Urine MMP7 as a kidney injury biomarker.

Matrix metalloproteinase 7 (MMP-7) is a secreted endopeptidase involved in the degradation of extracellular matrix components and the activation of cytokines and growth factors. The regulation of MMP-7 can be transcriptionally regulated by AP-1 or Wnt/ß-catenin or post-translationally by proteolytic activation. MMP-7 expression is low or absent in the healthy kidney, but is significantly upregulated in kidney injury, including AKI and CKD. The function of MMP-7 in kidney disease may differ for CKD and AKI; it may have a profibrotic role in CKD and an anti-apoptotic and regenerative function in AKI. Additionally, the potential of MMP-7 as a biomarker has been studied in different kidney diseases, and the results are promising. Recently, combined unbiased kidney proteomics and transcriptomics approaches identified kidney MMP-7 as the protein having the strongest association with both fibrosis and eGFR and confirmed the predictive role of plasma MMP-7 levels for kidney function decline in over 11 000 individuals. Additionally, urinary MMP-7, combined with urinary cystatin C (CysC) and retinol binding protein (RBP) was reported to provide information on tubular injury in focal segmental glomerulosclerosis and minimal change disease. We now present an overview of research on MMP-7 expression and function in kidney diseases and discuss its potential as a biomarker of kidney diseases.

Ocular manifestations of the genetic causes of focal and segmental glomerulosclerosis.

Genetic forms of focal and segmental glomerulosclerosis (FSGS) often have extra-renal manifestations. This study examined FSGS-associated genes from the Genomics England Renal proteinuria panel for reported and likely ocular features. Thirty-two of the 55 genes (58%) were associated with ocular abnormalities in human disease, and a further 12 (22%) were expressed in the retina or had an eye phenotype in mouse models. The commonest genes affected in congenital nephrotic syndrome (NPHS1, NPHS2, WT1, LAMB2, PAX2 but not PLCE1) may have ocular manifestations . Many genes affected in childhood-adolescent onset FSGS (NPHS1, NPHS2, WT1, LAMB2, SMARCAL1, NUP107 but not TRPC6 or PLCE1) have ocular features. The commonest genes affected in adult-onset FSGS (COL4A3-COL4A5, GLA ) have ocular abnormalities but not the other frequently affected genes (ACTN4, CD2AP, INF2, TRPC6). Common ocular associations of genetic FSGS include cataract, myopia, strabismus, ptosis and retinal atrophy. Mitochondrial forms of FSGS (MELAS, MIDD, Kearn's Sayre disease) are associated with retinal atrophy and inherited retinal degeneration. Some genetic kidney diseases (CAKUT, ciliopathies, tubulopathies) that result in secondary forms of FSGS also have ocular features. Ocular manifestations suggest a genetic basis for FSGS, often help identify the affected gene, and prompt genetic testing. In general, ocular abnormalities require early evaluation by an ophthalmologist, and sometimes, monitoring or treatment to improve vision or prevent visual loss from complications. In addition, the patient should be examined for other syndromic features and first degree family members assessed.

Review of the Role of Rituximab in the Management of Adult Minimal Change Disease and Immune-Mediated Focal and Segmental Glomerulosclerosis.

Background: Minimal change disease and primary FSGS are podocytopathies but are also immune-mediated diseases. Rituximab acts via multiple mechanisms by tilting the balance between autoreactive B and T cells in favor of regulatory B and T cells. The consequences are decreased production of cytokines, chemokines, and permeability factors by these cells. In the past decade, we have seen the discovery of autoantibodies mediating nephrotic syndrome (anti-annexin A2 antibody, anti-UCHL1 antibody, and anti-nephrin antibody), and rituximab decreases their production. Rituximab also binds to podocyte SMPDL3b and has direct podocyte actions. Summary: Rituximab's role in managing these primary podocytopathies has been discussed in this brief review. Rituximab has been used extensively in children and adults with frequently relapsing and steroid-dependent nephrotic syndrome. However, rituximab is not very promising in adult steroid-resistant nephrotic syndrome. Although ofatumumab would cause prolonged B-cell depletion and is fully humanized, it is unclear if it is superior to rituximab in preventing relapse of nephrotic syndrome. Key Messages: Rituximab therapy can induce prolonged remission in adults with frequently relapsing and steroid-dependent nephrotic syndrome. However, no good data exist on using rituximab in steroid-resistant nephrotic syndrome.

A Study of Focal and Segmental Glomerulosclerosis according to the Columbia Classification and Its Correlation with the Clinical Outcome.

Introduction Focal and segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome in both adults and children. The "Columbia classification of FSGS" includes five variants; not otherwise specified (NOS), tip, perihilar, cellular, and collapsing variants that may have different prognostic and therapeutic implications. Materials and Methods This is a retrospective study and was carried out in the Department of Histopathology, Apollo Hospitals, Hyderabad. Of a total of 11,691 kidney biopsies over a 7-year period, from 2006 to 2012, 824 cases were diagnosed as FSGS, of which 610 cases in which detailed clinical findings were available were included in this study. FSGS was then categorized according to the Columbia classification. Results FSGS, NOS was the predominant histomorphological variant. Serum creatinine was significantly high in the collapsing variant, followed by NOS. Follow-up data was available for 103 cases,72.8% had complete remission, 10.6% had partial remission, and in 16.5 % there was no remission. Relapses were observed in 6.7% cases, two patients (1.9%) succumbed, and 4.8% cases progressed to chronic kidney disease. Conclusion This study showed that perihilar variant was less prevalent, with tip and cellular variants being more prevalent in Indian subcontinent compared to Western literature. Collapsing variant was also less common.

High Rate of Mutations of Adhesion Molecules and Extracellular Matrix Glycoproteins in Patients with Adult-Onset Focal and Segmental Glomerulosclerosis.

(1) Background: Focal and segmental glomerulosclerosis (FSGS) is a pattern of injury that results from podocyte loss in the setting of a wide variety of injurious mechanisms. These include both acquired and genetic as well as primary and secondary causes, or a combination thereof, without optimal therapy, and a high rate of patients develop end-stage renal disease (ESRD). Genetic studies have helped improve the global understanding of FSGS syndrome; thus, we hypothesize that patients with primary FSGS may have underlying alterations in adhesion molecules or extracellular matrix glycoproteins related to previously unreported mutations that may be studied through next-generation sequencing (NGS). (2) Methods: We developed an NGS panel with 29 genes related to adhesion and extracellular matrix glycoproteins. DNA was extracted from twenty-three FSGS patients diagnosed by renal biopsy; (3) Results: The average number of accumulated variants in FSGS patients was high. We describe the missense variant ITGB3c.1199G>A, which is considered pathogenic; in addition, we discovered the nonsense variant CDH1c.499G>T, which lacks a Reference SNP (rs) Report and is considered likely pathogenic. (4) Conclusions: To the best of our knowledge, this is the first account of a high rate of change in extracellular matrix glycoproteins and adhesion molecules in individuals with adult-onset FSGS. The combined effect of all these variations may result in a genotype that is vulnerable to the pathogenesis of glomerulopathy.

Adult-Onset Focal Segmental Glomerulosclerosis With Steroid-Dependent Nephrotic Syndrome Caused by a Novel TBC1D8B Variant: A Case Report and Literature Review.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with a variety of potential causes, including rare variants of podocyte-related genes. Recently, it has been found that variants in the TBC1D8B gene on the X chromosome can lead to early-onset focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome by affecting endocytosis and recycling of nephrin. Here, we report a 19-year-old Chinese patient with nephrotic syndrome and normal kidney function. He had a complete remission of nephrotic syndrome after full-dose prednisone and cyclosporine treatment. Unfortunately, a relapse of nephrotic syndrome occurred during prednisone tapering. Focal segmental glomerulosclerosis was proven by a kidney biopsy, and a hemizygous pathogenic variant located in the TBC (Tre-2-Bub2-Cdc16) domain of TBC1D8B was detected by whole-exome sequencing. By comparing our case with reports of other patients with TBC1D8B variants, we suggest possible genotype-phenotype correlations. To our knowledge, this is the first report identifying a pathogenetic variant in the TBC domain of TBC1D8B in an adult-onset focal segmental glomerulosclerosis patient with steroid-dependent NS. With this report, we broaden the clinical and genetic spectrum of X-linked genetic FSGS.

Protecting glomerulus: role of angiotensin-II type 2 receptor.

Podocyte injury due to either drug, toxin, infection, or metabolic abnormality is a great concern as it increases the risk of developing focal segmental glomerulosclerosis (FSGS) and proteinuric kidney diseases. The direct podocyte injury due to doxorubicin is associated with an increase in proinflammatory cytokines and induction of cathepsin L. The increased activity of cathepsin L in turn may degrade the glomerular slit diaphragm resulting in proteinuric kidney injury. The angiotensin-II type 2 receptor (AT2R) has earlier been reported to be associated with the preservation of slit diaphragm proteins and prevention of proteinuria. Recent in vivo findings by Zhang and colleagues further support the anti-proteinuric role of AT2R in preventing podocyte injury via down-regulating cytokines ccl2, and hence, cathepsin L, thereby, limiting the progression of FSGS.

Extracellular Vesicles Released from Stem Cells as a New Therapeutic Strategy for Primary and Secondary Glomerulonephritis.

Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.

Treatment of post-transplant recurrent FSGS in children using plasmapheresis and augmentation of immunosuppression.

BACKGROUND: Up to 60% of pediatric renal transplant recipients with end-stage renal disease due to primary focal and segmental glomerulosclerosis (FSGS) may develop recurrent disease. Such recurrence is associated with poor prognosis if no remission is achieved. We report a single center experience with a protocol based on plasmapheresis and increased immunosuppression that resulted in a high long-lived remission rate. METHODS: This retrospective cohort study included consecutive pediatric renal transplant patients with recurrent FSGS treated with a standardized protocol using plasmapheresis and cyclophosphamide to supplement usual post-transplant immunosuppression with calcineurin inhibitors and steroids. Relapse was defined as urinary protein/creatinine ratio > 1.0 g/g and remission as < 0.5 g/g. RESULTS: Seventeen patients with FSGS recurrence post-transplant were treated. All had therapy resistant FSGS in native kidneys and had been on dialysis from 4 to 10 years. Of the 17, one died perioperatively from a pulmonary thromboembolism. Fifteen others achieved a complete remission within 3 months of treatment for FSGS recurrence. After a median follow-up period of 4 years, there were no recurrences of significant proteinuria. One patient achieved remission with rituximab. CONCLUSION: The addition of plasmapheresis and cyclophosphamide to a calcineurin- and steroid-based immunosuppression regime was highly successful in inducing high remission rates with recurrent FSGS. Prospective trials are needed to evaluate further the efficacy of increased immunosuppression along with plasmapheresis in this setting.

Treatment of Focal and Segmental Glomerulosclerosis Secondary to High Altitude Polycythemia with Acetazolamide.

Vizcarra-Vizcarra, Cristhian A., Eduardo Chávez-Velázquez, Carmen Asato-Higa, and Abdías Hurtado-Aréstegui. Treatment of focal and segmental glomerulosclerosis secondary to high altitude polycythemia with acetazolamide. High Alt Med Biol. 23:286-290, 2022.-Focal segmental glomerulosclerosis (FSGS) is a morphological pattern, caused by glomerular injury and is the leading cause of nephrotic syndrome in adults. We present the case of a 59-year-old female patient, resident of a high-altitude city (3,824 m), who had polycythemia and nephrotic syndrome. A renal biopsy was performed, and the findings were compatible with FSGS. The patient received phlebotomy 500 ml three times, which reduced, partially, the hemoglobin concentration. However, she had refractory proteinuria, despite the use of enalapril and spironolactone. We observed that proteinuria worsened with the increase in hemoglobin levels. So, she was treated with acetazolamide 250 mg bid for 4 months, which reduced proteinuria and hemoglobin. During the coronavirus disease 2019 (COVID-19) pandemic, the patient did not take acetazolamide and again, she had an increase in hemoglobin and proteinuria levels. We conclude that acetazolamide may be an effective treatment in FSGS due to high altitude polycythemia.

CD44-negative parietal-epithelial cell staining in minimal change disease: association with clinical features, response to corticosteroids and kidney outcome.

BACKGROUND: Activation of parietal-epithelial cells (PECs) with neo-expression of CD44 has been found to play a relevant role in the development of focal and segmental glomerulosclerosis (FSGS). The aim of this study was to analyse whether the expression of CD44 by PECs in biopsies of minimal change disease (MCD) is associated with the response to corticosteroids, with kidney outcomes and/or can be considered an early sign of FSGS. METHODS: This multicentric, retrospective study included paediatric and adult patients with MCD. Demographic, clinical and biochemical data were recorded, and biopsies were stained with anti-CD44 antibodies. The association between PECs, CD44 expression and the response to corticosteroids, and kidney outcomes were analysed using logistic, Kaplan-Meier and Cox regression analyses. RESULTS: A total of 54 patients were included: 35 (65%) <18 years and 19 (35%) adults. Mean follow-up was 68.3 ± 37.9 months. A total of 19/54 patients (35.2%) showed CD44-positive staining. CD44-positive patients were younger (14.5 ± 5 versus 21.5 ± 13, P = 0.006), and showed a higher incidence of steroid-resistance [11/19 (57.8%) versus 7/35 (20%), P = 0.021; odds ratio: 5.5 (95% confidence interval 1.6-18), P = 0.007] and chronic kidney disease [9/19 (47.3%) versus 6/35 (17.1%), P = 0.021; relative risk: 3.01 (95% confidence interval 1.07-8.5), P = 0.037]. Follow-up re-biopsies of native kidneys (n = 18), identified FSGS lesions in 10/12 (83.3%) of first-biopsy CD44-positive patients versus 1/6 (16.7%) of first-biopsy CD44-negative patients (P = 0.026). CONCLUSIONS: In patients with a light microscopy pattern of MCD, CD44-positive staining of PECs is associated with a higher prevalence of steroid resistance and worse kidney outcomes, and can be considered an early sign of FSGS.

Review of intravitreal VEGF inhibitor toxicity and report of collapsing FSGS with TMA in a patient with age-related macular degeneration.

Intravitreal vascular endothelial growth factor (VEGF) receptor blockade is used for a variety of retinal pathologies. These include age-related macular degeneration (AMD), diabetic macular edema (DME) and central retinal vein obstruction. Reports of absorption of intravitreal agents into systemic circulation have increased in number and confirmation of depletion of VEGF has been confirmed. Increasingly there are studies and case reports showing worsening hypertension, proteinuria, renal dysfunction and glomerular disease. The pathognomonic findings of systemic VEGF blockade, thrombotic microangiopathies (TMAs), are also being increasingly reported. One lesion that occurs in conjunction with TMAs that has been described is collapsing focal segmental glomerulosclerosis (cFSGS). cFSGS has been postulated to occur due to TMA-induced chronic glomerular hypoxia. In this updated review we discuss the mechanistic, pharmacological, epidemiological and clinical evidence of intravitreal VEGF toxicity. We review cases of biopsy-proven toxicity presented by our group and other investigators. We also present the third reported case of cFSGS in the setting of intravitreal VEGF blockade with a chronic TMA component that was crucially found on biopsy. This patient is a 74-year-old nondiabetic male receiving aflibercept for AMD. Of the two prior cases of cFSGS in the setting of VEGF blockade, one had AMD and the other had DME. This case solidifies the finding of cFSGS and its association with chronic TMA as a lesion that may be frequently encountered in patients receiving intravitreal VEGF inhibitors.

Crystal-Induced Podocytopathy Producing Collapsing Focal Segmental Glomerulosclerosis in Monoclonal Gammopathy of Renal Significance: A Case Report.

Monoclonal gammopathy-associated crystalline podocytopathy causing collapsing focal segmental glomerulosclerosis (FSGS) is very rare and has been associated with pamidronate therapy. We present the case of a 53-year-old man with vision loss secondary to corneal crystals deposition, nephrotic-range proteinuria, and reduced glomerular filtration rate without associated comorbid conditions. Two kidney biopsies were initially reported as primary FSGS but the patient did not respond to high-dose corticosteroid immunosuppression therapy. Repeat review of biopsies with additional electron microscopy analysis revealed crystalline inclusions in podocytes leading to collapsing FSGS. Subsequent workup revealed an immunoglobulin G κ serum monoclonal protein. Bone marrow biopsy revealed 5% κ-restricted plasma cells with cytoplasmic crystalline inclusions. To our knowledge, this is the first case of monoclonal gammopathy of clinical significance manifesting as crystalline podocytopathy leading to collapsing FSGS and keratopathy leading to vision loss. Crystalline podocytopathy should be considered in the differential diagnosis of collapsing glomerulopathy, and careful ultrastructural examination of the kidney biopsy specimen is crucial to establish this diagnosis.

Pathogenic Variants in the Genes Affected in Alport Syndrome (COL4A3-COL4A5) and Their Association With Other Kidney Conditions: A Review.

Massively parallel sequencing identifies pathogenic variants in the genes affected in Alport syndrome (COL4A3-COL4A5) in as many as 30% of individuals with focal and segmental glomerulosclerosis (FSGS), 10% of those with kidney failure of unknown cause, and 20% with familial immunoglobulin A (IgA) glomerulonephritis. FSGS associated with COL4A3-COL4A5 variants is usually present by the onset of kidney failure and may develop because the abnormal glomerular membranes result in podocyte loss and secondary hyperfiltration. The association of COL4A3-COL4A5 variants with kidney failure or IgA glomerulonephritis may be coincidental. However, pathogenic variants in these conditions occur more often than they should by chance, which suggests that the variants are disease-causing. COL4A3-COL4A5 variants are also found in cystic kidney diseases after autosomal dominant polycystic kidney disease has been excluded. COL4A3-COL4A5 variants should be suspected in individuals with FSGS, kidney failure of unknown cause, or familial IgA glomerulonephritis, especially where there is persistent hematuria and a family history of hematuria or kidney failure.

RAGE and αVß3-integrin are essential for suPAR signaling in podocytes.

The soluble urokinase plasminogen activator receptor (suPAR) has been implicated in the pathogenesis of kidney diseases including primary and recurrent focal and segmental glomerulosclerosis (FSGS), diabetic nephropathy, and acute kidney injuries (AKI). Elevated serum suPAR concentration is a negative prognostic indicator in multiple critical clinical conditions. This study has examined the initial transduction steps used by suPAR in cultured mouse podocytes. We now report that the receptor for advanced glycation end-products (RAGE) co-immunoprecipitates with αV and ß3 integrin subunits, which have been previously shown to initiate suPAR signal transduction at the podocyte cell surface. siRNA knock-down of RAGE attenuated Src phosphorylation evoked by either suPAR or by glycated albumin (AGE-BSA), a prototypical RAGE agonist. suPAR effects on Src phosphorylation were also blocked by the structurally dissimilar RAGE antagonists FPS-ZM1 and azeliragon, as well as by cilengitide, an inhibitor of outside-in signaling through αV-integrins. FPS-ZM1 also blocked Src phosphorylation evoked by AGE-BSA. FPS-ZM1 blocked increases in cell surface TRPC6 abundance, cytosolic reactive oxygen species (ROS) and activation of the small GTPase Rac1 evoked by either suPAR or AGE-BSA. In addition, FPS-ZM1 inhibited Src phosphorylation evoked by serum collected from a patient with recurrent FSGS during a relapse. The magnitude of this inhibition was indistinguishable from the effect produced by a neutralizing antibody against suPAR. These data suggest that orally bioavailable small molecule RAGE antagonists could represent a useful therapeutic strategy for a wide range of clinical conditions associated with elevated serum suPAR, including primary FSGS and AKI.

Successful Reuse of Kidney Graft After Early Recurrence of Primary Focal and Segmental Glomerulosclerosis.

Primary focal and segmental glomerulosclerosis (FSGS) frequently recurs after transplantation and is associated with a poor prognosis. We describe here the successful kidney graft reuse in an adult recipient, 8 months after early primary FSGS recurrence resistant to all available therapeutics. Patient 1, a 23-year-old man, followed for kidney failure secondary to primary FSGS, was first transplanted in 2018 with a deceased donor graft. Unfortunately, we observed an immediate recurrence of biopsy-proven primary FSGS. After 4 lines of treatment (intravenous cyclosporine+corticosteroids, plasma exchanges, immunoadsorption, and rituximab), the patient was still highly nephrotic and kidney function was slowly deteriorating. After approval from both the patient and the health authority (Biomedicine Agency), the graft was detransplanted 8 months after transplantation and reimplanted in patient 2, a 78-year-old nonimmunized and anephric recipient (bi-nephrectomy 2 years previously for bilateral renal carcinoma). We observed immediate kidney function and progressive resolution of proteinuria (serum creatinine of 1.2mg/dL and proteinuria of 0.1 g/d 1 year later). Biopsies performed after surgery showed persistent FSGS lesions with a decrease in overall foot-process effacement. To our knowledge, this is the first reported case showing that kidney graft transfer may still be a viable option for refractory primary FSGS several months after transplantation.

Efficacy and safety of rituximab in adult frequent-relapsing or steroid-dependent minimal change disease or focal segmental glomerulosclerosis: a systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of rituximab (RTX) in adult frequent-relapsing (FR) or steroid-dependent (SD) nephrotic syndrome (NS), including minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), are still inconclusive. METHODS: We performed a systematic review and meta-analysis registered in  PROSPERO (CRD42019148102) by pooling data of cohort studies or case series on adult patients with difficult-to-treat NS. Steroid-resistant NS was excluded. The primary outcomes were the complete remission (CR) rate and the relapse rate. Partial remission (PR) rate, no response (NR) rate and adverse events were the secondary outcomes. A random-effects model was performed for all the outcomes. RESULTS: We included 21 studies involving 382 adult MCD/FSGS subjects with a median follow-up duration from 12 to 43 months. RTX treatment induced a pooled 84.2% CR rate [95% confidence interval (CI): 67.7-96.3%], while MCD patients had a high 91.6% CR rate and FSGS patients a moderate 43% CR rate. However, 27.4% (95% CI 20.7-34.5%) of the patients relapsed during the follow-up. The pooled PR and NR rates were 5.8% (95% CI 1.2-12.5%) and 5.2% (95% CI 0.0-15.0%), respectively. RTX was associated with trivial adverse events and good tolerance. CONCLUSIONS: In summary, by pooling results of current pilot studies, RTX may be an effective and relatively safe alternative for most adult FR or SD MCD/FSGS to displace calcineurin inhibitors or prednisone in the hierarchy of treatment. More clinical trials comparing RTX with other immunosuppressants and concerning the long-term adverse events are needed.

Focal and segmental glomerulosclerosis in adults: early clinical course and prognostic factors for short-term outcome / Glomeruloesclerosis focal y segmentariaenadultos: evoluciónclínicatemprana y factorespronósticos de resultados a cortoplazo

ABSTRACT Background: Primary focal and segmental glomerulosclerosis progresses to end-stage renal disease in every other patient, and therefore determinants of its long-term outcome have been extensively studied. Immediate response to treatment has been regarded as a positive prognostic predictor and short-term manifestation of the disease could affect its determinants. Therefore, we have sought to assess the early clinical course of primary adult focal and segmental glomerulosclerosis and analyze its prognostic factors. Methods: We have retrospectively assessed clinical course of primary focal and segmental glomerulosclerosis ("not otherwise specified" histological variant) in 84 adults. Renal function was expressed as serum creatinine concentration and equilibrated glomerular filtration rate (MDRD equation). Proteinuria was expressed as protein to urinary creatinine ratio, assessed in the morning voiding sample. The evaluation of these parameters was performed every 3 months after diagnosis. Statistical analysis was achieved using package Statistica. Results: As result of treatment, complete remission of proteinuria, was attained in 30 subjects (35.7%), partial remission in 37 persons (44%), whereas in 17 patients protein excretion rate remained unchanged (20.2%). The severity of glomerular injury, at initial presentation of the disease, correlated with its early (12 months) outcome: patients attaining early complete remission have had the lowest initial proteinuria, higher serum albumin and total protein concentrations than those who have failed to achieve remission. Pharmacotherapy with prednisone, but not with calcineurin inhibitors or mycophenolate mofetil was demonstrated to significantly affect achievement of remission. Conclusions: Early remission of proteinuria in response to treatment is feasible in 44% of patients with primary focal and segmental glomerulosclerosis, it is best achieved in subjects presenting with mild glomerular injury, and in patients treated with prednisone. Higher serum albumin and total protein concentrations predict better response to induction of remission.

RESUMEN Antecedentes: La glomeruloesclerosis focal y segmentaria se convierteennefropatía terminal enuno de cada dos pacientes, por lo que losfactoresdeterminantes de susdesenlaces a largo plazohansidoobjeto de muchosestudios. La respuestainmediata al tratamiento se considera un factor pronóstico favorable, y las manifestaciones a cortoplazo de la enfermedadpuedenafectarlosfactoresdeterminantes. Portodoello, hemosbuscadoevaluar la evoluciónclínicatemprana de la glomeruloesclerosis focal y segmentariaprimaria, y analizarsusfactorespronósticos. Material y métodos: Hemosrealizado un estudioretrospectivo para evaluar la evoluciónclínica de la glomeruloesclerosis focal y segmentariaprimaria (variantehistológica "sin otraespecificación") en 84 pacientesadultos. Se evaluó la función renal a través de la creatininasérica y filtrado glomerular equilibradocalculadomediante la ecuación MDRD. La proteinuria se expresócomorelaciónproteína/creatininaurinaria, evaluadaen la muestramiccionalmatutina. La evaluación de estosparámetros se realizócada 3 mesesdespués del diagnóstico. El análisisestadístico se logróutilizando el paqueteStatistica. Resultados: Como resultado del tratamiento, se obtuvounaremisióncompleta de la proteinuria en 30 sujetos (35,7%), unaremisiónparcialen 37 personas (44%), mientras que, en 17 pacientes, la tasa de excreción de proteínas se mantuvo sin cambios (20,2%). En la presentacióninicial de la enfermedad, la gravedad de la lesión glomerular se correlacionó con suresultadotemprano (12 meses): lospacientes que lograronunaremisióncompletatempranamostraronlosnivelesmásbajos de proteinuria inicial, y concentracionesmásaltas de albúminasérica y proteínastotales que aquellos que no alcanzaron la remisión. Se demostró que la farmacoterapia con prednisona -pero no con inhibidores de calcineurina o micofenolato de mofetilo- condiciona de forma significativa el logro de la remisión. Conclusiones: La remisióntemprana de la proteinuria enrespuesta al tratamientoesfactibleen el 44% de lospacientes con glomeruloesclerosis focal y segmentariaprimaria; se obtienenmejoresresultadosensujetos que presentanunalesión glomerular leve y enpacientestratados con prednisona. Las concentracionesmásaltas de albúminasérica y proteínastotalespredicenunamejorrespuesta para inducir la remisión.

A case of dasatinib-induced focal segmental glomerulosclerosis in a patient with Philadelphia chromosome positive chronic myeloid leukemia.

Focal segmental glomerulosclerosis is a common glomerular histological lesion, which is usually characterised by non-nephrotic range proteinuria or nephrotic syndrome. It may be idiopathic or occurs secondarily to drugs, diabetes, obesity or HIV nephropathy and other infections. Dasatinib, a tyrosine kinase inhibitor that has been used for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia, has a few renal adverse effects. Exceptional cases with non-nephrotic range proteinuria have been reported in relation with dasatinib. In this case, we report a patient with symptoms of nephrotic syndrome and nephrotic range proteinuria, who was diagnosed as focal segmental glomerulosclerosis by kidney biopsy after treated with dasatinib.