Glomerular Capillary Wall Research Articles

Glomerular Capillary Hypertrophy in the Diabetic Rat Normalizes Wall Shear Stress: A Modeling Study

Diabetes mellitus (DM) reduces renal hemodynamic autoregulation, leading to increased glomerular pressure (ΔP) and afferent plasma flow (Qa) which is assumed to increase glomerular capillary wall shear stress (SS). However, glomerular capillaries undergo hypertrophy in DM, causing an increase in capillary diameter that would theoretically reduce capillary wall SS (Seyer‐Hansen, Kjartan. Kid. Int. 23.4 (1983): 643–646.). The actual magnitudes of SS in the glomerular capillaries have not been estimated in DM and are of significance because in response to increased SS, endothelial cells increase expression of adhesion molecules and growth factors associated with glomerulopathy.We developed a mathematical model of blood flow through an anatomically‐accurate rat glomerular capillary network to estimate the magnitudes of SS on the glomerular capillary walls in DM and control. Individual filtration rates and wall SS were calculated for each capillary segment of the network based on values of Qa, ΔP and single nephron GFR (SNGFR) obtained from micropuncture studies. To validate mechanical predictions of our model, we compared our calculated SS magnitudes to results from intravital imaging studies of blood flow in rat glomeruli (Ferrell, Nicholas, et al. Am. J. Physiology‐Renal 308.6 (2015): F588‐F593.). To calculate SS magnitudes in the rat glomerulus in control and DM, we performed simulations with parameters obtained from micropuncture studies using normal rats and rats with streptozotocin induced Type I diabetes. In this study, DM increased Qa and ΔP by 74.6% and 33.3%, respectively but reduced the filtration coefficient (Kf) such that filtration fraction (FF) was maintained (Zatz, Roberto, et al. J. clin. Inv. 77.6 (1986): 1925–1930).The model was calibrated using an algorithm previously described (Remuzzi, Andrea, et al. Am. J. Physiology‐Renal 263.3 (1992): F562‐F572). Our model's calculated mean glomerular capillary wall SS was within 10% of the mean SS predicted using intravital imaging, validating our model for use in predicting mechanical aspects of blood flow in the glomerulus. Our simulations demonstrated a wide variance in SS throughout the glomerular capillary network, consistent with previous modeling results. Using parameters from micropuncture experiments and taking into account hypertrophy of the glomerular capillaries, the model predicted mean SS values of 42.1 dynes/cm2 in control and 42.3 dynes/cm2 in DM.We have developed and validated an anatomically‐accurate mathematical model of glomerular filtration for use in predicting functional and mechanical results of varied glomerular pressure, afferent plasma flow and Kf. Using this model, we demonstrated that hypertrophy of the capillaries normalizes capillary wall SS in DM, which may be a protective mechanism limiting the increase in SS and the consequent glomerular injury.Support or Funding InformationThis work was supported by the National Institute of General Medical Sciences IDeA Program (CoBRE P30GM103337) (principal investigator: L. G. Navar) O. Richfield is a graduate student supported by NSF IGERT Grant NSF DGE‐1144646.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Development of the Kidney Glomerular Filtration Barrier

The kidney glomerular capillary wall filters blood plasma, yielding a dilute filtrate that is subsequently modified and concentrated by the nephron tubular epithelium during the process of urine formation. The glomerular filtration barrier itself consists of: (a) an inner fenestrated vascular endothelium; (b) outer epithelial podocyte layer with regular, interdigitating cytoplasmic extensions (foot processes) and associated slit diaphragms; and (c) an intervening basement membrane between the endothelial and podocyte layers (glomerular basement membrane [GBM]). This unique three‐layered structure restricts passage of plasma albumin, which, along with larger serum proteins, are retained in the circulation, and only trace amounts are normally found in the proximal filtrate.Exactly how the filtration barrier operates is debated, but damage to any one layer results in loss of albumin and larger proteins into the urine (proteinuria), and, ultimately, can cause renal failure. Our work has focused on examining morphogenesis of the glomerulus and assembly of the GBM. To address these questions, and among other approaches, we grafted embryonic‐day 12 transgenic mouse kidneys bearing transcriptional reporters into newborn wildtype or mutant kidneys (where nephrogenesis is still underway), and examined the resulting hybrid tissues for mutation correction.We and others showed that glomerular endothelial cells derive from angioblasts within metanephroi, podocytes develop from metanephric mesenchyme, and the GBM originates from fusion of subendothelial and sub‐podocyte basement membranes during glomerulogenesis. Further, the GBM of immature glomeruli contains collagen α1α2α1(IV) and laminin α1β1γ1. During glomerular maturation, these GBM isoforms are replaced by collagen α3α4α5(IV) and laminin α5β2γ1. Differentiating endothelial cells and podocytes synthesize collagen α1α2α1(IV) and both laminin isoforms, but collagen α3α4α5(IV) derives solely from maturing podocytes. Although mechanisms for collagen and laminin isoform substitutions are unknown, laminin transitioning is abrupt and precedes that for collagen IV, which occurs slowly. These developmentally distinct timetables suggest that different molecular and/or cellular controls account collagen IV and laminin isoform replacement.Why the GBM undergoes compositional changes during glomerular formation is also uncertain, but this may be important for acquisition of glomerular barrier properties. Patients with mutations to COL4A3, A4, and/or A5, which are genes that encode collagen α3α4α5 (IV), usually develop Alport syndrome, a condition presenting with proteinuria, abnormal GBM composition and GBM delamination, loss of podocyte foot processes, and progressive renal failure. Studies on the Col4a3 knockout mouse, an experimental model of Alport disease, are shedding light on how the GBM informs glomerular barrier development and maintenance.Support or Funding InformationFunds came from NIH grants P01DK065123 and P30GM122731.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Significance of subepithelial deposits in patients diagnosed with IgA nephropathy

Subepithelial deposits are observed in rare adult IgA nephropathy (IgAN) cases and are a key diagnostic finding in IgA-dominant infection-related glomerulonephritis (IgA-IRGN). Sometimes, it is difficult to distinguish IgA-IRGN from IgAN without a precise clinical history. We hypothesized that some IgA-IRGN cases might be diagnosed as IgAN with subepithelial deposits (IgAN-SD) and aimed to clarify the significance of subepithelial deposits in patients diagnosed with IgAN. We examined 464 patients diagnosed with IgAN at Nagasaki University Hospital and affiliated hospitals between 1996 and 2013. The differences in clinicopathological findings between IgAN-SD and IgAN with no subepithelial deposits (IgAN-NSD) were investigated. In addition to clinical data and typical IgAN pathological features, we analyzed complement levels, immunoglobulin localization, light chain staining patterns, and intramembranous deposits. There were 214 men and 250 women with a mean age of 38.8 ± 18.3 years. Subepithelial deposition was observed in 51 patients (11%). Compared to patients with IgAN-NSD, those with IgAN-SD had significantly lower mean serum protein (6.4 g/dL vs. 6.7 g/dL; p = 0.02), albumin (3.7 g/dL vs. 3.9 g/dL; p = 0.02), and complement (C3) (94 mg/dL vs. 103 mg/dL; p = 0.02) levels. Diffuse mesangial hypercellularity (M) (65% vs. 45%; p<0.01), endocapillary hypercellularity: (E) (43% vs. 28%; p = 0.03), and IgA staining in the glomerular capillary wall (22% vs. 8%; p<0.01) were more common in patients with IgAN-SD. The incidence of light chain lambda predominance was lower in patients with IgAN-SD (47% vs. 63%; p = 0.03). Hump-shaped subepithelial deposits and intramembranous deposits were observed in nine and 17 patients with IgAN-SD, respectively. Patients with IgAN-SD tended to have the characteristics of IgA-IRGN rather than IgAN-NSD. Since the therapeutic strategies for IgA-IRGN differ from those for IgAN, we should review the clinical history and pay careful attention to the clinical course in cases with atypical findings, such as subepithelial deposits.

Upregulated microRNAs in membranous glomerulonephropathy are associated with significant downregulation of IL6 and MYC mRNAs.

Membranous glomerulonephropathy (MGN) is a glomerulopathy characterized by subepithelial deposits of immune complexes on the extracapillary side of the glomerular basement membrane. Insertion of C5b-9 (complement membrane-attack complex) into the membrane leads to functional impairment of the glomerular capillary wall. Knowledge of the molecular pathogenesis of MGN is actually scanty. MicroRNA (miRNA) profiling in MGN and unaffected tissues was performed by TaqMan Low-Density Arrays. Expression of miRNAs and miRNA targets was evaluated in Real-Time polymerase chain reaction (PCR). In vitro transient silencing of miRNAs was achieved through transfection with miRNA inhibitors. Ten miRNAs (let-7a-5p, let-7b-5p, let-7c-5p, let-7d-5p, miR-107, miR-129-3p, miR-423-5p, miR-516-3p, miR-532-3p, and miR-1275) were differentially expressed (DE) in MGN biopsies compared to unaffected controls. Interleukin 6 (IL6) and MYC messenger RNAs (mRNAs; targets of DE miRNAs) were significantly downregulated in biopsies from MGN patients, and upregulated in A498 cells following let-7a-5p or let-7c-5p transient silencing. Gene ontology analysis showed that DE miRNAs regulate pathways associated with MGN pathogenesis, including cell cycle, proliferation, and apoptosis. A significant correlation between DE miRNAs and mRNAs and clinical parameters (i.e., antiphospholipid antibodies, serum creatinine, estimated glomerular filtration, proteinuria, and serum cholesterol) has been detected. Based on our data, we propose that DE miRNAs and their downstream network may be involved in MGN pathogenesis and could be considered as potential diagnostic biomarkers of MGN.

Development of membranoproliferative glomerulonephritis-like glomerulopathy in a patient with neutrophilia resulting from endogenous granulocyte-colony stimulating factor overproduction: a case report

BackgroundThe pathophysiologic role of exogenous granulocyte-colony stimulating factor (G-CSF) administration is reportedly linked to the progression of glomerulonephritis. However, the relationship between endogenous G-CSF overproduction and the progression of glomerulopathy has not been well investigated.Case presentationA 76-year-old woman presented with neutrophilia at a medical check-up and thorough examination revealed a high level of serum G-CSF. She subsequently developed mild renal dysfunction and proteinuria. Her renal biopsy showed lobulation of the glomeruli with mesangial proliferation and glomerular capillary walls with a double contour but no immune complex deposition, suggesting membranoproliferative glomerulonephritis-like glomerulopathy. Thereafter, her proteinuria levels fluctuated in parallel with the changes in her blood neutrophil count and finally reduced considerably in association with her decreased neutrophil count.ConclusionsThe unique features of this case suggest that endogenous overproduction of G-CSF could play an important role in the pathogenesis of active glomerulonephritis.

Urinary Alpha-1-Acid Glycoprotein Is a Sensitive Marker of Glomerular Protein Leakage at Altitude.

Talks, Ben J., Susie B. Bradwell, John Delamere, Will Rayner, Alex Clarke, Chris T. Lewis, Owen D. Thomas, and Arthur R. Bradwell. Urinary alpha-1-acid glycoprotein is a sensitive marker of glomerular protein leakage at altitude. High Alt Med Biol. 19:295–298, 2018.—Proteinuria is an established feature of ascent to altitude and may be caused by a loss of negative charges on glomerular capillary walls (GCWs). To test this hypothesis, we measured two similar sized but oppositely charged proteins in urine: negatively charged alpha-1-acid glycoprotein (α1-AGP, 41–43 kDa) and positively charged dimeric lambda free light chains (λ-FLCs, 50 kDa). Twenty-four-hour urinary leakage was compared with albumin, a 66 kDa negatively charged protein. We studied 23 individuals (ages 23–78 years, male = 17) at baseline (140 m) and daily during an expedition to 5035 m. The results showed a significant increase in median urinary leakage of α1-AGP (p < 0.0001; 6.85-fold) and albumin (p = 0.0006; 1.65-fold) with ascent to altitude, but no significant increase in leakage of λ-FLCs (p = 0.39; 1.14-fold). α1-AGP correlated with the daily ascent profile (p = 0.0026) and partial pressure of oxygen (p = 0.01), whereas albumin showed no correlation (p = 0.19). Urinary α1-AGP was a more sensitive marker of altitude proteinuria than urinary albumin and λ-FLCs, and supported the possibility of loss of GCW negative charges at altitude.

Complement activation associated with ADAMTS13 deficiency may contribute to the characteristic glomerular manifestations in Upshaw-Schulman syndrome

IntroductionUpshaw-Schulman syndrome (USS) is a congenital form of thrombotic thrombocytopenic purpura (TTP) associated with loss-of-function mutations in the ADAMTS13 gene, possibly leading to aberrant complement activation and vascular injury. However, USS is extremely rare, and there have been no systematic studies correlating histopathological severity with local ADAMTS13 expression and complement activation. Materials and methodsHere, we compared histopathological features, ADAMTS13 immunoreactivity, and immunoreactivity of complement proteins C4d and C5b-9 among renal biopsy tissues from five USS cases, ten acquired TTP cases, and eleven controls. ResultsPathological analysis revealed chronic glomerular sclerotic changes in the majority of USS cases (4 of 5), with minor glomerular pathology in the remaining case. In two of these four severe cases, more than half of the glomerular segmental sclerosis area was localized in the perihilar region. The average number of ADAMTS13-positive cells per glomerulus was significantly lower in USS cases than controls (p < 0.05). Conversely, C4d staining was significantly more prevalent in the glomerular capillary walls of USS cases than controls (p < 0.05), while C5b-9 staining did not differ significantly among groups. ConclusionsThese findings suggest that the severity of glomerular injury in USS is associated with deficient ADAMTS13 expression and local complement activation, particularly in vascular regions with higher endothelial shear stress. We suggest that C4d immunostaining provides evidence for complement-mediated glomerular damage in USS.

Optimization of Protein and Peptide Drugs Based on the Mechanisms of Kidney Clearance.

Development of proteins and peptides into drugs has been considered as a promising strategy to target certain diseases. However, only few proteins and peptides have been approved as new drugs into the market each year. One major problem is that proteins and peptides often exhibit short plasma half-life times, which limits the application for their clinical use. In most cases a short half-life time is not effective to deliver sufficient amount of drugs to the target organs and tissues, which is generally caused by fast renal clearance and low plasma stability due to proteolytic degradation during systemic circulation, because that the most common clearance pathway of small proteins and peptides is through glomerular filtration by the kidneys. In this review, enzymatic degradation of proteins and peptides were discussed. Furthermore, several approaches to lengthen the half-life of peptides and proteins drugs based on the unique structures of glomerular capillary wall and the mechanisms of glomerular filtration were summarized, such as increasing the size and hydrodynamic diameter; increasing the negative charge to delay the filtration; increasing plasma protein binding to decrease plasma clearance.

What Is the Glomerular Ultrafiltration Barrier?

Since the unique features of the three-layered glomerular capillary wall between the blood and the urine were first visualized by electron microscopy, the identity of the definitive components that restrict the filtration of albumin, Igs, and other large plasma constituents has been controversial.

Directed differentiation of human induced pluripotent stem cells into mature kidney podocytes and establishment of a Glomerulus Chip.

Protocols have been established to direct the differentiation of human induced pluripotent stem (iPS) cells into nephron progenitor cells and organoids containing many types of kidney cells, but it has been difficult to direct the differentiation of iPS cells to form specific types of mature human kidney cells with high yield. Here, we describe a detailed protocol for the directed differentiation of human iPS cells into mature, post-mitotic kidney glomerular podocytes with high (>90%) efficiency within 26 d and under chemically defined conditions, without genetic manipulations or subpopulation selection. We also describe how these iPS cell-derived podocytes may be induced to form within a microfluidic organ-on-a-chip (Organ Chip) culture device to build a human kidney Glomerulus Chip that mimics the structure and function of the kidney glomerular capillary wall in vitro within 35 d (starting with undifferentiated iPS cells). The podocyte differentiation protocol requires skills for culturing iPS cells, and the development of a Glomerulus Chip requires some experience with building and operating microfluidic cell culture systems. This method could be useful for applications in nephrotoxicity screening, therapeutic development, and regenerative medicine, as well as mechanistic study of kidney development and disease.

Clinical and prognostic significance of glomerular C1q deposits in primary MN

BackgroundAlthough complement activation is believed to be important in mediating PMN, the pathways involved and clinical consequences remain controversial. Many cases of idiopathic or primary membranous nephropathy (PMN) present with subepithelial C1q deposits along with IgG and C3 on glomerular capillary walls but without deposits of IgA or IgM (“full house”) by immunofluorescence or any causes of secondary MN. We sought to define the clinical and pathological significance of these C1q deposits in PMN by comparing a variety of clinical parameters, outcomes and other serum and urine factors in patients with and without significant glomerular C1q deposits. MethodsTwo-hundred eighty-eight patients with biopsy-proven PMN were enrolled. We compared the clinical and pathological features, treatment responses and kidney outcomes, between patients with and without C1q deposition. Circulating anti-PLA2R antibodies and complement components in plasma and urine were detected by ELISA. ResultsGlomerular C1q deposition was detected on capillary walls by immunofluorescence in 66/288 (22.9%) patients. C1q-positive patients presented with lower concentrations of serum IgG (5.3 ± 3.1 vs. 6.6 ± 3.5 g/l, p = 0.008), a higher frequency of IgA (37.9% vs. 15.8%, p < 0.001), IgM (48.5% vs. 31.5%, p = 0.011) and C3c (100% vs. 88.3%, p = 0.004) deposits in glomeruli and more stage III of MN (24.2% vs. 11.7%, p < 0.001) by pathologic criteria. Other features, including gender, age, anti-PLA2R antibody positivity and concentrations, proteinuria, albumin and serum creatinine, were not different between the patients with and without C1q deposition (p > 0.05). The IgG subclasses of anti-PLA2R antibodies in circulation or in glomeruli showed no difference (p > 0.05). C1q deposition, and C1q concentrations in circulation and urine had no apparent effect on the treatment responses or kidney outcomes (p > 0.05). ConclusionThe classical pathway of complement is activated in some patients with PMN, but may not play an essential role in mediating the kidney injury seen in this disease.

Cobalamin C Deficiency Induces a Typical Histopathological Pattern of Renal Arteriolar and Glomerular Thrombotic Microangiopathy

IntroductionCobalamin C (cblC) deficiency is the most common inborn error of vitamin B12 metabolism. Renal failure attributed to thrombotic microangiopathy (TMA) has occasionally been described in the late-onset presentation of cblC deficiency, but kidney lesions associated with cblC deficiency remain poorly defined. This study aims to describe the characteristics of kidney disease in cblC deficiency, and to provide a comparative histological analysis with cblC-independent renal TMA.MethodsWe performed a multicenter retrospective study including 7 patients with cblC deficiency and 16 matched controls with cblC-independent TMA. The patients included were aged 6 to 26 years at the time of the first manifestations. All patients presented with acute renal failure, proteinuria, and hemolysis; 5 patients required dialysis.ResultsThe histological study revealed arteriolar and glomerular TMA in all patients. After comparison with the cblC-independent TMA control group, a vacuolated aspect of the glomerular basement membrane and the intensity of glomerular capillary wall IgM deposits were more present in cblC deficiency patients than in controls. Six patients were treated with hydroxycobalamin. All of them improved, with disappearance of hemolysis, and 3 of the 4 patients requiring renal replacement therapy were weaned off dialysis.ConclusionThis study provides a precise description of kidney pathology in cblC deficiency. Due to major therapeutic implications, we suggest that patients with renal TMA be screened for cblC deficiency regardless of age, particularly when the kidney biopsy provides evidence of long-lasting TMA, including a vacuolated aspect of the glomerular basement membrane and glomerular capillary wall IgM deposition.

IgA kappa light and heavy chain deposition disease in multiple myeloma.

A 46-year-old patient was referred to our unit with acute renal failure, his serum creatinine having risen from 137 to 431 μmol/l in eight months. He was born in the Republic of the Congo and had lived in France since 2009. He had no significant previous medical history. On admission, clinical examination was normal except for high blood pressure. Blood analyses confirmed renal impairment. Urine analyses were significant for proteinuria (urinary protein to creatinine ratio 1 g/g), haematuria (105 red cells/ml) and leucocyturia (104 white cells/ml). Serum protein electrophoresis revealed an M-spike and urine protein electrophoresis showed light-chain proteinuria. The paraprotein was identified by immunofixation as immunoglobulin (Ig) A kappa. Bone marrow examination showed 28% clonal plasma cells. Kidney biopsy revealed Congo red-negative thickening of glomerular capillary walls and tubular basement membranes, with peritubular multinucleated giant cells (top left). Electron microscopy showed granular electron-dense material along the lamina rara interna of the glomerular capillary walls and along the outer aspect of the tubular basement membranes (top right). Immunofluorescence confirmed the diagnosis of light and heavy chain deposition disease (LHCDD) by demonstrating staining for IgA heavy chain (bottom left) and kappa light chain (bottom right), without staining for lambda light chain. Haemodialysis was initiated and the patient received first line chemotherapy with bortezomib, cyclophosphamide and dexamethasone. Eight months later, he exhibited an excellent partial haematological response. However, his renal function did not improve and he still required dialysis. Light and heavy chain deposition disease is a very uncommon subtype of monoclonal immunoglobulin deposition disease and only small numbers of cases of IgA kappa LHCDD have been reported. The authors thank the HUPNVS of Assistance Publique - Hôpitaux de Paris for funding publication fees.

A portable culture chamber for studying the effects of hydrostatic pressure on cellular monolayers

Hydrostatic pressure is one of the most fundamental and common mechanical stimuli in the body, playing a critical role in the homeostasis of all organ systems. Kidney function is affected by high blood pressure, namely hypertension, by the increased pressure acting on the glomerular capillary walls. This general effect of hypertension is diagnosed as a chronic disease, but underlying mechanistic causes are still not well understood. This paper reports a portable and adaptive device for studying the effects of hydrostatic pressure on a monolayer of cells. The fabricated device fits within a conventional incubation system and microscope. The effects of various pressures and durations were evaluated on a confluent layer of human endothelial cells. We found that a fluid pressure (i.e. hydrostatic pressure) can alter the morphology of the cells and that returning to an ambient pressure can reverse the changes in morphology. Thus, this study provides a proof-of-principle demonstration that this tool can be utilized for exploring the effects of hydrostatic pressure on mammalian cells.

Inverse correlation between vascular endothelial growth factor back-filtration and capillary filtration pressures

Vascular endothelial growth factor A (VEGF) is an essential growth factor during glomerular development and postnatal homeostasis. VEGF is secreted in high amounts by podocytes into the primary urine, back-filtered across the glomerular capillary wall to act on endothelial cells. So far it has been assumed that VEGF back-filtration is driven at a constant rate exclusively by diffusion. In the present work, glomerular VEGF back-filtration was investigated in vivo using a novel extended model based on endothelial fenestrations as surrogate marker for local VEGF concentrations. Single nephron glomerular filtration rate (SNGFR) and/or local filtration flux were manipulated by partial renal mass ablation, tubular ablation, and in transgenic mouse models of systemic or podocytic VEGF overexpression or reduction. Our study shows positive correlations between VEGF back-filtration and SNGFR as well as effective filtration rate under physiological conditions along individual glomerular capillaries in rodents and humans. Our results suggest that an additional force drives VEGF back-filtration, potentially regulated by SNGFR.

The features in IgA-dominant infection-related glomerulonephritis distinct from IgA nephropathy: a single-center study.

IgA-dominant infection-related glomerulonephritis (IgA-IRGN) is a unique form of IRGN, which needs to be distinguished from IgA nephropathy (IgAN). Thirteen patients with IgA-IRGN (IgA-IRGN group) and 122 with IgAN (IgAN group) were selected from 1788 patients who underwent kidney biopsy between 2000 and 2015 in Kitano Hospital. Data selected included clinical and serological parameters; light and electron microscope findings; immunofluorescence findings; and prognostic parameters like renal and overall survival and creatinine increase by > 50%. In addition, a 26-patient IgAN cohort (matching-IgAN), matching with IgA-IRGN group with respect to age, sex, estimated glomerular filtration rate (eGFR), and proteinuria was segregated for comparison. Compared to IgAN group, IgA-IRGN group were older, had lower hemoglobin, higher CRP, lower eGFR, heavier proteinuria, lower serum albumin, and higher serum IgG and IgA levels (p < 0.05). Endocapillary hypercellularity, deposition of immune complexes along the glomerular capillary wall, and subendothelial and subepithelial electron dense deposits were more frequently observed (p < 0.05); and they were more susceptible to renal dysfunction and poorer prognosis. After propensity score-matching, serum albumin was significantly lower in the IgA-IRGN group. Significantly subendothelial and subepithelial deposits were frequently observed in this group. Matching-IgAN group showed relatively advanced sclerotic lesions with more global sclerosis and fibrous crescent. Local inflammation involved glomerular capillary wall in IgA-IRGN, in contrast to relatively chronic and sclerotic renal lesion in IgAN, might result in poorer prognosis in former, even under indistinguishable condition of deteriorated renal function and proteinuria.

LCAT deficiency as a cause of proteinuria and corneal opacification

A 44-year-old woman was diagnosed with corneal dystrophy (figure 1) and anaemia. Analytically, she showed an altered lipid profile (cholesterol 172 mg/dL, triglycerides 173 mg/dL, high-density lipoprotein (HDL) cholesterol 6.6...

Fundus changes in type III membranoproliferative glomerulonephritis: a case report

BackgroundMembranoproliferative glomerulonephritis (MPGN) is characterized by mesangial cell proliferation and is classified into types I, II and III based on structural changes in the glomerular capillary walls. The drusen-like deposits of MPGN type II have been studied, but the fundus changes in MPGN type III have yet to be clarified. We report a case of MPGN type III with multiple deposits in the retinal pigment epithelium (RPE).Case presentationA 40-year-old Japanese woman with MPGN type III developed numerous yellow-white patches in the central macula of both eyes. Optical coherence tomography (OCT) showed deposits between the RPE and Bruch’s membrane. Fluorescein angiography showed choroidal neovascularization (CNV) and OCT confirmed it as type 1 (sub RPE) CNV with fibrin tissue and subretinal fluid in the right eye. After 12 months, the CNV and subretinal fluid resolved spontaneously but the RPE deposits remained in both eyes. Her final visual acuity was 20/20 in the right eye and 20/16 in the left eye.ConclusionWe report a case of MPGN type III with multiple deposits in the RPE and CNV, suggesting that various fundus changes occur in MPGN type III and careful fundus follow-up is necessary to prevent vision loss.

Low molecular weight heparin may benefit nephrotic remission in steroid‑sensitive nephrotic syndrome via inhibiting elastase.

Low molecular weight heparin (LMWH) has a structure similar to heparan sulfate, which exerts anti-inflammatory effects via inhibiting elastase (Ela) activity. Release of Ela along the glomerular capillary wall may induce glomerular injury and proteinuria. The present study aimed to investigate the influence of LMWH on steroid-sensitive nephrotic syndrome (SSNS) and the potential underlying mechanism. A total of 40 SSNS patients and 20 healthy controls were recruited. SSNS patients were treated with LMWH and prednisone simultaneously (LMWH+pred group) or with prednisone alone (pred group). Proteinuria, urinary glycosaminoglycans (GAGs), serum Ela and urinary creatinine levels were measured. The nephrotic period of SSNS was 15.93±5.78 days. The nephrotic period of SSNS in LMWH+pred group was significantly reduced compared with the pred group (14.13±4.56 vs. 18.63±6.49 days; P<0.05). At the follow-up of the SSNS patients, there was no statistically significant difference in number of relapses between the LMWH+pred and pred groups. Proteinuria (2.51±0.97 g/24 h), urinary GAG levels (4.92±0.87 mg/mmol creatinine) and serum Ela levels (77.64±10.99 ng/l) were significantly greater in the nephrotic period of SSNS compared with the remission period (0.107±0.026 g/24 h, 1.53±0.27 mg/mmol Cr and 41.92±7.81 ng/l, respectively) and the healthy control group (0.098±0.027 g/24 h, 1.40±0.26 mg/mmol creatinine and 38.43±9.83 ng/l, respectively; P<0.05). During the remission period, urinary GAG and serum Ela levels in the LMWH+pred group were significantly reduced compared with the pred group (P<0.05), whereas proteinuria did not differ between these groups (P>0.05). Positive correlations were revealed between urinary GAG excretion and proteinuria (r=0.877; P<0.05), proteinuria and serum Ela levels (r=0.844; P<0.05) and serum Ela levels and urinary GAG excretion (r=0.881; P<0.05). The results of the present study indicated that elevated serum Ela levels may induce proteinuria by degrading GAGs in the glomerular basement membrane in children with SSNS. LMWH may benefit nephrotic remission of SSNS via inhibiting Ela.

Location of glomerular immune deposits, not codeposition of immunoglobulin G, influences definitive renal outcomes in immunoglobulin A nephropathy.

It has been suggested that the prognosis of immunoglobulin (IgA) nephropathy (IgAN) is adversely affected if there is codeposition of IgG in the glomeruli or if immune deposits are present in the glomerular capillary walls. We sought to understand how these variables affect clinical outcome. A total of 80 IgAN biopsies were retrospectively divided into groups: (i) IgA without IgG deposition versus IgA + IgG and (ii) immune deposits restricted to the mesangium versus mesangium and peripheral capillary walls (PCWs). The association of these groups with the composite primary outcome of renal replacement therapy, renal transplant, death or doubling of serum creatinine (SCr) concentration was determined. The change in estimated glomerular filtration rate (eGFR) was also assessed. Covariates examined were age, sex, race, SCr and proteinuria level at biopsy and at follow-up, duration of follow-up, treatment, Oxford score and presence of crescents. IgG codeposition showed a trend toward endocapillary hypercellularity (P = 0.082); there were no other baseline differences between the IgA (n = 55) and IgA + IgG (n = 25) groups. At a median follow-up time of 29 months, the combined primary outcome was reached in 24 patients, 16 with IgA and 8 with IgA + IgG (P = 0.82). Patients with immune deposits in the PCWs (n = 21) presented with higher baseline proteinuria than those with deposits limited to the mesangium (n = 59; P = 0.025), were more likely to have crescents/segmental glomerular necrosis on biopsy (P = 0.047) and were more likely to reach the combined primary outcome (P = 0.026). Biopsies with crescents/segmental glomerular necrosis were associated with endocapillary hypercellularity (P < 0.001). In this multicenter IgAN cohort, IgG co-deposition and the location of glomerular immune deposits in the PCWs were both associated with greater histologic activity on renal biopsy, but only the location of glomerular immune deposits in the PCWs was associated with a significantly increased risk for end-stage renal disease, transplant, death and/or doubling of SCr.