Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Focal segmental glomerulosclerosis (FSGS) is characterized by steroid resistant nephrotic syndrome and progression to end-stage renal disease. Proteinuria in certain patients with FSGS may be caused by a circulating factor (FSGS permeability factor [FSPF]). The current report documents the biochemical characteristics and the biological and molecular effects of 70% ammonium sulfate supernatant of plasma from patients with recurrence of FSGS after transplantation (FSGS 70% supernatant). FS permeability activity, defined as the capacity of plasma from patients with FSGS to increase albumin permeability (P(alb)) of isolated glomeruli, was assessed in vitro. Permeability activity was not affected by lyophilization. FSPF bound strongly to matrices containing Mono-Q anion exchanger or protein A. It eluted from matrix-bound Cibacron blue F3GA over a wide range of salt concentrations, indicating a potential binding with other proteins, such as albumin. FSPF caused a maximal increase in P(alb) within 2 mins of incubation in vitro. Cellular proteins isolated from glomeruli with increased P(alb) showed decreased tyrosine phosphorylation of focal adhesion kinase, paxillin, and other proteins. Tyrosine phosphatase ]inhibition prevented the increase in P(alb). Intravenous administration of as little as 3 mg protein in FSGS 70% supernatant increased P(alb), while 9 mg or more were required to produce proteinuria. We conclude that FSPF is a low-molecular-weight protein, carries an anionic charge, and binds to protein A. Effects of FSPF on the glomerular permeability barrier are rapid and dose dependent and involve signaling through altered phosphorylation of cellular proteins. Identification of these biochemical and biological characteristics may be used to design strategies for removing FSPF from circulation and for purification and identification of this factor.
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PMID:The focal segmental glomerulosclerosis permeability factor: biochemical characteristics and biological effects. 1470 81

Glomerular endothelial cell (GEC) dysfunction due to oxidative stress and enhanced proinflammatory cytokines plays an important role in inducing proteinuria and procoagulant activity, namely blood hypercoagulability, hyperviscosity and local intravascular coagulation and altered hemorheology in NS. A dysfunctioning GEC releases fewer endothelium-dependent vasodilators but produces more vasoconstrictors. Severe intrarenal hemodynamic alteration associated with hemodynamic maladjustment with preferential constriction at the efferent arteriole has been uniquely implicated in severe GN and NS-FSGS. Such a constriction exerts three significant hemodynamic impacts. Proximal to the efferent arteriolar constriction, it induces (i) an overestimated GFR due to hyperfiltration and (ii) an elevated intraglomerular hydrostatic pressure. Distal to the efferent arteriolar constriction, it (iii) exaggeratedly reduces PTCF which correlates with the TIF.
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PMID:A hemodynamically mediated mechanism of renal disease progression in severe glomerulonephritides or nephrosis. 1472 39

Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.
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PMID:Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. 1497 89

Idiopathic NS (nephrotic syndrome) is characterized by massive proteinuria, due to a leak in the glomerular barrier to proteins. Genetic defects that affect the function and the composition of the glomerular capillary wall, in particular of the visceral epithelial cells, have recently been recognized as the cause of familial forms of NS. MCNS (minimal change NS) and FSGS (focal and segmental glomerulosclerosis) are common non-familial forms of NS in which the causative defect has not yet been identified. Several studies have shown that non-familial NS is associated with the presence of circulating permeability factors and with complex disturbances in the immune system. Thus far, there is no direct evidence that these factors directly alter glomerular permeability to proteins, and some of these factors may be a consequence, rather than a cause, of NS. In this review, we will briefly highlight the mechanisms that underlie proteinuria in general and focus on the immunological disturbances associated with idiopathic NS, with attention to potential mechanisms whereby the immune system may directly act on the glomerular capillary filter.
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PMID:Role of the immune system in the pathogenesis of idiopathic nephrotic syndrome. 1515 84

The putative mechanisms of proteinuria in idiopathic focal glomerulosclerosis and of its post-transplant recurrence are discussed. It is proposed that a balance between circulating factors with permeability activity on glomeruli and putative inhibitors play a key role. The characterization of inductors is currently in progress; most inhibitors appear to be apolipoproteins (mainly apoJ and apo E) but we cannot exclude other substances. The goal is now to evaluate the concentration of both inducers and inhibitors of glomerular permeability in vivo. Permeability activity in plasma of patients with FSGS with and without recurrence of the disease may be evaluated by an in vitro functional essay with isolated glomeruli. Published data on permeability activity evaluated with this method in different proteinuric states gave, however, controversial results and this test cannot be readily considered of clear clinical utility. Only the definitive characterization and quantification in vivo of the different molecules that play a role in FSGS may furnish adequate answer.
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PMID:Glomerular albumin permeability as an in vitro model for characterizing the mechanism of focal glomerulosclerosis and predicting post-transplant recurrence. 1526 58

Glomerular diseases continue to be the leading cause of end-stage renal disease globally. Hence it is important to recognize the glomerular disease pattern in any given geographical area to understand the pathobiology in the region as well as the incidence and progression of the disorder. A total of 498 renal biopsies were performed on patients with proteinuria, hematuria, and mild to moderate renal impairment during a period of 13 years (between January 1990 and December 2002) at a tertiary care hospital. Primary glomerular disease accounted for two-thirds of the glomerular diseases, which was 44.8% of all renal biopsies. The most common histological lesion was minimal change disease (30%). Focal segmental glomerulosclerosis was the second most common lesion (23.8%) followed by membranoproliferative glomerulonephritis (14.3%). Secondary glomerular disease included 33.6% of glomerular diseases with 22.7% with lupus nephritis as the commonest lesion (38.9%) followed by diabetic nephropathy (31.9%) and hypertension (20.4%). Tubulointerstitial diseases accounted for 13.1% of all renal biopsies, whereas transplant diseases were noted in 12.2%. The miscellaneous group including inadequate biopsies, which constituted 7.2% of all the tissues. The results of this analysis were compared with surveys from other parts of the world.
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PMID:The spectrum of glomerular diseases in the kingdom of bahrain: an epidemiological study based on renal biopsy interpretation. 1535 Apr 79

An obese male patient with steroid-dependent nephrotic syndrome since age 6 years had a thirty-third relapse at the age of 29 years. Renal biopsy showed focal segmental glomerulosclerosis. Proteinuria disappeared after treatment with prednisolone. He went into complete remission and renal function remained normal at the age of 31 years. Focal segmental glomerulosclerosis associated with obesity was suspected. Long-term follow-up with renal biopsy is necessary in obese children with steroid-dependent nephrotic syndrome.
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PMID:A male patient with steroid-dependent nephrotic syndrome for 25 years and obesity-associated focal segmental glomerulosclerosis. 1548 Sep 5

Studied were the effects of myocardial infarction (MI) on mild renal function loss in unilateral nephrectomized (UnX) rats. UnX was performed, followed after 1 wk by a variable MI (UnX + MI; n = 24). Rats with only UnX (n = 15) or MI (n = 9) and double sham animals (CON, n = 15) served as controls. Renal outcome was measured by proteinuria and plasma creatinine. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function and systolic BP were measured. A division into small and large infarcts after UnX was made a priori, resulting in two groups, one with a mild MI (<20%; n = 15) and one with a moderate MI (>20%; n = 9). Mild proteinuria up to 55.5 mg/d was observed in the UnX + mild MI group, whereas proteinuria rose significantly higher to 124.5 mg/d in the UnX + moderate MI group. Incidence of FGS was significantly increased in both UnX + MI groups compared with all other groups. The average MI size was 18%, 17%, and 25% in the MI, UnX + mild MI, and UnX + moderate MI group, respectively. LVP in both UnX + MI groups was correlated with proteinuria, indicative of a cardio-renal interaction. Clinically, these data imply that more patients are at risk for cardiovascular events and that after such an event, their chance of more renal function loss increases. Finding the underlying mechanism will enable improved protection for both kidneys and heart.
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PMID:Myocardial infarction enhances progressive renal damage in an experimental model for cardio-renal interaction. 1557 13

The hypothesis that apoptosis represents a proximate mechanism by which tubule cells are damaged in FSGS was tested. Thirty kidney biopsy specimens from children with idiopathic early FSGS were studied retrospectively. Unexpected, apoptosis was evident in both proximal and distal tubule cells. There was a significant correlation between the degree of proteinuria and the number of apoptotic cells. Fas protein was detected predominantly in the tubule cells that underwent apoptosis. When compared with patients with other chronic proteinuric states, those with FSGS displayed a proliferation/apoptosis ratio in favor of proliferation in the glomerulus but dramatically in favor of apoptosis in the tubules. When both proteinuria and apoptosis were included in a stepwise logistic regression procedure, only apoptosis was found to predict independently the development of ESRD. Prolonged incubation of cultured Madin-Darby canine kidney (distal/collecting) cells with albumin also resulted in a dose- and duration-dependent induction of apoptosis and activation of the Fas pathway, lending support to the novel finding of distal tubule cell apoptosis in patients with FSGS. The results indicate that an elevated tubule cell apoptosis rate at the time of initial biopsy represents an independent predictor of progression to ESRD in patients with early FSGS.
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PMID:Induction of renal tubular cell apoptosis in focal segmental glomerulosclerosis: roles of proteinuria and Fas-dependent pathways. 1560 49

Recurrence of focal glomerulosclerosis (FSGS) following renal transplantation is a common cause of allograft loss and clinical morbidity. Recent attempts to control proteinuria and morbidity with plasmapheresis (PP) have met with limited success. Our experience with the use of mycophenolate mofetil (MMF) and angiotensin blockade (AB) in the management of refractory FSGS pre transplant suggested its potential benefit in post-transplant recurrence. This report presents our 25-year experience in pediatric renal transplantation of patients with FSGS divided into two treatment eras: Era 1-prior to use of daclizumab (anti-IL-2R) and Era 2-after daclizumab. A total of 179 pediatric patients were transplanted during the 25-year period. FSGS was confirmed in 27 (15%); 16 of 28 allografts (57%) had recurrence of FSGS during the post-transplant period. In Era 1, only 6 of 16 (38%) recurred in the allograft, while 10 of 12 (83%) recurred during Era 2. The odds ratio of recurrence of FSGS in the allograft after induction with anti-IL-2R was 8.3 (95% confidence interval=1.3-52, P =0.02). Only 2 patients in Era 1 received PP, while 10 in Era 2 were entered into an intensive PP protocol followed by maintenance with AB consisting of angiotensin receptor blockers alone, or in combination with angiotensin-converting enzyme inhibitor. Although proteinuria decreased an average of 80+/-16% with PP, the response was variable and severe morbid edema persisted in poor responders. Maximum benefit occurred with the addition of AB and MMF. After a follow-up of 27+/-15 months, proteinuria has shown a sustained decrease of 94+/-8% below baseline. In conclusion, our experience suggests that, with recurrent FSGS, a limited course of PP followed by maintenance therapy with AB and MMF improves symptoms and may preserve allograft function.
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PMID:Recurrent focal glomerulosclerosis in pediatric renal allografts: the Miami experience. 1560 84


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