Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In puromycin aminonucleoside (PAN)-treated nephrotic rats, sodium retention is associated with increased (Na+/K+)-ATPase activity in the cortical collecting ducts (CCD). This study was undertaken to determine whether stimulation of (Na+/K+)-ATPase in the CCD is a feature of other experimental nephrotic syndromes, whether it might be responsible for renal sodium retention, and whether it is mediated by increased plasma vasopressin levels or activation of calcineurin. For this purpose, the time courses of urinary excretion of sodium and protein, sodium balance, ascites, and (Na+/K+)-ATPase activities in microdissected CCD were studied in rats with PAN or adriamycin nephrosis or HgCl2 nephropathy. The roles of vasopressin and calcineurin in PAN nephrosis were evaluated by measuring these parameters in Brattleboro rats and in rats treated with cyclosporin or tacrolimus. Despite different patterns of changes in urinary sodium and protein excretion in the three nephrotic syndrome models, there was a linear relationship between CCD (Na+/K+)-ATPase activities and sodium excretion in all three cases. The results also indicated that there was no correlation between proteinuria and sodium retention, but ascites was present only when proteinuria was associated with marked reduction of sodium excretion. Finally, the lack of vasopressin in Brattleboro rats or the inhibition of calcineurin by administration of either cyclosporin or tacrolimus did not prevent development of the nephrotic syndrome in PAN-treated rats or stimulation of CCD (Na+/K+)-ATPase. It is concluded that stimulation of Na(+/K+)-ATPase in the CCD of nephrotic rats might be responsible for sodium retention and that this phenomenon is independent of proteinuria and vasopressin and calcineurin activities.
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PMID:Collecting duct (Na+/K+)-ATPase activity is correlated with urinary sodium excretion in rat nephrotic syndromes. 1075 19

Calcium-oxalate crystal deposition in kidney transplant biopsy specimen led us to investigate the impact of calcineurin inhibitor treatment on urinary excretion of lithogenic and stone inhibitory substances in 53 children after successful kidney transplantation (KTx) receiving cyclosporine A (CsA) or tacrolimus. We compared the values obtained with those of 12 patients with recurrent nephrotic syndrome under CsA and of 6 patients with Rasmussen encephalitis (RE) under tacrolimus therapy. Renal ultrasound examinations were repeatedly performed. Hypocitraturia was found in 69% of patients, with KTx patients having a significantly lower urinary citrate excretion than those receiving calcineurin inhibitors for other reasons. Secondly, we found hyperoxaluria in 35% of patients, again especially in those after KTx. No significant difference in urinary substances was seen comparing CsA with tacrolimus treatment. Urolithiasis was found in one and calcium-oxalate crystal deposition in biopsy specimen of three KTx patients. Calcineurin inhibitor treatment can lead to significant hypocitraturia, especially in patients after KTx receiving the highest dose of medication. Hyperoxaluria is primarily the result of a removal of significant body oxalate stores, deposited during dialysis, but may not be suspected as a specific side effect of calcineurin inhibitor therapy. Both findings can increase the risk for urolithiasis or nephrocalcinosis.
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PMID:Hypocitraturia as a risk factor for nephrocalcinosis after kidney transplantation. 1578

Childhood idiopathic nephrotic syndrome (NS) is a chronic glomerular disorder, and if untreated, is associated with increased risk of life-threatening infections, thromboembolism, lipid abnormalities, and malnutrition. The aim of the management of NS in children is to induce and maintain complete remission with resolution of proteinuria and edema without encountering serious adverse effects of therapy. Over 90% of cases in children are due to minimal change disease (MCD) and a majority of them will respond to corticosteroid therapy. Steroid sensitive NS is considered to be a relatively benign condition; progression to end stage renal failure is extremely rare and over 80% achieve spontaneous remission in later childhood. The early disease is characterized by a relapsing course, placing the child at risk of acute complications. The occurrence of frequent relapses necessitates clear therapeutic strategies in order to maintain sustained remission and minimize steroid toxicity. Numerous therapeutic regimens have been proposed utilizing steroid sparing agents such as alkylating agents, principally, cyclophosphamide and chlorambucil, calcineurin inhibitors namely cyclosporin A and immunomodulatory drug levamisole with variable success and associated side-effects. It is therefore important that the benefits and risks of these agents are weighed before considering their use in the treatment of patients with NS.
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PMID:Treatment of steroid sensitive nephrotic syndrome. 1618 79

Successful immunosuppressive therapy is critical for the treatment of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and nephrosis. However, a considerable number of patients have shown clinical resistance to therapy. Bacterial infection might influence the clinical response of patients to immunosuppressive drugs, but few studies have been carried out to investigate the effect of bacterial superantigens on the efficacy of the drugs in these patients. We evaluated the suppressive efficacy of prednisolone, methylprednisolone, cyclosporine, and tacrolimus on the blastogenesis of PBMCs obtained from 12 ANCA-associated vasculitis patients (ANCA patients), eight patients with nephrotic syndrome, and eight healthy subjects. PBMC-stimulation index was calculated from the formula: [3H]thymidine incorporated in the presence of stimulant (dpm)/[3H]thymidine incorporated in the absence of stimulant (dpm). In vitro drug concentrations giving 50% inhibition (IC50s) of PBMC blastogenesis stimulated with concanavalin A (con A) or toxic shock syndrome toxin 1 (TSST-1) derived from Staphylococcus aureus (S. aureus) were calculated. The IC50 values for the four drugs evaluated in TSST-1-stimulated PBMCs were significantly higher than those evaluated in con A-stimulated PBMCs in both ANCA patients and nephrosis patients (p<0.012-0.044). Whereas, the IC50 values for these immunosuppressive drugs, except methylprednisolone, were not significantly different between con A- and TSST-1-stimulated PBMCs in healthy subjects. The stimulation index was not significantly different between the con A- and TSST-1-stimulated PBMCs in either of the subject groups. These observations raise the possibility that TSST-1 induced by S. aureus infection attenuates the clinical efficacy of glucocorticoids and calcineurin inhibitors in ANCA patients and nephrosis patients.
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PMID:Bacterial superantigen TSST-1 attenuates suppressive efficacy of glucocorticoids and calcineurin inhibitors against blastogenesis of peripheral blood mononuclear cells from patients with antineutrophil cytoplasmic antibody-associated vasculitis and nephrosis. 1664 78

Sirolimus has been associated with high-range proteinuria when used in replacement of calcineurin inhibitors in renal transplant recipients with chronic allograft nephropathy (CAN). Primary FSGS was demonstrated previously in some such patients, but the coexistence of CAN lesions made the interpretation uneasy. However, nephrotic syndrome and FSGS were observed recently in three patients who received sirolimus de novo, without medical history of primary FSGS or CAN. Markers of podocyte differentiation were studied in kidney biopsies of the three patients who received sirolimus de novo and of five patients who switched to sirolimus. All patients developed FSGS lesions of classic type (not otherwise specified), but only switched patients exhibited advanced sclerotic lesions. Immunohistochemistry showed that some podocytes in FSGS lesions had absent or diminished expression of the podocyte-specific epitopes synaptopodin and p57, reflecting dedifferentiation, and had acquired expression of cytokeratin and PAX2, reflecting a immature fetal phenotype. Such a pattern of epitope expression provides evidence for podocyte dysregulation. Moreover, a decrease in vascular endothelial growth factor expression was observed in some glomeruli. In conclusion, sirolimus induces FSGS that is responsible for proteinuria in some transplant patients.
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PMID:High sirolimus levels may induce focal segmental glomerulosclerosis de novo. 1769 6

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

There are 3 clearly distinct clinical entities that occur after HCT: TMA, idiopathic CKD, and nephrotic syndrome. The potentially independent role of GVHD and chronic inflammation in the development and progression of idiopathic CKD warrants further investigation. CKD after HCT is a relatively common occurrence. As the indications for and number of transplants performed world wide increases, so will the burden of kidney disease. Identifying those patients at risk for the development of CKD will be important for potential intervention and prevention of CKD and progression to end-stage renal disease in this patient population. There are those patients who will develop CKD that is not related to TBI or the conditioning regimen but rather to complications and/or therapy that occur after HCT, specifically aGVHD and cGVHD and prolonged calcinuerin inhibitor use. The burden of management will fall not only to the nephrologists but the oncologist as well to ensure close monitoring of renal function, blood pressure, and urinalyses posttransplant. It may be that our energies have been misdirected in trying to reduce exposure to TBI, and rather we should try to decrease the inflammatory and cytokine effects of GVHD and reduce exposure to calcineurin inhibitors to prevent CKD in this population of patients.
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PMID:Chronic kidney disease after pediatric hematopoietic cell transplant. 1816 26

Patient survival after cardiac, liver, and hematopoietic stem cell transplant (HSCT) is improving; however, this survival is limited by substantial pretransplant and treatment-related toxicities. A major cause of morbidity and mortality after transplant is chronic kidney disease (CKD). Although the majority of CKD after transplant is attributed to the use of calcineurin inhibitors, various other conditions such as thrombotic microangiopathy, nephrotic syndrome, and focal segmental glomerulosclerosis have been described. Though the immunosuppression used for each of the transplant types, cardiac, liver and HSCT is similar, the risk factors for developing CKD and the CKD severity described in patients after transplant vary. As the indications for transplant and the long-term survival improves for these children, so will the burden of CKD. Nephrologists should be involved early in the pretransplant workup of these patients. Transplant physicians and nephrologists will need to work together to identify those patients at risk of developing CKD early to prevent its development and progression to end-stage renal disease.
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PMID:Chronic kidney disease after liver, cardiac, lung, heart-lung, and hematopoietic stem cell transplant. 1841 1

Focal and segmental glomerular sclerosis (FSGS) is a heterogeneous disease from a clinical, etiological and clinical point of view. FSGS may be idiopathic, usually associated with nephrotic syndrome, which requires an ''etiological'' treatment approach. In addition, hereditary and secondary forms of FSGS have been described. The response to therapy, including steroids, cytotoxic drugs and calcineurin inhibitors, is considered the best clinical indicator of outcome. Many uncertainties exist regarding the best therapeutic approach to FSGS in patients presenting with chronic renal failure. In this setting, before planning any treatment, the physician should always assess the presence of superimposed functional renal insufficiency and evaluate the severity of the renal impairment, the histological picture, previous immunosuppressive treatments, and the individual patient's risk for side effects. Keeping in mind these considerations and in the absence of appropriate studies, we can formulate the following suggestions: 1. there is no absolute contraindication to the use of full-dose prednisone as initial therapy, although the likelihood of a good response is low; 2. the use of cytotoxic drugs is not recommended unless the patient presents with a steroid-responsive form of the disease; 3. in patients with a glomerular filtration rate of less than 40 mL/min, the use of calcineurin inhibitors should be avoided.
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PMID:[Choosing the right treatment approach in focal and segmental glomerular sclerosis with chronic renal failure]. 1904 92

The recent discovery of genes involved in familial forms of nephrotic syndrome represents a break-through in nephrology. To date, 15 genes have been characterized and several new loci have been identified, with a potential for discovery of new genes. Overall, these genes account for a large fraction of familial forms of nephrotic syndrome, but they can also be recognized in 10-20% of sporadic cases. These advances increase diagnostic and therapeutic potentials, but also add higher complexity to the scenario, requiring clear definitions of clinical, histopathological and molecular signatures. In general, genetic forms of nephrotic syndrome are resistant to common therapeutic approaches (that include steroids and calcineurin inhibitors) but, in a few cases, drug response or spontaneous remission suggest a complex pathogenesis. Finally, syndromic variants can be recognized on the basis of the associated extra-renal manifestations. In this educational review, clinical, histological and molecular aspects of various forms of familial nephrotic syndrome have been reviewed in an attempt to define a rational diagnostic approach. The proposed model focuses on practical and economic issues, taking into consideration the impossibility of using genetic testing as starting diagnostic tool. The final objective of this review is to outline a diagnostic flow-chart for clinicians and geneticists and to generate a rational scheme for molecular testing.
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PMID:Familial forms of nephrotic syndrome. 1906 79


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