Light chain deposition disease (LCDD)

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Chapter

17

SECTION 2B - Diseases with monoclonal light chain deposition

Light chain deposition disease (LCDD)

Contents

Summary: sFLC measurements are important in LCDD 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 that were previously unrecognised.

17.1. Introduction

In LCDD, monoclonal 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 [1][2][3]. This rare disease differs from AL amyloidosis by being more frequent in younger women (30-50 years) and renal failure is a common presenting feature. The deposits usually contain κ FLCs (Vκ1and Vκ4) without amyloid P component. Some of the patients have serum and urine monoclonal proteins detectable by electrophoretic tests.

17.2. Diagnosis of LCDD using serum free light chain assays

Serum FLC concentrations were measured in 19 patients with LCDD by Katzmann et al. [4], and were abnormal in 17 (Table 17.1 and Figure 17.1). One sample was falsely negative by serum FLC analysis but positive by serum IFE. In a subsequent publication by the same authors, 7 further patients were studied and all had raised serum FLC concentrations [5]. Clinical case history No 8 illustrates the clinical sensitivity of the FLC tests compared with conventional serum and urine electrophoretic assays (Figure 17.2) [6].

Figure 17.1.Serum FLCs and serum and urine electrophoretic tests in 19 patients with LCDD. BM = bone marrow. (Courtesy of JA Katzmann).
Classification
Elevated
FLC
 Abnormal
FLC κ/λ ratio
Serum IFE κ +ve 8/9 8/9
Serum IFE λ +ve 3/3 3/3
Serum IFE -ve; Urine IFE κ +ve 4/4 4/4
Serum and uIFE -ve. BMPCs κ +ve 1/3 2/3
Total abnormal for serum FLCs 16 17

Table 17.1. Detection rates by sFLCs in 19 LCDD patients. BM: bone marrow.

Clinical case history No 8

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

A 66-year-old man suffering from asthenia and anaemia was investigated for serum protein abnormalities. SPE and serum and urine IFE tests showed no evidence of monoclonal immunoglobulins (Figure 17.2). Serum immunoglobulins were normal/low: IgG 8.5g/L; IgA 0.4g/L and IgM 0.2g/L. However, serum FLC concentrations were highly abnormal: κ 294mg/L; λ 71.6mg/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.

Figure 17.2 LCDD showing normal SPE (scanning densitometry) and IFE, but sFLCs were highly abnormal (κ 294mg/L: λ 71.6mg/L and κ/λ ratio: 4.1). T: Protein stain. (Courtesy of Dr Lucile Musset).

17.3. Monitoring LCDD using serum free light chain assays

It is logical to monitor these patients using serum FLC assays and initial reports indicate that changes in concentrations are as helpful as in patients with AL amyloidosis. Case history 9 illustrates the utility of serum FLC analyses in a patient who was difficult to monitor by other methods [7].

A series of 17 patients with biopsy-proven LCDD was studied by Wechalekar et al. [8] sFLCs were abnormal with a clonal bias in 15 (88%): 11 (64%) had κ excess, 4 (23%) had λ excess while 2 (11%) had polyclonal increased FLCs. The median κ levels were 317mg/L (range 8.5-2,260) while the median λ levels were 64mg/L (range 17- 10,700).

A total of 10 patients received systemic chemotherapy for the underlying plasma cell dyscrasias as follows:- VAD - 4, C-VAMP - 1, VAD followed by autologous stem cell transplant - 2, melphalan and prednisone - 1 and intermediate dose melphalan - 2. 8 (80%) patients had sFLC responses with a median decrease of 63% (range 31 - 95%) compared with pre-treatment values. One 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 normalization of FLC levels. Renal function improved in 2, remained unchanged in 5 (including 3 patients with end-stage renal failure) and worsened in 1 patient. Both patients with abnormal liver function and cardiac involvement showed improvement. The median overall survival was 59 months.

The authors concluded that measurement of sFLCs detected 33% more patients with LCDD than SPE and IFE. The assay was also useful for monitoring response to treatment. Detection of abnormal sFLCs may shorten time to diagnosis in patients without monoclonal intact immunoglobulins. Measurements of FLCs was recommended as a useful addition to the screening tests for patients with suspected LCDD and also for monitoring responses to chemotherapy [9].

Hassoun et al. [10], 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 PBSCT with good responses that could be monitored with sFLCs.

It is important to note that patients with chronic kidney disease due to deposition of monoclonal FLCs are difficult to identify and monitor [11][12]. 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.

Clinical case history No 9

Clinical case history No 9. Light chain deposition Light chain deposition disease monitored with serum FLC 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 140mL/min and urinary protein quantification was 2.4g/24 hours. A renal biopsy demonstrated normal histology and immuno-fluorescence tests. He was managed with a 120mg daily dose of frusemide and antihypertensives. Follow-up was initially uneventful with renal function remaining stable.

10 years later he presented with nephrotic syndrome. Serum biochemistry showed: creatinine 165µmol/L (NR 60-120µmol/L), albumin 33g/L (NR >40g/L), cholesterol 8.7mmol/L (NR <5.5mmol/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.

He 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 526.0mg/L (normal range 3.3 - 19.4mg/L), λ 64.6 mg/L (normal range 12.7 - 26.3mg/L) and κ/λ ratio 8.14 (normal range 0.26 - 1.65) (Figure 17.3). Subsequently he developed atrial fibrillation. A 24-hour tape showed irregularities in the atrial chamber and intermittent disruption of AV node conduction. He had a dual chamber pacemaker 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 67mL/min and a 24 hour urine protein leakage of 13.8g. In order to delay the need for dialysis he was treated with 3 cycles of VAMP chemotherapy (vincristine 0.4mg/day for 4 days, doxorubicin 9mg/m2/day for 4 days and methylprednisolone 1g/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 0.1g/L.

For the following year renal function remained stable but then the κ/λ ratio and serum creatinine concentrations began to increase again. He 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.

Figure 17.3 Monitoring of a patient with LCDD using sFLC assays (Courtesy of Ian Brockhurst, Leicester, UK).

Test Questions
  1. What proportion of patients with LCDD have raised serum FLCs?


Chapter 16 Back to Contents Page Chapter 18

References

  1. ↑ Solomon A, Weiss DT, Herrera GA. Light-chain deposition disease. In: Mehta J, Singhal S, eds. Myeloma, Informa Healthcare, 2002: 507 – 18
  2. ↑ Buxbaum JN, Chuba JV, Hellman GC, Solomon A, Gallo GR. Monoclonal immunoglobulin deposition disease: light chain and light and heavy chain deposition diseases and their relation to light chain amyloidosis. Clinical features, immunopathology, and molecular analysis. Ann Intern Med 1990; 112: 455 – 64 PMID: 2106817
  3. ↑ Buxbaum J, Gallo G. Nonamyloidotic monoclonal immunoglobulin deposition disease. Light-chain, heavy-chain, and light- and heavy-chain deposition diseases. Hematol Oncol Clin North Am 1999; 13: 1235 – 48 PMID: 10626147
  4. ↑ Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell AR, Kyle RA. Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem 2002; 48: 1437 – 44 PMID: 12194920
  5. ↑ Katzmann JA, Abraham RS, Dispenzieri A, Lust JA, Kyle RA. Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice. Clin Chem 2005; 51: 878 – 81 PMID: 15774572
  6. ↑ Guis L, Diemert MC, Ghillani P, Choquet S, Leblond V, Vernant JP, Musset L. The quantitation of serum free light chains: Three case reports. Clin Chem 2004; 50: F38a
  7. ↑ Brockhurst I, Harris KP, Chapman CS. Diagnosis and monitoring a case of light-chain deposition disease in the kidney using a new, sensitive immunoassay. Nephrol Dial Transplant 2005; 20: 1251 – 3 PMID: 15784642
  8. ↑ Wechalekar AD, Lachmann HJ, Goodman HJB, Bradwell AR, Hawkins PN. Role of serum free light chains in diagnosis and monitoring response to treatment in light chain deposition disease. Haematologica 2005; 90: 1414a
  9. ↑ Kuypers DR, Lerut E, Claes K, Evenepoel P, Vanrenterghem Y. Recurrence of light chain deposit disease after renal allograft transplantation: potential role of rituximab? Transpl Int 2007; 20: 381 – 5 PMID: 17326779
  10. ↑ Hassoun H, Rafferty BT, Flombaum C, D'Agati VD, Klimek VM, Cohen A, et al. High dose chemotherapy and autologous stem cell transplantation with melphalan in patients with monoclonal immunoglobulin deposition disease associated with Multiple Myeloma. Blood 2007; 110: 5113a
  11. ↑ Sanders PW, Herrera GA, Kirk KA, Old CW, Galla JH. Spectrum of glomerular and tubulointerstitial renal lesions associated with monotypical immunoglobulin light chain deposition. Lab Invest 1991; 64: 527 – 37 PMID: 1901926
  12. ↑ Pozzi C, D'Amico M, Fogazzi GB, Curioni S, Ferrario F, Pasquali S, et al. Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors. Am J Kidney Dis 2003; 42: 1154 – 63 PMID: 14655186
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