Progressive Glomerular Disease Research Articles

Allele frequency of nonsense mutation responsible for hereditary nephropathy in English cocker spaniel dogs

Hereditary nephropathy is a primary progressive glomerular disease in dogs associated with the c.115A>T mutation in the COL4A4 gene in English cocker spaniel (ECS) dogs. The disease is inherited in an autosomal recessive manner. Hereditary nephropathy has been described in this breed since the late 1940s. To date, there are no data on the prevalence of this disease in Brazil, so the aim of this study was to evaluate the allelic frequency of this mutation in ECS dogs in this country. The DNA samples were purified from blood samples or buccal swabs from 221 ECS dogs. Fragments of the DNA containing the mutation were amplified by PCR and submitted to direct gene sequencing. The allele frequency of the mutation was 0.9%. The presence of the mutation in the ECS dog population in Brazil reveals the importance of performing the genotyping tests in these dogs as a method of diagnosing the disease and identifying heterozygous animals, aiming to reduce clinical cases of disease through mating.

Podocyte-associated messenger ribonucleic acids profile in urine of patients with idiopathic nephrotic syndrome and lupus nephritis.

Background: Podocytes associated proteins are essential in the maintenance of a healthy glomerular filtration barrier, a spectrum of different glomerular diseases occurs due to podocyte abnormalities. Urinary podocytes mRNAs are a more accurate tool for monitoring the progression of different glomerular diseases than proteinuria.Methods: Quantification of podocyte mRNAs in urinary sediment by real time polymerase chain reaction (PCR) of idiopathic nephrotic syndrome, lupus nephritis patients (LN) and the healthy controls, each group contains 15 individuals to be correlated with proteinuria level and eGFR (by MDRD equation).Results: the urinary podocyte mRNAs in both idiopathic nephrotic syndrome and LN groups differed significantly in comparison to that of controls, there was a significant correlation when comparing renal function tests and estimated glomerular filtration rate (by MDRD equation) between nephrotic, LN groups and control group, the value of podocin showed significant correlation in active LN subgroup with its corresponding value in the non-active LN subgroup.Conclusions: This study has revealed that urine pellet podocyte mRNAs can be used as a tool for monitoring the progression of idiopathic nephrotic syndrome and lupus nephritis patients and that urinary podocin can be used as a marker for lupus nephritis activity.

Autophagy and Glomerular Diseases.

Autophagy is an endogenous and essential process which maintains cellular homeostasis and directs cell fate. The glomerular diseases are one main part of the kidney diseases, often associated with poor clinical outcomes. The regulation of autophagy contributes to the progression of various glomerular diseases, including focal segmental glomerulosclerosis, lupus nephritis, and so on.For example, it has been demonstrated that prevention of autophagic flux in the kidney epithelium and podocytes is sufficient to trigger a degenerative disease of the kidney with many of the manifestations of human FSGS. We review the roles of autophagy in glomerular diseases. Therapies in clinical use, and in preclinical or clinical development, are also discussed in relation to their effects on autophagy in glomerular diseases.

Tubular injury triggers podocyte dysfunction by β-catenin-driven release of MMP-7.

Proteinuric chronic kidney disease (CKD) remains a major health problem worldwide. While it is well established that the progression of primary glomerular disease induces tubulointerstitial lesions, how tubular injury triggers glomerular damage is poorly understood. We hypothesized that injured tubules secrete mediators that adversely affect glomerular health. To test this, we used conditional knockout mice with tubule-specific ablation of β-catenin (Ksp-β-cat-/-) and subjected them to chronic angiotensin II (Ang II) infusion or Adriamycin. Compared with control mice, Ksp-β-cat-/- mice were dramatically protected from proteinuria and glomerular damage. MMP-7, a downstream target of β-catenin, was upregulated in treated control mice, but this induction was blunted in the Ksp-β-cat-/- littermates. Incubation of isolated glomeruli with MMP-7 ex vivo led to nephrin depletion and impaired glomerular permeability. Furthermore, MMP-7 specifically and directly degraded nephrin in cultured glomeruli or cell-free systems, and this effect was dependent on its proteolytic activity. In vivo, expression or infusion of exogenous MMP-7 caused proteinuria, and genetic ablation of MMP-7 protected mice from Ang II-induced proteinuria and glomerular injury. Collectively, these results demonstrate that β-catenin-driven MMP-7 release from renal tubules promotes glomerular injury via direct degradation of the key slit diaphragm protein nephrin.

RETRACTED ARTICLE: Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria

Injury to podocytes is a principle cause of initiation and progression of both immune and non-immune mediated glomerular diseases that result in proteinuria and decreased function of the kidney. Current advances in regenerative medicine shed light on the therapeutic potential of cell-based strategies for treatment of such disorders. Thus, there is hope that generation and transplantation of podocytes from induced pluripotent stem cells (iPSCs), could potentially be used as a curative treatment for glomerulonephritis caused by podocytes injury and loss. Despite several reports on the generation of iPSC-derived podocytes, there are rare reports about successful use of these cells in animal models. In this study, we first generated a model of anti-podocyte antibody-induced heavy proteinuria that resembled human membranous nephropathy and was characterized by the presence of sub-epithelial immune deposits and podocytes loss. Thereafter, we showed that transplantation of functional iPSC-derived podocytes following podocytes depletion results in recruitment of iPSC-derived podocytes within the damaged glomerulus, and leads to attenuation of proteinuria and histological alterations. These results provided evidence that application of iPSCs-derived renal cells could be a possible therapeutic strategy to favorably influence glomerular diseases outcomes.

The Influence of a Nanopatterned Scaffold that Mimics Abnormal Renal Mesangial Matrix on Mesangial Cell Behavior.

The alteration of mesangial matrix (MM) components in mesangium, such as type IV collagen (COL4) and type I collagen (COL1), is commonly found in progressive glomerular disease. Mesangial cells (MCs) responding to altered MM, show critical changes in cell function. This suggests that the diseased MM structure could play an important role in MC behavior. To investigate how MC behavior is influenced by the diseased MM 3D nanostructure, we fabricated the titanium dioxide (TiO2)-based nanopatterns that mimic diseased MM nanostructures. Immortalized mouse MCs were used to assess the influence of disease-mimic nanopatterns on cell functions, and were compared with a normal-mimic nanopattern. The results showed that the disease-mimic nanopattern induced disease-like behavior, including increased proliferation, excessive production of abnormal MM components (COL1 and fibronectin) and decreased normal MM components (COL4 and laminin α1). In contrast, the normal-mimic nanopattern actually resulted in cells displaying normal proliferation and the production of normal MM components. In addition, increased expressions of α-smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1) and integrin α5β1 were detected in cells grown on the disease-mimic nanopattern. These results indicated that the disease-mimic nanopattern induced disease-like cell behavior. These findings will help further establish a disease model that mimics abnormal MM nanostructures and also to elucidate the molecular mechanisms underlying glomerular disease.

The tetraspanin CD9 controls invasive migration and proliferation of parietal epithelial cells and glomerular disease progression

Introduction Crescentic glomerulonephritis (CGN) and focal segmental glomerulosclerosis (FSGS) are life-threatening diseases leading to irreversible renal failure. Increasing evidence supports the notion that glomerular parietal epithelial cells (PEC) are implicated in the formation of crescents in CGN and in glomerular scarring during FSGS. However, the mechanisms underlying the change in PEC phenotype remain unclear, as do those driving their oriented migration towards the glomerular tuft and their increased capacity to proliferate and form hypercellular and sclerotic lesions. Methodes Aiming to identify factors underlying PEC activation, we revealed increased expression of CD9 using comparative deep RNA sequencing of mouse and human normal and diseased glomeruli, confirmed expression by immunohistochemistry, and investigated roles of this tetraspanin in CGN and FSGS pathogeny. As CD9 de novo expression in glomeruli was observed in PEC in human CGN and FSGS and, given the recognized role of PEC in the progression of extracapillary lesions, we generated mice with a specific Cd9 deletion in PEC (iPec-Cd9lox/lox mice) that were challenged in experimental CGN and FSGS models. Cd9 gene knock-down were performed in a PEC line to evaluate its influence on migration, spreading and proliferation. Results During the CGN model, iPec-Cd9 wt/wt control mice showed a rapid increase in albuminuria, renal failure and severe glomerular crescentic lesions. Conversely, iPec-Cd9lox/lox mice displayed marked renal protection. We challenged iPec-Cd9lox/lox mice with the DOCA-salt and unilateral nephrectomy FSGS model. Glomerular ultrastructure and function was preserved in iPec-Cd9lox/lox DOCA mice, whereas iPec-Cd9 wt/wt DOCA mice exhibited flocculo-capsular synechiae and sclerosis. In vitro, we found that CD9 deficiency impairs the ability of PECs to proliferate and to migrate towards a steep gradient of chemoattractant in microfluidic channels. Conclusion These results indicate that de novo expression of CD9 in PECs participates in crescents in experimental CGN and is also critically involved in the development of glomerular lesions in FSGS.

The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression

The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. A key question is how parietal epithelial cells (PECs) invade glomerular capillaries, thereby promoting injury and kidney failure. Here we show that expression of the tetraspanin CD9 increases markedly in PECs in mouse models of CGN and FSGS, and in kidneys from individuals diagnosed with these diseases. Cd9 gene targeting in PECs prevents glomerular damage in CGN and FSGS mouse models. Mechanistically, CD9 deficiency prevents the oriented migration of PECs into the glomerular tuft and their acquisition of CD44 and β1 integrin expression. These findings highlight a critical role for de novo expression of CD9 as a common pathogenic switch driving the PEC phenotype in CGN and FSGS, while offering a potential therapeutic avenue to treat these conditions.

Podocyte histone deacetylase activity regulates murine and human glomerular diseases

We identified 2 genes, histone deacetylase 1 (HDAC1) and HDAC2, contributing to the pathogenesis of proteinuric kidney diseases, the leading cause of end-stage kidney disease. mRNA expression profiling from proteinuric mouse glomeruli was linked to Connectivity Map databases, identifying HDAC1 and HDAC2 with the differentially expressed gene set reversible by HDAC inhibitors. In numerous progressive glomerular disease models, treatment with valproic acid (a class I HDAC inhibitor) or SAHA (a pan-HDAC inhibitor) mitigated the degree of proteinuria and glomerulosclerosis, leading to a striking increase in survival. Podocyte HDAC1 and HDAC2 activities were increased in mice podocytopathy models, and podocyte-associated Hdac1 and Hdac2 genetic ablation improved proteinuria and glomerulosclerosis. Podocyte early growth response 1 (EGR1) was increased in proteinuric patients and mice in an HDAC1- and HDAC2-dependent manner. Loss of EGR1 in mice reduced proteinuria and glomerulosclerosis. Longitudinal analysis of the multicenter Veterans Aging Cohort Study demonstrated a 30% reduction in mean annual loss of estimated glomerular filtration rate, and this effect was more pronounced in proteinuric patients receiving valproic acid. These results strongly suggest that inhibition of HDAC1 and HDAC2 activities may suppress the progression of human proteinuric kidney diseases through the regulation of EGR1.

Retinal manifestations in patients with complement-mediated membranoproliferative glomerulonephritis

Abstract Complement-mediated membranoproliferative glomerulonephritis is a rare progressive glomerular disease. In some patients it can be associated with retinal lesions. Therefore, the purpose of this study was to assess a case series with this diagnosis in our hospital. A cross-sectional study was conducted on 8 patients diagnosed with complement-mediated membranoproliferative glomerulonephritis. Funduscopy, optical coherence tomography (OCT) and Swept Source domain OCT angiography were performed. Only 1 of the 8 patients showed drusen-like deposits that were located under the retinal pigment epithelium in the OCT, with the presence of associated choroidal neovascularization being ruled out in OCT angiography. Therefore, membranoproliferative glomerulonephritis may produce retinal alterations with drusen or retinal pigment epithelium detachment, and requires an appropriate differential diagnosis to be made with age-related macular degeneration. The follow-up of these patients is important in order to detect vision-threatening complications.

A novel splicing variant of small nucleolar RNA host gene 4 is a podocyte-selective non-coding RNA upregulated in response to puromycin aminonucleoside-induced podocyte injury.

Podocytes are terminally differentiated cells that function as the glomerular filtration barrier in the kidney, and podocyte injury leads to serious proteinuria and podocyte leakage into urine. Recent studies have demonstrated that the number of urinary podocytes is correlated with the progression of glomerular diseases. Therefore, urinary podocytes may serve as an indicator of podocyte injury. In this study, to explore podocyte injury-related genes, we performed comprehensive transcriptome analysis of primary rat podocytes cultured in the presence or absence of puromycin aminonucleoside (PAN), an agent commonly used to induce podocyte injury. RNA-seq revealed that a transcript containing the intronic sequence of small nucleolar RNA host gene 4 (Snhg4) was expressed in podocytes and upregulated by PAN. RT-qPCR analysis demonstrated that this transcript, but not Snhg4, was selectively expressed in podocytes. Therefore, we designated the novel transcript Snhg4-pod. 5'- and 3'-RACE experiments revealed that Snhg4-pod is a novel splice variant of Snhg4 lacking a poly(A) tail. PAN induced Snhg4-pod expression in podocytes in a dose-dependent manner along with their mitochondria-mediated apoptotic cell death. Further, Snhg4-pod was detected in urinary sediments from PAN-induced nephrotic rats. Our findings suggest that Snhg4-pod may serve as a novel marker for the diagnosis of glomerular injury.

Intravital imaging of adriamycin-induced renal pathology using two-photon microscopy and optical coherence tomography

Adriamycin (doxorubicin), a common cancer chemotherapeutic drug, can be used to induce a model of chronic progressive glomerular disease in rodents. In our studies, we evaluated renal changes in a rat model after Adriamycin injection using two-photon microscopy (TPM), optical coherence tomography (OCT) and Doppler OCT (DOCT). Taking advantage of deep penetration and fast scanning speed for three-dimensional (3D) label-free imaging, OCT/DOCT system was able to reveal glomerular and tubular pathology noninvasively and in real time. By imaging renal pathology following the infusion of fluorophore-labeled dextrans of different molecular weights, TPM can provide direct views of glomerular and tubular flow dynamics with the onset and progression of renal disease. Specifically, glomerular permeability and filtration, proximal and distal tubular flow dynamics can be revealed. 6–8 weeks after injection of Adriamycin, TPM and OCT/DOCT imaging revealed glomerular sclerosis, compromised flow across the glomerular wall, tubular atrophy, tubular dilation, and variable intra-tubular flow dynamics. Our results indicate that TPM and OCT/DOCT provide real-time imaging of renal pathology in vivo that has not been previously available using conventional microscopic procedures.

Urinary exosome miR-146a is a potential marker of albuminuria in essential hypertension

BackgroundThere is increasing interest in using extracellular vesicle-derived microRNAs (miRNAs) as biomarkers in renal dysfunction and injury. Preliminary evidence indicates that miRNAs regulate the progression of glomerular disease. Indeed, exosomes from the renal system have provided novel evidence in the clinical setting of albuminuria. Thus, the aim of this study was to quantify the urinary miRNAs present in exosome and microvesicles (MVs), and to assess their association with the presence of increased urinary albumin excretion in essential hypertension.MethodsExosomes were collected from urine specimens from a cohort of hypertensive patients with (n = 24) or without albuminuria (n = 28), and from 20 healthy volunteers as a control group. Urinary exosomes were phenotyped by Western blot, tunable resistive pulse sensing, and electronic microscopy. Expression of miR-146a and miR-335* was analysed by qRT-PCR and any associations between albuminuria and exosomal miRNAs were analysed.ResultsUrinary miRNAs are highly enriched in exosome subpopulations compared to MVs, both in patients with or without increased albuminuria (p < 0.001), but not in the control group. High albuminuria was associated with 2.5-fold less miR-146a in exosomes (p = 0.017), whereas miR-146a levels in MV did not change. In addition, exosome miR-146a levels were inversely associated with albuminuria (r = 0.65, p < 0.0001), and discriminated the presence of urinary albumin excretion presence [area under the curve = 0.80, 95% confidence interval: 0.66–0.95; p = 0.0013].ConclusionsOur results indicate that miRNAs were enriched in the urinary exosome subpopulation in hypertensive patients and that low miR-146a expression in exosomes was associated with the presence of albuminuria. Thus, urinary exosome miR-146a may be a potentially useful tool for studying early renal injury in hypertension.

Manifestaciones retinianas en pacientes con glomerulonefritis membranoproliferativa mediada por complemento

Complement-mediated membranoproliferative glomerulonephritis is a rare progressive glomerular disease. In some patients it can be associated with retinal lesions. Therefore, the purpose of this study was to assess a case series with this diagnosis in our hospital. A cross-sectional study was conducted on 8 patients diagnosed with complement-mediated membranoproliferative glomerulonephritis. Funduscopy, optical coherence tomography (OCT) and Swept Source domain OCT angiography were performed. Only 1 of the 8 patients showed drusen-like deposits that were located under the retinal pigment epithelium in the OCT, with the presence of associated choroidal neovascularization being ruled out in OCT angiography. Therefore, membranoproliferative glomerulonephritis may produce retinal alterations with drusen or retinal pigment epithelium detachment, and requires an appropriate differential diagnosis to be made with age-related macular degeneration. The follow-up of these patients is important in order to detect vision-threatening complications.

LUPUS NEPHRITIS

Categorization of proteinuria and hematuria in patients with lupus nephritis at atertiary care center Lahore. Objectives: Distribution of proteinuria and hematuria has a pivotalrole in renal complications of systemic lupus erythematosus (SLE). Proteinuria and hematuriahas been included as an independent descriptor in the SLE disease activity index (SLEDAI).Hence this study aims to categorize the proteinuria and hematuria in local population. DataSource: Fatima Memorial Hospital. Design of Study: Descriptive study. Setting: This studywas conducted in the Department of Morbid Anatomy and Histopathology, at University ofHealth Sciences, Lahore. Samples were collected from the department of pathology at FatimaMemorial Hospital Lahore. Period: In 2015 from January till December. Methods: Urine wascollected from 38 cases both male and female patients immediately prior to biopsy for evaluationof lupus nephritis. Relevant laboratory investigations, serum Antinuclear antibody (ANA) andAnti-double stranded DNA (Anti dsDNA) levels and renal function tests were recorded. Theproteinuria and hematuria were detected and categorized by dipstick methods. Proteinuria wascategorized on the following scale: 1+ = 200 - 500 mg/24 hours, 2+ = 500 - 1500 mg/24hours, 3+ = 2500-3500 mg/24 hours and 4+ = &gt;3500 mg/24 hours. Microscopic hematuriais categorized via RBC/HPF: 0–2 (negative), 3–10 (1+), 11–50 (2+), 51–100 (3+), and 100+(4+). Microscopic hematuria was categorized as RBC/HPF: 0–2 (negative), 3–10 (1+), 11–50(2+), 51–100 (3+), and 100+ (4+). Results: Among 38 patients the male to female ratio was1:5. Mean age of the patients was 26.55 ± 8.13 years with age range of 14-49 years. A total of37 (97.3 %) cases had proteinuria. The intensity of proteinuria was graded as 1+ in 4 (10.53%),2+ in 14 (36.84%) and 3+ in 19 (50%) patients. Haematuria was present in 31 (81.58%) cases.Among these patients, the intensity was graded as 1+ in 11 (28.95%), 2+ in 9 (23.68 %) and3+ in 11 (28.95%) cases. Serum ANA and anti dsDNA were positive in all cases regardless ofdisease progression. None of the variable showed any significant association when comparedstatistically. Conclusions: The grade of proteinuria increases rapidly with progression of thelupus nephritis in SLE which may be partly due to delayed diagnosis and brisk activity of therenal flares and partly as complication in SLE treatment in our population. Hematuria in thepresence of proteinuria alone can suggest glomerular disease progression without the need forextensive urological investigations.

Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury

Podocyte injury and loss contribute to the progression of glomerular diseases, including diabetic kidney disease. We previously found that the glomerular expression of Sirtuin-1 (SIRT1) is reduced in human diabetic glomeruli and that the podocyte-specific loss of SIRT1 aggravated albuminuria and worsened kidney disease progression in diabetic mice. SIRT1 encodes an NAD-dependent deacetylase that modifies the activity of key transcriptional regulators affected in diabetic kidneys, including NF-κB, STAT3, p53, FOXO4, and PGC1-α. However, whether the increased glomerular SIRT1 activity is sufficient to ameliorate the pathogenesis of diabetic kidney disease has not been explored. We addressed this by inducible podocyte-specific SIRT1 overexpression in diabetic OVE26 mice. The induction of SIRT1 overexpression in podocytes for six weeks in OVE26 mice with established albuminuria attenuated the progression of diabetic glomerulopathy. To further validate the therapeutic potential of increased SIRT1 activity against diabetic kidney disease, we developed a new, potent and selective SIRT1 agonist, BF175. In cultured podocytes BF175 increased SIRT1-mediated activation of PGC1-α and protected against high glucose-mediated mitochondrial injury. Invivo, administration of BF175 for six weeks in OVE26 mice resulted in a marked reduction in albuminuria and in glomerular injury in a manner similar to podocyte-specific SIRT1 overexpression. Both podocyte-specific SIRT1 overexpression and BT175 treatment attenuated diabetes-induced podocyte loss and reduced oxidative stress in glomeruli of OVE26 mice. Thus, increased SIRT1 activity protects against diabetes-induced podocyte injury and effectively mitigates the progression of diabetic kidney disease.

Nephrin as a biomarker of sickle cell glomerulopathy in Malawi.

Glomerulopathy is an increasingly identified complication in young patients with sickle cell disease (SCD). Hyperfiltration and albuminuria followed by declining glomerular filtration rates and eventual end-stage renal disease (ESRD) is assumed to be the typical progression of glomerular disease. There are only a few reported biomarkers to identify early-stage renal disease in SCD. We detail the renal profile of 101 children with SCD in Malawi and propose a novel urinary biomarker for the identification of early renal disease. Among children with sickle cell anemia, 24.8% had a urine albumin-creatinine ratio of 30mg/g or above. In univariate analysis, only patients with higher urinary nephrin, a urinary marker of glomerular injury, had significantly greater odds of having albuminuria. In multivariable analysis, nephrin remained significantly associated with albuminuria. A nephrin-creatinine ratio (NCR) cut-point of 622ng/mg, the 50th percentile, was associated with a 45.8 times greater odds of having albuminuria in children with nephrinuria above this value. Further analysis revealed this urinary NCR cut-point to have 96% sensitivity, 64% specificity, 47% positive predictive value, and 98% negative predictive value for the presence of albuminuria. These data suggest that a substantial number of children with SCD in Malawi have renal disease and could be at risk for worsening nephropathy and ESRD as they age. Our data suggest that urinary nephrin could be utilized as an early marker of glomerular disease in SCD.

The associations of Bmi-1 with progression of glomerular chronic kidney disease .

Our previous studies indicated that Bmi-1 plays an important role in hypoxia-induced tubular epithelial-mesenchymal transition and the development of kidney fibrosis in cellular and animal models. However, circulating Bmi-1 levels in human chronic kidney disease (CKD) and their relation to progression remains unknown. We conducted a post-hoc analysis of a prospective cohort study. The blood samples and clinical data of 230 patients with glomerular CKD and 67 healthy adults were prospectively collected between January 2010 and June 2012. Serum Bmi-1 was measured using enzyme-linked immunosorbent assay (ELISA). CKD patients had significantly higher serum Bmi-1 concentrations than the healthy controls (496.4 (363.1-675.4) pg/mL compared with 257.3 (235.4-303.8) pg/mL, p<0.001). Serum Bmi-1 level inversely correlated with the estimated glomerular filtration rate (eGFR) (r = -0.346, p<0.001). In addition, positive correlations were identified between serum Bmi-1 levels and serum creatinine, blood urea nitrogen, cystatin C concentration, and the severity of tubulointerstitial fibrosis (r=0.248, p<0.001; r=0.245, p<0.001; r=0.273, p<0.001; r=0.536, p<0.001, respectively). Kaplan-Meier survival curves showed that a higher serum Bmi-1 level was associated with a shorter duration of renal survival. Cox multivariate analyses further demonstrated that serum Bmi-1 concentration was an independent prognostic factor for CKD patients (HR=6.48, p<0.001). Our study showed that high circulating Bmi-1 levels were associated with adverse kidney disease outcome, suggesting that Bmi-1 is a novel biomarker for glomerular CKD progression. More data from larger longitudinal studies are required to validate our findings. .

Basement Membrane Defects in Genetic Kidney Diseases.

The glomerular basement membrane (GBM) is a specialized structure with a significant role in maintaining the glomerular filtration barrier. This GBM is formed from the fusion of two basement membranes during development and its function in the filtration barrier is achieved by key extracellular matrix components including type IV collagen, laminins, nidogens, and heparan sulfate proteoglycans. The characteristics of specific matrix isoforms such as laminin-521 (α5β2γ1) and the α3α4α5 chain of type IV collagen are essential for the formation of a mature GBM and the restricted tissue distribution of these isoforms makes the GBM a unique structure. Detailed investigation of the GBM has been driven by the identification of inherited abnormalities in matrix proteins and the need to understand pathogenic mechanisms causing severe glomerular disease. A well-described hereditary GBM disease is Alport syndrome, associated with a progressive glomerular disease, hearing loss, and lens defects due to mutations in the genes COL4A3, COL4A4, or COL4A5. Other proteins associated with inherited diseases of the GBM include laminin β2 in Pierson syndrome and LMX1B in nail patella syndrome. The knowledge of these genetic mutations associated with GBM defects has enhanced our understanding of cell–matrix signaling pathways affected in glomerular disease. This review will address current knowledge of GBM-associated abnormalities and related signaling pathways, as well as discussing the advances toward disease-targeted therapies for patients with glomerular disease.

Impact of body mass index on progression of primary immunoglobulin a nephropathy.

The role of obesity in the progression of primary glomerular diseases is controversial. A few studies report overweight/obesity as a risk factor for disease progression in immunoglobulin A nephropathy (IgAN), and the real impact of it still remains unclear. The aim of this study was to elucidate the effect of body mass index (BMI) on disease progression and proteinuria in patients with IgAN in Indian population. A cohort of biopsy-proven primary IgAN patients diagnosed between March 2010 and February 2015 who had a follow-up for a minimum of 12 months were included in the study. We defined two groups of patients according to the BMI value at diagnosis: non-obese group (Group N) with BMI <23 Kg/m2 and the overweight/obese group (Group O) with BMI >23 Kg/m2 as per Asia-Pacific task force criteria. Baseline characteristics were compared between the groups. The estimated glomerular filtration rate (eGFR) and urine protein-creatinine ratio (UPCR) were followed up at entry time, 6 months, 12 months, and at the end of follow-up. Outcomes studied were change in eGFR, proteinuria, and progression to end-stage renal disease. Statistical analysis was done using the Statistical Package for the Social Sciences version 15.0. Of 51 patients, 25 (49%) had BMI <23 kg/m2 (Group N) and 26 (51%) had BMI >23 kg/m2 (Group O) (P = 0.01). The baseline clinical, histopathological, and treatment characteristics of both the groups were comparable. The BMI at the time of diagnosis did not have any significant effect on eGFR (P = 0.41) or proteinuria (P = 0.99) at presentation. At the end of follow-up, both the groups had a similar reduction of proteinuria (UPCR) (P = 0.46) and eGFR (P = 0.20). Two patients in each group have reached chronic kidney disease Stage 5. In the present study, BMI at presentation did not have any impact on eGFR or proteinuria, either at diagnosis or at follow-up. It needs further large multicenter randomized control studies to see the effect of BMI on progression of IgAN.