Steroid Minimization Research Articles

Assessing Long-Term Adverse Outcomes in Older Kidney Transplant Recipients: A Propensity Score-Matched Comparison of Early Steroid Withdrawal Versus Continuous Steroid Immunosuppression Using a Large Real-World Database.

Steroids are widely used in maintenance immunosuppression treatment in kidney transplant recipients. Older individuals undergo age-related immunosenescence that consequently decreases their ability to process and evoke a response to foreign antigens. Thus, steroids may not be necessary in preventing allograft rejection and may consequently increase older recipients' risk of long-term steroid-related adverse effects. The objective of this study was to analyze the adverse outcomes of long-term steroid immunosuppression in older kidney transplant recipients using real-world electronic medical record data. The TriNetX database "US Collaborative Network" was utilized to perform a propensity score-matched case-control study comparing 1-year, 3-year, and 5-year adverse effects of steroid immunosuppression in older adults (aged ≥65 years) kidney transplant recipients who underwent either an early-steroid withdrawal (ESW) maintenance regimen or a steroid continuous immunosuppression (SCI) regimen between 31 December, 2010 and 31 December, 2020. Early-steroid withdrawal was defined as tacrolimus plus mycophenolate mofetil maintenance with no prednisone after the seventh day post-transplant. Steroid continuous immunosuppression was defined as tacrolimus plus mycophenolate mofetil plus prednisone maintenance. Cohorts were matched on age, race/ethnicity, and risk factors for adverse steroid-related outcomes and rejection. Outcomes included post-transplant diabetes mellitus, dyslipidemia osteoporosis/fractures, myocardial infarction, glaucoma/cataract, stroke, pulmonary embolism, and malignancy. Secondary outcomes analyzed incidences of infection-related outcomes, graft-related outcomes, and recipient mortality. After matching, there were 304 recipients in each group (ESW, SCI). Mean age at the time of transplant was 69.2±3.7 years (ESW) and 69.2±3.4 years (SCI, p=0.96). The Kaplan-Meier analysis showed recipients who underwent SCI had increased incidences of post-transplant diabetes mellitus at 1 year (22.36% vs 30.37%, p=0.01) and 3 years (34.89% vs 44.29%, p=0.01), but this became non-significant at 5 years post-transplant (41.97% vs 42.6%, p=0.34). Incidences of acute pancreatitis were higher for the SCI cohort at 3 years (p=0.02) as well as incidences of acute myocardial infarction at 5 years post-kidney transplant (6.75% vs 14.39%, p<0.01). No difference was found for other adverse outcomes. Early-steroid withdrawal recipients experienced significantly fewer infection-related outcomes, such as cytomegalovirus, BK virus, sepsis/bacteremia, and fungal infections, compared with SCI recipients. Last, recipients who underwent ESW experienced fewer incidences of rejection and death-censored graft failure at 5 years post-transplant. There is currently no standard maintenance immunosuppression protocol for older kidney transplant recipients. Death-censored graft survival, rejection, and patient survival were improved with ESW. Steroid minimization may be beneficial in this population given that it lowers the risk of drug-induced adverse effects.

Low dose tacrolimus exposure and early steroid withdrawal with strict body weight control can improve post kidney transplant glucose tolerance in Japanese patients.

The development of diabetes mellitus (DM) after living donor kidney transplantation (KT) is a risk factor for worsening transplant kidney function, cardiac disease, and cerebrovascular disease, which may affect prognosis after KT. At our institution, all patients' glucose tolerance is evaluated perioperatively by oral glucose tolerance tests (OGTTs) at pre-KT, and 3, 6, and 12 month (mo.) after KT. We analyzed the insulinogenic index (ISI) and homeostasis model assessment beta cell (HOMA-β) based on the immunoreactive insulin (IRI) levels to determine how glucose tolerance changed after KT in 214 patients who had not been diagnosed with DM before KT. In addition, we analyzed the body mass index (BMI) which may also influence glucose tolerance after KT. The concentration of tacrolimus (TAC) in blood was also measured as the area under the curve (AUC) to examine its effects at each sampling point. The preoperative-OGTTs showed that DM was newly diagnosed in 22 of 214 patients (10.3%) who had not been given a diagnosis of DM by the pre-KT fasting blood sugar (FBS) tests. The glucose tolerance was improved in 15 of 22 DM patients at 12 mo. after KT. ISI and IRI deteriorated only at 3 mo. after KT but improved over time. There was a trend of an inverse correlation between HOMA-β and TAC-AUC. We also found inverse correlations between IRI and an increase in BMI from 3 to 12 mo. after KT. Early corticosteroid withdrawal or the steroid minimization protocol with tacrolimus to maintain a low level of diabetogenic tacrolimus and BMI decrease after KT used by our hospital individualizes lifestyle interventions for each patient might contribute to an improvement in post-KT glucose tolerance.

#3816 HYPERBARIC OXYGEN TREATMENT IN CALCIFIC UREMIC ARTERIOLOPATHY PATIENTS IN ADDITION TO CONVENTIONAL MULTIDISCIPLINARY CARE

Abstract Background and Aims Calcific uremic arteriolopathy (CUA), also referred to as calciphylaxis, is a rare and serious complication in patients with advanced kidney disease. CUA has limited treatment options and poor prognosis, with one- year survival often reported to be below 50% after diagnosis [1,2]. Hyperbaric oxygen therapy (HBOT) may improve wound healing by increasing tissue oxygenation, and has been suggested as adjuvant treatment for CUA patients [3]. We added HBOT to our conventional multidisciplinary care of CUA patients in 2012 and this study aims to evaluate long- term outcomes of CUA patients after this. Method Data from all CUA patients treated at our institution from 2012 to 2022 were retrospectively retrieved from hospital records. This is a single-centre study, but patients from different Norwegian hospitals were referred for treatment at our centre. Conventional multidisciplinary care of CUA in our centre included sodium-thiosulphate, dialysis if indicated medical optimization of calcium- phosphate homeostasis, substitution of vitamin K2, withdrawal of warfarin and iron and vitamin D if used, minimization of systemic steroids, in addition to optimization of weight- and nutritional status. Our centre is restrictive with surgical revisions to CUA patients. Results 25 CUA patients received a total number of 1493 HBOT treatments in addition to conventional CUA multidisciplinary care in the study period. Median HBOT per patient was 45 (range 1–267). One year after CUA diagnosis, 20 out of 25 patients were alive (80%). Fifteen out of the 20 patients, who were alive at one year after CUA diagnosis, had completely resolved CUA lesions (75%). Five patients died within the first year after CUA diagnosis, due to acute cardiovascular disease (n = 3) and infection (n = 2). Our impression is that HBOT is well- tolerated and associated with less wound- associated pain. Conclusion Our results suggest that HBOT is well- tolerated in CUA patients. After we included HBOT in our multidisciplinary care of CUA patients, 80% of the patients were alive one- year after CUA diagnosis.

The Sound of Interconnectivity; The European Vasculitis Society 2022 Report

The first European Vasculitis Society (EUVAS) meeting report was published in 2017. Herein, we report on developments in the past 5 years which were greatly influenced by the pandemic. The adaptability to engage virtually, at this critical time in society, embodies the importance of networks and underscores the role of global collaborations. We outline state-of-the-art webinar topics, updates on developments in the last 5 years, and proposals for agendas going forward. A host of newly reported clinical trials is shaping practice on steroid minimization, maintenance strategies, and the role of newer therapies. To guide longer-term strategies, a longitudinal 10-year study investigating relapse, comorbidity, malignancy, and survival rates is at an advanced stage. Disease assessment studies are refining classification criteria to differentiate forms of vasculitis more fully. A large international validation study on the histologic classification of anti-neutrophil cytoplasmic antibody (ANCA) glomerulonephritis, recruiting new multicenter sites and comparing results with the Kidney Risk Score, has been conducted. Eosinophilic granulomatosis with polyangiitis (EGPA) genomics offers potential pathogenic subset and therapeutic insights. Among biomarkers, ANCA testing is favoring immunoassay as the preferred method for diagnostic evaluation. Consolidated development of European registries is progressing with an integrated framework to analyze large clinical data sets on an unprecedented scale.

Rituximab Dosing in Glomerular Diseases: A Scoping Review.

Purpose of Review:Rituximab is increasingly prescribed for glomerular diseases. However, the recently published Kidney Disease Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Glomerular Diseases lacks details on recommended dosing regimens for most individual glomerular diseases. We performed this scoping review summarizing the evidence for rituximab dosing in glomerular disease.Sources of Information:PubMed database.Methods:The PubMed search methodology was developed with a medical librarian and performed by the first, with review by a second, author. Randomized controlled trials (RCTs) and prospective cohort studies (PCSs) examining rituximab efficacy and/or safety in antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), membranous nephropathy (MN), lupus nephritis (LN), or podocytopathies (minimal change disease or focal segmental glomerulosclerosis [FSGS]) were included. Fifty-three studies (14 RCTs and 39 PCSs) were included.Key Findings:We identified 16 different rituximab dosing regimens studied as induction therapy for one or more of the 5 glomerular diseases of interest. The most frequently studied rituximab induction regimens were 1000 mg as 2 doses 2 weeks apart (17 studies, 32%) and 4 doses of 375 mg/m2/week (18 studies, 33.9%). Twenty-six studies (49%) examined rituximab as monotherapy or in conjunction with corticosteroids alone, while the remaining studies examined rituximab as part of combination immunosuppression. Adapting treatment to achieve B-cell depletion, with frequent evaluation of disease-specific biomarkers, might prove the optimal approach to achieving and maintaining remission. Rituximab might also enable steroid minimization or avoidance.Limitations:Restriction of the search to a single database and to studies published in the English language, and with an accompanying abstract, could have led to selection bias. While the search was limited to prospective observational studies and RCTs, no formal assessment of study quality was performed.

Reconsidering Dexamethasone for Antiemesis when Combining Chemotherapy and Immunotherapy.

Whether the immune suppressive action of glucocorticoid steroids, such as dexamethasone, might reduce the benefits of cancer immunotherapy has long been a concern. Observations that established tumor regressions in response to immune checkpoint inhibitors (ICIs) often persist, despite the use of steroids to mitigate ICI-related autoimmune breakthrough, are not sufficiently reassuring, because these observations do not address the potential blunting of immune priming at the initiation of ICI therapy. With increasing indications for ICI in combination with chemotherapy, this issue merits reconsideration. Professional society guidance advises that dexamethasone should be used as first-line prophylaxis for nausea and vomiting in patients receiving ICI and highly emetogenic chemotherapy combination regimens. Here, we review the availability of data on this subject and propose an alternative approach focused on the adoption of steroid minimization or sparing for prophylaxis of nausea until the underlying immune biology is better understood.

Long-Term Infectious and Noninfectious Outcomes of Monthly Alemtuzumab as a Calcineurin Inhibitor- and Steroid-Free Regimen for Pancreas Transplant Recipients.

Multiple doses of alemtuzumab for immunosuppressive therapy of patients with hematologic malignancies and hematopoietic stem cell transplant have been associated with a high rate of infection. In transplantation, limited alemtuzumab dosing has been successfully used as induction immunosuppression. The effect of multiple doses of alemtuzumab, used as maintenance therapy to minimize steroid and/or calcineurin inhibitor toxicity in solid organ transplant recipients, is unknown. We evaluated the infectious and noninfectious outcomes of 179 pancreas transplant recipients treated with alemtuzumab for induction and maintenance therapy (extended alemtuzumab exposure (EAE)) from 2/28/2003 through 8/31/2005, compared with 159 pancreas transplant recipients with standard induction and maintenance (SIM) therapy performed before (1/1/2002 until 12/31/2002) and after (1/1/2006 until 12/31/2006) the implementation of EAE. EAE was associated with higher risk of overall infections (hazard ratio (HR) 1.33 (1.06–1.66), P=0.01), bacterial infections (HR 1.33 (1.05–1.67), P=0.02), fungal infections (HR 1.86 (1.28–2.71), P < 0.01), and cytomegalovirus infections (HR 2.29 (1.39–3.77), P < 0.01). In addition, EAE was associated with higher risk of acute cellular rejection (HR 2.09 (1.46–2.99), P < 0.01). In conclusion, while a limited alemtuzumab dosing is safe and effective for induction therapy in pancreas transplantation, EAE combined with steroid and calcineurin minimization is associated with a high risk of infectious complications and acute cellular rejection.

Study of weight and body mass index on graft loss after transplant over 5 years of evolution.

Patients frequently experience a weight gain after organ transplantation. This increase in weight is the result of multiple factors, and is usually intensified by glucocorticoids and immunosuppressive drugs. It can also delay graft function and cause serious health problems. The objective of this study was to study the obesity as well as its causes and consequences in kidney transplant patients. The sample population consisted of 282 renal transplant patients, 170 men and 112 women, 18-74 years of age, who were monitored over a period of five years. For the purposes of our research, the patients were divided into two groups: (1) normal weight 18.5 ≤ BMI <25; (2) overweight 25 ≤ BMI ≤30. The association between BMI as an independent variable and graft survival was determined by means of a Cox regression analysis. Overweight patients were characterized by a higher comorbidity prevalence. In the Cox multivariate analysis, the initial BMI, evaluated as a continuous variable continued to be an independent predictor of delayed graft function and chronic nephropathy. This study evaluated the BMI as a continuous value instead of a categorical value. In conclusion, our results suggest that an increase in BMI without categorical variation can be an independent risk factor for graft loss. Consequently, obesity prevention for renal transplant patients should include dietary counseling and management, moderate physical activity, and steroid minimization.

Alemtuzumab Induction and Steroid Minimization in IgA Nephropathy: A Matched-Cohort Analysis.

Immunoglobulin A nephropathy is the most common primary glomerulonephritis in adults. Transplant can be complicated by immunoglobulin A nephropathy recurrence in up to 60% of allografts, sometimes causing graftloss.The use of alemtuzumab for induction therapy in the setting of steroid minimization for recipients with immunoglobulin A nephropathy is unclear. Here, we investigated patient and graft outcomes in patients with this condition who were induced with alemtuzumab and a steroid minimization protocol. We performed a retrospective analysis of a database containing 29 patients with immunoglobulin A nephropathy and 646 other recipients who underwent transplant and were induced with alemtuzumab and steroid minimization treatment between March 2006 and May 2015. A matched cohort generated using propensity scoring was also analyzed. Recipients with immunoglobulin A nephropathy were significantly younger at transplant (37.3 ± 11.9 vs 55.6 ± 13.4 years; P < .001), less likely to be African American (6.9% vs 23.2%; P = .04), less likely to have diabetes mellitus (10.3% vs 39.8%; P < .001), and more likely to have private insurance (72.4% vs 45.9%; P = .007). There were no significant differences in graft and patient survival. Recipients with immunoglobulin A nephropathy experienced a higher rate of 1-year rejection (24.1% vs 21.4%; P = .043). Of the 29 patients with immunoglobulin A nephropathy, 8 experienced recurrence (27.6%; average time of 1120.5 ± 982.9 days), with all 8 patients having allograftloss. Matched pair analyses did not yield significant differences in outcomes. Recurrence rate of immunoglobulin A nephropathy in those induced with alemtuzumab in the setting of steroid minimization is similar to previously reported rates. Although recipients with immunoglobulin A nephropathy had significantly higher 1-year rejection rate, no other differences in graft or patient survival were shown versus recipients without this condition.

Kidney transplant practice patterns and outcome benchmarks over 30years: The 2018 report of the NAPRTCS.

The NAPRTCS has collected clinical information on children undergoing renal transplantation since 1987 and now includes information on 12920 renal transplants in 11870 patients. Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in patient and allograft outcomes after pediatric renal transplantation in addition to identifying factors associated with both favorable and poor outcomes. The registry has served to document and influence practice patterns, clinical outcomes, and changing trends in renal transplantation and also provides historical perspective. This report highlights current practices in an era of major changes in DD kidney allocation and continuing steroid minimization. This report presents outcomes of the patients in the NAPRTCS transplant registry up to end of 2017. In particular, an increase in the cumulative incidence of late first AR has occurred in the most recent cohort, while all prior cohorts had a lower cumulative incidence of late first AR.

Steroid-Associated Side Effects in Patients With Primary Proteinuric Kidney Disease

IntroductionThe goal of this study was to assess the occurrence of steroid-associated adverse events (SAAE) in patients with primary proteinuric kidney disease.MethodsThe Kidney Research Network Registry consists of children and adults with primary proteinuric kidney disease. SAAEs of interest were hypertension, hyperglycemia and diabetes, overweight and obesity, short stature, ophthalmologic complications, bone disorders, infections, and psychosis. Events were identified using International Classification of Diseases, Ninth Revision/Tenth Revision codes, blood pressures, growth parameters, laboratory values, and medications. Poisson generalized estimating equations tested the association between steroid onset and dose on SAAE risk.ResultsA total of 884 participants were included in the analysis; 534 (60%) were treated with steroids. Of these, 62% had at least one SAAE. The frequency of any SAAE after initiation of steroids was 293 per 1000 person-years. The most common SAAEs were hypertension (173.7 per 1000 person-years), diabetes (78.7 per 1000 person-years), obesity (66.8 per 1000 person-years), and infections (46.1 per 1000 person-years). After adjustment for demographics, duration of kidney disease, estimated glomerular filtration rate (eGFR), proteinuria, and other therapies, steroid exposure was associated with a 40% increase in risk of any SAAE (Relative risk [RR]: 1.4; 95% confidence interval [CI]: 1.3–1.6). A 1-mg/kg per day increase in steroid dose was associated with a 2.5-fold increase in risk of any SAAE.ConclusionMost patients with primary proteinuric kidney disease treated with steroids experienced at least one SAAE. Steroid therapy increased risk of hypertension, diabetes, weight gain, short stature, fractures, and infections after adjusting for disease-related factors. This study highlights the importance of surveillance and management of SAAE and provides rationale for the development of steroid minimization protocols.

Low dose valganciclovir as cytomegalovirus prophylaxis in post-renal transplant recipients induced with alemtuzumab: A single-center study

ObjectivesAlemtuzumab (Ale) is a recombinant monoclonal antibody which binds to CD52 causing profound lymphodepletion, thus allowing its use in renal transplantation induction therapy. However, patients may be at increased risk for opportunistic infections, such as Cytomegalovirus (CMV). We analyzed CMV infection in renal allograft recipients administered low-dose valganciclovir (VGCV) prophylaxis with alemtuzumab induction and steroid minimization. Materials and methodsIn this retrospective analysis, 678 kidney transplant recipients were evaluated, with 606 included for analysis. Patients were excluded for receiving induction therapy other than Ale, or for lack of follow-up within 1 year. VGCV prophylaxis was stratified by recipient CMV risk status and low-dose (450 mg) VGCV was given 3 times a week to low and moderate risk patients and daily to high risk individuals. Subject records were examined for recipient demographics, donor and recipient CMV serostatus, CMV viremia, and invasive infection. ResultsOf the 606 recipients, 154 were defined as low risk for CMV infection (donor and recipient both negative, or D−/R−), 236 as moderate risk without mismatch (D+/R+), 122 as moderate risk with mismatch (D−/R+), and 94 as high risk (D+/R−). Twenty-nine (29) individuals (4.8%) tested positive by PCR for CMV viremia and 10 (1.7%) patients developed invasive CMV disease, including colitis (n = 4), esophagitis (n = 1), enteritis (n = 1), nephritis (n = 1), and pneumonia (n = 3). High risk recipients (D+/R−) accounted for the majority of invasive CMV disease (n = 5), followed by moderate risk (n = 4). CMV viremia was also more common in high risk and moderate risk (D+/R+) individuals. Overall rejection rate for our study population was 27%. ConclusionIn this institution's experience, CMV incidence was reduced compared to historically reported data by using low-dose (450 mg) VGCV prophylaxis in combination with Ale induction and steroid minimization. However, overall rejection rate was significantly higher in our population, possibly influenced by the degree of steroid minimization.

Natural history of mineral metabolism, bone turnover and bone mineral density in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol.

The skeletal effects of renal transplantation are not completely understood, especially in patients managed with a steroid minimization immunosuppressive protocol and long term. We enrolled 69 adult transplant recipients (39 males; ages 51.1 ± 12.2 years), free of antiresorptive therapy and managed with a steroid minimization immunosuppressive protocol, into a 5-year prospective observational study to evaluate changes in areal bone mineral density (aBMD), mineral metabolism and bone remodelling. Dual energy X-ray absorptiometry, laboratory parameters of mineral metabolism (including parathyroid hormone, sclerostin and fibroblast growth factor 23) and non-renal cleared bone turnover markers (BTMs) (bone-specific alkaline phosphatase, trimeric N-terminal propeptide and tartrate-resistant acid phosphatase 5b) were assessed at baseline and 1 and 5 years post-transplantation. The mean cumulative methylprednisolone exposure at 1 and 5 years amounted to 2.5 ± 0.8 and 5.8 ± 3.3 g, respectively. Overall, bone remodelling activity decreased after transplantation. Post-transplant aBMD changes were minimal and were significant only in the ultradistal radius during the first post-operative year {median -2.2% [interquartile range (IQR) -5.9-1.2] decline, P = 0.01} and in the lumbar spine between Years 1 and 5 [median 1.6% (IQR -3.2-7.0) increase, P = 0.009]. BTMs, as opposed to mineral metabolism parameters and cumulative corticosteroid exposure, associated with aBMD changes, both in the early and late post-transplant period. Most notably, aBMD changes inversely associated with bone remodelling changes. In summary, in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol, BMD changes are limited, highly variable and related to remodelling activity rather than corticosteroid exposure.

Steroid withdrawal improves blood pressure control and nocturnal dipping in pediatric renal transplant recipients: analysis of a prospective, randomized, controlled trial.

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 ± 3.8years, 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.

Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus

IntroductionDespite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization.MethodsWe conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein–cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months.ResultsThe study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2–12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8–8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms.ConclusionIn high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

Kidney Fibrosis: Origins and Interventions.

All causes of renal allograft injury, when severe and/or sustained, can result in chronic histological damage of which interstitial fibrosis and tubular atrophy are dominant features. Unless a specific disease process can be identified, what drives interstitial fibrosis and tubular atrophy progression in individual patients is often unclear. In general, clinicopathological factors known to predict and drive allograft fibrosis include graft quality, inflammation (whether "nonspecific" or related to a specific diagnosis), infections, such as polyomavirus-associated nephropathy, calcineurin inhibitors (CNI), and genetic factors. The incidence and severity of chronic histological damage have decreased substantially over the last 3 decades, but it is difficult to disentangle what effects individual innovations (eg, better matching and preservation techniques, lower CNI dosing, BK viremia screening) may have had. There is little evidence that CNI-sparing/minimization strategies, steroid minimization or renin-angiotensin-aldosterone system blockade result in better preservation of intermediate-term histology. Treatment of subclinical rejections has only proven beneficial to histological and functional outcome in studies in which the rate of subclinical rejection in the first 3 months was greater than 10% to 15%. Potential novel antifibrotic strategies include antagonists of transforming growth factor-β, connective tissue growth factor, several tyrosine kinase ligands (epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor), endothelin and inhibitors of chemotaxis. Although many of these drugs are mainly being developed and marketed for oncological indications and diseases, such as idiopathic pulmonary fibrosis, a number may hold promise in the treatment of diabetic nephropathy, which could eventually lead to applications in renal transplantation.

Steroid Minimization Regimens for Management of Nephrotic Syndrome

Steroid Minimization Regimens for Management of Nephrotic Syndrome

FIRST RUSSIAN EXPERIENCE OF EARLY CONVERSION TO EVEROLIMUS IN THE KIDNEY TRANSPLANTATION FROM EXPANDED CRITERIA DONORS: A SUMMARY OF 5-YEAR OBSERVATION

Introduction. Kidney transplant (KTx) with reduced functional reserve is more sensitive to the toxic effects of calcineurin inhibitors (CNI). Immunosuppressive (IST) approach included m-TOR inhibitors in case of KTx from the ECD lead to decreasing levels of cyclosporine (CsA) in the blood. Despite of presence international pilot studies we having not yet strong recommendation for real combination of CsA and Everolimus. In this article we presented 5-yeras results of the first Russian experience of systematic use Everolimus as basic IST in KTx from ECDs. Patients and methods. The group of recipients (n=41) was formed during the operation; received a bilateral kidney transplants from the same ECDs. Comparison group (n=19) received standard IST consisting of CsA, MMF and steroids. Study group included 22 recipients who received an another kidney from the same ECD and IST, based on early (starting from the 90th day after transplantation) conversion from MMF to Everolimus-1.5mg/day (target concentration-3-6ng/mL). Simultaneously with the appointment Everolimus, dosing occurred immediately Neoral decrease by 50% and then, in accordance with the target concentration (C0-30-50ng/ml). Implementing a program of gradual minimization of the dose steroids in patients of the study group. Results. Both groups were comparable in terms of level of serum creatinine and glomerular filtration rate of up to 3 months after transplantation. As a result of the introduction of a new scheme of ICN in the study group, for the 60-month observation GFR study group was 46±15 ml/min/1.73m 2 , the control is reduced to 28±7 ml/min/1.73m 2 ;P&lt;0.05. Conclusion. Early administration of Everolimus is strongly recommended in all cases of the use of grafts for KTx obtained from the ECDs. This approach helps to minimize of nephrotoxity of CNT, provides the prevention of chronical transplant nephropathy, the stable renal function, and contributes to the survival and renal transplant recipients.

Lymphocyte-depleting induction and steroid minimization after kidney transplantation: A review

Steroid minimization after kidney transplantation has become more widely practiced as transplant clinicians seek the potential benefits such as reduced cardiovascular risk factors, improved growth in pediatric patients, and improved compliance with the immunosuppression regimen. Steroid avoidance (i.e. no steroids after the first week) is generally favored compared to later withdrawal. Induction therapy is routine in this setting, frequently rabbit antithymocyte globulin (rATG, Thymoglobulin®) or off-license use of alemtuzumab. Direct comparisons of steroid minimization regimens versus standard steroid regimens are rare. However, the available data show that the risk of acute rejection is low when rATG or alemtuzumab induction is given to support steroid-avoidance regimens after kidney transplantation. Steroid avoidance may be inadvisable in patients at high immunological risk or at risk of recurrent glomerular disease. Steroid withdrawal after day 8 may be possible without additional risk of rejection in patients given rATG induction, but while encouraging, the data are too sparse for firm conclusions. In summary, steroid avoidance may be beneficial for patients after renal transplantation, with the potential to avoid or reduce steroid-related comorbidities. Whilst depleting induction therapy could be the treatment of choice, results of prospective randomized, controlled studies are eagerly awaited.

Immunosuppression in the elderly renal allograft recipient: a systematic review.

The Elderly are the fastest growing part of kidney transplant recipients. The best immunosuppressive strategy is unknown. We performed a systematic search of randomized controlled trials and observational studies focused on safety and efficacy of different immunosuppression strategies in elderly kidney recipients. Data extraction and risk of bias evaluation were systematically performed. Ten studies were included: 2 randomized clinical trials and 8 observational. A marginal benefit was found for early renal function with delayed tacrolimus or complete tacrolimus avoidance using mycophenolate mofetil (MMF). Observational cohort studies looked at different antibody induction strategies, calcineurin-inhibitors based maintenance immunosuppression, calcineurin-inhibitor-free sirolimus-based therapy and use of MMF versus azathioprine. Treatment with interleukin-2 receptor antibody induction, calcineurin-inhibitor minimization with MMF and steroid minimization is advisable in the low immunologic risk elderly recipient, considering the increased risk of toxicities, infection and malignancies. In the high immunologic risk elderly recipient, taking into account the morbid consequences of acute rejection in the elderly, observational studies support antibody induction with depletive antibodies, calcineurin-inhibitor, MMF and steroids; calcineurin-inhibitor-minimization is not recommended. There is very limited evidence for the benefits and harms of different immunosuppression strategies in the elderly. Most of the published literature are observational studies, and randomized controlled trials are urgently needed.