American Journal of Kidney Diseases
Volume 51, Issue 4 , Pages 697-701, April 2008

Marfan Syndrome, MPGN, and Bacterial Endocarditis

  • Peter Boseman, MD

      Affiliations

    • Department of Internal Medicine, Mayo Clinic, Rochester, MN
    • ,
  • Matthew Lewin, MD

      Affiliations

    • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
    • ,
  • John Dillon, MD

      Affiliations

    • Department of Internal Medicine, Mayo Clinic, Rochester, MN
    • ,
  • Sanjeev Sethi, MD, PhD

      Affiliations

    • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
    • Corresponding Author InformationAddress correspondence to Sanjeev Sethi, MD, PhD, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 1st St SW, Rochester, MN 55905.

Received 18 May 2007; accepted 28 August 2007. published online 04 March 2008.

Article Outline

Index Words: Kidney, Marfan syndrome, bacterial endocarditis, streptococci, membranoproliferative glomerulonephritis, MPGN

 

Marfan syndrome is an autosomal dominant connective tissue disorder characterized by ocular, skeletal, and cardiovascular manifestations. Cardiovascular manifestations include dilatation and dissection of the proximal aorta and mitral valve prolapse. Marfan syndrome is estimated to have a prevalence of 1 case/10,000 people, and at least 25% of cases occur in the absence of a family history, suggesting parental germ-line defects.1, 2, 3

Renal complications are uncommon in patients with Marfan syndrome. We describe a patient with Marfan syndrome with proteinuria and renal insufficiency. Renal biopsy showed membranoproliferative glomerulonephritis (MPGN) that led to the detection of an unsuspected systemic disease involving the kidney. In this report, we discuss one of the important secondary causes of MPGN.

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Case Report 

Clinical History 

A 72-year-old man with a history of Marfan syndrome presented to his primary physician with new-onset back pain, morning stiffness, and fevers. He previously had been well. An infectious workup initially suggested prostatitis, for which he was given a course of antibiotics. His symptoms persisted, and 3 months later, he was seen by rheumatology and started on prednisone therapy for suspected seronegative arthritis involving the spine. He did not respond and was given escalating doses of steroids in addition to sulindac. He developed fluid retention, but was losing weight. During the next 5 months, he lost 20 pounds and was extremely fatigued. He developed anemia with a hemoglobin level of 8.5 g/dL (85 g/L). Workup for gastrointestinal bleeding had negative results. He was referred to the rheumatology division of our institution for further evaluation.

Medical history was notable for mitral valve prolapse, 4.7-cm ascending aortic aneurysm with resultant aortic regurgitation, and mildly decreased ejection fraction (40%). Medications at the time of presentation at our institution included prednisone, 10 mg/d; spironolactone, 6.25 mg/d; furosemide, 200 mg twice daily; tamsulosin; acetaminophen; a calcium supplement; and glucosamine/chondroitin.

Physical examination showed a thin, frail, elderly gentleman. Vital signs were as follows: weight, 64 kg; temperature, 36.6°C; blood pressure, 141/63 mm Hg; heart rate, 73 beats/min; and body mass index, 21 kg/m2. He had a grade 2/6 diastolic murmur at the left sternal border. There was a trace of lower-extremity edema.

Laboratory workup showed the following values: hemoglobin, 8.5 g/dL (85 g/L); white blood cells, 10,800/μL (11 × 109/L; 84% polymorphonuclear neutrophils, 5% lymphocytes); mean corpuscular volume, 86.2; platelets, 123,000/μL (123 × 109/L); creatinine, 1.3 mg/dL (115 μmol/L), with estimated glomerular filtration rate of 57 mL/min/1.73 m2 (0.95 mL/s/1.73 m2); total protein, 4.7 g/dL (47 g/L); albumin, 2.5 g/dL (25 g/L); and aspartate aminotransferase, 19 U/L. A hepatitis panel was negative, cryoglobulins were negative, C3 level was 50 mg/dL (normal, 75 to 175 mg/dL [0.5 g/L]), C4 level was less than 3 mg/dL (normal, 14 to 40 mg/dL), perinuclear antineutrophil cytoplasmic antibody (ANCA) and cytoplasmic ANCA titers were negative, antinuclear antibody was negative, and anti–proteinase 3 level was increased at 92.4 EU/mL (normal, <5.0 EU/mL). Urinalysis showed greater than 100 red blood cells/high-power field, with greater than 25% dysmorphic; 31 to 40 white blood cells/ high-power field; occasional hyaline, granular, and fatty casts; and few bacteria. Twenty-four–hour urine collection showed 1,525 mg of protein.

Serum and urine electrophoresis results were negative for monoclonal proteins. Cerebrospinal fluid did not show evidence of infection. A computed tomographic scan of the chest, abdomen, and pelvis was unremarkable.

A nephrology consult was obtained for presumed glomerulonephritis. Because of increased proteinase 3 antibody levels and multisystem illness, renal biopsy was performed for suspicion of a possible pauci-immune ANCA-associated vasculitis.

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.

  • View full-size image.
  • 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.

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.

Diagnosis 

MPGN. The diagnosis included a comment to consider secondary causes of MPGN, including chronic infections.

Clinical Follow-up 

The renal biopsy report suggested secondary causes of MPGN, including chronic infections such as bacterial endocarditis. As a result of clinical history and renal biopsy results, blood cultures were obtained. Six of 6 cultures were positive for streptococci, suggesting bacterial endocarditis. The organism was identified as Abiotrophia granulicatella, a nutritionally variant streptococcus. Transesophageal echocardiogram showed significant aortic valve vegetation with evidence of valvular destruction. The patient was admitted to a local hospital for antibiotic therapy. He was started on antibiotic therapy for endocarditis and blood culture results eventually were negative. However, he was readmitted on several occasions for congestive heart failure exacerbations. He eventually underwent aortic valve replacement for complete aortic valve incompetence. Unfortunately, he never recovered from his surgery. He remained in the hospital for approximately 6 weeks postoperatively before he died.

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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.

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Acknowledgements 

The authors thank Cari R. Sloma, PhD, for help with description of the streptococci.

Support: None.

Financial Disclosure: None.

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References 

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 Originally published online as doi:10.1053/j.ajkd.2007.08.031 on February 29, 2008.

PII: S0272-6386(07)01663-0

doi:10.1053/j.ajkd.2007.08.031

American Journal of Kidney Diseases
Volume 51, Issue 4 , Pages 697-701, April 2008

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