Avances en el tratamiento de cáncer de próstata resistente a la castración: énfasis en nuevas terapias hormonales / Advances in the treatment of castration-resistant prostate cancer: emphasis in new hormonal therapies

Prostate cancer represents the second cancer-related cause of death in North American and Chilean men. The main treatment for incurable stages of disease is surgical or pharmacological castration. However, with time and despite the addition of anti-androgens, the disease progresses to a clinical state that has been commonly referred to as “hormone refractory”. In recent years, the concept of hormone refractoriness has been challenged and replaced by “castration resistance”, acknowledging that further and optimal hormonal manipulation can be attained, beyond achieving testosterone levels at castration range. The purpose of this review is to summarize the recent therapeutic breakthroughs in the management of metastatic castrate resistant prostate cancer (mCRPC), with greater emphasis in the newer hormonal therapy agents such as Abiraterone and Enzalutamide. Future combination and sequential treatment strategies are contextualized in the current era of personalized cancer medicine and genomic characterization of prostate cancer.

Familial lecithin-cholesterol acyltransferase deficiency

Familial lecithin-cholesterol acyltransferase deficiency is an uncommon autosomal recessive disorder from a heritable defect in esterification of plasma cholesterol. In 1968, the disease was described by Gjone and Norum in Norway. Our case was a 38-year-old woman. Her disease was manifested by presence of lower extremities edema, proteinuria, corneal opacities, increased plasma cholesterol, and hemolytic anemia. Suspicion of the disease was based on renal biopsy, which revealed mesangial expansion and capillary wall widening with clusters of foamy cells in the mesangium. Immunofluorescence study was nonspecific, but specific findings of electron microscopy showed deposition of lipid in the glomerular basement membrane and mesangium. This is the first report of lecithin-cholesterol acyltransferase deficiency in Iran. The diagnosis was confirmed by a low high-density lipoprotein cholesterol concentration, decreased activity of lecithin-cholesterol acyltransferase in plasma, and positive familial history of the disease

Mesangioproliferative glomerulonephritis: an important glomerulonephritis in nephrotic syndrome of young adult.

Mesangioproliferative glomerulonephritis (MesPGN) consists 10% of the total renal biopsy of glomerulonephritis. Aim of the present study was to find out clinicopathological changes in MesPGN and differences between diffuse and focal variety. MesPGN was seen mostly in young adults with mean age of 28.63 years for males and 26.3 years for females. Male predominance was noted (M:F ratio - 1.4:1). About 70.83% patient presented with edema feet, followed by hypertension (29.19%), fever (16.66%), oliguria, nausea and vomiting (10.41%). Urine analysis in 50 patients revealed that 70% patients presented with nephrotic-range proteinuria, 36% patients with microscopic hematuria and 56% patients with leukocyturia. Statistically, no significant difference was found in clinical features of diffuse and focal MesPGN. Microscopic comparison between diffuse and focal variety showed that significant increase of focal glomerular basement membrane thickening, focal endothelial cell proliferation, focal smooth muscle hyperplasia, hyaline sclerosis and vasculitis was more common in diffuse variety. In focal variety, Capillary loop congestion, periglomerulitis, cloudy swelling and vacuolar degeneration in tubules were significantly more as compared to diffuse variety. Details of the clinical features, special laboratory tests and histological details revealed that diffuse variety had systemic diseases, which included Wegner's granulomatosis, microscopic polyangitis, Henoch's schonlein purpura, systemic lupus erythematosus (two cases) and one case each of Kimura's disease, pyelonephritis and tuberculosis. Only one case of focal MesPGN showed tuberculosis. Thus, our study concludes that MesPGN is an important cause of nephrotic syndrome among young adults. Secondly, search for some other diseases should be made and thirdly, if biopsy shows focal mesangial cell proliferations in minimal change glomerulonephritis (MCGN), it should be diagnosed as focal MesPGN rather than MCGN because these cases show recurrences.

Bases moleculares da glomerulopatia diabética / Molecular bases of diabetic nephropathy

O principal determinante da nefropatia diabética é a hiperglicemia, mas hipertensão e fatores genéticos também estão envolvidos. O glomérulo é o foco de lesão, onde proliferação celular mesangial e produção excessiva de matriz extracelular decorrem do aumento da glicose intracelular, por excesso de glicose extracelular e hiperexpressão de GLUT1. Seguem-se aumento do fluxo pela via dos polióis, estresse oxidativo intracelular, produção intracelular aumentada de produtos avançados da glicação não enzimática (AGEs), ativação da via da PKC, aumento da atividade da via das hexosaminas e ativação de TGF-beta1. Altas concentrações de glicose também aumentam angiotensina II (AII) nas células mesangiais por aumento intracelular da atividade da renina (ações intrácrinas, mediando efeitos proliferativos e inflamatórios diretamente). Portanto, glicose e AII exercem efeitos proliferativos celulares e de matriz extracelular nas células mesangiais, utilizando vias de transdução de sinais semelhantes, que levam a aumento de TGF-beta1. Nesse estudo são revisadas as vias que sinalizam os efeitos da glicose e AII nas células mesangiais em causar os eventos-chaves relacionados à gênese da glomerulopatia diabética. As alterações das vias de sinalização implicadas na glomerulopatia, aqui revisadas, suportam dados de estudos observacionais/ensaios clínicos, onde controle metabólico e anti-hipertensivo, especificamente com inibidores do sistema renina-angiotensina, têm-se mostrado importantes - e aditivos - na prevenção do início e progressão da nefropatia. Novas estratégias terapêuticas dirigidas aos eventos intracelulares descritos deverão futuramente promover benefício adicional.

The determinant of the diabetic nephropathy is hyperglycemia, but hypertension and other genetic factors are also involved. Glomerulus is the focus of the injury, where mesangial cell proliferation and extracellular matrix occur because of the increase of the intra- and extracellular glucose concentration and overexpression of GLUT1. Sequentially, there are increases in the flow by the poliol pathway, oxidative stress, increased intracellular production of advanced glycation end products (AGEs), activation of the PKC pathway, increase of the activity of the hexosamine pathway, and activation of TGF-beta1. High glucose concentrations also increase angiotensin II (AII) levels. Therefore, glucose and AII exert similar effects in inducing extracellular matrix formation in the mesangial cells, using similar transductional signal, which increases TGF-beta1 levels. In this review we focus in the effect of glucose and AII in the mesangial cells in causing the events related to the genesis of diabetic nephropathy. The alterations in the signal pathways discussed in this review give support to the observational studies and clinical assays, where metabolic and antihypertensive controls obtained with angiotensin-converting inhibitors have shown important and additive effect in the prevention of the beginning and progression of diabetic nephropathy. New therapeutic strategies directed to the described intracellular events may give future additional benefits.

Leishmania (Leishmania) chagasi-infected mice as a model for the study of glomerular lesions in visceral leishmaniasis

Renal involvement in visceral leishmaniasis (VL) is very frequent but the pathogenesis of this nephropathy is poorly understood. In previous studies using dogs with VL we have detected new immunopathological elements in the glomeruli such as T cells and adhesion molecules. Although Leishmania (Leishmania) chagasi-infected dogs and hamsters are considered to be good models for VL, their use is limited for immunopathologic studies. The use of isogenic mouse strains susceptible to L. (L.) chagasi infection was an alternative but, on the other hand, the renal lesions of these animals have not yet been characterized. Thus, our purpose in the present study was to characterize mice infected with L. (L.) chagasi as a suitable model to study VL nephropathy. Kidney samples were obtained from control mice (N = 12) and from BALB/c mice (N = 24) injected intraperitoneally with 20 million L. (L.) chagasi amastigotes 7, 15, and 30 days after injection and processed for histopathological studies and detection of IgG deposits. Glomerular hypercellularity was clearly visible and, upon Mason's trichrome and periodic acid methenamine silver staining, a pattern suggestive of mesangial proliferative glomerulonephritis was observed in mice with VL. Time-dependent IgG deposits were also seen in infected mice. We consider L. (L.) chagasi-infected mice to be a suitable model for studies of the immunopathogenesis of glomerular lesions in VL.

Two Cases of Isolated Diffuse Mesangial Sclerosis with WT1 Mutations

Here we report two cases of isolated diffuse mesangial sclerosis (IDMS) with early onset end-stage renal failure. These female patients did not show abnormalities of the gonads or external genitalia. Direct sequencing of WT1 PCR products from genomic DNA identified WT1 mutations in exons 8 (366 Arg>His) and 9 (396 Asp>Tyr). These mutations have been reported previously in association with Denys-Drash syndrome (DDS) with early onset renal failure. Therefore we suggest that, at least in part, IDMS is a variant of DDS and that investigations for the WT1 mutations should be performed in IDMS patients. In cases with identified WT1 mutations, the same attention to tumor development should be required as in DDS patients, and karyotyping and serial abdominal ultrasonograms to evaluate the gonads and kidney are warranted.

Immunoglobulin A nephropathy in patients with non-insulin dependent diabetes mellitus

The occurrence of immunoglobulin A nephropathy (IgAN) in patients with noninsulin dependent diabetes mellitus (NIDDM) is a rare event and of pathogenetic interest. It is not clear whether this is merely coincidence. We report here five patients with IgAN in NIDDM associated with or without diabetic glomerulosclerosis. All of the patients were Korean males. In three patients, diabetes mellitus was diagnosed at the same time with diagnosis of IgAN, and the known duration of the diabetes in the other two patients were three and seven years, respectively. There was no evidence of diabetic retinopathy in four patients, but it was found in one patient. In all cases, the diagnosis of IgAN was made by immunohistology.

Influência do bloqueio da enzima de conversäo na evoluçäo da nefropatia induzida por adriamicina / Influence of the block enzyme in the evolution of adriamycin-induced nephropathy

Com o objetivo de avaliar os efeitos do enalapril sobre a proteinúria, tráfego de macromoléculas para o mesângio e sobre a evoluçäo das lesöes renais, na nefropatia por ADR, foram estudados 4 grupos de animais seguidos por 24 semanas: 2 grupos incoculados com ADR na dose de 3 mg/kg IV (ADR; ADR-ENA com enalapril - 50 mg/l água beber) e 2 inoculados com salina na dose 3 mlkg IV

Clinicopathological study of acute renal failure following viperine snake bite.

Fifty patients of acute renal failure following Viperine snake bite were studied. Oliguria (100%), local swelling (48%) and bleeding tendencies (42%) were the predominant clinical features encountered. Of the 25 patients in whom detailed coagulation studies were done, 24 patients had disseminated intravascular coagulation (DIC) and 1 had primary fibrinolysis. DIC was commoner with Russell's viper bite (62%) in comparison to Echis carinatus bites (40%). Renal histology obtained in 29 cases revealed tubular necrosis (35%), cortical necrosis (24%) tubular degeneration (17%) and glomerular changes (17%). Ballooning of glomerular capillaries (59%), splitting of glomerular basement membrane (40.7%), swelling of endothelial cells (29.6%), and focal proliferation of mesangial cells (17%) were the significant glomerular changes encountered. 20 (40%) patients succumbed, DIC (50%), irreversible shock (30%) and septicaemia (20%) being the immediate causes of death. Development of oliguria within 24 hours of snake bite and cortical necrosis were associated with higher mortality.

Mesangeolise e nefroesclerose maligna / Mesangiolisis and malignant nephosclerosis

Os autores estudaram retrospectivamente 13 casos de nefroesclerose maligna primária em material de necrópsia, correspondendo a pacientes adultos (20-57 anos), na sua maioria masculinos e pretos. A presença de lesöes típicas de mesangeolise foi encontrada em 4 casos. Nenhum destes casos apresentava quadro de microangiopatia trombótica clássica. Aventadas as características clinicopatológicas da doença hipertensiva, somente os sinais de fundoscopia positiva para hipertensäo arterial maligna estiveram freqüentemente associados a mesangeolise. Os autores sugerem a mesangeolise como mais um marcador para a nefroesclerose maligna em estudo histológico

A Study of Glomerullar Minimal Lesion and Minimal Mesangial Proliferation with or without Nephrotic Syndrome; Pathologic, Immunopathologic and Clinical Correlations

A total of 394 cases of minimal lesion were reviewed and reassessed clinically and by laboratory investiga- tion, for 4 years from 1979 to 1982. Association with nephrotic syndrome is significantly higher in the cases with histologically normal-appearing mesangium than in the cases with mesangial proliferation. In 43% of the cases of minimal lesion, a minimal but prominent mesangial deposit of Immunoglobulin M with or without C3 deposit was found, and frequently accompanied with nephrotic syndrome, which is not sufficient to accept the condition as a specific disease entity such as "IgM Nephropathy" in our present study. Minimal lesion with a minimal but unmistakable deposit of lgA on the mesangium was noted less frequently and was accompanied or unaccompanied by nephrotic syndrome, a condition which call for an investigation clarify the characteristics and the extent of lgA(Berger's) nephropathy. Response to steroids in minimal lesion nephrotic syndrome was better in children and in the cases without mesangial proliferation, but was unrelated to either hematuria or immunoglobulin deposit. However, the cases with mesangial proliferation are significantly lesser in therapeutic response. Transformation to another morphological type of original glomerular change during follow-up was not observed in 4 available cases of minimal lesion nephrotic syndrome. Henoch-Sch nlein purpura was seen more commonly in children, and lgA(Berger's) nephropathy more commonly in adults.