Premature ageing and glomerulonephritis

Nicola Joss1,, J. Michael Boulton-Jones1 and Ian More2

1 Renal Unit, Glasgow Royal Infirmary, 2 Pathology Department, Western Infirmary, Glasgow, UK

Keywords: acquired cutis laxa; complement; mesangiocapillary glomerulonephritis; multiple myeloma; paraprotein



   Introduction
 Top
 Introduction
 Case
 Discussion
 References
 
We present a case of a 37-year-old man with multiple myeloma, acquired cutis laxa, complement activation, and renal disease. The acquired form of cutis laxa may be associated with multiple myeloma, SLE, and coeliac disease [17]. Multiple myeloma can result in various types of renal disease, most commonly cast nephropathy, but also AL amyloid and light-chain-deposition disease, all of which have characteristic appearances on renal biopsy. Multiple myeloma is rarely associated with complement activation. As far as we know, this case, in which all conditions were present, is unique.



   Case
 Top
 Introduction
 Case
 Discussion
 References
 
A 37-year-old man presented to our renal unit with a 6-month history of a changing skin appearance accompanied by a 2-month history of ankle swelling and shortness of breath. His only past medical history was of oesophagitis, for which he was taking omeprazole. He was taking no other medications. He had no significant family history. On examination he looked very much older than his years, with marked sagging of his skin due to loss of elastic recoil, particularly affecting his face and abdomen (Figure 1Go). There was no associated skin rash. He had marked peripheral oedema, BP 180/100 mmHg. Urinalysis showed 4+ protein and 3+ blood.



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Fig. 1. Appearance of the patient aged 38.

 
Initial investigations revealed a haemoglobin of 9.9 g/dl with a normal WBC and platelet count. Serum creatinine was 280 µmol/l, blood urea was 6.9 mmol/l, other electrolytes including adjusted calcium were normal. Serum albumin was low at 25 g/l and 24-h urine albumin excretion was 6.1 g in keeping with nephrotic syndrome. IgA was 1.3 g/l, IgM 0.5 g/l, and IgG 3.9 g/l; serum electrophoresis revealed a paraprotein <5 g/l in the mid gamma region, which was composed of lambda light chains. The same paraprotein was identified in the patient's urine. A bone marrow trephine identified 30% plasma cells most of which secreted lambda light chains. C3 was 0.59 g/l (0.88–1.82) and C4 0.21 g/l (0.19–0.45) with gross elevation of C3d, consistent with alternative complement pathway activation. CH50 was low and C3 nephritic factor was not found. Hepatitis C virus, hepatitis B surface antigen, cryoglobulins, ANA, and anti-dsDNA were negative.

We proceeded to renal biopsy. On light microscopy (LM), all 23 glomeruli were abnormal. The main feature was of marked mesangial prominence, which in some areas gave on accentuated lobular appearance. Neither crescents nor casts were identified. Amyloid stains were negative. These changes were consistent with a LM appearance of mesangiocapillary glomerulonephritis. Immunofluorescence (IF) studies revealed strong granular mesangial and linear staining of the capillary loops and tubular basement membranes with lambda light chains. It also showed strong mesangial and, to a lesser extent, capillary loop staining for C3. Electron microscopy (EM) showed mesangial interposition, the presence of fibrillary material in the mesangial and subendothelial areas, and particulate granular material in the tubular basement membranes and, to a lesser extent, the glomerular capillary loop basement membranes (Figure 2Go). The diameter of the fibrils was 14–21 nm and were identified as laminin by immunoperoxidase staining. Electron-dense subendothelial and mesangial immune complexes were not identified.



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Fig. 2. Electron microscopy: subendothelial and mesangial deposits. Arrow shows the main area of fibrillary deposits. Measurement bar 10 mm=700 nm.

 
Multiple myeloma was treated with idarubicin and dexamethasone and the patient was given diuretics and hypotensive agents. Ten months later the paraprotein could not be identified in his serum and a repeat bone marrow showed no excess plasma cells. His C3 had risen to 0.72 g/l and his C3d level had reduced but was still detectable. However, the patient remained nephrotic, had progressive renal failure, and required dialysis 8 months after presentation. Six months later, his urine output increased, his predialysis creatinine started to fall and dialysis was withdrawn, and his renal function has stabilized with a creatinine of 300 µmol/l. There had been no change in his appearance.



   Discussion
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 Introduction
 Case
 Discussion
 References
 
This man has a clinical diagnosis of acquired cutis laxa syndrome. Investigations revealed lambda light-chain myeloma with light-chain deposition in the kidney. Alternative complement pathway activation was present and complement deposition was also found in the glomerulus.

Acquired cutis laxa is a rare condition that can be diagnosed both clinically and by skin biopsy, which characteristically shows elastic fibre fragmentation. It results in sagging of the skin with loss of elastic recoil. Abnormalities may also be found in the pulmonary, gastrointestinal and urogenital systems. It is a rare condition and a literature search found only 59 cases. It is generally reported as an isolated finding or following a drug or urticarial reaction. However, it has been reported in seven patients with multiple myeloma or paraproteinaemia and occasionally occurs with other systemic diseases including SLE and coeliac disease [17]. The features of patients with cutis laxa and paraproteinaemia are shown in Table 1Go, which also includes a case of acquired cutis laxa, nephrotic syndrome with alternative-pathway complement activation and mesangiocapillary glomerulonephritis. It is not clear in this case whether screening for a paraprotein was performed, although the diagnosis was unlikely because IgA and IgM were normal and IgG was slightly low at 4.75 g/l, which could be the result of nephrotic syndrome itself [8].


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Table 1. Features of patients with cutis laxa renal disease, and paraproteinaemia

 
Unfortunately, in the majority of previous reports of multiple myeloma and cutis laxa, complement levels were not recorded and renal function and urinary abnormalities were not discussed in detail and, if renal abnormalities were detected, a renal biopsy was not performed. In the case report where normal C3 and C4 were found [2], specific tests for complement activation were not performed and normal C3 and C4 levels do not exclude complement activation.

We, therefore, present a unique patient with multiple myeloma, light-chain nephropathy, alternative-pathway complement activation, and acquired cutis laxa syndrome. The likely mechanism for connecting these diagnoses is that the light chains activated complement via the alternative pathway. This has been described previously in a patient with hypocomplementaemic mesangiocapillary glomerulonephritis associated with multiple myeloma [9]. The lambda light chain in this patient was found to activate the alternative complement pathway by reacting with factor H, thus preventing the stabilization of C3 convertase, resulting in persistent alternative complement pathway activation. IF showed intensive coarse granular deposits of C3 in mesangium and capillary walls, and EM revealed intramembranous, subendothelial and mesangial deposits. Another example found multiple myeloma in association with a C3 nephritic-factor-like activity in the patient's serum [10]. In this case a renal biopsy showed proliferative glomerulonephritis with marked C3 deposition in the mesangium and glomerular basement membrane and subendothelial, intramembranous, subepithelial, and mesangial deposits by EM. Our patient's complement levels returned to normal at the same time as the paraprotein could no longer be detected, suggesting the link between complement activation and light chains.

There are obvious similarities to partial lipodystrophy, complement activation, C3 nephritic factor, and MCGN type II. In these cases, complement activation predates the renal disease and is likely to cause the damage to adipose tissue. Perhaps in our patient, complement activation (caused by the paraprotein) damaged elastin production or elastic tissue directly. In a previous case of acquired cutis laxa, C3 and C1q deposits were found by IF examination of a skin biopsy [4]. Complement activation may have contributed to the development of glomerular disease, as complement activation is associated with subendothelial and intramembranous deposits of various types.

To summarize, light-chain excess caused complement activation by the alternative pathway, which may have facilitated the development of an atypical MCGN. It is likely that the light chain has caused destruction of elastin either directly or indirectly through complement activation.



   Notes
 
Correspondence and offprint requests to: Nicola Joss, Renal Unit, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 O5F, UK Back



   References
 Top
 Introduction
 Case
 Discussion
 References
 

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  9. Meri S, Koistinen V, Miettinen A et al. Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis. J Exp Med1992; 175: 939–950[Abstract]
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Received for publication: 14. 4.00
Revision received 24. 7.00.



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