Evidence from the large VALIGA cohort validates the subclassification of focal segmental glomerulosclerosis in IgA nephropathy.

Evidence from the Oxford IgA nephropathy (IgAN) cohort supports the clinical value of subclassifying focal segmental glomerulosclerosis lesions (S1). Using the larger Validation in IgA (VALIGA) study cohort, we investigated the association between podocytopathic changes and higher proteinuria, kidney outcome and response to immunosuppressive therapy. All biopsies were evaluated for glomeruli with segmental capillary occlusion by matrix ("not otherwise specified", NOS lesion), simple capsular adhesion without capillary occlusion (Adh), tip lesions, and podocyte hypertrophy (PH). S1 required a NOS lesion and/or Adh. A Chi-Squared Automatic Interaction Detection method was used to identify subgroups of FSGS lesions associated with distinctive proteinuria at biopsy. We assessed survival from a combined event (kidney failure or 50% decline in estimated glomerular filtration rate). Finally, we evaluated within each subgroup if immunosuppression was associated with a favorable outcome using propensity analysis. In 1147 patients, S1 was found in 70% of biopsies. Subclassification found NOS lesions in 44%, Adh in 59%, PH in 13%, and tip lesions in 3%, with much overlap. Four subgroups were identified with progressively higher proteinuria: from lowest, S1 without NOS, S1 with NOS but without Adh/PH, to highest, S1 with NOS and Adh but without PH, and S1 with NOS and PH. These four subgroups showed progressively worse kidney survival. Immunosuppression was associated with a better outcome only in the two highest proteinuria subgroups. Propensity analysis in these two groups, adjusted for clinical and pathological findings, found a significantly reduced time-dependent hazard of combined outcome with corticosteroids. Podocyte hypertrophy and glomeruli with simple adhesions appeared to reflect active lesions associated with a response to corticosteroids, while other S1 lesions defined chronicity. Thus, our findings support subclassifying S1 lesions in IgAN.

Identification of Genetic Causes of Focal Segmental Glomerulosclerosis Increases With Proper Patient Selection.

OBJECTIVE: To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. PATIENTS AND METHODS: Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. RESULTS: The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P<.001), absence of nephrotic syndrome (OR, 8.2; 95% CI, 1.9 to 58.1; P=.004), and female sex (OR, 5.1; 95% CI, 1.5 to 19.9; P=.01) were strong predictors of finding a causative genetic variant in the entire cohort. The most common variants were in the collagen genes (52.4%; 11/21), followed by the podocyte genes (38.1%; 8/21). CONCLUSION: In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.

Predictive value of sub classification of focal segmental glomerular sclerosis in Oxford classification of IgA nephropathy.

BACKGROUND: The Oxford classification of IgA nephropathy (IgAN) was revised in 2016 which lacked sufficient evidence for prognostic value of subclassification of focal segmental glomerular sclerosis (S lesion), and the proper proportion of S lesion for subclassification remains undetermined. AIM: This study aimed to explore the predictive value of the new subclassification of S score on renal outcomes of IgAN patients. METHODS: 348 patients with IgAN-associated S lesion were enrolled. According to the optimal cut-off of 25% established by receiver operating characteristic (ROC) curves, we divided S1 patients into two groups: S1a group (S lesion < 25%) and S1b group (S lesion ≥ 25%). IgAN patients with mild lesion (M0E0S0T0C0) were set as the control group. The clinical features at renal biopsy, pathological findings, and follow-up parameters (follow-up time ranged from 1 to 5 years) were collected. We used univariate and multivariate analyses to assess whether the subclassification of S score could refine risk prediction and clinical utility. RESULTS: We demonstrated that S lesion ≥ 25% was associated with a more rapid GFR loss and a lower rate of complete remission of proteinuria even adjusted for multiple clinic pathological variables, compared to S1a group (All p values <.05). And the ratio of glomeruli with T lesion and crescents were higher in patients with S lesion ≥ 25%. Data showed that IgAN patients with S lesion ≥ 25% were at an increased risk of poor renal outcomes even with immunosuppression. CONCLUSION: This study might recommend new subclassification of S scores (S0 (no S lesion), S1 (S lesion <25% of glomeruli), and S2 (S lesion ≥ 25% of glomeruli)) for the Oxford classification. This model may also help to evaluate pros and cons of immunosuppressive therapy in IgAN patients with different level of S lesion.KEY MESSAGESS lesion ≥ 25% is an independent risk factor for poor renal outcome in IgAN patients.This new subclassification of S scores may help to evaluate pros and cons of immunotherapy in IgAN patients with different level of S lesion.

Genetic studies of focal segmental glomerulosclerosis: a waste of scientific time?

Many genetic causes of focal segmental glomerulosclerosis (FSGS) have been described. A paradox is that the science in the molecular biology, which generally appears of high quality, is not mirrored by a similarly critical analysis of the renal pathology. FSGS has been applied to such a wide range of conditions that it can reasonably be said to have no useful meaning. Attempts to refine the term have been largely ignored. Study of 252 papers on genetic causes of FSGS found various clinical features. Many papers took the reported diagnosis without question. Few papers reported a pathological review, almost half reported FSGS and up to six other conditions caused by any particular gene, some reported FSGS with recognisable glomerular disorders, over 80% did not apply the Columbia classification, and in nearly all with photomicrographs, the images were not useful for refinement of FSGS. Some workers commented on a lack of genotype-phenotype correlation. One reason is a disregard of the principle that scientific investigation requires an unambiguous definition of the condition studied, to allow others to replicate or refute the findings. Genetic studies of FSGS should use a similarly rigorous approach to renal pathology to that used in molecular biology.

Utility of Columbia classification in focal segmental glomerulosclerosis: renal prognosis and treatment response among the pathological variants.

BACKGROUND: The utility of the Columbia classification (Col-class) for focal segmental glomerulosclerosis (FSGS) has not yet been fully proven. METHODS: We extracted 201 FSGS patients from 10 nephrology centers in Japan and investigated the difference of a composite renal endpoint, defined as doubling of serum creatinine and/or development of end-stage renal disease, in pathological variants. Sensitivity analysis was used to prove the utility of the Col-class to predict renal outcomes. Additionally, the renal protective effects of steroids and/or immunosuppression (steroid/IS) were investigated in patients stratified according to the Col-class. RESULTS: The patients were classified into the following variants: not otherwise specified [NOS; n = 121 (60.1%)], perihilar [n = 31 (15.4%)], cellular [n = 19 (9.5%)], tip [n = 17 (8.5%)] and collapsing [n = 13 (6.5%)]. No tip variant patients reached the renal endpoint. The renal outcome in the collapsing variant was significantly poorer than that in the NOS [hazard ratio (HR) 3.71; P = 0.005]. In the sensitivity analysis, the area under the receiver operating characteristic curve for the renal endpoint was increased by adding Col-class to a model including common risk factors (P = 0.021). In a subgroup treated without steroid/IS, the outcome in the cellular variant was worse than that in the NOS (HR 5.10; P = 0.040) but the difference was not observed in the subgroup with steroid/IS (HR 0.54; P = 0.539). CONCLUSIONS: The Col-class is useful to predict renal prognosis in Japanese patients with FSGS. In addition to good prognosis in the tip variant and poor in the collapsing variant, good clinical course in the cellular variant treated with steroid/IS was suggested.

Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach.

FSGS describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. Subclasses of FSGS include primary, genetic, and secondary forms, the latter comprising maladaptive, viral, and drug-induced FSGS. Despite sharing certain clinical and histologic features, these subclasses differ noticeably in management and prognosis. Without an accepted nongenetic biomarker that discriminates among these FSGS types, classification of patients is often challenging. This review summarizes the clinical and histologic features, including the onset and severity of proteinuria as well as the presence of nephrotic syndrome, that may aid in identifying the specific FSGS subtype. The FSGS lesion is characterized by segmental sclerosis and must be differentiated from nonspecific focal global glomerulosclerosis. No light microscopic features are pathognomonic for a particular FSGS subcategory. The characteristics of podocyte foot process effacement on electron microscopy, while helpful in discriminating between primary and maladaptive FSGS, may be of little utility in detecting genetic forms of FSGS. When FSGS cannot be classified by clinicopathologic assessment, genetic analysis should be offered. Next generation DNA sequencing enables cost-effective screening of multiple genes simultaneously, but determining the pathogenicity of a detected genetic variant may be challenging. A more systematic evaluation of patients, as suggested herein, will likely improve therapeutic outcomes and the design of future trials in FSGS.

Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group.

Since the Oxford Classification of IgA nephropathy (IgAN) was published in 2009, MEST scores have been increasingly used in clinical practice. Further retrospective cohort studies have confirmed that in biopsy specimens with a minimum of 8 glomeruli, mesangial hypercellularity (M), segmental sclerosis (S), and interstitial fibrosis/tubular atrophy (T) lesions predict clinical outcome. In a larger, more broadly based cohort than in the original Oxford study, crescents (C) are predictive of outcome, and we now recommend that C be added to the MEST score, and biopsy reporting should provide a MEST-C score. Inconsistencies in the reporting of M and endocapillary cellularity (E) lesions have been reported, so a web-based educational tool to assist pathologists has been developed. A large study showed E lesions are predictive of outcome in children and adults, but only in those without immunosuppression. A review of S lesions suggests there may be clinical utility in the subclassification of segmental sclerosis, identifying those cases with evidence of podocyte damage. It has now been shown that combining the MEST score with clinical data at biopsy provides the same predictive power as monitoring clinical data for 2 years; this requires further evaluation to assess earlier effective treatment intervention. The IgAN Classification Working Group has established a well-characterized dataset from a large cohort of adults and children with IgAN that will provide a substrate for further studies to refine risk prediction and clinical utility, including the MEST-C score and other factors.

Evidence from the Oxford Classification cohort supports the clinical value of subclassification of focal segmental glomerulosclerosis in IgA nephropathy.

Focal segmental glomerulosclerosis (FSGS) is a common finding in IgA nephropathy (IgAN). Here we assessed FSGS lesions in the Oxford Classification patient cohort and correlated histology with clinical presentation and outcome to determine whether subclassification of the S score in IgAN is reproducible and of clinical value. Our subclassification of lesions in 137 individuals with segmental glomerulosclerosis or adhesion (S1) identified 38% with podocyte hypertrophy, 10% with hyalinosis, 9% with resorption droplets within podocytes, 7% with tip lesions, 3% with perihilar sclerosis, and 2% with endocapillary foam cells. Reproducibility was good or excellent for tip lesions, hyalinosis, and perihilar sclerosis; moderate for podocyte hypertrophy; and poor for resorption droplets, adhesion only, and endocapillary foam cells. Podocyte hypertrophy and tip lesions were strongly associated with greater initial proteinuria. During follow-up of patients without immunosuppression, those with these features had more rapid renal function decline and worse survival from a combined event compared to S1 patients without such features and those without FSGS. Also in individuals with podocyte hypertrophy or tip lesions, immunosuppressive therapy was associated with better renal survival. In IgA nephropathy, the presence of podocyte hypertrophy or tip lesions, markers of podocyte injury, were reproducible. These features are strongly associated with proteinuria and, in untreated patients, carry a worse prognosis. Thus, our findings support reporting podocytopathic features alongside the S score of the Oxford Classification.

Minimal change disease and idiopathic FSGS: manifestations of the same disease.

Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the key histological findings in patients with idiopathic nephrotic syndrome (INS). Although MCD and idiopathic FSGS are often considered to represent separate entities based on differences in their presenting characteristics, histology and outcomes, little evidence exists for this separation. We propose that MCD and idiopathic FSGS are different manifestations of the same progressive disease. The gradual development of FSGS in patients with non-remitting or relapsing INS has been well documented. Moreover, FSGS is the uniform result of substantial podocyte loss in animal models, and a common feature of virtually all progressive human glomerulopathies. As evidence suggests a common aetiology, the pathogenesis of MCD and idiopathic FSGS should be studied together. In clinical trials, idiopathic FSGS should be considered to represent an advanced stage of disease progression that is less likely to respond to treatment than the earlier stage of disease, which is usually defined as MCD.

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.

A case of recurrent focal segmental glomerulosclerosis after kidney transplantation associated with variant conversion in the Columbia classification.

Focal segmental glomerulosclerosis commonly recurs following kidney transplantation. A 33-year-old man underwent living donor kidney transplantation. Proteinuria appeared two months after transplantation, and an episode biopsy on postoperative day 66 revealed recurrent focal segmental glomerulosclerosis lesions of the cellular variant by Columbia classification. We reviewed the native kidney biopsy and confirmed collapsing variant focal segmental glomerulosclerosis. Plasma exchange therapy was performed, and his proteinuria temporarily resolved. A second allograft biopsy performed on postoperative day 200 showed no evidence of focal segmental glomerurosclerosis. He experienced incomplete remission with a proteinuria of 0.5 g/day during the subsequent three years until his urinary protein level rose to 1.3 g/day. A third biopsy performed on postoperative day 1248 showed focal segmental glomerulosclerosis cellular variant lesions. Plasma exchange was resumed in combination with additional rituximab, but his proteinuria persisted. Intermittent plasma exchange was performed 42 times in total. However, his proteinuria continued, and his renal function gradually worsened. A fourth biopsy performed on postoperative day 2540 showed focal segmental glomerulosclerosis collapsing variant lesions with severe interstitial fibrosis and tubular atrophy. He ultimately required hemodialysis seven years after transplantation. Intensive therapy with long-term intermittent plasma exchange and rituximab suppressed proteinuria and preserved graft function for seven years, at which time graft failure occurred. We here present the clinical course and histological findings from consecutive allograft biopsies.

[Collapsing variant of focal segmental glomerulosclerosis by parvovirus B19: case report]. / Glomeruloesclerose segmentar e focal (GESF) colapsante associada ao parvovírus B19: relato de caso.

OBJECTIVE: To describe the clinical and laboratory profile of focal segmental glomerulosclerosis (FSGS) of the collapsing subtype in association with infection by parvovirus B19 (PVB19). CASE REPORT: Female patient, 37 years old, mulatto, developed pharyngalgia and fever with partial improvement after penicillin. After one week we observed reduced urinary output and lower limb edema. Smoker, family and personal history negative for hypertension, diabetes or kidney disease. Patient presented with olyguria, hypertension and edema, also hypochromic microcytic hypoproliferative anemia, nephritic range proteinuria, microscopic hematuria and renal dysfunction. All rheumatologic investigation, HIV and hepatitis serology were negative. Unremarkable renal ultrasound. PCR positive for PVB19 in bone marrow aspirate and blood and renal biopsy conclusive of collapsing FSGS subtype. Spontaneous remission occurred within two weeks of the profile. The blood PVB19 PCR was repeated within a month and resulted negative. This finding demonstrated PVB19 acute infection or viral reactivation in association with collapsing FSGS. CONCLUSION: There is demonstrated the temporal association of PVB19 viremia and collapsing FSGS, due primary infection or viral reactivation. The association of collapsing FSGS and PVB19 is described in the literature, demonstrating virus presence in kidney tissue, but the real relationship of virus in the pathogenesis of this glomerulopathy remains unclear.

Glomeruloesclerose segmentar e focal (GESF) colapsante associada ao parvovírus B19: relato de caso / Collapsing variant of focal segmental glomerulosclerosis by parvovirus B19: case report

Objetivo: Descrever quadro clínico-laboratorial de glomeruloesclerose segmentar e focal (GESF) subtipo colapsante em associação com infecção por parvovírus B19 (PVB19). Relato do caso: Paciente feminino, 37 anos, parda, iniciou quadro de faringoalgia e febre aferida com melhora parcial após penicilina. Com uma semana, observou redução de débito urinário e edema de membros inferiores. Tabagista, com histórico familiar e pessoal negativos para hipertensão, diabetes ou nefropatias. À admissão, apresentava-se com oliguria, hipertensão e edema, associados à anemia microcítica e hipocrômica hipoproliferativa, proteinúria nefrótica, hematúria microscópica e alteração da função renal. A investigação reumatológica e sorologias para hepatites e HIV foram negativas. Ultrassonografia de rins e vias urinárias sem alterações. PCR foi positivo para PVB19 em aspirado de medula óssea e sangue. A biópsia renal conclusiva de GESF subtipo colapsante. Ocorreu remissão espontânea com duas semanas do quadro. Em retorno ambulatorial, o PCR em sangue periférico foi negativo para PVB19, sugerindo associação de GESF colapsante a fase aguda ou reativação da infecção viral. Conclusão : Este relato registra a associação temporal entre GESF colapsante e viremia pelo PVB19, seja por infecção aguda ou reativação de infecção latente. A associação GESF colapsante e PVB19 é descrita na literatura, com demonstração da presença do vírus em tecido renal, porém, a real relação do vírus na patogênese dessa glomerulopatia permanece indefinida. .

Objective: To describe the clinical and laboratory profile of focal segmental glomerulosclerosis (FSGS) of the collapsing subtype in association with infection by parvovirus B19 (PVB19). Case report: Female patient, 37 years old, mulatto, developed pharyngalgia and fever with partial improvement after penicillin. After one week we observed reduced urinary output and lower limb edema. Smoker, family and personal history negative for hypertension, diabetes or kidney disease. Patient presented with olyguria, hypertension and edema, also hypochromic microcytic hypoproliferative anemia, nephritic range proteinuria, microscopic hematuria and renal dysfunction. All rheumatologic investigation, HIV and hepatitis serology were negative. Unremarkable renal ultrasound. PCR positive for PVB19 in bone marrow aspirate and blood and renal biopsy conclusive of collapsing FSGS subtype. Spontaneous remission occurred within two weeks of the profile. The blood PVB19 PCR was repeated within a month and resulted negative. This finding demonstrated PVB19 acute infection or viral reactivation in association with collapsing FSGS. Conclusion: There is demonstrated the temporal association of PVB19 viremia and collapsing FSGS, due primary infection or viral reactivation. The association of collapsing FSGS and PVB19 is described in the literature, demonstrating virus presence in kidney tissue, but the real relationship of virus in the pathogenesis of this glomerulopathy remains unclear. .

Valor diagnóstico de los niveles séricos del receptor soluble de la uroquinasa en adultos con síndrome nefrótico idiopático / Diagnostic value of soluble urokinase-type plasminogen activator receptor serum levels in adults with idiopathic nephrotic syndrome

Introducción: Estudios recientes sugieren que los niveles del receptor soluble de la uroquinasa (suPAR) podrían ser útiles para diferenciar la glomeruloesclerosis focal y segmentaria (GFS) idiopática de otras glomerulopatías causantes de síndrome nefrótico, pero estos datos no han sido confirmados en estudios independientes. El objetivo de nuestro estudio es analizar si los niveles circulantes de suPAR son útiles para identificar la enfermedad renal primaria en enfermos afectos de síndrome nefrótico secundario a GFS, enfermedad por cambios mínimos o nefropatía membranosa (NM) idiopática. Métodos: Se realizaron mediciones de niveles de suPAR circulante en el momento del diagnóstico en 60 pacientes con síndrome nefrótico secundario a GFS, enfermedad por cambios mínimos (ECM) y NM. Se analizaron las correlaciones entre niveles de suPAR y variables demográficas, clínicas y bioquímicas. La sensibilidad y la especificidad de suPAR para diferenciar a los enfermos con GFS se analizaron mediante curvas ROC. Resultados: Tras ajustar por edad y función renal, los niveles de suPAR fueron significativamente más elevados en enfermos con GFS que en ECM (p < 0,001), pero no hubo diferencias entre GFS y NM (p = 0,12). Un valor de suPAR ≥ 3452 pg/ml tuvo una sensibilidad del 73,7 % y una especificidad del 72,5 %, con un área bajo la curva (ABC) de 0,782 ± 0,124, p = 0,001, para identificar a los enfermos con GFS. Tras excluir a los enfermos con NM, un valor ≥ 3531 pg/ml tuvo una especificidad del 99,93 % para diferenciar entre ECM y GFS. Conclusiones: Los valores de suPAR por sí solos no diferencian entre los tres tipos de glomerulopatía. Sin embargo, tras excluir el diagnóstico de NM, un nivel de suPAR > 3531 pg/ml podría tener una elevada especificidad (pero baja sensibilidad) para el diagnóstico de GFS

Introduction: Recent studies suggest that soluble urokinase-type plasminogen activator receptor (suPAR) levels could be useful for distinguishing idiopathic focal segmental glomerulosclerosis (FSGS) from other glomerulopathies that cause nephrotic syndrome, but these data have not been confirmed in independent studies. The objective of our study is to analyse whether circulating levels of suPAR are useful for identifying primary kidney disease in patients with nephrotic syndrome secondary to FSGS, minimal change disease or idiopathic membranous nephropathy (MN). Methods: We measured circulating suPAR at diagnosis in 60 patients with nephrotic syndrome secondary to FSGS, minimal change disease (MCD) and membranous nephropathy (MN). The correlations between suPAR levels and demographic, clinical and biochemical variables were analysed. The sensitivity and specificity of suPAR in distinguishing FSGS patients were analysed by ROC curves. Results: After adjusting for age and renal function, suPAR levels were significantly higher in patients with FSGS than in those with MCD (p<.001), but there were no differences between FSGS and MN (P=.12). A suPAR value ≥3452pg/ml had a sensitivity of 73.7% and a specificity of 72.5%, with an area under the curve (AUC) of 0.782±0.124, p=.001, for identifying patients with FSGS. After excluding patients with MN, a value ≥3531pg/ml had a specificity of 99.93% for distinguishing between MCD and FSGS. Conclusions: suPAR values alone do not distinguish between the three types of glomerulopathy. Nevertheless, after excluding the diagnosis of MN, a suPAR level >3531pg/ml could have a high specificity (but a low sensitivity) in the diagnosis of FSGS

Valor de los niveles séricos del receptor soluble de la uroquinasa en el diagnóstico diferencial entre glomeruloesclerosis focal y segmentaria idiopática y secundaria / Value of soluble urokinase receptor serum levels in the differential diagnosis between idiopathic and secondary focal segmental glomerulosclerosis

Antecedentes: Se ha descrito que el nivel circulante del receptor soluble de la uroquinasa (suPAR) podría ser útil para diferenciar la glomeruloesclerosis focal y segmentaria idiopática de las formas secundarias, pero los resultados publicados son discordantes. En el presente estudio, se analiza la variabilidad intraindividual, las variables clínicas y anatomopatológicas asociadas con los niveles de suPAR y si los niveles circulantes de suPAR permiten diferenciar las formas de glomeruloesclerosis focal y segmentaria (GFS) idiopáticas de las GFS secundarias, independientemente de la presencia de síndrome nefrótico y de la fase de actividad. Métodos: Se estudiaron 35 pacientes afectos de GFS idiopática y 48 con GFS secundaria (83 en total). Se realizaron mediciones de suPAR circulante en el momento del diagnóstico y/o tras la remisión y se analizaron las correlaciones entre niveles de suPAR y variables demográficas, clínicas y bioquímicas. La capacidad de suPAR para diferenciar entre ambas formas de GFS se analizó mediante curvas ROC y análisis de regresión logística. Resultados: En ambas formas de GFS, los niveles de suPAR fueron independientes de la proteinuria y del subtipo histopatológico de GFS y se asociaron significativamente a la edad y a la función renal. Tras ajustar por ambas variables, los niveles de suPAR fueron significativamente superiores en los enfermos con GFS idiopática, tanto en fase de síndrome nefrótico como en situación de remisión parcial o total. El nivel de suPAR con mayor sensibilidad (80 %) y mayor especificidad (73 %) para discriminar entre formas idiopáticas y secundarias fue de 3443,6 pg/ml (área bajo la curva [ABC] 0,78 ± 0,083, p < 0,001). En el análisis de regresión logística, tras ajustar por edad, función renal y presencia de síndrome nefrótico, los niveles de suPAR se asociaron de forma independiente con el diagnóstico de GFS idiopática, pero el modelo tuvo un mal ajuste para categorías de riesgo bajas, en las que tendió a clasificar las formas primarias como secundarias (χ 2 = 11,2 p = 0,027). Conclusiones: Los niveles de suPAR carecen de sensibilidad para diferenciar entre GFS idiopática y secundaria. Sin embargo, valores de suPAR superiores a 4000 ng/ml son altamente específicos de GFS primaria, por lo que, ante un patrón morfológico de GFS asociado a proteinuria no nefrótica, indicarían una baja probabilidad de GFS secundaria (AU)

Background: It has been reported that the circulating level of the soluble urokinase receptor (suPAR) could be useful for distinguishing idiopathic from secondary focal segmental glomerulosclerosis, but the results published are conflicting. In this study, we analyse the intraindividual variability and clinical and anatomopathological variables associated with the suPAR levels and if circulating suPAR levels allow the different forms of focal segmental glomerulosclerosis (FSGS) to be distinguished, i.e., idiopathic forms from secondary FSGS, regardless of the presence of nephrotic syndrome and the activity phase. Method: We studied 35 patients affected by idiopathic FSGS and 48 with secondary FSGS (83 in total). We carried out measurements of circulating suPAR at the time of diagnosis and/or after remission and we analysed correlations between suPAR levels and demographic, clinical and biochemical variables. The ability of suPAR to distinguish between both forms of FSGS was analysed by ROC curves and logistic regression analysis. Results: In both forms of FSGS, suPAR levels were independent of proteinuria and the histopathological subtype of FSGS and they were significantly associated with age and renal function. After adjusting for both variables, suPAR levels were significantly higher in patients with idiopathic FSGS, both in the nephrotic syndrome phase and in partial or complete remission. The most sensitive suPAR level (80%) and the most specific (73%) for discriminating between idiopathic and secondary forms was 3443.6pg/ml (area below curve [ABC] 0.78±0.083, P<.001). In the logistic regression analysis, after adjusting for age, renal function and presence of nephrotic syndrome, suPAR levels were independently associated with the diagnosis of idiopathic FSGS, but the model was poorly adjusted for low risk categories in which it tended to classify primary forms as secondary forms (χ 2 = 11.2 p=.027). Conclusions: SuPAR levels lack sensitivity for differentiating between idiopathic and secondary FSGS. However, suPAR values greater than 4000ng/ml are highly specific to primary FSGS, and as such, with a morphological FSGS pattern associated with non-nephrotic proteinuria, they would indicate a low probability of secondary FSGS (AU)

Validation of the new classification of pauci-immune glomerulonephritis in a United States cohort and its correlation with renal outcome.

BACKGROUND: Renal biopsies provide important diagnostic and prognostic information in ANCA associated glomerulonephritis. A new classification for prognostication of pauci-immune glomerulonephritis (GN) based on four categories (Mixed, Crescentic, Sclerotic and Focal) was proposed by an international working group of renal pathologists (IWGRP). The goal of our study was to apply the proposed classification system to a United States cohort of vasculitis patients and determine the association of IWGRP class with estimated glomerular filtration rate (eGFR) at one year. METHODS: Seventy-six cases of pauci-immune glomerulonephritis diagnosed from 1995 to 2011 from a single center were identified for this retrospective study. Clinical data were collected by abstraction from medical records. Histology was reviewed by a pathologist and classified according to the new classification. MDRD formula was used to calculate eGFR. We correlated IWGRP class to renal function at presentation and at one year. ×2, ANOVA, and linear regression analysis were performed as appropriate. RESULTS: Renal biopsies were categorized as focal: n = 20, crescentic: n = 18, mixed: n = 27, sclerotic: n = 11. The baseline e-GFR was lowest in the crescentic class and highest in the focal class. In linear regression analysis investigating e-GFR at 1 year; age and baseline e-GFR were independent predictors of e-GFR at 1 year. CONCLUSIONS: The e-GFR at diagnosis and age were predictors of e-GFR at 1 year. Pathologic class at diagnosis may also be a helpful tool in risk stratification at diagnosis.

[Primary focal segmental glomerular sclerosis in children: epidemiology and prognosis]. / Hyalinose segmentaire et focale primitive de l'enfant : épidémiologie et facteurs pronostiques.

Focal segmental glomerulosclerosis (FSGS) is the morphologic description of a glomerular lesion which is "focal", meaning a few but not all of the total sampled glomeruli have and "segmental" solidification of the tuft that is an accumulation of extracellular matrix with obliteration of the capillary lumina (sclerosis). It represents 20% of nephrotic syndrome in children and adults. To study the role of epidemiology, clinical presentation, histology, and treatment in the prognosis of HSF child, we retrospectively analyzed 23 children with primary focal segmental glomerulosclerosis (FSGS) hospitalized in pediatric nephrology unit of Children's Hospital Harrouchi Abderrahim, CHU Ibn Rochd Casablanca from January 2000 to December 2012. The main age at onset was 7.5 years with a male predominance. Hematuria was seen in 22% of patients, hypertension in 48% of patients, and moderate renal insufficiency in one patient at presentation. According to the histological classification of Columbia, 40% of patients have a non-specific HSF (NOS), including six patients who have responded to treatment and one patient progressed to renal failure, 13% have a perihilar HSF (PH) with a good prognosis, 8% have a HSF cell (CELL), which evolved to renal failure, 35% of HSF was a tubular pole (TIP) including five patients responded to treatment and 4% was a HSF collapsing (COL) having a renal failure at admission. The FSGS's prognosis is related to several predictive factors.

Histologic variants of primary focal segmental glomerulosclerosis: presentation and outcome.

INTRODUCTION: The clinical significance of histologic variants of primary focal segmental glomerulosclerosis (FSGS) remains unclear. With the aim to determine presentation and outcome of the variants of FSGS in a hispanic population, we studied our cases of this glomerulopathy. METHODS: In this retrospective study, all renal biopsies with FSGS (1998-2009), were classified according to the Columbia's classification. We analyzed histological, clinical and follow-up data and compared among variants. RESULTS: Among 291 cases, 224 (77.0%) corresponded to NOS variant, 40 cases (13.7%) to tip variant (TIP), 14 cases (4.8%) to perihilar (PH), 10 cases (3.4%) to collapsing (COLL) and three cases (1.0%) to cellular variant (CELL). Median age: 26 years (range 1 to 79); 74 patients (25.4%) were < 15 years of age. Hypertension and renal dysfunction were more frequent in PH and COLL cases. PH presented frequently as nonnephrotic proteinuria. There were fewer histologic chronic lesions in TIP cases. There was remission in 23.5% of patients with NOS, 57.7% of patients with TIP, 22.2% of patients with COLL and 0 patients with PH (p < 0.01). Chronic kidney disease (CKD) was less frequent in TIP than in the other variants (p = 0.03). There were not statistical differences for end-stage renal disease among variants. CONCLUSIONS: Glomerular histological appearance is not a good indicator of outcome. COLL is a disease with many differences to the other variants and bad prognosis; PH is a variant mainly of adults, with frequent evolution to CKD. TIP appears as a less aggressive, although not benign, variant.