLC analysis for monitoring LCDD [8] (see Chapter 25).

Wechalekar et al. [10] monitored 10 LCDD patients receiving systemic chemotherapy as follows: vincristine, adriamycin (doxorubicin), dexamethasone (VAD; 4 patients), cyclophosphamide and vincristine, adriamycin, melphalan, methyl-prednisolone (CVAMP; 1 patient), VAD followed by autologous stem cell transplant (2 patients), melphalan and prednisone (1 patient), and intermediate-dose melphalan (2 patients). Eight (80%) patients had sFLC responses, with a median decrease of 63% (range 31 - 95%), compared with pretreatment values. One patient had no change in sFLC levels (which did not show clonal bias pre-treatment) but had a very good partial response of the intact monoclonal immunoglobulin. Only 2 patients had complete normalisation of FLC levels. The authors concluded that sFLC anaylsis was useful for monitoring response to treatment.

Hassoun et al. [15] reported on 5 patients with LCDD, one with light and heavy chain DD and one with light chain crystal DD. All had abnormal sFLCs at diagnosis. Patients were given high-dose melphalan and peripheral blood stem cell transplant (PBSCT) with good responses that could be monitored with sFLCs.

Minarik et al. [16] presented a series of 3 patients with LCDD treated with bortezomib-based induction regimens. All 3 patients had highly abnormal sFLCs at diagnosis, and treatment lead to a rapid and deep reduction in sFLC levels, within two cycles of treatment.

It is important to note that patients with chronic kidney disease due to deposition of monoclonal FLCs are difficult to identify and monitor [17][6]. It is likely that many patients have detectable monoclonal FLCs in serum but are undiagnosed from urine studies. This issue is discussed in detail in Chapter 20.5.

Case history 9 illustrates the utility of sFLC analyses in a patient who was difficult to monitor by other methods [18].

Clinical case history No 9

Clinical case history No 9. Light chain deposition disease monitored with sFLC assays.(Courtesy of I Brockhurst, Leicester, UK).

A 49-year-old Caucasian male presented to the nephrologists with flu-like symptoms, hypertension and face, hand and leg swelling. Serum electrolytes were normal, creatinine clearance was 140 mL/min and urinary protein quantification was 2.4 g/24 hours. A renal biopsy demonstrated normal histology and immunofluorescence tests. The patient was managed with a 120 mg daily dose of furosemide and antihypertensives. Follow-up was initially uneventful with renal function remaining stable.

10 years later the patient presented with nephrotic syndrome. Serum biochemistry showed: creatinine 165 μmol/L (NR 60-120 μmol/L), albumin 33 g/L (NR >40 g/L), cholesterol 8.7 mmol/L (NR <5.5 mmol/L) and urinalysis revealed 3+ proteinuria. A further renal biopsy showed nodular glomerulosclerosis with evidence of LCDD on electron microscopy. Congo red staining was negative. SPE, immunoglobulin levels and urinary Bence Jones protein assays were all normal.

The patient was referred to the haematology department to rule out an underlying B-cell clonal disorder. Bone marrow aspirate and trephine revealed normal cellular marrow with no morphological or immunophenotypic evidence of MM and, again, Congo Red staining was negative. An iodine123 labelled, serum amyloid P scan showed no evidence of amyloid deposition. Serum was tested for sFLCs with the following results: κ 526.0 mg/L (normal range 3.3-19.4 mg/L), λ 64.6 mg/L (normal range 12.7-26.3 mg/L) and κ/λ ratio 8.14 (normal range 0.26-1.65) (Figure 17.3). The patient subsequently developed atrial fibrillation. A 24-hour tape showed irregularities in the atrial chamber and intermittent disruption of AV node conduction. A dual chamber pacemaker was fitted and cardiac biopsy performed, which showed no evidence of amyloid or light chain deposition.

Within 2 months his renal function had deteriorated further with a serum creatinine of 210 μmol/L, creatinine clearance of 67 mL/min and a 24-hour urine protein leakage of 13.8 g. In order to delay the need for dialysis he was treated with 3 cycles of VAMP chemotherapy (vincristine 0.4 mg/day for 4 days, doxorubicin 9 mg/m2/day for 4 days and methylprednisolone 1 g/m2 for 5 days per cycle). Subsequent to the chemotherapy, renal function improved and this was also observed in the sFLC levels and κ/λ ratio. 3 months after the chemotherapy, 24-hour urinary protein excretion was 0.1 g/L.

For the following year renal function remained stable but then the κ/λ ratio and serum creatinine concentrations began to increase again. The patient was treated with a further 3 cycles of VAMP and similar improvements in renal function and sFLC levels were seen. The patient has remained reasonably well since.

Monitoring light chain deposition disease with serum free light chains. Serum free light chains indicate response to treatment and relapse
Figure 17.3. Monitoring of a patient with LCDD using sFLC assays (Courtesy of Ian Brockhurst, Leicester, UK)
.
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References

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