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• W2018300612 abstract "The development of chronic kidney disease (CKD) was evaluated in a large cohort of pediatric lung transplant recipients. Retrospective chart review identified 125 patients undergoing first lung transplant at St. Louis Children's Hospital and surviving 1 year. Mean age at transplant was 10.3 ± 0.55 years, while mean time after transplant was 4.9 years. Serum creatinine nearly doubled from baseline 0.48 mg/dL ± 0.02 (n = 125) to 0.87 mg/dL ± 0.04 (n = 120) at 1 year, and tripled to 1.39 mg/dL ± 0.15 (n = 23) by 7 years after transplant. The glomerular filtration rate (GFR), as estimated by the Schwartz formula, decreased from baseline 163 ± 5.9 mL/min/1.73 m2 (n = 109) to 88 ± 2.5 (n = 104), reaching 69 ± 9.0 (n = 6) by 10years (p <0.01). Seven patients developed end-stage kidney disease, and by 5 years after transplant, 38% of patients reached GFR <60 mL/min. Older age at transplant and primary diagnosis of cystic fibrosis (CF) were both associated with decreased renal survival by Kaplan–Meier (KM) analysis. In summary, pediatric lung transplant recipients experience significant loss of renal function over time, as observed in other solid organ transplant recipients, and is most dramatic in adolescents. The development of chronic kidney disease (CKD) was evaluated in a large cohort of pediatric lung transplant recipients. Retrospective chart review identified 125 patients undergoing first lung transplant at St. Louis Children's Hospital and surviving 1 year. Mean age at transplant was 10.3 ± 0.55 years, while mean time after transplant was 4.9 years. Serum creatinine nearly doubled from baseline 0.48 mg/dL ± 0.02 (n = 125) to 0.87 mg/dL ± 0.04 (n = 120) at 1 year, and tripled to 1.39 mg/dL ± 0.15 (n = 23) by 7 years after transplant. The glomerular filtration rate (GFR), as estimated by the Schwartz formula, decreased from baseline 163 ± 5.9 mL/min/1.73 m2 (n = 109) to 88 ± 2.5 (n = 104), reaching 69 ± 9.0 (n = 6) by 10years (p <0.01). Seven patients developed end-stage kidney disease, and by 5 years after transplant, 38% of patients reached GFR <60 mL/min. Older age at transplant and primary diagnosis of cystic fibrosis (CF) were both associated with decreased renal survival by Kaplan–Meier (KM) analysis. In summary, pediatric lung transplant recipients experience significant loss of renal function over time, as observed in other solid organ transplant recipients, and is most dramatic in adolescents. Chronic kidney disease (CKD) has become a major problem after otherwise successful organ transplantation. By 3 years after transplant, 16% of recipients of nonrenal organ transplants progress to chronic renal failure, defined as glomerular filtration rate (GFR) < 60 mL/min, (1Ojo AO Held PJ Port FK et al.Chronic renal failure after transplantation of a nonrenal organ..N Engl J Med. 2003; 349: 931-940Crossref PubMed Scopus (1794) Google Scholar). Pro-gressive CKD occurs in pediatric liver (2Bartosh SM Alonso EM Whitington PF Renal outcomes in pediatric liver transplant patients..Clin Transplant. 1992; 11: 354Google Scholar, 3Berg UB Ericzon BG Nemeth A Renal function before and long after liver transplantation in children..Transplantation. 2001; 72: 631-637Crossref PubMed Scopus (59) Google Scholar, 4McDiarmid SV Ettenger RB Fine RN Busutill RW Ament ME Serial decrease in glomerular filtration rate in long-term pediatric liver transplantation survivors treated with cyclosporine..Transplantation. 1989; 47: 314Crossref PubMed Scopus (52) Google Scholar) and heart (5Hornung TS de Goede CG O'Brien C Moghal NE Dark JH O'Sullivan FP Renal function after pediatric cardiac transplantation: the effect of early cyclosporin dosage..Pediatrics. 2001; 107: 1346-1350Crossref PubMed Scopus (33) Google Scholar,6Pradhan M Leonard MB Bridges ND Jabs KL Decline in renal function following thoracic organ transplantation in children..Am J Transplant. 2002; 2: 652-657Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar) transplant recipients at rates comparable to adults, while pediatric lung transplant recipients experience a 30% decline in renal function over the first 6 months after transplant (7Tsimaratos M Viard L Kreitmann B et al.Kidney function in cyclosporine-treated paediatric pulmonary transplant recipients..Transplantation. 2000; 69: 2055-2059Crossref PubMed Scopus (20) Google Scholar). St. Louis Children's Hospital is the largest pediatric lung transplant center in North America, providing the opportunity to characterize the long-term development of CKD in a large cohort of pediatric lung transplant recipients. Although improved allograft survival is due to primary immunosuppression with the calcineurin inhibitors cyclosporine and tacrolimus, these agents are responsible for significant acute and chronic nephrotoxicity. Acute reductions in GFR follow exposure to calcineurin inhibitors in both transplant and nontransplant patients requiring immunosuppression therapy. Despite improved formulations, monitoring and dosing schedules that permit less drug exposure, the chronic nephropathy first described by Myers (8Myers BD Ross J Newton L Luetscher J Perloth M Cyclosporin-associated nephropathy..N Engl J Med. 1984; 311: 699-705Crossref PubMed Scopus (1084) Google Scholar) remains a concern. End-stage kidney disease occurs in approximately 10% of nonrenal solid organ recipients by 10 years (9Goldstein DJ Zuech N Sehgal V Weinberg AD Drusin R Cohen D Cyclosporine-associated end stage nephropathy after cardiac transplantation: incidence and progression..Transplant. 1997; 6: 664-668Crossref Scopus (202) Google Scholar, 10Lindelow B Bergh CH Herlitz H Waagstein F Predictors and evolution of renal function during 9 years following heart transplantation..J Am Soc Nephrol. 2000; 11: 951-957Crossref PubMed Google Scholar, 11Navis G Broekroelofs J Mannes GP et al.Renal hemodynamics after lung transplantation. A prospective study..Transplantation. 1996; 61: 1600-1605Crossref PubMed Scopus (33) Google Scholar, 12Zaltzman JS Pei Y Maurer J Patterson A Cattran DC Cyclosporine nephrotoxicity in lung transplant recipients..Transplantation. 1992; 54: 875-878Crossref PubMed Scopus (76) Google Scholar), and progressive renal injury can be demonstrated by renal biopsy and function studies, even after dose reduction (13Griffiths MH Crowe AV Papadaki L et al.Cyclosporine toxicity in heart and lung transplant patients..Q J Med. 1996; 89: 751-763Crossref Scopus (45) Google Scholar). Renal dysfunction in both children and adults is often under appreciated when assessed solely by serum creatinine (14Chan JC Williams DM Roth KS Kidney failure in infants and children..Pediatr Rev. 2002; 23: 47-60Crossref PubMed Scopus (64) Google Scholar, 15Levey AS Bosch JP Lewis JB Greene T Rogers N Roth D A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.Modification of diet in renal disease study group..Ann Intern Med. 1991; 30: 461-470Google Scholar, 16Schwart GJ Brion LP Spitzer A The use of plasma creatinine concentration for estimating glomerular filtration rate in infants,children, and adolescents..Pediatr Clin North Am. 1987; 34: 571-590Crossref PubMed Scopus (1522) Google Scholar, 17Broekroelofs J Stegeman CA Navis GJ et al.Creatinine-based estimation of rate of long term renal function loss in lung transplant recipients. Which method is preferable?.J Heart Lung Transplant. 2000; 19: 256-262Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar). In healthy children, serum creatinine increases progressively with acquisition of lean muscle mass during growth, which may mask increases in creatinine due to falling GFR. When normalized to body surface area, however, GFR is constant from approximately 18 months of age through early adulthood. This is true for direct measurements of GFR, such as by iothalamate or inulin clearance, as well as estimated GFR based on serum creatinine and body size, as in the Schwartz formula. Malnutrition with decreased lean body mass results in disproportionately lower serum creatinine values relative to GFR (18Brion LP Boeck MA Gauthier B Nussbaum MP Schwartz GJ Estimation of glomerular filtration rate in anorectic adolescents..Pediatr Nephrol. 1989; 3: 16-21Crossref PubMed Scopus (42) Google Scholar), which may be prevalent in disorders such as cystic fibrosis (CF), the most common diagnosis leading to pediatric lung transplantation (19Schindler R Radke C Paul K Frei U Renal problems after lung transplantation of cystic fibrosis patients..Nephrol Dial Transplant. 2001; 16: 1324-1328Crossref PubMed Scopus (16) Google Scholar). The present study describes the long-term changes in renal function seen after pediatric lung transplantation in the largest cohort to date, examining the effect of age at transplant, underlying disease and the progression of CKD. A retrospective chart review was performed for patients who received their first lung transplants between 1/1/90 and 12/31/00 at St. Louis Children's Hospital and survived at least 1 year. Parameters recorded at initial evaluation, at transplant, 6, 12 and 18 months, then annually, included height, weight, serum creatinine, calcineurin agent and trough levels. GFR was estimated by the Schwartz formula (16Schwart GJ Brion LP Spitzer A The use of plasma creatinine concentration for estimating glomerular filtration rate in infants,children, and adolescents..Pediatr Clin North Am. 1987; 34: 571-590Crossref PubMed Scopus (1522) Google Scholar), where GFR=k∗|/Crp(mL/min/1.73m2,normal>100) where l = height, Crp = plasma creatinine, k = 0.55 for age>2 years, 0.45 for age <2 years. No correction was made for nutritional status, or for post-pubertal status in males. The estimated GFR is normalized to a standard body surface area of 1.73 m2, allowing comparison between age groups. Last follow-up date was defined as the date of last clinic visit, repeat lung transplant, death or initiation of renal replacement therapy (dialysis or kidney transplantation). The estimated GFR was used to classify CKD according to the National Kidney Foundation recommended schema (20National Kidney Foundation (NKF)Kidney Disease Outcome Quality Initiative (K/DOQI) Advisory Board. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification,and stratification; kidney disease outcome quality initiative. Am J Kidney Dis 2002; 39: S1–S246.Google Scholar). The unmodified Schwartz equation for GFR has been well validated for children of normal height and weight (16Schwart GJ Brion LP Spitzer A The use of plasma creatinine concentration for estimating glomerular filtration rate in infants,children, and adolescents..Pediatr Clin North Am. 1987; 34: 571-590Crossref PubMed Scopus (1522) Google Scholar), but has been shown to overestimate the true GFR in children with chronic disease (18Brion LP Boeck MA Gauthier B Nussbaum MP Schwartz GJ Estimation of glomerular filtration rate in anorectic adolescents..Pediatr Nephrol. 1989; 3: 16-21Crossref PubMed Scopus (42) Google Scholar). Anthropometric data was therefore obtained for all patients at the time of transplant, and expressed as standard deviation scores (Z-scores), allowing group comparison across the entire pediatric age range. The EPI2000 nutritional analysis module (Center for Disease Control and Prevention, Atlanta, GA) was used to generate standard deviation scores (Z-scores) for height and weight, based on United States norms (21Kuczmarski RJ, Ogden CL, Guo SS et al. 2000 CDC growth charts for the United States: methods and development. Vital & health statistics-series 11: data from the national health survey 2002;1–190.Google Scholar). Recipients were stratified by age at transplant in the following cohorts: infants, aged 0–2 years; preschool, aged 2+ to 5 years; school-aged, aged 5+ to 12 years; teens, aged 12+ to 18 years and young adults, aged>18 years. Statistical analyses were performed using Student's two-tailed f-test for continuous variables, ANOVA for categorical measures and ANOVA for repeated measures for time series. ΔGFR was defined as the annual rate of loss of GFR and was derived from the slope of the linear regression of the GFR versus time interval after transplant, in recipients with three or more post-transplant GFR estimates. Linear regression analysis was performed to identify significant variables, followed by stepwise multivariate regression. Survival analysis was performed by the method of Kaplan–Meier (KM) with log-rank test to determine significance differences, followed by Cox proportional hazards model. The small number of patients reaching stage 4 or 5 CKD precluded KM analysis using this endpoint. Results are expressed as mean ± standard error, with median values and ranges given where appropriate. Analyses were performed using StatView v5.0.1, with significance was set at p <0.05. During the study period, 147 first lung transplant procedures were performed at St. Louis Children's Hospital, with 125 recipients alive at the 12-month follow-up visit, and overall 1-year patient survival of 85%. Patient age ranged from 2 months to 23.6 years, with mean age 10.3 ± 0.6 years and female predominance (62%). Patient characteristics are presented in Table 1. The most common indication for transplant was chronic lung disease secondary to CF, 46%, followed by pulmonary hypertension. Three diagnosis groups were defined for analysis: CF; primary pulmonary disease (P), such as interstitial fibrosis and surfactant protein deficiency; and cardiopulmonary disease (CV), which included both primary and secondary pulmonary hypertension. Recipients with CF were significantly older than either those with P or CV (Table 2).Table 1Recipient characteristics for 1 year survivors of pediatric lung transplants at St. Louis Children's Hospital, 1990–2002. Diagnosis groups are based on primary underlying cause of end-stage lung diseaseN(%)Age group0–1 year26212–5 year436–12 year322513–18 year5746>18 year65GenderFemale7963DiagnosisCystic fibrosis5946Pulmonary3225Cardiovascular3225Systemic22 Open table in a new tab Table 2Baseline renal function and growth parameters for 1-year survivors of pediatric lung transplant recipients. Glomerular filtration rate (GFR) is estimated from the Schwartz formula, using height and serum creatinine at the time of transplant. Weight and height standard deviation scores (Z-scores) were calculated based on year 2000 CDC standardsAge at transplantCreatinine (mg/dL)GFR (mL/min/1.73 m2)WeightZ-scoreHeightZ-scoreOverall10.3 ± 0.60.48 ± 0.02165 ± 5.8–1.79 ± 0.15–1.98 ± 0.19GenderMale10.5 ± 0.90.52 ± 0.04155 ± 8.4–1.96 ± 0.23–2.09 ± 0.24Female10.1 ± 0.70.45 ± 0.04173.0 ± 7.7–1.69 ± 0.20–1.91 ± 0.27Underlying diagnosisCF13.6 ± 0.40.40 ± 0.03179 ± 6.9–2.37 ± 0.13***p <0.0001 versus CV, Pulm.–2.34 ± 0.19Pulmonary5.1 ± 1.00.38 ± 0.05*p <0.05 versus CF, <0.01 versus CV.180 ± 17.0–1.37 ± 0.23–1.72 ± 0.29Cardiovascular8.8 ± 1.20.55 ± 0.04128 ± 7.3**p <0.0001 versus CF, <0.0005 versus Pulm.–1.41 ± 0.30–1.83 ± 0.39Age groupInfants (0–2)0.8 ± 0.10.30 ± 0.02#p <0.005 versus Preschool, <0.0001 versus Teen.134 ± 12.8#p <0.05 versus School, Teen.–1.60 ± 0.64–1.88 ± 0.15Preschool (2–5)3.3 ± 0.40.50 ± 0.07157 ± 39.6–1.77 ± 0.62–1.65 ± 0.15School (6–12)8.8 ± 0.40.67 ± 0.04175 ± 10.7–1.34 ± 0.21–1.80 ± 0.15Teen (13–18)14.6 ± 0.20.90 ± 0.04p <0.05 versus Preschool.170 ± 8.1–2.18 ± 0.20–2.19 ± 0.15* p <0.05 versus CF, <0.01 versus CV.** p <0.0001 versus CF, <0.0005 versus Pulm.*** p <0.0001 versus CV, Pulm.# p <0.005 versus Preschool, <0.0001 versus Teen.## p <0.05 versus Preschool.### p <0.05 versus School, Teen. Open table in a new tab The majority of patients received bilateral lung transplants from cadaveric donors (89.6%), with 13 receiving living donor lobar transplants. Eleven patients were double organ recipients, including eight simultaneous heart-lung and three liver-lung (two simultaneous) procedures. Maintenance immunosuppression consisted of triple therapy with cyclosporine, azathioprine and steroids in the majority of patients, with anti-lymphocyte induction therapy (ATGAM, Upjohn, Kalamazoo, MI or OKT3, OrthoBiotech, NJ) used in the majority of patients transplanted between 1/1/90 and 9/1/93, and daclizumab (Zenapax, Roche, Nut- ley, NJ) was used in the majority of recipients from 6/1/99 forward thereafter. Tacrolimus was continued in place of cyclosporine in two patients who received it prior to lung transplantation for other indications. Over the study period, 26.7% of patients who initially received cyclosporine were changed to tacrolimus, primarily due to the development of persistent rejection or bronchiolitis obliterans. Mean cyclosporine level at 6-month post-transplant was 276 ± 18, without significant decline until after 72 months of follow-up (222 ± 31), and did not differ between diagnosis groups. Mean follow-up was 4.9 years, with 46% of patients alive at the end of the study period. Recipients exhibited significant growth delay at baseline, with mean height and weight Z-scores –1.99 ± 0.19 and –1.78 ± 0.15 (both p <0.0001), as shown in Table 2. Both height and weight were proportionately involved, however, as mean weight-for-height Z-score was –0.27 ± 0.31, with no significant differences noted between diagnosis groups. Patients with CF had significantly lower height and weight scores than those with other diagnoses, (p <0.05), while within the CF patients, teens (aged 12–18) with CF were more severely affected than younger children. Baseline creatinine differed between age groups, as would be expected, ranging from 0.30 ± 0.11 (n = 25) in the infants (age 0–2) to 0.55 ± 0.23 (n = 58), in the teens (Table 2). Mean serum creatinine increased in all patients after transplantation, from 0.48 ± 0.02 (n = 125) to 0.87 ± 0.04 at 12 months (n = 120), and peaked at 1.39 ± 0.15 (n = 23) at 7 years after transplant, as shown in Figure 1. This increase was seen in all age groups, but was more pronounced in the older cohorts. These differences became disproportionately larger with increasing time after transplant, until at 84 months after transplant, mean creatinine increased to 0.76 ± 0.18 (n = 5) in the infants versus 1.71 ± 0.99 in the teens (n = 7), with p < 0.001. While increasing creatinine may reflect increased lean body mass secondary to growth in the younger age groups, only modest changes in height and weight were observed in teens after transplant. When grouped by underlying disease, patients with underlying pulmonary disease had significantly lower baseline creatinine relative to CF or CV disease, consistent with their younger age at transplant. Mean GFR at baseline in infants was lower than in older children, and also in those in the CV diagnosis relative to the CF or Pulmonary groups (Table 2). There was no significant change in GFR between the date of evaluation or listing for transplant, and the actual transplant date (data not shown). After transplant, mean GFR fell from 163 ± 5.9 mL/min/1.73 m2 (n = 109) to 88 ± 2.5 (n = 104) at 12 months, to 69 ± 9.0 (n = 6) at 10-year posttransplant (p = 0.04, ANOVA for repeated measures), as shown in Figure 2. GFR declined by 29.1% in the first 6 months after transplant, with mean fall of 59 mL/min (p <0.001), with slower declines thereafter. By 12 months, 15% of recipients had CKD of stage 3 or greater (GFR <60 mL/min/1.73 m2); this proportion slowly increased with time, as shown in Figure 3. Infants (age <2 years at transplant) had the smallest decline in GFR over the first year (–20 mL/min/1.73 m2, p = 0.18), while the teens had the largest fall (–84 mL/min/1.73 m2, p <0.0.001). At 10 years following transplant, only one of six survivors had estimated GFR> 90 mL/min/1.73 m2; the remainder ranged from 40 to 78 mL/min/1.73 m2.Figure 3Chronic Kidney Disease (CKD) becomes increasingly prevalent after lung transplant. CKD stages are based on estimated GFR according to the NKF schema, with stage 3 representing CKD with GFR < 60 mL/min/1.73 m2. Labels indicate number of patients per stage, at given follow-up time.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Older recipients had greater declines in GFR, which was especially prominent in patients older than 12 years at transplant, falling from 170 ± 8 to 76 ± 5 at 60 months; most of these patients had CF as their underlying diagnosis. The youngest patients (age < 2 at transplant) had no significant change in GFR over the study period, falling from 110 ± 11 to 88 ± 6 by 60 months (p = 0.27, ANOVA for repeated measures). The rate of change of GFR after 1 year (ΔGFR) was calculated by linear regression for each patient, with 94 of 98 evaluable patients (95%) exhibiting a negative slope, and a mean loss of –5.2 mL/min/1.73 m2/year. In univariate regression models, ΔGFR correlated weakly with age at transplant (p = 0.13), but not with diagnosis group, gender, donor type, number of organs transplanted, mean cyclosporine level, height or weight Z-scores. Seven patients (5.5%) progressed to end-stage kidney failure (ESKF, stage 5) at times ranging from 2.0 to 10.5 years after transplant, with mean time of 7.0 years. Five patients were treated with chronic dialysis, while two underwent preemptive living donor kidney transplants. Five of the seven patients who progressed to ESKF had CF as an underlying diagnosis. One patient had interstitial pulmonary fibrosis subsequent to a bone marrow transplant for acute leukemia, with prolonged tacrolimus therapy as prophylaxis for graft versus host disease. Using KM survival analysis and Cox proportional hazards models, progression to stage 3 CKD (GFR <60 mL/min) was investigated for the effect(s) of diagnosis group, age at transplant, gender, mean CSA level and Z-scores for height and weight. Older age at transplant and CF were both associated with decreased renal survival in KM analysis, as shown in Figures 4 and 5, respectively. While the small numbers of patients at>5 years after transplant limits the analysis (Figure 4 and 5), the early differences in renal survival appear to be maintained. In the proportional hazards model, however, the only significant variable affecting renal survival was the age at transplant. This is consistent with the interaction between the diagnosis of CF and age at transplant, namely that CF patients progressed to lung transplant at a significantly older age. Overall patient survival was likewise dependent on age at transplant and underlying diagnosis. Younger age at transplant and primary cardiovascular disease were associated with improved patient survival, in both KM analysis and Cox models.Figure 5Renal survival after pediatric lung transplant differs according to age at transplant. Progression to stage 3 CKD was assessed by Kaplan–Meier (KM) survival analysis, with patients grouped by age. More rapid progression was observed in the older patients. Patients aged 2–5 years at transplant were grouped with infants (age 0–1 year at transplant) for KM analysis. Values below figure indicate number of patients at risk, per diagnostic group, at transplant and at 1, 3, 5, 7 and 9 years after transplant.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The short-term success of pediatric lung transplantation provides effective therapy for end-stage pulmonary disease of many causes, but survivors are faced with new complications directly related to therapy. The dramatic loss of renal function observed over the first year continues at a slower rate with subsequent follow-up, but the risk of CKD, especially end-stage disease, increases with increasing survival. Recipients are at continued riskfor acute renal failure during subsequent infections, rejection, and retransplantation procedures, which can significantly impact outcome (22Hmiel SP, Beck AM, Cole BR. Continuous venovenous hemofiltration(cvvh) after lung transplantation [Abstract]. , Proceedings of the 1st Conference on Pediatric Continuous Renal Replacement Therapy, Orlando FL June 20–22, 2000.Google Scholar). In particular, recipients with GFR <60 mL/min/1.73 m2 had significantly worse outcomes for second transplants (unpublished data). The decline in renal function after lung transplantation is multifactorial in etiology. Contributing factors include pre-transplant renal insults, such as the antibiotics amphotericin B and aminoglycosides, renal underperfusion during the transplant procedure, and necessary post-transplant nephrotoxins such as cyclosporine and tacrolimus. The transplanted lung exhibits exquisite sensitivity to excess fluid, yet the routine use of diuretics to minimize pulmonary congestion may also contribute to chronic renal underperfusion. Combined with higher CNI levels, renal vasoconstriction accelerates the development of chronic CNI toxicity in animal models (23Burdmann EA Andoh TF Nast CC et al.Prevention of experimental cyclosporine-induced interstitial fibrosis by losartan and enalapril..Am J Physiol. 1995; 269: F491-F499PubMed Google Scholar). Despite the disparity between liver, lung and heart transplant recipients in underlying illnesses, age, operative procedures and postoperative management, the overall decline in renal function after lung transplant is strikingly similar to other nonrenal organ transplant recipients (1Ojo AO Held PJ Port FK et al.Chronic renal failure after transplantation of a nonrenal organ..N Engl J Med. 2003; 349: 931-940Crossref PubMed Scopus (1794) Google Scholar, 2Bartosh SM Alonso EM Whitington PF Renal outcomes in pediatric liver transplant patients..Clin Transplant. 1992; 11: 354Google Scholar, 3Berg UB Ericzon BG Nemeth A Renal function before and long after liver transplantation in children..Transplantation. 2001; 72: 631-637Crossref PubMed Scopus (59) Google Scholar, 4McDiarmid SV Ettenger RB Fine RN Busutill RW Ament ME Serial decrease in glomerular filtration rate in long-term pediatric liver transplantation survivors treated with cyclosporine..Transplantation. 1989; 47: 314Crossref PubMed Scopus (52) Google Scholar, 5Hornung TS de Goede CG O'Brien C Moghal NE Dark JH O'Sullivan FP Renal function after pediatric cardiac transplantation: the effect of early cyclosporin dosage..Pediatrics. 2001; 107: 1346-1350Crossref PubMed Scopus (33) Google Scholar, 6Pradhan M Leonard MB Bridges ND Jabs KL Decline in renal function following thoracic organ transplantation in children..Am J Transplant. 2002; 2: 652-657Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 7Tsimaratos M Viard L Kreitmann B et al.Kidney function in cyclosporine-treated paediatric pulmonary transplant recipients..Transplantation. 2000; 69: 2055-2059Crossref PubMed Scopus (20) Google Scholar). This appears true for both the early rapid decline in GFR, as previously described by Tsimartros (7Tsimaratos M Viard L Kreitmann B et al.Kidney function in cyclosporine-treated paediatric pulmonary transplant recipients..Transplantation. 2000; 69: 2055-2059Crossref PubMed Scopus (20) Google Scholar) in the first 6 months after lung transplant, as well as the later effects described here for patients studied after at least 1-year post-transplant. Patients receiving cyclosporine for nontransplant indications experience similar losses in renal function (24Feutren G Mihatsch MJ Risk factors for cyclosporine-induced nephropathy in patients with autoimmune disease..N Engl J Med. 1992; 326: 1654-1660Crossref PubMed Scopus (428) Google Scholar), which correlate with early CNI levels (5Hornung TS de Goede CG O'Brien C Moghal NE Dark JH O'Sullivan FP Renal function after pediatric cardiac transplantation: the effect of early cyclosporin dosage..Pediatrics. 2001; 107: 1346-1350Crossref PubMed Scopus (33) Google Scholar,6Pradhan M Leonard MB Bridges ND Jabs KL Decline in renal function following thoracic organ transplantation in children..Am J Transplant. 2002; 2: 652-657Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). While difficult to prove conclusively, the weight of evidence indicates that the progressive CKD after solid organ transplant is primarily due to chronic calcineurin inhibitor nephrotoxicity. The mechanism of chronic CNI nephropathy is unclear, but is likely due to chronic vasoconstriction, with release of fi-brogenic growth factors such as transforming growth factor beta (TGF-ß) (25Langham RG Egan MK Dowling JP Gilbert RE Thomson NM Transforming growth factor-beta1 and tumor growth factor-betainducible gene-H3 in nonrenal transplant cyclosporine nephropathy..Transplantation. 2001; 72: 1826-1829Crossref PubMed Scopus (37) Google Scholar,26Khanna A Plummer M Bromberek C Bresnahan BA Hariharan S Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus and cyclosporine nephrotoxicity..Kidney Int. 2002; 62: 2257-2263Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). TGF-ß expression is increased by CNIs and has been implicated in both glomerulosclerosis and interstitial fibrosis. Maneuvers that protect experimental animals from CNI nephropathy, such a calcium channel blockers or ACE-I (25Langham RG Egan MK Dowling JP Gilbert RE Thomson NM Transforming growth factor-beta1 and tumor growth factor-betainducible gene-H3 in nonrenal transplant cyclosporine nephropathy..Transplantation. 2001; 72: 1826-1829Crossref PubMed Scopus (37) Google Scholar), have had limited clinical success (27Kirk AJ Omar I Bateman DN Dark JH Cyclosporine-associated hypertension in cardiopulmonary transplantation. The beneficial effect of nifedipine on renal function..Transplantation. 1989; 48: 428-430Crossref PubMed Scopus (29) Google Scholar). Several small studies suggest that substitution of sirolimus (28Snell GI Levvey BJ Chin W et al.Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment..J Heart Lung Transplant. 2002; 21: 540-546Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar) or mycophenolate (29Soccal PM Gasche Y Favre H Spiliopoulos A Nicod LP Improvement of drug-induced chronic renal failure in lung transplantation..Transplantation. 1999; 68: 164-165Crossref PubMed Scopus (24) Google Scholar) for CNI may stabilize renal function in the late post-transplant period. The early loss of function appears irreversible, as neither these substitutions nor the lower CNI level targets at 1 year after transplant result in improved function (10Lindelow B Bergh CH Herlitz H Waagstein F Predictors and evolution of renal function during 9 years following heart transplantation..J Am Soc Nephrol. 2000; 11: 951-957Crossref PubMed Google Scholar,30Rice JE Shipp AT Carlin JB Vidmar SI Weintraub RG Late reduction in cyclosporine dosage does not improve renal function in pediatric heart transplant recipients..J Heart Lung Transplant. 2002; 21: 1109-1112Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar,31English RF Pophal SA Bacanu S-A Fricker J et al.Long-term comparison of tacrolimus- and cyclosporine-induced nephrotoxicity in pediatric heart-transplant recipients..Am J Transplant. 2002; 2: 769-773Crossref PubMed Scopus (61) Google Scholar). The late effects on renal function were apparent in this analysis, with mean progression to stage 3 CKD at 9.11 years, although the range was quite broad. In renal transplantation, tacrolimus therapy has been associated with improved renal hemodynamics (32Dello Strologo L Pontesilli C Montini G et al.Renal hemodynamic effect of tacrolimus in renal transplanted children..Pediatr Nephrol. 2001; 16: 773-776Crossref PubMed Scopus (2) Google Scholar), improved function and decreased levels of TGF-ß1. In the present analysis, despite 25% of patients receiving tacrolimus as their primary CNI at the last observation, few of these patients had received tacrolimus therapy for greater than 12 months, precluding a separate analysis at this time. The decline in the function most apparent in teenaged recipients, especially those with CF, suggests that renal reserve at the time of transplant is already impaired, placing them at higher risk post-transplant. The recipients with CF are at a higher risk for further nephrotoxic insults post-transplant as well, with a higher risk of serious infections such as fungal, and thus potential exposure to nephrotoxic anti-microbials, as well as increased risk of CF-associated diabetes mellitus. It is unclear whether patients with CF-associated diabetes mellitus will exhibit a similar or higher risk of nephropathy as other type 1 diabetics. Alternatively, these patients exhibit a significant risk of bronchiolitis obliterans syndrome (BOS), which is treated initially with augmented immunosuppression including anti-lymphocyte antibodies (OKT-3, ATGAM), increased cyclosporine dosage or conversion to tacrolimus. In addition to increasing CNI exposure, the riskof infections and thus potential nephrotoxin exposure increases as well. While the present analysis focused primarily on the pretransplant factors that may impact renal function, investigation of these post-transplant factors is essential to developing renal protection strategies, and is the focus of current studies. The youngest patients exhibit an initial decline in GFR, but showed little subsequent loss. This pattern may reflect the potential for ongoing renal growth, or adaptation to the presence of calcineurin inhibitors. The lack of further decrease must be interpreted with caution, however, as healthy infants exhibit a sustained increase in GFR during the first 3 years of life, from approximately 30 mL/min/ 1.73 m2 at birth to 136 mL/min/1.73 m2 by age 3 (16Schwart GJ Brion LP Spitzer A The use of plasma creatinine concentration for estimating glomerular filtration rate in infants,children, and adolescents..Pediatr Clin North Am. 1987; 34: 571-590Crossref PubMed Scopus (1522) Google Scholar). It is thus unlikely that these recipients will attain full adult levels of renal function, and that these children will remain at the risk of progressive CKD throughout childhood, adolescence and into adulthood. Pradhan (6Pradhan M Leonard MB Bridges ND Jabs KL Decline in renal function following thoracic organ transplantation in children..Am J Transplant. 2002; 2: 652-657Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar) reported similar result in a cohort of 18 thoracic organ recipients under the age of two at transplant. The failure to attain age-appropriate levels of GFR was more apparent when their results were expressed as % expected GFR for age <3 years, with an initial fall in GFR and subsequent stabilization, similar to the results reported here. As GFR corrected for body surface area remains essentially constant from the age of three until adulthood, 75% of the normal GFR is approximately 100 mL/min/1.73 m2, surprisingly close to that observed in our infant transplant recipients at 3 and 5 years post-transplant. Progressive renal insufficiency leads to many wellcharacterized complications, including poor growth, anemia,hypertension, secondary hyperparathyroidism with metabolic bone disease and electrolyte abnormalities (33Hogg RJ, Furth S, Lemley KV et al. for the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics2003; 111: 1416–1421.Google Scholar).While these complications are clinically apparent at GFR < 3 mL/min (CKD stage 4 or 5), children may be more sensitive to these metabolic derangements in CKD stage 3. Assessment for these complications should become a component of the long-term care of these patients, as early recognition and management can limit the morbidity.When treatment of these conditions is superimposed upon the post-transplant regimen, the number of medications, and the potential for interactions, increases dramatically.This can lead to intentional and unintentional nonadherence,with further compromise of clinical condition (34Nevins TE Non-compliance and its management in teenagers..Pediatr Transplant. 2002; 6: 475-479Crossref PubMed Scopus (79) Google Scholar).Although this analysis could not demonstrate an impact upon patient survival, the three patients receiving maintenance hemodialysis for ESRD died within 6 months of starting dialysis, while the patient undergoing peritoneal dialysis did well, similar to previous reports (35Jayasena SD Riaz A Lewis CM Neild GH Thompson FD Woolfson RG Outcome in patients with end-stage renal disease following heart or heart-lung transplantation receiving peritoneal dialysis..Nephrol Dial Transplant. 2001; 16: 1681-1685Crossref PubMed Scopus (33) Google Scholar). As renal function declines, the Schwartz formula estimate of GFR is known to overestimate true GFR as measured by inulin or iothalamate clearance (16Schwart GJ Brion LP Spitzer A The use of plasma creatinine concentration for estimating glomerular filtration rate in infants,children, and adolescents..Pediatr Clin North Am. 1987; 34: 571-590Crossref PubMed Scopus (1522) Google Scholar), and thus the true decline in renal function may be greater than estimated here. Furthermore, the Schwartz formula assumes a normal muscle mass for height, and overestimates the GFR in patients with chronic malnutrition and other chronic diseases We made no attempt to correct for body habitus or nutritional status in this study, although reducing the Schwartz formula constant from 0.55 to 0.45, as did Tsimaratos (17Broekroelofs J Stegeman CA Navis GJ et al.Creatinine-based estimation of rate of long term renal function loss in lung transplant recipients. Which method is preferable?.J Heart Lung Transplant. 2000; 19: 256-262Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar), would further reduce the GFR in our patients. Our results could be considered an upper estimate the true GFR. The actual incidence of CKD may therefore be considerably higher, as was demonstrated in the elegant studies of Berg in pediatric liver transplant recipients (3Berg UB Ericzon BG Nemeth A Renal function before and long after liver transplantation in children..Transplantation. 2001; 72: 631-637Crossref PubMed Scopus (59) Google Scholar), and Navis (5Hornung TS de Goede CG O'Brien C Moghal NE Dark JH O'Sullivan FP Renal function after pediatric cardiac transplantation: the effect of early cyclosporin dosage..Pediatrics. 2001; 107: 1346-1350Crossref PubMed Scopus (33) Google Scholar) in adult lung transplant recipients. These results suggest that prospective measurements of GFR, such as I125-Iothalamate clearance, should be performed in these patients as part of their ongoing care. As alternative immunosuppressive strategies are being explored to further improve the long-term survival of pediatric lung transplant recipients, attention should be directed to minimizing toxicity to other organ systems, and thus ensure recipients the best possible quality of life. Current recipients should be monitored closely for the development of CKD, with appropriate referral and management. The authors would like to thank Charles Huddleston M.D., Eric Mendeloff M.D., Barbara Cole M.D., for reviewing the manuscript, and Pegi Shaner RN, Donna Watkins RN and Debbie Springheart RN for clarifying patient information." @default.
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