Corticosteroid-induced hypersensitivity reactions.

OBJECTIVE: To review and present data on the prevalence, clinical manifestations, diagnostic techniques, and management options in patients with hypersensitivity reactions to corticosteroid preparations. DATA SOURCES: All English language articles pertaining to human subjects were reviewed using the Pubmed database from 1964 to June 2002. Indexing terms used were anaphylaxis OR allergic OR anaphylactoid OR hypersensitivity AND steroid OR corticosteroid. Further cross-references were obtained after reviewing articles from the aforementioned search. STUDY SELECTION: A total of 11,493 articles were identified with the above search terms. Only those articles, including letters and editorials, describing systemic reactions to steroids were included in the review. Excluded from our review were articles dealing with contact dermatitis to topical steroid preparations. This resulted in a total of 80 articles which were reviewed. RESULTS: Although rare, steroid-induced hypersensitivity reactions do occur. They range from minor rashes to the more serious cardiovascular collapse. The mechanisms of steroid-induced adverse events vary from patient to patient, some being classic immunoglobulin E-mediated whereas others are pseudoallergic in nature. Skin testing and provocative challenges offer two ways to diagnose such reactions. Treatment consists of substituting the steroid with an alternative preparation which can be tolerated by the patient. CONCLUSIONS: Although little is known about the epidemiology of steroid-induced hypersensitivity, because most data are derived from case reports, it is clear that steroid-induced hypersensitivity is a heterogeneous entity, with no single uniform mechanism. A great deal of work still needs to be done so that the pathogenesis of such adverse events can be clearly determined and effective therapeutic interventions devised.     

Efficacy of bortezomib for reducing donor‐specific antibodies in children and adolescents on a steroid minimization regimen

AMR is increasingly being recognized as an important cause of renal allograft injury, contributing to significant morbidity and graft loss. There are few controlled trials and no well‐established treatment guidelines for AMR in renal transplant recipients. We retrospectively reviewed the outcome of four pediatric renal transplant recipients on a steroid minimization immunosuppression protocol treated with bortezomib for elevated DSA and acute AMR from 2012 to 2013. All patients received four doses of bortezomib 1.3 mg/m² given on days one, four, eight, and 11. All patients also received other treatments prior to bortezomib, which may have included rituximab, methylprednisolone, plasmapheresis, and/or IVIg. While bortezomib in addition to other therapies significantly decreased DSA titers, DSA remained very elevated months after treatment. All four patients had immediate improvement or stabilization of renal function but one eventually lost her graft. There were no adverse events related to bortezomib six months after treatment.     

Early and late recipient graft function and donor outcome after laparoscopic vs open adult live donor nephrectomy for pediatric renal transplantation

BACKGROUND: Laparoscopically procured live donor kidney grafts are increasingly transplanted into pediatric recipients. The safety and efficacy of this changed surgical practice are unknown. HYPOTHESIS: Outcomes of laparoscopic vs open donor grafts in recipients 18 years and younger are equivalent. DESIGN AND SETTING: Retrospective review at an academic tertiary care referral center. PATIENTS: Eleven consecutive pediatric recipients of laparoscopically procured kidneys between April 1, 1997, and December 31, 2001, were pair matched for age with 11 recipients of openly procured kidneys between December 1, 1991, and March 31, 1997; the 22 adult donors were also studied. MAIN OUTCOME MEASURES: Recipients: surgical complications, graft function and survival. Donors: perioperative morbidity and length of hospital stay. RESULTS: Twenty (91%) of 22 kidneys were donated by a parent of the recipient. In recipients of laparoscopically procured grafts, we observed significantly lower creatinine clearances and higher creatinine levels on days 1, 4, and 6, but by 1 month, graft function was similar in both groups. No significant differences in surgical complications, delayed function, acute and chronic rejection, and graft survival rates were found. No laparoscopic or open donor required blood transfusion, reoperation, or hospital readmission. One laparoscopic donor (9%) was converted to open nephrectomy. For laparoscopic vs open donors, median operative time was longer (difference, 67 min; P =.08), but median postoperative length of stay was significantly shorter (3 vs 5 days; P =.02). CONCLUSIONS: Laparoscopic live donor nephrectomy has no adverse impact on pediatric recipient outcomes. For donors, the laparoscopic operation is safe and the hospital stay is shortened. These results support the continued use of laparoscopically procured live donor kidneys in pediatric renal transplantation.     

Conversion from tacrolimus to neoral for postrenal transplant diabetes

Diabetes mellitus (DM) is a well-recognized complication of immunosuppressive therapy in the post-transplant (Tx) period. The DM encountered in the setting of tacrolimus therapy has been managed in the past by tacrolimus dose reduction and a rapid corticosteroid taper; frequently insulin therapy is also required to maintain normoglycemia. However, the dose reduction of immunosuppressive agents has often resulted in acute allograft rejection. We are reporting our experience in managing three pediatric renal Tx recipients who developed DM in the post-Tx period while on triple immunosuppressive therapy including tacrolimus and corticosteroids. All of our patients were managed by substitution of tacrolimus with conventional doses of neoral while maintaining their usual corticosteroid dose. All three patients had resolution of hyperglycemia and none experienced acute rejection. Tacrolimus was then successfully reinitiated 4.6 months later; at last follow-up, all of our patients have good allograft function and have maintained a normal blood sugar. In conclusion, we feel that conversion of patients from tacrolimus to neoral should be attempted as a safer alternative to tacrolimus dose reduction, for managing post-Tx DM in tacrolimus treated patients. Received: 28 April 2000 / Revised: 21 July 2000 / Accepted: 27 July 2000     

Predictive value of pretransplant inflammatory markers in renal allograft survival and rejection in children

Pretransplant (pre-Tx) inflammation has been associated with acute rejection (AR) in adult Tx recipients. Our study was performed to determine whether a single pre-Tx serum C-reactive protein (CRP), Neopterin (Neo), and IL-12 determination could predict outcome in pediatric renal Tx recipients. Pre-Tx sera from 51 children transplanted between 1985 and 2000 were analyzed for serum CRP, Neo, and IL-12 for correlation with Tx-related variables. Endpoints were graft loss and AR. Kaplan-Meier and log-rank statistics were used to compare rejection-free and overall graft survival at different quartiles for each marker. Cox regression analysis was performed to determine the independent effects of various pre-Tx variables on the endpoints. The mean age of the children at Tx was 11 years. The mean CRP, Neo, and IL-12 were 1.3 mg/L, 1.78 ng/mL and 123 pg/mL, respectively. At last-follow-up (mean 4.9 years after Tx), 50% of the children had experienced AR and 29% had lost their grafts. The mean CRP, Neo, and IL-12 were not different between the patients with versus without AR or graft loss (P > .4 for all). Neither rejection-free survival nor graft survival was affected by CRP, Neo, or IL-12 quartiles (log-rank test). Cox regression analysis demonstrated no predictive value of any marker on the outcomes. Unlike adults, a single pre-Tx determination of inflammatory markers was not predictive of AR or graft loss in children. The pathogenesis of AR may be different in children with a lesser contribution of alloantigen-independent factors such as chronic infections.     

Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue

BACKGROUND: Little is known about the incidence and evolution of proteinuria as a complication of sirolimus rescue in children. This study describes pediatric renal transplant (Tx) recipients who were treated with sirolimus and who developed heavy proteinuria. Risk factors for the development of proteinuria and its time course are explored. METHODS: Data at various time points after sirolimus introduction were abstracted from the records of children treated at the author's center. The repeated measures general linear model and the Student's paired t test were used to analyze changes in laboratory values over time. RESULTS: Of the 13 children on sirolimus, 12 developed heavy proteinuria after a mean interval of 1 month. The mean urine protein (Up)-to-creatinine (c) ratio increased from 1.1 to a peak value of 3.9 (P=0.003) at 4.6 months after the start of sirolimus. Although not statistically significant, children on no calcineurin inhibitor (CNI) had a greater increase in the Up/c than those on low-dose CNI. At last follow-up, with the use of angiotensin receptor blockers (ARB), the Up/c declined to 2.2. No predictors could be identified for the development of proteinuria. CONCLUSIONS: Heavy proteinuria is common after the use of sirolimus as rescue therapy in children with renal Tx. Whether this is attributable to a toxic effect of the sirolimus itself or to lower CNI exposure is uncertain. Early detection of proteinuria is important to enable prompt intervention. Most children have a reduction in their Up/c with the use of ARB and can therefore be continued on sirolimus.     

Bilateral infundibulopelvic stenosis without renal insufficiency: Is surgery necessary?

The following case describes the clinical course of a patient with bilateral infundibulopelvic stenosis from her initial presentation at age 2 through the age of 14 years. This condition is associated with hypoplasia of segments of the upper collecting system and is characterized by dilated calyces that drain through stenotic infundibulae. Our patient is unique in that, although her renal function has slowly deteriorated with time, she has a persistently non-obstructive pattern on dynamic imaging studies. Only a minority of patients reported in the literature with this condition progress to renal insufficiency or failure. Although some patients have undergone surgery for presumed obstruction, surgical intervention has no proven benefit. Patients are at risk for hyperfiltration injury and should be followed for the development of hypertension, proteinuria and renal insufficiency. Without evidence of obstruction, medical management remains the cornerstone of treatment.     

Unusual Pattern of Dyslipidemia in Children Receiving Steroid Minimization Immunosuppression after Renal Transplantation

Background and objectives: Corticosteroids are an important contributor to posttransplant hyperlipidemia. Since 2004, we have used a steroid minimization immunosuppression protocol. This study investigated the effect of steroid minimization on dyslipidemia in pediatric renal allograft recipients.Design, setting, participants, & measurements: Children (<18 years) who underwent renal transplants at our center from January 2001 to January 2008 were studied. Data analyzed included age, gender, race, body mass index, cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, and steroid dose. Data between the cohorts receiving maintenance steroids and steroid-minimization were compared using multivariable analyses. The primary outcome measures were the prevalence of, and the effect of steroid use, on dyslipidemia.Results: Twenty-nine patients were studied. Sixteen were receiving maintenance steroids, and 13 were on a steroid minimization regimen. Mixed effects analysis of covariance models demonstrated that at 1 month, children receiving maintenance steroids had higher cholesterol compared with the steroid minimization group. Statistically significant differences in total cholesterol were not seen at other time points. Similar findings were noted for the LDL cholesterol, LDL/HDL, and cholesterol/HDL ratios. At 1 month, the serum HDL cholesterol was substantially lower in the steroid minimization group. Differences in the HDL cholesterol levels remained significant throughout the first year.Conclusions: Steroid use is a significant independent risk factor for hypercholesterolemia during the first post-transplant month. The significance of lower HDL cholesterol among patients receiving steroid minimization needs further study and may be cause for concern.Post-transplant hyperlipidemia affects the majority of solid organ transplant recipients (1,2). While hyperlipidemia has been shown to contribute to an increased cardiovascular risk in adult patients after renal transplantation, a similar link in pediatric recipients has not been established. Changes in serum lipid profiles reported after transplantation include an increase in total cholesterol, triglyceride, LDL cholesterol, and VLDL cholesterol (2–4). On the other hand, the effect of renal transplantation on HDL cholesterol is variable (5,6). Factors including age, body mass index (BMI), pretransplant lipid levels, presence of diabetes, use of antihypertensive medications, and immunosuppressive agents have been implicated as being contributory to posttransplantation hyperlipidemia (7). As part of our institutional protocol, all renal transplant recipients after 1999 have been managed preemptively with fixed-dose pravastatin for its potential benefits in reducing acute rejection (8,9), regardless of the recipients'' serum lipid levels.A previous study from our center evaluated the effect of pravastatin on lipid levels in a cohort of pediatric renal transplant recipients who were receiving maintenance steroids. The preemptive use of pravastatin reduced the incidence of hypercholesterolemia and also lowered LDL (10). An unexpected finding in our study was a substantial decrease in HDL levels over time in the cohort that was treated with pravastatin; data on HDL levels were not available in the control population. Multivariate analyses showed that the two predictors of low HDL were lower prednisone dose and lower creatinine clearance. However, an effect of pravastatin on reducing HDL could not be evaluated.Since 2004, our center has adopted a novel steroid minimization immunosuppression protocol; even in this cohort, preemptive pravastatin was used as part of our protocol. This gave us the opportunity to analyze retrospective data on serum lipid levels among our pediatric recipients who were managed by steroid minimization, comparing them to patients who received maintenance steroids, to study the effect of steroid elimination on the prevalence and pattern of dyslipidemia, in the setting of preemptive pravastatin use. Data from time points when patients were receiving sirolimus were excluded from the analyses due to the known effect of sirolimus in contributing to dyslipidemia.