Tamoxifen associated to the conservative CKD treatment promoted additional antifibrotic effects on experimental hypertensive nephrosclerosis.

CKD progression depends on the activation of an intricate set of hemodynamic and inflammatory mechanisms, promoting renal leukocyte infiltration, inflammation and fibrosis, leading to renal function loss. There are currently no specific drugs to detain renal fibrogenesis, which is a common end-point for different nephropathies. Clinical therapy for CKD is mostly based on the management of hypertension and proteinuria, partially achieved with renin-angiotensin-aldosterone system (RAAS) blockers, and the control of inflammation by immunosuppressive drugs. The aim of the present study was to verify if the administration of tamoxifen (TAM), an estrogen receptor modulator, clinically employed in the treatment of breast cancer and predicted to exert antifibrotic effects, would promote additional benefits when associated to a currently used therapeutic scheme for the conservative management of experimental CKD. Wistar rats underwent the NAME model of hypertensive nephrosclerosis, obtained by daily oral administration of a nitric oxide synthesis inhibitor, associated to dietary sodium overload. The therapeutic association of TAM to losartan (LOS), and mofetil mycophenolate (MMF) effectively reduced the severe hypertension, marked albuminuria and glomerular damage exhibited by NAME animals. Moreover, the association also succeeded in limiting renal inflammation in this model, and promoted further reduction of ECM interstitial accumulation and renal fibrosis, compared to the monotherapies. According to our results, the association of TAM to the currently used conservative treatment of CKD added significant antifibrotic effects both in vivo and in vitro, and may represent an alternative to slow the progression of chronic nephropathy.

NF-κB activation mediates crystal translocation and interstitial inflammation in adenine overload nephropathy.

Adenine overload promotes intratubular crystal precipitation and interstitial nephritis. We showed recently that these abnormalities are strongly attenuated in mice knockout for Toll-like receptors-2, -4, MyD88, ASC, or caspase-1. We now investigated whether NF-κB activation also plays a pathogenic role in this model. Adult male Munich-Wistar rats were distributed among three groups: C (n = 17), receiving standard chow; ADE (n = 17), given adenine in the chow at 0.7% for 1 wk and 0.5% for 2 wk; and ADE + pyrrolidine dithiocarbamate (PDTC; n = 14), receiving adenine as above and the NF-κB inhibitor PDTC (120 mg·kg⁻¹·day⁻¹ in the drinking water). After 3 wk, widespread crystal deposition was seen in tubular lumina and in the renal interstitium, along with granuloma formation, collagen accumulation, intense tubulointerstitial proliferation, and increased interstitial expression of inflammatory mediators. Part of the crystals were segregated from tubular lumina by a newly formed cell layer and, at more advanced stages, appeared to be extruded to the interstitium. p65 nuclear translocation and IKK-α increased abundance indicated activation of the NF-κB system. PDTC treatment prevented p65 migration and normalized IKK-α, limited crystal shift to the interstitium, and strongly attenuated interstitial fibrosis/inflammation. These findings indicate that the complex inflammatory phenomena associated with this model depend, at least in part, on NF-κB activation, and suggest that the NF-κB system may become a therapeutic target in the treatment of chronic kidney disease.

Transient improvement of hypertension-induced chronic renal failure with mycophenolate mofetil treatment.

A young female with essential hypertension developed progressive azotemia; renal biopsy showed hypertensive nephrosclerosis with considerable tubulointerstitial disease and cellular infiltration. The addition of mycophenolate mofetil (MMF) to her antihypertensive treatment resulted in a dramatic improvement of renal function during the following three months. When the patient discontinued MMF treatment, end-stage renal failure rapidly developed. This patient represents the first report of the beneficial use of MMF in non-immune chronic renal disease and demonstrates that significant functional improvement may be obtained with the addition of MMF to the treatment of hypertensive nephrosclerosis for patients in whom there is significant tubulointerstitial inflammatory infiltration.

Intrauterine food restriction as a determinant of nephrosclerosis.

We previously showed that 3-month-old rats subjected to a 50% intrauterine food restriction had a decreased number of nephrons with increased glomerular diameter, which suggests compensatory hypertrophy. Hypertrophy could be the early event of glomerular damage. In this study, we extended our investigation and performed functional, morphological, and immunohistochemical evaluations in 3- and 18-month-old rats that underwent a 50% intrauterine food restriction (RT3 and RT18, respectively) and age-matched control rats (C3 and C18, respectively). Our findings showed that glomerular filtration rate was significant decreased in RT18 rats (2.42 +/- 0.15 mL/min/kg; n = 28; P: < 0.05) compared with C18 control rats (4.19 +/- 0.10 mL/min/kg; P: < 0.05) and the percentage of glomeruli with sclerosis was greater in RT18 rats (13.01% +/- 2.95%; n = 9; P: < 0.01) than in C18 rats (2.71% +/- 0.35%; n = 6). RT18 rats also showed more intense tubulointerstitial lesions and immunohistochemical alterations in the renal cortex. Immunohistochemical studies showed increased fibronectin and desmin expression in glomeruli and tubulointerstitium and increased vimentin and alpha-smooth muscle actin in the tubulointerstitial area from the renal cortex of RT18 rats (P: < 0.05). Desmin was also increased at the edge of glomeruli from RT18 rats, suggesting podocyte injury. Our data show that when food restriction is imposed during pregnancy, permanent damage occurs in the kidney of the offspring. Glomerular lesions were more severe than the tubulointerstitial damage in these animals.

Nefroesclerose hipertensiva: visäo do patologista / Hypertensive nephrosclerosis: the patologist's approach

A nefroesclerose benigna tem como principais características lesões hialinas de arteríolas aferentes, hipertrofia medial de artéria interlobular, fibrose intersticial, atrofia tubular e glomerulopatia hipertensiva ou isquêmica. Embora o quadro completo seja bastante sugestivo de nefroesclerose benigna, as lesões isoladamente não são patognomônicas e podem estar presentes também na nefropatia diabética, na nefrotoxicidade crônica por ciclosporina e em meio às alterações do parênquima renal dos idosos. O exame da amostra renal à microscopia óptica, imunofluorescência e microscopia eletrônica auxiliam no diagnóstico diferencial. A nefroesclerose maligna caracteriza-se por lesão predominante de arteríolas aferentes e artérias interlobulares, às vezes estendendo-se aos capilares glomerulares com necrose fibrinóide da parede dos vasos, obliteração da luz, focos de edema, necrose e hemorragia interticiais e glomerulopatia isquêmica. O diagnóstico diferencial com o quadro histológico da síndrome hemolítica-urêmica e freqüente.

Mecanismos fisiopatológicos da hipertensäo arterial primária em negros / Physiopathologic mechanisms of primary hypertension in blacks

A hipertensäo arterial primária tem provavelmente uma determinaçäo genética, independentemente de raças. Entretanto, os mecânismos patogênicos através dos quais esses genes se expressaräo fenotipicamente dependem, de um lado, da interaçäo do indivíduo com o meio e, de outro, de seus próprios marcadores bioquímicos e endócrinos intermediários. Esta revisäo mostra que nos negros a doença se expressa com mais intensidade do que em brancos, com os mecanismos patogênicos levando com mais frequência e mais precocemente ao aumento da resistência vascular periférica, hipertrofia ventricular esquerda e nefroesclerose. Alteraçöes bioquímicas e endócrinas promovem menor excreçäo renal de sódio e expansäo de volume

Nefropatía diabélica: estudio clínico-patológico / Diabetic nephropathy: clinico-pathological study

La nefropatía diabética resulta una entidad de extraordinaria importancia para el médico en su vida práctica diaria. En este trabajo se organizó el material que hasta el presente se encontraba recopilado en protocolos de necropsias de pacientes que tenían el diagnóstico de diabetes mellitus (43 en total) y se encontraron alteraciones renales en 21 de ellos. Posteriormente fueron revisadas las historias clínicas de esos 21 pacientes, estableciéndose una correlación entre los elementos clínico-humorales de los mismos y los hallazgos anatomopatológicos. Un alto porcentaje (24,4

) de los pacientes fallecieron a causa de pielonefritis aguda supurada, entidad, por cierto, excepcional en pacientes no diabéticos, en ausencia de obstrucción o reflujo. El sexo femenino predominó en todos los casos. Los patrones nodular y mixto de glomeruloesclerosis diabética se presentaron en pacientes con mayor tiempo de evolución de su enfermedad que el patrón difuso, siendo su evolución mucho más tórpida, con mayor número y más graves complicaciones. Parece existir franca predisposición de los pacientes diabéticos a la infección urinaria o a proceso séptico a otro nivel. Las complicaciones propias de las alteraciones vasculares del diabético son extraordinariamente frecuentes, sobre todo en aquellos pacientes portadores de glomeruloesclerosis diabética. La insulino-dependencia parece ser indicador de mal pronóstico de los diabéticos (AU)

Nefropatía diabélica: estudio clínico-patológico / Diabetic nephropathy: clinico-pathological study

La nefropatía diabética resulta una entidad de extraordinaria importancia para el médico en su vida práctica diaria. En este trabajo se organizó el material que hasta el presente se encontraba recopilado en protocolos de necropsias de pacientes que tenían el diagnóstico de diabetes mellitus (43 en total) y se encontraron alteraciones renales en 21 de ellos. Posteriormente fueron revisadas las historias clínicas de esos 21 pacientes, estableciéndose una correlación entre los elementos clínico-humorales de los mismos y los hallazgos anatomopatológicos. Un alto porcentaje (24,4%) de los pacientes fallecieron a causa de pielonefritis aguda supurada, entidad, por cierto, excepcional en pacientes no diabéticos, en ausencia de obstrucción o reflujo. El sexo femenino predominó en todos los casos. Los patrones nodular y mixto de glomeruloesclerosis diabética se presentaron en pacientes con mayor tiempo de evolución de su enfermedad que el patrón difuso, siendo su evolución mucho más tórpida, con mayor número y más graves complicaciones. Parece existir franca predisposición de los pacientes diabéticos a la infección urinaria o a proceso séptico a otro nivel. Las complicaciones propias de las alteraciones vasculares del diabético son extraordinariamente frecuentes, sobre todo en aquellos pacientes portadores de glomeruloesclerosis diabética. La insulino-dependencia parece ser indicador de mal pronóstico de los diabéticos

The significance of focal sclerotic lesions of glomeruli in children.

To establish the relationship between the type of focal sclerotic lesion of glomeruli and the development of progressive renal disease, the clinical courses of 20 children with focal segmental and 7 with focal global sclerosis were analyzed. Only five patients, all of them with focal segmental sclerosis, did not have the nephrotic syndrome, although all had proteinuria. Results suggest that patients with focal global sclerosis have a course identical to that of children with the minimal lesion form of nephrotic syndrome: onset in early childhood, response to steroid therapy, and a relapsing, nonprogressive course. Focal segmental sclerosis, in constrast, is characterized by older age at onset, high incidence of nephritic symptoms, lack of response to steroid therapy, and a progressive course with histologic and functional deterioration. Since most published reports have not distinguished between these two entities, a more favorable prognosis in focal segmental sclerosis may be inferred than is actually the case.