Indices of progression of IgA nephropathy are modulated by α-tocopherol in rats

Background. We have previously shown that α-tocopherol prevents oxidative stress in experimental IgA nephropathy (IgAN) when administered before or concurrent with the induction of IgAN. We now seek to determine whether α-tocopherol can ameliorate the disease after IgAN is established. Methods. Using the classic IgAN model, 25 male Lewis rats were sorted into five groups of five animals each: 4-week control, 4-week bovine gamma globulin (BGG) treatment, 6-week control, 6-week BGG treatment, and 6-week BGG treatment with α-tocopherol administration started after 4 weeks. Serum α-tocopherol concentrations, kidney and plasma malondialdehyde concentrations, and kidney transforming growth factor beta-1 (TGFβ1) mRNA were analyzed. Results.α-Tocopherol modulated IgAN after the disease was established in the 4-week BGG model, as indicated by the reduction in tissue oxidative stress, dampening of fibrogenic cytokine (TGFβ1), and abatement of proteinuria in α-tocopherol-treated animals compared with untreated rats. Conclusions. These results substantiate the anti-oxidant role of α-tocopherol in diminishing the indices associated with progression of experimental IgAN. The ability of α-tocopherol to reduce the progression of injury after establishment of the disease reflects the clinical situation, and thus holds promise for human therapy. Received: October 13, 1999 / Accepted: February 3, 2000     

Does pregnancy influence the course of IgA nephropathy? Proposal for an observational study

Whether or not pregnancy adversely affects the course of IgA nephropathy (IgAN) remains a matter of debate. Studies have produced conflicting results to date, probably due to differences in patient selection, renal disease severity, grades of hypertension and proteinuria or the administration of different therapies. Since numerous variables can influence the long-term outcome, it is necessary to evaluate data from a large number of patients to minimize the effect of confounding factors. However, the number of patients considered in most studies is small, and long-term prognosis is not yet reported in the literature. In the case of a chronic disease with a slow course such as IgAN, a long observation period is needed to draw substantial conclusions about the prognostic value of pregnancy. We propose a multicenter, retrospective, observational study to clarify whether pregnancy negatively affects the long-term prognosis of women with IgAN. Data of women who became pregnant and of women who did not conceive during the follow-up will be collected at the time of renal biopsy and every 5 yrs to evaluate possible differences in the course of maternal renal disease between the two groups. In particular, the following endpoints will be compared: renal function and the onset of hypertension and proteinuria. Possible differences in therapy will be analyzed to investigate whether different treatment approaches in the two groups could have influenced the disease course.     

Additive effect of PPAR-�� agonist and ARB in treatment of experimental IgA nephropathy

Our recent in vitro study demonstrated peroxisome proliferator-activated receptor-γ (PPAR−γ) agonist potentiated the anti-inflammatory effect of angiotensin receptor blocker (ARB) in tubular epithelial cell under milieu mimicking IgA nephropathy (IgAN). Here we studied the therapeutic effect of combining a PPAR-γ agonist, rosiglitazone (Ros), with an ARB, losartan (Los), in experimental IgAN induced in Lewis rats by oral and intravenous immunization with bovine gamma-globulin (BGG). The rats were randomly divided into six groups: control, IgAN, IgAN with unilateral nephrectomy (IgAN/1K), and IgAN/1K receiving Ros, Los, or Ros + Los. Medication was given 1 week after nephrectomy until killing. Rats developing IgAN had hematuria, mesangial hypercellularity with IgA deposition, glomerular damage, and tubulointerstitial infiltration of CD25+ leukocytes accompanied by increased renal expression of TGF-β, AngII receptor subtype-1 (ATR1) and ICAM-1. The renal histopathology, albuminuria, and renal expression of TGF-β, ATR1 and ICAM-1 worsened with unilateral nephrectomy. Ros or Los reduced the renal expression of PCNA, TGF-β, ATR1, and ICAM-1 in IgAN rats with nephrectomy. Despite no difference between rats treated with monotherapy, combined therapy offered additive effect with decreased renal expression of TGF-β, ATR1 and ICAM-1 and attenuation of renal injury. Our animal study suggests combined PPAR-γ agonist and ARB holds promise for future therapy for IgAN.     

Does feeding in infancy effect the development of IgA nephropathy?

Gut permeability to antigens is immature at birth, and while early administration of antigenic foods delays its maturation, breast-feeding accelerates it. We aimed to evaluate whether exposure to antigenic foods in early life is associated with a predisposition for immunoglobulin A nephropathy (IgAN). Three groups of children with IgAN (group 1), non-IgA glomerulopathies (group 2), and healthy controls (group 3) were formed. Parents filled out a questionnaire regarding gestational and postnatal ages, birth weight, and feeding by breast milk, formula, cow’s milk, and complementary foods. All groups were similar for age, gender, birth weight, rate and duration of breast-feeding, and rate of formula feeding. Cow’s milk consumption rate was higher in groups 1 and 2 than in group 3. Whereas introduction of formula was earlier in groups 1 and 2 than in group 3, feeding by cow’s milk and weaning were earlier in group 1 than in the other groups. The respective best cutoff ages were 3.5 [odds ratio (OR) 28)], 3.75 (OR 5.7), and 5.5 (OR 10.5) months for formula, cow’s milk, and complementary foods, respectively, for predicting the presence of IgAN. The results of this preliminary study indicate that early introduction of antigenic foods might increase the risk of future primary IgAN.     

Pathogenic IgA in IgA nephropathy: still the blind men and the elephant?

IgA nephropathy (IgAN), the most common glomerulonephritis worldwide, remains an important cause of end-stage renal failure. The pathology is characterized by mesangial deposition of IgA. The disease is now recognized as arising from anomalies of the IgA molecule and the kidneys are innocent bystanders. The immunochemical nature of the IgA molecule and its mesangial uptake command a pivotal role in the pathogenesis of IgAN.     

Do the laparoscopic skills of trainees deteriorate over time?

Introduction

Without ongoing practice, acquired motor skills may deteriorate over time. The purpose of this study is to document the level of retention of laparoscopic skills over time.

Methods

Thirty-three general-surgery PGY 1, 2, and 3 residents trained to established criteria and passed an exam for each of seven technical skills (camera navigation, instrument navigation, camera/instrument coordination, grasping, lifting and grasping, cutting, and clip applying) on a virtual simulator (LapSim^® Surgical Science Ltd., Göteborg, Sweden). Six months later, the residents again completed the exam for each of the seven skills. During the 6 months, the simulators were available, but additional practice was not required. The retesting process consisted of three attempts, the first of which was acclimatization. The results of the subsequent two exams were compared with baseline data.

Results

At retest, the number of residents who passed clip applying (7, 21%) and cutting tasks (18, 55%) was significantly lower than for the other five tasks (p < 0.05). In failed tests, instrument wandering and tissue damage were more common than increases in task time. Upper-level residents were significantly more likely to pass than first-year residents were (p < 0.01). Time of day did not influence passing rates.

Conclusion

Six months after training to criteria, instrument and tissue-handling skills deteriorated more than the speed with which a task is completed. Evidence of skill retention was present for some but not all tasks. Fine motor skills, required to perform more difficult tasks, deteriorated more than skills needed for easier tasks.

     

Has the management of shoulder dislocation changed over time?

Anterior shoulder dislocation is a disabling injury affecting all ages, young and old alike. Recently, the treatment of traumatic shoulder dislocation has included immobilisation for varying periods of time followed by physiotherapy. This study is the first in this country to address the demographic data and recurrence rates of shoulder dislocation. Three hundred and eight patients (170 men and 138 women) were followed up for an average of 5.9 years. The most frequent mechanism of injury was a fall (65.66% of cases), and in 92.1% of the patients, the shoulder was reduced in the Emergency Department without the need for sedation or general anaesthesia. The overall recurrence rate in all ages was 50%, but rose to 88.9% in the 14–20-year age group. The duration of immobilisation did not affect the rate of re-dislocation of the humeral head. We believe that conventional shoulder immobilisation in a sling offers no benefits, and it would be preferable not to immobilise the shoulder at all.

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Résumé Les luxations antérieures de l’épaule sont une affection qui peut survenir à n’importe quel age, aussi bien chez les jeunes que chez les patients plus agés. Jusqu’à ce jour, le traitement des luxations de l’épaule comprend une immobilisation suivi d’une période de rééducation. Cette étude est la première qui met en évidence des données démographiques et des résultats concernant la récidive de la luxation. Trois cent huit patients (170 hommes et 138 femmes) ont été suivis pendant une période de 5,9 ans. Le mécanisme le plus fréquent a été la chute (65,66%) et dans 92,1% des cas la luxation a été réduite aux services d’urgence, sans anesthésie générale et sans sédation particulière. Le taux de récidive quel que soit l’age a été de 50% mais augmente à 88,9% dans le groupe des patients les plus jeunes (14 à 20 ans). Le temps d’immobilisation n’affecte pas le taux de reluxation. Nous pensons que l’immobilisation conventionnelle de l’épaule n’apporte aucun bénéfice et qu’il est préférable de ne pas immobiliser celle-ci à la suite d’une luxation.

     

Myofibroblasts, predictors of progression of mesangial IgA nephropathy?

The limited knowledge of the cellular mediators of renal scarringhampers progress in the management of progressive chronic renalfailure (CRF). We have studied 38 patients with biopsy-provenmesangial IgA nephropathy with emphasis on attempting to definethe role of myofibroblasts(-smooth muscle actin/SMA-positivecells) in renal scarring. In 18 untreated patients, correlationswere undertaken between known histological parameters of progressionas well as the presence of myofibroblasts in tissues and theclinical outcome. -SMA staining by an avidin-biotin-peroxidasemethod was confined to a large extent to the vascular smoothmuscle cells of normal kidneys but extended to the tubulointerstitiumand periglomerular space in scarred kidneys. Mild glomerularstaining was also noted. The interstitial immunostain followeda similar distribution to that of interstitial type III collagen.Morphometric analysis showed the interstitial SMA staining tobe a reliable histological predictor of outcome as it discriminatedbetween progressors and non-progressors (²=4.923, P=0.026).The intensity of the interstitial -SMA staining correlated withrenal functional outcome; inversely with the reciprocal of serumcreatinine slopes (r=-0.466, P<0.025) and positively withthe serum creatinine value at the end of the observation period(r=0.704, P<0.00l). Other histological parameters that correlatedwith outcome included the degree of tubulointerstitial (TI)inflammatory infiltrate (r=-0.425, P<0.05 with 1/Cr slopeand r=0.760, P< with serum creatinine) and the intensityof the TI staining for collagen IV (r=-0.567 and 0.667 respectively).In 20 patients treated with prednisolone and azathioprine, asecond renal biopsy showed the persistence of interstitial myofibroblastsin the absence of progressive fibrosis. In conclusion, stainingof renal biopsies of patients with mesangial IgA for -SMA-positivecells may identify the myofibroblasts as important mediatorsof TI scarring and have useful prognostic implications.     

Underglycosylation of IgA in IgA nephropathy: More than a diagnostic marker?

Moldoveanu et al. present a diagnostic test for IgA nephropathy based on the presence of undergalactosylated IgA in serum. This underglycosylated IgA appears to be overrepresented in serum of IgA nephropathy patients and is most likely related to mesangial IgA deposition. Further studies on the nature, production, regulation, and cellular and molecular interactions of this undergalactosylated IgA may facilitate disease diagnosis and provide further insight into the pathogenesis of this important disease.     

Enhanced Bruton’s tyrosine kinase activity in the kidney of patients with IgA nephropathy

International Urology and Nephrology - Bruton’s tyrosine kinase (BTK) is a vital biological molecule that contributes to immune regulation. Previous studies have showed that BTK can be...     

Serum levels of galactose-deficient IgA in children with IgA nephropathy and Henoch-Schönlein purpura

IgA nephropathy and Henoch-Schönlein purpura nephritis (HSPN) are related diseases characterized by deposits of IgA1-containing immune complexes in the renal mesangium. Adult patients with IgA nephropathy have aberrantly glycosylated IgA1 (galactose-deficient O-linked glycans) in the circulation and renal deposits. However, IgA1 glycosylation has not been studied in pediatric patients with IgA nephropathy. Using our quantitative lectin enzyme-linked immunosorbent assay (ELISA) test, we measured serum levels of galactose-deficient IgA1 of children with IgA nephropathy and HSPN and controls. Children with IgA nephropathy and HSPN had serum levels higher than those of healthy children or renal-disease controls with C1q nephropathy. Furthermore, lectin ELISA identified patients with HSPN whose clinical course mimicked that of IgA nephropathy. In summary, pediatric patients with IgA nephropathy and HSPN have an aberrancy in the glycosylation in IgA1 O-linked glycans that is similar to that in adults with IgA nephropathy.     

In vitro effects of α-tocopherol on teratozoospermic semen samples

A strong positive correlation exists between teratozoospermia and reactive oxygen species production, which in turn has negative effects on their in vitro fertilisation outcome. Our aim of this study was to determine potential protective effects of α-tocopherol on teratozoospermia motility, viability, acrosome reaction and DNA integrity after 1-h in vitro incubation. Teratozoospermic semen samples were obtained from 15 volunteers aged between 20 and 30 years after 3-5 days of sexual abstinence. Samples were washed, centrifuged and incubated in 37 °C and 5% CO(2) until sperm swimmed-up. Spermatozoa were counted in the supernatant and divided into four groups, each contained 2 × 10(6) sperm/ml(-1). Groups one to four were incubated for 1 h with Ham's F-10 solution as control group, 10 μm A23187, 40 μmα-tocopherol and 10 μm A23187 + 40 μmα-tocopherol respectively. The results indicated that α-tocopherol has ability to enhance teratozoospermia viability and motility, while there were no ameliorative effects on acrosome reaction and DNA fragmentation. A23187 induced acrosome reaction in teratozoospermia and α-tocopherol significantly diminished this effect. In conclusion, although α-tocopherol could improve teratozoospermia motility and viability, its effects on DNA integrity and acrosome reaction ability as supplementation IVF culture media are not obvious.     

The effect of renin–angiotensin system blockade on the incidence of end-stage renal disease in IgA nephropathy

Background

The impact of renin–angiotensin system blockade (RASB) on the incidence of end-stage renal disease (ESRD) remains unclear in IgA nephropathy (IgAN).

Methods

This study assessed associations between RASB treatment and the incidence of ESRD in IgAN using propensity score approaches. We retrospectively analyzed 1273 patients with IgAN biopsied between 1979 and 2010. Propensity scores were calculated using logistic regression. Associations between RASB and ESRD were examined using a Cox regression model adjusted by inverse probability of treatment weighted, regression, stratification and matching.

Results

During follow-up (median 5.1 years), 130 patients developed ESRD. With Cox regression adjusted by inverse probability of treatment weighted, RASB use was significantly associated with a lower risk of ESRD (hazard ratio 0.58; 95 % confidence interval 0.42–0.80). Significant associations were observed for other propensity score-based approaches. In stratified analysis, a beneficial association between RASB and ESRD was observed in patients ≥35 years, with hypertension, reduced estimated glomerular filtration rate (<60 mL/min/1.73 m²), mesangial proliferation and segmental glomerulosclerosis (P for interaction <0.05), and tended to be greater in patients with proteinuria (≥1.0 g/24 h), extracapillary proliferation and receiving methylprednisolone pulse therapy (P for interaction <0.10).

Conclusion

Treatment with RASB was associated with a lower incidence of ESRD in the real-world practice of IgAN.

     

Effect of α-tocopherol,taurine and selenium on the attenuation of ischemia/reperfusion injury of splanchnic organs

Background: Splanchnic artery occlusion shock is caused by increased capillary permeability and cellular injury precipitated by oxygen derived free radicals following ischemia and reperfusion of splanchnic organs. The purpose of this study was to assess the role of several wellknown oxygen-derived free radical scavengers in ameliorating or preventing this syndrome. Study design: Anesthetized rats were subjected to periods of occlusion of the visceral arteries and reperfusion. Tocopherol, taurine, selenium or a ‘cocktail’ of these three agents was injected subcutaneously for 4 consecutive days prior to operation. Mean arterial blood pressure was measured throughout the experimental period. Fluorometry and technetium-99m pyrophosphate counting of the visceral organs were performed as well as a histologic grading system for intestinal viability. Results: Final mean arterial blood pressure associated with the ‘cocktail’ and selenium groups was 79.1 ± 27.4 mmHg and 83.6 ± 17.8 mmHg, respectively. These values were significantly higher than the control group, 40.8 ± 11.4 mmHg (P < 0.05). Similar patterns of the benefit of selenium in contrast with the other groups were obtained with fluorescein perfusion, radioisotopic activity and histologie analysis. Conclusion: Pretreatment with selenium of splanchnic ischemia and reperfusion in the rat improves mean arterial blood pressure and microcirculatory visceral perfusion. Further analysis of the precise protective mechanism of selenium for reperfusion injury will enable visceral organs to withstand the consequences of increased capillary leakage and oxidant injury.     

Is IgA nephropathy the commonest primary glomerulopathy among young adults in the USA?

Over the past decade, focal segmental glomerulosclerosis (FSGS) has emerged as the most common primary glomerulopathy in adults in the USA. However in our practice, we became aware of increased numbers of patients with IgA nephropathy (IgAN). In order to further examine this, a retrospective analysis of renal biopsy diagnoses from adults was done from our biopsy database. Adult renal biopsies received from 3/1/2001 to 2/28/2005 were analyzed to determine the frequency of common primary glomerulopathies, which included FSGS, IgAN, membranous nephropathy (MN), minimal change disease, and membranoproliferative glomerulonephritis Type I (MPGN). The patients were grouped as all adults (>or=20 years) and young adults (20-39 years). The distribution of common primary glomerulopathies among the two age groups, expressed as a percentage of all non-transplant diagnoses (n = 4,504), was IgAN 6.9/3.4%, FSGS 9.6/3.2%, MN 6.8/1.6%, minimal change disease 2.5/0.9%, MPGN 1.2/0.2%. IgAN was as common as FSGS in young adults in our biopsy population (IgAN/FSGS 154/143 1.08:1). IgAN was the most common primary glomerulopathy in young adult Caucasians (IgAN/FSGS 2.1:1). IgAN was also the most common cause of end-stage renal disease (ESRD) in young adult Caucasians. In contrast, IgAN was rare in African Americans in whom FSGS remains more common (FSGS/IgAN 9.7:1). These findings from a large renal biopsy referral center serving 24 Midwestern and Southern states suggest that IgAN may be the most common primary glomerulopathy and the most common cause of ESRD in young adult Caucasians in the USA.     

IgA-antigliadin antibodies in patients with IgA nephropathy: the secondary phenomenon?

Circulating IgA-antigliadin antibodies (IgA-AGA) are often found in patients with IgA nephropathy (NP). IgA-AGA are sensitive markers of an abnormal immune system reaction to gluten, seen particularly in patients with celiac disease. However, a lack of IgA-antireticulin and IgA-antiendomysium antibodies and often jejunal mucosal atrophy of patients with IgA NP suggest that most patients do not have latent celiac disease. To examine the relationship between IgA-AGA and clinical data, enzyme-linked immunosorbent assays for IgA-AGA were performed in 28 patients with IgA NP and in 50 healthy persons. The results were calculated in arbitrary units (AU). The cutoff level for a negative or a positive test was found to be 60 AU, calculated according to the AGA test result (mean + 3 SD) in 50 healthy persons. The following clinical data were assessed: age, gender, disease duration, daily proteinuria, blood pressure, serum creatinine, and creatinine clearance. Control sera were negative for IgA-AGA. Positive IgA-AGA tests were observed in 14 of the 28 patients (p < 0.0001 vs. controls) and high levels of IgA-AGA (AU >90) in 6 of the 28 patients (p < 0.001 vs. controls). The mean duration of the disease of the patients with positive IgA-AGA was significantly longer as compared with the patients who had a negative antibody test. IgA-AGA correlated with age (p < 0.05, r = 0. 56), disease duration (p < 0.05, r = 0.40), and blood pressure (p < 0.05, r = 0.48). Antireticulin and antiendomysium antibody tests were negative in all patient and control sera. We conclude that IgA-AGA are associated with the progression of IgA NP. Our findings support the current concept about the pathogenesis of IgA NP, where the defective IgA production itself may be the primary and intestinal lesions as well as the production of IgA-AGA the secondary phenomenon.