Glomerular Basement Membrane Changes Research Articles

#3084 Familial nephropathy associated with a combined mutations of Alport and Nail Patella syndrome genes in the same family

Abstract Introduction Alport syndrome is a genetic condition stemming from mutation in Type IV collagen and is characterized by kidney disease and frequently hearing loss and ocular abnormalities. Renal involvement is from an abnormality of the glomerular basement membrane with hematuria and proteinuria progressing eventually to renal failure. In the vast majority, the inheritance is X- linked affecting the alpha 5 chain of type IV collagen while in about 15 percent of the patients the inheritance is autosomal recessive or dominant with mutations affecting alpha 3 or 4 chains of type IV collagen. Sensorineural deafness is common and ocular abnormalities may include lenticonus, corneal opacities, fleck retinopathy and temporal retinal thinning. Nail Patella syndrome (NPS) is a rare genetic condition from mutation in the LMX1B gene on chromosome 9 with an autosomal dominant inheritance. Glomerular disease is from characteristic glomerular basement membrane changes and is associated with nail, pelvic girdle and limb abnormalities. A forme fruste with glomerular lesions but lacking extrarenal features is recognized but uncommon. We present a family with mutations in both COL4A5 and LMX1B presenting with hematuria and proteinuria Case Presentation A 23 year old female was evaluated for hematuria and proteinuria. Her history was notable for kidney biopsy at the age thirteen showing focal and segmental glomerulosclerosis (FSGS). She was treated with tacrolimus for four years from age thirteen through seventeen. Patient was reportedly diagnosed with Nail Patella Syndrome after genetic testing. Her family history was notable for hematuria in her brother and hematuria and proteinuria in her mother. On physical examination she was noted to have no nail or skeletal abnormalities associated with Nail Patella Syndrome. Her labs were notable for a serum creatinine of 0.6 mg/dl and proteinuria of 155 mg/g creatinine of proteinuria. Urine microscopy revealed dysmorphic hematuria. Radiological imaging did not show skeletal abnormalities observed in Nail Patella Syndrome but genetic testing identified a pathogenic variant in COL4A5 c.919G>A (p.Gly307Ser) in addition to a variant of uncertain significance in LMX1B c.349G>A (p.Gly117Ser). Her brother aged 20 had a creatinine of 0.87 mg/dl with dysmorphic hematuria and no proteinuria. Genetic testing showed the same pathogenic variant in COL4A5 as in his sibling. His mother aged 55 was subsequently evaluated and had a creatinine 0.73 mg/dl with dysmorphic hematuria and 152 mg/g of proteinuria. Genetic testing was with the same variant in COL4A5 noted in her two children. Renal biopsy was extensive thinning and segmental lamellation of the glomerular basement membrane with eight percent FSGS. The typical “moth-eaten” appearance of the glomerular basement membrane characteristic of NPS was not evident. Segmental staining was observed with alpha 5 unit of Type IV collagen. Audiology and retinal optical coherence optometry studies are pending. Discussion Alport syndrome and Nail Patella Syndrome are rare genetic disorders that cause variable degrees of renal insufficiency from glomerular base membrane defects and are associated with characteristic extra renal manifestations. This is the first report of an inherited nephritis with combined mutations in COL4A5 and LMX1B. The clinical features and renal biopsy are compatible with Alport Syndrome and the significance of the mutation in LMX1B is uncertain. Conclusion This is the first case report of a combined mutation in COL4A5 and LMX1B gene presenting with hematuria and minimal proteinuria with preserved kidney function.

IgA-nephropathy in children with alport syndrome

BACKGROUND. The widespread use of genetic methods in clinical practice has shown that pathogenic variants in COL4A3, COL4A4, COL4A5 genes associated with Alport syndrome (AS) are detected in 10 % of sporadic and in 20 % of familial cases of IgA nephropathy (IgAN), which suggested a relationship between the two diseases. THE AIM was to determine the frequency and characteristics of the course of IgAN in children with AS. PATIENTS AND METHODS. A single-centre retrospective pilot study included 102 patients with AS. The inclusion criteria were: age 2-18 years, genetic and/or morphological confirmation of AS, availability of morphological data of pts. The comparison group included children and adolescents 2-18 years with morphologically confirmed primary IgAN; the exclusion criterion was the presence of AS-specific glomerular basement membrane changes. IgAN was classified according to the MESTC scale. Demographic (gender, age), clinical (arterial hypertension, AH) and laboratory data (proteinuria (Pr, mg/m2/day), (Schwartz eGFR, ml/min/1.73m2) at the time of the biopsy and at the last examination of patients were assessed. Arterial pressure ≥95‰ for sex, age, height was defined as AH. Pr >100 mg/m2/day, Pr≥500 mg/m2/day and Pr>1000 mg/m2/day were defined as proteinuria, high-level proteinuria and nephrotic level proteinuria, respectively. The statistic parametric and nonparametric methods were used ("Statistica 10", StatSoft Russia). RESULTS. IgAN was detected in 3 of 102 children with AS (q=0.03): 2 girls had heterozygous variants in COL4A3 and COL4A4, a boy had X-linked AS. Two patients had nephrotic proteinuria, 1 had SRNS at onset of IgAN. The comparison group included 25 children with IgAN (17M). Baseline patients age (9±4.2 vs 13±2.7 years), frequency of AH (q1=0.66 vs q2=0.28), eGFR decrease (q1=0.33 vs q2=0.44), eGFR level (91±24 vs 90.8±24 ml/ min/1.73 m2), morphological characteristics of IgAN did not differ significantly by groups; patients with AS were more likely to have nephrotic proteinuria (q1=1 vs q2=0.32, p=0.023). At follow-up (3.8±1.4 years), the groups were comparable in age (12.3±5.2 vs 15±1.8 years), AH frequency (q1=0.66 vs q2=0.5), eGFR level (87±16 vs 91±13 ml/min/1.73m2); children with AS had higher grade Pr (800[0;1150] vs 30[10;100] mg/m2/day, p=0.048) and more often had high-level Pr (q1=0.66 vs q2=0.06, p=0.006) at follow-up observation. The AS was associated with the development of nephrotic-level Pr at onset (r=0.41, p=0.008) and with high-level Pr (r=0.38, p=0.012) during follow-up. CONCLUSION. IgAN was detected in 3 % of children with AS. The presence of COL4A3, COL4A4, COL4A5 genes variants is associated with more pronounced proteinuria at the onset of IgAN and its preservation in the follow-up, and may be a risk factor for more severe course glomerulonephritis. The main limitations of the study: small sample size and duration of follow-up.

Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition

Natriuretic peptides exert multiple effects by binding to natriuretic peptide receptors (NPRs). Osteocrin (OSTN) binds with high affinity to NPR-C, a clearance receptor for natriuretic peptides, and inhibits degradation of natriuretic peptides and consequently enhances guanylyl cyclase-A (GC-A/NPR1) signaling. However, the roles of OSTN in the kidney have not been well clarified. Adriamycin (ADR) nephropathy in wild-type mice showed albuminuria, glomerular basement membrane changes, increased podocyte injuries, infiltration of macrophages, and p38 mitogen-activated protein kinase (MAPK) activation. All these phenotypes were improved in OSTN- transgenic (Tg) mice and NPR3 knockout (KO) mice, with no further improvement in OSTN-Tg/NPR3 KO double mutant mice, indicating that OSTN works through NPR3. On the contrary, OSTN KO mice increased urinary albumin levels, and pharmacological blockade of p38 MAPK in OSTN KO mice ameliorated ADR nephropathy. In vitro, combination treatment with ANP and OSTN, or FR167653, p38 MAPK inhibitor, reduced Ccl2 and Des mRNA expression in murine podocytes (MPC5). OSTN increased intracellular cyclic guanosine monophosphate (cGMP) in MPC5 through GC-A. We have elucidated that circulating OSTN improves ADR nephropathy by enhancing GC-A signaling and consequently suppressing p38 MAPK activation. These results suggest that OSTN could be a promising therapeutic agent for podocyte injury.

Rare Glomerular Presentation of Essential Cryoglobulinemia without HCV Infection

Membranoproliferative glomerulonephritis (MPGN) is characterized by mesangial cell proliferation and structural changes in glomerular capillary walls and double-contoured glomerular basement membrane (GBM). Usually, it is connected with cryoglobulinemia which is defined by the presence of a circulating, a cold-precipitating immunoglobulin. The chemical and immunological features of the cryoglobulins are used to define three types of cryoglobulinemia. In this report we describe the third case of MPGN type II with essential cryoglobulinemia without HCV infection, which is usually defined in the literature as MPGN type II. Here, we present 61-years old woman previously diagnosed with MPGN in 2012 at another institution. At that time, she was not examined in terms of cryoglobulinemia. Initially she was treated with pulses of methylprednisolone, then oral corticosteroids until cessation when complete remission was achieved. Meanwhile, she had two relapses of the disease. In October 2020 we re-evaluated her and found out positive cryoglobulins in repeating testing. Serological studies for anti-neutrophil cytoplasmic antibodies (ANCA), myeloperoxidase and proteinase 3, anti-double stranded DNA antibodies, anti-hepatitis C antibodies, anti-HIV antibodies and anti-hepatitis B surface antibodies were all negative. Serum M protein or monoclonal IgM were not detected. Percutaneous renal biopsy was compatible with the diagnosis of MPGN. Based on clinical, laboratory and histological evaluation, it was concluded that the patient had a MPGN with essential cryoglobulinemia. Therapy with mycophenolate mofetil had a beneficial effect on the course of disease and the patient achieved partial remission and stabile renal function for the last 3 months of follow-up. Since the therapy for MPGN with essential cryoglobulinemia is not standardized, further research in the field is needed.

Knockout of aminopeptidase A in mice causes functional alterations and morphological glomerular basement membrane changes in the kidneys

Aminopeptidase A is one of the most potent enzymes within the renin-angiotensin system in terms of angiotensin II degradation. Here, we examined whether there is a kidney phenotype and any compensatory changes in other renin angiotensin system enzymes involved in the metabolism of angiotensin II associated with aminopeptidase A deficiency. Kidneys harvested from aminopeptidase A knockout mice were examined by light and electron microscopy, immunohistochemistry and immunofluorescence. Kidney angiotensin II levels and the ability of renin angiotensin system enzymes in the glomerulus to degrade angiotensin II exvivo, their activities, protein and mRNA levels in kidney lysates were evaluated. Knockout mice had increased blood pressure and mild glomerular mesangial expansion without significant albuminuria. By electron microscopy, knockout mice exhibited a mild increase of the mesangial matrix, moderate thickening of the glomerular basement membrane but a striking appearance of knob-like structures. These knobs were seen in both male and female mice and persisted after the treatment of hypertension. In isolated glomeruli from knockout mice, the level of angiotensin II was more than three-fold higher as compared to wild type control mice. In kidney lysates from knockout mice angiotensin converting enzyme activity, protein and mRNA levels were markedly decreased possibly as a compensatory mechanism to reduce angiotensin II formation. Thus, our findings support a role for aminopeptidase A in the maintenance of glomerular structure and intra-kidney homeostasis of angiotensin peptides.

Myelin bodies in LMX1B-associated nephropathy: potential for misdiagnosis.

Myelin figures, or zebra bodies, seen on electron microscopy were historically considered pathognomonic of Fabry disease, a rare lysosomal storage disorder caused by alpha-galactosidase A deficiency and associated with X-linked recessive mode of inheritance. More recently, iatrogenic phospholipidosis has emerged as an important alternate cause of myelin figures in the kidney. We report two families with autosomal dominant nephropathy presenting with proteinuria and microscopic hematuria, and the kidney biopsies were notable for the presence of myelin figures and zebra bodies. Laboratory and genetic work-up for Fabry disease was negative. Genetic testing in both families revealed the same heterozygous missense mutation in LMX1B (C.737G>A, p.Arg246Gln). LMX1B mutations are known to cause nail-patella syndrome, featuring dysplastic nails and patella with or without nephropathy, as well as isolated LMX1B-associated nephropathy in the absence of extrarenal manifestations. LMX1B mutation-associated nephropathy should be considered in hereditary cases of proteinuria and/or hematuria, even in the absence of unique glomerular basement membrane changes indicative of nail-patella syndrome. In addition, LMX1B mutation should be included in the differential diagnosis of myelin figures and zebra bodies on kidney biopsy, so as to avoid a misdiagnosis.

20(S)-Ginsenoside Rg3 Protects Kidney from Diabetic Kidney Disease via Renal Inflammation Depression in Diabetic Rats.

20(S)-Ginsenoside Rg3 (20(S)-Rg3) has been shown to induce apoptosis by interfering with several signaling pathways. Furthermore, it has been reported to have anticancer and antidiabetic effects. In order to detect the protective effect of 20(S)-Rg3 on diabetic kidney disease (DKD), diabetic rat models which were established by administering high-sugar, high-fat diet combined with intraperitoneal injection of streptozotocin (STZ), and age-matched wild-type (WT) rat were given 20(S)-Rg3 for 12 weeks, with three groups: control group (normal adult rats with saline), diabetic group (diabetic rats with saline), and 20(S)-Rg3 treatment group (diabetic rats with 20(S)-Rg3 (10 mg/kg body weight/day)). The biochemical indicators and the changes in glomerular basement membrane and mesangial matrix were detected. TUNEL staining was used to detect glomerular and renal tubular cell apoptosis. Immunohistochemical staining was used to detect the expression of fibrosis factors and inflammation factors in rat kidney tissues. Through periodic acid-Schiff staining, we observed that the change in renal histology was improved and renal tubular epithelial cell apoptosis decreased significantly by treatment with 20(S)-Rg3. Plus, the urine protein decreased in the rats with the 20(S)-Rg3 treatment. Fasting blood glucose, creatinine, total cholesterol, and triglyceride levels in the 20(S)-Rg3 treatment group were all lower than those in the diabetic group. Mechanistically, 20(S)-Rg3 dramatically downregulated the expression of TGF-β1, NF-κB65, and TNF-α in the kidney. These resulted in a significant prevention of renal damage from the inflammation. The results of the current study suggest that 20(S)-Rg3 could potentially be used as a novel treatment against DKD.

Diabetic nephropathy and type 1 diabetes mellitus: what is new?

Introduction Diabetic nephropathy is the leading cause of renal failure in developed and developing countries. Earlier, more sensitive and specific markers of kidney damage might help diagnose and treat diabetic nephropathy at an earlier stage to prevent the progression to renal failure. Aim of the study Is to detect early changes in glomerular basement membrane in children with type1 diabetes mellitus. Patients and Methods This study included 170 children, 120 with diabetes mellitus type1 and 50 apparently healthy children serving as controls. The study and control group were subjected to complete history taking, through clinical examination. They were also subjected to some laboratory investigations including renal function tests, glycosylated haemoglobin (HbA1c), urinary albumin excretion by detecting albumin creatinine ratio (ACR), glomerular filtration rate and urinary podocalyxin (U- PCX) by EIA. Results Our study showed that urinary podocalyxin in diabetic children and adolescents was significantly higher than the control group (P < 0. 000), and it correlated positively with glycosylated haemoglobin (HbA1c) and albuminuria (r = 0. 577 and P < 0. 02) and (r = 0. 554 and P < 0. 000). Our results showed that microalbuminuric children had highly significant U- PCX than normoalbuminuric ones. Conclusion We conclude that urinary podocalyxin could be more sensitive and specific marker of kidney damage than microalbuminuria and thus it could be a useful biomarker for detecting early diabetic nephropathy. Also, U-PCX correlate positively with HbA1c concluding that hyperglycaemic state may cause glomerular damage in early stage of diabetic nephropathy and that duration of diabetes may not play a role in that process.

Features of Autosomal Recessive Alport Syndrome: A Systematic Review

Alport syndrome (AS) is one of the most frequent hereditary nephritis leading to end-stage renal disease (ESRD). Although X-linked (XLAS) inheritance is the most common form, cases with autosomal recessive inheritance with mutations in COL4A3 or COL4A4 are being increasingly recognized. A systematic review was conducted on autosomal recessive Alport syndrome (ARAS). Electronic databases were searched using related terms (until Oct 10th, 2018). From 1601 articles searched, there were 26 eligible studies with 148 patients. Female and male patients were equally affected. About 62% of patients had ESRD, 64% had sensorineural hearing loss (SNHL) and 17% had ocular manifestation. The median at onset was 2.5 years for hematuria (HU), 21 years for ESRD, and 13 years for SNHL. Patients without missense mutations had more severe outcomes at earlier ages, while those who had one or two missense mutations had delayed onset and lower prevalence of extrarenal manifestations. Of 49 patients with kidney biopsy available for electron microscopy (EM) pathology, 42 (86%) had typical glomerular basement membrane (GBM) changes, while 5 (10%) patients showed GBM thinning only. SNHL developed earlier than previously reported. There was a genotype phenotype correlation according to the number of missense mutations. Patients with missense mutations had delayed onset of hematuria, ESRD, and SNHL and lower prevalence of extrarenal manifestations.

Therapeutic effects of Salvia miltiorrhiza injection combined with telmisartan in patients with diabetic nephropathy by influencing collagen IV and fibronectin: A case-control study.

Involvement of collagen IV (ColIV) and fibronectin (FN) in the occurrence and development of diabetic nephropathy (DN) and the effects of telmisartan and Salvia miltiorrhiza injection in the treatment of the patients were investigated. Two hundred and fifty-eight patients with stage IV DN were selected as the case group, and another 110 normal healthy subjects were incorporated as the control group. Involved patients were subdivided into different groups according to different treatment therapies; patients in the telmisartan group (T group) were given oral telmisartan; patients in the Salvia miltiorrhiza injection + telmisartan (S + T group) were administered with Salvia miltiorrhiza injection combined with telmisartan treatment, and there was a group of patients who received no intervention as the placebo group. After intervention, levels of glycemic indexes and renal damage indexes indicated downwards trends both in the T group and the S + T group when compared to the placebo group; besides, levels in the S + T group were much lower than those in the T group (all P<0.05). Additionally, in comparison among the above three intervention groups, differences in the fasting blood glucose, 2 h post-prandial blood glucose, glycosylated hemoglobin, blood urea nitrogen, serum creatinine and urinary albumin excretion rate were significant after treatment (all P<0.05). Further, before intervention, both Co1IV and FN in the urine were increased in the case group compared to the control group (all P<0.05). After intervention, both levels were apparently decreased. There were remarkable differences of Co1IV and FN levels in the urine when compared among three different intervention groups after treatment (P<0.05). Increased ColIV and FN levels may be partially responsible for the development of DN. Salvia miltiorrhiza injection with telmisartan have beneficial synergistic effects for DN patients through attenuating the increase in ColIV and FN, reversing hyperglycemia state and postponing ultrastructure changes of glomerular basement membrane.

Glomerulogenesis and the role of endothelium.

Earlier works of the glomerulogenesis described morphological steps and protein expression during in-vivo and in-vitro kidney development. Recent technologies using cell-specific or conditional knock-out mice for several factors provide important knowledge about cross-talk signaling among resident cells as local events. Based on the recent advancement, this review revisits comprehensive morphological development of the glomerulus. Interactions of presumptive podocyte vascular endothelial growth factor with vascular endothelial growth factor-2 on angioblasts initiate glomerular vascularization. In induced pluripotent stem cells or organoid-derived nephron formation, the lack of endothelium and mesangial cells under differentiated podocytes suggests the presence of another unknown mechanism for glomerular neovascularization. Mesangial cell migration is prerequisite for glomerular looping by interaction of endothelial platelet-derived grothe factor beta and mesangial platelet-derived growth factor receptor beta and requires the coreceptor neuropilin1. Development of the filtration barrier is promoted by cross-talk among resident cells and may need shear stress. The components of the glomerular basement membrane change during glomerulogenesis, and endothelium and podocytes produce laminin and type IV collagen α1 and α2, whereas type IV collagen α3, α4, α5 is derived only from podocytes. Glomerulogenesis progresses by dynamic cellular migration/differentiation induced by cross-talk signaling in resident cells. Glomerular vasculogenesis and subsequent capillary development provide insight into glomerular regeneration and remodeling for medical application.

Urine Specific Proteins and Alpha-1 Antitrypsin Concentrations to Assess the Severity of Lupus Nephritis

Background. Current biomarkers for evaluating disease activity or severity in lupus nephritis (LN) are considered to be unsatisfactory. Pathological changes in glomerular basement membrane and selectivity of electrical discharge are causing specific patterns of urine proteins excretion. Together with alpha-1 antitrypsin (AAT), they are expected to become new biomarkers to assess LN activity. Method. Seventy-one urine samples were collected from healthy controls and LN patients. Patterns of urine specific proteins were determined using column chromatography and SDS-PAGE tests, LN activity was calculated using SLEDAI-renal domain score, and AAT concentrations was measured by ELISA. Result. The majority of proteins in the control group have molecular weights of >66 kDa (88%) and 21- to 25-kDa proteins were observed only in the case group. The p values for differences in urine AAT concentration between active LN and healthy controls, inactive LN and healthy controls, and active LN and inactive LN were 0.004, 0.046, and 0.054, respectively, whereas those for urine AAT/creatinine ratio were 0.489, 0.019, and 0.915, respectively. Conclusion: There were differences in the patterns of the molecular weight of proteins and urine AAT concentrations between case group and control group. However, no such differences were identified between active and inactive LN.

The Value of Serum Prolidase Activity in Progression of Microalbuminuria in Patients With Type 2 Diabetes Mellitus.

Prolidase is a cytosolic exopeptidase that plays a pivotal role in collagen turnover. Diabetic nephropathy (DN) is associated with structural changes in glomerular basement membrane accompanied with increased amounts of collagen. Prolidase is known to be abundant in kidney and collagen accumulation is increased in DN, so we aimed to determine the value of serum prolidase activity (SPA) in predicting the progression of nephropathy in type 2 diabetes mellitus (DM). Thirty type 2 DM patients having microalbuminuria (microalbuminuric group), 30 type 2 DM patients without albuminuria (normoalbuminuric group), and 28 healthy controls (control group) were enrolled. Study groups had similar age, sex distribution, and body mass index (BMI). Metabolic parameters, SPA and urinary microalbumin were determined. SPA was significantly higher in microalbuminuric group when compared with normoalbuminuric and control groups (P = 0.05 and P < 0.001, respectively). Triglyceride levels were significantly higher and high density lipoprotein cholesterol (HDL-C) levels were significantly lower in microalbuminuric group compared to control group (Both P < 0.05). SPA showed a negative correlation with HDL-C level and a positive correlation with urinary albumin excretion (r = -0.219, P < 0.05 and r = 0.39, P < 0.001 respectively). In regression analysis, albumin excretion was the sole parameter influencing SPA. SPA appears to be higher in type 2 DM patients having microalbuminuria compared to patients without microalbuminuria and healthy controls. The pathophysiological role and the significance of SPA in predicting DN need to be further evaluated.

Cyclosporine versus everolimus: effects on the glomerulus

Inhibitors of the mammalian target of rapamycin (mTOR) have been associated with proteinuria. We studied the development of proteinuria in renal transplant recipients (RTR) treated with the mTOR inhibitor everolimus in comparison with a calcineurin inhibitor. We related the presence of proteinuria to histopathological glomerular findings in two-yr protocol biopsies. In a single-center study, nested in a multicenter randomized controlled trial, we determined eGFR, proteinuria, and renal biopsy data (light- and electron microscopy) of RTR receiving prednisolone/everolimus (P/EVL) (n = 16) in comparison with patients treated with prednisolone/cyclosporine A (P/CsA) (n = 7). All patients had been on the above-described maintenance immunosuppression for 18 months. Renal function at two yr after transplantation did not differ between patients receiving P/EVL or P/CsA (eGFR 45.5 vs. 45.7 mL/min/1.73 m(2)). Proteinuria was slightly increased in P/EVL vs. P/CsA group (0.29 vs. 0.14 g/24 h, p = 0.06). There were no differences in light- or electron microscopic findings. We could not demonstrate increased podocyte effacement or changes in glomerular basement membrane (GBM) thickness in P/EVL-treated patients. In conclusion, long-term treatment with everolimus leaves the GBM and podocytes unaffected.

Multipotent mesenchymal stromal cells protect against kidney injury

Multipotent mesenchymal stromal cells protect against kidney injury

Protective effect of lycopene on deltamethrin-induced histological and ultrastructural changes in kidney tissue of rats

Deltamethrin is globally used in crop protection and control of malaria and other vector-borne diseases. It has a potent insecticidal activity with an appreciable safety margin. However, a number of studies have demonstrated nephrotoxicity of deltamethrin in mammalian and nonmammalian species. Lycopene, a carotenoid occurring naturally in tomatoes, has attracted considerable attention as an antioxidant. This study was focused on investigating the possible protective effect of coadministration of lycopene on deltamethrin toxicity. In this study, male albino rats were divided into four groups of 10 animals each: group I served as control, which received standard diet; group II received oral administration of deltamethrin (1.28mg/kg per day) for 30days; group III received both deltamethrin and lycopene (1mg/kg per day); group IV received lycopene (1mg/kg per day). After the experiment, the animals were anesthetized and the cytokine, tumor necrosis factor-α (TNF-α), in the serum was measured; the kidney was taken for histological and ultrastructural studies. Deltamethrin significantly increased the TNF-α. The histopathological examination of kidney showed mild necrotic changes. Ultrastructural changes in renal proximal tubules of deltamethrin-treated group included an increased number and irregular shape of mitochondria with sparse fragmented cristae, serious ultrastructural lesions in renal proximal tubular lining cells, vacuolar degeneration in the epithelial cells, increased number of lysosomes and loss of apical microvilli. In addition, focal segmental thickening and the duplication of glomerular basement membrane and podocyte changes were observed. Histopathological and ultrastructural study showed some protective effect of lycopene on kidney tissues.

Glutathione transferase kappa deficiency causes glomerular nephropathy without overt oxidative stress

Glutathione transferase kappa (GSTK1-1) is a highly conserved, mitochondrial enzyme potentially involved in redox reactions. GSTK1-1-deficient mice were generated to further study the enzyme's biological role. Reduced and total glutathione levels in liver and kidney were unchanged by GSTK1-1 deficiency and NADPH quinone oxidoreductase 1 expression was not elevated indicating that there is no general underlying oxidative stress in Gstk1−/− mice. Electron microscopy of liver and kidney showed no changes in mitochondrial morphology with GSTK1-1 deficiency. The death of a number of Gstk1−/− males with urinary tract problems prompted close examination of the kidneys. Electron microscopy revealed glomerular basement membrane changes at 3 months, accompanied by detectable microalbuminuria in male mice (albumin:creatinine ratio of 2.66±0.83 vs 1.13±0.20 mg/mmol for Gstk1−/− and wild-type (WT), respectively, P=0.001). This was followed by significant foot process effacement (40–55% vs 10% for Gstk1−/− and WT, respectively) at 6 months of age in all Gstk1−/− mice examined. Kidney tubules were ultrastructurally normal. Compared with human disease, the Gstk1−/− kidneys show changes seen in glomerulopathies causing nephrotic syndrome. Gstk1−/− mice may offer insights into the early development of glomerular nephropathies.

Variable renal phenotype in a family with an INF2 mutation

Recent advances in the genetics of glomerular diseases have identified several causative genes of nephrotic syndrome and/or glomerular proteinuria. In 2010, the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, was identified as a novel causative gene of the autosomal dominant form of focal segmental glomerulosclerosis (FSGS). Here, we describe an additional familial case of FSGS associated with INF2 mutations. In the family, two siblings and their father had a heterozygous p.E220K mutation on INF2. This mutation manifested in these three individuals as incidentally detected proteinuria without overt nephrotic syndrome, but at different ages of 7, 9, and 30 years, respectively. Two siblings had nephrotic range proteinuria, and one developed end-stage renal disease 5years later. Conversely, their father had a modest degree of proteinuria, and maintained normal renal function until age 47. A renal biopsy of one of the siblings revealed FSGS with irregular podocyte foot process morphology and focal glomerular basement membrane changes. This is the second paper describing a familial case of FSGS associated with INF2 mutations as well as intrafamilial phenotype variability.

Cellular Origins of Type IV Collagen Networks in Developing Glomeruli

Laminin and type IV collagen composition of the glomerular basement membrane changes during glomerular development and maturation. Although it is known that both glomerular endothelial cells and podocytes produce different laminin isoforms at the appropriate stages of development, the cellular origins for the different type IV collagen heterotrimers that appear during development are unknown. Here, immunoelectron microscopy demonstrated that endothelial cells, mesangial cells, and podocytes of immature glomeruli synthesize collagen alpha 1 alpha 2 alpha1(IV). However, intracellular labeling revealed that podocytes, but not endothelial or mesangial cells, contain collagen alpha 3 alpha 4 alpha 5(IV). To evaluate the origins of collagen IV further, we transplanted embryonic kidneys from Col4a3-null mutants (Alport mice) into kidneys of newborn, wildtype mice. Hybrid glomeruli within grafts containing numerous host-derived, wildtype endothelial cells never expressed collagen alpha 3 alpha 4 alpha 5(IV). Finally, confocal microscopy of glomeruli from infant Alport mice that had been dually labeled with anti-collagen alpha 5(IV) and the podocyte marker anti-GLEPP1 showed immunolabeling exclusively within podocytes. Together, these results indicate that collagen alpha 3 alpha 4 alpha 5(IV) originates solely from podocytes; therefore, glomerular Alport disease is a genetic defect that manifests specifically within this cell type.

Comparison between light and electron microscopy in canine and feline renal pathology: a preliminary study

The aim of this study is to compare the accuracy and clinical use of light and transmission electron microscopy in detecting the early stages of renal pathologies in domestic animals. We examined 30 samples of renal tissue from cats and dogs referred to the Veterinary Hospital of the Department of Animal Pathology for different systemic diseases. The progressions of the kidney pathologies were classified using the scheme system proposed by the International Renal Interest Society. All samples were submitted for conventional histology and ultrastructural examination. Our study shows that electron microscopy is necessary to complete the histological examinations, especially to define early stages of kidney diseases (minimal changes disease, epithelial tubular pathologies, tubular basement membrane and glomerular basement membrane changes). Electron microscopy can be more accurate in defining the level of focal lesion, and permits discrimination between different clinical and pathological alterations such as fibrillary deposits. In conclusion, transmission electron microscopy associated with clinical, histological, histochemical and immunological examinations, is an essential method for diagnosis and prognosis of renal disease.