Marfan Syndrome, MPGN, and Bacterial Endocarditis

Case Report 

Kidney Biopsy 

Light Microscopy 

There were 25 glomeruli present in 2 cores, of which 2 glomeruli were globally sclerosed. Glomeruli showed moderate mesangial expansion with increased mesangial matrix and cellularity, and there also was segmental endocapillary proliferation with both mononuclear and polymorphonuclear leukocytes. Capillary walls were thickened with subendothelial expansion by cellular elements and new basement membrane formation, resulting in double contours (Fig 1). The changes resulted in lobular accentuation of glomerular tufts. There was no evidence of crescents, fibrinoid necrosis/karyorrhexis, or thrombosis. The interstitium showed few focal infiltrates, and there was mild tubular atrophy and interstitial fibrosis. Arteries and arterioles showed mild sclerosis of the intima. There was no evidence of arteritis.

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Figure 1. Periodic acid–Schiff–stained section shows a hypercellular glomerulus with mesangial expansion, lobular accentuation, and double contours (original magnification ×20).

Immunofluorescence Microscopy 

Two glomeruli showed granular staining for immunoglobulin G (1+/3+; Fig 2A) and C3 (2+/3+; Fig 2B) along glomerular capillary walls. The remaining immunoglobulins were negative.

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Figure 2. Immunofluorescence microscopy shows (A) immunoglobulin G (IgG; 1+/3+) and (B) C3 (2+/3+) along capillary walls (original magnification ×40).

Electron Microscopy 

There were 3 glomeruli present. Ultrastructural examination of glomeruli showed prominent leukocyte infiltration of glomerular capillaries (Fig 3). Few glomerular capillaries showed subendothelial expansion by electron-dense deposits, cellular elements, and new basement membrane formation, resulting in double contours. Subepithelial and intramembranous deposits were not present. Endothelial cells showed swelling and loss of fenestrations and did not contain tubuloreticular structures. The mesangium was expanded by matrix and mononuclear cells. Electron-dense deposits were not seen in the mesangium.

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Figure 3. Electron microscopy shows prominent leukocyte accumulation and double contours along the glomerular capillaries (original magnification ×1,400).

Discussion 

We present a case of chronic kidney disease in a patient with Marfan syndrome who developed secondary MPGN from an underlying undetected bacterial endocarditis. To the best of our knowledge, MPGN has not been described in patients with Marfan syndrome, although this is unusual because patients with valvular defects are predisposed to bacterial endocarditis and therefore secondary MPGN. Marfan syndrome is a genetic disorder of elastic connective tissue, usually associated with a mutation in the gene for fibrillin 1, a chief component of elastic tissue. Patients usually show a characteristic phenotype of disproportionately long legs, long arms, and large hands (arachnodactyly) and often have hypermobile joints. Other findings, when they appear, can occur in a variety of organ systems, but primarily involve the ocular and cardiac systems. Visual loss can occur, most commonly from lens dislocation. Chest pain may occur and should prompt an evaluation by means of echocardiography for ascending aortic aneurysm and dissection. Aortic regurgitation secondary to aortic root dilation can occur and, when severe enough, warrants surgical valve and aortic root repair. Mitral valve prolapse can occur.4 As with any patient with a known cardiac valvular abnormality, a patient with Marfan syndrome who develops such systemic symptoms as fever or vague aches and pains should be evaluated for endocarditis. Cardiac complications are the chief cause of morbidity in patients with Marfan syndrome.

Renal lesions previously described in patients with Marfan syndrome include focal and segmental glomerulosclerosis,5 aortic dissection with renal insufficiency,6 and an association with polycystic kidney disease.7 Although bacterial endocarditis is well described in patients with Marfan syndrome8, 9 and MPGN is a well-known complication of bacterial endocarditis (discussed later), MPGN was not described in patients with Marfan syndrome.

Bacterial endocarditis was associated with diffuse proliferative glomerulonephritis,10, 11 ANCA-positive crescentic glomerulonephritis,12, 13 and MPGN.14, 15 In one series that studied intravenous drug abusers, acute endocarditis was a common cause of glomerulonephritis in these patients.16 Bacterial endocarditis can also involve the interstitium, resulting in cortical infarction, acute interstitial nephritis, and acute tubular necrosis.

With regard to the organisms involved, blood cultures in our case grew Abiotrophia granulicatella, a nutritionally variant streptococcus. Nutrient-variant streptococcus refers to organisms within the genera Abiotrophia and Granulicatella. These organisms were once believed to be nutritional mutants of viridans group streptococcal strains because they require vitamin B16 for growth (as such, they will not grow on blood agar, but will only grow on chocolate agar). These organisms normally are found in oral flora, but were shown to be infrequently isolated opportunistic agents of infections in immunocompromised hosts. They were shown to be agents of endocarditis (both native and prosthetic valves), ophthalmic infections, brain abscess after neurosurgery, and iatrogenic meningitis after myelography.17

Although bacterial endocarditis is an important cause of secondary MPGN, other chronic bacterial infections also can result in MPGN. These include tuberculosis, meningococcal meningitis, brucellosis, and Mycoplasma pneumoniae infections. Chronic shunt infections also are a common cause of MPGN (shunt nephritis).18, 19 Bacteria associated with MPGN are listed in Table 1.

Table 1. Bacterial Infections Implicated in Membranoproliferative Glomerulonephritis

	Staphylococcusspecies20, 21, 22, 23
	Mycobacteriumtuberculosis24
	Streptococci23
	Propionibacteriumacnes25
	Mycoplasmapneumoniae26
	Brucellaspecies27
	Coxiellaburnetii10
	Nocardiaspecies28, 29
	Meningococcusspecies30

Bacterial endocarditis leads to persistent antigenemia and activation of the immune system. This in turn leads to chronic deposition of immune complexes in the subendothelial region of glomerular capillary walls. The subendothelial deposits could result from either in situ formation of immune complexes caused by deposition of the bacterial antigens or from preformed circulating immune complexes. Accumulation of subendothelial deposits is followed by complement activation and hence the prominent finding of C3 on immunofluorescence studies and low serum complement titers. The immune complexes and activated complement fragments (C3a and C5a) in turn attract leukocytes, and during the active phase of the process, the renal biopsy specimen often shows a proliferative/exudative picture,15 with ensuing endothelial and glomerular capillary wall injury. Subsequently, during the reparative phase the following changes occur: (1) endothelial and mesangial cells generate basement membrane–like material along with entrapment of immune complexes and cellular elements to form double contours, and (2) mesangial expansion occurs because of an increase in mesangial cellularity by mesangial cells and infiltrating mononuclear cells and increase in mesangial matrix.

In summary, bacterial infections are an important cause of MPGN, and a workup for an underlying chronic infection is imperative when the renal biopsy shows MPGN. Also, bacterial endocarditis should be in the differential diagnosis of renal failure in patients with Marfan syndrome, particularly when the renal biopsy shows MPGN. If clinically indicated, a low threshold should be maintained for drawing blood cultures and considering an echocardiogram as part of the workup of secondary causes of MPGN.