Atypical focal segmental glomerulosclerosis associated with a new PODXL nonsense variant.

BACKGROUND: Podocalyxin (PODXL) is a highly sialylated adhesion glycoprotein that plays an important role in podocyte's physiology. Recently, missense and nonsense dominant variants in the PODXL gene have been associated with focal segmental glomerulosclerosis (FSGS), a leading cause of nephrotic syndrome and kidney failure. Their histologic description, however, was superficial or absent. METHODS: We performed exome sequencing on a three-generation family affected by an atypical glomerular nephropathy and characterized the disease by light and electron microscopy. RESULTS: The disease was characterized by FSGS features and glomerular basement membrane duplication. Six family members displayed chronic proteinuria, ranging from mild manifestations without renal failure, to severe forms with end-stage renal disease. Exome sequencing of affected twin sisters, their affected mother, healthy father, and healthy maternal uncle revealed a new nonsense variant cosegregating with the disease (c.1453C>T, NM_001018111) in the PODXL gene, which is known to be expressed in the kidney and to cause nephropathy when mutated. The variant is predicted to lead to a premature stop codon (p.Q485*) that results in the loss of the intracytoplasmic tail of the protein. CONCLUSION: This is the first description of a peculiar association combining a PODXL stop-gain variant and both FSGS and membranoproliferative glomerulonephritis features, described by light and electron microscopy.

Pathological Analysis of Early Transplant Glomerulopathy in Renal Allografts Using Low-Vacuum Scanning Electron Microscopy.

AIM: Low-vacuum scanning electron microscopy (LVSEM) has been reported to aid in diagnosis of renal biopsy. This study evaluated early transplant glomerulopathy in kidney transplant recipients using LVSEM. METHODS: We selected 4 biopsies of cg0, 5 biopsies of cg1a, 5 biopsies of cg1b, and 4 biopsies of cg2 lesions that had been evaluated by light microscopy (LM) and transmission electron microscopy from recipients with acute/active or chronic, active antibody-mediated rejection (AABMR or CAABMR). Renal allograft paraffin sections (1 µm thickness) were stained with periodic acid-methenamine silver and observed using LVSEM. The cg score was based on the Banff classification. The parameter "percentage of duplicated capillary number" was calculated as follows: in 1 glomerulus with glomerular basement membrane (GBM) duplication, the total duplicated capillary number/the total number of capillaries ×100. RESULTS: In all 4 biopsy specimens with AABMR showing cg0, LVSEM revealed GBM duplication not identified by LM. The average percentage of duplicated capillary number per glomerulus with GBM duplication was higher when observed by LVSEM than when observed by LM in all cg1b and cg2 biopsy specimens. CONCLUSION: LVSEM revealed early GBM duplication in AABMR. Early GBM duplication might progress in the very early phase of AABMR. GBM duplication was more frequently detected by LVSEM than by LM in biopsy specimens with early chronic, active antibody mediated rejection. Thus, LVSEM may be useful in diagnosis of early transplant glomerulopathy.

Glomerular basement membrane duplication is a predictor of the prognosis of diabetic nephropathy in patients with type 2 diabetes.

BACKGROUND: Several clinical parameters and pathological findings are known to be predictors of the deterioration of diabetic nephropathy (DN). Glomerular basement membrane duplication (GBM-DP) is a pathological feature representing endothelial injury, which is commonly observed in DN. In the present study, we investigated the association between GBM-DP and the renal prognosis in DN. METHODS: The study enrolled 80 patients with renal biopsy-proven DN who were managed at Chiba-East Hospital from 2005 to 2012. We confirmed the pathological findings according to the Renal Pathology Society classifications, and we further evaluated the GBM-DP, which was defined as double contours of the GBM that expanded more than 10% of capillary loops in the most affected nonsclerotic glomerulus. We used Cox regression models to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), with adjustment for age, sex, systolic blood pressure, HbA1c, estimated glomerular filtration rate (eGFR), and urinary protein excretion (UP) at baseline. RESULTS: Of the 80 patients, 56 were male (70.0%) and the mean age was 59.1 years. The median eGFR and UP were 42 ml/min/1.73 m2 (IQR 30, 59) and 3.1 g/gCr (IQR 1.2, 5.2). Twenty-seven patients progressed to ESRD and one patient died during the median observational period of 2.9 years (IQR 1.5, 4.3). The multivariable analyses showed that GBM-DP was significantly associated with ESRD (HR 3.18 [95% confidence interval (CI): 1.02-9.87], p = 0.045). CONCLUSION: We newly identified GBM-DP as a strong prognostic predictor in DN patients. Further study is needed to clarify the pathogenic mechanism of GBM-DP in DN.

Glomerular C4d deposits can mark structural capillary wall remodelling in thrombotic microangiopathy and transplant glomerulopathy: C4d beyond active antibody-mediated injury: a retrospective study.

Peritubular capillary C4d (ptc-C4d) usually marks active antibody-mediated rejection, while pseudolinear glomerular capillary C4d (GBM-C4d) is of undetermined diagnostic significance, especially when seen in isolation without concurrent ptc-C4d. We correlated GBM-C4d with structural GBM abnormalities and active antibody-mediated rejection in 319 renal transplant and 35 control native kidney biopsies. In kidney transplants, ptc-C4d was associated with GBM-C4d in 97% by immunofluorescence microscopy (IF) and 61% by immunohistochemistry (IHC; P < 0.001). Transplant glomerulopathy correlated with GBM-C4d (P < 0.001) and presented with isolated GBM-C4d lacking ptc-C4d in 69% by IF and 40% by IHC. Strong isolated GBM-C4d was found post year-1 in repeat biopsies with transplant glomerulopathy. GBM-C4d staining intensity correlated with Banff cg scores (rs = 0.45, P < 0.001). Stepwise exclusion and multivariate logistic regression corrected for active antibody-mediated rejection showed significant correlations between GBM duplication and GBM-C4d (P = 0.001). Native control biopsies with thrombotic microangiopathies demonstrated GBM-C4d in 92% (IF, P < 0.001) and 35% (IHC). In conclusion, pseudolinear GBM-C4d staining can reflect two phenomena: (i) structural GBM changes with duplication in native and transplant kidneys or (ii) active antibody-mediated rejection typically accompanied by ptc-C4d. While ptc-C4d is a dynamic 'etiologic' marker for active antibody-mediated rejection, isolated strong GBM-C4d can highlight architectural glomerular remodelling.