Pharmacological inhibition of Vanin-1 is not protective in models of acute and chronic kidney disease.

Oxidative stress is a key concept in basic, translational, and clinical research to understand the pathophysiology of various disorders, including cardiovascular and renal diseases. Although attempts to directly reduce oxidative stress with redox-active substances have until now largely failed to prove clinical benefit, indirect approaches to combat oxidative stress enzymatically have gained further attention as potential therapeutic strategies. The pantetheinase Vanin-1 is expressed on kidney proximal tubular cells, and its reaction product cysteamine is described to negatively affect redox homeostasis by inhibiting the replenishment of cellular antioxidative glutathione stores. Vanin-1-deficient mice were shown to be protected against oxidative stress damage. The aim of this study was to elucidate whether pharmacological inhibition of Vanin-1 protects mice from oxidative stress-related acute or chronic kidney injury as well. By studying renal ischemia-reperfusion injury in Col4α3-/- (Alport syndrome) mice and in vitro hypoxia-reoxygenation in human proximal tubular cells we found that treatment with a selective and potent Vanin-1 inhibitor resulted in ample inhibition of enzymatic activity in vitro and in vivo. However, surrogate parameters of metabolic and redox homeostasis were only partially and insufficiently affected. Consequently, apoptosis and reactive oxygen species level in tubular cells as well as overall kidney function and fibrotic processes were not improved by Vanin-1 inhibition. We thus conclude that Vanin-1 functionality in the context of cardiovascular diseases needs further investigation and the biological relevance of pharmacological Vanin-1 inhibition for the treatment of kidney diseases remains to be proven.

Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury.

Glomerular crescents are most common in rapidly progressive glomerulonephritis but also occur in non-inflammatory chronic glomerulopathies; thus, factors other than inflammation should trigger crescent formation, eg vascular damage and plasma leakage. Here we report that Alport nephropathy in Col4A3-deficient Sv129 mice is complicated by diffuse and global crescent formation in which proliferating parietal epithelial cells are the predominant cell type. Laminin staining and transmission and acellular scanning electron microscopy of acellular glomeruli documented disruptions and progressive disintegration of the glomerular basement membrane in Col4A3-deficient mice. FITC-dextran perfusion further revealed vascular leakage from glomerular capillaries into Bowman's space, further documented by fibrin deposits in the segmental crescents. Its pathogenic role was validated by showing that the fibrinolytic activity of recombinant urokinase partially prevented crescent formation. In addition, in vitro studies confirmed an additional mitogenic potential of serum on murine and human parietal epithelial cells. Furthermore, loss of parietal cell polarity and unpolarized secretion of extracellular matrix components were evident within fibrocellular crescents. Among 665 human Alport nephropathy biopsies, crescent formation was noted in 0.4%. We conclude that glomerular vascular injury and GBM breaks cause plasma leakage which triggers a wound healing programme involving the proliferation of parietal cells and their loss of polarity. This process can trigger cellular and fibrocellular crescent formation even in the absence of cellular inflammation and rupture of the Bowman's capsule.

Evolução da síndrome de alport em crianças brasileiras / The evolution of alport syndrome in Brazilian children

Objetivo: Apresentar a evolução de crianças com Síndrome de Alport e determinar manifestações preditivas de Insuficiência renal crônica. Material eMétodos: Revisão dos prontuários de todas as crianças com diagnóstico confirmado de S. Alport por biópsia com microscopia eletrônica. Resultados:Vinte e dois pacientes, de vinte diferentes famílias, com idade inicial de 7 ± 6.5 anos, com tempo médio de acompanhamento de 8 ± 8 anos foramestudados. A queixa mais freqüente foi de hematúria macroscópica com antecedente familiar de insuficiência renal crônica (IRC), seguida da de hematúriamicroscópica e antecedente familiar de hematúria . Dezenove casos tiveram evolução pôndero-estatural dentro do canal de crescimento. Hipertensãoarterial e anemia somente foram detectadas nos casos com evolução para IRC e após a sua instalação. Perda auditiva neuro-sensorial foi encontrada aos10 ± 4 anos em 09/22, sendo que todos evoluíram para IRC (p= 0,002). Proteinúria nefrótica surgiu entre oito e 12 anos de idade e somente nos casoscom evolução para IRC (p= 0,002). A média do clearance de creatinina nas faixas etárias de 4 a < 8; 8 a <12; 12 a <16 e nos >= 16 anos foramrespectivamente de 123,0; 107,1; 84,8 e 69,7 ml/min/1.73 m2 . Doze pacientes (seis de cada sexo) evoluíram para IRC classe IV, com idade média de15 ± 4 anos. Conclusões: A presença de hematúria macroscópica e o aparecimento de perda auditiva neuro-sensorial e proteinúria nefrótica forampreditivos de evolução para IRC terminal.

Objective: To present the clinical course of children with Alport Syndrome and determine predictive factors for end stage renal failure. Material e Methods:Revision of charts of patients with Alport Syndrome diagnosed by electronic microscopy of kidney biopsies. Results: Twenty-two patients, from twentydifferent families, mean age of 7± 6.5 years, mean follow-up of 8±8 years were studied. The most frequent finding was macroscopic hematuria inassociation with familiar history of chronic renal failure followed by microscopic hematuria in conjunction with familiar history of hematuria. Nineteen patientshad weight and stature inside growth channel. Hypertension and anemia only were detected in patients that already had chronic renal failure. Neurosensorialhearing loss appeared at the mean age of 10 ± 4 years in 9/22, and all of them developed chronic renal failure (p=0.002). Nephrotic proteinuriaappeared when children were between 8 and 12 year-old, and only in patients that developed chronic renal failure (p=0.002). The mean of creatinineclearance in ages from 4 to < 8 years, 8 to <12 years,12 to <16 years, and >= 16 yearswere respectively 123.0, 107.1, 84.8, and 69.7 ml/min/1.73 m2.Twelve patients (six of each sex) developed class IV chronic renal failure, at a mean age of 15 ± 4 years. Conclusion: Macroscopic hematuria, neurosensorialhearing loss and nephrotic proteinuria were predictable of progression to chronic renal failure in childhood.

Women's decision-making in prenatal screening.

With serum screening (MS-AFP and hCG testing for Down's syndrome) women have to make several decisions in a limited time: whether to participate in the screening in the first place; then, if increased risk for fetal abnormality is detected, whether to have a diagnostic test, and finally, what to do if fetal abnormality is detected. The aim of this study was to examine how women themselves in an unselected population describe their decision-making in the different phases of serum screening. Women receiving a positive result from serum screening in two Finnish towns from September 1993 to March 1994 and a group of individually matched controls were invited to semistructured interviews; 45 index and 46 control women (79% of those invited) participated between their 29th and 37th weeks of gestation (mean 31 weeks). Although serum screening was most often presented as voluntary or as an option, half the women described participation as a routine or self-evident act; only one-fourth of the women described actively deciding about participation. After a positive screening result, women's reactions to diagnostic tests, and their intentions if disability would be detected, varied greatly. Most of the women actively decided about having diagnostic tests, but for 23% participation in diagnostic testing was called a self-evident act. Women's intentions regarding abortion varied from a firm decision to abort to a firm decision not to abort, and many remained ambivalent. Prenatal screening, which demands the making of several decisions in a limited time and is offered to all pregnant women as part of established maternity care, is not based on every participant's active decision-making and thus creates an ethical problem. This problem should receive special attention from those who develop, introduce and decide on new health care practices.

Evaluation in patients with Alport syndrome of knowledge of the disease and attitudes toward prenatal diagnosis.

Cloning of the COL4A5 gene has now made possible prenatal testing for Alport syndrome with X-linked dominant inheritance. We interviewed 27 females and 24 males with Alport syndrome to evaluate their knowledge of the disease and its transmission, and their attitudes to prenatal testing. Twenty-two males and 8 females were on renal replacement therapy. In all cases transmission was compatible with X-linked disease. Only 59% of the interviewees (74% of women, 42% of men) knew that gender was the major determinant in progression of the disease. Knowledge of the mode of inheritance was adequate in only 25%, in both sexes. Seventy percent of the participants (78% of women, 63% of men) would use prenatal testing. Of the women in favor of prenatal diagnosis, 67% and 39% would terminate pregnancy in the case of an affected male or female fetus, respectively. Of the men in favor of prenatal diagnosis, 53% would consider termination of an affected fetus. In summary, a majority would use prenatal testing, but only one or two thirds of them wished to use selective abortion. As in other inherited disorders, there is a discrepancy between the demand for prenatal diagnosis and the decision to terminate pregnancy. Most of the participants who would terminate a pregnancy had, however, little knowledge of the clinical and genetic aspects of Alport syndrome on which to base such a decision. An important aspect of genetic counselling is to assist consultants in reaching a decision regarding future reproductive behaviour which is appropriate to their situation. This study underlines the need to improve education and counselling to assure appropriate use of prenatal testing.

Binding of anti-DNA antibodies and inhibition of glomerulonephritis in MRL-lpr/lpr mice by heparin.

Heparin was found to inhibit the DNA binding of antibodies eluted from kidneys of both humans and MRL-lpr/lpr mice with systemic lupus erythematosus. Treatment of MRL-lpr/lpr mice with low doses of heparin significantly inhibited renal damage. These results suggest that low-dose heparin might be useful in preventing renal damage in patients with lupus nephritis.

Síndrome de alport en infantes, adolescentes y adultos jóvenes

En esta revisión bibliográfica tratamos de definir este síndrome desde sus vertientes clínica, metabólica y genética, dando alguna orientación acerca de sus principios epidemiológicos. Seguidamente, revisamos su etiopatogenia y su naturaleza genética, con sus patrones hereditarios de transmisión, la naturaleza bioquímica conocida y describimos las variantes que descritas hasta el momento. A continuación, consideramos las principales manifestaciones histopatológicas, aún cuando éstas no suelen mostrar ninguna especificidad. Nos detenemos algo más en sus manifestaciones clínicas y en los principales hallazgos de laboratorio a la vez que en el curso que toma su historia natural de acuerdo a los diferentes grupos de edad...