mycophenolic-acid and Hypertension

Most pregnancies are successful in women with systemic lupus erythematosus, particularly if the disease is quiescent and there are no signs of active nephritis. There is no major impact of immunosuppression on maternal outcome. However, high doses of cyclosporine and glucocorticoids are used which may favor development of hypertension or preeclampsia. Some immunosuppressive drugs may exert toxic effects on the fetus. Glucocorticoids may cause small birth weight, and azathioprine and calcineurin inhibitors may be associated with lower birth weight, gestational age and prematurity. Cyclophosphamide may cause fetal malformation when given in the first trimester. Mycophenolate and leflunomide are teratogenic drugs and should be withdrawn before conception in case of programmed pregnancy or should be rapidly discontinued in case of unexpected pregnancy. Option counseling for pregnancy and correct use of immunosuppressive drugs are prerequisites for a successful pregnancy in women with lupus.

Topics: Contraindications; Cyclosporine; Female; Glucocorticoids; Humans; Hypertension; Immunosuppression Therapy; Isoxazoles; Leflunomide; Lupus Erythematosus, Systemic; Maternal Exposure; Mycophenolic Acid; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Withholding Treatment

Focal segmental glomerulosclerosis (FSGS) is a pathologic condition that represents many disease entities. The goals of therapy are to cure the disease. When this is not possible, the secondary goals are to reduce proteinuria to avoid the complications of nephrotic syndrome and to delay progression of kidney disease. Proteinuria remission is one of the most important independent predictors of kidney survival. Children with FSGS who do not achieve partial or complete remission have a 50% risk of progression to ESRD within 5 years whereas those who enter complete remission have a 5-year kidney survival rate of 90%. Treatment of idiopathic FSGS commonly involves immune-based and nonimmunologic therapy options. This manuscript will review the current state of FSGS therapy for children.

Topics: Adrenal Cortex Hormones; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Monoclonal, Murine-Derived; Antihypertensive Agents; Child; Cyclosporine; Glomerulosclerosis, Focal Segmental; Humans; Hypertension; Immunosuppressive Agents; Mycophenolic Acid; Obesity; Rituximab; Tacrolimus; Treatment Outcome; Vitamin D Deficiency

Focal segmental glomerulosclerosis (FSGS) is the histologic end point of many disease processes that affect the kidney. Clinically, adults with FSGS present with proteinuria that may be accompanied by the nephrotic syndrome. Once identifiable (secondary) causes are excluded, the diagnosis of idiopathic FSGS, a challenging glomerular disease to understand and manage, is made. On the basis of mostly retrospective data, first-line treatment for idiopathic FSGS patients with nephrotic-range proteinuria is a prolonged course of corticosteroids. However, steroid resistance is common and portends an increased risk of long-term decline in kidney function and end-stage kidney disease in these patients compared with responders. Multiple other immunosuppression regimens have been used in steroid-resistant FSGS, some of which have been studied in randomized controlled trials. Here, we review the data on the treatment for idiopathic FSGS in adults.

Topics: Adult; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Hypertension; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Proteinuria; Treatment Outcome

This review summarizes the focus shift from ischemia-reperfusion injury and avoidance of rejection to long-term outcome after pediatric renal transplantation over the past decade. Although there has been excellent 1-year graft and patient survival, low rejection rates can be achieved with modern immunosuppression after pediatric renal transplantation, and patient survival is improved substantially in comparison with dialysis, pediatric renal transplant recipients experience a high prevalence of infections, malignancies, medication side effects, nonadherence, and, most importantly, cardiovascular morbidity and mortality. Additional challenges occur because of a high prevalence of obesity after transplantation and vascular calcifications. There is also in an underappreciation of chronic kidney disease (CKD) in transplant recipients. The etiology of CKD is multifactorial and can affect graft and patient survival. The rigors of treatment for CKD are less compared with CKD in nontransplant recipients. Almost all immunosuppressive drugs are implicated with a risk of hypertension, hyperlipidemia, and diabetogenicity, all of which contribute to cardiovascular morbidity. Corticosteroids exhibit the most substantial risk and also stunt growth. Effective new treatment protocols such as the recent European Tacrolimus and WIthdrawal of STeroids (TWIST) study with rapid steroid withdrawal after 5 days provide promising results without increasing the rejection risk. The shift in focus on long-term complications allows for improved graft outcome. Side effects of immunosuppressive medications require continued attention to further improve long-term outcomes.

Topics: Child; Graft Rejection; Humans; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Reperfusion Injury

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Disease Susceptibility; Drug Administration Schedule; Hemolytic-Uremic Syndrome; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Neoplasms; Postoperative Complications; Sirolimus

Cyclosporine microemulsion (CyA) and tacrolimus (Tac) are the principal immunosuppressants prescribed for adult and pediatric renal transplantation. In the majority of patients, these calcineurin inhibitors have been used in combination with other immunosuppressive drugs, such as azathioprine or mycophenolate mofetil (MMF). In this review we will address the question of what calcineurin inhibitor we should use in an individual pediatric renal transplant patient. Well-designed randomized studies in children showed no difference in short-term patient and graft survival with cyclosporine microemulsion and tacrolimus. However Tac is significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population when used in conjunction with azathioprine and corticosteroids. This difference disappears when calcineurin inhibitors are used in combination with MMF as both Tac and CyA produce similar rejection rates and graft survival. However, Tac is associated with improved graft function at 1 and 2 yr post-transplant. Adverse events of hypomagnesaemia and diarrhea seem to be higher in Tac group whereas hypertrichosis, flu syndrome and gum hyperplasia occurs more frequently in the CyA group. The incidence of post-transplant diabetes mellitus was almost identical between Tac and CyA treated patients. The recommendation drawn from the available data is that both CyA and Tac can be used safely and effectively in children. However Tac may be preferable to CyA because of steroid sparing effect and less hirsutism. We recommend that cyclosporine should be chosen when patients experience Tac-related adverse events. Nevertheless, the best calcineurin inhibitor should be decided on individual patients according to variable risk factors, such as risk of rejection in sensitized patient or delayed graft function. The possibility of adverse events should also be considered.

Topics: Azathioprine; Calcineurin Inhibitors; Child; Clinical Trials as Topic; Cyclosporine; Growth and Development; Hematologic Neoplasms; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Care; Sirolimus; Tacrolimus

This work summarizes recent evidence that suggests that renal infiltration with immune cells plays a role in the pathogenesis of salt-sensitive hypertension. The presence of immunocompetent cells is a conspicuous finding in conditions associated with hypertension induced or maintained by a high salt intake. Studies in models of salt-sensitive hypertension following angiotensin II infusion and nitric oxide synthesis inhibition indicate that a reduction in the tubulointerstitial infiltration of lymphocytes and macrophages during the induction period results in protection from the subsequent development of salt-sensitive hypertension. Reduction of the renal immune infiltrate in spontaneously hypertensive rats results in near normalization of the blood pressure. The reduction in the immune infiltrate is associated with a reduction in the number of cells expressing angiotensin II (some of which are immune cells) and a reduction in renal oxidative stress. Since increased intrarenal angiotensin activity tends to reduce filtered sodium and increase sodium reabsorption, and the tubulointerstitial damage resulting from oxidative stress can induce a shift to the right in the pressure-natriuresis relationship, these findings suggest potential mechanisms by which the immune infiltrate could induce or worsen salt-driven hypertension.

Topics: Animals; Humans; Hypertension; Kidney; Lymphocytes; Mycophenolic Acid; Sodium Chloride

Arterial hypertension is highly prevalent after renal transplantation and may contribute to the risk of cardiovascular disease. Also, arterial hypertension has been reported to be an independent risk factor for graft failure. Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may be important contributing factors to post-transplant hypertension. Recent data from multicenter trials and from conversion studies (cyclosporine to tacrolimus) suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive drugs, including mycophenolate mofetil and rapamycin, are not nephrotoxic and they do not have any hypertensive effect. New immunosuppressive combinations including mycophenolate mofetil in a triple therapy regimen (associated with corticosteroids and cyclosporine) can reduce blood pressure so that corticosteroids can be stopped or cyclosporine reduced or even eliminated. Non-nephrotoxic regimens using rapamycin (sirolimus) as basic immunosuppression, associated with azathioprine or mycophenolate mofetil, could reduce the incidence of post-transplant arterial hypertension. Also, in renal transplant patients initially immunosuppressed with rapamycin, cyclosporine and corticosteroids, after the elimination of CSA, a lower blood pressure is achieved. In summary, new protocols with mycophenolate mofetil and/or rapamycin may permit several combinations that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation.

Topics: Adrenal Cortex Hormones; Blood Pressure; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Sirolimus; Tacrolimus; Time Factors

In this review, therapeutic trials for treatment of IgA nephropathy (Berger's disease) are reviewed and discussed. No disease-specific therapy exists. For treatment of hypertensive patients, angiotensin converting enzyme (ACE) inhibitors are preferred. They also decrease proteinuria and probably slow disease progression. However, there are still no controlled data on the effectiveness of ACE-inhibitors in the absence of hypertension or proteinuria. Renewed enthusiasm for treatment with fish oil arose after the publication of a randomized controlled trial in 1994 and long-term follow-up data of the trial cohort in 1998. Corticoid therapy in IgA nephropathy has been advocated for patients with nephrotic syndrome or crescentic disease. A recent non-randomised trial with long-term follow-up suggests that, in the presence of moderate proteinuria, corticosteroids may ameliorate renal function if administered before the creatinine clearance has decreased below 70 ml/min. Preliminary data suggest that mycophenolate mofetil (MMF) may reduce the risk of clinically significant IgA nephropathy recurring in kidney allografts. Many other promising treatment approaches have been tested, but in most instances results are insufficient for unequivocal conclusions. Several randomized controlled clinical trials are currently testing prednisone, fish oil, ACE-inhibitors, cyclophosphamide, MMF and vitamin E. In the absence of a disease-specific treatment, control of hypertension, proteinuria and probably dyslipidemia are pivotal. Chronic or recurrent infection including ton-sillitis should be treated effectively. Control of daily protein intake to 0.7-0.8 g/kg body weight may retard disease progression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Cyclosporine; Disease Progression; Fish Oils; Glomerulonephritis, IGA; Humans; Hypertension; Immunosuppressive Agents; Mycophenolic Acid; Proteinuria; Steroids; Treatment Outcome

Variable effects of steroid minimization strategies on blood pressure in pediatric renal transplant recipients have been reported, but data on the effect of steroid withdrawal on ambulatory blood pressure and circadian blood pressure rhythm have not been published so far.. In a prospective, randomized, multicenter study on steroid withdrawal in pediatric renal transplant recipients (n = 42) on cyclosporine, mycophenolate mofetil, and methylprednisolone, we performed a substudy in 28 patients, aged 11.2 ± 3.8 years, for whom ambulatory blood pressure monitoring (ABPM) data were available.. In the steroid-withdrawal group, the percentage of patients with arterial hypertension, defined as systolic and/or diastolic blood pressure values recorded by ABPM > 1.64 SDS and/or antihypertensive medication, at month 15 was significantly lower (35.7%, p = 0.002) than in controls (92.9%). The need of antihypertensive medication dropped significantly by 61.2% (p < 0.000 vs. control), while in controls, it even rose by 69.3%. One year after steroid withdrawal, no patient exhibited hypertensive blood pressure values above the 95th percentile, compared to 35.7% at baseline (p = 0.014) and to 14.3% of control (p = 0.142). The beneficial impact of steroid withdrawal was especially pronounced for nocturnal blood pressure, leading to a recovered circadian rhythm in 71.4% of patients vs. 14.3% at baseline (p = 0.002), while the percentage of controls with an abnormal circadian rhythm (35.7%) did not change.. Steroid withdrawal in pediatric renal transplant recipients with well-preserved allograft function is associated with less arterial hypertension recorded by ABPM and recovery of circadian blood pressure rhythm by restoration of nocturnal blood pressure dipping.

Topics: Adolescent; Allografts; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Child; Circadian Rhythm; Cyclosporine; Female; Glomerular Filtration Rate; Glucocorticoids; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Prospective Studies; Transplantation, Homologous; Withholding Treatment

Steroids have had the main role in renal transplant for more than 4 decades. However, chronic use of steroids is associated with many comorbidities, owing to a lack of assessing cost-benefit of steroid avoidance in live-donor renal allotransplants. In this prospective, randomized, controlled study, we aimed to assess the cost-benefit of a steroid-free immunosuppression regimen among Egyptian live-donor renal transplants.. One hundred patients were randomly allocated to receive tacrolimus, mycophenolate mofetil, and steroids for only 3 days (n=50 patients; study group) or tacrolimus, mycophenolate mofetil, and steroids on a maintenance basis (n=50 patients; control group). All patients received basiliximab (Simulect) induction, with median follow-up of 12 months.. Both groups showed comparable graft and patient survivals, rejection episodes, and graft functioning. Posttransplant comorbidities were significantly more prevalent in the steroid-maintenance group. Hypertension was detected in 4% of steroid-free group versus 24% in the steroid-maintenance group (P = .0009). Posttransplant diabetes mellitus, serious infections, and hyperlipidemia were significantly more prevalent in the steroid-maintenance group (P < .05). Associated hospitalization costs were 2.2-fold higher in the steroid-maintenance group than they were in the steroid-free group. One year after transplant, the cost of managing posttransplant comorbidities was significantly higher in steroid-maintenance group, despite comparable costs of immunosuppression.. In low, immunologic risk recipients of live-donor renal transplants, using basiliximab induction and maintenance with tacrolimus, mycophenolate mofetil, steroid avoidance was associated with lower first annual total costs despite comparable immunosuppression costs, which was attributed to lower costs of associated morbidities.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Basiliximab; Comorbidity; Contraindications; Cost-Benefit Analysis; Diabetes Mellitus; Female; Graft Rejection; Humans; Hyperlipidemias; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Steroids; Tacrolimus; Transplantation, Homologous; Treatment Outcome; Young Adult

We conducted a multicenter randomized study in liver transplantation to compare standard-dose tacrolimus to reduced-dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post-transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety-five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37-0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49-0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29-0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced-dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full-dose tacrolimus in adult liver transplantation.

Topics: Adult; Diabetes Complications; Diarrhea; Dose-Response Relationship, Drug; Female; France; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Leukopenia; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Thrombocytopenia; Treatment Outcome

Chronic kidney disease (CKD) has emerged as a significant cause of morbidity and a risk factor for mortality after orthotopic liver transplantation (OLT). The use of calcineurin inhibitor (CNI)-based immunosuppression is an important etiologic factor for developing CKD. CNI discontinuation or minimization protocols with replacement of the CNI with non-nephrotoxic drugs, such as mycophenolate mofetil (MMF) or sirolimus (SRL), may have the potential to preserve or recover renal function.. In this prospective, randomized, single-center study with CNI discontinuation, OLT recipients with CKD (measured glomerular filtration rate [GFRm] 15-45 mL/min/1.73 m(2)) were randomized to either SRL or MMF-based immunosuppression. The main objective was to study the effect of CNI discontinuation on renal function. Secondary aims were to assess the frequency of biopsy-proven acute rejection episodes (BPAR) and adverse events (AE). Renal function was followed with GFRm using 51-Chromium EDTA clearance at baseline, 3 months, and 1 year. Patients were stratified according to baseline GFRm > versus <30 mL/min/1.73 m(2). The 25 patients were enrolled for MMF (n = 13) or SRL (n = 12). The median age at inclusion was 59 years (range, 25-66) and the median number of years after OLT was 4.4 (range, 1-13). Twenty-two patients were followed up for a year; MMF (n = 12) and SRL (n = 10).. Mean GFRm for the whole cohort (n = 25) was 31+/-8 mL/min/1.73 m(2) at baseline. After 3 months the GFRm (n = 23) increased to 40+/-10 mL/min/1.73 m(2) (P = .0001) and at 1 year 42 +/- 11 mL/min/1.73 m(2) (n = 22). There was not significant difference between the MMF and the SRL study arms. The cohort (n = 8) with baseline GFRm <30 mL showed a 63% (P = .003) increased filtration after 1 year. There was no significant difference in the frequency or severity of AE between the study arms with the exception of oral ulcerations and persistent hypertriglyceridemia in the SRL group. Two deaths occurred, 1 in each study arm, both probably unrelated to the change in immunosuppression. There were no BPAR episodes.. CNI discontinuation and replacement with either MMF or SRL resulted in a significant improvement in renal function even in those patients with severe CKD. The protocol was effective with no acute rejection episodes. The SRL arm showed a higher frequency of oral apthous ulcerations and hypertriglyceridemia. Future studies addressing long-term renal function after CNI discontinuation are needed.

Topics: Adult; Antihypertensive Agents; Calcineurin Inhibitors; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Liver Transplantation; Mycophenolic Acid; Prospective Studies; Sirolimus

Although mycophenolate mofetil (MMF) monotherapy has been successfully used in liver transplant recipients suffering from calcineurin-inhibitor (CNI)-related chronic toxicity, still no consensus has been reached on its safety, efficacy and tolerability. We attempted the complete weaning off CNI in 42 individuals presenting chronic renal dysfunction and/or dyslipidemia and/or arterial hypertension and simultaneously introduced 1.5 gm/day MMF. CNI could be completely withdrawn in 41 cases. A total of 32 (75%) patients are currently on

Topics: Adult; Aged; Calcineurin Inhibitors; Cholesterol; Dyslipidemias; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Time Factors; Triglycerides

Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid-free regimen in a 6-month, open-label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5-15 ng/ml in the first month and 5-10 ng/ml thereafter). One intra-operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C-positive patients (8.6%) and hepatitis C-negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post-transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid-free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Female; Graft Rejection; Humans; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Infections; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Safety; Tacrolimus

Calcineurin inhibitor (CNI)-free regimens posttransplantation have been claimed to conserve graft function in addition to reduce the risk factors for cardiovascular and malignant disease in renal transplant recipients.. The primary aim of this prospective, open-label, randomized, parallel-group, single-center study was to compare the effect of complete CNI-avoidance posttransplant (daclizumab + mycophenolate mofetil + prednisolone: Dac-group, n=27) with the standard CNI-based immunosuppressive protocol at our transplant unit (cyclosporine A + mycophenolate mofetil + prednisolone: CsA-group, n=27) on renal function (glomerular filtration rate [GFR] determined as plasma clearance of 51Cr-EDTA) in a selected low immunogenic risk population (DR-matched, PRA-negative de novo cadaveric transplant recipients).. There were no significant difference in GFR at week 10 (P=0.61), but GFR was significantly (P=0.029) lower in the Dac-group (52+/-20 ml/min) at month 12 than in the CsA-group (69+/-29 ml/min). One-year patient and graft survival did not differ between the two groups. Overall acute rejection rate was 70.4% (19/27) in the Dac-group and 29.6% (8/27) in the CsA-group (P=0.006).. The strategy to select DR-matched, PRA-negative de novo cadaveric transplant recipients for a CNI-avoidance protocol was not successful. The incidence of acute rejection was unacceptable high even though anti-CD25 antibody induction as well as initial higher mycophenolate mofetil doses (3 g/day) were applied, and renal function was significantly lower in the CNI-avoidance patients at 1 year. Other strategies need to be examined for avoidance of CNI's in the early posttransplant period.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; Cyclosporine; Daclizumab; Diabetes Mellitus; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Histocompatibility; Humans; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Tacrolimus; Tissue Donors; Urinary Tract Infections

Evidence that was obtained in several experimental models and in strains of hypertensive rats indicates that infiltration of inflammatory cells and oxidative stress in the kidney play a role in the induction and maintenance of hypertension. Similar evidence is lacking in human hypertension, at least in part, because immunosuppressive treatment is unjustified in patients with hypertension. For addressing this issue, patients who were prescribed by their private physicians mycophenolate mofetil (MMF) for the treatment of psoriasis or rheumatoid arthritis and had, in addition, grade I essential hypertension and normal renal function were studied. Eight patients were studied before MMF was started, during MMF treatment, and 1 mo after MMF treatment had been discontinued. Other treatments and diet were unchanged in the three phases of the study. MMF therapy was associated with a significant reduction in systolic, diastolic, and mean BP. Urinary excretion of TNF-alpha was reduced progressively by MMF treatment and increased after MMF was discontinued. Reduction of urinary malondialdehyde, TNF-alpha, and RANTES excretion during MMF administration did not reach statistical significance but had a direct positive correlation with the BP levels. These data are consistent with the hypothesis that renal immune cell infiltration and oxidative stress play a role in human hypertension.

Topics: Aged; Arthritis, Rheumatoid; Blood Pressure; Chemokine CCL5; Dose-Response Relationship, Drug; Female; Humans; Hypertension; Immunosuppressive Agents; Inflammation; Male; Middle Aged; Mycophenolic Acid; Psoriasis; Tumor Necrosis Factor-alpha

Chronic steroid therapy in kidney transplantation has myriad side effects and steroid avoidance has become feasible. This prospective study compared the safety and efficacy of steroid avoidance in tacrolimus (TAC)/mycophenolate mofetil (MMF) and TAC/sirolimus (SRL) combinations in kidney transplantation.. In all, 150 kidney recipients were analyzed: 75 each in TAC/MMF and TAC/SRL groups. The primary endpoint was acute rejection. Surveillance biopsies were completed to analyze subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN). Acute rejection and SCAR were treated by methylprednisolone. Two-year patient and graft survival, renal function, and adverse effects were monitored.. Acute rejection was seen in 12% of TAC/MMF and 8% of TAC/SRL patients. Two-year actuarial patient survival was 95% and 97%, and graft survival 90% and 90% in TAC/MMF and TAC/SRL groups, respectively. Surveillance biopsy showed cumulative incidence of SCAR was 27 % in TAC/MMF and 16 % in TAC/SRL groups at 2 years (P = 0.04). Overall, 33% of recipients in TAC/MMF and 20% in TAC/SRL received methylprednisolone for acute rejection/SCAR. Moderate/severe CAN was 10% in TAC/SRL group and 22% in TAC/MMF group(P = 0.06). New-onset diabetes mellitus (NODM) was 4% each in both groups. All recipients remain free of maintenance steroid therapy.. Steroid avoidance in tacrolimus-based immunosuppression with MMF or SRL provides equivalent 2-year patient and graft survival with a low incidence of acute rejection and NODM. SCAR and CAN are lower in TAC/SRL compared to TAC/MMF group. The impact of decreased SCAR and CAN in TAC/SRL group on longer-term graft survival and function is to be evaluated.

Topics: Acute Disease; Adult; Biopsy; Body Mass Index; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hypertension; Kidney Transplantation; Lipids; Lymphocele; Male; Middle Aged; Monitoring, Immunologic; Mycophenolic Acid; Sirolimus; Steroids; Tacrolimus; Wound Healing

Mycophenolate mofetil (MMF)-based immunosuppression has reduced the acute rejection rate in adults and in children in the early posttransplantation period. Three-year posttransplantation results have been reported for adults but not for children thus far. In the present open-labeled study, patients 18 years old and younger were evaluated prospectively for up to 3 years after renal transplantation (RTX).. Eighty-six patients receiving MMF in combination with cyclosporine and prednisone without induction were evaluated for patient survival, transplant survival, renal function, arterial blood pressure, adverse events, and opportunistic infections. These patients were compared with a historic control group (n=54) receiving azathioprine (AZA) instead of MMF.. Patient survival after 3 years was 98.8% in the MMF group and 94.4% in the AZA group (NS). Intent-to-treat analysis of graft survival demonstrated superiority for MMF (98% vs. 80%; P<0.001). Cumulative acute rejection episodes occurred in 47% of patients in the MMF group versus 61% in the AZA group (P<0.05). Renal function was not significantly different, neither after 3 years nor in the long-term calculation. Antihypertensive medication was administered to 73% to 84% of patients, similar in both groups. Opportunistic infections were recorded only for MMF. Infection rates were comparable to those reported in adults.. These results suggest that MMF is safe and beneficial as a longer term maintenance immunosuppressive drug in children and adolescents.

Topics: Acute Disease; Adolescent; Azathioprine; Blood Pressure; Child; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Prospective Studies; Treatment Outcome

This is the first report of a randomized, multicenter, clinical trial comparing the combination of sirolimus or mycophenolate mofetil (MMF) with tacrolimus-based immunosuppression in kidney transplantation. Results at 6 months of follow-up are presented.. Before transplantation, patients were randomized to receive tacrolimus plus corticosteroids with sirolimus (n=185) or MMF (n=176). The primary endpoint of the study was the incidence of biopsy-confirmed acute rejection. Patient and graft survival, renal function, and composite endpoints also were evaluated. Safety was assessed by monitoring laboratory parameters and adverse events.. By 6 months of follow-up, the incidence of biopsy-confirmed acute rejection was similar in both treatment groups (13.0% tacrolimus+sirolimus vs. 11.4% tacrolimus+MMF; P=0.64 log-rank). Patient survival (97.3% tacrolimus+sirolimus vs. 97.7% tacrolimus+MMF) and graft survival (93.0% tacrolimus+sirolimus vs. 95.5% tacrolimus+MMF) were equivalent (P=0.53, overall survival log-rank). There was a significantly higher incidence of study drug discontinuation in patients receiving sirolimus (21.1% vs. 10.8%; P=0.008). Renal function was significantly better in the MMF-treatment group (serum creatinine 1.44+/-0.45 mg/dL vs. 1.77+/-1.42 mg/dL; P=0.018). Hyperlipidemia was significantly more prevalent in the sirolimus-treatment group. Diastolic blood pressure was significantly higher in sirolimus-treated patients. There were significantly more leukopenia and gastrointestinal adverse events in the MMF-treatment group. The incidence of posttransplant diabetes mellitus was 7.6% in the sirolimus group and 7.7% in the MMF group.. Tacrolimus is equally effective in renal transplantation when combined with sirolimus or MMF. The tacrolimus-MMF combination may be superior in terms of improved renal function and improved cardiovascular risk factors including hyperlipidemia and hypertension.

Topics: Acute Disease; Adult; Cardiovascular Diseases; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Sirolimus; Survival Analysis; Tacrolimus; Time Factors

Calcineurin inhibitors (CIs) cause substantial long-term morbidity and mortality among orthotopic liver transplantation (OLT) patients. Our aim was to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) among OLT patients with CI-related side effects.. Thirty three adult patients, including 29 men and 4 women of mean age 57 years, underwent OLT between 1986 and 2000 under treatment with CIs (28 cyclosporine and five tacrolimus). Mean follow-up after OLT was 59 months. Adverse effects were renal dysfunction in 26, hypertension in 23, and neurotoxicity in two. MMF was added gradually while simultaneously reducing the dosage of CI.. After a mean 15-months follow-up of MMF treatment, CIs had been withdrawn in 28 patients (85%). The mean time from the initiation of MMF and CI withdrawal was 5 months. During the first year of follow-up chronic renal dysfunction improved in 16 of 26 patients (61.6%) accompanied by a decreased serum creatinine and urea and an increase in creatinine clearance. Among 13/23 (56.5%) hypertensive patients, there was a significant decrease in blood pressure or the number of antihypertensive drugs (P<.05). One patient with neurotoxicity improved. Twenty-two patients (66%) displayed adverse events: five rejections (15%) including four acute episodes, controlled by CI re-introduction, and one chronic reaction. The most frequent adverse effects were herpes simplex infection in 10 patients (30%), asthenia in nine (27%), diarrhea in five (15%) and thrombocytopenia in four (12%). Nevertheless, only six patients (19%) required MMF dose reduction, namely, three patients with GI intolerance, two with repeated VHS infections, and one with anemia.. MMF monotherapy improves renal function and blood pressure levels in more than 50% of patients with chronic renal impairment and hypertension after OLT. Many of the side effects of MMF were mild; it was safe accompanied by a low incidence of rejection reactions.

Topics: Adult; Blood Pressure; Creatinine; Cyclosporine; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Reproducibility of Results; Tacrolimus; Time Factors

Black American heart transplant recipients receiving cyclosporine-based primary immunoprophylaxis suffer higher rates of allograft rejection with hemodynamic compromise, infections, and posttransplant coronary artery disease. We examined the hypothesis that a combination of tacrolimus and mycophenolate mofetil "resurrects" clinical outcome of black Americans to those seen in white heart transplant recipients.. Sixty-three adult primary heart transplant recipients were included in this study. Twenty black American and 21 white patients who received tacrolimus-based primary immunoprophylaxis were enrolled in this prospective, observational parallel cohort investigation. A separate group of 22 black American patients were randomly allocated to receive cyclosporine-microemulsion-based primary prophylaxis and served as the control population for assessing outcomes in the black American group. Adjunctive immunosuppression included mycophenolate mofetil and corticosteroids. The primary end-point was the freedom from allograft rejection requiring treatment at 1 year. Secondary end-points included rejection with hemodynamic compromise, and patient or graft survival. Adverse events evaluated included development of infections requiring hospitalization and nonimmunological outcomes including hyperlipidemia, hypertension, and diabetes mellitus (new onset or worsened).. Tacrolimus-treated black American patients had greater freedom from allograft rejection requiring treatment at 1 year than those treated with cyclosporine (64% vs. 37%, P=0.01). No differences were noted between tacrolimus-treated black Americans and whites in the primary end point (64% and 67% respectively, P=nonsignificant [NS]). Tacrolimus-based immunosuppression was associated with better 1-year survival in black Americans compared with cyclosporine (95% vs. 73%, P=0.04), and this end point was similar to that achieved in tacrolimus-treated white heart transplant recipients (95%). No differences in infection rates were noted among either group. Cyclosporine-treated black Americans suffered more hyperlipidemia and worse hypertension than tacrolimus-treated patients.. Compared with cyclosporine, an immunosuppressive strategy using tacrolimus in black Americans achieves superior efficacy with regard to allograft rejection, higher allograft survival, and similar safety. Furthermore, tacrolimus-based immunosuppression is similar in immunological efficacy and safety in black Americans and in white heart transplant recipients.

Topics: Adult; Aged; Black or African American; Black People; Body Weight; Creatinine; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Hemodynamics; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous; Treatment Outcome; White People

Topics: Azathioprine; Biopsy; Blood Pressure; Cholesterol; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Proteinuria; Tacrolimus; Triglycerides

The long-term complications of immunosuppressive therapy such as diabetes, hypercholesterolemia, and hypertension are a major source of morbidity in liver transplant recipients. In this prospective, randomized, open-label study we completely withdrew prednisone (PRED) 14 days after liver transplantation in an effort to decrease these metabolic complications. Patients were maintained on mycophenolate mofetil (MMF) in combination with either cyclosporine (CsA; Neoral formulation) or tacrolimus (TAC). Thus, we also were able to compare CsA to TAC in patients not receiving PRED with respect to efficacy, toxicity, and effect on posttransplant metabolic complications.. A total of 71 patients were randomized to receive either TAC-MMF (n=35) or CsA-MMF (n=36) after liver transplantation and were analyzed for patient and graft survival. Fifty-eight patients continued the immunosuppressive protocol for at least 6 months after transplantation and were analyzed for the incidence of acute rejection and the prevalence of diabetes, hypertension, and hypercholesterolemia.. The 6-month patient survival rates were 94.4% for CsA-MMF and 88.6% for TAC-MMF. Corresponding 6-month graft survival rates were 88.7% and 85.71% with no immunologic graft losses in either group. The incidence of biopsy-proven acute rejection was 46% for CsA-MMF and 42.3% for TAC-MMF. Six patients were converted from CsA to TAC (four for recurrent rejection) and seven patients were converted from TAC to CsA (four for neurotoxicity). Only one patient (in the TAC-MMF group) developed new-onset posttransplant diabetes. In contrast, four of eight patients in the CsA-MMF group who were diabetic before transplant became nondiabetic in the first 3 months after transplant. The mean serum cholesterol level was significantly lower in the TAC-MMF group than in the CsA-MMF group (145.2+/-41.8 mg/dl and 190.3+/-62.2, respectively; P<0.001) and the incidence of hypertension was lower in the TAC-MMF group (12% vs. 30.3% in the CsA-MMF group, P<0.01). Both groups had a lower incidence of metabolic complications compared with a historical group (n=100) maintained on CsA and PRED (10 mg/day at 6 months).. MMF in combination with either TAC or CsA allows withdrawal of PRED 14 days after liver transplantation with a moderate rejection rate and no immunologic graft losses. Early PRED withdrawal decreases posttransplant diabetes, hypercholesterolemia, and hypertension, but patients maintained on TAC have lower serum cholesterol levels and a lower incidence of hypertension than CsA-treated patients.

Topics: Acute Disease; Adult; Cyclosporine; Diabetes Mellitus; Drug Administration Schedule; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Transplantation; Mycophenolic Acid; Prednisone; Prospective Studies; Survival Analysis; Tacrolimus; Time Factors

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that primarily affects women of childbearing age. While immune system dysfunction has been implicated in the development of hypertension (HTN) in SLE, the effect of immunomodulatory drugs on blood pressure (BP) control in SLE patients is unknown. In the present study, we hypothesized that first-line immunomodulatory therapies prescribed to SLE patients would have a beneficial impact on BP. We retrospectively analyzed the Research Data Warehouse containing de-identified patient data (n = 1,075,406) from the University of Mississippi Medical Center for all patients with a clinical diagnosis of SLE. BP responses were analyzed in SLE patients that were initially prescribed a single therapy (methotrexate, hydroxychloroquine, azathioprine, mycophenolate mofetil (MMF), or prednisone). Of the 811 SLE patients who met criteria, most were hypertensive (56%), female (94%), and black (65%). Individuals prescribed MMF or hydroxychloroquine had significantly decreased BP and improved BP control at follow-up (>7 days and <3 months after initial visit). Our results suggest that MMF and hydroxychloroquine have beneficial effects on BP, independent of adjunctive antihypertensive therapies and existing renal disease.

Topics: Antihypertensive Agents; Female; Humans; Hydroxychloroquine; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mycophenolic Acid; Retrospective Studies

The association of different therapeutic approaches with long-term cardiovascular and metabolic outcomes in patients with pemphigus remains to be precisely evaluated.. To assess the risk of long-term cardiovascular and metabolic outcomes and all-cause mortality in patients with pemphigus managed by rituximab compared with those receiving treatment with first-line corticosteroid-sparing agents (azathioprine and mycophenolate mofetil [MMF]).. A global population-based retrospective cohort study compared 961 patients with pemphigus that was managed with rituximab with those treated with azathioprine or MMF (n = 961) regarding the risk of several cardiovascular and metabolic outcomes. Propensity score matching was performed to optimize comparability. Patients were enrolled from the Global Collaborative Network of TriNetX platform.. Risk of myocardial infarction, stroke, peripheral vascular disease, pulmonary embolism, hypertension, hyperlipidemia, type 2 diabetes, obesity, osteoporosis, and avascular bone necrosis.. Of 1602 participants, 855 (53.4%) were women and 747 (46.6%) were men; the mean (SD) age was 54.8 (16.6) years for those treated with rituximab and 54.4 (18.2) years for those treated with azathioprine or MMF. Compared with those treated by azathioprine/MMF, patients treated with rituximab experienced a lower risk of myocardial infarction (relative risk [RR], 0.45; 95% CI, 0.24-0.86; P = .01), stroke (RR, 0.42; 95% CI, 0.26-0.69; P < .001), peripheral vascular disease (RR, 0.47; 95% CI, 0.28-0.79; P = .003), hypertension (RR, 0.48; 95% CI, 0.38-0.63; P < .001), hyperlipidemia (RR, 0.45; 95% CI, 0.32-0.64; P < .001), type 2 diabetes (RR, 0.63; 95% CI, 0.51-0.77; P < .001), obesity (RR, 0.49; 95% CI, 0.34-0.72; P < .001), and osteoporosis (RR, 0.46; 95% CI, 0.30-0.71; P < .001). The all-cause mortality was comparable between patients in both groups (hazard ratio, 0.94; 95% CI, 0.62-1.43; log-rank P = .77).. The results of this cohort study suggest that rituximab was associated with protection against long-term cardiovascular and metabolic outcomes compared with conventional immunosuppressants. This agent might be particularly preferred in individuals with preexisting cardiovascular and metabolic risk factors.

Topics: Azathioprine; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Myocardial Infarction; Pemphigus; Peripheral Vascular Diseases; Retrospective Studies; Rituximab; Stroke

Kidney transplantation (KT) restores the fertility of women with end-stage kidney disease (ESKD), thus offering them the possibility of having children. However, pregnancy after kidney transplantation is associated with high maternal-fetal morbidity. The purpose of this work is to report the experience of our service in pregnancies in kidney transplant recipients.. We retrospectively studied the records of transplant recipients who had one or more pregnancies after KT. We analyzed clinical (blood pressure, weight gain, oedema, duration of pregnancy, obstetric complication) and biological (creatinine, urinary albumin excretion) parameters.. Between 1998 and 2020, twenty-one pregnancies occurred in 12 transplant recipients. The average age of patients at the time of conception was 29 ± 5 years with a delay between KT and pregnancy of 43 ± 29 months. Seven pregnancies began with arterial hypertension (HTA) controlled under treatment, proteinuria before conception was negative in all pregnancies and renal function was normal with an average creatinine level of 10.1 ± 1,27 mg/L. Prior to pregnancy, immunosuppression regimens were based on anticalcineurin (n = 21) combined either with mycophenolate mofetil (MMF) (n = 10) or azathioprine (n = 8) or alone (n = 3). Immunosuppression regimens were all associated with corticosteroid therapy. Three months before conception, MMF was relayed by azathioprine in seven pregnancies, on the other hand three other unplanned pregnancies, started under MMF. During pregnancy, the appearance of proteinuria greater than 0,5 g/24 h was noted in three pregnancies in the third trimester. Pregnancy hypertension was found in three pregnancies, one of which progressed to pre-eclampsia. As for renal function, it remained stable with an average creatinine level of 10,3 mg/l in the 3rd trimester. Two cases of acute pyelonephritis were noted. No episode of acute rejection was noted during and 3 months after pregnancy. The delivery was performed by caesarean section in 44.4 %, after an average term of 37 week of amenorrhea ± 2.04 with three cases of prematurity. The average birth weight was 3 110 g ± 450 g. There was one case of spontaneous abortion and two cases of fetal death in utero. After post-partum, renal function remained stable in five patients. In six cases, there was impaired renal function either by acute rejection or secondary to chronic allograft nephropathy.. In our department, a quarter of transplant recipients were able to carry a pregnancy with a rate of 89 % of successful pregnancies. Pregnancy after KT requires special planning and monitoring. A multidisciplinary collaboration between transplant nephrologist, gynecologist and pediatrician is necessary by referring to the recommendations.. La transplantation rénale (TR) permet de restaurer la fertilité des femmes en insuffisance rénale chronique terminale (IRCT), leur offrant ainsi la possibilité d’avoir des enfants. Toutefois, la grossesse après greffe rénale est associée à une morbidité materno-fœtale élevée. Le but de ce travail est de rapporter l’expérience de notre service dans les grossesses chez les transplantées rénales.. Nous avons étudié rétrospectivement les dossiers de transplantées ayant eu une ou plusieurs grossesses après TR. Nous avons analysé des paramètres cliniques (tension artérielle, prise de poids, œdèmes, durée de grossesse, complications obstétricales) et biologiques (créatininémie, excrétion urinaire d’albumine).. Entre 1998 et 2020, 21 grossesses ont eu lieu chez 12 transplantées. L’âge moyen des patientes au moment de la conception était de 29 ± 5 ans avec un délai entre la TR et la grossesse de 43 ± 29 mois. Sept grossesses ont débuté avec une hypertension artérielle (HTA) contrôlée sous traitement, la protéinurie avant conception était négative dans toutes les grossesses et la fonction rénale était normale avec une créatininémie moyenne de 10,1 ± 1,27 mg/L. Avant les grossesses, les régimes d’immunosuppression étaient à base d’anticalcineurine (n = 21), associé soit à du mycophénolate mofétil (MMF) (n = 10) soit à de l’azathioprine (n = 8), ou seul (n = 3). Les régimes d’immunosuppression ont tous été associés à une corticothérapie. Trois mois avant la conception, le MMF a été relayé par l’azathioprine dans sept grossesses, et trois autres grossesses non programmées ont débuté sous MMF. Au cours des grossesses, on a noté l’apparition d’une protéinurie supérieure à 0,5 g/24 h dans trois grossesses au troisième trimestre. L’HTA gravidique a été retrouvée dans trois grossesses, dont une a évolué vers une pré-éclampsie. Quant à la fonction rénale, elle est restée stable avec une créatininémie moyenne de 10,3 mg/L au troisième trimestre. Deux cas de pyélonéphrite aiguë ont été notés. Aucun épisode de rejet aigu n’a été noté au cours et trois mois après la grossesse. L’accouchement a été réalisé par césarienne dans 44,4 %, après un terme moyen de 37 semaines d’aménorrhée, ± 2,04 avec trois cas de prématurité. Le poids de naissance moyen était de 3 110 g ± 450 g. On a noté un cas d’avortement spontané et deux cas de mort fœtale in utero. Après le post-partum, la fonction rénale est restée stable chez cinq patientes. Dans six cas, on a assisté à une altération de la fonction rénale par un rejet aigu ou secondaire à une néphropathie chronique d’allogreffe.. Dans notre service, un quart des transplantées a pu mener une grossesse avec une productivité de 89 % de ces grossesses. La grossesse après la TR nécessite une planification et une surveillance particulière. Une collaboration multidisciplinaire entre néphrologue transplanteur, gynécologue et pédiatre est nécessaire en se référant aux recommandations.

Topics: Azathioprine; Cesarean Section; Child; Child, Preschool; Creatinine; Female; Graft Rejection; Hospitals; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies

C3 glomerulonephritis (C3GN) can be a devastating disease with poor response to immunosuppressive therapy. Complement inhibition with eculizumab has had equivocal results in patients with C3GN.. We report a case of a 6-year-old boy with C3GN presenting with nephrotic syndrome, severe hypertension and impaired kidney function. He did not respond to initial treatment with prednisone and mycophenolate (mofetil and sodium), and subsequent treatment with standard dosing of eculizumab. Pharmacokinetic studies identified a lack of eculizumab exposure and subsequent intensification of treatment with weekly dosing of eculizumab led to significant clinical improvement: his kidney function normalized, hypertension (weaned off 3 antihypertensive drugs), edema and proteinuria improved. Additionally, exposure to mycophenolic acid (MPA), active metabolite of mycophenolate, determined by area under the concentration-time curve of MPA was low throughout, despite significant dosing escalation.. This case report demonstrates that individualized therapy guided by therapeutic drug monitoring might be needed in patients with nephrotic range proteinuria treated with eculizumab and mycophenolate (mofetil and sodium), an important finding that needs to be considered for further treatment trials.

Topics: Child; Drug Monitoring; Glomerulonephritis; Humans; Hypertension; Immunosuppressive Agents; Male; Mycophenolic Acid; Proteinuria

Kidney transplantation (KT) restores the fertility of women with end-stage kidney disease (ESKD), thus offering them the possibility of having children. However, pregnancy after kidney transplantation is associated with high maternal-fetal morbidity. The purpose of this work is to report the experience of our service in pregnancies in kidney transplant recipients.. We retrospectively studied the records of transplant recipients who had one or more pregnancies after KT. We analyzed clinical (blood pressure, weight gain, oedema, duration of pregnancy, obstetric complication) and biological (creatinine, urinary albumin excretion) parameters.. Between 1998 and 2020, twenty-one pregnancies occurred in 12 transplant recipients. The average age of patients at the time of conception was 29 ± 5 years with a delay between KT and pregnancy of 43 ± 29 months. Seven pregnancies began with arterial hypertension (HTA) controlled under treatment, proteinuria before conception was negative in all pregnancies and renal function was normal with an average creatinine level of 10.1 ± 1,27 mg/L. Prior to pregnancy, immunosuppression regimens were based on anticalcineurin (n = 21) combined either with mycophenolate mofetil (MMF) (n = 10) or azathioprine (n = 8) or alone (n = 3). Immunosuppression regimens were all associated with corticosteroid therapy. Three months before conception, MMF was relayed by azathioprine in seven pregnancies, on the other hand three other unplanned pregnancies, started under MMF. During pregnancy, the appearance of proteinuria greater than 0,5 g/24 h was noted in three pregnancies in the third trimester. Pregnancy hypertension was found in three pregnancies, one of which progressed to pre-eclampsia. As for renal function, it remained stable with an average creatinine level of 10,3 mg/l in the 3rd trimester. Two cases of acute pyelonephritis were noted. No episode of acute rejection was noted during and 3 months after pregnancy. The delivery was performed by caesarean section in 44.4 %, after an average term of 37 week of amenorrhea ± 2.04 with three cases of prematurity. The average birth weight was 3 110 g ± 450 g. There was one case of spontaneous abortion and two cases of fetal death in utero. After post--partum, renal function remained stable in five patients. In six cases, there was impaired renal function either by acute rejection or secondary to chronic allograft nephropathy.. In our department, a quarter of transplant recipients were able to carry a pregnancy with a rate of 89 % of successful pregnancies. Pregnancy after KT requires special planning and monitoring. A multidisciplinary collaboration between transplant nephrologist, gynecologist and pediatrician is necessary by referring to the recommendations.. La transplantation rénale (TR) permet de restaurer la fertilité des femmes en insuffisance rénale chronique terminale (IRCT), leur offrant ainsi la possibilité d’avoir des enfants. Toutefois, la grossesse après greffe rénale est associée à une morbidité materno-fœtale élevée. Le but de ce travail est de rapporter l’expérience de notre service dans les grossesses chez les transplantées rénales.. Nous avons étudié rétrospectivement les dossiers de transplantées ayant eu une ou plusieurs grossesses après TR. Nous avons analysé des paramètres cliniques (tension artérielle, prise de poids, œdèmes, durée de grossesse, complications obstétricales) et biologiques (créatininémie, excrétion urinaire d’albumine).. Entre 1998 et 2020, 21 grossesses ont eu lieu chez 12 transplantées. L’âge moyen des patientes au moment de la conception était de 29 ± 5 ans avec un délai entre la TR et la grossesse de 43 ± 29 mois. Sept grossesses ont débuté avec une hypertension artérielle (HTA) contrôlée sous traitement, la protéinurie avant conception était négative dans toutes les grossesses et la fonction rénale était normale avec une créatininémie moyenne de 10,1 ± 1,27 mg/L. Avant les grossesses, les régimes d’immunosuppression étaient à base d’anticalcineurine (n = 21), associé soit à du mycophénolate mofétil (MMF) (n = 10) soit à de l’azathioprine (n = 8), ou seul (n = 3). Les régimes d’immunosuppression ont tous été associés à une corticothérapie. Trois mois avant la conception, le MMF a été ­relayé par l’azathioprine dans sept grossesses, et trois autres grossesses non programmées ont débuté sous MMF. Au cours des grossesses, on a noté l’apparition d’une protéinurie supérieure à 0,5 g/24 h dans trois grossesses au troisième trimestre. L’HTA gravidique a été retrouvée dans trois grossesses, dont une a évolué vers une pré-éclampsie. Quant à la fonction rénale, elle est restée stable avec une créatininémie moyenne de 10,3 mg/L au troisième trimestre. Deux cas de pyélonéphrite aiguë ont été notés. Aucun épisode de rejet aigu n’a été noté au cours et trois mois après la grossesse. L’accouchement a été réalisé par césarienne dans 44,4 %, après un terme moyen de 37 semaines d’aménorrhée, ± 2,04 avec trois cas de prématurité. Le poids de naissance moyen était de 3 110 g ± 450 g. On a noté un cas d’avortement spontané et deux cas de mort fœtale in utero. Après le post-partum, la fonction rénale est restée stable chez cinq patientes. Dans six cas, on a assisté à une altération de la fonction rénale par un rejet aigu ou secondaire à une néphropathie chronique d’allogreffe.. Dans notre service, un quart des transplantées a pu mener une grossesse avec une productivité de 89 % de ces grossesses. La grossesse après la TR nécessite une planification et une surveillance particulière. Une collaboration multidisciplinaire entre néphrologue transplanteur, gynécologue et pédiatre est nécessaire en se référant aux recommandations.

Topics: Azathioprine; Cesarean Section; Child; Child, Preschool; Creatinine; Female; Graft Rejection; Hospitals; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies

The severity of the 2019 coronavirus disease (COVID-19) and its effects remain unpredictable. Certain factors, such as obesity, hypertension, and type 2 diabetes mellitus, may increase the severity of the disease. Rheumatology experts suggest that patients with active autoimmune conditions and controlled autoimmune diseases on immunosuppressive therapy may be at higher risk of developing severe COVID-19. In this retrospective observational study, we aimed to examine the patterns of COVID-19 in patients with underlying rheumatological diseases and their association with disease severity and hospital outcomes. A total of 34 patients with underlying rheumatological diseases who tested positive for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) by polymerase chain reaction (PCR) were included between March 2020 and April 2021 at King Fahd Hospital of the University. The study population consisted of 76.47% female and 23.53% male patients, with a mean age ranging from 20 to 40 years. Female gender (p=0.0001) and younger age (p=0.004) were associated with milder disease. The most frequent rheumatological disease was systemic lupus erythematosus (SLE) (38.24%), which was associated with a milder infection (p=0.045). Patients treated with mycophenolate mofetil (MMF) had a milder disease course (p=0.0037). Hypertension was significantly associated with severe COVID-19 disease (p=0.037). There was no significant relationship between SLE and the need for ICU admission. Patients on hydroxychloroquine and MMF tended to develop milder disease, and there was no association between the severity of the infection and the treatment with steroids.

Topics: Adult; Autoimmune Diseases; COVID-19; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Lupus Erythematosus, Systemic; Male; Mycophenolic Acid; Rheumatic Diseases; SARS-CoV-2; Saudi Arabia; Young Adult

Augmentation of intrarenal angiotensinogen (AGT) leads to further formation of intrarenal angiotensin II (Ang II) and the development of hypertensive kidney injury. Recent studies demonstrated that macrophages and the enhanced production of pro-inflammatory cytokines can be crucial mediators of renal AGT augmentation in hypertension. Accordingly, this study investigated the effects of immunosuppression by mycophenolate mofetil (MMF) on intrarenal AGT augmentation. Ang II (80 ng/min) was infused with or without daily administration of MMF (50 mg/kg) to Sprague-Dawley rats for 2 weeks. Mean arterial pressure (MAP) in Ang II infused rats was slightly higher (169.7 ± 6.1 mmHg) than the Ang II + MMF group (154.7 ± 2.0 mmHg), but was not statistically different from the Ang II + MMF group. MMF treatment suppressed Ang II-induced renal macrophages and IL-6 elevation. Augmentation of urinary AGT by Ang II infusion was attenuated by MMF treatment (control: 89.3 ± 25.2, Ang II: 1194 ± 305.1, and Ang II + MMF: 389 ± 192.0 ng/day). The augmentation of urinary AGT by Ang II infusion was observed before the onset of proteinuria. Elevated intrarenal AGT mRNA and protein levels in Ang II infused rats were also normalized by the MMF treatment (AGT mRNA, Ang II: 2.5 ± 0.2 and Ang II + MMF: 1.5 ± 0.1, ratio to control). Ang II-induced proteinuria, mesangial expansion and renal tubulointerstitial fibrosis were attenuated by MMF. Furthermore, MMF treatment attenuated the augmentation of intrarenal NLRP3 mRNA, a component of inflammasome. These results indicate that stimulated cytokine production in macrophages contributes to intrarenal AGT augmentation in Ang II-dependent hypertension, which leads to the development of kidney injury.

Topics: Angiotensin II; Angiotensinogen; Animals; Blood Pressure; Hypertension; Immunosuppression Therapy; Kidney; Kidney Diseases; Mycophenolic Acid; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger

Kidney transplant (KT) recipients are at an increased risk for severe COVID-19 because of their immunosuppressed state. A 42-year-old KT patient was diagnosed with COVID-19 three months after KT. Despite lymphopenia and several risk factors, he had a mild disease course. Nasopharyngeal real-time reverse transcriptase polymerase chain reaction for SARS-CoV-2 became negative 48 days after detection. SARS-CoV-2 IgG antibodies became negative after day 40. TTV DNA load increased with the onset COVID-19 and reduced after its resolution. This is the first report where TTV DNA load was measured during the course of COVID-19.

Topics: Adult; Antibodies, Viral; Comorbidity; COVID-19; COVID-19 Nucleic Acid Testing; COVID-19 Serological Testing; Diabetes Mellitus; DNA Virus Infections; DNA, Viral; Glucocorticoids; Graft Rejection; Humans; Hypertension; Immunocompromised Host; Immunoglobulin G; Immunoglobulin M; Immunosuppressive Agents; Kidney Transplantation; Kinetics; Lymphopenia; Male; Mycophenolic Acid; Obesity; Prednisolone; SARS-CoV-2; Severity of Illness Index; Tacrolimus; Torque teno virus; Viral Load

Microbiota has a role in the host blood pressure (BP) regulation. The immunosuppressive drug mofetil mycophenolate (MMF) ameliorates hypertension. The present study analyzes whether MMF improves dysbiosis in a genetic model of hypertension. Twenty weeks old male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were randomly divided into three groups: untreated WKY, untreated SHR, and SHR treated with MMF for 5 weeks. MMF treatment restored gut bacteria from the phyla Firmicutes and Bacteroidetes, and acetate- and lactate-producing bacteria to levels similar to those found in WKY, increasing butyrate-producing bacteria. MMF increased the percentage of anaerobic bacteria in the gut. The improvement of gut dysbiosis was associated with an enhanced colonic integrity and a decreased sympathetic drive in the gut. MMF inhibited neuroinflammation in the paraventricular nuclei in the hypothalamus. MMF increased the lower regulatory T cells proportion in mesenteric lymph nodes and Th17 and Th1 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that MMF reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity due to reduced sympathetic drive in the gut associated to the reduced brain neuroinflammation.

Topics: Animals; Antihypertensive Agents; Aorta, Thoracic; Bacteria; Blood Pressure; Cells, Cultured; Colon; Cytokines; Disease Models, Animal; Dysbiosis; Gastrointestinal Microbiome; Hypertension; Inflammation Mediators; Mycophenolic Acid; Neuroimmunomodulation; Paraventricular Hypothalamic Nucleus; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System; T-Lymphocytes

This is a report of a case with mucous membrane pemphigoid (MMP) with severe eye involvement and concurrent COVID-19 treated successfully using simultaneous high dose intravenous immunoglobulin (IVIg) and anti-viral treatment as hydroxychloroquine, lopinavir/ritonavir, and ribavirin. He had finished a 2-g cycle of rituximab (RTX) in late January. He was receiving mycophenolate mofetil (MMF) for one month and 30 mg prednisolone for three months until his hospitalization. Prednisolone was tapered to 15 mg when current COVID-19 was suspected, considering his recent cough, dyspnea, and fever.

Topics: Adult; Anti-Bacterial Agents; Antiviral Agents; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Deprescriptions; Diabetes Mellitus, Type 2; Drug Combinations; Drug Therapy, Combination; Humans; Hypertension; Immunoglobulins, Intravenous; Immunologic Factors; Iran; Lopinavir; Male; Mycophenolic Acid; Oseltamivir; Pandemics; Pemphigoid, Benign Mucous Membrane; Pneumonia, Viral; Prednisolone; Ritonavir; Rituximab; SARS-CoV-2; Tomography, Spiral Computed

The short-term outcomes of lupus nephritis (LN) are variable and unpredictable among individuals. We aimed to evaluate the clinical and histopathological features and short-term renal outcomes in LN patients.. This was a prospective cohort study carried out at nephrology and rheumatology units in Egypt between 2018 and 2019. A total of 100 patients with biopsy-proven LN were studied. Patients were evaluated for response after six months.. The female-to-male ratio was 8.1:1. About 70% of patients were hypertensive at disease onset, with rates for classes I, II, III, IV, V and VI LN being 1%, 7%, 20%, 53%, 14% and 6%, respectively. Among the immunosuppressive drugs used for induction, mycophenolate mofetil (MMF) represented the most commonly used (44%) followed by cyclophosphamide (CYC; 37%). After six months of follow-up, about two thirds of patients achieved remission. There was no significant difference in remission rate between MMF and CYC. On multivariate analysis, serum creatinine (SCr) at presentation was the most significant predictor of renal recovery. According to the receiver operating characteristic curve, the cut-off value of SCr was 1.6 mg/dL, with a sensitivity of 76% and specificity of 71% predicting renal recovery. Repeat renal biopsy was needed in 10 patients; class and treatment strategy changed in 40% and 70% of them, respectively.. Our findings in Egyptian LN patients compare favourably with most studies.

Topics: Adult; Comorbidity; Creatinine; Cyclophosphamide; Egypt; Female; Hospitals, University; Humans; Hypertension; Immunosuppressive Agents; Kidney; Logistic Models; Lupus Nephritis; Male; Multivariate Analysis; Mycophenolic Acid; Predictive Value of Tests; Prospective Studies; Remission Induction; Sex Factors; Treatment Outcome; Young Adult

Topics: Abdominal Pain; Adolescent; Anemia; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Arthralgia; Arthritis; Biopsy; Computed Tomography Angiography; Diagnosis, Differential; Drug Therapy, Combination; Exanthema; Female; Humans; Hypertension; IgA Vasculitis; Immunologic Factors; Kidney; Methylprednisolone; Mycophenolic Acid; Myeloblastin; Nephritis; Pulse Therapy, Drug; Rituximab; Urticaria

Topics: Acute Disease; Adult; Antirheumatic Agents; Drug Therapy, Combination; Enzyme Inhibitors; Exophthalmos; Eye Pain; Female; Glucocorticoids; Humans; Hydroxychloroquine; Hypertension; Lupus Erythematosus, Systemic; Mycophenolic Acid; Opioid-Related Disorders; Prednisone; Retinal Hemorrhage; Tomography, X-Ray Computed; Visual Acuity

Blood pressure visit-to-visit variability is a novel risk factor for deleterious long-term cardiac and renal outcomes in the general population. We hypothesized that patients with systemic lupus erythematosus (SLE) have greater blood pressure visit-to-visit variability than control subjects and that blood pressure visit-to-visit variability is associated with a higher comorbidity burden.. We studied 899 patients with SLE and 4172 matched controls using de-identified electronic health records from an academic medical center. We compared blood pressure visit-to-visit variability measures in patients with SLE and control subjects and examined the association between blood pressure visit-to-visit variability and patients' characteristics.. Patients with SLE had higher systolic blood pressure visit-to-visit variability 9.7% (7.8-11.8%) than the control group 9.2% (7.4-11.2%),. Patients with SLE had higher blood pressure visit-to-visit variability than controls, and this increased blood pressure visit-to-visit variability was associated with greater Charlson comorbidity scores, several clinical characteristics and immunosuppressant medications. In particular, hydroxychloroquine prescription was associated with lower blood pressure visit-to-visit variability.

Topics: Adrenal Cortex Hormones; Adult; Blood Pressure; Case-Control Studies; Comorbidity; Cyclophosphamide; Databases, Factual; Female; Humans; Hydroxychloroquine; Hypertension; Inflammation; Logistic Models; Lupus Erythematosus, Systemic; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Risk Factors; Severity of Illness Index

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new-onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post-LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498-509 2017 AASLD.

Topics: Adult; Age Factors; Aged; Cardiovascular Diseases; Cyclosporine; Diabetes Mellitus, Type 1; Dyslipidemias; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Male; Metabolic Syndrome; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prevalence; Prospective Studies; Risk Factors; Severity of Illness Index; Spain; Survival Analysis; Tacrolimus; Transplant Recipients

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that predominantly affects women and is associated with prevalent hypertension, renal injury, and cardiovascular disease. Immune system dysfunction is recognized as an important factor in the pathogenesis of hypertension. We recently showed that preventing autoimmunity prevents the development of hypertension in an experimental model of SLE (female NZBWF1 mice). The present study tests the hypothesis that mycophenolate mofetil (MMF), an immunosuppressive therapy used clinically to treat SLE by depleting proliferating B and T lymphocytes, can improve blood pressure control.. Female SLE and control (NZW/LacJ) mice were treated daily for 8 weeks with 60 mg/kg MMF. Circulating CD45R. These data suggest that MMF selectively depleted CD45R

Topics: Albuminuria; Animals; Antibodies, Antinuclear; Arterial Pressure; B-Lymphocytes; Blood Pressure; Diabetic Nephropathies; Disease Models, Animal; DNA; Female; Hypertension; Immunoglobulin G; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mice; Mice, Inbred NZB; Mycophenolic Acid; T-Lymphocytes

Cardiovascular disease (CVD) is the second major cause of death in kidney-transplanted children. Cardiovascular risk factors (CVRF) prevalence after transplant may increase. The effect of immunosuppressive therapy has not been fully studied in children. The objective of the study was to measure and compare CVRF prevalence in kidney-transplanted children, depending of immunosuppressive therapy.. The study was an observational, transversal, retrospective, comparative study of pediatric patients transplanted at UMAE Hospital General Centro Medico La Raza. All patients were treated with prednisone and mycophenolic acid and any of cyclosporine, tacrolimus, or sirolimus. Demographic, clinical, and biochemical variables and immunosuppressive therapy were evaluated. We used analysis of variance, χ(2), and Fisher tests with the SPSS 18.0 statistical program.. One hundred fifteen patients were studied. Sixty-five (56.5%) were male, and median age was 18.5 ± 2.3 years. Seventy-eight (67.2%) were transplanted from a living related donor. Prevalence of anemia and nephrotic proteinuria was significantly less in patients treated with tacrolimus. Those treated with cyclosporine had a significantly greater prevalence of increased LDL-cholesterol, increased serum phosphorus, and increased calcium-phosphorus. Those treated with tacrolimus had lower, not significant, prevalence of hypertension, hyperuricemia, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and low serum HDL-cholesterol than those treated with sirolimus and cyclosporine. In multivariate analysis, patients treated with cyclosporine had significantly more probability of increased phosphorus (OR, 10.65; 95% CI, 2.75-41.16, P = .001) and calcium-phosphorus (OR, 37.94; 95% CI, 3.45-416.17, P = .003) than those treated with tacrolimus.. Patients treated with tacrolimus had less prevalence of CVRF than those treated with cyclosporine or sirolimus. Tacrolimus is the best immunosuppressive option to diminish CVRF in children after kidney transplantation.

Topics: Adolescent; Adult; Cardiovascular Diseases; Child; Cyclosporine; Female; Humans; Hypertension; Hypertriglyceridemia; Hyperuricemia; Immunosuppressive Agents; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Prevalence; Retrospective Studies; Risk Factors; Sirolimus; Tacrolimus; Young Adult

Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.. Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively.. The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed.. KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

Topics: Adolescent; Adult; Angiolymphoid Hyperplasia with Eosinophilia; Anti-Inflammatory Agents; China; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Hematuria; Humans; Hypertension; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Middle Aged; Mycophenolic Acid; Phytotherapy; Plant Preparations; Prednisone; Prognosis; Proteinuria; Recurrence; Renal Insufficiency; Retrospective Studies; Tacrolimus; Tripterygium; Young Adult

Lupus nephritis (LN) therapy has limited efficacy due to its toxicity, and LN patients suffer high risks of renal and cardiovascular morbidity and mortality. Calcineurin inhibitors (CNIs) have been used for over >30 years in LN treatment and are an established alternative therapy for Class V nephritis, but uncertainty remains about their role in proliferative disease or in the maintenance of remission. More recently, the combination of CNIs with mycophenolate mofetil (MMF) and glucocorticoid combination therapy, 'multitarget' therapy and the use of tacrolimus as opposed to ciclosporin has received attention. Is the evidence now sufficient to support the routine use of regimens including CNIs in LN? Although CNIs appear to have similar efficacy to MMF-based regimens as induction therapy, and are comparable with azathioprine as maintenance treatment, CNI toxicities, such as new-onset hypertension, hyperglycaemia and nephrotoxicity, have been problematic. Multitarget therapy improves the rate of complete remission in short-term studies, but whether this benefit is maintained over the longer term is uncertain. However, patient tolerability is lower and the frequency of serious events is higher in multitarget versus cyclophosphamide-based regimens, and there is a paucity of evidence from non-Asian ethnic groups. CNI-based therapy is also complicated by the absence of standardized dosing and the need for drug level monitoring, as well as by pharmacogenetic differences. Also, multitarget therapy increases the complexity and the cost of treatment. There is insufficient evidence to support the routine use of CNI-based or multitarget therapy for proliferative LN. Further data on long-term renal and cardiovascular outcomes and strategies to improve tolerability and safety are required.

Topics: Azathioprine; Calcineurin Inhibitors; Cyclophosphamide; Cyclosporine; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Kidney; Lupus Nephritis; Mycophenolic Acid

There is continued and significant debate regarding the salient etiologies associated with graft loss and racial disparities in kidney transplant recipients.. This was a longitudinal cohort study of all adult kidney transplant recipients, comparing patients with early graft loss (<5 years) to those with graft longevity (surviving graft with at least 5 years of follow-up) across racial cohorts [African-American (AA) and non-AA] to discern risk factors.. 524 patients were included, 55% AA, 151 with early graft loss (29%) and 373 with graft longevity (71%). Consistent within both races, early graft loss was significantly associated with disability income [adjusted odds ratio (AOR) 2.2, 95% CI 1.1-4.5], Kidney Donor Risk Index (AOR 3.2, 1.4-7.5), rehospitalization (AOR 2.1, 1.0-4.4) and acute rejection (AOR 4.4, 1.7-11.6). Unique risk factors in AAs included Medicare-only insurance (AOR 8.0, 2.3-28) and BK infection (AOR 5.6, 1.3-25). Unique protective factors in AAs included cardiovascular risk factor control: AAs with a mean systolic blood pressure <150 mm Hg had 80% lower risk of early graft loss (AOR 0.2, 0.1-0.7), while low-density lipoprotein <100 mg/dl (AOR 0.4, 0.2-0.8), triglycerides <150 mg/dl (AOR 0.4, 0.2-1.0) and hemoglobin A1C <7% (AOR 0.2, 0.1-0.6) were also protective against early graft loss in AA, but not in non-AA recipients.. AA recipients have a number of unique risk factors for early graft loss, suggesting that controlling cardiovascular comorbidities may be an important mechanism to reduce racial disparities in kidney transplantation.

Topics: Adult; Aged; BK Virus; Black or African American; Cardiovascular Diseases; Cohort Studies; Dyslipidemias; Female; Graft Rejection; Graft Survival; Health Status Disparities; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Medicare; Middle Aged; Mycophenolic Acid; Odds Ratio; Polyomavirus Infections; Prednisone; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; United States

The spontaneously hypertensive rat (SHR) strain exists in lines that contrast strongly in susceptibility to renal injury in hypertension. These inbred lines share common ancestry, and only 13% of their genomes arise from different ancestors.. We used next gen sequencing to detect natural allelic variation in 5 genes of the immunoreceptor signaling pathway (IgH, Dok3, Src, Syk, and JunD) that arise from different ancestors in the injury-prone SHR-A3 and the resistant SHR-B2 lines. We created an intercross between these lines, and in the F2 progeny, we observed that the inheritance of haplotype blocks containing the SHR-A3 alleles of these 5 genes correlated with increased albuminuria and histological measures of renal injury. To test whether accumulated genetic variation in this pathway may create a therapeutic target in hypertensive renal injury, rats of both lines were treated with the immunosuppressant mycophenolate mofetil (MMF). MMF reduced proteinuria (albumin to creatinine ratio) from 6.6 to 1.2 mg/mg (P<0.001) in SHR-A3. Glomerular injury scores were reduced in MMF-treated SHR-A3 from 1.6 to 1.4 (P<0.002). Tubulo-interstitial injury was reduced in MMF-treated SHR-A3 from 2.62 to 2.0 (P=0.001). MMF treatment also reduced renal fibrosis in SHR-A3 (3.9 versus 2.0; P<0.001).. Polygenic susceptibility to renal injury in hypertension arises in association with genetic variation in genes that participate in immune responses and is dramatically improved by reduction of immune system activity.

Topics: Albuminuria; Alleles; Animals; Blood Pressure; Genetic Predisposition to Disease; Genetic Variation; Glomerular Filtration Rate; Haplotypes; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Lymphocytes; Mycophenolic Acid; Rats; Rats, Inbred SHR; Receptors, Immunologic; Sequence Analysis, DNA; Signal Transduction

Topics: Antihypertensive Agents; Cyclophosphamide; Cyclosporine; Drug Substitution; Drug Therapy, Combination; Fatigue; Glomerulosclerosis, Focal Segmental; Gynecomastia; Humans; Hypertension; Male; Mastodynia; Middle Aged; Muscle Weakness; Mycophenolic Acid; Prednisone; Proteinuria; Tacrolimus

Autoregulation is critical for protecting the kidney against arterial pressure elevation and is compromised in some forms of hypertension. Evidence indicates that activated lymphocytes contribute importantly to cardiovascular injury in hypertension. We hypothesized that activated lymphocytes contribute to renal vascular dysfunction by impairing autoregulation and P2X(1) receptor signaling in ANG II-infused hypertensive rats. Male Sprague-Dawley rats receiving ANG II infusion were treated with a lymphocyte proliferation inhibitor, mycophenolate mofetil (MMF) for 2 wk. Autoregulation was assessed in vitro and in vivo using the blood-perfused juxtamedullary nephron preparation and anesthetized rats, respectively. ANG II-treated rats exhibited impaired autoregulation. At the single vessel level, pressure-mediated afferent arteriolar vasoconstriction was significantly blunted (P < 0.05 vs. control rats). At the whole kidney level, renal blood flow passively decreased as renal perfusion pressure was reduced. MMF treatment did not alter the ANG II-induced hypertensive state; however, MMF did preserve autoregulation. The autoregulatory profiles in both in vitro or in vivo settings were similar to the responses from control rats despite persistent hypertension. Autoregulatory responses are linked to P2X(1) receptor activation. Accordingly, afferent arteriolar responses to ATP and the P2X(1) receptor agonist β,γ-methylene ATP were assessed. ATP- or β,γ-methylene ATP-induced vasoconstriction was significantly attenuated in ANG II-infused hypertensive rats but was normalized by MMF treatment. Moreover, MMF prevented elevation of plasma transforming growth factor-β1 concentration and lymphocyte and macrophage infiltration in ANG II-infused kidneys. These results suggest that anti-inflammatory treatment with MMF prevents lymphocyte infiltration and preserves autoregulation in ANG II-infused hypertensive rats, likely by normalizing P2X(1) receptor activation.

Topics: Adenosine Triphosphate; Albuminuria; Angiotensin II; Animals; Arterioles; Homeostasis; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Lymphocyte Activation; Lymphocytes; Macrophages; Male; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2X1; Renal Circulation; Transforming Growth Factor beta1

Follicular carcinoma of the thyroid is a relatively rare malignancy in childhood even in paediatric solid organ transplant recipients. The risk of developing de novo malignancies after liver transplantation is higher compared to the general population. We report an 18-yr-old girl who had successfully undergone liver transplantation five yr earlier for neonatal sclerosing cholangitis complicated by the development of dysplastic nodules. Baseline immunosuppression was with tacrolimus and prednisolone. Mycophenolate mofetil was later added in view of steroid-resistant episodes of graft rejection. She subsequently suffered from marked obesity and essential hypertension needing antihypertensive medication. Five yr after liver transplantation, she presented with a right-sided thyroid swelling that was rapidly progressive with no associated lymphadenopathy and normal systemic examination. Ultrasound of her neck revealed a solid lesion in the right lobe of the thyroid gland with ill-defined margins, and a diagnostic right thyroid lobectomy confirmed the diagnosis of follicular carcinoma with focal capsular and vascular invasion. She underwent total thyroidectomy and currently remains well on thyroxine supplements. Our report highlights the need for high level of suspicion and prompt investigation into any abnormal lesion in the long-term follow-up of solid organ transplant recipients.

Topics: Adenocarcinoma, Follicular; Adolescent; Female; Humans; Hypertension; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Obesity; Prednisolone; Tacrolimus; Thyroid Neoplasms; Treatment Outcome

T cells contribute to hypertension in male experimental models; data in females is lacking even though women are more likely to develop immune disorders. The goal of this study was to determine whether immune cells contribute to hypertension in female spontaneously hypertensive rats (SHR) and define the T cell profile in whole blood and kidneys of male and female SHR. We hypothesized that inflammatory cells contribute to hypertension in female SHR; however, male SHR have a higher blood pressure so we hypothesize they will have a heightened inflammatory profile. The lymphocyte inhibitor mycophenolate mofetil (MMF) was administered in a dose-dependent manner to SHR. At the highest dose (50 mg·kg(-1)·day(-1)), blood pressure was significantly decreased in both sexes, yet the percent decrease in blood pressure was greater in females (female: 12 ± 1%; males: 7 ± 1%, P = 0.01). Circulating and renal T cell profiles were defined using analytical flow cytometry. Female SHR had more circulating CD3(+), CD4(+), and pro-inflammatory CD3(+)CD4(+)RORγ(+) Th17 cells, whereas males had more immune-suppressive CD3(+)CD4(+)Foxp3(+) T regulatory cells. In the kidney, females had greater numbers of CD8(+) and T regulatory cells than males, whereas males had greater CD4(+) and Th17 cell infiltration. MMF decreased circulating and renal T cells in both sexes (P < 0.0001), although the effect of MMF on T cell subtypes was sex specific with females having greater sensitivity to MMF-induced decreases in lymphocytes. In conclusion, there is a lymphocyte contribution to the maintenance of hypertension in the female SHR and sex of the animal impacts the T cell profile.

Topics: Animals; Blood Pressure; Female; Hypertension; Immunosuppressive Agents; Kidney; Male; Mycophenolic Acid; Rats; Rats, Inbred SHR; Sex Factors; T-Lymphocytes

Topics: Aged; Anti-Inflammatory Agents; Atrial Fibrillation; Autoantibodies; Autoantigens; Autoimmune Diseases; Brain Diseases; Carotid Stenosis; Diabetes Mellitus; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; Endarterectomy, Carotid; Female; Humans; Hypertension; Methylprednisolone; Mycophenolic Acid; Potassium Channels, Voltage-Gated; Smoking; Stroke

The present study evaluated the influence and mechanism of action of dietary protein intake in Dahl SS hypertension and renal disease. Rats were fed isocaloric diets with low (6%), normal (18%), or high (30%) amounts of protein and 0.4% NaCl from 5 to 12 weeks of age; the NaCl content of the diets was then increased to 4.0% NaCl from 12 to 15 weeks of age. Rats fed the high-protein diet developed the highest mean arterial blood pressure and urine albumin-to-creatinine ratio when fed the 4.0% NaCl diet (153 ± 7 mm Hg and 8.0 ± 2.4, respectively) compared to rats fed normal protein (132 ± 3 mm Hg, 1.2 ± 0.3) or low-protein (132 ± 6 mm Hg, 0.3 ± 0.1) diets. Significantly greater numbers of infiltrating T lymphocytes were observed in kidneys of SS rats fed the high-protein diet (18.9 ± 3 × 10⁵ cells) than in rats fed the low-protein diet (9.1 ± 3 × 10⁵ cells). Furthermore, treatment of SS rats fed the high-protein diet with the immunosuppressant agent mycophenolate mofetil (20 mg/kg per day, ip) significantly reduced the number of infiltrating T cells in the kidneys (from 18.9 ± 2.7 to 10.6 ± 2.0 × 10⁵ cells) while decreasing blood pressure (from 133 ± 3 to 113 ± 4 mm Hg) and the albumin/creatinine ratio (from 10.9 ± 2.3 to 5.4 ± 1.2). These results demonstrate that restriction of protein intake protects the Dahl SS rats from hypertension and kidney disease and indicates that infiltrating immune cells play a pathological role in Dahl SS rats fed a high-protein diet. Moreover, the results show that hypertension in Dahl SS rats is sensitive to both NaCl and protein intake.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Creatinine; Dietary Proteins; Hypertension; Kidney; Kidney Diseases; Mycophenolic Acid; Rats; Rats, Inbred Dahl; Rats, Sprague-Dawley; Sodium Chloride, Dietary; T-Lymphocytes; Time Factors

Limited data exist for the use of alemtuzumab (AL) induction in liver transplantation (LT) recipients. We compared the outcomes of hepatitis C virus-negative LT recipients who received AL induction followed by tacrolimus and mycophenolate mofetil without steroids to cohort who received no AL induction, tacrolimus, and a steroid taper. Fifty-five AL-induced recipients were compared to 85 non-AL-induced recipients with similar characteristics. Two-year patient survival (80% versus 88.2%, P = 0.0665) and graft survival (76.4% versus 82.4%, P = 0.1792) were not significantly different between the AL and non-AL groups, respectively. Other outcomes, including acute rejection (20% versus 30.3%), renal dysfunction (creatinine levels: 1.3 ± 0.3 versus 1.4 ± 0.6 mg/dL), and immunosuppressant monotherapy (29.1% versus 44.3%), were not significantly different between the AL and non-AL groups, respectively (P > 0.05). The number of rejection episodes (12 versus 42, P = 0.02) and the number of patients with new-onset hypertension (3 versus 15, P = 0.03) were lower in the AL group, although the incidence of all posttransplant infections was higher with AL (63.6% versus 44.3%, P = 0.03), primarily because of an increase in viral infections. In conclusion, a steroid-free AL induction regimen was associated with less hypertension and rejection but with more infectious complications; thus, the overall benefit of AL induction in LT recipients is called into question.

Topics: Adult; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Chi-Square Distribution; Chicago; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Assessment; Risk Factors; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Virus Diseases

Unilateral and bilateral hand transplantations have been performed worldwide with good mid-term functional results. An above-elbow bilateral transplantation was performed in a 29-year-old male patient from a fully HLA-mismatched donor. Alemtuzumab induction and steroid-free maintenance immunosuppression with tacrolimus and mycophenolate was used. Due to acute rejection, steroids were introduced at 6 months. Three acute rejection episodes occurred, one treated with alemtuzumab. New-onset diabetes after transplant, dyslipemia and worsening of previous high blood pressure required treatment. At 26 months post-transplantation, the patient has excellent elbow active movement, active flexion and extension of the thumb and fingers, useful sensation and a gainful job. Based on the functional results of the case reported, bilateral trans-humeral transplantation could be a viable treatment for selected bilateral above-elbow amputees.

Topics: Adult; Alemtuzumab; Amputation, Surgical; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Arm; Diabetes Complications; Hand Transplantation; HLA Antigens; Humans; Hypertension; Immunosuppressive Agents; Male; Mycophenolic Acid; Steroids; Tacrolimus; Transplantation; Transplantation, Homologous

Lupus nephritis (LN) is an ominous complication of systemic lupus erythematosus, and the risk factors for the disease progression are not well characterized.. In a retrospective study, the authors evaluated the mode of presentation and outcomes of 163 consecutive patients with biopsy-proven LN, who presented to the center between January 1999 and September 2008. Using stepwise logistic regression analysis, the authors assessed risk factors independently associated with response to treatment and to progression to end-stage renal disease (ESRD) in proliferative LN (PLN).. Ninety percent of the patients belonged to minority population. Among 122 patients with class III and IV LN (PLN), 76 patients received intravenous cyclophosphamide and 38 patients received mycophenolate for induction, whereas 34 patients received intravenous cyclophosphamide and 63 patients received mycophenolate for maintenance. Thirty-six (30%) patients with PLN progressed to ESRD, and 3 patients died over a mean follow-up of 37.5 months. In multivariate analysis, chronicity index (CI) (P = 0.0007) and hypertension (P = 0.042) positively correlated with progression to ESRD and death, and CI was associated with increased probability of nonresponse to treatment (P = 0.001). In addition, mycophenolate as maintenance agent was associated with increased likelihood of sustained complete remission and partial remission (P = 0.045).. In patients with LN, hypertension and a high CI are independent risk factors for progression to ESRD or death. Furthermore, a high CI is associated with poor response, and mycophenolate as a maintenance agent may improve the response to treatment.

Topics: Adult; Cyclophosphamide; Disease Progression; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Logistic Models; Lupus Nephritis; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Remission Induction; Retrospective Studies; Risk Factors; Texas; Young Adult

1. The interplay between the immune and renin-angiotensin systems is emerging as a crucial factor in the development and progression of hypertension. The aim of the present study was to determine the involvement of immune cells in the hypertension and renal injury produced by a non-angiotensin II-dependent form of hypertension, namely deoxycorticosterone acetate (DOCA)-salt-induced hypertension, in rats. 2. Male Sprague-Dawley rats underwent uninephrectomy and received either a sustained-release pellet of DOCA s.c. and 0.9% NaCl (saline) to drink for 21 days or a placebo pellet and water to drink for 21 days. Additional groups of DOCA-salt- and placebo-treated rats were treated concurrently with the immune suppressant mycophenolate mofetil (MMF; 30 mg/kg per day). Rats were placed in metabolic cages for 24 h urine collection prior to and at weekly intervals during the 21 day experimental period. 3. Mycophenolate mofetil significantly attenuated the development of hypertension in DOCA-salt rats compared with untreated DOCA-salt hypertensive rats (mean arterial pressure by telemetry on Day 18,146 ± 7 vs 180 ± 3 mmHg, respectively; P < 0.001), as well as proteinuria (87 ± 27 vs 305 ± 63 mg/day, respectively, on Day 21) and albuminuria (51 ± 15 vs 247 ± 73 mg/day, respectively, on Day 21). Creatinine clearance was better preserved in MMF-treated DOCA-salt rats compared with untreated DOCA-salt rats (0.74 ± 0.07 vs 0.49 ± 0.09 mL/min, respectively; P < 0.05), but was still significantly reduced compared with that in the placebo group (1.15 ± 0.12 mL/min; P < 0.05). Finally, MMF treatment significantly attenuated the DOCA-salt-induced rise in renal cortical T-lymphocyte and macrophage infiltration (P < 0.05). 4. These data indicate that immune cells play a deleterious role in both the hypertension and renal injury associated with DOCA-salt hypertension.

Topics: Albuminuria; Animals; Desoxycorticosterone; Hypertension; Immunosuppressive Agents; Male; Mycophenolic Acid; Nephrectomy; Random Allocation; Rats; Rats, Sprague-Dawley

To report a severe interaction between simvastatin and rapamycin resulting in rhabdomyolysis and acute renal failure in a liver transplant patient.. A 56-year-old man with hepatitis C virus cirrhosis (Child B) was diagnosed with hepatocellular carcinoma and underwent liver transplantation in April 2007. He was immunosuppressed with tacrolimus (FK) and mycophenolate mofetil (MMF). Postoperative complications were arterial hypertension and renal insufficiency. In June 2007, liver dysfunction was detected and acute rejection was diagnosed by biopsy. He received three 500-mg boluses of methylprednisolone and FK levels were maintained between 10 and 12 ng/mL. Laboratory values revealed persistent rejection and MMF was stopped with initiation of rapamicin. One month later, hyperlipidemia appeared as a consequence of rapamicin therapy; simvastatin was administered. In August 2007, the patient was readmitted due to severe muscule pain and the inability to ambulate. Laboratory values were: total bilirubin 16 mg/dL, serum creatinine 4.3 mg/dL, and total creatine kinase (CK) 42,124 U/L. With the suspicion of rhabdomyolysis, leading to worsening of his basal renal insufficiency, rapamycin and tacrolimus were stopped. Hemodialysis was initiated owing to renal failure and hyperkalemia. Some hours later, the patient developed ventricular fibrillation and respiratory failure and succumbed.. Calcineurin inhibitors (CNI), corticosteroids, and mammalian target of rapamycin (m-TOR) inhibitors are associated with adverse dyslipidemic effects. To reduce the overall cardiovascular risk in these patients, lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been widely used. CNI and m-TOR inhibitors, as well as most statins, are metabolized by cytochrome P450 (CYP)3A4; thus, pharmacokinetic interactions between these drugs are possible. Previous reports have indicated an increased risk of rhabdomyolysis in the presence of concomitant drugs that inhibit simvastatin metabolism.. Concomitant administration of statin therapy and drugs that inhibit cytochrome P450 (CYP)3A4 increased the risk of rhabdomyolysis in a patient suffering liver and renal dysfunction.

Topics: Acute Kidney Injury; Anticholesteremic Agents; Drug Therapy, Combination; Fatal Outcome; Hepatitis C; Humans; Hypertension; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Rhabdomyolysis; Simvastatin; Tacrolimus

Pemphigus is a serious, potentially fatal chronic autoimmune bullous disease with cutaneous and mucosal manifestations. Early diagnosis and treatment are essential.. We performed a retrospective cohort study that included patients diagnosed with pemphigus in the dermatology department of Hospital Universitario Virgen Macarena, Seville, Spain, in 2005 and 2006. We reviewed demographic, clinical, and therapeutic data.. Twenty-three patients, the majority women, were included in the study. Clinical onset usually occurred between 30 and 60 years of age. The most common variant was pemphigus vulgaris (79 %), and the sites most frequently affected were the oral mucosa, trunk, and scalp. Oral corticosteroids were the initial treatment of choice in all patients, and azathioprine and mycophenolate mofetil were given as adjuvant therapy. Complete remission was induced in 8.68 % of patients and partial remission in 91.32 %. The main complications were infections, osteopenia and osteoporosis, and cataracts.

Topics: Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Cushing Syndrome; Drug Therapy, Combination; Female; Hospitals, University; Hospitals, Urban; Humans; Hypertension; Immunosuppressive Agents; Infections; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Pemphigus; Retrospective Studies; Spain

The prevalence of renal insufficiency before and at 1, 12, and 60 months after liver transplantation (LTx; primary endpoint) and the changes in the glomerular filtration rate (GFR) at same time points according to the immunosuppressive regimen (coprimary endpoint) were investigated. The primary outcome was determined for the entire cohort, whereas the coprimary endpoint was determined only for 2 groups of patients: those who started and remained on a calcineurin inhibitor (CNI) alone, that is, the CNI-alone group (n = 624), and those who started and remained on a CNI in combination with mycophenolate mofetil (MMF), that is, the MMF group (n = 117). GFR was <60 mL/minute/1.73 kg/m(2) in 11%, 48%, 51% and 58% of the patients at baseline and at 1, 12, and 60 months, respectively. The decrease in GFR was significantly lower in the MMF group compared to the CNI-alone group at 12 and 60 months (-16% versus -30% and -15% versus -33%, respectively), whereas the GFR decrease at 1 month was not different between the 2 groups. There were no significant differences between the 2 groups in CNI doses or blood levels at 12 and 60 months. In conclusion, there was a worsening of renal failure in 83% of patients post-LTx; 58% and 5% had GFRs of <60 and <30 mL/minute/1.73 kg/m(2), respectively, at 5 years after LTx. The reduction of the GFR was significantly less marked in the MMF group compared to the CNI-alone group, and this could be related to less important CNI exposure early after LTx. It seems likely that early intervention for CNI reduction is best for reducing the use of CNIs in the long term.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Drug Therapy, Combination; Female; France; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney; Linear Models; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Renal Insufficiency; Retrospective Studies; Risk Assessment; Steroids; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

The present study determined the effect of immune suppression with mycophenolate mofetil (MMF) on sodium-sensitive hypertension following recovery from ischemia reperfusion (I/R)-induced acute renal failure. Male Sprague-Dawley rats fed 0.4% NaCl chow were subjected to 40 min bilateral I/R or control sham surgery. After 35 days of recovery, when plasma creatinine levels had returned to normal, the rats were switched to 4.0% NaCl chow for 28 days and administered vehicle or MMF (20 mg.kg(-1).day(-1) ip). High-salt mean arterial pressure was significantly higher in I/R rats (144 +/- 16 mmHg) compared with vehicle-treated sham rats (122 +/- 2 mmHg). Treatment of I/R rats with MMF during the period of high salt intake prevented the salt-induced increase in arterial pressure (114 +/- 3 mmHg). Conscious creatinine clearance was lower in I/R rats (0.27 +/- 0.07 ml.min(-1).100 g body wt(-1)) compared with vehicle-treated sham rats (0.58 +/- 0.04 ml.min(-1).100 g body wt(-1)); MMF treatment prevented the decrease in creatinine clearance in I/R rats (0.64 +/- 0.07 ml.min(-1).100 g body wt(-1)). I/R injury also significantly increased glomerular tissue damage and increased the presence of ED-1 positive (macrophages) and S100A4 positive cells (fibroblasts) in the renal interstitium. The I/R rats treated with MMF exhibited a significant reduction in infiltrating macrophages and fibroblasts and decreased histological damage. The present data indicate that infiltrating immune cells mediate or participate in the development of sodium-sensitive hypertension and renal damage in rats apparently recovered from renal I/R injury.

Topics: Acute Kidney Injury; Animals; Blood Pressure; Cell Movement; Creatinine; Disease Models, Animal; Fibroblasts; Hypertension; Immunosuppressive Agents; Ischemia; Kidney; Macrophages; Male; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Sodium Chloride, Dietary; Time Factors

Activation of the renin-angiotensin system contributes to the progression of chronic kidney disease. Based on the known cellular effects of ANG II to promote inflammation, we posited that stimulation of lymphocyte responses by ANG II might contribute to the pathogenesis of hypertensive kidney injury. We therefore examined the effects of the immunosuppressive agent mycophenolate mofetil (MMF) on the course of hypertension and kidney disease induced by chronic infusion of ANG II in 129/SvEv mice. Although it had no effect on the severity of hypertension or cardiac hypertrophy, treatment with MMF significantly reduced albuminuria and ameliorated kidney injury, decreasing glomerulosclerosis and reducing lymphocyte infiltration into the renal interstitium. Attenuation of renal pathology with MMF was associated with reduced expression of mRNAs for the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha and the profibrotic cytokine transforming growth factor-beta. As infiltration of the kidney by T lymphocytes was a prominent feature of ANG II-dependent renal injury, we carried out experiments examining the effects of ANG II on lymphocytes in vitro. We find that exposure of splenic lymphocytes to ANG II causes prominent rearrangements of the actin cytoskeleton. These actions require the activity of Rho kinase. Thus, ANG II exaggerates hypertensive kidney injury by stimulating lymphocyte responses. These proinflammatory actions of ANG II seem to have a proclivity for inducing kidney injury while having negligible actions in the pathogenesis of cardiac hypertrophy.

Topics: Albuminuria; Angiotensin II; Animals; Cardiomegaly; Cell Proliferation; Cytoskeleton; Disease Models, Animal; Hypertension; Immunosuppressive Agents; Interferon-gamma; Kidney Diseases; Male; Mice; Mice, Knockout; Mycophenolic Acid; Sodium Chloride, Dietary; T-Lymphocytes; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents

The goal of this study was to test the hypothesis that renal infiltration of immune cells in Dahl S rats on increased dietary sodium intake contributes to the progression of renal damage, decreases in renal hemodynamics, and development of hypertension. We specifically studied whether anti-immune therapy, using mycophenolate mofetil (MMF), could help prevent increases in renal NF-kappaB activation, renal infiltration of monocytes/macrophages, renal damage, decreases in glomerular filtration rate (GFR) and renal plasma flow, and increases in arterial pressure. Seventy-four 7-to 8-wk-old Dahl S, Rapp strain rats were maintained on an 8% Na, 8% Na + MMF (20 mg.kg(-1).day(-1)), 0.3% Na, or 0.3% Na + MMF diet for 5 wk. Arterial and venous catheters were implanted at day 21. By day 35, renal NF-kappaB in 8% Na rats was 47% higher than in 0.3% Na rats and renal NF-kappaB was 41% lower in 8% Na + MMF rats compared with the 8% Na group. MMF treatment significantly decreased renal monocyte/macrophage infiltration and renal damage and increased GFR and renal plasma flow. In high-NA Dahl S rats mean arterial pressure increased to 182 +/- 5 mmHg, and MMF reduced this arterial pressure to 124 +/- 3 mmHg. In summary, in Dahl S rats on high sodium intake, treatment with MMF decreases renal NF-kappaB and renal monocyte/macrophage infiltration and improves renal function, lessens renal injury, and decreases arterial pressure. This suggests that renal infiltration of immune cells is associated with increased arterial pressure and renal damage and decreasing GFR and renal plasma flow in Dahl salt-sensitive hypertension.

Topics: Animals; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Glutathione; Heart Rate; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Macrophages; Male; Mycophenolic Acid; NF-kappa B; Proteinuria; Rats; Rats, Inbred Dahl; Renal Circulation; Sodium Chloride, Dietary; Superoxide Dismutase; Superoxides; Time Factors; Vascular Resistance

Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg.kg(-1).day(-1) by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone (n = 5) or neither lead nor MMF (n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-kappaB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-kappaB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Creatinine; Hypertension; Immunosuppressive Agents; Inflammation; Kidney Diseases; Lead; Lymphocytes; Macrophages; Male; Malondialdehyde; Mycophenolic Acid; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Superoxides; Transcription Factor RelA

Idiopathic membranous nephropathy (IMN) is one of the most common causes of primary nephrotic syndrome in adults. However, it is a relatively rare entity in the pediatric population and there is a paucity of data about the incidence, prognosis, and optimal treatment of IMN in children and adolescents. We conducted this study to evaluate pediatric patients with IMN in order to clarify the presentation, response to therapy, and clinical outcome.. A retrospective chart review was performed on patients identified with biopsy-proven IMN between 1988-2005. Patients with systemic lupus erythematosus or hepatitis-related lesions were excluded. The following data were tabulated: age, gender, ethnicity, presenting clinical and laboratory findings, proteinuria in a first morning urine specimen, estimated glomerular filtration rate (GFRe), histopathology, type and duration of treatment, and clinical status at final evaluation.. 13 cases of IMN were identified out of 460 renal biopsies performed for evaluation of primary kidney disease during the study interval. Mean age was 9.6 +/- 4.6, gender 6 M:7 F, ethnicity 8 W:2 B:3 H. At the initial visit hematuria was present in 9 patients, edema in 5, nephrotic-range proteinuria in 5, and hypertension in 3. Mean urinary protein:creatinine ratio 3.3 +/- 2.5 and all patients had a normal GFRe. Classic glomerular findings of IMN were seen in all renal specimens, with concomitant interstitial changes in 2 cases. Treatment included an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in 11 cases. Most patients were also given immunosuppressive medications - prednisone in 10, a calcineurin inhibitor in 5, and mycophenolate mofetil or azathioprine in 3 patients. At the last follow-up, 42 +/- 35 months after the diagnostic biopsy, 7 children were hypertensive and the urine protein:creatinine ratio was 2.3 +/- 3.1. The mean GFRe was 127 +/- 57 mL/min/m2. Three patients had Chronic Kidney Disease Stage 3, all of whom were also hypertensive.. IMN is a rare but serious glomerulopathy in pediatrics. We estimate that it accounts for approximately 3% of renal biopsies. Long-term prognosis is guarded because approximately 50% of patients may have evidence of progressive kidney disease.

Topics: Adolescent; Biopsy; Child; Child, Preschool; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Male; Mycophenolic Acid; Prednisone; Prognosis; Proteinuria; Retrospective Studies; Time Factors; Treatment Outcome

Administration of the NO inhibitor N(wdelta)-nitro-L-arginine methyl ester (NAME) and a high-salt diet (HS) promotes severe albuminuria and renal injury, which regresses upon discontinuation of treatments.. We investigated whether these changes reappear after reinstitution of HS, and whether they are prevented by treatment with the antilymphocyte agent mycophenolate mofetil (MMF) or the AT-1 receptor blocker losartan (L). Adult male Munich-Wistar rats received NAME and HS. A control Group (C) received only HS. After 20 days, rats receiving HS and NAME exhibited severe hypertension and albuminuria. After a 30-day recovery period, hypertension was attenuated and albuminuria had virtually disappeared.. Rats were then distributed among the following groups: HS, receiving HS; NS, receiving a normal salt (NS) diet; HS-MMF, receiving HS and MMF; HS-LOS, receiving HS and L; HS-HDZ, receiving HS and hydralazine (HDZ). Sixty days later, NS rats showed only slight albuminuria and renal damage or inflammation. In contrast, HS rats developed severe hypertension, marked glomerulosclerosis with interstitial expansion and renal infiltration by macrophages and angiotensin II-positive cells. The group treated with losartan had lowered blood pressure and a lack of albuminuria or renal injury. MMF provided similar protection without altering blood pressure, suggesting a nonhemodynamic effect, a hypothesis reinforced by the finding that HDZ lowered blood pressure without preventing renal injury.. These results indicate that treatment with HS and NAME predisposes to the development of hypertension and renal injury upon salt overload, characterizing a new model of chronic nephropathy.. The response to MMF or L, but not HDZ, suggests a key role for inflammatory rather than hemodynamic factors.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Hydralazine; Hypertension; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Losartan; Male; Mycophenolic Acid; Nitric Oxide; Rats; Rats, Wistar; Sodium Chloride, Dietary

Experiments were performed to determine the importance of activation or infiltration of immune cells in the kidney during the development of hypertension and renal disease in Dahl salt-sensitive rats (SS/Mcw) fed a 4.0% NaCl diet. Compared with vehicle-treated rats, chronic administration of mycophenolate mofetil ([MMF] 30 mg/kg per day, IP), an immunosuppressive agent that has cytostatic effects on T and B cells, decreased cell-specific markers of T and B cells by 50% to 60% in the kidneys of SS/Mcw rats (n=5 per group). Further studies were performed on Dahl SS/Mcw rats, which were instrumented with chronic indwelling catheters and studied after 3 weeks on the 4.0% NaCl diet. Rats were administered MMF or 5% dextrose vehicle daily during the 3-week period of high NaCl intake. Mean arterial blood pressure in the rats administered MMF (122+/-2 mm Hg; n=11) was significantly decreased compared with vehicle-treated rats (139+/-4 mm Hg; n=9). Furthermore, the rate of protein (112+/-13 mg per day) and albumin excretion (15+/-3 mg per day) in the MMF-treated rats was significantly lower than the protein and albumin excretion rate in vehicle-treated rats (167+/-25 and 31+/-7 mg per day, respectively). Creatinine clearance and body weight were not different between the groups, averaging 0.52+/-0.08 mL/min per gram kidney weight and 322+/-10 g, respectively, in the MMF-treated group. These experiments indicate that the activation of the immune system or renal infiltration of immune cells plays an important role in the development of hypertension and renal disease in Dahl SS/Mcw rats consuming an elevated NaCl diet.

Topics: Albumins; Animals; Blood Pressure; Creatinine; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Diseases; Male; Mycophenolic Acid; Proteins; Rats; Rats, Inbred Dahl; Sodium Chloride

Calcineurin inhibitors (CNIs) are frequently associated with side effects such as nephrotoxicity and hypertension, so CNI withdrawal from immunosuppressive regimens is desirable in certain cases. The proliferation signal inhibitors/mammalian target of rapamycin inhibitors everolimus and sirolimus may play an important role in achieving CNI withdrawal. Studies on sirolimus have shown that conversion from CNIs is associated with improvements in renal function and hypertension. A case report is presented of a renal transplant recipient who experienced hypertension and recurrent cutaneous neoplasia while receiving a ciclosporin (CsA)-based immunosuppressive regimen. After transplantation, the patient received full-dose CsA and prednisolone. After 7 years, the patient's serum creatinine increased from 1.9 mg/dl to 2.5 mg/dl, and mycophenolate mofetil (MMF, 1000 mg/day) was introduced, enabling the CsA dose to be reduced to 100 mg b.i.d. The patient also required resection of five cutaneous neoplastic lesions; this led to the decision to stop CsA and start treatment with everolimus 1.5 mg/day, which was increased to 3.0 mg/day to achieve target trough blood levels of 3 ng/ml. To avoid over-immunosuppression, the MMF dose was reduced to 500 mg/day. After conversion, the patient experienced a substantial improvement in blood pressure, from 175/85 mmHg to 155/70 mmHg. Serum creatinine levels decreased to 1.6 mg/dl, and there has been no recurrence of cutaneous neoplasia in 9 months of follow-up. Therefore, conversion to everolimus from CsA in a renal transplant recipient led to improvements in blood pressure and resolution of recurrent cutaneous neoplasia, with no evidence of rejection or changes in renal function.

Topics: Blood Pressure; Calcineurin Inhibitors; Creatinine; Cyclosporine; Drug Therapy, Combination; Everolimus; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Postoperative Complications; Prednisolone; Sirolimus; Skin Neoplasms; Treatment Outcome; Withholding Treatment

To analyze our results with mycophenolate mofetil (MMF) in stable liver transplantation (LT) patients presenting with adverse events (AE) related to prolonged use of calcineurin inhibitors (CNI).. Conversion to MMF was performed in 56 out of 323 LT patients from 91-02: 24 (43%) were converted to MMF in monotherapy and 32 (57%) to MMF+low doses of CNI. The indication for conversion was chronic renal insufficiency (CRI) in all patients. The mean time between AE and conversion was 38.7+/-30 months (r: 2-101 m). Post-conversion follow-up was 39+/-20 months (r: 3-72 m).. The calculated creatinine clearance (Crauckoft), improved significantly in all patients. In those converted to MMF, improvement was seen during the first 18 months for urea and during the first 6 months for creatinine. In patients converted to MMF+CNI, improvement was maintained throughout the conversion period for both urea and creatinine. Eleven (19.6%) patients underwent acute rejection (2 severe episodes in the MMF group and 1 death). Hypertension was present in 31 patients but only improved in 4 (7%). Dyslipemia was found in 12 and improved in 4 (7%). DM was present in 14 and improved in 1 (2%).. Conversion to MMF in monotherapy is useful in stable LT patients with CRI due to CNI, although this result is offset by more severe rejections. Therefore, for AE secondary to CNI, we propose an early conversion to MMF+low doses of CNI as a first step. If liver function remains stable and AEs persist or progress, conversion to MMF in monotherapy is recommended, as a second step, with close monitoring of the patient.

Topics: Aged; Calcineurin Inhibitors; Creatinine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Hypertension; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Liver; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Renal Insufficiency, Chronic; Retrospective Studies; Survival Analysis; Treatment Outcome; Urea

A young female with essential hypertension developed progressive azotemia; renal biopsy showed hypertensive nephrosclerosis with considerable tubulointerstitial disease and cellular infiltration. The addition of mycophenolate mofetil (MMF) to her antihypertensive treatment resulted in a dramatic improvement of renal function during the following three months. When the patient discontinued MMF treatment, end-stage renal failure rapidly developed. This patient represents the first report of the beneficial use of MMF in non-immune chronic renal disease and demonstrates that significant functional improvement may be obtained with the addition of MMF to the treatment of hypertensive nephrosclerosis for patients in whom there is significant tubulointerstitial inflammatory infiltration.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Captopril; Drug Therapy, Combination; Female; Humans; Hydralazine; Hypertension; Kidney Failure, Chronic; Mycophenolic Acid; Nephrosclerosis; Treatment Outcome

Renal dysfunction after liver transplantation is a major management problem. Predictors of improvement in renal dysfunction after calcineurin inhibitor therapy (CNI) withdrawal and replacement with either mycophenolate mofetil (MMF) or azathioprine (AZA) have not previously been examined.. Retrospective analysis of 33 post-transplant patients with creatinine clearance (CrCl) below 50 mL/min who were changed from CNI to either MMF or AZA. Following CNI withdrawal patients were divided into two groups: those with improved CrCl after switching and those without, to identify the variables associated with improved renal function.. Variables associated with improved CrCl were: absence of hypertension or diabetes, shorter time between transplantation and switch, deterioration in CrCl in months prior to switch and treatment with MMF (compared with AZA).. Our findings suggest CNI withdrawal should be targeted to a subgroup of patients whose renal function is most likely to improve.

Topics: Azathioprine; Calcineurin Inhibitors; Creatinine; Diabetes Complications; Enzyme Inhibitors; Female; Follow-Up Studies; Forecasting; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; IMP Dehydrogenase; Kidney; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Safety; Time Factors; Treatment Outcome

Hypertension, a common complication after renal transplantation, has many potential etiologies. Erythrocyte sodium lithium countertransport (Na/LiCT) is a sensitive membrane protein that has been observed to be abnormal in several hypertension-related diseases. We have shown that the kinetics of Na/LiCT were abnormal in renal transplant recipients treated with usual dose of cyclosporine (CsA). We postulated that CsA might be a cause of post-renal transplantation hypertension. There is evidence showing that the severity of CsA nephrotoxicity is dependent on the dose. Mycophenolate mofetil (MMF) may allow CsA dose reduction without increasing the risk of rejection. We studied the impact of CsA dose reduction in association with MMF on the kinetics of erythrocyte Na/LiCT in renal transplants. In 15 renal allograft recipients, 2 g/d MMF were introduced and the CsA dose reduced to reach whole-blood levels between 70 and 100 ng/mL within 1 month. CsA doses and levels, renal function parameters, blood pressure, and the kinetics of Na/LiCT were evaluated before and 6 months after CsA dose reduction. Overall, renal transplant recipients with usual doses of CsA showed a lower Km with a higher Vmax/Km ratio for erythrocyte Na/LiCT than normal controls (Km, 40 +/- 4 vs 74 +/- 11; P <.05; Vmax/Km, 10.2 +/- 1.7 vs 6.1 +/- 0.9; P <.05). After 6 months of CsA dose reduction, the Km and Vmax/Km of Na/LiCT were similar to those of normal controls (Km, 66 +/- 8 vs 74 +/- 11; P >.05; Vmax/Km, 5.7 +/- 1.2 vs 6.1 +/- 0.9; P >.05). These results demonstrate that reduction of CsA dose in combination with MMF may improve the kinetics of Na/LiCT and lessen the long-term side effects of CsA without increasing the risk of rejection.

Topics: Adolescent; Adult; Aged; Antiporters; Biomarkers; Cyclosporine; Erythrocytes; Female; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Reference Values

To study whether prevention of renal injury using the anti-inflammatory drugs pentosan polysulphate (PPS) and mycophenolate mofetil (MMF) is associated with improvement of glomerular haemodynamics, PPS and MMF were compared with losartan. The awake systolic blood pressure (SBP), proteinuria (Uprot) and micropuncture studies were performed 30 days after five-sixths nephrectomy in untreated rats and in rats treated with PPS (100 mg/kg per day), MMF (30 mg/kg per day) or losartan (30 mg/kg per day). In the rats receiving no treatment, there was a rise in SBP (to 180-200 mmHg) and in Uprot, which were prevented by losartan. In the PPS and MMF groups, the SBP was elevated but the Uprot did not increase. In the untreated rats the total glomerular filtration rate (GFR) decreased (-80%) and the single-nephron GFR (37-42%), plasma flow (67-127%) and glomerular pressure (10-15 mmHg) increased. These changes were prevented by PPS and MMF to the same extent as by losartan: the rise in single-nephron GFR and plasma flow were reduced by 50% and the glomerular pressure was normal. In rats receiving losartan, this was due to the fall in arterial pressure, whereas in PPS- and MMF-treated rats it was due to a rise in afferent resistance, indicating autoregulatory capacity. Total GFR was similar, despite the lower single-nephron GFR in treated groups, suggesting a larger proportion of functioning nephrons. Losartan, PPS and MMF significantly reduced glomerular sclerosis and tubular dilation and atrophy in association with a reduction in the lymphocyte and macrophage infiltrate. These results suggest an interaction between the haemodynamic and inflammatory changes that perpetuate each other during progression of renal injury. Renal protection provided by anti-inflammatory drugs is partially mediated by the prevention of glomerular haemodynamic alterations.

Topics: Animals; Glomerular Filtration Rate; Hypertension; Kidney; Mycophenolic Acid; Nephrectomy; Pentosan Sulfuric Polyester; Rats; Systole

Topics: Adolescent; Antihypertensive Agents; Azathioprine; Child; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppression Therapy; Kidney Transplantation; Morbidity; Mycophenolic Acid; Prevalence; Recurrence; Retrospective Studies

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Flow Velocity; Blood Pressure; Brachial Artery; Child; Child Welfare; Child, Preschool; Creatinine; Cyclosporine; Female; Follow-Up Studies; Heart Transplantation; Humans; Hypertension; Immunosuppressive Agents; Male; Michigan; Mycophenolic Acid; Nitric Oxide; Prednisone; Treatment Outcome; Vasodilation

It has recently been proposed that tubulointerstitial damage plays a key role in the pathogenesis of sodium-dependent hypertension. Since components, enzymes and substrates, of the kallikrein-kinin system (KKS) are synthesized by connecting and collecting tubules, respectively, it is expected that damage of any origin, involving the tubulointerstitial compartment, may affect the functionality of these nephron segments and impair blood pressure control. Therefore, we analyzed renal kallikrein expression in the 5/6 renal ablation model, which is characterized by a progressive tubulointerstitial damage and systemic hypertension. In addition, we studied the renal expression of this enzyme after treatment of healthy and 5/6 nephrectomized rats with mycophenolate mofetil (MMF), an immunosuppressive drug known to reduce tubulointerstitial damage in this model. Twenty-six male Sprague-Dawley rats were included in this study. Seven 5/6 nephrectomized rats (Nx), 4 sham-operated (Sham) rats and 5 Nx rats treated with MMF (Nx + MMF) were studied 4 weeks after surgery. For comparison, 6 healthy rats treated with MMF at the same dose were compared with 4 vehicle-treated controls. Tubulointerstitial damage was significantly high in Nx compared with Nx-MMF and sham-operated rats. Blood pressure was significantly higher in Nx (178 +/- 7.8 mm Hg) than in Sham (120 +/- 2.0 mm Hg, p < 0.05) and Nx + MMF animals (154 +/- 5.6 mm Hg, p < 0.05). Renal kallikrein expression, quantified by a computer image system was significantly lower in the Nx group (1,696 +/- 437 density/mm(2)) than in Sham (9,779 +/- 4,068 density/mm(2), p < 0.05), and in Nx + MMF groups (4,640 +/- 1,578 density/mm(2), p < 0.05). Healthy animals treated with MMF did not show tubulointerstitial damage, changes in blood pressure nor changes in the expression of immunoreactive renal kallikrein suggesting that improvement in kallikrein expression after MMF treatment of 5/6 nephrectomy was not due to a direct effect of the drug on kallikrein-producing cells. Our results suggest that protection of the KKS after 5/6 nephrectomy may have additional renoprotective effects and may reduce the progression of renal disease.

Topics: Animals; Blood Pressure; Hypertension; Immunohistochemistry; Immunosuppressive Agents; Kallikreins; Kidney; Kidney Tubules; Male; Mycophenolic Acid; Nephrectomy; Rats; Rats, Sprague-Dawley

Prevalence of arterial hypertension suddenly rose in patients after renal transplantation since cyclosporine A was introduced. Arterial hypertension is now diagnosed in 67-90% of patients after renal transplantation. It has not only negative effect on cardiovascular system but also shortens survival of renal graft. Ambulatory blood pressure monitoring (ABPM) enables evaluation of diumal profile of BP and efficacy of treatment. This diagnostic tool is very useful in the management of these patients. Nocturnal hypertension was 2.5 times more frequent than daytime elevation of BP in the group of 58 consecutive renal transplant patients treated with calcineurin inhibitors who were assessed by ABPM at our department. Lack of nocturnal dip of BP was observed in most of the patients. Conversion from calcineurin inhibitors (cyclosporine A, tacrolimus) to sirolimus or mycophenolate mofetil may improve BP profile in this group of patients.

Topics: Adult; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Circadian Rhythm; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Poland; Sirolimus; Tacrolimus

Recent studies have suggested that subtle microvascular and tubulointerstitial injury in the kidney can cause salt-sensitive hypertension. To test this hypothesis, we determined whether the mild renal disease induced by transient blockade of nitric oxide (NO) synthesis would result in salt-sensitive hypertension and whether prevention of the renal injury by coadministration of the immunosuppressive agent mycophenolate mofetil (MMF) would block the development of salt sensitivity. N(omega)-nitro-L-arginine-methyl ester (L-NAME; 70 mg/100 ml in the drinking water) was administered for 3 wk to rats with or without MMF (30 mg x kg(-1) x day(-1) by gastric gavage), followed by a 1-wk "washout" period in which the MMF was continued, which was followed in turn by placement on a high-salt (4% NaCl) diet for an additional 4 wk. Renal histology was examined at 3 and 8 wk, and blood pressure was measured serially. L-NAME treatment resulted in acute hypertension and the development of mild renal injury. During the washout period, blood pressure returned to normal, only to return to the hypertensive range on exposure of the animals to a high-salt diet. MMF treatment prevented the development of hypertension in response to a high-salt diet. This correlated with the ability of MMF to inhibit specific aspects of the renal injury, including the development of segmental glomerulosclerosis, the infiltration of T cells and ANG II-positive cells, and the thickening of afferent arterioles.

Topics: Animals; Blood Pressure; Body Weight; Glomerulosclerosis, Focal Segmental; Hypertension; Immunosuppressive Agents; Kidney; Lymphocytes; Macrophages; Male; Mycophenolic Acid; Nephritis, Interstitial; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin

Corticosteroids have been a cornerstone of immunosuppression for four decades despite their adverse side effects. Past attempts at steroid withdrawal in pediatric renal transplantation have had little success. This study tests the hypothesis that a complete steroid-free immunosuppressive protocol avoids steroid dependency for suppression of the immune response with its accompanying risk of acute rejection on steroid withdrawal.. An open labeled prospective study of complete steroid avoidance immunosuppressive protocol was undertaken in 10 unsensitized pediatric recipients (ages 5-21 years; mean 14.4 years) of first renal allografts. Steroids were substituted with extended daclizumab use, in combination with tacrolimus and mycophenolate mofetil. Protocol biopsies were performed in the steroid-free group at 0, 1, 3, 6, and 12 months posttransplantation. Clinical outcomes were compared to a steroid-based group of 37 matched historical controls.. Graft and patient survival was 100% in both groups. Clinical acute rejection was absent in the steroid-free group at a mean follow-up time of 9 months (range 3-13.7 months). Protocol biopsies in the steroid-free group (includes 10 patients at 3 months, 7 at 6 months, and 4 at 12 months) revealed only two instances of mild (Banff 1A) subclinical rejection (reversed by only a nominal increase in immunosuppression) and no chronic rejection. At 6 months the steroid-free group had no hypertension requiring treatment (P=0.003), no hypercholesterolemia (P=0.007), and essentially no body disfigurement (P=0.0001). Serum creatinines, Schwartz GFR, and mean delta height Z scores trended better in the steroid-free group. In the steroid-free group, one patient had cytomegalovirus disease at 1 month and three had easily treated herpes simplex stomatitis, but with no significant increase in bacterial infections or rehospitalizations over the steroid-based group. The steroid-free group was more anemic early posttransplantation (P=0.004), suggesting an early role of steroids in erythrogenesis; erythropoietin use normalized hematocrits by 6 months.. Complete steroid-free immunosuppression is efficacious and safe in this selected group of children with no early clinical acute rejection episodes. This protocol avoids the morbid side effects of steroids without increasing infection, and may play a future critical role in avoiding noncompliance, although optimizing renal function and growth.

Topics: Adolescent; Adult; Anemia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biopsy; Child; Cohort Studies; Daclizumab; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infections; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Steroids; Survival Analysis; Tacrolimus

Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hypertension, which can be prevented by the immunosuppressor mycophenolate mofetil (MMF) given during the AngII infusion. This study examined the contribution of glomerular hemodynamics (GFR dynamics) in the post-AngII hypertensive response to a high-salt diet (HSD) and the effect of MMF treatment. During AngII administration, rats developed severe hypertension (systolic BP [SBP], 185 +/- 3.9 mmHg), proteinuria, afferent and efferent vasoconstriction, and glomerular hypertension. Rats that received AngII+MMF showed similar responses to AngII; however, they developed lower proteinuria (P < 0.05). At 2 wk, AngII was withdrawn and SBP returned toward normal. Rats were then placed on an HSD (4% NaCl), resulting in a progressive increase in SBP (155 +/- 8.2 mmHg at week 1 and 163 +/- 4.5 mmHg at week 5). GFR dynamic alterations persisted after AngII was stopped, i.e., afferent and efferent vasoconstriction, decreased glomerular plasma flow and single-nephron GFR, and lower ultrafiltration coefficient. These changes correlated with the thickening of the afferent arteriole and with focal tubulointerstitial injury. In the AngII+MMF group, SBP remained unchanged throughout the HSD period (146 +/- 2.3 mmHg at week 1 and 148 +/- 4.4 mmHg at week 5) in association with less afferent arteriolar thickening and tubulointerstitial injury. Single-nephron GFR, glomerular plasma flow, efferent resistance, and ultrafiltration coefficient returned to normal with a significant reduction in afferent resistance. These results suggest a critical role of cortical vasoconstriction in salt-sensitive hypertension. The MMF-induced prevention of these changes suggests that immune mechanisms are involved in the vasoconstrictive response.

Topics: Angiotensin II; Animals; Drug Synergism; Hemodynamics; Hypertension; Immunosuppressive Agents; Kidney; Kidney Cortex; Kidney Glomerulus; Male; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Sodium Chloride; Vasoconstriction

The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described.. Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described.. Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposi's sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant.. We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.

Topics: Adolescent; Adult; Cytomegalovirus Infections; Female; Glycated Hemoglobin; Graft Rejection; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Tacrolimus; Transplantation, Homologous