The factors affecting blood pressure in pediatric renal transplant recipients

To investigate the parameters affecting systemic blood pressure in pediatric renal transplant recipients, we retrospectively examined the data from 19 adolescent renal transplant recipients including 6 girls overall, mean age of 15,47 +/- 3.56 years. Serum creatinine (Scr), fractional extraction of sodium (FENa), whole blood trough cyclosporine(C0), plasma total cholesterol (TC) and triglyceride levels, and systolic and diastolic blood pressure (SBP and DBP) were monitored during a total of 677 visits. SBP and DBP, classified as <95p (groups 1s and 1d) and >95p (groups 2s and 2d), were correlated with differences between groups 1 and 2. Group 2s Scr and FENa levels were higher than group 1s (P =.002 and P =.048, respectively), whereas C0 and FENa levels were higher in Group 2d than Group 1d (P = 0.028 and P = 0.036, respectively). Among the entire group, SBP and DBP positively correlated with C0; Scr and SBP, with FENa. While there was a positive correlation between SBP and C0 in groups 1s and 2s (r = 0.188, P <.000; and r = 0.145, P =.040), DBP was only associated with C0 in group 1d (P =.03, r = 0.156). In contrast, DBP showed a positive correlation with Scr in group 2d (P =.023, r = 0.132), and SBP with Scr in Group 1s. C0 and Scr levels were correlated in Groups 1s, 1d and 2d. At high BP levels (>95p), SBP is mostly affected by C0; DBP, with Scr. However, in both groups these two parameters positively correlate with each other. Thus, in adolescent renal transplant recipients the cause of high blood pressure does not appear to be solely related to cyclosporine related to induced allograft dysfunction.     

Differences in bioavailability between oral cyclosporine formulations in maintenance renal transplant patients.

Previous studies of healthy volunteers and small numbers of transplant recipients have suggested that the oral solution formulation of Sandimmune (cyclosporine [CsA]; Sandoz Pharmaceuticals, East Hanover, NJ) is bioequivalent to the soft gelatin capsule (SGC) formulation. However, there is conflicting evidence as to whether the two formulations are bioequivalent in all patients; to date, there are no published studies that explicitly address their bioequivalence in patients. We conducted a randomized, open-label, two-sequence, two-period, crossover study. Of 20 maintenance renal transplant recipients shown by a screening pharmacokinetic (PK) profile to be poor absorbers of CsA, half were randomized to receive first the SGC formulation and half the oral solution formulation for a period of 7 days. Each patient then underwent a 12-hour PK profile on the last day of the assigned formulation before a crossover to receive the other formulation and repeat the 7-day treatment and PK profile cycle. The results showed that peak and total exposure to CsA was greater with the SGC formulation. The SGC-oral solution ratios indicated an average 38% greater peak and 11% greater total exposure for the SGC formulation (P < 0.01 and P = 0.09, respectively). Trough levels were more similar between formulations, with SGC showing an average of 5% greater troughs (P > 0.10). In our selected population of malabsorbers, the SGC formulation made a difference in drug exposure.     

Evaluation of kidney function in renal transplant patients receiving long-term cyclosporine

We prospectively assessed renal function in a group of 29 renal transplant patients receiving cyclosporine (CsA) in order to determine the course of their renal function over time and the relationship between different markers of glomerular function. We measured serum creatinine, DPTA, and creatinine clearances, and urinary albumin excretion. The clinical course of 24 patients (83%) permitted repeat studies over a period of 32 +/- 1 (SEM) months, and in these patients DTPA clearance, creatinine clearance, and the serum creatinine concentration did not vary with time. Five of the patients (17%) lost their grafts and returned to dialysis. On initial evaluation patients who lost their grafts had a lower DPTA clearance than those whose function was maintained (29 +/- 3 v 46 +/- 2 mL/min/1.73 m2 body surface area [BSA], respectively, P less than 0.005) and all of them had a DTPA clearance of less than 40 mL/min/1.73 m2 BSA. There was an inverse correlation between the log of the urinary albumin excretion and the DTPA clearance (n = 33, r = -0.59, P less than 0.001), a direct correlation with the serum creatinine concentration (N = 33, r = 0.89, P less than 0.0001), but no correlation with time after transplantation. Thus, despite the continued use of CsA, renal function over time was stable in patients who underwent repeated studies, as was the relationship between the DTPA clearance and the clinically used markers of transplant function, the serum creatinine concentration, and the creatinine clearance.     

Evaluation of factors contributing to mortality in pediatric renal transplant recipients.

From 1969 to 1985, 303 renal allografts (290 cadaveric) were placed in 215 pediatric recipients. A review of actuarial recipient and allograft survival 2 years posttransplant showed good results in patients over 6 years of age (greater than 90% for patients, about 70% for allografts) but less satisfactory results in younger patients (75% for patients, about 45% for allografts). Thirty-nine patients died. Loss of allograft function preceded death in 67% of cases and was due to rejection (61%), renal vascular thrombosis (35%), and recurrence of original disease (4%). On retrospective analysis, 13 deaths might have been preventable with current diagnostic and therapeutic modalities. Allograft dysfunction from thrombosis occurs at a higher frequency in the young child and may be confused with rejection. Treatment of rejection without biopsy, overagressive treatment of a chronically failing graft, and failure to withdraw immunosuppressive therapy in face of infection are poorly tolerated in the very young recipient and are prominent causes of preventable mortality. Transplant nephrectomy and repeated attempts at transplantation are poorly tolerated in very young patients. Patient survival is very dependent on the success of the initial allograft in children.     

Protocol biopsies in pediatric renal transplant recipients on cyclosporine versus tacrolimus-based immunosuppression

Background

Protocol biopsies can detect subclinical rejection and early signs of calcineurin inhibitor-induced nephrotoxicity.

Methods

In a prospective study, protocol biopsies 3 and 12 months after transplant in transplanted children from two centers were studied. One center used cyclosporine (CsA)-based immunosuppression and the other center used tacrolimus. Patients were on CsA (n?=?26, group 1) or on tacrolimus (n?=?10, group 2). Patients received basiliximab induction, mycophenolate mofetil, and prednisone.

Results

In patients on CsA, 26 kidney biopsies were performed during the 6 months after transplantation. Eighteen protocol biopsies were performed at 3 months post transplant; 13 were normal and five showed rejection (two borderline and three Banff II rejections). Eight biopsies were motivated by an increase of serum creatinine; four were normal and four revealed signs of acute rejection (two borderline and two Banff II). Twelve protocol biopsies were performed after 12 months; all were normal. For patients on tacrolimus (n?=?10), ten protocol transplant biopsies were performed at 3 months post-transplant; none showed signs of rejection. No biopsy was performed for an increase of serum creatinine. There were no differences in patient age, number of human leukocyteantigen (HLA) incompatibilities, or other patient characteristics.

Conclusions

Patients on tacrolimus had less acute rejection episodes detected on protocol biopsies 3 months after transplant. Protocol biopsies seem to play an important role in the detection of subclinical rejection in patients on CsA.     

Effect of cyclosporine A on long-term allograft function in pediatric renal transplant recipients

There have been concerns regarding long-term adverse effects of cyclosporine A (CSA) on renal allograft function. In a retrospective study, we compared long-term allograft function up to 70 months after renal transplantation in pediatric recipients treated with and without CSA, using iothalamate clearance to assess glomerular filtration rate. Patients received CSA, prednisone, and azathioprine (CSA group,n=16) or prednisone and azathioprine alone (Pred/AZA,n=11). At 48 months post transplant, the iothalamate clearances (mean±SD) were 57.9±26.8 ml/min per 1.73 m² in the CSA group and 68.5±20.2 in the Pred/AZA group (P>0.05). The mean of the slopes of individual iothalamate clearances versus time during the first 70 months following transplantation were –0.156 in the CSA group and –0.095 in the Pred/AZA group. Neither slope was statistically different from zero. These data suggest that allograft function is not significantly depressed by CSA at 48 months post transplantation and that there is no greater rate of decline in allograft function up to 70 months post transplantation in patients receiving CSA when compared with the AZA/Pred group.     

Long-term assessment of renal function under cyclosporine in pediatric heart transplant recipients.

Renal function was monitored in eight children who were long-term survivors of heart transplantation and who were treated with cyclosporine. Both creatinine clearance and true glomerular filtration rate remained normal 17 to 69 months after transplantation. The survival rate was 80% at 6, 12, and 24 months, and the rejection rate in survivors was only 0.37. Thus adequacy of renal function can be preserved, without jeopardizing overall transplant results, by using small doses of cyclosporine.     

Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination

BACKGROUND: Sirolimus (Rapamune; SRL) in combination with cyclosporine (CsA) reduces the incidence of acute rejection episodes in renal allograft recipients. This study evaluated whether renal function could be improved by elimination of CsA from an SRL-based regimen. METHODS: This phase 2, open-label, controlled, randomized study was conducted at 17 centers in the United States and Europe. Two hundred forty-six first cadaveric renal allograft recipients were enrolled, and 197 were randomized to full-dose CsA (microemulsion) plus fixed-dose SRL (2 mg/day; group A, n=97) or reduced-dose CsA plus concentration-controlled SRL (troughs 10-20 ng/mL; group B, n=100). Most patients with acute tubular necrosis-delayed graft function that resolved later than posttransplantation day 7 were not randomized but were assigned to a third group (nonrandomized, n=49) and received up to 5 mg per day of SRL as part of their individualized treatment regimen. All patients received standard doses of corticosteroids. At the end of posttransplantation month 2, eligible patients (those not treated for rejection within 3 weeks) in group B had CsA tapered and eliminated over the subsequent 4 to 6 weeks. RESULTS: At 12 months after transplantation, renal function was significantly better in the CsA-elimination arm. In patients who were on therapy and who had not experienced an acute rejection episode before month 6, serum creatinine level was significantly lower (1.38 mg/dL vs. 1.82 mg/dL, P < 0.001) and calculated glomerular filtration rate (Nankivell method) was significantly higher (73.5 mL/min vs. 57.1 mL/min, P < 0.001) in group B than in group A. In the intention-to-treat population, rates of biopsy-confirmed acute rejection at 12 months were similar between groups A and B (18.6% vs. 22.0%, respectively; P = 0.598). In addition, graft survival (92.8% and 95.0%) and patient survival (96.9% and 96.0%) rates at 12 months were not significantly different between groups A and B, respectively. Furthermore, there were no significant differences between black and nonblack recipients within treatment groups in terms of rejection rates and graft survival at 12 months. Black recipients in group B had better serum creatinine levels at 12 months compared with black recipients in group A (1.55 mg/dL vs. 2.69 mg/dL, respectively, P = 0.011), as did nonblack recipients in group B compared with nonblack recipients in group A (1.53 mg/dL vs. 1.75 mg/dL, respectively, P = 0.055). Black patients in group A had higher mean serum creatinine levels (2.69 mg/dL) than nonblack patients in group A (1.75 mg/dL, P = 0.028). Hypertension, edema, hypomagnesemia, and dyspnea were reported significantly less frequently in patients randomly assigned to undergo CsA elimination compared with patients in group A (P < 0.05); group B patients had a significantly greater (P < 0.05) incidence of abnormal liver function tests, diarrhea, hypokalemia, and thrombocytopenia. CONCLUSION: Concentration-controlled SRL with early elimination of CsA is safe and results in improved renal function. Reduced exposure to CsA does not result in a clinically significant increase in the incidence of acute rejection episodes. This is true for both black and nonblack recipients. SRL may be used to reduce the exposure of renal allograft recipients to the nephrotoxic effects of CsA.     

Everolimus in pediatric de nova renal transplant patients

BACKGROUND: The steady-state pharmacokinetics of everolimus were longitudinally assessed in pediatric de novo kidney allograft recipients during a 6-month period. METHODS: Nineteen patients received everolimus 0.8 mg/m2 (maximum 1.5 mg) twice daily as a dispersible tablet in water in addition to cyclosporine and corticosteroids. Everolimus and cyclosporine trough concentrations were obtained on days 3, 5, 6, and 7 and at months 1, 2, 3, and 6; an everolimus pharmacokinetic profile was obtained on day 7 and month 3. RESULTS: There were 9 boys and 10 girls with a median age of 9.9 (range, 1-16) years. Steady-state pharmacokinetic parameters were as follows (median, range): C(min) (trough level), 4.7 (2.3- 9.5) ng/mL; peak concentration, 13.5 (5.9-22.2) ng/mL; area under the concentration-time curve (AUC), 77 (53-147) ng x hr/mL; and apparent oral clearance, 10.2 (5.5-15.6) L/hr/m2. Clearance (unadjusted for demographic factors) was positively correlated with age (r=0.66), body surface area (r=0.68), and weight (r=0.67). There were no trends in C(min) or AUC versus patient age when everolimus was dosed on a mg/m2 basis. Everolimus C(min) were stable over time with median values of 3.9, 3.4, and 3.1 ng/mL at months 1, 3, and 6, respectively. Intra- and interpatient variability in AUC was 29% and 35%, similar to that in adults. During the observation period, eight patients maintained stable AUCs and nine patients had increases or decreases, generally between 30% and 50% compared with the AUC at week 1. The concurrent median cyclosporine C(min) were generally at the lower end of conventional target ranges: 156, 83, and 69 ng/mL at months 1, 3, and 6, respectively. There were no graft losses and only three mild or moderate, reversible rejection episodes occurred. Everolimus was generally safe and well tolerated. CONCLUSIONS: These data support the use of body surface area-adjusted dosing for everolimus in pediatric patients. Although exposure is generally stable over time with moderate variability in AUC, therapeutic monitoring would be a helpful adjunct for individualizing everolimus exposure, assessing regimen adherence, and adjusting doses as the child matures.     

Risk factors affecting survival in heart transplant patients

BACKGROUND: Certain cardiovascular risk factors have been linked to morbidity and mortality in heart transplant (HT) patients. The sum of various risk factors may have a large cumulative negative effect, leading to a substantially worse prognosis and the need to consider whether HT is contraindicated. The objective of this study was to determine whether the risk factors usually available prior to HT result in an excess mortality in our setting that contraindicates transplantation. MATERIALS AND METHODS: Consecutive patients who underwent heart transplantation from November 1987 to January 2004 were included. Heart-lung transplants, retransplants, and pediatric transplants were excluded. Of the 384 patients, 89% were men. Mean age was 52 years (range, 12 to 67). Underlying disease included ischemic heart disease (52%), idiopathic dilated cardiomyopathy (36%), valvular disease (8%), and other (4%). Variables considered risk factors were obesity (BMI >25), dyslipidemia, hypertension, prior thoracic surgery, diabetes, and history of ischemic heart disease. Survival curves by number of risk factors using Kaplan-Meier and log-rank for comparison of curves. RESULTS: Overall patient survival at 1, 5, 10, and 13 years was 76%, 68%, 54%, and 47%, respectively. Survival at 10 years, if fewer than two risk factors were present, was 69%; 59% if two or three factors were present; and 37% if more than three associated risk factors were present (P = .04). CONCLUSIONS: The presence of certain risk factors in patients undergoing HT resulted in lower survival rates. The combination of various risk factors clearly worsened outcomes. However, we do not believe this should be an absolute contraindication for transplantation.     

Risk factors for hyperlipidemia in long-term pediatric renal transplant recipients

Hyperlipidemia (HL) is a common problem in adult renal transplant (TP) recipients, contributing to an increased risk of cardiovascular disease and chronic TP nephropathy. There are multiple causes of HL post renal TP in adult patients, including pre TP HL, immunosuppressive agents, renal dysfunction, hypoalbuminemia secondary to nephrotic syndrome, obesity, and conditions that lead to end-stage renal disease (ESRD). We evaluated the incidence and risk factors of HL in 62 pediatric renal TP recipients (15.4±4.2 years, range-3.0–22.3 years) with long-term (6.7±3.1 years) functioning [glomerular filtration rate (GFR) 66.7±23.2 ml/min per 1.73 m²] allografts. The mean serum cholesterol (C) level was 205.5±43.6 mg/dl. Thirty-two patients (51.6%) exhibited elevated serum C levels. The mean serum triglyceride (TG) level was 157.3±88.4 mg/dl. Serum TG levels were elevated in 32 patients (51.6%). In patients with elevated serum levels of either C or TG, the mean low-density lipoprotein level (LDL) was 138.6±44.1 mg/dl (normal <130 mg/dl) and the high-density lipoprotein (HDL) level 54.6±15.9 mg/dl (normal>34 mg/dl). Of those patients studied, 45.5% had high LDL levels, whereas 9.1% exhibited low HDL levels. The two risk factors for elevated serum C levels in our patient population were pre-TP HL and increased years since TP. The only risk factor for elevated serum TG levels was reduced GFR. A family history of HL had a significant deleterious impact upon serum levels of C (P=0.01), but did not affect serum TG levels (P=0.7). Years on dialysis prior to TP, history of prior TP, gender, body mass index, and disease leading to ESRD had no influence upon the development of post-TP HL. We conclude that post-renal TP HL is a significant problem in pediatric renal TP recipients. Received: 13 January 1999 / Revised: 19 May 1999 / Accepted: 21 May 1999     

Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus

Sirolimus is a new immunosuppressive agent used as treatment to prevent acute renal allograft rejection. One of the complications of renal transplantation and subsequent long-term immunosuppression is bone loss associated with osteoporosis and consequent fracture. Two open-label, randomized, phase 2 studies comparing sirolimus versus cyclosporine (CsA) included indices of bone metabolism as secondary end-points. Markers of bone turnover, serum osteocalcin and urinary N-telopeptides, were measured over a 1-year period in 115 patients receiving either CsA or sirolimus as a primary therapy in combination with azathioprine and glucocorticoids (study A) or mycophenolate mofetil (MMF) and glucocorticoids (study B). Urinary excretion of N-telopeptides and the concentrations of serum osteocalcin were consistently higher in the CsA-treated patients and significantly different at week 24 for N-telopeptides and at weeks 12, 24, and 52 for osteocalcin. In conclusion, future trials are warranted to test whether a sirolimus-based regimen conserves bone mineral density compared with a CsA-based regimen.     

Total peripheral vascular resistance in pediatric renal transplant patients

BACKGROUND: Abnormal cardiovascular reactivity at rest and during physical exercise may be a risk factor for left ventricular hypertrophy (LVH) in pediatric renal transplanted (Tx) patients. Data on total peripheral vascular resistance (TPR) are not available. METHODS: Eleven renal Tx patients treated with cyclosporine (7 females and 4 males; mean age 14.6 +/- 3.3 years; mean time since transplantation 43 +/- 35 months) were evaluated for 24-hour blood pressure (BP), TPR and echocardiographic left ventricular mass (LVM). TPR values of patients were compared with data of a group of 11 healthy controls matched for sex and age. RESULTS: Twenty-four-hour ambulatory blood pressure monitoring showed that all but one patient had normal daytime BP values and six patients showed a reduced or inverse nocturnal dip. LVH was found in 72% of the patients. In comparison with healthy controls, patients showed significantly elevated TPR at rest and during exercise suggesting an increased vascular tone. The degree of LVH in these patients is severe and appears disproportionate to the BP values. CONCLUSION: The high incidence of LVH can reflect an augmented cardiovascular reactivity associated with a disturbed circadian pattern. The increase in TPR and the reduction of the nocturnal fall of BP also might contribute to the development of LVH in young renal Tx patients.