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Nephrotic syndrome in a patient with IgA deficiency-associated mesangioproliferative glomerulonephritis
Pathology (2000) 32, pp. 56– 58
NEPHROTIC SYNDROME IN A PATIENT WITH IgA DEFICIENCY-ASSOCIATED MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS MINA JOHN *, MINH LAM †, BRUCE LATHAM †, BARRY SAKER ‡
AND
MARTYN AH FRENCH *
Departments of *Clinical Immunology, †Pathology and ‡Nephrology, Royal Perth Hospital, Perth, Australia
Summary A case of mesangioproliferative glomerulonephritis in a 55-year-old woman with selective IgA deficiency and serum antinuclear antibodies who presented with nephrotic syndrome is described. The patient did not have clinical or laboratory features of systemic lupus erythematosus (SLE) other than antinuclear antibodies. Histology of the patient’s renal biopsy revealed a mesangioproliferative glomerulonephritis and direct immunofluorescence showed that paramesangial deposits contained predominant IgM with lesser IgG, C3 and C1q. These findings are identical to those previously described in a form of glomerulonephritis associated with IgA deficiency and would be atypical for lupus nephritis. Glomerulonephritis is not a well recognized complication of IgA deficiency, though it has been rarely reported in the literature. This case provides further evidence that IgA deficiency is associated with a unique immune complex-mediated glomerulopathy with characteristic immunopathological and ultrastructural features. It is the first reported case to present with nephrotic syndrome. Key words: IgA deficiency, mesangioproliferative glomerulonephritis , nephrotic syndrome. Accepted 28 September 1999.
INTRODUCTION Selective IgA deficiency may occur in up to 1:600 individuals, making it the most common primary immunodeficiency disorder.1 Aside from recurrent sinopulmonary infections and allergic disease, IgA deficient patients are predisposed to developing autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, celiac disease, hemolytic anemia and thyroiditis. Antinuclear antibodies and anti-DNA antibodies without evidence of clinical disease may also occur.1 Elevated levels of circulating immune complexes containing IgG and IgM have been documented in patients with selective IgA deficiency and these may mediate some cases of vasculitis, thyroiditis and polyarthritis.2 A form of glomerulonephritis has also been reported.3,4 Three previously reported cases of glomerulonephritis had mesangial proliferation and predominant glomerular IgM identified by immunofluorescence or immunoperoxidase techniques. A polyethylene glycol (PEG) precipitation method identified IgM containing immune
complexes in two of the three cases. Electron microscopy identified paramesangial deposits in all cases.3 It was proposed that elevated levels of IgM-immune complexes, possibly evoked by recurrent respiratory tract infections or an immune response against dietary bovine milk proteins, deposit in the glomeruli of IgA-deficient individuals.3,5 As the literature is sparse and limited to case reports or small series, the association of IgA deficiency with a unique form of glomerulonephritis has not been clearly established. We describe the clinical features and renal biopsy findings in a patient who presented with nephrotic syndrome and was found to have selective IgA deficiency.
CASE REPORT A 55-year-old woman with a past history of trigeminal herpes zoster infection and benign breast mass presented with ankle swelling and recurrent occipital headaches. She did not smoke, drink alcohol or take any medications. She was noted to be hypertensive (175/105 mmHg) and to have pitting edema of the ankles. Investigations showed normal creatinine, hypoalbuminemia (serum albumin 27 g/l, reference range 30–50 g/l), minor hematuria and nephrotic range proteinuria (7.82 g/day; reference range, 0.02–0.15 g/day). Measurement of serum immunoglobulins showed undetectable IgA but total IgG, IgG subclasses and IgM concentration s within the normal reference ranges. Her serum contained a high concentration of antinuclear antibodies (25 IU/l) with a homogeneou s pattern of immunofluorescence on Hep2000 cells but the serum concentration of anti-double-stranded DNA antibodies, C3 and C4 were normal. Antibodies to extractable nuclear antigens (ENAs) were not detected. Hepatitis B and C virus serology were negative. She was treated with antihypertensive medications with prompt resolution of headaches. A renal biopsy was performed when her blood pressure was controlled. The differential diagnosis included idiopathic membranous glomerulonephriti s or lupus membranous nephritis. Since biopsy, she has been asymptomatic, normotensive and has maintained normal renal function after 6 months of follow up. She has ongoing nephrotic range proteinuria (10 g/d).
PATHOLOGICAL FINDINGS Microscopic findings A 14 mm core of renal tissue showing cortex and medulla from the left kidney was obtained. Sixteen glomeruli were identified, not one of which was sclerosed. All the glomeruli showed a mild increase in both mesangial matrix and cellularity. Paramesangial deposits were seen with the trichrome stains. The tubulointerstitial pattern was normal. The blood vessels within the biopsy were normal (Fig. 1).
ISSN 0031–3025 printed/ISSN 1465– 3931 online/00/010056 – 03 © 1999 Royal College of Pathologists of Australasia
NEPHROTIC SYNDROME
57
Fig. 1 Glomerulus with increased mesangial matrix and cellularity (H&E, original magnification, ´ 100).
Fig. 3 Electron micrograph of glomerulus showing large, electron dense mesangial and paramesangial deposits (arrow) (original magnification, ´ 4086).
Immunfluorescence findings Ten m m sections of OCT embedded renal biopsy tissue were incubated with FITC-conjugated antibodies to polyclonal immunoglobulin (Silenus), IgG (Silenus), IgM (Silenus), IgA (Silenus), C3 (Silenus), C1q (Serotec) and fibrinogen (Silenus). The specimen contained five well-preserved glomeruli, all of which contained abundant, granular pattern IgM (Fig. 2), lesser IgG, C3 and scant C1q, all in a mesangial distribution. No glomerular IgA or fibrinogen was identified.
sional platelet aggregates were also seen. No subepithelial deposits were identified. Approximately 40% of podocyte processes were effaced (Fig. 3).
Electron microscopy findings The ultrathin section showed three glomeruli to be present. There was a moderate increase in mesangium due predominantly to an increase in mesangial cell processes. In addition, a number of relatively large electron dense deposits were present in a mesangial and paramesangial distribution. The endothelium was focally activated with endothelial blebbing and margination of leucocytes. Occa-
Fig. 2 Glomerulus stained with fluorescein-labelled anti-IgM antibody, showing abundant, mesangial IgM deposits (original magnification, ´ 25).
DISCUSSION The histopathology and ultrastructural findings in this case resemble IgA nephropathy, but with predominant IgM rather than IgA, as previously described in patients with selective IgA deficiency.3,4 Though the patient had antinuclear antibodies, the findings were not those of lupus nephritis, in which predominant IgG or polyclonal immunoglobulin is expected.6 The absence of serum antibodies to double-stranded DNA, and to ENAs, and normal complement levels, the absence of any other symptoms of lupus, and the benign clinical course without specific treatment also argue against SLE with nephritis in this patient. We propose that the renal lesion and serum antinuclear antibodies are both separate associations of selective IgA deficiency. Clearly, the recognition of a specific form of renal disease associated with IgA deficiency, distinct from lupus nephritis is important as the latter diagnosis may mandate immunosuppressive therapy and portend progression to renal failure. In contrast, IgA deficiency-associated glomerulonephritis may follow a benign course and not require therapy.3 Unlike all previous case reports in which patients presented with only minor urinary sediment abnormalities, 3,4 our patient presented with nephrotic syndrome. It may be that there is a spectrum of clinical presentations (as in IgA nephropathy) ranging from mild urinary sediment abnormalities to nephrotic syndrome or hypertension. Few cases of glomerulonephritis and IgA deficiency have been well characterized. Uniformity in the diagnostic label applied to this condition is also lacking. One previous case of a patient with IgA, IgG2 and IgG4 deficiency and identical renal biopsy histopathology and immunofluorescence findings to our case has been presented as a case of “IgM nephropathy”.4 The single case of membranous
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Pathology (2000), 32, February
JOHN ET AL.
nephropathy reported in an IgA-deficient patient may have represented lupus nephritis as the patient went on to develop clinical SLE.7 A case of minimal change glomerulonephritis and IgA deficiency has been reported.7 Other authors have referred to “mesangioproliferative glomerulonephritis”, “focal glomerulonephritis” or “glomerulonephritis” without detailing immunofluorescence or electron microscopy findings. Documentation of the immunopathological and clinical features of these and future cases would be useful in further characterizing this entity as a unique complication of IgA deficiency. Address for correspondence: Dr Mina John, Department of Clinical Immunology, Royal Perth Hospital, GPO Box X2213, Perth WA 6000
References 1. Burrows PD, Cooper MD. IgA Deficiency. Adv Immunol 1997; 65: 45–76. 2. Kwitko AO, McKenzie PE, Shearman DJ, et al. Circulating immune complexes in IgA deficiency. Clin Exp Immunol 1979; 38(1): 45– 51. 3. French MAH, Shortland JR, Coward RA, Brown CB. Glomerulonephritis and IgA deficiency. Clin Nephrol 1987; 27(4): 199–205. 4. Oymak O. IgM nephropathy in a patient with combined deficiency of IgA, IgG2 and IgG4. Clin Nephrol 1997; 47(3): 202–3. 5. van der Woude FJ, Hoedemaeker PJ, van der Giessen M, et al. Do food antigens play a role in the pathogenesis of some cases of human glomerulonephritis? Clin Exp Immunol 1983; 51(3): 587– 94. 6. Hricik DE, Chung-Park M, Sedor JR. Medical progress: glomerulone phritis. New Eng J Med 1998; 339(13): 888– 99. 7. Yewdall V, Cameron, Nathan AW, et al. Systemic lupus erythematosu s and IgA deficiency. J Clin Lab Immunol 1983; 10(1): 13– 8.
NEPHROTIC SYNDROME IN A PATIENT WITH IgA DEFICIENCY-ASSOCIATED MESANGIOPROLIFERATIVE GLOMERULONEPHRITIS MINA JOHN *, MINH LAM †, BRUCE LATHAM †, BARRY SAKER ‡
AND
MARTYN AH FRENCH *
Departments of *Clinical Immunology, †Pathology and ‡Nephrology, Royal Perth Hospital, Perth, Australia
Summary A case of mesangioproliferative glomerulonephritis in a 55-year-old woman with selective IgA deficiency and serum antinuclear antibodies who presented with nephrotic syndrome is described. The patient did not have clinical or laboratory features of systemic lupus erythematosus (SLE) other than antinuclear antibodies. Histology of the patient’s renal biopsy revealed a mesangioproliferative glomerulonephritis and direct immunofluorescence showed that paramesangial deposits contained predominant IgM with lesser IgG, C3 and C1q. These findings are identical to those previously described in a form of glomerulonephritis associated with IgA deficiency and would be atypical for lupus nephritis. Glomerulonephritis is not a well recognized complication of IgA deficiency, though it has been rarely reported in the literature. This case provides further evidence that IgA deficiency is associated with a unique immune complex-mediated glomerulopathy with characteristic immunopathological and ultrastructural features. It is the first reported case to present with nephrotic syndrome. Key words: IgA deficiency, mesangioproliferative glomerulonephritis , nephrotic syndrome. Accepted 28 September 1999.
INTRODUCTION Selective IgA deficiency may occur in up to 1:600 individuals, making it the most common primary immunodeficiency disorder.1 Aside from recurrent sinopulmonary infections and allergic disease, IgA deficient patients are predisposed to developing autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis, celiac disease, hemolytic anemia and thyroiditis. Antinuclear antibodies and anti-DNA antibodies without evidence of clinical disease may also occur.1 Elevated levels of circulating immune complexes containing IgG and IgM have been documented in patients with selective IgA deficiency and these may mediate some cases of vasculitis, thyroiditis and polyarthritis.2 A form of glomerulonephritis has also been reported.3,4 Three previously reported cases of glomerulonephritis had mesangial proliferation and predominant glomerular IgM identified by immunofluorescence or immunoperoxidase techniques. A polyethylene glycol (PEG) precipitation method identified IgM containing immune
complexes in two of the three cases. Electron microscopy identified paramesangial deposits in all cases.3 It was proposed that elevated levels of IgM-immune complexes, possibly evoked by recurrent respiratory tract infections or an immune response against dietary bovine milk proteins, deposit in the glomeruli of IgA-deficient individuals.3,5 As the literature is sparse and limited to case reports or small series, the association of IgA deficiency with a unique form of glomerulonephritis has not been clearly established. We describe the clinical features and renal biopsy findings in a patient who presented with nephrotic syndrome and was found to have selective IgA deficiency.
CASE REPORT A 55-year-old woman with a past history of trigeminal herpes zoster infection and benign breast mass presented with ankle swelling and recurrent occipital headaches. She did not smoke, drink alcohol or take any medications. She was noted to be hypertensive (175/105 mmHg) and to have pitting edema of the ankles. Investigations showed normal creatinine, hypoalbuminemia (serum albumin 27 g/l, reference range 30–50 g/l), minor hematuria and nephrotic range proteinuria (7.82 g/day; reference range, 0.02–0.15 g/day). Measurement of serum immunoglobulins showed undetectable IgA but total IgG, IgG subclasses and IgM concentration s within the normal reference ranges. Her serum contained a high concentration of antinuclear antibodies (25 IU/l) with a homogeneou s pattern of immunofluorescence on Hep2000 cells but the serum concentration of anti-double-stranded DNA antibodies, C3 and C4 were normal. Antibodies to extractable nuclear antigens (ENAs) were not detected. Hepatitis B and C virus serology were negative. She was treated with antihypertensive medications with prompt resolution of headaches. A renal biopsy was performed when her blood pressure was controlled. The differential diagnosis included idiopathic membranous glomerulonephriti s or lupus membranous nephritis. Since biopsy, she has been asymptomatic, normotensive and has maintained normal renal function after 6 months of follow up. She has ongoing nephrotic range proteinuria (10 g/d).
PATHOLOGICAL FINDINGS Microscopic findings A 14 mm core of renal tissue showing cortex and medulla from the left kidney was obtained. Sixteen glomeruli were identified, not one of which was sclerosed. All the glomeruli showed a mild increase in both mesangial matrix and cellularity. Paramesangial deposits were seen with the trichrome stains. The tubulointerstitial pattern was normal. The blood vessels within the biopsy were normal (Fig. 1).
ISSN 0031–3025 printed/ISSN 1465– 3931 online/00/010056 – 03 © 1999 Royal College of Pathologists of Australasia
NEPHROTIC SYNDROME
57
Fig. 1 Glomerulus with increased mesangial matrix and cellularity (H&E, original magnification, ´ 100).
Fig. 3 Electron micrograph of glomerulus showing large, electron dense mesangial and paramesangial deposits (arrow) (original magnification, ´ 4086).
Immunfluorescence findings Ten m m sections of OCT embedded renal biopsy tissue were incubated with FITC-conjugated antibodies to polyclonal immunoglobulin (Silenus), IgG (Silenus), IgM (Silenus), IgA (Silenus), C3 (Silenus), C1q (Serotec) and fibrinogen (Silenus). The specimen contained five well-preserved glomeruli, all of which contained abundant, granular pattern IgM (Fig. 2), lesser IgG, C3 and scant C1q, all in a mesangial distribution. No glomerular IgA or fibrinogen was identified.
sional platelet aggregates were also seen. No subepithelial deposits were identified. Approximately 40% of podocyte processes were effaced (Fig. 3).
Electron microscopy findings The ultrathin section showed three glomeruli to be present. There was a moderate increase in mesangium due predominantly to an increase in mesangial cell processes. In addition, a number of relatively large electron dense deposits were present in a mesangial and paramesangial distribution. The endothelium was focally activated with endothelial blebbing and margination of leucocytes. Occa-
Fig. 2 Glomerulus stained with fluorescein-labelled anti-IgM antibody, showing abundant, mesangial IgM deposits (original magnification, ´ 25).
DISCUSSION The histopathology and ultrastructural findings in this case resemble IgA nephropathy, but with predominant IgM rather than IgA, as previously described in patients with selective IgA deficiency.3,4 Though the patient had antinuclear antibodies, the findings were not those of lupus nephritis, in which predominant IgG or polyclonal immunoglobulin is expected.6 The absence of serum antibodies to double-stranded DNA, and to ENAs, and normal complement levels, the absence of any other symptoms of lupus, and the benign clinical course without specific treatment also argue against SLE with nephritis in this patient. We propose that the renal lesion and serum antinuclear antibodies are both separate associations of selective IgA deficiency. Clearly, the recognition of a specific form of renal disease associated with IgA deficiency, distinct from lupus nephritis is important as the latter diagnosis may mandate immunosuppressive therapy and portend progression to renal failure. In contrast, IgA deficiency-associated glomerulonephritis may follow a benign course and not require therapy.3 Unlike all previous case reports in which patients presented with only minor urinary sediment abnormalities, 3,4 our patient presented with nephrotic syndrome. It may be that there is a spectrum of clinical presentations (as in IgA nephropathy) ranging from mild urinary sediment abnormalities to nephrotic syndrome or hypertension. Few cases of glomerulonephritis and IgA deficiency have been well characterized. Uniformity in the diagnostic label applied to this condition is also lacking. One previous case of a patient with IgA, IgG2 and IgG4 deficiency and identical renal biopsy histopathology and immunofluorescence findings to our case has been presented as a case of “IgM nephropathy”.4 The single case of membranous
58
Pathology (2000), 32, February
JOHN ET AL.
nephropathy reported in an IgA-deficient patient may have represented lupus nephritis as the patient went on to develop clinical SLE.7 A case of minimal change glomerulonephritis and IgA deficiency has been reported.7 Other authors have referred to “mesangioproliferative glomerulonephritis”, “focal glomerulonephritis” or “glomerulonephritis” without detailing immunofluorescence or electron microscopy findings. Documentation of the immunopathological and clinical features of these and future cases would be useful in further characterizing this entity as a unique complication of IgA deficiency. Address for correspondence: Dr Mina John, Department of Clinical Immunology, Royal Perth Hospital, GPO Box X2213, Perth WA 6000
References 1. Burrows PD, Cooper MD. IgA Deficiency. Adv Immunol 1997; 65: 45–76. 2. Kwitko AO, McKenzie PE, Shearman DJ, et al. Circulating immune complexes in IgA deficiency. Clin Exp Immunol 1979; 38(1): 45– 51. 3. French MAH, Shortland JR, Coward RA, Brown CB. Glomerulonephritis and IgA deficiency. Clin Nephrol 1987; 27(4): 199–205. 4. Oymak O. IgM nephropathy in a patient with combined deficiency of IgA, IgG2 and IgG4. Clin Nephrol 1997; 47(3): 202–3. 5. van der Woude FJ, Hoedemaeker PJ, van der Giessen M, et al. Do food antigens play a role in the pathogenesis of some cases of human glomerulonephritis? Clin Exp Immunol 1983; 51(3): 587– 94. 6. Hricik DE, Chung-Park M, Sedor JR. Medical progress: glomerulone phritis. New Eng J Med 1998; 339(13): 888– 99. 7. Yewdall V, Cameron, Nathan AW, et al. Systemic lupus erythematosu s and IgA deficiency. J Clin Lab Immunol 1983; 10(1): 13– 8.