Evidence Of Glomerular Damage Research Articles

Role of Tumor Necrosis Factor Alpha in Disease Using a Mouse Model of Shiga Toxin-Mediated Renal Damage

Mice have been extensively employed as an animal model of renal damage caused by Shiga toxins. In this study, we examined the role of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) in the development of toxin-mediated renal disease in mice. Mice pretreated with TNF-alpha and challenged with Shiga toxin type 1 (Stx1) showed increased survival compared to that of mice treated with Stx1 alone. Conversely, mice treated with Stx1 before TNF-alpha administration succumbed more quickly than mice given Stx1 alone. Increased lethality in mice treated with Stx1 followed by TNF-alpha was associated with evidence of glomerular damage and the loss of renal function. No differences in renal histopathology were noted between animals treated with Stx1 alone and the TNF-alpha pretreatment group, although we noted a sparing of renal function when TNF-alpha was administered before toxin. Compared to that of treatment with Stx1 alone, treatment with TNF-alpha after toxin altered the renal cytokine profile so that the expression of proinflammatory cytokines TNF-alpha and interleukin-1beta (IL-1beta) increased, and the expression of the anti-inflammatory cytokine IL-10 decreased. Increased lethality in mice treated with Stx1 followed by TNF-alpha was associated with higher numbers of dUTP-biotin nick end labeling-positive renal tubule cells, suggesting that increased lethality involved enhanced apoptosis. These data suggest that the early administration of TNF-alpha is a candidate interventional strategy blocking disease progression, while TNF-alpha production after intoxication exacerbates disease.

Effects of whole blood, crystalloid, and colloid resuscitation of hemorrhagic shock on renal damage in rats: an ultrastructural study

Purpose: The aim of this study was to determine the effects of whole blood, crystalloid, and colloid treatment on histopathologic damage of kidney induced by hemorrhagic shock in rats. Methods: Fifty-six male Sprague Dawley rats were divided into 8 groups. The carotid artery was cannulated, and systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate (HR), and rectal temperature (RT) were observed during the procedure. The jugular vein also was cannulated, and the SAP was decreased by aspiration of 75% of blood through the jugular vein in the control (nonresuscitated) and study (resuscitated) groups, whereas blood was not diminished in the sham group. The hemorrhagic shock was permitted to last 45 minutes; then, the study group rats were resuscitated with heparinized shed autologous whole blood (WB), normal saline (NS), Lactated Ringer’s solution (LR), hydroxyethyl starch 6% (HES6), hydroxyethyl starch 10% (HES10), or dextran 40 (D40). Histopathologic evaluation was performed under light and electron microscope. Results: The RT, SAP, and DAP decreased, and HR increased significantly in the control and study groups during the shock period compared with those of sham group. After volume resuscitation, these parameters changed to preshock levels. Electron and light microscopic examinations of kidneys showed severe proximal tubular degeneration with moderate glomerular damage in the control group; moderate proximal tubular degeneration with mild glomerular damage in the NS, LR, HES6, and HES10 groups; and mild proximal tubular degeneration with no evidence of glomerular damage in the WB and D-40 groups. Conclusions: The characteristic ultrastructural features of hemorrhagic shock appear to be severe tubular degeneration and mild to moderate changes in glomeruli. Resuscitation of hemorrhagic shock with whole blood or dextran 40 solution appears to be most favorable therapy in preventing ultrastructural renal damage in rats.

Mesangial kinetics after partial nephrectomy in rats fed a normal or a low-protein diet

Mesangial kinetics of aggregated BSA (aggBSA) were studied in rats subjected to 1 1/3 nephrectomy (4/6 Nx) fed either a normal (16%) or a low-protein (8%) diet. At 4 weeks postsurgery, ablated rats exhibited modest elevations in blood pressure but had neither significant proteinuria nor evidence of glomerular damage. Following injection of aggBSA into 4/6 Nx rats (16% diet) there was a marked increase in mesangial localization at 4 h compared with control animals, followed by rapid clearance over 4-8 h, in keeping with increased trafficking in this model. The increased trafficking was significantly reduced by dietary protein restriction with 4/6 Nx rats fed an 8% protein diet exhibiting mesangial kinetics not significantly different from control animals. Control animals exhibited identical kinetics irrespective of diet. In separate studies, the 8% protein diet significantly reduced proteinuria and glomerulosclerosis when compared with untreated animals when studied at 30 weeks postsurgery.

Progressive renal toxicity due to ifosfamide

A prospective and follow up study of renal tubular and glomerular function in 11 children receiving ifosfamide treatment was conducted. Each child received between four and 14 courses of ifosfamide, given as a continuous infusion of 3 g/m2 over 24 hours for two or three days. Evidence of renal toxicity was seen in all patients. There was a treatment related rise in urinary tubular markers (N-acetyl-glucosaminidase and alpha 1 microglobulin). Recovery was limited, so that by the fourth course of treatment all values remained abnormal. There was an associated treatment related reduction in plasma phosphate concentration. Urinary albumin also showed a treatment related rise, but with fewer abnormal values. Electrophoresis was used to confirm tubular or glomerular patterns. Glomerular toxicity was less severe and occurred in fewer patients. The follow up study showed persistence of tubular damage in all seven patients examined, and there was evidence of glomerular damage in five of the seven children. Children receiving ifosfamide need to be carefully monitored for renal toxicity both during treatment and at follow up.

Progressive renal toxicity due to ifosfamide.

A prospective and follow up study of renal tubular and glomerular function in 11 children receiving ifosfamide treatment was conducted. Each child received between four and 14 courses of ifosfamide, given as a continuous infusion of 3 g/m2 over 24 hours for two or three days. Evidence of renal toxicity was seen in all patients. There was a treatment related rise in urinary tubular markers (N-acetyl-glucosaminidase and alpha 1 microglobulin). Recovery was limited, so that by the fourth course of treatment all values remained abnormal. There was an associated treatment related reduction in plasma phosphate concentration. Urinary albumin also showed a treatment related rise, but with fewer abnormal values. Electrophoresis was used to confirm tubular or glomerular patterns. Glomerular toxicity was less severe and occurred in fewer patients. The follow up study showed persistence of tubular damage in all seven patients examined, and there was evidence of glomerular damage in five of the seven children. Children receiving ifosfamide need to be carefully monitored for renal toxicity both during treatment and at follow up.

Assessment of renal tubular function and damage and their clinical significance.

Renal function is usually assessed by making some estimate of glomerular filtration rate (GFR). Renal damage is usually detected through an increase in the excretion of protein in the urine, which is usually taken as evidence of glomerular damage rather than tubular damage. Renal tubular function or damage is rarely specifically tested or looked for in routine practice because tubular dysfunction is rarely clinically important and is difficult to detect simply, and the generalised loss of tubular function in chronic renal diseases goes hand in hand with the loss of glomerular function and does not need to be assessed separately. During recent years, however, there has been a rapidly increasing interest in the detection of'.renal tubular damage and in the assessment of renal tubular function. There are three general reasons for this change of emphasis. One reason is an increasing clinical need for the detection of minor changes in renal function (tubular or glomerular). A second reason is that certain characteristics of the kidney and renal tubular function, some only recently defined, make it possible to devise tests which will detect very small changes in tubular function. The third reason is that increasingly simple techniques are available to measure the urine components that form the basis of these sensitive tests of tubular function. What has not been much emphasised, although it was for us a major reason for interest in the topic, is the concept that the renal tubular cell can be used as a sample cell for generalised cell damage with the likely advantage that lesser degrees of damage can be detected in the cells of the kidney than in cells of other organs of the body. The clinical need to detect lesser degrees of renal damage is based on the hope that it will be possible to identify patients at risk of progression to more serious damage in situations and at a time when treatment might prevent that progression. In addi­ tion, these more sensitive tests make it possible to study the relation between cause and effect (for