Proteinuria in thrombotic microangiopathy is associated with partial podocytopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) results in acute kidney injury, but the cause of heavy proteinuria in this disorder is puzzling. The goal of this study was to determine if there were significant effacement of foot processes and CD133-positive hyperplastic podocytes in TMA to explain the proteinuria. METHODS: The study included 12 negative controls (renal parenchyma removed from renal cell carcinoma) and 28 thrombotic microangiopathy due to different etiologies. The percent of foot process effacement was estimated, and proteinuria level was obtained for each TMA case. Both groups of cases were stained for CD133 by immunohistochemical method, and the number of positive CD133 in hyperplastic podocytes was counted and analyzed. RESULTS: Nineteen (19) of 28 (68%) TMA cases had nephrotic range proteinuria (urine protein/creatinine >3). Twenty-one (21) of 28 (75%) TMA cases showed positive CD133 staining in scattered hyperplastic podocytes within Bowman's space but was absent in control cases. The percent of foot process effacement (56 ± 4%) correlated with proteinuria (protein/creatinine ratio 4.4 ± 0.6) (r = 0.46, p = .0237) in TMA group. CONCLUSION: Our data indicate that the proteinuria in TMA can be associated with significant effacement of foot processes. CD133-positive hyperplastic podocytes can be seen in the majority of TMA cases of this cohort, indicating a partial podocytopathy.

Resolving primary membranous glomerulopathy (MGN) reveals a dynamically metabolic pathway from sub-epithelium to glomerular basement membranes.

In idiopathic (primary) membranous glomerulopathy (MGN), there is a phenomenon of subepithelial deposits (stages 1 and 2) transitioned to intramembranous deposits, with lucent resolving features (stages 3 and 4). This phenomenon has not been described in other types of immune complex mediated glomerulonephritis with either subendothelial or mesangial deposits. The goal of this study was to evaluate what unique immunostaining pattern could occur in primary MGNs with intramembranous resolving features. PLA2R and IgG4 immunostains were performed in 50 primary MGNs, and 39 secondary MGNs after the clinical history was reviewed. Primary MGNs with resolving features were further evaluated in detail. A total of 84% (42/50) of primary MGN cases had diffuse positive immunostaining for IgG4 in the glomeruli, and most of them were also positive for PLA2R staining. Eight of the remaining primary MGN cases (8/50) with positive PLA2R but negative IgG4 staining in the glomeruli had diffuse resolving features as observed by electron microscopy. All secondary MGNs were stained negatively for both IgG4 and PLA2R except for one case with positive IgG4 staining but negative staining for PLA2R. Our data indicate that IgG4 staining on paraffin tissue is a very reliable screening tool to confirm the presence of primary MGN. Primary MGN with PLA2R+/IgG4- stains were seen in those with intramembranous resolving features. This finding is consistent with the known weak-binding capacity of IgG4 to the glomerular basement membranes. The transitional phenomenon from PLA2R+/IgG4+ subepithelial deposits to PLA2R+/IgG4- intramembranous resolving deposits in primary MGN implies that there may be a continuous metabolic activity from podocyte to glomerular basement membrane.

Malignant Tumors Identified in Adult Polycystic Kidney Disease Can Be Derived from Both Proximal Tubular and Distal Tubular Origins.

Adult polycystic kidney disease (APKD) is a genetic disorder leading to premature renal dysfunction and failure. The prevalence of malignant renal tumors occurring in the APKD setting has been rarely reported. OBJECTIVE: To better characterize malignant renal tumors in nephrectomy specimens of APKD and apply modern pathologic evaluation. METHODS: We reviewed our database of APKD specimens over the past 11 years (from 2012 to 2023) for primary malignant tumors within the kidneys of APKD. RESULTS: Of 48 nephrectomy specimens with APKD evaluated, 10 malignant renal tumors were identified, indicating a prevalence of 20.8 % (10/48). These included three clear cell (cc) renal cell carcinomas (RCC) (ranging from 1 mm to 6.7 cm), three papillary RCCs (2.5, 3.5, and 14 cm with lymph node metastasis), two cases of clear cell papillary (CCP) RCC, one acquired cystic disease (ACD) with associated RCC (4 mm), and one urothelial adenocarcinoma. The urothelial adenocarcinoma was found near a tubulovillous adenoma in a collecting duct and stained positively for GATA3 and Uroplakin-2 but was negative for PAX8 & CDX2. The tumor showed extensive invasion into perirenal fatty tissue and the rectum. Next generating sequencing (NGS) analysis of the tumor showed mutations in TERT, RB1, TP53, ERBB2, and TET1 genes, further supporting its urothelial origin. CONCLUSIONS: We found a prevalence of 20.8%, which was higher than in previous reports of malignant renal tumors in patients who underwent resections for APKD. Renal tumors were mostly from damaged proximal tubular origins (clear cell or papillary RCC), but less commonly were from distal tubular or urothelial cells as well (clear cell papillary RCC and urothelial adenocarcinoma).