Light chain deposit disease: a frequent cause of diagnostic difficulty

Clive L. Hall1, and Danielle S. Peat2

1 Department of Nephrology, Royal United Hospital, Bath and 2 Department of Histopathology, Southmead Hospital, Bristol, UK

Keywords: LCDD; monoclonal gammopathy; nodular glomerulosclerosis; TBM thickening; diagnostic difficulty

Introduction

Light chain deposit disease (LCDD) [1] is an uncommon monoclonal gammopathy which should be considered carefully in patients who have both renal disease and a lymphoplasmacytic disorder capable of producing monoclonal light chains—myeloma, macroglobulinaemia, lymphoma, chronic lymphatic leukaemia [24]. The diagnosis is straightforward when monoclonal light chains are present in the serum and/or urine and the renal biopsy shows characteristic morphological changes and stains clearly for kappa or lambda light chains. The diagnosis of LCDD is often difficult as patients may not have a known or demonstrable lymphoplasmacytic disorder [35], monoclonal light chains may be detectable only intermittently and at low concentrations in the serum and/or urine [3,4,6] and the demonstration of light chains in the renal biopsy may be difficult even with specific monoclonal light chain antibodies due to high non-specific background staining [7]. We wish to report a patient who presented these diagnostic difficulties.

Case

In April 1996 a 67-year-old caucasian lady was referred with a 2-year history of lethargy, 3 months of spontaneous bruising, a mild thrombocytopenia and a raised creatinine. The patient smoked 15 cigarettes per day and was receiving simvastatin 10 mg daily for hypercholesterolaemia. Otherwise the history was negative with no personal or family history of renal disease, hypertension or diabetes mellitus.

Physical examination was normal except for 2+ microhaematuria and 2+ proteinuria on labstix urinalysis. In particular her BP was 122/78 mmHg, fundoscopy was normal and there was no hepatosplenomegaly, lymphadenopathy or purpura.

The abnormal investigations were a serum creatinine of 198 µmol/l, creatinine clearance 38 ml/min, urinary protein concentration 0.41 g/l, a platelet count of 96x109/l and an immunoparesis (IgG 4.7, IgA 0.4, IgM 0.2 g/l). The haemoglobin was 11.6 g/dl, WBC 4.7x109/l and viscosity 1.60 mpas and other investigations were negative or within normal limits including serum electrolytes, liver and thyroid function tests, blood sugar, rheumatoid factor, ANF, ANCA and DNA binding antibodies, cryoglobulins, HBsAg, serum and urine paraprotein, MSSU, urinary cystology, INR and KCCT. Chest X-ray and abdominal ultrasound were normal and a percutaneous renal biopsy was performed uneventfully.

The renal biopsy (Figure 1Go, 18 glomeruli) revealed both diffuse and nodular glomerulosclerosis with increased mesangial matrix, extensive interstitial fibrosis (IF) and tubular atrophy (TA) with thickening of the tubular basement membrane (TBM) and arteriolar hyalinosis. The glomerular nodules were non-argyrophilic and not characteristic of diabetes (Figure 1Go). Immunohistochemistry was negative for immunoglobulins and complement and electronmicroscopy (EM) revealed nodular expansion in the mesangial matrix with entrapped mesangial cell nuclei but no amyloid fibrils or paracrystalline structures (Figure 2Go).



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Fig. 1. Glomerulus showing increase in matrix with non-argyrophilic nodules expanding the mesangium (PA silver, original magnification x400).

 


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Fig. 2. Nodular electron dense areas in mesangium consistent with LCDD (electronmicroscopy, original magnification x1950).

 
The differential diagnosis of nodular glomerulosclerosis includes diabetes mellitus, amyloidosis, cryoglobulinaemia and LCDD. Diabetes was excluded by a normal blood sugar, HbA1c and glucose tolerance test; amyloid by the absence of Congo red staining or amyloid fibrils in the biopsy and cryoglobulinaemia by the lack of circulating cryoglobulins or paracrystalline glomerular deposits. The renal biopsy, therefore indicated LCDD but did not stain convincingly for kappa or lambda light chains. Repeat serum immunoelectropheresis (IEP) confirmed an immunoparesis but did not reveal a monoclonal band. However, repeat IEP of four urine specimens identified low concentrations of monoclonal kappa light chains in two specimens at 2.8 and 5.6 mg/mmol of creatinine, the equivalent of 15 mg/l and 30 mg/l respectively. On bone marrow aspiration and biopsy the plasmacytoid cells were increased to 8% with a significant decrease in the other stem cell lines. CT scans of chest and abdomen and a skeletal survey were normal. Thus, the diagnosis was LCDD due to monoclonal gammopathy of unknown significance with low-grade kappa light chain proteinuria.

During the investigation period the serum creatinine increased to 288 µmol/l and the creatinine clearance declined to 16 ml/min. Treatment was started with cycles of vincristine, adriamycin and dexamethasone at monthly intervals for four months followed by prednisolone and melphalan at monthly intervals for 18 months. At follow-up 3 years after the start of treatment the patient is well with a serum creatinine of 144 µmol/l, creatinine clearance 36 ml/min, haemoglobin 13.3 g/dl, platelet count 83x109/l and with no detectable light chains in the serum or urine.

Discussion

Although LCDD is a systemic disease with frequent cardiac, hepatic and gastrointestinal involvement patients usually present with the nephrotic syndrome (NS) or asymptomatic proteinuria with renal impairment which may be progressive and rapidly so in some cases [46]. The renal biopsy reveals nodular glomerulosclerosis in some 50% of the nephrotic patients and 25% of the non-nephrotic patients [6]. Most of the remaining biopsies show changes similar to MCGN but without Ig or C deposits and 10% show only mesangial changes [3,6]. Thickening of the TBM is a characteristic feature of LCDD [3,6]. The diagnostic histological finding on immunohistochemistry is the deposition of a single light chain isotype (kappa in 80% of cases) in the glomerular capillaries and nodules and along Bowmans capsule and the TBM [48]. Immunohistochemistry for kappa and lambda light chains may yield false-negative results or be difficult to interpret due to high background staining [7,9]. Other diagnostic difficulties are that the monoclonal light chains may be present in the serum and/or urine only intermittently and at low concentrations and some 40% of patients with LCDD do not have a demonstrable lymphoplasmacytic disorder even when followed up for periods of 2–17 years [3,4]. EM may be helpful demonstrating granular EDD in the mesangium and in all renal basement membranes [3,4,5]. Thus both the clinical and histological diagnosis of LCDD require a high degree of suspicion.

Although the median survival time from diagnosis is some 18 months [4], there is evidence that chemotherapy, especially if started early, slows progression to chronic renal failure as in our patient and postpones death from the extra renal manifestations of LCDD and from the underlying lymphoplasmacytic disorder [3]. The 1-year survival on haemodialysis of patients with chronic renal failure due to LCDD is some 20% and a few patients have received kidney transplants with occasional long-term survivors and with recurrence of LCDD in the kidney transplant [10].

Thus, LCDD should be considered routinely in the differential diagnosis of patients with the nephrotic syndrome or chronic renal impairment whose biopsies show nodular glomerulosclerosis with thickening of the TBM, especially when there is evidence of a lymphoplasmacytic disorder. The diagnosis should be confirmed or excluded by repeated IEP or immunofixation of serum and concentrated urine specimens for monoclonal light chains, histological examination with immunostaining of the bone marrow, lymphoid tissue and the renal biopsy for kappa and lambda light chains.

Notes

Correspondence and offprint requests to: C. L. Hall, Department of Nephrology, Royal United Hospital, Bath BA1 3NG, UK. Back

References

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Received for publication: 13. 1.01
Revision received 7. 2.01.