Glomerular Abnormalities Research Articles

Rapamycin Attenuates the Severity of Murine Adriamycin Nephropathy

Background: Rapamycin is an immunosuppressive drug with potent antifibrotic activity. We evaluated the effect of rapamycin on murine adriamycin nephropathy, a model of progressive glomerulosclerosis and tubulointerstitial fibrosis. Methods: Adriamycin nephropathy was induced in Balb/c mice by a single intravenous injection of adriamycin. The mice were treated orally with either saline or rapamycin, beginning at the time of adriamycin injection or rapamycin starting 1 week after adriamycin injection. The mice were sacrificed 6 weeks after adriamycin injection. Results: Saline-treated mice developed massive proteinuria and impaired renal function. Kidney sections from saline-treated mice showed marked focal segmental glomerulosclerosis, tubular dilation with protein cast deposition, interstitial fibrosis, and numerous infiltrating macrophages and T lymphocytes. The intrarenal expression of Collagen I and RANTES was also increased. In contrast, both groups of rapamycin-treated mice had markedly reduced proteinuria and preserved renal function, with only mild histological abnormalities. The intrarenal expression of Collagen I and RANTES was reduced, concomitant with a significant reduction in interstitial inflammatory cell infiltration. Conclusions: Rapamycin is effective in attenuating the glomerular and tubulointerstitial abnormalities in adriamycin nephropathy_.The beneficial effects of rapamycin are mediated, at least in part, through reduced RANTES expression and inflammatory cell infiltration.

Glomerular angiotensinogen protein is enhanced in pediatric IgA nephropathy

Enhanced intrarenal renin-angiotensin system (RAS) is implicated in the development and progression of renal injury. To investigate whether angiotensinogen (AGT) expression is involved in glomerular RAS activity and glomerular injury, we examined glomerular AGT expression and its correlation with expression of other RAS components, and levels of glomerular injury in samples from patients with immunoglobulin A nephropathy (IgAN) (23) and minor glomerular abnormalities (MGA) (8). Immunohistochemistry showed that AGT protein was highly expressed by glomerular endothelial cells (GEC) and mesangial cells in nephritic glomeruli of IgAN compared with glomeruli of MGA. Levels of glomerular AGT protein were well correlated with levels of glomerular angiotensin II (ang II), transforming growth factor-β (TGF-β), α-smooth-muscle actin, glomerular cell number, and glomerulosclerosis score but not with those of glomerular angiotensin-converting enzyme and ang II type 1 receptor. Real-time polymerase chain reaction (RT-PCR) and Western blot analyses using cultured human GEC indicated that ang II upregulated AGT messenger ribonucleic acid (mRNA) and protein expression in a dose- and time-dependent manner. These data suggest that activated glomerular AGT expression is likely involved in elevated local ang II production and, thereby, may contribute to increased TGF-β production and development of glomerular injury in IgAN. Augmentation of GEC-AGT production with ang II stimulation might drive further glomerular injury in a positive-feedback loop.

Proteomic analysis of human proximal tubular cells exposed to high glucose concentrations

Hyperglycemia is a major key factor in the pathogenesis of microvascular complications of diabetes, including diabetic nephropathy (DN). Most studies to date have focused on the glomerular abnormalities found in DN. However, nephromegaly in the early stages of diabetes and the correlation of tubulointerstitial pathology rather than glomerular pathology with declining renal function in DN suggests the involvement of the tubulointerstitium. The etiology of the tubulointerstitial pathology in DN, however, is not fully understood. In this study, to understand the DN pathways, we constructed an initial 2-DE reference map for primitively cultured human proximal tubule (HK-2) cell in the presence of 5 mM and 25 mM glucose, which correspond to blood glucose concentrations during the normal and hyperglycemia conditions, respectively. Differentially expressed HK-2 cell cellular proteins at the high glucose concentration were identified via ESI-Q-TOF MS/MS and confirmed by Western blotting; enolase 1 (up-regulated) and lactate dehydrogenase (down-regulated). The regulation of these proteins will help in understanding DN mechanism through the glycolysis metabolic pathways in high glucose stimulated HK-2 cells.

Persistent haematuria and proteinuria due to glomerular disease in related Abyssinian cats.

Eight cases of glomerular disease in young, related Abyssinian cats are described. Haematuria was the most consistent feature. Six cats developed the nephrotic syndrome. The short-term prognosis was good for cats with haematuria and fair for cats with the nephrotic syndrome as oedema resolved in three of the six cats. Light microscopic examination of renal biopsies from three cats was considered normal or revealed only mild abnormalities. In the three cases subjected to necropsy, histological abnormalities included mild mesangial hypercellularity and adhesions between the glomerular tuft and Bowman's capsule consistent with a focal proliferative glomerulopathy. Further investigation into this glomerulopathy will require ultrastructural and immunohistochemical studies to characterise the glomerular abnormality and genetic analyses to investigate its potential to be an inherited disease. Glomerular disease, potentially a familial one, should be considered in the investigation of persistent haematuria or proteinuria in Abyssinian and related cats.

Kidney Transplant Histology After One Year of Continuous Therapy With Sirolimus Compared With Tacrolimus

Analysis of 1-year surveillance biopsies was carried out for kidney transplant recipients participating in a randomized trial comparing tacrolimus- and sirolimus-based immunosuppression. The analysis was restricted to recipients remaining on assigned regimen throughout the first posttransplant year. Biopsies from 57 of 84 (68%) tacrolimus-randomized recipients were compared with 38 of 81 (47%) of sirolimus-randomized recipients, the discrepancy being explained by a higher rate of sirolimus discontinuation for non-graft-related complications. Included recipients from the two groups did not differ for baseline characteristics or 1-year iothalamate clearance. Histologic analysis indicated no differences between the groups for glomerular, arterial/arteriolar, or acute interstitial abnormalities. There were, however, significantly higher mean scores in the tacrolimus group for interstitial fibrosis and tubular atrophy with a trend toward higher estimated percent interstitial fibrosis. The results indicate that sirolimus may be associated with reduced early graft fibrosis compared with tacrolimus. This potential benefit is offset by lower success rate in maintaining the regimen and was not accompanied by superior glomerular filtration rate at 1 year.

Renal injury in the extremely obese patients with normal renal function

We studied the glomerular architecture in renal biopsies of 95 patients undergoing bariatric surgery for extreme obesity but whose renal function was normal. The comparison group was 40 control patients having protocol biopsies. These latter patients had normal weight and renal function, were non-diabetic, non-hypertensive, and were undergoing nephrectomy or donating a kidney. Logistic regression models determined associations between the clinical and biochemical variables and glomerular lesions. Arterial hypertension, sleep apnea syndrome (SAS), and microalbuminuria were prevalent in the obese patients, as was hyperglycemia to a lesser extent. Focal and segmental glomerulosclerosis was present in only five extremely obese (EO) patients but absent in controls. Increased mesangial matrix, podocyte hypertrophy, mesangial cell proliferation, and glomerulomegaly were more frequent in the obese cohort than in the control group. Body mass index was a significant independent risk factor associated with glomerular lesions in all 135 patients and in the 95 EO patients, whereas SAS was associated with glomerulomegaly only in the EO. Our study shows that EO patients who lack overt clinical renal symptoms have a variety of glomerular abnormalities that correlate with body mass.

Transgenerational epigenetic effects of the endocrine disruptor vinclozolin on pregnancies and female adult onset disease

Endocrine disruptor exposure during gonadal sex determination was previously found to induce male rat adult onset transgenerational disease (F1-F4 generation), and this was associated with an alteration in the epigenetic (i.e., DNA methylation) programming of the male germ line. The current study was designed to characterize the transgenerational disease phenotypes of the female adult offspring. Pregnant rats (F0 generation) were treated transiently with vinclozolin (i.e., fungicide with anti-androgenic activity) on embryonic (E) days E8-E14 of gestation. F1 control and vinclozolin generation offspring from different litters were mated to produce F2 offspring, and similarly F2 generation animals produced F3 generation offspring. Observations demonstrated that 9 out of 105 pregnant rats (8.6%) from the vinclozolin F1-F3 generations exhibited uterine hemorrhage and/or anemia late in pregnancy. None (0 out of 82) of the control F1-F3 generation females had similar pregnancy problems. Complete blood cell counts and serum chemistry profiles demonstrated that selected vinclozolin generation animals, but not controls, exhibited marked regenerative anemia in late pregnancy. Examination of kidney histology revealed moderate or severe glomerular abnormalities in 67% of the vinclozolin F2 and F3 generation adult females compared with 18% of the controls. Adult female vinclozolin generation animals also developed various types of tumors in 6.5% of the animals (11 out of 170), while 2% of control-line animals (3 out of 151) developed mammary tumors. Observations demonstrate that vinclozolin exposure during gonadal sex determination promotes a transgenerational increase in pregnancy abnormalities and female adult onset disease states.

Ultrasound Imaging of Renal Vaso-Occlusive Events in Transgenic Sickle Mice Exposed to Hypoxic Stress

One of the major clinical manifestations of sickle cell disease (SCD) is vaso-occlusive crisis in response to hypoxic exposure, leading to acute and chronic organ damages, especially in kidneys. In a SCD transgenic murine model, ultrasound imaging allowed us to characterize the circulatory changes in renal arteries during vaso-occlusive crisis. Cardiac output, heart rate and renal blood flow velocities (BFV) were measured in 10 male transgenic and 10 male wild-type (WT) mice with a conventional echograph (Vivid 7, GE Medical), before and after hypoxic exposure (8%O 2, 18h). To assess entrapment of red cells, histologic study of the kidneys was performed in both groups. Hypoxic exposure decreased heart rates in both groups (–17%, p < 0.001). Cardiac output remained stable in WT, and decreased in transgenic (–26%, p < 0.01). Peak systolic BFV in the renal artery was not modified in both groups. End-diastolic and mean BFV remained stable in WT, but decreased in sickle transgenic (–56%, p < 0.01 and –47%, p < 0.001, respectively). Transgenic mice displayed marked congestion in peritubular capillaries and glomerular abnormalities with trapped sickle red cells, whereas WT did not present any histologic injury. Five hours after hypoxic exposure, blood flow velocities returned to basal values in both groups. Decrease in end-diastolic and mean BFV in absence of peak systolic BFV after hypoxic exposure strongly indicated that the increase in vascular resistance in kidneys related to sickling of red cells. Thus, ultrasound imaging of the renal artery in mouse is a powerful, noninvasive, easy-to-repeat method to evidence circulatory changes in murine models of vascular renal human diseases. (E-mail: philippe.bonnin@lrb.aphp.fr)

Familial Nephropathy and Multiple Exostoses With Exostosin-1 (EXT1) Gene Mutation

Glomerular deposition of fibrillar collagen is a characteristic finding of genetically distinct conditions, including nail-patella syndrome and collagen type III glomerulopathy. A case of familial nephropathy in which steroid-sensitive nephrotic syndrome and glomerular deposits of fibrillar collagen are associated with multiple exostoses due to mutation of the EXT1 gene is described. This gene encodes a glycosyltransferase required for synthesis of heparan sulfate glycosaminoglycans. There is deficiency of heparan sulfate and perlecan, together with accumulation of collagens, in the matrix of EXT1-associated osteochondromas. Similar glomerular basement membrane abnormalities could offer an explanation for both the renal ultrastructural changes and steroid-sensitive nephrotic syndrome.

Intramembranous electron-dense deposits in a nephrotic patient with mixed connective tissue disease: unusual response to corticosteroid therapy.

A 56-year-old female patient, who had had minor change nephrotic syndrome (MCNS), was referred to us because of a fever and a massive proteinuria. Six years before, she had first noticed leg oedema, leading to the detection of nephrotic-range proteinuria. The diagnosis of MCNS at that time was based on minor glomerular abnormality by the light microscopy examination. She had then been treated with corticosteroid, after which her proteinuria had promptly disappeared. Her corticosteroid had then been gradually withdrawn, and no relapse had occurred for 6 years. At her first visit with us, she had a fever and sclerodactylia as well as swollen hands and Raynaud’s phenomenon, and laboratory examinations showed a high titer of anti-nuclear and anti-RNP antibodies, resulting in a diagnosis of mixed connective tissue disease (MCTD). She also had a massive proteinuria (3.2 g/day), and a kidney re-biopsy was performed (Figure 1). She was treated again with corticosteroid (prednisolone 20 mg daily) and her proteinuria had completely disappeared within a week.

Asbestos-Induced Autoimmunity in C57Bl/6 Mice

Environmental impacts on autoimmunity have significant public health implications. Epidemiological studies have shown associations between exposure to airborne silicates, such as crystalline silica or asbestos, and autoimmunity, but the etiology remains unclear. The purpose of this study was to test the hypothesis that asbestos could lead to a specific pattern of autoantibodies and pathology indicative of systemic autoimmune disease (SAID). Female C57Bl/6 mice were instilled intratracheally with 2 doses × 60 μ g/mouse of amphibole asbestos (tremolite), wollastonite (a non-fibrogenic control fiber), or saline alone. Serum samples were collected and urine was checked for protein bi-weekly for 7 months. By 26 weeks, the asbestos-instilled animals had a significantly higher frequency of positive anti-nuclear antibody (ANA) tests compared to wollastonite and saline groups. The majority of positive ANAs showed homogeneous or combined homogeneous/speckled patterns, and tested positive for antibodies to dsDNA and SSA/Ro 52. Serum isotyping showed no significant changes in IgM, IgA, or IgG subclasses. However, there was an overall decrease in the mean IgG serum concentration in asbestos-instilled mice. IgG immune complex deposition was demonstrated in the kidneys of asbestos-instilled mice, with evidence of glomerular and tubule abnormalities suggestive of glomerulonephritis. Flow cytometry demonstrated moderate changes in the percentages of CD25+ T-suppressor cells and B1a B-cells in the superficial cervical lymph nodes of the asbestos-instilled mice. These data demonstrate that asbestos leads to immunologic changes consistent with the development of autoimmunity. This study provides a non-autoimmune prone murine model for use in future elucidation of mechanisms involved in asbestos-induced autoimmune disease.

A case of minimal change nephrotic syndrome withA case of minimal change nephrotic syndrome with acute renal failure complicating Hashimoto’s disease

A 63-year-old man was admitted to our hospital for evaluation of generalized edema. Coexistence of severe hypothyroidism and nephrotic syndrome was detected by laboratory examination. High titer of both antimicrosomal antibody and antithyroid peroxidase antibody indicated Hashimotoâs disease. Renal biopsy showed minimal change glomerular abnormality, but no findings of membranous nephropathy. A series of medical treatments, including steroid therapy, thyroid hormone and human albumin replacement therapy, were administered. However, acute renal failure accompanied by hypotension, was not sufficiently prevented. After 9 sessions of plasmapheresis therapy, the severe proteinuria and low serum albumin levels were improved. Even after resting hypotension was normalized, neither renal function nor thyroid function were fully recovered. After discharge, renal function gradually returned to normal, and the blood pressure developed into a hypertensive state concomitant with the normalization of thyroid function. This report is a rare case of autoimmune thyroid disease complicated with minimal change nephrotic syndrome. In most cases of nephritic syndrome, acute renal failure (ARF) has been reported to coexist with hypertension. Although pseudohypothyroidism is well-known in nephrotic pathophysiology, complications of actual hypothyroidism are uncommon. It is suggested that the development of hypotension and ARF could be enhanced not only by hypoproteinemia, but also by severe hypothyroidism.

Transplant Glomerulopathy: Ultrastructural Abnormalities Occur Early in Longitudinal Analysis of Protocol Biopsies

Transplant glomerulopathy (TXG) presents a distinctive pattern of glomerular abnormalities. The aim of this study was to describe its sequential ultrastructural pathology. A paired cohort study of 228 protocol biopsies, from our longitudinal database (n = 1345), compared TXG (7 patients, 95 biopsies) and controls (8 patients, 133 biopsies). Ultrastructural morphometry and C4d immunoperoxidase were evaluated from implantation to 5 years after transplantation against sequential histology and functional changes. TXG was predated by early glomerular endothelial cell activation; typified by vacuolation, hypertrophy, serration and expansion of lamina rara interna from 39 +/- 23 days after transplantation. Endothelial cells were transformed into an activated phenotype, containing numerous mitochondria, Golgi and ribosomes. Transition from fenestrated to continuous endothelium, mesangial matrix expansion and podocyte fusion occurred late. Endothelial cell activation also occurred in peritubular capillaries (PTC) followed by basement membrane multi-lamination (p < 0.05-0.001). Light microscopy changes of TXG occurred at 2.3 years. PTC C4d deposition was intermittently expressed over time, correlating with endothelial abnormalities, glomerular C4d and donor-specific antibodies (DSA) (p < 0.05-0.001). In summary, endothelial and subendothelial ultrastructural abnormalities in glomerular and peritubular capillaries are sensitive, early markers of TXG, likely due to stimulation of endothelial cells into an activated phenotype by antibody-mediated sub-lytic complement deposition.

The Prevalence of Renal Dysfunction in Young Adults with Sickle Cell Disease.

Sickle cell disease is typified by dramatic acute painful episodes, which consume the majority of patients' and healthcare providers' attention. However, the cumulative damage to vital organs that occurs in this disease is often the determinant of early death. The kidneys are a major target organ in sickle cell disease and renal failure is a highly morbid event. It is also strongly associated with early death. Glomerular hyperfiltration is often the earliest sign of renal injury. This is followed by return to apparently normal filtration rates, then successively lower rates, culminating in end-stage renal disease. Microalbuminuria follows hyperfiltration and progresses to frank proteinuria. We evaluated the prevalence of renal dysfunction in a cohort of patients with sickle cell disease managed at the University of Tennessee Cancer Institute's adult sickle cell program. At entry into the program, patients underwent a routine battery of tests, including 24 hour urine collection for measurement of creatinine clearance and urine protein. Our findings are summarized in the table below. [Display omitted] By the age of 25 years, almost 80% of patients with sickle cell disease showed significant abnormality of glomerular filtration and 40% had significant proteinuria. This worsens with age. By a median of 37 years, 2 in 3 patients have developed significant proteinuria and hypofiltration has become the predominant pattern of glomerular filtration abnormality. Since renal injury is reversible in the early stages, more emphasis needs to be placed on aggressive early screening, surveillance and intervention. Intervention at the stage of hyperfiltration and microalbuminuria is easier and much more likely to be successful. Patients and their healthcare providers need to be educated on the high prevalence of renal damage. Efforts at education, screening, surveillance and, where necessary, treatment should begin well before adolescence.

Increased Goodpasture Antigen-Binding Protein Expression Induces Type IV Collagen Disorganization and Deposit of Immunoglobulin A in Glomerular Basement Membrane

Increased expression of Goodpasture antigen-binding protein (GPBP), a protein that binds and phosphorylates basement membrane collagen, has been associated with immune complex-mediated pathogenesis. However, recent reports have questioned this biological function and proposed that GPBP serves as a cytosolic ceramide transporter (CERT(L)). Thus, the role of GPBP in vivo remains unknown. New Zealand White (NZW) mice are considered healthy animals although they convey a genetic predisposition for immune complex-mediated glomerulonephritis. Here we show that NZW mice developed age-dependent lupus-prone autoimmune response and immune complex-mediated glomerulonephritis characterized by elevated GPBP, glomerular basement membrane (GBM) collagen disorganization and expansion, and deposits of IgA on disrupted GBM. Transgenic overexpression of human GPBP (hGPBP) in non-lupus-prone mice triggered similar glomerular abnormalities including deposits of IgA on a capillary GBM that underwent dissociation, in the absence of an evident autoimmune response. We provide in vivo evidence that GPBP regulates GBM collagen organization and its elevated expression causes dissociation and subsequent accumulation of IgA on the GBM. Finally, we describe a previously unrecognized pathogenic mechanism that may be relevant in human primary immune complex-mediated glomerulonephritis.

Alterações renais nas doenças falciformes

A doença falciforme associa-se a anormalidades renais estruturais glomerulares e tubulares, alterações hemodinâmicas e da síntese dos hormônios renais (eritropoetina, renina e prostaglandinas). Estas se iniciam na infância, em conseqüência da anemia crônica, fluxo sangüíneo aumentado, e eventos de veno-oclusão intraparenquimatosos, principalmente na medular renal. Na doença SS, a taxa de filtração glomerular encontra-se elevada desde os primeiros anos de vida e decresce com a idade. Decorrente de anormalidade tubular distal está a hipostenúria com as manifestações clínicas de poliúria, noctúria, enurese e susceptibilidade a desidratação, diminuição da capacidade de acidificar urina e excretar potássio. As anormalidades de túbulo proximal se traduzem por secreção aumentada de creatinina e ácido úrico, reabsorção aumentada de fosfatos e b2-microglobulina. A hipersecreção de creatinina superestima a taxa de filtração glomerular (FG), tornando o clearance de creatinina impróprio como detector precoce da deterioração da função renal. A proteinúria ocorre em 29%-50% dos pacientes acima de 10 anos de idade; 2/3 destes evoluem para insuficiência renal crônica de evolução ruim. A literatura apresenta benefícios consistentes com o uso de inibidores de enzimas conversoras de angiotensina (IECA) na redução da proteinúria, que talvez tenha impacto na progressão da insuficiência renal. Microalbuminúria (MA) é um marcador sensível da glomerulopatia falcêmica que precede a proteinúria. Na população pediátrica documenta-se prevalência de 19%, estando associado com idade, síndrome torácica aguda, níveis de Hb baixos e altas de leucometrias. Recomenda-se screening para MA a partir de 10 anos de idade. Em andamento estudo multicêntrico com uso precoce de hidroxiuréia na prevenção das lesões orgânicas crônicas (Baby HUG).

The role of renal biopsy in women with kidney disease identified in pregnancy

Renal disease may present for the first time in pregnancy, either as symptomatic disease or as a consequence of antenatal screening. The role of antenatal and post-partum percutaneous renal biopsy in the management of such patients is discussed. We describe two series of women; the first is a series of 20 women presenting with renal disease of a severity to warrant renal biopsy during pregnancy whilst the second, comprises 75 women who had an initial presentation of renal disease in pregnancy and underwent post-partum renal biopsy. Biopsy during pregnancy revealed a glomerular disorder in 19/20 (95%) with immediate change of management in 9/20 (40%). In 17/20 (85%) there was delivery of a live infant at median gestation of 36 weeks (range 25-40). Follow-up of women [median 103.3 months (2.5-256)] showed 9/20 (45%) had a GFR of <60 ml/min/1.73 m(2) [six at end-stage renal failure (ESRF)] and 3/20 were dead. The majority (62/75; 82.6%) of women undergoing post-partum renal biopsy presented with significant proteinuria (40% pre-eclampsia) during pregnancy not resolving post-partum. A glomerular abnormality was found in 64%. At last follow-up of 47 women [median 51.5 months (range 1-212)], 14 patients (29.7%) had significant proteinuria and 20 (42.6%) had a GFR<60 ml/min/1.73 m(2). Six women (12.7%) had ESRF. Diagnosis and follow-up of renal disease diagnosed in pregnancy is important as progressive disease occurs in this group. Routine antenatal screening provides a useful diagnostic opportunity to detect asymptomatic renal disease. In a selected sub-group, renal biopsy during pregnancy can be helpful in initiation of correct treatment and allowing progression of pregnancy to fetal viability.

Desmin as a marker of proteinuria in early stages of membranous nephropathy in elderly patients

Idiopathic membranous nephropathy (IMN) is the most common cause of nephrotic syndrome in adults worldwide. Many patients with IMN are elderly, but little is known about the relationship regarding the morphological stage determined by electron microscopy (EM), the amount of proteinuria, and the expression of glomerular podocyte markers such as desmin and nephrin in nephrotic glomeruli in IMN. We studied 59 patients with histopathologically proven IMN. We compared the clinical features, EM stage classification, and the immunohistochemical features of glomerular expression of podocyte markers, including desmin and nephrin, between older (age > or = 60 years) and younger (age < 60 years) patients. We also investigated these parameters in patients with minimal-change nephrotic syndrome (MCNS), minor glomerular abnormalities (MGA), and normal kidneys as age-matched controls. Prevalence of nephrotic syndrome was significantly higher in the older (52.9%) than the younger group (20.0%) of IMN. The level of proteinuria was higher in early stages (Stages I + II) than in late stages (Stages III + IV) in IMN. The glomerular expression of desmin in podocytes was significantly higher in IMN as compared to MCNS, MGA, or age-matched controls. Desmin expression was significantly increased in earlier EM stages (Stages I + II) and in higher proteinuric group (daily proteinuria > or = 1 g) of older patients with IMN. Reciprocally, the reduced expression of nephrin was associated with the early EM stages (Stages I + II) of patients with IMN. We conclude that the expression of desmin in podocytes is upregulated in patients with IMN as compared to other glomerular diseases including MCNS or MGA, or to controls. In elderly patients with IMN, desmin expression was associated with early EM stages and heavy proteinuria, which may reflect phenotypic alteration of the podocyte.

A Protein Toxin from the Sea Anemone Phyllodiscus semoni Targets the Kidney and Causes a Severe Renal Injury with Predominant Glomerular Endothelial Damage

Envenomation by the sea anemone Phyllodiscus semoni causes fulminant dermatitis and, rarely, acute renal failure in humans. Here, we investigated whether the venom extracted from the nematocysts (PsTX-T) was nephrotoxic when administered intravenously in rats and whether PsTX-T induced activation of the complement system. Although small dose of PsTX-T induced acute tubular necrosis in rats resembling pathology seen in patients, kidneys displayed glomerular injury with glomerular endothelial damage, thrombus formation, mesangiolysis, and partial rupture of glomerular basement membrane, accompanied by severe tubular necrosis at 24 hours after administration of 0.03 mg of PsTX-T per animal, similar to the glomerular findings typical of severe hemolytic uremic syndrome. The early stage injury was accompanied by specific PsTX-T binding, massive complement C3b, and membrane attack complex deposition in glomeruli in the regions of injury and decreased glomerular expression of complement regulators. A pathogenic role for complement was confirmed by demonstrating that systemic complement inhibition reduced renal injury. The isolated nephrotoxic component, a 115-kd protein toxin (PsTX-115), was shown to cause identical renal pathology. The demonstration that PsTX-T and PsTX-115 were highly nephrotoxic acting via induction of complement activation suggests that inhibition of complement might be used to prevent acute renal damage following envenomation by P. semoni.

A familial childhood-onset relapsing nephrotic syndrome

A familial childhood-onset relapsing nephrotic syndrome