Deep learning-based segmentation and quantification of podocyte foot process morphology suggests differential patterns of foot process effacement across kidney pathologies.

Morphological alterations at the kidney filtration barrier increase intrinsic capillary wall permeability resulting in albuminuria. However, automated, quantitative assessment of these morphological changes has not been possible with electron or light microscopy. Here we present a deep learning-based approach for segmentation and quantitative analysis of foot processes in images acquired with confocal and super-resolution fluorescence microscopy. Our method, Automatic Morphological Analysis of Podocytes (AMAP), accurately segments podocyte foot processes and quantifies their morphology. AMAP applied to a set of kidney diseases in patient biopsies and a mouse model of focal segmental glomerulosclerosis allowed for accurate and comprehensive quantification of various morphometric features. With the use of AMAP, detailed morphology of podocyte foot process effacement was found to differ between categories of kidney pathologies, showed detailed variability between diverse patients with the same clinical diagnosis, and correlated with levels of proteinuria. AMAP could potentially complement other readouts such as various omics, standard histologic/electron microscopy and blood/urine assays for future personalized diagnosis and treatment of kidney disease. Thus, our novel finding could have implications to afford an understanding of early phases of kidney disease progression and may provide supplemental information in precision diagnostics.

Heterozygous missense variant in TRPC6 in a boy with rapidly progressive infantile nephrotic syndrome associated with diffuse mesangial sclerosis.

Transient receptor potential channel C6 encoded by TRPC6 is involved in slit diaphragm formation in podocytes, and abnormalities of the TRPC6 protein cause various glomerular diseases. The first identified pathogenic variant of TRPC6 was found to cause steroid-resistant nephrotic syndrome that typically developed in adulthood and then slowly led to end-stage renal disease, along with a renal pathology of focal segmental glomerulosclerosis. Here, we report a patient with rapidly progressing infantile nephrotic syndrome and a heterozygous missense TRPC6 variant. The patient, a 2-year-old Japanese boy, developed steroid-resistant nephrotic syndrome at age 11 months. His renal function deteriorated rapidly, and peritoneal dialysis was introduced at age 1 year and 6 months. His renal pathology, obtained at age 1 year and 1 month, was consistent with diffuse mesangial sclerosis (DMS). Clinical exome analysis and custom panel analysis for hereditary renal diseases revealed a reported heterozygous missense variant in TRPC6 (NM_004621.5:c.523C > T:p.Arg175Trp). This is the first report of a patient with a TRPC6-related renal disorder associated with DMS.

Potential value of three-dimensional ultrasonography in diagnosis of diabetic nephropathy in Chinese diabetic population with kidney injury.

BACKGROUND: To explore the potential value of three-dimensional ultrasonography (3DUS) and contrast-enhanced ultrasound (CEUS) in the diagnosis of diabetic nephropathy (DN) in Chinese diabetic patients with kidney injury. METHODS: Patients with type 2 diabetes mellitus and kidney injury in our hospital were enrolled, and the clinical characteristics as well as the laboratory data of patients were collected; 3DUS and CEUS were used to evaluate the morphological structure and blood perfusion of kidneys. Eligible patients were categorized into two groups based on renal biopsy results: DN group and non-diabetic renal diseases (NDRD) group. Correlation analysis and logistic regression analysis were applied to identify the risk factors of DN development. RESULTS: A total of 115 patients aged from 24 to 78 years old were recruited in the experiment, of which 64 patients (55.65%) and 51 patients (44.35%) were in the DN group and NDRD group, respectively. After correction to CKD stage, BMI and right kidney volume index were retained to identify patients with DN. The ROC of the logistic regression model had an AUC of 0.703 (95% CI: 0.591-0.815) and it was higher than both indicators. CONCLUSION: 3DUS has potential value in the diagnosis of diabetic nephropathy in Chinese diabetic population with kidney injury and may act as an auxiliary diagnosis for DN. More prospective and well-designed studies with larger samples are needed to verify the result.

Micro-CT imaging and structural analysis of glomeruli in a model of Adriamycin-induced nephropathy.

Glomeruli number and size are important for determining the pathogenesis of glomerular disease, chronic kidney disease, and hypertension. Moreover, renal injury can occur in specific cortical layers and alter glomerular spatial distribution. In this study, we present a comprehensive structural analysis of glomeruli in a model of Adriamycin (doxorubicin) nephropathy. Glomeruli are imaged (micro-CT at 10 × 10 × 10 µm3) in kidney specimens from C57Bl/6 mouse cohorts: control treated with saline ( n = 9) and Adriamycin treated with 20 mg/kg Adriamycin ( n = 7). Several indices were examined, including glomerular number, glomerular volume, glomerular volume heterogeneity, and spatial density at each glomerulus and in each cortical layer (superficial, midcortical, and juxtamedullary). In the Adriamycin-treated animals, glomerular number decreased significantly in the left kidney [control: 8,298 ± 221, Adriamycin: 6,781 ± 630 (mean ± SE)] and right kidney (control: 7,317 ± 367, Adriamycin: 5,522 ± 508), and glomerular volume heterogeneity increased significantly in the left kidney (control: 0.642 ± 0.015, Adriamycin: 0.786 ± 0.018) and right kidney (control: 0.739 ± 0.016, Adriamycin: 0.937 ± 0.023). Glomerular spatial density was not affected. Glomerular volume heterogeneity increased significantly in the superficial and midcortical layers of the Adriamycin cohort. Adriamycin did not affect glomerular volume or density metrics in the juxtamedullary region, suggesting a compensatory mechanism of juxtamedullary glomeruli to injury in the outer cortical layers. Left/right asymmetry was observed in kidney size and various glomeruli metrics. The methods presented here can be used to evaluate renal disease models with subtle changes in glomerular endowment locally or across the entire kidney, and they provide an imaging tool to investigate diverse interventions and therapeutic drugs.

PKD1-associated autosomal dominant polycystic kidney disease with glomerular cysts presenting with nephrotic syndrome caused by focal segmental glomerulosclerosis.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) may manifest non-nephrotic range proteinuria, but is rarely complicated with nephrotic syndrome. Limited number of reports describe the histology of ADPKD with nephrotic syndrome in detail. CASE PRESENTATION: We encountered a 23-year-old man with polycystic kidney disease (PKD) with small kidney volume and nephrotic syndrome, which eventually progressed to end-stage renal disease. Renal histology showed typical focal segmental glomerulosclerosis and remarkable glomerular cyst formation, but did not reveal tubular cysts. PKD1 mutation was detected in him and his father, who also had PKD with small kidney volume. CONCLUSIONS: In contrast to tubular cysts which develop along ADPKD progression, glomerular cysts may likely be associated with ADPKD with slower volume progression manifesting small kidney volume. Although previous investigations report that ADPKD with smaller kidney volume is attributed to slower decline in renal function, coexistence of nephrotic-range proteinuria implies complication of other glomerular diseases and needs histological evaluation since it may lead to poor renal outcome.

Contribution of Electron Microscopy to the Clinicopathologic Diagnosis in Childhood Glomerular Renal Diseases.

Background: Electron microscopy (EM) provides another diagnostic assessment of glomerular lesions in addition to light and fluorescent microscopy. Objectives: We evaluated the contribution of diagnostic EM in childhood glomerular diseases. Patients and methods: Forty-eight renal biopsies which were assessed by EM between 2000 and 2014 were evaluated. Results: There were 21 (44%) females and 27 (56%) males, ages ranged between 6 and 204 months. EM findings were compatible with light and immunofluorescence microscopy in 65%, made additional contributions to diagnosis in 31% (especially in focal segmental glomerulosclerosis, Alport disease, membranoproliferative glomerulonephritis, dense deposit disease, thin basement membrane disease, and nephronophthisis), and was non-contributory in 4%. Conclusion: Electron microscopic evaluation supports other histopathological diagnoses in most cases, contributes additional diagnostic information in pediatric glomerular disease, especially in FSGS, thin glomerular basement membrane nephropathy, Alport disease, MPGN, and dense deposit disease, and its utilization should clinically justify the increase in cost and testing time.

Oligonephronia and Wolf-Hirschhorn syndrome: A further observation.

Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder caused by a partial deletion of chromosome 4 (4p16.3p16.2). We describe a case of a male 9 years old children with WHS proteinuria and hypertension. Laboratory data showed creatinine 1.05 mg/dl, GFR 65.9 ml/min/1.73 m2 , cholesterol 280 mg/dl, triglyceride 125 mg/dl with electrolytes in the normal range. Urine collection showed protein 2.72 g/L with a urine protein/creatinine ratio (UP /UCr ratio) of 4.2 and diuresis of 1,100 ml. Renal ultrasound showed reduced kidney dimensions with diffusely hyperechogenic cortex and poorly visualized pyramids. Renal biopsy showed oligonephronia with focal segmental glomerulosclerosis associated with initial tubulointerstitial sclerotic atrophy. The child began therapy with Angiotensin-converting enzyme inhibitors (ACE-inhibitors) to reduce proteinuria and progression of chronic kidney disease. In the literature the anomalies of number of glomeruli oligonephronia and oligomeganephronia (OMN) are described in two forms, one without any associated anomalies, sporadic, and solitary and the other with one or more anomalies. Our review of the literature shows that the pathogenesis of this anomaly is unknown but the role of chromosome 4 is very relevant. Many cases of OMN are associated with anomalies on this chromosome, in the literature cases series we observed this association in 14/48 cases (29.2%) and in 7 of these 14 cases with WHS. Our case and the review of literature demonstrate how periodic urinalysis and renal ultrasound monitoring is recommended in patients affected by WHS and the renal biopsy must be performed when there is the onset of proteinuria.

Intravascular lymphoma forming massive aortic tumors complicated with sarcoidosis and focal segmental glomerulosclerosis: a case report and literature review.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma characterized by proliferation of B cells within small vessels. Herein, we report a case of a 77-year-old man who presented with IVLBCL and massive tumor formation on the aortic wall who was previously diagnosed with sarcoidosis and focal segmental glomerulosclerosis (FSGS). To our knowledge, this is the first reported case of an IVLBCL with aortic tumor formation. CASE PRESENTATION: A 77-year-old ambulatory man with sarcoidosis and FSGS had neurological symptoms for nine months. The patient presented to the emergency department with sudden left leg pain, and was diagnosed with acute femoral artery occlusion. Emergency thrombectomy was performed subsequently. Pathological evaluation of the thrombi revealed that its surface was filled with large atypical B cells. Bone marrow biopsy showed infiltration of large atypical B cells within the small vessels. IVLBCL was suspected and further examination was planned, but the patient died due to sudden respiratory and cardiac arrest on hospital day twelve. Autopsy revealed intravascular tumors adherent to the aortic arch, left ventricle, and the abdominal aorta. All enlarged lymph nodes and the ventricular septum of the heart showed hyalinized lesions with granular formation consistent with sarcoidosis. The patient was diagnosed with IVLBCL with aortic tumor formation complicated with sarcoidosis and FSGS. CONCLUSIONS: IVLBCL may present with tumor formation on the aortic wall. Although the cause of its affinity to the aortic wall is yet unknown, autopsy findings imply that arteriosclerosis may have contributed to the tumor formation. The literature suggests that T-cell abnormalities could possibly be the common etiology of intravascular lymphoma, sarcoidosis, and FSGS.

α-1-Antitrypsin detected by MALDI imaging in the study of glomerulonephritis: Its relevance in chronic kidney disease progression.

Idiopathic glomerulonephritis (GN), such as membranous glomerulonephritis, focal segmental glomerulosclerosis (FSGS), and IgA nephropathy (IgAN), represent the most frequent primary glomerular kidney diseases (GKDs) worldwide. Although the renal biopsy currently remains the gold standard for the routine diagnosis of idiopathic GN, the invasiveness and diagnostic difficulty related with this procedure highlight the strong need for new diagnostic and prognostic biomarkers to be translated into less invasive diagnostic tools. MALDI-MS imaging MALDI-MSI was applied to fresh-frozen bioptic renal tissue from patients with a histological diagnosis of FSGS (n = 6), IgAN, (n = 6) and membranous glomerulonephritis (n = 7), and from controls (n = 4) in order to detect specific molecular signatures of primary glomerulonephritis. MALDI-MSI was able to generate molecular signatures capable to distinguish between normal kidney and pathological GN, with specific signals (m/z 4025, 4048, and 4963) representing potential indicators of chronic kidney disease development. Moreover, specific disease-related signatures (m/z 4025 and 4048 for FSGS, m/z 4963 and 5072 for IgAN) were detected. Of these signals, m/z 4048 was identified as α-1-antitrypsin and was shown to be localized to the podocytes within sclerotic glomeruli by immunohistochemistry. α-1-Antitrypsin could be one of the markers of podocyte stress that is correlated with the development of FSGS due to both an excessive loss and a hypertrophy of podocytes.

Novel diagnostic and therapeutic techniques reveal changed metabolic profiles in recurrent focal segmental glomerulosclerosis.

Idiopathic forms of Focal Segmental Glomerulosclerosis (FSGS) are caused by circulating permeability factors, which can lead to early recurrence of FSGS and kidney failure after kidney transplantation. In the past three decades, many research endeavors were undertaken to identify these unknown factors. Even though some potential candidates have been recently discussed in the literature, "the" actual factor remains elusive. Therefore, there is an increased demand in FSGS research for the use of novel technologies that allow us to study FSGS from a yet unexplored angle. Here, we report the successful treatment of recurrent FSGS in a patient after living-related kidney transplantation by removal of circulating factors with CytoSorb apheresis. Interestingly, the classical published circulating factors were all in normal range in this patient but early disease recurrence in the transplant kidney and immediate response to CytoSorb apheresis were still suggestive for pathogenic circulating factors. To proof the functional effects of the patient's serum on podocytes and the glomerular filtration barrier we used a podocyte cell culture model and a proteinuria model in zebrafish to detect pathogenic effects on the podocytes actin cytoskeleton inducing a functional phenotype and podocyte effacement. We then performed Raman spectroscopy in the < 50 kDa serum fraction, on cultured podocytes treated with the FSGS serum and in kidney biopsies of the same patient at the time of transplantation and at the time of disease recurrence. The analysis revealed changes in podocyte metabolome induced by the FSGS serum as well as in focal glomerular and parietal epithelial cell regions in the FSGS biopsy. Several altered Raman spectra were identified in the fractionated serum and metabolome analysis by mass spectrometry detected lipid profiles in the FSGS serum, which were supported by disturbances in the Raman spectra. Our novel innovative analysis reveals changed lipid metabolome profiles associated with idiopathic FSGS that might reflect a new subtype of the disease.

Renal ultrasound findings secondary to COVID-19 related collapsing focal segmental glomerulosclerosis - A case report.

SARS-CoV-2 (COVID-19) is well known to have extrapulmonary manifestations, including acute renal failure. While radiologic findings of COVID-19 pulmonary-involvement have been described, renal findings associated with COVID-19 have not. We present a case of a 38-year-old Afro-Caribbean female diagnosed with COVID-19 whose renal ultrasound showed increased parenchymal echogenicity, decreased global color Doppler signal with elevated resistive indices, but no large vessel thrombi. Non-targeted renal biopsy demonstrated collapsing focal segmental glomerulosclerosis (FSGS), likely secondary to COVID-19 infection, which may be a specific manifestation of this disease that has been predominantly reported in Black patients. We report several findings on renal ultrasound with duplex Doppler not previously associated with COVID, specifically with FSGS, which in conjunction can be useful to both the radiologist and the clinician, potentially pointing them in the direction of this diagnosis and early treatment.

The use of electron microscopy in the diagnosis of focal segmental glomerulosclerosis: are current pathological techniques missing important abnormalities in the glomerular basement membrane?

Background: There is an increasing appreciation that variants of the collagen IV genes may be associated with the development of focal segmental glomerulosclerosis (FSGS). On electron microscopy, such variants may produce characteristic changes within the glomerular basement membrane (GBM). These changes may be missed if glomerular lesions histologically diagnosed as FSGS on light microscopy are not subjected to electron microscopy. Methods: We conducted a retrospective cohort analysis of all patients presenting to two hospitals who received a primary histological diagnosis of FSGS to see if these samples underwent subsequent electron microscopy. Each such sample was also scrutinised for the presence of characteristic changes of an underlying collagen IV disorder Results: A total of 43 patients were identified. Of these, only 30 underwent electron microscopy. In two samples there were histological changes detected that might have suggested the underlying presence of a collagen IV disorder. Around one in three biopsy samples that had a histological diagnosis of FSGS were not subjected to electron microscopy. Conclusion: Renal biopsy samples that have a histological diagnosis of primary FSGS not subjected to subsequent electron microscopy may potentially miss ultrastructural changes in the GBM that could signify an underlying collagen IV disorder as the patient's underlying disease process. This could potentially affect both them and their families' investigative and management decisions given potential for implications for transplant, heritability and different disease pathogenesis. This represents a gap in care which should be reflected upon and rectified via iterative standard care and unit-level quality assurance initiatives.

Prediction of tubulo-interstitial injury by Doppler ultrasound in glomerular diseases: value of resistive and atrophic indices.

BACKGROUND: Doppler ultrasound is increasingly used in Nephrology for diagnosis of renovascular hypertension and evaluation of allograft dysfunction. However, its utility in glomerular disease remains controversial. OBJECTIVES: Using Doppler Ultrasound, we prospectively tested the role of resistive and atrophic indices in predicting tubulointerstitial lesions in patients with glomerular disease as demonstrated by renal biopsy. METHODS: Seventy one patients with primary or secondary glomerular diseases were examined by Doppler ultrasonography immediately before renalbiopsy. The resistive and atrophic indices (RI & AI) were calculated and compared with histologic changes in biopsy specimen. RESULTS: Receiver Operator Characteristics analysis showed RI of 0.60 as an optimal value for discriminating tubulointerstitial changes with sensitivity of 82.7% and specificity of 92%. An AI of 0.65 was shown to be optimal for discriminating tubulointerstitial injury with sensitivity of 69.2% and specificity of 85%. The combination of the two indices had not been found to be superior to either index alone. There was a significant correlation between atrophic and resistive indices. (r=0.358, p< 0.01). It was observed that older age, smoking, elevated AI and RI, low GFR, high serum cholesterol and Hypertension were found to be significantly associated with the presence of tubulointerstitial injury in the univariate analysis whereas only elevated AI and RI were found to predict tubulointerstitial injury in multivariate analysis. CONCLUSION: Measurement of RI by Doppler ultrasound can be considered as a supplementary diagnostic tool in glomerular diseases to predict the severity of tubulointerstitial injury.

Focal segmental glomerulosclerosis due to a relapsing non-Hodgkin's lymphoma diagnosed by positron emission tomography.

Glomerulonephritis rarely appears associated with Hodgkin's disease or non-Hodgkin's lymphoma (NHL). We present a patient with a relapse of a non-Hodgkin's lymphoma which first presented as nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS). This case report discusses the unusual association of non-Hodgkin's lymphoma and focal segmental glomerulosclerosis, as well as the crucial role of positron emission tomography in detecting the relapsing lymphoma.

CADASIL: Ultrastructural insights into the morphology of granular osmiophilic material.

INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary systemic vascular disorder. Granular osmiophilic material (GOM) is its ultrastructural marker. We reviewed tissue biopsies from CADASIL patients to establish whether ultrastructural observations help clarify the pathogenic mechanism of CADASIL. Given the resemblance of the GOM deposits to the immunoglobulin deposits seen in glomerulonephritis and focal segmental glomerulosclerosis (FSGS), their morphologies were investigated and compared. METHODS: Skin, skeletal muscle, kidney, and pericardium tissue biopsies from 13 patients with a clinical and molecular diagnosis of CADASIL, and kidney biopsies from five patients with IgA nephropathy and five patients with primary FSGS were subjected to ultrastructural examination. RESULTS: In CADASIL patients, several GOM deposits from all sites were partially or totally surrounded by an electron-lucent halo. The deposits frequently had a more electron-dense portion with a regular outline on the inner side and a less osmiophilic, looser outer side displaying a less regular profile. The uniformly dense deposits tended to be more osmiophilic if located close to the cell membrane and less osmiophilic if laid farther away from it. The immunoglobulin deposits from the glomerulonephritis and FSGS patients lacked both the granular pattern and the halo. CONCLUSIONS: This study demonstrates that GOM deposits may have a nonuniform morphology and describes in detail an electron-lucent halo surrounding several of them. It is conceivable that the halo is the morphological evidence and possibly the cause of an aberrant NOTCH3 processing, already suspected to be involved in CADASIL.

Association of Renal Elasticity and Renal Function Progression in Patients with Chronic Kidney Disease Evaluated by Real-Time Ultrasound Elastography.

Glomerulosclerosis and tubulointerstitial fibrosis are associated with lower renal parenchymal elasticity. This study was designed to evaluate the predictive ability of renal elasticity in patients with chronic kidney disease (CKD). 148 non-CKD patients and 227 patients with CKD were recruited. 145 (38.7%) were female, 166 (73.1%) had diabetes, the mean estimated glomerular filtration rate (eGFR) was 33.9 ± 15.8 ml/min/1.73 m2 and the median urinary protein-to-creatinine ratio (UPCR) 502 (122-1491) mg/g. Patients with later stages of CKD had lower renal elasticity values, indicating stiffer kidneys (p < 0.001), and smaller kidney (p < 0.001). Renal elasticity correlated with log-transformed UPCR (ß = -7.544, P < 0.001). Renal length correlated with age (ß = -0.231, P < 0.001), sex (ß = -3.730, P < 0.001), serum albumin level (ß = -3.024, P = 0.001), body mass index (ß = 0.390, P = 0.009) and eGFR (ß = 0.146, P < 0.001). In fully-adjusted logistic regression model, the odds ratio (OR) per 10 unit change in renal elasticity for rapid renal deterioration was 0.928 (95% CI, 0.864-0.997; P = 0.042). The OR per 1 mm change in renal length for rapid renal deterioration was 1.022 (95% CI, 0.994-1.050; P = 0.125). Renal elasticity is associated with proteinuria and rapid renal deterioration in patients with CKD.

Long-term treatment with chaethomellic acid A reduces glomerulosclerosis and arteriolosclerosis in a rat model of chronic kidney disease.

The high prevalence of end-stage renal disease emphasizes the failure to provide therapies to effectively prevent and/or reverse renal fibrosis. Therefore, the aim of this study was to evaluate the effect of long-term treatment with chaethomellic acid A (CAA), which selectively blocks Ha-Ras farnesylation, on renal mass reduction-induced renal fibrosis. Male Wistar rats were sham-operated (SO) or subjected to 5/6 renal mass reduction (RMR). One week after surgery, rats were placed in four experimental groups: SO:SO rats without treatment (n=13); SO+CAA: SO rats treated with CAA (n=13); RMR:RMR rats without treatment (n=14); and RMR+CAA:RMR rats treated with CAA (n=13). CAA was intraperitoneally administered in a dose of 0.23µg/kg three times a week for six months. Renal fibrosis was evaluated by two-dimensional ultrasonography and histopathological analysis. The kidneys of the RMR animals treated with CAA showed a significantly decrease in the medullary echogenicity (p<0.05) compared with the RMR rats that received no treatment. Glomerulosclerosis and arteriolosclerosis scores were significantly lower (p<0.001) in the RMR+CAA group when compared with the RMR group. There were no significant differences in interstitial fibrosis, interstitial inflammation and tubular dilatation scores between the RMR+CAA and RMR groups. These data suggest that CAA can be a potential future drug to attenuate the progression of chronic kidney disease.

Practical Application of Columbia Classification for Focal Segmental Glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a heterogeneous clinicopathological entity. Two frameworks for the classification of FSGS have been described: etiologic and morphologic. The etiologic classification is distinguished among genetic, adaptive, virus-associated, drug-induced, and idiopathic types. Morphologic classification is commonly referred to as the Columbia classification published in 2004, which distinguishes five variants: collapsing, tip, cellular, perihilar, and not otherwise specified (NOS). This classification is based on light microscopic patterns with rigorously defined specific criteria, which can be applied to primary and secondary forms of FSGS, and has been widely used over the past 10 years both as a diagnostic and as a prognostic clinical tool. This paper defines common histopathological features of FSGS, distinguished characters among five variants, and points out the confusion about terminology of variants, because most were proposed in the past with different definitions. Despite good interobserver reproducibility of this classification system, difficulty in its application may arise in the interpretation of lesions with mixed features of more than one variant in the same tissue specimen and with late lesions, because other variants may evolve into the NOS variant over time.

Recurrence and Treatment after Renal Transplantation in Children with FSGS.

Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease and a common pathologic diagnosis of idiopathic nephrotic syndrome (NS), especially in steroid-resistant cases. FSGS is known to recur after kidney transplantation, frequently followed by graft loss. However, not all patients with FSGS suffer from recurrence after kidney transplantation, and genetic and secondary FSGS have a negligible risk of recurrence. Furthermore, many cases of recurrence achieve remission with the current management of recurrence (intensive plasmapheresis/immunosuppression, including rituximab), and other promising agents are being evaluated. Therefore, a pathologic diagnosis of FSGS itself should not cause postponement of allograft kidney transplantation. For patients with a high risk of recurrence who presented with classical symptoms of NS, that is, severe edema, proteinuria, and hypoalbuminemia, close monitoring of proteinuria is necessary, followed by immediate, intensive treatment for recurrence.

The Application of Digital Pathology to Improve Accuracy in Glomerular Enumeration in Renal Biopsies.

BACKGROUND: In renal biopsy reporting, quantitative measurements, such as glomerular number and percentage of globally sclerotic glomeruli, is central to diagnostic accuracy and prognosis. The aim of this study is to determine the number of glomeruli and percent globally sclerotic in renal biopsies by means of registration of serial tissue sections and manual enumeration, compared to the numbers in pathology reports from routine light microscopic assessment. DESIGN: We reviewed 277 biopsies from the Nephrotic Syndrome Study Network (NEPTUNE) digital pathology repository, enumerating 9,379 glomeruli by means of whole slide imaging. Glomerular number and the percentage of globally sclerotic glomeruli are values routinely recorded in the official renal biopsy pathology report from the 25 participating centers. Two general trends in reporting were noted: total number per biopsy or average number per level/section. Both of these approaches were assessed for their accuracy in comparison to the analogous numbers of annotated glomeruli on WSI. RESULTS: The number of glomeruli annotated was consistently higher than those reported (p<0.001); this difference was proportional to the number of glomeruli. In contrast, percent globally sclerotic were similar when calculated on total glomeruli, but greater in FSGS when calculated on average number of glomeruli (p<0.01). The difference in percent globally sclerotic between annotated and those recorded in pathology reports was significant when global sclerosis is greater than 40%. CONCLUSIONS: Although glass slides were not available for direct comparison to whole slide image annotation, this study indicates that routine manual light microscopy assessment of number of glomeruli is inaccurate, and the magnitude of this error is proportional to the total number of glomeruli.