Mercuric chloride-induced renal tubular necrosis in the rat.

A light microscopic study of the renal tubulonecrotic lesion in rats given a small dose of HgCl2 is described. The changes consist of a rapidly developing vacuolation of the cytoplasm with loss of basophilic staining within 4 h that leads to cell breakdown, fragmentation and dissolution by 48 h. Nuclear changes appear to set in later. Permanent patchy fibrotic lesions were found in the kidneys at 10 days. The animals pass a large amount of urine of low osmolarity, low Na+, K+ and Cl- for a period of 3 days accompanied by an increased water intake. Nevertheless there appeared to be no water or ionic imbalance between daily inputs and outputs. Blood urea levels were greatly increased for 3 days, but did not return to normal by the 10th day.     

Mercuric chloride-induced renal tubular necrosis in the rat

A light microscopic study of the renal tubulonecrotic lesion in rats given a small dose of HgCl2 is described. The changes consist of a rapidly developing vacuolation of the cytoplasm with loss of basophilic staining within 4 h that leads to cell breakdown, fragmentation and dissolution by 48 h. Nuclear changes appear to set in later. Permanent patchy fibrotic lesions were found in the kidneys at 10 days. The animals pass a large amount of urine of low osmolarity, low Na+, K+ and Cl- for a period of 3 days accompanied by an increased water intake. Nevertheless there appeared to be no water or ionic imbalance between daily inputs and outputs. Blood urea levels were greatly increased for 3 days, but did not return to normal by the 10th day.     

Partial protection by chlorpromazine in mercuric chloride-induced acute renal failure in rats

Previous studies have demonstrated that the anesthetic amine, chlorpromazine hydrochloride (CPZ), prevents cell necrosis in experimentally induced ischemic liver and heart disease and decreases the extent of galactosamine-induced cell death in the liver. The present model was designed to determine whether CPZ exerts a similar beneficial effect in kidney in a nephrotoxic model of acute renal failure in rats induced by the administration of mercuric chloride (2 mg/kg of body weight). The functional and structural changes in the kidney were evaluated and quantitated in animals pretreated with CPZ (40 mg/kg of body weight) or saline and then subjected to nephrotoxic injury. Compared to controls, the glomerular filtration rate was significantly lower (p less than 0.001) in saline- and CPZ-pretreated rats receiving mercuric chloride. Twenty-four hours after mercuric chloride administration the glomerular filtration rate was 446 +/- 38 microl/minute/gm of kidney weight, the fractional sodium excretion was 0.4 +/- 0.2%, and the urinary osmolality was 1440 +/- 193 mOsmoles/kg of H2O in the CPZ-treated animals compared to 26 +/- 18 microl/minute/gm of kidney weight (p less than 0.001), 10.1 +/- 9.8% (p less than 0.025), and 353 +/- 28 mOsmoles/kg of H2O (p less than 0.005), respectively, in the animals receiving mercuric chloride alone. The percentage of proximal tubule cell necrosis was 26.5 +/- 8.9% in the CPZ-pretreated group compared to 88.1 +/- 3.6% in the untreated group (p less than 0.001). Metabolic cage studies were performed to follow the time course of this model for 48, 72, and 96 hours after mercury injection. The serum creatinine values and fractional sodium excretions were significantly less in animals receiving CPZ compared to the untreated group at all time intervals examined. The serum urea nitrogen concentration and glomerular filtration rate were similar for the two groups after 48 hours, but the serum urea nitrogen level was significantly lower and the glomerular filtration rate higher after 72 and 96 hours in the animals pretreated with CPZ. In agreement with these findings were observations that animals pretreated with CPZ had significantly fewer necrotic cells 48 and 72 hours after mercury administration, and tubular regeneration appeared to be markedly accelerated. These results suggest that pretreatment with CPZ markedly lessens the degree of structural and functional impairment seen in mercuric chloride-induced acute renal failure in rats and increases the rate of recovery.     

Circulating T-cell populations during mercuric chloride-induced nephritis in the Brown Norway rat.

Fluorescence-activated cell sorter analysis was used to study the peripheral lymphocyte populations during mercuric chloride (HgCl2)-induced autoimmune nephritis in the Brown Norway (BN) rat. Sequential studies showed a transient loss of T cells from peripheral blood attributable to decreases in the percentage of T-helper cells. In addition, there was a decrease in the percentage of T-cytotoxic/suppressor cells prior to the appearance of circulating anti-GBM antibodies, followed by elevated levels of T-suppressor cells during down-regulation of the response. This method may allow closer inspection of the events linking changes in T-cell populations and induction and termination of an autoimmune response.     

Alterations in renal cortex cation homeostasis during mercuric chloride and gentamicin nephrotoxicity

To help better understand the role of changes in cellular cation homeostasis in the pathogenesis of renal tubular cell injury, the alterations in cation content of renal cortex and isolated renal cortical mitochondria occurring during models of nephrotoxicity secondary to gentamicin and HgCl₂ were determined both during a developing phase of injury prior to the appearance of cell necrosis and after advanced injury when cell necrosis was present. At 3 hr after 5 mg/kg HgCl₂ or after 4 daily doses of 100 mg/kg gentamicin, tubular cell integrity was still intact but mitochondrial functional changes were present. There were no alterations of renal cortex tissue electrolytes at this stage in the HgCl₂ model but tissue K⁺, and more prominently, tissue Mg²⁺ were decreased in the gentamicin model. K⁺ and Mg²⁺ contents of isolated mitochondria were slightly reduced after HgCl₂. Only K⁺ content was slightly reduced after gentamicin. No evidence for tissue or mitochondrial Ca²⁺ overload was present in either model. At 12 hr after 5 mg/kg HgCl₂ or after 10 daily 100 mg/kg doses of gentamicin, widespread areas of tubular cell necrosis were present and the function of isolated mitochondria was severely compromised. Tissue electrolytes at this stage of injury in both models were characterized predominantly by a twofold increase in Na⁺ content and five- to sixfold increases in Ca²⁺. Isolated mitochondria showed marked decreases in K⁺ content and marked increases in content of Na⁺ and Ca²⁺. These data suggest that neither cellular and mitochondrial Ca²⁺ overload nor substantial changes in cellular Na⁺ and K⁺ homeostasis can be implicated in the early stages of renal tubular cell injury produced by gentamicin and HgCl₂.     

Demonstration of antinuclear antibodies in mercuric chloride-induced glomerulopathy in the rat.

Serial administration of mercuric chloride to PVG/C rats induced a glomerulopathy associated with immune complex deposition along the glomerular basement membrane and in the mesangial area. These deposits could be demonstrated by immunofluorescence and electron microscopy 5 to 8 weeks after the first injection of mercuric chloride. At this time antinuclear antibodies could be demonstrated in the sera and in the eluates from the renal cortices from diseased animals. These findings suggest a possible role for antibodies directed against nuclear antigen in the pathogenesis of this type of experimental glomerular disease.     

Kinetics of biglycan, decorin and thrombospondin-1 in mercuric chloride-induced renal tubulointerstitial fibrosis

We investigated the kinetics of decorin, biglycan and thrombospondin-1 in mercuric chloride-treated Brown Norway (BN) rats. BN rats were injected subcutaneously with 1 mg/kg b.w. of mercuric chloride one or three times. The kidney was examined histopathologically and the kinetics of decorin, biglycan and thrombospondin-1 was also examined using immunohistochemistry and real time RT-PCR. As a result, mercuric chloride induced tubular injury and subsequent tubulointerstitial fibrosis. In this lesion, the expression of thrombospondin-1 mRNA was most prominently elevated. The expression of decorin mRNA was next, but biglycan mRNA expression was not elevated. Moreover, decorin and thrombospondin-1 proteins were localized in tubular epithelial cells and peritubular interstitium. Moreover, kinetics of their mRNA expressions was relatively similar to the kinetics of TGF-beta1 mRNA expression previously reported. The present findings suggest that decorin and thrombospondin-1 may participate in the development of tubulointerstitial fibrosis and may have some relation with TGF-beta1 in mercuric chloride-treated BN rats.     

肾移植术后早期急性排斥反应与急性肾小管坏死的鉴别诊断及护理

急性排斥反应和急性肾小管坏死都是肾移植术后常见并发症,两者术后都是以少尿、无尿为主要特点,术后早期较难鉴别。我科从1998年11月至2005年6月共进行同种异体肾移植术268例,其中发生急性排斥反应30例,发生率为11.19%;急性肾小管坏死27例,发生率为10.07%,现报告如下。1临床资料本组268例肾移植术患者中,发生急性排斥反应30例,男性17例,女性13例,年龄9~68岁,经用甲基强的松龙冲击治疗及OKT3、ATG、ALG等治疗,26例逆转,1例因移植肾自发性破裂而摘除,3例移植肾;发生急性肾小管坏死27例,男性12例,女性15例,年龄28~69岁,经透析治疗后25例均…     

Cyclosporin A induces long-term unresponsiveness in mercuric chloride-induced autoimmune glomerulonephritis.

Mercuric chloride induces a transient systemic T-lymphocyte dependent autoimmune syndrome in Brown Norway rats. Two weeks after the first HgCl2 injection maximum serum levels of anti-GBM antibodies and nephrotic range proteinuria are detected. CyA treatment during HgCl2 administration completely prevented these autoimmune phenomena. Moreover, a prolonged unresponsiveness to HgCl2 was induced, lasting for at least 5 weeks after combined pretreatment with CyA and HgCl2. This unresponsiveness could not be adoptively transferred with peripheral lymphoid cells. Suppression of development of HgCl2-induced proteinuria was adoptively transferred with lymphoid cells from HgCl2-treated donors in remission phase. Unresponsiveness to HgCl2, induced by CyA plus HgCl2 pretreatment, could be broken by reconstitution with naive lymphoid cells. These results suggest that the tolerogenic effect of CyA in HgCl2-induced autoimmunity is not mediated by active suppression; instead, the observed unresponsiveness might be due to direct functional deletion of autoreactive T-lymphocytes. A serendipitous finding was the dissociation in time between synthesis of anti-GBM antibodies and development of proteinuria, suggesting a role for cellular effector mechanisms in the induction of proteinuria.     

Renal regeneration following d-serine induced acute tubular necrosis.

Regeneration of the ray kidney was observed for six days after inducing acute tubular necrosis of the proximal pars recta with d-serine (80 mg/100 g body weight. Regenerating cells appear by two days post-treatment, and re-epithelialization of the nephron is completed within six days, with the most mature cells approaching normal morphology. Regeneration originates from viable cells adjacent to the necrotic zone which divide and follow a template provided by the intact basement membrane. Transient, cytoplasmic regenerative activity among developing tubular cells is characterized by the presence of large, irregularly shaped nuclei, prominent nucleoli, abundant ribosomes and lysosomes, and abnormal mitochondrial configurations. Microfilaments appear to be involved in the formation of apical microvilli and the basal labyrinth of plasmalemmal convolutions. These data suggest that d-serine induced acute tubular necrosis of the proximal pars recta may be followed by rapid, patterned regeneration along an intact basement membrane, and that microfilaments are involved in differentiation of cellular morphology.     

Early haemodialysis in acute tubular necrosis

The study was conducted in 35 cases of acute tubular necrosis of varied aetiology. Cases were divided in 2 groups, Group A--17 cases treated conservatively and Group B--18 cases managed by early haemodialysis. Criteria for early haemodialysis were blood urea < 120 mg% and serum creatinine < 7 mg%. Before starting therapy both the groups had comparable biochemical and renal parameters (p > 0.05). Overall mortality was lower in Group B as compared to Group A (22.2% Vs 29.4). Complication events such as uraemic encephalopathy, pulmonary oedema, haematemesis and malena, thrombophlebitis and vomiting were significantly lower in Group B (p < 0.05). Hospital stay was also significantly lower (p < 0.05) in Group B (18 +/- 2.5 days Vs 28 +/- 3 days), this can reduce the cost of treatment also.     

Light and electron microscopical changes seen in acute tubular necrosis in renal allografts

Seven renal biopsy specimens taken from three renal-allografted patients clinically suspected of having acute tubular necrosis were examined by light microscopy and five of these specimens were also examined by electron microscopy. The common findings in these three patients were as follows: The tubular lumina in all parts were dilated and the tubular epithelia were flat. Large vacuoles were occasionally observed within the tubular epithelial cell cytoplasm. These alterations were prominent in proximal convoluted tubules. Electron microscopically, the microvilli of the brush border of proximal convoluted tubules were loose and relatively short. The basal infoldings of proximal convoluted tubules were reduced or had disappeared. It could not be confirmed whether the large intracytoplasmic vacuoles apparent by light microscopic observation were intracytoplasmic or widened lateral intercellular spaces upon electron microscopy. In the most markedly damaged allograft of the three, a grayish hematoxylinophilic substance, which corresponded to autophagosomes with electron-dense round bodies upon electron microscopy, was often observed in the tubular epithelia. In addition, immature or regenerative tubular epithelia were observed. Most of these alterations were similar to those of acute ischemic change seen in non-renal transplantation.     

Use of methyl prednisolone and antioxidants in mercuric chloride-induced experimental vasculitis.

The systemic vasculitides are characterized by necrotizing inflammation of blood vessels. Neutrophils are implicated in tissue damage by their presence at the site of injury. They can mediate injury by release of cellular contents including proteinases, cytokines and reactive oxygen species. Antioxidants such as vitamin E and N-acetyl cysteine (NAC) may therefore be predicted to ameliorate oxidative damage in vivo and could be a cheap and non-toxic form of therapy. We examined this hypothesis in an experimental model of vasculitis which has some similarities to human disease, and in which depletion of neutrophils ameliorates tissue injury. Mercuric chloride (HgCl2) treatment induces an autoimmune syndrome and necrotizing leucocytoclastic vasculitis in the Brown Norway (BN) rat; anti-myeloperoxidase (MPO) and anti-glomerular basement (GBM) antibodies are present, and vasculitis is reduced by antimicrobials. Methyl prednisolone given intravenously was effective in reducing tissue injury, demonstrating that the model was responsive to a treatment used in man. Vitamin E and NAC were given as daily injections intraperitoneally to BN rats either before, during or after HgCl2 administration. Serial blood samples were taken for anti-MPO and IgE antibodies, which were assayed by ELISA. Necropsies were performed on animals killed at peak disease. At doses of 50-200 mg/kg per day vitamin E had no beneficial effect on tissue injury, regardless of timing of treatment. NAC at 100 or 200 mg/kg also had no significant protective effect on vasculitis. Autoantibody and IgE levels were not affected by either methyl prednisolone or the antioxidants. The lack of benefit of vitamin E and NAC suggests that oxidative damage, whether generated by neutrophils or other cells, does not play a major role in the pathogenesis of vasculitis, and that antioxidant therapy is unlikely to be of benefit in systemic vasculitis in man.     

Myeloid bodies in drug-induced acute tubular necrosis

A growing list of drugs, metals, and chemicals has been implicated as the cause of functional and structural damage specifically to the proximal tubular epithelium. Renal biopsies were obtained from three patients who had developed nephrotoxic agent-related acute renal failure. Two of the patients had received gentamicin and viomycin; the third patient had heavy exposure to chromium. All three biopsies showed acute tubular necrosis (ATN) on light microscopy. Electron microscopy revealed that the proximal tubular cells and, to a lesser degree, the distal tubular cells, contained abundant, variably sized myeloid bodies. In our previous experimental study of viomycin-induced ATN in rats, similar ultrastructural findings of a gradual increase in the number of myeloid bodies in the proximal tubular cells were also observed. The constant presence of myeloid bodies in the tubular epithelial cells following drug-induced tubular necrosis suggests that they may represent lysosomal isolation of drug-bound cytoplasmic structures, as a cellular mechanism to degrade toxic substances and, therefore, may serve as an ultrastructural marker of cellular drug uptake and drug disposition.     

参附液防治初发期急性肾小管坏死的实验研究

给Sprasue-Dawley雄性成年大鼠肌注甘油引起急性肾小管坏死,在初发期给不同实验组以不同处理。观察到:参附组的第48小时亚组动物存活率明显高于单纯禁水组(P<0.025),第3、12、24、48小时亚组SUN、Scr升高值与肾小管管型数,第24、48小时亚组肾小管坏死数,均明显低于单纯禁水组和生理盐水组(P<0.05-P<0.001),光镜电镜下肾脏病理形态改变亦明显轻于该二组。以上各指标,参附组却与纠正对照异搏停组相近。实验结果表明,参附液有防治初发期急性肾小管坏死的作用。     

Acute renal failure due to acute tubular necrosis caused by direct invasion of Orientia tsutsugamushi

We describe a scrub typhus patient with acute renal failure for whom a diagnosis was made based on serology as well as immunohistochemical (IHC) staining and an electron microscopic examination (EM) of a renal biopsy specimen. For our case, we demonstrated by IHC staining and EM that renal failure was caused by acute tubular necrosis due to a direct invasion of Orientia tsutsugamushi.