Síndrome nefrótico idiopático: recomendaciones de la Rama de Nefrología de la Sociedad Chilena de Pediatría. Parte 2 / Idiopathic Nephrotic Syndrome: recommendations of the Nephrology Branch of the Chilean Society of Pediatrics. Part two

El síndrome nefrótico idiopático es la glomerulopatía más frecuente en la infancia, afecta a 1-3/100 mil niños menores de 16 años y se presenta con más frecuencia entre los 2 y 10 años. Su causa es desconocida, y la mayoría de las veces responde a corticoides, con buen pronóstico a largo plazo. El síndrome nefrótico corticorresistente representa un 10-20% de los síndromes nefróticos idiopáticos en pediatría. Tiene mal pronóstico, y su manejo constituye un desafío terapéutico significativo. La mitad de los pacientes evoluciona a insuficiencia renal crónica terminal en un plazo de 5 años, estando expuestos además a las complicaciones secundarias a un síndrome nefrótico persistente y a efectos adversos de la terapia inmunosupresora. El objetivo fundamental del tratamiento es conseguir una remisión completa, pero una remisión parcial se asocia a una mejor sobrevida renal que la falta de respuesta. Este documento surgió de un esfuerzo colaborativo de la Rama de Nefrología de la Sociedad Chilena de Pediatría con el objetivo de ayudar a los pediatras y nefrólogos infantiles en el tratamiento del síndrome nefrótico idiopático en pediatría. En esta segunda parte, se discute el manejo del síndrome nefrótico corticorresistente, así como de las terapias no específicas.

Idiopathic nephrotic syndrome is the most common glomerular disease in childhood, affecting 1 to 3 per 100,000 children under the age of 16. It most commonly occurs in ages between 2 and 10. Its cause is unknown, and its histology corresponds to minimal change disease in 90% of cases, or focal segmental glomerulosclerosis. Steroid-resistant nephrotic syndrome represents 10-20% of idiopathic nephrotic syndrome in pediatrics. It has a poor prognosis, and its management is a significant therapeutic challenge. Half of patients evolve to end-stage renal disease within 5 years, and are additionally exposed to complications secondary to persistent NS and to the adverse effects of immunosuppressive therapy. The primary goal of treatment is to achieve complete remission, but even a partial remission is associated with a better renal survival than the lack of response. This paper is the result of the collaborative effort of the Nephrology Branch of the Chilean Society of Pediatrics with aims at helping pediatricians and pediatric nephrologists to treat pediatric idiopathic nephrotic syndrome. In this second part, handling of steroid-resistant nephrotic syndrome as well as nonspecific therapies are discussed.

[Idiopathic Nephrotic Syndrome: recommendations of the Nephrology Branch of the Chilean Society of Pediatrics. Part One]. / Síndrome nefrótico idiopático: recomendaciones de la Rama de Nefrología de la Sociedad Chilena de Pediatría. Parte 1.

Idiopathic nephrotic syndrome is the most common glomerular disease in childhood, affecting 1 to 3 per 100,000 children under the age of 16. It most commonly occurs in ages between 2 and 10. Its cause is unknown and its histology corresponds to minimal change disease in 90% of cases, or focal segmental glomerulosclerosis. 80 to 90% of cases respond to steroids (steroid-sensitive nephrotic syndrome) with good prognosis and long-term preservation of renal function over time. 70% of patients with SSNS have one or more relapses in their evolution, and of these, 50% behave as frequent relapsing or steroid-dependent, a group that concentrate the risk of steroid toxicity. Patients with steroid-resistant nephrotic syndrome have a poor prognosis and 50% of them evolve to end-stage renal disease. The goal of therapy is to induce and maintain remission of the disease, reducing the risk secondary to proteinuria while minimizing the adverse effects of treatments, especially with prolonged use of corticosteroids. This paper is the result of the collaborative effort of the Nephrology Branch of the Chilean Society of Pediatrics with aims at helping pediatricians and pediatric nephrologists to treat pediatric SNI. In this first part, recommendations of steroid-sensitive nephrotic syndrome are discussed.

[Idiopathic Nephrotic Syndrome: recommendations of the Nephrology Branch of the Chilean Society of Pediatrics. Part two]. / Síndrome nefrótico idiopático: recomendaciones de la Rama de Nefrología de la Sociedad Chilena de Pediatría. Parte 2.

Idiopathic nephrotic syndrome is the most common glomerular disease in childhood, affecting 1 to 3 per 100,000 children under the age of 16. It most commonly occurs in ages between 2 and 10. Its cause is unknown, and its histology corresponds to minimal change disease in 90% of cases, or focal segmental glomerulosclerosis. Steroid-resistant nephrotic syndrome represents 10-20% of idiopathic nephrotic syndrome in pediatrics. It has a poor prognosis, and its management is a significant therapeutic challenge. Half of patients evolve to end-stage renal disease within 5 years, and are additionally exposed to complications secondary to persistent NS and to the adverse effects of immunosuppressive therapy. The primary goal of treatment is to achieve complete remission, but even a partial remission is associated with a better renal survival than the lack of response. This paper is the result of the collaborative effort of the Nephrology Branch of the Chilean Society of Pediatrics with aims at helping pediatricians and pediatric nephrologists to treat pediatric idiopathic nephrotic syndrome. In this second part, handling of steroid-resistant nephrotic syndrome as well as nonspecific therapies are discussed.

Interstitial expression of angiotensin II and AT1 receptor are increased in patients with progressive glomerulopathies.

In animal models, interstitial angiotensin II (ang II) and AT1 receptor (AT1R) are key mediators of renal inflammation and fibrosis in progressive chronic nephropathies. We hypothesized that these molecules were overexpressed in patients with progressive glomerulopathies. In this observational retrospective study, we described the expression of ang II and AT1R by immunohistochemistry in kidney biopsies of 7 patients with minimal change disease (MCD) and in 25 patients with progressive glomerulopathies (PGPs). Proteinuria, serum albumin, and serum creatinine were not statistically different between MCD and PGP patients. Total expression of ang II and AT1R was not statistically different between MCD (108.7+/-11.5 and 73.2+/-13.6 cells/mm(2), respectively) and PGN patients (100.7+/-9.0 and 157.7+/-13.8 cells/mm(2), respectively; p>0.05). Yet, interstitial expression of ang II and AT1R (91.6+/-16.0 and 45.6+/-5.4 cells/mm(2), respectively) was higher in patients with PGN than in those with MCD (22.0+/-4.1 and 17.9+/-2.9 cells/mm(2), respectively, p<0.05), as was the proportion of interstitial fibrosis (11.0+/-0.7% versus 6.1+/-1.2%, p<005). In patients with MCD, ang II and AT1R expressions predominate in the tubular compartment (52% and 36% of the positive cells, respectively). In those with PGP, the interstitial expression of ang II and AT1R predominates (58% and 45%, respectively). In conclusion, interstitial expression of ang II and AT1R is increased in patients with progressive glomerulopathies. The relationship of these results and interstitial fibrosis and disease progression in humans warrants further investigations.

Interstitial inflammation, sodium retention, and the pathogenesis of nephrotic edema: a unifying hypothesis.

BACKGROUND: The pathophysiology of edema in the nephrotic syndrome is controversial. Some investigators believe that sodium retention may result from a primary renal defect that causes an "overfilled" blood volume. In contrast, other authors believe that fluid escapes the vascular compartment due a low oncotic pressure, and sodium retention is a compensatory physiological response to an "underfilled" blood volume. The patients that best fit the "underfilled" hypothesis are children with minimal-change nephrotic syndrome (MCNS). METHODS: We analyzed critically the available evidence for and against each proposed pathogenic mechanism in the light of recent evidence indicating that the inflammatory infiltrate may play a role in primary renal sodium retention. RESULTS: Inflammatory infiltrate in the kidney is a constant characteristic in nephrotic syndrome associated with primary sodium retention and it is absent in most cases of MCNS in children CONCLUSIONS: We propose that primary sodium retention in the nephrotic syndrome depends on the existence and the intensity of renal inflammatory infiltrate, conspicuously absent in most cases of MCNS in children and present in other conditions associated with massive proteinuria. The tubulointerstitial inflammatory infiltrate is associated with increased vasoconstrictive mediators that result in increased tubular sodium reabsorption and with glomerular hemodynamic changes that reduce filtered sodium load.

Tubular NF-kappaB and AP-1 activation in human proteinuric renal disease.

BACKGROUND: Nuclear factor-kappaB (NF-kappaB) and activated protein-1 (AP-1) are transcription factors that regulate many genes involved in the progression of renal disease. Recent data have shown that NF-kappaB is activated in tubules and glomeruli in various experimental models of renal injury. In vitro studies also suggest that proteinuria could be an important NF-kappaB activator. We therefore approached the idea that NF-kappaB may be an indicator of renal damage progression. METHODS: Paraffin-embedded renal biopsy specimens from 34 patients with intense proteinuria [14 with minimal change disease (MCD) and 20 with idiopathic membranous nephropathy (MN)] and from 7 patients with minimal or no proteinuria (IgA nephropathy) were studied by Southwestern histochemistry for the in situ detection of activated transcription factors NF-kappaB and AP-1. In addition, by immunohistochemistry, we performed staining for the NF-kappaB subunits (p50 and p65) and AP-1 subunits (c-fos, c-jun). By immunohistochemistry and/or in situ hybridization, the expression of some chemokines [monocyte chemoattractant protein-1 (MCP-1), RANTES, osteopontin (OPN)] and profibrogenic cytokines [transforming growth factor-beta (TGF-beta)], whose genes are regulated by NF-kappaB and/or AP-1, were studied further. RESULTS: NF-kappaB was detected mainly in the tubules of proteinuric patients, but rarely in nonproteinuric IgA nephropathy (IgAN) patients. In addition, there was a significant relationship between the intensity of proteinuria and NF-kappaB activation in MCD (r = 0.64, P = 0.01) and MN patients (r = 0.64, P < 0.01). Unexpectedly, patients with MCD had a significantly higher NF-kappaB tubular activation than those with MN (P < 0.01). To assess whether there was a different composition of NF-kappaB protein components, immunostaining was performed for the NF-kappaB subunits p50 and p65. However, no differences were noted between MCD and MN patients. In those patients, there was a lower tubular activation of AP-1 compared with NF-kappaB. Moreover, a strong correlation in the expression of both transcription factors was observed only in MN (r = 0.7, P = 0.004). Patients with progressive MN had an overexpression of MCP-1, RANTES, OPN, and TGF-beta, mainly in the proximal tubules, while no significant expression was found in MCD patients. CONCLUSIONS: On the whole, our results show that a tubular overactivation of NF-kappaB and AP-1 and a simultaneous up-regulation of certain proinflammatory and profibrogenic genes are markers of progressive renal disease in humans. Increased activation of solely NF-kappaB and/or AP-1 may merely indicate the response of tubular renal cells to injury.

Glomerulonefrite em pediatria / Gomerulonephritis in children

Os autores apresentam uma apreciaçäo clínico-patológica das glomerulonefrites na infância, relatando sua experiência no HUPE-UERJ). 1) GN com lesäo mínima: 128 casos (54,7% pré-escolares e 67,9% do sexo masculino): com prognóstico muito bom. 2) Esclerose focal e segmentar: 37 casos, quatro em remissäo, 11 com SN em atividade, 16 evoluíram para IRC (sete óbitos) e seis näo foram acompanhados. 3) GN membranosa: 10 casos, quatro em remissäo, quatro com SN em atividade e dois foram perdidos do acompanhamento. 4) GN endoteliomesangial: 257 casos, todos evoluíram para cura embora 15,3% apresentassem complicaçöes graves. 5) GN mesangial: oito casos, dois em remissäo, três com SBN em atividade, um em IRC e dois óbitos. 6) GN crescêntica: 11 pacientes, sete estäo bem, um em IRC e três morreram. 7) GN membranoproliferativa: seis pacientes: um em remissäo, dois em IRC, dois com SN em atividade e um faleceu

Lesión glomerular mínima / Minimal glomerular lesion

Se consideran la presentación clínica, la evolución, el tratamiento y el pronóstico de la lesión glomerular mínima (LGM) en el adulto y se analizan 43 pacientes con sindrome nefrótico idiopático por LGM. Se describen las alteraciones histológicas que la caracterizan; glomérulos normales en microscopía óptica y fusión de los pedicelios de las células epiteliales en microscopía electrónica. Se discute la etiopatogenia y se refiere como probable mecanismo patogénico una disfunción de las células T, con producción de linfokinas, que disminuiría la carga negativa de la membrana basal glomerular, con producción de proteinuria. Se refiere que clinicamente se presenta como un sindrome nefrótico con excelente respuesta al tratamiento corticoideo, que en 80 por ciento de los casos evoluciona con empujes y recaídas y sin deterioro de la función renal. Se discuten los resultados del tratamiento, la iatrogenia corticoidea en los pacientes recaedores frecuentes y corticodependientes y los beneficios de la asociación de drogas citotóxicas (AU)

Lesión glomerular mínima / Minimal glomerular lesion

Se consideran la presentación clínica, la evolución, el tratamiento y el pronóstico de la lesión glomerular mínima (LGM) en el adulto y se analizan 43 pacientes con sindrome nefrótico idiopático por LGM. Se describen las alteraciones histológicas que la caracterizan; glomérulos normales en microscopía óptica y fusión de los pedicelios de las células epiteliales en microscopía electrónica. Se discute la etiopatogenia y se refiere como probable mecanismo patogénico una disfunción de las células T, con producción de linfokinas, que disminuiría la carga negativa de la membrana basal glomerular, con producción de proteinuria. Se refiere que clinicamente se presenta como un sindrome nefrótico con excelente respuesta al tratamiento corticoideo, que en 80 por ciento de los casos evoluciona con empujes y recaídas y sin deterioro de la función renal. Se discuten los resultados del tratamiento, la iatrogenia corticoidea en los pacientes recaedores frecuentes y corticodependientes y los beneficios de la asociación de drogas citotóxicas

[Longitudinal study in children with the nephrotic syndrome and minimal glomerular lesion]. / Estudio longitudinal en niños con síndrome nefrótico y lesión glomerular mínima.

Twenty-one children with idiopathic nephrotic syndrome and minimal changes on renal biopsy were followed during all the disease. The average of follow-up was 37 months, with a range from 12 to 124 months. Recurrent proteinuria was the most important feature during the follow-up; 14 out of the patients showed frequent relapses, but only 2 patients showed major complication (peritonitis, septicemia) during relapses. Frequent relapses appeared most frequently in patients who began the disease before their fourth birthday, showed allergic history, had hypertension and red blood cells in urine, or had recurrent infections and finally, in those where proteinuria reappeared soon after prednisone therapy was ended. Prednisone alone was successful to induce remission, but it did not prevent frequent relapses. The association clorambucil-prednisone allowed lengthening of the period of remission and possibly for this reason the rate of relapses fell during the first 37 months of the follow-up. There are no signs which permit to predict the length of the disease and the frequent relapses can occur even after many years from the beginning of the disease. Special care of these patients avoids major complications.