Leal C. Herlitz M.D.

Columbia University Medical Center, New York, NY

Case Presentation

57 year-old Caucasian man with past medical history significant for hypertension, hyperlipidemia and coronary artery disease (status-post cardiac catheterization 6 months earlier) presents with progressive renal insufficiency and nephrotic range proteinuria.  The patient’s serum creatinine has doubled over the last year from a baseline of 1.5 to 3.1 mg/dl. Proteinuria has been noted for several months and is now nephrotic range at 7 g/24 hrs. Urinalysis shows 4+ protein and no red blood cells, leukocytes or casts. Serologic testing is negative or normal for hepatitis B and C antibodies, ANA and ANCA.  SPEP and UPEP reveal no evidence of a monoclonal spike.  Additional laboratory values include normal C3 and C4, hematocrit of 28% and albumin 3.7 g/dl. Physical examination reveals BP 160/80, no edema and no rash.

Pathology Diagnosis:

Atheroembolic renal disease, multifocal, severe.

Discussion

Atheroembolic renal disease (AERD) is an important part of the differential diagnosis of progressive renal insufficiency in older patients. The incidence of AERD is not well established. Autopsy series have reported incidences ranging from 0.8% to 77%, depending on the patient population. One retrospective analysis of all inpatient nephrology consultations showed a 4% incidence of clinically significant renal atheroembolism (see Mayo et. al.). Risk factors for AERD include age >55 years, hypertension, smoking, hypercholesterolemia, diabetes mellitus, and iatrogenic risk factors such as recent invasive medical procedures (angiography, vascular surgery etc.) or long-term anticoagulant or antithrombolytic therapy.  Importantly, renal atheroembolism has no identifiable iatrogenic cause in up to 25% of cases and should be considered in patients even without iatrogenic risk factors.

Clinical and laboratory features of patients with AERD are variable. Most commonly, patients present either with acute renal failure or acute on chronic renal failure. Atheroembolic disease often involves multiple organs including the skin, nervous system, eyes and gastrointestinal system.  Classically, cutaneous manifestations include livedo reticularis, infarcts of the nail beds and ischemic digits. Constitutional symptoms like fever and malaise may also be present and accompanied by elevated ESR, increased CRP and/or hypocomplementemia. Urinalysis can vary from bland sediment to microscopic hematuria and rarely even red cell casts. Proteinuria may be present and is usually mild, but may be nephrotic range (as in this case). Urinary or peripheral eosinophilia is sometimes present but is often transient and mild.

Due to the patient population and clinical manifestations, the most common entities in the differential diagnosis include systemic or renal vasculitis, bacterial endocarditis with thromboembolization, thrombotic microangiopathy (such as thrombotic thrombocytopenic purpura), acute tubular injury from ischemia, contrast nephropathy, hypertensive arterionephrosclerosis, renal artery stenosis and interstitial nephritis.

The renal biopsy diagnosis of AERD is relatively straight forward but because of the patchy nature of the process, biopsy may not demonstrate the findings described below.  The diagnosis is made when cholesterol clefts are seen within renal vessels or glomeruli.  The clefts result when the cholesterol crystals dissolve out of the tissue during processing, leaving a void in the tissue.  Often the crystals are surrounded by giant cells or imbedded in the thickened intima of a vessel wall. In acute lesions, eosinophils or neutrophils may surround occluded vessels.  These changes are often seen in a background of ongoing ischemic injury which eventually leads to cortical scarring.  

There is no definitive therapy for AERD. Preventive measures are aimed at decreasing atherosclerotic risk factors and minimizing iatrogenic risk factors such as invasive vascular procedures or anticoagulation/thrombolytic therapy. Supportive measures such as RAS blockade for pre-dialysis patients and hemodialysis for patients with severe renal impairment are the primary treatments available. Prognosis is very poor with a high rate of mortality (associated with advanced age and the prevalence of cardiovascular disease). Theriault et.al. reviewed patients with AERD severe enough to require dialysis and reported that 12 of 43 patients were eventually able to come off hemodialysis after a mean delay of 409 +/- 336 days.

References

Mayo RR, Swartz RD: Redefining the incidence of clinically detectable atheroembolism. Am J Med 100: 524-529, 1996.

Mittal BV, Alexander MP, Rennke HG and Singh AK: Atheroembolic renal disease: A silent masquerader. Kidney Int, 73: 126-130, 2008.

Modi KS, Rao VK: Atheroembolic renal disease. J Am Soc Nephrol 12: 1781-1787, 2001.

Theriault J, Agharazzi M, Dumont M et.al.: Atheroembolic renal failure requiring dialysis: Potential for renal recovery. Neph Clin Pract 94: c11-c18, 2003.