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49 year old woman presents with accelerated hypertension, renal insufficiency and nephrotic range proteinuria |
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Leal C. Herlitz, M.D.
Columbia University Medical Center, New York, NY
Clinical Information
49 year-old African American woman presents to the emergency room with blood pressure of 210/116, which falls to 130/82 within 2 hours after receiving anti-hypertensive therapy. Past medical history is significant for a seizure disorder which is medicated with valproic acid and carbemazepine. She takes no other medications and has no history of diabetes. Social history is notable for cigarette smoking (1 to 2 packs per day for the last 35 years). After her initial presentation she is referred to a nephrologist for follow-up. Laboratory work-up in the outpatient setting shows serum creatinine of 2.09 mg/dL, 24 hour urine protein of 3.3 g/day, urinalysis with 3+ protein and bland sediment and albumin of 3.6 g/dL. Serum electrolytes and serum glucose are within normal range. Serologic work-up is negative or normal for ANA, anti-DNA, C3, C4, HepB surface antigen, HepC antibody, ANCA and anti-GBM antibodies. Physical exam reveals a non-obese female with no edema. A biopsy is performed.
What is your biopsy diagnosis?
a. Nodular diabetic glomerulosclerosis (15)
b. Chronic membranoproliferative glomerulonephritis (17)
c. Amyloidosis (21)
d. Smoking associated nodular glomerulosclerosis (50)
e. Focal segmental glomerulosclerosis (secondary to hypertension) (51)
Total Votes (154)
Figure 1
PAS 400x magnificationA glomerulus showing nodular expansion of the mesangium by strongly PAS-positive matrix material. Glomerular basement membranes also show moderate diffuse thickening. No GBM duplication is seen and the glomerulus appears normocellular
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Figure 2
H&E 600x magnificationA glomerulus with prominently increased mesangial matrix and focal inframembranous hyaline accumulation (at 2 o’clock) with lipid vacuoles
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Figure 3
Trichrome 400x magnificationGlomerulus with segmental nodular expansion of the mesangium by matrix material (blue). No immune-type fuchsinophilic (red) deposits are seen
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Figure 4
Jones methenamine silver stain 400x magnificationArtery and arteriole with moderately severe sclerosis. The artery shows prominent reduplication of the elastica (a feature commonly seen in hypertension) and the arteriole shows intimal hyalinosis
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Figure 5
PAS 600xThe hilus of a glomerulus, notable for the presence of numerous small endothelial lined channels, representing a form of vascular proliferation (neovasculrization)
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Figure 6
Immunofluorsecence for Albumin (400x magnification). Note: IgG, IgM, IgA, C3, C1q, fibrin, kappa and lambda are negative (not shown).Linear staining of the glomerular basement membranes and Bowman’s capsule as well as smudgy staining of the mesangium (nonspecific trapping within mesangial nodules)
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Figure 7
Electron microscopy (5000x magnification)Prominently increased mesangial matrix and globally thickened glomerular basement membranes that are normal in texture and contour. No immune type electron dense deposits are seen. Podocytes display mild foot process effacement
Full size image(1.9 MB)
Final pathologic diagnosis
Smoking-associated nodular glomerulosclerosis (answer D)
Discussion
Smoking associated nodular glomerulosclerosis is a relatively recently described entity. Previously called “idiopathic nodular glomerulosclerosis” the entity is now known to have a strong association with heavy tobacco use (past or present) and hypertension. Histologic findings include a marked increase in mesangial matrix (which should be PAS-positive and trichrome blue, figures 1 and 3). Glomerular basement membranes should show mild to moderate diffuse thickening without evidence of immune complex deposition. Some glomeruli may display prominent hyaline accumulation (figure 2). Frequently, proliferation of small capillaries is seen at the glomerular hilus (figure 5). Immunofluorescence often shows linear staining of basement membranes for albumin (figure 6) and sometimes IgG. Electron microscopy shows markedly increased mesangial matrix without evidence of electron dense immune deposits (figure 7). Morphologically this disorder may closely resemble other diseases, most notably nodular diabetic glomerulosclerosis, so careful clinical pathologic correlation is needed.Nodular mesangial slcerosis is a histologic pattern that may be seen in a variety of conditions. The most common cause of nodular mesangial sclerosis is diabetes which is classically associated with Kimmelstiel-Wilson nodules, defining the entity of nodular diabetic glomerulosclerosis. Dysproteinemia related renal diseases including amyloidosis and monoclonal immunoglobulin deposition disease may have a nodular appearance but should be recognized as dysproteinemia-related based on immunofluorescence studies which should show evidence of monoclonal immune deposits. Chronic membranoproliferative glomerulonephritis often has a nodular appearance by light microscopy but should show immune deposits by immunofluorescence and electron microscopy. Glomerular diseases characterized by organized deposits such as fibrillary and immunotactoid glomerulonephritis, fibronectin glomerulopathy and collagen III glomerulopathy may show mesangial nodules by light microscopy but display unique diagnostic features by electron microscopy. Diseases associated with chronic hypoxia, including cyanotic congenital heart disease and cystic fibrosis have also been associated with nodular glomerulosclerosis. Cases without an identifiable cause for nodular sclerosis were referred to as “idiopathic nodular glomerulosclerosis” but the majority of these “idiopathic” cases have now been linked to smoking and hypertension.The largest published series (23 patients) of “idiopathic” nodular glomerulosclerosis was the first to make the connection between smoking and nodular sclerosis. Patients tended to be older Caucasian males with a high prevalence of hypertension and history of heavy smoking (mean cumulative intake of approximately 53 pack years). Over 90% of the patients were heavy smokers, with 57% of them actively smoking at the time of renal evaluation and 43% having quit smoking at some point in the past. Proteinuria and renal insufficiency were the most common presenting features and 70% of patients had >3 grams/day of proteinuria. Median time from biopsy to ESRD was approximately 2 years. Continued smoking or the absence of RAS blockade negatively impacted renal survival.The proposed pathogenesis of nodular sclerosis in the setting of smoking revolves around the formation of advanced glycation end products (AGE) which are known to cause oxidative stress and angiogenesis. AGE are also present in diabetes and cause accumulation of certain extracellular matrix components.
References
Markowitz GS, Lin J, Valeri AM et.al. Idiopathic nodular glomerulosclerosis is a distinct clinicopathologic entity linked to hypertension and smoking. Hum Pathol 33:826-835. 2006.Nasr SH and D’Agati VD. Nodular glomerulosclerosis in the nondiabetic smoker. JASN 18:2032-2036. 2007. |