Pathogenesis Of Renal Failure Research Articles

Oxidative Stress in the Pathogenesis and Evolution of Chronic Kidney Disease: Untangling Ariadne's Thread.

Amplification of oxidative stress is present since the early stages of chronic kidney disease (CKD), holding a key position in the pathogenesis of renal failure. Induction of renal pro-oxidant enzymes with excess generation of reactive oxygen species (ROS) and accumulation of dityrosine-containing protein products produced during oxidative stress (advanced oxidation protein products—AOPPs) have been directly linked to podocyte damage, proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) as well as tubulointerstitial fibrosis. Vascular oxidative stress is considered to play a critical role in CKD progression, and ROS are potential mediators of the impaired myogenic responses of afferent renal arterioles in CKD and impaired renal autoregulation. Both oxidative stress and inflammation are CKD hallmarks. Oxidative stress promotes inflammation via formation of proinflammatory oxidized lipids or AOPPs, whereas activation of nuclear factor κB transcription factor in the pro-oxidant milieu promotes the expression of proinflammatory cytokines and recruitment of proinflammatory cells. Accumulating evidence implicates oxidative stress in various clinical models of CKD, including diabetic nephropathy, IgA nephropathy, polycystic kidney disease as well as the cardiorenal syndrome. The scope of this review is to tackle the issue of oxidative stress in CKD in a holistic manner so as to provide a future framework for potential interventions.

The role of osteopontin in kidney diseases.

Osteopontin (OPN) is a pleiotropic glycoprotein expressed in various cell types in animals and in humans, including bone, immune, smooth muscle, epithelial and endothelial cells. Moreover, OPN is found in kidneys (in the thick ascending limbs of the loop of Henle and in distal nephrons) and urine. The protein plays an important role in mineralization and bone resorption. In addition, OPN is involved in the regulation of immunity and inflammation, angiogenesis and apoptosis. It was demonstrated that OPN and some OPN gene polymorphic variants are associated with the pathogenesis and progression of multiple disorders, such as cancer, autoimmune, neurodegenerative and cardiovascular diseases. Moreover, recent studies suggested that OPN is associated with the pathogenesis of renal failure. In this review, I briefly discussed the role of OPN and its gene polymorphisms in kidney physiology, as well as in various kidney diseases. Most studies reported that OPN expression is elevated in urolithiasis, and also in acute and chronic kidney diseases, and in renal allograft dysfunction. Moreover, it was demonstrated that polymorphic variants of the OPN gene may be associated with renal failure. However, some reports suggested that OPN is essential for tubulogenesis, and that it inhibits calcium oxalate crystal formation and retention, nitric oxide synthesis, cell apoptosis and promotes cell regeneration. Thus, further studies are required to fully understand the role of OPN in kidney physiology and pathology. Eventually, these studies may result in the identification of OPN as a valuable marker for renal dysfunction prognosis and treatment.

Multiple Myeloma and Renal Failure

Renal failure (RF) occurs in approximately 20-30% of multiple myeloma (MM) patients at diagnosis and in more than 50% of patients with advanced disease. The pathogenesis of RF is related to the production of monoclonal light chains that can damage either the tubule (myeloma kidney) or the glomeruli (light chain deposition disease or amyloid light-chain amyloidosis). In the past, the prognosis of patients with MM and RF was considered poor due to the limited number of effective and non-nephrotoxic drugs that were available. At present, novel drugs acting both on MM clone and on bone marrow microenvironment have been introduced into clinical practice; among them, bortezomib-containing regimens have proved to be the most effective. High-dose myeloablative therapy followed by autologous stem cell rescue can also be proposed in younger patients with no other relevant comorbidities.

Pathogenesis of Renal Failure in Multiple Myeloma: Any Role of Contrast Media?

The spectrum of kidney disease-associated monoclonal immunoglobulin and plasma cell malignancies is remarkably broad and encompasses nearly all nephropathologic entities. Multiple myeloma with kidney impairment at presentation is a medical emergency since the recovery of kidney function is associated with survival benefits. In most cases, kidney impairment may be the first clinical manifestation of malignant plasma cell dyscrasias like multiple myeloma and light chain amyloidosis. Multiple myeloma per se cannot be considered a main risk factor for developing acute kidney injury following intravascular administration of iodinated contrast media. The risk is increased by comorbidities such as chronic kidney disease, diabetes, hypercalcemia, dehydration, and use of nephrotoxic drugs. Before the administration of contrast media, the current recommended laboratory tests for assessing kidney function are serum creatinine measurement and the estimation of glomerular filtration rate by using the CKD-EPI equation. The assessment of Bence Jones proteinuria is unnecessary for evaluating the risk of kidney failure in patients with multiple myeloma, since this test cannot be considered a surrogate biomarker of kidney function.

Impact of Hyperuricemia on Cardiovascular System in ESRD Patients

Background: Hyperuricemia was found to be associated with hypertension, coronary heart disease, metabolic syndrome and chronic kidney disease. However there are no specific data about the relationship of uric acid to cardiovascular disease and mortality in ESRD patients on chronic hemodialysis. So, we aimed to study the impact of hyperuricemia on cardiovascular system in chronic kidney disease and in ESRD patients on regular hemodialysis Patients and methods: This study included 100 patients in Ashmoun hospital, nephrology department. Patients were chosen and divided into two groups: Group A, 50cases with chronic kidney disease and Group B, 50cases of ESRD on regular hemodialysis. All cases were subjected to full clinical examination, measurement of eGFR, laboratory tests for blood urea, serum creatinine and serum uric acid and ECG. Results: Serum uric acid was significantly higher in dialysis group than CKD group (p 0.05). Conclusion: In cases of CKD uric acid is involved in the pathogenesis of renal failure and hypertension. In patients with ESRD, hyperuricemia is not a risk factor for the development of cardiac disease; but it shows reversed epidemiology and becomes a marker of good nutritious status. Further studies should be done on wider scales to evaluate the impact of hyperuricemia on cardiovascular system in hemodialysis patients.

The Decline of Autophagy Contributes to Proximal Tubular Dysfunction During Sepsis

Severe sepsis associated with overproduction of tumor necrosis factor α and reactive oxygen species leads to energy depletion and cellular damage. Both reactive oxygen species and damaged organelles induce autophagy for recycling nutrients to combat pathological stress. To study whether autophagy plays a beneficial role in the pathogenesis of renal failure during sepsis, rats were subjected to cecal ligation and puncture (CLP) or sham operation. Temporal relationship of autophagy and renal dysfunction were examined in vivo. The results showed that the level of lipidated microtubule-associated protein light chain 3 (LC3-II), a marker of autophagy, elevated transiently at 3 h but declined at 9 h until 18 h after CLP. Light chain 3 aggregation in renal tissue showed a similar trend to the change of LC3-II protein. High levels of blood urea nitrogen and creatinine as well as low tubular sodium reabsorption occurred at 18 h after CLP. The distribution of autophagy located primarily in angiotensin-converting enzyme-positive, which is concentrated in proximal tubule, but calbindin D28k (calcium-binding protein D28K, a marker of distal tubule)-negative cells in renal cortex. Therefore, NRK-52E (proximal tubule epithelial cell line) cells were used to further examine cell viability and DNA fragmentation after silencing or inducing autophagy. We found that knockdown of Atg7 (autophagy-related gene 7) exaggerates, whereas preincubation of rapamycin (an autophagy inducer) diminishes tumor necrosis factor α-induced cell death. These results suggest that the decline of sepsis-induced autophagy contributes to the proximal tubular dysfunction, and maintenance of sufficient autophagy prevents cell death. These data open prospects for therapies that activate autophagy during sepsis.

Abstract 5217: Endothelial Vasomotor Dysfunction in the Brachial Artery Predicts Development of Early Stage Renal Dysfunction in Patients With Type 2 Diabetes Mellitus

Endothelial dysfunction in renal vasculature is implicated in the pathogenesis of renal failure in type 2 diabetes mellitus (DM). Endothelial dysfunction occurs in systemic vasculature of DM patients, and there may be a relationship between endothelial dysfunction in the brachial artery and renal vasculature. This study examined whether endothelial vasomotor dysfunction in the brachial artery predicts early renal dysfunction in DM patients. Methods: Flow-mediated endothelium-dependent dilation (FMD, % increase in artery diameter from baseline) in the brachial artery was measured in 275 consecutive DM patients with normal renal function at enrollment (serum creatinine levels [sCr] <1.0 mg/dl, urinary albumin excretion [UAE] < 25 mg/day and estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73 m 2 at baseline). They were prospectively followed for 1.5 years. The end point was development of early stage renal dysfunction, defined as occurrence of one or more of the following events: sCr ≥ 1.2 mg/dL, UAE ≥ 30 mg/day and eGFR < 60 mL/min/1.73 m 2 . Results: During the follow-up period, early stage renal dysfunction developed in 63 (46.7%) patients with impaired FMD (< 5.2%, 50 th percentile of the distribution) and in 17 (12.1 %) patients with the preserved FMD (≥ 5.2%) (p < 0.0001). Using multivariate logistic analysis, the impaired FMD was an independent predictor of the development of early stage renal dysfunction (OR; 5.1, 95%CI; 2.62 - 9.68, p < 0.0001) after adjustment with covariates, including hypertension, age, use of anti-diabetic drugs and CRP levels. Using a c -statistic, the predictive value of impaired FMD was significantly incremental over that of the conventional known risks including hypertension, age, use of anti-diabetic drug and CRP levels for progression of renal dysfunction (area under the ROC curve; 0.88 and 0.72, respectively, p = 0.01). Dilator response of the brachial artery to nitrates had no significant predictive value. Conclusions: Endothelial vasomotor dysfunction in the brachial artery is an independent predictor of development of early renal dysfunction in DM patients. The measurement of FMD is useful for identifying patients with type 2 DM at risk of developing future renal dysfunction.

Experimental supratrigonal cystectomy: II—evaluation of urinary calculi, infection, and bladder dysfunction in the pathogenesis of renal failure

The objective of this study was to evaluate the role of urolithiasis, infection, and bladder dysfunction in the pathogenesis of renal failure in rats subjected to supratrigonal cystectomy. One group of Sprague-Dawley rats was submitted to supratrigonal cystectomy, a second to cystectomy during which a suspension of Proteus mirabilis was injected into the bladder stump, and a third to sham surgery (controls). The animals were sacrificed two months after surgery. Blood pressure and serum urea and creatinine were measured before surgery and at sacrifice when a careful inspection of the urinary tract was performed to determine the presence of hydronephrosis and calculi. Microbiological analyses were performed on urine aspirated from the bladder and on the kidneys. Significant differences were found between values of systolic blood pressure and serum urea and creatinine recorded prior to the surgical procedure and those recorded at sacrifice in each group except the control group. Renal failure was present in all animals subjected to cystectomy. Urinary calculi were documented in 5/10 animals subjected to cystectomy only and in all rats inoculated with P. mirabilis. Hypertension was documented in 43.75% of animals subjected to cystectomy. Pyelonephritis was diagnosed only in animals with urinary calculi, in each of which urine culture was also positive. No cases of renal failure, hypertension, calculi, and/or pyelonephritis were detected in the sham group. The findings of this study indicate that kidney failure in rats subjected to supratrigonal cystectomy is related to the severe bladder dysfunction induced by the surgical procedure.

Chronic Renal Failure and Shortened Lifespan in COL4A3+/− Mice

A heterozygous mutation in autosomal Alport genes COL4A3 and COL4A4 can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3(+/-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3(+/-) mice was found to be significantly shorter than in healthy controls (21.7 versus 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of > 0.1 g/L started after 3 mo of life and increased to > 3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 versus 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-beta and connective tissue growth factor. The renal phenotype in COL4A3(+/-) mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3(+/-) mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.

Gene profiling of polycystic kidneys

While the genetic basis of autosomal dominant polycystic kidney disease (ADPKD) has been clearly established, the pathogenesis of renal failure in ADPKD remains elusive. Cyst formation originates from proliferating renal tubular epithelial cells that de-differentiate. Fluid secretion with cyst expansion and reactive changes in the extracellular matrix composition combined with increased apoptosis and proliferation rates have been implicated in cystogenesis. To identify genes that characterize pathogenical changes in ADPKD, we compared the expression profiles of 12 ADPKD kidneys, 13 kidneys with chronic transplant nephropathy and 16 normal kidneys using a 7 k cDNA microarray. RT-PCR and immunohistochemical techniques were used to confirm the microarray data. Hierarchical clustering revealed that the gene expression profiles of normal, ADPKD and rejected kidneys were clearly distinct. A total of 87 genes were specifically regulated in ADPKD; 26 of these 87 genes were typical for smooth muscle, suggesting epithelial-to-myofibroblast transition (EMT) as a pathogenetic factor in ADPKD. Immunohistology revealed that smooth muscle actin, a typical marker for myofibroblast transition, and caldesmon were mainly expressed in the interstitium of ADPKD kidneys. In contrast, up-regulated keratin 19 and fibulin-1 were confined to cystic epithelia. Our results show that the end stage of ADPKD is associated with increased markers of EMT, suggesting that EMT contributes to the progressive loss of renal function in ADPKD.

Role of endotoxin and nitric oxide in the pathogenesis of renal failure in obstructive jaundice.

There is an increased incidence of postoperative renal failure in patients with obstructive jaundice. The purpose of this study was to investigate the role of endotoxaemia and nitric oxide in this association. In bile duct-ligated, sham-operated and control rats, plasma total bilirubin levels, creatinine clearance and plasma endotoxin were determined. Endothelium-dependent vasodilatation to acetylcholine, and endothelium-independent vasodilatation to nitroglycerine and forskolin were evaluated in isolated perfused rat kidney. Twenty-one of 27 bile-duct ligated rats had endotoxaemia. Plasma bilirubin levels were higher and creatinine clearance was significantly reduced in the bile duct-ligated endotoxin-positive group compared with values in the other groups. Furthermore, in the isolated perfused rat kidney from rats with endotoxaemia, basal perfusion pressure and renal vascular relaxation to acetylcholine and nitroglycerine which is mediated by guanosine cyclic 3',5'-cyclic monophosphate (cGMP) were significantly reduced, but relaxation to forskolin mediated by adenosine cyclic 3',5'-cyclic monophosphate did not change. Endotoxaemia in obstructive jaundice may induce overproduction of nitric oxide that may lead to impairment of cGMP-associated vasodilatation and disrupt autoregulation of the renal vascular bed. This may contribute to renal failure in obstructive jaundice.

Fibrinogen in the 'hepato-renal syndrome': an experimental study.

The pathogenesis of renal failure in jaundice is controversial. Several factors have been incriminated, including intravascular coagulation. We have investigated this hypothesis by by studying the deposition of radioactive fibrinogen in the kidney of jaundiced rats. Fibrinogen labelled with 125I was injected into rats whose bile duct was subsequently ligated. The radioactivity in the kidney was compared to that in blood and the renal uptake ratio calculated. This ratio (mean +/- s.e.mean) rose from 0.24 (+/- 0.04) to 2.93 (+/- 0.43) after ligation of the common bile duct. In contrast, in control rats who underwent a sham operation, the uptake ratio rose from 0.31 (+/- 0.03) to 0.96 (+/- 0.08). This deposition of 125I fibrinogen in the kidneys of jaundiced rats was significantly greater (P < 0.001) than that in control rats. The deposition was specific to the kidney compared with that in the heart, bowel, muscle and liver. In the control animal the uptake of 125I fibrinogen by the kidney was not different from that by other viscera.

Advanced glycation end product is implicated in amyloid‐related kidney complications

Background. Kidney failure is a common complication in familial amyloidotic polyneuropathy (FAP). It has been suggested that advanced glycation end products (AGEs) play an important role in the development and pathogenesis of FAP. Material and methods. To evaluate the impact of AGEs on FAP patients' kidney dysfunction, we measured AGE in serum and urine of 28 FAP patients and 18 healthy controls by AGE‐specific enzyme‐linked immunosorbent assay (ELISA). Immunohistochemistry utilizing antibodies to AGE and the receptor for AGE (RAGE) were used on kidney tissue from 3 FAP patients and 3 diabetic patients to disclose a correlation between amyloid deposits and AGE–RAGE. Results. The glomeruli of FAP patients were heavily deposited with amyloid and the glomerular size was enlarged. The space between Bowman's capsule and glomerulus was totally covered by the enlarged glomerulus. AGE and RAGE were deposited in glomeruli and tubuli and correlated with amyloid deposits. Decreased AGE levels in the liver‐transplanted FAP patients' serum compared with that of non‐transplanted patients were noted, and AGE concentration in serum tended to be higher in non‐transplanted FAP patients compared with normal control subjects. There were no differences in the AGE urine levels in FAP patients compared with controls. No correlation could be found between AGE in urine and serum compared with serum albumin, serum creatinine and creatinine clearance. Conclusions. The accumulation of AGE, RAGE and amyloid in the kidney of FAP patients suggests that these molecules play an important role in the origin and pathogenesis of renal failure in FAP patients.

Type 2 Diabetic Nephropathy

Type 2 diabetes mellitus is now the leading cause of end-stage renal disease in the United States and other developed countries ([1][1]). The pathogenesis of renal failure in type 2 diabetes is complex ([1][1],[2][2]), but a role of the renin-angiotensin system (RAS) has been recognized for more

A Mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse

The development of kidney disease is influenced by both genetic and environmental factors. Searching for models of glomerulopathy that display strong gene-environment interaction, we examined the determinants of anthracycline-induced nephropathy, a classic, strain-dependent experimental model applied to rodents in the past four decades. We produced three crosses derived from mice with contrasting susceptibility to doxorubicin (DOX) nephropathy and, surprisingly, we found that this widely studied model segregates as a single-gene defect with recessive inheritance. By genome-wide analysis of linkage, we mapped the trait locus to chromosome 16A1-B1 (DOXNPH locus) in all three crosses [peak logarithm of odds (lod) score of 92.7, P = 1 x 10(-65)]; this interval represents a susceptibility locus for nephropathy. Gene expression analysis indicated that susceptibility alleles at the DOXNPH locus are associated with blunted expression of protein arginine methyltransferase 7 (Prmt7) on chromosome 8, a protein previously implicated in cellular sensitivity to chemotherapeutic agents (lod = 12.4, P = 0.0001). Therefore, Prmt7 expression serves as a molecular marker for susceptibility to DOX nephropathy. Finally, increased variation in the severity of kidney disease among affected mice motivated a second genome-wide search, identifying a locus on chromosome 9 that influences the severity and progression of nephropathy (DOXmod, peak lod score 4.3, P = 0.0018). These data provide genetic and molecular characterization of a previously unrecognized Mendelian trait. Elucidation of DOX nephropathy may simultaneously provide insight into the pathogenesis of renal failure and mechanisms of cytotoxicity induced by chemotherapeutic agents.

Letter to the Editor: Immune Complex: Does It Have a Role in Pathogenesis of Renal Failure in Dengue Infection?

Dengue infection is a major public health problem. When acute renal failure complicates dengue infection, it is usually associated with severe disease as in dengue hemorrhagic fever or dengue shock syndrome. The role of immune complex in development of renal failure in dengue infection is still unclear. Here, the author used a computational medicine technology to study the property of the dengue virus-immunoglobulin complex. According to this study, the diameter of derived complex is much smaller, compared with the diameter of glomerulus. Entrapment of the immune complex is believed to occur when a previous glomerular lesion causes narrowing of the glomerulus's diameter. Therefore, the immune complex should not have a significant role in pathogenesis of renal failure in dengue infection.

Nuclear factor kappaB activity determines the sensitivity of kidney epithelial cells to apoptosis: implications for mercury-induced renal failure.

Nuclear factor kappa B (NF-kappaB) is a thiol-dependent transcriptional factor that promotes cell survival and protects cells from apoptotic stimuli. Numerous studies have demonstrated increased sensitivity to apoptosis associated with inhibition of NF-kappaB activation in various cell types. We have previously demonstrated that mercuric ion (Hg(2+)), one of the strongest thiol-binding agents known, impairs NF-kappaB activation and DNA binding at low microM concentrations in kidney epithelial cells. In the present studies we investigated the hypothesis that inhibition of NF-kappaB activation by Hg(2+) and other selective NF-kappaB inhibitors would increase the sensitivity of kidney epithelial (NRK52E) cells to apoptogenic agents to which these cells are normally resistant. Fewer than 10% of untreated cells in culture were found to be apoptotic when evaluated by DNA fragmentation (TUNEL) assay. Treatment of cells with Hg(2+) in concentrations up to 5 microM or with tumor necrosis factor-alpha (TNF) (300 units/ml) did not significantly increase the proportion of apoptotic cells, compared with untreated controls. However, when TNF was given following Hg(2+) pretreatment (0.5 to 5 microM for 30 min), the proportion of cells undergoing apoptosis increased by 2- to 6-fold over that seen in untreated controls. Kidney cells pretreated with specific NF-kappaB inhibitors (Bay11-7082 or SN50) prior to TNF also showed a significant increase in apoptosis. Increased sensitivity to apoptotic cell death following these treatments was significantly attenuated in cells transfected with a p65 expression vector. In studies in vivo, rats pretreated by intraperitoneal injection with Hg(2+) (0.75 mg/kg) 18 h prior to administration of bacterial lipopolysaccharide (LPS) (10 mg/kg) displayed impaired NF-kappaB activation and an increased mitochondrial cytochrome c release in kidney cortical cells. These findings are consistent with the view that prevention of NF-kappaB activity in vitro or in vivo enhances the sensitivity of kidney cells to apoptotic stimuli to which these cells are otherwise resistant. Since apoptosis is known to play a seminal role in the pathogenesis of renal failure caused by toxicant injury to tubular cells, the present findings suggest that inhibition of NF-kappaB activity may define a molecular mechanism underlying the pathogenesis of Hg(2+) toxicity in kidney cells.

Endothelin is an important determinant of renal function in a rat model of acute liver and renal failure.

Renal failure occurs in approximately 55% of patients with acute liver failure. We have previously shown that plasma endothelin 1 concentrations are elevated in patients with acute liver failure and the hepatorenal syndrome. There are few reported satisfactory animal models of liver failure together with functional renal failure. In this study, a rat model of acute liver failure induced by galactosamine that also develops renal failure was first characterised. This model was used to investigate the hypothesis that endothelin 1 is an important mediator involved in the pathogenesis of renal impairment that occurs in acute liver failure. Acute liver failure was induced in male Sprague-Dawley rats by intraperitoneal injection of galactosamine together with treatment with the endothelin receptor antagonist Bosentan. Twenty four hour urine collections were made using a metabolic cage. Renal blood flow was measured in anaesthetised animals. This model developed renal failure and liver failure in the absence of any significant renal pathology, and with an accompanying fall in renal blood flow. Plasma concentrations of endothelin 1 were increased twofold following the onset of liver and renal failure (p<0.05), and there was significant upregulation of the endothelin receptor A (ET(A)) in the renal cortex (p<0.05). Administration of Bosentan prevented the development of renal failure when given before or 24 hours after the onset of liver injury (p<0.05) but had no effect on liver injury itself, or on renal blood flow. This study demonstrates that this animal model has many of the features needed to be regarded as a model of renal failure that occurs in acute liver failure. The observation that plasma levels of endothelin 1 and ET(A) receptors are increased and upregulated, and that renal failure is prevented by an endothelin antagonist supports the hypothesis originally put forward that ET(A) is important in the pathogenesis of renal failure that occurs in patients with acute liver failure.

Pathogenesis of puumala and other hantavirus infections.

Hantaviruses are rodent/insectivore-borne negative-stranded RNA viruses which belong to the Bunyaviridae family. They do not cause any symptomatic disease in their adult carrier rodents, but in humans they are aetiologic agents of haemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS), both associated with a significant mortality. In cell culture hantaviruses do not cause cytopathic effects and the mechanisms of disease in man are not well understood. Increased capillary permeability is a central phenomenon in the pathogenesis of hantavirus infections. Although the viruses have in vivo a predilection for endothelial cells, it is presumed that inflammatory mediators of the host immune response play a significant role in the capillary leak that may produce abrupt hypotension and shock in severely ill patients. Mediators released by activated macrophages including NO and TNF-alpha are considered important. The pathogenesis of renal failure in HFRS also awaits to be resolved. This review summarises what is known about these phenomena and discusses also the molecular basis of the putative virulence factors of hantaviruses. Finally, the genetic predisposition and HLA association with severe Puumala virus infection will be discussed. Copyright 1998 John Wiley & Sons, Ltd.

Escherichia coli verotoxin binding to human paediatric glomerular mesangial cells.

Haemolytic uraemic syndrome (HUS) remains the leading cause of acute renal failure in children. Although an Escherichia coli-produced verotoxin (VT) has been implicated in the pathogenesis of HUS, the precise mechanisms of disease are not well defined. We hypothesise that the pathogenesis of renal failure in HUS includes the binding of E. coli VT to the glomerular mesangial cell, with consequent effects on renal function. Using human paediatric mesangial cells, we studied the binding and biological effects of the purified verotoxin VT-1. We isolated, purified and characterised paediatric glomerular mesangial cells. The mesangial cells were characterised by their immunoreactivity with both smooth muscle actin and vimentin antibodies, and lack of immunoreactivity with cytokeratin or factor VIII antibodies. Using an fluorescein isothiocyanate-conjugated VT (10(-7)-10(-8) M), we demonstrated specific binding to the mesangial cell membrane by immunofluorescence microscopy. We also demonstrated a dose-dependent inhibition of mesangial cell mitogenesis at concentrations from 10(-9) to 10(-17) M. Our data demonstrate that VT-1 binds to paediatric human glomerular mesangial cells and this binding results in specific biological actions, including an inhibition of cell mitogenesis.