1 Division of Nephrology 2 Division of Haematology, University of Roma `La Sapienza', Italy
Sir,
The hypothesis that a polyclonal B cell expansion, triggered by an antigenic stimulus, could in some cases switch over to a lymphoproliferative disorder, has been advanced in various reports [14]. Though IgA nephropathy is a frequent disorder, to our knowledge cases raising the possibility of a causal relationship with a developing IgA myeloma have not been previously reported.
Case.
A 56-year-old woman was referred to our hospital because of progressive dyspnea, advanced renal insufficiency and severe hypertension.
At the age of 24 she experienced a short-lived episode of gross haematuria accompanied by a febrile illness and dull loin pain. In this occasion the patient's blood pressure was 115/60 mmHg and BUN was 13 mg/dl. On intravenous pyelography the kidneys, ureters and bladder appeared normal. Macroscopic haematuria recurred 1 year later; the diagnosis of `sympharyngitic nephritis' was made and tonsillectomy was performed. In the following years numerous urinalysis showed persistent microscopic haematuria.
At 49 years of age serum creatinine was 1.1 mg/dl and BUN 16 mg/dl; microscopic haematuria was still present.
At the age of 51 BUN was 30 mg/dl and serum creatinine 2.5 mg/dl, Hb 9.5 g/dl, total serum protein 7 g/dl. Urinalysis: protein +, Hb ++; microscopic haematuria was still present. Blood pressure was 160/105 mmHg. At this time neither serum immunoglobulin or immuno-electrophoresis were recorded. Antihypertensive therapy was initiated.
At 54 years of age, increasing weakness developed associated with anorexia. Her blood pressure was 160/110; BUN 56 mg/dl, serum creatinine 3.5 mg/dl, Hb 9.5 g/dl, total serum protein 7 g/dl, albumin 52%, 1 2%,
2 6%, ß 33%,
8.5% with a monoclonal spike in ß; serum immunoglobulin; IgG 732 mg/dl (n.v. 8001800), IgA 2770 mg/dl (n.v. 90450), IgM <28 mg/dl (n.v. 70280); serum protein immuno-electrophoresis identified a monoclonal dimeric IgA
protein; serum calcium was 10 mg/dl, serum uric acid 7 mg/dl; urinalysis: Hb ++, protein +; the urinary sediment contained 1015 red cells per high power field. BenceJones proteinuria was negative. Bone marrow biopsy showed 7% plasma cells. Chest roentgenogram was normal. A complete X-ray survey was negative for lytic bone lesions. Ultrasonography demonstrated small kidneys with reduced cortex/medulla ratio.
A diagnosis of plasma cell dyscrasia of unknown significance was made at that time. Eight months before admission, blood pressure was 170/110 mmHg; BUN 79 mg/dl, serum creatinine 7.4 mg/dl; Hb 6.4 g/dl; the serum protein level was 8.4 g/dl; the presence of a monoclonal dimeric IgA protein was confirmed on serum immuno-electrophoresis; urinary protein +, Hb ++, the sediment contained 3040 red cells per high power field, hyaline and granular casts; BenceJones proteinuria was positive.
On admission blood pressure was 210/120 mmHg. The physical examination revealed a pale, dyspnoic woman with ++ peripheral oedema. Laboratory tests demonstrated: serum creatinine 13.4 mg/dl, BUN 135 mg/dl, Ca 7.94 mg/dl, P 5.8 mg/dl, Hb 5.9 g/dl, WBC 1770 cu mm, Platelets 57000 cu mm; total serum protein 6.5 g/dl; IgG 318 mg/dl (n.v. 8001600), IgA 1900 mg/dl (n.v. 90490), IgM 13 mg/dl (n.v. 50150). Urine was positive for protein + and Hb ++. Protein immuno-electrophoresis identified a serum dimeric IgA monoclonal protein and a monoclonal
light chain in the urine. A bone marrow biopsy showed 28% plasma cells. A complete skeletal X-ray demonstrated diffuse bone demineralization, without osteolytic lesions. Renal ultrasonography showed bilateral shrunken kidneys. The diagnosis was multiple myeloma IgA
and ESRD. Haemodialytic treatment was started with antihypertensive therapy and melphalan plus prednisone were initiated.
Two years later the patient was fairly well on chronic haemodialytic treatment, her blood pressure had returned to normal, and melphalan and prednisone therapy was continued under haematological supervision.
Comment.
A definite diagnosis of IgA glomerulonephritis can only be made when a renal biopsy including immunofluorescence are available. Nevertheless the history of this patient suggests the presence of IgA-GN. At the time of the diagnosis of sympharyngitic nephritis was made (1964), IgA nephropathy had not yet been identified by Berger and Hinglais [5].
A case of HenochSchönlein nephritis associated with IgA monoclonal gammopathy has been reported by Dosa et al. [6]. Droz et al. have reported a case of IgA nephropathy associated with an increase in polyclonal IgA and a monoclonal IgA
in the serum, with only monoclonal IgA
deposition in the kidney [7]; both authors interpreted the occurrence of IgA nephropathy as secondary to the IgA monoclonal gammopathy.
In our patient, the history of persistent haematuria for 30 years before the identification of a monoclonal gammopathy, seems to suggest a different pathogenetic relationship between a polyclonal disorder and an IgA monoclonal gammopathy which terminated with clinically overt IgA myeloma.
IgA-GNF is a relatively common disorder, with a prevalence of 12 in 1000. The possibility that monoclonal gammopathy should have been present for 24 years is unlikely. In patients older than 50 years, the time when it was recognized in our patient, monoclonal gammopathy is present in 1% of the population and the IgA type in 0.1%. Thus the probability that the events might have occurred independently in the same patient is 1:909000 or 454000, respectively. The yearly incidence of multiple myeloma is around 30 per 100000 in the age group over 25, and the serum M component will be IgA in 20%, resulting in a probability of 1:17000000 or 1:8500000 that the two diseases are casually associated.
A number of human and murine myeloma proteins exhibiting various antibody activity have been documented over the past several years [1,2]; it seems likely that, at least in some cases, the myeloma protein is the product of a persistingly stimulated clone of cells already participating in an immune polyclonal response going on at the time when the neoplastic transformation occurred.
Noteworthy, more recently it has been hypothesized that in some patients who are infected with HCV, an initial polyclonal B lymphocyte activation might switch to abnormal proliferation of a clone of B cells producing a monoclonal IgM rheumatoid factor responsible for Type II mixed cryoglobulinaemia [3,4,8,9], which in a minority of cases ends in overt B-cell malignancy [10].
In the present case we hypothesize that (i) the dimeric IgA, which characterized the myeloma, might be related to pre-existing IgA nephropathy, and that (ii) the development of the malignant clone was possibly triggered by recurrent exposure to some antigen implicated in IgA stimulation.
References