Case 647 -- A 30-year old woman with nephrotic syndrome

Contributed by Eumenia Castro, MD and Sheldon Bastacky, MD


The patient is a 30-year old woman presenting with lower extremity edema during and following a pregnancy in 2005. She underwent a renal biopsy in 2005 which established the diagnosis of membranoproliferative glomerulonephritis-type III (Strife variant). She was treated with ACE inhibitors, but no steroids or cytoxic drugs over the next four years. In the initial biopsy, there were minimal chronicity changes with only one of twenty-six (1/26; 4%) glomeruli being globally sclerotic. Presently, the patient has nephrotic syndrome. Blood pressure is 110/70 mm Hg on anti-hypertensive medication. Pertinent laboratory data include: creatinine 0.6 mg/dl, BUN 13 mg/dl, urine protein 4.4 gm/24 hrs (4+ by dip stick), ANA-negative, ANCA-negative, hepatitis-B/C serology-negative, cryoglobulin screen-negative, urine sediment-inactive (no cells or casts). Kidneys are normal size by ultrasound. The clinical differential diagnosis includes: persistent/recurrent type-III membranoproliferative glomerulonephritis and a new glomerular cause of nephrotic syndrome.


The biopsy was received in transport media and consisted of two cores of renal tissue measuring 1.4 and 1.6 cm in length, each measuring 0.1 cm in diameter. The 1.6 cm core was submitted for light microscopy (formalin fixative; block A). The 1.4 cm core was divided for immunofluorescence and electron microscopy (Karnovsky' s fixative).


The tissue examined by light microscopy consisted of renal cortex and attached capsule. The profiles of approximately 48 glomeruli were identified in the paraffin, frozen, and plastic sections, of which 12 (25%) were globally sclerotic. The non-obsolescent glomeruli were enlarged (Figure LM-1), and exhibited a mesangial and focal lobular endocapillary proliferative pattern of injury by H&E (Figure LM-2). Silver stain revealed the presence of prominent glomerular basement membrane double contours (tram-tracking) and glomerular basement membrane tortuosity (Figures LM -3 and LM-4). Some of the capillary loops were markedly narrowed due to the mesangial interposition, while many of the capillary loops remain patent (Figure LM-5). Some glomeruli contained a few circulating mononuclear cells within the glomerular capillaries (Figure LM-5). There were no necrotizing lesions, crescents, hyaline thrombi, hyalinosis lesions, spikes, or glomerular basement membrane breaks. There were rare atrophic tubules, comprising less than 5% of the cortical tubular profiles. Occasional hyaline casts were identified. Silver stain revealed the presence of protein resorption droplets in many of the proximal tubular epithelial cells (Figure LM-7). There were many aggregates of foam cells (Figures LM-6, LM-8, and LM-9) distributed throughout the sampled cortex. There were rare interstitial lymphocytes, concentrated mostly in the small foci of tubular atrophy (Figure LM-8). Trichrome stain revealed no appreciable interstitial fibrosis. Approximately four small arteries were present in the paraffin and frozen sections, ranging from normal to showing mild medial thickening (Figure LM-9). There was no evidence of vasculitis, thromboembolism, or thrombotic microangiopathy.


Immunofluorescence microscopy showed granular, C3-predominant GBM and mesangial staining (Figure IF-1); evidence of glomerular proteinuria, and one artery with weak intimal staining for IgM suggesting mild chronic vascular injury.


The ultrastructural findings are based on the examination of two glomeruli with mesangial through focal mesangiocapillary proliferation, diffuse marked glomerular capillary wall thickening, and one podocyte with protein resorption droplets visible on a toluidine blue stained plastic section (Figure TL-1). The podocytes exhibit extensive and widespread foot process effacement (Figure EM-1). A few podocytes contained lipoprotein resorption droplets (Figure EM-2). The mesangial areas were expanded, and several contained electron dense deposits of the immune complex type (Figure EM-3). The glomerular basement membranes were markedly thickened and irregular, with tortuosity, variable areas of lucency within the lamina densa, and areas of mesangial interposition (Figure EM-4). There were many intramembranous and smaller numbers of subepithelial and subendothelial electron dense deposits of the immune complex type. Many of the intramembranous electron dense deposits appeared partially resorbed (Figure EM-5). There were several large (hump-like) subepithelial immune complex deposits (Figure EM-6). There were also several subendothelial immune complex deposits and deposits within interposed mesangium. The glomerular basement membrane was irregularly thickened associated with focally marked glomerular basement membrane remodeling (Figure EM-7). No glomerular basement membrane breaks were identified. The glomerular capillaries ranged from patent to markedly narrowed secondary to mesangial interposition. Within some of the glomerular capillaries, there were circulating red blood cells and an occasional circulating granulocytic white blood cell. The endothelial cells ranged from normal in most of the capillaries to focally swollen with loss of fenestrations. No endothelial cell tubuloreticular inclusions were identified. Several tubules were examined, and were remarkable for focal lipoprotein resorption droplets and occasional tubular cells with intracellular edema. Peritubular capillaries were unremarkable. A few foam cells were present in the interstitium. No extraglomerular immune complex deposits were identified. No protein deposits with organized substructure were identified.


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