Proteinuria In Glomerular Diseases Research Articles

Obesity at Time of Diagnosis Is Associated with Proteinuria in Glomerular Disease

Obesity at Time of Diagnosis Is Associated with Proteinuria in Glomerular Disease

MO227RELATIONSHIP BETWEEN KIDNEY DAMAGE AND COGNITIVE FUNCTIONS IN PATIENTS WITH GLOMERULOPATHIES

Abstract Background and Aims Mild Cognitive Impairment (MCI) has been found to be highly prevalent amongst patients with Chronic Kidney Disease (CKD). In this cohort, the prevalence of MCI was estimated to be between 30% and 63%. Mild cognitive impairment is an intermediate state between normal aging and dementia. An individual suffering from MCI has difficulty in remembering, sustaining attention, or decision making which can negatively affect their daily lives. The aim of this study was to verify the role of different glomerular diseases diagnosed by kidney biopsy on the MCI through a retrospective study. Method We recruited 45 patients with bioptic diagnosis of the following glomerular diseases: Focal Segmental Glomerulo Sclerosis (FSGS), minimal change disease (MCD), membranous glomerular disease (MG), IgA nephropathy. The renal function was analyzed using clinical variables, while Cognitive functions using the MoCA test. Patients were divided into two groups based on 24h proteinuria. Results The MoCA score was directly correlated to the uric acid levels (R=0.13; p=0.03). The MoCa score in the group with higher proteinuria levels was significantly lower than those of the group with lower proteinuria levels (p = 0.03). Finally, the MoCA score in subjects with FSGS or MCD is significantly higher compared the other groups (p<0.05). Conclusion Our data suggest that serum uric acid and proteinuria in glomerular diseases influence cognitive functions. Interestingly, uric acid plays a neuroprotective role, as low levels of uric acid reduce the MoCA score. This result agrees with previous observations of a protective role of uric acid on dopamine neurons. Conversely, the extent proteinuria seems to negatively affect cognitive functions, suggesting a role of the endothelial dysfunction. Finally, glomerulopathies with a lower degree of inflammation (FSGS, MCD) have minor impact on cognitive functions.

MicroRNA-466o-3p mediates β-catenin-induced podocyte injury by targeting Wilms tumor 1.

Podocytes are highly specialized cells that play an essential role in maintaining the integrity and function of the glomerular filtration barrier. Wilms tumor 1 (WT1) and β-catenin are two master regulators that play opposing roles in podocyte biology and mutually antagonize each other. However, exactly how β-catenin inhibits WT1 remains incompletely understood. In this study, we demonstrated the role of miR-466o-3p in mediating β-catenin-triggered podocyte injury by targeting WT1. The expression of miR-466o-3p was upregulated in cultured podocytes after β-catenin activation and in glomerular podocytes in adriamycin (ADR) nephropathy, remnant kidney after 5/6 renal ablation, and diabetic kidney disease. Bioinformatics analysis and luciferase reporter assay confirmed that miR-466o-3p directly targeted WT1 mRNA. Furthermore, overexpression of miR-466o-3p downregulated WT1 protein and promoted podocyte injury in vitro. Conversely, inhibition of miR-466o-3p alleviated β-catenin-induced podocyte dysfunction. In mouse model of ADR nephropathy, overexpression of miR-466o-3p inhibited WT1, aggravated podocytes injury and deteriorated proteinuria. In contrast, inhibition of renal miR-466o-3p by antagomiR, either prior to or after ADR injection, substantially restored WT1, alleviated podocytes injury and reduced renal fibrosis. These studies reveal a critical role for miR-466o-3p, a novel microRNA that has not been characterized previously, in mediating β-catenin-triggered WT1 inhibition. Our findings also uncover a new pathogenic mechanism by which β-catenin promotes podocyte injury and proteinuria in glomerular diseases.

Increased dynamin expression precedes proteinuria in glomerular disease.

Dynamin plays an essential role in maintaining the structure and function of the glomerular filtration barrier. Specifically, dynamin regulates the actin cytoskeleton and the turnover of nephrin in podocytes, and knocking down dynamin expression causes proteinuria. Moreover, promoting dynamin oligomerization with Bis‐T‐23 restores podocyte function and reduces proteinuria in several animal models of chronic kidney disease. Thus, dynamin is a promising therapeutic target for treating chronic kidney disease. Here, we investigated the pathophysiological role of dynamin under proteinuric circumstances in a rat model and in humans. We found that glomerular Dnm2 and Dnm1 mRNA levels are increased prior to the onset of proteinuria in a rat model of spontaneous proteinuria. Also, in zebrafish embryos, we confirm that knocking down dynamin translation results in proteinuria. Finally, we show that the glomerular expression of dynamin and cathepsin L protein is increased in several human proteinuric kidney diseases. We propose that the increased expression of glomerular dynamin reflects an exhausted attempt to maintain and/or restore integrity of the glomerular filtration barrier. These results confirm that dynamin plays an important role in maintaining the glomerular filtration barrier, and they support the notion that dynamin is a promising therapeutic target in proteinuric kidney disease. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Potential signaling pathway and molecular mechanism of CD2AP associated with proteinuria in glomerular disease

Potential signaling pathway and molecular mechanism of CD2AP associated with proteinuria in glomerular disease

Podocyte and endothelial cell injury lead to nephrotic syndrome in proliferative lupus nephritis.

Nephrotic syndrome (NS) is a major manifestation of lupus nephritis (LN). The dysregulation of podocytes, the glomerular basement membrane (GBM) and endothelial cells (ECs) results in proteinuria in glomerular diseases. The aim of our study was to clarify whether the dysregulation of these barriers is associated with NS in proliferative LN and membranous LN. Fifty-six patients with NS, including minimal change NS in 15, primary membranous nephropathy (PMN) in 13, class III/IV LN in 15, and class V LN in 13, were enrolled in this study. Subjects with idiopathic haematuria were assigned as controls. Glomerular expression of Wilms tumour protein 1 (WT1), nephrin, synaptopodin and podocalyxin was evaluated by immunohistochemistry (IHC) and real-time quantitative reverse transcription polymerase chain reaction. EC injury was evaluated by CD31 immunostaining and electron microscopy (EM). Reduced expression of WT1, nephrin and synaptopodin was found in PMN, class III/IV LN and class V LN as compared with controls by IHC and mRNA analysis. Reduced expression of these molecules was not different between class III/IV LN and class V LN. Reduced numbers of CD31-positive ECs were found in class III/IV LN as compared with class V LN. EC injury showing subendothelial widening on EM was apparent in class III/IV LN as compared with class V LN. Foot process effacement was found only along the GBM showing EC injury in class III/IV LN. Our study suggests that coexistence of podocyte and EC injury may lead to NS in proliferative LN. Podocyte damage alone leads to NS in membranous LN.

Determination of the optimal target level of proteinuria in the management of patients with glomerular diseases by using different definitions of proteinuria.

Proteinuria is a major determinant of adverse renal outcome, and its reduction slows renal progression in glomerular diseases. However, the optimal target of proteinuria in glomerular diseases is unclear, and discrepancies in the definition of proteinuria produce ambiguous findings. Here we investigated the optimal target of proteinuria by using different definitions of proteinuria. We analyzed 574 IgA nephropathy (IgAN), 175 membranous nephropathy (MGN), and 177 focal segmental glomerulosclerosis (FSGS) cases from 3 Korean kidney centers. We evaluated the impact of proteinuria on renal outcome with 2 definitions: time-average proteinuria (TAP) and time-varying proteinuria (TVP). The endpoint was renal progression, defined as a 50% decline in glomerular filtration rate or end-stage renal disease. During a median follow-up of 57.3 months, the primary outcome occurred in 54 patients with IgAN, 26 with MGN, and 30 with FSGS. Multivariate Cox regression using TAP indicated that there was a linear association between proteinuria and risk of renal progression in IgAN. However, moderate proteinuria was not associated with an increased risk of renal progression in MGN and FSGS. In contrast, the analysis by TVP showed that the risk significantly increased in proportion to proteinuria during follow-up in all 3 diseases. Our findings suggest that TVP-based model can delineate association between proteinuria and risk of renal progression better than TAP-based model, considering that TVP reflects the dynamic change of proteinuria over time. Thus, proteinuria reduction to the lowest possible level is required to improve renal outcomes in patients with glomerular diseases.

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.

Long-term data on tacrolimus treatment in lupus nephritis.

Calcineurin inhibitors are effective immunosuppressants. They also reduce proteinuria in glomerular diseases but are potentially nephrotoxic. Short-term data suggest that tacrolimus (TAC) combined with corticosteroids is effective in LN, but long-term data are lacking. This study examined the long-term outcomes and tolerability of TAC for the treatment of LN. We retrospectively reviewed 29 LN patients who received TAC treatment for 46.9 months (s.d. 37.9). In 17 patients with class III/IV or V LN and persistent proteinuria >2 g/day despite induction immunosuppression, response rates after 12 and 24 months of add-on TAC treatment were 66.7% and 80.0%, respectively. In 10 patients with nephrotic syndrome due to class V LN who were given prednisolone and TAC as initial treatment, the response rate was 60.0% and 90.0% after 12 and 24 months, respectively. TAC facilitated steroid minimization in two patients with lupus podocytopathy. As a group, proteinuria decreased from 3.6 g/day (s.d. 2.6) to 1.0 (s.d. 1.1) (P < 0.05). Four patients developed end-stage renal failure, with 3-, 5- and 8-year renal survival rates of 93%, 83% and 83%, respectively. In the remaining patients, serum creatinine and estimated GFR remained stable after 36 months. One patient with pre-existing chronic renal failure developed TAC nephrotoxicity. Four renal flares occurred, all associated with low TAC blood levels. Six patients (20.1%) had deterioration of hypertension and one patient (3.4%) had new-onset diabetes mellitus. Six patients (20.1%) had infections that required hospitalization. Two deaths occurred: one due to pneumonia and one to breast cancer. The results suggest efficacy of TAC in LN, especially in reducing proteinuria, and its role as a long-term maintenance agent warrants further investigation.

Proteinuria in Chronic Kidney Disease and its Management

Proteinuria is a marker of kidney damage and an important risk factor for progression of chronic kidney disease as well as cardiovascular morbidity and mortality. Albumin is the principal component of proteinuria in glomerular disease. The presence of persistent albumin in the urine is a clear sign of glomerular abnormality. Microalbuminuria describes the urinary excretion of small amounts of albumin which identifies the very early stage of diabetic kidney disease. The albumin creatinine ratio is the preferred method of detecting microalbuminuria. There is strong evidence that treatment in the early stages of chronic kidney disease reduces progression of kidney damage. The levels of proteinuria in both diabetic and non-diabetic kidney disease at which management should be addressed have been reviewed. This article also reviews the interventions recommended for early stages of chronic kidney disease to reduce the risk of progression to end stage kidney failure. Angiotensin converting enzyme inhibitors and angiotensin 2 receptor blockers are more effective in reducing proteinuria and retarding the progression of kidney disease in comparison to other therapies which lower systemic blood pressure to a similar degree. DOI: http://dx.doi.org/10.3329/medtoday.v25i1.16070 Medicine Today 2013 Vol.25(1): 36-41

Reactive oxygen species modulate the barrier function of the human glomerular endothelial glycocalyx.

Reactive oxygen species (ROS) play a key role in the pathogenesis of proteinuria in glomerular diseases like diabetic nephropathy. Glomerular endothelial cell (GEnC) glycocalyx covers the luminal aspect of the glomerular capillary wall and makes an important contribution to the glomerular barrier. ROS are known to depolymerise glycosaminoglycan (GAG) chains of proteoglycans, which are crucial for the barrier function of GEnC glycocalyx. The aim of this study is to investigate the direct effects of ROS on the structure and function of GEnC glycocalyx using conditionally immortalised human GEnC. ROS were generated by exogenous hydrogen peroxide. Biosynthesis and cleavage of GAG chains was analyzed by radiolabelling (S35 and 3H-glucosamine). GAG chains were quantified on GEnC surface and in the cell supernatant using liquid chromatography and immunofluorescence techniques. Barrier properties were estimated by measuring trans-endothelial passage of albumin. ROS caused a significant loss of WGA lectin and heparan sulphate staining from the surface of GEnC. This lead to an increase in trans-endothelial albumin passage. The latter could be inhibited by catalase and superoxide dismutase. The effect of ROS on GEnC was not mediated via the GAG biosynthetic pathway. Quantification of radiolabelled GAG fractions in the supernatant confirmed that ROS directly caused shedding of HS GAG. This finding is clinically relevant and suggests a mechanism by which ROS may cause proteinuria in clinical conditions associated with high oxidative stress.

Angiopoietin-Like 3 Induces Podocyte F-Actin Rearrangement through IntegrinαVβ3/FAK/PI3K Pathway-Mediated Rac1 Activation

Glomerular podocytes are highly differentiated cells whose foot processes, which are mainly maintained by the architecture of actin filaments, have a unique morphology. A rearrangement of F-actin in podocytes causes changes in their motility that involve foot process effacement and proteinuria in glomerular diseases. Members of the Rho family small GTPases, especially RhoA, Rac1, and Cdc42, are key molecules in the regulation of actin cytoskeleton rearrangement. Our previous study showed that angiopoietin-like 3 (Angptl3) can increase the motility of podocytes in vitro. In this study, we found that recombinant Angptl3 treatment, together with the activation of Rac1, could cause F-actin rearrangement in podocytes. We also found that these effects could be blocked by an integrin α V β 3 inhibitor, implicating integrin α V β 3 as the Angptl3 receptor in its effects on actin cytoskeleton rearrangement. In addition, we studied the molecular pathway for this process. Our results showed that in podocytes, Angptl3 could induce actin filament rearrangement, mainly in lamellipodia formation, and that this process was mediated by integrin α V β 3-mediated FAK and PI3K phosphorylation and Rac1 activation. Our results might provide a new explanation for the effect of Angptl3 on increasing podocyte motility.

Transcriptional suppression of nephrin in podocytes by macrophages: Roles of inflammatory cytokines and involvement of the PI3K/Akt pathway

Expression of nephrin, a crucial component of the glomerular slit diaphragm, is downregulated in patients with proteinuric glomerular diseases. Using conditionally immortalized reporter podocytes, we found that bystander macrophages as well as macrophage-derived cytokines IL-1β and TNF-α markedly suppressed activity of the nephrin gene promoter in podocytes. The cytokine-initiated repression was reversible, observed on both basal and inducible expression, independent of Wilms’ tumor suppressor WT1, and caused in part via activation of the phosphatidylinositol-3-kinase/Akt pathway. These results indicated a novel mechanism by which activated macrophages participate in the induction of proteinuria in glomerular diseases.

Chemokines in Renal Diseases

The chemokines, members of a large family of chemotactic cytokines, act as directional cues for sorting inflammatory cell subsets to sites of inflammation or lymphoid microenvironments. In addition to their effects on migration, chemokines can also activate effector function in leukocytes and are involved in cell proliferation and angiogenesis. Therefore, it is not surprising that chemokines play important roles in a wide range of human diseases, including genetic immunodeficiencies, infections, autoimmune diseases, and malignant tumors. In this report, we have reviewed recent developments (since mid 2003) in chemokines in renal diseases. In animal models, chemokines are produced at the site of injury, leading to inflammatory cell recruitment. The therapeutic impact of the blockade of CCR1, CCR2, CCR4, CCR5, or the corresponding ligands has been further studied in various renal disease models. Recent studies on the role of the chemokine receptors in human diseases have demonstrated the expression of CXCR1, CXCR3, CCR2, and CCR5 on different subsets of inflammatory cells. The number of CCR5- and CXCR3-positive interstitial infiltrating cells (mainly T cells) correlates with renal function and proteinuria in glomerular diseases. Polymorphisms of chemokines and chemokine receptors are of impact on renal disease courses and allograft survival. Chemokine receptor blockade has approached clinical applications in nonrenal diseases and awaits the application in patients with kidney diseases.

Role of iron in progressive renal disease

The importance of iron in renal injury is derived from the ease with which iron is reversibly oxidized or reduced, enabling it to participate in the production of free radicals. Experimental evidence for the role of oxidants and iron in progressive renal disease falls into two broad categories. First, considerable data implicate oxidants in the proteinuria of glomerular disease. To the extent that proteinuria is an important determinant of progression, reduction of proteinuria would result in retardation of progression. Evidence also suggests a role of oxidants and iron in diabetic nephropathy, a major cause of end-stage kidney disease. Second, more direct studies have examined the role of oxidants and iron in models of progressive renal disease. These studies include the demonstration of increased iron in the kidney in models of progressive kidney disease; enhanced generation of oxidants, providing a mechanism by which iron can be mobilized; and more direct evidence of the beneficial effect of iron-deficient diets and iron chelators. Although the collective information on the role of oxidants and iron derived from in vitro studies and animal models of glomerular disease and progressive renal failure is impressive, control studies of patients are needed to show the efficacy of antioxidants and/or iron chelators in retarding the progression of renal failure and may offer an important therapeutic modality to patients with renal disease.

Characterization of nephropathy induced by immunization with high molecular weight dextran.

Injection of DEAE dextran into Lewis rats can produce proteinuria and has been reported as a model of IgA nephropathy. Cationic diethyl aminoethyl (DEAE) dextran of molecular weight 500 kDa was injected into male Lewis rats. After a pre-immunization period of 3 weeks, the animals were divided into two groups: group 1 (n = 14) received daily i.v, injections of 3.5 mg of antigen, group 2 (n = 14) was injected with 1.5 mg three times per week for a total period of 6 weeks. I.v. treatment was initiated with gradually increasing doses of DEAE dextran in both groups for 1 week, after which the maintenance dose was reached. We observed the appearance of proteinuria in a nephrotic range after 5 weeks of i.v. injections in group 1 (urinary excretion: 332 +/- 83 mg/24 h, controls: 53 +/- 14 mg/24 h). In group 2, the proteinuria was almost equal to protein excretion of healthy rats of the same weight (67 +/- 20 mg/24 h). The serum and urine creatinine were normal. By light microscopy of kidney biopsies, the presence of focal and segmental proliferation of mesangial cells after 6 weeks of i.v. injections was identified. Immunohistochemistry revealed no deposition of IgA, IgM, IgG, or C3. Using anti-ED1 antibodies, there was no evidence of interstitial infiltration of monocytes/macrophages after 6 weeks of i.v. injections. Staining for proliferating cell nuclear antigen (PCNA) did not show the presence of proliferating cells either in glomeruli or in the interstitium. Staining with FITC-WGA lectin revealed focal and segmental loss of the negative charge in the capillary wall. By electron microscopy there was deposition of dextran in the basal membrane and segmental and focal damage of the podocyte foot processes. As the chemokine RANTES may be involved in glomerular injury, we examined the kidneys of proteinuric and non-proteinuric rats for the presence of RANTES. By indirect immunofluorescence only the proteinuric rats showed RANTES deposition in the mesangium. Injection of rats with DEAE dextran leads to dose-dependent proteinuria without deposition of immune complexes but with podocyte damage. This is associated with local expression of the chemokine RANTES which may play a role in proteinuria of glomerular disease.

Matrix metalloproteinase (stromelysin-1) increases the albumin permeability of isolated rat glomeruli

Matrix metalloproteinases (MMPs) secreted by connective tissue cells are capable of acting on extracellular matrix components of glomerular basement membrane at a slow rate and thus may play a role in the control of protein permeability and in the progression of certain kinds of glomerulonephritis. We have used an in vitro assay to measure the direct effect of three MMPs and human neutrophil elastase on glomerular albumin permeability (P albumin). Glomeruli were isolated from normal male Sprague-Dawley rats and suspended in isolation medium with or without interstitial collagenase, gelatinase-A, stromelysin-1, or elastase and were incubated at 37°C for up to 4 hours. A tissue-specific inhibitor of matrix metalloproteinases (TIMP-1) and a plasma proteinase inhibitor, α 2-macroglobulin (α 2M), were used to block the activity of MMPs. P albumin was calculated from the change in glomerular volume in response to an applied oncotic gradient. In this study stromelysin-1 (10 μg/ml) and elastase (5 μg/ml) increased P albumin significantly. Stromelysin-1 increased P albumin after 4 hours, whereas elastase had an effect after 2 hours. Lower concentrations of stromelysin-1 or shorter incubation time had no effect on P albumin. Incubation for up to 4 hours with interstitial collagenase (10 μg/ml) or gelatinase-A (10μg/ml) had no effect on P albumin. Coincubation with TIMP-1 and α 2M blocked the stromelysin-1-mediated increase in P albumin. We conclude that stromelysin-1 is capable of affecting the glomerular filtration barrier directly and that it may play an important role in causing proteinuria in glomerular diseases.

EFFECT OF GLOMERULAR POLYANION REMOVAL ON PROTEINURIA

Recent evidence suggests that in addition to the mechanical barrier to glomerular filtration, there is an electrical barrier, probably provided by glomerular polyanion (GPA), a negatively-charged glycoprotein lining glomerular epithelial foot processes. Loss of GPA may cause proteinuria in glomerulonephritis. Conversely, albumin infusion into normal animals reduces GPA and increases proteinuria. Since loss of GPA can be produced by perfu-sion of kidneys with a polycation (e.g. protamine sulfate, Seiler et al. Science 189:390, 1975) without apparent damage to the glomerular basement membrane, we determined whether polycation infusion increases proteinuria. Systemic infusion of protamine (at doses lower than those used by Seiler to avoid systemic toxicity) resulted in transient (<80 min) but significant decreases in GPA as determined by double-blind rending of both control and affected kidneys stained with alcian blue and colloidal iron. In 12 additional animals infusion of comparable doses of protamine was associated with increase in proteinuria from 24.1±4.4 (SE) to 61.2±17.0 ug/min (p<.05 by paired t test) during the period of decreased polyanion. Since GFR fell from 1.98±0.41 to 1.48±0.29 ml/min. proteinuria increased even more per unit of GFR. Serum protein levels did not increase.These observations support the thesis that glomerular polyanion reduces the passage of protein into the glomerular filtrate and that loss of polyanion contributes to the proteinuria in glomerular diseases.

Permselectivity of of the glomerular capillary wall. Studies of experimental glomerulonephritis in the rat using neutral dextran.

Polydisperse [3h] dextran was infused into eight Munich-Wistar rats in the early autologous phase of nephrotoxic serum nephritis (NSN), thereby permitting direct measurements of pressures and flows in surface glomeruli and fractional clearances for dextrans [(U/P) dextran/(U/P) inulin] ranging in radius from 18 to 42 A. Despite glomerular injury, evidenced morphologically and by a marked reduction in the glomerular capillary ultrafiltration coefficient, the glomerular filtration rate remained normal because of a compensating increase in the mean net ultrafiltration pressure. In NSN rats, as in normal controls, inulin was found to permeate the glomerular capillary wall without measurable restriction, and dextrans were shown to be neither secreted nor reabsorbed. For dextran radii of 18, 22, 26, 30, 34, 38, and 42 A, (U/P) dextran/(U/P) inulin in NSN and control rats, respectively, averaged 0.90 vs. 0.99, 0.81 vs. 0.97, 0.63 vs. 0.83, 0.38 vs 0.55, 0.20 vs. 0.30, 0.08 vs. 0.11, and 0.02 vs. 0.03. Using a theory based on macromolecular transport through pores, the results indicate that in NSN rats, effective pore radius is the same as in controls, approximately 50 A. In NSN, however, the ratio of total pore surface area to pore length, a measure of the number of pores, is reduced to approximately 1/3 that of control, probably due to a reduction in capillary surface area. These results suggest that proteinuria in glomerular disease is not due simply to increases in effective pore radius or number of pores, as previously believed. Using a second theoretical approach, based on the Kedem-Katchalsky flux equations, dextran permeability across glomerular capillaries was found to be slightly lower, and reflection coefficient slightly higher in NSN than in control rats.