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)

The terms minimal change nephropathy and focal segmental glomerulosclerosis describe histopathological entities diagnosed by renal biopsy, typically in patients presenting with heavy proteinuria and its consequences including nephrotic syndrome. Numerous alterations in the immune response have been reported, but there is uncertainty about whether these play a causal role. In both conditions, there is evidence of injury to glomerular epithelial cells (podocytes), a cell type with limited potential for repair or replacement. The mechanisms of injury are poorly understood but may include immunologically mediated processes such as the effects of soluble mediators produced by lymphocytes. Empirical immunosuppressive therapy with corticosteroids, alkylating agents, and/or calcineurin antagonists is often effective, but the potential for toxicity of these drugs is enormous, and more specific forms of treatment are needed. The focus in recent years has been on the podocyte, and in particular the potential importance of mutations/polymorphisms in podocyte-specific genes as predisposing factors, mechanisms of podocyte injury including study of the role of podocytes as active participants in disease pathogenesis, indices of podocyte injury as markers of disease activity or possible diagnostic tools, and strategies for podocyte repair including the recognition that existing therapies may have effects (beneficial or adverse) on podocytes. Future improvements in the understanding of these diseases and in our ability to successfully treat them can be confidently expected as a result of rapid advances in the study of podocyte biology in health and disease.
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PMID:Minimal change nephropathy and focal segmental glomerulosclerosis. 1795 43

Decreased renal neuronal nitric oxide synthase (nNOS) is present in various chronic kidney diseases although there is relative little known in chronic allograft nephropathy (CAN). Female sex increases the risk of acute rejection and calcineurin-inhibitor toxicity but decreases the risk of CAN. Rapamycin (RAPA) is an alternative immunosuppress although there is no information whether it is effective in females. We therefore investigated the efficacy of RAPA in both sexes and the impact of RAPA on renal cortex structure and nNOS expression. Male (M) and female (F) F344 kidneys were transplanted into same sex Lewis (ALLO) or F344 (ISO) recipients and treated with 1.6 mg/kg/day of RAPA for 10 days. Grafts were removed for renal histology and endothelial (e)NOS and neuronal (n)NOS protein measurements at 22 weeks. All ALLO rats survived without acute rejection. ALLO F survived with mild proteinuria and CAN at 22 weeks similar to ALLO M, while ISO F had better outcome than ISO M. Cortical nNOSalpha was undetectable in all RAPA groups; however, nNOSbeta transcript and protein were compensatory increased. Both ALLO and ISO F showed higher medullary nNOSalpha but lower cortical eNOS abundance than M groups. In male ALLO RAPA decreased renal cortical nNOSalpha but increased nNOSbeta expression. This may represent compensatory upregulation of nNOSbeta when nNOSalpha-derived NO is deficient.
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PMID:Renal cortex neuronal nitric oxide synthase in response to rapamycin in kidney transplantation. 1797 7

The 40th Annual Meeting of the American Society of Nephrology was held in San Francisco, California, U.S.A., October 31-November 5, 2007. This meeting offered the latest findings in basic and clinical nephrology science and was attended by more than 11,000 nephrologists and related scientists from around the world. Recent data on the results of new drugs for the treatment of renal anemia that are under development, such as the continuous erythropoietin receptor activator (CERA), Hematidetrade mark, or the orally active prolyl hydroxylase inhibitors (FG-2216, FG-4592) were presented. The effect of clopidogrel on arteriovenous fistula patency and suitability, and the effects of the use of high-flux membranes on mortality in incident hemodialysis patients were also shown. The renoprotective effects of high doses of candesartan in chronic kidney disease patients with proteinuria or the additional antiproteinuric effects of aliskiren on top of angiotensin AT(1) receptor antagonism in patients with diabetic nephropathy were demonstrated. Recent studies that evaluated the efficacy and safety of new immunosuppressive strategies without calcineurin inhibitors in renal transplant recipients were also reviewed during the congress.
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PMID:The latest advances in kidney diseases and related disorders. 1830 99

Despite their efficacy, the calcineurin inhibitors (CNIs) ciclosporin and tacrolimus carry a risk of debilitating adverse effects, especially nephrotoxicity, that affect the long-term outcome and survival of children who are given organ transplants. Simple reduction in dosage of CNI has little or no long-term benefit on their adverse effects, and complete withdrawal without threatening graft outcome may only be possible after liver transplantation. Until the last decade, the only option was to increase corticosteroid and/or azathioprine doses, which imposed additional long-term hazards. Considered here are the emerging generation of new agents offering an opportunity for improving long-term graft survival, minimizing CNI-related adverse events and ensuring patient well-being.A holistic, multifaceted strategy may need to be considered - initial selection and optimized use and monitoring of immunosuppressant regimens, early recognition of indicators of patient and graft dysfunction, and, where applicable, early introduction of CNI-sparing regimens facilitating CNI withdrawal. The evidence reviewed here supports these approaches but remains far from definitive in paediatric solid organ transplantation. Because de novo immunosuppression uses CNI in more than 93% of patients, reduction of CNI-related adverse effects has focused on CNI sparing or withdrawal.A recurring theme where sirolimus and mycophenolate mofetil have been used for this purpose is the importance of their early introduction to limit CNI damage and provide long-term benefit: for example, long-term renal function critically reflects that at 1 year post-transplant. While mycophenolic acid shows advantages over sirolimus in preserving renal function because the latter is associated with proteinuria, sirolimus appears the more potent immunosuppressant but also impairs early wound healing. The use of CNI-free immunosuppressant regimens with depleting or non-depleting antibodies plus sirolimus and mycophenolic acid needs much wider investigation to achieve acceptable rejection rates and conserve renal function. The adverse effects of the alternative immunosuppressants, particularly the dyslipidaemia associated with sirolimus, needs to be minimized to avoid replacing one set of adverse effects (from CNIs) with another. While we can only conjecture that judicious combinations with the second generation of novel immunosuppressants currently in development will provide these solutions, a rationale of low-dose therapy with multiple immunosuppressants acting by complementary mechanisms seems to hold the promise for efficacy with minimal toxicity until the vision of tolerance achieves reality.
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PMID:Calcineurin inhibitor sparing in paediatric solid organ transplantation : managing the efficacy/toxicity conundrum. 1857 58

Massive urinary protein excretion has been observed after conversion from calcineurin inhibitors to mammalian target of rapamycin (mToR) inhibitors, especially sirolimus, in renal transplant recipients with chronic allograft nephropathy. Because proteinuria is a major predictive factor of poor transplantation outcome, many studies focused on this adverse event during the past years. Whether proteinuria was due to sirolimus or only a consequence of calcineurin inhibitors withdrawal remained unsolved until high range proteinuria has been observed during sirolimus therapy in islet transplantation and in patients who received sirolimus de novo. Podocyte injury and focal segmental glomerulosclerosis have been related to mToR inhibition in some patients, but the pathways underlying these lesions remain hypothetic. We discuss herein the possible mechanisms and the significance of mToR blockade-induced proteinuria.
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PMID:mToR inhibitors-induced proteinuria: mechanisms, significance, and management. 1863 65

Sirolimus (SRL) is a recently available immunosuppressive agent. SRL, is a macrolide isolated from Streptomyces hydroscopicus that, in complex with its cellular receptor, FK binding protein, potently inhibits downstream signaling by the mammalian target of rapamycin (mTOR). It has been shown to reduce the incidence of acute rejection episode after renal transplantation. SRL by itself does not seem to cause significant nephrotoxicity in most animals and human studies in normal conditions. However, when combined with calcineurin inhibitors, serum creatinine levels often increase. The mechanisms for the synergism of this side-effect are still discussed. Furthermore, recent clinical data have shown that the administration of SRL immediately after renal transplant delay the recovery from delayed graft function. This effect may be secondary to the inhibition of the proliferation of the renal tubular cells which is a normal process for tubular repair. Some experimental data have confirmed this hypothesis. Finally, in the long-term, SRL use has been associated with a significant increase of proteinuria which may in the long-term increase the risk of graft loss of cardio-vascular morbio-mortality. For all these reasons, SRL nephrotoxicty has become an important issue after renal transplantation. The review will discuss the clinical and the experimental data regarding this complication, which has been underestimated.
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PMID:Sirolimus early graft nephrotoxicity: clinical and experimental data. 1869 Sep 29

The immunosuppressive action of the calcineurin inhibitor cyclosporine A (CsA) stems from the inhibition of nuclear factor of activated T cells (NFAT) signaling in T cells. CsA is also used for the treatment of proteinuric kidney diseases. As it stands, the antiproteinuric effect of CsA is attributed to its immunosuppressive action. Here we show that the beneficial effect of CsA on proteinuria is not dependent on NFAT inhibition in T cells, but rather results from the stabilization of the actin cytoskeleton in kidney podocytes. CsA blocks the calcineurin-mediated dephosphorylation of synaptopodin, a regulator of Rho GTPases in podocytes, thereby preserving the phosphorylation-dependent synaptopodin-14-3-3 beta interaction. Preservation of this interaction, in turn, protects synaptopodin from cathepsin L-mediated degradation. These results represent a new view of calcineurin signaling and shed further light on the treatment of proteinuric kidney diseases. Novel calcineurin substrates such as synaptopodin may provide promising starting points for antiproteinuric drugs that avoid the serious side effects of long-term CsA treatment.
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PMID:The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. 1919 81

Incidence of cardiovascular complications, cancers and chronic allograft nephropathy (CAN) suggests reduction of immunosuppressive dosages. Some studies analyzed the effects of minimization of immunosuppression until the avoidance of immunosuppressive drugs. However minimization seems to be related to a higher incidence of acute rejection. Induction of tolerance after transplantation and use of immunological tests that could monitor the immune reactivity are required. The aim of this study is to evaluate immunological state in a group of recipients after deceased and living donor kidney transplantation and to minimize immunosuppressive therapy monitoring simultaneously clinical and immunological parameters. We analyzed 41 patients, 38 from deceased donors and 3 from living donor kidney transplantation. All patients were treated with triple immunosuppressive therapy: cyclosporine or sirolimus or tacrolimus, mycophenolate mofetil and steroids. In all recipients the presence of CD8+CD28- T suppressor cells (Ts) was analyzed. Patients were divided in 2 groups, according to the presence of Ts. In patients with Ts, (Group A, n=19), mycophenolate mofetil (MMF) was progressively reduced and then stopped. Steroids were subsequently reduced and then interrupted, maintaining an immunosuppressive therapy with low doses of calcineurin inhibitors (CNI) or sirolimus (SIR). 22 patients were without presence of Ts: we enrolled for the study only patient acute rejection free, without proteinuria and with creatinine levels stable (Group B, n=19). In these patients, MMF was reduced and then stopped, while steroids were decreased to 5 mg at alternate days, maintaining CNI or SIR at medium therapeutic dosages (minimized therapy). Patient and graft overall survival in Group A and in Group B were respectively at 100% and 94.7%. Incidence of acute rejection was respectively at 0% in group A and 15.7% in Group B. Presence of episodes of acute rejection in Group B confirms risk of later minimization of steroids and the relevance of the analysis of recipient immunological reactivity before modification of immunosuppressive therapy. A careful evaluation of recipient immune reactivity with the presence of T regulatory cells can allow adequate and personalized immunosuppressive regimens, without high risks of acute rejection.
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PMID:Minimization of immunosuppressive therapy and immunological monitoring of kidney transplant recipients with long-term allograft survival. 1877 59

Conversion from calcineurin inhibitors (CNI) to proliferation signal inhibitors (PSI), such as sirolimus or everolimus (EV), may improve the course of chronic allograft nephropathy. Herein we have presented a case of a kidney recipient with chronic cyclosporine (CsA) nephrotoxicity who was converted from CsA to EV at 5.5 years posttransplantation. There were no significant changes in immunofluorescence (IFL) or in electron microscopy (EM) in the preconversion biopsy. Two months after conversion, proteinuria and creatinine increased. The biopsy showed focal, segmental necrosis of the glomerular tuft with the formation of segmental cellular crescents and increased endocapillary cellularity. IFL showed granular deposits of IgG, IgM, and C3 mostly along the capillary walls; it was negative for C4d. EM revealed electron-dense deposits within the glomerular basement membrane (GBM) and in the subendothelial region with significant reduction in the capillary lumina due to GBM reduplication and widening of lamina rara interna with the formation of fibrillary structures therein: focal, segmental glomerulosclerosis. EV was withdrawn and we administered tacrolimus and steroid pulses with improvement. Five months after the withdrawal of EV, a third graft biopsy showed remission of the necrotizing glomerulonephritis. However, the patient demanded dialysis at 17 months after conversion to EV. We concluded that necrotizing glomerulonephritis with immune complex deposition in a renal allograft was possibly induced by late conversion from CNI to EV. Reconversion to CNI may be recommended in cases of PSI-associated posttransplantation glomerulonephritis but the long-term prognosis is uncertain.
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PMID:Late conversion to everolimus complicated with necrotizing glomerulonephritis in a renal allograft recipient: case report. 1924 76

Renal disease is a major cause of mortality and morbidity in systemic lupus erythematosus. Among the histological classes of lupus nephritis, membranous nephropathy comprises only one-fifth of all cases. Reported survival and rates of end-stage renal disease in membranous lupus nephropathy (MLN) vary considerably, because of substantial heterogeneity among the published studies. The risk of progression from MLN to renal failure is generally reduced in the absence of proliferative lesions, but patients are, nevertheless, at risk of thromboembolic complications. The optimal therapy for MLN remains elusive because of a lack of controlled trials; however, cardiovascular protection and blockade of the renin-angiotensin system should be instituted early in all patients. Mixed membranous and proliferative lupus nephritis should be treated in the same way as pure proliferative lupus nephritis. If MLN is not accompanied by proliferative lesions but is associated with clinically relevant proteinuria, renal insufficiency or failure to respond to supportive therapies, immunosuppressive treatment is indicated. Treatment options include glucocorticoids combined with azathioprine, calcineurin inhibitors or alkylating agents. The efficacy of mycophenolate mofetil in MLN remains to be confirmed. Controlled trials to compare existing immunosuppressive agents and experimental modalities such as sirolimus, rituximab and infliximab should be undertaken in the future.
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PMID:Membranous nephropathy in systemic lupus erythematosus: a therapeutic enigma. 1932 86


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