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![Índices de Selectividad
• [(IgG )u (Albumin )s ]/ [(IgG)s (albumin)u ]
• Alfa2Macroglobulina/albumina
• IgM/Albumina
• IgG/transferrina](https://image.slidesharecdn.com/proteinuria1-150924002752-lva1-app6892/85/Proteinuria1-14-320.jpg)
Subido porSilvana Alcala
Proteinuria1
El documento resume los conceptos básicos de la proteinuria, incluyendo su definición, mecanismos fisiopatológicos, tipos, técnicas de medición, aplicaciones clínicas, consecuencias y tratamiento. Explica que la proteinuria se refiere a un aumento en la excreción de proteínas a través de la orina, y describe los diferentes tipos como glomerular, tubular y ortostática. También cubre los métodos para medir la proteinuria y la albuminuria, así como las implicaciones clínicas como la progresión
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Proteinuria1
- 1. L/O/G/O www.themegallery.com Proteinuria Dra. Silvana AlcalaFerrara Dra Lara
- 2. Excreción Fisiológica Mecanismos Fisiopatologicos Tiposde Proteinuria Tecnicas de Medida4 1 2 3 Agenda Aplicaciones clínicas5 Consecuencias6 Tratamiento7
- 3. Proteinuria: Definición • Aumentoen la Excreción de Proteínas a través de la Orina • No existe un valor discriminante universal que la defina, ya que depende – espécimen utilizado para su medida – la forma de expresión de los resultados – Población en la que se valora – Guia Consultada – Tipo de Proteina • Proteínas Totales > 300mg/24h= Indice 0,3 = PCR 300mg/gr • Albuminuria > 30mg/24h = ARC 30mg/g
- 7. Physiological Reviews 1April 2008 Vol. 88 no. 2, 451-487 - - - - • Prot Totales<200mg/24h (30-130) • Albumina <30mg/24h (8-15) • Filtración Alto Peso Molecular Bajo Peso Molecular <20,000Da • Selectividad por tamaño: 5 nm (50 A) • Selectividad por Carga Albumina Globulina α2-microglobulina, apoproteinas, enzimas Hormonas Peptídicas Excreción Urinaria Fisiológica de Proteinas.
- 8. • Reabsorción • Secreción –Proteina de Tamm-horsfall – IgA, Urokinasa • Excreción – Normal: 30-130mg/dia – Máximo: hasta 200mg/dia – Albuminuria: 30mg/dia Excreción Urinaria Fisiológica de Proteinas. Despopoulos A. Color Atlas of Physiology. Thieme.3th ed. 2003
- 10. Mecanismos Fisiopatológicos deProteinuria Disrupción de la Barrera de Filtración Disfunción Tubular Sobreproducción de Proteinas Plasmaticas Reabsorción incompleta de Bajo Peso Molecular filtradas Producción de Proteinas Tubulares por daño a Epitelio ↑ Permeabilidad - Alto Peso Molecular – Albuminuria, Globulinas Plasmaticas: Bajo Peso molecular – Cadenas liviana de Ig Albuminuria baja con Proteinuria Alta Physiological Reviews 1 April 2008 Vol. 88 no. 2, 451-487
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- 13. Tipos de Proteinuria GlomerularTubular Albuminuria y Otras de > P.M Raro supera 2gr/24h Borramiento de pedicelos Prot de A.P-M > Alb Selectiva NO Selectiva Prot de Bajo P.M menos proporción Alb β2-Microglobulina Daño en T.P Composición Heterogénea Variable, pero Cuando supera 3,5 gr/24 se puede Aseverar origen Glomerular IgG/Alb < 0,1 IgG/Alb > 0,5 Cap 52, Brenner,The Kidney 9th Ed.
- 14. Índices de Selectividad •[(IgG )u (Albumin )s ]/ [(IgG)s (albumin)u ] • Alfa2Macroglobulina/albumina • IgM/Albumina • IgG/transferrina
- 15. Otros Tipos deProteinuria • Proteinuria Ortostática – En posición supina y desaparece en ortostatismo. – En niños y adolescentes, y tiende a desaparecer adultez – Inferior a 1 g/m2/día – Se debe a alteraciones hemodinámicas en el glomérulo renal – No se ha asociado a incremento de riesgo ni mal pronostico • Functional Proteinuria – Ocurre con Fiebre, ejercicio, estados hiperadrenérgicos, – Se considera benigna – Origen hemodinámico, por aumento de Flujo plasmático de nefrona Comprehensive Clinical Nephrology 4th Ed.
- 16. Técnicas de Medidade Proteinuria Mas sensible a albumina + Variables segun casa comercial Faso Positivo: pH≥9, Infecciones Falso Negativo: cadenas Ligeras Tira reactiva Acido Sulfosalicílico Electroforesis Identifica Proteinas específicas Método Turbidimétrico > Sensible para Albumina Incluye Globulinas, BenceJones Negative:<15mg/dL Trace: 15-30 mg/dL 1+: 30-100 mg/dL 2+: 100-300 mg/dL 3+: 300-1000 mg/dL 4+: >1000 mg/dL Cap 25, Brenner,The Kidney 9th Ed. Rojo de Pyrogalol Mètodo colorimetrico
- 17. Técnicas de Medidade ALBUMINA Albumina-específica Cociente Alb/Creat Tira reactiva Inmunoanálisis turbidimétrico Nefelomètricos Radioinmunoensayo Nefrologia 2011;31(3):331-45 Cromatografía Liquida ELISA Cap 25, Brenner,The Kidney 9th Ed /.
- 18. • No existeactualmente ningún procedimiento de medida ni material de referencia para la determinación de proteína en orina, lo que da lugar a una gran variabilidad entre los resultados obtenidos en diferentes laboratorios. Esta variación afecta, sobre todo, a las concentraciones bajas y disminuye para las más elevadas en parte debido a la mayor concentración relativa de albúmina que presentan estas últimas • Distintos programas de control externo de la calidad evidencian que existen diferencias entre los resultados obtenidos por distintos laboratorios y en las unidades de expresión de los mismos86. Ello es consecuencia de la inexistencia de un procedimiento analítico de referencia; de un material de referencia internacional; de la presencia en orina de diferentes formas moleculares de la albúmina Nefrologia 2011;31(3):331-45
- 19. • Indice Pr/Cr– Alb/Cr • Mayor variabilidad inter-individuoOrina Aleatoria Primera Orina Orina 24 h • Indice Pr/Cr – Alb/Cr • Mejor que orina Aleatoria • Elimina variación según grado de hidratación • Correlación con Proteinuria en 24 h • Mide Proteinas totales • Promedia variaciones de excreción durante el día • Imprecisión en recolección/no practico La eliminación variable de proteínas a lo largo del día, resultado de factores como el grado de hidratación, la actividad física o la ingesta proteica Espécimen de la Muestra
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- 21. Relación entre categoríasde albuminuria y proteinuria
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- 23. Aplicación Clínica Progresión de ERC Descriptionof the contents Enf. Cardiovascular Mas especifico y sensible ERC Biomarcador AlbuminuriaRisk Factor De daño Renal Marcador
- 24. Consecuencias Glomerulares • Daño Podocitario vacuolization,fusion of foot processes, and focal detachment of epithelial cells from the underlying basement membrane • Mesangio Proliferación y deposición de matriz mesangial • Celulas Endoteliales Apoptosis Hipoxia Post Glomerular.
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- 27. Tratamiento Inhibidores de SRAA Estatinas Pentoxifilina Control dePA Verapamil Diltiazem Estudio VITAL • Disminución del estres oxidative • Impide perox Lipidica en Podocitos • Estudio MRC/BHF Supresión de Genes Mitogénicos y Profibróticos (rats) Monocyte chemoattractant protein-1. Dosis-dependiente Hipotensor independiente Estudio ABCD AASK No Hidropirid inicos ParicalcitolAnti Proteinuricas • Reduce Presión Intreglomerular • Antihipertrófico/Antifibrótico • ↑ Nefrina
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- #4 espécimen utilizado para su medida (orina de 24 horas o parcial), la forma de expresión de los resultados (en términos de concentración o de excreción) población en la que se valora (adultos o niños, hombres mujeres) Guia Consultada. Tipo de
- #7 Glomerular filtration barrier. Two podocyte foot processes bridged by the slit membrane, the GBM, and the porous capillary endothelium are shown. The surfaces of podocytes and of the endothelium are covered by a negatively charged glycocalyx containing the sialoprotein podocalyxin (PC). The GBM is mainly composed of type IV collagen (α3, α4, and α5), laminin 11 (α5, β2, and γ1 chains), and the heparan sulfate proteoglycan agrin. The slit membrane represents a porous proteinaceous membrane composed of (as far as known) nephrin, NEPH1-3, P-cadherin, and FAT1. The actinbased cytoskeleton of the foot processes connects to both the GBM and the slit membrane. Regarding the connections to the GBM, β1α3 integrin dimers specifically interconnect the TVP complex (talin, paxillin, vinculin) to laminin 11; the β- and α-dystroglycans interconnect utrophin to agrin. The slit membrane proteins are joined to the cytoskeleton by variousadaptor proteins, including podocin, zonula occludens protein 1 (ZO-1; Z), CD2-associated protein (CD), and catenins (Cat). Among the nonselective cation channels (NSCC), TRPC6 associates with podocin (and nephrin, not shown) at the slitmembrane. Only the angiotensin II (Ang II) type 1 receptor (AT1) is shown as an example of the many surface receptors. Additional abbreviations: Cas, p130Cas; Ez, ezrin; FAK, focal adhesion kinase; ILK, integrin-linked kinase; M, myosin; N, NHERF2 (Na+- H+ exchanger regulatory factor); S, synaptopodin. (Modified from reference 11.)
- #8 Normally, large quantities of high-molecular-weight (HMW) plasma proteins traverse the glomerular capillaries, mesangium, or both without entering the urinary space. Both charge- and size-selective properties of the capillary wall prevent all but a tiny fraction of albumin, globulin, and other large plasma proteins from crossing. Smaller proteins (<20,000 Da) pass readily across the capillary wall. Because the plasma concentration of these proteins is much lower than that of albumin and globulins, however, the filtered load is small. Moreover, LMW proteins are normally reabsorbed by the proximal tubule. Thus, proteins such as α2-microglobulin, apoproteins, enzymes, and peptide hormones are normally excreted in only very small amounts in the urine.4 Most healthy individuals excrete between 30 and 130 mg/day of protein, and the upper limit of normal total urine protein excretion is generally given as 150 to 200 mg/day for adults.144 The upper limit of normal albumin excretion is usually given as 30 mg/day Models of Glomerular Charge Selectivity As mentioned previously, the fact that negative electrical charges are present in the glomerular membrane (in the glycocalyx of endothelial cells, the negatively charged heparin sulfate of the GBM, and the glycoproteins of the cell membrane of podocytes) strongly suggests that circulating proteins that are negatively charged, like albumin, are restricted within the circulation not only because of their size but also because of their electrical charges
- #9 Most healthy individuals excrete between 30 and 130 mg/day of protein, and the upper limit of normal total urine protein excretion is generally given as 150 to 200 mg/day for adults.144 The upper limit of normal albumin excretion is usually given as 30 mg/day.144 A very small amount of protein that normally appears in the urine is the result of normal tubular secretion. Tamm- Horsfall protein is an HMW glycoprotein (23 × 106 Da) that is formed on the epithelial surface of the thick ascending limb of the loop of Henle and early distal convoluted tubule.4 Tamm-Horsfall protein, also known as uromodulin, binds and inactivates the cytokines interleukin-1 and tumor necrosis factor.145,146 Immunoglobulin A (IgA) and urokinase are also secreted by the renal tubule and appear in the urine in small Paamounts.
- #12 FIGURE 21-1 Schema showing the interaction of risk factors for progression of chronic kidney disease (CKD) with pathophysiologic mechanisms that contribute to a vicious cycle of progressive nephron loss. Ang II, angiotensin II; FSGS, focal and segmental glomerulosclerosis; PGC, glomerular capillary hydraulic pressure; SNGFR, single-nephron glomerular filtration rate; TIF, tubulointerstitial fibrosis. (Adapted from Taal MW, Brenner BM: Predicting initiation and progression of chronic kidney disease: developing renal risk scores, Kidney Int 70:1694-1705, 2006.)
- #14 Higher amounts of albumin and HMW proteins suggest glomerular proteinuria, whereas isolated increases in LMW protein fractions are more suggestive of tubular proteinuria. It is unusual for tubular proteinuria to exceed 1 to 2 g/day, and only a small fraction of protein excretion due to tubular damage should be albumin. Tubular proteins are heterogeneous; however, α2-microglobulin is often a major constituent. β2-Microglobulin is an LMW (11.8-kDa) protein that has been identified as the light chain of class I major histocompatibility antigens (e.g., human leukocyte antigens A, B, and C). β2-Microglobulin is most commonly measured in urine using radioimmunoassay or ELISA. It is freely filtered at the glomerulus and is avidly taken up and catabolized by the proximal tubule. Not surprisingly, therefore, detectable urinary levels of β2-microglobulin have been associated with many pathologic conditions involving the proximal tubule, including aminoglycoside- induced damage, Balkan endemic nephropathy, heavy metal nephropathies, radiocontrast nephropathy, and kidney transplant rejection. The sensitivity and specificity of this test of tubular injury have generally not been established. Selectivity index IgG albumin = [(IgG )u (Albumin )s ]/ [(IgG)s (albumin)u ] selective proteinuria is more often seen in patients with minimal change disease and predicts a good response to treatment with corticosteroids
- #15 Macromolecule filtration depends on convective and diffusive transport, which is influenced by glomerular hemodynamic conditions (flow and pressure) and water filtration. As described later, several investigators developed theoretical models to derive intrinsic sieving properties of the capillary wall from estimation of macromolecule filtration in experimental and in human studies
- #17 Falso Positivo: detergentes amo benzethonium chloride or pyrogallol red–molybdate colorimetric method nio cuaternario, clorhexidina
- #18 Urine albumin concentrations can be quantified by a number of assays, including the following: 1. Radioimmunoassay can be carried out using a double-antibody technique. Albumin in a urine sample competes with a known amount of radiolabeled albumin for fixed binding sites of antibodies. Free albumin can be separated from bound albumin by immunoabsorption of the (albuminbound) antibody. Albumin concentration in the sample is inversely proportional to the radioactivity.148 2. The immunoturbidimetric technique depends on the turbidity of a solution when albumin in a sample of urine reacts with a specific antibody. The turbidity is measured using a spectrophotometer, and the absorbency is proportional to the albumin concentration.149 3. When albumin in the urine sample reacts with a specific antibody, it forms light-scattering antigen-antibody complexes that can be measured with a laser nephelometer. The amount of albumin is proportional to scatter in the signal.150 4. The competitive enzyme-linked immunosorbent assay (ELISA) has also been used to measure urine albumin. 5.HPLC has also been used to measure urine albumin. This assay also measures the immuno-unreactive intact albumin that is not recognized by immunologic methods. However, the clinical significance of this immuno-unreactive intact albumin is not fully understood.152 Currently, there is no standardized procedure for measuringurine albumin and reporting results in standardized units. Although the correlation among results obtained using most of these quantitative assays is very good, a good correlation only indicates a strong linear relationship. For example, the correlation coefficients (r values) between radioimmunoassay and immunoturbidimetry and between radioimmunoassay and nephelometry were both 0.98.153 Intraassay coefficients of variation for immunoturbidimetry and nephelometry were found to be 6.6% and 11.5% at low concentrations (10 to 60 mg/L) and 11.1% and 4.1% at high concentrations (90 to 120 mg/L), respectively.153 Interassay coefficients of variation were 11.4% and 11.5% at low concentrations (10 to 60 mg/L) and 5.4% and 1.4% at high concentrations (90 to 120 mg/L), respectively, for these two techniques.153 However, the study comparing these assays had few samples in the midrange of albumin concentration (16 to 90 mg/L), and here there were considerable differences in results between the radioimmunoassay and the nephelometry assay.153 In another study, results obtained by radioimmunoassay, immunoturbidimetry, nephelometry, and HPLC varied by up to threefold.154 Other studies have also found similar variations among different immunoassays.155
- #28 Protein overload of proximal tubular cells as a consequence of increased glomerular permeability to proteins activates intracellular signals that promote cell apoptosis or cause increased production of inflammatory and vasoactive mediators and growth factors. These substances are released into the interstitium, inducing progressive inflammation and injury. ECM, Extracellular matrix; EGF, epidermal growth factor; EMT, epithelial to mesenchymal transdifferentiation; ET-1, endothelin-1; FGF, fibroblast growth factor; MCP-1, monocyte chemoattractant protein-1; PDGF, platelet-derived growth factor; RANTES, regulated upon activation, normal T cell expressed, and secreted; TGF-β, transforming growth factor-β.
- #29 Macromolecule filtration depends on convective and diffusive transport, which is influenced by glomerular hemodynamic conditions (flow and pressure) and water filtration. As described later, several investigators developed theoretical models to derive intrinsic sieving properties of the capillary wall from estimation of macromolecule filtration in experimental and in human studies
- #30 the Appropriate Blood Pressure Control in Diabetes (ABCD) study (35), and the African American Study of Kidney Disease and Hypertension (AASK) Pérdida de Peso Abandono de Tabaco Dieta baja en sal