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Flavio Vincenti - One of the best experts on this subject based on the ideXlab platform.

  • new insights into the pathogenesis and the therapy of recurrent Focal Glomerulosclerosis
    American Journal of Transplantation, 2005
    Co-Authors: Flavio Vincenti, Gian Marco Ghiggeri
    Abstract:

    Recurrent Focal Glomerulosclerosis (FSGS) in renal allografts has remained a frustrating and enigmatic disease. Recent studies on gene mutations encoding podocin and other components of the slit-diaphragm in patients with native kidney nephrotic syndrome have underscored the heterogenecity of the idiopathic form of FSGS. While familial FSGS rarely recurs following transplantation, the sporadic variety of FSGS is associated with a 30% recurrence rate. The patients with the sporadic variety of FSGS who have homozygous or complex heterozygous podocin mutations have a low recurrence rate. In the other patients with sporadic FSGS, a more complex and likely multifactorial etiology accounts for the recurrence of FSGS. The role of CD80 expression on podocytes is intriguing but requires confirmation in kidney biopsies of patients with recurrent FSGS. Recent findings on podocin genomics, the permeability factor and CD80 expression may ultimately lead to a better understanding of recurrent FSGS as well as a more effective approach to its prevention and treatment.

  • plasmapheresis reduces proteinuria and serum capacity to injure glomeruli in patients with recurrent Focal Glomerulosclerosis
    American Journal of Kidney Diseases, 1994
    Co-Authors: Mary Artero, Ram Sharma, Virginia J Savin, Flavio Vincenti
    Abstract:

    To test the hypothesis that a circulating mediator is associated with recurrent idiopathic Focal Glomerulosclerosis (FGS), we studied the effect of plasmapheresis on reducing proteinuria in patients with the disease. An in vitro assay measured the capacity of sera before and after plasmapheresis to cause increased albumin permeability (P albumin ) in isolated rat glomeruli. Nine patients (five males aged 2 to 66 years) who underwent plasmapheresis for recurrent FGS were identified. Study variables included age, sex, time from diagnosis of recurrence to first pheresis, glomerular hyalinosis, complications, outcome, and proteinuria before and after plasmapheresis. Rat glomeruli were isolated in medium containing 4 g/dL bovine serum albumin, and P albumin was determined from the change in glomerular volume in response to an albumin gradient after incubation of the glomeruli in a 1:50 dilution of patient serum. Plasmapheresis reduced proteinuria from a mean of 12 ± 7.46 g/24 hr to 5.1 ± 7.39 g/24 hr ( P = 0.03). Six patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had lasting remissions. Preplasmapheresis biopsies in the patients who did not achieve remissions showed both epithelial foot process effacement and glomerular sclerosis. Serum samples were available from four patients for albumin testing in vitro. P albumin was reduced from a mean of 0.76 ± 0.17 before pheresis to 0.18 ± 0.31 after ( P = 0.07). Therefore, the mechanism by which plasmapheresis reduces proteinuria in patients with recurrent FGS involves the decreased capacity of sera from these patients to injure the glomerular permeability barrier. Plasmapheresis is likely to be effective in the therapy of recurrent FGS if the diagnosis is made promptly following the appearance of proteinuria, there is no significant hyalinosis on preplasmapheresis biopsy, and plasmapheresis is initiated immediately.

  • Recurrent Focal Glomerulosclerosis: Natural history and response to therapy
    The American journal of medicine, 1992
    Co-Authors: Mary Artero, Claude G. Biava, William J. C. Amend, Stephen J. Tomlanovich, Flavio Vincenti
    Abstract:

    Abstract purpose: Recurrent Focal Glomerulosclerosis (FGS) has been well documented since it was first reported in 1972. However, the course of the disease after transplantation and the optimal treatment regimen have not been well defined since the introduction of newer treatment modalities. patients and methods: We reviewed all the charts of patients with biopsy-proven FGS who received renal transplants at our institution from January 1980 through December 1990. Case histories consistent with diagnoses other than primary FGS (such as reflux nephropathy or intravenous drug use) were eliminated from the study. During this time period, 78 allografts were received by 71 patients with FGS. Independent variables that were analyzed included sex, race, time in months between the diagnosis of FGS and end-stage disease (dialysis or transplantation), age at time of transplantation, type of dialysis, source of allograft (cadaveric or living related), haplotype matching, donor-specific transfusions, age and sex of the donor, posttransplantation acute tubular necrosis, rejection episodes, immunosuppression regimen, use of plasmapheresis and angiotensin converting enzyme (ACE) inhibitors, and outcome. results: FGS recurred in 25 allografts (32%) of 21 patients. Biopsy-proven diagnosis of recurrence was made a mean of 7.5 months (range: 0.5 to 44 months) after transplantation. Patients who had rapid progression to end-stage disease tended to experience more frequent recurrences. Of seven patients who received a second transplant, five patients lost the first graft to recurrent FGS, and four of those patients (80%) had a recurrence in the second allograft. Recurrent disease developed in 34% of patients concurrently treated with cyclosporine and in 28% of those treated with prednisone and azathioprine alone (NS). Patients with recurrent FGS who were treated with ACE inhibitors benefited from a significant reduction of proteinuria. Six patients underwent plasmapheresis after diagnosis of the recurrence. Three of five patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had reversal of epithelial foot process effacement and remission of proteinuria. End-stage disease eventually developed in 14 allografts (56%) an average of 23.7 months (range: 1 to 65 months) after diagnosis of recurrent disease. The cause of failure was chronic rejection in four allografts and recurrent disease in the remaining 10 allografts. conclusions: FGS recurs in approximately 30% of allografts and causes graft loss in half of these. Patients who have lost a first allograft to recurrent FGS are at high risk for developing recurrent disease in a second allograft. Prolonged allograft survival is possible in patients with recurrent FGS and may best be obtained with a combination of treatment modalities including cyclosporine (perhaps in higher dosages than are routinely used in clinical renal transplantation), ACE inhibitors, and early use of plasmapheresis. The efficacy of these modalities supports the notion that recurrent FGS is caused by a circulating humoral mediator.

Nosratola D. Vaziri - One of the best experts on this subject based on the ideXlab platform.

  • Role of intrarenal angiotensin system activation, oxidative stress, inflammation, and impaired nuclear factor-erythroid-2-related factor 2 activity in the progression of Focal Glomerulosclerosis.
    The Journal of pharmacology and experimental therapeutics, 2011
    Co-Authors: Hyun Ju Kim, Tadashi Sato, Bernardo Rodriguez-iturbe, Nosratola D. Vaziri
    Abstract:

    The Imai rat is a model of spontaneous Focal Glomerulosclerosis, which leads to heavy proteinuria, hyperlipidemia, hypertension, and progressive renal failure. Treatment with AT1 blockers (ARBs) ameliorates proteinuria, hyperlipidemia, and nephropathy in this model. Progression of renal disease in 5/6 nephrectomized rats is associated with activation of the intrarenal angiotensin system, up-regulation of the oxidative, inflammatory, and fibrogenic pathways, and impaired activity of nuclear factor-erythroid-2-related factor 2 (Nrf2), the master regulator of genes encoding antioxidant molecules. We hypothesized that progressive nephropathy in the Imai rat is accompanied by oxidative stress, inflammation, and impaired Nrf2 activation and that amelioration of nephropathy with AT1 receptor blockade in this model may be associated with the reversal of these abnormalities. Ten-week-old Imai rats were randomized to the ARB-treated (olmesartan, 10 mg/kg/day for 24 weeks) or vehicle-treated groups. Sprague-Dawley rats served as controls. At 34 weeks of age Imai rats showed heavy proteinuria, hypoalbuminemia, hypertension, azotemia, Glomerulosclerosis, tubulointerstitial inflammation, increased angiotensin II expressing cell population, up-regulations of AT1 receptor, AT2 receptor, NAD(P)H oxidase, and inflammatory mediators, activation of nuclear factor-κB and reduction of Nrf2 activity and expression of its downstream gene products in the renal cortex. ARB therapy prevented nephropathy, suppressed oxidative stress and inflammation, and restored Nrf2 activation and expression of the antioxidant enzymes. Thus progressive Focal Glomerulosclerosis in the Imai rats is associated with oxidative stress, inflammation, and impaired Nrf2 activation. These abnormalities are accompanied by activation of intrarenal angiotensin system and can be prevented by ARB administration.

  • Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in Focal Glomerulosclerosis.
    Kidney international, 2003
    Co-Authors: Tadashi Sato, Kaihui Liang, Nosratola D. Vaziri
    Abstract:

    Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in Focal Glomerulosclerosis. Background Imai rats exhibit spontaneous Focal Glomerulosclerosis (FGS) with progressive proteinuria and hyperlipidemia leading to renal insufficiency by age 34 weeks. Recently, we reported marked down-regulations of skeletal muscle and adipose tissue lipoprotein lipase (LPL) and very low-density lipoprotein (VLDL) receptor in male Imai rats at 32 weeks of age. Dietary protein restriction and oral adsorbent AST-120 (AST) have been shown to slow progression of renal disease and attenuate hyperlipidemia in the Imai rats. This study tested the hypothesis that amelioration of proteinuria by protein restriction or use of oral adsorbent AST-120 beginning at 10 weeks of age may improve renal disease and LPL and VLDL receptor deficiencies in Imai rats. Methods Ten-week-old male Imai rats were randomly assigned to those fed either a regular diet, low protein diet (LPD), or regular diet containing the adsorbent preparation, AST-120. Ten-week-old male Sprague-Dawley rats served as controls. The animals were observed for 24 weeks. Six rats were included in each group. All diets were prepared in powder form. Results The untreated 34-week-old Imai rats showed severe proteinuria, hypoalbuminemia, 50% reduction in creatinine clearance, hypercholesterolemia, hypertriglyceridemia, and elevated plasma VLDL concentration. This was associated with significant reductions in plasma post-heparin LPL activity, hepatic lipase activity, as well as adipose tissue and skeletal muscle immunodetectable LPL and VLDL receptor proteins. Protein restriction mitigated the decline in creatinine clearance, ameliorated proteinuria, hypoalbuminemia, hypertension, and hypercholesterolemia, lowered plasma VLDL, and improved plasma postheparin LPL activity, hepatic lipase activity, LPL, and VLDL receptor proteins in skeletal muscle and adipose tissue. Similar improvements were observed in all parameters with AST administration. Conclusion Moderate protein restriction and use of oral adsorbent can slow progression of renal disease and, thereby, ameliorate LPL, hepatic lipase, and VLDL receptor deficiencies and the associated hyperlipidemia in rats with spontaneous FGS.

  • Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous Focal Glomerulosclerosis.
    Kidney international, 2003
    Co-Authors: Nosratola D. Vaziri, Tadashi Sato, Kaihui Liang
    Abstract:

    Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous Focal Glomerulosclerosis. Background Imai rats exhibit spontaneous Focal Glomerulosclerosis (FGS), which is marked by heavy proteinuria, severe hyperlipidemia, and progressive renal insufficiency beginning at 8 to 10 weeks of age. In an earlier study, we reported severe skeletal muscle and adipose tissue lipoprotein lipase, and very low-density lipoprotein (VLDL) receptor deficiencies, which account for elevated plasma VLDL and triglycerides in Imai rats at 34 weeks of age. In this study, we investigated key factors involved in cholesterol metabolism. Methods Male Imai and Sprague-Dawley control rats were fed a regular rat chow and observed from age 8 through 34 weeks. Hepatic 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7α-hydroxylase, low-density lipoprotein (LDL) receptor and acyl Co A:cholesterol acyltransferase (ACAT) were measured by Western blot and plasma lecithin:cholesterol acyltransferase (LCAT) protein was measured by enzyme-linked immunosorbent assay (ELISA). Results At 34 weeks of age, the Imai rats showed severe proteinuria, hypoalbuminemia, 60% reduction in glomerular filtration rate (GFR), elevated plasma total and LDL cholesterol and LDL/high-density lipoprotein (HDL) ratio. Imai rats showed a twofold elevation of hepatic HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, but no significant change in cholesterol 7α-hydroxylase, the rate-limiting enzyme in cholesterol catabolism to bile acids. This was accompanied by and largely due to a threefold down-regulation of hepatic LDL receptor, which limits hepatic uptake of LDL; and a threefold up-regulation of hepatic ACAT ( P Conclusion The study revealed marked abnormalities of the key proteins involved in regulation of hepatic cholesterol metabolism. These abnormalities can account for severe dysregulation of cholesterol metabolism in Imai rats with spontaneous FGS, which closely resembles FGS in humans.

  • Down-regulation of lipoprotein lipase and VLDL receptor in rats with Focal Glomerulosclerosis.
    Kidney international, 2002
    Co-Authors: Tadashi Sato, Kaihui Liang, Nosratola D. Vaziri
    Abstract:

    Down-regulation of lipoprotein lipase and VLDL receptor in rats with Focal Glomerulosclerosis. Background Patients and animals with nephrotic syndrome and those with chronic renal failure (CRF) often exhibit hypertriglyceridemia and impaired very low-density lipoprotein (VLDL) clearance. Imai rats that were originally derived from Sprague-Dawley rats develop spontaneous proteinuria, hyperlipidemia, progressive renal insufficiency and histologic changes of Focal Glomerulosclerosis (FGS), closely resembling human FGS. This study was undertaken to test the hypothesis that elevation of plasma triglyceride and VLDL concentrations in the Imai rats is associated with deficiency of lipoprotein lipase (LPL) and VLDL receptor which are the main pathways of triglyceride-rich lipoprotein clearance. Methods Male Imai and Sprague-Dawley control rats were fed regular rat chow and studied at 10 and 34 weeks of age. Tissue LPL and VLDL-r protein abundance (Western analysis) and post-heparin lipolytic activity were determined. Results At 10 weeks of age, Imai rats showed mild proteinuria, moderate hyperlipidemia, normal creatinine clearance and blood pressure. By 34 weeks of age, the study animal exhibited severe proteinuria, marked hyperlipidemia, significant renal insufficiency and hypertension. This was associated with a severe progressive reduction in skeletal muscle and adipose tissue LPL and VLDL-r protein abundance and depressed plasma post heparin, lipolytic activity. Conclusion Progressive hyperlipidemia in the Imai rats with spontaneous FGS is accompanied by severe combined LPL and VLDL-r deficiencies that can, in part, account for the associated hypertriglyceridemia and elevated plasma VLDL concentrations.

Jack F.m. Wetzels - One of the best experts on this subject based on the ideXlab platform.

  • Plasma exchange improves graft survival in patients with recurrent Focal Glomerulosclerosis after renal transplantation
    Transplant International, 2004
    Co-Authors: Jeroen K. J. Deegens, Sandra Croockewit, Margret B. Andresdottir, Jack F.m. Wetzels
    Abstract:

    Recurrence of primary Focal Glomerulosclerosis (FGS) after renal transplantation is associated with poor graft survival. Plasma exchange (PE) can reduce proteinuria and even induce complete remission of proteinuria. It is, however, unknown whether the use of PE therapy improves long-term graft survival. In our center, PE has been used to treat recurrent FGS after renal transplantation since 1994. Thus far, 13 patients have been treated with PE for recurrent FGS and followed for up to 77 months after the onset of the recurrence. We reviewed the transplantation data in these patients, and, for comparison, ten patients who underwent transplantation between 1973 and 1991 and were not treated with PE served as historical controls. Recurrence of FGS occurred within 4 weeks of transplantation in 74% of the patients. PE was started within 14 days of the onset of proteinuria in 85% of the patients. Two patients lost their graft within the first month of transplantation due to untreatable rejection; the remaining 11 patients (85%) achieved complete ( n =7) or partial ( n =4) remission. Seven patients remained in remission after a short period of treatment with PE (≤18 sessions in 2 months), whereas four patients needed prolonged treatment (median of 58 sessions). The need for prolonged PE was associated with a late (>30 days after transplantation) recurrence of FGS ( P =0.02). A comparison with the historical control group revealed not only a significant reduction in proteinuria, but also significantly better long-term graft survival in the treated group, 85% and 30%, respectively, at 5 years ( P =0.02). In conclusion, PE is an effective form of treatment for recurrent FGS, especially if initiated early. Failure to maintain stable remission after the initial period of PE does not necessarily imply a poor outcome, and sustained remissions can be achieved after prolonged treatment.

  • Antibody-induced albuminuria and accelerated Focal Glomerulosclerosis in the Thy-1.1 transgenic mouse.
    Kidney international, 2002
    Co-Authors: Karel J.m. Assmann, Jacco P.h.f. Van Son, H.b.p.m. Dijkman, S. Mentzel, Jack F.m. Wetzels
    Abstract:

    Antibody-induced albuminuria and accelerated Focal Glomerulosclerosis in the Thy-1.1 transgenic mouse. Background Podocytes play an important role in the development of proteinuria and Focal Glomerulosclerosis. Previously we have demonstrated that a combination of two monoclonal antibodies (mAb) against aminopeptidase A (APA), an enzyme present on podocytes, induces a massive acute albuminuria in mice. The present study examined the relationship between the acute antibody-induced albuminuria and the development of Focal Glomerulosclerosis in the Thy-1.1 transgenic mouse. This mouse expresses a hybrid human-mouse Thy-1.1 antigen on the podocytes, and slowly but spontaneously develops albuminuria and Focal Glomerulosclerosis. Methods Five-week-old non-albuminuric Thy-1.1 transgenic and non-transgenic control mice were injected with anti-APA and anti-Thy-1.1 mAb or saline. Albuminuria was measured at days 1, 7, 14 and 21. At day 21 kidneys were processed for light microscopy, immunofluorescence, and electron microscopy. Results Injection of anti-APA and anti-Thy1.1 mAb in Thy-1.1 transgenic mice induced an albuminuria at day 1 that persisted at day 21. The acute albuminuria after injection of anti-APA mAb was more prominent but transient in non-transgenic mice. In non-trangenic mice no albuminuria could be induced with anti-Thy 1.1 mAb. Light microscopy revealed normal glomeruli at day 1 in all transgenic mice, however, at day 21 advanced glomerulosclerotic lesions were seen in mice injected with either anti-APA mAb (37±19% of glomeruli affected) or anti-Thy-1.1 mAb (71±5%). Non-transgenic mice did not reveal sclerotic lesions at any time investigated. In the transgenic mice the percentage of Focal Glomerulosclerosis at day 21 did not correlate with albuminuria at day 21. However, we found a highly significant correlation between percentage of Focal Glomerulosclerosis and the time-averaged albuminuria over the three-week study period (P Conclusion Injection of a combination of anti-APA or anti-Thy-1.1 mAb into one mo old, non-albuminuric Thy-1.1 transgenic mice induces an acute albuminuria at day 1 that is accompanied by an accelerated Focal Glomerulosclerosis at day 21. We suggest that the Thy-1.1 transgenic mouse is an excellent model to study specifically the relation between podocytic injury, albuminuria and the development of Focal Glomerulosclerosis.

  • Recurrent Focal Glomerulosclerosis: natural course and treatment with plasma exchange
    Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 1999
    Co-Authors: Margret B. Andresdottir, Karel J.m. Assmann, Nouaf Ajubi, Sandra Croockewit, Luuk B. Hibrands, Jack F.m. Wetzels
    Abstract:

    Background. Focal Glomerulosclerosis (FGS) can recur after renal transplantation and prognosis is poor in untreated patients. A circulating plasma factor has been implicated in the pathogenesis of a recurrent FGS and treatment with plasma exchange has proven effective in decreasing proteinuria in some patients. Methods. We retrospectively studied the course of disease in patients with recurrent FGS, transplanted in our centre. Seven patients transplanted between 1991 and 1997, received treatment with plasma exchange, whereas 10 patients, transplanted between 1973 and 1991, were left untreated and served as historical controls. Results. The time of onset of proteinuria (> 3.5 g/day) was comparable in the untreated and treated patients (9 and 10 days respectively), as was the average proteinuria at that time (5.5 and 5.8 g/day respectively). In the untreated patients, proteinuria persisted and eventually all grafts were lost, on average 43 months after the diagnosis of a recurrence. In five cases (50%) the recurrence was the single cause of graft loss. The clinical course was different in the seven patients who were treated with plasma exchange. In five of these patients, the recurrence occurred within 3 weeks after transplantation. Plasma exchange was started 1-14 days after onset of proteinuria in these patients. Two lost their grafts after 0.7 and 1.0 months because of untreatable rejection. In the remaining three patients the plasma exchange resulted in abrupt disappearance of the proteinuria, and the response has been lasting for 2-3.2 years. In these patients the only histological abnormality was foot effacement on electron-microscopy. In two patients the recurrence became manifest at 9 weeks and 5.8 years after transplantation respectively. These two patients relapsed after the initial course of plasma exchange, but responded to repeated session, and are currently being treated once a month. They have been followed for 1.7 and 1.4 years after the onset of proteinuria and their urinary protein levels are 0.23 and 1.2 g/10 mmol creatinine. Conclusions. The prognosis of untreated recurrent FGS is poor. Treatment with plasma exchange can lead to complete remission of proteinuria and relapsing patients may respond to repeated sessions. Best results are obtained when plasma exchange is started early, when there are no visible lesions on light-microscopy.

Mary Artero - One of the best experts on this subject based on the ideXlab platform.

  • Glomerular albumin permeability as an in vitro model for characterizing the mechanism of Focal Glomerulosclerosis and predicting post-transplant recurrence
    Pediatric transplantation, 2004
    Co-Authors: Gian Marco Ghiggeri, Mary Artero, Michele Carraro, Giovanni Candiano, Luca Musante, Maurizio Bruschi, Cristina Zennaro, Fabrizio Ginevri, Gianluca Caridi, Faccini L
    Abstract:

    :  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.

  • plasmapheresis reduces proteinuria and serum capacity to injure glomeruli in patients with recurrent Focal Glomerulosclerosis
    American Journal of Kidney Diseases, 1994
    Co-Authors: Mary Artero, Ram Sharma, Virginia J Savin, Flavio Vincenti
    Abstract:

    To test the hypothesis that a circulating mediator is associated with recurrent idiopathic Focal Glomerulosclerosis (FGS), we studied the effect of plasmapheresis on reducing proteinuria in patients with the disease. An in vitro assay measured the capacity of sera before and after plasmapheresis to cause increased albumin permeability (P albumin ) in isolated rat glomeruli. Nine patients (five males aged 2 to 66 years) who underwent plasmapheresis for recurrent FGS were identified. Study variables included age, sex, time from diagnosis of recurrence to first pheresis, glomerular hyalinosis, complications, outcome, and proteinuria before and after plasmapheresis. Rat glomeruli were isolated in medium containing 4 g/dL bovine serum albumin, and P albumin was determined from the change in glomerular volume in response to an albumin gradient after incubation of the glomeruli in a 1:50 dilution of patient serum. Plasmapheresis reduced proteinuria from a mean of 12 ± 7.46 g/24 hr to 5.1 ± 7.39 g/24 hr ( P = 0.03). Six patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had lasting remissions. Preplasmapheresis biopsies in the patients who did not achieve remissions showed both epithelial foot process effacement and glomerular sclerosis. Serum samples were available from four patients for albumin testing in vitro. P albumin was reduced from a mean of 0.76 ± 0.17 before pheresis to 0.18 ± 0.31 after ( P = 0.07). Therefore, the mechanism by which plasmapheresis reduces proteinuria in patients with recurrent FGS involves the decreased capacity of sera from these patients to injure the glomerular permeability barrier. Plasmapheresis is likely to be effective in the therapy of recurrent FGS if the diagnosis is made promptly following the appearance of proteinuria, there is no significant hyalinosis on preplasmapheresis biopsy, and plasmapheresis is initiated immediately.

  • Recurrent Focal Glomerulosclerosis: Natural history and response to therapy
    The American journal of medicine, 1992
    Co-Authors: Mary Artero, Claude G. Biava, William J. C. Amend, Stephen J. Tomlanovich, Flavio Vincenti
    Abstract:

    Abstract purpose: Recurrent Focal Glomerulosclerosis (FGS) has been well documented since it was first reported in 1972. However, the course of the disease after transplantation and the optimal treatment regimen have not been well defined since the introduction of newer treatment modalities. patients and methods: We reviewed all the charts of patients with biopsy-proven FGS who received renal transplants at our institution from January 1980 through December 1990. Case histories consistent with diagnoses other than primary FGS (such as reflux nephropathy or intravenous drug use) were eliminated from the study. During this time period, 78 allografts were received by 71 patients with FGS. Independent variables that were analyzed included sex, race, time in months between the diagnosis of FGS and end-stage disease (dialysis or transplantation), age at time of transplantation, type of dialysis, source of allograft (cadaveric or living related), haplotype matching, donor-specific transfusions, age and sex of the donor, posttransplantation acute tubular necrosis, rejection episodes, immunosuppression regimen, use of plasmapheresis and angiotensin converting enzyme (ACE) inhibitors, and outcome. results: FGS recurred in 25 allografts (32%) of 21 patients. Biopsy-proven diagnosis of recurrence was made a mean of 7.5 months (range: 0.5 to 44 months) after transplantation. Patients who had rapid progression to end-stage disease tended to experience more frequent recurrences. Of seven patients who received a second transplant, five patients lost the first graft to recurrent FGS, and four of those patients (80%) had a recurrence in the second allograft. Recurrent disease developed in 34% of patients concurrently treated with cyclosporine and in 28% of those treated with prednisone and azathioprine alone (NS). Patients with recurrent FGS who were treated with ACE inhibitors benefited from a significant reduction of proteinuria. Six patients underwent plasmapheresis after diagnosis of the recurrence. Three of five patients in whom the diagnosis was made early in the course of the disease and in whom plasmapheresis was initiated immediately had reversal of epithelial foot process effacement and remission of proteinuria. End-stage disease eventually developed in 14 allografts (56%) an average of 23.7 months (range: 1 to 65 months) after diagnosis of recurrent disease. The cause of failure was chronic rejection in four allografts and recurrent disease in the remaining 10 allografts. conclusions: FGS recurs in approximately 30% of allografts and causes graft loss in half of these. Patients who have lost a first allograft to recurrent FGS are at high risk for developing recurrent disease in a second allograft. Prolonged allograft survival is possible in patients with recurrent FGS and may best be obtained with a combination of treatment modalities including cyclosporine (perhaps in higher dosages than are routinely used in clinical renal transplantation), ACE inhibitors, and early use of plasmapheresis. The efficacy of these modalities supports the notion that recurrent FGS is caused by a circulating humoral mediator.

Tadashi Sato - One of the best experts on this subject based on the ideXlab platform.

  • Role of intrarenal angiotensin system activation, oxidative stress, inflammation, and impaired nuclear factor-erythroid-2-related factor 2 activity in the progression of Focal Glomerulosclerosis.
    The Journal of pharmacology and experimental therapeutics, 2011
    Co-Authors: Hyun Ju Kim, Tadashi Sato, Bernardo Rodriguez-iturbe, Nosratola D. Vaziri
    Abstract:

    The Imai rat is a model of spontaneous Focal Glomerulosclerosis, which leads to heavy proteinuria, hyperlipidemia, hypertension, and progressive renal failure. Treatment with AT1 blockers (ARBs) ameliorates proteinuria, hyperlipidemia, and nephropathy in this model. Progression of renal disease in 5/6 nephrectomized rats is associated with activation of the intrarenal angiotensin system, up-regulation of the oxidative, inflammatory, and fibrogenic pathways, and impaired activity of nuclear factor-erythroid-2-related factor 2 (Nrf2), the master regulator of genes encoding antioxidant molecules. We hypothesized that progressive nephropathy in the Imai rat is accompanied by oxidative stress, inflammation, and impaired Nrf2 activation and that amelioration of nephropathy with AT1 receptor blockade in this model may be associated with the reversal of these abnormalities. Ten-week-old Imai rats were randomized to the ARB-treated (olmesartan, 10 mg/kg/day for 24 weeks) or vehicle-treated groups. Sprague-Dawley rats served as controls. At 34 weeks of age Imai rats showed heavy proteinuria, hypoalbuminemia, hypertension, azotemia, Glomerulosclerosis, tubulointerstitial inflammation, increased angiotensin II expressing cell population, up-regulations of AT1 receptor, AT2 receptor, NAD(P)H oxidase, and inflammatory mediators, activation of nuclear factor-κB and reduction of Nrf2 activity and expression of its downstream gene products in the renal cortex. ARB therapy prevented nephropathy, suppressed oxidative stress and inflammation, and restored Nrf2 activation and expression of the antioxidant enzymes. Thus progressive Focal Glomerulosclerosis in the Imai rats is associated with oxidative stress, inflammation, and impaired Nrf2 activation. These abnormalities are accompanied by activation of intrarenal angiotensin system and can be prevented by ARB administration.

  • Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in Focal Glomerulosclerosis.
    Kidney international, 2003
    Co-Authors: Tadashi Sato, Kaihui Liang, Nosratola D. Vaziri
    Abstract:

    Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in Focal Glomerulosclerosis. Background Imai rats exhibit spontaneous Focal Glomerulosclerosis (FGS) with progressive proteinuria and hyperlipidemia leading to renal insufficiency by age 34 weeks. Recently, we reported marked down-regulations of skeletal muscle and adipose tissue lipoprotein lipase (LPL) and very low-density lipoprotein (VLDL) receptor in male Imai rats at 32 weeks of age. Dietary protein restriction and oral adsorbent AST-120 (AST) have been shown to slow progression of renal disease and attenuate hyperlipidemia in the Imai rats. This study tested the hypothesis that amelioration of proteinuria by protein restriction or use of oral adsorbent AST-120 beginning at 10 weeks of age may improve renal disease and LPL and VLDL receptor deficiencies in Imai rats. Methods Ten-week-old male Imai rats were randomly assigned to those fed either a regular diet, low protein diet (LPD), or regular diet containing the adsorbent preparation, AST-120. Ten-week-old male Sprague-Dawley rats served as controls. The animals were observed for 24 weeks. Six rats were included in each group. All diets were prepared in powder form. Results The untreated 34-week-old Imai rats showed severe proteinuria, hypoalbuminemia, 50% reduction in creatinine clearance, hypercholesterolemia, hypertriglyceridemia, and elevated plasma VLDL concentration. This was associated with significant reductions in plasma post-heparin LPL activity, hepatic lipase activity, as well as adipose tissue and skeletal muscle immunodetectable LPL and VLDL receptor proteins. Protein restriction mitigated the decline in creatinine clearance, ameliorated proteinuria, hypoalbuminemia, hypertension, and hypercholesterolemia, lowered plasma VLDL, and improved plasma postheparin LPL activity, hepatic lipase activity, LPL, and VLDL receptor proteins in skeletal muscle and adipose tissue. Similar improvements were observed in all parameters with AST administration. Conclusion Moderate protein restriction and use of oral adsorbent can slow progression of renal disease and, thereby, ameliorate LPL, hepatic lipase, and VLDL receptor deficiencies and the associated hyperlipidemia in rats with spontaneous FGS.

  • Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous Focal Glomerulosclerosis.
    Kidney international, 2003
    Co-Authors: Nosratola D. Vaziri, Tadashi Sato, Kaihui Liang
    Abstract:

    Molecular mechanisms of altered cholesterol metabolism in rats with spontaneous Focal Glomerulosclerosis. Background Imai rats exhibit spontaneous Focal Glomerulosclerosis (FGS), which is marked by heavy proteinuria, severe hyperlipidemia, and progressive renal insufficiency beginning at 8 to 10 weeks of age. In an earlier study, we reported severe skeletal muscle and adipose tissue lipoprotein lipase, and very low-density lipoprotein (VLDL) receptor deficiencies, which account for elevated plasma VLDL and triglycerides in Imai rats at 34 weeks of age. In this study, we investigated key factors involved in cholesterol metabolism. Methods Male Imai and Sprague-Dawley control rats were fed a regular rat chow and observed from age 8 through 34 weeks. Hepatic 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, cholesterol 7α-hydroxylase, low-density lipoprotein (LDL) receptor and acyl Co A:cholesterol acyltransferase (ACAT) were measured by Western blot and plasma lecithin:cholesterol acyltransferase (LCAT) protein was measured by enzyme-linked immunosorbent assay (ELISA). Results At 34 weeks of age, the Imai rats showed severe proteinuria, hypoalbuminemia, 60% reduction in glomerular filtration rate (GFR), elevated plasma total and LDL cholesterol and LDL/high-density lipoprotein (HDL) ratio. Imai rats showed a twofold elevation of hepatic HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, but no significant change in cholesterol 7α-hydroxylase, the rate-limiting enzyme in cholesterol catabolism to bile acids. This was accompanied by and largely due to a threefold down-regulation of hepatic LDL receptor, which limits hepatic uptake of LDL; and a threefold up-regulation of hepatic ACAT ( P Conclusion The study revealed marked abnormalities of the key proteins involved in regulation of hepatic cholesterol metabolism. These abnormalities can account for severe dysregulation of cholesterol metabolism in Imai rats with spontaneous FGS, which closely resembles FGS in humans.

  • Down-regulation of lipoprotein lipase and VLDL receptor in rats with Focal Glomerulosclerosis.
    Kidney international, 2002
    Co-Authors: Tadashi Sato, Kaihui Liang, Nosratola D. Vaziri
    Abstract:

    Down-regulation of lipoprotein lipase and VLDL receptor in rats with Focal Glomerulosclerosis. Background Patients and animals with nephrotic syndrome and those with chronic renal failure (CRF) often exhibit hypertriglyceridemia and impaired very low-density lipoprotein (VLDL) clearance. Imai rats that were originally derived from Sprague-Dawley rats develop spontaneous proteinuria, hyperlipidemia, progressive renal insufficiency and histologic changes of Focal Glomerulosclerosis (FGS), closely resembling human FGS. This study was undertaken to test the hypothesis that elevation of plasma triglyceride and VLDL concentrations in the Imai rats is associated with deficiency of lipoprotein lipase (LPL) and VLDL receptor which are the main pathways of triglyceride-rich lipoprotein clearance. Methods Male Imai and Sprague-Dawley control rats were fed regular rat chow and studied at 10 and 34 weeks of age. Tissue LPL and VLDL-r protein abundance (Western analysis) and post-heparin lipolytic activity were determined. Results At 10 weeks of age, Imai rats showed mild proteinuria, moderate hyperlipidemia, normal creatinine clearance and blood pressure. By 34 weeks of age, the study animal exhibited severe proteinuria, marked hyperlipidemia, significant renal insufficiency and hypertension. This was associated with a severe progressive reduction in skeletal muscle and adipose tissue LPL and VLDL-r protein abundance and depressed plasma post heparin, lipolytic activity. Conclusion Progressive hyperlipidemia in the Imai rats with spontaneous FGS is accompanied by severe combined LPL and VLDL-r deficiencies that can, in part, account for the associated hypertriglyceridemia and elevated plasma VLDL concentrations.