PODOCYTE MACROPHAGE TRANSDIFFERENTIATION - ELECTRON MICROSCOPIC OBSERVATIONS IN TWO DISTINCT CLINICAL SETTINGS

Podocytes are terminally differentiated cells forming an integral part of the glomerular ultrafiltration barrier.Transdifferentiation of  podocytes has been demonstrated in many glomerulonephritides leading to acquisition of macrophage epitopes by dysregulated podocytes and this phenomenon has been termed Podocyte Macrophage Transdifferentiation (PMT). We document evidence of PMT in the form of electron microscopically observable acquisition of macrophage functions by podocytes in two distinct clinical settings – first in a case of renal amyloidosis and second in a case of Hepatitis B associated Membranous Nephropathy. 

Renal biopsies received at our institution for pathological analysis were subjected to detailed electron microscopic (EM) evaluation following light microscopic (LM) and immunofluorescence (IF) studies. Features of PMT demonstrable at ultrastructural level, such as morphologic evidence of phagocytic activities by podocytes were identified in two cases and documented. 

Case 1:  A 73year old Indian female presented with facial puffiness and pedal edema of 4 months duration. Her Serum creatinine was 1.33 mg/dL and 24hour urine protein 1.4gms. Her free light chain assay showed kappa 73mg/L, lambda 277.6mg/dL and kappa lambda ratio of 0.26. She underwent renal biopsy to ascertain cause of proteinuria. LM evaluation revealed renal amyloidosis, AL immunophenotype (lambda 3+ on IF). EM analysis confirmed amyloidosis involving mesangium and capillary walls. The overlying podocytes showed features of severe injury with subepithelial spikes of amyloid distorting podocyte-GBM relationship. Notable was intracellular localisation of amyloid within many of the podocytes. Since amyloid by definition is extracellular, its presence within podocytes was studied further, showing podocyte cytoplasmic processes surrounding and encircling few of the amyloid deposits (Figure 1A&B) similar to phagocytic activity by macrophages.

Case 2:  A 34year old Indian male was detected to have proteinuria of 1.75 gms per day with UP/UC ratio of 1.68 and serum creatinine 0.63mg/dL. Hepatitis B surface antigen and E antigen were positive on serological tests with quantitative PCR for HBV showing 400000000 IU/L. Renal biopsy showed Membranous Nephropathy on LM. EM showed Stage 2 Membranous Nephropathy with subendothelial and mesangial immune complex deposits favouring a secondary membranous nephropathy. In addition, an enlarged podocyte with a lysosomal autophagic vesicle was observed overlying a capillary wall with membranous pattern of injury (Figure 2). Autophagy in podocyte lysosomes serves in the uptake and degradation of various proteins and is morphologically consistent with scavenging activities attributable to macrophages. 

We have reported morphological features of PMT observed by electron microscopic examination of renal biopsies in two distinct clinical scenarios. To this date, PMT has been identified by demonstration of loss of podocyte epitopes and acquisition of macrophage epitopes using relevant markers in various glomerulonephritides. Real time visualisation of podocytes exhibiting macrophage like phagocytic functionalities has not yet been recorded and we provide illustrative evidence of the same in this report.