Pathogenesis Of Proteinuria Research Articles

Insulin resistance before type 2 diabetes onset is associated with increased risk of albuminuria after diabetes onset: A prospective cohort study.

Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset. Baseline body composition, insulin sensitivity by hyperinsulinaemic-euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow-up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g). Separate associations of M-low, M-high and AIR (per 1-SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%). Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M-low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p = .03; M-high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p = .02; mg/kg-metabolic body size/min (log)]. In separate adjusted models, lower M-low and M-high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p = .004; HR 1.31, 95% CI 1.06, 1.63, p = .01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p = .3). Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria.

194-OR: Lower Insulin Sensitivity before the Onset of Type 2 Diabetes Is Associated with Increased Risk of Albuminuria after Diabetes Onset

Background: Reduced renal insulin signaling is implicated in the pathogenesis of albuminuria, a marker of kidney failure, cardiovascular disease, and mortality. We sought to investigate whether insulin action and secretion, measured prior to diabetes onset, are associated with development of albuminuria after diabetes onset. Methods: Baseline body composition, insulin sensitivity by hyperinsulinemic-euglycemic clamp at submaximal and max insulin stimulation (240 and 2400 pmol/m2/min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test (acute insulin response, AIR) were measured in 166 Indigenous American adults who subsequently developed diabetes. After diabetes onset and during median follow-up of 12.3 years, 44 participants (27%) developed albuminuria. The separate associations of M-low, M-high, and AIR (per 1-SD change) with risk of albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) were identified by Cox regression models adjusted for age, sex, and body fat (%). Results: Participants who developed albuminuria were of similar age (26.8 ± 5.6 vs. 27.1 ± 6.0 years), sex distribution (50% vs. 46% male), body fat (36.6 ± 6.0 vs. 35.8 ± 8.0%), and AIR (3.1 ± 0.3 vs. 3.0 ± 0.3, pmol/L [log]) as those who did not develop albuminuria, but had lower insulin sensitivity (M-low: 0.32 ± 0.06 vs. 0.36 ± 0.11, p = 0.007, M-high: 0.85 ± 0.11 vs. 0.90 ± 0.12, p = 0.03; mg/kg-metabolic body size/min [log]). In separate adjusted models, lower M-low and M-high (i.e., lower insulin sensitivity) were both associated with increased risk for albuminuria (HR 1.67, 95% CI 1.12, 2.50, p = 0.01; HR 1.35, 95% CI 1.03, 1.79, p = 0.03), whereas AIR was not (HR 1.18, 95% CI 0.79, 1.75, p = 0.42). Conclusion: Lower insulin sensitivity is associated with development of albuminuria, suggesting a role for insulin signaling in the pathogenesis of proteinuria and is a potential therapeutic target for prevention of cardiovascular and kidney disease. Disclosure M.R.Willig: None. E.J.Stinson: None. H.C.Looker: None. C.M.Mitchell: None. R.L.Hanson: None. R.G.Nelson: None. J.Krakoff: None. D.C.Chang: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK069015-36)

Podocyte Glucocorticoid Receptors Are Essential for Glomerular Endothelial Cell Homeostasis in Diabetes Mellitus.

BackgroundProteinuria and glomerular segmental fibrosis are inevitable complications of diabetic nephropathy though their mechanisms are poorly understood. Understanding the clinical characteristics and pathogenesis of proteinuria and glomerular segmental fibrosis in diabetic nephropathy is, therefore, urgently needed for patient management of this severe disease.Methods and ResultsDiabetes mellitus was induced in podocyte‐specific glucocorticoid receptor knockout (GRPKO) mice and control littermates by administration of streptozotocin. Primary podocytes were isolated and subjected to analysis of Wnt signaling and fatty acid metabolism. Conditioned media from primary podocytes was transferred to glomerular endothelial cells. Histologic analysis of kidneys from diabetic GRPKO mice showed worsened fibrosis, increased collagen deposition, and glomerulomegaly indicating severe glomerular fibrosis. Higher expression of transforming growth factor‐βR1 and β‐catenin and suppressed expression of carnitine palmitoyltransferase 1A in nephrin‐positive cells were found in the kidneys of diabetic GRPKO mice. Podocytes isolated from diabetic GRPKO mice demonstrated significantly higher profibrotic gene expression and suppressed fatty acid oxidation compared with controls. Administration of a Wnt inhibitor significantly improved the fibrotic features in GRPKO mice. The glomerular endothelium of diabetic GRPKO mice demonstrated the features of endothelial‐to‐mesenchymal transition. Moreover, endothelial cells treated with conditioned media from podocytes lacking GR showed increased expression of α‐smooth muscle actin, transforming growth factor‐βR1 and β‐catenin levels.ConclusionsThese data demonstrate that loss of podocyte GR leads to upregulation of Wnt signaling and disruption in fatty acid metabolism. Podocyte–endothelial cell crosstalk, mediated through GR, is important for glomerular homeostasis, and its disruption likely contributes to diabetic nephropathy.

Involvement of Hemopexin in the Pathogenesis of Proteinuria in Children with Idiopathic Nephrotic Syndrome.

Hemopexin (Hpx) is considered a factor in the pathogenesis of idiopathic nephrotic syndrome (INS). The aim of the study was to evaluate the serum and urine values of Hpx (sHpx and uHpx) in children with INS, analyze the role of Hpx, and assess its usefulness as a marker of the disease course. 51 children with INS and 18 age-matched controls were examined. Patients were divided into subgroups depending on the number of relapses (group IA—the first episode of INS, group IB—with relapses) and according to method of treatment (group IIA treated with gluco-corticosteroids (GCS), group IIB treated with GCS and other immunosuppressants). Hpx concentrations were determined by enzyme-linked immunosorbent assay (ELISA). sHpx and uHpx values in relapse were elevated in the whole INS group versus controls (p < 0.000). In remission their levels decreased, but still remained higher than in the control group (p < 0.000). In group IB uHpx levels were increased during remission as compared to group IA (p < 0.006). No significant impact of immuno-suppressants on sHpx was observed, but uHpx excretion in group IIA was higher in relapse (p < 0.026) and lower in remission (p < 0.0017) as compared to group IIB. The results suggest the role of Hpx in the pathogenesis of INS. Hpx may be a useful indicator for continuation of treatment, but it requires confirmation by further controlled studies.

Understanding the Instruments of Proteinuria

An enormous assemblage of proof demonstrates that proteinuria is a solid indicator of dreariness, a reason for aggravation, oxidative pressure and movement of persistent kidney illness, and improvement of cardiovascular sickness. The cycles that lead to proteinuria are intricate and include factors like glomerular hemodynamic, cylindrical ingestion, and dissemination slopes. Modifications in different distinctive sub-atomic pathways and cooperations may prompt the indistinguishable clinical end points of proteinuria and persistent kidney illness. Glomerular illnesses incorporate a wide scope of resistant and nonimmune put-downs that may target and consequently harm a few parts of the glomerular filtration boundary. In a considerable lot of these conditions, the renal instinctive epithelial cell (podocyte) reacts to injury along characterized pathways, which may clarify the resultant clinical and histological changes. The new revelation of the atomic segments of the cut stomach, particular construction of podocyte-podocyte association, has been a significant leap forward in understanding the vital job of the epithelial layer of the glomerular boundary and the pathogenesis of proteinuria. This paper gives an outline and update on the design and capacity of the glomerular filtration hindrance and the pathogenesis of proteinuria, featuring the part of the podocyte in this setting. Likewise, current antiproteinuric restorative methodologies are momentarily remarked.

A case of minimal change disease after the administration of anti receptor activator of nuclear factor kappa B ligand (RANKL) monoclonal antibody: a case report

BackgroundMinimal change disease (MCD) is one of the causes of idiopathic nephrotic syndrome in adults. The pathogenesis of proteinuria in MCD has not been fully understood. Recently, it has been reported that the receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL) may contribute to the podocyte biology in kidney diseases. Denosumab is a human anti-RANKL monoclonal antibody used to treat osteoporosis. Here we report a case of MCD after denosumab administration.Case presentationA 59-year-old male without any episodes of proteinuria was given denosumab to treat osteoporosis. Two weeks after its administration, he noticed a foamy urine and bilateral pretibial edema. Laboratory tests revealed that he had severe proteinuria (15g/g Cr), hypoproteinemia (4.0g/dL), and hypoalbuminemia (1.5g/dL). Based on the results, he was diagnosed with nephrotic syndrome. The proteinuria selectivity index was 0.05, indicating selective proteinuria. Renal biopsy showed minor glomerular abnormality with less tubulointerstitial damage, and electron microscopy showed extensive foot process effacement, indicating MCD. With all these results, glucocorticoid therapy of 50mg/day prednisolone was started. After 4weeks of treatment, the urinary protein level remains high (3.1g/g Cr). Prednisolone therapy was continued, and the levels of proteinuria decreased gradually to the range of partial remission (1.2g/g Cr) with another 7weeks of prednisolone treatment, but complete remission was not achieved.ConclusionsThis might be a case wherein RANKL inhibition is associated with the pathogenesis of MCD. Further studies will be needed to elucidate the causal relationship of RANK-RANKL signaling to the pathogenesis of MCD.

Nestin protects podocyte from injury in lupus nephritis by mitophagy and oxidative stress

Podocyte injury is the main cause of proteinuria in lupus nephritis (LN). Nestin, an important cytoskeleton protein, is expressed stably in podocytes and is associated with podocyte injury. However, the role of nestin in the pathogenesis of proteinuria in LN remains unclear. The correlations among nestin, nephrin and proteinuria were analyzed in LN patients and MRL/lpr lupus-prone mice. The expression of nestin in mouse podocyte lines (MPCs) and MRL/lpr mice was knocked down to determine the role of nestin in podocyte injury. Inhibitors and RNAi method were used to explore the role of mitophagy and oxidative stress in nestin protection of podocyte from damage. There was a significantly negative correlation between nestin and proteinuria both in LN patients and MRL/lpr mice, whereas the expression of nephrin was positively correlated with nestin. Knockdown of nestin resulted in not only the decrease of nephrin, p-nephrin (Y1217) and mitophagy-associated proteins in cultured podocytes and the podocytes of MRL/lpr mice, but also mitochondrial dysfunction in podocytes stimulated with LN plasma. The expression and phosphorylation of nephrin was significantly decreased by reducing the level of mitophagy or production of reactive oxygen species (ROS) in cultured podocytes. Our findings suggested that nestin regulated the expression of nephrin through mitophagy and oxidative stress to protect the podocytes from injury in LN.

Abstract MP74: Association of Albuminuria With Incident Atrial Fibrillation: The Multi-ethnic Study of Atherosclerosis (MESA)

Background: Atrial fibrillation (AF) shares risk factors with atherosclerotic cardiovascular disease (CVD). Albuminuria (AU) is an established risk factor for renal failure and CVD. Endothelial dysfunction, inflammation and hemostasis underlie the pathogenesis of AU. However, the association of AU with incident AF and its effect modifiers are not fully understood. Purpose: To assess the association of AU with incident AF and to identify its effect modifiers. Methods: We studied MESA participants, free of clinical CVD and AF at baseline, with urine samples at exam 1. Participants were followed for incident AF ascertained by follow up visit ECGs, hospital discharge diagnoses or Medicare claims data. Participants were compared by the presence or absence of AU (albumin-creatine ratio of ≥30). Kaplan-Meier curves were used to estimate the cumulative rate of incident AF and log-rank test to evaluate statistical significance. Hazard ratio (HR) and 95% confidence interval (CI) were computed by Cox proportional hazard models. Final adjusted model included CHARGE-AF risk score covariates with socioeconomic variables, current alcohol use, renal function, and lipid lowering medication use. Results: A total of 6376 participants were analyzed (median age 62 years, male 47.4%, White race 38.8%, mean BMI 28.3 ± 5.5). During median follow-up of 13.9 years, there were a total of 924 AF events. Participants with AU had a higher incidence of AF than those without AU at 10 years (23.9% vs 10.4%, p &lt; 0.05, Figure 1A ). In fully adjusted model, AU was significantly associated with incident AF [HR 1.53 (95% CI 1.27 - 1.85, p &lt; 0.01). Low high-density lipoprotein cholesterol (&lt; 40 mg/dL) and high triglyceride (≥ 150 mg/dL) augmented the association between AU and incident AF (p-interaction &lt; 0.05 for all, Figure 1B ). Conclusion: AU was significantly associated with incident AF after adjusting for conventional risk factors in a multi-racial prospective cohort. Lipid markers were identified as effect modifiers in the association of AU with AF.

Histopathology Interstitial Severity Index Associated with Glomerular and Tubular Severity Index in Nephrotic Syndrome Patients

Introduction: Nephrotic syndrome is characterized by massive proteinuria due to leakage of glomerular basal membrane, and subsequent process in tubular and interstitial tissue. It should be elucidated whether the severity of histopathological lesions in compartments of kidney tissue play a role and whether lesion in those compartments associated one to another. Aim: The study aims to correlate severity histopathologic lesions among compartments in kidney tissue. Method: All patients with nephrotic syndrome were biopsied and the cores were stained with Hematoxylin-Eosin, PAS, Masson’s Trichrome to look at glomerular, tubular, interstitial and vascular involvements. Glomerular abnormalities including mesangial hypercellularity, endocapillary hypercellularity, membranous; tubular, interstitial, and vascular severities were scored according to type, activity, severity and distribution in histopathologic features. Results: This study included 46 patients consisted of 16 (34.8%) males and 30 (65.2%) females, aged 26 ± 10 years, SBP 121.7 ± 13.10 and DBP 78.21 ± 7.80 mmHg, diagnosed with 14 lupus and 32 non-lupus nephrotic syndrome. Histopathologic abnormalities showed glomerular index was 4.26 ± 2.34, tubular index was 3.09 ± 1.90, interstitial index was 3.02 ± 1.48, vascular index was 0-3, pathologic index was 10.56 ± 4.54. There was significant correlation of severity index between interstitial and glomerular lesions (R=0.49, P=0.001), and between interstitial and tubular lesions (R=0.45, P=0.002). However, there were no significant correlations of severity index between interstitial and vascular lesions, and glomerular and tubular lesions. Conclusion: There are significant correlations of severity index between interstitial with glomerular and tubular lesions. It may implicate that histopathological process in interstitial tissue plays a central role in the pathogenesis of proteinuria in nephrotic syndrome.

Hypoxia induces ZEB2 in podocytes: Implications in the pathogenesis of proteinuria.

The glomerular filtration barrier (GFB) plays a critical role in ensuing protein free urine. The integrity of the GFB is compromised during hypoxia that prevails during extreme physiological conditions. However, the mechanism by which glomerular permselectivity is compromised during hypoxia remains enigmatic. Rats exposed to hypoxia showed a decreased glomerular filtration rate, podocyte foot-processes effacement, and proteinuria. Accumulation of hypoxia-inducible factor-1α (HIF1α) in podocytes resulted in elevated expression of zinc finger E-box binding homeobox 2 (ZEB2) and decreased expression of E- and P-cadherin. We also demonstrated that HIF1α binds to hypoxia response element localized in the ZEB2 promoter. Furthermore, HIF1α also induced the expression of ZEB2-natural antisense transcript, which is known to increase the efficiency of ZEB2 translation. Ectopic expression of ZEB2 induced loss of E- and P-cadherin and is associated with enhanced motility of podocytes during hypoxic conditions. ZEB2 knockdown abrogated hypoxia-induced decrease in podocyte permselectivity. This study suggests that hypoxia leads to activation of HIF1α-ZEB2 axis, resulting in podocyte injury and poor renal outcome.

Novel Role for Sphingolipid Metabolism in Radiation Nephropathy

The molecular mechanisms of radiation nephropathy remain largely unidentified. Sphingomyelin phosphodiesterase acid like 3b (SMPDL3b) is a lipid modulating enzyme that plays a major role in podocyte injury, and in the pathogenesis of proteinuria in glomerular diseases. The current study investigates the role of bioactive sphingolipids and SMPDL3b in radiation-induced podocytopathy, and identifies a monoclonal antibody targeting CD20, rituximab, as a radioprotector. Immortalized human podocytes were X-irradiated with 8 Gy ± rituximab (100 μg/mL) 30 minutes prior to radiation. Metabolic activity and viability were assessed. Transcriptional and translational levels of SMPDL3b were measured by RT-PCR and Western blot respectively. Cytoskeletal remodeling and morphological changes were detected using immunofluorescence microscopy. C57BL6 mice, 12-14 week-old, were subjected to bilateral kidney irradiation (14 Gy) using a CT-image guided X-irradiator and functional parameters of kidney damage measured every 10 weeks for 40 weeks (BUN, hematocrit, serum creatinine, urine albumin and creatinine ratio). Histological assessments (H&E, Picro-sirius red, and Periodic Acid Schiff), podocyte number, and SMPDL3B expression were measured in harvested kidneys post-RT. In culture, podocytes viability and metabolic activity decreased after X-irradiation. Cytoskeletal remodeling, manifesting as loss of lamellipodia and remodeling of cortical actin, was detected. Ezrin, an actin binding protein, relocated from the plasma membrane to the cytosol as early as 2h post radiation. Ceramide levels increased while sphingosine-1 phosphate (S1P) and sphingosine levels decreased. In contrast, overexpression of SMPDL3b and exogenous S1P rescued podocytes from radiation-induced cytoskeletal changes. Treatment with rituximab protected podocytes from SMPDL3b loss and caspase-3 cleavage. In irradiated animals, kidney weight and volume were reduced significantly, SMPDL3b expression and podocyte number decreased, changes that were not evident after rituximab administration. Loss of SMPDL3b expression and podocyte number were associated with reduction in functional and histological parameters. Radiation-injury induces downregulation of SMPDL3b, and elevation of ceramide levels as well as early cytoskeletal remodeling. Overexpression of SMPDL3b or pretreatment with rituximab is radioprotective in cultured podocytes and animals. These findings suggest a potential role for SMPDL3b in radiation-induced podocytopathy.

Serum Interleukin 13 Level in Steroid Sensitive Nephrotic Syndrome

Background: There are studies indicating the relationship between interleukin 13 and pathogenesis of nephrotic syndrome. To find this relationship, we measured serum IL13 concentration in acute and remission phases in children with steroid sensitive nephrotic syndrome. Methods: The serum of 15 patients was achieved for measurement of IL-13 in two phases: acute phase and remission phase. To this end, we used Biofarm ELIZA kites. Results: The mean concentration of serum IL-13 was 430 ± 279 ng/mL (227 - 960 ng/mL) before starting steroid treatment. The mean concentration of serum IL-13 was 428 ± 259 ng/mL (215.6 - 960 ng/mL) after 4 weeks of steroid treatment. The difference between pre and post treatment of serum IL-13 levels was not significant (P = 0.91). Conclusions: We showed serum IL13 does not significantly decrease after steroid treatment. Although the role of IL13 in increasing glomerular permeability has been shown in previous studies, the local IL13 may be more important than the systemic form. It also can be postulated that mediators other than IL13 also have primary roles in pathogenesis of proteinuria. However, we need more studies to determine the role of IL13 in the pathogenesis of nephrotic syndrome.

Hyperoside pre-treatment prevents glomerular basement membrane damage in diabetic nephropathy by inhibiting podocyte heparanase expression

Glomerular basement membrane (GBM) damage plays a pivotal role in pathogenesis of albuminuria in diabetic nephropathy (DN). Heparan sulfate (HS) degradation induced by podocyte heparanase is the major cause of GBM thickening and abnormal perm-selectivity. In the present study, we aimed to examine the prophylactic effect of hyperoside on proteinuria development and GBM damage in DN mouse model and the cultured mouse podocytes. Pre-treatment with hyperoside (30 mg/kg/d) for four weeks could significantly decrease albuminuria, prevent GBM damage and oxidative stress in diabetes mellitus (DM) mice. Immunofluorescence staining, Real time PCR and Western blot analysis showed that decreased HS contents and increased heparanase expression in DN mice were also significantly improved by hyperoside pre-treatment. Meanwhile, transmission electron microscope imaging showed that hyperoside significantly alleviated GBM thickening in DN mice. In addition, hyperoside pre-treatment inhibited the increased heparanase gene (HPR1) promoter activity and heparanase expression induced by high glucose or reactive oxidative species (ROS) in cultured podocytes. Our data suggested that hyperoside has a prophylactic effect on proteinuria development and GBM damage in DM mice by decreasing podocyte heparanase expression.

Podocytes and the quest for precision medicines for kidney diseases

In this review, I describe a 30-year journey in the quest for precision medicines for patients with kidney diseases. In 1987, when I started my reseach career, most scientists studying glomerular disease biology were focused on mesangial cells. The crucial role of the podocyte in many kidney diseases characterized by proteinuria, including focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, had not yet been recognized. We were not aware of genetic causes or drivers of kidney diseases nor of molecular markers and cell culture systems for mechanistic studies of podocyte biology. Tools for generating podocyte-specific knockout mice did not exist, and the key role of the podocyte actin cytoskeleton in the pathogenesis of proteinuria had not yet been identified. Clinically, treatment options for proteinuric kidney diseases were empiric, non-specific, and restricted to steroids and cyclosporine, without an understanding of their underlying mechanism of action. Since then, we have come a long way: a host of genetic causes for FSGS affecting podocytes has been identified, and with the advent of next generation sequencing approaches, the number of genetic causes continues to increase. Thinking "outside the box," empowered me to turn my attention to podocytes, develop the first differentiated podocyte cell culture system, and pioneer studies on the critical role of the podocyte actin cytoskeleton. Now, with the advent of iPSCs, we can build on these efforts by generating human podocytes and kidney organoids from patient cells, which, in combination with CRISPR-Cas9 gene editing and big data analyses, represent important next generation tools for bringing urgently needed precision medicines to patients with kidney disease. These new directions in kidney research should also increase the feasibility of much needed clinical trials in the kidney space. From Heidelberg to Boston, it has been an amazing scientific adventure. I will close with my thoughts about the path forward in making precision medicines for kidney diseases a reality.

Podocyte-specific soluble epoxide hydrolase deficiency in mice attenuates acute kidney injury.

Soluble epoxide hydrolase: EC 3.3.2.10.

Early Renal Disease in Children with Sickle Cell Disease from Malawi

Sickle cell nephropathy (SCN) is a prevalent complication among adults with sickle cell disease (SCD) and has been observed in younger populations, suggesting potential early renal involvement in pediatric patients. Initial hyperfiltration and albuminuria followed by frank proteinuria, leading to declining GFR and eventual end stage renal disease is assumed to be the typical progression of SCN; however, few clinical biomarkers exist to identify early-stage renal disease. We describe the renal profile in 119 children with SCD at Kamuzu Central Hospital in Lilongwe, Malawi and propose a novel urinary biomarker for the identification of children with early renal disease. Among children with confirmed HbSS disease (females 47.9%; median age 9.0 years, IQR: 5, 11), 21.6% were found to have a urinary albumin to creatinine ratio (UACR) 30mg/g or above. Baseline laboratory and clinical parameters stratified by UACR are shown in Tables 1 and 2. Patients with increased levels of UACR were found to be significantly older, and have significantly elevated plasma levels of lactate dehydrogenase (LDH), total bilirubin, and indirect bilirubin when compared to those without albuminuria (p<0.05). No association was seen between albuminuria and either hemoglobin or plasma hemoglobin. Albuminuria was also significantly associated with elevated levels of nephrin, a urinary marker of glomerular injury (p<0.01). Multivariable logistic regression was used to investigate risk factors that are associated with albuminuria (UACR >= 30). Urine nephrin was significantly associated with albuminuria (regression coefficient estimate: 0.00188, SE: 0.000571, p = 0.0010). Additional analysis using a nephrin cut-point of 293 pg/mL, the median value in the cohort, revealed a 17.8 times greater odds of having albuminuria in children with nephrinuria above this value. These data taken together suggests that a significant proportion of children with SCD in Malawi exhibit renal involvement early in life and could be at risk for worsening nephropathy and end-stage renal disease as they grow older. Our data further indicates that urinary nephrin could be utilized as an early marker of glomerular disease in SCN and possibly prompt earlier intervention in these children. The discordant association of albuminuria with clinical markers of hemolysis suggests that hemolysis may not play a substantial role in the pathogenesis of albuminuria in this population. Increased surveillance of children with SCD for renal complications can ultimately inform management strategies to improve outcomes and increase life expectancy among children with SCD. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Sphingomyelinase-like phosphodiesterase 3b mediates radiation-induced damage of renal podocytes.

The molecular mechanisms responsible for the development of proteinuria and glomerulosclerosis in radiation nephropathy remain largely unknown. Podocytes are increasingly recognized as key players in the pathogenesis of proteinuria in primary and secondary glomerular disorders. The lipid-modulating enzyme sphingomyelin phosphodiesterase acid-like 3B (SMPDL3b) is a key determinant of podocyte injury and a known off target of the anti-CD20 antibody rituximab (RTX). The current study investigates the role of sphingolipids in radiation-induced podocytopathy. After a single dose of radiation (8 Gy), several ceramide species were significantly elevated. In particular, C16:00, C24:00, and C24:1 ceramides were the most abundant ceramide species detected. These changes were paralleled by a time-dependent drop in SMPDL3b protein, sphingosine, and sphingosine-1-phosphate levels. Interestingly, SMPDL3b-overexpressing podocytes had higher basal levels of sphingosine-1-phosphate and maintained basal ceramide levels after irradiation. Morphologically, irradiated podocytes demonstrated loss of filopodia and remodeling of cortical actin. Furthermore, the actin binding protein ezrin relocated from the plasma membrane to the cytosol as early as 2 h after radiation. In contrast, SMPDL3b overexpressing podocytes were protected from radiation-induced cytoskeletal remodeling. Treatment with RTX before radiation exposure partially protected podocytes from SMPDL3b loss, cytoskeletal remodeling, and caspase 3 cleavage. Our results demonstrate that radiation injury induces early cytoskeletal remodeling, down-regulation of SMPDL3b, and elevation of cellular ceramide levels. Overexpression of SMPDL3b and pretreatment with RTX confer a radioprotective effect in cultured podocytes. These findings indicate a potential role for SMPDL3b and RTX in radiation-induced podocytopathy.-Ahmad, A., Mitrofanova, A., Bielawski, J., Yang, Y., Marples, B., Fornoni, A., Zeidan, Y. H. Sphingomyelinase-like phosphodiesterase 3b mediates radiation-induced damage of renal podocytes.

Pathogenesis of proteinuria in idiopathic minimal change disease: molecular mechanisms.

Minimal change disease (MCD) is the most common type of nephrotic syndrome in children and adolescents. The pathogenesis of proteinuria in this condition is currently being reassessed. Following the Shalhoub hypothesis, most efforts have been placed on identifying the putative circulating factor, but recent advancement in podocyte biology has focused attention on the molecular changes at the glomerular capillary wall, which could explain the mechanism of proteinuria in MCD. This report critically reviews current knowledge on the different postulated mechanisms at the glomerular capillary wall level for increased permeability to plasma proteins in MCD. The report helps describe the rationale behind novel therapies and suggests future targeted therapies for MCD.

ManNAc, a new therapeutic agent to reduce Angptl4-induced proteinuria in MCD

Current therapies used in minimal change disease (MCD) were originally designed to cure other diseases. They are only partially efficient, and present inconvenient side effects. Therefore, understanding the molecular mechanisms implicated in the pathogenesis of proteinuria in MCD could lead to new therapeutic strategies. A new experimental transgenic rat model of human MCD was generated. These NPHS2-Angptl4 transgenic rats over-express two different forms of the glycoprotein Angptl4 from the podocyte. The majority of the protein shows a lack of sialylation that is implicated in the pathogenesis of proteinuria. Supplementation of ManNAc, a precursor of sialic acid, significantly reduces albuminuria in those rats by increasing sialylation of the hyposialylated form of Angptl4. After treatment of the first episode of MCD with glucocorticoids in patients, ManNAc could be used as a maintenance drug, especially to reduce the frequency and intensity of relapse. ManNAc is a promising therapeutic agent for patients with MCD.

Capillary Rarefaction Associates with Albuminuria: The Maastricht Study.

Albuminuria may be a biomarker of generalized (i.e., microvascular and macrovascular) endothelial dysfunction. According to this concept, endothelial dysfunction of the renal microcirculation causes albuminuria by increasing glomerular capillary wall permeability and intraglomerular pressure, the latter eventually leading to glomerular capillary dropout (rarefaction) and further increases in intraglomerular pressure. However, direct evidence for an association between capillary rarefaction and albuminuria is lacking. Therefore, we examined the cross-sectional association between the recruitment of capillaries after arterial occlusion (capillary density during postocclusive peak reactive hyperemia) and during venous occlusion (venous congestion), as assessed with skin capillaroscopy, and albuminuria in 741 participants of the Maastricht Study, including 211 participants with type 2 diabetes. Overall, 57 participants had albuminuria, which was defined as a urinary albumin excretion ≥30 mg/24 h. After adjustment for potential confounders, participants in the lowest tertile of skin capillary recruitment during postocclusive peak reactive hyperemia had an odds ratio for albuminuria of 2.27 (95% confidence interval, 1.07 to 4.80) compared with those in the highest tertile. Similarly, a comparison between the lowest and the highest tertiles of capillary recruitment during venous congestion yielded an odds ratio of 2.89 (95% confidence interval, 1.27 to 6.61) for participants in the lowest tertile. In conclusion, lower capillary density of the skin microcirculation independently associated with albuminuria, providing direct support for a role of capillary rarefaction in the pathogenesis of albuminuria.