IgA Variant of Anti-glomerular Basement Membrane Glomerulonephritis Associated with Pulmonary Hemorrhage and Microangiopathic Hemolytic Anemia

Abstract

A 70-year-old man with uremia was referred because of hemoptysis. A chest X-ray showed diffuse infiltration in the right lung field. Laboratory data were remarkable for renal failure, anemia, and thrombocytopenia. Furthermore, laboratory evidence of microangiopathic hemolytic anemia was present. A kidney biopsy revealed diffuse crescentic glomerulonephritis with linear staining of IgA along the glomerular basement membrane (GBM). No thrombotic microangiopathy was noted on renal biopsy. Circulating IgG anti-GBM antibody was not detected, and IgA anti-GBM antibody was not tested. The patient was treated with plasmapheresis and pulse steroid therapy, which resulted in an immediate improvement in the pulmonary hemorrhage and hematological abnormalities. However, the patient did not regain renal function and remained on hemodialysis.

• anti-glomerular basement membrane disease
• IgA
• microangiopathic hemolytic anemia
• pulmonary hemorrhage

INTRODUCTION

Anti-glomerular basement membrane (GBM) disease is a rare but aggressive form of glomerulonephritis (GN) mediated by circulating autoantibodies reactive with the GBM. These antibodies bind in a linear pattern to the non-collagenous domain of the α3 chain of type IV collagen of GBM.¹ The immunoglobulins are almost exclusively of the IgG subtype. The occurrence of GN characterized by linear staining of non-IgG class immunoglobulin along the GBM is quite rare, with only 13 previously reported cases in the worldwide literature, including 11 IgA, 2 IgM, and 1 lambda light chain.^2–12 Herein, we report an unusual case of IgA anti-GBM disease presenting with rapidly progressive GN, pulmonary hemorrhage (PH), and microangiopathic hemolytic anemia (MAHA).

CASE REPORT

A 70-year-old man who had been diagnosed with uremia with undetermined cause and had begun hemodialysis for 3 months was referred to our hospital because of hemoptysis. He had a previous history of hypertension. Renal dysfunction was first detected at a local hospital in August 2010, with a serum creatinine level of 2.8 mg/dL. Urinalysis at that time showed hematuria and proteinuria. The second report of renal function test was recorded at the same hospital in March 2011, with a serum creatinine level of 4.0 mg/dL and urine protein-to-creatinine ratio of 2283 mg/g. The patient was lost to follow-up until he presented to another hospital in August 2011 because of uremia requiring renal replacement therapy (unavailable data of renal function test). Then, he was put into hemodialysis program. The patient was referred to our hospital in November 2011 with a 1-week history of hemoptysis. A chest X-ray showed diffuse infiltration in the right lung field (Figure 1). There was no fever, arthralgia, or skin lesion. The patient had clear consciousness. Crackles were heard in the right basal lung field. Laboratory studies revealed the following: white blood cell count of 5600/μL, hemoglobin of 6.4 g/dL, hematocrit of 18.1%, platelet count of 31,000/μL, corrected reticulocyte count of 4.1%, lactate dehydrogenase of 850 U/L, haptoglobin of <7.2 mg/dL, creatinine of 9.99 mg/dL, total protein of 5.1 g/dL, and albumin of 2.7 g/dL. Schistocytes were detected on peripheral smear. Prothrombin time and partial thromboplastin time were normal. Coombs’ tests were negative. The patient had been nearly anuric, and his urinalysis showed protein of 300 mg/dL and red blood cell of >100/high-power field. Serum complements C3 and C4 were 86.1 mg/dL (normal range 90–180 mg/dL) and 26.2 mg/dL (normal range 10–40 mg/dL), respectively. Serology was negative for antinuclear antibody, antineutrophil cytoplasmic antibody (ANCA), and IgG anti-GBM antibody (using indirect immunofluorescence). Tests for IgA anti-GBM were unavailable. Cryoglobulin was not detected. Microbiological studies of sputum specimens collected by spontaneous expectoration were negative for bacteria, fungi, and mycobacteria.

Figure 1. A chest X-ray on admission showing diffuse infiltration in the right lung field.

With a presumed diagnosis of pulmonary-renal syndrome, a kidney biopsy was performed on the 7th hospital day. The specimen contained 23 glomeruli, of which 18 were globally sclerotic. Of the remaining five viable glomeruli, three had fibrocellular crescents and two had fibrous crescents. No thrombotic microangiopathy was noted. Immunofluorescence studies revealed staining of IgA (2+) and IgG (1+) in a linear pattern along the peripheral capillary loops (Figure 2). Immunofluorescence staining was negative for IgM, C3, and C1q. No electron-dense deposits were identified on electron microscopy. The findings of renal biopsy suggested anti-GBM disease. The patient was treated with two sessions of plasmapheresis and pulse methylprednisolone (500 mg/day × 3 days) followed by oral prednisone (1 mg/kg/day) and oral cyclophosphamide (1 mg/kg/day), which resulted in an immediate improvement in the PH and hematological abnormalities. However, the patient did not regain renal function and remained on hemodialysis.

Figure 2. Immunofluorescence studies of renal biopsy showing 2+ staining of IgA in a linear pattern along the peripheral capillary loops.

DISCUSSION

Pulmonary-renal syndrome is defined as a combination of PH and GN. A variety of autoimmune disorders can cause this syndrome. Similar to the differential diagnosis of rapidly progressive GN, the immunopathology of pulmonary-renal syndrome comprises three major categories: anti-GBM antibody-mediated disease, which has a linear immunoglobulin deposits; immune complex-mediated diseases, which have granular immune deposits; and ANCA-associated diseases, which have a paucity of immune deposits. In our patient, the presence of significant IgA deposition in a linear pattern along the GBM suggested an anti-GBM antibody-mediated mechanism.

A rare form of anti-GBM GN mediated by IgA autoantibodies has been described in 11 reports that are reviewed and summarized in Table 1. Anti-GBM antibodies may be found in the circulation by indirect immunofluorescence or radioimmunoassay. However, the circulating anti-GBM antibodies may be transitory such that the antibodies are not always detected. Furthermore, standard assays for circulating anti-GBM antibodies are designed to detect only IgG. Therefore, serum containing a non-IgG class antibody would be reported as negative by standard assays, and IgA anti-GBM antibodies need to be tested separately. In addition, the specificity of IgA anti-GBM antibodies has seldom been characterized, and it is uncertain whether the epitope of α3(IV) collagen specific to IgG anti-GBM antibodies is the target. In previous reports, one patient with recurrent anti-GBM disease had a monoclonal IgA1-kappa antibody targeting collagenase-sensitive epitopes within α1/α2(IV) collagen,¹³ and another patient with crescentic GN and subepidermal blisters developed IgA autoantibodies against the α5 and α6(IV) collagen.¹¹

Table 1. Clinical and histological features of patients with IgA form of anti-GBM GN.

Case no. [reference]	Age (years)/gender	Renal biopsy findings	Hematuria  (RBC/HPF)	Proteinuria (g/day)	Creatinine at biopsy	C3/C4	Anti-GBM antibodies	Associated condition	Outcome
1 [2]	55/M	Focal necrotizing crescentic GN	Numerous	0.3	CCr 70	NI/NR	IgG(−), IgA(+)	PH	Dead of PH
2 [3]	55/M	Focal necrotizing crescentic GN	Numerous	Positive	11.1	NI/NR	IgG(+), IgA(−)	PH	Creatinine 1.9 mg/dL
3 [4]	NR	NR	NR	NR	NR	NR/NR	IgG(+), IgA(+)	NR	NR
4 [5]	13/M	Focal mesangial GN	Numerous	Negative	1.0	Low/low	IgG(−), IgA(NT)	None	Remission
5 [5]	76/F	Normal glomeruli	Negative	Negative	0.8	NI/NI	IgG(NT), IgA(−)	RCC	Nephrectomy
6 [7]	55/M	Thin basement membrane disease	Numerous	<0.2	CCr 105	NI/NR	IgG(−), IgA(+)	None	Persistent hematuria
7 [8]	62/M	Diffuse crescentic GN	Numerous	7.3	5.8	NI/NI	IgG(−), IgA(+)	None	ESRD
8 [9,13]	54/M	Focal segmental glomerulosclerosis	Numerous	1.4	1.2	NR/NR	IgG(−), IgA(+)	PH	ESRD^a
9 [10]	35/M	Focal necrotizing crescentic GN^b	Positive	5.2	20.0	Low/NI	IgG(−), IgA(NT)	Crohn’s disease	Dead of pneumonia
10 [11]	72/M	Diffuse crescentic GN	Numerous	6.2	5.6	NI/NI	IgG(+), IgA(+)	Blisters^c	ESRD
11 [12]	74/F	Focal necrotizing crescentic GN	Positive	1.5	1.25	NI/NI	IgG(−), IgA(+)	Lupus nephritis	Creatinine 1.13mg/dL
12 [our case]	70/M	Diffuse crescentic GN	Numerous	2.3	9.99	Low/NI	IgG(−), IgA(NT)	PH, MAHA	ESRD

Notes: GN, glomerulonephritis; RBC, red blood cell; HPF, high-power field; GBM, glomerular basement membrane; PH, pulmonary hemorrhage; RCC, renal cell carcinoma; MAHA, microangiopathic hemolytic anemia; ESRD, end-stage renal disease; NR, not reported; NI, normal; NT, not tested.

^aRecurrent anti-GBM disease presenting with crescentic GN and PH after kidney transplantation.

^bPostmortem diagnosis by autopsy.

^cSkin lesions characterized by recurrent, diffuse, pruritic, and sometimes vesicular eruptions.

The spectrum of renal manifestations in IgA anti-GBM GN ranges from isolated hematuria with normal renal function to rapidly progressive renal failure requiring renal replacement therapy. Hypocomplementemia was present in two of nine patients with available data. There is also a broad spectrum of glomerular histological findings in IgA anti-GBM GN, including normal glomeruli,⁵ focal mesangial GN,⁵ thin basement membrane glomerulopathy,⁷ focal segmental glomerulosclerosis,⁹ focal necrotizing and crescentic GN,^2,3,10,12 and diffuse crescentic GN.^8,11

Organ damage in anti-GBM disease can be confined to the kidneys, the lungs, or both. In the classic IgG form of anti-GBM disease, the spectrum of clinical presentations ranges from isolated renal disease without overt pulmonary involvement in approximately 35% of patients to PH without renal involvement in <5% of patients, and PH accompanies GN in approximately 60% of patients. There have been reports of four cases, including ours, of IgA anti-GBM disease with pulmonary involvement, of which all concomitantly had clinical signs of renal involvement.^2,3,9

MAHA has been reported also in association with anti-GBM disease.^14,15 Stave et al.¹⁴ reported a series of 12 patients with anti-GBM disease, of which 6 had clinical laboratory evidence of MAHA and 6 had histological evidence of thrombotic microangiopathy on renal biopsy. Notably, there were two patients who had MAHA alone without thrombotic microangiopathy on renal biopsy, as was the case with our patient. In some instances, anti-GBM disease coincided with thrombotic thrombocytopenic purpura.^16–18 It has been speculated that interleukin-12 might be involved in the common pathogenesis of both anti-GBM disease and thrombotic thrombocytopenic purpura.¹⁹

In conclusion, similar to the classic IgG form of anti-GBM disease, IgA variant of anti-GBM GN could be associated with PH. Early diagnosis of the disease responsible for pulmonary-renal syndrome is crucial because of the danger of irreversible loss of renal function or mortality from fulminant PH, which could be prevented in many cases by appropriate treatment. Furthermore, we describe the first case of IgA anti-GBM disease concomitant with MAHA.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.