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)

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.
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PMID:Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing. 1609 17

Sirolimus (SRL) is suspected to induce proteinuria. We retrospectively studied proteinuria in a population of liver (n = 29) and kidney transplant (n = 30) recipients switched to SRL with progressive diminution or withdrawal of calcineurin inhibitors (CNI). We also observed estimated glomerular filtration rate (GFR), modification of treatment with antiproteinuric drugs, and changes in concentration of SRL. Collection of data started 3 months before SRL introduction at a mean follow-up of 21 months. Following SRL introduction, proteinuria was not detected in the 28 liver transplant patients, and was stable in the two others. In the kidney transplant group, proteinuria did not occur in 12 patients, remained stable in three, and was slightly increased in 14 (0.57 +/- 0.93 g/d vs 1.83 +/- 1.26 g/d). For all patients, eGFR remained stable; there was no difference in management of antiproteinuric drugs. As suspected, cyclosporin (CsA) and tacrolimus (FK) serum concentrations were decreased. We observed a significant correlation between the variation of proteinuria and the variation of serum concentration of CsA or FK (respectively, P = .001 and P = .007). On the other hand, we did not find any correlation between variation in proteinuria and concentration of SRL. This retrospective study suggests that in our cohort of liver transplant patients without previous renal damage, SRL did not provoke proteinuria. On the other hand, the slight aggravation of proteinuria in a subgroup of kidney transplant patients seems to be linked to the hemodynamic renal effects due to CNI withdrawal.
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PMID:Is sirolimus responsible for proteinuria? 1618 22

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

Conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) has become an option in patients with chronic allograft nephropathy or other conditions. However, in some cases an increase of proteinuria has been reported after such therapeutic intervention. The aim of this study was to characterize the clinical course of this so far unexplained proteinuria after conversion. We performed a retrospective analysis evaluating 94 renal transplant patients from various Spanish centers. Proteinuria (629 determinations) and clinical developments were analyzed between 6 months before and 6 months after conversion. Patients were divided into three groups according to mean proteinuria before conversion (group A: <300 mg/d; group B: 300 to 2000 mg/d; and group C: >2 g/d). The mean proteinuria level was 1.69 g/24 h (n = 312 determinations) before and 2.36 g/24 h after conversion (n = 317 determinations; P = .006), which corresponds to an overall increase of 25% (1.55 to 1.69 g/24 h considering only determinations of 1 month before and 1 month after conversion; P = NS). We could not detect any clear correlation between proteinuria and serum creatinine nor between changes of proteinuria and changes of serum creatinine. A variance analysis for repeated measures showed an increase in proteinuria compared to the preconversion values (P = .003), and when the three groups of preconversion proteinuria were evaluated separately it could be observed that this change in the evolution of proteinuria was almost completely dependent of an increase in the group C (preconversion proteinuria greater than 2 g/d; P = .03), whereas in the other two groups changes were almost irrelevant. Finally, the switch to SRL in renal transplant recipients is followed by an increase in the level of proteinuria predominantly dependent of an increase in patients with high levels of preconversion proteinuria, whereas it seems to be irrelevant in patients without or with light or moderate proteinuria. These results suggest that this might not be a direct effect of SRL.
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PMID:Evolution of proteinuria after conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) in renal transplant patients: a multicenter study. 1638 55

Autoimmunity results from loss of mechanisms controlling self-reactivity. Autoimmune disorders play an increasingly important role and CD40-CD40 ligand (CD40L) interaction on immunocompentent cells is able to break established immunotolerance. To study the effects of the calcineurin-inhibitor FK506 on CD40L-induced systemic autoimmunity, CD40L transgenic (tg) mice, which spontaneously develop a mixed connective tissue-like disease, were treated with FK506 after onset of overt autoimmunity. Interestingly, FK506-treated CD40L tg mice showed significantly reduced autoimmune dermatitis scores and markedly decreased numbers of lesional infiltrating leukocytes. This finding was associated with diminished lymphadenopathy induced by FK506 treatment. Furthermore, FK506 suppressed the development of cytotoxic/autoreactive CD8(+) T cells as evidenced by the reduced expression of T cell activation markers in treated CD40L tg mice. Importantly, FK506 induced a significant reduction in autoantibody titers in the serum of CD40L tg animals. As CD40L tg mice develop nephritis leading to loss of renal function proteinuria was determined after FK506 injections. Notably, FK506 treatment re-established renal function as indicated by significantly reduced uric protein concentrations of treated CD40L tg mice. Together, these findings show the beneficial therapeutic effects of FK506 for the treatment of CD40L-induced autoimmunity. Additionally, these results demonstrate that FK506 is able to suppress ongoing severe autoimmune responses.
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PMID:FK506 controls CD40L-induced systemic autoimmunity in mice. 1670 68

The mTOR inhibitor sirolimus improves renal transplant function compared with the nephrotoxic calcineurin inhibitors. We evaluated retrospectively the adverse events in 119 of 134 patients getting sirolimus which seemed to be caused by sirolimus. Patients were converted to sirolimus because of malignancies (n = 47), a creeping creatinine (n = 33), or hypertension (n = 26). One cohort had started sirolimus from the time of transplantation (n = 28). A rise in serum lipids and a decrease in hemoglobin were seen relatively regularly, while arthralgia, peripheral edema, gastrointestinal complaints, skin disorders, electrolyte disturbances, and infections occurred only occasionally. Interestingly, 31% of patients developed doubling or more proteinuria. Among renal biopsies, 9/13 showed a glomerulopathy which in 6 cases was de novo and in 3 cases, a presumed recurrence of the primary kidney disease. Thus, we think that caution is required, particularly in connection with preexisting glomerular disease.
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PMID:Side effects of sirolimus. 1664 52

Chronic allograft nephropathy is a major cause for allograft loss in renal transplantation. Sirolimus was recently introduced as a potent non-nephrotoxic alternative to calcineurin inhibitors. In the present study, effects of a conversion protocol were investigated in pediatric chronic allograft nephropathy with declining glomerular filtration rate (GFR), defined by a Schwartz formula clearance below 60 mL/1.73 m(2)/min, steadily increasing serum creatinine and allograft biopsy. In eight children with a median age of 12.8 yr, sirolimus was started at median 32 months after transplantation with a loading dose of 0.24 mg/kg bodyweight (BW), followed by 0.2 mg/kgBW/day, aimed at trough levels of 15-20 ng/mL. Calcineurin inhibitors were reduced to 50% at the start of sirolimus and discontinued at median 7 days when target levels of sirolimus were reached. Following conversion, changes of GFR significantly stabilized (-2.9 vs. +0.4 mL/min/1.73 m(2)/month, p = 0.025). Individual GFR increased in five out of eight patients (p = 0.026), and only one child exhibited unaltered progression of graft failure. In the responders, mean serum creatinine improved by 0.3 mg/dL (p = 0.043). Effects were not dependent on GFR at conversion, or on time post-transplantation. Blood pressure, hematological parameters and proteinuria remained stable during the observation period, and serum lipids increased transiently. About half of the children suffered from infectious complications. No child had to be taken off sirolimus; there was no graft loss during the observation period. In conclusion, conversion from calcineurin inhibitors to sirolimus is an effective protocol with tolerable side effects to stabilize renal graft function for at least one yr in the majority of children with biopsy-proven chronic allograft nephropathy.
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PMID:Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy. 1671 6

Cardiovascular diseases are more common in renal transplant recipients than in the general population, and a number of 'traditional' risk factors, such as smoking, diabetes mellitus and dyslipidaemia, are known to be associated with an increased risk. However, concentrating solely on these risk factors can lead to an underestimation of the true risk in this patient population, because other factors such as C-reactive protein and homocysteine levels are also associated with cardiovascular morbidity and mortality. Renal insufficiency also appears to be a key cardiovascular risk factor in the general population, with increasing proteinuria and decreasing glomerular filtration rate related to increased risk. In renal transplant recipients, a high proportion of whom have some renal insufficiency, the role of graft dysfunction in cardiovascular risk is controversial. While some studies have shown no correlation between graft dysfunction and congestive heart failure or ischaemic heart disease, registry data suggest that increased post-transplant serum creatinine levels are strongly associated with cardiovascular risk. This is believed to be the result of cardiovascular disease developing in the pre-transplantation period, as renal transplantation has been shown significantly to improve cardiovascular risk. As such, renal transplant recipients should be routinely screened for cardiovascular disease pre-transplantation, and immunosuppressive therapy should be tailored to minimize further risk. Different immunosuppressive agents, such as corticosteroids and calcineurin inhibitors, are associated with different exposure to cardiovascular risk, and studies involving withdrawal of these agents have generally shown improvement in parameters such as blood pressure and dyslipidaemia. However, these benefits are often associated with an increased incidence of acute rejection, although overall graft loss and mortality rates are not affected. Further studies are required to determine optimal regimens for minimizing cardiovascular risk in renal transplant recipients.
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PMID:Cardiovascular risk factors in renal transplantation--current controversies. 1681 54

Mycophenolate mofetil (MMF) and sirolimus (SRL) are potent non-nephrotoxic xenobiotic immunosuppressants. Their complementary properties may provide the rationale for their combination in induction and maintenance regimens. MMF, a reversible inhibitor of inosin monophosphate dehydrogenase (IMPDH) acts as an antiproliferative drug; and SRL, an mTOR (mammalian target of rapamycin) inhibitor, inhibits cell proliferation driven by growth factors. Early experiences with the use of the SRL, MMF and steroid combination yielded insufficient prophylaxis of acute rejection. However, the introduction of induction therapy with mono- or polyclonal antilymphocyte antibodies to the SRL-MMF and steroid combination brings an efficient acute rejection prophylaxis, while improving renal function and/or reducing of chronic allograft nephropathy (CAN). However, adverse events related to the use of this drug combination (mainly haematological and surgery-related) result in a high rate of discontinuations in some trials, which may hamper the potential benefits of this calcineurin-inhibitor (CNI)-free strategy. Also, currently under investigation is whether in long-term immunosuppression, in MMF-treated patients, CNIs can be replaced by SRL to avoid and/or halt progression of chronic nephropathy and to improve graft survival. However, some authors reported a high proportion of patients with oral ulcers and proteinuria after switching to SRL. In short, refining the use of MMF and SRL may provide a better risk/benefit ratio to pave the way towards non-nephrotoxic immunosuppression.
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PMID:Mycophenolate mofetil and sirolimus combination in renal transplantation. 1693 Mar 95

Kidney disease after transplantation of a nonrenal organ has been described to be the result of the nephrotoxicity from the commonly used calcineurin-inhibitors as well as other factors. The aim of this study was to evaluate renal function and potential risk factors for the development of chronic renal failure among nonrenal organ recipients. We designed a single-center retrospective study including all 165 of our cardiac and liver recipients between February 1998 and October 2003, collecting clinical, analytic, and therapeutic data. We excluded double transplants and patients with survival less than 6 months. Creatinine clearance was calculated according to the Cockcroft-Gault and the Levey Modification of Diet in Renal Disease (MDRD)-5 equations. Although 165 patients received a cardiac or liver transplantation, 17 died in the first 6 months and three were double transplants; therefore we analyzed 145 patients: 107 (74%) cardiac transplantations and 38 (26%) liver transplantations. There were 106 male and 39 female recipients. The mean age (+/-SD) at the time of transplantation was 54 +/- 10 years and the mean follow-up was 2.9 +/- 1.7 years. Urinalysis before transplantation was only performed in 33 patients (22.8%) including three (2.1%) who had proteinuria. Serum creatinine increased until 12 months after transplantation (P < .001), then it recovered its average level. Creatinine clearance calculated using the aforementioned equations showed a similar pattern, with a progressive decline to 12 months (P < .05), with eventual stabilization or even improvement. The factors that we observed to increase the risk of renal damage were age, female sex, obesity, and the presence of proteinuria prior to transplantation. There was a good correlation (r = 0.96) between cyclosporine but not tacrolimus trough levels and serum creatinine at 48 hours after transplantation.
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PMID:Study of the renal function in nonrenal organ transplantation. 1711 81


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